Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:20]O.[C:22]1(=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[NH:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:20][N:23]1[C:24](=[O:31])[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]1=[O:32]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cccc(-c2cnc(N3CCOCC3)nc2)c1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(-c2cnc(N3CCOCC3)nc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
{2-Fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]phenyl}methanol (337 mg), 1H-isoindole-1,3(2H)-dione (257 mg) and triphenylphosphine (458 mg) were mixed with THF, and diethyl azodicarboxylate (40% toluene solution) (0.68 ml) was added thereto at 0° C., followed by stirring at room temperature overnight. The reaction mixture was stirred at 0° C. for 30 minutes, then filtered, washed with ice-cooled THF, and dried at 50° C. under reduced pressure to obtain 2-{2-fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl}-1H-isoindole-1,3(2H)-dione (452 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][CH3:9])[N:5]=[CH:4][C:3]=1[C:10]#[N:11].[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH2:7]([N:6]1[C:2]([NH:1][C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:3]([C:10]#[N:11])[CH:4]=[N:5]1)[CH2:8][CH3:9]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCn1ncc(C#N)c1N
Solvent: c1ccncc1
Product: CCCn1ncc(C#N)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 87.2 %

Procedure:
To a suspension of 5-amino-1-propyl-1H-pyrazole-4-carbonitrile (16.32 g) in pyridine (160 ml) was added triphenylmethyl chloride (36.35 g) at room temperature. After stirring at 60° C. for 5 hours, the reaction mixture was evaporated in vacuo. The residue was added to a mixture of tetrahydrofuran and brine, and the organic layer was separated and washed with brine. The extract was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. To the residue was triturated with diisopropyl ether to give 1-propyl-5-tritylamino-1H-pyrazole-4-carbonitrile (37.21 g) as a colorless solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([C:25]([F:24])([F:35])[F:36])=[CH:27][CH:28]=3)[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2cccc(CNC(=O)c3ccc(C(F)(F)F)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.45 g, 1.3 mmol) in acetonitrile (10 mL), was added 4-trifluoromethyl-benzoyl chloride (0.30 mL, 2.0 mmol) and N,N-diisopropyl ethylamine (0.58 mL, 3.3 mmol). The mixture was stirred at room temp overnight. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-4-trifluoromethyl-benzamide as a white solid (420 mg, 67% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.46 min (97.2%); mp, 253-255° C.; 1HNMR (DMSO-d6)2.18-2.24 (m, 1H, CHH), 2.59-2.94 (m, 6H, CHCH2, CH3), 4.94-5.11 (m, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 7.36-8.13 (m, 7H, Ar), 9.16 (t, J=5 Hz, 1H, CH2NH), 11.06 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.82, 23.28, 30.60, 42.31, 56.56, 117.68, 124.28, 125.39, 125.44, 125.57, 125.74, 128.16, 130.99, 131.41, 133.98, 137.96, 140.45, 148.50, 154.89, 161.10, 165.12, 169.54, 172.63. LCMS MH=473; Anal Calcd For C23H19N4O4F3+0.5H2O: C, 57.38; H, 4.19; N, 11.64; F, 11.84. Found: C, 57.01; H, 4.05; N, 11.53; F, 11.56.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15](=[O:21])[CH:16](Cl)[C:17](=O)[CH3:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[S:8][C:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:9][C:17]=1[CH3:18])=[O:21])[CH3:13]
Reactant: COc1ccc(C(N)=S)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1C
Yield: 69.7 %

Procedure:
A mixture of 4-methoxy-thiobenzamide (5 g, 30 mmol) and 2-chloro-3-oxo-butyric acid ethyl ester (4.6 mL, 33 mmol) in ethanol is stirred under reflux overnight. The reaction is concentrated and the residue is triturated with ether to give 2-(4-methoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester as a yellow solid (5.8 g, 70%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH:33]=[C:32]([S:34](Cl)(=[O:36])=[O:35])[N:31]=[CH:30]1.N1C=CC=CC=1>ClCCl>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[S:34]([C:32]1[N:31]=[CH:30][N:29]([CH3:28])[CH:33]=1)(=[O:36])=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNc2ccc(CN3CCN(c4ccccc4)CC3)cc2)cc1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1cnc(S(=O)(=O)N(Cc2ccccc2)c2ccc(CN3CCN(c4ccccc4)CC3)cc2)c1
Temperature: 25 °C

