Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=O.[CH:18]1([C:22](=O)[CH2:23][C:24]#[N:25])[CH2:21][CH2:20][CH2:19]1>>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:22]([CH:18]1[CH2:21][CH2:20][CH2:19]1)[C:23]([C:24]#[N:25])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccc(Cl)c1
Reactant: N#CCC(=O)C1CCC1
Product: N#Cc1c(C2CCC2)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chloro-phenyl)-(3-chloro-phenyl)-methanone (prepared as described in example 91 step A) and 3-cyclobutyl-3-oxo-propionitrile (prepared as described in example 104 step A). Yellow foam. MS (ESI): 353.3 (M+H)+.
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]4[CH:32]=[CH:31][S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:7][CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[C:27]4[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]5[CH:32]=[CH:31][S:30][CH:29]=5)[CH:26]=4)[NH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:39][CH2:38]1
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: CN1CCNCC1
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1CCN(CCCS(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccsc5)cc34)CC2)CC1
Yield: 16.3 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indole-7-carboxamide (40 mg, 0.13 mmol) and 1-methylpiperazine (0.068 mL, 0.65 mmol) were allowed to react in the presence of K2CO3 (74 mg, 0.65 mmol). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (11.2 mg, 17.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:6][CH:7]=1.[C:39](Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:6]=[CH:7][C:2]([NH:1][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:3][CH:4]=3)[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(N)cn2)cc1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(NC(=O)C(C)(C)C)cn2)cc1

Procedure:
N-{6-{2-(5-Aminopyridin-2-yloxy )ethoxy}-5-(4-methylphenyl)-pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide and pivaloyl chloride are treated in the same manner as in Example 135 to give N-[6-[2-{6-(4-tert-butylphenylsulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yloxy}ethoxy]pyridin-3-yl]-pivalamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=O>>[CH2:43]([N:42]([CH2:45][CH3:46])[CH2:40][CH2:39][O:37][C:36]1[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=3[CH2:18]2)=[CH:3][C:2]=1[F:1])[CH3:44]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Reactant: CCN(CC)C(=O)CCl
Product: CCN(CC)CCOc1ccc(CCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1F
Yield: 33.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N,N-diethylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.7 mg) was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[NH:12]C(OC(C)(C)C)=O)=[O:5].C1(C)C=CC=CC=1>O1CCOCC1>[CH3:2][O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[NH2:12])=[O:5]
Reactant: COC(=O)[C@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1CCCC[C@H]1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 4.0 M solution of hydrochloric acid in 1,4-dioxane (20 mL) was added to a solution of (1S,2R)-2-tert-butoxycarbonylamino-1-cyclohexanecarboxylic acid methyl ester (1.28 g, 4.97 mmol) in 1,4-dioxane (15 mL) at 25° C. The reaction mixture was stirred at 25° C. for 2 h, then toluene (40 mL) was added and the volatiles were removed in vacuo. The residue was partitioned between saturated sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate, decanted, and were concentrated in vacuo to afford the crude product, (1S,2R)-2-amino-cyclohexanecarboxylic acid methyl ester as a yellow oil, which was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([S:13][CH3:14])[C:11]=1[OH:12])[CH:7]=O)[CH3:2].[C:15]1([C:21](=O)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH2:30][C:31]([NH2:33])=[O:32].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:9]=[C:10]([S:13][CH3:14])[C:11]=1[OH:12])[CH3:2]
Reactant: CCOc1cc(C=O)cc(SC)c1O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(SC)c1O
Yield: 32.6 %

