Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:37])[C:9]2[N:10]=[C:11]([C:27]3[C:28]([CH3:36])=[N:29][N:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=34)[S:12][C:13]=2[C:14]2[N:18]=[CH:17][N:16](COCC[Si](C)(C)C)[N:15]=2)=[CH:4][CH:3]=1.Cl.O1CCOCC1.O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:37])[C:9]2[N:10]=[C:11]([C:27]3[C:28]([CH3:36])=[N:29][N:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=34)[S:12][C:13]=2[C:14]2[NH:18][CH:17]=[N:16][N:15]=2)=[CH:6][CH:7]=1
Reactant: Cc1nn2ccccc2c1-c1nc(N(C)c2ccc(Cl)cc2)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn2ccccc2c1-c1nc(N(C)c2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Yield: 84 %

Procedure:
N-(4-chlorophenyl)-N-methyl-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-4-amine (0.0566 g, 0.102 mmol) was treated with 4 M of Hydrochloric acid in 1,4-dioxane (6.0 mL, 24 mmol) and Water (1.0 mL, 56 mmol) at 35° C. to r.t. for 42 hours. The reaction solution was rotavaped, azeotroped with MeOH to give a crude residue. The material was dissolved in small amount of MeOH, diluted with Et2O, filtered to give a solid product. (0.037 g, 84% yield). LCMS: (FA) ES+ 422. 1H NMR (400 MHz, d1-chloroform & d4-methanol) δ 8.89 (0, 1H), 8.41 (d, J=6.78 Hz1-H8.26 (d, J=6.78 Hz, 1H), 7.36 (m, 1H), 7.10-7.12 (d, J=8.78 Hz, 2H), 6.87-6.90 (m, 3H), 3.51 (s, 3H), 2.72 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6](=[O:12])[N:5]3[CH2:13][C@@H:14]([CH2:15][N:16]4[CH2:21][CH2:20][C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])([CH3:22])[CH2:18][CH2:17]4)[N:3]1[C:4]=23.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[O:12]=[C:6]1[CH:7]=[CH:8][C:9]2[CH:10]=[CH:11][C:2](=[O:1])[N:3]3[C@H:14]([CH2:15][N:16]4[CH2:17][CH2:18][C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])([CH3:22])[CH2:20][CH2:21]4)[CH2:13][N:5]1[C:4]=23
Reactant: CC1(NC(=O)C(F)(F)F)CCN(C[C@@H]2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1(NC(=O)C(F)(F)F)CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Temperature: 80 °C
Yield: 45.8 %

Procedure:
A solution of N-(1-{[(2R)-4,9-dioxo-1,2,8,9-tetrahydro-4H,7H-imidazo[1,2,3-ij]-1,8-naphthyridin-2-yl]methyl}-4-methyl-4-piperidinyl)-2,2,2-trifluoroacetamide (375 mg, 0.909 mmol) in 1,4-dioxane (20 ml) at rt was treated with DDQ (248 mg, 1.091 mmol) and then heated at 80° C. for 1 h. The reaction was then cooled to rt. The reaction mixture was treated with saturated aqueous K2CO3 (5%, 100 ml), then with DCM (100 ml) and the mixture filtered through Kieselguhr. The organic fraction was separated and the aqueous layer extracted with DCM (2×100 ml). The combined organic solvents were then dried (MgSO4), filtered and evaporated to give the crude product as a yellow oil. Chromatography on silica (0-10% methanol:DCM, Rf=0.4 in 10% MeOH/DCM) gave the product as a clear oil (171 mg, 46%).
Reaction SMILES: C([C@H](N[C:12](=[O:27])[C@H:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:17]([F:26])[CH:16]=1)[CH3:14])CO)C1C=CC=CC=1.[OH:28]S(O)(=O)=O>O1CCOCC1.O>[F:26][C:17]1[CH:16]=[C:15]([C@H:13]([CH3:14])[C:12]([OH:27])=[O:28])[CH:20]=[CH:19][C:18]=1[NH:21][S:22]([CH3:25])(=[O:23])=[O:24]
Reactant: O=S(=O)(O)O
Reactant: C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)c1ccc(NS(C)(=O)=O)c(F)c1
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](C(=O)O)c1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of N-[(1S)-1-Benzyl-2-hydroxyethyl]-(2S)-2-[3-fluoro-4-(methylsulfonylamino)phenyl]propionamide (100 mg, 0.234 mmol) in 3 N H2SO4 (1 mL) and 1,4-dioxane (1 mL) was heated to 100° C. for 5 h and cooled to room temperature. The solution was diluted with water and extracted with CH2Cl2 several times. The combined organic layers were washed with water, dried over MgSO4, and concentrated in vacuo to afford (2S)-[3-Fluoro-4-(methylsulfonylamino)phenyl]propionic acid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH3:12])=[O:10])[C:5]1=[O:13]>CO>[OH:13][CH:5]1[CH:4]([CH3:3])[CH2:8][CH2:7][CH:6]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C1CCC(C)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCC(C)C1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.7 %

