Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:34][C:35]1[N:36]=[N:37][CH:38]=[CH:39][N:40]=1>N1C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:34][C:35]2[N:36]=[N:37][CH:38]=[CH:39][N:40]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nccnn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: O=C(Nc1nccnn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 8 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 400 mg, 1.40 mmol) in dry pyridine (5 mL) was treated with 1,3-dicyclohexylcarbodiimide (316 mg, 1.53 mmol). The reaction mixture was stirred at 25° C. for 3.5 h and then treated with 3-amino-1,2,4-triazine (296 mg, 3.08 mmol) and an additional amount of pyridine (1 mL). The reaction mixture was warmed at 100° C. for 20 h. The reaction mixture was concentrated in vacuo to remove pyridine. The resulting residue was diluted with ethyl acetate then filtered. The filtrate was washed with a 1N aqueous hydrochloric acid solution and washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,2,4]triazin-3-yl-propionamide (40.9 mg, 8%) as a yellow-orange solid: mp 81–83° C.; EI-HRMS m/e calcd for C17H18Cl2N4O (M+) 364.0858, found 364.0857.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:18]([C:19]3[O:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[C@@H:17]3[C:12]([C:13]4[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[CH3:33][S:34]([CH2:37][CH2:38][NH2:39])(=[O:36])=[O:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:18]([C:19]3[O:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[C@@H:17]3[C:12]([C:13]4[CH:28]=[CH:27][C:26]([C:29]([NH:39][CH2:38][CH2:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:31])=[CH:25][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CS(=O)(=O)CCN
Reactant: Cc1ccc([C@H]2[C@H]3CCc4cc(C(=O)O)ccc4C3=NN2c2ccc(C#N)c(Cl)c2)o1
Agent: Cl
Product: Cc1ccc([C@H]2[C@H]3CCc4cc(C(=O)NCCS(C)(=O)=O)ccc4C3=NN2c2ccc(C#N)c(Cl)c2)o1
Yield: 70 %

Procedure:
The title compound was prepared from (3R,3aR)-2-(3-chloro-4-cyanophenyl)-3-(5-methyl-2-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 40, and 2-(methylsulfonyl)ethanamine hydrochloride according to Method F (35 mg, 70% yield). 1H NMR (400 MHz, DMSO-d6) water_suppression, δ ppm 1.19-1.21 (m, 1H), 1.91 (d, J=9.88 Hz, 1H), 2.07 (s, 3H), 2.96 (d, J=16.84 Hz, 2H), 3.01 (s, 3H), 3.63-3.66 (m, 2H), 3.86 (br. s., 1H), 5.92 (d, J=16.47 Hz, 1H), 5.95 (br. s., 1H), 6.27 (d, J=2.93 Hz, 1H), 7.06 (br. s., 1H), 7.33 (br. s., 1H), 7.65-7.74 (m, 3H), 8.08 (d, J=8.05 Hz, 1H), 8.77 (t, J=5.49 Hz, 1H); ES-MS m/z 537 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:22])=[O:21].[C:15]1([S:20]([NH2:2])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=1
Reactant: CNCCC#Cc1ccccn1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: CN(CCC#Cc1ccccn1)S(=O)(=O)c1ccccc1Cl
Product: NS(=O)(=O)c1ccccc1
Yield: 35 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2-chlorobenzene-1-sulfonyl chloride (79 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 37 mg of 2-chloro-N-methyl-N-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide as a brown oil (Yield: 35%).
Reaction SMILES: [CH2:1]([CH2:4][SH:5])[CH2:2][NH2:3].Cl.Cl.O[CH2:9][C:10]1[N:11]=[CH:12][NH:13][C:14]=1[CH3:15].[BrH:16]>>[BrH:16].[BrH:16].[CH3:15][C:14]1[N:13]=[CH:12][NH:11][C:10]=1[CH2:9][S:5][CH2:4][CH2:1][CH2:2][NH2:3]
Reactant: Cc1[nH]cnc1CO
Reactant: NCCCS
Agent: Br
Agent: Cl
Product: Cc1nc[nH]c1CSCCCN

