Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[O:15][C:16]3[C:22]([Cl:23])=[CH:21][C:20]([Br:24])=[CH:19][C:17]=3[CH:18]=2)(=O)=O)=CC=1.[CH3:25][O:26][CH:27]([O:30][CH3:31])[CH2:28][NH2:29].O>O1CCOCC1>[Br:24][C:20]1[CH:21]=[C:22]([Cl:23])[C:16]2[O:15][C:14]([CH2:13][CH2:12][NH:29][CH2:28][CH:27]([O:30][CH3:31])[O:26][CH3:25])=[CH:18][C:17]=2[CH:19]=1
Reactant: COC(CN)OC
Reactant: Cc1ccc(S(=O)(=O)OCCc2cc3cc(Br)cc(Cl)c3o2)cc1
Solvent: C1COCCO1
Solvent: O
Product: COC(CNCCc1cc2cc(Br)cc(Cl)c2o1)OC
Temperature: 90 °C
Yield: 75.3 %

Procedure:
To a solution of the product of Example 84, step C (2.0 g, 4.65 mmol) in dioxane (10 mL) was added 2,2-dimethoxyethanamine (1.47 g, 13.95 mmol). The reaction mixture was heated to 90° C. for 3 h, cooled to ambient temperature, treated with water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo. Purification by flash column chromatography (SiO2, hexanes/ethyl acetate) gave N-(2-(5-bromo-7-chlorobenzofuran-2-yl)ethyl)-2,2-dimethoxyethanamine (1.27 g, 75%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.49 (d, J=1.8 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 6.44 (s, 1H), 4.48 (t, J=5.5 Hz, 2H), 3.38 (s, 6H), 3.09-2.94 (m, 4H), 2.78 (d, J=5.4 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[C:19](O)(=[O:23])[CH:20]([CH3:22])[CH3:21].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH:16][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC(C)C(=O)O
Reactant: Cc1ccc2c(c1)c1c(n2CCN)CCN(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)C(C)C)CCN(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.4 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanamine (100 mg, 0.411 mmol), isobutyric acid (36 mg, 0.411 mmol), N,N′-dicyclohexylcarbodiimide (93 mg, 0.452 mmol) and 4-dimethylaminopyridine (55 mg, 0.452 mmol) in dry dichloromethane (5.0 ml) were stirred at room temperature for 4 h. The reaction mixture was filtered through Celite and concentrated using rotary evaporator to afford 16 mg of N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)isobutyramide as TFA Salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml). 1H NMR (DMSO) 9.95 (bs, 1H), 7.9 (t, 1H), 7.4 (d 1H), 7.2 (s, 1H), 7.0 (d, 1H), 4.5-4.61 (m, 1H), 4.1-4.28 (m, 3H), 3.7-3.9 (m, 2H), 3.1-3.2 (m, 2H), 2.95 (s, 3H), 2.4 (s, 3H), 2.19-2.3 (m, 1H), 1.2-1.38 (m, 2H), 0.9 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][CH2:6][C:7](Cl)=[O:8].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[F:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:7](=[O:8])[CH2:6][CH2:5]2
Reactant: O=C(Cl)CCc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.1 %

Procedure:
A solution of 3-fluorodihydrocinnamoyl chloride (15.4 g) in carbon disulfide (78 ml) was added dropwise to a cold (-5° C.) mixture of aluminium chloride (13.9 g) in carbon disulfide (300 ml) for 30 minutes. During this time and for 30 minutes the mixture was allowed to warm to room temperature (1 hr), then it was heated to reflux (1 hr) and finally the volatiles were removed by distillation under reduced pressure. The residue was dissolved in methylene chloride (400 ml) and washed successively with 10% aqueous sodium hydroxide and water. After drying (magnesium sulfate) and solvent removal in vacuo, 5-fluoroindanone (2 g) was isolated by recrystallisation from hexane.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=2.[C:17]1([CH2:23][CH2:24]O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(C=C1CCP(C)C1(C)C)#N>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=2
Reactant: CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Reactant: OCCc1ccccc1
Agent: CP1CCC(=CC#N)C1(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2CCc1ccccc1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
A 211 mg portion of ethyl 2,3-dimethyl-1H-indole-5-carboxylate was dissolved in 10 ml of toluene, and 0.232 ml of 2-phenylethanol and 224 mg of cyanomethylene trimethylphospholan were added at room temperature, followed by stirring at 100° C. for 17 hours. After evaporation of the solvent under a reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:49 to 1:9) to obtain 107 mg of ethyl 2,3-dimethyl-1-(2-phenylethyl)-1H-indole-5-carboxylate as a colorless oily material.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[CH2:16]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH:17]([CH3:19])[CH3:18].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=2)[CH:8]=1
Reactant: CC(C)Cc1ccc(C=O)cc1
Reactant: COC(=O)CCc1cccc(CN)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCc1cccc(CNCc2ccc(CC(C)C)cc2)c1
Reaction time: 20 h
Yield: 30.1 %

