Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.[CH3:16][C:17]1[C:21]([NH2:22])=[C:20]([CH3:23])[O:19][N:18]=1>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:22][C:21]1[C:17]([CH3:16])=[N:18][O:19][C:20]=1[CH3:23]
Reactant: Cc1noc(C)c1N
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Solvent: CC(=O)O
Product: Cc1noc(C)c1Nc1c([N+](=O)[O-])cnc2ccc(Br)cc12
Reaction time: 4 h

Procedure:
A mixture of 6-bromo-4-chloro-3-nitro-quinoline (Stage A.4, 1.1 g, 3.83 mmol) and 3,5-dimethyl-4-aminoisoxazol (Aldrich, Buchs, Switzerland, 472 mg, 4.21 mmol) in acetic acid (10 ml) was stirred at it for 4 h. Then the RM was quenched with H2O (40 ml). The suspension was filtered, the solid cake was washed with H2O (2×) and dried under vacuum, before being dissolved in EtOAc. The solution was washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and evaporated to dryness to give the title compound as an orange solid (HPLC tR 2.96 min (Method A); M+H=363, 365; M−H=361, 363 MS-ES).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]1[CH2:22][S:21][CH2:20][C@@H:19]([CH3:23])[N:18]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:17]1=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]1[CH2:22][S:21][CH2:20][C@@H:19]([CH3:23])[N:18]([CH2:24][C:25]([OH:27])=[O:26])[C:17]1=[O:32])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC[C@@H](C)N(CC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC[C@@H](C)N(CC(=O)O)C1=O
Yield: 92.7 %

Procedure:
0.41 g of t-butyl α-{6(R)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-3(R)-methyl-5-oxoperhydro-1,4-thiazepin-4-yl}acetate (isomer B) synthesized as described in Example 30 was subjected to de-t-butylation with trifluoroacetic acid in the same manner as described in Example 3, to give 334 mg of the title compound as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]3)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]1[N:40]=[CH:41][C:42]([NH:45]C(=O)OC(C)(C)C)=[N:43][CH:44]=1>CN(C=O)C>[NH2:45][C:42]1[N:43]=[CH:44][C:39]([CH2:38][NH:1][C:2]2[CH:3]=[C:4]([NH:9][C:10](=[O:30])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]4)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=3)[CH:5]=[CH:6][C:7]=2[CH3:8])=[N:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Reactant: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(N)c3)cc2C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(NCc4cnc(N)cn4)c3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a solution N-(3-amino-4-methylphenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (70 mg, 0.17 mmol) in DMF (0.5 mL) were added K2CO3 (69 mg,0.50 mmol) and tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate (48 mg,0.17 mmol). The reaction mixture was stirred for 8 hours at room temperature after which, it was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography using (5% MeOH/CH2Cl2) as a solvent to afford title compound (50 mg, 47% yield). MS m/z: 628 [M+1].
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].Cl[C:10](Cl)([O:12]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:10]=[O:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccccc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C=Nc1ccccc1I
Reaction time: 4 h
Yield: 267.4 %

Procedure:
A solution of 2-iodo-phenylamine (30 g, 0.14 mol) in dichloromethane (800 ml) was added triphosgene (14.6 g, 49.3 mmol) and saturated sodium bicarbonate (544 ml) at 0° C. The resulted mixture was stirred for 4 hours. The organic layer was washed with brine (200 ml) and dried over sodium sulfate. After removal of solvent, the crude product 1-iodo-2-isocyanato-benzene (32.3 g, 96%) was obtained as a yellow oil which was used in next step without purification.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[CH:21]1[CH2:30][C:29]([CH3:32])([CH3:31])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:33](O)=[O:34])[CH:27]=2)[NH:22]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[CH:21]1[CH2:30][C:29]([CH3:31])([CH3:32])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:33]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:34])[CH:27]=2)[NH:22]1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2cc(N3CCOCC3)ccc2Cl)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cc(N3CCOCC3)ccc2Cl)Nc2ccc(C(=O)NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
To a suspension of 60% sodium hydride (650 mg, 16 mmol) in N,N-dimethylformamide (5 mL) was added methanesulfonamide (1.53 g, 16 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A23. A solution of 2-(2-chloro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (900 mg, 2.3 mmol) and 1,1′-carbonyldiimidazole (730 mg, 4.5 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B23. Solution B23 was added to Solution A23 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(2-chloro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (190 mg, 17%) as a white solid: MS (ESI) M+1=478.0.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([I:10])[CH:4]=1.[C-:11]#[N:12].[Li+]>CN(C=O)C>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:11]#[N:12])=[CH:4][C:5]=1[I:10]
Reactant: [C-]#N
Reactant: Fc1ccc(CBr)cc1I
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(F)c(I)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Bromomethyl-1-fluoro-2-iodo-benzene (33.8 g, 107 mMol) was added to 240 mL of a 0.5 M solution of lithium cyanide in DMF. The reaction mixture was heated to 80° C. under an atmosphere of dry N2 and stirred overnight at this temperature. The mixture was then cooled to ambient temperature and partitioned between Et2O and 0.1 N aqueous NaOH. The Et2O layer was then washed 4 more times with 0.1 N aqueous NaOH. The Et2O layer was then dried over MgSO4, filtered and concentrated under vacuum to give 24.7 9 of the titled compound as a red solid which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21].[NH2:23][C@H:24]([CH2:29][OH:30])[CH2:25][CH2:26][S:27][CH3:28]>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:23][CH:24]([CH2:29][OH:30])[CH2:25][CH2:26][S:27][CH3:28])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21]
Reactant: CSCC[C@H](N)CO
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(Cl)cc1C
Product: COC(=O)c1c(NC(CO)CCSC)cc(C)nc1Oc1c(C)cc(Cl)cc1C
Temperature: 134 °C

