Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:5][S:4][CH2:3]1.[C:11]1([NH:17][C:18]([NH2:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C1CCCCC1>O>[C:11]1([NH:17][C:18]([NH:20][C:2]2[CH2:3][S:4][CH2:5][C:6]=2[C:7]([O:9][CH3:10])=[O:8])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C1CSCC1=O
Reactant: NC(=O)Nc1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: C1CCCCC1
Product: COC(=O)C1=C(NC(=O)Nc2ccccc2)CSC1

Procedure:
14.4 parts by weight of methyl 3-keto-3,4-dihydrothiophene-4-carboxylate, 16.1 parts by weight of phenylurea and 0.5 part by weight of toluenesulfonic acid in 90 parts by weight of cyclohexane were refluxed for 3 hours, while stirring, in an apparatus equipped with a water separator. The mixture was cooled, and the residue was then filtered off under suction and recrystallized from ethanol. 16.1 parts by weight of N-phenyl-N'-(3-methoxycarbonyl-2,5-dihydrothien-4-yl)-urea of melting point 182°-184° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+]([O-])=O)[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N+:7]=1[O-].[OH-].[Na+].C([Br:24])(=O)C>P(Br)(Br)Br>[Br:24][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[CH:5]=1
Reactant: Cc1cccc(-c2cc([N+](=O)[O-])cc(C)[n+]2[O-])n1
Reactant: CC(=O)Br
Agent: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(-c2cc(Br)cc(C)n2)n1
Temperature: 0 °C

Procedure:
6,6'-Dimethyl-4-nitro-2,2'-bipyridine-N-oxide (0.50 g, 2.0 mmoles) was dissolved in acetyl bromide (10.0 ml) and phosphorus tribromide (2.5 ml). After refluxing for 1.5 hours the mixture was poured into 100 g ice and the solution was neutralized with 30% sodium hydroxide solution. The mixture was extracted with chloroform, the chloroform phase was dried and evaporated. The product was purified by means of flash chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:12][C:13]([CH3:15])=[CH2:14]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][C:13]([CH3:15])=[CH2:12])=[CH:4][CH:3]=1
Reactant: C=C(C)CCl
Reactant: Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)COc1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
A mixture of 4chlorophenol (10 g, 0.78 mol) and sodium hydride (1.9 g, 0.08 mol) is heated to reflux for 30 min in 30 ml of THF and then cooled. 3-Chloro-2-methyl-1-propene (7.3 g, 0.08 mol) in 10 ml THF is added and the mixture is heated to reflux. After 24 hr, an additional equivalent of 3-chloro-2-methyl-1-propene is added and the mixture heated under reflux for another 24 hr. The reaction mixture is cooled and diluted with ether to 150 ml, washed with 20% NaOH (2X) and with water until neutral, then dried and solvent is removed to yield 3-(4-chloro-phenoxy)-2-methyl-1-propene.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)=[CH:6][C:5]([N:18]2[C:22](=[O:23])[N:21]([CH:24]([F:26])[F:25])[C:20]([CH3:27])=[N:19]2)=[C:4]([F:28])[CH:3]=1.C(O)(=O)C.O1CCCC1.O>C(OCC)C.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][C:4]([F:28])=[C:5]([N:18]3[C:22](=[O:23])[N:21]([CH:24]([F:25])[F:26])[C:20]([CH3:27])=[N:19]3)[CH:6]=2)=[N:10][CH:11]=1
Reactant: Cc1nn(-c2cc(Oc3ccc([N+](=O)[O-])cn3)c(Cl)cc2F)c(=O)n1C(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(-c2cc(Oc3ccc(N)cn3)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
Iron filings (3.6 g, 0.064 mole) were added slowly to a stirred mixture of 7.0 g (0.017 mole) of 1-[4-chloro-2-fluoro-5-(5-nitropyridin-2-yloxy) phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 25 mL of glacial acetic acid, 12 mL of tetrahydrofuran, and 5 mL of water. The reaction mixture was stirred at room temperature for three hours and was then diluted with 20 mL of diethyl ether. The mixture was filtered through a pad of Celite® filter aid, and the filtrate was stored at 5° C. to 10° C. for approximately 18 hours. The filtrate was neutralized by the addition of solid sodium bicarbonate and water. The organic phase was separated from the aqueous phase. The aqueous phase was extracted several times with diethyl ether, and the extracts were combined with the organic phase. The combined organic phase was washed first with water, then with an aqueous, saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 6.0 g of 1-[5-(5-aminopyridin-2-yloxy)-4-chloro-2-fluorophenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42](Cl)(=[O:44])=[O:43])#[N:35].O>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:42]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[C:34]#[N:35])(=[O:44])=[O:43])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Cl)cc4c32)cc1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3ccccc3C#N)c3cnc4ccc(Cl)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-chloro-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 2, 50 mg, 0.14 mmol) and triethylamine (28 mg, 0.28 mmol) in dichloromethane (6 ml) was added 2-cyanobenzene-1-sulfonyl chloride (42 mg, 0.21 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 24 mg (33%); 1H NMR (CDCl3, 300 MHz): δ 9.698 (s, 1H), 8.496-8.525 (d, 1H, 8.7 Hz), 8.093-8.123 (d, 1H, J=9 Hz), 7.823-7.920 (m, 3H), 7.71-7.739(d, 2H, J=8.7 Hz), 7.525-7.563 (dd, 1H, J=9.3, 2.1 Hz), 7.46-7.488(d, 2H, J=8.4 Hz), 6.863-6.870 (d, 1H, 2.1 Hz), 1.798 (s, 6H); MS: m/z 528 (M+).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:18](/[CH3:23])=[C:19](/[F:22])\[CH2:20][OH:21])[C:3]=1[O:24][CH2:25][CH3:26].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:6]=2[CH:5]=[C:4](/[C:18](/[CH3:23])=[C:19](/[F:22])\[CH:20]=[O:21])[C:3]=1[O:24][CH2:25][CH3:26]
Reactant: CCOc1c(/C(C)=C(/F)CO)cc2c(c1Br)C(C)(C)CC=C2C(C)(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCOc1c(/C(C)=C(/F)C=O)cc2c(c1Br)C(C)(C)CC=C2C(C)(C)C

