Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]1[CH:10]([CH3:11])[CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH:18][C:19]([C:21]2[N:22]=[C:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[S:24][CH:25]=2)=[O:20])[CH2:7][CH:6]1[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[F:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:33])[C:26]=1[C:23]1[S:24][CH:25]=[C:21]([C:19]([NH:18][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:12]=2[CH:8]2[CH2:7][CH:6]([NH:34][C:35](=[O:36])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[CH:5]([OH:4])[CH:10]([CH3:11])[CH2:9]2)=[O:20])[N:22]=1
Reactant: CC(=O)OC1C(C)CC(c2ccncc2NC(=O)c2csc(-c3c(F)cccc3F)n2)CC1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC1CC(c2ccncc2NC(=O)c2csc(-c3c(F)cccc3F)n2)CC(NC(=O)OC(C)(C)C)C1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of (+/−)-2-(tert-butoxycarbonylamino)-4-(3-(2-(2,6-difluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)-6-methylcyclohexyl acetate in MeOH (0.03 M) was added potassium carbonate (3.0 equiv.) and the reaction was stirred at room temperature for 3 h. Upon completion, the reaction was partitioned between water and ethyl acetate. The aqueous phase was further extracted 3 more times with ethyl acetate. The organics were combined, dried with brine and sodium sulfate, filtered, and concentrated. Isolated tert-butyl(+/−)-5-(3-(2-(2,6-difluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate was obtained as an off-white solid in 87% yield. LC/MS=545.2 (M+H), Rt=0.75 min. To a solution of tert-butyl(+/−)-5-(3-(2-(2,6-difluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate (1.0 equiv.) in DCM (0.07M) at 0° C. was added DAST (1.0 equiv.) under a nitrogen atmosphere. The reaction was stirred for 1 h, upon which time, 2 more equivalents of DAST were added. After 30 min, the consumption of the starting material was complete. The reaction was quenched by the addition of water, the organic phase was dried with sodium sulfate, and concentrated. The crude material was purified via silica gel column chromatography eluting with ethyl acetate and hexanes (1:1) to afford tert-butyl(+/−)-5-(3-(2-(2,6-difluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)-2-fluoro-3-methylcyclohexylcarbamate as a clear oil in 60% yield. LC/MS=547.3 (M+H), Rt=0.92 min. The Boc group was removed by treating with 25% TFA in dichloromethane for 2 hours. Upon concentration under vacuo, the crude was purified via semi-prep HPLC. The pure fractions were lyophilized to yield N-(4-((+/−)-3-amino-4-fluoro-5-methylcyclohexyl)pyridin-3-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide as the desired product as the TFA salt in 74% yield. LC/MS=447.0 (M+H), Rt=0.56 min.
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][C:18]([OH:20])=O)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]>C1C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][C:18]([C:2]2[CH:1]=[CH:13][CH:14]=[CH:9][CH:10]=2)=[O:20])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(CC(=O)O)cc1OC
Solvent: c1ccccc1
Product: COc1ccc(CC(=O)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.8 %

Procedure:
Combine 3.9 g of oxalyl chloride, 2.0 g of 3,4-dimethoxyphenylacetic acid and 50 mL of benzene and stir the mixture at 60° C. for 2.5 h. Remove the excess oxalyl chloride by distillation and concentrate the solution to a volume of 20 mL. Cool the solution to room temperature and add slowly to a suspension of anhydrous aluminium chloride (1.6 g) in 300 mL of benzene over 12 h. Stir the reaction mixture for 6 h., pour into a mixture of ice and conc. hydrochloric acid, then extract with ethyl acetate. Dry the organic extract over Na2SO4, filter and concentrate the filtrate to a residue. Chromatograph the residue on silica gel using 3:7 ethyl acetate/hexane to give 847 mg of α-(3,4-dimethoxyphenyl)-acetophenone. 1H NMR (CDCl3): δ8.1-7.98 (2H, m); 7.62-7.4 (3H, m); 6.76-6.9 (3H, m); 4.24 (2H, s); 3.85 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][OH:8].[H-].[Na+].[S:16](Cl)(=[O:19])(=[O:18])[NH2:17]>CN(C=O)C>[S:16](=[O:19])(=[O:18])([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)[NH2:17]
Reactant: COc1ccc(CCO)cc1OC
Reactant: NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCOS(N)(=O)=O)cc1OC
Yield: 13.5 %