Procedure:
A solution of homocysteamine hydrochloride (22.0 g.) and 4-hydroxymethyl-5-methylimidazole hydrochloride (25.6 g.) in aqueous hydrobromic acid (500 ml.) was heated under reflux for one hour. Concentration under reduced pressure, followed by recrystallisation from methanol-isopropyl alcohol afforded 4-methyl-5-[(3-aminopropyl)thiomethyl]-imidazole dihydrobromide (24.5 g.), m.p. 200.5°-202.5°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH:9]([C:25]#[N:26])[CH2:10][CH2:11][C:12]([O:23][CH3:24])([CH3:22])[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH2:28][OH:29]>CO>[Si:15]([O:14][CH2:13][C:12]([O:23][CH3:24])([CH3:22])[CH2:11][CH2:10][CH:9]([N:7]([CH3:8])[C:6](=[O:27])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:25]([NH:28][OH:29])=[NH:26])([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17]
Reactant: COC(C)(CCC(C#N)N(C)C(=O)OC(C)(C)C)CO[Si](C)(C)C(C)(C)C
Reactant: NO
Solvent: CO
Product: COC(C)(CCC(C(=N)NO)N(C)C(=O)OC(C)(C)C)CO[Si](C)(C)C(C)(C)C
Temperature: 40 °C

Procedure:
To a solution of tert-butyl(5-{[tert-butyl(dimethyl)silyl]oxy}-1-cyano-4-methoxy-4-methylpentyl)methylcarbamate (4.37 kg, 10.91 mol) in MeOH (28 L) at 30° C. was added aqueous hydroxylamine (50% in water, 1.2 L, 19.63 mol). The resulting mixture was heated to 40° C. overnight, then cooled and concentrated in vacuo. The crude residue was dissolved in 1.5 L of toluene, concentrated under reduced pressure, and dried in vacuo. The crude material was used in the next step without further purification. LC-MS: 434.3.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]2[CH:14]=1)([CH3:3])[CH3:2].Cl[S:16]([O:19][Si](C)(C)C)(=[O:18])=[O:17]>ClC(Cl)C>[C:12]([C:10]1[CH:9]=[CH:8][N:7]2[C:14]([S:16]([OH:19])(=[O:18])=[O:17])=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]2[CH:11]=1)#[N:13]
Reactant: C[Si](C)(C)OS(=O)(=O)Cl
Reactant: CC(C)c1cn2ccc(C#N)cc2n1
Solvent: CC(Cl)Cl
Product: CC(C)c1nc2cc(C#N)ccn2c1S(=O)(=O)O
Temperature: 100 °C
Yield: 94.6 %

Procedure:
The 2-isopropylimidazo[1,2-a]pyridine-7-carbonitrile (2.00 g, 10.8 mmol) obtained in step 1 of Example 7 was dissolved in dichloroethane (22 mL). Under ice-cooled condition, trimethylsilyl chlorosulfonate (4.08 g, 21.6 mmol) was added, and the mixture was stirred at 100° C. for hours. The solvent was evaporated under reduced pressure, and the residue was slurried in heptane. The resulting crystals were collected by filteration to give 7-cyano-2-isopropylimidazo[1,2-a]pyridine-3-sulfonic acid (2.71 g, yield 95%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:11]([OH:13])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:45][C:46]1([CH2:50][C:51]([NH2:53])=[O:52])[CH2:49][O:48][CH2:47]1>CN(C=O)C.C(OCC)(=O)C>[C:51]([CH2:50][C:46]1([NH:45][C:11]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([CH:8]3[CH2:9][CH2:10]3)=[CH:6][N:5]=2)=[O:13])[CH2:49][O:48][CH2:47]1)(=[O:52])[NH2:53]
Reactant: NC(=O)CC1(N)COC1
Reactant: O=C(O)c1cc(Cl)c(C2CC2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)CC1(NC(=O)c2cc(Cl)c(C3CC3)cn2)COC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 25.6 %

