Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[C:10]([CH3:16])=[N:9]2)=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[NH2:21].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:13]([C:11]2[C:10]([CH3:16])=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:12]=2)=[O:15])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]([CH3:29])([CH3:28])[CH3:30]
Reactant: CC(C)(C)COc1ccc(N)cc1Br
Reactant: Cc1nn(-c2ccc(F)cc2)cc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccc(F)cc2)cc1C(=O)Nc1ccc(OCC(C)(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
1-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid (1.7 g), 3-bromo-4-neopentyloxyaniline (2 g), triethylamine (2.3 g) and diethyl cyanophosphate (1.9 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous dimethylformamide to give the title compound (1.4 g), melting point: 193–194° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7](=O)[N:6]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[C:5]2[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:4]=2[O:3]1.B.CO.Cl>O1CCCC1>[OH:11][CH:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][N:6]1[C:5]2[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:4]=2[O:3][C:2]([CH3:25])([CH3:1])[CH2:7]1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2N(CC(=O)c2ccccc2)C1=O
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CN(CC(O)c2ccccc2)c2cc([N+](=O)[O-])ccc2O1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 115.4 %

Procedure:
In an argon gas stream, 1.5 g of 3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-4-phenacyl-2H-1,4-benzoxazine was added to 30 ml of a 1.0 M solution of borane in tetrahydrofuran at 0°-10° C. The above solution was stirred at 70° C. for 1 hour, at the end of which time 5.6 ml of methanol was gradually added. After stirring at 70° C. for 15 minutes, 5.6 ml of concentrated hydrochloric acid was added and the mixture was further stirred at 70° C. for 1 hour. The solvent was then distilled off and the residue was diluted with 30 ml of water, made alkaline with potassium carbonate, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-n-hexane) to give 1.67 g of 3,4-dihydro-4-(2-hydroxy-2-phenylethyl)-2,2-dimethyl-6-nitro-2H- 1,4-benzoxazine as oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](O)=[O:26])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:35][CH2:36][CH3:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](=[O:26])[N:35]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:36][CH3:37])=[CH:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCc1ccccc1
Reactant: COc1cc2c(CC(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Product: CCN(Cc1ccccc1)C(=O)Cc1cnc(CNC(=O)OC(C)(C)C)c2cc(OC)c(OC)cc12

Procedure:
As described in Example 1, 94 mg of [1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid was coupled with benzyl-ethyl-amine to give 84 mg of {4-[(Benzyl-ethyl-carbamoyl)-methyl]-6,7-dimethoxy-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C28H35N3O5+H 494.6; found 494.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.[C:26]([N:29]=[C:30]=[S:31])(=[O:28])[CH3:27]>CC(C)=O>[C:26]([NH:29][C:30](=[S:31])[NH:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12)(=[O:28])[CH3:27]
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Reactant: CC(=O)N=C=S
Solvent: CC(C)=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(=S)NC(C)=O)nc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.7 %

