Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][CH2:7][CH2:8][O:9][CH3:10])[CH3:2].C(N(CC)CC)C.[N:19]#[N:20].[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[S:26][C:25]=2[CH:24]=[CH:23][C:22]=1[S:34]([NH:37][C@H:38]([C:46](Cl)=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:45])[NH2:44])(=[O:36])=[O:35]>C(Cl)(Cl)Cl>[N:19]#[N:20].[CH2:1]([O:3][C:4](=[O:11])[CH2:5][N:6]([C:46](=[O:47])[C@H:38]([CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45])[NH:37][S:34]([C:22]1[CH:23]=[CH:24][C:25]2[S:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[C:29]=2[CH:21]=1)(=[O:35])=[O:36])[CH2:7][CH2:8][O:9][CH3:10])[CH3:2]
Reactant: N=C(N)NCCC[C@H](NS(=O)(=O)c1ccc2sc3ccccc3c2c1)C(=O)Cl
Reactant: CCOC(=O)CNCCOC
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(CCOC)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2sc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2.42 g of N-(2-methoxyethyl) glycine ethyl ester and 4.0 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions N2 -(2-dibenzothienylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was stirred overnight at room temperature. At the end of this period, 50 ml of chloroform was added and the chloroform solution was washed twice with 25 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with ethyl ether to give 5.5 g of powdery N2 -(2-dibenzothienylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester
Reaction SMILES: Cl.[CH2:2]([NH:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C@@H:23]([C:25]([O:27][CH3:28])=[O:26])[NH2:24])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7])[CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[NH4+].[Cl-].[C:40]([O:43][CH2:44][CH3:45])(=[O:42])C>C1COCC1>[CH2:44]([O:43][C:40]([NH:24][C@H:23]([C:25]([O:27][CH3:28])=[O:26])[CH2:22][O:21][C:17]1[CH:16]=[C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]([NH:5][CH2:2][CH2:3][CH3:4])=[O:7])[CH:10]=2)[CH:20]=[CH:19][CH:18]=1)=[O:42])[CH3:45]
Reactant: CCOC(C)=O
Reactant: CCCNC(=O)Nc1cccc(-c2cccc(OC[C@H](N)C(=O)OC)c2)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)Nc1cccc(-c2cccc(OC[C@H](NC(=O)OCC)C(=O)OC)c2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound of Example 6 (256.0 mg, 0.63 mmol, 1 equiv) was suspended in THF (3 mL) and cooled to 0° C. Ethyl chloroformiate (88.5 mg, 0.82 mmol, 1.3 equiv) was added dropwise followed by N,N diisopropylethylamine (234.3 mg, 1.88 mmol, 3 equiv). The reaction mixture was allowed to warm to room temperature and stirred for one hour. It was worked up by addition of sat. aqueous NH4Cl soln. and ethyl acetate. The phases were separated and the organic layer was dried over NaSO4. After filtration and evaporation of the solvents the crude product was purified by chromatography (SiO2 CH/EtOAc 90:10). Yield 210.0 mg, 75.4% of a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.50 (s, 1H); 7.39-7.25 (m, 3H); 7.21 (d, 1H), 7.12 (d, 1H); 7.05 (s, 1H); 6.90 (brs, 1H); 6.81 (d, 1H); 5.80 (d, 1H); 5.10 (m, 1H); 4.75-4.65 (m, 1H); 4.42 (dd, 1H); 4.25 (dd, 1H); 4.20-4.10 (m, 2H); 3.79 (s, 3H); 3.20 (dd, 2H); 1.52 (sext, 2H); 1.22 (t, 3H); 0.95 (t, 3H). MS (DCI/NH3) 461 (M+NH4), 444 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.C([CH:14]([CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22])[C:15](Cl)=[O:16])C.O.[NH2:25][NH2:26]>CO>[CH3:8][C:6]1([CH3:9])[CH2:7][CH:2]([NH:1][C:15](=[O:16])[CH2:14][CH2:18][CH2:19][CH2:20][C:21]([NH:25][NH2:26])=[O:22])[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5]1
Reactant: CCC(CCCC(=O)Cl)C(=O)Cl
Reactant: NN
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: O
Solvent: CO
Product: CC1(C)CC(NC(=O)CCCCC(=O)NN)CC(C)(C)N1