Procedure:
To a solution of 4-chloro-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48b, 200 mg, 1.01 mmol) in DMF (4.0 ml) were added TBTU (357 mg, 1.11 mmol) and DIEA (654 mg, 866 μl, 5.06 mmol) and the reaction mixture was stirred at room temperature for 20 minutes. Addition of 2-(3-aminooxetan-3-yl)acetamide (158 mg, 1.21 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and extracted with water. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica, eluting with a ethyl acetate/heptane gradient to yield the title compound (80 mg, 26%) as a yellow solid. MS (ESI, m/z): 310.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]([C:19]([OH:21])=O)=[CH:9]2)=[CH:5][CH:4]=1.Cl.[CH3:25][NH:26][O:27][CH3:28].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(#N)C>[CH3:28][O:27][N:26]([CH3:25])[C:19]([C:10]1[C:11](=[O:18])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]([CH2:7][C:6]2[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:9]=1)=[O:21]
Reactant: CNOC
Reactant: COc1ccc(Cn2cc(C(=O)O)c(=O)c3ccccc32)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(Cn2cc(C(=O)N(C)OC)c(=O)c3ccccc32)cc1

Procedure:
Experimental conditions analogous to those described for Step 5 of Example 60, from crude 1-(4-Methoxy-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 1.03 g (10.6 mmol) of N,O-dimethylhydroxylamine hydrochloride, 6.1 mL (4.43 g, 43.8 mmol) of triethylamine and 6.3 mL (6.80 g, 10.7 mmol) of 50% 1-propanephosphonic acid cyclic anhydride in 30 mL acetonitrile to give 1.90 g of the product as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]([NH:21][C:22](=[O:40])[CH2:23][NH:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]3[NH:35][CH2:36][CH2:37][CH2:38][N:39]=3)[CH:28]=2)=[O:26])[CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:13]([Cl:15])[CH:14]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:53]([OH:65])[CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63]O>CC(N(C)C)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]([NH:21][C:22](=[O:40])[CH2:23][NH:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]3[NH:39][CH2:38][CH2:37][CH2:36][N:35]=3)[CH:28]=2)=[O:26])[CH2:17][C:18]([O:20][CH2:63][CH2:62][O:61][CH2:60][CH2:59][O:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53][OH:65])=[O:19])[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: O=C(O)CC(NC(=O)CNC(=O)c1cccc(NC2=NCCCN2)c1)c1cc(Cl)cc(Cl)c1
Reactant: OCCOCCOCCOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cccc(NC2=NCCCN2)c1)NC(CC(=O)OCCOCCOCCOCCO)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To the product of Example 200 (200 mg, 0.00033 mole) in DMA (1.5 mL) was added carbonyldiimidazole (67 mg, 0.00041 mole). The reaction was stirred at room temperature for 1 hour. Tetraethyleneglycol (214 mg, 0.0011 mole) was then added and the reaction mixture was stirred overnight at 60° C. The reaction was cooled to room temperature and the product was isolated by RPHPLC to yield the title compound (120 mg after lyophilization) as a hygroscopic white solid. MS and NMR were consistent with the desired structure.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:27]=[O:28])[CH2:2][CH2:3][CH3:4].[Se](=O)=[O:30].C(OCC)(=O)C.CCCCCC>C(O)(=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([C:18](=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:27]=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc2c(C=O)cnc(Cc3cccc(OC)c3)c2cc1OC
Reactant: O=[Se]=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCCCOc1cc2c(C=O)cnc(C(=O)c3cccc(OC)c3)c2cc1OC
Temperature: 120 °C
Yield: 62.8 %

