Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([CH:7]=1)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(Cl)cc1Br
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(Cl)cc1C=Cc1ccccc1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
Palladium acetate (21 mg, 7 mol %) was added to a solution of 2-bromo-4-chloroanisole (300 mg, 1.4 mmol), styrene (211 mg, 2 mmol), triethylamine (13 μL, 0.1 mmol) and triphenylphosphine (50 mg, 1.9 mmol) in acetonitrile (6 mL), and the mixture was refluxed for 8 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure and the obtained residue was diluted with ethyl acetate (15 mL). After the solution was washed successively with 2N hydrochloric acid, water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (118 mg, 35.6%) as a white powder.
Reaction SMILES: C[N:2]1[N:6]=[C:5]2[CH:7]=[CH:8][C:9]([NH:11][N:12]=[C:13]3[C:17]([NH2:18])=[N:16][N:15]=[C:14]3[NH2:19])=[CH:10][C:4]2=[N:3]1.CN1N=C2C=CC(N)=CC2=N1.CN1N=C2C=CC([N+]([O-])=O)=CC2=N1.C(#N)CC#N.O.NN>>[N:6]1[NH:2][N:3]=[C:4]2[CH:10]=[C:9]([NH:11][N:12]=[C:13]3[C:14]([NH2:19])=[N:15][N:16]=[C:17]3[NH2:18])[CH:8]=[CH:7][C:5]=12
Reactant: Cn1nc2ccc(NN=C3C(N)=NN=C3N)cc2n1
Agent: Cn1nc2ccc(N)cc2n1
Agent: Cn1nc2ccc([N+](=O)[O-])cc2n1
Agent: NN
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccc2n[nH]nc2c1

Procedure:
In a similar manner, 4-[(2-methyl-2H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine was prepared from 2-methyl-2H-benzotriazol-5-ylamine (which was prepared from methyl-5-nitro-2H-benzotriazole (2.0 g) in a manner similar to that described above) (0.24 g), malononitrile (0.2 g) and hydrazine hydrate (0.2 g) to yield 0.181 g. MS (m/z, ES+): 258 (M+1, 100%).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([O:17][CH3:16])[CH:23]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: COc1cc(B(O)O)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)ccn1

Procedure:
Prepared according to procedure F by stirring 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.5 g, 2.02 mmol), 2-methoxypyridin-4-ylboronic acid (0.31 g, 2.02 mmol), potassium carbonate (0.56 g, 4.03 mmol), Pd(PPh3)4 (0.23 g, 0.20 mmol), and toluene (4 mL) at 100° C. for 18 h. Purification by column chromatography (silica gel, 0-30% EtOAc in hexanes) gave 4-chloro-5,7-difluoro-2-(2-methoxypyridin-4-yl)-3-methylquinoline as an off-white solid. Mass Spectrum (ESI) m/e=321.1 (M+1).
Reaction SMILES: C1C2C(=CC=CC=2)C=C(N)[N:2]=1.[CH2:12]([O:14][CH:15]([O:19][CH2:20][CH3:21])[C:16](=[NH:18])[O-])[CH3:13].Cl.C1(CN)C=CC=CC=1.CO[Na]>CO>[CH2:12]([O:14][CH:15]([O:19][CH2:20][CH3:21])[C:16]([NH2:2])=[NH:18])[CH3:13]
Reactant: Nc1cc2ccccc2cn1
Reactant: CCOC(OCC)C(=N)[O-]
Agent: CO[Na]
Agent: Cl
Solvent: NCc1ccccc1
Solvent: CO
Product: CCOC(OCC)C(=N)N
Temperature: 70 °C

