Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=O)[NH:6]2.[CH3:15][C:16]1([CH3:23])[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][C:16]1([CH3:23])[CH2:21][CH2:20][CH:19]([NH:22][C:12]([C:5]2[NH:6][C:7]3[C:3]([CH:4]=2)=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=3)=[O:14])[CH2:18][CH2:17]1
Reactant: O=C(O)c1cc2c(F)cc(F)cc2[nH]1
Reactant: CC1(C)CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCC(NC(=O)c2cc3c(F)cc(F)cc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 4,6-difluoro-1H-indole-2-carboxylic acid (5 g, 25.36 mmol×4 batches) and 4,4-dimethylcyclohexylamine.HCl (I-6b: 4.6 g, 28.10 mmol, for each batch) in dry DMF (75 mL) was cooled to 0° C. and HATU (11.62 g, 30.57 mmol, for each batch) was added followed by DIPEA (22 mL, 127.9 mmol, for each batch) drop-wise and the mixture was stirred under inert atmosphere at room temperature for 17h. Ice-cold water (50 mL) was added to the reaction mixture with vigorous stirring. The precipitated solid was collected by filtration and dried thoroughly. The crude compound obtained from combining all the batches was purified by column chromatography over silica gel (100-200 mesh) using a solvent gradient of 30%-40% ethyl acetate in hexanes as eluent to afford 23 g of off-white solid. It was triturated with ether/hexanes (3:7) in five cycles to afford 20.6 g (66.2%) of 4,6-difluoro-N-(4,4-dimethylcyclohexyl)-1H-indole-2-carboxamide (2A) as an white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[C:5]([N:7]([CH3:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:6].C(Cl)(=O)C(Cl)=O.[C:31](O)([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[C:31]([O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:7]([C:5](=[O:6])[C:4]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:2]([Br:1])[CH:3]=1)[CH3:20])([CH3:34])([CH3:33])[CH3:32]
Reactant: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1CCCC(=O)O
Reactant: CC(C)(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1CCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
To a cooled solution (0° C.) of 4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acid (1.07 g, 2.60 mmol) in anhydrous DCM (10 mL), oxalyl chloride (0.34 mL, 3.90 mmol) was added dropwise. The mixture was stirred at room temperature for 4 hours, concentrated in vacuo and redissolved in anhydrous dichloromethane (5 mL). A solution of t-butanol (960 mg, 13 mmol) in anhydrous DCM (5 mL) was added and the mixture was stirred at room temperature overnight. After dilution with DCM, the mixture was washed with sat NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel column chromatography (EtOAc/Hexanes: 1/4 with gradient up to EtOAc/Hexanes 1/3) afforded 1.1 g of 4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acid tert-butyl ester as a colorless oil. MS [M+H]+ (fragment):411.7 (f; tR=3.10 min, (method 1)
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:24](=[O:37])[CH:23]=[CH:22]4)=[CH:13][N:12]=2)=[CH:6][CH:5]=1.[N+](=[CH2:41])=[N-]>C(OCC)C>[F:38][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH:17]3[CH2:41][CH:18]3[C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:24](=[O:37])[CH:23]=[CH:22]4)=[CH:13][N:12]=2)=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)CCOCn1c(=O)ccc2cc(/C=C/c3cnc(Nc4ccc(OC(F)F)cc4)nc3)ccc21
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: C[Si](C)(C)CCOCn1c(=O)ccc2cc(C3CC3c3cnc(Nc4ccc(OC(F)F)cc4)nc3)ccc21
Temperature: -10 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
To a stirred solution of (E)-6-(2-(2-((4-(difluoromethoxy)phenyl)amino)pyrimidin-5-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one (0.15 g, 0.280 mmol) in diethyl ether (10 mL) was added PdOAc2 (6.28 mg, 0.028 mmol). The reaction mixture was cooled to −10° C., and a cold solution of diazomethane in ether (generated from aqueous KOH (0.45 g) and NMU (0.6 g) at −15° C.) was added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was filtered through celite, diluted with diethyl ether, and washed with water and saturated NaCl solution. The organic layer was dried over sodium sulfate, concentrated, and purified by flash chromatography on silica gel column using 15% ethyl acetate in hexane to give 6-(2-(2-((4-(difluoromethoxy)phenyl)amino)pyrimidin-5-yl)cyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one as a yellow gum (0.075 g, 49%). LCMS: RT 2.317 min, (M+H) 551.
