Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH:25]3[CH2:27][CH2:26]3)CC3C=CC(OC)=CC=3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH:42]([F:44])[F:43])[CH:37]([C:45]([N:47]([CH3:49])[CH3:48])=[O:46])[CH2:36]1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH:25]3[CH2:26][CH2:27]3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH:42]([F:43])[F:44])[CH:37]([C:45]([N:47]([CH3:49])[CH3:48])=[O:46])[CH2:36]1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(CC(F)F)C(C(=O)N(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCCl
Product: CN(C)C(=O)C1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CCN1CC(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dimethylpiperazine-2-carboxamide (37 mg, 0.054 mmol) was taken up in DCE (0.5 mL) and anisole (0.029 mL, 0.268 mmol) was added, followed by TFA (0.124 mL, 1.608 mmol). The reaction was stirred at room temperature overnight. LCMS indicates mostly SM is present. An additional 30 eq. of TFA was added and the reaction was heated at 50° C. After 4 h, an additional 30 eq. of TFA was added, and the reaction heated for 1.5 h. The solvent was removed in vacuo and the material azeotroped 2× with toluene, then triturated with Et2O to remove anisole. The material was purified by preparative HPLC to provide 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dimethylpiperazine-2-carboxamide (20.1 mg) as a yellow solid.
Reaction SMILES: N[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].CC[N:13](CC)CC.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C1COCC1>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:13][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)(=[O:4])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CC
Reactant: NCC(=O)c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccccc2C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 2-amino acetophenone (1.0 g, 7.39 mmol), THF (15 mL) and Et3N (2.39 g, 23.64 mmol). To the solution p-methoxy benzoyl chloride (1.32 g, 7.76 mmol) in THF (15 mL) was added slowly at 0° C. and stirred for 30 min at 0° C. Then the reaction mixture was stirred for 24 h at rt under nitrogen. The reaction mixture was poured into ice water. The crude product was collected and crude product was purified by column chromatography using 25% EtOAc in hexane to give 1.865 g of N-(2-acetylphenyl)-4-methoxybenzamide (93%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:19][C:20]#[N:21]>>[Cl:1][C:2]1[C:11](/[CH:12]=[C:19](/[C:18]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:16]([O:15][CH3:14])[CH:17]=2)\[C:20]#[N:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2ccccc2nc1Cl
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2cc3ccccc3nc2Cl)cc1OC
Yield: 84.9 %

Procedure:
2-Chloro-3-quinolinecarboxaldehyde (200 mg) was condensed with 3,4-dimethoxybenzyl cyanide (185 mg) through Method A (production step 2), to thereby yield the target product (yield: 311 mg, 85%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:30](Br)[CH3:31].[CH3:33][CH2:34]OC(C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH2:15][N:16]([CH2:30][CH3:31])[CH2:33][CH3:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2Cl)CC1
Reactant: CCBr
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CC(c1ccccc1Cl)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
To 4[-2-Amino-1-(2-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (201) (2.15 g, 6.34 mmol) in DMF (15 mL) was added K2CO3 (4.38 g , 31.71 mmol) and ethyl bromide (2.07 g, 19.03 mmol). The reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (100 mL) The organic phase was concentrated to dryness. The crude material was purified by chromatography (silica gel 60 mesh, eluting with 5% MeOH in CHC13) yielding 1.55 g (62%) pure product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+]([O-])=O)[C:18]=1[C:19]#[N:20])([O-:16])=[O:15]>>[C:19]([C:18]1[C:17]([N+:14]([O-:16])=[O:15])=[CH:24][CH:23]=[CH:22][C:21]=1[O:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])#[N:20]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCCCO
Product: CC(C)(C)OC(=O)NCCCCOc1cccc([N+](=O)[O-])c1C#N
Yield: 7 %

