Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]([CH2:15][S:16][CH3:17])(C(O)=O)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(CSC)(C(OCC)=O)C(OCC)=O)C1C=CC=CC=1.CO.Cl>O>[CH3:17][S:16][CH2:15][CH:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([OH:11])=[O:10]
Reactant: CSCC(Cc1ccccc1)(C(=O)O)C(=O)O
Agent: CCOC(=O)C(CSC)(Cc1ccccc1)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CO
Product: CSCC(Cc1ccccc1)C(=O)O
Temperature: 100 °C
Reaction time: 4 h
Yield: 17.1 %

Procedure:
Preparation of 2-benzyl-2-(methylthiomethyl)malonic acid—Powdered potassium hydroxide (4.8 g, 86 mmol, 5.0 equiv) was added to a stirred solution of diethyl 2-benzyl-2-(methylthiomethyl)malonate (5.3 g, 17 mmol, 1.0 equiv) in 3:1 methanol:water (28 mL) at 23° C. The resulting pale yellow suspension was heated to 100° C. and stirred for 4 h. The cooled reaction mixture was acidified to pH≈9 with concentrated hydrochloric acid and washed with diethyl ether (4×50 mL). The aqueous layer was acidified to pH≈1 with concentrated hydrochloric acid and extracted with dichloromethane (4×60 mL). The combined organic layers were dried (Na2SO4), gravity-filtered, and concentrated by rotary evaporation to afford the title compound as a white powder (3.1 g, 72%): 1H NMR (300 MHz, DMSO-d6) δ 7.13-7.34 (m, 5H), 3.15 (s, 2H), 2.73 (s, 2H), 2.08 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[C:3](=[S:5])[NH2:4].[C:17]([O:21][C:22]([N:24]([C@H:26]([CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C:27](O)=[O:28])[CH3:25])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:17]([O:21][C:22](=[O:23])[N:24]([CH3:25])[C@@H:26]([C:27](=[O:28])[NH:1][C@@H:2]([C:3](=[S:5])[NH2:4])[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)([CH3:19])([CH3:20])[CH3:18]
Reactant: NC(=S)[C@H](N)Cc1ccc2ccccc2c1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)C(N)=S
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
(2R)-2-Amino-3-(2-naphthyl)propionthioamide (0.290 g; 1.2 mmol), (2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid (0.436 g; 1.3 mmol), HOBT (0.176 g; 1.3 mmol) and EDAC (0.267 g; 1.4 mmol) were dissolved in methylene chloride (20 ml) and stirred 12 hours at RT. Methylene chloride (40 ml) was added and the organic phase was washed with aqueous sodium hydrogensulfate (10%; 40 ml), aqueous sodium hydrogencarbonate (satd.; 40 ml) and dried (Magnesium sulfate). The solvent was removed in vacuo to afford 0,53 g of N-methyl-N-((1R)-2-(2-naphthyl)-1-((1R)-2-(2-naphthyl)-1-thiocarbamoylethylcarbamoyl)ethyl)carbamic acid tert-butylester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].[Br:10]Br.C(=O)([O-])[O-].[Na+].[Na+]>CC(O)=O.O>[Br:10][C:5]1[S:1][C:2]([CH2:6][C:7]([OH:9])=[O:8])=[CH:3][CH:4]=1
Reactant: BrBr
Reactant: O=C(O)Cc1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(Br)s1
Temperature: 25 °C

Procedure:
To a solution of 2-(thiophen-2-yl)acetic acid (2 g, 14 m mol) in HOAc (10 ml) was added dropwise bromine (2.25 g, 14 mmol) at 10˜20° C. for 30 min. The mixture was allowed to warm to room temperature for 3 hours. Then it was diluted with water (100 ml), neutralized to pH=5 with anhydrous sodium carbonate and extracted with EtOAc (100 ml×3). Dried over Na2SO4, filtered and concentrated to afford crude product as brown oil. MS (ESI): m/z 220.9 [M+1]+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[N+:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([O-:26])=[O:25].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:31](=[O:32])[C:30]3[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:35][CH:34]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 4-nitrobenzoyl chloride (12 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:18][C@H:19]([NH:21][CH2:22][CH2:23][CH3:24])[CH3:20])[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:5][CH:4]=1.ClC(Cl)C.[N:29]1([C:35]([N:37]2[CH2:42][CH2:41][CH:40]([CH:43]=O)[CH2:39][CH2:38]2)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)C.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:18][C@H:19]([N:21]([CH2:43][CH:40]3[CH2:41][CH2:42][N:37]([C:35]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:36])[CH2:38][CH2:39]3)[CH2:22][CH2:23][CH3:24])[CH3:20])[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: CCCN[C@H](C)Cc1cccc(NC(=O)c2ccc(OC)cc2)c1
Reactant: O=CC1CCN(C(=O)N2CCOCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: CCCN(CC1CCN(C(=O)N2CCOCC2)CC1)[C@H](C)Cc1cccc(NC(=O)c2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.8 %

