Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].O[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=2)[C:20](=[O:31])[N:19]1[CH2:32][C:33]([F:36])([F:35])[F:34].C(=O)([O-])O.[Na+]>C(COC)OC>[O:31]=[C:20]1[C:21]2[C:26](=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=2)[CH:18]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:19]1[CH2:32][C:33]([F:35])([F:34])[F:36]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C1c2ccc(C(F)(F)F)cc2C(O)N1CC(F)(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)CC1c2cc(C(F)(F)F)ccc2C(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 609.3 %

Procedure:
Under argon, ethyl (diethoxyphosphoryl)acetate (135 mg, 0.6 mmol) was dissolved in anhydrous dimethoxyethane (10 ml). 17.6 mg of NaH (60% in oil) were added at RT to this solution which was stirred at RT for 10 min. Afterward, a solution of 120 mg (0.04 mmol) of (RS)-3-hydroxy-2-(2,2,2-trifluoroethyl)-5-trifluoromethyl-2,3-dihydroisoindol-1-one in anhydrous dimethoxyethane (5 ml) was added and the mixture was subsequently stirred at reflux for 2 h. The reaction solution was left to cool; the reaction solution was then poured onto 50 ml of 5% sodium hydrogencarbonate solution and extracted twice with 20 ml each time of ethyl acetate; the organic phase was dried over MgSO4 and concentrated under reduced pressure, and the residue was purified by chromatography on silica gel using DIP as the eluent. 90 mg (61%) of ethyl (RS)-[3-oxo-2-(2,2,2-trifluoroethyl)-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl]acetate were obtained as a colorless oil which crystallized from heptane as a beige solid.
Reaction SMILES: [NH2:1][C@H:2]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][C:12]2=[O:18])[CH2:7][CH2:6]1)=[O:4].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C(#N)C>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:1][C@@H:2]([C:3]([N:5]2[CH2:10][CH2:9][CH:8]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][C:12]3=[O:18])[CH2:7][CH2:6]2)=[O:4])[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:32])=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN1CCN(C2CCN(C(=O)[C@H](N)C(C)(C)C)CC2)C(=O)C1
Solvent: CC#N
Product: CN1CCN(C2CCN(C(=O)[C@H](NC(=O)Nc3ccc(Cl)cc3)C(C)(C)C)CC2)C(=O)C1
Yield: 26.7 %

Procedure:
To a solution of 1-(1-((2R)-2-amino-3,3-dimethylbutyroyl)-4-piperidinyl)-4-methylpiperazin-2-one (0.12 g) obtained in Example 103d) in acetonitrile (5 ml) was added 4-chlorophenyl isocyanate (57 mg), and mixed at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified with silica gel column (ethyl acetate) to obtain the title compound as colorless powder (46 mg, 27%).
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=2)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4cnc(N)nc4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (from Boron Molecular). LCMS calculated for C20H11N6O2 (M+H)+: m/z=377.2. Found 377.1.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([SH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.[OH-].[Li+].Cl>CN(C)C=O.CCOCC>[CH2:16]([S:23][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: SCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(SCc2ccccc2)c([N+](=O)[O-])c1
Yield: 73.5 %