Procedure:
A mixture of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-chloro-6-methyl-nicotinic acid methyl ester and L-methioninol in N-methyl-2-pyrodone (NMP) was heated in a 134° C. oil bath for 3 hr. Standard work-up procedure and purification provided the title compound. 1H NMR(CDCl3) d 8.25(d,1H), 7.02(s,2H), 6.30(s,1H), 3.85(s,3H), 3.6-3.9(m,3H), 2.5-2.7(m,2H), 2.14(s,3H), 2.10(s,3H), 2.06(s,6H), 1.8-2.1 (m,2H)ppm.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].O1CCCC1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc(I)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc(I)ccc1F
Reaction time: 8 h
Yield: 88 %

Procedure:
Dissolve 2-fluoro-5-iodobenzaldehyde, (prepared essentially as described in Tet. Lett., 33, 7499, (1992)), (6.54 g, 26.1 mmol) in 4:1 tetrahydrofuran:methanol (200 mL) and treat with sodium borohydride (1.98 g, 52.3 mmol) and stir overnight. Concentrate the reaction mixture, then partition between ethyl acetate and water. Wash the organic layer with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter, and concentrate. Purify the crude oil by silica gel chromatography, eluting with 85:15 hexanes:ethyl acetate, to give the title compound as a white crystalline solid (5.8 g, 88%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2ccccc2)CC1

Procedure:
According to Reference Example 1, benzenesulfonylchloride and 1-Boc-4-(aminomethyl)piperidine were condensed to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[C:18]([C:20]1([C:23](O)=[O:24])[CH2:22][CH2:21]1)#[N:19]>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:23]([C:20]3([C:18]#[N:19])[CH2:22][CH2:21]3)=[O:24])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: N#CC1(C(=O)O)CC1
Product: C[C@]1(c2cc(NC(=O)C3(C#N)CC3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 1-cyano-cyclopropanecarboxylic acid (CAS 6914-79-0) following procedure I yielded the title compound as a white foam. MS (ISP): m/z=335.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[H][H]>O1CCCC1.CO.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([OH:11])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(N)cccc1O

Procedure:
2-Methyl-3-nitrophenol (70 g) in 100 ml of tetrahydrofuran and 400 ml of methanol at room temperature was hydrogenated under 5 psi of hydrogen gas using 3.5 g of 5% palladium on carbon as catalyst. After removal of catalyst by filtration, the filtrate was concentrated to give 56 g of analytically pure 3-amino-2-methylphenol. This aminophenol was then converted to the title compound (7.9 g) using the general method of Example 2, except that the hydrochloride salt was formed by adding hydrogen chloride/dioxane to a methanol solution of the free base. The nmr spectrum and elemental analysis were in agreement with those of title compound prepared by Example 3 (Method A).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:22]([NH:24][CH:25]([C:34](=[O:44])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16].C(O)(C(F)(F)F)=O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:22]([NH:24][CH:25]([C:34](=[O:44])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])[CH:19]([CH3:20])[CH3:21])=[O:16]
Reactant: CC(C)Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc2ccc(F)cc2)C(C)C)n(C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)O)C(=O)COc2ccc(F)cc2)C(C)C)n(C)c2ccccc12
Yield: 64.3 %