Procedure:
Shown in scheme O is the synthesis of intermediates compounds O-1 containing isoquinolin-3-amine. In a 250 ml of three-neck round bottom flask equipped with magnetic stir bar was charged the 2,2-diethoxyacetimidate (O-3) (6.7 g, 41.6 mmol) and MeOH (20 ml) then the phenyl methanamine hydrochloride (0.5 eq., 20.8 mmol) and MeONa (1 eq., 20.8 mmol) were added. The mixture was heated to 70° C. for 1 hr. The solution appeared dark. After the reaction finished, the MeOH solvent was removed by vacuum and the residue was dissolved in CH2Cl2 (100 ml). The organic phase washed with water (3×50 mL), then brine (1×30 mL). The organic layer was dried over magnesium sulfate, and filtered and the solvent reduced under vacuum. The product was purified by a silica gel column with 100% EA to give about 40.0% of desired product of 2,2-diethoxyacetamidine (O-2). The 2,2-diethoxyacetamidine (O-2) was dissolved in 6 ml of concentrated H2SO4 (99.9%) and the reaction was stirred at 40° C. for 72 hours. The solution was neutralized by 1M NaOH aqueous to PH 7.0. The crude was purified by silica gel column with 50:50 (petroleum ether: EA) to give final product O-1; yield from 13% to 70% depending on the substitution of phenyl methane amidine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:4][C:3]=1[Cl:30].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:22][CH2:23][C@H:24]([C:27]([N:53]5[CH2:58][CH2:57][O:56][CH2:55][CH2:54]5)=[O:28])[CH2:25][CH2:26]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:4][C:3]=1[Cl:30]
Reactant: Nc1c(Cl)cc(Nc2ncnc3cnc(N[C@H]4CC[C@H](C(=O)O)CC4)nc23)cc1Cl
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc(Nc2ncnc3cnc(N[C@H]4CC[C@H](C(=O)N5CCOCC5)CC4)nc23)cc1Cl

Procedure:
Prepared from 4-[(4-amino-3,5-dichlorophenyl)amino]-6-[(trans-4-carboxycyclohexyl)amino]pyrimido[5,4-d]pyrimidine by reaction with O-(benzotriazol-1-yl)-N,N,N',N',-tetramethyluronium tetrafluoroborate, triethylamine and morpholine. Melting point: 204°-207° C.; Rf : 0.53 (silica gel; petroleum ether/ethyl acetate/methanol=10:10:4)
Reaction SMILES: [CH:1]1([C@H:7]([CH2:20][CH:21]=[CH2:22])[CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:23]#[N:24].[Na+].O>CS(C)=O>[CH:1]1([C@H:7]([CH2:20][CH:21]=[CH2:22])[CH2:8][C:23]#[N:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=CC[C@H](COS(=O)(=O)c1ccc(C)cc1)C1CCCCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CC[C@H](CC#N)C1CCCCC1
Temperature: 90 °C

Procedure:
To the crude product, (S)-toluene-4-sulfonic acid 2-cyclohexyl-pent-4-enyl ester, in DMSO (40 mL) was added NaCN, and the resulting mixture was heated at 90° C. for 1.5 h. The reaction mixture was cooled to room temperature and treated with H2O (20 mL). The reaction mixture was then extracted with diethylether (3×25 mL), dried (MgSO4) and concentrated in vacuo to yield a residue which was purified by Kugelrohr distillation (0.19 mm Hg, 80-90° C.) to yield (R)-3-cyclohexyl-hex-5-enenitrile.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:6]1=2.[C:20]1([O:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:1][N:2]([CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:6]1=2)[C:27](=[O:28])[O:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)CCN1CCCCc2cc([N+](=O)[O-])ccc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: CN(CCN1CCCCc2cc([N+](=O)[O-])ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 81.9 %

Procedure:
A solution of N,N-dimethyl-2-(7-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)ethanamine (400 mg, 1.52 mmol) in 10 mL CH2Cl2 was treated dropwise with phenylchloroformate (286 μL, 2.28 mmol). The reaction was stirred at room temperature for 21 hours then partitioned between CH2Cl2 (100 mL) and 1N NaOH (20 mL). After extraction, the organic layer was separated and the aqueous layer was extracted with additional CH2Cl2 (50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to give a yellow residue. This residue was subjected to flash chromatography on silica gel using CH2Cl2 to give a yellow residue (460 mg, 82.0%). 1H-NMR (CDCl3) δ 7.99 (dd, J=2.7, 9.0 Hz, 1H), 7.93 (d, J=2.7 Hz, 1H), 7.40-7.34 (m, 2H), 7.23-7.18 (m, 1H), 7.10-7.04 (m, 2H), 6.87 (dd, J=6.3, 2.7 Hz, 1H), 3.65-3.55 (m, 4H), 3.39-3.31 (m, 2H), 3.11 and 3.05 (2×s, 3H), 2.88-2.85 (m, 2H), 1.85-1.65 (m, 4H). MS (ESI): 370.2 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH2:2][CH3:3].N1C2C(=CC=CC=2)C(=O)[C:16]1=O.BrCC(C)C>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH:2]([CH3:16])[CH3:3]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Solvent: CC(C)CBr
Product: CC(C)CN1C(=O)C(=O)c2ccccc21

