Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].Cl.[O:30]([NH2:32])[CH3:31]>C(O)C>[CH3:31][O:30][N:32]=[C:21]([C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[CH:20][CH:19]=1)[CH3:22]
Reactant: CON
Reactant: CC(=O)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CON=C(C)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
The title compound was prepared as a ca. 9.5:0.5 mixture of two isomers by using a procedure similar to the one described for example 216 from example 208 (0.070 g, 0.230 mmol), ethanol (1.5 ml), sodium acetate (0.018 g, 0.230 mmol) and methoxylamine hydrochloride (0.019 g, 0.230 mmol). Off-white solid (0.020 g, 26%). M.P.: 155-157° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (d, J=2.6 Hz, 1H), 8.61 (d, J=8.8 Hz, 0.05H), 8.55 (d, J=8.8 Hz, 0.95H), 8.36 (d, J=8.4 Hz, 1H), 8.02 (m, 3H), 7.81 (dd, J=8.8, 1.7 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.16 (s, 2H), 4.01 (s, 2.85H), 3.79 (s, 0.15H), 2.32 (s, 2.85H), 2.24 (s, 0.15H).
Reaction SMILES: I[CH3:2].[H-].[Na+].[OH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[C:21](=[O:22])[N:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:26][CH:25]=4)[C:19]([CH2:38][CH2:39][CH3:40])=[N:18][C:17]=3[CH3:41])[CH:14]=2)[O:9][C:8]([CH3:43])([CH3:42])[CH2:7]1>CN(C)C=O.C(OCC)(=O)C>[CH3:2][O:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[C:21](=[O:22])[N:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:26][CH:25]=4)[C:19]([CH2:38][CH2:39][CH3:40])=[N:18][C:17]=3[CH3:41])[CH:14]=2)[O:9][C:8]([CH3:42])([CH3:43])[CH2:7]1
Reactant: CCCc1nc(C)c(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(C)c(-c2ccc3c(c2)C(OC)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 66.1 %

Procedure:
A mixture of iodomethane (0.76 g), 60% sodium hydride (0.22 g) and 4′-{[5-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.56 g) in N,N-dimethylformamide (5 mL) was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.38 g, 66%).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:7][CH2:6][C@H:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4]1.C(O)C.CCCCCC>CCCCCC.C(O)C>[CH3:1][N:2]([CH3:19])[C@H:3]1[CH2:7][CH2:6][C@H:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4]1
Reactant: CN(C)C1CC[C@H](c2c[nH]c3ccc(C#N)cc23)C1
Solvent: CCO
Solvent: CCCCCC
Product: CN(C)[C@H]1CC[C@H](c2c[nH]c3ccc(C#N)cc23)C1
Reaction time: 0.33 h

Procedure:
The (3R)- and (3S)-diastereomers of (1S)-3-(3-dimethylaminocyclopentyl)-1H-indole-5-carbonitrile were resolved by chiral HPLC on a Chiral Technologies Chiralpak AD column (20μ, 50×500 mm) with a mobile phase of 10% ethanol in hexane-0.1% diethylamine at a flow rate of 75 mL/min. Analytical HPLC retention times refer to the following analytical chiral HPLC method: Chiralpak AD column, 4.6×250 mm with 10 μm packing. Solvents: 10% Ethanol/hexane (0.10% diethyl amine added in hexane as modifier). Flow: 1 mL/min for 20 min. UV detector at 280 nm. Loop volume: 20 μL. Injection load: 20 μL of a 1 mg/mL solution in ethanol.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:14][N:13]([C:15]2[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=2)[C:12](=[O:21])[C:11]1([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[N+:31]([O-])([OH:33])=[O:32].[OH-].[Na+]>O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:14][N:13]([C:15]2[C:19]([N+:31]([O-:33])=[O:32])=[CH:18][N:17]([CH3:20])[N:16]=2)[C:12](=[O:21])[C:11]1([CH3:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc(N2CC(COCc3ccccc3)C(C)(C)C2=O)n1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])c(N2CC(COCc3ccccc3)C(C)(C)C2=O)n1

