Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClC(Cl)C>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[CH:21][C:22]([C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:11])=[CH:23][CH:24]=1
Reactant: O=C1CCC(=O)O1
Reactant: Fc1ccccc1-c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(O)CCC(=O)c1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
To 6.2 g (46.5 mmol) of aluminum trichloride suspended in 50 ml of dichloroethane were added 3.02 g (30.2 retool) of succinic anhydride and 4.0 g (23.2 mmol) of 2-fluorobiphenyl were added thereto and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into hydrochloric acid containing ice, and extracted with chloroform. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then recrystallized from chloroform to obtain 5.6 g (89% yield) of the desired compound.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:9]2[C:10]([C:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:17].O.[C:21](O)(C(F)(F)F)=O>C(Cl)Cl>[O:17]=[C:6]1[NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:21])=[O:15])[C:9]=2[N:5]1[CH2:4][CH:3]=[O:2]
Reactant: COC(Cn1c(=O)[nH]c2cccc(C(=O)[O-])c21)OC
Reactant: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cccc2[nH]c(=O)n(CC=O)c12
Yield: 61 %

Procedure:
The solution of 3-(2,2-dimethoxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (0.4 g, 1.4 mmol) in methylene chloride (10 mL) with water (3 mL) and TFA (3 mL) was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure to remove the excess trifluoroacetic acid, diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, re-extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 2-oxo-3-(2-oxoethyl)-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (0.2 g, 61%): 1H NMR (500 MHz, DMSO-d5) δ 11.43 (s, 1H), 9.61 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.12-7.09 (m, 1H), 4.95-4.94 (m, 2H), 3.79 (s, 3H); MS (ESI+) m/z 234 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](=[O:19])C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl.C(OCC)(=[O:27])C>O1CCCC1.O>[CH2:1]([O:8][C:9]([NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]([OH:19])=[O:27])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C1CCCCC1NC(=O)OCc1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CCCCC1C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
The ester of step 1 (26.45 g, 86.62 mmol) was dissolved in 250 mL of tetrahydrofuran and treated with a solution of lithium hydroxide monohydrate (10.65 g, 256 mmol) in 250 mL of water and stirred at ambient temperature for 24 h. The reaction mixture was cooled to 0° C. and neutralized with 300 mL of a 1N HCl solution. Ethyl acetate (400 mL) was added and the organic layer was separated, dried over sodium sulfate, filtered and concentrated to give a crude solid. The product was purified by recrystallizing from ethyl acetate/hexanes to give 19.60 g of a white solid. Yield: 82%, MS: 278 (M+H+), mp=120.1-123.1° C.
Reaction SMILES: [OH-].[K+].C(OC([N:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)=O)C>O.COCCO>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][CH2:10][CH2:9][NH:8][C:14]=2[CH:15]=1)([O-:21])=[O:20]
Reactant: CCOC(=O)N1CCCOc2ccc([N+](=O)[O-])cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: O=[N+]([O-])c1ccc2c(c1)NCCCO2
Temperature: 110 °C
Yield: 78.9 %

Procedure:
1.00 M of Potassium hydroxide in Water (25 mL) was added to 2-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester (2.84 g, 10.7 mmol) in 2-Methoxyethanol (50 mL) and the reaction was heated at 110° C. After overnight heating, the mixture was cooled, extracted with DCM (2×50 mL); the combined organics were washed with water (50 mL) and brine (50 mL), dried and conc. in vacuo. The residue was chromatographed (120 g SiO2, ISCO, 0-20% EtOAc:Hex) to afford 2-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene as an orange solid (1.64 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH3:46][N:47]([CH3:54])[C:48]1[CH2:49][NH:50][CH2:51][CH2:52][N:53]=1.C(N(C(C)C)CC)(C)C>>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:50]3[CH2:51][CH2:52][N:53]=[C:48]([N:47]([CH3:54])[CH3:46])[CH2:49]3)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)C1=NCCNC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN=C(N(C)C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 101.8 %

