Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)CO.[Br:5][C:6]1[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([CH:19]=O)=[C:8]([C:21]([O:23]CC)=O)[CH:7]=1.O.[NH2:27][NH2:28]>O>[Br:5][C:6]1[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9]2[CH:19]=[N:27][NH:28][C:21](=[O:23])[C:8]=2[CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1cc(Br)n(COCC[Si](C)(C)C)c1C=O
Solvent: OCCO
Solvent: O
Product: C[Si](C)(C)CCOCn1c(Br)cc2c(=O)[nH]ncc21
Temperature: 125 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To 2.1 L of ethylene glycol solution containing 430 g (1.14 mol) of ethyl 5-bromo-2-formyl-1-(2-trimethylsilylethoxymethyl)-1H-pyrrol-3-carboxylate obtained in Reference example 15-(f) was added 290 ml (5.98 mol) of hydrazine monohydrate at 60° C., and the mixture was stirred at 125° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water, and precipitated solid was collected by filtration and washed with water. The obtained crude solid was recrystallized from 3 L of a mixed solvent (toluene/cyclohexane=1/1 (V/V)) to obtain 289 g of the title compound as a beige solid. (Yield: 74%)
Reaction SMILES: [C:1]1([CH:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:12]/[CH:13]=[CH:14]\[CH2:15]Cl>>[C:1]1([C@@H:7]([N:8]2[CH2:15][CH:14]=[CH:13][CH2:12]2)[CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC/C=C\CCl
Reactant: NC(CO)c1ccccc1
Product: OC[C@@H](c1ccccc1)N1CC=CC1
Yield: 58 %

Procedure:
This was prepared from R-(−)-(2-phenylglycinol and cis-1,4-dichloro-2-butene in 58% yield according to the procedures similar to those described in Preparation 1.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:32][C:33]1[CH:38]=[C:37]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[O:12])=[CH:21][CH:20]=3)[CH:16]=[C:17]2[C:22]([N:24]2[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]2)=[O:23])[CH:36]=[CH:35][CH:34]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(Cl)c1)N1CCN(C2CCC2)CC1
Yield: 10 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless solid (10%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.I[CH2:26][C@H:27]1[O:31][C:30](=[O:32])[N:29]([C:33]2[CH:34]=[CH:35][C:36]3[S:41][CH2:40][C:39](=[O:42])[NH:38][C:37]=3[CH:43]=2)[CH2:28]1.CCN(C(C)C)C(C)C.Cl>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:26][C@H:27]5[O:31][C:30](=[O:32])[N:29]([C:33]6[CH:34]=[CH:35][C:36]7[S:41][CH2:40][C:39](=[O:42])[NH:38][C:37]=7[CH:43]=6)[CH2:28]5)[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: O=C1CSc2ccc(N3C[C@@H](CI)OC3=O)cc2N1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSc2ccc(N3C[C@@H](CN4CCN(c5cc6c(cc5F)c(=O)c(C(=O)O)cn6C5CC5)CC4)OC3=O)cc2N1
Temperature: 80 °C

Procedure:
A mixture of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxo-3-quinoline carboxylic acid (commercial; 331 mg), 6-((S)-5-iodomethyl-2-oxooxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one (prepared according to WO 2008/126034; 395 mg) and DIPEA (0.5 ml) in DMSO (6 ml) was heated at 80° C. for 24 h. The reaction mixture was allowed to reach rt, poured on 0.1N HCl (50 ml) and filtered. The resulting solid was purified by CC (DCM/MeOH 19:1 to 9:1 to 4:1, followed by DCM/MeOH 19:1+1% AcOH), affording after concentration under reduced pressure and subsequent stirring in MeOH/EA a beige solid.
Reaction SMILES: Cl.Cl.Cl[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([CH2:17][CH2:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][C:21]=2[F:32])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]1.[SH:33][C:34]1[S:35][CH2:36][CH2:37][N:38]=1.C(N(CC)CC)C>CN(C)C=O.O>[F:32][C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:20]=1[CH2:19][CH2:18][CH2:17][C:9]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][S:33][C:34]3[S:35][CH2:36][CH2:37][N:38]=3)[CH2:7][CH2:8]1)=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCCl)CC1
Reactant: SC1=NCCS1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCSC2=NCCS2)CC1
Temperature: 80 °C
Reaction time: 23 h
Yield: 21 %

