Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:23]C)[N:13]3[CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][O:19][CH2:18]3)=[C:9]([NH2:25])[N:8]=2)[CH2:3][CH2:2]1.Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:25][C:9]1[N:8]=[C:7]([NH:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:23])[N:13]2[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][O:19][CH2:18]1
Reactant: COc1nc2c(N)nc(NCCC3CC3)nc2n1CC1CCCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc(NCCC2CC2)nc2c1[nH]c(=O)n2CC1CCCOC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
To a solution of N2-(2-cyclopropylethyl)-8-(methoxy)-9-(tetrahydro-2H-pyran-3-ylmethyl)-9H-purine-2,6-diamine (198 mg) in methanol (19.1 ml) at room temperature was added 4.0M hydrogen chloride in 1,4-dioxane (3.57 ml) to give a colorless solution. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralised with 2M NaOH and concentrated in vacuo. The resulting solid was taken up in water (50 ml) and filtered off to give a white solid. This solid was recrystallised from ethanol:water (1:1) and filtered to afford an off-white crystalline solid (113 mg).
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[N:15]1([C:21]2[CH:26]=[CH:25][C:24]([C:27]34[CH2:32][CH:31]3[CH2:30][NH:29][CH2:28]4)=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.[CH3:42][O:43][CH2:44][CH2:45]Cl>CN(C=O)C>[CH3:42][O:43][CH2:44][CH2:45][N:29]1[CH2:30][CH:31]2[C:27]([C:24]3[CH:23]=[CH:22][C:21]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:26][CH:25]=3)([CH2:32]2)[CH2:28]1
Reactant: COCCCl
Reactant: c1cc(C23CNCC2C3)ccc1N1CCOCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCN1CC2CC2(c2ccc(N3CCOCC3)cc2)C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 37.2 %

Procedure:
To a solution of dihydrochloride salt of 1-(4-morpholin-4-yl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Example XXI) (250 mg, 0.89 mmol) in anhydrous DMF (5 mL) were added DIPEA (0.63 mL, 3.56 mmol) and 2-methoxyethyl chloride (0.12 mL, 1.3 mmol) at r.t. and reaction mixture was stirred at 100° C. for 16 h. Progress of the reaction was monitored by TLC. On completion, reaction mixture was then concentrated and the crude product was purified by column chromatography (silica gel, 0.25:9.75 MeOH:CHCl3) to afford the title compound as viscous liquid (100 mg, 37%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[CH2:10]([SH:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([S:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N+:3]=1[O-:9]
Reactant: CCCCCCCCS
Reactant: [O-][n+]1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCSc1cccc(Cl)[n+]1[O-]

Procedure:
The 2.01 g (0.0122 moles) of 2,6-dichloropyridine N-oxide and 2.10 g (85%) (0.0122 moles) of 1-octylmercaptan was reacted with 0.488 g (0.0122 moles) of ground sodium hydroxide in 8.2 ml of DMSO at 80° C. for 6 hours to give 2-chloro-6-octylthiopyridine N-oxide. It was reacted with 1.47 g (0.0367 moles) of ground sodium, hydroxide at 80° C. for 3 hours to give 1-hydroxy-6-octylthiopyridine-2(1H)-one. After cooling, it was added 180 ml of water and was adjusted with 6N HCL to pH 3. The precipitate was filtered, washed with water and washed with 150 ml of petroleum ether to give 1.34 g (43%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[C:11]([F:21])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30](Cl)[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34].[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][CH2:41][NH2:42]>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[C:11]([F:21])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([NH:42][CH2:41][CH2:40][CH2:39][N:38]([CH3:43])[CH3:37])[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34]
Reactant: CN(C)CCCN
Reactant: O=C(Nc1cc(F)cc(N2CCOCC2)c1)c1ccc(Cl)c(NC(=O)c2cc(Cl)ccc2[N+](=O)[O-])c1
Product: CN(C)CCCNc1ccc([N+](=O)[O-])c(C(=O)Nc2cc(C(=O)Nc3cc(F)cc(N4CCOCC4)c3)ccc2Cl)c1
Yield: 76 %

