Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.O>CN(C)C(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc(Cl)nc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Clc1ccc(N2CCNCC2)nc1
Yield: 50.2 %

Procedure:
Following the general procedure of Example 33, Step 1, and making non-critical variations, 2,5-dichloropyridine (Aldrich; 5.10 g), piperazine (14.8 g), water (50 mL), and N,N-dimethylacetamide (2 mL) give 3.42 g of 1-(5-chloropyridin-2-yl)piperazine; mp 92-107° C.; IR 1480, 1244, 1390, 1589 815 cm-1 ; 1H NMR (CDCl3) δ2.98, 3.47, 6.58, 7.42, 8.11.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1O.[OH-].[Na+]>O>[C:2]1([C:1]2[O:9][C:16]3[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 117.5 °C

Procedure:
PPA (160 g) is added to benzoic acid (14.26 g, 0.117 mol) and 2-amino-5-nitrophenol (20 g, 0.117 mol). The mixture is heated at 115-120° C. for 30 minutes and cooled, and water (200 ml) is added dropwise, followed by addition of 32% NaOH (pH=10). The product is filtered off, washed with water and filtered off. It is recrystallized from isopropyl ether. Yield: 25 g (90%); Elem. anal. C13H8N2O3; theory C, 65.00; H, 3.35; N, 11.66. found C, 64.56; H, 3.22; N, 11.43. IR (KBr): 1551, 1515, 1340 cm−1.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([Br:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[Br:12]N1C(=O)CCC1=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:12][C:8]1[N:6]2[CH:7]=[C:2]([Br:1])[N:3]=[C:4]([Br:11])[C:5]2=[N:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Brc1cn2c(Br)cnc2c(Br)n1

Procedure:
A solution of 0.8 g (2.9 mmol) of 6,8-dibromoimidazo[1,2-a]pyrazine and 1.2 g of N-bromosuccinimide in 40 ml of chloroform is brought to reflux for two hours. After being cooled, the organic solution is treated with aqueous Na2CO3 solution. The chloroform phase is collected and then evaporated. 1 g -(Yld=97%) of 3,6,8-tribromoimidazo[1,2-a]pyrazine (m.p. 161° C.) is obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:8]([C:13]2[CH:14]=[C:15]([CH:17]=[C:18]([C:20]3[NH:28][C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[N:21]=3)[CH:19]=2)[NH2:16])=[N:9][CH:10]=[CH:11][CH:12]=1.CCN(CC)CC.[NH4+].[Cl-]>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:13]2[CH:14]=[C:15]([NH:16][S:2]([CH3:1])(=[O:4])=[O:3])[CH:17]=[C:18]([C:20]3[NH:28][C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[N:21]=3)[CH:19]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(-c2nc3cccnc3[nH]2)cc(-c2ncccc2Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cc(-c2nc3cccnc3[nH]2)cc(-c2ncccc2Cl)c1
Reaction time: 8 h
Yield: 37.5 %

Procedure:
Methanesulfonyl chloride (10.0 μL, 0.12 mmol) was added to a solution of Example 183 (32.1 mg, 0.1 mmol) in CH2Cl2 (2 mL) followed by Et3N (20.0 μL, 0.15 mmol) at 0° C. The resulting mixture was stirred overnight and saturated NH4Cl solution (50 mL) was added and the mixture extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting material was purified by LCMS (acetonitrile-water gradient) to give the title compound (15 mg, 38%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.99 (s, 3H) 7.33 (dd, J=7.21, 4.42, Hz, 1 H) 7.52 (dd, J=5.27, 3.48 Hz, 1 H) 7.83 (t, J=5.21 Hz, 1 H) 7.87 (d, J=5.11 Hz, 2 H) 8.03 (t, J=5.11 Hz, 1 H) 8.21 (t, J=5.11 Hz, 1 H) 8.34 (d, J=5.11 Hz, 2 H) 8.51 (d, J=5.42, Hz, 1 H) 8.56 (d, J=5.91 Hz, 1 H). MS (ES) [M+H] calculated for C18H15ClN5O2S, 400.06; found 400.02.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:19][C:20](=[O:36])[C:21]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[CH:8][CH:7]=1.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1>>[CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:19][C:20](=[O:36])[C:21]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:43]2[CH:44]=[CH:45][C:40]([C:39]([F:50])([F:49])[F:38])=[CH:41][CH:42]=2)=[CH:10][CH:11]=1
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2O)cc1)C(=O)OC
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)OC

