Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[O:11][CH2:12][C:13](=[O:20])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][CH:4]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[C:24]([CH:31]=O)=[CH:23]1.[ClH:33]>C(O)C>[ClH:33].[NH:22]1[C:30]2=[N:29][CH:28]=[CH:27][CH:26]=[C:25]2[C:24]([CH:31]=[C:12]2[O:11][C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[CH3:21])=[CH:4][CH:5]=3)=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:23]1
Reactant: CCOC(=O)C1=C(Nc2ccc(N(C)C)cc2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(N(C)C)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 35 %

Procedure:
To a solution of ethyl 2-{[4-(dimethylamino)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.073 g, 0.20 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.029 g, 0.20 mmol) in ethanol (1.5 mL), 2M hydrochloric acid in ethanol (0.33 mL, 0.66 mmol) was added at ambient temperature. The mixture was refluxed for 1 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.034 g, y. 35%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][CH3:12].[OH-].[K+].Br[C:16]1[CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:20][CH:21]=1.O>CN(C)C(=O)C>[F:23][C:22]([F:25])([F:24])[C:18]1[CH:17]=[C:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([S:9][CH2:10][CH2:11][CH3:12])[CH:4]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CCCSc1cc(O)ccc1C
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCSc1cc(Oc2cccc(C(F)(F)F)c2)ccc1C
Reaction time: 14 h

Procedure:
4-Methyl-3-(n-propylthio)phenol (8.4 g, 0.05 mole) and 85.5 % potassium hydroxide (3.3 g, 0.05 mole) were dissolved in N,N-dimethylacetamide (50 ml) above 90° C. 3-Bromotrifluoromethylbenzene (11.2 g, 0.05 mole) and Cu powder (0.5 g, 0.008 mole) were added to this solution below 90° C and the mixture was stirred at 110°-160° C for 14 hr. After cooling, the reaction mixture was poured into water (150 ml) and extracted twice benzene. The combined organic layers were washed with 5 % sodium hydroxide solution, 5 % hydrochloric acid solution, and water, then dried over sodium fulfate. The solvent was removed, and the residue was purified by column chromatography on silica gel using n-hexane benzene (2 : 1). The yield of 4-methyl-3-n-propylthiophenyl 3-trifluoromethylphenyl ether was 8.9 g (54.8 %), colorless oil, nD25 1.5319. Anal. Found: C, 62.61; H, 5.33. Calcd. for C17H17F3OS : C, 62.56; H, 5.25 %.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl[CH:8]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:8]2[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9]2)[CH:6]=1
Reactant: COC(=O)C1CC(Cl)C1
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C1CC(n2cc(Br)cn2)C1
Temperature: 70 °C

Procedure:
A mixture of 4-bromo-1H-pyrazole (500 mg, 3.40 mmol), methyl 3-chlorocyclobutanecarboxylate (607 mg, 4.08 mmol), and potassium carbonate (1.18 g, 8.50 mmol) in DMF (5 mL) was heated to 70° C. for 24 hours. The reaction mixture was cooled to ambient temperature and diluted with diethyl ether (200 mL). The mixture was washed with water (2×50 mL) and then brine (25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by column chromatography on silica (0-100% diethyl ether/hexanes) to afford methyl 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanecarboxylate (Isomer 1) and methyl 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanecarboxylate (Isomer 2). Methyl 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanecarboxylate (Isomer 1): MS ESI calc'd. for C9H12BrN2O2 [M+H]+ 259 and 261. found 259 and 261. 1H NMR (500 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.59 (s, 1H), 5.02-4.95 (m, 1H), 3.65 (s, 3H), 3.20-3.14 (m, 1H), 2.75-2.66 (m, 2H), 2.64-2.56 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][S:18]([CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:36][C:33]3[CH:32]=[CH:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:35][CH:34]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:20])=[O:19]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)(=O)Cc1ccccc1Nc1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(Nc5ccccc5CS(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
164 d) N(8)-(2-Methanesulfonylmethyl-phenyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepare from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonylmethyl-phenyl)-amine (75.0 mg, 0.223 mmol) and 4-(4-Methyl-piperazin-1-yl)-phenylamine (47.0 mg, 0.246 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.013 g, 12%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.96 (d, J=6.8 Hz, 1H), 7.70 (s, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.43-7.37 (m, 2H), 7.18 (t, J=7.4 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.83 (d, J=7.8 Hz, 1H), 6.70 (s, 1H), 6.67 (t, J=7.1 Hz, 1H), 4.45 (s, 2H), 3.18-3.13 (m, 4H), 2.94 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH:5]([C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1)[OH:6]>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[C:5]([C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]
Reactant: COCOc1cccnc1C(O)c1ccc(F)c(Br)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COCOc1cccnc1C(=O)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
A mixture of 2-(3-bromo-4-fluoro-α-hydroxy-benzyl)-3-methoxymethoxypyridine (14.0 g), activated manganese dioxide (41.8 g) and ethyl acetate (200 mL) was stirred overnight at room temperature, which was then subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was purified by means of a silica gel column (ethyl acetate--hexane) to afford 2-(3-bromo-4-fluorobenzoyl)-3-methoxymethoxypyridine (13.0 g) (compound B-5). Physical properties and spectrum data of the product are shown in Table 3 and Table 4.
Reaction SMILES: [C:1](=O)([O-])[NH2:2].[CH3:5][C:6]([CH3:8])=O.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])C>O1CCOCC1>[CH2:6]1[CH2:8][CH2:18][N:20]2[C:21](=[N:2][CH2:1][CH2:24][CH2:23]2)[CH2:22][CH2:5]1
Reactant: CC(C)=O
Reactant: CCN(CC)CC
Reactant: NC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1COCCO1
Product: C1CCC2=NCCCN2CC1

