Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].CCO.[CH3:6][O:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[N:10](C(OCC)=O)[N:9]=1.Cl>O>[CH3:6][O:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[NH:10][N:9]=1
Reactant: CCOC(=O)n1nc(OC)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
Potassium hydroxide (0.6 g) was added to an EtOH (20 ml) solution containing ethyl 3-methoxy-5-nitro-1H-indazol-1-carboxylate (1.24 g) obtained in the 3rd step, followed by stirring at room temperature for 0.5 hours. Water and concentrated hydrochloric acid (1 ml) were added dropwise to the reaction solution. A solid precipitate was collected by filtration and washed with water. A light yellow solid of 3-methoxy-5-nitro-1H-indazole (636 mg) was thus obtained.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[C:27]([F:30])([F:29])[F:28])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.ClC1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[ClH:37].[F:30][C:27]([F:28])([F:29])[C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1
Reactant: Fc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2)c(C(F)(F)F)c1
Agent: Cl
Agent: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Product: Fc1ccc(C(OC2CNC2)c2ccc(Cl)cc2)c(C(F)(F)F)c1

Procedure:
This material was prepared from 1-benzhydryl-3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydryloxy]azetidine (124) (3.8 mmol) using the procedure described for compound (9) (1.45 g, 97%).
Reaction SMILES: Br[C:2]1[C:7]([SiH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][N:3]=1.[Br-].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Zn+].N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[CH:11]1([C:5]2[CH:6]=[C:7]([SiH:8]([CH3:10])[CH3:9])[C:2]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)=[N:3][CH:4]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: [Zn+]c1ccccn1
Reactant: C[SiH](C)c1cc(C2CCCCC2)cnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Agent: [Br-]
Solvent: C1CCOC1
Product: C[SiH](C)c1cc(C2CCCCC2)cnc1-c1ccccn1
Temperature: 25 °C

Procedure:
To a reaction container equipped with a cooling apparatus, 2.61 g of tetrakis(triphenylphosphine)palladium, 6.75 g of 2-bromo-5-cyclohexyldimethylsilylpyridine obtained in the above-mentioned Example 2-1 and 135 mL of tetrahydrofuran were added. To the obtained mixture, 45.26 mL of 2-pyridyl zinc bromide (0.5 M/tetrahydrofuran solution) was added with stirring at room temperature. The obtained mixture was stirred at 50° C. for 9 hours to effect reaction. The reaction mixture was cooled until room temperature and then, 200 mL of 28% aqueous ammonia solution was added thereto. The obtained mixture was extracted three times with 230 mL of chloroform. The obtained organic layers were mixed and dried with magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated to obtain a crude product. The crude product was purified with silica gel column chromatography followed by further distillation to obtain 4.04 g of 5-cyclohexyldimethylsilyl-2,2′-bipyridine.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.CN1CCOCC1.[C:24]1([CH2:30][S:31](Cl)(=[O:33])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:30]([S:31]([NH:1][C:2]1[C:3](=[O:16])[N:4]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:33])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)Cn1cccc(N)c1=O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)Cn1cccc(NS(=O)(=O)Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of 3-amino-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.12 g, 5.0 mmol), and N-methylmorpholine (1.5 mL, 10.0 mmol) in methylene chloride (40 mL) was added α-toluenesulfonyl chloride (950 mg, 5.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Additional methylene chloride (50 mL) was added. The resulting solution was washed with saturated NaHCO3 (2×50 mL), 10% citric acid (3×50 mL) and brine (50 mL), and dried over Na2SO4 and filtered and the filtrate was concentrated to give a solid which was washed with ethyl acetate/hexane (1:2, 60 mL) to give the title compound as a white solid (1.8 g, 96%). 1H-NMR (300 MHz, CDCl3) δ7.42 (br s, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.31 (m, 5H), 6.92 (d, J=7.0 Hz, 1H), 6.14 (t, J=7.2 Hz, 1H), 4.58 (s, 2H), 4.34 (s, 2H), 1.51 (s, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>C1COCC1>[S:1]1[C:5]([CH:20]([OH:21])[C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=2)=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=Cc1ccc(Cl)cc1
Reactant: c1ccc2sccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)c1cc2ccccc2s1

Procedure:
a-(2-benzo[b]thienyl)-4-chlorobenzyl alcohol was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 m, 9.7 mmoles, 5.7 ml), 4-chlorobenzaldehyde (9.7 mmoles, 1.4 g) and THF (20 ml). The crude material (2.45 g) was taken forward without further purification.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1>ClCCl>[CH2:2]([C:1]([CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:4])[CH3:3]
Reactant: CCC(=O)Cl
Reactant: Cc1ccncc1
Solvent: ClCCl
Product: CCC(=O)Cc1ccncc1
Reaction time: 8 h