Procedure:
Using an analogous procedure to that described in the sixth paragraph of the portion of Note a) immediately above which is concerned with the preparation of starting materials. 4-chloro-3-(5-chloro-2-nitrobenzamido)-N-(3-fluoro-5-morpholinophenyl)benzamide was reacted with 3-dimethylaminopropylamine to give 4-chloro-3-[5-(3-dimethylaminopropylamino)-2-nitrobenzamido]-N-(3-fluoro-5-morpholinophenyl)benzamide in 76% yield; NMR Spectrum: (DMSOd6) 1.62–1.74 (m, 2H), 2.12 (s, 6H), 2.27 (t, 2H), 3.08–3.13 (m, 4H), 3.18–3.22 (m, 2H), 3.69–3.74 (m, 4H), 6.58 (d, 1H) 6.67 (m, 2H), 7.15–7.2 (m, 2H), 7.42 (t, 1H), 7.69 (d, 1H), 7.68 (d, 1H), 7.82 (d, 1H), 8.04 (d, 1H), 8.26 (s, 1H), 10.32 (s, 1H); Mass Spectrum: M+H+ 599.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 4 h
Yield: 90.1 %

Procedure:
To a solution of the 4-fluoro-3-nitrobenzoic acid (0.12 mol, 22.2 g) in 100 mL of anhydrous DCM was added 10 drops of anhydrous DMF. To this solution was added drop wise over 60 min, oxalyl chloride (0.144 mol, 12.6 mL). During the addition, the solid slowly dissolved to give rise to a yellow solution. The mixture was stirred for an additional 4 h and the solvent was stripped down to give a yellow oil. This oil was distilled under vacuum (110° C., 1.5 mm Hg) to give 4-fluoro-3-nitrobenzoyl chloride as a light yellow liquid (22.0 g, 90% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[O:34][CH2:33][CH2:32][S:31](=[O:36])(=[O:35])[C:30]=2[CH:37]=1.Cl>CN1C(=O)CCC1.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:25][C:26]3[CH:27]=[CH:28][C:29]4[O:34][CH2:33][CH2:32][S:31](=[O:36])(=[O:35])[C:30]=4[CH:37]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: CN1C(=O)N(c2c(F)cccc2Br)Cc2cnc(S(C)(=O)=O)nc21
Reactant: Nc1ccc2c(c1)S(=O)(=O)CCO2
Agent: Cl
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CN1C(=O)N(c2c(F)cccc2Br)Cc2cnc(Nc3ccc4c(c3)S(=O)(=O)CCO4)nc21
Temperature: 120 °C

Procedure:
83 mg 3-(2-bromo-6-fluorophenyl)-3,4-dihydro-7-methanesulphonyl-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one and 80 mg 6-Amino-2,3-dihydro-benzo[1,4]oxathiine-4,4-dioxide (starting material h)) in 0.8 ml NMP were treated with 0.2 ml 2M HCl in ether and heated to 120° C. for 6 hrs. From this mixture 21 mg of the title product were isolated by preparative HPLC-MS (mp: 230–233° C.).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:10][C:11](=[O:34])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[CH:13]=1)[CH3:9]>C(Cl)Cl>[NH:24]1[CH2:23][CH2:22][CH:21]([CH2:20][CH2:19][O:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[C:11]([O:10][CH2:8][CH3:9])=[O:34])[CH2:26][CH2:25]1
Reactant: CCOC(=O)c1cccc(OCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cccc(OCCC2CCNCC2)c1
Reaction time: 8 h
Yield: 163.9 %

Procedure:
TFA (25 ml) was added to a solution of N-Boc-3-(2-piperidin-4-yl-ethoxy)-benzoic acid ethyl ester (8.5 g, 22 mmol) in DCM (100 ml). Stirring overnight followed by evaporation of the solvents afforded 10 g of the title compound as the TFA salt. LC-MS (m/z): 279 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][N:4]=1.C(N(CC)CC)C.[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>ClCCl>[C:26]([C:30]1[CH:31]=[CH:32][C:33]([C:34]([NH:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)[CH:7]=2)=[O:35])=[CH:37][CH:38]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.2 %