Procedure:
Namely, the substituted iminosulfonamide derivative (7) is reacted with the carbamate derivative (8) in a solvent such as acetone, acetonitrile or dioxane in the presence of an inorganic base such as potassium carbonate or an organic base such as triethylamine or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) to obtain the compound of the present invention (1:X=O).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:37][CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:13]([NH:15][C@H:16]([C:23]([NH:25][C@H:26](C=NNC(N)=O)[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24])[CH2:17][C:18]2[N:22]=[CH:21][NH:20][CH:19]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.C=O.[C:50](=[O:53])(O)[O-].[Na+]>CO>[C:1]1([CH2:11][CH:12]([CH2:37][CH2:38][CH2:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:13]([NH:15][C@H:16]([C:23]([NH:25][C@H:26]([CH:50]=[O:53])[CH2:27][CH:28]([CH3:29])[CH3:30])=[O:24])[CH2:17][C:18]2[N:22]=[CH:21][NH:20][CH:19]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])O
Reactant: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CCCCc1ccccc1)Cc1cccc2ccccc12
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)C[C@@H](C=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CCCCc1ccccc1)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1.82 g of N-[2-(1-naphthylmethyl)-6-phenylhexanoyl]-L-histidyl-L-leucinal semicarbazone in 80 ml of methanol were added 29 ml of 1N-hydrochloric acid and 7.6 ml of a 37 wt% formaldehyde solution while ice-cooling under an argon atmosphere. The mixture was stirred for 1.5 hours at room temperature, and then a 5% aqueous sodium bicarbonate solution was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.55 g of N-[2-(1-naphthylmethyl)-6-phenylhexanoyl]-L-histidyl-L-leucinal as a white powder.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20](Br)[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CC1(C)C(C)(C)OB([C:41]2[CH:42]=[C:43]3[CH:49]=[N:48][NH:47][C:44]3=[N:45][CH:46]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([C:41]3[CH:42]=[C:43]4[CH:49]=[N:48][NH:47][C:44]4=[N:45][CH:46]=3)[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC1(C)OB(c2cnc3[nH]ncc3c2)OC1(C)C
Reactant: Cc1cc2nc(Br)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
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: O
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3cnc4[nH]ncc4c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 100 °C

Procedure:
To a solution of (S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (51 mg, 0.095 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (28 mg, 0.123 mmol) in degassed 1,4-dioxane (250 μL) and water (25 μL) was added aqueous K2CO3 (95 μL of a 2.0 M solution) and tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol). The reaction mixture was heated at 100° C. for 6 h, cooled and partitioned between ethyl acetate and brine. The organic layer was separated, dried over Na2SO4 and concentrated. The crude material was used without any further purification. LCMS-ESI+: calc'd for C31H34ClN4O3S: 577.2 (M+H+); Found: 577.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH:10]([CH3:23])[C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][C:57]1[CH:58]=[C:59]([C:64]2[CH:69]=[CH:68][C:67]([C:70]#[N:71])=[C:66]([F:72])[CH:65]=2)[CH:60]=[CH:61][C:62]=1[NH2:63]>CN(C=O)C.O>[C:19]([O:18][C:16]([NH:15][C@H:11]([C:12]1[NH:63][C:62]2[CH:61]=[CH:60][C:59]([C:64]3[CH:69]=[CH:68][C:67]([C:70]#[N:71])=[C:66]([F:72])[CH:65]=3)=[CH:58][C:57]=2[N:56]=1)[C@@H:10]([CH3:23])[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:24])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: N#Cc1ccc(-c2ccc(N)c(N)c2)cc1F
Reactant: CC(C(=O)OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](C(=O)OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(-c3ccc(C#N)c(F)c3)ccc2[nH]1
Temperature: 0 °C