Procedure:
As described in General Procedure H-1, (2E)-3-(4-bromo-8-tert-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-en-1-ol (Compound A-141, 45 mg, 0.11 mmol), tetrapropylammonium perruthenate (10 mg, 0.028 mmol) and 4-methylmorpholine N-oxide (31 mg, 0.26 mmol) were reacted in acetonitrile and dichloromethane to give the title compound after purification by flash column chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]([O:10][CH2:11][Cl:12])=[O:9]>C(Cl)Cl>[N:1]1([C:8]([O:10][CH2:11][Cl:12])=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)OCCl
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C(OCCl)N1CCOCC1
Reaction time: 0.25 h

Procedure:
Morpholine (1 equiv.) is slowly added to a 0.1M solution of chloromethyl chloroformate (10 equiv.) in methylene chloride at low temperature. After 15 min at low temperature and a suitable time at 25° C. the reaction mixture is filtered and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography giving chloromethyl morpholine-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][NH:18][CH:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.[H-].[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: Fc1ccc(Br)c(OC2CCN(c3noc(-c4cc[nH]c4)n3)CC2)c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)c1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-(2-bromo-5-fluorophenoxy)-1-[5-(1H-pyrrol-3-yl)-1,2,4-oxadiazol-3-yl]piperidine (60 mg, 0.15 mmol) in DMF (491 μL) was added sodium hydride (11.8 mg, 0.3 mmol). After 5 min, ethyl bromoacetate (25 μL, 0.22 mmol) was added and the mixture was heated at 80° C. for 3 h. The mixture was poured onto ice cold 1N HCl (2 mL) and extracted with EtOAc (3×2 mL). The combined organic fractions were washed with water (2 mL) and then dried over Na2SO4. The solvent was evaporated. Purification by Combiflash chromatography (SiO2-12 g, gradient elution of 30-60% EtOAc/hexanes over 25 min) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:16][NH2:17]>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([NH:17][CH3:16])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(F)cc1Cl
Reactant: CN
Product: CNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., to a stirred ice-water suspension (˜200 mL) of 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoic acid was slowly added a precooled 40% methylamine (13 mL). The reaction mixture was then stirred for 2 hours before being acidified to pH˜2. The desired product was precipitated and filtered out. After being dried overnight, the pure 2-chloro-4-fluoro-5-[(methylamino)sulfonyl]benzoic acid was obtained as white solid (9.8 g, 100%).
Reaction SMILES: [Cl:1][C:2]1([Cl:19])[C:8](=[O:9])[CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([O:17][CH3:18])[CH2:15][CH3:16].[N+](=[CH2:22])=[N-].CN(N=O)S(C1C=CC(C)=CC=1)(=O)=O.[OH-].[K+]>CCOCC.C(O)C.C(O)(=O)C>[Cl:19][C:2]1([Cl:1])[C:8](=[O:9])[CH2:22][CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([O:17][CH3:18])[CH2:15][CH3:16]
Reactant: CCC(CCCCC1CCC2C1C(=O)C2(Cl)Cl)OC
Reactant: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOCC
Product: CCC(CCCCC1CCC2C1CC(=O)C2(Cl)Cl)OC