Procedure:
To a solution of 3-ethoxy-4-hydroxy-5-(methylthio)benzaldehyde (Intermediate 50) (300 mg, 1.42 mmol), 1,2-diphenylethanone (330 mg, 1.68 mmol) and urea (170 mg, 2.80 mmol) in ethanol (5 mL) was added conc. HCl (0.3 mL) and the reaction mixture was refluxed under N2 atmosphere overnight. The resulting mixture was cooled and purified by silica gel column to give desired product (200 mg, yield 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]1.[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:23]([C:28]1[N:8]([CH2:9][CH:10]2[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]2)[C:7]2[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:21])[CH3:20])=[CH:3][C:2]=2[N:1]=1)([CH3:27])([CH3:24])[CH3:22]
Reactant: CC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c(N)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(3-Amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)acetamide (1.32 g, 4.44 mmol) was dissolved in 100 mL of DCM containing DMAP (108 mg, 0.89 mmol). Trimethylacetyl chloride (0.60 mL, 4.88 mmol) was added dropwise and the solution was stirred at rt for 2 h. The solution washed with saturated aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over anhydrous Na2SO4. Part of the product precipitated during the washings and was filtered. The organic phase was evaporated and combined with the precipitate. The product was dissolved in 30 mL of AcOH and placed in 6 sealed tubes (5 mL/tube). Each tube was heated at 150° C. in a Personal Chemistry microwaves instrument for 2.5 h. The fractions were pooled and the solvent was evaporated. The product was dissolved in EtOAc and washed with aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The product was purified by silica gel flash chromatography using 2:1/acetone:hexanes as eluent. Yield: 1.11 g (68%). 1H NMR (400 MHz, METHANOL-D4) δ 1.40-1.49 (m, 2H), 1.52 (s, 9H), 1.60-1.65 (m, 2H), 1.67-1.77 (m, 1H), 1.96-2.06 (m, 3H), 2.11 (s, 3H), 2.15-2.23 (m, 1H), 4.28 (d, J=7.62 Hz, 2H), 7.35-7.39 (m, 1H), 7.40-7.44 (m, 1H), 7.85 (d, J=1.76 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:12]1[S:16][C:15]([NH:17][C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34]CC)=[O:33])[CH2:27][CH2:26]3)[CH:19]=2)=[N:14][CH:13]=1)=[O:11].[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:12]1[S:16][C:15]([NH:17][C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:27][CH2:26]3)[CH:19]=2)=[N:14][CH:13]=1)=[O:11]
Reactant: CCOC(=O)CN1CCN(c2cc(Nc3ncc(C(=O)Nc4c(C)cccc4Cl)s3)nc(C)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)cc(N2CCN(CC(=O)O)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A mixture of ethyl 2-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-ylamino)-2-methylpyrimidin-4-yl)piperazin-1-yl)acetate (4) (0.21 g, 0.40 mmol) in 10 mL of MeOH was added 1.0 N NaOH (2.4 mL, 2.4 mmol) at rt. The mixture was stirred at rt for 1 h to become a clear solution. The HPLC indicated the reaction was complete with a single peak with Rt 2.417 min. The solvents in the solution were reduced to a small volume. The remaining liquid was treated with H2O (10 mL). The aqueous solution was washed with CH2Cl2 (2×10 mL) and then adjusted to pH 6-7 with 1 N HCl (2.4 mL) to result in white precipitation. The solid was collected on a filter, washed with water to give 0.18 g of 2-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-ylamino)-2-methylpyrimidin-4-yl)piperazin-1-yl)acetic acid (IV) (90% yield). HPLC>99% pure. LC/MS (ES+) 502/504 (M+H, 100), HRMS calcd for C22H24ClN7O3S 502.1428, found 502.1413.1H NMR (DMSO-d6) δ 11.49 (br s, 1H), 9.89 (s, 1H), 8.23 (s, 1H), 7.41(dd, J=7.5, 1.6 Hz, 1H), 7.28 (m, 2H), 6.07 (s, 1H), 3.55 (s, 4H0, 3.19 (s, 2H), 2.61 (t, J=4.7 Hz, 4H), 2.42 (s, 3H), 2.24 (s, 3H). Anal. Calcd for C22H24ClN7O3S 0.85H2O: C, 51.08; H, 5.01; Cl, 6.85; N, 18.95; S, 6.20; H2O, 2.96%. Found: C, 51.23; H, 4.97; Cl, 7.08; N, 19.09; S, 5.92; H2O, 2.94%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]3[CH:19]=2)=[CH:6][CH:5]=1)([O-])=O.C1CC=CCC=1>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]3[CH:19]=2)=[CH:8][CH:9]=1
Reactant: Cc1cccn2cc(-c3ccc([N+](=O)[O-])cc3)nc12
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: Cc1cccn2cc(-c3ccc(N)cc3)nc12
Temperature: 25 °C
Yield: 54.4 %