Procedure:
To a solution of (2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-3-methyl-4-oxobutanoic acid (Preparation 66, 713 mg, 2.11 mmol) in DMF (15 mL) was added NMM (267 mg, 2.64 mmol) and the mixture was cooled to 0° C. HATU (871 mg, 2.29 mmol) was added and the reaction stirred warming to room temperature for 2 hours. 3′,4′-diamino-3-fluoro-[1,1′-biphenyl]-4-carbonitrile (Preparation 81, 400 mg, 1.76 mmol) was added and the reaction stirred at room temperature for 18 hours. The reaction was diluted with water and extracted with EtOAc. The organic layer was collected, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 20-40% EtOAc in heptanes. The residue was dissolved in AcOH (10 mL) and heated to 40° C. for 2 days. The reaction was cooled and concentrated in vacuo, azeotroping with DCM to afford a foam. The residue was purified using silica gel column chromatography eluting with DCM:EtOAc 94:6 to afford the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:29])[NH:22][C:23]3[S:24][C:25]([Br:28])=[CH:26][N:27]=3)=[CH:17][C:16]=2[NH:30][C:31]2[C:32]3[CH:40]=[CH:39][C:38]([CH:41]([CH3:43])[CH3:42])=[N:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[S:24][C:25]([Br:28])=[CH:26][N:27]=3)=[O:29])=[CH:17][C:16]=2[NH:30][C:31]2[C:32]3[CH:40]=[CH:39][C:38]([CH:41]([CH3:43])[CH3:42])=[N:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ncc(Br)s4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ncc(Br)s4)ccc3Sc3ccc(N)cc3)ncnc2n1
Yield: 76 %

Procedure:
The product of Example 15B was reacted with trifluoroacetic acid using the procedure form Example 13E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title compound (120 mg, 76%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 3.15-3.30 (m, 1 H) 5.64 (s, 2 H) 6.65 (d, J=8.46 Hz, 2 H) 6.84 (d, J=8.46 Hz, 1 H) 7.15 (d, J=8.46 Hz, 2 H) 7.65 (d, J=8.46 Hz, 1 H) 7.64 (s, 1 H) 7.92 (dd, J=8.46, 1.84 Hz, 1 H) 8.10 (d, J=1.47 Hz, 1 H) 8.59 (s, 1 H) 8.89 (d, J=8.46 Hz, 1 H) 10.14 (s, 1 H) 12.85 (s, 1 H); MS (ESI+) m/z 592/594 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH2:10]([CH:12]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:16]=1[NH2:17])[CH2:13][CH3:14])[CH3:11]>C(O)C>[Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[N:17]/[C:16]2[C:18]([CH:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[CH:19][CH:20]=[CH:21][C:15]=2[CH:12]([CH2:10][CH3:11])[CH2:13][CH3:14])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CCC(CC)c1cccc(C(CC)CC)c1N
Solvent: CCO
Product: CCC(CC)c1cccc(C(CC)CC)c1/N=C/c1cccc(Br)n1

Procedure:
A mixture of 8.00 g (43 mmol) of 6-bromopyridine-2-carbaldehyde, 10.0 g (43 mmol) of 2,6-bis(1-ethylpropyl)aniline in 80 ml of ethanol was refluxed for 8 h. The obtained solution was evaporated to dryness and the residue was re-crystallized from 20 ml of methanol. Yield 11.2 g (65%) of yellow crystalline powder. Anal. calc. for C22H29BrN2: C, 65.83; H, 7.28; N, 6.98. Found: C, 66.01; H, 7.23; N, 6.90. 1H NMR (CDCl3): δ 8.21 (m, 1H, 5-H in Py), 8.15 (s, 1H, CH═N), 7.69 (m, 1H, 4-H in Py), 7.59 (m, 1H, 3-H in Py), 7.10 (m, 1H, 4-H in dipentylphenyl), 7.03-7.04 (m, 2H, 3, 5-H in dipentylphenyl), 2.48 (m, 2H, CHEt2), 1.54 (m, 8H, CH2Me), 0.74 (t, J=7.3 Hz, 12H, CH2Me).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH2:11][CH2:12][OH:13])=[CH:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]=12.[F:21][C:22]([F:32])([F:31])[O:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH2:11][CH2:12][O:13][C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:31])[F:32])=[CH:29][CH:28]=3)=[CH:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]=12
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)n1cc(CCO)c2ccnc(Cl)c21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1cc(CCOc2ccc(OC(F)(F)F)cc2)c2ccnc(Cl)c21
Reaction time: 0.33 h
Yield: 96.7 %