Procedure:
To a solution of 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 60 mg, 0.177 mmol) in acetone (1.182 mL) was added acetyl isothiocyanate (0.020 mL, 0.230 mmol). The reaction mixture was stirred at room temperature for 6 h. LC/MS showed still half of the starting material left. Another 0.5 equivalent of acetyl isothiocyanate was added and the reaction mixture was heated at 35° C. overnight. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 2-8% methanol/dichloromethane). 4-(3-Acetylthioureido)-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (34 mg, 43.6% yield) was obtained as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH:6]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH:6]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[CH:4]=1
Reactant: COC(=O)c1cc(OC)c2ncsc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc(O)c2ncsc2c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a stirred solution of methyl 4-methoxy-1,3-benzothiazole-6-carboxylate (20.0 g, 0.0897 mol) in anhydrous CH2Cl2 (300 mL) was added drop wise BBr3 (112.5 g, 0.448 mol) at −78° C. Then the resulting mixture was stirred at −78° C. for 3 hours and allowed to warm to room temperature overnight. TLC (EtOAc/Petroleum ether 1:4) showed the reaction was complete. The reaction mixture was concentrated in vacuum and methanol (100 mL) was added drop wise to the residue. Then the mixture was concentrated again in vacuum. The residue was washed with water and recrystallized from methanol to afford the desired product (12 g, 64%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 10.671 (s, 1H), 9.437 (s, 1H), 8.252-8.248 (s, 1H), 7.488-7.484 (s, 1H), 3.898 (s, 3H).
Reaction SMILES: [C:1]1([CH:13]2[CH2:18][CH2:17][N:16](C([O:21][CH2:22][C:23]3C=CC=CC=3)=O)[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.O.C([OH:32])C>C(O)(=O)C.[C].[Pd]>[C:22]([OH:32])(=[O:21])[CH3:23].[NH:16]1[CH2:15][CH2:14][CH:13]([C:1]2[N:2]=[N:3][N:4]3[C:9]=2[C:8]2[CH:10]=[CH:11][NH:12][C:7]=2[N:6]=[CH:5]3)[CH2:18][CH2:17]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Reactant: CCO
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: c1cc2c(ncn3nnc(C4CCNCC4)c23)[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
5% Palladium-carbon (0.87 g) was added to benzyl 4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate (4.88 g, 13.0 mmol) obtained in Synthetic Examplea 26 in a mixture of acetic acid (60 mL), water (6 mL) and ethanol (10 mL), and after then the reaction system was flushed with hydrogen, the reaction mixture was stirred at room temperature for one day and then filtered. The filtrate was concentrated, and the resulting yellow solid was washed with ethanol to give the title compound as a colorless solid (3.30 g, yield 84%).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].C(=O)(O)[O-].[Na+].ClCC(N)=O>C(Cl)(Cl)Cl>[O:13]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:3](=[O:4])[CH2:2]1
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)CCl
Agent: NC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1COc2ccccc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chloroacetyl chloride (104 g) is added slowly to a stirred mixture of o-aminophenol (96 g), sodium bicarbonate (100 g) and chloroform (1400 ml). After the addition is complete the reaction mixture is stirred at room temperature for 2 hours. The resulting chloroacetamide derivative, which separates in the course of the reaction, is filtered and added with stirring to 1 liter of NaOH, producing 2H-1,4-benzoxazin-3(4H)-one, which is filtered and washed with H2O, m.p. 169°-170°. The latter (30 g) is added portionwise to a suspension of 26 g of LiAlH4 in 1500 ml of anhydrous ether, keeping the temperature at 10° during the addition. After the addition is complete the reaction mixture is heated to reflux for 2 hours. It is then cooled, decomposed with water and filtered. The organic layer is separated and dried over anhydrous sodium sulfate; the solvent is removed in the rotary evaporator and the oily product obtained distilled to yield 3,4-dihydro-2H-1,4 -benzoxazine (b760 265°-267°). In a like manner as in Example 1, the latter benzoxazine is converted to the corresponding 4-nitroso derivative, which is worked up as described in Example 110 to give 4-amino-3,4-dihydro-2H-1,4-benzoxazine hydrochloride [m.p. 160° (dec.)] and finally the title compound m.p. 255° (dec.).
Reaction SMILES: [H-].[Na+].[C:3]([O:8]C)(=O)[C@H:4]([CH3:6])[OH:5].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[OH:5][C@@H:4]([CH3:6])[C:3]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)[C@H](C)O
Reactant: C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@H](O)C(=O)N1CCOCC1

Procedure:
Under a nitrogen atmosphere, 60% sodium hydride (1.92 g, 0.048 mol) was added slowly portionwise to a mixture of methyl L-lactate (50.0 g, 0.48 mol) and morpholine (46 mL, 0.528 mol) with stirring in an ice-bath, and the resulting mixture was stirred at 50° C. for 3 hours. Toluene was added thereto and evaporated under reduced pressure. This procedure was repeated further twice to give B-1.
Reaction SMILES: C(O[C:6](=[O:22])[NH:7][C@H:8]1[CH2:21][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH:19]=O)=[CH:17][C:18]=3[C:10]=2[CH2:9]1)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:30][O:31][NH2:32]>C(O)C>[CH3:30][O:31][N:32]=[CH:19][C:16]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH2:21][C@H:8]([NH:7][C:6](=[O:22])[C:10]([CH3:18])([CH3:11])[CH3:9])[CH2:9][C:10]=3[C:18]=2[CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2[nH]c3ccc(C=O)cc3c2C1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CON=Cc1ccc2[nH]c3c(c2c1)C[C@@H](NC(=O)C(C)(C)C)C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottom flask add [(R)-7-formyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid tert-butyl ester (1.00 g; 3.33 mmol), ethanol (10 ml), potassium carbonate (552 mg, 4 mmol), and O-methylhydroxylamine hydrochloride (334 mg; 4.0 mmol). Stir the mixture at room temperature for 1 h. Remove the solvent in vacuo and add water (15 mL). Stir the mixture 30 min and filter to give 790 mg (72%). MS (m/z): 330 (M+1).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].N.O.[N-:18]=C=O>CO>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH2:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Reactant: [N-]=C=O
Agent: N
Solvent: CO
Solvent: O
Product: CC(C)(C)N=NC1(NC(N)=O)CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 9.25 grams (0.0442 moles) of 1-t-butylazo-1-isocyanatocyclohexane in 50 ml of methanol in a 250 ml 3-neck round bottom flask equipped with a magnetic stirrer, thermometer, gas addition tube and dry ice condenser was added gaseous ammonia until a gentle ammonia reflux was maintained in the condenser. The reaction was stirred for 90 minutes at room temperature, poured into 300 ml water and the solid that formed was filtered off. The filter cake was air dried leaving 9.0 grams (90% crude yield) of a white powder. The product melted at 115°-117° C. and its infrared spectrum contained a strong carbonyl band at 1670 cm-1 and sharp NH bands at 3250 cm-1 3330 cm-1 and 3440 cm-1. The isocyanate band at 2225 cm-1 was absent.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=2)[CH:13]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[C:25]([C:27]1[N:28]=[C:29]([C:40](O)=[O:41])[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=1)#[N:26].[K]>>[C:9]([O:8][CH2:7][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:40]([C:29]2[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[C:27]([C:25]#[N:26])[N:28]=2)=[O:41])=[C:14]([C:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=2)[CH:13]=1)[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Reactant: CC(=O)OCC(COC(C)=O)c1ccc(N)c(C2=CCCCC2)c1
Agent: [K]
Product: CC(=O)OCC(COC(C)=O)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1

