Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=[CH2:9])[CH2:5][CH2:4]1)[CH3:2].C12BC(CCC1)CCC2.[C:19]1([S:25]([N:28]2[C:32]3[CH:33]=[N:34][C:35]([C:38]#[N:39])=[C:36](Br)[C:31]=3[C:30]3[CH:40]=[CH:41][CH:42]=[N:43][C:29]2=3)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O.Cl[Pd]Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:19]1([S:25]([N:28]2[C:32]3[CH:33]=[N:34][C:35]([C:38]#[N:39])=[C:36]([CH2:9][CH:6]4[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]4)[C:31]=3[C:30]3[CH:40]=[CH:41][CH:42]=[N:43][C:29]2=3)(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C=C1CCN(CC)CC1
Reactant: N#Cc1ncc2c(c1Br)c1cccnc1n2S(=O)(=O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCC(Cc2c(C#N)ncc3c2c2cccnc2n3S(=O)(=O)c2ccccc2)CC1
Temperature: 65 °C
Yield: 43.5 %

Procedure:
A mixture of 1-ethyl-4-methylene-piperidine (540 mg, 4.32 mmol) and 9-borabicyclo[3.3.1]nonane (0.5M in THF, 8.0 mL, 4.0 mmol) was heated at 65° C. for 3.5 h. The resultant cooled solution was then added portionwise to a degassed suspension of 9-benzenesulfonyl-5-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (420 mg, 1 mmol), bis(diphenylphosphino)ferrocene dichloropalladium(II) (90 mg, 0.11 mmol) and potassium carbonate (180 mg, 1.3 mmol) in water (1 mL) and dimethylformamide (10 mL). The resultant orange solution was heated at 65° C. for 2 h then allowed to cool to ambient temperature and partitioned between dichloromethane (20 mL) and a saturated aqueous solution of sodium chloride (15 mL). The aqueous phase was extracted with dichloromethane (3×10 mL) and the combined organic phase was washed with a saturated aqueous solution of sodium chloride (20 mL), dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography (silica, 10 g column, Si-SPE, 0-20% MeOH in DCM) to afford the title compound (200 mg, 43%). 1H NMR (CDCl3, 400 MHz): 9.81 (s, 1H), 8.76 (dd, J=4.8, 1.5 Hz, 1H), 8.66 (d, J=8.0 Hz, 1H), 8.29-8.24 (m, 2H), 7.66-7.60 (m, 1H), 7.58-7.48 (m, 3H), 3.41 (d, J=7.2 Hz, 2H), 2.89 (q, J=7.3 Hz, 2H), 2.56-2.44 (m, 2H), 2.33-2.08 (m, 3H), 1.94-1.74 (m, 4H), 1.35 (t, J=7.3 Hz, 3H). LCMS (Method G): RT=3.01 min, M+H+=460.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([CH2:15][CH3:16])[C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH:18]1([CH2:21][O:22][CH:23]2[CH2:29][CH:28]3[NH:30][CH:25]([CH2:26][CH2:27]3)[CH2:24]2)[CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:18]1([CH2:21][O:22][CH:23]2[CH2:24][CH:25]3[N:30]([CH2:2][CH2:3][CH2:4][N:5]4[C:10]5[CH:11]=[CH:12][CH:13]=[C:14]([CH2:15][CH3:16])[C:9]=5[O:8][CH2:7][C:6]4=[O:17])[CH:28]([CH2:27][CH2:26]3)[CH2:29]2)[CH2:20][CH2:19]1
Reactant: CCc1cccc2c1OCC(=O)N2CCCCl
Reactant: C1CC1COC1CC2CCC(C1)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cccc2c1OCC(=O)N2CCCN1C2CCC1CC(OCC1CC1)C2
Temperature: 60 °C
Reaction time: 90 h
Yield: 20.6 %