Procedure:
[2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (319 mg, 1.28 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (117 μL, 1.40 mmol) and 4-tert-butylbenzoyl chloride (274 μL, 1.40 mmol) were added and the reaction was stirred at room temperature for 10 minutes. The crude mixture was absorbed onto silica and purified by column chromatography to give the title compound as an off-white solid (274 mg, 52% yield). MS (ES+) m/e=411. 1H NMR (CDCl3) δH 1.36 (12H, s), 1.39 (9H, s), 4.10 (3H, s), 7.55 (2H, d), 7.86 (2H, d), 8.28 (1H, s), 8.36 (1H, br s), 9.07 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH:5]([NH2:7])[CH3:6].N1C=CC=CC=1.Cl[C:18]([O:20][CH3:21])=[O:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([NH:7][C:18](=[O:19])[O:20][CH3:21])[CH3:6])[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cl
Reactant: CC(N)c1cccc(Br)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)NC(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
To a solution of 23.8 g of 3-bromo-α-methylbenzylamine in toluene (120 ml), 14.1 g of pyridine was added at room temperature. To this solution, 18.6 g of methyl chloroformate was dropwise added under cooling with ice, followed by stirring at room temperature for 2 hours. The reaction solution was poured into a citric acid aqueous solution and extracted with ethyl acetate. The organic layer was washed with a citric acid aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 10.5 g of methyl N-[1-(3-bromophenyl)ethyl]carbamate as a colorless transparent viscous liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[N:21]=[C:20]([CH3:22])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][CH:17]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:16]2[CH:17]=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[C:20]([CH3:22])[N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Yield: 87.5 %

Procedure:
A mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (440 mg; 2.2 mmol), 6-chloro-2-methyl-3-nitro-pyridine (346 mg; 2.0 mmol), and triethylamine (420 μL; 3.0 mL) is dissolved in dimethylformamide (6 mL) and the resulting mixture is irradiated in a mono-mode microwave oven for 14 hours at 100° C. The reaction mixture is treated by aq. sat. ammonium chloride (5 mL), the precipitate formed is filtered, then rinsed with water (2 mL) and dried under high vacuum to afford the desired product (590 mg; 1.75 mmol).
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][N:12]3[CH2:15][CH2:16][C:17]#[N:18])=[CH:7][C:6]=2Br)[CH2:4][CH2:3][CH2:2]1.[C:26]([Zn]C#N)#[N:27].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C(#N)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]>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][N:12]3[CH2:15][CH2:16][C:17]#[N:18])=[CH:7][C:6]=2[C:26]#[N:27])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)c(Br)cc2c1=O
Reactant: N#C[Zn]C#N
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)c(C#N)cc2c1=O

Procedure:
A solution of EXAMPLE 82A (0.50 g), dicyanozinc (0.29 g), 2-(di-tert-butylphosphino)biphenyl (0.15 g), and tris(dibenzylideneacetone)dipalladium(0) (0.11 g) in acetonitrile (20 mL) was refluxed for 1 hour then cooled and filtered; and the filtrate was diluted with water and filtered.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])[CH2:2][CH3:3].N1C=CC=CC=1.[Br:19]Br>C(Cl)(Cl)(Cl)Cl>[CH2:11]([O:10][C:1]([O:4][CH2:5][CH3:6])([O:7][CH2:8][CH3:9])[CH:2]([Br:19])[CH3:3])[CH3:12]
Reactant: BrBr
Reactant: CCOC(CC)(OCC)OCC
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(OCC)(OCC)C(C)Br
Reaction time: 24 h
Yield: 80.7 %

