Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.O[C:28]1([C:43]2[C:44]([OH:52])=[CH:45][C:46]3[O:50][CH2:49][CH2:48][C:47]=3[CH:51]=2)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:29]1=[O:42]>>[OH:52][C:44]1[C:43]([CH:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:29]2=[O:42])=[CH:51][C:47]2[CH2:48][CH2:49][O:50][C:46]=2[CH:45]=1
Reactant: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCC3)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: CCCCCN1C(=O)C(c2cc3c(cc2O)OCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (76%): MS (ES+) m/z 338.3 (M+1).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([NH:14][C@@H:15]([C:17]2[N:21]([CH2:22][CH3:23])[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]4)[CH:26]=3)=[N:19][N:18]=2)[CH3:16])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10].O>CO>[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([NH:14][C@@H:15]([C:17]2[N:21]([CH2:22][CH3:23])[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH2:32][CH2:33][CH:34]([OH:37])[CH2:35][CH2:36]4)[CH:26]=3)=[N:19][N:18]=2)[CH3:16])(=[O:12])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CCn1c(Oc2cccc(N3CCC(=O)CC3)c2)nnc1[C@@H](C)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCn1c(Oc2cccc(N3CCC(O)CC3)c2)nnc1[C@@H](C)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
NaBH4 (0.021 g) was added at 0° C. to a solution of the compound (0.150 g) of Example 8 in methanol (3.0 ml), and the mixture was stirred at room temperature for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over MgSO4, filtered, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH SiO2, methanol/chloroform=1/50 to 1/10) and then recrystallized (ethyl acetate-hexane) to give 0.113 g of the titled compound (Compound 93) as a colorless powder.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])O[C:6]1=[O:16].[O:18]=[S:19]1(=[O:35])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:21]([CH2:29]C(OCC)=O)=[N:20]1.[H-].[Na+].C(O)(=O)C>C1COCC1.Cl>[O:35]=[S:19]1(=[O:18])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:21]([C:29]2[C:6](=[O:16])[N:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH3:17])[C:10]3[C:9]([C:8]=2[OH:15])=[CH:14][CH:13]=[CH:12][N:11]=3)=[N:20]1
Reactant: CC(C)CCn1c(=O)oc(=O)c2cccnc21
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2ccccc2N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccnc21
Temperature: 20 °C
Yield: 8.2 %

Procedure:
To a solution of the product of Example 12A (0.216 g, 0.92 mmol) and the product of Example 1C (0.247 g, 0.922 mmol) in anhydrous THF (7.5 mL) under nitrogen at 20° C. was added sodium hydride (95%, 0.089 g, 3.7 mmol). The reaction was heated at reflux for 3 hours, cooled to 20° C., and added dropwise glacial acetic acid (2.4 mL). The resulting mixture was heated at reflux for 1 hour, cooled to 25° C., and diluted with aqueous hydrochloric acid (0.5 M, 35 mL). The resulting precipitate was collected by filtration, washed with water and dried. The crude product was purified by flash column chromatography on silica gel eluting with hexanes and ethyl acetate (3:1) to give the title compound as a white solid (0.031 g, 20%). MS (ESI−) m/z 411 (M−H)−. The sodium salt of the title compound was prepared according to the procedure of Example 1D. MS (ESI−) m/z 411 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 0.95 (s, 3H), 0.98 (s, 3H), 1.47 (m, 2H), 1.64 (m, 1H), 4.30 (t, J=7.72 Hz, 2H), 7.13 (dd, J=7.72, 4.78 Hz, 1H), 7.26 (d, J=8.09 Hz, 1H), 7.30 (d, J=7.72 Hz, 1H), 7.55 (t, J=7.72 Hz, 1H), 7.66 (d, J=8.09 Hz, 1H), 8.37 (dd, J=7.72, 1.84 Hz, 1H), 8.53 (dd, J=4.78, 2.21 Hz, 1H), 15.94 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:32])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23](OC(=O)C)[CH:24]=[CH2:25])=[C:17]([CH3:30])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:31]=1.[C:33]1([P:39]2(=[O:45])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:11]([CH3:32])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]=[CH:24][CH2:25][N:42]4[CH2:41][CH2:40][P:39](=[O:45])([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH2:44][CH2:43]4)=[C:17]([CH3:30])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:31]=1
Reactant: O=P1(c2ccccc2)CCNCC1
Reactant: C=CC(OC(C)=O)c1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Product: Cc1c(C=CCN2CCP(=O)(c3ccccc3)CC2)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12