Procedure:
Following a procedure similar to that described in Preparation 1(i), but using 446 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 178 mg of N,N'-carbonyldiimidazole, 289 mg of 3-dimethylamino-1,2,5,6-tetrahydropyrazine bis(trifluoroacetate) and 289 μl of diisopropylethylamine, 460 mg of the title compound were obtained, as a powder.
Reaction SMILES: [CH3:1][C@@:2]1([OH:22])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[CH:11]([CH2:12][C@@H:13]2[O:21][C@@H:14]2[CH2:15]1)[CH2:10][CH2:9]3.O.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[CH3:1][C@@:2]1([OH:22])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[CH:11]([CH2:12][C@H:13]([OH:21])[C@@H:14]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:15]1)[CH2:10][CH2:9]3
Reactant: C1CNCCN1
Reactant: C[C@]12C[C@H]3O[C@H]3CC1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]2(C)O
Solvent: O
Solvent: ClCCl
Product: C[C@]12C[C@H](N3CCNCC3)[C@@H](O)CC1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]2(C)O
Temperature: 150 °C
Yield: 60.2 %

Procedure:
To compound 28 (103 mg, 0.34 mmol) was added water (1 mL) and piperazine (3.5 g, 41 mmol). The solution was subsequently heated at 150° C. over a period of 24 h. The resulting mixture was diluted with dichloromethane (50 mL) and washed with water, dried with Na2SO4, filtered and evaporated under reduced pressure. The crude compound was purified by flash chromatography (DCM/MeOH: 9:1 containing 1.0% of TEA) to yield compound 29 (80 mg, 60%). 1H NMR (CDCl3) δ: 0.85 and 0.86 (2s, 18-CH3 and 19-CH3), 1.20 (s, 17α-CH3) 0.65-1.90 (residual CH and CH2), 2.50-3.30 (broad m, 2×CH2N, 2×CH2NH and 2α-CH), 3.85 (m, 3β-CH).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:9]=2[NH:8][C:7]1=[O:19])=[O:5])[CH3:2].[CH2:20](I)[CH3:21].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:9]=2[N:8]([CH2:20][CH3:21])[C:7]1=[O:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCc2ccc(OC)cc2NC1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C1CCc2ccc(OC)cc2N(CC)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.4 %

Procedure:
A suspension of 3(R,S)-ethoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (0.45 g, 1.71 mmol), ethyl iodide (0.41 mL, 5.1 mmol) and Cs2CO3 (1.672 g, 5.1 mmol) in acetonitrile (5 mL) was stirred at room temperature for 6 hrs. The reaction mixture was filtered and the solid was washed with acetonitrile. The combined filtrate and washer were evaporated under reduced pressure. The crude product was purified by flash chromatography on a short silica gel column using EtOAc/hexane (3:7) as an eluent. The title compound (0.241 g, 48%) was obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:28]=[CH:27][NH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:23][C:24]4[N:25]([C:14]=2[CH2:15]3)[N:26]=[CH:27][CH:28]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: Nc1cc[nH]n1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cnc3ccnn3c1C2