Reaction SMILES: CO[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.COC(=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[O-].[Na+].Cl>C(Cl)(Cl)Cl.O>[CH2:14]([C:3]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccccc1
Reactant: COC(=O)c1cccnc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(Cc1ccccc1)c1cccnc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
The mixture of 27.4 g (0.2 mol) of nicotinic acid methyl ester and 30 g (0.2 mol) of phenylacetic acid methyl ester is treated in small amounts under nitrogen with 16.2 g (0.3 mol) of sodium methylate at 20°-25°C. The reaction mixture is stirred for 20 hours at 60°-70°C, in the process of which the alcohol which is formed is blown off. Then 60 ml of concentrated hydrochloric acid is added dropwise to the solid substance and the mixture is boiled for 3 hours under reflux. The still hot yellow solution is treated with 30 ml of water and cooled to 50°C. Then 60 ml of chloroform are added and the reaction mixture is cooled to 5°C. The white crystals which form are collected by suction filtration and washed with chloroform; they melt at 225°C (from ethanol).
Reaction SMILES: Cl.[Cl:2][C:3]1[S:4][C:5]([CH2:8]Cl)=[CH:6][N:7]=1.O.C(=O)([O-])[O-:12].[Na+].[Na+].Cl>C(OCC)(=O)C>[ClH:2].[Cl:2][C:3]1[S:4][C:5]([CH2:8][OH:12])=[CH:6][N:7]=1
Reactant: O=C([O-])[O-]
Reactant: ClCc1cnc(Cl)s1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: OCc1cnc(Cl)s1
Temperature: 80 °C

Procedure:
2-Chloro-5-chloromethylthiazole hydrochloride (100 g, 0.49 mole), and water (100 mL) were charged to a flask. The mixture was stirred and heated to 80° C. for 2.5 hours. The reaction mixture was cooled to about 15° C. and sodium carbonate (51.5 g) was added (to raise the pH to about 8-9). The product was extracted with ethyl acetate (1×500 mL and 1×250 mL). The combined organic extracts were stirred for 20 minutes with 3 g of decolorizing carbon (Norit® SA3 about 100 mesh) and filtered through celite. The celite and flask were washed with an additional 100 mL of ethyl acetate and combined with the filtrate. The filtrate was concentrated under reduced pressure to provide a yellow-orange oil. The oil was dissolved in 500 mL of ethyl acetate and cooled to -10° C., under a nitrogen atmosphere. A solution of HCl (17.82 grams, 1 eq.) in ethyl acetate was slowly added. The temperature was maintained below -5° C. After the addition was complete the slurry formed was stirred for 30 minutes. The product was filtered under vacuum and the flask and product washed with ethyl acetate(100 mL). The title compound, an off white powder, was purged with nitrogen gas until dry. Yield: 63.3 g; 69.6%.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[N:30]([CH2:41][CH3:42])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:10][N:9]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O1CCCC1>[F:51][C:2]([F:1])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:45]=1)[CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[N:30]([CH2:41][CH3:42])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCOC)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCN(CCCCCC(=O)O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCOC)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
