Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:32])[O:13][C:14](=O)[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:17]=2)=[CH:3]1.[NH3:33]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:32])[NH:33][C:14](=[O:13])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:17]=2)=[CH:3]1
Reactant: N
Reactant: Cn1cc(C2=C(c3cn(-c4ccccc4)c4ccccc34)C(=O)OC2=O)c2ccccc21
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cn(-c4ccccc4)c4ccccc34)C(=O)NC2=O)c2ccccc21

Procedure:
150 mg of 3-(1-methyl-3-indolyl)-4-(1-phenyl-3-indolyl)furan-2,5-dione were treated with 3 ml of DMF and 10 ml of 33% aqueous ammonia at 80° C. for 4 hours. The mixture was cooled and extracted with ethyl acetate. The ethyl acetate extract was dried and concentrated. The residue was crystallized from ethyl acetate/hexane to give 120 mg of 3-(1-methyl-3-indolyl)-4-(1-phenyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 135°-137° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:24]=4[O:23][CH3:22])[CH2:29]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Reactant: COc1cc2c(c(OC)c1)CCNC2
Agent: Cl
Product: COc1cc2c(c(OC)c1)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccccc13)C2
Yield: 23.5 %

Procedure:
Reaction of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 8 (23.5% yield): 1H NMR (300 MHz, DMSO-d6) δ 2.70 and 3.00 (2m, 2H), 3.48 and 4.03 (2m, 2H), 3.74 and 3.75 (m, 3H), 3.46 and 3.87 (s, 3H), 4.24 and 4.78 (2s, 2H), 6.33-6.51 (m, 2H), 7.38-7.44 (m, 2H), 7.72-7.78 (m, 1H), 7.91-7.99 (m, 1H), 8.07-8.17 (m, 2H), 8.52-8.62 (m, 2H); MS (ESI) m/z 444 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12](C)[N:13]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:23])[CH:4]=1.C(OC(O)C(F)(F)F)C>>[F:25][C:2]([F:1])([F:24])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:23])[CH:4]=1
Reactant: CC1CCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc2N1CC(F)(F)F
Agent: CCOC(O)C(F)(F)F
Product: O=c1cc(C(F)(F)F)c2cc3c(cc2[nH]1)CCCN3CC(F)(F)F

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 192 (Structure 33 of Scheme VI, where R1=H, n=1) and trifluoroacetaldehyde ethyl hemiacetal. 1H NMR (400 MHz, CDCl3) 11.32 (br. s, 1H), 7.11 (s, 1H), 7.02 (s, 1H), 6.99 (s, 1H), 3.88 (q, 2H, J=8.9), 3.47 (t, 2H, J=5.6), 2.93 (t, 2H, J=6.3), 2.03 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C@H:11]([C@@H:26]([OH:28])[CH3:27])[C:12]([NH:14][NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:30][C:31]([Si:34](Cl)([CH3:36])[CH3:35])([CH3:33])[CH3:32].N1C=CN=C1>>[Si:34]([O:28][C@@H:26]([CH3:27])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:29])[C:12]([NH:14][NH:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1)=[O:13])([C:31]([CH3:33])([CH3:32])[CH3:30])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: c1c[nH]cn1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Yield: 83.8 %

Procedure:
N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-cyano benzohydrazide (12.1 g, 29.3 mmol) was reacted with TBDMSCl (13.2 g, 88.0 mmol) and imidazole (68.1 g, 146.0 mmol) in a manner analogous to that described for the preparation of intermediate 7b. Purification of the compound was accomplished by pouring the reaction mixture into ice-cold water and filtering off the solid precipitate. This was taken up in methylene chloride (400 mL) and sequentially washed with water (2×100 mL) and brine (100 mL). This was dried over sodium sulfate, tittered and concentrated down to roughly 100 mL. Hexanes were then added producing a white solid. This was filtered out and washed with hexanes to give the product as a white solid (12.92 g, 84%). 1H NMR (400 MHz, CDCl3, δ in ppm) 9.32 (m, 2H), 7.89 (AA′XX′, J=8.4 Hz, 2H), 7.71 (AA′XX′, J=8.6 Hz, 2H), 7.37 (d, J=8.4 Hz, 1H), 6.47 (d, J=8.8 Hz, 1H), 5.37 (d, J=6.2 Hz, 1H), 4.49 (m, 1H), 3.99 (m, 1H), 2.33 (s, 3H), 1.25 (d, J=6.2 Hz, 3H), 0.92 (s, 9H), 0.14 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([OH:15])=O)=[C:8]2NC1C=CC(C(NC2CCN(CC3C=CC=CC=3)CC2)=O)=CC=1.FC(F)(F)C1C=C(C[N:48]2CCC(N)CC2)C=CC=1.FC(F)(F)C1C=C(C=CC=1)CCl.O1C2(CCNCC2)OCC1.O>>[N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:8]=[C:9]([C:13]([NH2:48])=[O:15])[CH:10]=1
Reactant: NC1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Reactant: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)O)cnc12
Agent: C1CC2(CCN1)OCCO2
Agent: FC(F)(F)c1cccc(CCl)c1
Solvent: O
Product: NC(=O)c1cnc2ccccc2c1