Procedure:
A solution of 176 g (1 mole) of triethyl orthopropionate and 96 g (1.2 moles) of pyridine in 1 l of carbon tetrachloride was placed in a 2 l flask and 160 g (1 mole) of bromine was slowly added over two hours to the solution under ice-cooling. The resultant reaction mixture was allowed to stand at room temperature for one day to form a precipitate, which was then filtered off. The filtrate was concentrated by evaporation of the solvent and the residue was subjected to distillation under reduced pressure to afford 206 g (81%) of 1,1,1-triethoxy-2-bromopropane with a boiling point of 85° C./13 mmHg.
Reaction SMILES: [CH3:1][OH:2].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8]([CH:12]=1)[C:9](Cl)=[O:10]>ClCCl>[CH3:1][O:2][C:9](=[O:10])[C:8]1[CH:12]=[C:4]([Cl:3])[CH:5]=[CH:6][C:7]=1[F:13]
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Reactant: CO
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Methanol (20 ml) was added to a solution 5-chloro-2-fluoro-benzoyl chloride (1.2 g, 6.2 mmol) in dichloromethane (10 ml) in an ice-bath. The reaction mixture was warmed to room temperature, stirred for 3 h and then concentrated to afford 5-chloro-2-fluoro-benzoic acid methyl ester (1.17 g, 100%). 1H NMR (CDCl3), δ (ppm): 7.93 (m, 1H), 7.48 (m, 1H), 7.12 (m, 1H), 3.96 (s, 3H). Step 2: 5-Chloro-2-fluoro-benzoic acid hydrazide: A mixture of 5-chloro-2-fluoro-benzoic acid methyl ester (1.17 g, 6.2 mmol) and hydrazine monohydrate (0.451 ml, 9.3 mmol) in ethanol (20 ml) was stirred at room temperature overnight. The reaction mixture was concentrated and then the residue was triturated with diethyl ether to afford 5-chloro-2-fluoro-benzoic acid hydrazide (497 mg, 42%, white solid). 1H NMR (DMSO), δ (ppm): 9.66 (bs, 1H), 7.58 (m, 2H), 7.36 (m, 1H), 4.58 (bs, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:12]#[N:13])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4].[BH4-].[Na+].[H][H]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([CH2:12][NH2:13])[C:7]2([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C#N)CC12CCCC2
Reactant: [H][H]
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C1(CN)CC12CCCC2
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a solution of 1-cyano-spiro[2.4]heptane-1-carboxylic acid methyl ester (3.45 g, 19.3 mmol) in methanol (240 mL) was added cobalt chloride hexahydrate (CoCl2—6H2O) (9.16 g, 38.5 mmol) to give a deep purple colored solution. Sodium borohydride (7.30 g, 193 mmol) was added portionwise over 10 minutes with caution to control the evolution of hydrogen and the exothermic reaction that ensued to give a black solution. The reaction mixture was stirred for 30 minutes under nitrogen after the addition was completed. The reaction was quenched carefully by the addition of 0.5N HCl (1.3 L). The solution was made alkaline (pH˜9) by the addition of concentrated ammonium hydroxide. The mixture was extracted with ethyl acetate (4×400 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to afford 3.07 g (87%) of 1-aminomethyl-spiro[2.4]heptane-1-carboxylic acid methyl ester as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 0.74 (br d, 1H), 1.4–1.7 (m, 10H), 1.9 (m, 1H), 2.58 (d, J=13.8 Hz, 1H), 3.16 (d, J=13.8 Hz, 1H), 3.48 (s, 3H); MS (APCI) m/z 184 [M+H]+.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:15].[CH3:16][C:17]1[O:21][C:20]([C:22]([F:25])([F:24])[F:23])=[C:19]([S:26](Cl)(=[O:28])=[O:27])[CH:18]=1>N1C=CC=CC=1>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:15][S:26]([C:19]1[CH:18]=[C:17]([CH3:16])[O:21][C:20]=1[C:22]([F:25])([F:23])[F:24])(=[O:28])=[O:27]
Reactant: Nc1cccc2cc(C3=NCCS3)[nH]c12
Reactant: Cc1cc(S(=O)(=O)Cl)c(C(F)(F)F)o1
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)Nc2cccc3cc(C4=NCCS4)[nH]c23)c(C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
To a mixture of 2-(4,5-dihydro-1,3-thiazol-2-yl)-1H-indole-7-amine (100 mg) and pyridine (3 mL) was added 5-methyl-2-trifluoromethylfuran-3-sulfonyl chloride (150 mg) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (90 mg, yield 46%) as pale-yellow crystals. M+1=430.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1(C#N)[CH2:14][CH2:13][CH2:12]1.C[Mg]I.IC.[Mg].CC[O:25][CH2:26][CH3:27]>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([C:26](=[O:25])[CH3:27])[CH2:14][CH2:13][CH2:12]1
Reactant: CCOCC
Reactant: N#CC1(c2ccc3ccccc3c2)CCC1
Agent: C[Mg]I
Agent: [Mg]
Solvent: CI
Solvent: Cc1ccccc1
