Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH2:19][C:20]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([C:29]#[N:30])=[CH:28][C:22]=3[N:21]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH3:2].[BH4-].[Na+]>CO.O>[CH2:1]([C:3]1[C:4]([CH2:19][C:20]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([C:29]#[N:30])=[CH:28][C:22]=3[N:21]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:13]([OH:18])[C:14]([F:17])([F:15])[F:16])[CH3:2]
Reactant: CCc1cc(C)c2[nH]cc(C(=O)C(F)(F)F)c2c1Cc1nc2cc(C#N)ccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1cc(C)c2[nH]cc(C(O)C(F)(F)F)c2c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-((5-ethyl-7-methyl-3-(2,2,2-trifluoroacetyl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (60 mg, 0.114 mmol) in MeOH (10 mL) was added portionwise NaBH4 (21.6 mg, 0.572 mmol). The mixture was stirred at room temperature for 3 h, and then for 16 h at 60° C. The reaction mixture was diluted with H2O. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic phase was washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel flash column chromatography [CH2Cl2/(2M NH3 in MeOH)=94/6, isocratic] to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3 with about 5 μL TFA) δ ppm 9.50 (br. s., 1H), 7.83 (s, 1H), 7.54 (d, J=8.30 Hz, 1H), 7.47 (d, J=8.30 Hz, 1H), 7.42 (br. s., 1H), 6.95 (s, 1H), 5.56 (q, J=7.28 Hz, 1H), 4.78 (d, J=17.40 Hz, 1H), 4.64 (d, J=17.43 Hz, 1H), 2.74 (q, J=7.45 Hz, 2H), 2.45 (s, 3H), 1.12 (t, J=7.52 Hz, 3H). HRMS calcd. for C22H19F3N4O (M+H)+ 413.1584. found 413.1583.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:12][C:11]([F:13])([F:14])[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[O:2])=[CH:5][CH:6]=1)([OH:19])[C:15]([F:16])([F:18])[F:17]
Reactant: COC(OC)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
2-(4-Dimethoxymethyl-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (350 mg, 1.1 mmol) was dissolved in DCM (5 ml). A 50% aqueous TFA (5 ml) was added and the solution was allowed to stir for 2h. The solvent was removed under vacuum, and the reaction mixture was partitioned between ethyl acetate and a 1M sodium carbonate solution. The organic layer was washed with carbonate two additional times, and then it was washed with brine. It was dried over MgSO4, and the solvent was removed to yield the title product (300 mg (100%), 1.1 mmol) as a white solid. 1H NMR (DMSO-d6) δ=10.1 (s, 1H), 9.05 (s, 1H), 8.12 (d, J=8.5 Hz, 2H), 7.96 (d, J=8.2 Hz, 2H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH:13]=2)[N:3]=1.Cl.O1CCOCC1.O=P(Cl)(Cl)[Cl:30]>C(#N)C>[Cl:30][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH:13]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)NC(=O)Cn1cc(Nc2nccc(O)n2)cn1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CC(C)NC(=O)Cn1cc(Nc2nccc(Cl)n2)cn1

Procedure:
To a mixture of 2-(4-(4-hydroxypyrimidin-2-ylamino)-1H-pyrazol-1-yl)-N-isopropylacetamide (6.0 g, 22 mmol) in acetonitrile (300 mL) was added 4M HCl in dioxane (12 mL, 48 mmol) then POCl3 (10 g). The mixture was heated to reflux for 0.5 h then concentrated in vacuo. The residue was slurried with water and adjusted to pH 9 with aqueous sodium hydrogen carbonate. The remaining solid was collected by filtration and purified by column chromatography (50% v/v DCM/ethyl acetate) to afford 2-(4-(4-chloropyrimidin-2-ylamino)-1H-pyrazol-1-yl)-N-isopropylacetamide II-1 (2.30 g, 36%) as a white solid. LC-MS (Method A), RT=8.28 min. (ES+) 295.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([OH:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>O.CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][C:21]([OH:23])=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)Cc1ccccc1O
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)c1ccc(COc2ccccc2CC(=O)O)cc1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
A mixture of 4-(tert-butyl)benzyl bromide (2.240 g, 9.861 mmol), 2-hydroxyphenylacetic acid (1.00 g, 6.572 mmol), potassium carbonate (3.996 g, 28.918 mmol), chloroform (6 ml) and methanol (6 ml) was refluxed for 2 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (1.007 g, 51.4%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10](=[CH:11][C:12]3[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])[C:9](=[O:19])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([NH2:28])[CH:24]=[CH:25][C:26]=1[F:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:2]2[C:3]3[C:10](=[CH:11][C:12]4[NH:13][C:14]([CH3:18])=[CH:15][C:16]=4[CH3:17])[C:9](=[O:19])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ncnc(Cl)c32)[nH]1
Product: Cc1cc(C)c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]1
Yield: 57 %