Procedure:
To a mixture of 4-((benzyloxy)methyl)-3,3-dimethyl-1-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one (459 mg) and acetic anhydride (3.0 mL) was added fuming nitric acid (0.12 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, water was added thereto, and the mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (343 mg).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=O.[Cl:15][C:16]1[N:17]=[CH:18][N:19]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH2:30])=[S:29])=[CH:23][C:22]=2[O:31][CH3:32])[CH:20]=1>C(O)C.CCOC(C)=O>[Cl:15][C:16]1[N:17]=[CH:18][N:19]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]3[S:29][C:2]4[CH2:7][CH2:6][CH2:5][CH:4]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[C:3]=4[N:30]=3)=[CH:23][C:22]=2[O:31][CH3:32])[CH:20]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(Cl)c1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-n1cnc(Cl)c1
Yield: 26 %

Procedure:
A mixture of 2-bromo-6-phenylcyclohexanone (89 mg, 0.352 mmol, from preparation AAA) and 1-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)thiourea (99 mg, 0.352 mmol, from step 4 of preparation A) was heated in ethanol (0.60 mL) at 80° C. for 3 h. The crude reaction was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo. The crude product was purified using preparatory TLC (60% acetone/hexanes) to give 42 mg (26% yield) of the titled compound as a white solid. LC-MS (M+H)+ 437.0. 1H NMR (400 MHz, chloroform-d) δ ppm 7.50 (d, J=1.51 Hz, 1 H) 7.45 (d, J=2.52 Hz, 1 H) 7.28-7.36 (m, 2 H) 7.14-7.23 (m, 3H) 7.08 (d, J=8.31 Hz, 1 H) 7.00 (d, J=1.51 Hz, 1 H) 6.60 (dd, J=8.44, 2.39 Hz, 1 H) 4.05 (t, J=6.30 Hz, 1H) 3.47 (s, 3 H) 2.68-2.89 (m, 2 H) 2.20-2.28 (m, 1 H) 1.98 (dd, J=7.30, 5.29 Hz, 1 H) 1.78-1.93 (m, 2 H).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:26][C:27]1([CH3:61])[C:51]2[C:31]([CH:32]=[C:33]3[CH:50]=[C:49]4[C:36]([C:37]5[C:42]([C:43]6[C:48]4=[CH:47][CH:46]=[CH:45][CH:44]=6)=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:35][C:34]3=2)=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28]1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:61][C:27]1([CH3:26])[C:51]2[C:31]([CH:32]=[C:33]3[CH:50]=[C:49]4[C:36]([C:37]5[C:42]([C:43]6[C:48]4=[CH:47][CH:46]=[CH:45][CH:44]=6)=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:35][C:34]3=2)=[CH:30][C:29]([C:2]2[C:3]3[C:8]([C:9]([C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:17]=4)=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:28]1
Reactant: Brc1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)C=C(c2c3ccccc3c(-c3ccc4ccccc4c3)c3ccccc23)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 53 %