Procedure:
2-(2,6-Dichloro-phenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ5-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one was prepared following the procedure of Example 1 form acetic acid 1-[2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester and 4-phenyl-[1,4]azaphosphinane 4-oxide. 1HNMR (400 MHz, DMSO-d6+TFA) δ 11.38 (br s, 1H), 10.71 (br s, 1H), 7.90-7.60 (m, 9H), 7.56 (t, 1H, J=7.8 Hz), 7.22 (br d, 1H, J=15.3 Hz), 7.70-6.40 (br m, 1H), 4.23 (s, 3H), 4.18 (br m, 2H), 4.00 -4.15 (br m, 4H), 2.60-2.40 (br n, 4H), 2.39 (s, 1H); ESMS (m/z): found, 606 (M+1)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[OH:16][C@H:17]([C@H:19]1[CH2:23][NH:22][C:21](=[O:24])[CH2:20]1)[CH3:18].Cl[C:26]1[C:27]2[N:28]([N:42]=[CH:43][CH:44]=2)[CH:29]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=2)[N:31]=1>CN(C=O)C>[CH3:41][O:40][C:34]1[CH:33]=[C:32]([C:30]2[N:31]=[C:26]([O:16][C@@H:17]([C@H:19]3[CH2:23][NH:22][C:21](=[O:24])[CH2:20]3)[CH3:18])[C:27]3[N:28]([N:42]=[CH:43][CH:44]=3)[CH:29]=2)[CH:37]=[CH:36][C:35]=1[O:38][CH3:39]
Reactant: COc1ccc(-c2cn3nccc3c(Cl)n2)cc1OC
Reactant: C[C@H](O)[C@H]1CNC(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn3nccc3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
A solution of 1M sodium bis(trimethylsilyl) amide in THF (0.18 mL, 0.18 mmol) was added to a solution of (R)-4-((R)-1-hydroxyethyl)pyrrolidin-2-one 1.18 (22.9 mg, 0.18 mmol) in DMF (1 mL) at room temperature, forming a white precipitate. After 8 minutes, a solution of 4-chloro-6-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrazine 5.03 (34 mg, 0.12 mmol) in DMF (1.1 mL) was added under argon. Dark brown solution stirred at room temperature overnight. Mixture was quenched by addition of water, brine and ethyl acetate and layers were separated. Aqueous was extracted with ethyl acetate and combined organic layers were washed with 50% brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Resulting residue was purified by silica gel column chromatography (0-10% methanol in dichloromethane) to yield (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 5.04.
Reaction SMILES: CS(Cl)(=O)=O.O[CH:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=2[O:10][CH2:9][CH2:8]1.C(N(CC)CC)C.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)Cl>[CH3:18][O:17][C:16]1[C:11]2[O:10][CH2:9][CH2:8][CH:7]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: C1CCNCC1
Reactant: COc1cccc2c1OCCC2O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1OCCC2N1CCCCC1
Reaction time: 2 h

Procedure:
Methane sulfonyl chloride (14.9 ml) is added dropwise to a solution of the product obtained in Step 1. (31.6 g) and triethylamine (29.3 ml) in methylene chloride (750 ml) cooled to 0° C. under nitrogen. The reaction mixture is stirred for 11/2 hours; piperidine (175 ml) is added and the reaction mixture is stirred under nitrogen overnight. The reaction mixture is washed with sat'd aq. sodium bicarbonate, sat'd NaCl, dried, filtered and evaporated in vacuo yielding the desired product as its hydrochloride salt.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]1[C:34]2[CH:35]=[CH:36][C:37]([CH:39]=O)=[CH:38][C:33]=2[O:32][CH2:31][CH2:30]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:39][C:37]3[CH:36]=[CH:35][C:34]4[O:29][CH2:30][CH2:31][O:32][C:33]=4[CH:38]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc5c(c4)OCCO5)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 1,4-benzodioxan-6-carboxaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 527.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[S:11]([NH:14][CH2:15][CH3:16])(=[O:13])=[O:12])#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O>[CH2:15]([N:14]1[C:1](=[NH:2])[C:3]2[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=2[S:11]1(=[O:13])=[O:12])[CH3:16]
Reactant: CCNS(=O)(=O)c1cccc(OC)c1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCN1C(=N)c2c(OC)cccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.3 %