Procedure:
The title compound (57% yield) was prepared from 4-chloro-5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one and 3-chloro-4-fluoro-phenylamine according to the procedure described for Example 12 without the conversion to the HCl salt. 1H NMR (360 MHz, DMSO-d6) δ 13.10 (br s, 1H, NH), 11.60 (br s, 1H, NH), 9.10 (s, 1H), 8.27 (s, 1H, H-vinyl), 7.70 (m, 1H), 7.3-7.4 (m, 3H), 6.04 (br s, 1H), 2.33 (s, 3H, CH3), 2.16 (s, 3H, CH3). MS 384.3 [M++1].
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[CH:15]=[C:14]([CH2:16][CH2:17][C:18](O)=[O:19])[N:13]=[CH:12]1>>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:18](=[O:19])[CH2:17][CH2:16][C:14]2[N:13]=[CH:12][NH:11][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1c[nH]cn1
Reactant: NCCCc1ccccc1
Product: O=C(CCc1c[nH]cn1)NCCCc1ccccc1

Procedure:
The preparation is carried out as in Example 1 with 3-phenylpropanamine and 3-(1H-imidazol-4-yl)propanoic acid, the acid being here added after the reaction of the amine component with N,N'-carbonyldiimidazole. The title compound is extracted from water with diethyl ether, purified by chromatography and recrystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]#[N:16])[C:12]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O>O1CCOCC1>[OH:3][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[C:13]([C:15]#[N:16])[C:12]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=3)=[N:11]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-n2cc(C#N)c(Nc3ccc(S(C)(=O)=O)cc3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)c1ccc(-n2cc(C#N)c(Nc3ccc(S(C)(=O)=O)cc3)n2)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
1-(4-acetylphenyl)-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile (30 mg, 0.079 mmol) and sodium borohydride (5.97 mg, 0.158 mmol) were stirred in dioxane (1 mL) at 60° C. overnight. Additional sodium borohydride (5.97 mg, 0.158 mmol) was added and stirring at 60° C. continued for 24 hours. Room temperature was attained, water was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated in DCM to give 1-[4-(1-hydroxyethyl)phenyl]-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]#[C:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:7])=[S:32])=[CH:4][C:3]=1[C:11]#[C:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(C(=O)O)cc1C#Cc1cnc2ccccc2c1
Solvent: C1CCOC1
Product: Cc1ccc(C(O)=S)cc1C#Cc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-methyl-3-[(quinolin-3-yl)ethynyl]benzoic acid (0.3 g, 1.3 mmol) and Lawesson's reagent (0.5 ml, 1.3 mmol) in THF (10 ml) was stirred at ambient temperature for 1 hr under an atmosphere of nitrogen. The reaction mixture was concentrated and the crude product was purified by flash chromatography on silica gel (elution with 10% ethyl acetate in n-hexane) to provide 4-methyl-3-[(quinolin-3-yl)ethynyl]thiobenzoic acid.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([N:16]1[C:20]([C:21](SC)=[O:22])=[C:19]([CH:25]=O)[N:18]=[C:17]1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[C:13]#[C:14][CH3:15].[CH2:40]([O:47][C:48]([NH:50][CH:51](P(OC)(OC)=O)[C:52]([O:54][CH3:55])=[O:53])=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[CH3:55][O:54][C:52]([C:51]1[N:50]([C:48]([O:47][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:49])[C:21](=[O:22])[C:20]2[N:16]([CH2:12][C:13]#[C:14][CH3:15])[C:17]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:29][CH2:28]3)=[N:18][C:19]=2[CH:25]=1)=[O:53]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C(=O)SC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(C(=O)OC)n(C(=O)OCc3ccccc3)c(=O)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.079 g of 1,8-diazabicyclo[5.4.0]-7-undecene and then 5 ml of dichloromethane containing 0.194 g of t-butyl 4-[1-(2-butynyl)-4-formyl-5-methylsulfanylcarbonyl-1H-imidazol-2-yl]piperazine-1-carboxylate were added to a 2 ml dichloromethane solution of 0.174 g of methyl benzyloxycarbonylamino-(dimethoxyphosphoryl)-acetate, and the mixture was stirred at room temperature for 16 hours. The solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.147 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (3:2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=1[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)Cl.Cl.[OH-].[Na+]>CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(Oc2ccc([N+](=O)[O-])cc2F)c(OCc2ccccc2)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCOCC
Product: CCc1ccc(Oc2ccc(N)cc2F)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
To a solution of 2-(benzyloxy)-4-ethyl-1-(2-fluoro-4-nitro phenoxy)benzene (25 g; 68 mmol) in ether (86 mL), under argon cooled to 0° C., was added a suspension of tin dichloride (153 g; 801 mmol) in HCl (50 mL; 2 mol). The mixture was allowed to warm up to room temperature overnight, then a 10% NaOH solution was added dropwise. The resulting mixture was extracted with ethyl acetate (5*400 mL). Combined organic phases were washed with water (400 mL) and brine, then dried over Na2SO4 and concentrated. The residue was purified on silica gel (ethyl acetate/cyclohexane 1:9) to yield the title compound as a light brown solid (15.8 g; 68.8%)
Reaction SMILES: [CH:1]([N:3]1[C:6](=[O:7])[CH:5]([NH:8][C:9](=[O:18])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]1[S:19][C:20](OC(=O)C)([CH3:22])[CH3:21])=[O:2]>C1C=CC=CC=1>[CH:1]([N:3]1[C:6](=[O:7])[CH:5]([NH:8][C:9](=[O:18])[CH2:10][O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:4]1[S:19][C:20]([CH3:22])=[CH2:21])=[O:2]
Reactant: CC(=O)OC(C)(C)SC1C(NC(=O)COc2ccccc2)C(=O)N1C=O
Solvent: c1ccccc1
Product: C=C(C)SC1C(NC(=O)COc2ccccc2)C(=O)N1C=O
Reaction time: 3 h