Procedure:
Ethyl 4-chloro-3-nitrobenzoate (10 g) and benzyl mercaptan (5.41 g) were dissolved in N,N-dimethylformamide and whilst stirring, lithium hydroxide monohydrate (1.83 g) was added. The mixture was stirred overnight then poured into ether and 2N hydrochloric acid. The organic phase was washed with water, dried over anhydrous magnesium sulphate and evaporated to yield ethyl 4-benzylthio-3-nitrobenzoate (10.16 g), obtained as an oil, NMR (CDCl3) δ1.41 (3H, t), 4.24 (2H,s), 4.40 (2H,q), 7.3-7.47 (5H), 7.53 (1H,d), 8.14 (1H,dd), 8.86 (1H,d).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[C:3]1[C:16]([NH2:18])=[O:17].Cl[C:20]1[C:21]([CH2:41][OH:42])=[C:22]([N:26]2[CH:35]=[CH:34][C:33]3[C:28](=[C:29]([F:39])[CH:30]=[C:31]([CH:36]4[CH2:38][CH2:37]4)[CH:32]=3)[C:27]2=[O:40])[CH:23]=[CH:24][CH:25]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH:36]1([C:31]2[CH:32]=[C:33]3[C:28](=[C:29]([F:39])[CH:30]=2)[C:27](=[O:40])[N:26]([C:22]2[C:21]([CH2:41][OH:42])=[C:20]([C:5]4[CH:4]=[C:3]([C:16]([NH2:18])=[O:17])[N:2]([CH3:1])[CH:6]=4)[CH:25]=[CH:24][CH:23]=2)[CH:35]=[CH:34]3)[CH2:38][CH2:37]1
Reactant: O=c1c2c(F)cc(C3CC3)cc2ccn1-c1cccc(Cl)c1CO
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc1C(N)=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cccc(-n3ccc4cc(C5CC5)cc(F)c4c3=O)c2CO)cc1C(N)=O
Temperature: 125 °C
Yield: 15 %

Procedure:
To a 10 mL microwave vial, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxamide (100 mg, 400 μmol, Eq: 1.00), 2-(3-chloro-2-(hydroxymethyl)phenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one (137 mg, 400 μmol, Eq: 1.00), X-phos (19.1 mg, 40.0 μmol, Eq: 0.1), Pd2(dba)3 (18.3 mg, 20.0 μmol, Eq: 0.05), and potassium phosphate tribasic (212 mg, 1.00 mmol, Eq: 2.50) were added, followed by 1,4-dioxane (5 ml) and water (0.5 ml) to give a dark brown suspension. The reaction mixture was stirred while purging with argon for 10 min. The solution was heated at 125° C. in a microwave for 30 min. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with 50 mL of dichloromethane and extracted with water. The aqueous was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 25%-50% [60:10:1 dichloromethane:methanol:aqueous ammonium hydroxide]/dichloromethane gradient) to give 4-[3-(6-cyclopropyl-8-fluoro-1-oxo-1H-isoquinolin-2-yl)-2-hydroxylmethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid amide (25.9 mg, 15%) as a white solid: LC/MS-ESI observed [M+H]+ 432.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[N:11][N:10]=[N:9]2)=[C:4]([N+:14]([O-])=O)[CH:3]=1.[Cl-].[NH4+].O>CO.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[N:11][N:10]=[N:9]2)=[C:4]([NH2:14])[CH:3]=1
Reactant: Cc1nnnn1-c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: Cc1nnnn1-c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A suspension of 1-(4-bromo-2-nitro-phenyl)-5-methyl-IH-tetrazole (1.13 g, 3.98 mmol) in methanol (40 mL, not completely dissolved in methanol even at hot conditions) was treated sequentially with ammonium chloride (3.19 g, 59.7 mmol), zinc dust (2.60 g, 39.8 mmol), and water (20 mL). Initially after the addition, the reaction was exothermic. The reaction mixture was then stirred for 1 h at 25° C. The reaction mixture was then filtered, and the residue was washed with methanol (50 mL) and ethyl acetate (100 mL). The filtrate was concentrated in vacuo, and the organic compound was extracted into ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 5-bromo-2-(5-methyl-tetrazol-1-yl)-phenylamine 0.90 g, 97%) as a white solid EI-HRMS m/e calcd for C8H8BrN5 (M+) 252.9963, found 252.9962.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:19]=4[S:20][C:3]=1[C:4]=23.Br.[Br:28][CH2:29][CH2:30][NH2:31]>CCO>[BrH:28].[CH2:16]([N:13]([CH2:14][CH3:15])[CH2:12][CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([NH:1][CH2:29][CH2:30][NH2:31])=[C:3]3[S:20][C:19]4[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:18]=4[C:5]([C:4]=23)=[N:6]1)[CH3:17]
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1cc(OC)ccc1-2
Reactant: NCCBr
Agent: Br
Solvent: CCO
Product: CCN(CC)CCn1nc2c3c(c(NCCN)ccc31)Sc1cc(OC)ccc1-2
Yield: 39.9 %

