Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:8]2[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)#[N:2].[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[NH4+].O>CS(C)=O>[CH2:15]([C:10]1[C:9]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:8]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:3][C:1]3[N:35]=[N:36][NH:37][N:2]=3)[CH:6]=2)[N:11]=1)[CH:16]([CH3:17])[CH3:18]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCC#N)cc23)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCc4nn[nH]n4)cc23)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 93.5 %

Procedure:
To a solution of tert-butyl {[6-(cyanomethoxy)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.46 g, 1.0 mmol) and sodium azide (0.13 g, 2.0 mmol) in dimethyl sulfoxide (10 ml) was added ammonium chloride (0.22 g, 4.0 mmol), and the mixture was stirred at 70° C. for 24 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give tert-butyl {[2-isobutyl-4-(4-methylphenyl)-6-(2H-tetrazol-5-ylmethoxy)quinolin-3-yl]methyl}carbamate (0.47 g, yield 93%) as pale-yellow crystals.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]3[N:11]([C:16]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[F:28])=[O:20])=[CH:17][N:18]=3)[N:12]=[C:13](Cl)[CH:14]=2)[CH:5]=[CH:4][CH:3]=1.[C@H:29]1([NH2:36])[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]1>CN1C(=O)CCC1>[NH2:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([NH:36][C:13]2[CH:14]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)[C:10]3[N:11]([C:16]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[F:28])=[O:20])=[CH:17][N:18]=3)[N:12]=2)[CH2:30][CH2:31]1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Nc3cccc(Br)n3)cc(Cl)nn12
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CN1CCCC1=O
Product: N[C@H]1CC[C@H](Nc2cc(Nc3cccc(Br)n3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 100 °C

Procedure:
A mixture of 8-(6-bromopyridin-2-ylamino)-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 17A (550 mg, 1.189 mmol) and trans-cyclohexane-1,4-diamine (1.086 g, 9.51 mmol) in NMP (4 mL) was heated at 100° C. overnight. The reaction mixture was cooled to room temperature, and then added to ice water. The yellow solid was collected by filtration, and rinsed with water. The still wet solid pad was azeotroped with DCM/MeOH three times. The resulting solid residue was treated with a small amount of MeOH, filtered and dried to give 17B (456 mg, 71%) as a yellow solid. MS (m+1)=540. HPLC Peak Rt=2.870 minutes. (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33]>>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([C:28]([F:27])([F:38])[F:39])[CH:30]=2)[CH2:7]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc(C(F)(F)F)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-(trifluoromethyl)-benzoic acid acid.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[BrH:20]>O.C(O)C>[Br:20][C:6]1[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COC(=O)c1cc(N)cc2ccccc12
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(Br)cc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4.34 g (62.9 mmol) of sodium nitrite in 40 mL of water was added dropwise to a 0° C. solution of 11.5 g (57.2 mmol) of methyl 3-amino-1-naphthoate in 300 mL of ethanol and 60 mL of 48% aqueous hydrobromic acid while maintaining an internal reaction temperature below 10° C. After complete addition of the aqueous solution the resulting dark red reaction mixture was stirred at 0° C. for an additional 30 min. The cooled (0° C.) reaction mixture was then added over 20 min. to a suspension of 8.21 g (57.2 mmol) of cuprous bromide in 60 mL of ethanol and 60 mL of 48% aqueous hydrobromic acid heated to 95° C. After stirring for 30 min. the reaction mixture was cooled to 0° C. and carefully partitioned between ethyl ether (250 mL) and water (600 mL). The organic layer was separated and the aqueous layer was extracted with ethyl ether (2×300 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was passed through a plug of silica gel eluting with 30% dichloromethane in hexanes and the filtrate concentrated in vacuo. Flash chromatography on a Biotage® purification apparatus (silica gel, 7% dichloromethane/hexanes) yielded the title compound as a colorless solid. 1H NMR (DMSO-d6): δ 8.67 (d, J=8.4 Hz, 1 H), 8.50 (s, 1 H), 8.15 (s, 1 H), 8.02 (d, J=8.0 Hz, 1 H), 7.68-7.71 (m, 1 H), 7.63-7.66 (t, J=7.6 Hz, 1 H), 3.94 (s, 3H). LC/MS 265.0 (M+1) and 267.0 (M+3).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH2:29].CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH:29][CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1
Reactant: Nc1ccc(F)cc1F
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCNc2ccc(F)cc2F)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), 2,4-difluoroaniline (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. The crude product is purified by HPLC to give 7-(2-(2,4-difluorophenylamino)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=396.53).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][NH:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:2].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>N1C=CC=CC=1>[CH2:9]([O:8][N:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CCCCCNOCc1ccccc1
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCC(=O)O
Temperature: 100 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
N-Benzyloxy-N-(4-cyanobutyl)succinamic acid (6) was synthesized by charging a flask with 2.8 g (13.7 mmol) of (5) in 23 mL of pyridine and 2.1 g (20.8 mmol) of succinic anhydride, heated at 100° C. for 1.5 hours and then allowed to cool to room temperature and to stir overnight. The pyridine was removed under vacuum and the residue was dissolved in a is minimal amount of chloroform and filtered. The chloroform was removed and the residue was dissolved in ether, which was extracted three times with 20% potassium bicarbonate (3×50 mL). The aqueous solutions were combined, acidified and extracted with ether. This solution was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was then chromatographed on 70-230 mesh silica gel by eluting with 5% methanol in chloroform to give 4.12 g (98%) of (6): NMR δ 1.56-1.7 (m, 2 H), 1.7-1.97 (m, 2 H), 2.36 (to 2 H), 2.60-2.80 (m, 4 H); 3.68 (t, 2 H), 4.85 (s, 2 H), 7.4 (s, 5 H); IR (CHCl3) 3670, 2930, 2240, 1710, 1650, 1415, 1200 cm-1. Anal. calcd. for C16H20N2O4 : C, 63.17; H, 6.64. Found: C, 63.36; H, 6.74. A sample of (6) was crystallized from hexane/EtoAc, mp 71° C.
Reaction SMILES: NC1C2C[C:9](C)(C)[O:10]C=2C(C(OC)=O)=CC=1.N[C:18]1[C:23]2[CH2:24][C:25]([CH3:28])([CH3:27])[O:26][C:22]=2[C:21]([C:29]([OH:31])=[O:30])=[CH:20][C:19]=1[Cl:32]>>[Cl:32][C:19]1[CH:20]=[C:21]([C:29]([OH:31])=[O:30])[C:22]2[O:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]=2[C:18]=1[O:10][CH3:9]
Reactant: CC1(C)Cc2c(N)c(Cl)cc(C(=O)O)c2O1
Reactant: COC(=O)c1ccc(N)c2c1OC(C)(C)C2
Product: COc1c(Cl)cc(C(=O)O)c2c1CC(C)(C)O2