Product: CC(=O)C1(c2ccc3ccccc3c2)CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-(2-naphthyl)cyclobutanecarbonitrile (48.2 g) in toluene (100 ml) was added dropwise under nitrogen to a stirred solution of methylmagnesium iodide [prepared in the usual manner from iodomethane (22 ml) and magnesium (8.16 g)] in ether (60 ml), then the mixture was stirred at ambient temperature for 18 hours. The resulting solid was collected by filtration, washed with ether (50 ml), and added in portions to a mixture of concentrated hydrochloric acid (125 ml) and water (200 ml). The mixture was heated at 100° C. with occasional stirring for 10 minutes, then it was cooled to ambient temperature. The product was extracted into toluene (3×200 ml), then the extracts were washed with water (200 ml), and the solvent was removed in vacua. The residue was triturated with petroleum ether (b.p. 40-60° C.) (100 ml), and the resulting solid was collected by filtration and dried in vacuo to give 1-[1-(2-naphthyl)cyclobutyl]ethanone as a yellow solid (35 g) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14]([C@@H:15]([OH:25])/[CH:16]=[CH:17]/[C:18]([CH3:24])([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([CH3:26])[CH2:12][C:11]1=[O:27].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14]([C@@H:15]([O:25][C:35](=[O:37])[CH3:36])/[CH:16]=[CH:17]/[C:18]([CH3:23])([CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([CH3:26])[CH2:12][C:11]1=[O:27]
Reactant: CCCCC(C)(C)/C=C/[C@H](O)[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC(C)(C)/C=C/[C@H](OC(C)=O)[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the crude optically active (5Z,11alpha,13S,14E)-13-(hydroxy)-11,16,16-trimethyl-9-oxoprosta-5.14-dien-1-oic acid methyl ester (9.2 g) in methylene chloride (100 mL) was treated with pyridine (5.5 mL) and 4-dimethylaminopyridine (0.5 g), cooled to 0°, and treated with acetic anhydride (3.4 mL). The resulting mixture was stirred overnight at room temperature and then washed with 2 N HCL, water. NaHCO3 solution, and brine (75 mL of each). After drying over sodium sulfate, the solvent was stripped off leaving 9.7 g (~100%) of crude optically active (5Z,11alpha,13S,14E)-13-(acetyloxy)-11,16,16-trimethyl-9-oxoprosta-5,14-dien-1-oic acid methyl ester is a yellow oil. This material was used as is in Example XXII.
Reaction SMILES: Cl.[NH:2]([C:4]1[C:5](=[O:10])[NH:6][CH:7]=[CH:8][N:9]=1)[NH2:3].C(N(CC)CC)C.C[O:19][C:20](=O)[N:21]=[C:22](SC)[C:23]([C:37]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([O:45][CH2:46][CH2:47][O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[C:38]=1[F:56])=[N:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:35]=[C:34]([CH3:36])[O:33][N:32]=2)=[CH:27][CH:26]=1>CN(C=O)C>[Si:49]([O:48][CH2:47][CH2:46][O:45][C:39]1[C:38]([F:56])=[C:37]([CH:23]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[N:35]=[C:34]([CH3:36])[O:33][N:32]=3)=[CH:29][CH:30]=2)[C:22]2[NH:21][C:20](=[O:19])[N:2]([C:4]3[C:5](=[O:10])[NH:6][CH:7]=[CH:8][N:9]=3)[N:3]=2)[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=1)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]
Reactant: NNc1ncc[nH]c1=O
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCO[Si](C)(C)C(C)(C)C)c1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OCCO[Si](C)(C)C(C)(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncc[nH]c3=O)c(=O)[nH]2)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
3-Hydrazino-1H-pyrazin-2-one hydrochloride (24 mg) and triethylamine (0.033 ml) were added to 3 ml of a DMF solution containing 70 mg of (2-{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene)carbamic acid methyl ester (Example (200a)). The resulting mixture was stirred at 85° C. for 16 hours and then concentrated under reduced pressure. The residue was dissolved in 5 ml of methanol, and 58 mg of sodium cyanotrihydroborate and 0.056 ml of acetic acid were further added thereto. The mixture was stirred at room temperature for 15 hours. To this reaction mixture, 40 ml of ethyl acetate and 20 ml of water were added. The organic layer was washed with 20 ml of water and then with 20 ml of saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (34 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]([N:19]3[CH2:23][CH2:22][CH2:21][C@@H:20]3[CH3:24])=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:25]([O:27]C)=[O:26])[CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]([N:19]3[CH2:23][CH2:22][CH2:21][C@@H:20]3[CH3:24])=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:25]([OH:27])=[O:26])[CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)c(F)c3)c(N3CCC[C@@H]3C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a solution of (S)-methyl 2-(3,4-difluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (80 mg, 0.23 mmol) in methanol (10 mL) was added sodium hydroxide (40 mg, 1 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted the pH to 6 with 3N HCl, and filtered to give (S)-2-(3,4-difluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (44.5 mg, 58%).