Procedure:
Reaction of a solution of 4.5 g (0.0122 mol) of 5-amino-N,N-diethyl-8-methoxy-2H[1]benzothiopyrano-[4,3,2-cd]indazole-2-ethanamine and 7.5 g (0.0366 mol) of 2-bromoethylamine, hydrobromide, in 40 ml of EtOH as described in Example 38 gave 2.4 g of product.
Reaction SMILES: O=O.[CH3:3][C:4]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=1[OH:6].S(=O)(=O)(O)O>C(O)(=O)C>[CH3:3][C:4]1[C:5](=[O:6])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1
Reactant: Cc1cc(O)ccc1O
Agent: O=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC1=CC(=O)C=CC1=O
Temperature: 40 °C
Yield: 61.4 %

Procedure:
Oxygen was passed into a solution of 0.68 g (2 mmol) of iron 5,14-dihydrodibenzo[b,i][5,9,14,18]tetraaza[14]annulene in 150 ml of 85% by weight aqueous acetic acid and, during this, a solution of 12.4 g (100 mmol) of methylhydroquinone and 0.5 g of concentrated sulfuric acid in 75 ml of 85% by weight acetic acid was added dropwise while stirring vigorously at 40° C. After oxygen up-take ceased, the mixture was subjected to a steam distillation. The distillate was extracted with tert-butyl methyl ether. The organic phase was shaken with aqueous sodium bicarbonate solution and then with water, separated from the aqueous phase, dried over magnesium sulfate, filtered and evaporated to dryness to yield 7.5 g (46%) of 2-methylbenzoquinone in the form of a yellow powder. Melting point 66°-68° C.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([C:11]1[CH:12]=C([CH:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:19]=1)C(O)=O)([CH3:10])([CH3:9])[CH3:8]>CN(C)C=O.ClCCl>[C:20]([C:18]1[CH:17]=[C:1]([CH:12]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:19]=1)[C:2]([Cl:4])=[O:3])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (0.542 g, 0.37 ml, 4.27 mmol) was added dropwise to a solution of 3,5-di-tert-butylbenzoic acid (0.200 g, 0.853 mmol) and dichloromethane (4 ml). N,N-Dimethylformamide (1 drop) was added and the colorless solution stirred at RT for 3 h. The solution was concentrated to afford 3,5-di-tert-butylbenzoyl chloride as a yellow oil.
Reaction SMILES: [Mg].[C:2]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Cl)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].II.[Cl:16][CH2:17][Si:18]([CH3:21])([CH3:20])Cl.[Cl-].[NH4+]>C(OCC)C>[CH3:20][Si:18]([CH3:21])([CH2:10][C:9]1[CH:12]=[CH:13][C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:7][CH:8]=1)[CH2:17][Cl:16]
Reactant: C[Si](C)(Cl)CCl
Reactant: CC(C)(C)c1ccc(CCl)cc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(C[Si](C)(C)CCl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.2 g (0.05M) of magnesium shavings are charged into 20 ml of diethyl ether. After the addition of about 1 ml of 4-tert-butylbenzyl chloride, the batch is heated to boiling point and a number of iodine crsytals are added. After the onset of the reaction, the rest of the 4-tert-butylbenzyl chloride (a total of 10 g [0.055M] in 80 ml of diethyl ether) is added dropwise such that the temperature is kept at 25°-30° C. The reaction mixture is stirred further for 2 hours at room temperature. 7.2 g (0.05M) of chloromethyldimethylchlorosilane in 20 ml of diethyl ether are then added dropwise at room temperature, and the mixture is stirred further overnight at room temperature. With ice cooling, 100 ml of a saturated solution of ammonium chloride are added to the reaction mixture, and the organic phase is separated, diluted with ethyl acetoacetate and washed three times with water. The batch is dried over sodium sulfate and filtered, and the filtrate is concentrated under a water jet vacuum. The crude intermediate so obtained is cooled to 0° C. and filtered, affording 11.2 g (88% of theory) of the desired intermediate as filtrate. For further purification, the product can be distilled under a water jet vacuum (boiling point: 149°-150° C./2000 Pa).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])[CH:4]=1.[CH3:17][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[F:16][C:2]([F:15])([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH:10]([CH3:14])[C:11]([O:13][CH3:17])=[O:12])[CH:4]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(Oc1cc(C(F)(F)F)ccn1)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(C)Oc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-trifluoromethyl-2-pyridyloxy)propionic acid (Step A, 15 g, 55 mol) in 100 mL of methylene chloride and 100 mL of methanol at 0° C. was added trimethylsilyldiazomethane (2 M solution in hexane) until a yellow color persisted. After stirring at room temperature for 15 min, the reaction mixture was concentrated to dryness, and the residue was purified by flash chromatography on silica gel eluted with 0 to 10% ethyl acetate in hexane to give methyl 2-(4-trifluoromethyl-2-pyridyloxy)propionate, which was used immediately for methylation following the procedure described in Reference Example 13, Step B substituting ethyl iodide with methyl iodide. 1H NMR (500 MHz, CD3OD): δ 8.25 (d, 1H), 7.18 (d, 1H), 7.15 (s, 1H), 3.65 (s, 3H), 1.65 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]=[C:11]([C:17](=[O:28])[C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([Cl:26])[C:19]=2F)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[N:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C:19]3[C:18](=[CH:23][C:22]([F:24])=[C:21]([F:25])[C:20]=3[Cl:26])[C:17](=[O:28])[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10]2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(=CNc1cnc(Cl)c(N)c1)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2cnc(Cl)c(N)c2)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a solution of 180 mg ethyl 3-[(5-amino-6-chloropyridin-3-yl)amino]-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate in 3 ml N,N-dimethylformamide was added 57 mg of potassium carbonate, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water, and extracted by adding ethyl acetate. The organic layer was separated and dried over magnesium sulfate, and the solvent was distilled off. The solid content was collected by filtration to obtain 125 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].F[C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([S:27]([NH:30][C:31]4[CH:36]=[CH:35][N:34]=[CH:33][N:32]=4)(=[O:29])=[O:28])=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[CH:11][CH:10]=1>CN(C=O)C>[CH2:3]([O:4][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([S:27]([NH:30][C:31]4[CH:36]=[CH:35][N:34]=[CH:33][N:32]=4)(=[O:29])=[O:28])=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[CH:11][CH:10]=1)[CH:2]([CH3:5])[CH3:1]
Reactant: COc1nc(F)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(OCC(C)C)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40404 %