Procedure:
1.50 g (6.24 mmol) 2-Cyano-N-ethyl-3-methoxy-benzenesulfonamide were added to a solution of 2.59 g (18.7 mmol) potassium carbonate in a mixture of 15 ml 1,4 dioxane and 6 ml of water. The solution was stirred for 24 h at room temperature. The solution was neutralized by addition of 10% HCl (pH=7). The solution was extracted twice with ethyl acetate. The organic layers were dried over Na2SO4 and concentrated. The crude product which still contained starting material was dissolved in a mixture of ethyl acetate and 10% HCl and vigorously shaken. The layers were separated and the aqueous layer was neutralized by addition of sodium bicarbonate. The aqueous layer was extracted twice with ethyl acetate. The organic layers were dried over Na2SO4 and concentrated to yield 830 mg (3.45 mmol) of the title compound having a melting point (Tmp) of 111-114° C.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]1)C1C=CC=CC=1.C(OCC)(=O)C>[OH-].[OH-].[Pd+2].CO>[NH2:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([OH:21])([CH3:19])[CH3:20])[CH2:14][CH2:13]1
Reactant: CC(C)(O)[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(O)[C@H]1CC[C@H](CN)CC1
Reaction time: 1 h

Procedure:
A 500 mL Parr bottle was charged with 150 mg Pd(OH)2, 3.3 g (10.7 mmol) trans-[4-(1-hydroxy-1-methyl-ethyl)-cyclohexylmethyl]-carbamic acid benzyl ester, 100 mL ethyl acetate and 100 mL MeOH. The bottle was placed under 50 psi H2 and shaken for 1 hour. The material was filtered through Celite and concentrated to give 1.57 g of a white solid.
Reaction SMILES: C1(NC(C2C3C=C(C4C(Br)=CN=C([NH:23][CH2:24][CH2:25][CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)N=4)SC=3C=CC=2)=O)CC1.Cl[C:33]1[N:38]=[C:37]([C:39]2[S:43][C:42]3[CH:44]=[C:45]([C:48]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[O:49])[CH:46]=[CH:47][C:41]=3[CH:40]=2)[C:36]([CH3:56])=[CH:35][N:34]=1.C(OC(N1CCC(CCN)CC1)=O)(C)(C)C>>[CH3:56][C:36]1[C:37]([C:39]2[S:43][C:42]3[CH:44]=[C:45]([C:48]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[O:49])[CH:46]=[CH:47][C:41]=3[CH:40]=2)=[N:38][C:33]([NH:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:34][CH:35]=1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCC4CCNCC4)ncc3Br)cc12
Reactant: Cc1cnc(Cl)nc1-c1cc2ccc(C(=O)N3CCOCC3)cc2s1
Agent: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Product: Cc1cnc(NCCC2CCNCC2)nc1-c1cc2ccc(C(=O)N3CCOCC3)cc2s1

Procedure:
Using the method of 2-[5-bromo-2-(2-piperidin-4-ylethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide, the title compound is synthesized from [2-(2-chloro5-methylpyrimidin-4-yl)-benzo[b]thiophen-6-yl]-morpholin-4-yl-methanone and 4-(2-aminoethyl)-piperidine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid. ES+(m/z) 466 [M+H].
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]CC2C=CC=CC=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]>CO.[C].[Pd]>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)OC
Reaction time: 7 h
Yield: 96 %