Procedure:
A solution of 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt (400 mg, 1.74 mmol), 4-isobutylbenzaldehyde (311 mg, 1.91 mmol), and triethylamine (0.26 mL, 1.91 mmol) in CH2Cl2 (4 mL) was stirred at room temperature for 4 h. Sodium triacetoxyborohydride (590 mg, 2.78 mmol) was added and the reaction was stirred for 20 h. Aqueous NaHCO3 was added and the aqueous solution was washed with CH2Cl2. The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (65% EtOAc in hexanes) provided the title compound of Step A (178 mg). 1H NMR (400 MHz, CDCl3) δ 7.26-7.04 (m, 8H), 3.77 (s, 2H), 3.75 (s, 2H), 3.63 (s, 3H), 2.91 (t, 2H), 2.60 (t, 2H), 2.41 (d, 2H), 1.80 (m, 1H), 0.85 (m, 6H); MS 340 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C[O-].[Na+].CO.Cl[CH:12]([CH3:15])[C:13]#[N:14]>CN(C)C=O>[C:13]([CH:12]([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[CH3:15])#[N:14]
Reactant: c1nc[nH]n1
Reactant: CC(Cl)C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C#N)n1cncn1
Temperature: 0 °C
Yield: 70.2 %

Procedure:
In this example, a mixture containing 13.47 gms (0.195 mole) of 1,2,4-triazole and 10.53 gms (0.195 mole) of sodium methoxide in 200 mls of dimethylforamide was refluxed until no further evolution of the methanol by-product was observed. The reaction mixture was then cooled to 0° C. and then 19.23 gms of 2-chloropropionitrile dissolved in 25 mls of dimethylforamide were added dropwise with stirring. The mixture was then stirred overnight (about 12 to 14 hours) at room temperature and then filtered. The dimethylforamide was then removed by vacuum evaporation. The residue was dissolved in methylene chloride and filtered through neutralized silica gel. The filtrate was evaporated affording 16.73 gms of the title compound as a brown liquid.
Reaction SMILES: C([N:8]([CH2:22][CH:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Br:30])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([O:19]C)[C:12]=1[Cl:21])C1C=CC=CC=1>Br>[BrH:30].[Cl:21][C:12]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:22][CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Br:30])[C:16]=2[CH:15]=[C:14]([OH:17])[C:13]=1[OH:19]
Reactant: COc1ccc(CCN(Cc2ccccc2)CC(O)c2ccccc2Br)c(Cl)c1OC
Agent: Br
Product: Oc1cc2c(c(Cl)c1O)CCNCC2c1ccccc1Br

Procedure:
A solution of 4.0 g of the above hydrochloride in 250 ml of 48% hydrobromic acid is stirred and refluxed for two hours. The reaction mixture is evaporated in vacuo to yield 6-chloro-1-(2-bromophenyl)-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Product: O=[N+]([O-])c1cnc(N2CCCC2)nc1