Procedure:
NaBH4 (9.98 g, 0.260 mol) was added in portions to a solution of methyl 3-methyl-2-oxocyclopentanecarboxylate (41.2 g, 0.26 mol) in MeOH (250 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 5 h. The reaction was quenched with saturated aqueous NH4Cl (500 mL) and the resulting mixture was extracted with EtOAc (250 mL×5). The combined organic phases were washed with brine (500 mL×2), dried over anhydrous sodium sulfate, and concentrated to afford methyl 2-hydroxy-3-methylcyclopentanecarboxylate (34.0 g).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[C:21]([Br:23])[CH:20]=[C:19]([CH3:24])[C:18]=2[O:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.O>CO.C(Cl)Cl>[Br:23][C:21]1[CH:20]=[C:19]([CH3:24])[C:18]([O:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)=[C:17]([CH:22]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:30]
Reactant: CCOC(=O)C1(NC(=O)c2cc(Br)cc(C)c2OC2CCC2)Cc2ccccc2C1
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(Br)cc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1OC1CCC1
Reaction time: 38 h
Yield: 95.9 %

Procedure:
A 30 mL reaction vial is charged with 2-(5-bromo-2-cyclobutoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (0.29 g, 0.61 mmoles) is charged with 1,4-dioxane (4 mL) and MeOH (4 mL). A stirring bar is added and stirring is initiated. After dissolution, water (2 mL) is added followed by the LiOH monohydrate (65 mg, 1.55 mmol). After 38 h, tlc analysis (silica, 10% MeOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜6 mL). The contents of the flask are poured into a separatory funnel which contains EtOAc (30 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic phases are washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated by pumping to constant weight to give off white solid (0.26 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:17][CH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1
Reactant: CCOC(=O)c1cc(C)nc(C(F)(F)F)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Temperature: 100 °C

Procedure:
A mixture of ethyl 6-methyl-2-(trifluoromethyl)pyrimidine-4-carboxylate (1.1 g, 4.5 mmol, prepared as described in WO 2007/090748), N-bromosuccinimide (2.86 g, 16.1 mmol) and benzoyl peroxide (0.21 g, 0.9 mmol) in carbon tetrachloride (9 mL) was heated in a sealed vessel to 100° C. overnight. The mixture was diluted with dichloromethane (DCM), filtered and the solvent was removed in vacuo. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded the product, which on removal of solvent, was an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:34])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][C@H:25]([N:28]4[CH2:32][CH2:31][CH2:30][C@@H:29]4[CH3:33])[CH2:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C1(S)C=CC=CC=1.[ClH:42]>O1CCOCC1>[ClH:42].[CH3:33][C@H:29]1[CH2:30][CH2:31][CH2:32][N:28]1[C@H:25]1[CH2:26][CH2:27][N:23]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][C:15]([NH:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:34])=[CH:22][CH:21]=2)[CH2:24]1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc(CC(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)C1
Agent: Cl
Agent: Sc1ccccc1
Solvent: C1COCCO1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc(CC(=O)NC3CCNCC3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-{2-[4-((2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-acetylamino}-piperidine-1-carboxylic acid tert-butyl ester (2.92 g, 6.2 mmol) was dissolved in 5 mL of dioxane. To this solution was added 1.0 g of PhSH, followed by addition of 4N HCl in dioxane (6.2 mL, 24.8 mmol, 4 equiv.). The solution was stirred at rt overnight. HCl was removed by passing N2 through the solution which was absorbed by NaOH aq solution. The solvent was removed by reduced pressure distillation. The residue was further dried under high vacuum to get 2.7 g (100%) of the title compound as a powder.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][NH:3][CH2:2]1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:3]2[CH2:2][CH2:1][C:14]3[C:13]4[CH:12]=[CH:11][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]=4[NH:7][C:6]=3[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4]2)=[O:31])=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1cc(C(=O)OCC)ccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1cc(C(=O)OCC)ccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using diethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5,8-dicarboxylate and 4-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 10.78 (1H, br s), 8.13 (2H, m), 7.81 (1H, m), 7.63 (2H, m), 7.53 (1H, d), 7.17 (2H, m), 4.39 (2H, q), 4.26 (4H, m), 3.28 (2H, t), 1.42 (3H, t), 1.23 (3H, t); MS (ES): 451 (MH+).
Reaction SMILES: [C:1]([C:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7](O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)([Br:15])=O>CN(C=O)C>[Br:15][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[NH:10][C:9](=[O:11])[CH:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: CC(C)(C)c1cc(O)cc(=O)[nH]1
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Br)cc(=O)[nH]1
Temperature: 90 °C
Yield: 79.7 %