Procedure:
Was prepared in an analogous manner to 1-propylindoline-2,3-dione using isatin (purchased from Fisher Scientific) and 1-bromo-2-methyl propane (purchased from Fisher Scientific). 1H NMR δ (dd, 2H), 7.13 (t, 1H), 6.90 (d, 1H), 3.55 (d, 2H), 2.16 (m, 1H), 1.00 (d, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[C:10]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)=[C:10]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3ccccc3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(-c2ccc(CN3CCNCC3)c(Oc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
A 100 mL round-bottom flask, was charged with tert-butyl 4-[[4-(3-methylphenyl)-2-phenoxyphenyl]methyl]piperazine-1-carboxylate (1.00 g, 2.18 mmol, 1.00 equiv), trifluoroacetic acid (1 mL), dichloromethane (10 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 0.800 g (crude) of 1-[[4-(3-methylphenyl)-2-phenoxyphenyl]methyl]piperazine as yellow oil LCMS (ESI, m/z): 359 [M+H]+.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(N(CC)CC)C.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)/[C:18](=[CH:22]\[C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1)/[C:17]([CH3:31])=[C:16]2[CH2:32][N:33]=[C:34]=[O:35]>C1COCC1>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)/[C:18](=[CH:22]\[C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1)/[C:17]([CH3:31])=[C:16]2[CH2:32][NH:33][C:34]([N:3]([OH:4])[CH3:2])=[O:35]
Reactant: CSc1ccc(/C=C2/C(C)=C(CN=C=O)c3cc(F)ccc32)cc1
Reactant: CNO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1ccc(/C=C2/C(C)=C(CNC(=O)N(C)O)c3cc(F)ccc32)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of N-methyl hydroxylamine hydrochloride (9.82 g, 117.6 mmol) in THF (150 mL) at room temperature there was added triethylamine (16.3 mL, 117.6 mmol) and the mixture stirred for 10 minutes. There was added, over 15 minutes, a solution of the isocyanate from Step 1 in THF (100 mL). After 2 hours of stirring at room temperature, the THF was evaporated and the residue, on trituration with water, afforded a yellow solid which was filtered. This solid was stirred in ether (150 mL) and filtered again. This crude material was chromatographed on silica gel eluting with 5% ethanol in methylene chloride. The more polar component of the mixture was stirred with methylene chloride (50 mL) for 2 hours and filtered and the solid crystallized from ethyl acetate to afford the pure title product as yellow crystals, mp 190-192° C. dec.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])=[CH:7][C:6]=1[Cl:27].[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1>>[Cl:27][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCBr)c(Cl)c1
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(CCOc2ccc(NC(=O)COc3ccc(C(F)(F)F)cc3Cl)cc2Cl)CC1