Ethyl 6-{[2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl]-ethyl-amino}-hexanoate (113 mg) is dissolved in a mixed solvent of ethanol (2 ml) and tetrahydrofuran (1 ml), and thereto is added 1M-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 2 hours. The reaction solution is made weakly acidic with a 10% aqueous citric acid solution, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→49:1) to give 6-{[2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl]-ethyl-amino}-hexanoic acid (111 mg). MS (m/z): 711 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][S:12]([CH3:14])=[O:13])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1.N1CCCC1>CO>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19](/[C:20](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:11][S:12]([CH3:14])=[O:13])/[C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CS(=O)COc1ccc(Cl)cc1C=O
Solvent: CO
Solvent: C1CCNC1
Product: CS(=O)COc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Yield: 91.3 %

Procedure:
In a manner similar to the method described in Example 9b, 5-chloro-2-methanesulfinylmethoxy-benzaldehyde (0.4 g, 1.72 mmol) was reacted with 6-chlorooxindole (0.31 g, 1.86 mmol) and pyrrolidine (0.13 g, 1.86 mmol) in methanol (10 mL) to give the title compound as a yellow solid (0.6 g).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5].CC(C)([O-])C.[K+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>CS(C)=O>[F:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])[N:8]=1)=[O:5]
Reactant: COC(=O)CBr
Reactant: O=C(Nc1ccn(Cc2ccc(O)cc2C(F)(F)F)n1)c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)COc1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,6-difluoro-N-(1-{[4-hydroxy-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide (for a preparation see Example 36)(81 mg, 0.204 mmol) in DMSO (0.5 ml) was added potassium t-butoxide (23 mg, 0.205 mmol). The reaction was stirred for 15 min before adding methyl bromoacetate (0.020 ml, 0.211 mmol, Aldrich). The reaction was heated to 60° C. and stirred overnight, under nitrogen. The reaction mixture was filtered through a hydrophobic frit and the filtrate diluted with methanol (0.5 ml) and the sample purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a brown gum (38.5 mg); LCMS: (System 4) MH+=470, tRET=2.90 min.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:7]=3[C:6]=2[C:5]=1[Cl:25].[F:26][C:27]1[CH:36]=[CH:35][C:30]([O:31][CH2:32][CH2:33]Br)=[CH:29][CH:28]=1>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:33][CH2:32][O:31][C:30]3[CH:35]=[CH:36][C:27]([F:26])=[CH:28][CH:29]=3)[C:8]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][C:7]=3[C:6]=2[C:5]=1[Cl:25]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(Cl)c(Cl)c3c2CC1
Reactant: Fc1ccc(OCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccc(F)cc3)c3ccc(Cl)c(Cl)c23)CC1
Reaction time: 0.42 h
Yield: 84.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 68 mg, 1.7 mmol) was added to a solution of tert-butyl 9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.40 g, 1.1 mmol) in DMF (6 mL). After 25 min, 4-fluorophenoxy ethyl bromide (0.34 mL, 2.3 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 22 h and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptane/EtOAc (17:3) to give 0.46 g (82%) of a white solid: mp 163.5-165.5° C.; 1H NMR (300 MHz, CDCl3) δ 7.16 (m, 2H), 6.92 (m, 2H), 6.70 (m, 2H), 4.44 (m, 2H), 4.12 (m, 2H), 3.73 (m, 4H), 3.51 (m, 2H), 3.12 (m, 2H), 1.48 (s, 9H); IR (diffuse reflectance) 1675, 1507, 1449, 1405, 1365, 1354, 1298, 1249, 1242, 1221, 1209, 1170, 1120, 835, 828 cm−1; MS (FAB) m/z 493 (M+H+), 494, 493, 492, 439, 438, 437, 436, 435, 57, 42; HRMS (EI) calcd for C25H27Cl2FN2O3 492.1383, found 492.1385; Anal. Calcd for C25H27Cl2FN2O3: C, 60.86; H, 5.51; N, 5.68; found: C, 60.93; H, 5.60; N, 5.69.