Procedure:
To a solution of compound 17a (9.7 g, 60 mmol) in DMF (100 mL) was added POBr3 (17.2 g, 60 mmol) and the mixture was heated at 90° C. for 2 h. Then the resulting mixture was concentrated. Water was added and the mixture was extracted with EA. The organic layer was washed with brine, concentrated and purified by CC (PE/EA=5/1) to give compound 17b (11 g, 80%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].Cl>[Pt]=O.CO>[F:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)c1cccc(-c2ccncc2)c1F
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: CC(=O)c1cccc(C2CCNCC2)c1F

Procedure:
Preparation according to preparation 9: 1-(2-fluoro-3-pyridin-4-ylphenyl)ethanone (0.2 g, 0.93 mmol), hydrochloric acid (0.05 ml, conc.) methanol (5 ml), platinum oxide (0.02 g). Yield: 0.2 g. MS m/z (relative intensity, 70 eV) 221 (M+, 25), 220 (37), 178 (96), 149 (41) 101 (20).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[N:15][C:16]([CH:19]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])=[CH:17][CH:18]=1)=[O:12])(C)(C)C.Cl>C(O)C>[NH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:12])[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([S:28]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)(=[O:30])=[O:29])[C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])=[N:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: Cl
Solvent: CCO
Product: NCCNC(=O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To an ethanol (2 ml) solution of t-butyl[2-[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine-3-carbonyl]amino]ethyl]carbamate (50 mg, 0.0880 mmol) was added concentrated hydrochloric acid (2 ml). The resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure. The solid thus obtained was washed with diethyl ether to give the title compound (44 mg, 0.0880 mmol, quant.) as 1.5 hydrochloride (white powder).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[N:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:15]1([N:13]2[C:12](=[O:21])[C:6]3=[CH:7][NH:8][C:9]4[CH:10]=[CH:11][C:2]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[N:3][C:4]=4[C:5]3=[N:14]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C1CNCCN1
Reactant: O=c1c2c[nH]c3ccc(F)nc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Yield: 84 %

Procedure:
Compound 5a was stirred with excess of piperazine at 175° C. for 24 hours. The precipitates were collected by filtration and washed with ethyl acetate and purified using column chromatography to obtain title compound in 84% yield. 1H-NMR (DMSO-d6) δ (ppm): 2.88 (4H, brm), 3.64 (4H, brm), 7.11 (2H, tt, J=7.42, 1.10 Hz), 7.23 (1H, d, J=9.34 Hz), 7.41 (2H, m), 7.84 (1H, d, J=9.06 Hz), 8.22, (2H, m), 8.51 (1H, s). m/z 347.4 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCc1ccc(OC)c(O)c1
Product: CCOC(=O)CCc1ccc(OC)c(OCc2ccccc2)c1

Procedure:
In substantially the same manner as in Reference Example 92, ethyl 3-(3-hydroxy-4-methoxyphenyl)propionate was reacted with benzyl bromide to yield ethyl 3-(3-benzyloxy-4-methoxyphenyl)propionate. The product was recrystallized from hexane to give colorless needles, m.p.49.5-50.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[NH:14][C:13]=3[CH:18]=2)[C:5]([CH3:19])=[CH:4][N:3]=1.Cl.[F:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([NH2:29])=[CH:24][C:23]=1[O:30][CH3:31].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33].ClC1N=CC=CN=1>CC(O)C>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[F:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([NH:29][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[CH:11][C:12]4[O:16][C:15](=[O:17])[NH:14][C:13]=4[CH:18]=3)[C:5]([CH3:19])=[CH:4][N:3]=2)=[CH:24][C:23]=1[O:30][CH3:31]
Reactant: COc1cc(N)cc(C)c1F
Reactant: Cc1cnc(Cl)nc1Nc1ccc2oc(=O)[nH]c2c1
Agent: Cl
Agent: Clc1ncccn1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2ncc(C)c(Nc3ccc4oc(=O)[nH]c4c3)n2)cc(C)c1F
Temperature: 77.5 °C
Reaction time: 22 h