Procedure:
Following the same procedure, 19.9 g of methyl 4-amino-2,2-dimethyl-2,3-dihydro-7-benzofurancarboxylate was transformed into 20.1 g of 4-amino-5-chloro-2,2-dimethyl-2,3-dihydro-7-benzofurancarboxylic acid, m.p. 176°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[NH2:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=O>>[Cl:25][C:23]1[CH:24]=[C:16]2[C:17]([C:18](=[O:20])[N:12]([S:9]([C:3]3[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[C:13](=[O:14])[NH:15]2)=[CH:21][CH:22]=1
Reactant: O=C=NS(=O)(=O)c1cc(Cl)ccc1Cl
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1S(=O)(=O)c1cc(Cl)ccc1Cl
Yield: 59.1 %

Procedure:
1.12 g (4.42 mmol) of 2,5-dichlorobenzenesulfonylisocyanate and 882 mg (4.42 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 1.06 g of the above-identified compound (yield 58.6%). Properties: colorless crystal, Melting point: 254°-256° C., PMR (δppm, DMSO-d6):7.17 (1H,s), 7.24 (1H,d), 7.71 (1H,d), 7.80-7.89 (2H,m), 8.18 (1H,s).
Reaction SMILES: [O-:1][N+:2]1[O:6][N:5]=[C:4]([O:7][CH2:8][CH2:9][C:10]([NH:12][C@@H:13]([CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[C:14]([O:16]C(C)(C)C)=[O:15])=[O:11])[C:3]=1[S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31]>ClCCl.C(O)(C(F)(F)F)=O>[O-:1][N+:2]1[O:6][N:5]=[C:4]([O:7][CH2:8][CH2:9][C:10]([NH:12][C@@H:13]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14]([OH:16])=[O:15])=[O:11])[C:3]=1[S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)(=[O:31])=[O:32]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)CCOc1no[n+]([O-])c1S(=O)(=O)c1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC[C@H](NC(=O)CCOc1no[n+]([O-])c1S(=O)(=O)c1ccccc1)C(=O)O