Procedure:
A mixture of 0.7 g of ethyl 1-(2-chloroethyl)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate dihydrochloride, 0.18 g of 2-mercaptothiazoline and 0.63 cm3 of triethylamine in 10 cm3 of dimethylformamide was stirred under an inert atmosphere for 23 hours at a temperature in the region of 80° C. After cooling to about 20° C., the reaction mixture was taken up in water, extracted with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The evaporation residue was added to a solution of 0.18 g of 2-mercaptothiazoline and 0.06 g of 10% sodium hydride in 10 cm3 of dimethylformamide, and the mixture was then heated at a temperature in the region of 80° C. for 15 hours. After cooling to about 20° C., the reaction mixture was taken up in water, extracted with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure on a column of silica gel (particle size 70-200μ; diameter 2 cm; mass 40 g), eluting with a mixture of dichloromethane/ethanol (95/5 by volume) and collecting 10-cm3 fractions. Fractions 11 to 24 were combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.15 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(4,5-dihydrothiazol-2-ylthio)ethyl]piperidine-4-carboxylate was obtained in the form of a brown oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]([CH2:19][CH2:20]OS(C)(=O)=O)[CH2:12][CH2:13]OS(C)(=O)=O)[C:5]=2[O:4][CH2:3][CH2:2]1.[NH2:26][C@@H:27]([CH2:29][OH:30])[CH3:28].[Br-].[Li+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:12][CH2:13][N:26]([CH:27]([CH3:28])[CH2:29][OH:30])[CH2:20][CH2:19]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: C[C@@H](N)CO
Reactant: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cccc2c1OCCO2
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Product: CC(CO)N1CCN(c2cccc3c2OCCO3)CC1
Temperature: 82 °C

Procedure:
Dimesylate III (67.0 g, 0.17 mol), D-alaninol (14.0 g, 0.19 mol), lithium bromide (31.0 g, 0.35 mol), and potassium carbonate (74.8 g, 0.54 mol) are mixed together with acetonitrile (750 mL). The resulting suspension is refluxed (82° C.) for 27 h with monitoring by HPLC. The reaction mixture is cooled, filtered, and insoluble residue washed with acetonitrile. Mother liquor is concentrated to a small volume, filtered through 200 cm3 of silica gel, and eluted with 1.5 L of MeOH 10% in EtOAc. After removing solvent on rotary evaporator, the residue is redissolved in EtOAc (200 mL). This solution is washed with water (2×50 mL), dried with MgSO4 and concentrated to produce IV as thick golden oil that slowly crystallizes upon standing; yield 29.4 g (63%) and purity 88.3 area % (LC-MS). Melting point=91-92° C. 1H NMR (CDCl3) δ6.78 (t, J=7.5 Hz, 1H), 6.55 (m, 2H), 4.29 (m, 4H), 3.45 (dd, J=11, 5 Hz, 1H), 3.38 (t, J=11 Hz, 1H), 3.10 (br m, 4H), 2.86 (m, 3H), 2.63 (m, 2H), 0.96 (d, J=7.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1N.N([O-])=O.[Na+].[I-:14].[K+]>Cl.O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[I:14]
Reactant: [I-]
Reactant: Nc1cc(Cl)ccc1Br
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccc(Br)c(I)c1
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 63.7 %

