Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([NH:14][CH3:15])[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19].[NH:20]1[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21]1>C(#N)C>[CH3:30][C:28]([CH3:31])([O:27][C:26]([NH:25][CH:22]1[CH2:23][CH2:24][N:20]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:19])[C:6]([C:16]([OH:18])=[O:17])=[CH:7][N:8]3[NH:14][CH3:15])=[CH:3][C:2]=2[F:1])[CH2:21]1)=[O:32])[CH3:29]
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CC#N
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NC(=O)OC(C)(C)C)C3)c(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To 1.00 g (3.68 mmol) of 6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 0.56 g (1.0 equivalent) of 1,8-diazobicyclo-[5,4,0]undec-7-ene and 0.68 g of 1,1-dimethylethyl 3-pyrrolidinylcarbamate. The mixture was refluxed for one hour and stirred at room temperature overnight. The solids were filtered and washed with ether to give 0.92 g of 7-[3-[[(1,1dimethylethoxy)carbonyl]amino]-1-pyrro-lidinyl]-6,8-difluoro-1,4-dihydro-1-(methylamino)-4-oxo-3quinolinecarboxylic acid. A portion of this material (0.38 g) was treated with 10 ml of trifluoroacetic acid for 2 hours and was concentrated. The residue was taken up in aqueous sodium hydroxide to pH 12.5 and then treated with hydrochloric acid to pH 7.0. The solids were filtered to give 0.24 g of 7-(3-amino-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid, mp 210°-211° C.
Reaction SMILES: [O:1]1[C@H:6]([CH2:7][CH3:8])[C@H:2]1[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH2:11]([NH:18][C@H:2]([C@H:6]([OH:1])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@H]1O[C@@H]1C(=O)O
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC[C@@H](O)[C@@H](NCc1ccccc1)C(=O)O
Yield: 75 %

Procedure:
To 14.2 g (0.05 mol) of the (2S,3R)-2,3-epoxypentanoic acid obtained in (4) above were added 500 ml of water and 6.4 g (0.16 mol) of sodium hydroxide, and 42.6 g (0.15 mol) of benzylamine (VI) was added thereto, followed by refluxing for 8 hours. Water was evaporated, and the concentrate was adjusted to pH 5 to 6 with diluted hydrochloric acid and extracted with 500 ml of ethyl acetate. After drying, ethyl acetate was removed by evaporation to yield 8.36 g (0.0375 mol, 75%) of the title compound. Optical rotation [α]D25 =+12.84° (c=0.1, CHCl3 :CH3OH=1:1 by volume)
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[CH:19][C:6]2/[C:7](=[CH:16]/[C:17]#[N:18])/[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1)=[O:2].[CH3:21][Mg]Cl.[Cl-].[NH4+]>C1COCC1>[OH:2][CH:1]([C:3]1[CH:20]=[CH:19][C:6]2/[C:7](=[CH:16]/[C:17]#[N:18])/[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1)[CH3:21]
Reactant: N#C/C=C1\c2ccccc2CCc2cc(C=O)ccc21
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Temperature: -10 °C
Yield: 91.7 %

Procedure:
[step 2] (E)-(2-Formyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonitrile (218 mg, 0.84 mmol) obtained in step 1 was dissolved in THF (4 mL), methylmagnesium chloride (3 mol/L THF solution; 0.42 mL, 1.26 mmol) was added at −78° C., and the mixture was warmed to −10° C. over 40 min. Saturated aqueous ammonium chloride solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 50/50) to give (E)-[2-(1-hydroxyethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (212 mg, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([NH:19][C:20]4([C:23]5[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=5)[C:26]([OH:28])=O)[CH2:22][CH2:21]4)=[O:18])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35].Cl.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:37][O:36][C:34](=[O:35])[CH2:33][NH:32][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([C:20]2([NH:19][C:17]([C:16]3[C:11]4[CH:10]=[N:9][N:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)[C:12]=4[CH:13]=[N:14][CH:15]=3)=[O:18])[CH2:22][CH2:21]2)[CH:24]=1
Reactant: O=C(O)c1cccc(C2(NC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)CC2)c1
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1cccc(C2(NC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)CC2)c1
Reaction time: 4 h