Procedure:
Treatment of the product of Example 84 (72 mg, 0.118 mmol) with TFA as described in Example 80 gave the titled product (42.0 mg, 68%) as a pale yellow powder. MS 30H36FN3O6, [M+Na]+=576, [M−H]−=552. TLC (hexane/EtOAc, 50/50): Rf=0.33.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10]Cl>>[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][N:4]1[CH:5]=[N:6][C:2]([NH2:1])=[N:3]1
Reactant: ClCc1ccccc1Cl
Reactant: Nc1nc[nH]n1
Product: Nc1ncn(Cc2ccccc2Cl)n1

Procedure:
Prepared in analogy to example 3a) starting with 3-amino-1,2,4-triazole and 2-chloro benzyl chloride. The title compound was obtained as a colorless oil (Yield=11%). MS ISP (m/e): 209.0 & 211.0 (100 & 44) [(M+H)+].
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:6]=1.[CH3:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[CH3:23][C:24]1[N:25]([C:2]2[O:3][C:4]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:6]=2)[CH:26]=[CH:27][N:28]=1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(C(F)(F)F)cc1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(C(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 2-chloro-4-(4-trifluoromethylphenyl)-5-oxazolepropionate (1.33 g), 2-methylimidazole (1.33 g), potassium carbonate (2.00 g) and N-methylpyrrolidone (10 mL) was stirred at 110° C. for 2 h. The reaction mixture was poured into iced water (100 mL), and the precipitated crystals were collected by filtration, washed with water and air-dried to give the title compound as crystals. Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals (1.07 g, 71%). melting point: 94-95° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][S:42]([CH3:41])(=[O:44])=[O:43])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1sc(-n2cnc3ccc(CCCCO)cc32)nc1-c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(-n2cnc3ccc(CCCCOS(C)(=O)=O)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of 0.266 g (0.583 mmole) of 4-(3-chloro-phenyl)-2-[6-(4-hydroxy-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid ethyl ester (I.41d), 0.152 mL (0.875 mmole) of ethyldiisopropylamine and 5 mL of dichloromethane at 0 degrees was added 0.054 mL (0.7 mmole) of methanesulfonyl chloride. The mixture was stirred at ambient temperature for 1 hour and then diluted with 30 mL of dichloromethane. The mixture was washed with 10 mL of saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-2:98) to give 0.248 g of 4-(3-chloro-phenyl)-2-[6-(4-methanesulfonyloxy-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid ethyl ester (I.41e) as a yellow solid.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:13][S:14]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.3 %

Procedure:
To an ice cooled solution of 37 g (46.1 ml, 0.5 mol) of isobutyl alcohol and 75.75 g (104.3 ml, 0.75 mol) of triethylamine in 1800 ml of dichloromethane is added dropwise 63 g (42.57 ml, 0.55 mol) of methanesulfonyl chloride. The temperature of the reaction mixture during the addition is ca. 10°. The reaction mixture is then stirred for 1.5 hours at 10°. The reaction mixture is then diluted with dichloromethane, washed with ice water, cold 10% HCl, saturated KHCO3, saturated NaCl and dried (MgSO4). Solvent is removed in vacuo to yield 68 g (90%) of the isobutyl methanesulfonate as an oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[CH2:8][NH:9]C(=O)OC(C)(C)C.[Br:17][C:18]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[NH2:9][CH2:8][C@H:3]1[C@@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][N:4]1[C:20]([C:19]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:18]=1[Br:17])=[O:21]
Reactant: C[C@H]1CCCN[C@H]1CNC(=O)OC(C)(C)C
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Product: Cc1ccc(Br)c(C(=O)N2CCC[C@H](C)[C@@H]2CN)c1