Procedure:
19.8 g of propionyl chloride dissolved in 20 ml of dichloromethane was added dropwise over 1 hour to 10 gm of 4-methylpyridine dissolved in 50 ml dichloromethane and maintained below 10° C. After addition, the reaction was brought to ambient temperature, stirred for 8 hours, then brought to reflux for 1 hour. The reaction mixture was quenched into saturated sodium carbonate solution, the organic layer separated and the solvent removed under reduced pressure. The residual 4-methylpyridine was removed by azeotropic distillation under reduced pressure with toluene. Ethanol was added and the mixture refluxed for 6 hours. The solvent was removed under reduced pressure to give 4.45 g of good (4-pyridinylmethyl) ethyl ketone.
Reaction SMILES: B(Br)(Br)Br.C[N:6]([C:11](=[O:33])[C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[C:23]([OH:29])=[C:22]([C:30]#[N:31])[CH:21]=2)=[C:14]([Cl:32])[CH:13]=1)[CH2:7][C:8]([OH:10])=[O:9]>ClCCl>[Cl:18][C:16]1[CH:17]=[C:12]([CH:13]=[C:14]([Cl:32])[C:15]=1[O:19][C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[C:23]([OH:29])=[C:22]([C:30]#[N:31])[CH:21]=1)[C:11]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:33]
Reactant: CC(C)c1cc(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc(C#N)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(C(=O)NCC(=O)O)cc2Cl)cc(C#N)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
Boron tribromide (1 N in dichloromethane, 0.11 mL) was added to a solution of methyl-N-[3,5-dichloro-4-(3-cyano-4-hydroxy-5-isopropylphenoxy)benzoyl]glycine (7 mg, 16 μmol) in dichloromethane (0.5 mL) at −78° C. The resulting reaction mixture was stirred at room temperature for 16 h and thereafter quenched by ice water. The organic solvent was removed with evaporation and the remaining residue was acidified by hydrochloric acid (1 N) and extracted by ethyl acetate. Drying over sodium sulfate, concentration and purification on a silica SPE column (0.5 g, 3 mL, gradient elution: chloroform/methanol/acetic acid from 1:0:0 to 98:2:0.5) gave 3 mg (44%) of N-[3,5-dichloro-4-(3-cyano-4-hydroxy-5-isopropyl-phenoxy)benzoyl]glycine. LC-MS (ES−1): m/z 421.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([OH:19])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[S:23].[H-].[Na+].[OH-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][C:22]([N:21]([CH3:25])[CH3:20])=[S:23])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CN(C)C(=S)Cl
Reactant: Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(C)C(=S)Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of 65.0 g of 3-chloro-2-(4-chloro-3-hydroxyphenyl)-5-trifluoromethylpyridine in 200 ml of dimethylformamide, and then 31.3 g of dimethylthiocarbamoyl chloride, were added dropwise to a suspension of 6.7 g of 80% sodium hydride in 300 ml of anhydrous dimethylformamide. The solution was stirred at 80° C. for one hour and then poured into 2.5 1 of 1% by weight sodium hydroxide solution. After extraction three times with 250 ml of tert-butyl methyl ether each time the combined organic phases were washed twice with 150 ml of water each time and then dried over sodium sulfate and concentrated until crystallization started. After removal of the crystals, the mother liquor was concentrated further until more of the product started to crystallized out.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].O.[OH-].[Li+].C(O)C.O.O1CCCC1>O>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(N2CCC(NC(=O)OC(C)(C)C)C2)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)c(C(=O)O)c2)C1
Yield: 99.6 %

Procedure:
Prepared as described in Example 5b) using (+/−)-2-chloro-5-[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-pyrrolidinyl]-benzoic acid, ethyl ester (Example 7a, 0.25 g), lithium hydroxide monohydrate (1.36 ml of a 3M solution in water), 1:1 ethanol/water (7 ml) and tetrahydrofuran (1 ml) to give the subtitle compound as a solid (0.23 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22][OH:23])[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][O:23][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cccc(Cl)c1
Product: CN1c2cc(OCc3cccc(Cl)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3-chlorophenyl)methanol.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](OCC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:29])[N:27]=2)[CH2:22]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reactant: C1COCCN1
Agent: C[Al](C)C
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N3CCOCC3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (1.0 g, 2.14 mmol) (obtained as described in Reference Example 2(1)) in benzene (50 ml) was added a solution of 0.67M morpholine-trimethylaluminium in benzene (6.42 ml) at room temperature under an atmosphere of nitrogen. The reaction mixture was heated under reflux for 2 hours. After checking the completion of the reaction, 10% aqueous acetic acid solution (50 ml) and ethyl acetate (100 ml) were added to the reaction mixture in an ice bath, and then the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→1:3) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-morpholinocarbonyl-1,3-thiazol-2-yl)azetidine (1.05 g, yield 97%) as a pale brown solid.
Reaction SMILES: [CH2:1]([N:8]1[C:18](=O)[C:17]([F:21])([F:20])[C:11]2([S:16][CH2:15][CH2:14][CH2:13][S:12]2)[C:10]([F:23])([F:22])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([N:8]1[CH2:9][C:10]([F:22])([F:23])[C:11]2([S:12][CH2:13][CH2:14][CH2:15][S:16]2)[C:17]([F:21])([F:20])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N(Cc2ccccc2)C(=O)C(F)(F)C2(SCCCS2)C1(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: FC1(F)CN(Cc2ccccc2)CC(F)(F)C12SCCCS2