Procedure:
A 7 ml vial was charged with 4-(3-chloropropyl)-8-ethyl-4H-benzo[1,4]oxazin-3-one (0.21 g, 0.83 mmol), 3-cyclopropylmethoxy-8-aza-bicyclo[3,2,1]octane (0.16 g, 0.87 mmol), K2CO3 (0.23 g, 1.7 mmol), acetonitrile (4 ml) a shaken at 60° C. for 90 hours The reaction mixture was evaporated to dryness and purified by prep TLC (SiO2; heptanes/EtOAc 1:1) followed by Prep HPLC to give the title compound (0.068 g, 20.5%). 1H NMR (CDCl3) 1H NMR (CDCl3) d 7.05-6.84 (m, 3H), 4.56 (s, 2H), 4.04-3.98 (m, 2H), 3.53-3.49 (m, 1H), 3.19-3.11 (m, 4H), 2.67-2.59 (m,2H), 2.42-2.37 (m, 2H), 2.07-1.74 (m, 1OH), 1.21-1.15 (m, 3H), 1.06-0.93 (m, 1H), 0.51-0.44 (m, 2H), 0.21-0.14 (m, 2H); 13C NMR (CDCl3) d 164.60, 143.25, 133.02, 128.66, 123.99, 122.32, 113.20, 72.78, 72.23, 67.74, 58.59, 49.56, 39.83, 35.73, 26.45, 26.17, 23.03, 14.50, 11.04, 2.94.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].N1C=CC=CC=1.[Br:26]Br>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([Br:26])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2c1C
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ncc2[nH]c3ccc(Br)cc3c2c1C
Reaction time: 1 h
Yield: 38 %

Procedure:
0.5 g of 4-methyl-β-carbolin-3-carboxylic acid ethyl ester (melting point 235°-239° C.) is dissolved in 25 ml of chloroform and 1.7 ml of pyridine and a solution of 1 ml of bromine in 21 ml of chloroform is added dropwise thereto at 0° C. After standing for one hour while cooling with ice and after dilution with 50 ml of the methylene chloride, the mixture is extracted by washing with sodium thiosulphate solution, dilute aqueous ammonia solution and water. After drying with sodium sulphate, filtering off and distilling off the solvent in vacuo, 6-bromo-4-methyl-β-carbolin-3-carboxylic acid ethyl ester is obtained in 38% yield, Melting point 231°-232° C. (from acetone).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([O:18]C)=[O:17])=[C:9]2[CH3:20])=[CH:4][CH:3]=1>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([OH:18])=[O:17])=[C:9]2[CH3:20])=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(C)n(-c2ccc(Cl)cc2)c(C)cc1=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)c(C(=O)O)c(C)n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.2 %

Procedure:
16 g of N-(4-chlorophenyl)-3-carbomethoxy-2,6-dimethylpyrid-4-one is suspended in 450 g of 5% aqueous sodium hydroxide and stirred at room temperature for 24 hours. Acidification yields 14.2 g of N-(4-chlorophenyl)-3-carboxy-2,6dimethylpyrid-4-one (m.p. 260-61.5° decomp.) which is converted to its sodium salt (m.p. >310°) by neutralization with sodium hydroxide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[C:23]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31]([CH3:47])=[C:32]([CH2:34][CH2:35]OS(C3C=CC(C)=CC=3)(=O)=O)[N:33]=2)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[CH:24][CH:25]=3)[O:30][C:31]=2[CH3:47])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1)Oc1ccccc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (495 mg, 1.7 mmol), and toluene-4-sulfonic acid 2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethyl ester (2.2 mmol) and Cs2CO3 (700 mg, 2.2 mmol) are combined in anhydrous DMF (25 mL) and stirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixture was then cooled and diluted with ethyl acetate (100 mL), and washed with water then brine. The organic layer was dried with Na2SO4 and concentrated in vacuo to a viscous yellow oil. The residue was purified by flash column chromatography (100 g silica, 60×15 mL fractions, gradient elution 0–20% ethyl acetate in hexanes) to provide the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7](=[O:9])[NH2:8])=[CH:5][N:4]([C:10]2([CH2:23][C:24]#[N:25])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[N:3]=1.C([O-])(=O)C.[K+].[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34](Br)[CH:33]=1.C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(O)C>[Br:31][C:32]1[CH:33]=[C:34]([NH:1][C:2]2[C:6]([C:7](=[O:9])[NH2:8])=[CH:5][N:4]([C:10]3([CH2:23][C:24]#[N:25])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]3)[N:3]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(N)n2)CC1
Reactant: Brc1cccc(Br)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3cccc(Br)c3)n2)CC1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
tert-Butyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (Intermediate 35-1) (500 mg, 1.44 mmol), potassium acetate (211 mg, 2.15 mmol), 1,3-dibromobenzene (0.69 mL, 5.74 mmol) and 2-propanol (7.2 mL) were combined in a vial and purged with a stream of N2 gas for 10 minutes. Pd2(dba)3 (52 mg, 0.060 mmol) and 2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-i-propylbiphenyl (103 mg, 0.220 mmol) were then added. The reaction vessel was capped and the reaction mixture was heated to 85° C. and allowed to stir for 16 hours. The mixture was then cooled to ambient temperature, filtered through celite, eluting with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound, Example #12-1.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[Cl-].[OH:11][NH3+:12].C(N(CC)CC)C>>[OH:11][N:12]=[C:8]([C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[NH2:9]
Reactant: Cc1ccc(C#N)cn1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: Cc1ccc(C(N)=NO)cn1