Procedure:
The title compound was synthesized following the same general protocol as described in Example 11 using rac-cis-tert-butyl ((3-methylpiperidin-2-yl)methyl)carbamate and 2-bromo-5-methylbenzoic acid. ESI-MS (m/z): 325, 327, [M]+, [M+2]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[N:11]=1.C(O)C>O>[CH3:21][O:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2ccc(N)nc2n1
Reactant: O=C(O)c1ccco1
Solvent: CCO
Solvent: O
Product: COc1ccc2ccc(NC(=O)c3ccco3)nc2n1
Temperature: 4 °C
Yield: 83.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2-furancarboxylic acid (8.95 g), N,N'-carbonyldiimidazole (12.8 g) and 2-amino-7-methoxy-1,8-naphthyridine (10.5 g). The product produced by precipitation in water (15.5 g; m.p. 199° C.) is dissolved in boiling ethanol (500 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×10 cc) and dried at 45° C. under reduced pressure (0.067 kPa). N-(7-Methoxy-1,8-naphthyridin-2-yl)-2-furancarboxamide (13.5 g) is produced, m.p. 201° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:19][C:18]3[C:13](=[C:14]([OH:20])[CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:19][C:18]3[C:13](=[C:14]([O:20][CH2:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCc1ccncc1
Reactant: CC(C)(C)c1ccc(N2Cc3cccc(O)c3C2=O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(N2Cc3cccc(OCc4ccncc4)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(4-t-Butyl-phenyl)-7-hydroxy-2,3-dihydro-isoindol-1-one (0.201 g), 4-hydroxymethylpyridine (96 mg) and PPh3 (0.212 g) were dissolved in THF (20 mL). DIAD (0.16 mL) was added and the mixture was stirred at RT for 2 h. Solvent was evaporated and the residue was purified by silica gel chromatography (70 g, 100% EtOAc) to afford 2-(4-t-butyl-phenyl)-7-(pyridin-4-ylmethoxy)-2,3-dihydro-isoindol-1-one as a white solid. MS: (ES+) 373(M+H). Calc'd. for C24H24N2O2-372.46.
Reaction SMILES: Cl.[C:2]1([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([NH:27]C(=O)C)=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:15]=3)[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[NH4+]>C(O)C>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([NH:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc3[nH]nc(-c4ccccc4)c3c2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(S(=O)(=O)Nc2ccc3[nH]nc(-c4ccccc4)c3c2)cc1
Temperature: 20 °C
Yield: 26 %

Procedure:
4-Amino-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide can be obtained in the following way: 1.5 ml of an aqueous 5N hydrochloric acid solution are added to a suspension of 0.3 g of N-[4-(3-phenyl-1H-indazol-5-ylsulfamoyl)-phenyl]acetamide in 6 ml of 95% ethanol. The reaction mixture is then refluxed for 30 minutes then cooled to a temperature in the region of 20° C. 20 ml of water and 1 ml of an aqueous 32% ammonium hydroxide solution are then added to the reaction mixture, which is then extracted successively with 30 ml and 15 ml of ethyl acetate. The organic extracts are pooled, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography on a silica column (particle size 40-63 μm), eluting with a dichloromethane/methanol (95/5 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The solid thus obtained is taken up in 9 ml of ethanol in the presence of 3S black and dissolved under hot conditions, and the mixture is filtered under hot conditions through sintered glass and then recrystallized. The crystals are filtered off through sintered glass, washed with 0.5 ml of 95% ethanol then with 2 times 2 ml of diisopropyl ether, partially dried and then dried under reduced pressure (3 kPa) at a temperature in the region of 50° C. 70 mg of 4-amino-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a light beige powder melting at 249° C. (CI mass analysis: m/z 365 (M+H)+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH:19]=[C:18]3[CH3:26])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:26][C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[C:15]([O:14][C@H:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[CH:16]=2)[C:21](=[O:25])[NH:20][CH:19]=1
Reactant: Cc1c[nH]c(=O)c2ccc(O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c[nH]c(=O)c2ccc(O[C@H]3CCCNC3)cc12
Reaction time: 2 h

Procedure:
The crude (S)-3-(4-Methyl-1-oxo-1,2-dihydroisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester was dissolved in 2 ml of DCM and excess TFA added (0.2 ml). After stirring for 2 hours the solvent was removed under reduced pressure and the residue dissolved in methanol and partially purified by ion exchange chromatography. Further purification by prep-HPLC gave (S)-4-methyl-6-(piperidin-3-yloxy)-2H-isoquinolin-1-one, El-MS: m/z=259.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15](Cl)=[O:16].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>>[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[NH:18][C:15]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=2)=[O:16]
Reactant: CC(C)c1ccc2ncc(C(=O)Cl)c(O)c2c1
Reactant: Nc1nccs1
Product: CC(C)c1ccc2ncc(C(=O)Nc3nccs3)c(O)c2c1
Yield: 10.5 %

Procedure:
Using the procedure of Example 1, 10.74 g of the product of Step D and 3.9 g of 2-amino-thiazole were reacted to obtain 1.28 g of N-(2-thiazolyl)-4-hydroxy-6-isopropyl-quinoline-3-carboxamide melting above 340° C.