Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]([C:18]2([NH:33]C(=O)OC(C)(C)C)[CH2:23][CH2:22][N:21]([C:24]3[C:25]4[CH:32]=[CH:31][NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][C:18]1([C:16]([NH:15][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[O:17])[CH2:19][CH2:20][N:21]([C:24]2[C:25]3[CH:32]=[CH:31][NH:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:22][CH2:23]1
Reactant: CN(C)CCCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
1-(4-Chlorophenyl)-N4,N4-dimethylbutane-1,4-diamine (Intermediate 57) (330 mg, 1.46 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (526 mg, 1.46 mmol) and DIPEA (0.763 mL, 4.37 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (609 mg, 1.60 mmol) was added and the resulting solution was stirred at 50° C. for 2 hours. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 10% MeOH with ammonia in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(1-(4-chlorophenyl)-4-(dimethylamino)butylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (423 mg, 51.0%) as a colourless gum. tert-Butyl 4-(1-(4-chlorophenyl)-4-(dimethylamino)butylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (423 mg, 0.74 mmol) was dissolved in DCM (5.00 mL) and TFA (1 mL) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness to afford crude product which was triturated with diethyl ether to afford 4-amino-N-(1-(4-chlorophenyl)-4-(dimethylamino)butyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (245 mg, 35.8%) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br.C([Li])CCC.[O:22]1[C:26]2([CH2:31][CH2:30]C(=O)[CH2:28][CH2:27]2)[O:25][CH2:24][CH2:23]1>O1CCCC1.CCCCCC.O>[C:4]1([CH:3]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:1]3([CH2:30][CH2:31][C:26]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:27][CH2:28]3)[O:2]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(c1ccccc1)c1ccccc1Br
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: c1ccc(C2OC3(CCC4(CC3)OCCO4)c3ccccc32)cc1
Temperature: -50 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
To a cooled (-50° C.) stirred solution of 27.7 g of 2-bromobenzhydryl methyl ether in 80 ml of dry tetrahydrofuran is added dropwise under nitrogen 60 ml of 2.4 M n-butyllithium in hexane. The mixture is stirred for 2 hours and a solution of 15.9 g of 1,4-dioxaspiro[4.5]decan-8-one in 50 ml of dry tetrahydrofuran is added dropwise, maintaining the temperature at -40° to -30° C. The mixture is stirred overnight at -70° to +10° C., diluted with 100 ml of water and extracted with 100 ml of dichloromethane. The organic phase is washed with water (2×50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. A solution of the residue in 400 ml of ethanol is stirred with 50 ml of hydrogen bromide/ether at room temperature for 3 hours. The solvent is removed under reduced pressure and the remaining oil crystallizes from 100 ml of methanol to give 39.6% of product, mp 130°-132° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[Br:25][C:26]1[CH:31]=[CH:30][C:29](CO)=[C:28]([CH3:34])[CH:27]=1>C(Cl)Cl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:20][Br:24])=[C:28]([CH3:34])[CH:27]=1
Reactant: Cc1cc(Br)ccc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(Br)ccc1CBr
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.3 %

Procedure:
Triphenylphosphine (11.35 g, 43.27 mmol) followed by carbon tetrabromide (14.35 g, 43.27 mmol) were added to a solution of (4-bromo-2-methyl-phenyl)-methanol (7.25 g, 36 mmol) in CH2Cl2 (200 mL). The mixture was stirred at room temperature for 5 hours. The solution was concentrated to 15 mL. The residue was purified by flash column chromotography (1% to 10% EtOAc in Hexane) gave the product as brown oil (9.25 g, 81% yield). 1H NMR (400 MHz, CDCl3) δ: 2.39 (3H, s) 4.45 (2H, s) 7.17 (1H, d, J=8.08 Hz) 7.29 (2H, m) 7.30 (1H, dd, J=8.08, 2.02 Hz) 7.34 (1H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH2:19][O:20][CH:21]2[CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33](OC)=[O:34])[CH:28]=3)[CH2:25][CH2:24][N:23]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:22]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH2:19][O:20][CH:21]2[CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][OH:34])[CH:28]=3)[CH2:25][CH2:24][N:23]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:22]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cc(OCc3ccccc3)c3ccccc3c2)c1
Agent: [BH4-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(CO)c2)C(OCc2cc(OCc3ccccc3)c3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(e), by reducing tert-butyl (3RS,4RS)-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-4-(3-methoxycarbonyl-phenyl)-piperidine-1-carboxylate with lithium borohydride there was obtained tert-butyl (3RS,4RS)-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-4-(3-hydroxymethyl-phenyl)-piperidine-1-carboxylate as a colourless solid; MS: 554 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([N:11]1[CH2:20][C:19]2[C:18](=[O:21])[NH:17][C:16]3[CH:22]=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:15]=3[C:14]=2[CH2:13][CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CS(C)=O.O>[C:3]([N:11]1[CH2:20][C:19]2[C:18](=[O:21])[N:17]([CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:16]3[CH:22]=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:15]=3[C:14]=2[CH2:13][CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1cc2[nH]c(=O)c3c(c2cc1OC)CCN(C(=O)c1ccccc1)C3
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c3c(c(=O)n(CCN4CCCCC4)c2cc1OC)CN(C(=O)c1ccccc1)CC3
Reaction time: 0.08 h
Yield: 88.1 %