Procedure:
A mixture of the product of Step A (1.48 g) and 1,4-cyclohexadiene (6.2 mL) and palladium (10% wt on activated carbon) (1.4 g) in ethanol (100 mL) was stirred at reflux temperature for 2 hours and cooled to ambient temperature and stirred for 12 hours. The reaction mixture was filtered through a pad of celite and the celite pad rinsed with ethanol (100 mL) and methanol (100 mL). The filtrate was collected and evaporated to yield the title compound (710 mg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)O1.Cl[C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][N:33]=1>>[C:36]([C:35]1[CH:39]=[CH:40][C:32]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH2:21][CH2:22]4)=[N:14][C:13]=3[CH:29]=2)=[N:33][CH:34]=1)(=[O:37])[NH2:38]
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Reactant: NC(=O)c1ccc(Cl)nc1
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)cn4)ccc3o2)CC1
Yield: 16.3 %

Procedure:
Following the General Procedure-3, the titled compound (40 mg) was prepared from Intermediate 14 (250 mg, 0.6 mmol) and 6-chloronicotinamide (94 mg, 0.6 mmol) as an off-white solid. M.P.: 227-230° C. MS (m/z): 409.1 [M+H]+.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:11]=[CH:10][C:9]([NH:12]N)=[CH:8][CH:7]=2)[CH:5]=1.[CH2:14]([N:21]1[CH2:28][CH:27]2[CH:23]([CH2:24][N:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH:33](OC)OC)[CH2:26]2)[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>S(=O)(=O)(O)O>[CH2:14]([N:21]1[CH2:28][C@@H:27]2[CH2:26][N:25]([CH2:29][CH2:30][CH2:31][C:32]3[C:10]4[C:9](=[CH:8][CH:7]=[C:6]([N:4]5[CH:3]=[N:2][N:1]=[CH:5]5)[CH:11]=4)[NH:12][CH:33]=3)[CH2:24][C@@H:23]2[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(CCCCN1CC2CN(Cc3ccccc3)CC2C1)OC
Reactant: NNc1ccc(-n2cnnc2)cc1
Agent: O=S(=O)(O)O
Product: c1ccc(CN2C[C@H]3CN(CCCc4c[nH]c5ccc(-n6cnnc6)cc45)C[C@H]3C2)cc1
Temperature: 25 °C
Yield: 36.3 %