Procedure:
8-Methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-1-[[3-(trifluoromethyl)phenyl]methyl]-4-piperidinyl]-3-quinolinecarboxamide was prepared as a hygroscopic solid (0.46 hydrate) by coupling 8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxylic acid and 1-[[3-(trifluoromethyl)phenyl]methyl]-4-piperidinamine as described for Example 17, Step 5. 1-[[3-(trifluoromethyl)phenyl]methyl]-4-piperidinamine can be prepared from 3-(triflouromethyl)benzyl chloride and 1,4-dioxa-8-azaspiro[4.5]-decane as described in U.S. Pat. Nos. 3,875,165 and 4,816,464: mp 132°-138° C.; 1H NMR (Me2SO-d6, 400 MHz) δ 9.48 (s, 1 H), 8.76 (s, 1 H), 8.39 (d, J=7.6 Hz, 1 H), 7.97 (d, J=7.8 Hz, 1 H), 7.68 (d, J=8.7 Hz, 2 H), 7.10-7.65 (m, 12 H), 6.87 (d, J=8.7 Hz, 2 H), 3.94 (s, 3 H), 3.62-3.80 (m, 1 H), 3.35-3.60 (m, 5 H), 2.6-2.9 (m, 4 H), 1.95 (m, 4 H), 1.3-1.8 (m, 8 H); Karl Fischer, 0.46 moles of H2O.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]2[CH2:17][CH2:16][CH2:15][NH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH3:18][C:19]1[N:20]=[C:21]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[S:22][C:23]=1[C:24](Cl)=[O:25]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:24]([C:23]3[S:22][C:21]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[N:20][C:19]=3[CH3:18])=[O:25])[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: Cc1nc(-c2cccs2)sc1C(=O)Cl
Reactant: CCOc1cc(C2=NNCCC2)ccc1OC
Product: CCOc1cc(C2=NN(C(=O)c3sc(-c4cccs4)nc3C)CCC2)ccc1OC
Yield: 78.7 %