Procedure:
A solution of 0.051 g of 1-formyl-2-(2-acetyloxy-2-propyl-mercapto)-3-(N-phenyloxyacetyl-amino)-azetidin-4-one in 3 ml of anydrous benzene is treated with 0.13 g of tristriphenyl-phosphine-rhodium chloride and boiled for 3 hours under reflux. The initially red solution turns brown, with a small quantity of a precipitate forming. After cooling, the precipitate is filtered off and the filtrate is evaporated under reduced pressure. The residue is chromatographed on 5 g of acid-washed silica gel, with fractions of 5 ml each being collected. The elution is carried out with 10 ml of benzene, 30 ml of a 9:1-, 25 ml of a 4:1- and 10 ml of a 1:1-mixture of benzene and ethyl acetate and then with 25 ml of ethyl acetate. Fractions 2-6 yield a rhodium complex having a strong CO-absorption at 5.18μ in the infra-red absorption spectrum. A small quantity of 1-formyl-2-isopropenylmercapto-3-(N-phenyloxyacetyl-amino)-azetidin-4-one can be isolated from fractions 10- 12, while fractions 15- 17 yield the 2-isopropenylmercapto-3-(N-phenyloxyacetyl-amino)-azetidin-4-one of the formula ##STR23## in an amorphous form. The product is obtained in crystalline form when the solution of the eluate is filtered through 0.5 g of acid-washed silica gel and the product is eluted with a 1:1-mixture of benzene and ethyl acetate, m.p. 156°-158°; [α]D20 = -70° ± 2° (c = 0.665 in chloroform); infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.07μ, 5.65μ, 5.96μ, 6.29μ, 6.59μ, 6.74μ, 8.19μ, 9.25μ and 9.92μ.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:30]=[CH:31][C:32]=1[CH2:33][O:34]C(C)(C)C(C)(C)C)[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]([CH3:29])[CH2:22][CH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26])[CH:18]=[CH:19][CH:20]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:30]=[CH:31][C:32]=1[CH2:33][OH:34])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]([CH3:29])[CH2:22][CH2:23][CH2:24][C:25]([CH3:26])([OH:27])[CH3:28])[CH:18]=[CH:19][CH:20]=1
Reactant: CC(CCCC(C)(C)O)c1cccc(OCc2ccc(COC(C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(CCCC(C)(C)O)c1cccc(OCc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 3(i), by reacting 50 mg (0.08 mmol) of 6-{3-[3-(tert-butyldimethylsilanyloxymethyl)-4-(1,1,2,2-tetramethylpropoxymethyl)benzyloxy]phenyl}-2-methylheptan-2-ol with 0.17 ml of tetrabutylammonium fluoride 1M/THF, a colourless oil (m=29 mg; Y=94%) is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[CH2:29]([NH2:32])[CH2:30][NH2:31]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:31][CH2:30][CH2:29][NH2:32])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: NCCN
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)NCCN)cc3C)cc12

