Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10](/[CH:24]=[CH:25]/[CH:26]=[O:27])[CH:11]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3].O1CCCC1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[OH:27][CH2:26]/[CH:25]=[CH:24]/[C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:14]([C:15]#[N:16])=[C:13]2[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1
Reactant: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(/C=C/C=O)cc23)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(/C=C/CO)cc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.8 %

Procedure:
To a solution of 2-isobutyl-4-(4-methylphenyl)-6-[(1E)-3-oxoprop-1-en-1-yl]quinoline-3-carbonitrile (4.04 g, 11.4 mmol) in methanol (30 ml)-tetrahydrofuran (30 ml) was added sodium borohydride (216 mg, 5.69 mmol) at 0° C. and the mixture was stirred at room temperature for 10 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 6-[(1E)-3-hydroxyprop-1-en-1-yl]-2-isobutyl-4-(4-methylphenyl)quinoline-3-carbonitrile (3.08 g, yield 76%) as yellow crystals. Subsequently, tert-butyl {[6-(3-hydroxypropyl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate was synthesized by a method similar to the method shown in Example 39(1).
Reaction SMILES: [F:1][C:2]1[C:10]([N:11]([S:18]([CH2:21][CH2:22][CH2:23][F:24])(=[O:20])=[O:19])S(CCC)(=O)=O)=[CH:9][CH:8]=[C:7]([F:25])[C:3]=1[C:4]([O-:6])=[O:5].[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[C:10]([NH:11][S:18]([CH2:21][CH2:22][CH2:23][F:24])(=[O:19])=[O:20])=[CH:9][CH:8]=[C:7]([F:25])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)[O-])c1F)S(=O)(=O)CCCF
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1c(F)ccc(NS(=O)(=O)CCCF)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
2,6-Difluoro-3-(N-(3-fluoropropylsulfonyl)propylsulfonamido)benzoate (38 g, 120 mmol) was dissolved in 5:2 THF/MeOH (250 mL), and a solution of lithium hydroxide (8.77 g, 366 mmol) in water (50 mL) was added. The reaction mixture was stirred at room temperature for four hours. The majority of the organic solvents were then removed in vacuo. 2.5N HCl (500 mL) was slowly added to the mixture, and the resulting solid was filtered and rinsed with cold ether to give 2,6-difluoro-3-(3-fluoropropylsulfonamido)benzoic acid as a solid (29.3 g, 81% yield). 1H NMR (400 MHz, CDCl3 ppm) 9.85 (s, 1H), 7.54 (dt, 1H), 7.21 (dt, 1H), 4.54 (td, 2H), 2.20-2.00 (m, 2H), 3.24-3.18 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8]([C:14](=O)/[CH:15]=[CH:16]/N(C)C)=[CH:9][N:10]([CH2:11][CH2:12][CH3:13])[C:5]2=[C:4]([CH3:21])[CH:3]=1.Cl.[NH:23]([C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)[C:24]([NH2:26])=[NH:25].[OH-].[Na+]>COCCO>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([C:14]3[CH:15]=[CH:16][N:26]=[C:24]([NH:23][C:27]4[CH:28]=[C:29]([S:33]([NH2:36])(=[O:34])=[O:35])[CH:30]=[CH:31][CH:32]=4)[N:25]=3)=[CH:9][N:10]([CH2:11][CH2:12][CH3:13])[C:5]2=[C:4]([CH3:21])[CH:3]=1
Reactant: CCCn1cc(C(=O)/C=C/N(C)C)c2nc(Cl)cc(C)c21
Reactant: N=C(N)Nc1cccc(S(N)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CCCn1cc(-c2ccnc(Nc3cccc(S(N)(=O)=O)c3)n2)c2nc(Cl)cc(C)c21
Temperature: 150 °C

