Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:5]=[CH:4][C:9]([CH3:8])=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NNc1cccc(F)c1
Agent: Cl
Solvent: CCO
Product: Cc1ccn(-c2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 99.4 %

Procedure:
Add hydrochloric acid (5M, 12 mL, 60 mmol) to a mixture of 4,4-dimethoxybuta-2-one (6.61 g, 6.67 mL, 50 mmol) and 3-fluorophenylhydrazine hydrochloride (8.13 g, 50 mmol) in ethanol (50 mL). Heat and stir under reflux under nitrogen for 7.5 hr., cool to room temperature, allow to stand for 60 hr. Evaporate the ethanol in vacuo, and chromatograph the residue on silica eluting with DCM. Evaporate the dichlormethane to give 1-(3-fluoro-phenyl)-3-methyl-1H-pyrazole as a liquid (4.38 g, 49%). MS (m/z): 171.1 (M+1).
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:19])[F:18])=[C:12]([O:20][CH:21]([F:23])[F:22])[CH:11]=2)[CH2:8][CH2:7]C(=O)[CH2:5][CH2:4]1)#[N:2].[CH:24]([O:29][CH3:30])([O:27][CH3:28])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:30][O:29][C:24]1([O:27][CH3:28])[CH2:5][CH2:4][C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:18])[F:19])=[C:12]([O:20][CH:21]([F:22])[F:23])[CH:11]=2)([C:1]#[N:2])[CH2:8][CH2:7]1
Reactant: N#CC1(c2ccc(OC(F)F)c(OC(F)F)c2)CCC(=O)CC1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC1(OC)CCC(C#N)(c2ccc(OC(F)F)c(OC(F)F)c2)CC1
Yield: 98.2 %

Procedure:
A mixture of 4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexan-1-one (1.34 g, 4.05 mmol), trimethyl orthoformate (0.53 mL, 4.85 mmol) and a catalytic amount of p-toluenesulfonic acid in methanol (40 mL) was heated gently under an argon atmosphere for 2 h. The mixture was cooled and then concentrated The residue was partitioned between 5% aqueous sodium carbonate and ethyl acetate, was extracted twice with ethyl acetate, the organic extract was dried (potassium carbonate) and the solvent was removed in vacuo to provide an oil (1.5 g, 98%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])=[CH:24][CH:23]=1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][Si:29]([CH:30]([CH3:32])[CH3:31])([CH:33]([CH3:35])[CH3:34])[CH:36]([CH3:37])[CH3:38])=[CH:24][CH:23]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)[Si](Oc1ccc(C(CCNC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1)(C(C)C)C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1ccc(C(CCNC(=O)OC(C)(C)C)C(=O)O)cc1)(C(C)C)C(C)C
Reaction time: 2 h