Reaction SMILES: CN(C)C=O.Cl.Cl[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[NH2:16][C:17](=[O:48])[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:29][CH2:30][C:31]([OH:33])=[O:32])[N:22]([CH2:34][C:35]2[CH:36]=[C:37]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:39][CH:40]=2)[C:21]=1[CH3:47])=[O:19].[Na]>O>[NH2:16][C:17](=[O:48])[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:29][CH2:30][C:31]([O:33][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:32])[N:22]([CH2:34][C:35]2[CH:36]=[C:37]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:38]=[CH:39][CH:40]=2)[C:21]=1[CH3:47])=[O:19]
Reactant: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1cccc(-c2ccccc2)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)OCCN3CCOCC3)cccc2n1Cc1cccc(-c2ccccc2)c1
Temperature: 60 °C

Procedure:
In a flask containing 10 ml of dimethylformamide was added with stirring 133 mg. of 4-(2-chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3) and 231 mg. of CsCO3 and 300 mg. of ((3-(2-amino-1,2-dioxoethyl)-1-((1,1′-biphenyl)-3-ylmethyl)-2-methyl-1H-indol-4-yl)oxy)acetic acid, sodium salt. The slurry was heated to 60° C. until a solution formed. Heating was continued overnight until reaction was complete. 20 ml of H2O was added to the flask and the organic soluble phase extracted with three 20 ml. portions of ethyl acetate. The ethyl acetate solution was washed with water and dried over and dried over Na2SO4. Removal of solvent gave product verified by IR and NMR to be the title compound. Molecular Formula: C32H22N3O6
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:26])[CH2:7][N:8]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:26])[CH2:7][N:8]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CC(=O)N2C[C@@H](CO)n3c2c1ccc3=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CN2C(=O)CN(C(=O)OCc3ccccc3)c3ccc(=O)n1c32
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Phenylmethyl (1S)-1-(hydroxymethyl)-3,8-dioxo-1,2,3,4-tetrahydro-5H,8H-2a,5,8a-triazaacenaphthylene-5-carboxylate (242 mg, 0.681 mmol) (for a preparation see Example 13(g)) was dissolved in DCM (10 ml) at room temperature under argon and then treated with triethylamine (0.114 ml, 0.817 mmol). The mixture was then cooled using an ice-water bath. Methanesulfonyl chloride (0.058 ml, 0.749 mmol) was then added and the reaction was allowed to warm up to room temperature. After 1 h the mixture was washed with sat NaHCO3 (10 ml). The aqueous layer was extracted with DCM (2×50 ml) and the combined organic extracts dried on MgSO4, filtered and evaporated to afford the product as a yellow foam (232 mg, 95% purity by LCMS, 74.7%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH:15]([CH3:26])[CH2:14]2)[CH:3]=1.[NH2:27][CH2:28][C:29]1([NH2:33])[CH2:32][O:31][CH2:30]1>>[NH2:33][C:29]1([CH2:28][NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH:15]([CH3:26])[CH2:14]3)[CH:3]=2)[CH2:32][O:31][CH2:30]1
Reactant: Cc1ccc2nc(N3Cc4ccccc4S(=O)(=O)C(C)C3)cc(Cl)c2c1
Reactant: NCC1(N)COC1
Product: Cc1ccc2nc(N3Cc4ccccc4S(=O)(=O)C(C)C3)cc(NCC3(N)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 69-1 in Scheme 30 by using 4-(4-chloro-6-methylquinolin-2-yl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (d, J=7.83 Hz, 1 H), 7.92 (brs, 1 H), 7.66 (s, 2 H), 7.52-7.41 (m, 2 H), 7.30 (dd, J=8.59, 1.77 Hz, 1 H), 6.19 (s, 1 H), 5.18 (brs, 1 H), 5.10 (brs, 1 H), 4.66-4.55 (m, 4 H), 3.68 (d, J=2.02 Hz, 2 H), 3.65-3.57 (m, 1 H), 3.35-3.30 (m, 3 H), 2.43 (s, 3 H), 1.60-1.40 (brs, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a mixture of 2-aminophenol (1.09 g, 10.0 