Procedure:
A suspension of 2-bromo-5-chlorobenzenamine (11.348 g, 54.963 mmol) in concentrated HCl (100 mL) was cooled to 0° C. and treated dropwise over 20 minutes (using an addition funnel) with a solution of sodium nitrite (4.5506 g, 65.955 mmol) in water (20 mL). The reaction was stirred at 0° C. for 75 minutes. A solution of potassium iodide (27.372 g, 164.89 mmol) in water (50 mL) was added, and the reaction was stirred at 23° C. After 1 hour, the reaction was heated to 70° C. After 18 hours, the reaction was diluted with EtOAc (500 mL) and washed with water (300 mL), 2N NaOH solution (300 mL), saturated sodium thiosulfate solution (300 mL) and brine (250 mL), dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (eluant: hexane) affording 11.11 g of 1-bromo-4-chloro-2-iodobenzene.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:20]=[CH:19][C:14]2[O:15][CH2:16][CH2:17][O:18][C:13]=2[CH:12]=1)([O-])=O.C(O)(=O)C.O>[Fe].C1(C)C=CC=CC=1>[O:15]1[CH2:16][CH2:17][O:18][C:13]2[CH:12]=[C:11]([NH:10][C:5]3[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:20]=[CH:19][C:14]1=2
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc2c(c1)OCCO2
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Nc1ccccc1Nc1ccc2c(c1)OCCO2
Yield: 91.5 %

Procedure:
A mixture of 6.3 g (23 mmol) of N-(2-nitrophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-amine, 9.0 g (161 mmol) of iron powder, acetic acid (1 ml), water (35 ml) and toluene (70 ml) were heated to reflux for 8 hours. The reaction mixture was filtered aid to separate the waste. The organic layer of the filtrate was batched off, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 5.1 g (yield: 91%) of N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzene-1,2-diamine) as a brown liquid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][C:36]1[CH:65]=[CH:64][C:39]([C:40]([NH:42][C:43]2[CH:44]=[C:45]([C:57]3[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=3)[CH:46]=[CH:47][C:48]=2[NH:49]C(=O)OC(C)(C)C)=[O:41])=[CH:38][CH:37]=1.CN1CCOCC1>CN(C=O)C.O.C(#N)C>[NH2:49][C:48]1[CH:47]=[CH:46][C:45]([C:57]2[CH:58]=[CH:59][C:60]([F:63])=[CH:61][CH:62]=2)=[CH:44][C:43]=1[NH:42][C:40](=[O:41])[C:39]1[CH:64]=[CH:65][C:36]([NH:35][C:8](=[O:10])[CH2:7][N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])=[CH:37][CH:38]=1
Reactant: O=C(O)CN1CCCC1=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)c1ccc(NC(=O)CN2CCCC2=O)cc1
Temperature: 55 °C
Reaction time: 40 h