Procedure:
To benzyl 4-(tert-butoxycarbonylamino)-2-(4-(triisopropylsilyloxy)phenyl)butanoate (E304) in EtOAc was added Pd/C (10%) and the solution was kept under a H2 atmosphere for 2 h. The mixture was filtered over Celite and the solvent was evaporated to give 4-(tert-butoxycarbonylamino)-2-(4-(triisopropylsilyloxy)phenyl)butanoic acid (E305).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH:5]1[CH2:12][CH:11]2[NH:13][CH:7]([CH2:8][O:9][CH2:10]2)[CH2:6]1.C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>ClCCl>[CH2:26]([O:25][C:23]([N:13]1[CH:7]2[CH2:6][CH:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])[CH2:12][CH:11]1[CH2:10][O:9][CH2:8]2)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)CC1CC2COCC(C1)N2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1CC2COCC(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of (3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid methyl ester (Compound AG) (179 mg, 0.90 mmol) in 10 mL of dichloromethane was added triethylamine (0.5 mL, 3.6 mmol). The mixture was stirred at room temperature for 15 mins and then benzyl chloroformate (0.25 mL, 1.8 mmol) was added dropwise at 0° C. After the reaction mixture was stirred at room temperature for 2 hours, it was concentrated in vacuo. The residue was purified by flash column chromatography to afford 7-methoxycarbonylmethyl-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester as colorless oil (Compound AI) (0.13 g, 44%) MS: calc'd (MH+) 334, measured (MH+) 334.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].CCN=C=NCCCN(C)C.Cl.[CH2:24]([NH2:29])[CH2:25][CH:26]([CH3:28])[CH3:27].O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:29][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: CC(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)CCNC(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-3-fluorobenzoic acid (2.00 g, 9.13 mmol) was dissolved in dichloromethane (20 mL) and cooled in an ice/water bath as EDCl (2.10 g, 10.9 mmol) was added. After addition, the reaction mixture was allowed to warm to ambient temperature and stirred for 30 minutes before adding isoamylamine (1.59 g, 18.3 mmol). After 12 hours, water was added and the reaction mixture was extracted with ethyl ether. The combined organic layers were washed sequentially with 1N HCl, 1N NaOH and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by chromatography on silica gel eluting with 5% ethyl acetate in heptane to afford the title compound (I-5a).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:17]1([CH2:20]Br)[CH2:19][CH2:18]1>CN(C)C=O>[CH:17]1([CH2:20][N:14]2[CH2:15][CH:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:10][CH2:11][CH2:12][C:13]2=[O:16])[CH2:19][CH2:18]1
Reactant: BrCC1CC1
Reactant: O=C1CCCC(c2ccccc2)CN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCC(c2ccccc2)CN1CC1CC1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 0.793 g, 19.8 mmol) was added to a solution of 6-phenylazepan-2-one (2.50 g, 13.2 mmol) and cyclopropylmethyl bromide (1.92 mL, 19.8 mmol) in N,N-dimethylformamide (30 mL) at 0° C., then the mixture allowed to warm to ambient temperature. After 18 h the mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water (3×) and saturated brine, dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (1% methanol/dichloromethane→5% methanol/dichloromethane) gave the title compound (2.33 g). MS 244 (M+1).
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].O.[CH2:8]1[CH2:12]O[CH2:10][CH2:9]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:2]1([CH:4]=[CH2:4])[CH2:8][CH2:4][CH:2]([CH:1]2[CH2:12][CH2:12][CH:8]([CH2:9][CH2:10][CH2:1][CH2:2][CH3:3])[CH2:9][CH2:10]2)[CH2:3][CH2:3]1)[CH2:10][CH2:9][CH2:8][CH3:12]
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: C=CC1(CCCCC)CCC(C2CCC(CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 17.84 g of KOtBu in 100 ml of THF is added dropwise at 0C to a suspension of 53.20 g of 4,4,′-dipentylbicyclohexyl-4-carbaldehyde and 56.80 g of methyltriphenylphosphonium bromide in 300 ml of THF. The mixture is stirred at RT overnight, water is added, and the mixture is extracted with MTB ether. The combined organic phases are subjected to conventional work-up, giving 4,4′-dipentyl-4-vinylbicyclohexyl.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:13][C:14](=[O:16])[CH3:15])[CH:12]=1)[CH:8]=[CH2:9])(=[O:3])[CH3:2]>C(OCC)(=O)C.C(O)C.[C].[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:8][CH3:9])[CH:10]=[C:11]([O:13][C:14](=[O:16])[CH3:15])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: C=Cc1cc(OC(C)=O)cc(OC(C)=O)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cc(OC(C)=O)cc(OC(C)=O)c1
Yield: 76.9 %

Procedure:
3,5-Diacetoxystyrene (580 mg) is dissolved in a mixture of ethyl acetate (6 ml) and ethanol (2 ml), and the mixture is subjected to catalytic reduction with using 10% palladium-carbon (51.4% aqueous, 50 mg) under atmospheric pressure. Two hours thereafter, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; hexane/ethyl acetate) to give 1,3-diacetoxy-5-ethylbenzene (450 mg).
Reaction SMILES: [NH2:1][C:2]1[C:16]([C:17]([OH:19])=[O:18])=[C:5]2[N:6]=[C:7]([O:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH:8]=[CH:9][N:4]2[N:3]=1.CCN(CC)CC.CN(C(O[N:35]1[N:43]=[N:42][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN1C(=O)CCC1>[NH2:1][C:2]1[C:16]([C:17]([O:19][N:35]2[CH:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]3[N:42]=[N:43]2)=[O:18])=[C:5]2[N:6]=[C:7]([O:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CN(C)CCOc1ccn2nc(N)c(C(=O)O)c2n1
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CN(C)CCOc1ccn2nc(N)c(C(=O)ON3N=NC4C=CC=CC43)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.4 %