Procedure:
A solution of the compound obtained in Step A (3 g-5.5 mmol) in 100 ml of dichloromethane and 15 ml of TFA is stirred for 6 hours under argon. The solvents are distilled off in vacuo. The residue is triturated in diisopropyl ether, filtered off with suction and then dried in vacuo to yield the expected product in the form of white crystals.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]1[CH2:64][CH2:63][CH:62]([NH2:65])[CH2:61][CH2:60]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:65][CH:62]5[CH2:63][CH2:64][N:59]([CH3:58])[CH2:60][CH2:61]5)=[O:28])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCOc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (t, J=6.7 Hz, 3 H) 1.60 (m, 6 H) 1.74 (m, 4 H) 1.95 (m, 4 H) 2.18 (s, 3 H) 2.79 (d, J=10.6 Hz, 2 H) 3.73 (m, 1 H) 4.05 (t, J=13.9 Hz, 2 H) 4.19 (d, J=7.1 Hz, 2 H) 4.74 (m, 1 H) 7.40-7.59 (m, 2 H) 7.91 (s, 1 H) 8.11 (d, J=7.6 Hz, 1 H) 8.26 (m, 2 H). [M+H] calc'd for C28H37F2N7O3, 558; found 558.
Reaction SMILES: [C:1]([C@@H:4]([C@H:8]1[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9]1)[CH2:5][CH:6]=[CH2:7])([OH:3])=O.ON1C2N=CC=CC=2N=N1.Cl.CN(CCCN=C=NCC)C.Cl.[NH2:39][C@@H:40]([C:52]([CH3:55])([CH3:54])[CH3:53])[C:41]([NH:43][C@@H:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH3:45])=[O:42].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:14][C:10]1([CH3:15])[O:9][C@@H:8]([C@@H:4]([CH2:5][CH:6]=[CH2:7])[C:1]([NH:39][C@H:40]([C:41]([NH:43][C@@H:44]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH3:45])=[O:42])[C:52]([CH3:53])([CH3:54])[CH3:55])=[O:3])[C:12](=[O:13])[O:11]1
Reactant: C[C@@H](NC(=O)[C@@H](N)C(C)(C)C)c1ccccc1
Reactant: C=CC[C@@H](C(=O)O)[C@@H]1OC(C)(C)OC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C)[C@@H]1OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A portion of the crude (4S)-4-[(1R)-1-carboxy-but-3-enyl]-2,2-dimethyl-1,3-dioxolan-5-one from b) above (calculated from the NMR to contain 1.54 g, 7.19 mmol) and 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (1.09 g, 7.55 mmol) in anhydrous dichloromethane (30 mL) were mixed and cooled to 0° C. under nitrogen. N-(Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.60 g, 8.27 mmol) was added, and the mixture was stirred for 1.5 h at 0° C. (2S)-Amino-3,3-dimethyl-N-[(1R)-1-phenylethyl]butanamide hydrochloride (Preparation 1)(2.15 g, 7.55 mmol) was added, followed by diisopropylethylamine (1.37 mL, 7.55 mmol). After another 45 min, the mixture was allowed to warm to room temperature. After 3 h at room temperature, the mixture was partitioned between ethyl acetate (200 mL) and pH 7 aqueous phosphate buffer (100 mL). The organic layer was washed with sodium bicarbonate, brine, dried (Na2SO4), and concentrated under reduced pressure. The resulting foam crystallised upon addition of ether, and the white solid (1.89 g) was filtered off. Recystallisation from ethyl acetate/hexane gave (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-N-[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]pent-4-enamide as a white solid (1.30 g, 42%, as a single diastereomer).
Reaction SMILES: [F:1][CH:2]([F:16])[C@H:3]1[CH2:8][C@H:7]([OH:9])[C@H:6]([NH:10]C(=O)C)[C@@H:5]([OH:14])[C@@H:4]1[OH:15].[OH-].[Na+]>CCO.O>[NH2:10][C@H:6]1[C@@H:7]([OH:9])[CH2:8][C@H:3]([CH:2]([F:1])[F:16])[C@@H:4]([OH:15])[C@@H:5]1[OH:14]
Reactant: CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](C(F)F)C[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](C(F)F)C[C@@H]1O
Yield: 30.8 %