Procedure:
Into a three-neck round-bottom flask, 5-(2-chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one (33.2 g, 120 mmol) and 4-fluoro-3-methoxy-5-methylbenzenamine hydrochloride (32.19 g, 168 mmol) were added, followed by i-PrOH (750 mL) and TFA (23.1 mL, 300 mmol). The reaction mixture was stirred under nitrogen atmosphere with gentle refluxing (note: with overhead stirrer at internal temperature of 75-80° C.). After 22 h, by LC-MS, the reaction was >95% complete (note: when ≦3% of the 2-chloropyrimidine starting material remained, the reaction did not progress much further even after another day or two). The reaction mixture was cooled to room temperature, precipitate was collected by filtration, washing with i-PrOH (˜50 mL×2). Compound 5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one trifluoroacetate was obtained as a light tan color solid (still a little bit damp) and was added to a NaHCO3 aqueous solution (15.12 g (180 mmol) of NaHCO3 dissolved in 1 L of H2O). The aqueous suspension was stirred at rt overnight. Solid was collected by filtration, washing with H2O (˜150 mL×3), and was further dried under high vacuum. Free base compound 5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one was obtained as an off-white solid: 44.51 g (93.8% yield).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[ClH:10]>O>[Cl:10][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(F)c(F)c1
Reactant: Cl
Solvent: O
Product: Fc1cnc(Cl)c(F)c1
Temperature: 25 °C

Procedure:
To a microwave tube is added 2,3,5-trifluoropyridine (2.0 g, 15 mmol), concentrated HCl (12.5 mL, 150 mmol). The mixture is irradiated with microwave for 30 min at 130° C. The reaction mixture is cooled to ambient temperature, diluted with 100 mL of water, extracted with dichloromethane three times. The organic phase is further washed with brine, dried over Na2SO4 and dried to give 2-chloro-3,5-difluoropyridine as a greenish solid. The compound is used without further purification.
Reaction SMILES: [O:1]=[CH:2][CH2:3][C@H:4]1[NH:7][C:6](=[O:8])[C@@H:5]1[N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].[BH4-].[Na+]>CO.ClCCl>[OH:1][CH2:2][CH2:3][C@H:4]1[NH:7][C:6](=[O:8])[C@@H:5]1[N:9]1[C:10](=[O:19])[C:11]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]2[C:13]1=[O:14]
Reactant: O=CC[C@H]1NC(=O)[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C1N[C@H](CCO)[C@H]1N1C(=O)c2ccccc2C1=O
Yield: 51.5 %

Procedure:
To a solution of (3R,4R)-4-(2-oxoethyl)-3-phthalimidoazetidin-2-one (52 mg) in a mixture of methanol (3ml) and dichloromethane (1 ml) was added a solution of sodium borohydride (8 mg) in methanol (2 ml) at 0° C. during one hour. The reaction was quenched by addition of acetic acid (two drops). After evaporation in vacuo, the residue was chromatographed on silica gel (1.6 g; eluting with 3 to 5% methanol in dichloromethane) to give 32 mg of crude crystals. Crystallization from a mixture of methanol and ether afforded 27 mg(51.5%) of (3R,4R)-4-(2-hydroxyethyl)-3-phthalimidoazetidin-2-one. IR (Nujol): 3350(br), 3250, 1750, and 1705 cm-1 ; NMR (DMSO-d6) δ: 1.79 (q, J=6 Hz, 2H), 3.46 (m, 2H), 3.97 (dt, J=2.5 and 6 Hz, 1H), 4.47 (brs, 1H), 4.89 (d, J=2.5 Hz, 1H), 7.86 (s, 4H), and 8.42 (brs, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.CO.C(Cl)Cl.C1(C)C=CC=CC=1>[C:14]1([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([CH2:3][CH2:2][NH2:1])=[CH:5]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Ic1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: NCCc1cn(-c2ccccc2)c2ccccc12
Yield: 87.2 %