Procedure:
Analogously to Example 2, reaction of 1.04 g of 3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro4H-pyridazine with 1.08 g of 4-methyl-2-thiophen-2-ylthiazole-5-carbonyl chloride (“CA”) gives the compound 1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-thiophen-2-ylthiazol-5-yl)methanone (1.54 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH:12]1[CH:16]2[O:17][CH2:18][CH:19]([OH:20])[CH:15]2[O:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:28][S:29]([O:20][CH:19]1[CH2:18][O:17][CH:16]2[CH:12]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][O:14][CH:15]12)(=[O:31])=[O:30]
Reactant: OC1COC2C(OCCOCc3ccccc3)COC12
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1COC2C(OCCOCc3ccccc3)COC12
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a suspension of 6-(2-(benzyloxy)ethoxy)hexahydrofuro[3,2-b]furan-3-ol (1.50 g, 5.36 mmol) in anhydrous DCM (20 mL) was added N,N-diethylethanamine (1.20 mL, 8.60 mmol) and N,N-dimethylpyridin-4-amine (0.13 g, 1.07 mmol) under the nitrogen atmosphere, and the mixture was cooled down to 0° C. To the mixture was added methanesulfonyl chloride (0.50 mL, 6.50 mmol) at 0° C., and then the mixture was moved to room temperature and stirred overnight. The mixture was diluted with DCM (50 mL), washed with brine (50 mL) and dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica chromatography (EtOAc/PE (v/v)=2/1) to give the title compound as yellow liquid (1.81 g, 94%).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([CH3:7])[CH:6]=1.CC[Mg+].[Br-].[Sn:12](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16]>C(Cl)Cl>[CH2:21]([Sn:12]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[N:3]=[CH:4][N:5]([CH3:7])[CH:6]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1cnc(I)c1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-iodo-1-methylimidazole (0.424 g, 2.04 mmol) in CH2Cl2 at rt was added EtMgBr (3.0 M in Et2O, 0.75 mL, 2.25 mmol) and the resulting solution was allowed to stir for 30 min at rt. To this solution was then added Bu3SnCl (0.60 mL, 2.21 mmol) and the mixture was stirred for another 7 h. The resulting mixture was then washed (sat. NH4C1, H2O, brine), dried (Na2SO4) and evaporated to give the title compound, which was used directly in the following step without further purification:
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]=[C:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:10][C:9]=3[C:8]2=O)=[CH:4][CH:3]=1.Cl.[Cl:26][C:27]1[CH:34]=[C:33]([NH:35][NH2:36])[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]>>[Cl:26][C:27]1[CH:34]=[C:33]([N:35]2[CH:6]([C:5]3[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=3)[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:14]=4[CH2:15][CH2:16]3)=[N:36]2)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: N#Cc1ccc(NN)cc1Cl
Reactant: CCOC(=O)c1ccc2c(c1)CCC(=Cc1ccc(F)cc1)C2=O
Agent: Cl
Product: CCOC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1c1ccc(F)cc1
Yield: 83 %

Procedure:
The title compound was prepared from ethyl 6-(4-fluorobenzylidene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (Preparation 16; 324 mg, 1.0 mmol) and 2-chloro-4-hydrazinylbenzonitrile hydrochloride (Preparation 1; 306 mg, 1.5 mmol) according to Method B (yellow solid, 394 mg, 0.830 mmol, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (m, 1H), 1.31 (t, J=7.12 Hz, 3H), 1.79 (m, 1H), 2.95 (m, 2H), 3.97 (ddd, J=13.49, 11.21, 4.83 Hz, 1H), 4.31 (q, J=6.98 Hz, 2H), 5.94 (d, J=11.28 Hz, 1H), 7.15 (m, 6H), 7.66 (d, J=8.86 Hz, 1H), 7.80 (s, 1H), 7.85 (dd, J=8.19, 1.75 Hz, 1H), 8.16 (d, J=8.06 Hz, 1H). ES-MS m/z 474 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27](O)=[O:28])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33][NH:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[CH3:33][N:34]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([CH2:23][C@@H:19]2[CH2:20][CH2:21][CH2:22][C@H:18]2[C:9]2[O:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH:25]=1
Reactant: O=C(O)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: CNCCc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CCc1ccccn1)C(=O)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a mixture of 3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzoic acid (120 mg, 0.284 mmol) and 2-(2-methylaminoethyl)pyridine (0.047 ml, 0.341 mmol) in DMF (5 ml) was added 1-hydroxybenzotrioxazole (58 mg, 0.426 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.568 mmol). After stirring the mixture at room temperature for 2 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with water, saturated sodium hydrogencarbonate solution, water, and brine. The resultant mixture was dried over magnesium sulfate, and evaporated in vacuo. The resultant residue was purified by silica gel column chromatography (methylene chloride: MeOH, 15:1 elution), then treated with 4N hydrogen chloride in EtOAc (1ml) to give N-methyl-N-[2-(pyridin-2-yl)ethyl]-3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzamide (140.9 mg, 86%).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2[CH:45]=[CH:46][CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.CN1CC[C@@H](N)C1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:49][C@@H:44]5[CH2:45][CH2:46][N:48]([CH3:47])[CH2:43]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN1CC[C@@H](N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methyl-3-(R)-amino pyrrolidine dihydrochloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.90 (m, 12 H) 2.18 (m, 1 H) 2.26 (s, 3 H) 2.32-2.56 (m, 2 H) 2.60-2.68 (m, 2 H) 3.34 (s, 3 H) 3.95 (s, 3 H) 4.07 (t, J=13.52 Hz, 2 H) 4.34-4.54 (m, 2 H) 7.51 (d, J=8.0 Hz, 1 H), 7.54 (br. s., 1 H) 7.90 (s, 1 H), 8.21 (s, 1 H) 8.27 (d, J=8.0 Hz, 1 H) 8.40 (br. s., 1 H). Melting point: 98-99° C. [M+H] calculated for C27H35F2N7O3, 544; found 544.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6](Cl)=[O:7].[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>CCOCC>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: OCc1ccccc1
Reactant: O=C(Cl)C1CCCO1
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(OCc1ccccc1)C1CCCO1
Reaction time: 0.67 h