Procedure:
N-(2,2,6,6-tetramethyl-4-piperidinyl)-N'-aminoadipamide was prepared by reacting 4-amino-2,2,6,6-tetramethylpiperidine with ethyl adipoyl chloride, followed by hydrazinolysis of the resulting ester with 85% hydrazine hydrate in methanol.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[S-:8][C:9]#[N:10].[K+]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][S:8][C:9]#[N:10])[CH3:7]
Reactant: N#C[S-]
Reactant: CCOC(=O)CCl
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CSC#N
Yield: 99.1 %

Procedure:
A solution of ethyl chloroacetate (20 g, 0.16 mol) and potassium thiocyanate (12.7 g, 0.13 mol) in ethanol (100 ml) was refluxed for 3 h. The solution was filtered and concentrated under reduced pressure to afford 18.7 g of thiocyanato-acetic acid ethyl ester (97%). A mixture of cyclopropylammonium acetate (0.50 g, 4.27 mmol) and thiocyanato-acetic acid ethyl ester (0.62 g, 4.27 mmol) was heated to 90° C. for 3 h, and left at rt overnight. The reaction mixture was partitioned between 6N HCl and dichloromethane. The layers were separated. The aqueous layer was made basic by the addition of 6N ammonium hydroxide, and then concentrated to dryness. The crude was triturated with dichloromethane and the solution separated from the solid by filtration. This solution was dried over sodium sulfate and concentrated to dryness. The crude was purified on a silica gel column with 100% ethyl acetate to afford 2-cyclopropylamino-thiazol-4-one (244 mg, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][S:13]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([NH:22][CH2:23][C:24](O)=[O:25])=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:5].C(OC([N:41]1[CH2:47][CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=O)(C)(C)C>>[ClH:1].[N:41]1([C:24](=[O:25])[CH2:23][NH:22][C:20](=[O:21])[C:19]2[CH:18]=[CH:17][C:16]([S:13](=[O:14])(=[O:15])[NH:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:4](=[O:5])[C:3]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:2]=3[Cl:1])=[CH:28][CH:27]=2)[CH2:47][CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccc(Cl)cc2Cl)cc1
Product: Cl
Product: O=C(NCC(=O)N1CCCNCC1)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccc(Cl)cc2Cl)cc1

Procedure:
The title compound was prepared from {4-[2-(2,4-dichloro-benzoyl)-phenylsulfamoyl]-benzoylamino}-acetic acid (Example 6.1/c)) and [1,4]diazepane-1-carboxylic acid tert-butyl ester (Fluka) according to the method described in Example 11.1. MS (EI) 589.3 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[NH:11][C:10]2[C:12]([C@H:27]3[CH2:31][CH2:30][CH2:29][O:28]3)=[C:13]([F:26])[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[N:20][CH:21]=3)=[CH:15][C:9]=2[N:8]=1)=[O:5])[CH3:2].N1C=NN=N1.CC(N([P:44]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)C(C)C)C.C1C=C(Cl)C=C(C(OO)=[O:69])C=1>CN(C=O)C>[P:44]([O:25][C:22]([C:19]1[N:18]=[CH:17][C:16]([C:14]2[C:13]([F:26])=[C:12]([C@H:27]3[CH2:31][CH2:30][CH2:29][O:28]3)[C:10]3[NH:11][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:8][C:9]=3[CH:15]=2)=[CH:21][N:20]=1)([CH3:24])[CH3:23])([O:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)([O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:69]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)c(F)c([C@H]3CCCO3)c2[nH]1
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Agent: c1nnn[nH]1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)OP(=O)(OCc4ccccc4)OCc4ccccc4)nc3)c(F)c([C@H]3CCCO3)c2[nH]1
Temperature: 0 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To 1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-7-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazol-2-yl]urea (23) (10.24 g, 23.66 mmol) in a 1 L round bottom flask under N2 at 23° C. was added DMF (200 mL) followed by a solution of tetrazole (105.2 mL of 0.45 M in MeCN, 47.32 mmol) followed by N-dibenzyloxyphosphanyl-N-isopropyl-propan-2-amine (12.26 g, 11.93 mL, 35.49 mmol). After 4.5 h more N-dibenzyloxyphosphanyl-N-isopropyl-propan-2-amine (4 mL) was added. After stirring a further 16 h the reaction was cooled to 0° C. (ice-water bath) then treated with mCPBA (15.17 g, 61.52 mmol). The mixture was stirred at 0° C. for 30 min then at 23° C. for 30 min after which the reaction mixture was partitioned between water (400 mL) and EtOAc (700 mL). The organic layer was separated, washed with saturated aqueous sodium bicarbonate (500 mL), 10% aqueous sodium bisulfate (500 mL), saturated aqueous sodium bicarbonate (500 mL), and brine (500 mL) then dried (magnesium sulfate), filtered and concentrated. The residue was purified by MPLC using an ISCO COMBIFLASH brand flash chromatography purification system (330 g column) eluting with a 0-10% EtOH in DCM linear gradient over 16.5 column volumes at a 200 mL/min flow rate. After concentration in vacuo, (R)-dibenzyl 2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-ylphosphate (24) (13.89 g, 20.17 mmol, 85.27%) was obtained as a white solid. ESMS (M+1)=689.5; 1H NMR (300 MHz, CD3OD) δ8.88 (d, J=1.6 Hz, 2H), 7.37 (d, J=6 Hz, 1H), 7.30 (m, 10H), 5.38-5.33 (m, 1H), 5.12-5.01 (m, 4H), 4.24 (dd, J=6.8, 14.9 Hz, 1H), 3.98 (dd, J=6.9, 15.1 Hz, 1H), 3.35-3.27 (m, 3H), 2.52 (q, J=5.9 Hz, 1H), 2.14-2.05 (m, 2H), 1.91 (s, 6H) and 1.22-1.14 (m, 3H) ppm.
Reaction SMILES: [CH2:1]([N:3](C(OC(C)(C)C)=O)[C@H:4]([CH3:9])[CH2:5][C:6]([OH:8])=[O:7])[CH3:2].[ClH:17]>C(OCC)(=O)C>[ClH:17].[CH2:1]([NH:3][C@H:4]([CH3:9])[CH2:5][C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCN(C(=O)OC(C)(C)C)[C@H](C)CC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN[C@H](C)CC(=O)O