Procedure:
Prepared analogously to Example 145 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and ethyl piperidine-4-carboxylate.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:47]1([C:50]2[S:51][CH:52]=[C:53]([C:55](O)=[O:56])[N:54]=2)[CH2:49][CH2:48]1.C(N(CC)CC)C>CN(C=O)C>[CH:47]1([C:50]2[S:51][CH:52]=[C:53]([C:55]([N:28]3[CH2:29][C:30]4([CH2:35][CH2:34][N:33]([CH2:36][C:37]5[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=5)[CH2:32][CH2:31]4)[O:25][CH2:26][CH2:27]3)=[O:56])[N:54]=2)[CH2:49][CH2:48]1
Reactant: O=C(O)c1csc(C2CC2)n1
Reactant: OCCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1csc(C2CC2)n1)N1CCOC2(CCN(Cc3cc(F)cc(CCO)c3)CC2)C1
Reaction time: 0.5 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.34 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-5-fluorophenyl)ethanol (example 55, step c) (0.21 g), 2-cyclopropylthiazole-4-carboxylic acid (example 57, step c) (0.12 g) and triethylamine (0.38 mL) in DMF (7 mL) and the resulting yellow solution was stirred for 30 min. The mixture was partitioned between ethyl acetate and brine (100 mL), the organic layer was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.15 g.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[S:8])[NH:4][CH:5]=[CH:6][CH:7]=1.Br[C:10]1[CH:11]=[C:12]([O:18][C:19]2[C:20]([CH3:25])=[N:21][CH:22]=[CH:23][CH:24]=2)[C:13]([C:16]#[N:17])=[N:14][CH:15]=1.[H-].[Na+].O>CN(C=O)C>[CH3:1][C:2]1[C:3]([S:8][C:10]2[CH:11]=[C:12]([O:18][C:19]3[C:20]([CH3:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[C:13]([C:16]#[N:17])=[N:14][CH:15]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncccc1Oc1cc(Br)cnc1C#N
Reactant: Cc1ccc[nH]c1=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccnc1Sc1cnc(C#N)c(Oc2cccnc2C)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
3-Methylpyridine-2(1H)-thione (0.906 g, 7.24 mmol) and 5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (2.00 g, 6.89 mmol) were dissolved in DMF (12 mL) and the mixture was cooled to 0° C. Sodium hydride (95%; 0.183 g, 7.24 mmol) was slowly added and the reaction was warmed to ambient temperature and stirred overnight. The reaction mixture was poured into water (100 mL), stirred for 30 minutes, then filtered to afford a solid which was purified over silica gel (2:3 hexanes:ethyl acetate). Concentration of the second UV active fraction to elute afforded 5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)picolinonitrile (1.40 g, 4.19 mmol, 60.7% yield) as a pale yellow/off white powder/crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[N:8]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1cccc(Cl)c1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(Cl)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 3-chloro-N2-phenylbenzene-1,2-diamine (495 mg, 2.26 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (470 mg, 2.48 mmol), HOAt (338 mg, 2.48 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (477 mg, 2.48 mmol) and 4-methylmorpholine (0.550 mL, 4.97 mmol) in anhydrous DCM (15 mL) was stirred at RT for 19 h. The reaction mixture was diluted with DCM (100 mL) and washed with a saturated solution of NaHCO3. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (20 mL) and heated at 70° C. for 22 h. After cooling to RT, volatiles were removed in vacuo and the residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in DCM) affording [(S)-1-(7-Chloro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester as pale yellow oil (quantitative). LCMS: RT 3.83 min [M+H-tBu]+ 316.0.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([C:10]2([C:18]#[N:19])[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:20][Mg]Br.CCOCC>C1COCC1>[F:17][C:13]1([F:16])[CH2:12][CH2:11][C:10]([C:7]2[CH:8]=[N:9][C:4]([C:1]([OH:3])([CH3:20])[CH3:2])=[CH:5][CH:6]=2)([C:18]#[N:19])[CH2:15][CH2:14]1
Reactant: CC(=O)c1ccc(C2(C#N)CCC(F)(F)CC2)cn1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C2(C#N)CCC(F)(F)CC2)cn1
Temperature: -50 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A solution of 1-(6-acetyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (17 mg, 0.064 mmol) in THF (1.2 mL) was cooled at −50° C. and treated with a 3.0 M solution of methylmagnesium bromide in ether (110 μL, 0.32 mmol). After stirring at −50° C. for 3 hours, the reaction was quenched by adding saturated aqueous ammonium chloride (5 mL) and stirred at room temperature for a few minutes. AcOEt (5 mL) was added and the biphasic mixture was stirred vigorously for a few seconds. The layers were separated and the aqueous layer was extracted again with AcOEt (5 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by preparative TLC, eluting with 60% AcOEt in hexanes to afford 4,4-difluoro-1-[6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-cyclohexanecarbonitrile as a colorless oil (8.7 mg, 48%). LC-MS (m/z) 280.0 (MH+); tR=1.11.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=1.O.[NH2:21][NH2:22]>C(O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][C:16](=[O:18])[NH:21][N:22]=2)=[CH:9][CH:8]=1
Reactant: O=C(O)CCC(=O)c1ccc(N2CCCC2=O)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(N3CCCC3=O)cc2)=NN1