Procedure:
1.0 g (8.5 mmol) of 6-methylpyridine-3-carbonitrile, 882 mg (12.7 mmol) of hydroxylammonium chloride and 1.4 ml (10.2 mmol) of triethylamine were reacted according to the General Method 5A. Yield: 1.11 g (87% of theory)
Reaction SMILES: C[N:2]([CH3:18])[CH:3]=[C:4]([C:7](=[O:17])[C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[Cl:16])[C:5]#[N:6].[CH:19]1(N)C[CH2:20]1>C1(C)C=CC=CC=1>[CH:18]1([NH:2][CH:3]=[C:4]([C:7](=[O:17])[C:8]2[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[C:5]#[N:6])[CH2:20][CH2:19]1
Reactant: NC1CC1
Reactant: CN(C)C=C(C#N)C(=O)c1cc(F)c(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: N#CC(=CNC1CC1)C(=O)c1cc(F)c(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
14.35 g of 3-dimethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylonitrile are refluxed with 3.2 g of cyclopropylamine and 60 ml of toluene. When the evolution of gas is finished after about 30 minutes, the toluene is removed by distillation in vacuo, and the residue is recrystallized from ethanol/light petroleum. 13.8 g of 3-cyclopropylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylonitrile of melting point 94°-95° C. are obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:22][O:23][CH3:24])[C:3]=1[C:25]([O:27][CH3:28])=[O:26].[C:29](#[N:31])[CH3:30]>Cl>[F:19][C:18]([F:21])([F:20])[C:17]1[CH:16]=[CH:15][C:29]([NH:31][C:2]2[C:11]3[C:6](=[N:7][C:8]([C:12]4[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=4)=[CH:9][CH:10]=3)[N:5]=[C:4]([CH2:22][O:23][CH3:24])[C:3]=2[C:25]([O:27][CH3:28])=[O:26])=[CH:30][CH:12]=1
Reactant: CC#N
Reactant: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(Cl)c1C(=O)OC
Agent: Cl
Product: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(Nc2ccc(C(F)(F)F)cc2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve methyl 4-chloro-2-methoxymethyl-7-[3-(trifluoromethyl)pyridin-2-yl]-[1,8]naphthyridine-3-carboxylate (212 mg, 0.52 mmol) in acetonitrile (5 mL) and add 4 drops 2M HCl (Et2O). Stir the mixture for 3 hours at room temperature. Filter off the resulting yellow precipitate to yield the title compound as its hydrochloride salt. MS 537.20 (M+1). 1H NMR δ (Free base, CDCl3) 9.91 (1H, s), 8.88 (1H, m), 8.16 (2H, m), 7.67-7.55 (4H, m), 7.12 (1H, d), 6.99 (1H, d), 4.42 (2H, s), 4.02 (3H, s), 3.95 (3H, s).
Reaction SMILES: [NH2:1][C:2]([CH3:27])([CH3:26])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[CH3:26][C:2]([NH:1][C:35](=[O:37])[CH3:36])([CH3:27])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24]
Reactant: CC(=O)Cl
Reactant: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(C)(C)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, a solution of (2-amino-2-methylpropyl)(7-benzyloxy-3-nitroquinolin-4-yl)amine (6.5 g, 17.5 mmol), prepared in Part A of Example 45, in dichloromethane (200 mL) was cooled to 0° C.; triethylamine (4.87 mL, 35.0 mmol) and acetyl chloride (1.37 mL, 19.2 mmol) were sequentially added. The reaction was stirred at 0° C. for 30 minutes, allowed to warm to ambient temperature, and stirred for three hours. The reaction was washed with saturated aqueous sodium bicarbonate (2×) and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide N-[1,1-dimethyl-2-(3-nitro-7-benzyloxyquinolin-4-ylamino)ethyl]acetamide as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example J26) (219 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow solid (271 mg, 69%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[O:23]=[S:24]1(=[O:31])[CH2:28][CH2:27][CH:26]([NH:29][CH3:30])[CH2:25]1>>[O:23]=[S:24]1(=[O:31])[CH2:28][CH2:27][CH:26]([N:29]([CH3:30])[C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:25]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CNC1CCS(=O)(=O)C1
Product: CN(C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)C1CCS(=O)(=O)C1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and N-(1,1-dioxidotetrahydrothien-3-yl)-N-methylamine to give 256. MS: (ESI+)=445.1
Reaction SMILES: [N:1]1([C@H:13]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14]2)[C:12]2[C:4](=[CH:5][N:6]=[C:7]3[C:11]=2[CH:10]=[CH:9][NH:8]3)[N:3]=[N:2]1.[CH3:19][O:20][CH2:21][CH2:22]Br.C(=O)([O-])[O-].[K+].[K+].[ClH:30].CO>C(Cl)Cl.CN(C=O)C>[ClH:30].[CH3:19][O:20][CH2:21][CH2:22][NH:18][C@H:15]1[CH2:16][CH2:17][C@H:13]([N:1]2[C:12]3[C:4](=[CH:5][N:6]=[C:7]4[C:11]=3[CH:10]=[CH:9][NH:8]4)[N:3]=[N:2]2)[CH2:14]1
Reactant: COCCBr
Reactant: N[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COCCN[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Temperature: 135 °C

