Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[N+:19]([O-:21])=[O:20])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:22]([O-])([OH:24])=[O:23]>S(=O)(=O)(O)O>[C:1]([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[C:12]([N+:22]([O-:24])=[O:23])[CH:13]=[CH:14][CH:15]=2)[C:10]=1[N+:19]([O-:21])=[O:20])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Nc1ccc2ccccc2c1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)Nc1ccc2cccc([N+](=O)[O-])c2c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 55.1 %

Procedure:
2-Ethoxalylamino-1-nitronaphthalene (11.5 g, 0.04 mol) was dissolved in 80 ml of sulfuric acid (d 1.84)by portionwise addition, with vigorous stirring on an ice-bath. Nitric acid (1.66 ml, 0.04 mol, d 1.52) in 20 ml of sulfuric acid (d 1.84) was added dropwise during 1 h at 0° C., and the mixture was stirred at this temperature for a further hour. The mixture was cautiously poured into 600 ml of ice/water with vigorous stirring. The yellow solid was collected, washed with water, and boiled with 300 ml of ethanol. The hot suspension was filtered and the undissolved residue was washed with 200 ml of ether to yield 7.35 g (55%) of the title compound, m.p. 232.7-233.4° C. (acetic acid),1H-NMR (DMSO-d6) 1.33 (t,J=7Hz,3H,CH3), 4.34 (q,J=7Hz,2H,CH2), 7.7-8.6 (m,5H,ArH), 11.12 (s,1H,NH).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-dodecylamine (1.049 g, 5.59 mmol), triethylamine (0.86 ml, 6.15 mmol) and acetyl chloride (0.44 ml, 6.15 mmol) in dichloromethane (10 ml) was stirred at room temperature for 3h. The mixture was quenched with water and the organic phase was separated. Evaporation of the dried (magnesium sulfate) organic phase gave a solid, which was recrystallized from hexane to give the titled amide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH:13]([CH3:15])[CH3:14])[NH:5][C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10]Cl.[H-].[Na+].CN(C=O)C>C1COCC1>[N:5]1([C@@H:4]([CH:13]([CH3:15])[CH3:14])[C:3]([O:2][CH3:1])=[O:16])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:12]
Reactant: COC(=O)[C@@H](NC(=O)CCCCCl)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C(C)C)N1CCCCC1=O
Reaction time: 1.5 h
Yield: 100.5 %

Procedure:
A solution of 105 mg (0.42 mmol) of the product of Step A in 10 mL of dry THF was treated with 17 mg (0.43 mmol) of 60% NaH in oil dispersion at 0° C. for 1 h. TLC analysis indicated starting material was present and 2 mL of DMF was added. After 1.5 h. at 0° C., the solvent was evaporated and the mixture was worked up in the standard to give 90 mg of product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([C:26]([N:28]2[C:36]3[C:31](=[CH:32][C:33]([F:37])=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH:19]=1>CN1C(=O)CCC1>[F:37][C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][CH:34]=1)[N:28]([C:26]([C:20]1[N:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:18]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:19]=1)=[O:27])[CH2:29][CH2:30]2
Reactant: COc1cc(Cl)cc(C(=O)N2CCc3cc(F)ccc32)n1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)cc(C(=O)N2CCc3cc(F)ccc32)n1

Procedure:
436 mg (2.00 mmol) 1-Piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one and 200 mg (0.652 mmol) of (4-chloro-6-methoxy-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone in 2 mL NMP were stirred overnight at 120° C. The reaction mixture was purified by preparative HPLC. The product-containing fractions were combined and evaporated down using the rotary evaporator.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:21][N:20](S(CC5CCCC5)(=O)=O)[CH2:19]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:19][N:20]([C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH2:21]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCC(=O)Cl
Reactant: O=S(=O)(CC1CCCC1)N1CC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Product: COCC(=O)N1CC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 51 %

Procedure:
According to the procedure for compound 469 using methoxyacetyl chloride afforded 11.7 mg (51% yield) of 468, as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](Cl)=[O:11].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1cc2ccccc2s1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1ccccc1)c1cc2ccccc2s1
Temperature: 50 °C
Reaction time: 5 h
Yield: 76.6 %