Procedure:
Using the general procedure, tryptamine (0.160 g, 1.00 mmol) was coupled with iodobenzene (134 μL, 1.20 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (32 μL, 0.20 mmol, 20 mol %) and toluene (1.0 mL) to give the crude product. Column chromatography (2×15 cm, methylene chloride (saturated with ammonia):methanol 50:1) provided 0.206 g (87% yield) of the product as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.65 (m, 1H), 7.55 (m, 1H), 7.47 (m, 4H), 7.31 (m, 1H), 7.1-8 (m, 3H), 3.06 (t, J=7 Hz, 2H), 2.94 (t, J=7 Hz, 2H), 1.40 (bs, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9]O)[CH:5]=[CH:4][N:3]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:18]>N#N>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][Cl:18])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Cl)c1Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: N#N
Solvent: CN(C)C=O
Product: ClCc1ccnc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2,3-Dichloro-pyridin-4-yl)-methanol (0.256 g, 1.44 mmol) was dissolved in 5 mL anhydrous under N2. Anhydrous DMF (0.111 mL, 1.44 mmol) was added followed by dropwise addition of POCl3 (0.134 mL, 1.44 mmol). The reaction was stirred at RT overnight. After 16 h the reaction was quenched by the addition of sat aq NaHCO3. The mixture was extracted 3× with DCM. The organic phases were dried over Na2SO4, filtered, and concentrated to provide the pure titled compound. 1H NMR (CDCl3) δ8.33 (d, 1H, J=4.9 Hz), 7.44 (d, 1H, J=4.9 Hz), 4.68 (s, 2H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([NH2:12])([C:10]#[N:11])[CH2:6][CH2:5]1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:12][C:7]1([C:10]#[N:11])[CH2:8][CH2:9][N:4]([CH2:5][C:6]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: CC(=O)N1CCC(N)(C#N)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#CC1(N)CCN(Cc2ccccc2)C1

Procedure:
3-Amino-3-cyano-1-benzylpyrrolidine was prepared by a method analogous to that of Example 1-part (a) with the exception that no sodium carbonate was added to the reaction mixture. The product was extracted from the crude reaction with 3×100 mL of EtOAc and was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@H:9]3[CH2:13][N:12]([CH3:14])[C:11](=[O:15])[C@H:10]3[C:4]=2[CH:3]=1.[OH-].[K+].C(OCC)(=[O:26])C>C(O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]([CH2:13][NH:12][CH3:14])[C@H:10]([C:11]([OH:15])=[O:26])[C:4]=2[CH:3]=1
Reactant: CCOC(C)=O
Reactant: CN1C[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@@H]2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CNC[C@@H]1c2ccccc2Oc2ccc(Cl)cc2[C@H]1C(=O)O
Yield: 52 %

Procedure:
To a solution of cis- 11-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (V) (2 gram, 6.7 mmol) in ethanol (20 mL), was added potassium hydroxide (3.8 g, 67 mmol). The reaction mixture was heated to reflux for 5 hours. The reaction mixture was evaporated and water was added (50 mL). The water phase was washed with diethyl ether (2×25 mL). The aqueous phase was acidified with concentrated hydrochloric acid to a pH between 5 and 6, resulting in a gum precipitate. Ethyl acetate was added (25 mL), which slowly dissolved the gum and resulted in the formation of fine crystals of the product. The crystals were filtered and dried to give trans-8-chloro-10,11-dihydro-11-[(methylamino)-methyl]-dibenz[b,f]oxepin-10-carboxylic acid (I) (1.1 g, 52%); mp 154.4° C.; 1H-NMR (399.87 MHz in MeOD relative to TMS) δ 2.09 (s, 3H), 2.45 and 2.66 (2×m, 2H), 3.23 (s, 1H), 3.50 (m, 1H), 3.92 (d, 1H), 6.96-7.20 (m, 6H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.CN(C)C=O.N1C=CN=C1.[CH3:19][C:20]([Si:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)Cl)([CH3:22])[CH3:21]>O>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:1][CH:2]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](Oc1ccc(Br)cc1)(c1ccccc1)c1ccccc1
Yield: 95.1 %

Procedure:
80.89 g of p-bromophenol, 400 ml of dimethylformamide, 31.18 g of imidazole and 125.89 g of 1,1-dimethyl-ethyl-diphenylchlorosilane were stirred for 2 hours at ambient temperature and the reaction medium was poured into 2 liters of water. Extraction was carried out with ethyl acetate, followed by decanting, drying and evaporating under reduced pressure. After crystallization from pentane, separation was carried out, followed by drying to obtain 179.24 g of the expected product with a Rf=0.53 (thin layer chromatography, support: silica, eluant: cyclohexane/AcOEt 95/5) and a melting point of 56° C.