Procedure:
To a stirred solution of 6-butoxy-7-methoxy-1-(3-methoxy-benzyl)-isoquinoline-4-carbaldehyde (200 mg, 0.53 mmol) in acetic acid (5 mL) was added selenium dioxide (175 mg, 1.58 mmol). The reaction mixture was heated at 120° C. for 1 h. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 6-butoxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carbaldehyde as a yellow solid (131 mg, 63% yield).
Reaction SMILES: [CH2:1]([C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[CH2:12][C:11]2[CH:17]=[C:18]([C:21](OC(C)(C)C)=[O:22])[CH:19]=[CH:20][C:10]=2[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]1[CH2:38][NH:39][CH3:40].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>>[CH2:1]([C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[CH2:12][C:11]2[CH:17]=[C:18]([C:21]([N:39]([CH3:40])[CH2:38][C:30]3[N:29]([CH3:28])[C:37]4[C:32]([CH:31]=3)=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:22])[CH:19]=[CH:20][C:10]=2[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1cc2ccccc2n1C
Reactant: CN1Cc2cc(C(=O)OC(C)(C)C)ccc2N[C@H](Cc2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccc2c(c1)CN(C)C(=O)[C@@H](Cc1ccccc1)N2
Yield: 99 %

Procedure:
According to the procedure of Example 8, except using tert-butyl (2R)-2-benzyl-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.75 g, 2.1 mmole), 1-methyl-2-(methylaminomethyl)indole (0.34 g, 2.1 mmole), Et3N (0.59 mL, 4.2 mmole), HOBt.H2O (0.28 g, 2.1 mmole), and EDC.HCl (0.41 g, 2.1 mmole), the title compound (0.97 g, 100%) was prepared as an off-white solid following flash chromatography on silica gel (gradient: 80-90% EtOAc/hexanes): MS (ES) m/e 467.1 (M +H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.N1C(C)=CC(C)=CC=1C.[Li+].[I-].Cl>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C#Cc2ccccc2)cc1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: Oc1ccc(C#Cc2ccccc2)cc1

Procedure:
A procedure similar to that described1 was used. A sample of 1-methoxy-4-(phenylethynyl)-benzene (0.4 g, 1.9 mmol) was added collidine (3 mL), LiI (1.5 g) and the solution heated under reflux for 5 h (>95% conversion). The solution was poured into water acidified with HCl, extracted with ether (3×50 mL) and dried (MgSO4). The ether was evaporated and the residue chromatographed (PE) eluting the title compound 0.3 g (80%): mp 125°-128° C. (cyclohexane) (lit2 mp 91°-92° C., lit3 mp 83°-84° C.); 1H NMR (300 MHz, DMSO-d6) δ6.80 (d, J=8.77 Hz, 2H, C2H), 7.37 (d, 2H, C3H), 7.35-7.42 (m, 3H), 7.46-7.50 (m, 2H), 9.92 (s, 1H, OH); 13C NMR (300 MHz, DMSO-d6 ) δ87.32 (acetylenic C), 89.98 (acetylenic C), 112.42 (sp2C), 115.74, 122.90 (sp2C), 128.20, 128.66, 131.06, 133.00, 158.06 (COH); IR (CDCl3) 3596 (OH), 3066 (w), 3039 (w), 2217 (w, acetylenic stretch), 1605, 1512, 1429 (w), 1328 (w), 1261 (s), 1219, 1171 (s), 1140 (w), 1099 (w), 834, 805 (w) cm-1. MS (El) m/e 194 (M+, 100), 165 (29.4), 97 (11.3).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([NH2:18])=[O:17])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([Sn](CCCC)(CCCC)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1)CCC.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[C:2]1[S:6][C:5]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([NH2:18])=[O:17])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: NC(=O)c1cccc2[nH]c(-c3ccc(Br)s3)nc12
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2[nH]c(-c3ccc(-c4ccccn4)s3)nc12