Procedure:
A mixture of 5.0 g (0.027 mole) of 3,4-dimethoxy phenethyl alcohol in 12 ml DMF was added dropwise to a suspension of sodium hydride (1.20 g, 60% in oil; 0.09 mole) in 40 ml DMF at 0°-5° C. The suspension was stirred for 20 min under argon after which sulfamoyl chloride (3.54 g, 0.03 mole) was added portionwise at 0°-5° C. After stirring for 20 min the resultant suspension was poured into ice and extracted twice with Et2O. The combined organic phases were washed with saturated brine, dried over potassium carbonate and concentrated in vacuo to a white solid which was recrystallized in EtOAc/hexane to give 0.95 g (13%) of the title compound as a solid, mp 106°-108° C. Both 13C and 1H NMR in CDCl3 confirmed the structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](OCC)=[O:14])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][OH:14])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnoc1-c1ccc(Br)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To a solution of ethyl 5-(4-bromophenyl)isoxazole-4-carboxylate (9.50 g) in tetrahydrofuran (70 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 70 ml) at 0° C. The mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(4-bromophenyl)-4-isoxazolylmethanol (8.03 g, yield 98%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 104–105° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[B:11]([OH:13])[OH:12])=[O:4].[CH2:14]([N:18]([CH2:22][CH2:23]O)[CH2:19][CH2:20]O)[CH2:15][CH2:16][CH3:17]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[B:11]1[O:13][CH2:23][CH2:22][N:18]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:19][CH2:20][O:12]1)=[O:4]
Reactant: COC(=O)c1ccccc1B(O)O
Reactant: CCCCN(CCO)CCO
Solvent: Cc1ccccc1
Product: CCCCN1CCOB(c2ccccc2C(=O)OC)OCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a suspension of (2-methoxycarbonylphenyl)boronic acid (5.0 g, 27.8 mmol) in toluene (40 mL) was added N-butyldiethanolamine (4.8 mL, 29.2 mmol, 1.05 equiv.) via a syringe. The mixture was heated at 50° C. for two hours. After cooling to room temperature, the toluene was evaporated under reduced pressure and the remaining clear colorless crude oil was treated with heptanes (˜500 mL). The heptanes mixture was then sonicated ˜5 min and the resulting suspension was allowed to stand at room temperature overnight. The solid that precipitated was collected by filtration, washed with heptanes, and dried in a vacuum oven overnight to yield a white solid as the 2-(2′-methoxycarbonylphenyl)-6-butyl[1,3,6,2]dioxazaborocan. 1H NMR (DMSO-d6) δ: 7.55-7.59 (m, 1H), 7.17-7.29 (m, 2H), 7.12-7.14 (m, 1H), 3.85-3.92 (m, 2H), 3.78-3.82 (m, 1H), 3.78 (br. s., 1H), 3.67 (s, 3H), 3.26-3.30 (m, 1H), 3.12 (dt, J=5.2, 2.6 Hz, 2H), 3.03-3.11 (m, 2H), 2.41-2.49 (m, 4H), 1.45-1.55 (m, 2H), 0.98-1.05 (m, 2H), 0.83 (s, 1H), 0.71-0.77 (m, 3H). Amount obtained, 8.3 g, (98.1% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CCOC(C)=O.O>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([O:1][C@H:2]2[CH2:19][CH2:18][C@@:17]3([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]4[C@@H:16]3[CH2:15][CH2:14][C@@:12]3([CH3:13])[C@H:8]4[CH2:9][CH2:10][C:11]3=[O:21])[CH2:3]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)C(=CC[C@@H]4[C@@H]3CC[C@]3(C)C(=O)CC[C@@H]43)C2)cc1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 3β-hydroxyandrost-5-en-17-one (10.00 g) in pyridine (66 mL), toluene-4-sulfonyl chloride (13.20 g) and DMAP (10 mg) were added at 0° C. under stirring. The reaction was allowed to warm to room temperature and stirred for 15 hr. After dilution with EtOAc (300 mL) the mixture was poured into iced water. The organic layer was separated, washed with 1N H2SO4, water and brine, dried and evaporated to dryness to give 3β-(p-toluensulfonyloxy)androst-5-en-17-one (14.70 g, 96%), as a white solid. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 7.81 (2H, m), 7.48 (2H, m), 5.35 (1H, m), 4.26 (1H, m), 2.46 (3H, s), 2.54-0.93 (19H, m), 1.05 (3H, s), 0.85 (3H, s).
Reaction SMILES: [C:1](OCC)(=O)[C:2]([O:4]CC)=[O:3].C1(S([N:20]2[CH:24]=[CH:23][CH:22]=[C:21]2[C:25](=O)[CH3:26])(=O)=O)C=CC=CC=1.[O-]CC.[Na+].Cl.[NH:33]([C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[N:39][CH:40]=1)[NH2:34]>C(O)C>[CH3:42][O:41][C:38]1[N:39]=[CH:40][C:35]([N:33]2[C:25]([C:21]3[NH:20][CH:24]=[CH:23][CH:22]=3)=[CH:26][C:1]([C:2]([OH:4])=[O:3])=[N:34]2)=[CH:36][CH:37]=1
Reactant: COc1ccc(NN)cn1
Reactant: CC(=O)c1cccn1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2nc(C(=O)O)cc2-c2ccc[nH]2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
Under cooling with ice, diethyl oxalate (3.10 mL) and 1-[1-(phenylsulfonyl)pyrrol-2-yl]-1-ethanone (2.49 g) were added to sodium ethoxide (1.63 g) in ethanol (20 mL), followed by stirring at room temperature for 5 hours. To the reaction mixture, 5-hydrazino-2-methoxypyridine hydrochloride (2.52 g) obtained from Referential Example 1 and ethanol (20 mL) were added, and the resultant mixture was refluxed under heat for 14.5 hours, and then cooled in air. The reaction solvent was removed under reduced pressure, and the residue was partitioned by use of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The aqueous layer was extracted again with ethyl acetate. The organic layers were combined, and then dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, the residue was purified through silica gel column chromatography (ethyl acetate-hexane), to thereby give 1-(6-methoxy-3-pyridyl)-5-[1-(phenylsulfonyl)pyrrol-2-yl] pyrazole-3-carboxylic acid ethyl ester as an oily product (3.28 g, 72%). To the thus-obtained ethyl ester (3.28 g) in ethanol (22 mL), aqueous 1N sodium hydroxide (22 mL) was added, followed by stirring at room temperature for 2 days. Aqueous 1N hydrochloric acid was added to the reaction mixture, and the precipitated solid was recovered by filtration, to thereby give the title compound as a solid (1.40 g, 68%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[C:11]([NH:19][NH2:20])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[N:8]1[CH:9]=[CH:10][C:5]([C:1](=[N:20][NH:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH3:3])=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccncc1
Reactant: NNC(=O)c1ccccc1
Solvent: CCO
Product: CCC(=NNC(=O)c1ccccc1)c1ccncc1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A mixture of 4.05 gm (0.03 mole) of 4-propionylpyridine, 4.08 gm (0.03 mole) of benzhydrazide and 100 ml of Ethanol is refluxed 6 hr. The hot solution is filtered. The filtrate is cooled to room temperature and then chilled in the refrigerator. The product is collected, washed with Skellysolve B and dried to yield 5.36 gm (71%) of the title compound having a melting point of 177.6° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[N:7]2.C([O-])([O-])=O.[Na+].[Na+].[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1B(O)O>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:21]1[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:20]=1[CH3:19])[CH:8]=[N:7]2
Reactant: Cc1cccc(C)c1B(O)O
Reactant: Clc1cnc2cccc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cccc(C)c1-c1cnc2cccc(Br)c2n1
Temperature: 80 °C
Yield: 12.2 %