Procedure:
A suspension of 0.066 m NaH in 75 cc dimethylsulfoxide was cooled in a cold water bath and treated portionwise with 10 g (0.028 m) of 3-benzoyl-1,2,3,4-tetrahydro-8,9-dimethoxy-benzo[c][2,7]naphthyridin-5(6H)-one in 10 min. After stirring for 5 min the reaction was treated with 5.5 g (0.03 m) of N-(2-chloroethyl)piperidine hydrochloride in 2 min. After stirring an additional 2 hr the reaction was diluted with water to 800 ml to give 11.5 g of crude solid product, used as is for hydrolysis.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([N:11]1[CH2:15][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:13][C:12]1=[O:24])[CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8].O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][C:14]1[CH2:15][N:11]([CH:4]([CH2:5][CH2:6][C:7]([CH3:8])([CH3:9])[CH3:10])[C:3]([OH:25])=[O:2])[C:12](=[O:24])[CH:13]=1
Reactant: COC(=O)C(CCC(C)(C)C)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)CCC(C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a flask was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5-dimethyl-hexanoic acid methyl ester (34 mg, 0.093 mmol) in tetrahydrofuran (2 mL). To this mixture at 25° C. was added a solution of lithium hydroxide monohydrate (8 mg, 0.19 mmol) in water (2 mL). The mixture was then stirred for 1.5 h at 25° C. and then treated with a 1N aqueous hydrochloric acid solution to pH=2 and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5-dimethyl-hexanoic acid (32 mg, 98% as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>ClCCl.C(OCC)(=O)C>[CH2:32]([O:31][C:29]([N:11]1[CH2:12][CH2:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:9][CH2:10]1)=[O:30])[CH3:33]
Reactant: Clc1ccc(C2(c3ccc(Br)cc3)CCNCC2)cc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC(c2ccc(Cl)cc2)(c2ccc(Br)cc2)CC1
Reaction time: 3 h
Yield: 94 %

Procedure:
To a stirring suspension of 4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine* (0.28 g, 0.80 mmol) in dichloromethane (10 ml), were added triethylamine (0.45 ml, 3.2 mmol) and ethyl chloroformate (0.085 ml, 0.88 mmol). The reaction mixture was stirred for 3 hours, diluted with ethyl acetate and washed with 1N HCl, saturated sodium hydrogen carbonate and brine. The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the title compound (0.29 g, 94% yield). LCMS: (PS-A2), Rt 4.02 [M+H]+ 422, 424.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:24]=3[F:32])[CH:14]=2)=[CH:9][CH:8]=1)[CH3:5].Cl[Sn]Cl>CO>[Cl:1][CH2:2][CH2:3][N:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=3[F:32])[CH:14]=2)=[CH:11][CH:12]=1)[CH3:5]
Reactant: CN(CCCl)Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1
Agent: Cl[Sn]Cl
Solvent: CO
Product: CN(CCCl)Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a solution of 86 (375 mg, 0.79 mmol) in MeOH (15 ml) was added SnCl2×2H2O (891 mg, 5, eq, 3.95 mmol) and the reaction mixture was heated to reflux for 3 hours. The mixture was cooled to RT and poured onto ice/water then basified to pH 9. The mixture was filtered and the aqueous solution was extracted with EtOAc and the EtOAc was washed with brine solution. The organic phase was collected, dried over Na2SO4, filtered and concentrated and the 4-(2-(4-(((2-chloroethyl)(methyl)amino)methyl)phe-nyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine (87) (348 mg, 100% yield) was used immediately in the next step with no additional purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[CH:10][S:9][C:8]=12.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.C(OCC)(=O)C>C1COCC1>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])[C:10]1[S:9][C:8]2=[C:4]([S:3][C:2]([F:1])([F:12])[F:13])[N:5]=[CH:6][N:7]2[CH:11]=1)[CH2:24][CH2:25][CH3:26]
Reactant: FC(F)(F)Sc1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SC(F)(F)F)c2s1
Temperature: -65 °C