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 3-aminopyrazole.
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:30]1(B(O)O)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[OH:1][C:2]1([CH:8]([C:23]2[CH:24]=[CH:25][C:26]([O:29][C:38]3[C:39]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:35]=[CH:36][CH:37]=3)=[CH:27][CH:28]=2)[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: OB(O)c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(O)cc2)C2(O)CCCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(Oc3cccc4ccccc34)cc2)C2(O)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of tert-butyl 4-[2-(1-hydroxycyclohexyl)-2-(4-hydroxyphenyl)ethyl]piperazine-1-carboxylate (120 mg, 0.30 mmol), naphthalene-1-boronic acid (54 mg, 0.31 mmol) in dry dichloromethane (2 mL) was added copper (II) acetate (19 mg, 0.10 mmol), triethylamine (71 □L, 0.51 mmol), and powdered 4 Å sieves (100 mg) was stirred at room temperature for 16 h, after which time the reaction was filtered through a pad of Celite®, which was washed with dichloromethane (20 mL), and concentrated in vacuo. The product was purified via Biotage Horizon (FLASH 25 S, silica, gradient from 10% EtOAc/hexane to 60% EtOAc/hexane) to yield tert-butyl 4-{2-(1-hydroxycyclohexyl)-2-[4-(1-naphthyloxy)phenyl]ethyl}piperazine-1-carboxylate as a colorless oil. MS (ESI) m/z 531; HRMS: calcd for C33H42N2O4+H+, 531.32173; found (ESI, [M+H]+), 531.3203.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH2:8]([OH:13])[C:9]([F:12])([F:11])[F:10].Br[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1>O>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([O:13][CH2:8][C:9]([F:12])([F:11])[F:10])=[N:16][CH:17]=1
Reactant: OCC(F)(F)F
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)COc1ccc(Br)cn1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Sodium hydride (18.6 g, 60%, 464 mmol) was introduced into DMF (500 ml) under nitrogen. Trifluoroethanol (32.2 ml, 443 mmol) was added dropwise at 10° C. After 1 hour, 2,5-dibromopyridine (100 g, 422 mmol) was added portionwise, and the mixture was stirred in a water bath for 24 hours at 20° C. It was then stirred with water and extracted with heptane/ethyl acetate 9:1. Distillation of the crude product (105 g) yielded 5-bromo-2-trifluoroethoxypyridine, 82.1 g (purity 93%), colorless fluid, b.p. 97-104° C. at 18 mbar.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>CC1C=CC(S(O)(=O)=O)=CC=1.O.C1COCC1>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc2[nH]cnc2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Yield: 96 %

Procedure:
A round-bottom flask was charged with 20 (1.76 g, 10 mmol), p-TsOH.H2O (38 mg, 0.2 mmol), 3,4-dihydro-2H-pyran (1.26 g, 15 mmol) and THF (20 mL). The reaction mixture was degassed with nitrogen and heated at reflux for 18 h, and then the solvent was removed under reduced pressure. The residue was diluted with DCM (250 mL) and water (50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (0.5 to 1.0% MeOH) to afford 2.5 g (90%) of methyl 1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carboxylate (22) as a grey oil: MS (ESI) m/z=261.2 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[H-].[Na+].[C:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>CN(C)C=O>[C:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])=[CH:19][CH:18]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc(CBr)cc1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 79 %

Procedure:
Using 0.3 g of (3,3,3-trifluoropropyl)malononitrile, 3 ml of N,N-dimethylformamide, 0.08 g of sodium hydride (60% in oil), and 0.4 g of 4-acetylbenzyl bromide, and according to the process described in the Production Example 1, there was obtained 0.43 g of 2-(4-acetylbenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (6)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:11]=[C:12]([CH3:18])[C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[C:6]=2[CH:19]=1.CN(C)[C:22]1[O:23][C:24](=[O:32])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:27]=1.C(O)(=O)C>O>[CH3:17][O:16][C:13]1[C:12]([CH3:18])=[CH:11][C:10]([C:7]2[C:6]3[CH:19]=[C:2]([N:1]4[C:24](=[O:32])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[NH:27][C:22]4=[O:23])[CH:3]=[CH:4][C:5]=3[O:9][N:8]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(-c2noc3ccc(N)cc23)cc1C
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2noc3ccc(-n4c(=O)cc(C(F)(F)F)[nH]c4=O)cc23)cc1C