Procedure:
Argon was bubbled into a mixture of 8-bromo-2-chloroquinoxaline (210e; 0.50 g, 2.05 mmol), Na2CO3 (1.09 g, 10.27 mmol), Pd(PPh3)4 (Strem; 0.119 g, 0.103 mmol), 2,6-dimethylbenzeneboronic acid (Aldrich; 0.31 g, 2.05 mmol) in 9 mL ACN and 3 mL water for 1 min. The reaction was sealed and heated to 80° C. overnight. The temperature was increased to 100° C. and the reaction was heated 8 h. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with MeOH/DCM and adsorbed onto 2 g silica gel, dried, and purified by silica gel chromatography (40 g ISCO gold column) using 0-30% EtOAc/hexanes. The product-containing fractions were concentrated to afford 8-bromo-2-(2,6-dimethylphenyl)quinoxaline (0.08 g, 0.25 mmol, 12% yield) as an oil that solidifies very slowly to a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.83 (1H, s), 8.09-8.19 (2H, m), 7.67 (1H, dd, J=8.2, 7.6 Hz), 7.27-7.33 (1H, m), 7.16-7.23 (2H, m), 2.18 (6H, s). m/z (ESI, +ve) 313.0/315.0 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH:14][C:15]1[N:20]=[C:19]([C:21](OCC)=[O:22])[C:18]([N+:26]([O-])=O)=[C:17]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])[N:16]=1)=O)(C)(C)C.ClC1N=C([C:45](OCC)=[O:46])C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=1.C([N:69]1CCCC1CN)(OC(C)(C)C)=O.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N:29]1[C:45](=[O:46])[NH:26][C:18]2[C:17]1=[N:16][C:15]([NH:14][CH2:13][C@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[N:20][C:19]=2[C:21]([NH2:69])=[O:22]
Reactant: CCOC(=O)c1nc(Cl)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCCC1CN
Reactant: CCOC(=O)c1nc(NC[C@H]2CCCN2C(=O)OC(C)(C)C)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(NC[C@H]3CCCN3)nc21
Yield: 97 %