Procedure:
Prepared essentially as described in Example 69a, using 2-chloro-5-nitro-pyrimidine and pyrrolidine. 1H NMR (DMSO-d6) δ 9.11 (s, 2H), 3.62 (m, 4H), 1.97 (m, 4H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:25](=[O:26])[CH:24]3[CH:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)[C:18]2=[O:27])[CH2:9][CH2:8]1.[NH3:29]>>[O:27]=[C:18]1[CH:19]2[CH:24]([CH:23]=[CH:22][CH:21]=[CH:20]2)[C:25](=[O:26])[N:17]1[CH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][CH2:5][CH2:4][C:3]([NH2:29])=[O:2])[CH2:8][CH2:9]1
Reactant: COC(=O)CCCC1CCN(CCCCN2C(=O)C3C=CC=CC3C2=O)CC1
Reactant: N
Product: NC(=O)CCCC1CCN(CCCCN2C(=O)C3C=CC=CC3C2=O)CC1
Temperature: 70 °C
Yield: 40 %

Procedure:
A solution containing 7.0 M methanolic ammonia (50 mL) and compound 3 (0.90 g, 2.33 mmol) was heated in a sealed tube at 70° C. for 72 hours. The solution was then cooled to ambient temperature, and concentrated under vacuum. The resulting residue was subjected to column chromatography eluting with 0-3% methanol in dichloromethane to afford the desired product 4 (0.5 g, 40%) as a colorless, viscous oil: 1H NMR (300 MHz, CDCl3) δ 1.25 (m, 3H), 1.55 (m, 2H), 1.62-1.80 (m, 4H), 1.90 (m, 2H), 2.18 (t, 2H), 2.34 (t, 2H), 2.90 (d, 2H) 3.68 (s, 3H), 5.40 (br, 2H), 7.68 (d, 2H), 7.82 (d, 2H).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[C:35][Si](C)(C)C)[CH:29]=2)=[O:27])[CH2:22][CH2:21]1>C1COCC1>[C:34]([C:30]1[CH:29]=[C:28]([C:26]([N:23]2[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]2)=[O:27])[CH:33]=[CH:32][CH:31]=1)#[CH:35]
Reactant: CN1CCN(C(=O)c2cccc(C#C[Si](C)(C)C)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cccc(C(=O)N2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
1M TBAF in THF (0.30 mL, 0.30 mmol) was added to a solution of (4-methylpiperazin-1-yl){3-[(trimethylsilyl)ethynyl]phenyl}methanone (90 mg, 0.30 mmol) in dry THF (1.5 mL) and the mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue taken up with EtOAc (3 mL), washed with brine, dried over sodium sulfate and evaporated to afford the title compound (53 mg, 78%).
Reaction SMILES: C([Li])CCC.[CH3:6][Si:7]([C:10]#[CH:11])([CH3:9])[CH3:8].[CH2:12]([O:14][P:15](Cl)[O:16][CH2:17][CH3:18])[CH3:13]>O1CCCC1>[CH3:6][Si:7]([C:10]#[C:11][P:15]([O:16][CH2:17][CH3:18])[O:14][CH2:12][CH3:13])([CH3:9])[CH3:8]
Reactant: C#C[Si](C)(C)C
Reactant: CCOP(Cl)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(C#C[Si](C)(C)C)OCC
Temperature: -20 °C

Procedure:
n-Butyllithium (26.02 ml, 1.55M in hexane) was added dropwise over thirty minutes to a stirred solution of trimethylsilylacetylene (5.18 ml) in dry tetrahydrofuran (25 ml), whilst maintaining the temperature below -65° C. After twenty minutes, diethylchlorophosphite (4.71 ml) was added dropwise over twenty minutes, then stirring continued for a further ninety minutes at -65° C. The stirred mixture was allowed to warm to -20° C., quenched by dropwise addition of saturated ammonium chloride solution (10 ml), then allowed to reach room temperature, diluted with water (10 ml) and extracted with chloroform (4×25 ml). The extracts were dried over magnesium sulphate and evaporated under reduced pressure to give diethyl trimethylsilylethynylphosphonite as a brown oil (7.34 g, 83% pure by GC).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:19]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:21])=[CH:22][CH:23]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Yield: 91 %