Procedure:
To a mechanically stirred solution of 53 (2.2 g, 9.7 mmol) in ethyl acetate (180 mL) at -15° C. was vigorously bubbled HCl gas for 30 min. The cooling bath (ethanol/ice) was removed and the solution purged with argon for 1.0 h to remove excess HCl. Concentration furnished the amine HCl 54 as a yellow oil.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](O)[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:5]1=[O:25])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:27]>C1(C)C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([Cl:27])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:5]1=[O:25])(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)N1C(=O)C(=C(O)c2ccc(C)cc2)c2cc([N+](=O)[O-])ccc21
Solvent: Cc1ccccc1
Product: CC(=O)N1C(=O)C(=C(Cl)c2ccc(C)cc2)c2cc([N+](=O)[O-])ccc21

Procedure:
3.55 g (10.5 mmol) of 1-acetyl-3-[1-hydroxy-1-(4-methyl-phenyl)methylidene}-5-nitro-2-indolinone and 2.40 g (11.5 mmol) of PCl5 are heated in 60 ml toluene for 2 hours at 80° C. The mixture is evaporated down in vacuo, fresh toluene is added to the evaporation residue, it is evaporated down again and this procedure is repeated once more. The evaporation residue is dissolved in a little toluene with heating. During slow cooling an isomer, probably the (Z) isomer, crystallised out. A mixture of the (Z) and (E) isomers was also obtained from the mother liquor by column chromatography on silica gel with CH2Cl2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:7])[CH2:5][OH:6].CO[C:19](OC)([CH3:21])[CH3:20].B(F)(F)F.CCOCC>CC(C)=O>[CH3:1][O:2][C:3]([C:4]1([CH3:7])[CH2:5][O:6][C:19]([CH3:21])([CH3:20])[N:8]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:16]
Reactant: COC(C)(C)OC
Reactant: COC(=O)C(C)(CO)NC(=O)OC(C)(C)C
Agent: FB(F)F
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)C1(C)COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a stirring solution of 3 (9.342 g, 40 mmol) in acetone (115 mL) in a flame dried round bottom flask under an inert atmosphere was added 2,2-dimethoxypropane (66 mL). To this solution was added BF3.OEt2 (0.30 mL, cat.) and stirring was continued at rt for 2 h. The reaction mixture was then concentrated in vacuo to an orange oil which was purified by flash chromatography to provide 4 (9.392 g, 85%) as a white solid. Rf=0.55 (1:3 EtOAc/hexanes). Compound was observed as an uneven mixture of rotomers.
Reaction SMILES: [C:1]1([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][C:16]([C:18](Cl)=[O:19])=[CH:17][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([NH2:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C>O1CCCC1>[CH2:21]([NH:33][C:18]([C:16]1[CH:15]=[CH:14][C:10]2[C:11](=[O:13])[O:12][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][C:9]=2[CH:17]=1)=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: O=C(Cl)c1ccc2c(=O)oc(-c3ccccc3)nc2c1
Reactant: CCCCCCCCCCCCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNC(=O)c1ccc2c(=O)oc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The synthesis started out from 2-phenyl-7-chlorocarbonyl-4H-3,1-benzoxazin-4-one, whose synthesis is descried in L. Jakisch et al., Journal of Polymer Science: Part A: Polymer Chemistry 2003; 41(5): 655-667 (there compound 10a). 2.855 g (10 mmol) of this substance was suspended in 100 ml of dry tetrahydrofuran at 0° C. in a 250 ml three-necked flask provided with magnetic stirrer, reflux condenser and drying tube. A mixture of 1.854 g (10 mmol) of n-dodecylamine, 1.012 g (10 mmol) of triethylamine and 20 ml of dry tetrahydrofuran was then slowly added dropwise at from 0 to 5° C. The reaction mixture was subsequently stirred at room temperature for 2 hours, and the resultant precipitate of triethylammonium chloride was then filtered off with suction and the filtrate was evaporated on a rotary evaporator. The solid residue was washed with water and dried at 60° C. under reduced pressure. Recrystallization from ethanol gave 2.85 g of product.