Procedure:
The starting material, 6,6-dichloro-2-(5-methoxyhept-1-yl)bicyclo[3.2.0]heptan-7-one {7,7-dichloro-4-(5-methoxyheptyl)bicyclo[3.2.0]heptan-6-one} (5 g), is dissolved in 100 ml of ether and transferred to a 500 ml, round-bottomed flask. An excess of diazomethane is generated in situ by reacting N-methyl-N-nitroso-p-toluene sulfonamide (60 g) with potassium hydroxide in ethanol. The diaxomethane is allowed to react for 50 minutes, after which time acetic acid is added to destroy any remaining diazomethane. The solution is extracted with ether and dried over anhydrous sodium sulfate and yields the crude product as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([OH:10])=[C:4]([Cl:11])[CH:3]=1.[H-].[Na+].[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([O:10][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:4]([Cl:11])[CH:3]=1
Reactant: COCCOCCl
Reactant: CCc1cc(Br)cc(Cl)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc(Br)cc(Cl)c1OCOCCOC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A solution of 4-Bromo-2-chloro-6-ethyl-phenol dissolved in THF (10 mL) was added to a cooled 0° C. suspension of NaH (0.43 g, 10.8 mmol, 60% dispersion in mineral oil) in THF (20 ml). After the addition was complete the reaction mixture was warmed up to room temperature and stirred for 30 mins. 2-Methoxyethoxymethyl chloride (1.34 mL, 11.7 mmol) was added and the reaction was stirred for 15 hours. The reaction mixture was quenched with 1N HCl and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a yellow oil. Purification by flash column chromatography (0% to 10% EtOAc in hexanes) gave the title compound as a clear oil (2.4 g, 76%). 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J=7.3 Hz, 3H), 2.70 (q, J=7.6 Hz, 2H), 3.40 (s, 3H), 3.61 (m, 2H), 3.98 (m, 2H), 5.15 (s, 2H), 7.24 (s, 1H), 7.37 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[F:11])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1.CN1C(=O)N(C)CCC1.CCOC(C)=O>[F:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=1[C:2](=[O:3])[CH2:1][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC(=O)c1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCC(=O)c1c(F)cccc1F
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2,6-Difluoroacetophenone (5 g, 32 mmol) in dry THF (40 ml) and DMPU (8 ml) was added a solution of lithium bis(trimethylsilyl)amide (1.0M, 45 ml) at −60° C. under argon. After stirring for 10 minutes at −60° C., tert-Butyl bromoacetate (6.99 g, 35.8 mmol) was added rapidly. The reaction mixture was stirred for an additional 10 minutes and then warmed to room temperature for 4 hours. The crude mixture was taken in EtOAc and washed with water and brine. The aqueous layer was extracted one more time with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate, 2:1) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11](=O)[CH:10]([CH2:13][C:14](O)=[O:15])[N:9]([CH2:17][CH2:18][CH3:19])[C:8]2=[O:20])=[CH:4][CH:3]=1>C1COCC1>[OH:15][CH2:14][CH2:13][CH:10]1[CH2:11][N:7]([CH2:6][C:5]2[CH:21]=[CH:22][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8](=[O:20])[N:9]1[CH2:17][CH2:18][CH3:19]
Reactant: CCCN1C(=O)N(Cc2ccc(C)cc2)C(=O)C1CC(=O)O
Solvent: C1CCOC1