Procedure:
To a ice cold solution of 2-methylpropan-1-ol (110 mg, 1.483 mmol) in DMF (1483 μl) was added sodium hydride (59.3 mg, 1.483 mmol) under nitrogen and stirred for 10 min to this was then added a solution of 1-(6-fluoro-2-methoxypyridin-3-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (122 mg, 0.297 mmol) in DMF (1483 μl) and stirred for 16 h slowly raising the temperature to ambient temperature. The reaction mixture was quenched with MeOH, concentrated and purified via reverse phase HPLC (0.1% NH4OH in ACN and water as mobile phase) to obtain 1-(6-isobutoxy-2-methoxypyridin-3-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide as light yellow solid (56 mg, 120 mmol, 41% yield). m/z (ESI) 466.2 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].B.CNC.CO.Cl>O1CCCC1>[Br:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CBr)c1ccccc1
Agent: B
Agent: CNC
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: OC(CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
2-Bromoacetophenone (1 g) was dissolved in tetrahydrofuran (8 ml), and a solution of borane-dimethylamine (326 mg) in tetrahydrofuran (6 ml) was added thereto at room temperature. After the reaction mixture was stirred at room temperature for 60 hours, methanol (1 ml) and 1 M hydrochloric acid aqueous solution (5 ml) were added thereto, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent by distillation from the organic layer, the residue was purified by silica gel column chromatography to obtain the title compound from a fraction eluted with hexane-ethyl acetate (5:1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][CH2:22][CH2:23][CH3:24].I([O-])(=O)(=O)=[O:26].[Na+].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.CO>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([CH2:22][CH2:23][CH3:24])=[O:26]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCS(=O)c1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 40 °C
Yield: 73.9 %