Procedure:
Acetic acid 3-acetoxy-2-(4-amino-3-cyclohex-1-enyl-phenyl)-propyl ester (as prepared in the previous step) was coupled to 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 1, step (d)) as described in Example 1, step (f) to obtain the title compound: Mass spectrum (ESI, m/z): Calcd. for C30H40N4O6Si, 581.2 (M+H). found 581.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22](O)[CH3:23])[C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[C:19]=1[C:20]#[N:21].CN(C)C=O.S(Cl)([Cl:32])=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]([Cl:32])[CH3:23])[C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[C:19]=1[C:20]#[N:21]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1cc(Cl)c(C#N)c2c1OCCN(C(=O)OC(C)(C)C)C2
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(Cl)c1cc(Cl)c(C#N)c2c1OCCN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h

Procedure:
The tert-butyl 7-chloro-6-cyano-9-(1-hydroxyethyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.090 g, 0.26 mmol) was dissolved in methylene chloride (3 mL) and N,N-dimethylformamide (0.020 mL) and cooled in an ice bath. The thionyl chloride (0.037 mL, 0.51 mmol) was added slowly, and the reaction was stirred for 1 h and then diluted with methylene chloride (30 mL). The reaction mixture was cooled in an ice bath, and water saturated sodium bicarbonate was added. The organic layer was washed with water, brine, dried over magnesium sulfate, and concentrated to give tert-butyl 7-chloro-9-(1-chloroethyl)-6-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate as an oil. LCMS calculated for C17H20Cl2N2O3Na (M+Na)+: m/z=393.1; found: 393.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH2:15])[C:10]=1[CH2:11][CH3:12].[CH3:22][N:23]1[CH:27]=[C:26]([S:28](Cl)(=[O:30])=[O:29])[N:25]=[CH:24]1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH:15][S:28]([C:26]2[N:25]=[CH:24][N:23]([CH3:22])[CH:27]=2)(=[O:30])=[O:29])[C:10]=1[CH2:11][CH3:12]
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CCc1nn(CCN)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nn(CCNS(=O)(=O)c2cn(C)cn2)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
A solution of the amine of Example 43 (98 mg, 0.30 mmol) in dimethylformamide (3.75 ml) was treated with 1-methylimidazole-4-sulphonyl chloride (60 mg, 0.33 mmol) and triethylamine (46 μL, 0.33 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure. The residue was partitioned between dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic extract was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (95:5, by volume) to afford the title compound (55 mg) as a white solid, m.p. 172-174° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:24]#[N:25])[N:6]=1)=O.Cl.[NH2:27][CH2:28][CH2:29][S:30]([NH2:33])(=[O:32])=[O:31].C[O-].[Na+]>CCO>[S:30]([CH2:29][CH2:28][NH:27][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:24]#[N:25])[N:6]=1)=[O:2])(=[O:32])(=[O:31])[NH2:33]
Reactant: NCCS(N)(=O)=O
Reactant: COC(=O)c1nc(C#N)c2ccc(=O)n(Cc3ccccc3)c2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1nc(C(=O)NCCS(N)(=O)=O)c(O)c2c1ccc(=O)n2Cc1ccccc1
Temperature: 140 °C
Yield: 22.6 %