Procedure:
Prepared as in Example 197c from tert-butyl 4-hydroxybutylcarbamate and 2,6-dinitrobenzonitrile in 7% yield as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.35 (s, 9H), 1.52-1.55 (m, 2H), 1.72-1.76 (m, 2H), 2.94-2.99 (m, 2H), 4.24 (t, J=6.8 Hz, 2H), 6.86 (brs, 1H), 7.69-7.72 (m, 1H), 7.85-7.90 (m, 2H).
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[O:10]=[C:11]1[C:20]2[CH:21]=[C:22]([S:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:23]=[CH:24][C:19]=2[O:18][CH2:17][C:16]2[CH:15]=[CH:14][S:13][C:12]1=2.[Cl-].[NH4+]>C1COCC1>[CH3:30][O:29][C:27](=[O:28])[CH2:26][S:25][C:22]1[CH:23]=[CH:24][C:19]2[O:18][CH2:17][C:16]3[CH:15]=[CH:14][S:13][C:12]=3[C:11]([OH:10])([CH:3]3[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]3)[C:20]=2[CH:21]=1
Reactant: CN1CCC(Cl)CC1
Reactant: COC(=O)CSc1ccc2c(c1)C(=O)c1sccc1CO2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)CSc1ccc2c(c1)C(O)(C1CCN(C)CC1)c1sccc1CO2
Yield: 18.1 %

Procedure:
A Grignard reagent prepared from magnesium (2.8 g, 116 mmol), 4-chloro-1-methylpiperidine (15.5 mL, 116 mmol), and THF (180 mL) was ice-cooled, and a THF (120 mL) solution of the compound obtained in Example 22 (18.5 g, 58 mmol) was added dropwise thereto. After allowing the mixture to react for 30 minutes, a saturated ammonium chloride was added thereto, and a product was extracted with ethyl acetate. The organic layer was sequentially washed with a saturated ammonium chloride and with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, and the solvents were distilled off under a reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2), to give 4.4 g (18%) of the captioned compound.
Reaction SMILES: [O:1]([CH3:13])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].N1C=CN=C1.[Si:19](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[Si:19]([O:12][CH2:11][C@H:9]1[O:10][C@@H:2]([O:1][CH3:13])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 50 °C
Yield: 88.3 %

Procedure:
To a stirred solution of methyl β-D-glucopyranoside (5 g, 25.7 mmol) in 51 mL of dry DMF was added at room temperature imidazole (5.46 g, 80.2 mmol) followed by tert-butyldiphenylsilyl chloride (11.3 mL, 43.4 mmol). The solution was heated to 50° C. for 24 hours and the DMF was removed under reduced pressure. The reaction mixture was diluted with 200 mL of ethyl acetate and washed with H2O (1×100 mL), saturated aqueous NaCl (1×100 mL), and dried over magnesium sulfate. Concentration and flash chromatography (silica, 4% methanol in dichloromethane) provided pure target compound (9.82 g, 88%) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(Br)c1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Br)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (843 mg, 0.005 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (2.64 g, 0.020 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(3-bromo-phenoxy)-but-2-enoic acid ethyl ester (1.50 g, 0.004 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-2-[4-(3-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (490 mg, 25%) as yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH2:12][O:11][CH2:10][C:9]1([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.CCOC(C)=O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1(C)COCC(=O)N1Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1(C)COCCN1Cc1ccccc1
Temperature: 0 °C

Procedure:
Dissolve methyl 4-benzyl-3-methyl-5-oxomorpholine-3-carboxylate in THF (10 volumes) and cool to 0° C. Add borane dimethylsulfide complex (1.5 eq) and allow to warm to room temperature. Add water (5 volumes) followed by EtOAc (10 volumes). Separate the organic layer, wash with saturated aqueous NaCl, dry over sodium sulfate, filtered, and concentrate to give methyl 4-benzyl-3-methylmorpholine-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:11]2[CH:16]=[C:15]([Cl:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:11]3[CH:16]=[C:15]([Cl:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1Cl
Reactant: Cc1ncc[nH]1
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(Cl)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2,6-dichloro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-chloro-4-(3-chloro-4-methoxybenzylamino)- thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)#[N:13]
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc2c(Oc3ccc4[nH]ccc4c3)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.6 %

Procedure:
A suspension of 4-chloro-6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline (100 mg, 0.26 mmol), (prepared as described for the starting material in Example 1), 5-hydroxyindole (42 mg, 0.32 mmol) and cesium carbonate (129 mg, 0.39 mmol) in DMF (1 ml) was stirred for 10 minutes at ambient temperature followed by 1.5 hours at 70° C. After cooling, water (5 ml) was added. The precipitate was filtered, washed with water and dried under vacuum. The solid was purified by column chromatography, eluting with methanol/methylene chloride/ethyl acetate (5/45/50) to give 6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-5-yloxy)quinoline (28 mg, 22%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(2-pyridylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (378 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 2 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2-pyridylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (260 mg) as yellow crystals.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:26][C:27]1[CH:28]=[C:29]2[C:33](=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:35]=1)[NH:32][CH:31]=[CH:30]2.C([SiH](CC)CC)C>ClCCl>[Br:26][C:27]1[CH:28]=[C:29]2[C:33](=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:11]1[CH2:10][CH2:9][S:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12]1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: O=C1CCSC(c2ccccc2)C1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CCSC(c4ccccc4)C3)c[nH]c12
Reaction time: 2 h