Procedure:
A mixture of 5-amino-3-(6-methoxy-m-tolyl)-1,2-benzisoxazole (8.40 g, 0.033 mol), 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (7.60 g, 0.036 mol), and acetic acid is refluxed for three hours, cooled, poured onto ice, and diluted with water. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and dried to give the title product as a pink solid which is identified by NMR spectral analyses.
Reaction SMILES: [NH3:1].[F:2][C:3]1([F:34])[C:7](=S)[NH:6][C:5]2([C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:20]=3)[O:15][C:14]3[C:9]2=[CH:10][C:11]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:12][CH:13]=3)[CH2:4]1>C1COCC1>[F:2][C:3]1([F:34])[C:7]([NH2:1])=[N:6][C:5]2([C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:20]=3)[O:15][C:14]3[C:9]2=[CH:10][C:11]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:12][CH:13]=3)[CH2:4]1
Reactant: FC1(F)CC2(NC1=S)c1cc(-c3cccnc3)ccc1Oc1ncc(-c3cccnc3)cc12
Reactant: N
Solvent: C1CCOC1
Product: NC1=NC2(CC1(F)F)c1cc(-c3cccnc3)ccc1Oc1ncc(-c3cccnc3)cc12
Temperature: 55 °C
Reaction time: 12 h

Procedure:
Ammonia gas was bubbled through a solution of 4′,4′-difluoro-3,7-di(pyridin-3-yl)spiro[chromeno[2,3-b]pyridine-5,2′-pyrrolidine]-5′-thione (0.019 g, 0.041 mmol) in THF (0.691 mL) at 55° C. for 2 minutes. Mercuric chloride (0.019 g, 0.070 mmol) was added in one portion and ammonia gas was bubbled through for 5 more minutes while heating at 55° C. (THF solution replenished as necessary to maintain a volume of ˜0.6 mL). The resulting reaction was stirred at 55° C. under nitrogen atmosphere for 12 hours to completion. After cooling, the reaction was filtered with CH2Cl2, MeOH, and 2:1 mixture of CHCl3/i-PrOH. The filtrate was diluted with a 10:1 mixture of saturated aqueous ammonium chloride/ammonium hydroxide (10 mL), the layers were separated and the aqueous layer was extracted with a 2:1 mixture of CHCl3/i-PrOH (3×20 mL). The combined organic extracts were washed with a 10:1 mixture of saturated aqueous ammonium chloride/ammonium hydroxide, water, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to afford a residue that was purified by silica gel chromatography (1:20 MeOH in CH2Cl2, followed by 1:10 2 M ammonia MeOH solution in CH2Cl2) to provide 4′,4′-difluoro-3,7-di(pyridin-3-yl)-3′,4′-dihydrospiro[chromeno[2,3-b]pyridine-5,2′-pyrrol]-5′-amine as an off-white solid after triturating with diethyl ether and pentane. MS m/z=442.0 [M+H].
Reaction SMILES: CS(OC[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[CH:31]=[CH:32][CH:33]=[CH:34][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:35][O:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][N:42]([CH2:45]CN)[CH2:41][CH2:40]1>C(N(CC)CC)C>[CH3:35][O:36][CH2:37][CH2:38][N:39]1[CH2:40][CH2:41][N:42]([CH2:45][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[N:16]=[CH:17][C:22]4[CH2:21][CH:20]([C:19]5[CH:18]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:23]=4[N:24]=3)=[CH:12][CH:13]=2)[CH2:43][CH2:44]1
Reactant: COCCN1CCN(CCN)CC1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2)C3)cc1
Solvent: CCN(CC)CC
Product: COCCN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3C(c3ccccc3)C4)cc2)CC1