Procedure:
A mixture of 3-methyl-2-(2-propylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.22 g), sodium periodate (0.27 g), methanol (2 ml), and water (4 ml) was stirred with heating at 40° C. for 1.5 hours. To the reaction mixture cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were added, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.17 g of 3-methyl-2-(2-propylsulfinylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 8).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:15](Cl)([N:17]=[C:18]=[O:19])=[O:16]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[O:14][C:18](=[O:19])[NH:17][C:15](=[O:16])[C:11]=3[CH2:12][CH2:13]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1CCCC1c1cc(F)cc(F)c1
Reactant: O=C=NC(=O)Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1cc(F)cc(F)c1)CC2
Temperature: 130 °C
Yield: 10.9 %

Procedure:
A mixture of 2-(3,5-difluorophenyl)cyclopentanone (4.765 g, 24.29 mmol) and carbonisocyanatidic chloride (4.61 g, 43.7 mmol) was heated at 58° C. for 1 h and at 130° C. for 2 h. Upon cooling to room temperature, the reaction mixture was dissolved in ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 7-(3,5-difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (700 mg, 2.64 mmol, 10.87% yield). LC-MS (M+H)+=266.1. 1H NMR (500 MHz, CDCl3) δ ppm 8.79 (1H, br s), 6.68-6.86 (3H, m), 4.22 (1H, br s), 2.87 (1H, dt, J=7.0, 4.4 Hz), 2.63-2.82 (2H, m), 2.15 (1H, br s).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:7]=1[Br:16])=[O:4].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:17][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:7]=2[Br:16])=[O:4])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Br)c1
Reactant: Nc1ccccc1
Product: NS(=O)(=O)c1ccc(NC(=O)CNc2ccccc2)c(Br)c1
Yield: 80.6 %

Procedure:
2-Chloro-N-(2-bromo-4-sulphamoylphenyl)-acetamide (16.4g) and aniline (9.0 g) were heated together for 60 min. on a water bath at 90° the product was worked up as in Example 1(b) to yield 15,5 g beige crystals m.p.: 179°-181°.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl.O>[CH3:19][S:20]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCC2(CC1)OCCO2
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Temperature: 0 °C

Procedure:
To an ice cold solution of the alcohol from Step 1 (4.59 g, 29 mmol) and triethylamine (8.0 mL, 57 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (3.3 mL, 43 mmol). The reaction was then diluted with water (80 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried over MgSO4 and concentrated to give the title compound as a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[C:9]([CH:17]=[O:18])[NH:8][C:7]=1[CH3:19])=[O:5])C.[OH-].[Na+].O>CO.CCOC(C)=O>[CH3:16][N:14]([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]1[C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:19])[NH:8][C:9]=1[CH:17]=[O:18]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1[nH]c(C=O)c(CCCN(C)C)c1C(=O)O
Temperature: 80 °C
Reaction time: 19 h
Yield: 93.2 %

Procedure:
A mixture of 4-(3-dimethylaminopropyl)-5-formyl-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (300 mg, 1.13 mmol) and sodium hydroxide in MeOH (4 mL)/water (2 mL) was stirred at 80° C. for 19 hr. The reaction was then diluted with EtOAc. The aqueous layer was separated, neutralized and concentrated. The residue was dissolved in MeOH, filtered and the filtrate was concentrated to give 251 mg (94%) of 4-(3-dimethylaminopropyl)-5-formyl-2-methyl-1H-pyrrole-3-carboxylic acid.