Procedure:
React 4.9 mmol of the product of Example 21 with lithium aluminum hydride, using the general procedure set forth in Example 1. Purify by silica gel chromatography using methylene chloride/methanol/saturated NH4OH as eluant to yield the title compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[C:7]2[N:13]=[CH:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)=[C:17]([O:31][CH3:32])[CH:16]=3)[C:8]2=[N:9][CH:10]=1)[NH2:4].[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46](O)=O)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:32][O:31][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:14][N:11]1[C:8]2=[N:9][CH:10]=[C:5]([C:3]3[N:4]=[C:46]([CH:43]4[CH2:44][CH2:45][N:40]([C:38]([O:37][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:39])[CH2:41][CH2:42]4)[O:1][N:2]=3)[CH:6]=[C:7]2[N:13]=[CH:12]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(C(N)=NO)cnc43)cc2OC)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(-c5noc(C6CCN(C(=O)OC(C)(C)C)CC6)n5)cnc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a stirred solution of N′-hydroxy-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine-6-carboximidamide (0.38 g, 0.75 mmol) in N,N-dimethylformamide (10 mL) was added 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.21 g, 0.92 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.35 g, 0.92 mmol) and N,N-diisopropylethylamine (0.19 g, 1.50 mmol). The reaction mixture was stirred at room temperature. After 1 h, the mixture was diluted with ethyl acetate and brine. The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 1,4-dioxane (20 mL) and heated to 85° C. After 16 h, the reaction mixture was allowed to cool to room temperature and was concentrated. The crude product was purified by silica gel chromatography (2% methanol/dichloromethane elute) to provide 0.14 g (25%) of tert-butyl 4-(3-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:37])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]5([C:35]#[N:36])[CH2:34][CH2:33]5)[CH:27]=4)[CH:19]=3)=[N:13][N:12]2[CH:38]=1)=[O:7])(=O)C.[OH-].[Na+]>CO>[C:35]([C:32]1([C:28]2[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=2)[C:25]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([CH:38]=[C:9]([NH:8][C:6](=[O:7])[CH2:5][OH:4])[N:10]=4)[N:13]=3)[CH:19]=2)=[O:37])[CH2:34][CH2:33]1)#[N:36]
Reactant: CC(=O)OCC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)CO)cn5n4)c3)c2)CC1
Yield: 49.6 %

Procedure:
Using 2-{[6-(3-{[3-(1-cyanocyclopropyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]amino}-2-oxoethyl acetate (130 mg, 0.254 mmol), 1N aqueous sodium hydroxide solution (1.5 mL) and methanol (3 mL) as starting materials and in the same manner as in Example 396, the title compound (59 mg, 50%) was obtained as a pale-yellow powder.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:25]=[CH:24][C:10]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[N:21][OH:22])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[C:26]([C:28]1[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>O>[F:6][C:7]1[CH:25]=[CH:24][C:10]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][C:20]3[CH:27]=[C:26]([C:28]4[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=4)[O:22][N:21]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccc(F)cc2)nc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccc(F)cc4)nc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
To a tetrahydrofuran (10.0 mL) solution of (6-(4-fluoro-benzyloxy)-pyridin-3-yl)-acetohydroximoyl chloride (133 mg, 0.450 mmol) described in Manufacturing Example 58-1-5 and 3-ethynyl-pyridin-2,6-diamine (30.0 mg, 0.225 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (94.1 μL, 0.675 mmol), which was stirred for 3 hours at room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The is residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=3:1) to obtain the title compound (67.4 mg, 76.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:4]=1[CH2:5][N:6]([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[N:28](S(C3C=CC(C)=CC=3)(=O)=O)[C:29]([C:31]3[C:39]4[C:34](=[CH:35][C:36]([O:42][CH3:43])=[C:37]([O:40][CH3:41])[CH:38]=4)[N:33]([CH3:44])[CH:32]=3)=[CH:30][C:23]=12)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:4]=1[CH2:5][N:6]([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][C:36]([O:42][CH3:43])=[C:37]([O:40][CH3:41])[CH:38]=4)[N:33]([CH3:44])[CH:32]=3)=[CH:30][C:23]=12)[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=1)=[O:8]
Reactant: COc1ccc(CN(Cc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)C(=O)Nc2ccc(OC(F)(F)F)cc2)c(OC)c1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(CN(Cc2ccnc3[nH]c(-c4cn(C)c5cc(OC)c(OC)cc45)cc23)C(=O)Nc2ccc(OC(F)(F)F)cc2)c(OC)c1
Yield: 32.6 %