Product: CCCN1C(=O)N(Cc2ccc(C)cc2)CC1CCO
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A solution of [1-(4-methyl-benzyl)-2,5-dioxo-3-propyl-imidazolidin-4-yl]-acetic acid (3.23 g, 10.6 mmol) in THF (50 mL) is treated dropwise with 1 M solution of borane-THF complex in THF (53.1 mL, 53.1 mmol) and then stirred at room temperature under N2 for 4 hours. The reaction is quenched with methanol (30 mL) and stirred at room temperature for 16 hour. The solvent is removed to give crude product that is purified by flash chromatography using 97.5/2.5 CH2Cl2:MeOH to afford 2.46 g (84%) 4-(2-hydroxy-ethyl)-1-(4-methyl-benzyl)-3-propyl-imidazolidin-2-one. 1H NMR. MS (ES+) Calc'd for C16H25N2O2 (M+1) 277. Found m/z 277 (100%).
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:24][CH2:23][C:22]2[C:21]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:20][C:19]([NH2:36])=[CH:18][C:17]=2[CH2:16]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>ClCCCl>[F:35][C:32]([F:33])([F:34])[C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:21]2[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]=3[CH:18]=[C:19]([NH2:36])[CH:20]=2)=[CH:31][CH:30]=1
Reactant: Nc1cc2c(c(Nc3ccc(C(F)(F)F)cc3)c1)CCN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Nc1cc2c(c(Nc3ccc(C(F)(F)F)cc3)c1)CCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
1-Chloroethyl chloroformate (864 mg, 6 mmol) was added dropwise to the solution of 2-benzyl-N5-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-5,7-diamine (1.2 g, 3 mmol) and diisopropylethyl amine (774 mg, 6 mmol) in 1,2-dichloroethane (30 mL, anhydrous) at 0° C. After addition, the reaction mixture was stirred at room temperature for 1 hr. Solvent was removed in vacuo, residue was dissolved in methanol (10 mL) and was stirred at room temperature for 10 h. Solvent was removed in vacuo and solid residue was washed by diethyl ether. Product was obtained as a light brown solid (834 mg, 90%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]2[CH2:24][NH:23][CH2:22]2)=[CH:16][CH:15]=1>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:23]2[CH2:24][CH:21]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)[CH2:22]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: Fc1ccc(NC2CNC2)cc1
Product: COC(=O)c1cc(Cl)cnc1N1CC(Nc2ccc(F)cc2)C1
Yield: 78.4 %

Procedure:
The title compound (D84) (79 mg) was prepared according to the experimental procedure described in Description 62 starting from Methyl 2,5-dichloronicotinate (62.06 mg, 0.3 mmol) and N-(4-fluorophenyl)azetidin-3-amine (D54) (60 mg, 0.361 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:12]=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[S:14][CH:15]=1)[CH:6]=[CH:5]2.C(N(CC)CC)C.Cl[CH2:38][CH2:39][O:40][CH:41]=[O:42]>ClCCl>[CH2:39]([O:40][C:41]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:12]=[C:13]([O:16][CH:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]3)[S:14][CH:15]=1)[CH:6]=[CH:5]2)=[O:42])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nc(-n3ccc4cc(N)ccc43)cs2)CC1
Reactant: O=COCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc2c(ccn2-c2csc(OC3CCN(C(=O)OC(C)(C)C)CC3)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.6 %