Procedure:
To a solution of N-((1S,2R,3R,4S,6S)-4-(difluoromethyl)-2,3,6-trihydroxycyclohexyl)acetamide (176 mg, 1.48 mmol) in EtOH (2 mL) and water (3 mL) was added NaOH (736 mg, 18.4 mmol). The mixture was heated at reflux for 2 h. Solvents were evaporated and the residue was purified by silica gel column chromatography, eluted with 20% 2 M NH3 MeOH solution in DCM to give the product (1R,2R,3S,4S,6S)-3-amino-6-(difluoromethyl)cyclohexane-1,2,4-triol (90.0 mg, 62%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]=[C:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH2:22][CH2:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[N:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C>CO.[Pd]>[C:7]1([CH:6]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([CH2:22][CH2:23][CH2:24][C:25]4[CH:34]=[CH:33][C:32]5[CH2:31][CH2:30][CH2:29][NH:28][C:27]=5[N:26]=4)=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH2:5][C:4]([OH:35])=[O:3])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C=C(c1ccccc1)n1ccc2cc(CCCc3ccc4cccnc4n3)ccc21
Agent: [Pd]
Solvent: CO
Product: O=C(O)CC(c1ccccc1)n1ccc2cc(CCCc3ccc4c(n3)NCCC4)ccc21
Yield: 9.4 %

Procedure:
3-[5-(3-[1,8]Naphthyridin-2-yl-propyl)-indol-1-yl]-3-phenyl-acrylic acid ethyl ester (30.0 mg, 0.484 mmol) in methanol (2 mL) was stirred under hydrogen in the presence of 10% palladium on carbon (15.0 mg) at room temperature for 3 days. Then, the reaction mixture was filtered through celite and purified via column chromatography on silica gel (methylene chloride/methanol) (95/5) to give the title product as yellow oil (20.0 mg, 66% yield). 1H NMR (CDCl3) δ 8.2 (d, 1H), 8.0 (m, 1H), 7.45 (m, 2H), 7.27 (m, 2H), 6.9-7.2 (m, 4H), 6.5 (1H), 6.3 (1H), 6.20 (m, 1H), 6.10 (m, 1H), 4.15 (m, 2H), 3.4 (m, 2H), 3.3 (m, 4H), 2.6 (m, 4H), 2.1 (m, 2H), 1.89 (m, 2H). Mass Spectrum (LCMS, ESI) calculated for C30H34N3O2 468.27 (M+H); found 468.3.
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.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:22]=[CH:23][C:24]#[N:25])(=[O:21])=[O:20])=[CH:15][CH:14]=1.N1C=CC=CC=1>>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH:22]=[CH:23][C:24]#[N:25])(=[O:21])=[O:20])=[CH:17][CH:18]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(S(=O)(=O)C=CC#N)cc2)cc1

Procedure:
4.9 grams (0.025 mol) of para-toluenesulfonyl chloride, and 4.5 g (0.025 mol) of 3-(4-aminobenzenesulfonyl) acrylonitrile in chlorofrom are reacted for 48 hours at room temperature in the presence of 2.2 ml (0.027 mol) of pyridine, and the reaction mixture is worked up as in Example 1. The product, recrystallized from ethanol, and having a melting point of 172°-175° C, is 3-[4-(4-methylbenzenesulfonamido)benzenesulfonyl]acrylonitrile: ##SPC13##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][N:12]([C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=3)[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: Brc1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccc(Br)cn3)CC2C1
Temperature: 90 °C
Yield: 62 %