Procedure:
A mixture of (S)-methyl 2-ethoxy-3-(4-benzyloxyphenyl)propanoate of the formula (9c) (56 g) in aqueous methanol (300 ml) and slurry of 5% palladium carbon (6 g in 60 ml water) was taken in hydrogenation flask and hydrogenated on Parr shake flask at 60 psi pressure for 6-8 h at room temperature. Completion of the reaction was monitored by TLC. After completion of the reaction, the catalyst was filtered and the filtrate was evaporated to yield tile compound of the formula (1) (39 g, 96%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:11][C:10]=1[O:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.S(=O)(=O)(O)O.[N+:36]([O-])([OH:38])=[O:37]>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[C:23]([N+:36]([O-:38])=[O:37])[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C(=O)OCc2ccccc2)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
Benzyl 4-(benzyloxy)-3-methoxybenzoate (135 g) was dissolved in dichloromethane (339 ml). Glacial acetic acid (175.5 g) was added and the mixture cooled to 10° C. Concentrated sulfuric acid (151.6 g) was added in a controlled manner maintaining the temperature of the reaction mixture below 25° C. Concentrated nitric acid (61.6 g) was then added in 15 minutes keeping the temperature of the reaction mixture below 25° C. The reaction mixture was then heated to 40° C. and stirred for 3 hours. The lower aqueous layer was removed and the organic layer was washed twice with water (2×168 ml). The organic layer was distilled to at atmospheric pressure to remove dichloromethane (186 ml). Isopropanol (339 ml) was added to the reaction mixture at 40° C. The reaction mixture was held at 40° C. for 15 minutes. The resulting suspension was then cooled to 20° C. within 30 minutes, then to 5° C. and held at this temperature for one hour. The product (benzyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate) was isolated by filtration, washed with isopropanol (336 ml) and dried at less than 25° C. Yield: 135.7 g, 89.6%; NMR Spectrum (CDCl3) 3.9 (s, 3H), 5.2 (s, 2H), 5.3 (s, 2H), 7.1 (s, 1H), 7.3-7.4 (m, 10H), 7.5 (s, 1H); Mass Spectrum (M+H)+=394.1.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]([S:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:5]3[CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1.C[Mg+].[Br-].[Li]C(CC)C.[CH:35](=[O:37])[CH3:36]>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:19][C:4]2[C:3]3[C:2]([CH:35]([OH:37])[CH3:36])=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[N:6]3[CH2:12][CH2:13][CH:14]([CH2:15][C:16]([OH:18])=[O:17])[C:5]=23)=[CH:21][CH:22]=1
Reactant: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: CC=O
Agent: C[Mg+]
Agent: [Br-]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(O)c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of (+/−)-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid (Example 7, 100 mg, 0.22 mmol) in THF (4 mL) at −78° C. was added 3M MeMgBr (0.26 mmol) followed by the addition of 1.3M sec-BuLi (0.31 mmol). The reaction mixture was stirred at −78° C. for 5 minutes and an excess of acetaldehyde was added. The reaction was stirred at −78° C. for 30 minutes and quenched with saturated aqueous NH4Cl. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with EtOAc/Hexanes/AcOH (20:30:1) to provide 65 mg of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].CCN(CC)CC.N1C=CC=CC=1.[SH2:24].N#N>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4](=[S:24])[NH2:5]
Reactant: S
Reactant: N#Cc1c(F)cccc1Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1c(F)cccc1Cl
Temperature: -19 °C
Yield: 71.8 %