Procedure:
To a suspension of 2-amino-5-[2-(dimethylamino)ethoxy]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (80 mg, 0.3016 mmol) in NMP (1 mL) was added Et3N (37.24 mg, 51.29 μL, 0.3680 mmol). To the mixture was added TBTU (Boron Tetrafluoride Ion (1)) (109.0 mg, 0.3396 mmol) portionwise over a 5 minutes. The mixture was allowed to stir at room temperature for 20 minutes before being partitioned between ethylacetate and water. The aqueous layer was extracted twice with ethylacetate and the combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo to afford the product 3a,7a-dihydro-1H-benzo[d][1,2,3]triazol-1-yl 2-amino-5-(2-(dimethylamino)ethoxy)pyrazolo[1,5-a]pyrimidine-3-carboxylate as an oil (92 mg, 80% yield).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][N:3]1[C:9]1[CH:10]=[CH:11][C:12]([CH3:27])=[C:13]([CH:26]=1)[C:14]([NH:16][CH2:17][C:18]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:15].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([NH2:38])=[O:37]>CS(C)=O.O>[C:36]([CH2:35][N:7]1[C:6](=[O:8])[CH:5]=[N:4][N:3]([C:9]2[CH:10]=[CH:11][C:12]([CH3:27])=[C:13]([CH:26]=2)[C:14]([NH:16][CH2:17][C:18]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:15])[C:2]1=[O:1])(=[O:37])[NH2:38]
Reactant: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)NCC1(O)CCCCCC1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-n2ncc(=O)n(CC(N)=O)c2=O)cc1C(=O)NCC1(O)CCCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 45.5 %

Procedure:
A slurry of 5-(3,5-Dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxy-cycloheptylmethyl)-2-methyl-benzamide (200.0 mg, 0.537 mmol) and Cs2CO3 (290.3 mg, 0.891 mmol) were stirred in DMSO (1.79 mL, 0.3 M) at ambient temperature for 15 minutes. 2-Bromoacetamide (74.1 mg, 0.537 mmol) was added and the reaction stirred at ambient temperature for 14 hours. The reaction was diluted with water (15-fold) and the aqueous extracted with CH2Cl2 (3×). The organics were dried over sodium sulfate, and concentrated in vacuo to a tan oil. The crude was triterated from IPE/Et2O/CH2Cl2 to give the title compound as a tan solid (105 mg). LCMS (m/z) 430.5 M+1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=12.[F:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[OH:25].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[F:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[O:25][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=12
Reactant: COC(=O)c1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 180 °C
Yield: 58.7 %

Procedure:
A mixture of 37 (4.0 g, 17.6 mmol), 2-fluoro-4-nitrophenol (5.5 g, 35.0 mmol) and K2CO3 (12.1 g, 87.5 mmol) in Ph2O was heated at 180° C. for 5 hours. The mixture was cooled to room temperature, diluted with EtOAc and washed with water. The organic phase was collected, dried over anhydrous sodium sulfate and the solvents were removed under reduced pressure. The residue was purified by flash chromatography using hexane—AcOEt (70:30) as an eluent. The product from the column was re-crystallized from a mixture of ethyl acetate-hexanes to afford 38 (3.6 g, 59% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.69 (d, J=5.2 Hz, 1H), 8.47 (dd, J=2.4 and 10.0 Hz, 1H), 8.27 (s, 1H), 7.77 (dd, J=8.0 and 9.2 Hz, 1H), 7.06 (dd, J=0.8 and 5.2 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC(OCC(C)C)=O.[NH2:30][C:31]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](O)=[O:34]>C(Cl)Cl.CN1CCOCC1>[O:34]=[C:33]1[C:32]2[CH:36]=[CH:37][CH:38]=[C:39]([C:40]([F:41])([F:42])[F:43])[C:31]=2[N:30]=[C:19]([CH:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:21]1
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NC(COCc1ccccc1)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Yield: 39.9 %

Procedure:
Using the procedure of Step A of Example 7, a solution of 29.5 g of BOC-O-benzyl L-serine in 200 ml of methylene chloride, 27.5 ml of N-methyl-morpholine, 26.2 g of isobutyl chloroformate in methylene chloride and 20.5 g of 2-amino-3-trifluoromethyl benzoic acid in 200 ml of methylene chloride and 11 ml of N-methyl-morpholine were reacted for 16 hours. The mixture was extracted with methylene chloride and chromatography on silica gel (eluent: methylene chloride) yielded 18.5 g of 1,1-dimethylethyl N-[1-[4-oxo-8-trifluoromethyl-4H-3,1-benzoxazin-2-yl]-2-(phenylmethoxy)-ethyl]-carbamate melting at 98° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:31])([CH:28]([F:30])[F:29])[CH:11]=[CH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)=[CH:6][CH:5]=1)[CH3:2].[H][H]>[Ni].C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:31])([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:15]=2)[CH:28]([F:30])[F:29])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(C(C)(C=CCc2ccc(F)c(Oc3ccccc3)c2)C(F)F)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOc1ccc(C(C)(CCCc2ccc(F)c(Oc3ccccc3)c2)C(F)F)cc1