Procedure:
7-Trifluoromethylthioimidazo[5,1-b]thiazole (590 mg) was dissolved in 10 ml of THF under an argon atmosphere, and the solution was cooled to −65° C. Tri-n-butylstannyl chloride (2.07 ml) and 7.2 ml of a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution were added dropwise in that order to the cooled solution. The temperature of the mixture was raised to −40° C. over a period of 30 min. Ethyl acetate (40 ml) was added to the reaction solution, and the mixture was washed with 40 ml of brine. The organic layer was dried over anhydrous magnesium sulfate, and was then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to prepare 951 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[CH:7]([NH:23][C:24](=[O:45])[CH:25]([NH:30]CC1C2C=CC=CC=2C2C1=CC=CC=2)[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>O1CCCC1>[C:1]([O:5][C:6](=[O:46])[CH:7]([NH:23][C:24](=[O:45])[CH:25]([NH2:30])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)CC(NCC1c2ccccc2-c2ccccc21)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CC(C)CC(N)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.8 %

Procedure:
A solution of the product from Example AH (3-(4-benzyloxy-phenyl)-2-{2-[(9H-fluoren-9-ylmethyl)-amino]-4-methyl-pentanoylamino}-propionic acid tert-butyl ester) (12.2 g, 20.0 mmol) in 500 mL of tetrahydrofuran was treated with piperidine (80 mL). The resulting solution was stirred at room temperature for 48 hours. The reaction mixture was concentrated and the residue purified by chromatography (silica gel, gradient elution EtOAc—15% EtOH/EtOAc). The resulting yellow solid was broken up in heptane to give the title compound as a white solid (6.77 g, 77%), mp=56-60° C.
Reaction SMILES: CC(C)([O-])C.[Na+].Cl.Cl.[NH2:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=1.Cl[C:20]1[CH:25]=[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:37])=[CH:22][N:21]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:37][C:23]1[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29](=[O:30])[NH:31][CH3:32])=[CH:25][C:20]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=2)=[N:21][CH:22]=1
Reactant: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Reactant: Nc1cnn(CC(=O)O)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1cc(Nc2cnn(CC(=O)O)c2)ncc1Cl
Temperature: 150 °C
Yield: 74.1 %

Procedure:
Sodium tert-butoxide (876 mg, 9.12 mmol) was added to a suspension of 2-(4-aminopyrazol-1-yl)acetic acid dihydrochloride (542 mg, 2.53 mmol) in 1,4-dioxane (15 mL). 2-[(2,5-Dichloropyridin-4-yl)amino]-N-methylbenzamide (300 mg, 1.01 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (94 mg, 0.16 mmol) were added and the resulting suspension was purged with nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (74.2 mg, 0.08 mmol) was added and the mixture was again purged with nitrogen. The mixture was heated at 150° C. for 60 minutes in a microwave reactor and then allowed to cool to room temperature. The mixture was evaporated and the residue partitioned between CH2Cl2 (60 mL) and a 0.1N solution of NaOH (60 mL). The aqueous layer was separated, washed with CH2Cl2 (30 mL) and then adjusted to pH4 by the addition of a 2N solution of HCl. The mixture was filtered and the filtrate evaporated. The residue was triturated with a 1:1 mixture of CH2Cl2/MeOH (150 mL), filtered and the solid washed with a 1:1 mixture of CH2Cl2/MeOH (3×150 mL). The combined filtrates were evaporated to afford 2-[4-[[5-chloro-4-[[2-(methylcarbamoyl)phenyl]amino]pyridin-2-yl]amino]pyrazol-1-yl]acetic acid (300 mg, 74% yield) which was used in the next step without further purification; 1H NMR spectrum: (300 MHz, DMSO) δ 2.78 (3H, d), 4.41 (2H, s), 6.68 (1H, s), 7.10 (1H, dd), 7.28 (1H, s), 7.51 (1H, dd), 7.57 (1H, d), 7.73 (1H, d), 7.77 (1H, s), 7.98 (1H, s), 8.66 (1H, s), 8.75 (1H, q), 10.04 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=401.3 and 403.3.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([SH:12])[NH:9]2)=[CH:4][C:3]=1[F:19].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH2:27]Br>CN(C)C=O>[CH2:16]([O:15][C:13]([C:7]1[C:6](=[O:18])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([F:19])[CH:4]=2)[N:9]2[CH2:26][CH2:27][S:12][C:8]=12)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1c(S)[nH]c2cc(Cl)c(F)cc2c1=O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3cc(Cl)c(F)cc3c1=O)CCS2
Temperature: 25 °C