Procedure:
(R)-Ethyl 2-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methylamino)-6-(2-methoxy-phenylamino)-5-nitropyrimidine-4-carboxylate. Ethyl 2-chloro-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (See Example 30.A) (0.300 g, 0.852 mmol), (R) 1-boc-(aminomethyl)pyrrolidine (0.207 g, 1.02 mmol) and diisopropylethylamine (0.164 g, 1.27 mmol) were reacted according to General Procedure C, except at room temperature and in dimethylformamide (5 mL). The crude reaction mixture was condensed and purified using Biotage chromatography (0-100% ethyl acetate in hexanes) to afford the title compound (0.430 g, 97%). MS (ESI) m/z 517.5 [M+1]+.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:38]=[CH:37][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:27])[CH2:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH:65]2[CH2:67][O:66]2)=[CH:59][CH:58]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:29]([NH:28][C:26]([N:23]1[CH2:22][CH2:21][CH:20]([C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:10]3[CH:37]=[CH:38][C:7]([CH2:6][CH2:5][NH:4][CH2:67][C@H:65]([OH:66])[CH2:64][O:63][C:60]4[CH:61]=[CH:62][C:57]([OH:56])=[CH:58][CH:59]=4)=[CH:8][CH:9]=3)[CH2:13][CH2:14]2)=[O:19])[CH2:25][CH2:24]1)=[O:27])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCNC(=O)N1CCC(C(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)CC1
Solvent: O=CO
Product: CCCCCCCCNC(=O)N1CCC(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)CC1
Yield: 26.9 %

Procedure:
4-({4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}carbonyl)-N-octyl-1-piperidinecarboxamide formate(0.41 g, 0.771 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.27 g, 0.668 mmol) according to Procedure G to give the title compound (0.16 g, 0.180 mmol).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:8]([O:32][CH3:33])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[C:19](C4N=CC=CC=4C(N)=O)=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=[N:43]C=C(C=1)C(O)=O.[CH3:50][C:51]1[N:52]=[N:53][S:54][C:55]=1[C:56](Cl)=[O:57]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[C:8]([O:32][CH3:33])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[C:19]([NH:43][C:56]([C:55]4[S:54][N:53]=[N:52][C:51]=4[CH3:50])=[O:57])=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cncc(C(=O)O)c1
Reactant: COc1c(NC(=O)c2cc3cccc(-c4ncccc4C(N)=O)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Cc1nnsc1C(=O)Cl
Product: COc1c(NC(=O)c2cc3cccc(NC(=O)c4snnc4C)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Yield: 50 %

Procedure:
Was prepared as described for -[2-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-benzo[b]thiophen-7-yl]-nicotinamide starting with 5-methoxy-nicotinic acid to provide 20 mg (50%) of the title compound 4-Methyl-[1,2,3]thiadiazole-5-carbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([O:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[C:18]([NH2:20])[S:19][C:15]=2[CH:14]=1)(=[O:11])=[O:10].Cl[C:24]([O:26][CH3:27])=[O:25].O>N1C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([O:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[C:18]([NH:20][C:24]([O:26][CH3:27])=[O:25])[S:19][C:15]=2[CH:14]=1)(=[O:11])=[O:10]
Reactant: COC(=O)Cl
Reactant: Nc1nc2ccc(OS(=O)(=O)c3c(Cl)cccc3Cl)cc2s1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)Nc1nc2ccc(OS(=O)(=O)c3c(Cl)cccc3Cl)cc2s1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a solution of 1 g of 2-amino-1,3-benzothiazol-6-yl 2,6-dichlorobenzenesulfonate in 25 cm3 of pyridine is added 0.308 cm3 of methyl chloroformate. The solution is stirred at a temperature in the region of 20° C. overnight. After addition of 0.62 cm3 of methyl chloroformate, the mixture is stirred for 72 hours at a temperature in the region of 20° C. 50 cm3 of water are added, and the precipitate formed is filtered off by suction and then washed with three times 10 cm3 of water and dried under reduced pressure. 785 mg of 2-[(methoxycarbonyl)amino]-1,3-benzothiazol-6-yl 2,6-dichlorobenzenesulfonate are obtained in the form of a beige-coloured powder, the characteristics of which are as follows:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([OH:23])=O.[OH:24][C:25]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:26]=1[NH2:27]>ClCCl.O>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([NH:27][C:26]1[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:25]=1[OH:24])=[O:23]
Reactant: Nc1cc(Cl)ccc1O
Reactant: O=C(O)Cc1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccccc1Cl)Nc1cc(Cl)ccc1O
Reaction time: 1.5 h