Procedure:
2.0 g (4.69 mmol) 4-(4-Ethoxyphenyl)-5,5-difluoro-1-(4-fluoro-3-phenoxyphenyl)-4-methyl-2-pentene was hydrogenated with hydrogen at atmospheric pressure with hydrogen in the presence of 0.2 g Raney nickel in 30 ml ethanol. After the calculated amount of hydrogen had been taken up, the catalyst was filtered off and the solvent removed under reduced pressure. After chromatography on silica gel, using hexane/toluene, 1.8 g of the desired product remained i.e. 89.6% of theory.
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[C:10]([S:17]([NH:20][C@H:21]([C:29]([OH:31])=O)[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])(=[O:19])=[O:18])[CH:9]=[CH:8]2.C(OCC)C.S(Cl)([Cl:39])=O>>[N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[C:10]([S:17]([NH:20][C@H:21]([C:29]([Cl:39])=[O:31])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])(=[O:19])=[O:18])[CH:9]=[CH:8]2
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cc2cc1OC
Reactant: O=S(Cl)Cl
Agent: N#N
Solvent: CCOCC
Product: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2.00 g of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:9]2[CH2:10][CH2:11][CH:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])[CH2:8]2)=[CH:13][CH:14]=1)=[O:23]
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Reactant: Cc1ccccc1C(=O)Cl
Product: Cc1ccccc1C(=O)Nc1ccc([C@H]2CCC(N3CCC[C@@H]3C)C2)cc1

Procedure:
The title compound was synthesized essentially in the same manner as Example 28 by employing 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14) and 2-methylbenzoyl chloride.
Reaction SMILES: Br[CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>O1CCCC1>[O:13]1[CH2:14][CH2:15][N:10]([CH2:2][C:3]([OH:5])=[O:4])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=C(O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Dissolve t-butyl bromoacetate (1 eq) in tetrahydrofuran and add morpholine (2.2 eq) via syringe. Stir the reaction mixture at room temperature for 2 hours, filter and wash the filter cake with ethyl acetate. Combine the organic filtrates and wash with saturated sodium bicarbonate (2×), water (2×) and brine. Dry (Na2SO4), filter and evaporate the solvent in vacuo. Take up the oily residue in ethyl acetate, cool in ice and bubble hydrogen chloride gas into the solution. Stir at room temperature overnight, cool and filter to give morpholinoacetic acid (85%); mp 169°-170° C.; 1H NMR (D2O) δ3.75-4.29 (br m, 6), 3.59 (br s, 2), 3.28 (br s, 2).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([CH2:14][CH:15]=[CH2:16])[CH:5]=1.S(C)C.[OH-:21].[Na+].OO>C1COCC1>[OH:21][CH2:16][CH2:15][CH2:14][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:11])[C:7]=1[O:12][CH3:13])[C:3]([OH:2])=[O:17]
Reactant: C=CCc1cc(C(=O)OC)cc(OC)c1OC
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc(CCCO)c1OC
Temperature: 23 °C
Reaction time: 1.2 h
Yield: 89 %