Procedure:
To 8 g (0.0407 mol) of benzothiophene-2-carboxylic acid chloride in 150 ml of toluene there are added with stirring at room temperature 7.6 g (0.0814 mol) of anilin, then, when the addition is complete, the mixture is stirred for 5 hours at 50° C., the reaction mixture is then poured into water, and precipitate which has settled out is filtered off with suction, washed twice with water and dried. 7.9 g (77% of theory) of benzothiophene-2-carboxanilide of melting point 188° C. are obtained. ##STR10##
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[C:19]([Cl:35])[CH:18]=3)=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.O>CN(C)C=O>[Cl:35][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:7]([O:36][CH3:37])[CH:8]=3)[N:13]=[CH:12][CH:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34])=[O:25]
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
A starting compound (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-(2,4-difluorophenyl)urea, 50 mg), potassium carbonate (138 mg), and morpholine (0.044 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 32 mg (yield 64%) of the title compound.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:18]3[CH:30]=[CH:29][N:28]=[C:19]3[S:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl>[C:1]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:18]3[CH:30]=[CH:29][N+:28]([O-:39])=[C:19]3[S:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:15][CH2:16]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)N1CCN(C2=Nc3ccccc3Sc3nccn32)CC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(C2=Nc3ccccc3Sc3n2cc[n+]3[O-])CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To the solution of 0.5 g of 5-(4-carbobenzoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine in 5 ml of methylene chloride, cooled at 0° C., is added dropwise a solution of 0.26 g of m-chloroperbenzoic acid dissolved in 2 ml of methylene chloride. The mixture is stirred at 0° C. for 1.5 hrs., the solids are filtered, and the filtrates are washed with 10% aqueous potassium carbonate and water, then dried over magnesium sulfate and evaporated to dryness to give 5-(4-carbobenzoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine 1-oxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15].C(=O)=O.C(O)CO.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5]3[C:4]=1[C:13](=[O:17])[C:14](=[O:15])[C:6]=3[CH:7]=[CH:8][CH:9]=2
Reactant: COc1ccc2ccccc2c1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: OCCO
Product: COc1ccc2cccc3c2c1C(=O)C3=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
A solution of 2-methoxynaphthalene (5 g, 31.6 mmol) and oxalyl chloride (11 mL, 126 mmol) in 150 mL of dichloromethane was cooled to −15° C. (CO2/ethylene glycol) under nitrogen. Aluminum trichloride (10.5 g, 79 mmol) was added slowly over 30 minutes. After 3 hours, the mixture was poured onto 100 g of ice. The layers were separated, and the aqueous layer was washed with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over magnesium sulfate. The solution was concentrated to afford 4.5 g of a solid. The solid was triturated with dichloromethane to give 1.24 g of the title compound as a solid, mp 218°-220° C.; 1H NMR (DMSO-d6): δ8.38 (d, 1H), 8.25 (d, 1H), 7.90 (d, 1H), 7.63 (m, 2H), 4.07 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=O)[C:6]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:13][CH2:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH2:5]2.C(O)(=O)C.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:3]([F:24])=[C:4]2[C:8]([C:7]3[C:6]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:5]2)[CH2:13][CH2:14][C:15](=[O:19])[C:16]=3[CH2:17][CH3:18])=[CH:9][C:10]=1[F:11]
Reactant: CCCCC1(CCC(=O)CCC)Cc2c(cc(F)c(N)c2F)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCC12CCC(=O)C(CC)=C1c1cc(F)c(N)c(F)c1C2
Temperature: 100 °C
Yield: 47.7 %

Procedure:
The crude diketone from step 1 (about 1.05 mmol) was treated with acetic acid (5 mL) and 6N HCl (5 mL). The resulting solution was stirred and heated in an oil bath at 100° C. for 1.5 hours. After cooling to room temperature, the mixture was poured into a slurry of solid Na2CO3 in CH2Cl2, dried over MgSO4, then filtered through a pad of silica gel and the product washed off with EtOAc. The filtrate and washings were concentrated under vacuum. The crude product was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate, developing with 30% EtOAc in hexanes, to afford 7-amino-9a-butyl-4-ethyl-6,8-difluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.16 g, 48%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[NH:5][C:4](=[O:13])[C:3]=1[C:14]#[N:15].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[N:7][CH:8]=1)[NH:5][C:4](=[O:13])[C:3]([C:14]#[N:15])=[C:2]2[N:26]1[CH2:27][CH2:28][N:23]([C:21]([C:17]2[O:16][CH:20]=[CH:19][CH:18]=2)=[O:22])[CH2:24][CH2:25]1
Reactant: O=C(c1ccco1)N1CCNCC1
Reactant: N#Cc1c(Cl)c2cc(Cl)cnc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(Cl)cnc2[nH]c1=O
Yield: 71 %