Procedure:
The title compound was the prepared from (2S)-(5-bromo-2-heptyloxy-benzoylamino)-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.080 g, 0.140 mmol) and 4-trifluoromethylphenylboronic acid (0.050 g, 0.281 mmol) as per general procedure G to give (2S)-(5-bromo-2-heptyloxy-benzoylamino)-3-[2′-(4-trifluoromethyl-phenoxy)-biphenyl-4-yl]-propionic acid methyl ester which was further hydrolyzed as per general procedure C to give the title compound (0.020 g, 30% yield).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N[NH:12][C:13]([NH2:15])=[S:14].N>FC(F)(F)C(O)=O>[CH:1]1([CH2:7][CH2:8][C:9]2[S:14][C:13]([NH2:15])=[N:12][N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NNC(N)=S
Reactant: N#CCCC1CCCCC1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(CCC2CCCCC2)s1
Temperature: 0 °C
Reaction time: 4 h
Yield: 70.8 %

Procedure:
3-Cyclohexylpropionitrile (181 g) and 120 g of thiosemicarbazide were dissolved in 40 ml of trifluoroacetic acid, followed by stirring at a bath temperature of 70° to 80° C. for 4 hours. The reaction mixture was poured into ice-water, and 500 ml of concentrated aqueous ammonia was added thereto, followed by stirring at room temperature for 1.5 hours. The resulting precipitate was collected by filtration and washed with successive, small amounts of ethanol and diethyl ether to obtain 197 g of the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:19]1[CH:24]=[C:23]([CH:25]=[O:26])[C:22]([CH:27]=O)=[CH:21][CH:20]=1.CCOCC>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[CH2:27][C:22]3[C:23](=[CH:24][CH:19]=[CH:20][CH:21]=3)[C:25]2=[O:26])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Reactant: O=Cc1ccccc1C=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2Cc3ccccc3C2=O)ccc1OC
Yield: 69.4 %

Procedure:
A stirred mixture 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (100 mg, 0.37 mmol) and 1,2-phthalic dicarboxaldehyde (49 mg, 0.37 mmol) in acetic acid (2 mL) was heated to reflux for 15 min. Removal of solvent in vacuo and chromatography gave an oil which was stirred with ether (2 mL). The resulting suspension was filtered to yield 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindolin-1-one as a light yellow solid (100 mg, 70% yield): mp, 130.0-134.0° C.; 1H NMR (CDCl3) δ 1.45 (t, J s=7 Hz, 3H, CH3), 2.96 (s, 3H, CH3), 3.70 (dd, J=4.5, 14.7, Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J=6.9 Hz, 2H, CH2), 4.25 (d, J=16.5 Hz, 1 H, CHH), 4.31 (dd, J=10.3, 14.5 Hz, 1H, CHH), 4.46 (d, J=16 Hz, 1H, CHH), 5.71 (dd, J=4.5, 10.3 Hz, 1H, NCH), 6.84-7.01 (m, 3H, Ar), 7.38-7.56 (m, 3H, Ar), 7.85 (d, J=6.9 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.65, 41.33, 46.27, 52.33, 55.95, 56.00, 65.56, 111.45, 112.28, 119.30, 122.85, 123.85, 128.13, 129.89, 131.80, 132.27, 141.26, 148.88, 149.62, 169.09; Anal Calcd for C20H23NO5S: C, 61.68; H, 5.95; N, 3.60. Found: C, 61.68, H, 6.06; N, 3.62.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][C:17]1[C:18]([NH:25][C:26](=[O:28])[CH3:27])=[N:19][CH:20]=[C:21]([CH:23]=[CH2:24])[CH:22]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:24][CH2:23][C:21]3[CH:22]=[C:17]([CH3:16])[C:18]([NH:25][C:26](=[O:28])[CH3:27])=[N:19][CH:20]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1cnc(NC(C)=O)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ncc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1C

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, N-(3-methyl-5-vinylpyridin-2-yl)acetamide and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[NH2:24])[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]2[CH:18]=[CH:19][CH:20]=[C:9]2[CH2:8]1)=[O:6].[Cl:25][C:26]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(N(C(C)C)CC)(C)C>ClCCl>[CH:20]1[CH:19]=[CH:18][N:10]2[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]([C:5]([C:4]3[CH:21]=[CH:22][C:23]([NH:24][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:26]=4[Cl:25])=[C:2]([CH3:1])[CH:3]=3)=[O:6])[CH2:8][C:9]=12
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
A mixture of 0.40 g of 10,11-dihydro-10-(3-methyl-4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.40 g of 2,4-dichlorobenzoyl chloride and 0.75 g of diisopropylethylamine in 50 ml of dichloromethane is stirred at room temperature for 16 hours. The mixture is washed with water, dried (MgSO4) and the solution passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and hexane added to give crystals. Recrystallization from dichloromethane-hexane gives 0.52 g of crystals, m.p. 213°-215° C.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[C:30]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.Cl>[OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][CH3:30])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) and K2CO3 (72 mg, 0.52 mmol) in DMF (2.5 mL), was added MeI (148 mg, 1.04 mmol) and then stirred at room temperature for 4 h. The reaction mixture was diluted with 1.5 N HCl (50 mL) and extracted with ethyl acetate (3×25 mL). The separated organic layer was washed with 10% aq. NaHCO3 (25 mL), brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 58 mg (56%) of the title compound as an off white solid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[N:7][N:6]2[C:13]=1[S:14]([NH2:17])(=[O:16])=[O:15])[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.[OH2:29].[OH2:30].N>CN(C=O)C>[CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([S:11]([CH3:12])(=[O:30])=[O:29])=[N:7][N:6]2[C:13]=1[S:14]([NH2:17])(=[O:15])=[O:16])[CH3:2]
Reactant: O
Reactant: CCc1nc2ccc(SC)nn2c1S(N)(=O)=O
Agent: N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Product: CCc1nc2ccc(S(C)(=O)=O)nn2c1S(N)(=O)=O