Procedure:
To a solution of 2-phenylthian-4-one (SJTU) (0.900 g, 4.68 mmol) in dichloromethane (DCM) (15 mL), cooled on an ice bath to 0° C., under argon, was added dropwise trimethylsilyl trifluoromethanesulfonate (1.807 mL, 10 mmol) over 10 minutes, an additional portion of dry DCM (5 mL) was used to wash the addition funnel walls. To this mixture ethyl 5-bromo-1H-indole-7-carboxylate (1.340 g, 5.00 mmol) was added dropwise, in solution with of dry DCM, over 2 hours. Finally, triethylsilane (3.19 mL, 20 mmol) was added in one portion and the mixture was stirred 2 h at ca 0° C., and left stirring at 23° C. 16 h. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate, and the resulting biphasic mixture partitioned with DCM to afford 2.21 g of brow gummy oil. LCMS of product may indicate an overlapping mixture of ca 5:2 major to minor isomers (cis/trans).
Reaction SMILES: [CH3:1][N:2]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:4]=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[CH3:1][N:2]([CH2:20][C:21]([OH:23])=[O:22])[C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:4]=1
Reactant: CN(CC(=O)OC(C)(C)C)c1nccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: CN(CC(=O)O)c1nccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
tert-Butyl {methyl[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyrimidinyl]amino}acetate (0.20 g, 0.52 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred for 0.5 hr. Diisopropyl ether was added thereto. The obtained crystals were recrystallized from ethanol to give the titled compound (0.15 g, 87%) as pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19].C=O.[C:25]1(C)C=CC=CC=1>C(O)CCC>[OH:1][C:2]1[C:7]([CH2:25][N:20]([CH2:21][CH3:22])[CH2:18][CH3:19])=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: CCNCC
Reactant: Cc1ccccc1
Agent: C=O
Solvent: CCCCO
Product: CCN(CC)Cc1cc(C)cc(-n2nc3ccccc3n2)c1O

Procedure:
2-(2-Hydroxy-5-methylphenyl)-2H-benzotriazole (74.3 g, 0.33 mol), diethylamine (37.0 g, 0.51 mol) and paraformaldehyde (17.1 g) are dissolved in 85 mL of n-butanol. The mixture is heated with agitation at reflux (95° to 100° C.) for 44 hours. The solvent is removed by vacuum distillation, and the product, a yellow viscous liquid, is obtained in high yield (>99%). This Mannich base is identified by thin layer chromatography using toluene as the mobile phase.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([OH:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[NH3:17]>C(O)(C)C>[NH2:17][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:15][C@H:14]([OH:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: N
Reactant: OC1CC(c2nc(I)c3c(Cl)nccn23)C1
Solvent: CC(C)O
Product: Nc1nccn2c1c(I)nc2[C@H]1C[C@@H](O)C1
Temperature: 110 °C