Procedure:
A mixture of racemic trans 3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentylamine (95.0 mg, 392 μmol), 2-bromoethyl methyl ether (59.9 mg, 431 μmol), potassium carbonate (108 mg, 780 μmol) and DMF (2 mL) was heated to 135° C. for 15 minutes using microwave irradiation. The mixture was filtered, concentrated in vacuo and purified by column chromatography on silica gel (gradient: DCM to 10% [2M NH3 in methanol] in DCM) followed by reverse phase HPLC (5 to 50% acetonitrile in water, +0.1% NH4OH). The colourless residue was treated with 1.25 M HCl in methanol (2 eq) in DCM and concentrated to afford 17.6 mg of racemic trans (2-methoxy-ethyl)-[3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-amine hydrochloride was isolated as a beige gum. LCMS (Method A, ESI): RT=1.92 min, m+H=301.3; 1H NMR (400 MHz, DMSO) δ: 12.35 (s, 1H), 8.99 (s, 1H), 7.60 (t, 1H), 7.00 (dd, 1H), 5.65 (m, 1H), 3.59 (m, 1H), 3.47 (t, 2H), 3.28 (s, 3H), 2.83 (t, 2H), 2.47 (m, 2H, partially obscured by DMSO), 2.29-2.17 (m, 3H), 1.72 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>CC(N(C)C)=O>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[N:14][C:13]=2[N:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])[C:31]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Reactant: O=C=Nc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1c2cc(F)c(Cl)nc2n(-c2ccccc2F)c(=O)n1OCc1ccccc1
Yield: 77.8 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (300 mg, 7.52 mmol) with 2-fluorophenyl isocyanate (1.07 mL, 9.51 mmol) in DMA afforded 2.05 g of the title compound as a solid, mp 199-200° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]>C1COCC1.C(O)C.[Ni].O>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1cc(Cl)cc([N+](=O)[O-])c1N
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: NC(=O)c1cc(Cl)cc(N)c1N
Reaction time: 6 h