Procedure:
A mixture of 6.6 g (17.2 mmol) of 9-bromo-10-(naphthalene-2-yl)anthracene, 8.1 g (17.2 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.2 g (0.172 mmol) of Tetrakis(triphenylphosphine)palladium, 13 ml of 2M Na2CO3, 30 ml of EtOH and 100 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 5.9 g (yield 53%) of yellow product which was recrystallized from toluene. MS(m/z,FAB+): 646.4; 1H NMR (CDCl3, 400 MHz): chemical shift(ppm) 9.14 (s, 1H), 8.90 (d, J=7.80 Hz, 1H), 8.82 (d, J=7.92 Hz, 1H), 8.79 (s, 1H), 8.73 (d, J=7.88 Hz, 2H), 8.23 (d, J=7.72 Hz, 1H), 8.11 (d, J=8.24 Hz, 1H), 8.07˜8.02 (m, 2H), 7.96 (d, J=7.40 Hz, 1H), 7.89 (d, J=8.64 Hz, 2H), 7.78˜7.59 (m, 10H), 7.42˜7.33 (m, 4H), 7.20 (d, J=7.40 Hz, 1H), 1.76 (s, 6H).
Reaction SMILES: C([O:4][C@@H:5]1[NH:8][C:7](=O)[C@H:6]1[NH:10][C:11](=[O:26])[C:12]([C:16]1[N:17]=[C:18]([NH:21][C:22](=[O:25])[CH2:23][Cl:24])[S:19][CH:20]=1)=[N:13][O:14][CH3:15])(=O)C.[N-:27]=[N+:28]=[N-:29].[Na+].O>CN(C=O)C>[N:27]([CH:7]1[NH:8][C:5](=[O:4])[C@H:6]1[NH:10][C:11](=[O:26])[C:12]([C:16]1[N:17]=[C:18]([NH:21][C:22](=[O:25])[CH2:23][Cl:24])[S:19][CH:20]=1)=[N:13][O:14][CH3:15])=[N+:28]=[N-:29]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N[C@H]1OC(C)=O)c1csc(NC(=O)CCl)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C(=O)N[C@@H]1C(=O)NC1N=[N+]=[N-])c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
To a solution of 0.308 g of (3S,4S)-4-acetoxy-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine in 3 ml of DMF is added under ice-cooling a solution of 0.061 g of sodium azide is 2 ml of water. The mixture is stirred for 18 hours at room temperature, to which is added water, then the resulting precipitates are collected by filtration to give 0.216 g of (3S)-4-azido-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[O:4][CH2:3]1.[NH:25]1[C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[C:27]([CH:34]=O)=[N:26]1>CO.N1CCCCC1>[NH:25]1[C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[C:27](/[CH:34]=[C:3]2\[O:4][C:5]3[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]4)=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]\2=[O:1])=[N:26]1
Reactant: O=Cc1n[nH]c2ncccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2n[nH]c4ncccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
A solution of tert-butyl 4-[(3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0442 g, 0.133 mmol) synthesized in Example B45, Step 3 in methanol (3 mL) was added with 1H-pyrazolo[3,4-b]pyridine-3-carboxaldehyde (0.0206 g, 0.140 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0292 g, 48%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.[CH3:26][C:27]([S:30](Cl)=[O:31])([CH3:29])[CH3:28]>C(Cl)Cl>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:30]([C:27]([CH3:29])([CH3:28])[CH3:26])=[O:31])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: CC(C)(C)S(=O)Cl
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Solvent: ClCCl
Product: CC(C)(C)S(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 43.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.450 g, 1.22 mmol), 2-methylpropane-2-sulfinic chloride (0.205 g, 1.46 mmol), TEA (2.0 mL), DCM (10 mL) to afford 0.250 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.23 (s, 9H), 4.24 (m, 2H), 7.63-7.87 (m, 4H), 7.86 (d, J=8.7 Hz, 2H), 8.19 (d, J=9.0 Hz, 2H); MS (m/z): 472.095 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:24]C)[N:13]2[CH2:16][CH2:17][CH2:18][CH:19]2[CH2:23][CH2:22][O:21][CH2:20]2)=[C:9]([NH2:26])[N:8]=1)[CH2:3][CH2:4][CH3:5].Cl.O1CCOCC1>CO>[NH2:26][C:9]1[N:8]=[C:7]([O:6][C@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:24])[N:13]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][O:21][CH2:20]1
Reactant: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCOC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCC[C@@H](C)Oc1nc(N)c2[nH]c(=O)n(CCCC3CCOC3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a solution of 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-9-[3-(tetrahydro-3-furanyl)propyl]-9H-purin-6-amine (52 mg, 0.143 mmol) in methanol (5 ml) at room temperature was added 4M HCl in dioxane (0.894 ml, 3.58 mmol). The reaction mixture was stirred at room temperature for 18 hrs and concentrated in vacuo to give a white solid. This material was dissolved in methanol and loaded onto a 2 g aminopropyl SPE cartridge, eluting with methanol. The solvent was removed to give the title compound as a white solid (36 mg).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH:5]1([C:8]2[N:13]=[C:12]([C:14]([NH:16][C:17]3[CH:25]=[N:24][CH:23]=[CH:22][C:18]=3[C:19](O)=[O:20])=[O:15])[C:11]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1>>[N:1]1([C:19]([C:18]2[CH:22]=[CH:23][N:24]=[CH:25][C:17]=2[NH:16][C:14]([C:12]2[C:11]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:10][CH:9]=[C:8]([CH:5]3[CH2:7][CH2:6]3)[N:13]=2)=[O:15])=[O:20])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: C1CNC1
Product: O=C(Nc1cnccc1C(=O)N1CCC1)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 60 %