Procedure:
To a solution of 3-(1-{[1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-cyclopropyl)-benzoic acid (0.200 g, 0.480 mmol), Gly-OMe.HCl (68.1 mg, 0.543 mmol) and N,N-diisopropylethylamine (426 μL, 2.40 mmol) in DMF (4.5 mL) is added TBTU (192 mg, 0.600 mmol). After 4 hours, the mixture is concentrated in vacuo. The residue is dissolved in ethyl acetate (100 mL) and washed with 2N sodium hydroxide (3×50 mL), saturated aqueous ammonium chloride (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), brine (50 mL). The organic layer is dried over MgSO4, filtered and concentrated. The residue is purified by silica gel chromatography eluting with a gradient of 0-8% methanol in methylene chloride to give a foam, which is triturated with ether (3 mL), filtered, washed with cold ether (3×3 mL) and air dried to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Cl:17][C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][N:21]2[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O>[Si:6]([O:5][CH2:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[C:35]1[N:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]2=[N:19][C:18]=1[Cl:17])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC1(C)OB(c2ccc3nc(Cl)cn3c2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1-c1c(Cl)nc2ccccn12
Yield: 46.7 %

Procedure:
450 mg of (2-bromobenzyloxy)-tert-butyldimethylsilane, 500 mg of 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine and 1.46 g of caesium carbonate are dissolved in 8 ml of tetrahydrofuran and 1 ml of water. The mixture is degassed with argon for 10 min, 110 mg of [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium are added and the mixture is heated at the reflux of the solvent for 16 hours. After cooling, the reaction mixture is hydrolysed with water, and the organic phase, which has been extracted with dichloromethane, is separated, dried and concentrated under reduced pressure. The oil obtained is purified by silica gel chromatography, elution being carried out with a heptane/ethyl acetate mixture. 260 mg of compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1>C(O)CCC>[NH2:1][C:2]1[C:7]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[N:6][CH:5]=[N:4][C:3]=1[Cl:9]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: N#Cc1ccc(N)cc1
Solvent: CCCCO
Product: N#Cc1ccc(Nc2ncnc(Cl)c2N)cc1
Yield: 60.2 %

Procedure:
A solution of 5-amino-4,6-dichloropyrimidine (7.00 g, 42.7 mmol) and 4-aminobenzonitrile (5.04 g, 42.7 mmol) in n-butanol (130 ml) was heated at reflux for 16 hours. After cooling the mixture the solid which precipitated out was filtered off, and partitioned between dichloromethane (500 ml) and saturated aqueous sodium bicarbonate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give the title compound (6.31 g, 60%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:31])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)([O-])=[O:2].[Cl-].[NH4+]>O1CCCC1.O.[Zn]>[OH:2][NH:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:31])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH:21]=[C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)[C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)n1CCCCN1CC=C(c2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(NO)ccc2c(=O)n1CCCCN1CC=C(c2ccccc2)CC1
Temperature: 32 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
To a stirred solution of 7-nitro-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (2.1 g) in 50% aqueous tetrahydrofuran (210 ml) was added ammonium chloride (2.68 g) in water (27 ml). To this mixture was added zinc dust (1.65 g) by five portions over a period of 3 hours. The temperature was raised at 32° C. during the reaction. After additional stirring for 2 hours, the precipitated materials were filtered, washed with water and extracted with dimethylformamide (100 ml) under nitrogen. The organic extract was filtered and the filtered cake was washed with dimethylformamide (20 ml). The combined organic solution was diluted with water (24 ml), cooled in a refrigerator, and then treated with active charcoal (1.05 g) and silica gel (2.1 g). The charcoal and silica gel were filtered off and washed with 80% aqueous dimethylformamide (5 ml). To the combined solution was added dropwise cold water (96 ml) with stirring on an ice bath and the precipitated crystals were collected, washed with water, and then suspended in methanol (50 ml). To this mixture was added 10% hydrogen chloride in methanol (50 ml) and the mixture was stirred for 1 hour. The precipitated crystals were collected, washed with methanol, stirred with water, and then filtered and dried to give 7-hydroxyamino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.60 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10]C)=[O:9].O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][C:2]1[C:3]2[N:4]([N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1ccn2nc(-c3ccccc3)nc2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccn2nc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 118.3 %