Procedure:
To a solution of tert-butyl 7-chloro-3-(2-hydroxyethyl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (233 mg, 0.79 mmol) in PhMe (15 mL) was added 4-trifluoromethoxyphenol (0.15 mL, 1.2 mmol), triphenylphosphine (309 mg, 1.2 mmol), and diisopropylazodicarboxylate (0.23 mL, 1.2 mmol) at r.t. After 20 min, the mixture was concentrated in vacuo, and the crude material was purified on silica (gradient elution, 0-30% EtOAc/hexanes) to yield the title product (349 mg). HRMS (ESI) calc (M+H)+=457.1136. found 457.1133.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16]([C:18]1([C@H:21]2[CH2:25][N:24]([C@H:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:27])[C:23](=[O:34])[CH2:22]2)[CH2:20][CH2:19]1)=[O:17])[CH3:14].[O:35]=O.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:13]([O:15][C:16]([C:18]1([C@H:21]2[CH2:25][N:24]([C@H:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH3:27])[C:23](=[O:34])[C@@H:22]2[OH:35])[CH2:19][CH2:20]1)=[O:17])[CH3:14]
Reactant: O=O
Reactant: CCOC(=O)C1([C@@H]2CC(=O)N([C@@H](C)c3ccccc3)C2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@@H]2O)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
Under a nitrogen atmosphere, diisopropylamine (3.93 ml, 28.0 mmol) was dissolved in anhydrous tetrahydrofuran (200 ml) to which, after cooling to -78° C., was subsequently added dropwise an n-hexane solution of 1.69 M n-butyl lithium (15.9 ml, 26.9 mmol) over a period of 10 minutes. After 20 minutes of stirring at 0° C. and subsequent cooling to -78° C., to the resulting reaction solution was added dropwise anhydrous tetrahydrofuran solution (40 ml) of 4-(S)-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]-2-pyrrolidone (6.74 g, 22.4 mmol) over a period of 15 minutes. The reaction solution was stirred at -78° C. for 10 minutes and then the reaction vessel was charged with dried oxygen at the same temperature. The reaction solution was stirred at -78° C. for 20 minutes and then mixed-with a saturated ammonium chloride aqueous solution (200 ml). This was warmed up to room temperature and the organic layer was separated. The aqueous layer was extracted with diethyl ether (200 ml×2), and the organic layers were combined and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=2:1, to thereby obtain 5.21 g (73%) of the title compound as a colorless oil.
Reaction SMILES: O[C:2]1([C:14]2[N:15]=[CH:16][N:17]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]#[N:13])[CH:5]=[CH:4][C:3]1=2.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:47]2)=CC=1>C1(C)C=CC=CC=1>[SH:47][C:2]1([C:14]2[N:15]=[CH:16][N:17]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]#[N:13])[CH:5]=[CH:4][C:3]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#Cc1ccc2c(c1)CCCC2(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)CCCC2(S)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C

Procedure:
A solution of 1 mmol of 5-hydroxy-5-(1-trityl-1H-imidazol-4-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (Example 1d1) and 0.5 mmol of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulphide (Lawesson's reagent) [19172-47-5] in 10 ml of toluene is heated to reflux for 2 hours. The reaction mixture is cooled to room temperature and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH:20]([CH2:24][OH:25])[CH2:21]2)=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH:20]([CH2:24][O:25][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:21]2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)CC(CO)CC2
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CC(COS(=O)(=O)c1ccc(C)cc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20.96 g (110 mmol) of p-toluenesulphonic acid chloride are added at room temperature, while stirring, to a solution of 19.2 g (100 mmol) of 7-methoxy-1,2,3,4-tetrahydro-naphthalene-2-methanol in 80 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature with an ice bath. The reaction mixture is stirred at room temperature for 1 hour to complete the reaction and is then diluted with ice-water and extracted with diethyl ether. The organic phase is washed while ice-cold with 2N hydrochloric acid and water, is dried over sodium sulphate, filtered and concentrated by evaporation under reduced pressure. The resulting oil is crystallised from diethyl ether/pentane to yield p-toluenesulphonic acid (7-methoxy-1,2,3,4-tetrahydro-naphth-2-ylmethyl) ester of m.p. 64°-66°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[C@@:10]([C:14](O)=[O:15])([CH2:11]2)[C@@H:9]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>>[CH2:1]([N:8]1[CH2:13][CH:12]2[C@@:10]([C:14]([Cl:25])=[O:15])([CH2:11]2)[C@@H:9]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@]12CC1CN(Cc1ccccc1)[C@H]2c1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)[C@@]12CC1CN(Cc1ccccc1)[C@H]2c1ccccc1

Procedure:
To racemic Intermediate 39, one enantiomer being (1S,2S)-3-benzyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (0.16 g, 0.56 mmol) was added thionyl chloride (2 mL) dropwise with stirring. The homogeneous solution was refluxed gently for 2 hours. The solvent was removed at reduced pressure to yield the title compound (0.17 g, quantitative yield) as an oil, which was used without further purification.