Procedure:
According to the general method described in step 3 of example 53, reaction of azetidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (60%) as amorphous yellow solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) in dichloromethane (1.5 ml) was added at room temperature triethylamine (88.7 mg, 122 μl, 0.876 mmol) and methanesulfonyl chloride (43 mg, 29.2 μl, 376 μmol). The mixture was allowed to stir at room temperature for 18 h, and was afterwards evaporated. The crude material was further purified by flash chromatography on silica gel (dichloromethane/MeOH/NH4OH 150:10:1) and trituration with dichloromethane (1 ml) and heptane (5 mL) for 30 min to yield the title compound as a white solid (62 mg, 61%), MS (ISP) m/z=405.4 [(M+H)+], mp 142° C.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[C:30]1([CH:36]([NH2:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH2:3][NH:38][CH:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:37]
Reactant: CC(N)c1ccccc1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C=O)cn1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CNC(C)c2ccccc2)cn1

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted with 1-phenyl-ethylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 19.0, 24.9, 26.0, 27.0, 36.0, 43.2, 53.2, 57.9, 58.6, 58.9, 102.6, 102.9, 103.1, 105.2, 112.4, 112.6, 112.6, 126.8, 127.1, 128.6, 131.7, 137.8, 138.8, 145.7, 161.9, 164.4, 164.5, 169.3; MS m/z 512.3 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[N:5][C:4]=1SC)#[N:2].[CH3:27][NH2:28]>C(O)C>[C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[C:6]([C:17]2[CH:18]=[CH:19][C:20]([S:23][CH3:24])=[CH:21][CH:22]=2)=[N:5][C:4]=1[NH:28][CH3:27])#[N:2]
Reactant: CSc1ccc(-c2nc(SC)c(C#N)c(=O)n2-c2ccc(C)cc2)cc1
Reactant: CN
Solvent: CCO
Product: CNc1nc(-c2ccc(SC)cc2)n(-c2ccc(C)cc2)c(=O)c1C#N
Yield: 28.6 %

Procedure:
A suspension of 5-cyano-1-(4-methylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-1,6-dihydropyrimidine (2 g, 5.3 mmol) (prepared according to the procedure disclosed in example 6) in ethanol (20 ml) with methylamine (0.33 g, 10.6 mmol) was refluxed for 2 hr. Then the reaction mass poured on to ice and the resulted solid filtered, washed thoroughly with water. The resulted solid purified by column chromatography using ethyl acetate and hexane mixture as eluent to yield title compound (0.55 g, yield 25.5%, mp 268-271° C., purity 97.34% by HPLC). 1H-NMR (CDCl3):δ 2.32 (s, 3H), 2.43 (s, 3H), 2.95 (d, 3H), 5.8 (s, 1H, D2O exchangeable), 6.95-6.97 (d, 3H), 7.02-7.04 (d, 1H), 7.11-7.13 (d, 1H), 7.22-7.26 (m, 3H). IR (KBr) cm−1: 3294, 2919, 2205 (—CN), 1666 (—C═O). MS m/z: 363.1 (M+).
Reaction SMILES: NC1N=CC=C2C=1N[C:8](=[O:11])C2.[F:12][C:13]1[N:27]=[CH:26][CH:25]=[CH:24][C:14]=1[C:15]([N:17]([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[O:16]>>[CH:8]([C:24]1[C:14]([C:15]([N:17]([CH:18]([CH3:19])[CH3:20])[CH:21]([CH3:22])[CH3:23])=[O:16])=[C:13]([F:12])[N:27]=[CH:26][CH:25]=1)=[O:11]
Reactant: Nc1nccc2c1NC(=O)C2
Reactant: CC(C)N(C(=O)c1cccnc1F)C(C)C
Product: CC(C)N(C(=O)c1c(C=O)ccnc1F)C(C)C