Procedure:
(R)-N-{2-[3-(4-Methoxyphenylcarbonylamino)phenyl]-1-methylethyl}-propylamine (0.32 g), dichloroethane (20 ml) and 1-(morpholine-4-carbonyl)piperidine-4-carboxaldehyde (0.32 g) and were stirred under nitrogen for 30 minutes. Sodium triacetoxyborohydride (0.5 g) was added, and the mixture stirred at room temperature for about 72 hours. The mixture was diluted with diethyl ether (50 ml) and 10% sodium hydroxide solution (20 ml). The organic layer was dried with sodium sulfate, filtered, and the solvent evaporated in vacuo. The residue was chromatographed, eluting with methanol/dichloromethane to give (R)-N-{2-[3-(4-methoxyphenylcarbonylamino)phenyl]-1-methylethyl}-N-propyl-[1-(morpholine-4-carbonyl)piperidine-4-ylmethyl]amine, (0.42 g), [α]D25−42° (c 1.0 CH3OH); M+H 537.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]2[N:16]=[C:17]([CH3:22])[C:18](C(O)=O)=[C:14]2[CH:13]=[CH:12][C:11]=1[CH3:23].C([N:26](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]2[N:16]=[C:17]([CH3:22])[C:18]([NH2:26])=[C:14]2[CH:13]=[CH:12][C:11]=1[CH3:23]
Reactant: COc1ccc(-c2c(C)ccc3c(C(=O)O)c(C)nn23)c(Cl)c1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(C)ccc3c(N)c(C)nn23)c(Cl)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 8.5 %

Procedure:
A 0° C. solution of 7-(2-chloro-4-methoxyphenyl)-2,6-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (0.58 g, 1.8 mmol) and triethylamine (0.30 mL, 2.2 mmol) in toluene (10 mL) was treated with diphenylphosphoryl azide (0.40 mL, 1.8 mmol) and stirred for 2.5 hours at 0° C. The reaction mixture was poured into H2O, extracted with Et2O, washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to remove the Et2O. Toluene (20 mL) was added and the reaction was heated to reflux for 3 hours. The reaction was treated with 2N HCl (5 mL) and stirred at reflux for 1 hour then cooled to room temperature. The layers were separated and the aqueous layer was basified with solid K2CO3. The residue was extracted with CH2Cl2, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to give 0.046 g (9%) of a yellow oily solid as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=7.1 Hz, 1H), 7.35 (d, J=9.3 Hz, 1H), 7.13 (d, J=2.5 Hz, 1H), 7.01 (dd, J=8.5, 2.5 Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 3.90 (s, 3H), 2.38 (s, 3H), 2.08 (s, 3H); MS (EI) m/z 302.18 (M++H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[O:15])[CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(F)c[nH]1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(F)cn1CC(=O)c1ccc(Br)cc1
Temperature: 35 °C
Reaction time: 72 h

Procedure:
To a solution of 15.7 g (100 mmol) 4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester and 27.8 g (100 mmol) 2,4′-dibromoacetophenone in 150 ml acetone is added 16.6 g (120 mmol) cesium carbonate. The resulting suspension is stirred at 35° C. for 3 days. The reaction mixture is added to 600 ml water under stirring. The resulting precipitate is filtered off, washed with water and dried under vacuum to afford 1-[2-(4-bromo-phenyl)-2-oxo-ethyl]-4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester as light yellow solid; HPLC/MS 3.14 (B), [M+H] 354/356;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29](NC2C=CC=CC=2)=[O:30])=[CH:26][CH:27]=1>>[C:25]1([NH:28][C:29]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([NH:12][S:9]([C:4]4[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=4)(=[O:11])=[O:10])=[CH:21][CH:20]=3)[CH:16]=[CH:17]2)=[O:30])[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: O=S(=O)(Nc1ccc2[nH]ccc2c1)c1cc(Cl)cc(Cl)c1
Reactant: O=C(Nc1ccccc1)Nc1ccccc1
Product: O=C(Nc1ccccc1)n1ccc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21