Procedure:
As described for example 288, 6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (50 mg, 0.15 mmol) was converted, using morpholine instead of 4-aminotetrahydropyran, to the title compound (55 mg, 91%) which was obtained as a colourless gum. MS: m/e=399.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:38][O:39][CH2:40][CH:41]=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:41][CH2:40][O:39][CH3:38])[CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Reactant: COCC=O
Product: COCCN1CCC(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(N(C)C(=O)c3ccc(OC)c(C(F)(F)F)c3)C2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 104, the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(2-methoxy-ethyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using methoxyacetaldehyde instead of acetone and was obtained as a colorless oil. MS m/e: 616.4 [M]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH:21]([N:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[CH3:22])=[C:19]([OH:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH:21]([N:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)[CH3:22])=[C:19]([OH:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CC(c1c(O)ccc2c1O/C(=C\c1n[nH]c3ccccc13)C2=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(c1c(O)ccc2c1O/C(=C\c1n[nH]c3ccccc13)C2=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
A solution of tert-butyl (Z)-4-{1-[2-(1H-indazol-3-yl)methylene-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl]ethyl}piperazine-1-carboxylate (0.075 g, 0.15 mmol) in methylene chloride (3.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3.0 mL), and then the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was azeotroped twice with toluene under reduced pressure. The residual solid was added with water, and then the mixture was adjusted to pH 9 with saturated aqueous sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-hydroxy-7-[1-(piperazin-1-yl)ethyl]benzofuran-3(2H)-one (0.030 g, 50%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[N:16]=[CH:15][C:14]([C:17]3[NH:25][C:24]4[C:23](=[O:26])[N:22]([CH:27]5[CH2:29][CH2:28]5)[C:21](=[O:30])[N:20]([CH2:31][CH2:32][CH3:33])[C:19]=4[N:18]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:36](Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>N1C=CC=CC=1>[CH:27]1([N:22]2[C:23](=[O:26])[C:24]3[NH:25][C:17]([C:14]4[CH:13]=[CH:12][C:11]([N:10]([CH2:9][C:6]5[CH:7]=[N:8][C:3]([C:2]([F:1])([F:34])[F:35])=[CH:4][CH:5]=5)[C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[N:16][CH:15]=4)=[N:18][C:19]=3[N:20]([CH2:31][CH2:32][CH3:33])[C:21]2=[O:30])[CH2:28][CH2:29]1
Reactant: CCCn1c(=O)n(C2CC2)c(=O)c2[nH]c(-c3ccc(NCc4ccc(C(F)(F)F)nc4)nc3)nc21
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CCCn1c(=O)n(C2CC2)c(=O)c2[nH]c(-c3ccc(N(Cc4ccc(C(F)(F)F)nc4)C(=O)C(C)(C)C)nc3)nc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
8-(6-((6-(trifluoromethyl)pyridin-3-yl)methylamino)pyridin-3-yl)-1-cyclopropyl-3-propyl-1H-purine-2,6(3H,7H)-dione (35 mg, 0.07 mmol) was dissolved in pyridine (5 ml) at 60° C. After cooling, pivaloyl chloride (100 mg, 0.83 mmol) was added. The mixture was stirred at room temperature for 24 h. After quenching with ice, the mixture was evaporated and purified by silica gel column to give product (4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:25]=[CH:24][C:18]2[N:19]=[C:20]([S:22][CH3:23])[O:21][C:17]=2[CH:16]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]=[C:20]([S:22][CH3:23])[O:21][C:17]=4[CH:16]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CSc1nc2ccc(CCl)cc2o1
Reactant: Fc1cnc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a stirred solution of 6-fluoro-3H-imidazo[4,5-b]pyridine (502 mg, 3.66 mmol) from Step 2 of Example 70 in anhydrous DMF (10 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 220 mg, 5.49 mmol), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (858 mg, 4.03 mmol) from Step 3 of Example 56 in DMF (2 mL). The mixture was allowed to warm to rt and stir for a further 3 h. To the reaction mixture was added water and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed sequentially with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 30 to 50% ethyl acetate in petroleum ether to afford 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (698 mg, 61%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6): δ 8.71 (s, 1H), 8.41 (s, 1H), 8.07 (d, J=6.9 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.35 (d, J=6.3 Hz, 1H), 5.59 (s, 2H), 2.73 (s, 3H); LCMS (ESI) m/z 315 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH2:5][C:6]2=[CH2:7].[S:11](=[O:14])([OH:13])[O-:12].[Na+:15]>O>[C:6]1([CH2:7][S:11]([O-:14])(=[O:13])=[O:12])[CH2:8][CH2:9][C@H:3]([CH:2]([CH3:10])[CH3:1])[CH2:4][CH:5]=1.[Na+:15]
Reactant: O=S([O-])O
Reactant: C=C1CCC2CC1C2(C)C
Agent: [Na+]
Solvent: O
Product: CC(C)[C@@H]1CC=C(CS(=O)(=O)[O-])CC1
Reaction time: 8 h