Procedure:
A mixture of (E)-1-(5-chloro-7-methyl-1-propyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-3-(dimethylamino)prop-2-en-1-one (0.2 mmol), 3-guanidinobenzenesulfonamide hydrochloride (0.5 mmol) and NaOH (0.8 mmol) in 3 mL of 2-methoxyethanol was heated in a Microwave at 150° C. for 30 minutes. The reaction mixture was purified by column chromatography using EtOAc/PE (1:1, v/v) to elute 3-(4-(5-chloro-7-methyl-1-propyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyrimidin-2-ylamino)benzenesulfonamide which was re-crystallised from EtOAc to give white solid. 1H-NMR (DMSO-d6) δ: 0.92 (t, 3H, J=7.2 Hz, CH3), 1.87 (m, 2H, CH2), 4.42 (t, 2H, J=7.2 Hz, CH2), 7.19 (s, 1H, Ar—H or Ph-H), 7.34 (s, 2H, NH2), 7.43 (m, 1H, Ar—H or Ph-H), 7.49 (t, 1H, J=7.6 Hz, Ph-H), 7.62 (m, 1H, Ph-H), 8.02 (d, 1H, J=4.8 Hz, Pyrimidin-H), 8.55 (d, 1H J=5.2 Hz, Pyrimidin-H), 8.63 (s, 1H, Ar—H), 9.92 (s, 1H, NH). MS (ESI+) m/z 457.1245 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6]=2[CH:15]=1.[N+:16]([O-])([OH:18])=[O:17]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6]=2[CH:15]=1
Reactant: CCOC(=O)c1coc2ccc(Br)cc12
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1coc2cc([N+](=O)[O-])c(Br)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of ethyl 5-bromobenzofuran-3-carboxylate (95 g, 353 mmol) in CHCl3 (1000 mL), fuming HNO3 (192 mL, 95%) was added dropwise at −20° C. over 90 min and stirred at 0° C. for 1 hour. The reaction mixture was added to ice water and extracted with CH2Cl2. The organic layer was washed with NaHCO3 and brine. The solvent was removed by distillation to provide the crude product of ethyl 5-bromo-6-nitrobenzofuran-3-carboxylate (95 g, yield: 85%). It was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1.[C:15](#[N:18])[CH:16]=[CH2:17].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:17][CH2:16][C:15]#[N:18])[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1
Reactant: Cc1ccc2[nH]c3ccccc3c2c1
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)c1ccccc1n2CCC#N

Procedure:
The compound 6-methyl-9-cyanoethylcarbazole was prepared by stirring 6-methylcarbazole (0.05 mole) in acrylonitrile (0.20 mole) at 0°C. After adding about 1 cc. of benzyl trimethyl ammonium hydroxide, the mixture was stirred on a steam bath for one hour and then treated with boiling benzene (200 cc.). The benzene was distilled and evaporated to dryness. The yellow solid obtained was recrystallized from benzene with Norit treatment to yield 6-methyl-9-cyanoethylcarbazole as an off-white solid, melting range 124°-124.5°C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)[S:9][CH:10]=1)=O)C.[NH3:16]>CO>[NH:15]1[CH:14]=[CH:13][N:12]=[C:11]1[C:8]1[S:9][CH:10]=[C:6]([C:4]([NH2:16])=[O:3])[N:7]=1
Reactant: N
Reactant: CCOC(=O)c1csc(-c2ncc[nH]2)n1
Solvent: CO
Product: NC(=O)c1csc(-c2ncc[nH]2)n1
Temperature: 60 °C

Procedure:
A solution of 2-(1H-Imidazole-2-yl)-thiazole-4-carboxylic acid ethyl ester (190 mg) in 5 mL of MeOH is saturated with NH3 gas, and heated at 60° C. in a sealed tube overnight. After cooled, the reaction mixture is transferred to a round bottle flask and evaporated in vacuo to a solid. LRMS calcd 194, found 195 (MH+).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=1)([O-:17])=[O:16].OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][C:25]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)=[CH:9][CH:10]=2)=[O:26])=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)Nc1ccc(Nc2ccccc2)cc1
Reaction time: 15 h