Procedure:
In a Parr pressure reactor 3-(8-chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanol (4.159 g, 0.0119 mol) was dissolved with 2.0M ammonia in isopropyl alcohol (40 mL). The mixture was cooled to −20° C. and saturated with ammonia. The reaction was heated at 110° C. for 63 h at which point it was cooled and concentrated in vacuo. The crude product was purified using HPFC Jones 25 g silica gel column eluting with 5-8% MeOH: CH2Cl2 to yield the title compounds; MS (ES+): m/z 330.88 (100) [MH+], 331.89 (10) [MH++]; HPLC: tR=0.48 min (OpenLynx, polar—5 min); 1H NMR (CDCl3, 400 MHz) δ 2.55-2.76 (m, 2H) 3.06-3.22 (m, 2H) 3.32-3.50 (m, 1H) 4.51-4.69 (m, 1H) 6.15 (br. s., 2H) 7.24 (d, J=5.05 Hz, 1H) 7.39 (d, J=5.05 Hz, 1H).
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][CH2:8][C:9]1[C:17]2[C:16]([C:18](O)=[O:19])=[CH:15][CH:14]=[C:13]([CH3:21])[C:12]=2[NH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[CH2:25][N:26]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CN>CN(C=O)C.O>[CH3:25][NH:26][C:18]([C:16]1[C:17]2[C:9]([CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:23])[CH3:22])=[CH:10][NH:11][C:12]=2[C:13]([CH3:21])=[CH:14][CH:15]=1)=[O:19]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccc(C(=O)O)c2c(CCO[Si](C)(C)C(C)(C)C)c[nH]c12
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(C)c2[nH]cc(CCO[Si](C)(C)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-7-methyl-1H-indole-4-carboxylic acid (150 mg, 0.45 mmol), EDCI (104 mg, 0.54 mmol) and HOBt (91.2 mg, 0.68 mmol) in DMF (3 mL) was added diisopropylethylamine (0.39 mL, 2.25 mmol) at room temperature. A solution of methylamine (0.45 mL of 2.0 M in THF, 0.90 mmol) was added to the mixture and the mixture was stirred overnight at room temperature. The solution was diluted with H2O (5 mL) and extracted with EtOAc (3×10 mL). The organic solution was washed brine (20 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 40% EtOAc in hexanes) to give 140 mg (90%) of title compound as a pale yellow solid. 1H NMR (CDCl3): 300 MHz δ 8.28 (bs, 1H), 7.20 (m, 2H), 7.00 (d, J=7.35 Hz, 1H), 6.40 (bs, 1H), 3.91 (t, J=6.41 Hz, 2H), 3.08 (m, 5H), 2.54 (s, 3H), 0.88 (s, 9H), −0.08 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:10]([Br:12])=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[BrH:12]
Reactant: BrBr
Reactant: Nc1ccc(F)cc1C(=O)O
Solvent: ClC(Cl)Cl
Product: Br
Product: Nc1c(Br)cc(F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2-Amino-5-fluorobenzoic acid (5 g, 32.2 mmol) in chloroform (90 mL) was added bromine (1.82 mL, 35.4 mmol) in chloroform (10 mL) solution dropwise via an additional funnel. The mixture was stirred at room temperature for 16 hrs. and LC/MS showed about 50% conversion of the starting material. Additional bromine (1.8 mL) was added to the reaction and continued stirring for another 24 hrs. The resulting white precipitate was collected by filtration, washed thoroughly with dichloromethane and air-dried to give 2-amino-3-bromo-5-fluorobenzoic acid as its HBr salt. ES/MS m/z 234/236 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:33](=[O:34])[C:12]2=[N:13][N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][CH:23]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]2=[N:10]1.O.[CH3:36][N:37](C)C=O>[C-]#N.[Zn+2].[C-]#N.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:8][C:4]1[C:3]([N:9]2[C:33](=[O:34])[C:12]3=[N:13][N:14]([CH2:21][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH:32]=[CH:31][CH:30]=[N:29]5)=[CH:26][CH:27]=4)[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10]2)=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:36]#[N:37]
Reactant: O=c1c2nn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1c(F)cccc1Br
Reactant: CN(C)C=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cccc(F)c1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)nc-2c1=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-(2-Bromo-6-fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one [(Example 12) 46 mg, 0.089 mmol] was dissolved in degassed N,N-dimethylformamide (1.5 mL) and treated with zinc cyanide (18 mg, 0.15 mmol, 1.7 equiv) and bis(tri-tert-butylphosphine)palladium(0) (9.0 mg, 0.018 mmole, 0.2 equiv). The mixture was stirred under nitrogen at 100° C. for 30 minutes, cooled to ambient temperature, poured into water and extracted twice with ethyl acetate. The combined organic extracts were washed once with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100:0 to 90:10; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.32 (1H, d, J=7.8 Hz), 7.90 (1H, s), 7.72 (2H, d, J=9.4 Hz), 7.67-7.51 (7H, m), 7.44 (2H, d, J=9.4 Hz), 6.47 (1H, s), 5.89 (2H, s) ppm; low resolution mass spectrometry (ES+) m/z 461.9 [(M+H)+; calculated for C26H16FN7O: 461.4].