Procedure:
In a 1 liter, 3-neck flask, 70 grams (0.51 mole) β-pinene and 325 ml water was heated to reflux. Sodium bisulfite, 70 grams, was added at the rate of 13 grams per hour. The solution was refluxed for 7 hours and allowed to stand overnight.
Reaction SMILES: [SH2:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[CH:13]=[N:14][C:15]([C:16]#[N:17])=[C:11]3[CH2:10][N:9]([CH3:18])[C:8](=[O:19])[C:7]=2[CH:20]=1>N1C=CC=CC=1.C(N(CC)CC)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[CH:13]=[N:14][C:15]([C:16](=[S:1])[NH2:17])=[C:11]3[CH2:10][N:9]([CH3:18])[C:8](=[O:19])[C:7]=2[CH:20]=1
Reactant: S
Reactant: CN1Cc2c(C#N)ncn2-c2ccc(F)cc2C1=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CN1Cc2c(C(N)=S)ncn2-c2ccc(F)cc2C1=O
Reaction time: 64 h
Yield: 91 %

Procedure:
A stream of hydrogen sulphide was conducted for 1/2 hr. through a solution of 4.4 g (0.0172 mol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile in 100 ml of pyridine and 1 ml of triethylamine. The dark green solution was left to stand for 64 hrs., then de-gassed with a stream of nitrogen and subsequently completely freed from the solvents. The residue was partitioned between dichloromethane/tetrahydrofuran and water, extracted, concentrated, stirred vigorously in ether and filtered off under suction. There were obtained 4.55 g (91%) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-thiocarboxamide as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][N:14]([C:38](=[O:40])[CH3:39])[CH2:13][CH2:12]1)[C:17]([CH:19]1[CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCNCC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.5 %

Procedure:
To 3-[(4-Methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (58 mg, 0.132 mmol) in dichloromethane (1.3 ml) was added pyridine (64 ul, 0.789 mmol), followed by acetic anhydride (50 ul, 0.526 mmol) and a catalytic amount of DMAP. The resulting solution was stirred for 18 hours at room temperature and then quenched with a saturated solution of NaHCO3 (5 ml). The aqueous phase was separated and washed with ethyl acetate (2×5 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was then purified by preparative chromatography (100/90/16/1 CH2Cl2/CHCl3/MeOH/Et3N) to obtain 50 mg (78%) of 3-[(1-Acetyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.Cl.C([N:25]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[N:16]1([C:13]([NH2:25])=[O:15])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[CH:2]=1
Reactant: C1COCCN1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C1(c2cccnc2)CCNCC1
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)N1CCOCC1
Reaction time: 24 h

Procedure:
Combine 1-benzyl-(4-(pyridin-3-yl)-piperidine-4-carboxylic acid (2.5 g, 8.4 mmol) and morpholine (1.5 g, 16.9 mmol) in dimethylformamide (65 mL). Add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (2.2 g), 1-hydroxy-benzotriazole hydrate (HOBt) (1.6 g), and dimethylformamide (25 mL). After 24 hours, pour the reaction mixture into a saturated aqueous sodium bicarbonate solution and extract twice with diethyl ether. Combine the organic layers, dry over MgSO4, filter, and concentrate to about 50 mL to give solid. Collect the solid by filtration, rinse with diethyl ether, and dry to give 1-benzyl-(4-(pyridin-3-yl)-piperidine-4-carboxylic acid morpholine-amide: Rf =0.67 (silica gel, dichloromethane/methanol/concentrated ammonia 90/10/0.5).