Procedure:
This was synthesized by using 4-(6-phenyl-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, 2-(4-(2-methoxyethyl)piperazin-1-yl)ethanamine and triethylamine as described in general procedure 2 to afford the desired product. Yellow solid (34%). M.p.=52-54° C. 1H NMR 400 MHz (CDCl3) δ 8.40 (d, J=7.6 Hz, 1H), 8.17 (s, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.43 (t, J=6.4 Hz, 1H), 7.38 (t, J=6.4 Hz, 1H), 7.29-7.21 (m, 6H), 7.14 (d, J=2.0 Hz, 2H), 7.01 (d, J=7.6 Hz, 1H), 4.30 (t, J=7.2 Hz, 1H), 3.52 (t, J=6.0 Hz, 2H), 3.36 (s, 3H), 3.22-3.06 (m, 2H), 2.81 (t, J=8.0 Hz, 2H), 2.64-2.50 (m, 12H). LCMS m/e 520 (M+H).
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH2:17])=[NH:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.CN(C)[CH:20]=[CH:21][C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=O.[OH-].[Na+]>C(O)CC>[N:3]1([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:17]=[C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:21]=[CH:20][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: N=C(N)Nc1cccc(-n2ccnc2)c1
Reactant: CN(C)C=CC(=O)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Product: c1cncc(-c2ccnc(Nc3cccc(-n4ccnc4)c3)n2)c1
Yield: 67 %

Procedure:
Two and 73 hundredths grams of [3-(1H-imidazol-1-yl)phenyl]guanidine, dihydrochloride (2) from Example 1, 1.76 grams of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one, 25 ml of n-propanol and 2 equivalents (2 ml) of 10N NaOH at pH=11 is refluxed for twenty-four (24) hours. The products are isolated by quenching the reaction mixture including any precipitated solids into water followed by filtration. These filtered solids are re-suspended in water to remove inorganic salts, filtered and air dried to give 2.1 g (67% yield) of the desired product, mp 95°-120° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].N1CCCCC1>C(O)C>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH3:18]
Reactant: CCOC(=O)CC#N
Reactant: N#Cc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C(C#N)=Cc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
4-Cyanobenzaldehyde (3.00 g, 22.9 mmol) ad ethyl cyanoacetate (2.59 g, 22.9 mmol) are dissolved in absolute ethanol (100 ml). Piperidine (0.097 g, 1.14 mmol) is added, and the solution is stirred at room temperature until no more starting material is apparent by tic. This takes approx. 2 hours during which time a precipitate is formed. The precipitate is filtered and recrystallised, or alternatively, the crude reaction mixture is concentrated in vacuo and chromatographed over silica with cyclohexane/ethyl acetate mixtures as eluent to yield a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[NH:11][CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29](C)=[O:30])=[C:24]([CH3:32])[CH:23]=1>CN(C)C=O.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:29]([C:25]4[C:24]([CH3:32])=[CH:23][C:22]([CH3:21])=[CH:27][C:26]=4[CH3:28])=[O:30])[CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3
Reactant: CC(=O)c1c(C)cc(C)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3C(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.8 %

Procedure:
To a solution of 8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (32.9 mg, 0.125 mmol) in N,N-dimethylformamide (0.5 mL) was added sodium hydride (19.8 μL, 0.142 mmol) at 0° C. After 15 min, to the mixture was added 2,4,6-trimethylacetophenone (27.2 mg, 0.149 mmol). The reaction mixture was stirred at room temperature for 18 hrs. The mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed and brine (×1), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from n-hexane to give the title compound as a pale pink powder (24.0 mg, 0.0585 mmol, 47%).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:13]([C:15]#[N:16])=[CH:12][N:11]=[C:10]([O:17][CH3:18])[C:9]=3[C:8]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:29][C:30]([NH2:32])=[O:31].O>CN(C=O)C>[C:15]([C:13]1[C:14]2[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:29][C:30]([NH2:32])=[O:31])=[CH:21][CH:20]=3)[C:9]=2[C:10]([O:17][CH3:18])=[N:11][CH:12]=1)#[N:16]
Reactant: COc1ncc(C#N)c2c1c(-c1ccc(O)cc1)cn2C1CCCC1
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(C#N)c2c1c(-c1ccc(OCC(N)=O)cc1)cn2C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
To a solution of 1-cyclopentyl-3-(4-hydroxyphenyl)-4-methoxy-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (120 mg) and sodium hydride (dispersion in mineral oil, 22 mg) in DMF (3.0 mL) was added 2-bromoacetamide (120 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (37 mg).