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[OH-:16].[Na+]>O.[Zn]>[Cl:13][C:5]1[C:4]([Cl:14])=[CH:3][C:2]([Cl:1])=[C:7]([C:8]([OH:9])=[O:16])[C:6]=1[C:11]([OH:10])=[O:12]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: [OH-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Product: O=C(O)c1c(Cl)cc(Cl)c(Cl)c1C(=O)O
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 88534.9 %

Procedure:
This compound was prepared by modifications to the literature method of Syn. Lett., 1990, 339. A mixture of 3,4,5,6-tetrachlorphthalic anhydride (19) (Aldrich Chemical Co., 100 g, 0.35 mmol) and NaOH (50.0 g, 1.25 mmol) in water (1000 mL) was stirred at 50-60° C. (bath) for 45 min under a nitrogen atmosphere. Zinc dust (70.0 g, 1.07 mmol) was then added portionwise over 10 min, and the mixture was stirred at 70-80° C. for a further 6 h. The reaction was cooled to room temperature and filtered through a bed of Celite, and the filter and residue was washed successively with 0.1N NaOH (2×100 mL) and H2O (2×100 mL). The combined filtrate was acidified with conc. HCl to pH≦1, and the colourless precipitate was collected by filtration and washed with 0.1N HCl (3×100 mL). The damp solid was stirred with EtOAc (600 mL) and acidified with conc. HCl until all the solids had dissolved. The EtOAc layer was separated and the aqueous portion further extracted with the same solvent (2×100 ml, The combined EtOAc solution was dried (Na2SO4), filtered, and evaporated under reduced pressure give 3,4,6-trichlorophthalic acid (20) (83.5 g, 89%) as a colourless solid; m.p. (without recrystallisation) 151-153° C. (lit. m.p. 150-153° C.), 1H NMR identical to literature.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1)[CH2:20][CH3:21].C(N(CC)CC)C>C(Cl)Cl>[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:30][CH:31]=1)[CH2:20][CH3:21]
Reactant: CCCOCCOc1ccc(OB(O)O)cc1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Reaction time: 0.08 h
Yield: 34.5 %

Procedure:
To methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g) dissolved in methylene chloride (15 ml) was added 4-(2-propoxyethoxy)phenylboric acid (0.67 g) and molecular sieves 4A (0.8 g), and the resulting mixture was stirred for 5 minutes. To the reaction mixture were added cupric acetate (0.27 g) and triethylamine (1.04 ml), and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered through celite, and the filtrate was washed with ethyl acetate. The resulting solution was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2) to obtain methyl 7-[4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.23 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[C:15]([C:21]([OH:23])=O)[NH:16]3)=[CH:7][CH:6]=[CH:5][N:4]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][C:28]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)([OH:31])[CH2:27][CH2:26]1>>[OH:31][C:28]1([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)[CH2:29][CH2:30][CH:25]([NH:24][C:21]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[C:12]([O:11][CH2:10][CH2:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:26][CH2:27]1
Reactant: COc1ncccc1CCOc1cccc2[nH]c(C(=O)O)cc12
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: COc1ncccc1CCOc1cccc2[nH]c(C(=O)NC3CCC(O)(CCN4CC[C@H](O)[C@@H](C)C4)CC3)cc12