Procedure:
This compound was prepared from 4,6-dichloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (97) and 2-furoyl piperazine according to general procedure E to yield 2.27 g (71%) of 6-chloro-2-oxo-4-[4-(furan-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (101) as yellow solids. MP 303° C.; 1H-NMR (DMSO-d6): δ 3.76 (m, 4H), 3.93 (m, 4H), 6.65 (dd, J=1.6, 3.6 Hz, 1H), 7.09 (d, J=3.6 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.66 (d, J=2.4 Hz, 1H), 12.36 (s, 1H); EIMS: 384 (M+1).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:6]=1[CH2:7][N:8]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[C:9]1[N:10]=[N:11][N:12]([CH3:14])[N:13]=1)[CH2:3][CH3:4].[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]=O)[CH:39]=1.[BH4-].[Na+]>C(O)C>[F:28][C:26]([F:29])([F:27])[C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=1)[CH2:15][N:8]([CH2:7][C:6]1[CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=[CH:33][C:5]=1[CH:2]([NH:1][CH2:44][C:40]1[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=1)[CH2:3][CH3:4])[C:9]1[N:10]=[N:11][N:12]([CH3:14])[N:13]=1
Reactant: O=Cc1cccnc1
Reactant: CCC(N)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC(NCc1cccnc1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 864.6 %

Procedure:
To a solution of N-[2-(1-aminopropyl)-5-(trifluoromethyl)benzyl]-N-[3,5-bis(trifluoromethyl)benzyl]-2-methyl-2H-tetrazol-5-amine (60.0 mg, 0.01 mmoles) in ethanol (0.85 mL) was added 3-pyridinecarboxaldehyde (26.0 mg, 0.122 mmoles) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled to 0° C. and sodium borohydride (10.0 mg, 0.133 mmoles) was added in one portion. The reaction mixture was stirred in ice bath for 2 hours and then at room temperature for overnight. The reaction mixture was concentrated to remove ethanol and the residue was taken up in ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×) and the combined organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified using silica gel chromatography on the ISCO Combiflash system with a 1-9% methanol in dichloromethane gradient to yield the title compound (54.6 mg, 78% yield) as colorless gum.
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:19]2[S:20][CH:21]=[C:22]([Br:24])[CH:23]=2)[C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[C@@H:6]([CH3:25])[CH2:5]1)[CH:2]=[CH2:3]>C(O)C>[CH2:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:19]2[S:20][CH:21]=[C:22]([Br:24])[CH:23]=2)[C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[C@H:6]([CH3:25])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@H](C)N([C@H](c2cccc(O)c2)c2cc(Br)cs2)C[C@H]1C
Solvent: CCO
Product: C=CCN1C[C@@H](C)N([C@@H](c2cccc(O)c2)c2cc(Br)cs2)C[C@@H]1C
Yield: 21.1 %

Procedure:
A solution of 4.22 g (11 mmol) of (-)-p-ditoluoyl-L-tartaric acid in 15 mL of absolute ethanol was added to a suspension of 2.3 g (5.5 mmol) of (±)-3-((R*)-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)(4-bromo-2-thienyl)methyl)phenol (Example 42) in 5 mL of absolute ethanol. The mixture was heated to boiling and the resulting clear solution was allowed to crystallize at room temperature. After three crystallizations, the salt was converted to the free amine as in Example 65 and recrystallized from absolute ethanol to give 0.490 g (43% of theoretical for one enantiomer) of (±)-3-((S)-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)(4-bromo-2-thienyl)methyl)phenol as white crystals, mp 183°-185° C. Absolute configuration was determined by x-ray crystallography. [α]D20 =+14.50° (tetrahydrofuran, c=3.3). HPLC on β-cyclodextrin with methanol:0.1M ammonium acetate/1:1 gave one peak at tR =11 min. Calc. for C20H25BrN2OS: C, 57.00; H, 5.98; N, 6.65; Br, 18.96; S, 7.61. Found: C, 56.93; H, 5.99; N, 6.67; Br, 19.04; S, 7.67.
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]([OH:24])=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:61](O)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>ClCCl>[CH2:61]([O:23][C:22]([C:21]1[N:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:29][C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=3[F:38])[CH2:14][C:15]=12)=[O:24])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
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
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)OCc3ccccc3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 19.9 %