Procedure:
1.84 g (10 mmol) of 4-aminodiphenylamine, 1.81 g (10 mmol) of 4-nitrophenylacetic acid and 1.48 g (11 mmol) of hydroxybenzotriazole in 40 ml of THF are dissolved successively in a 100 ml flask. Then 2.27 g (11 mmol) of 1,3-dicyclohexylcarbodiimide (DCC) is added and the reaction mixture is agitated for 15 hours. A precipitate of dicyclohexylurea (DCU) forms which is filtered and rinsed with 100 ml of ethyl acetate. The filtrate is then washed successively with 50 ml of a saturated solution of Na2CO3, 50 ml of water, 50 ml of a molar solution of HCl and finally 2×50 ml of salt water. The organic phase is dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is purified rapidly on a silica gel column (eluent:heptane/ethyl acetate 1/1). The purest fractions are collected and evaporated under vacuum in order to produce a brown powder. The product is used as it is in the following stage.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[C:15]([NH2:16])=[C:10]2[CH2:11][NH:12][CH2:13][CH2:14][C:9]2=[N:8]1)=[O:6])[CH3:3].C(N(CC)C(C)C)(C)C.[F:26][C:27]1[CH:28]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:30]=[C:31]([F:33])[CH:32]=1>ClCCl>[CH2:2]([O:4][C:5]([N:7]1[C:15]([NH2:16])=[C:10]2[CH2:11][N:12]([S:34]([C:29]3[CH:28]=[C:27]([F:26])[CH:32]=[C:31]([F:33])[CH:30]=3)(=[O:36])=[O:35])[CH2:13][CH2:14][C:9]2=[N:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)n1nc2c(c1N)CNCC2
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc2c(c1N)CN(S(=O)(=O)c1cc(F)cc(F)c1)CC2
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a suspension of 3-amino-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-2-carboxylic acid ethyl ester hydrochloride (36.2 g, 127.8 mmol) in anhydrous dichloromethane (1 L), at 0°-5° C., N,N-diisopropylethylamine (111.3 mL, 639 mmol) was added. To the resulting solution, 3,5-difluorobenzenesulfonyl chloride (27.17 g, 127.8 mmol) was added portionwise. The mixture was stirred at 0°-5° C. for 1 hour then at room temperature for 3 hours. The organic phase was washed with NaHCO3 saturated solution, water and brine, dried over sodium sulfate filtered and evaporated. The crude, was triturated with diethylether (500 mL) to obtain the title compound as yellowish solid (45.48 g, 92%).
Reaction SMILES: C(Cl)Cl.[C-:4]#[N:5].[Na+].Cl[C:8]([O:10][CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:9]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[C:4]([C:8]([O:10][CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:9])#[N:5]
Reactant: CCCCC(CC)COC(=O)Cl
Reactant: [C-]#N
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCC(CC)COC(=O)C#N
Temperature: -60 °C
Yield: 94.9 %

Procedure:
A solution of 600 ml. of methylene chloride and 4 grams (0.01 moles) of Aliquat 336 was charged into a 2 1. 3-neck round bottom flask and cooled to approximately -60° C. with a dry ice/acetone bath. An aqueous solution of 120 grams (2.45 moles) of sodium cyanide in 250 ml. of water was added dropwise to the reaction mixture to provide a slurry of reactants. Next, 385.38 grams (2.0 moles) of 2-ethylhexyl chloroformate was added to the mixture while maintaining the temperature below approximately -40° C. The external cooling was then removed from the reaction flask and the mixture was allowed to warm slowly. After 19 minutes the mixture had warmed to -25° C. and the external cooling was replaced. After 9 more minutes the temperature of the reaction mixture was -17° C. at which point 100 ml. of water, 200 ml. of carbon tetrachloride and 100 ml. of ice was added and the layers were allowed to separate. The organic phase was separated, and the aqueous phase was extracted twice with methylene chloride. The organic extracts were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated under reduced pressure and the residue was distilled under vacuum to provide 347.85 grams of 99.7% pure 2-ethylhexyl cyanoformate (94.9% yield). bp=95° C. (12- 15 mm).
Reaction SMILES: N#N.C(OC([C@@:13]1([C:23]([NH2:25])=[O:24])[CH2:17][CH2:16][CH2:15][N:14]1[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])=O)C1C=CC=CC=1>C(O)C.[Pd]>[CH2:18]([N:14]1[CH2:15][CH2:16][CH2:17][C@H:13]1[C:23]([NH2:25])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CCN1CCC[C@]1(C(N)=O)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)CCN1CCC[C@H]1C(N)=O
Yield: 111.5 %