Procedure:
A solution of benzyl-[4-(4-phenyl-piperazin-1-yl methyl)-phenyl)-amine (30 mg, 0.08 mmol), 1-methylimidazole-4-sulfonyl chloride (51 mg, 0.27 mmol) and pyridine (24 μl, 0.30 mmol) in dry dichloromethane (2 ml) were heated to reflux for 15 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by column chromatography (5% methanol in dichloromethane) to afford the title compound as an off white solid (22 mg, 55%). HPLC retention time 7.04 min. Mass spectrum (ES+) m/z 502 (M+H). 1H-NMR (CDCl3) δH 2.54 (4H, m, 2×CH2), 3.16 (4H, m, 2×CH2), 3.45 (2H, br s, CH2), 3.71 (3H, s, CH3), 4.99 (2H, s, CH2), 6.84 (1H, t, J=7.3 Hz, ArH), 6.89 (2H, m, 2×ArH), 7.10 (2H, m, 2×ArH), 7.17-7.30 (10H, m, 10×ArH), 7.55 (1H, m, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.O.Cl[C:11]([CH3:15])([CH3:14])[C:12]#[CH:13]>[Cu].[Cu]Cl.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:11]([CH3:15])([C:12]#[CH:13])[CH3:14])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)Cl
Reactant: Nc1ccc(Br)cc1
Agent: Cl[Cu]
Agent: [Cu]
Solvent: CCOCC
Solvent: O
Product: C#CC(C)(C)Nc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-bromobenzenamine (4.0 g, 23 mmol), TEA (4.3 ml, 31 mmol), 2.0 ml of water, copper (0.058 g, 0.91 mmol) and copper(I) chloride (0.058 g, 0.59 mmol) in diethyl ether (9.8 ml, 20 mmol) was added 3-chloro-3-methylbut-1-yne (2.0 g, 20 mmol), dropwise. After stirring overnight, the reaction mixture was transferred to a seperatory funnel containing water and diethyl ether. The aqueous layer was washed 3× with EtOAc. The organic layers were combined, dried with MgSO4, filtered and concentrated. The crude oil was purified with by MPLC (100% DCM to 10% (91/10/1 DCM:MeOH:NH4OH)) to provide the product as an oil. MS m/z: 240 (M+2).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C.[CH:24]1([NH2:28])[CH2:27][CH2:26][CH2:25]1>C(O)C>[CH:24]1([NH:28][C:2]2[N:10]=[C:9]([F:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]([CH3:14])[CH3:13])[CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)n1cnc2c(Cl)nc(F)nc21
Reactant: NC1CCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cnc2c(NC3CCC3)nc(F)nc21
Yield: 67.9 %

Procedure:
6-chloro-2-fluoro-9-isopropyl-9H-purine (0.3 g, 1.4 mmol), diisopropylethylamine (0.2 g, 1.55 mmol) and cyclobutylamine (0.2 g, 2.8 mmol) were stirred together in ethanol (30 ml) at room temperature for 6 h. Volatiles were removed and the residue taken up in ethyl acetate, washed with water (50 ml), brine (50 ml), dried (MgSO4) and concentrated. The crude was purified by silica gel flash column chromatography (ethyl acetate:hexane 3:2) to give the pure product (237 mg, 68%) δH (CDCl3, 500 MHz) 1.56 (6H, d, J 7.5, CH[CH3]2), 1.76-1.74 (2 H, m, CH2 of Cyclobutyl), 1.98-1.94 (2 H, m, CH2 of cyclobutyl), 2.45 (2 H, s, br, CH2 of cyclobutyl)) 4.72-4.7 (2 H, m, CH of cyclobutyl and CHMe2), 6.35 (1 H, s, br, NH), 7.75 (1 H, s, ArH); δC (CDCl3, 500 MHz) 160.08 (C), 158.43 (C), 155.34 (C), 155.18 (C), 150.09 (C), 137.44 (CH), 47.26 (CH), 31.56 (2×CH2), 22.38 (2×CH3), 15.09 (CH2); m/z 250.2 (M+H)
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@:13]32[C@H:8]([C@H:9]([C:21](=O)[CH2:22]Br)[CH2:10][CH2:11][C@@H:12]3[CH3:20])[CH:7]=[C:6]1[CH3:25])(=[O:3])[CH3:2].[C:26]([NH2:30])(=[S:29])[CH2:27][CH3:28]>C(O)C>[C:1]([O:4][C@H:5]1[C@@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@@:13]32[C@H:8]([C@H:9]([C:21]2[N:30]=[C:26]([CH2:27][CH3:28])[S:29][CH:22]=2)[CH2:10][CH2:11][C@H:12]3[CH3:20])[CH:7]=[C:6]1[CH3:25])(=[O:3])[CH3:2]
Reactant: CCC(N)=S
Reactant: CC(=O)O[C@@H]1C(C)=C[C@H]2[C@H](C(=O)CBr)CC[C@H](C)[C@]23OC(C)(C)O[C@@H]13
Solvent: CCO
Product: CCc1nc([C@@H]2CC[C@@H](C)[C@]34OC(C)(C)O[C@H]3[C@H](OC(C)=O)C(C)=C[C@@H]24)cs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.7 %