Procedure:
A mixture of methyl 8-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (634 mg, 2.37 mmol) and lithium hydroxide monohydrate (398 mg, 9.49 mmol) in tetrahydrofurane (15 ml) and water (5 ml) is stirred for 3 days at 25° C. The mixture is diluted with water, acidified to pH=0 with hydrochloric acid 37% and extracted with ethyl acetate; the organic layer is washed with water and brine, dried with magnesium sulfate and the solvent is evaporated affording 8-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (710 mg, 118%) as a white solid. mp.: >250° C. MS: m/z=254.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][CH2:20][CH2:19][C:18]2[CH:17]=[C:16]([C:22](O)=[O:23])[CH:15]=[CH:14][C:13]1=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][CH2:20][CH2:19][C:18]2[CH:17]=[C:16]([C:22]([NH:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[O:23])[CH:15]=[CH:14][C:13]1=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCCc2cc(C(=O)O)ccc21)OCc1ccccc1
Reactant: Nc1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCc2cc(C(=O)Nc3ccncc3)ccc21)OCc1ccccc1
Yield: 33.4 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 7 using 5-(benzyloxycarbonylamino)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (2.50 g), thionyl chloride (2.75 g), 4-aminopyridine (724 mg) and triethylamine (1.55 g), the objective 5-(benzyloxycarbonylamino)-N-(4-pyridyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (1.03 g) was obtained as colorless crystals.
Reaction SMILES: [Na+:1].[Na+].[Na+].[NH2:4][C:5]1[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:10]2.O.O.O.C([O-])(=O)C.[Na+].[N+](C1C(S(O)(=O)=O)=C(C=CC=1)C([O:43][C:44](=O)[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([N+:51]([O-:53])=[O:52])[C:46]=1[S:54]([OH:57])(=[O:56])=[O:55])=O)([O-])=O>O>[Na+:1].[Na+:1].[Na+:1].[Na+:1].[N+:51]([C:47]1[C:46]([S:54]([OH:57])(=[O:55])=[O:56])=[C:45]([CH:50]=[CH:49][CH:48]=1)[C:44]([NH:4][C:5]1[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:20])=[O:21])=[CH:10]2)=[O:43])([O-:53])=[O:52]
Reactant: O=C(OC(=O)c1cccc([N+](=O)[O-])c1S(=O)(=O)O)c1cccc([N+](=O)[O-])c1S(=O)(=O)O
Reactant: Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12)c1cccc([N+](=O)[O-])c1S(=O)(=O)O
Yield: 353.6 %

Procedure:
To a solution of 20.0 g of 8-amino-1,3,6-naphthalenetrisulfonic acid trisodium salt and 8.75 g of sodium acetate trihydrate in 180 ml of water at room temperature is added 12.0 g of 3-nitrosulfobenzoic anhydride with stirring. A 400 ml portion of water is added. The mixture is stirred at room temperature for 21/2 hours and then filtered. The filtrate is cooled, acidified with 2-3 ml of concentrated hydrochloric acid an diluted with ethanol. The pink solid is collected by filtration, washed with 85% ethanol, ether and dried. The filtrate is concentrated to a low volume and diluted with ethanol giving a second crop which is collected and combined with the first crop giving a total of 27.6 g of 8-(3-nitro-2-sulfobenzamido)-1,3,6-naphthalene trisulfonic acid tetrasodium salt.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]=2[NH:4][CH:3]=1.[Li]C(C)(C)C.[F:17][C:18]([F:38])([F:37])[C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[N:25]=[CH:24]2)=[O:20]>C1COCC1>[Cl:11][C:10]1[C:5]2[NH:4][CH:3]=[C:2]([C:19]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[N:25]=[CH:24]4)([OH:20])[C:18]([F:37])([F:17])[F:38])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Clc1ncnc2c(Br)c[nH]c12
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1c[nH]c2c(Cl)ncnc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.1 %