Procedure:
A solution of 5.73 g of N2 -(benzyloxycarbonyl)-N1 -isopentyl-L-prolinamide in 600 ml of ethanol was hydrogenated over 0.8 g of 10% palladium-on-carbon catalyst for 3.75 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 3.4 g of N1 -isopentyl-L-prolinamide as an oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1([C:5](Cl)=[O:6])[CH2:4][CH2:3]1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][CH:10]=1>O1CCCC1>[Cl:1][C:2]1([C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:11][CH:10]=2)=[O:6])[CH2:4][CH2:3]1
Reactant: O=C(Cl)C1(Cl)CC1
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: C1CCOC1
Product: O=C1CCC(c2ccc(NC(=O)C3(Cl)CC3)cc2)=NN1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.8 %

Procedure:
A solution of 4.45 g (32.0 millimoles) of 1-chlorocyclopropanecarboxylic acid chloride in 20 ml of absolute tetrahydrofuran is added dropwise to a stirred suspension of 5.0 g (26.4 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone in 100 ml of absolute tetrahydrofuran. The mixture is then stirred for 20 hours at room temperature followed by 1 hour under reflux. The product is filtered off at 10° C., washed first with tetrahydrofuran and then with water, and recrystallized from dimethylformamide/water. 6.3 g (82% of theory) of 6-[p-(1-chlorocyclopropylcarbonylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone are isolated as colorless crystals, of melting point 231°-232° C.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:28][OH:29])=[CH:5][CH:4]=1
Reactant: NO
Reactant: Cc1cccc(C(CC(=O)c2ccncc2)c2ccc(N(C)C)cc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cccc(C(CC(=NO)c2ccncc2)c2ccc(N(C)C)cc2)c1

Procedure:
In analogy to example 1, step 2, from 3-(4-dimethylamino-phenyl)-1-pyridin-4-yl-3-m-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3:1) as a yellow foam, MS (ESI+): m/z=360.1 ([M+H]+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][CH:21]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)Cl>C1COCC1>[CH2:7]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][OH:25])=[CH:28][CH:29]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a 0° C. slurry of LAH (13.0 g, 343 mmol) in dry THF (400 mL) was added slowly methyl 4-dodecyloxybenzoate (100 g, 312 mmol) in dry THF (350 mL) over 1.5 hours. Upon addition, the mixture was stirred at room temperature for one hour, after which TLC (CH2Cl2) showed completion. Reaction was cooled to 0° C. and quenched by successive addition of H2O (13 mL), 15% NaOH (13 mL), and H2O (39 mL), and stirring continued until H2 evolution ceased. Reaction mixture was then filtered and the lithium salts rinsed generously with CH2Cl2. The filtrate was dried over MgSO4 and concentrated to give the title benzyl alcohol (80 g, 88%), which was taken to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[O:29][CH3:30]>O1CCCC1>[CH3:30][O:29][C:28]([NH:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1)=[O:31]
Reactant: Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Temperature: -10 °C
Yield: 49.1 %

Procedure:
A well stirred mixture of a solution of benzyl 4-amino-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (464 mg, 1.74 mmol) and triethylamine (0.49 mL, 3.47 mmol) in tetrahydrofuran was cooled to −10° C. and treated drop wise with methyl carbonochloridate (0.15 mL, 1.92 mmol). The reaction mixture was stirred at room temperature for 30 minutes followed by removal of volatiles under vacuum. The residue was dissolved in ethyl acetate and organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to yield benzyl 4-[(methoxycarbonyl)amino]-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (278 mg, 49.13%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:26]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27]1>>[CH:26]1([C:30]([NH:1][C:2]2[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]3[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:24])([F:25])[F:23])=[C:17]([CH3:19])[CH:18]=3)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=2)=[O:31])[CH2:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CCC1
Reactant: Cc1cc(C(C)NC(=O)c2ccnc(N)n2)cnc1OCC(F)(F)F
Product: Cc1cc(C(C)NC(=O)c2ccnc(NC(=O)C3CCC3)n2)cnc1OCC(F)(F)F

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.06 mmol, Step-1 of Example 223, single enantiomer) and cyclobutanecarbonyl chloride (33 mg, 0.28 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]([OH:17])[C:6]=2[CH:7]=1)[CH3:2].[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=1)(=[O:21])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]([O:17][C:25]3[CH:26]=[CH:27][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:23][CH:24]=3)[C:6]=2[CH:7]=1)[CH3:2]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: CCOC(=O)c1cc(O)c2cc(CC)oc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CC)oc2c1
Temperature: 100 °C
Yield: 60.6 %