Procedure:
To a stirred solution of (3aS,4R,6aS,7R,10S,10aS)-7-(2-bromoacetyl)-2,2,5,10-tetramethyl-4,6a,7,8,9,10-hexahydro-3aH-naphtho[1,8a-d][1,3]dioxol-4-yl acetate (Preparation 164, 500 mg) in ethanol (5 ml) was added thiopropionamide (110 mg). The reaction mixture was stirred at room temperature for 24 hours and then partitioned between saturated aqueous sodium chloride and ethyl acetate. The organic phase was dried (MgSO4), evaporated and purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (1:4) to give the product as a gum (345 mg).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[CH2:19][N:20]([CH3:22])[CH3:21])=[CH:10][C:9]=2[F:23])[C:3]1=[O:24].[Cl:25][C:26]1[S:30][C:29]([CH:31]=[CH:32][S:33](Cl)(=[O:35])=[O:34])=[CH:28][CH:27]=1>C(Cl)Cl>[Cl:25][C:26]1[S:30][C:29]([CH:31]=[CH:32][S:33]([NH:1][N:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH:18]=[CH:17][N:16]=[C:15]4[CH2:19][N:20]([CH3:21])[CH3:22])=[CH:10][C:9]=3[F:23])[C:3]2=[O:24])(=[O:35])=[O:34])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Reactant: CN(C)Cc1nccn1-c1ccc(N2CCCN(N)C2=O)c(F)c1
Solvent: ClCCl
Product: CN(C)Cc1nccn1-c1ccc(N2CCCN(NS(=O)(=O)C=Cc3ccc(Cl)s3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18.6 mg (0.046 mmol) of the diHCl salt of 1-amino-3-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-2-fluorophenyl)-tetrahydropyrimidin-2(1H)-one prepared as above, were dissolved in 3 mL of anhydrous CH2Cl2. To this solution placed under N2 atmosphere were added 50 μL of TEA followed by 11.2 mg (0.046 mmol) of 2-(5-chlorothiophen-2-yl)ethenesulfonyl chloride. The mixture was stirred at room temperature overnight. An additional 3 mL of CH2Cl2 were added, and the mixture was washed twice with 2 mL of saturated NaHCO3 solution. The organic phase was dried and concentrated to yield 17.2 mg of a brown oil. A pur compound was obtained after purification by preparative HPLC. 1H NMR (500 MHz, MeOD) δ 7.53 (t, 1H), 7.49 (s, 1H) 7.41 (d, J=10.4 Hz, 1H), 7.29 (s, 1H), 7.27 (d, J=8.2 Hz, 1H), 6.93 (d, J=3.8 Hz, 1H), 6.86 (d, J=3.8 Hz, 1H), 5.1 (m, 1H), 4.45 (q, 2H), 3.5 (m, 2H), 3.14 (m, 1H), 2.86 (s, 6H), 2.0 (m, 2H), ppm. LC-MS (ESI) 556.8 [M+NH4]+, tR=4.645 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna flow rate 2.5 ml/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4& B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C22H25ClFN6O3S2 [M+H]+ 539.1102, found 539.1105.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:14][C@@H:15]([OH:40])[C@@H:16]([NH:28][C:29](=[O:39])[O:30][C@@H:31]3[C@H:38]4[C@H:34]([O:35][CH2:36][CH2:37]4)[O:33][CH2:32]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C.[C:52]1([CH3:62])[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:62][C:52]1[CH:57]=[CH:56][C:55]([S:58]([O:27][CH2:26][CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][C@H:16]([NH:28][C:29]([O:30][C@@H:31]3[C@H:38]4[C@H:34]([O:35][CH2:36][CH2:37]4)[O:33][CH2:32]3)=[O:39])[C@H:15]([OH:40])[CH2:14][N:13]([S:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)(=[O:12])=[O:11])[CH2:41][CH:42]([CH3:44])[CH3:43])=[CH:19][CH:20]=2)(=[O:60])=[O:59])=[CH:54][CH:53]=1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCO)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(C[C@H](NC(=O)O[C@H]3CO[C@H]4OCC[C@H]43)[C@H](O)CN(CC(C)C)S(=O)(=O)c3ccc4c(c3)OCO4)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-[4-(2-hydroxyethoxy)benzyl]propylcarbamate (0.11 g, 0.18 mmol), triethyl amine (0.055 mL, 40 mg, 0.39 mmol), and 4-dimethylaminopyridine (2 mg), in dichloromethane at 0° C. was added p-toluenesulfonyl chloride (38 mg, 0.2 mmol) and the mixture was stirred at ambient temperature for 4 h. Solvent was evaporated and the residue was purified by chromatography (silica gel, dichloromethane/methanol, 98:2) to provide the title compound as a solid foam (0.105 g) 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H, dd), 1.37 (1H, quintuplet), 1.9-2.0 (1H, m), 2.3 (1H, dd), 2.38 (3H, s), 2.6-2.8 (2H, m), 2.9 (1H, d), 2.97 (1H, dd), 3.2-3.3 (1H, m), 3.4-3.5 (1H, m), 3.5-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.0 (2H, d), 4.3 (2H, t), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.7 (2H, d), 7.0-7.1 (3H, m), 7.2 (1H, d), 7.22 (1H, s), 7.29 (1H, d), 7.4 (2H, d), 7.8 (2H, d); MS: 791 (MH+)
Reaction SMILES: [CH3:1][NH2:2].[CH:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1(C)C=CC=CC=1>[CH:3](=[CH:1][NH2:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccccc1
Reactant: CN
Solvent: Cc1ccccc1
Product: NC=Cc1ccccc1
Temperature: 0 °C
Yield: 88 %