Procedure:
To a solution of 3-allyl-4,5-dimethoxybenzoic acid methyl ester (Example 30, Step 1, 10.2 g, 43.2 mmol) in THF (100 mL) at 0° C. was added BH3.SMe2 (4.10 mL, 43.2 mmol). After 45 min the reaction mixture was warmed to 23° C. After stirring for 1.2 h the reaction was cooled to 0° C. and slowly treated with 3.0 N NaOH (39 mL) followed 10 min later by addition of H2O2 (30 weight %, 60 mL). Following the addition, the mixture was allowed to reach 23° C., then heated to reflux for 2 h. After cooling to room temperature, the mixture was partitioned between brine (400 mL) and EtOAc (500 mL). The aqueous layer was separated and extracted with EtOAc (400 mL). The organic layer was discarded and the aqueous was adjusted to pH 5 by addition of 1.0 N HCl then the product was extracted with EtOAc (2×500 mL). The organic layer was dried over MgSO4 and then concentrated in vacuo to give 3-(3-hydroxypropyl)-4,5-dimethoxybenzoic acid (9.24 g, 89%) of the desired alcohol, which was used without further purification. ESMS: m/z 239.3 [M−H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[Cl:9][CH2:10][C:11](=[O:14])[CH2:12]I>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:9][CH2:10][C:11](=[O:14])[CH2:12][O:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: O=C(CCl)CI
Reactant: O=c1ccc(Cl)c[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(CCl)COc1ccc(Cl)cn1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
5-Chloro-2-pyridone (2.58 g.), silver carbonate (3.44 g.) and dry toluene (14 ml.) were stirred together under argon and heated to 65° C. for 20 minutes. A solution of 1-chloro-3-iodopropan-2-one (4 g.) in dry toluene (10 ml.) was added, and the mixture was stirred at 60°-65° C. for 3 hours, cooled, and filtered through "Hyflo" (trade mark) kieselguhr, washing the filter cake with toluene (15 ml.). The filtrate was evaporated to dryness, and the residue was purified by column chromatography on silica gel (100 g.), eluting with 10% v/v ethyl acetate in toluene. The first 130 ml. of eluate was discarded, and the next 60 ml. was collected, and evaporated to dryness to give 1-chloro-3-(5-chloropyrid-2-yloxy)propan-2-one, RF = 0.80 (50% v/v toluene in ethyl acetate).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH:10]=[CH:9]1>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=[O:12]
Reactant: O=C1C=CC(=O)O1
Reactant: COC(CN)OC
Solvent: ClCCl
Product: COC(CNC(=O)/C=C\C(=O)O)OC
Yield: 79.2 %

Procedure:
Aminoacetaldehyde dimethyl acetal (90 g, 0.857 mol) was added over 45 min to a 16° C. mixture of 84 g (0.857 mol) of purified maleic anhydride (azeotropic removal of H2O by distillation of xylene from crude anhydride) in 855 mL of CH2Cl2 (reaction temperature below 30° C.). After 1 h all of the amine had reacted and the solvent was removed on a rotary evaporator to yield a yellow solid. Recrystallization from MeOH gave 138 g (75% yield) of white solid, mp 91°-92° C. Further recrystallization (toluene/MeOH) gave mp 93°-94.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:16]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:17]=[CH2:18]>>[CH:7]1([NH:6][CH2:5][C:4]2[CH:3]=[C:2](/[CH:18]=[CH:17]/[CH2:16][NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:15]=[CH:14][CH:13]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Brc1cccc(CNC2CCCCC2)c1
Reactant: C=CCNC(=O)C(F)(F)F
Product: O=C(NC/C=C/c1cccc(CNC2CCCCC2)c1)C(F)(F)F

Procedure:
Heck coupling of N-(3-bromobenzyl)cyclohexanamine and N-allyl-2,2,2-trifluoroacetamide following the method described in Example 118 gave (E)-N-(3-(3-((cyclohexylamino)methyl)phenyl)allyl)-2,2,2-trifluoroacetamide as a colorless oil. Yield (0.20 g, 22%): 1H NMR (400 MHz, CD3OD) δ 7.55 (s, 1H), 7.48-7.50 (m, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.35-7.37 (m, 1H), 6.61 (d, J=16.0 Hz, 1H), 6.32 (dt, J=16.0, 6.4 Hz, 1H), 4.19 (s, 2H), 4.05 (d, J=6.4 Hz, 2H), 3.07-3.16 (m, 1H), 2.14-2.22 (m, 2H), 1.66-1.82 (m, 2H), 1.68-1.76 (m, 1H), 1.16-1.50 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]=[N:12][C:13]([CH:15]=O)=[CH:14][C:5]2=1.O.NN.[OH-].[K+]>C(O)CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]=[N:12][C:13]([CH3:15])=[CH:14][C:5]2=1
Reactant: O=Cc1cc2c(cn1)[nH]c1ccc(Br)cc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1cc2c(cn1)[nH]c1ccc(Br)cc12
Temperature: 150 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Following a published procedure (Tetrahedron, 2002, 5251) 6-bromo-9H-pyrido[3,4-b]indole-3-carbaldehyde (40 mg, 0.145 mmol), hydrazine hydrate (51 mg, 1.02 mmol) and KOH (29 mg, 0.509 mmol) were combined in 0.5 mL of ethylene glycol and heated to 150° C. overnight. The reaction was cooled to room temperature. Ice chips were added and the mixture was stirred in an ice bath for 1 hour. White precipitate formed which was filtered and dried to afford the desired compound in 73% yield.