Procedure:
Tetrahydrofuroyl chloride (15.0 g, 112 mmol) was added dropwise to a cold solution of benzyl alcohol (10.9 g, 101 mmol) and pyridine (20.0 g, 253 mmol) in Et2O (200 mL). The solution was stirred at 0° for 40 minutes, then filtered to remove the side product pyridine hydrochloride. The filtrate was washed with 0.1M HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL), and then dried over MgSO4. Filtration and evaporation of the solvent gave a yellow oil, which was distilled. Benzyl tetrahydrofuroate was obtained as a colorless oil (21.1 g), b.p. 118° to 120° at 0.5 mm Hg. Microanalysis calc'd for C12H14O3 (206.2): C, 69.89; H, 6.84; O, 23.27; Found: C, 69.62; H, 6.89.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([N:11]=[C:12]=[S:13])[CH2:4][CH2:3]1.C(Cl)Cl.[CH3:17][NH2:18]>C(O)C>[CH3:17][NH:18][C:12]([NH:11][CH:5]1[C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:2](=[O:1])[CH2:3][CH2:4]1)=[S:13]
Reactant: CN
Reactant: O=C1CCC(N=C=S)c2ccsc21
Solvent: ClCCl
Solvent: CCO
Product: CNC(=S)NC1CCC(=O)c2sccc21

Procedure:
A mixture of 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylisothiocyanate (5.0 g) and methylene chloride (100 ml) is stirred and a saturated solution of methylamine in ethanol (15 ml ethanol saturated with methylamine) added. The mixture is stirred for 15 hours then heated at reflux for 2 hours, cooled and evaporated to dryness in vacuo. The residue is triturated with water, the title thiourea collected and dried.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[N:3]=1.CC(C)=O.[C:22]([NH2:30])([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:23].[OH-].[Na+]>O>[Cl:8][C:6]1[N:7]=[C:2]([NH:30][C:22]([CH3:24])([CH3:23])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[N:3]=[C:4]([N:9]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[N:5]=1
Reactant: Clc1nc(Cl)nc(N2CC3CCC(CC3)C2)n1
Reactant: CC(C)(C)CC(C)(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(N2CC3CCC(CC3)C2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Thirty grams (0.11 mole) of 3-(4,6-dichloro-s-triazin-2-yl)-3-azabicyclo[3.2.2]nonane is dissolved in 300 ml. of acetone and then 370 ml. of water is added followed by 20 g. (0.15 mole) of tert-octylamine. After stirring for 10 minutes, 4.4 g. (0.11 mole) of NaOH in 30 ml. of water is added over 20 minutes. The reaction is then heated to reflux for 19 hours. After cooling to room temperature, one liter of water is added, stirred for one hour and the white precipitate filtered off. The precipitate is washed with water, dried overnight, dissolved in dichloromethane and filtered through Magnesol®. The Magnesol® is then washed with dichloromethane, solvent removed in vacuo and recrystallized from dichloromethane-hexanes giving 20 g. of colorless crystals, m.p. 159°-162.5° C.
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[N:13]1[C:17](N)=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[CH:14]1.C(Br)(Br)[Br:25].C(ON=O)(C)(C)C.C1(C)C=CC=CC=1>C(#N)C>[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[N:13]1[C:17]([Br:25])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[CH:14]1
Reactant: BrC(Br)Br
Reactant: Nc1c(SC(F)(F)F)ncn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: FC(F)(F)Sc1ncn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.44 %