Procedure:
Anhydrous monomethylamine (about 1-1.5 eq,) was introduced below the surface of a stirred solution of benzaldehyde (1062 g, 10.0 mol) in toluene (2000 ml) cooled to 0° C. The rate of addition of monomethylamine was adjusted so as to maintain the reaction temperature between 25°-30° C.; after 45 minutes the addition of monomethylamine was terminated. The organic phase was separated and concentrated in vacuo. Distillation of the residual oil afforded N-benzylidenemethylamine (1047g, 8.79 mol) in 88% yield. The product had a boiling point of 79° C. at 20 mm. [This N-benzylidinemethylamine starting material is reported by R. B. Moffett et al, Org. Syn. Coll. Vol. IV, 605-608 (1963)].
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[N:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[C:13]=[S:14].C(=O)([O-])O.[Na+].CC(O)C>O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([N:12]2[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:3][N:2]=[C:13]2[SH:14])=[CH:20][CH:19]=1
Reactant: COc1ccc(N=C=S)cc1
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(-n2c(-c3ccccc3)cnc2S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 17.5 parts of 2-amino-1-phenylethanone hydrochloride, 16.5 parts of 1-isothiocyanato-4-methoxybenzene, 10 parts of sodium hydrogen carbonate and 200 parts of 2-propanol is stirred first for 30 minutes at room temperature and further for 2 hours at reflux temperature. The reaction mixture is poured onto 500 parts of water. The product is filtered off and stirred and refluxed for 1 hour with 240 parts of hydrochloric acid solution 10%. After cooling, the product is filtered off, washed with water and 2-propanol, and dried, yielding 25.3 parts (90%) of 1-(4-methoxyphenyl)-5-phenyl-1H-imidazole-2-thiol; mp. 167.4° C.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=1)=O.[C:16]1([CH3:26])[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([NH2:25])=[NH:24])[CH:17]=1.[OH-].[Na+]>COCCO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:16]1([CH3:26])[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]2[N:25]=[C:5]([C:7]3[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=3)[CH:4]=[CH:3][N:24]=2)[CH:17]=1
Reactant: CN(C)C=CC(=O)c1ccc(C(=O)O)s1
Reactant: Cc1cccc(NC(=N)N)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Cc1cccc(Nc2nccc(-c3ccc(C(=O)O)s3)n2)c1
Temperature: 100 °C
Yield: 53.9 %