Procedure:
To a solution of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (7.0317 g, 33.2 mmol) in 180 mL toluene was added 2,5-dibromopyridine (22.03 g, 92.9 mmol), tris(dibenzylidenacetone)dipalladium (0) (Pd2(dba)3, Strem, 0.6087 g, 0.664 mmol), 2,2′-bis(diphenyphosphino)-1,1′binaphthyl (BINAP, Aldrich, 1.0506 g, 1.68 mmol), and NaOtBu (Aldrich, 4.778 g, 49.7 mmol. The reaction mixture was heated to 90° C. under dry N2 for 6 hours. The reaction mixture was cooled to room temperature and was filtered through diatomaceous earth and the residue was washed with 250 mL ethyl acetate. The combined organic extracts were concentrated under reduced pressure. The residue was purified via column chromatography (SiO2, gradient 5% to 60% EtOAc-hexanes) to give 7.71 g (20.6 mmol, 62% yield). H NMR (300 MHz) δ 1.45 (s, 9H) 2.94-3.14 (m, 2H) 3.17-3.38 (m, 4H) 3.51-3.76 (m, 4H) 6.46 (d, J=9 Hz, 1H) 7.59 (dd, J=9, 3 Hz, 1H) 8.05 ppm (s, 1H)
Reaction SMILES: Cl[CH:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([Br:16])[CH:10]=2)=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:4][NH:3]1.[OH-:21].[K+]>C(O)(C)(C)C>[Br:16][C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([Br:15])[CH:12]=1)[O:8][C:7]1[C:2](=[O:21])[NH:3][CH:4]=[CH:5][C:6]=1[C:17]([F:20])([F:19])[F:18]
Reactant: [OH-]
Reactant: FC(F)(F)C1=C(Oc2cc(Br)cc(Br)c2)C(Cl)NC=C1
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-chloro-3-(3,5-dibromophenoxy)-4-(trifluoromethyl)-1,2-dihydropyridine (1.64 g, 3.80 mmol) and potassium hydroxide (0.640 g, 11.4 mmol) were dissolved in tert-butanol in a round bottom flask and placed in an oil bath at 75° C. under N2. After 16 hours, the reaction mixture was allowed to cool to room temperature and quenched with saturated aqueous ammonium chloride (25 mL). This mixture was diluted with water (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (2×50 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to give the title compound as a white solid. 1H NMR (DMSO-d6) δ 12.68 (s, 1H), 7.58 (d, J=6.8 Hz, 1H), 7.54-7.52 (m, 1H), 7.24-7.22 (m, 2H), 6.47 (d, J=Hz, 1H). LRMS (M+1)=413.5.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[CH:10]=[O:11].[BH4-].[Na+].O>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[CH2:10][OH:11]
Reactant: Cn1cc([N+](=O)[O-])cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1cc([N+](=O)[O-])cc1CO
Reaction time: 0.33 h
Yield: 97.9 %

Procedure:
1-Methyl-4-nitro-1H-pyrrole-2-carbaldehyde (0.400 g, 2.08 mmol; see step (i) above) was placed in 50 mL of anhydrous ethanol under N2. NaBH4 (0.040 g, 1.04 mmol) was added in small portions over 5 min and the solution allowed to stir for 20 min. Water (10 mL) was added slowly to quench the reaction. The organics were then extracted with ethyl acetate (2×20 mL) and the resultant organic fractions dried (MgSO4), filtered and the solvent removed under reduced pressure to yield the sub-title compound as a light brown solid (0.318 g, 98%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13](=[O:15])[CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([NH:12][C:13](=[O:15])[CH3:14])[C:4]=2[N:3]=1
Reactant: CC(=O)Nc1cccc2ccc(C)nc12
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NC1CCCc2ccc(C)nc21
Yield: 56.7 %

Procedure:
Reaction of N-(2-methyl-quinol-8-yl)acetamide (159 mg, 0.795 mmol) using the general procedure for small scale hydrogenations (workup with NaOH in place of saturated NaHCO3) provided N-(2-methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamide (92 mg, 57%): 1H NMR δ 1.57-1.66 (m, 1H), 1.77-1.86 (m, 2H), 2.02 (s, 3H), 2.44 (s, 3H), 2.43-2.57 (m, 1H), 2.68-2.73 (m, 2H), 4.67-4.74 (m, 1H), 6.79 (br s, 1H), 6.92 (d, 1H, J=8 Hz), 7.24 (d, 1H, J=8 Hz); 13C NMR δ 21.6, 25.4, 25.8, 29.6, 31.0, 53.0, 123.4, 131.4, 139.2, 155.9, 157.2, 172.2; MS m/z: 227 (M+Na+). N-(2-Methyl-1,2,3,4-tetrahydroquinolin-8-yl)acetamide also was isolated (25 mg, 15%) as a tautomeric mixture of acyclic and cyclized isomers in an approximately 1:2 ratio which exhibited the following data: 1H NMR δ 1.21-1.25 (m), 1.45-1.61 (m), 1.90 (s), 1.90-1.95 (m), 2.20 (s), 2.71-2.91 (m), 3.32-3.43 (m), 4.00 (br s), 6.56 (dd, J=8, 8 Hz), 6.63 (dd, J=8, 8 Hz), 6.66 (br s), 6.83 (d, J=8 Hz), 6.87 (d, J=8 Hz), 6.94 (d, J=8 Hz), 7.02 (d, J=8 Hz), 7.06 (br s); MS m/z: 205 (M+H+).