Procedure:
2-Ethyl-6-methylthioimidazo[1,2-b]pyridazin-3-ylsulfonamide (1.10 g, 4.04 mmol) was dissolved in DMF (10.0 ml) and stirred under ice-cooling, during which m-chloro-perbenzoic acid (abbreviated into mCPBA) (70%, 2.48 g, 10.1 mmol) was added thereto. The mixture was stirred under ice-cooling for 1 hour and at TOM temperature for 3 hours, and then the reaction solution was poured into water (50.0 ml), and 25% ammonia water (1.0 ml) was added thereto. After the reaction solution was stirred for 5 minutes, the precipitated crystals were filtered and washed with water, to give the title compound as colorless crystals. The yield was 1.04 g (84.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O.C(N(CC)C(C)C)(C)C.Cl.Cl.[CH2:32]([O:39][C:40](=[O:48])[CH2:41][C@@H:42]([NH2:47])[CH2:43][N:44]([CH3:46])[CH3:45])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[CH2:32]([O:39][C:40](=[O:48])[CH2:41][C@@H:42]([NH:47][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]1[CH:17]=[CH:18][C:19]([F:20])=[C:2]([F:1])[CH:3]=1)[CH2:43][N:44]([CH3:45])[CH3:46])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=C(O)CCCCCCCOCc1ccc(F)c(F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
A solution of 8-(3,4-difluoro-benzyloxy)-octanoic acid (153 mg, 0.53 mmol), N,N-diisopropylethylamine (414 mg, 3.21 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetrametbyluronium-hexaflurophophate (244 mg, 0.64 mmol) in N,N-dimethylformamide was stirred for 1 h at room temperature, then a solution of (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride (198 mg, 0.64 mmol) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was stirred for 16 h at room temperature, then evaporated. Chromatography (SiO2, dichloromethane-[dichloromethane/methanol/25% aq. ammonia solution 110:10:1] gradient) produced (R)-3-[8-(3,4-difluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester (136 mg, 50%). Light yellow oil, m/e=505.4 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=O)[CH2:6][CH2:5]2.ClCCCl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:5][CH2:6][N:7]3[C:8]2=[C:9]([CH:10]=1)[C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[N:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=13
Reactant: CN1CCN(C(=O)Nc2ccccc2N2CCc3cc(Cl)ccc32)CC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCN(C2=Nc3ccccc3N3CCc4cc(Cl)cc2c43)CC1
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 29.5 %