Procedure:
5-(3-dimethylamino-acryloyl)thiophene-2-carboxylic acid (200 mg, 0.888 mmol), N-m-tolylguanidine (71.1 mg, 1.77 mmol) and NaOH (264 mg, 1.77 mmol) were dissolved in 2-methoxyethanol (2 mL) and heated at 100° C. for 48 hours. After cooling, the reaction was diluted with 10% Aqueous citric acid solution and the solids were collected by filtration. The solids were washed with water and Et2O and dried to afford 5-(2-m-tolylamino-pyrimidin-4-yl)thiophene-2-carboxylic acid (149 mg, 53.8%) as a yellow solid. MS: m/z 312 (M+H+).
Reaction SMILES: [OH:1][C@H:2]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[O:18][CH2:19][C:15]=2[C:14]=1[CH3:23])[CH2:3][N:4]1[CH:9]2[CH2:10][NH:11][CH2:12][CH:5]1[CH2:6][O:7][CH2:8]2.[CH3:24][C@H:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH:35]3[CH2:37][O:36]3)[CH:32]=2)[C:27](=[O:38])[O:26]1>>[OH:36][CH:35]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:38])[O:26][C@@H:25]([CH3:24])[CH2:34]2)[CH2:37][N:11]1[CH2:12][CH:5]2[N:4]([CH2:3][C@H:2]([OH:1])[C:13]3[C:14]([CH3:23])=[C:15]4[C:16](=[CH:21][CH:22]=3)[C:17](=[O:20])[O:18][CH2:19]4)[CH:9]([CH2:8][O:7][CH2:6]2)[CH2:10]1
Reactant: C[C@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Reactant: Cc1c([C@@H](O)CN2C3CNCC2COC3)ccc2c1COC2=O
Product: Cc1c([C@@H](O)CN2C3COCC2CN(CC(O)c2ccc4c(c2)C[C@H](C)OC4=O)C3)ccc2c1COC2=O

Procedure:
(3S)-6-(1-Hydroxy-2-(9-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)ethyl)-3-methylisochroman-1-one was prepared initially as a mixture of two diastereomers from 5-[(1R)-1-hydroxy-2-(3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one [INTERMEDIATE 17] and (3S)-3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one [INTERMEDIATE 24] in an analogous fashion to that described for the synthesis of EXAMPLE 1. The mixture of diastereomers was separated by preparative SFC-HPLC using a Chiralcel® OD column (30×250 mm) to afford the title single isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15](#[N:20])/[CH:16]=[CH:17]/[C:18]#[N:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH:14][CH:17]([CH2:16][C:15]#[N:20])[C:18]#[N:19]
Reactant: N#C/C=C/C#N
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Product: N#CCC(C#N)NNc1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A process according to claim 16, comprising reacting 2-(2,6-dichloro-4-trifluoromethylphenylhydrazine with fumaronitrile to afford 2-(2,6-dichloro-4-trifluoromethylphenylhydrazino)succinonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:11]1[CH2:20][CH2:19][CH2:18][C:17]2[N:16]=[CH:15][C:14]3[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=3[C:12]1=2)=O.B.Cl>O1CCCC1.C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:11]1[CH2:20][CH2:19][CH2:18][C:17]2[N:16]=[CH:15][C:14]3[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=3[C:12]1=2
Reactant: O=C(Cc1ccccc1Cl)N1CCCc2ncc3ccccc3c21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Clc1ccccc1CCN1CCCc2ncc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 82.6 %

Procedure:
A stirred colorless solution of 1-[(2-chlorophenyl)-acetyl]-1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine (5.7 g) in tetrahydrofuran (500 ml) was treated rapidly with 1M borane solution in tetrahydrofuran (68 ml, 0.068 mole of BH3, 4-fold excess) under nitrogen. A yellow color appeared within one minute. After stirring overnight at room temperature with exclusion of moisture, the reaction was quenched by dropwise addition of 10% sodium hydroxide solution (100 ml, gas evolution). The mixture was concentrated to remove the tetrahydrofuran and the aqueous residue was extracted with dichloromethane (2×250 ml). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a viscous gum (borane complex) which was dissolved in glacial acetic acid and treated portion-wise with concentrated hydrochloric acid (25 ml, gas evolution). The resultant solution was stirred for 3 hours at ambient temperature, decanted into ice water (500 ml), basified with 50% sodium hydroxide solution and extracted with dichloromethane (2×250 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to an oil (5.43 g). Thin layer chromatographic analysis (silica gel, ethyl acetate) indicated a mixture. The material was purified by HPLC (silica gel, sample applied in 25 ml of dichloromethane, eluted with ethyl acetate, 200 ml/min flow rate), and the appropriate fractions were combined and concentrated to an oil (2.90 g). A solution of the oil in methanol (10 ml) was treated with a slight excess of ethereal hydrogen chloride, followed by dilution with anhydrous ether almost to the cloud point. The solution was seeded with a material obtained from a small scale recrystallization, whereupon crystals precipitated rapidly. After standing 20 minutes (exclusion of light), the precipitate was isolated by vacuum filtration, washed thoroughly with ether and dried in vacuo at 40° C. to give 2.51 g of crystals, m.p. 218°-220° C.