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-N-(2-aminoethyl)-3-methylbenzamide was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and ethane-1,2-diamine following the procedures described for Example 117. 1H NMR (CDCl3): δ 8.59 (s, 1H), 8.37 (s, 1H), 8.07 (d, 1H), 7.63 (s, 1H), 7.51 (br, 2H), 7.12-7.21 (m, 2H), 6.25 (br, 2H), 3.48-3.52 (m, 2H), 3.08-3.15 (m, 4H), 2.94 (t, 2H), 2.51 (s, 3H), 2.34 (s, 3H). LRMS [M+H]=414.2
Reaction SMILES: Cl.[CH2:2]([S:6]([NH:9][C@@H:10]([CH2:15][NH2:16])[C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7])CCC.CS([Cl:21])(=O)=O>>[ClH:21].[CH3:2][S:6]([NH:9][C@@H:10]([CH2:15][NH2:16])[C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7]
Reactant: CCCCS(=O)(=O)N[C@@H](CN)C(=O)OC
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: COC(=O)[C@H](CN)NS(C)(=O)=O

Procedure:
23-7 was prepared as described above for the butylsulfonylamino analog (23-6) using methanesulfonyl chloride at the appropriate stage.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[CH:18]([CH3:20])[CH3:19])[N:14]([CH3:21])[CH:13]=[C:12]2[CH3:22])C1C=CC=CC=1>[Pd].CO>[CH:18]([C:17]1[CH:16]=[C:15]2[C:11]([C:12]([CH3:22])=[CH:13][N:14]2[CH3:21])=[CH:10][C:9]=1[OH:8])([CH3:20])[CH3:19]
Reactant: Cc1cn(C)c2cc(C(C)C)c(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CO
Product: Cc1cn(C)c2cc(C(C)C)c(O)cc12
Reaction time: 1.5 h
Yield: 79.5 %

Procedure:
5-Benzyloxy-6-isopropyl-1,3-dimethyl-1H-indole (0.270 g, 1.30 mmol) and Pd/C 10% (0.150 g) were added to 10 mL of methanol, and the mixture was hydrogenated in a Parr apparatus for 1.5 hours at 55 psi, at room temperature. The catalyst was removed by filtration and the solvent was removed in vacuo. The residue was purified with flash chromatography (5% ethyl acetate in hexanes) to yield 210 mg of 6-isopropyl-1,3-dimethyl-1H-indol-5-ol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:3]=1.[Cl:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH2:29])=[CH:24][CH:23]=1>O1CCOCC1.O.C(OCC)(=O)C>[Cl:8][C:6]1[N:7]=[C:2]([NH:29][CH2:28][C:25]2[CH:26]=[N:27][C:22]([Cl:21])=[CH:23][CH:24]=2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:5]=1
Reactant: Fc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1C(F)(F)F
Reactant: NCc1ccc(Cl)nc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1ccc(Nc2nc(Cl)nc(NCc3ccc(Cl)nc3)n2)cc1C(F)(F)F
Temperature: 50 °C
Yield: 60 %