Procedure:
To a chilled (−78° C.) solution of 7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (80 mg, 0.34 mmol, 1 equiv.) in 5 mL of THF was added tert-BuLi (1.7 M in pentane, 0.43 mL, 0.73 mmol, 2.1 equiv.) dropwise. After 5 minutes, a chilled (−78° C.) solution of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (106 mg, 0.34 mmol, 1 equiv.) in 1 mL of THF was added in one portion. After 15 minutes, the reaction was quenched with 15 mL of water, warmed to room temperature, diluted with 100 mL of saturated aqueous ammonium chloride, and then extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was dissolved in DMF and purified by reverse phase HPLC (5-95% CH3CN/water+0.1% TFA). The major fractions collected were made basic with saturated NaHCO3 and the CH3CN was concentrated in vacuo. The aqueous was extracted with EtOAc and washed with brine. The organic layers were dried, filtered, and concentrated in vacuo to provide 52 mg (32%) of the title compound as a white solid. MS m/z 462.56 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[NH:11][C:10]=2[CH3:19])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:10]=2[CH3:19])=[CH:6][CH:7]=1
Reactant: Cc1ccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c2c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2cc(C)ccc21
Reaction time: 24 h

Procedure:
A stirred solution of 3-[(4-chlorophenyl)thio]-2,5-dimethyl-1H-indole (300 mg) in dry N,N-dimethylformamide (15 ml) was treated with sodium hydride (42 mg of a 60% dispersion in mineral oil). After 10 minutes the reaction was treated with ethyl bromoacetate (116 μl) and stirring continued for 24 hours. The reaction was poured into distilled water (200 ml) and extracted with diethyl ether (3×100 ml). The extracts were dried (MgSO4), evaporated in vacuo and the residue purified by flash column chromatography eluting with 10% ethyl acetate in iso-hexane. The subtitle compound was obtained as a yellow solid (yield 130 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].C1N2CN3CN(C2)CN1C3.CCCCCC.FC(F)(F)[C:32](O)=[O:33]>>[CH:10]([C:6]1[CH:7]=[C:8]([CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[OH:13])[CH:32]=[O:33])([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CCCCCC
Product: CC(C)c1cc(C=O)cc(C(C)C)c1O
Yield: 0.26 %

Procedure:
18 g of 2,6-di isopropyl phenol and 1.8 g HMTA (hexamethylene tetraamine) in 60 ml TFA (trifluoro acetic acid) was refluxed 3.5 hours. Workup, chromatography on silica gel (CH2Cl2) and trituration with hexane gave 5.3 g, 0.26% yield, white solid, mp—103° C. (3,5,-di-iso-propyl 4 hydroxybenzaldehyde). NMR CDCl3 δ 9.87(1H, S, CHO), 7.63(2H, S), 3.19(2H, septet, J=7.7 Hz), 1.30(12H, d, J=7.7 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>ClCCl>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:17](=[O:20])[CH2:18][CH3:19])=[O:5]
Reactant: Nc1ccccc1C=O
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccccc1C=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.1 %