Procedure:
A mixture of ethyl 2-ethyl-4-hydroxy-1-benzofuran-6-carboxylate (0.80 g, 3.4 mmol), 4-fluorophenyl methyl sulfone (0.60 g, 3.4 mmol) and Cs2CO3 (1.12 g, 3.4 mmol) in DMF (40 mL) was heated to 100° C. overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 4:1). The mixture was poured into water (50 mL) and extracted with EtOAc (90 mL×3). The organic layer was washed with brine (50 mL×2), dried over Na2SO4 and concentrated. The product was purified via column chromatography on silica gel eluted with petroleum ether/EtOAc (20:1) to afford the desired compound (0.80 g, 60%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>ClCCCl.C(Cl)(Cl)Cl>[CH3:29][S:30]([N:1]([S:30]([CH3:29])(=[O:32])=[O:31])[C:2]1[CH:3]=[C:4]([C:10]2[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[N:19][C:20]3[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)cc1N
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)cc1N(S(C)(=O)=O)S(C)(=O)=O

Procedure:
To a solution of 3,4-dihydro-6-(3-amino-4-methoxyphenyl)-1,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.39 g) in 1,2-dichloroethane (5 ml) were added methanesulfonyl chloride (0.40 ml) and triethylamine (0.52 ml) successively, and the mixture was refluxed for 2.5 hours. After cooling, the reaction mixture was dissolved in chloroform, and washed with water. The organic layer was dried over magnesium sulfate, evaporated, and crystallized from ethanol to give 3,4-dihydro-6-[3-(dimethanesulfonylamino)-4methoxyphenyl]-1,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2-(1H)-pyrimidinone (0.33 g).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])C>OS(O)(=O)=O>[CH:4](=[O:3])[C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCC#CC(OCC)OCC
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCC#CC=O

Procedure:
A mixture of 2-pentadecynal diethyl acetal (4 g) and 10% aqueous H2SO4 (60 ml) was refluxed with efficient stirring, for one hour. An additional 40 ml dilute H2SO4 was added at this stage and the mixture heated for another two hours. After cooling, the reaction mixture was extracted with CH2Cl2, the extract dried (Na2SO4) and evaporated in vacuo to provide a yellow oil. Yield: 2.9 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[C:5](=[CH:15]\[N:16](C)C)/[C:6](=O)[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH3:2].Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28]N)=[CH:24][CH:23]=1>CO>[CH2:1]([O:3][C:4]([C:5]1[CH:15]=[N:16][N:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[C:6]=1[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[O:19])[CH3:2]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)C(OCC)OCC
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1C(OCC)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[1-dimethylamino-meth-(Z)-ylidene]-4,4-diethoxy-3-oxo-butyric acid ethyl ester (625 mg, 2.28 mmol) in methanol (10 mL) is added 4-fluorophenylhydrazine hydrochloride (410 mg, 2.5 mmol). The mixture is warmed at reflux. After 2 hours, the reaction mixture is cooled to room temperature, concentrated in vacuo, diluted with water (15 mL) and extracted with ether (3×15 mL). The combined ether layers are washed with brine (2×15 mL), dried over magnesium sulfate, filtered and concentrated. The residue is purified by silica gel chromatography eluting with a gradient of 0-10% EtOAc in hexanes to afford 5-diethoxymethyl-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+].[Cl-].[Na+]>CO>[F:10][C:6]1[CH:7]=[N:8][CH:9]=[C:2]([F:1])[C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1c(F)cncc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: OCc1c(F)cncc1F

Procedure:
At RT, 11.60 g of 3,5-difluoroisonicotinaldehyde (Example 113A, 81 mmol, 1 equivalent), dissolved in 100 ml of methanol, were added to 3.68 g of sodium borohydride (97.3 mmol, 1.2 equivalent) in 200 ml of methanol. After the evolution of gas had ceased (about 2 h), 200 ml of saturated aqueous sodium chloride solution were added and the mixture was extracted twice with in each case 200 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated. This gave 9.5 g (81% of theory) of the title compound.