Procedure:
10.4 g (0.04 mole) of 4-(4-(2-oxo-pyrrolidin-1-yl)-phenyl)-4-oxo-butyric acid and 2 g (0.04 mole) of hydrazine hydrate are stirred under reflux in 100 ml of ethanol for 1 hour, the mixture is cooled and the product is filtered off with suction. The solid which has precipitated is stirred with sodium bicarbonate solution, filtered off with suction, washed and dried.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]2([CH3:38])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27]C(=O)OC(C)(C)C)=[CH:26][C:20]=4[S:19](=[O:36])(=[O:35])[N:18]=3)[C:7]2=[O:37])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:17]([C:8]3[C:7](=[O:37])[C:6]([CH2:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)([CH3:38])[C:15]4[C:10]([C:9]=3[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:18][S:19](=[O:36])(=[O:35])[C:20]=2[CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CCC3CC3)C1=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(CCC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 157F (1.06 g, 2.00 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (10 mL) at room temperature for 1 hour. After concentrating in. vacuo, the resulting oil was partitioned between ethyl acetate and aqueous NaHCO3, the organic layer was removed and the aqueous layer extracted 3 times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in. vacuo to yield a solid that was used without further purification. 1H NMR (300 MHz, DMSO-d6): δ ppm−0.25 (m, 2H) 0.25 (m, 2H) 0.46 (m, 2H) 0.80 (m, 1H) 1.57 (s, 3H) 2.15 (m, 1H) 2.32 (m, 1H) 6.99 (m, 2H) 7.44 (d, J=8.82 Hz, 1H) 7.54 (m, 1H) 7.77 (d, J=4.04 Hz, 2H) 8.15 (d, J=7.72 Hz, 1H) 13.55 (s, 1H). MS (ESI+) m/z=438 (M+H)+, 455 (M+NH4)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][C:14]1[N:19]=[N:18][C:17]([O:20][C:21]2[C:26]3[C@@H:27]4[C@H:32]([CH2:33][CH2:34][C:25]=3[CH:24]=[CH:23][CH:22]=2)[NH:31][CH2:30][CH2:29][CH2:28]4)=[CH:16][CH:15]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:31]3[C@@H:32]4[C@@H:27]([C:26]5[C:21]([O:20][C:17]6[N:18]=[N:19][C:14]([CH3:13])=[CH:15][CH:16]=6)=[CH:22][CH:23]=[CH:24][C:25]=5[CH2:34][CH2:33]4)[CH2:28][CH2:29][CH2:30]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: Cc1ccc(Oc2cccc3c2[C@H]2CCCN[C@H]2CC3)nn1
Product: Cc1ccc(Oc2cccc3c2[C@H]2CCCN(C(=O)c4ccc5[nH]cnc5c4)[C@H]2CC3)nn1
Yield: 17 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-10-(6-methyl-pyridazin-3-yloxy)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 17% of theory; LC (method 1): tR=2.39 min; Mass spectrum (ESI+): m/z=440 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[C:18]2[N:19]=[C:20]3[N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23][CH2:22][N:21]3[C:17]=2[C:16]2[C:11](=[CH:12][C:13]([Br:33])=[CH:14][CH:15]=2)[N:10]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:33][C:13]1[CH:12]=[C:11]2[C:16]([C:17]3[N:21]4[CH2:22][CH2:23][CH2:24][NH:25][C:20]4=[N:19][C:18]=3[C:9]([NH2:8])=[N:10]2)=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c1nc1c(N)nc3cc(Br)ccc3c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2cc(Br)ccc2c2c1nc1n2CCCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (4 mL) was added to a solution of tert-butyl 6-amino-3-bromo-10,11-dihydropyrimido[1′,2′:1,2]imidazo[4,5-c]quinoline-8(9H)-carboxylate (0.16 g) in dichloromethane (0.400 mL), and the resulting solution was stirred for two hours at room temperature. An analysis by LC/MS indicated the presence of starting material, and additional trifluoroacetic acid was added. The reaction was stirred for an additional four hours, concentrated under reduced pressure, and purified according to the method of Examples 8 through 12 to provide 3-bromo-8,9,10,11-tetrahydropyrimido[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine trifluoroacetate, observed accurate mass 318.0367 (M+H).