Procedure:
To the 2-(2-oxopyrrolidin-1-yl)acetic acid (186 mgs, 1.3 mmol) in DMF (3 mL), was added HATU (570 mg, 1.5 mmol), tert-butyl 3-(4-aminobenzamido)-4′-fluorobiphenyl-4-ylcarbamate (421 mg, 1.0 mmol) and NMM (0.3 mL, 3.0 mmol) and stirred at 55° C. for 40 hours. The reaction mixture was then diluted with water and acetonitrile and the precipitate was filtered, washed with water and dried and used further without purification. To the above BOC protected compound, 4.0 M HCl dioxane (7 mL) was added and stirred at room temperature for 2 hour. The reaction mixture was then diluted with ether and stirred. The resulting solid was filtered, washed with ether and dried to give the title compound. C25H23FN4O3 446.9 (M+1). 1H NMR (400 MHz, DMSO-d6): δ 10.60 (s, 2H); 8.12 (d, J=8.4 Hz, 2H); 7.86 (s, 1H); 7.75 (d, J=8.4 Hz, 2H); 7.73-7.68 (m, 2H); 7.61-7.56 (m, 2H); 7.31 (m, 2H); 4.07 (s, 2H); 3.43-3.40 (m, 2H); 3.44-3.39 (m, 1H); 2.24-2.22 (m, 2H); 1.98-1.92 (m, 2H).
Reaction SMILES: [Li].[C:2](#[N:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(O)(C)C.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[Cl-].[NH4+]>N.C1COCC1>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][C:3]1([C:2]#[N:9])[CH:8]=[CH:7][CH2:6][CH:5]=[CH:4]1)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccccc1
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(C#N)C=CCC=C1
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
Lithium (0.17 g, 24 mmol) was added in portions to a solution of benzonitrile (0.99 mL, 1.0 g, 9.7 mmol) and t-BuOH (0.93 mL, 0.72 g, 9.7 mmol) in NH3 (50 mL) and THF (10 mL) under N2 at −78° C. After 10 minutes, ethyl bromoacetate (2.2 mL, 3.3 g, 20 mmol) was added dropwise. After 1 hour, ammonium chloride (4.0 g, 75 mmol) was added in portions. The reaction mixture was slowly warmed to room temperature while the NH3 was removed with a stream of N2. Water (25 mL) was added, and the mixture extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), and concentrated under reduced pressure. Flash chromatography (SiO2. CH2Cl2) afforded 1.12 g (60%) of product as an oil.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=O)(C)(C)C.[NH2:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([CH3:41])[C@@:38]([OH:43])([CH3:42])[C@H:37]([NH:44]C(=O)OC(C)(C)C)[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([CH3:41])[C@@:38]([OH:43])([CH3:42])[C@H:37]([NH2:44])[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@]1(C)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnc3c2CCO3)C[C@@H](N)[C@@]1(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To a mixture of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (75 mg, 0.21 mmol), tert-butyl [(3R,4S,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (62 mg, 0.16 mmol) and HATU (196 mg, 0.515 mmol) in DMF (2.0 mL), DIPEA (123 mg, 0.952 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. DCM (2.0 mL) was added to the resulting residue followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (25 mg, 29%). LCMS calc. for C24H27F2N6O3S (M+H)+: m/z=517.2. found 517.0. 1H NMR (500 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.78 (s, 1H), 7.64-7.46 (m, 3H), 7.24 (t, J=8.6 Hz, 2H), 4.47 (t, J=9.1 Hz, 2H), 3.97 (s, 1H), 3.37 (t, J=8.5 Hz, 2H), 2.87-2.79 (m, 2H), 2.79-2.72 (m, 1H), 2.63 (dd, J=10.8, 4.6 Hz, 1H), 2.60-2.55 (m, 1H), 1.85-1.76 (m, 1H), 1.39 (br, 2H), 0.98 (s, 3H), 0.73 (d, J=6.8 Hz, 3H) ppm.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[S:10]1[C:18]2[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C:13]=2[CH:12]=[C:11]1[C:26](OC)=[O:27].CO.[Cl-].[Na+]>C1(C)C=CC=CC=1>[OH:27][CH2:26][C:11]1[S:10][C:18]2[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C:13]=2[CH:12]=1
Reactant: COC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2sc(CO)cc2C1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
DIBAL-H (11.1 mmol) was added to a −78° C. cold solution of 5-tert-butyl 2-methyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (1.5 g, 5.3 mmol) in dry toluene (30 ml). The reaction mixture obtained was stirred at −78° C. for 1.5 hours. The course of the reaction was monitored by thin layer chromatography. Methanol (12 ml) was then added to the reaction mixture, the mixture was warmed slowly to 25° C. and thereafter saturated sodium chloride solution was added. The reaction mixture was filtered over Celite and the filter cake was washed with ethyl acetate. The organic phases were concentrated under reduced pressure. The crude product obtained in this way was employed in the next stage without further purification. The crude yield was 1.4 g.
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH3:8][C:9]1[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23](Cl)=[C:24]([Cl:29])[N:25]=[N:26][C:27]=2[CH3:28])=[CH:18][CH:17]=1>C(OCC)(=O)C>[Cl:29][C:24]1[N:25]=[N:26][C:27]([CH3:28])=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)[C:23]=1[N:10]1[C:9]([CH3:8])=[CH:13][C:12]([CH3:14])=[N:11]1
Reactant: Cc1nnc(Cl)c(Cl)c1-c1ccc(Cl)cc1
Reactant: Cc1cc(C)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C)n(-c2c(Cl)nnc(C)c2-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
29 mg of sodium hydride (55% oil dispersion) was added to tetrahydrofuran. Into this, a tetrahydrofuran solution of 3,5-dimethylpyrazole was added dropwise. The resultant mixture was added dropwise into 0.20 g of 5-(4-chloro-phenyl)-3,4-dichloro-6-methylpyridazine while cooling with ice. The mixture was stirred overnight at room temperature. To the reaction mixture was added ethyl acetate, and the mixture was washed with dilute hydrochloric acid water and brine sequentially. The organic layer was dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.27 g of the resultant residue was subjected to silica gel column chromatography, to obtain 50 mg of 3-chloro-5-(4-chlorophenyl)-4-(3,5-dimethyl-1-pyrazolyl)-6-m ethylpyridazine (hereinafter, described as compound (2) of the present invention) and 59 mg of 4-chloro-5-(4-chlorophenyl)-3-(3,5-dimethyl-1-pyrazolyl)-6-m ethylpyridazine.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]4[CH2:24][O:23][C:22]([CH3:26])([CH3:25])[O:21]4)[CH:18]=[C:13]3[CH:12]=[C:11]2[C:27]([C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)=[CH:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:29]1([CH:28]=[C:27]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]4[CH2:24][O:23][C:22]([CH3:25])([CH3:26])[O:21]4)[CH:18]=[C:13]3[CH:12]=2)[C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC1(C)OCC(Cc2cnc3c(c2)cc(C(=CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n3S(=O)(=O)c2ccccc2)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OCC(Cc2cnc3[nH]c(C(=CC4CCCC4)c4ccc(S(C)(=O)=O)cc4)cc3c2)O1
Yield: 88.6 %