Procedure:
The 7-amino-6-aza-oxindole 16 can also be prepared by lithiation of 2-fluoro-N,N-diisopropylnicotinamide 17 followed by quenching, such as with DMF, to give the 4-formyl-2-fluoro-N,N-diisopropylnicotinamide 18. The 4-formyl-2-fluoro-N,N-diisopropylnicotinamide can be reacted with an amine to give the 4-aminomethyl-2-fluoro-N,N-diisopropylnicotinamide 19 which can be reacted with another amine then cyclized under acidic conditions to afford the 7-amino-6-aza-oxindole 16.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=[O:13])[C:8]=2[C:17]([F:20])([F:19])[F:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>CO.O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[C:8]=2[C:17]([F:19])([F:20])[F:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1noc(-c2ccccc2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 202.2 %

Procedure:
To a solution of ethyl 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylate (3.6 g, 12 6 mmol) in methanol (100 mL) and water (20 mL) at room temperature was added lithium hydroxide, monohydrate (0.583 g, 13.9 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The methanol was removed under reduce pressure, and the residue was diluted with water (˜100 mL). Ethyl ether (200 mL) was added, and the pH of the aqueous layer was adjusted to <1 with a 1N aqueous solution of hydrochloric acid. The mixture was transferred to a separatory funnel, and after agitation, the layers were separated. The organic layer was washed with brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated to afford 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylic acid (3.12 g, 12.13 mmol, 96% yield) as a white, crystalline solid. The compound had an HPLC retention time=2.58 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS:(M+Na)=279.95. 1H NMR (400 MHz, CDCl3) δ ppm 7.53-7.64 (m, 3H), and 7.70 (d, J=7.5 Hz, 2H).
Reaction SMILES: [CH:1]([C@H:14]1[CH2:19][C@@H:18](OS(C)(=O)=O)[CH2:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[N:25]([C@@H:18]1[CH2:17][CH2:16][O:15][C@@H:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:19]1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Yield: 80.6 %

Procedure:
Cis-2-diphenylmethylpyran-4-yl methanesulfonate 4b (0.38 g, 1.10 mmol) was reacted with sodium azide (0.29 g, 4.4 mmol) in dry DMF (Procedure B) to yield compound 5b (0.26 g, 80%) as a liquid.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[C:8]([S:24][CH3:25])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18]C)=[O:17])[C:10](=[O:12])[CH:11]=1.O1CCOCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH-].[Na+].O>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[C:8]([S:24][CH3:25])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([OH:18])=[O:17])[C:10](=[O:12])[CH:11]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(SC)nc(OCc3ccc(F)cc3F)cc2=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(OCc2ccc(F)cc2F)cc(=O)n1-c1cc(C(=O)O)ccc1C
Yield: 100.9 %

Procedure:
A mixture of the ester (0.4 g, 0.0009 mol) obtained from step 3, in 2N NaOH (0.9 mL) and dioxane (0.5 mL) was stirred at room temperature for 1.5 h. The resulting clear solution was diluted with water (5.0 mL), acidified with 5% citric acid and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (2×15 mL), dried (Na2SO4), and concentrated to afford the title compound (0.38 g) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.06 (d, 1H, J=8.0 Hz), 7.81 (s, 1H), 7.51 (m, 2H), 6.99 (m 2H), 5.64 (s, 1H), 5.48 (s, 2H), 2.50 (s, 3H), and 2.15 (s, 3H); ES-HRMS m/z 419.0892(M+H calcd for C20H17N2O4SF2 requires 419.0872).