mmol) and triethylamine (2.09 mL, 15.0 mmol) in THF (20 mL) was added benzoyl chloride (1.16 mL, 10.0 mmol) in THF (4 mL) dropwise over a period of 5 min at 0° C. After addition was complete the reaction mixture was kept on stirring at room temperature for overnight. The reaction mixture was concentrated at reduced pressure. The residue was taken up in methanol, aqueous sodium hydroxide (NaOH) (8M, 5 mL) was added. After 5 min the pH of the reaction mixture was adjusted to 7.0 by addition of glacial acetic acid and concentrated in vacuo. The reaction mixture was dissolved in dichloromethane (CH2Cl2), washed successively with 1M aqueous hydrochloric acid (HCl), saturated aqueous sodium hydrogen carbonate (NaHCO3). The organic layer was dried over sodium sulphate (Na2SO4), filtered and concentrated to give desired product (1.69 g).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:18].Cl[CH2:20][CH2:21][N:22]=[C:23]=[S:24]>O1CCCC1>[S:24]1[CH2:20][CH2:21][N:22]=[C:23]1[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](=[CH:8][C:4]2[S:3][CH:7]=[CH:6][CH:5]=2)[C:10]1=[O:18]
Reactant: S=C=NCCCl
Reactant: O=C1Nc2ccccc2C1=Cc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C(=Cc2cccs2)c2ccccc2N1C1=NCCS1
Temperature: 0 °C

Procedure:
To a stirred suspension of NaH (0.51 gm; 21.1 mmole) in dry tetrahydrofuran (100 ml) is added dropwise a solution of 3-(2-thienylmethylene)-indolin-2-one prepared as described above (4.0 gm; 17.6 mmole) in dry tetrahydrofuran (100 ml). The resultant solution is stirred at room temperature for another hour, after which, it is cooled to 0° C in an ice bath, and a solution of chloroethylisothiocyanate (2.2 gm; 17.6 mmole) in dry tetrahydrofuran (50 ml) is added. The mixture is then heated at reflux temperature for 3.5 hours.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[CH:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([OH:42])=[O:41])=[CH:35][CH:34]=1)=O>>[C:40]([CH2:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:31][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:34][CH:35]=1)([OH:42])=[O:41]
Reactant: O=Cc1ccc(CC(=O)O)cc1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1cc(NCCCc2ccc(CC(=O)O)cc2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Yield: 93.2 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (296 mg) and (4-formylphenyl)acetic acid (360 mg) according to an analogous synthetic method to Example 212,the title compound (375 mg) was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[Si:7]([CH3:17])([CH3:16])[CH2:6]1.C[Si]1(C)C2C([F:29])=CC=CC=2C(=O)NC1.C([Li])CCC.ClCCCBr>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[C:15]([F:29])[C:8]=2[Si:7]([CH3:16])([CH3:17])[CH2:6]1
Reactant: C[Si]1(C)CN(CCCCl)C(=O)c2ccccc21
Reactant: C[Si]1(C)CNC(=O)c2cccc(F)c21
Agent: ClCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si]1(C)CN(CCCCl)C(=O)c2cccc(F)c21

Procedure:
3-(3-Chloropropyl)-1,1-dimethyl-8-fluoro-4-oxo-1,2,3,4-tetrahydro-3,1-benzazasiline is obtained in a manner similar to that described in Example 4 for the preparation of 3-(3-chloropropyl)-1,1-dimethyl-4-oxo-1,2,3,4-tetrahydro-3,1-benzazasiline, but using 4.8 g of 1,1-dimethyl-8-fluoro-4-oxo-1,2,3,4-tetrahydro-3,1-benzazasiline, 17.2 cm3 of n-butyllithium, 8.7 g of 1-chloro-3-bromopropane and 70 cm3 of tetrahydrofuran. After purification by flash chromatography on a silica column under a nitrogen stream at moderate pressure (0.5-1.5 bar) with a dichloromethane-methanol mixture (98-2 by volume) as eluent, 2.75 g of 3-(3-chloropropyl)-1,1-dimethyl-8-fluoro-4-oxo- 1,2,3,4-tetrahydro-3,1-benzazasiline are obtained.