Procedure:
Three grams (0.01 mol) of ethyl 7-chloro-6-fluoro-2-mercapto-4-oxo-1,4-dihydroquinoline-3-carboxylate was dissolved in 10 ml of dimethyl formamide, then 4.1 grams (0.03 mol) of anhydrous potassium carbonate was added thereto and, with stirring at a room temperature, 1.9 grams (0.01 mol) of ethylene dibromide was dropped thereinto. The mixture was stirred at a room temperature overnight. The content was concentrated under reduced pressure and water was added to the residue. Crystals separated out therefrom were collected by filtration immediately, washed with water, dried and the crystals were recrystallized from ethanol to give the title compound. Colorless crystals. Yield 3.5 grams (94 percent). All of melting point, elementary analysis data, infrared absorption spectra, and nuclear magnetic resonance spectra coincided with those in example 15.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].O=[C:7]([CH2:13][C:14](=O)[CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C>[OH:1][CH2:2][CH2:3][N:4]1[C:14]([CH3:15])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5]1
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: NNCCO
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(CCO)n1
Reaction time: 0.33 h
Yield: 113.5 %

Procedure:
A solution of 2-hydroxyethylhydrazine (15.2 g, 200 mmol) in ethanol (50 mL) was added over a period of 30 minutes to a solution of ethyl 2,4-dioxopentanoate (31.6 g, 200 mmol) in ethanol (200 mL). The reaction mixture was stirred for an additional 20 minutes and then concentrated under reduced pressure to provide 45 g of ethyl 1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-3-carboxylate a light brown oil. A portion (31.1 g) of this material was combined in a Parr vessel with methanol (25 mL) and concentrated ammonium hydroxide (25 mL). The vessel was sealed and the mixture was heated for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a brown resin. The resin was stirred with a mixture of chloroform and methanol until a solid appeared. The solid was isolated by filtration and then recrystallized from isopropanol to provide 7.01 g of 1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-3-carboxamide as a white solid. The rest of the ester was purified by IFC (silica gel eluting with a gradient of 50 to 100% ethyl acetate in hexanes) to provide 6.6 g of a pale yellow oil. This material was dissolved in concentrated ammonium hydroxide (25 mL) and allowed to stand at ambient temperature for 48 hours. A precipitate was isolated by filtration, rinsed with water, and dried to provide 3.74 g of 1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-3-carboxamide as white needles, mp 170-172° C. Anal. Calcd for C7H11N3O2: C, 49.70; H, 6.55; N, 24.84. Found: C, 49.59; H, 6.65; N, 24.92.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[O:9]=C(CCC([O-])=O)C([O-])=O>>[OH:9][C@@H:6]1[CH2:7][CH2:8][NH:1][C@@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C([O-])CCC(=O)C(=O)[O-]
Reactant: O=C(O)[C@@H]1CCCN1
Product: O=C(O)[C@H]1NCC[C@H]1O
Reaction time: 0.5 h

Procedure:
The enzyme reaction using purified L-proline-3-hydroxylase obtained in Example 5 was carried out. The reaction mixture was composed of 200 mM TES buffer (pH 7.0), 20 mM L-proline, 20 mM 2-ketoglutarate, 5 mM L-ascorbic acids 1 mM, ferrous sulfate, and 106 U of purified enzyme preparation, the total volume being 100 μl. The reaction was carried out at 35° C. for 30 minutes. As a result of the reaction, 18mM (2.4 g/1) of cis-3-hydroxy-L-proline was produced in the reaction mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:22]([C:26](Cl)=[O:27])=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]1=[O:29].[F:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=1[C:38]([F:41])([F:40])[F:39].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:22]([C:26]([NH:35][C:34]3[CH:36]=[CH:37][C:31]([F:30])=[C:32]([C:38]([F:41])([F:39])[F:40])[CH:33]=3)=[O:27])=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]1=[O:29]
Reactant: COc1cc2nccc(CN3CCc4c(C(=O)Cl)cccc4C3=O)c2cc1OC
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2nccc(CN3CCc4c(C(=O)Nc5ccc(F)c(C(F)(F)F)c5)cccc4C3=O)c2cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.5 %

Procedure:
2-((6,7-dimethoxyquinolin-4-yl)methyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carbonyl chloride (75 mg, 0.168 mmol) was suspended in dichloromethane (1 mL) then added a solution of 4-fluoro-3-trifluoromethylaniline (36 mg, 0.201 mmol) in dichloromethane (0.5 mL) and N,N-diisopropylethylamine (65 mg, 0.504 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was purified directly by silica gel chromatography (3% methanol/dichloromethane) to afford 2-((6,7-dimethoxyquinolin-4-yl)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (46 mg) as a pale yellow solid. MS (ESI, pos. ion) m/z: 554.2 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=3)[CH2:18][CH2:17]2)=[O:15])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])[CH3:2]
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)=O)c(C)nc3OC)CC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)O)c(C)nc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
1-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(100 mg, 0.23 mmol) was dissolved in anhydrous ethanol(15 ml) and NaBH4 (8.66 mg) was added. The reaction solution was stirred at room temperature for 2 hours. The mixture was concentrated under the reduced pressure to remove ethanol and purified by column chromatography (ethylacetate:hexane=2:1) to obtain the titled compound.