Procedure:
This compound is synthesized analogously to example 1 from 4-[2-(2-methoxy-pyridin-3-yl)-ethoxy]-1H-indole-2-carboxylic acid 16m and amine 14.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][N:8]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[C:9]=2[CH:10]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(Br)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Bromo-1H-indazol-4-amine (5 g) was dissolved in DMF (20 ml) and cooled in an ice bath. 60% Sodium hydride in mineral oil (0.94 g) was added portionwise and the reaction was left under an ice bath for 30 min. Benzenesulfonyl chloride (3 ml) in DMF (5 ml) was added slowly over 15 minutes and the reaction was left to warm up to room temperature overnight. Water (100 ml) was added and the reaction stirred for 20 minutes. Ethyl acetate (120 ml) was added and the water was separated, washed with ethyl acetate (50 ml×2) and the combined organics were washed with 7.5% lithium chloride (aq) (50 ml×2) then water (50 ml) before being separated and passed through a hydrophobic frit. The ethyl acetate was evaporated and the residue passed through a silica cartridge, eluting with DCM (ca. 300 ml) followed by diethyl ether (ca. 400 ml). Product containing pure fractions were combined and evaporated to dryness to give title compound, 5.9 g.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[C:10](F)=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([O:24]CC)=[O:23])=[CH:14][C:13]=2[CH:27]=1>>[Cl:8][C:9]1[C:10]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:20])([F:21])[F:19])[C:15]([C:22]([OH:24])=[O:23])=[CH:14][C:13]=2[CH:27]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Sc1ccccc1
Product: O=C(O)C1=Cc2cc(Cl)c(Sc3ccccc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from benzenethiol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 271.7–274.4° C. 1H NMR (acetone-d6/300 MHz) 7.86 (s, 1H), 7.60 (m, 6H), 6.29 (s, 1H), 5.74 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=7.2 Hz). FABLRMS m/z 385 (M−H). ESHRMS m/z 384.9904 (M−H, Calc'd 384.9913). Anal. Calc'd for C17H10ClF3O3S: C, 52.79; H, 2.61; Cl, 9.17; S, 8.29. Found: C, 52.80; H, 2.49; Cl, 9.71; S, 8.37.
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:14][C:15]1[C:19]([CH2:20][N:21]2[CH:25]=[C:24]([NH2:26])[CH:23]=[N:22]2)=[C:18]([CH3:27])[O:17][N:16]=1>>[CH3:14][C:15]1[C:19]([CH2:20][N:21]2[CH:25]=[C:24]([NH:26][C:9](=[O:11])[CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:12])[CH:23]=[N:22]2)=[C:18]([CH3:27])[O:17][N:16]=1
Reactant: CC(CC(=O)O)c1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)CC(C)c2ccccc2)cn1
Yield: 6 %

Procedure:
Prepared as in Example 4-8 from 3-phenylbutanoic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 6%.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][CH:6]([CH2:10][CH3:11])[C:7](Cl)=[O:8].[C:12]1([S:18][CH3:19])[CH:17]=[CH:16]C=CC=1.O.[CH:21](Cl)(Cl)Cl>>[CH3:5][C:6]([CH3:21])([CH2:10][CH3:11])[C:7]([C:19]1[S:18][CH:12]=[CH:17][CH:16]=1)=[O:8]
Reactant: CCC(C)C(=O)Cl
Reactant: ClC(Cl)Cl
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CCC(C)(C)C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of AlCl3 (35.4 g) in CHCl3 (500 mL) at -10° C. was added dropwise 2-methylbutyryl chloride (31.3 g) followed by thioanisole (31.2 mL). The mixture was then stirred at r.t. for 20 min. and was then cooled back to 0° C. Water (200 mL) was then added over 30 min. The CHCl3 layer was separated and dried over MgSO4. After filtration and removal of the solvent, the residue was dried under vacuum at 80° C. for 2 h to give 35 g of the title compound.