Procedure:
To a solution of EXAMPLE 44A (4 g) in THF (500 mL) and ethanol (500 mL) was added 50% Raney nickel in water (2 g). The reaction mixture was stirred under hydrogen (balloon) for 6 hours and filtered.
Reaction SMILES: [C@@H:1]([OH:5])([CH2:3][CH3:4])[CH3:2].O[C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]>>[C@@H:1]([O:5][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])([CH2:3][CH3:4])[CH3:2]
Reactant: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Reactant: CC[C@H](C)O
Product: CC[C@H](C)Oc1cc(C(=O)OC)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D14 (first part of synthesis) from (S)-sec-butanol and methyl 3-hydroxy-5-(2-oxopyrrolidin-1-yl)-benzoate (D41).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@:3]1([CH2:10][O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:7]([OH:9])=O.[F:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][NH2:30])=[N:27][CH:28]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][NH:30][C:7]([C@:3]2([CH2:10][O:11][Si:12]([CH:13]([CH3:14])[CH3:15])([CH:16]([CH3:17])[CH3:18])[CH:19]([CH3:20])[CH3:21])[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[O:9])=[N:27][CH:28]=1
Reactant: CC(C)[Si](OC[C@@]1(C(=O)O)CCCN1C)(C(C)C)C(C)C
Reactant: NNc1ccc(F)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OC[C@@]1(C(=O)NNc2ccc(F)cn2)CCCN1C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of Intermediate 85g (1.08 g, 3.58 mmol), (5-fluoro-pyridin-2-yl)-hydrazine (500 mg, 3.93 mmol) and DIPEA (1.38 g, 10.7 mmol) in DCM (120 mL) was added HATU (2.04 g, 5.37 mmol) and the mixture stirred at RT for 2 h. The solution was washed with 10% aq. K2CO3 solution, brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by FCC, using 0-6% [2M NH3 in MeOH] in DCM, to give the title compound as a pale yellow oil (1.37 g, 90%). LCMS (Method 4): Rt 2.74 min, m/z 425 [MH+].
Reaction SMILES: [F:1][C@H:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][OH:4].N1C=CC=CC=1.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>O>[S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)([O:4][CH2:3][C@H:2]([F:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:19])=[O:18]
Reactant: CCCCCC[C@@H](F)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCC[C@@H](F)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 6 h
Yield: 93.1 %

Procedure:
A reaction vessel was charged with 10.0 g of (2R)-2fluorooctanol and 25 ml of pyridine, and 13.0 g of tosyl chloride was added with stirring at 0°-5° C. After the reaction was effected for 6 hours, the mixture was poured into water and extracted with 100 ml of benzene. The resultant solution in benzene was washed sequentially with water, an aqueous solution of NaHCO3 and water in that order, and dried over Glauber's salt. The solvent was distilled off to obtain 19.0 g (yield 92.6%) of crude (2R)-2-fluorooctyl tosylate as the residue.
Reaction SMILES: C(O)(=O)C.Cl.[C:6]([C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)(=[O:10])[CH2:7][CH2:8][CH3:9]>O1CCOCC1.[Rh]>[CH:17]1([C:11]2([C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCCC(=O)C1(c2ccccc2)CCNCC1
Agent: [Rh]
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCCC(=O)C1(C2CCCCC2)CCNCC1
Temperature: 80 °C
Yield: 43.1 %

Procedure:
In a Parr bomb under a hydrogen pressure of 6 bar, 100 mg of rhodium on alumina and 0.2 ml of acetic acid are added to a solution of 100 mg (0.5 mmol) of 4-butyryl-4-phenylpiperidine hydrochloride in 10 ml of dioxane. The reaction medium is heated at 80° C. for 12 hours. The reaction is stopped and then filtered through Celite and washed with dichloromethane. The solvents are evaporated off and the residue is taken up in water, basified with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phases are dried over sodium sulfate. The solvents are evaporated off and the residue is chromatographed on silica gel (eluent: 9/1 dichloromethane/methanol). 51.2 mg of 1-(4-cyclohexylpiperidin-4-yl)-butan-1-one in the form of a white powder are obtained in a yield of 61%.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=O)[CH2:3][SH:4].B.O1CCCC1.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[NH2:1][C@H:2]([CH2:3][S:4][C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:5][OH:7]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@H](CS)C(=O)O
Agent: B
Solvent: C1CCOC1
Product: N[C@@H](CO)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
D-Cysteine (2.36 g, 19.48 mmol) was suspended in THF (40 mL) and cooled to 0° C. Borane-tetrahydrofuran complex (1 M in THF, 78 mL, 78 mmol) was added over 20 mins and the mixture was stirred at RT for 6 hours. The reaction was quenched with DMF (7 mL) and stirred for 25 mins. Trityl chloride (5.97 g, 21.43 mmol) was added and the mixture stirred for a further 16 hours. The reaction mixture was evaporated under vacuum. The residue was partitioned between DCM and water and the phases separated. The organic phase was passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 50% EtOAc/hexane, EtOAc, 10% MeOH/EtOAc and 20% MeOH/EtOAc gave the title compound.