Procedure:
2-Chloro-6-fluorobenzonitrile, (99.1%, 62.2 g, 0.40 mol) was weighed into a 1-L three-necked roundbottom flask equipped with a condenser and an overhead electric stirrer, along with Et3N (78 mL, 56.6 g, 0.56 mol) and 180 mL (176.04 g, 2.23 mol) of pyridine. The reactor was purged with a slow stream of N2 and vented to a 13% bleach solution. The stirring solution was cooled to -19° C. in a CCl4 /dry ice bath, and H2S gas (33.6 g, 0.99 mol) was sparged below the liquid surface at a rate of 0.4 g/min over a period of 82 min. During the gas addition, the solution temperature rose to -11° C. The yellow-green solution was allowed to gradually warm to 25° C. and stir overnight with a slow N2 purge of the reactor head space into bleach solution. The solution was poured into 1.6 L of ice water, stirred, and the resulting white crystals were collected on a buchner funnel and rinsed with additional water. After 2 h of air drying, the moist filter cake was vacuum oven dried for 5 h at 65° C. to give 54.5 g of 2-Chloro-6-Fluorobenzthioamide (72% wt. % yield), mp 155-160° C., having a GC area % purity of 98.8% and containing 1.2% 2-Chloro-6-fluorobenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:66]=[CH:65][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:66]=[CH:65][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)cc2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.9 %

Procedure:
To a solution of 100 mg (0.47 mmol) 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 150 mg of TBTU (0.47 mmol) in 7 ml DMF, were added 0.4 ml (2.34 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 141 mg (0.47 mmol) (4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 17 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; diethylether/heptane 1:1; then 8 g silicagel DCM/heptane 70:30 to 90:10) to give 112 mg off-white foam (47%). MS (EI) 496.1 (M)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1.[CH2:30]([NH2:34])[CH2:31][CH2:32][NH2:33]>>[O:28]=[S:20]1(=[O:29])[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[CH2:23][N:17]([C:4]2[CH:3]=[C:2]([NH:33][CH2:32][CH2:31][CH2:30][NH2:34])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:10]=3)[N:5]=2)[CH2:18][CH2:19]1
Reactant: NCCCN
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Product: NCCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(OC(F)(F)F)cc12

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 481, 1H NMR (400 MHz, CD3OD) δ ppm 8.16-8.15 (d, J=2.4 Hz, 1 H), 8.09-8.07 (dd, J=5.2, 8.0 Hz, 1 H), 7.94-7.92 (d, J=10 Hz, 1 H), 7.90-7.88 (d, J=8 Hz, 1 H), 7.72-7.70 (m, 2 H), 7.58-7.55 (m, 1 H), 6.03 (s, 1 H), 5.34 (s, 2 H), 4.55 (s, 2 H), 3.75 (s, 2 H), 3.62-3.59 (t, J=6.8 Hz, 2 H), 3.14-3.10 (t, J=8.0 Hz, 2 H), 2.15-2.11 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25]O.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: OCc1cccs1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(Cc1cccs1)c1cc(F)ccc1F
Yield: 69.7 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene(100 mg, 0.330 mmol) obtained in Example 5 and 2-thiophenemethanol (0.065 ml, 0.69 mmol) were dissolved in toluene (3 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (0.160 ml). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. The reaction mixture was then allowed to cool down. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by flash silica gel chromatography (using a hexane/ethyl acetate solvent mixture) to give a white solid. The resulting white solid was washed with hexane, whereby the title compound (92 mg, 0.23 mmol, 70%) was obtained as a white solid.
Reaction SMILES: CO.[Cl:3][C:4]1[C:14]([O:15][CH2:16][CH2:17][N:18]2[CH:22]=[N:21][N:20]=[N:19]2)=[C:13]([Cl:23])[CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7].[OH-].[Na+]>O>[Cl:3][C:4]1[C:14]([O:15][CH2:16][CH2:17][N:18]2[CH:22]=[N:21][N:20]=[N:19]2)=[C:13]([Cl:23])[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(Cl)c(OCCn2cnnn2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Cl)c(OCCn2cnnn2)c1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 85.7 %

Procedure:
To a methanol (15 ml) solution of ethyl 2,4-dichloro-3-[2-(1H-tetrazol-1-yl)ethoxy]benzoate (0.88 g) were added sodium hydroxide (0.16 g) and water (5 ml), and the mixture was stirred at room temperature for 7 hours. After the addition of water (20 ml) and concentration at reduced pressure, an aqueous sodium hydroxide solution was added and the mixture was washed with ethyl acetate (50 ml). The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off to obtain the desired 2,4-dichloro-3-[2-(1H-tetrazol-1-yl)ethyloxy]-benzoic acid (0.69 g).