Procedure:
A solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (460 mg, 0.74 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 4 mL, 4 mmol) was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL) and then washed with a saturated aqueous ammonium chloride solution, brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (315 mg, 88.5%) as a light yellow solid: LC/MS m/e calcd for C27H32N2O4S [M+H]+ 481.63, observed 481.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:18]C)=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][NH2:27])=[O:25].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.O.C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][NH:27][C:12](=[O:14])[C@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:18])[C@@H:15]([OH:17])[CH3:16])=[O:25]
Reactant: CCc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2cccc(Cl)c2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-ethylphenylamino)-3-hydroxybutanoic acid (800 mg, 2.98 mmol), 3-Chlorobenzhydrazide (508 mg, 2.98 mmol) and anhydrous THF (40 mL) were placed in a 100 mL round bottomed flask and the mixture was cooled to −15° C. 1-Hydroxybenzotriazole hydrate (403 mg, 2.98 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (857 mg, 4.47 mmol) at −15° C. followed by triethylamine (0.62 mL, 4.47 mmol). The reaction mixture was maintained at −15° C. and stirred for 1 h after which, stirring continued overnight while the mixture slowly warmed to room temperature. Water (40 mL) was added to the reaction mixture followed by citric acid (4 g) while stirring. EtOAc (60 mL) was then added to the mixture and the phases were partitioned. The organic phase was then washed with saturated aqueous sodium bicarbonate (40 mL) and the organic phase dried (Na2SO4). EtOAc was removed under vacuum and replaced by chloroform (60 mL). The insoluble hydrazide was then separated from the mixture by filtration and dried under reduced pressure to furnish a white solid (855 mg, 68%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.7 (br s, 2H), 7.96 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.46-7.7 (m, 2H), 6.64 (d, J=8.6 Hz, 1H), 5.3 (d, J=7 Hz, 1H), 4.19-4.03 (m, 1H), 3.98-3.87 (m, 1H), 2.35 (s, 3H) and 1.26 (d, J=6.35 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O.[Cl-].[Na+].O>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Brc1ccc(OCc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 100.1 %

Procedure:
To a solution of 4-bromophenol (8.65 g, 50 mmol) in dimethylsulfoxide (100 mL) was added potassium t-butoxide (6.45 g, 57.5 mmol) and the mixture was stirred for 20 mins. Benzyl bromide (10.26 g, 60 mmol) was then added and the reaction was stirred for 1 hr. It was then diluted with brine (150 mL) and extracted with ethylacetate (3×200 mL). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was distilled under vaccuum (0.8 mm Hg) to afford 13.17 g of 4-benzyloxybromobenzene as a white solid (b.p. 150°-155° C.).