Procedure:
To a mixture of 1,1′-carbonyl diimidazole (66.5 g, 0.41 mol) and dichloromethane (300 ml) was added 2-chlorophenylacetic acid (67.0 g, 0.39 mol) dissolved in dichloromethane (200 ml). The mixture was stirred for 1.5 hours and 2-hydroxy-5-chloroaniline (56.4 g, 0.39 mol) was added in one portion. After stirring overnight, the reaction mixture was diluted with water and the mixture was filtered to give the desired amide. The dichloromethane was separated and washed with water. Evaporation of the dichloromethane under reduced pressure afforded additional product which was triturated with a small amount of dichloromethane and combined with the material collected previously to give 108.5 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4].Br[C:46]1[CH:47]=[N:48][N:49]([CH3:51])[CH:50]=1>>[CH3:44][C:2]([CH3:1])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:46]3[CH:47]=[N:48][N:49]([CH3:51])[CH:50]=3)=[CH:15][CH:14]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4]
Reactant: Cn1cc(Br)cn1
Reactant: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)O
Product: Cn1cc(-c2ccc(Cn3c(CC(C)(C)C(=O)O)nc4cc(OCc5ccc6ccccc6n5)ccc43)cc2)cn1

Procedure:
The title compound was prepared with similar methods to those in Example 147 using 2,2-dimethyl-3-(5-(quinolin-2-ylmethoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazol-2-yl)propanoic acid and 4-bromo-1-methyl-1H-pyrazole. MS (ESI): mass calcd. for C33H31N5O3, 545.24; m/z found, 546.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.92 (d, J=8.6, 1H), 8.41 (d, J=8.5, 1H), 8.24 (d, J=8.1, 1H), 8.15 (s, 1H), 8.06-8.01 (m, 2H), 7.87-7.79 (m, 2H), 7.64 (d, J=9.1, 1H), 7.53 (d, J=8.2, 2H), 7.49 (d, J=2.3, 1H), 7.34 (dd, J=9.1, 2.3, 1H), 7.27 (d, J=8.3, 2H), 5.79 (s, 2H), 5.76 (s, 2H), 3.84 (s, 3H), 3.56 (s, 2H), 1.32 (s, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7]I.[CH3:9][C:10]1([CH3:30])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([C:20]2[CH:21]=[N:22][C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:11]1>CC(C)=O>[CH3:7][N:11]1[C:10]([CH3:30])([CH3:9])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: CI
Reactant: CC1(C)Cc2ccccc2C(c2cnc3ccccc3c2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN1C(c2cnc3ccccc3c2)c2ccccc2CC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.7 %

Procedure:
Potassium carbonate (500 mg, 3.6 mmol) and methyl iodide (0.33 mL, 5.0 mmol) were added to an acetone (2 mL) solution of 3-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl) quinoline (144 mg, 0.5 mmol) followed by stirring for 3 hours at room temperature, filtering, concentrating the filtrate and applying the resulting residue to chromatography to obtain 60 mg of the target compound (yield: 40%).
Reaction SMILES: [CH2:1](Br)[CH:2]([CH3:4])[CH3:3].[OH:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].C(OC1C=C(C=CC=1)C(O)=O)CC>>[CH2:1]([O:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC(C)CBr
Agent: CCCOc1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)COc1ccc(C(=O)O)cc1

Procedure:
The reaction of isobutyl bromide and ethyl 4-hydroxybenzoate in the presence of potassium carbonate was performed as described for Compound 24 to give 4-isobutoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.56 (s, COOH); 7.85 (d, J=8.8, 2 arom. H); 6.98 (d, J=8.8, 2 atom. H); 3.80 (d, J=6.4, (CH3)2CHCH2O); 2.01 (m, (CH3)2CHCH2O); 0.96 (d, J=6.4, (CH3)2CHCH2O). 13C-NMR (100 MHz, d6-DMSO): 166.97 (—C═O); 162.35; 131.32 (2 arom. C); 122.78; 114.22 (2 arom. C); 73.89; 27.60; 18.94.