Procedure:
A mixture of EXAMPLE 10A (184 mg), tri-ortho-tolylphosphine (52 mg), tris(dibenzylidineacetone)dipalladium(0) (52 mg), 2-(tri-n-butylstannyl)pyridine (420 mg) and triethylamine (238 L) in DMF (5 mL) was heated at 75° C. overnight. The mixture was cooled, diluted with dichloromethane and flash chromatographed (with 0-15% methanol in 2:1 ethyl acetate/hexane). Additional purification by HPLC (Zorbax, C-18, Mobile phase A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile; 0-100% gradient) provided the title compound. 1H NMR (DMSO-d6) δ 7.34-7.39 (m, 2H), 7.74-7.76 (m, 2H), 7.86-7.95 (m, 3H), 8.00-8.05 (m, 1H), 8.02 (s, 1H), 8.60 (d, J=4.6 Hz, 1H), 9.04 (brs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.Cl.C(=O)([O-])[OH:32].[Na+].[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[C:37]1[C:45](Cl)=[O:46]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:14]1[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=1[N:12]1[C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[N:21][N:22]=[C:11]1[CH2:10][NH:9][C:45]([C:37]1[NH:36][C:44]2[C:39]([CH:38]=1)=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:46])=[O:32]
Reactant: CCOC(=O)CCc1nnc2n1-c1sc(CC)cc1C(c1ccccc1Cl)=NC2
Reactant: O=C([O-])O
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(CCC(=O)O)nnc2CNC(=O)c2cc3ccccc3[nH]2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 3.4 %

Procedure:
4-(2-Chlorophenyl)-9-(2-ethoxycarbonylethyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (5.78 g) was heated with 5% hydrochloric acid for 3 hours, and the mixture was cooled to room temperature. Sodium hydrogencarbonate (25.2 g) and chloroform were added. Indole-2-carbonyl chloride (2.67 g) was added with vigorous stirring, and the mixture was stirred for 4 hours. The organic layer was concentrated, and the residue was dissolved in methanol (39 ml). The solution was hydrolyzed with 2M sodium hydroxide (3.9 ml) and the reaction mixture was made acidic. The mixture was extracted with ethyl acetate and the extract was dried over magnesium sulfate. The solvent was evaporated and the obtained residue was recrystallized from ethanol to give 0.26 g of 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3-(indole-2-carbonylaminomethyl) [1,2,4]triazol-5-yl)propionic acid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:25]3[C:20](=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:23][CH:24]=3)[N:19]([CH:30]([CH3:32])[CH3:31])[N:18]=2)=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C.C1CCCCC=1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([C:17]2[C:25]3[C:20](=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:23][CH:24]=3)[N:19]([CH:30]([CH3:32])[CH3:31])[N:18]=2)=[O:16])=[CH:13][CH:14]=1
Reactant: CC(C)n1nc(C(=O)c2ccc(OCc3ccccc3)cc2)c2cccc(C(F)(F)F)c21
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(C)n1nc(C(=O)c2ccc(O)cc2)c2cccc(C(F)(F)F)c21
Temperature: 70 °C
Yield: 98.2 %