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 (0.24 g, 0.44 mmol), 1-hydroxybenzotriazole (0.072 g, 0.53 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.102 g, 0.53 mmol) were dissolved in 10 mL of dichloromethane under stirring, and benzyl alcohol (0.1 mL, 0.88 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)-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 benzyl ester 33a (0.056 g, yield 20%) as a white solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([N:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C@H:24]([N:31]([C:39](=[O:41])[CH3:40])[C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[CH2:23][C@@H:22]3[CH3:42])=[O:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.C(O)C.[OH-].[Na+]>O1CCCC1>[C:39]([N:31]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C@H:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:21]([C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH:9]3[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)=[CH:14][CH:15]=2)=[O:20])[C@@H:22]([CH3:42])[CH2:23]1)(=[O:41])[CH3:40]
Reactant: CCOC(=O)C1CCC(Oc2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OC3CCC(C(=O)O)CC3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 62 %

Procedure:
(2S,4R)-4-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-cyclohexanecarboxylic acid ethyl ester (0.060, 0.10 mmol) was hydrolyzed to the acid by dissolving in tetrahydrofuran and ethanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature 10 hours. The mixture was cooled to room temperature, acidified to form a white precipitate. The solid was filtered to give (2S,4R)-4-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-cyclohexanecarboxylic acid as a white powder in 62% yield.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@@H:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:6][N:5]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])(=[O:3])[NH2:2].CO[CH:29](OC)[N:30]([CH3:32])[CH3:31].C(OCC)(=O)C>ClCCl>[CH3:13][S:10]([O:9][C@H:7]1[CH2:6][N:5]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:4]([C:1](=[O:3])[N:2]=[CH:29][N:30]([CH3:32])[CH3:31])[CH2:8]1)(=[O:11])=[O:12]
Reactant: COC(OC)N(C)C
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)C=NC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To (2S,4R)-2-carbamoyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3 g) was added N,N-dimethylformamide dimethylacetal (3 ml) and the mixture was stirred at 120° C. for 1 hour. The mixture was poured into a mixture of ethyl acetate and dichloromethane, washed with water and brine successively, and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-2-[N-(N,N-dimethylaminomethylene)carbamoyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine. The compound obtained above was dissolved in acetic acid (30 ml) and to this solution was added hydrazine hydrate (0.36 ml) at room temperature. After stirring at the same temperature for 2 hours, the mixture was poured into water and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine successively, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was subjected to a column chromatography on silica gel (90 g) eluting with a mixture of methanol and dichloromethane (1:20 V/V) to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(1H-1,2,4-triazol-3-yl)pyrrolidine (1.5 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:29](/[CH:30]=[CH:31]/[CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[C:11]3[CH:12]=[C:13]([C:16]([N:18]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:44]([O:46]CC)=[CH2:45])CCC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:44]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:29](/[CH:30]=[CH:31]/[CH2:32][N:33]3[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]3)=[C:11]3[CH:12]=[C:13]([C:16]([N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:17])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1)(=[O:46])[CH3:45]
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccn2nc(-c3ccc(Br)cc3)c(/C=C/CN3CCCCC3)c2c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2nn3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3c2/C=C/CN2CCCCC2)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a mixture of Example 41i.e. (E)-2-(4-bromophenyl)-N,N-diisopentyl-3-(3-(piperidin-1-yl)prop-1-en-1-yl)pyrazolo[1,5-a]pyridine-5-carboxamide (553 mg, 0.954 mmol) in toluene (14 mL) was added tributyl(1-ethoxy-vinyl)tin (1.03 g, 2.86 mmol) and tetrakis(triphenylphosphine) palladium (O) (55 mg, 0.05 mmol). The mixture was degassed by bubbling nitrogen into it for 10 minutes and was then heated to 120° C. for 4 h. The mixture was allowed to cool to room temperature and concentrated to a residue and dissolved in THF (12 mL). 1N HCl (3 mL) was added and the mixture was stirred at room temperature for 1 h. Sodium bicarbonate was slowly added until pH was reached 8-9 and the mixture was extracted with ethyl acetate (2×30 mL). The combined organics were washed with brine, filtered and concentrated under reduced pressure.