Procedure:
1-(2,4-Dimethoxybenzyl)-1-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]-3-(4-trifluoromethoxyphenyl)urea is prepared as described in Example 179a starting with 0.150 g of 1-(2,4-dimethoxybenzyl)-1-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]-3-(4-trifluoromethoxyphenyl)urea instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 1 cm3 of 5N potassium hydroxide. 0.040 g of 1-(2,4-dimethoxybenzyl)-1-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]-3-(4-trifluoromethoxyphenyl)urea is obtained, the characteristics of which are as follows:
Reaction SMILES: [H][H].C1OC1.[CH2:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C1OC1.C(C1(O)CCCCC1)CCCCCCCC>[CH2:6]([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: [H][H]
Reactant: CCCCCCCCCc1ccccc1O
Agent: CCCCCCCCCC1(O)CCCCC1
Solvent: C1CO1
Product: CCCCCCCCCC1CCCCC1

Procedure:
The consumed amount of hydrogen during the reaction was 136.6 mmoles and was 3.01 moles per 1 mole of charged nonylphenol ethylene oxide adduct. Nonylphenol ethylene oxide adduct residual in nonylcyclohexanol ethylene oxide adduct was determined by liquid chromatography. The amount was 120 ppm by weight. Further, nonylcyclohexane formed by hydrogenation decomposition reaction was determined by gas chromatography. The amount was 150 ppm by weight.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:10])=[C:7]([OH:9])[CH:8]=1)[CH3:2].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>CN(C=O)C>[C:14]([Si:11]([O:9][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]=1[F:10])([CH3:13])[CH3:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1ccc(F)c(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To 118A (3.75 g, 26.8 mmol) in DMF (20 mL) was added tert-butyldimethylsilyl chloride (6.1 g) and imidazole (2.6 g). The mixture was stirred at rt for overnight. It was then diluted with EtOAc/hexanes (1:4) and washed with water and brine. The organic extracts were dried and concentrated. The crude product was purified by column chromatography to give 118B (4.46 g, 66% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.21 (none, 6H) 0.99 (s, 9H) 1.18 (t, J=7.69 Hz, 3H) 2.54 (q, J=7.76 Hz, 2H) 6.64-6.76 (m, 2H) 6.93 (dd, J=10.55, 8.35 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([S:13][CH2:14][C:15](OC)=[O:16])=[N:6][CH:5]=1>C(O)(=O)C.[Fe]>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[N:6][C:7]2[S:13][CH2:14][C:15](=[O:16])[NH:10][C:8]=2[CH:9]=1)=[O:19]
Reactant: COC(=O)CSc1ncc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1cnc2c(c1)NC(=O)CS2
Temperature: 60 °C
Yield: 108.5 %

Procedure:
6-Methoxycarbonylmethylsulfanyl-5-nitro-nicotinic acid methyl ester (1.0 g) in acetic acid (50 mL) was treated with iron powder (10 g) and the mixture was stirred and heated at 60° C. for 1 hour, cooled and filtered. The filtrate was evaporated, treated with sodium bicarbonate solution and extracted with warm chloroform. It was dried (anhydrous sodium sulfate) and evaporated to give a white solid (0.85 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:18][O:19][C:20](=[O:25])[CH2:21][C:22](Cl)=[O:23]>>[CH3:18][O:19][C:20](=[O:25])[CH2:21][C:22]([NH:17][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:2]([F:1])[CH:3]=1)=[O:23]
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1ccc(OCc2cccc(F)c2)c(F)c1
Product: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)c(F)c1
Yield: 65 %

Procedure:
The title compound is prepared in analogy to example 1 from 3-fluoro-4-(3-fluoro-benzyloxy)-phenylamine and chlorocarbonyl-acetic acid methyl ester. Yield: 65%. Light yellow solid. MS: m/e=336.2 (M++H).