Procedure:
4-(1,2,4-Triazol-4-yl)phenylhydrazine (EP581538) (1.48 g, 8.4 mmol) was added in one portion to a stirred solution of 2-benzyl-5-(5,5-dimethoxypentyl)octahydro-pyrrolo[3,4-c]pyrrole (2.8 g, 8.4 mmol) in 4% sulphuric acid (50 ml) at room temperature. After 30 minutes at room temperature the mixture was heated to reflux under nitrogen for 72h. The reaction was then cooled to 0° C. and quenched with solid potassium carbonate. The aqueous was then extracted with in-butanol (x4). The combined extracts were evaporated and the residue purified by chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 (94:5:1→91:8:1→89:10:1) to give the title indole (1.3 g, 35%) as a yellow foam. An analytically pure sample was obtained by further chromatography of a small portion of the above sample on silica gel, eluting with Et2O/EtOH/NH3 (40:10:1) to give the title indole (150 mg) as a colourless solid. The 1.5 hydrogen oxalate. 0.5 hydrate. 0.1 etherate was prepared (Et2O/MeOH): mp 149-153° C. (Found: C, 61.12; H, 6.25; N, 14.07. C26H30N6.1.5(C2H2O4).0.5(H2O). 0.1(C4H10O) requires C, 61.16; H, 6.24; N, 14.26%). δ (360 MHz, d6 -DMSO) 1.98-2.08 (2H, m), 2.50-2.60 (1H, m), 2.70-2.82 (5H, m), 2.86-3.00 (5H, m), 3.06-3.14 (2H, m), 3.38-3.50 (1H, br m), 3.76 (2H, br s, CH2Ph), 7.26-7.38 (7H, m, Ar--H), 7.51 (1H, d, J=8.6 Hz, Ar--H), 7.82 (1H, d, J=2.0 Hz, Ar--H), 9.02 (2H, s, Triazole-H), 11.19 (1H, br s, N--H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:16]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[NH:15][N:14]=2)=[CH:9][CH:8]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[OH2:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][N:15]=[C:16]([N:24]3[CH2:29][CH2:28][N:27]([C:2]([O:4][CH3:5])=[O:3])[CH2:26][CH2:25]3)[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)Cl
Reactant: Clc1ccc(-c2n[nH]c(N3CCNCC3)c2-c2ccncc2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)N1CCN(c2n[nH]c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Product: O
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
Methyl chloroformate (55 mg) was added to a solution of 3-(4-chlorophenyl)-4-(4-pyridyl)-5-(4-piperazinyl) pyrazole (200 mg, 0.54 mmol; prepared as set forth in Example A-169) and 4-dimethylaminopyridine (5 mg) in pyridine (10 mL). The mixture was stirred at room temperature for 3 hours. Additional methyl chloroformate (30 mg) was added and stirring was continued for 24 hours. The solvent was removed in vacuo. The residue was treated with water and extracted with ethyl acetate. After drying the organic layer (MgSO4), the solvent was blown down to a volume of 10 mL and refrigerated. The resultant crystalline solid was filtered and air dried to give 103 mg (48%) of methyl 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate, monohydrate, mp 264-265° C. Anal. Calc'd. for C20H20ClN5O2.H2O: C, 57.76; H, 5.33; N, 16.84. Found: C, 57.98; H, 4.89; N, 16.44.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]([NH2:15])[CH:11]=[C:12]([Cl:14])[CH:13]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]([NH:15][C:16](=[O:18])[CH3:17])[CH:11]=[C:12]([Cl:14])[CH:13]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
200 ml of pyridine are added dropwise to 100 g of 3,5-dichlorophenylamine in 3000 ml of chloroform, followed by addition of 90 ml of acetic anhydride. The reaction mixture is stirred for 12 hours at room temperature. The solvents are evaporated off under reduced pressure and the residue obtained is recrystallized from 1000 ml of ethyl acetate; m.p.=182° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].C([O:14][C:15](=O)[CH:16]([CH3:20])[C:17]([CH3:19])=O)C>>[CH3:11][O:10][C:8]1[CH:7]=[C:6]2[C:4](=[C:3]([O:2][CH3:1])[CH:9]=1)[N:5]=[C:17]([CH3:19])[C:16]([CH3:20])=[C:15]2[OH:14]
Reactant: COc1ccc(N)c(OC)c1
Reactant: CCOC(=O)C(C)C(C)=O
Product: COc1cc(OC)c2nc(C)c(C)c(O)c2c1