Procedure:
To a stirred solution of tert-butyl 4-((4-(5-amino-1H-indol-1-yl)thiazol-2-yl)oxy)piperidine-1-carboxylate (intermediate-35) (0.100 g, 0.214 mmol) in dichloromethane (4 mL), triethylamine (0.036 g, 0.362 mmol), and chloroethylformate (0.026 g, 0.214 mmol) were added at 0° C. and stirred at room temperature for 10 minutes. The reaction was quenched with water and the mixture was extracted with dichloromethane. The organic layer was concentrated in vacuo and the residue was purified by flash column chromatography to give tert-butyl 4-((4-(5-((ethoxycarbonyl)amino)-1H-indol-1-yl)thiazol-2-yl)oxy)piperidine-1-carboxylate (0.010 g, 8.5%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:14])=O>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:14])=[N:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Product: O=[N+]([O-])c1cc(Br)cnc1Cl
Temperature: 100 °C
Yield: 45 %

Procedure:
To 5-bromo-3-nitropyridin-2-ol (78.A)(1 g, 5 mmol) was added 10 mL of phosphorus oxychloride. The reaction was heated at 100° C. for 1 hr., concentrated and worked up between EtOAc and saturated NaHCO3. The organic layer was concentrated, redissolved in DCM, filtered off the solids. The DCM layer was concentrated again to afford 450 mg (45%) of 78.B.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:16][C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: CSc1nsc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
Into 11 ml of N,N-dimethylformamide were dissolved 190 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 123 mg of benzyl alcohol, 59 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 0.5 hour under ice-cooling and for 4.5 hours at room temperature. The reaction mixture was added to saturated ammonium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 190 mg of 5-benzyloxy-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (1)).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:20])[C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]>N.CO.C1COCC1.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([N:9]([CH3:20])[C:10](=[O:19])[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)N(C)c2cccc(C#N)c2)cc1
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(=O)N(C)c2cccc(CN)c2)cc1
Reaction time: 14 h

Procedure:
450 mg (1.7 mmol) N-(3-Cyano-phenyl)-4-methoxy-N-methyl-benzamide were dissolved in 10 ml NH3 in methanol (10%) and 10 ml THF. 500 mg Sponge nickel catalyst were added and the mixture was hydrogenated for 14 h at 5 bar pressure. The mixture was filtered and the filtrate was evaporated.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][N:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2.OB(C)[C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:23]([O:22][C:20]([C:19]1[CH:18]=[C:17]([C:2]2[CH:10]=[CH:9][N:8]=[C:7]3[NH:6][C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=23)[CH:29]=[CH:28][CH:27]=1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CB(O)c1cccc(C(=O)OC(C)(C)C)c1
Reactant: COC(=O)c1cc2c(Cl)ccnc2[nH]1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc2c(-c3cccc(C(=O)OC(C)(C)C)c3)ccnc2[nH]1
Yield: 87.5 %

Procedure:
A stirred slurry of methyl 4-chloro-7-azaindole-2-carboxylate (100 mg, 0.48 mmol), tert-butyl 3-(hydroxy(methyl)boryl)benzoate (137 mg, 0.62 mmol), potassium phosphate (309 mg, 1.42 mmol), tetrakis(triphenylphosphine) palladium (28 mg, 0.02 mmol) in p-dioxane (3 mL)/water (1 mL) were heated at 100° C. for 15 hr. The reaction mixture was cooled, concentrated in vacuo and flash chromatographed (0-100% ethyl acetate:heptanes) to afford methyl 4-(3-(tert-butoxycarbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate as a white powder (148 mg). 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.62 (s, 9H) 3.99 (s, 3H) 7.28 (d, J=5.23 Hz, 1H) 7.36 (d, J=2.62 Hz, 1H) 7.59 (t, 1H) 7.90 (d, 1H) 8.09 (d, 1H) 8.35 (t, 1H) 8.64 (d, J=4.70 Hz, 1H); m/z (M+1)=353.2.