Procedure:
Yield: 124 mg (the product also contains 3,5-dichloro-N-(1H-indol-5-yl)-phenylsulphonamide and diphenylurea)
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20])#[N:12].C(OCC)C>C([O-])(O)=O.[Na+].O>[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:21])=[O:20])#[N:12]
Reactant: Cc1cc(O)cc(O)c1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 2-cyanobenzenesulfonyl chloride 2.02 g, 10.0 mmol) were mixed in saturated NaHCO3 (30 mL) and diethyl ether 30 mL). The biphasic mixture was stirred vigorously at room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a white solid (1.65 g, 57%). 1H-NMR (300 MHz, CDCl3) δ8.07 (m, 1H), 7.94 (m, 1H), 7.75-7.80 (m, 2H), 6.57 (s, 1H), 6.53 (s, 1H), 6.49 (s, 1H), 5,69 (br s, 1H), 2.22 (s, 3H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH:6]([O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:25][NH:26][C:27]([C:29]3[O:30][C:31]4[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=4[C:33]=3[CH3:34])=[O:28])[CH:21]=2)[C:16]=1[Br:39])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.Cl>CO>[Br:39][C:16]1[C:17]2[C:22](=[CH:21][C:20]([CH2:25][NH:26][C:27]([C:29]3[O:30][C:31]4[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=4[C:33]=3[CH3:34])=[O:28])=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([OH:40])=[O:4]
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(CNC(=O)c3oc4ccccc4c3C)ccc2c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)NCc2ccc3c(Br)c(OC(Cc4ccccc4)C(=O)O)ccc3c2)oc2ccccc12
Reaction time: 6 h

Procedure:
A mixture of 1 N NaOH (5 mL, 5 mmol) and 2-(1-bromo-6-{[(3-methyl-benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester (1.58 g, 2.76 mmol), prepared in the previous step, in 200 mL of methanol plus 5 mL of water was stirred under nitrogen at room temperature overnight and then at 60° C. for 6 h. 1 N HCl (6.2 mL, 6.2 mmol) was added and the reaction concentrated under reduced pressure to remove the methanol. The solid that precipitated was collected by filtration and dried under reduced pressure to give the title compound as an off-white solid, mp 110-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[NH:15][N:16]=2)[N:13]=1.Br[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[N:15]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[N:16]=2)[N:13]=1
Reactant: BrC1CCCCC1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=c1n(C2CCCCC2)nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 75 °C
Reaction time: 17 h
Yield: 34.1 %

Procedure:
A suspension of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (36 mg, 0.1 mmol), bromocyclohexane (40 μL, 0.3 mmol) and solid K2CO3 (42 mg, 0.3 mmol) in anhydrous DMF (1 mL) was stirred at 75° C. for 17 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional bromocyclohexane (50 μL, 0.375 mmol) was added, the reaction was allowed to continue at 75° C. for 24 h more. After cooling to room temperature, the reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL). The separated EtOAc layer was washed with saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-60%) in hexanes to yield a yellow glassy product, which was lyophilized in acetonitrile to afford 15 mg (34%) of the title compound as a yellow powder. LC/MS (method A): retention time=4.06 min, (M+H)+=439. 1H NMR (CDCl3, 400 MHz): δ 7.18-7.50 (m, 5H), 7.19 (d,J=8.8 Hz, 2H), 7.03 (d,J=8.8 Hz, 2H), 4.47 (m, 1H), 1.26-2.04 (m, 10H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]2[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(O)(C)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:9]=3)[N:14]=[C:13]([CH3:18])[C:12]=2[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:24][CH:25]=1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(Cl)cc2)c1S(C)(=O)=O
Reactant: C1COCCN1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCCCCCC
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccc(Cl)cc2)c1S(C)(=O)=O
Temperature: 110 °C
Yield: 43.1 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (40 mg, 0.039 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (37 mg, 0.078 mmol) and cesium carbonate (952 mg, 2.92 mmol). 6-Bromo-4-(4-chloro-phenyl)-3-methanesulfonyl-2-methyl-quinoline (compound of example 16) (800 mg, 1.95 mmol) in tert.-butanol (20 ml) was added, followed by morpholine (0.204 g, 2.33 mmol). The tube was sealed and heated at 110° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate with a gradient 100:0 to 40:60 to give a yellow solid (350 mg, 43%). MS: m/z=417 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])[CH:14]=1)[C:6](N(OC)C)=[O:7].[CH3:21][Mg]Br>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6](=[O:7])[CH3:21])[CH:12]=[C:13]([S:15]([F:17])([F:20])([F:19])([F:16])[F:18])[CH:14]=1
Reactant: COc1cc(C(=O)N(C)OC)cc(S(F)(F)(F)(F)F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1