Procedure:
Prepared according to procedure R using 2,4-dimethoxy aniline (1.99 g, 13.0 mmol), ethyl-2-methyl-acetoacetate (3.7 mL, 26.2 mmol), and PPA (6.78 g, 67.8 mmol) to afford 6,8-dimethoxy-2,3-dimethylquinolin-4-ol. Mass Spectrum (ESI) m/e=234.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[C:38](O)(=[O:41])[CH2:39][CH3:40]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:38](=[O:41])[CH2:39][CH3:40])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:26][CH2:27][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:29][CH2:30]1)=[O:24]
Reactant: CCC(=O)O
Reactant: Cc1ccc(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(N)(=O)=O)cnn23)c(Cl)c1
Product: CCC(=O)NS(=O)(=O)c1cnn2c(Nc3ccc(C)cc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 94.3 %

Procedure:
Using 7-(2-chloro-4-methylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.092 mmol) obtained in step 5 as a starting material and propionic acid (0.034 mL, 0.460 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.052 g, 93%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:11]2=[O:22])[S:5][C:6]=1[C:7]([OH:9])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:59][CH2:60][C:61]1[CH:62]=[N:63][CH:64]=[CH:65][CH:66]=1>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:11]2=[O:22])[S:5][C:6]=1[C:7]([NH:59][CH2:60][C:61]1[CH:62]=[N:63][CH:64]=[CH:65][CH:66]=1)=[O:9]
Reactant: Cc1nc(N2CCN(Cc3ccncc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCN(Cc3ccncc3)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.6 %

Procedure:
To a solution of 4-methyl-2-(2-oxo-3-(pyridin-4-ylmethyl)imidazolidin-1-yl)thiazole-5-carboxylic acid (0.67 g, 2.12 mmol) in anhydrous N,N-dimethyl formamide (10 mL) was added benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.94 g, 2.12 mmol), diisopropylethylamine (1.12 mL, 6.35 mmol) and 3-(aminomethyl)pyridine (0.22 mL, 2.12 mmol). The resulting solution was stirred at ambient temperature for 24 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (15 mL) and brine (15 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 10-20% methanol in ethyl acetate as an eluent to afford the title compound as a colorless solid (10%, 0.092 g): mp 233-235° C. (dichloromethane/hexanes): 1H NMR (300 MHz, CDCl3) δ 8.57-8.49 (m, 4H), 7.67 (d, J=7.7 Hz, 1H), 7.26-7.17 (m, 3H), 6.36 (br s, 1H), 4.56 (d, J=5.8 Hz, 2H), 4.45 (s, 2H), 4.12-4.07 (m, 2H), 3.50-3.45 (m, 2H), 2.58 (s, 3H): MS (ES+) m/z 409.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>CO.O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
117.8 g (0.42 mol) of 2-(4-nitrophenoxymethyl)quinoline were dissolved in 1 l of methanol/tetrahydrofuran (1:1). About 5 g of Raney nickel were added and the mixture was warmed to 35° C. 63.1 g (1.26 mol) of hydrazine hydrate were then added dropwise and the mixture was stirred overnight. The residue was filtered off, the solution was concentrated in vacuo and the residue was taken up with methylene chloride. The solution was then washed with water and conc. hydrochloric acid was added to the organic phase. The precipitate which deposited was filtered off, washed with 2N hydrochloric acid and dissolved in water, and the solution was rendered alkaline with 20% strength NaOH. The residue was dried in vacuo.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.Cl.[CH2:87]([O:89][NH2:90])[CH3:88]>>[CH2:87]([O:89][NH:90][C:40]([C:35]1[CH:34]=[CH:33][C:32]2[C:37](=[CH:38][CH:39]=[C:30]([C:2]([OH:1])([C:6]3[N:7]=[CH:8][N:9]([C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:10]=3)[CH:3]([CH3:5])[CH3:4])[CH:31]=2)[CH:36]=1)=[O:41])[CH3:88]
Reactant: CCON
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Product: CCONC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Yield: 77.4 %

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (1.77 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with O-ethylhydroxylamine hydrochloride (367 mg) in a similar manner as described in Example 24-(i) to give the titled compound (1.44 g) as a colorless powder.