Procedure:
To N-[2-(5-chloro-1-indolinyl)phenyl]-4-methyl-1-piperazinecarboxamide (13.5 g, 36.5 mmoles) was added a solution of polyphosphoric acid ethyl ester and 1,2-dichloroethane (250 ml). The solution was heated at 75° C. for 4 hours with exclusion of moisture. The solution was cooled and poured into a mixture of ice-sodium hydroxide solution (2 l) and dichloromethane (1.2 l). The mixture was stirred for 15 minutes. The layers were separated. The organic layer was washed with 2 l of 2N sodium hydroxide, then with brine (500 ml), and dried over anhydrous magnesium sulfate. Removal of the solvent at reduced pressure gave an oil. The oil was purified by flash chromatography on a silica gel column (1 kg, 230-400 mesh), packed and eluted initially with dichloromethane, then with dichloromethane containing an increasing methanol content in 1% increments to a final content of 5% (total 8 l). Concentration of the 5% methanol/dichloromethane eluent gave 3.8 g (28%) of product. Recrystallization from 2-propanol (50 ml) gave the analytical sample, mp 182°-183° C.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([N:19]=[C:20]=[S:21])[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[NH3:22]>C1COCC1>[Si:5]([O:8][CH:9]1[CH2:10][C:11]2[C:12]([NH:19][C:20]([NH2:22])=[S:21])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1)([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:7])[CH3:6]
Reactant: N
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2cccc(N=C=S)c2C1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCc2cccc(NC(N)=S)c2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of the product of Example 18C (1.25 g, 3.91 mmol) in THF (50 mL) was treated with 7N methanolic NH3 (5.6 mL, 3, 9.1 mmol), and the mixture was stirred at room temperature for 6 hours. The mixture was partitioned between EtOAc and H2O, and the separated organic phase was washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. Silica gel chromatography (98:2 to 95:5 CH2Cl2:CH3OH eluant) provided the title compound as a pale yellow solid, 1.27 g (97%). 1H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 1H), 6.6-7.8 (br, 2H), 6.99-7.13 (m, 3H), 4.08 (m, 1H), 2.73-2.92 (m, 4H), 1.84-1.92 (m, 1H), 1.60-1.68 (m, 1H). MS (ESI+) m/z 337 (M+H).
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#Cc1cc(N)ccc1N1CCCCC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
2-Chloro-5-nitrobenzonitrile (20 g) and piperidine (9.34 g) were added to acetonitrile (100 ml) and the mixture was stirred at the refluxing temperature for 1 hr. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization and the crystals were recrystallized from methanol to give 5-nitro-2-piperidinobenzonitrile (17 g). Subsequently, ammonium chloride (1.6 g) and iron powder (8.4 g) were added to a mixed solvent of water (40 ml) and ethanol (120 ml) and the mixture was heated to 65° C. 5-Nitro-2-piperidinobenzonitrile (10 g) was added by portions over 20 min and the mixture was stirred at the refluxing temperature for 30 min. The reaction mixture was ice-cooled and the reaction solution was filtrated. The solvent was evaporated under reduced pressure. An aqueous sodium hydroxide solution was added and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization and the crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (8.3 g). melting point: 148-149° C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:37][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[F:36]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)cn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 13.3 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(3,4-difluoro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.16 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (dichloromethane/MeOH) and crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.019 g, 12%). MS (ISP) 482.1 [(M+H)+]; mp 241.5° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[C:14]=1[Cl:25].[CH3:26][Al](C)C.[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1.C1(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)C=CC=CC=1>[Cl:25][C:14]1[C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=1[CH2:12][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][C:9]([NH2:11])=[N:10][C:2]=2[CH3:26]
Reactant: COc1cc(Cn2cnc3c(Cl)nc(N)nc32)c(Cl)c(OC)c1OC
Reactant: C[Al](C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(Cn2cnc3c(C)nc(N)nc32)c(Cl)c(OC)c1OC
Temperature: 25 °C

Procedure:
A suspension of 6-chloro-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine, see example 97) (0.2 mmol) and tetrakis(triphenylphosphino)-palladium (0.02 mmol) in dry THF (3 mL) was treated with trimethylaluminum (2M in toluene, 0.45 mmol) under nitrogen and heated to reflux for 3 h. The reaction mixture was cooled to r.t., diluted with toluene (5 mL) and quenched with methanol (0.5 mL) followed by ammonium chloride (1 mmol). The mixture was heated to reflux for 2 h and filtered, while hot, on Celite. See J. Med. Chem. 1999, 42, 2064–2086. TLC (100% EtOAc) Rf was 0.2. HPLC Rt: 4.800 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]([NH:6][C@@H:7]1[C@@H:14]2[C@@H:10]([CH2:11][NH:12][CH2:13]2)[CH2:9][CH2:8]1)=[O:5].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:29]([N:12]1[CH2:13][C@@H:14]2[C@@H:7]([NH:6][C:4](=[O:5])[CH:3]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:2]([CH3:21])[CH3:1])[CH2:8][CH2:9][C@@H:10]2[CH2:11]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(C(=O)c3ccccc3)C[C@@H]21)c1ccccc1
Reaction time: 0.08 h

Procedure:
3-Methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A (25 mg, 0.087 mmol), triethylamine (0.018 mL, 0.131 mmol), and benzoyl chloride (10.12 μL, 0.087 mmol) were combined in dichloromethane (5 mL). After 5 minutes, tlc shows no more starting material. The crude reaction mixture was concentrated and applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS-4) eluting with 1-10% methanol(2 N ammonia)/dichloromethane to give the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 7.49-7.42 (m, 2H), 7.41-7.35 (m, 3H), 7.33-7.27 (m, 3H), 5.43 (d, J=6.7, 1H), 3.97 (m, 1H), 3.74 (m, 2H), 3.56 (m, 2H), 3.39 (m, 1H), 2.74 (m, 2H), 2.48 (m, 1H), 2.38 (m, 2H), 2.07 (dd, J=4.6, 10.8, 1H), 1.94 (m, 1H), 1.52-1.31 (m, 2H), 1.01 (d, J=6.3, 3H), 0.68 (d, J=6.6, 3H); MS (ESI+) m/z 391 (M+H)+.