Procedure:
3,N-Dimethoxy-N-methyl-5-(pentafluorosulfanyl)benzamide (O3.007; 2.0 g) was dissolved in absolute THF (60 ml), and methylmagnesium bromide (5.2 ml, 3 M in diethyl ether) was added dropwise at 0° C. while stirring. After addition, the ice bath was removed and the mixture was stirred at RT for 2 h. 1 N hydrochloric acid was then added dropwise while cooling, followed by water and ethyl acetate. The organic phase was removed and the aqueous phase was extracted twice more with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (met. A). The product-containing fractions were combined, freed of the acetonitrile and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 1.63 g of the desired compound were obtained.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC(CCl)=CC=1>ClCCCl>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([C:8]2[S:9][C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=3[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: ClCc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc2c(-c3ccccc3)c(C(=O)c3ccc(Cl)cc3)sc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 200 ml. of 1,2-dichloroethane were added 10 g. (0.042 mole) of 3-phenyl-6-methoxybenzothiophene and 6.5 g. (0.042 mole) of 4-chlorobenzoyl chloride. The mixture was cooled to 0° C., and 5.73 g. of aluminum chloride were added. The mixture was stirred overnight, and an additional 10 percent of 4-chlorobenzyl chloride and aluminum chloride was added. The reaction mixture was maintained for approximately one hour, and ice then was added to the mixture. The resulting organic layer was separated from the aqueous, the aqueous layer was washed with chloroform which was then added to the organic layer. The organic layer was evaporated to dryness. To the resulting residue were added 250 ml. of methanol and 15 ml. of 5N sodium hydroxide. The mixture was refluxed for 40 minutes and then was evaporated. The residue was dissolved in ethyl acetate, and the ethyl acetate solution was washed successively with water and aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and evaporated to give the title compound, m.p. 115° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[C@H:6]([NH2:40])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][CH:8]=1>CO.O1CCCC1>[NH2:40][C@H:6]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:20][CH3:21])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:32])([CH3:33])[CH3:34])=[C:24]([CH3:36])[CH:23]=3)[CH2:37][CH3:38])=[CH:15][C:14]=2[CH3:39])=[CH:11][CH:12]=1)[C:5]([OH:41])=[O:4]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@@H](N)C(=O)OC)cc2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@@H](N)C(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.1 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.094 mL, 0.094 mmol) was added to a solution of (R)-amino-(4′-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)-acetic acid methyl ester (Example 167-(3); 16.6 mg, 0.031 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature for two days. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol:water=4:2:0.6) to give the target compound as a colorless oil (15.2 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]=[C:26]=[S:27])[CH:20]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:1][C:26]([NH:25][C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)=[S:27]
Reactant: S=C=Nc1cccnc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cccnc1
Yield: 95.2 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol) and 3-pyridyl isothiocyanate (0.565 g, 4.15 mmol). Trituration in hexanes/ethyl acetate (3:2) gave the product (1.441 g); m.p. 178-179° C.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([NH:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH2:21][C@@H:20]([C:29](=[O:49])[N:30]([CH:46]4[CH2:48][CH2:47]4)[CH2:31][C:32]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:34]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:50](Cl)(=[O:55])[C:51]([CH3:54])([CH3:53])[CH3:52]>CC#N>[CH:46]1([N:30]([CH2:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=2)[C:29]([C@@H:20]2[CH2:21][C@H:22]([N:24]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[C:50](=[O:55])[C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:23][NH:18][CH2:19]2)=[O:49])[CH2:47][CH2:48]1
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NCC3CC3)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC#N
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](N(CC3CC3)C(=O)C(C)(C)C)C2)C2CC2)c2ccccc21

Procedure:
The title compound is prepared analogously as described in Example ??? using (3R,5S)-3-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-5-(cyclopropylmethyl-amino)-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester and pivaloylchloride. MS: 523 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.24 min.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Cl:16])[C:8]=1[CH2:17][C:18]([OH:20])=[O:19].[CH3:21]O>>[CH3:21][O:19][C:18](=[O:20])[CH2:17][C:8]1[C:7]([Cl:6])=[CH:12][C:11]([N+:13]([O-:15])=[O:14])=[CH:10][C:9]=1[Cl:16]
Reactant: O=C(O)Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Concentrated sulfuric acid (2 mL, 37.33 mmol, 0.73 equiv) is added dropwise to a solution of (2,6-dichloro-4-nitro-phenyl)-acetic acid (EP 87218) (14.2 g, 51.1 mmol) in MeOH (500 mL). The resulting brown solution is stirred for 6 h at reflux. The reaction mixture is allowed to cool to rt and concentrated in vacuo. The residue is dissolved in EtOAc (400 mL) and a bit of water, washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. Purification of the crude product by silica gel column chromatography (Hexane/EtOAc, 2:1→1:1) provides the title compound as a yellow solid: ES-MS: 262.1/264.1 [M+H]+; tR=3.78 min (System 2); Rf=0.40 (Hexane/EtOAc, 2:1).