Procedure:
To a solution of 2.0 g (5.05 mmole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-amino-4-trifluoromethylsulfenylimidazole in 10 ml of acetonitrile was added 1 ml of bromoform and 1.20 ml (10.10 mmole) of t-butylnitrite at 0° C. The resulting mixture was stirred at RT under a nitrogen atmosphere for 1.5 h. Ten ml of toluene was added and the mixture was evaporated to dryness under vacuum. The residue was purified by column chromatography on silica gel using 5% ethyl acetate in hexane to give 800 mg (34.44% yield) of the desired product, mp 87.5° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10](O)[C:9]=2[N:8]=[CH:7][C:6]=1[CH3:16])[CH:2]=[CH2:3].P(Br)(Br)[Br:18].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([Br:18])[C:9]=2[N:8]=[CH:7][C:6]=1[CH3:16])[CH:2]=[CH2:3]
Reactant: C=CCOc1c(C)cnc2c1CCCC2O
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=CCOc1c(C)cnc2c1CCCC2Br

Procedure:
3.5 Grams of 4-allyloxy-8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline was dissolved in 40 ml of chloroform, to this solution was added dropwise a solution consisting of 2.8 g of phosphorus tribromide and 5 ml of chloroform under ice-cooled condition. The reaction mixture was stirred under ice-cooled condition for 2 hours, further stirred at room temperature for 2 hours. The reaction mixture was poured into a cold sodium hydroxide aqueous solution, then extracted with chloroform. The chloroform layer was washed with an aqueous solution saturated with sodium chloride, then dried with anhydrous magnesium sulfate. Chloroform was removed by evaporation, then the residue thus obtained was purified by a silica gel column chromatography (eluent: methylene chloride/methanol=100/1) to obtain 1.3 g of 4-allyloxy-8-bromo-3-methyl-5,6,7,8-tetrahydroquinoline.
Reaction SMILES: N(OC(C)(C)C)=O.[CH3:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:10]=1N.[CH3:19][S:20]SC>[Cu]>[CH3:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:10]=1[S:20][CH3:19]
Reactant: CSSC
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: CSc1c(C)cccc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 8 h

Procedure:
226 g (1.97 mmol) of tert-butyl nitrite and 100 g of copper powder are initially-charged in 300 ml of dimethyl disulfide, and a solution of 200 g (1.32 mol) of 2-methyl-6-nitroaniline in 700 ml of dimethyl disulfide is added dropwise at 50-55° C. The mixture is then stirred at 75° C. for 8 hours. For work-up, the solid is filtered off with suction and the solution is diluted with methylene chloride and extracted with dilute hydrochloric acid. The organic phase is washed with saturated aqueous NaHCO3 solution, dried over sodium sulfate, filtered off and concentrated using a rotary evaporator. Excess dimethyl disulfide is removed under oil pump vacuum. This gives 271 g (99%) of a dark-red oil, purity according to HPLC 87%.
Reaction SMILES: [CH:1]1([N:4]2[CH2:16][C@@H:7]3[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][N:6]3[C:5]2=[O:17])[CH2:3][CH2:2]1.[CH3:18]C(C)CN>>[CH2:1]([N:4]1[CH2:16][C@@H:7]2[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][N:6]2[C:5]1=[O:17])[CH:3]([CH3:2])[CH3:18]
Reactant: CC(C)CN
Reactant: COC(=O)[C@@H]1NCCN2C(=O)N(C3CC3)C[C@H]12
Product: COC(=O)[C@@H]1NCCN2C(=O)N(CC(C)C)C[C@H]12

Procedure:
Compound 101-C was prepared in analogy to compound 82-C by using 2-methylpropan-1-amine instead of cyclopropylamine.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[N:8][CH:7]=1)([CH3:3])[CH3:2].[C:15]1(=O)[CH2:20]CC[CH2:17][CH2:16]1>>[NH2:12][C:10]1[C:9]2[N:8]([C:15]([CH3:20])=[C:16]([CH3:17])[N:13]=2)[CH:7]=[C:6]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:14])[CH:11]=1
Reactant: O=C1CCCCC1
Reactant: CC(C)OC(=O)c1cnc(N)c(N)c1
Product: Cc1nc2c(N)cc(C(=O)OC(C)C)cn2c1C
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 5,6-diamino-nicotinic acid isopropyl ester (1 eq., 5.1 g) in cyclohexanone (50 ml) bromobutanone (1.2 equiv., 3.4 ml) was added over 10 min. The dark brown mixture was heated to 100° C. (inner temperature) and stirred 1.5 h at this temperature. The suspension was cooled to room temperature and the pale yellow solid was filtered off and was washed with TBME (3×10 ml). Drying under reduced pressure at 45° C. Yield: 6.0 g (74%).