Procedure:
A mixture of [4-(benzyloxy)phenyl][1-isopropyl-7-(trifluoromethyl)-1H-indazol-3-yl]methanone (0.17 g, 0.38 mmol) and 10% palladium on carbon (0.10 g) in 10 mL ethanol/cyclohexene (3:1, v/v) was heated at 70° C. for 0.5 hours. The catalyst was filtered (celite) and the filtrate concentrated in vacuo to give crude product. The residue was crystallized from Et2O/hexane to give 0.130 g of product as a white solid
Reaction SMILES: [OH:1][CH2:2][CH:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([CH3:11])[CH2:7][C@H:6]1[OH:12])[CH3:4].[H-].[Na+].[CH:15](I)([CH3:17])[CH3:16].O>C(COC)OC>[CH:15]([O:1][CH2:2][CH:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([CH3:11])[CH2:7][C@H:6]1[OH:12])[CH3:4])([CH3:17])[CH3:16]
Reactant: CC(CO)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)OCC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
20.0 g (0.12 mol) of (1R, 2S, 5R)-2-(2-hydroxy-1-methylethyl)-5-methylcyclohexanol was dissolved in 100 ml of dimethoxyethane, and 3.3 g (0.14 mol) of sodium hydride was added to the solution. The mixture was agitated for 30 min, and 23.7 g (0.14 mol) of isopropyl iodide was dropped thereinto and continued to agitate at room temperature for 24 hr. After the completion of the reaction, 300 ml of water was added to the reaction fluid and agitated. The reaction product was extracted with ether. The resultant ether phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off, thereby obtaining 18.3 g (yield: 73.6%) of (1R, 2S, 5R)-2-(2-isopropoxy-1-methylethyl)-5-methylcyclohexanol in the form of a colorless liquid. The mass spectrometry and NMR data of the obtained compound are as follows:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([C:12](=[O:17])[C:13]([F:15])([F:16])[F:14])[CH2:22][CH:21]=[CH2:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)C(F)(F)F
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCN(CCNC(=O)OC(C)(C)C)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
Dissolve N-(t-butyloxycarbonyl)-N'-(trifluoroacetyl)-ethylenediamine (500 mg, 1.95 mmol) in anhydrous dimethylformamide (10 mL), cool to 0° C. and treat with sodium hydride (56 mg, 1.85 mmol, 80% dispersion in mineral oil). Stir for 15 minutes and add allyl bromide (0.25 mL, 2.9 mmol). Stir for 2.5 hours, dilute with ethyl acetate (50 mL) and extract with water (25 mL). Separate the organic phase and wash with brine (2×20 mL). Extract the combined aqueous phases with ethyl acetate (2×5 mL), dry (Na2SO4) and evaporate the solvent in vacuo. Purify by chromatography (2:1 hexane/ethyl acetate to 3:2 hexane/ethyl acetate) to give N-(t-butyloxycarbonyl)-N'-(trifluoroacetyl)-N'-(allyl)ethylenediamine (562 mg, 100%).
Reaction SMILES: [CH2:1]1[O:14][C:13]2[C:3](=[CH:4][C:5]3[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=3[CH:12]=2)[O:2]1.C1C=CC=CC=1.[OH-].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>O>[Cl:23][CH2:24][C:25]([N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[C:3]3[O:2][CH2:1][O:14][C:13]3=[CH:12][C:6]=2[CH2:7][CH2:8]1)=[O:26]
Reactant: c1c2c(cc3c1OCO3)CCNCC2
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: O=C(CCl)N1CCc2cc3c(cc2CC1)OCO3
Reaction time: 0.17 h

Procedure:
One-tenth mole, 22.7 g, of 2,3,4,5-tetrahydro-7,8-methylenedioxy-1H-3-benzazepine was dissolved in 200 ml of water and 200 ml of benzene added. Forty ml of a 10% solution of sodium hydroxide was added to the vigorously stirred emulsion and 17 g (0.15 mole) of chloroacetyl chloride was added dropwise. As the pH approached 5, another 10-ml portion of 10% sodium hydroxide solution was added until a total of 100 ml has been added. After all the chloroacetyl chloride had been added, the mixture, which has an acid reaction, was stirred for another 10 minutes then allowed to stand overnight at room temperature.
Reaction SMILES: [ClH:1].[C:2]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)#[N:3].[CH2:17]([OH:19])[CH3:18]>CCOCC>[CH2:17]([O:19][C:2]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)=[NH:3])[CH3:18].[OH2:19].[ClH:1].[ClH:1]
Reactant: N#CC1c2ccccc2-c2ccccc21
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)C1c2ccccc2-c2ccccc21
Product: O
Reaction time: 8 h

Procedure:
Dry hydrogen chloride was passed for 3 hours into a solution of 9-cyanofluorene (15 67.85; g.; see, for example, J. Amer. Chem. Soc., 1949, 71, 1500) in ether (1 l.) ans absolute ethanol (45 ml.) at 0°C. The mixture was left at 0°C overnight, the solid filtered, washed with ether and dried under vacuum at room temperature to give the title compound as its hydrochloride hemihydrate (17.61 g., m.p. 262°-263°C dec.). Found: C, 68.5; H, 6.05; N, 4.95%. C16H13NO.HCl.1/2H2O requires C, 687.85; H, 6.05; N, 4.95%.