Procedure:
To a stirred solution of (4,6-Dichloro-[1,3,5]triazin-2-yl)-(4-fluoro-3-trifluoromethylphenyl)amine (XVII) (2.0 g, 6.11 mmol) in dioxane (5 mL) was added i-Pr2(Et)N (0.832 g, 6.44 mmol) and (6-chloropyridin-3-yl)methylamine (0.912 g, 6.44 mmol), and the mixture heated at 50° C. for 12 h. The mixture was cooled to ambient temperature and diluted with water and ethyl acetate. The organic phase was separated, washed with brine and concentrated under vacuum to give 1 6-chloro-N-(6-chloropyridin-3-ylmethyl)-N′-(4-fluoro-3-trifluoromethylphenyl)-1,3,5-triazine-2,4-diamine (XVIII) (1.60 g (60% yield): 1H NMR (DMSO) δ 8.32 (bs, 1H), 7.98 (bs, 1H), 7.58 (bd, 1H), 7.28 (m, 3H), 7.16 (t, J=9.0 Hz, 1H), 6.60 (bs, 1H), 4.64 (m, 2H); ESI/MS 433 (M+H), 431 (M−H).
Reaction SMILES: [C:1]([C:3]([C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[O:21][C:20]=2[C:19]([O:27][CH3:28])=[CH:18][CH:17]=1)([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:4][CH2:5][C:6](OC)=[O:7])#[N:2].[H-].[Na+].Cl>COCCOC>[C:1]([C:3]1([C:16]2[C:24]3[O:23][C:22]([CH3:26])([CH3:25])[O:21][C:20]=3[C:19]([O:27][CH3:28])=[CH:18][CH:17]=2)[CH2:4][CH2:5][C:6](=[O:7])[CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:10]1)#[N:2]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c2c1OC(C)(C)O2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C1CC(C#N)(c2ccc(OC)c3c2OC(C)(C)O3)CCC1=O
Temperature: 0 °C
Yield: 86.6 %

Procedure:
To a solution of Compound 12b (11 g, 27 mmol) obtained in Step B in 1,2-dimethoxyethane (161 mL) was added 60% sodium hydride (3.3 g, 83 mmol). After refluxing for 3 hours, the mixture was allowed to cool and poured into ice water, and the mixture was acidified with 6 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate=3/1) to give Compound 12c (8.4 g, 86%) as a white solid.
Reaction SMILES: [O:1](S(C)(=O)=O)[S:2]([CH3:5])(=O)=[O:3].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]3[CH2:25][CH2:24][CH2:23][NH:22][C:21]=3[N:20]=[C:19]([CH:27]([CH3:29])[CH3:28])[C:18]=2[C:30]([O:32][CH3:33])=[O:31])=[CH:13][CH:12]=1.N1C=C(C)C=C(C)C=1.C(OCC)(=O)C>C(Cl)Cl.C1(C)C=CC=CC=1.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]3[CH2:25][CH2:24][CH2:23][N:22]([S:2]([CH3:5])(=[O:3])=[O:1])[C:21]=3[N:20]=[C:19]([CH:27]([CH3:28])[CH3:29])[C:18]=2[C:30]([O:32][CH3:33])=[O:31])=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: COC(=O)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CCCN2
Agent: Cc1cncc(C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CCCN2S(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.1 %

Procedure:
A solution of (MeSO2)2O (15.9 g, 0.091 mol) in anhydrous CH2Cl2 (50 mL) was added to a solution of Part C methyl 4-(4-fluorophenyl)-2-isopropyl-5,6,7,8-tetrahydro-[1,8]naphthyridine-3-carboxylate (10. g, 0.030 mol) and 3,5-lutidine (20.9 mL, 0.182 mol) in anhydrous toluene (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 days. Ethyl acetate (200 mL) and H2O (50 mL) were added, and the resulting two phases were separated. The organic phase was washed with aqueous NaHCO3 (5%, 50 mL), followed by half-saturated brine (50 mL). The solvent was removed under reduced pressure to afford a yellowish oil which solidified slowly. The crude material was recrystallized from i-PrOH/H2O (85:15, 45 mL) to afford 10.5 g (85% yield) of methyl 4-(4-fluorophenyl)-2-isopropyl-8-methanesulfonyl-5,6,7,8-tetrahydro-[1,8]naphthyridine-3-carboxylate as a off-white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[SH:13][C:14]1[C:15]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:16]=2[S:17][C:18]=1[C:19]([NH2:21])=[O:20].C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[NH2:21][C:19]([C:18]1[S:17][C:16]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:15]=2[C:14]=1[S:13][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:20]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COc1ccc2sc(C(N)=O)c(S)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CSc2c(C(N)=O)sc3ccc(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Methyl 4-(bromomethyl)benzoate (479 mg, 2.09 mmol) is added to a room temperature solution of 3-mercapto-5-methoxybenzo[b]thiophene-2-carboxamide (200 mg, 0.84 mmol) in 12 mL of THF followed by NaHCO3 (351 mg, 4.18 mmol) and the reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate and washed with 1N HCl, saturated NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:dichloromethane (1:9 to 1:1) followed by recrystallization from ethyl acetate:hexane provides methyl 4-[[[2-(aminocarbonyl)-5-methoxybenzo[b]thien-3-yl]thio]methyl]-benzoate in 68% yield; mp=150°-152° C.