Procedure:
A mixture of 1-benzyl-5-cyano-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (20 mg, 0.060 mmol), 2-amino-ethanesulfonic acid amide HCl salt (30 mg, 0.24 mmol), and NaOMe (13 mg, 0.23 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. The mixture was concentrated to dryness, and the residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stiffing until pH about 1, and the aqueous layer was extracted with additional EtOAc. The organic layers were combined, dried over MgSO4, and concentrated. The crude product was first purified by column chromatography (0-5% MeOH/CH2Cl2), then by preparative TLC (10% MeOH/CH2Cl2) to give 5.8 mg of the title compound. MS: (−) m/z 426.24 (M−1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2([C:25]([NH:27][CH2:28][C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=3)=[O:26])[CH2:11][CH2:10][CH:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH2:8]2)[N:6]=1.[C:43](OC(=O)C)(=[O:45])[CH3:44].N1C=CC=CC=1>C(Cl)Cl>[C:43]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2([C:25]([NH:27][CH2:28][C:29]3[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=3)=[O:26])[CH2:11][CH2:10][CH:9]([N:12]3[CH2:13][CH2:14][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH2:16][CH2:17]3)[CH2:8]2)[N:6]=1)(=[O:45])[CH3:44]
Reactant: Nc1nc(C2(C(=O)NCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC(N3CCC(c4ccc(F)cc4)CC3)C2)cs1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc(C2(C(=O)NCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC(N3CCC(c4ccc(F)cc4)CC3)C2)cs1
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of 0.040 g of the compound from EXAMPLE 44, 0.20 g of acetic anhydride and 0.40 g of pyridine in 1.0 mL of CH2Cl2 was stirred overnight, evaporated and dried in vacuo. The residue was purified by preparative TLC (10% [aq. NH4OH/MeOH 1/9]/CH2Cl2). The title compound (0.037 g) was obtained as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.60-2.24 (m, 9H), 2.27(s, 3H), 2.50 (m, 4H), 2.85 (m, 1H), 3.20 (m, 2H), 4.55 (m, 2H), 6.83 (s, 1H), 6.97-7.20 (m,5H), 7.64 (s,2H), 7.76 (s, 1H), 9.06 (broad, 1H). LC-MS: m/z 657 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[S:23][C:13]=2[N:14]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: Fc1ccc(CNc2nc(-c3ccccn3)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(4-fluorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13]S(C(C)(C)C)=O)[CH3:12])=[C:7]([F:20])[CH:6]=1)([F:4])[CH3:3].Cl.C(OCC)C>O1CCOCC1>[F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH2:13])[CH3:12])=[C:7]([F:20])[CH:6]=1)([F:4])[CH3:3]
Reactant: C[C@H](NS(=O)C(C)(C)C)c1ccc(C(C)(F)F)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[C@H](N)c1ccc(C(C)(F)F)cc1F
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 105.8 %

Procedure:
To N—((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (349 mg, 1.135 mmol) was added 4M HCl in dioxane (3.01 mL) to give a purple solution. To the mixture was added diethylether (20 mL) and the mixture was stirred for 15 min at −10° C. The mixture was concentrated under reduced pressure to ˜2 mL of volume and diethylether (20 mL) was added. The solids were filtered off, rinsed with diethylether (4×10 mL) and dried under reduced pressure providing (S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethanamine (244 mg) as an off-white solid (HCl salt). LCMS m/z 204.1 (M+H)+, Rt 0.42 min.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25])[O:18][N:17]=3)=[O:15])=[C:9]([CH3:28])[N:8]2[CH3:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(SCCO)CSCCO>CCOC(C)=O.[Pd]>[CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19](/[CH:22]=[CH:23]\[C:24]([CH3:26])([CH3:25])[CH3:27])[O:18][N:17]=3)=[O:15])=[C:9]([CH3:28])[N:8]2[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C#CC(C)(C)C
Agent: [Pd]
Agent: OCCSCCSCCO
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1/C=C\C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2-Cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-(3,3-dimethylbut-1-yn-1-yl)-4-methylisoxazole-3-carboxamide (Example 7, Step 3)) (30 mg, 0.075 mmol) in EtOAc (3 mL) was treated with 2,2′-(ethane-1,2-diylbis(sulfanediyl))diethanol (13.72 mg, 0.075 mmol) and Pd-5% Barium sulphate (16.02 mg, 7.53 μmol). The mixture was degassed, thoroughly refilling with nitrogen and the mixture was stirred under an atmosphere of hydrogen at room temperature overnight. Further Pd-5% Barium sulphate (16.02 mg, 7.53 μmol) was added and the reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 16 hours. The resulting mixture was filtered through Celite® eluting with EtOAc and the solvent was removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-100% EtOAc in iso-hexane afforded the title compound;