Procedure:
To a solution of 2-aminobenzaldehyde (1.21 g, 10 mmol), and triethylamine (1.39 mL, 10 mmol) in dichloromethane (50 mL) was added propionyl chloride (1.04 mL, 12 mol). The reaction was stirred at room temperature for 3 days. The reaction solution was washed with water and then dried over magnesium sulfate and concentrated in vacuo to yield the crude product (1.65 g, 93%). The product was used without further purification. 1H NMR (400 MHz, CDCl3) δ 11.16 (s, 1H), 9.93 (s, 1H), 8.77 (d, J=8.5 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.62 (t, J=7.1 Hz, 1H), 7.22 (t, J=7.5 Hz, 1H), 2.51 (q, J=7.6 Hz, 2H), 1.29 (t, J=7.6 Hz, 3H); HPLC ret. time 1.34 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 177.2 (M+1)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:11][CH2:10][CH:9]([CH:12]([CH3:21])[CH2:13][NH:14][S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH2:8][CH:7]=1.[O:22]1CCCC1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]([CH3:21])[CH2:13][NH:14][S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH2:8][CH:7]1[OH:22]
Reactant: C1CCOC1
Reactant: CC(CNS(=O)(=O)C(C)C)C1CC=C(c2cccs2)CC1
Product: CC(CNS(=O)(=O)C(C)C)C1CCC(c2cccs2)C(O)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a 0° C. solution of 1 eq. of N-[2-[4-(2-thienyl)-3-cyclohexen-1-yl]propyl] 2-propanesulfonamide (see example 8) in tetrahydrofuran is added 0.67 eq. of borane dimethyl sulfide complex. The mixture is stirred at 0° C. for 4 hr and slowly quenched with ethanol. To the 0° C. solution is added 3N aqueous sodium hydroxide then 30% aqueous hydrogen peroxide. The mixture is stirred at 0° C. for one hr. The organic portion is separated and the aqueous portion is extracted two times with diethyl ether. The combined organic extracts are dried over MgSO4, filtered and concentrate in vacuo to provide the crude material. Chromatography (silica gel) of the crude material affords the purified title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:40][NH:41][CH3:42].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:26])[F:27])=[N:20][C:21]([C:22](=[O:23])[N:41]([CH3:42])[CH3:40])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Yield: 77 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), dimethylamine hydrochloride (44 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-dimethylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 9a (120 mg, yield 77%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>C(#N)C>[Br:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][C:9]([N:25]=[N+:26]=[N-:27])=[O:11])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)C=Cc1ccc(Br)o1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: [N-]=[N+]=NC(=O)C=Cc1ccc(Br)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
To a solution of 3-(5-bromo-2-furyl)acrylic acid (41.5 g) in acetonitrile (200 mL) were added triethylamine (23.0 g) and ethyl chloroformate (26.1 g). The mixture was stirred at room temperature for 30 min. To the obtained mixture was added a saturated aqueous solution of sodium azide (18.7 g) at 0° C. and the mixture was stirred at room temperature for 5 hr. The reaction mixture was filtered, and the obtained solid was washed with water. The solid was recrystallized from dichloromethane to give the title compound (20.7 g) as white solid.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:9][CH2:8]2)[O:4][N:3]=1.[CH2:10]([NH2:13])[CH2:11][NH2:12]>>[CH:7]1([C:5]2[O:4][N:3]=[C:2]([NH:12][CH2:11][CH2:10][NH2:13])[N:6]=2)[CH2:9][CH2:8]1
Reactant: Clc1noc(C2CC2)n1
Reactant: NCCN
Product: NCCNc1noc(C2CC2)n1
Temperature: 125 °C

Procedure:
3-Chloro-5-cyclopropyl-1,2,4-oxadiazol (72 mg, 0.5 mmol) and TEA (139 μl, 1 mmol) were dissolved in ethane-1,2-diamine (3 ml), placed in a sealed tube and heated at 125° C. for 2 hours. The mixture was cooled to room temperature and evaporated to dryness under reduced pressure and used directly in the next step MS(ESI) m/z=169.1 [M+1]+.