Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[Br:31][C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:39]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([Br:31])[CH:33]=4)=[O:40])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C=Nc1cccc(Br)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Br)c1)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 42.3 mg (0.21 mmol) of 3-bromophenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 43 mg (75.1% of theory) of the title compound are obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]1[N:12]([CH2:13][CH2:14][C:15](OCC)=[O:16])[CH2:11][CH2:10][N:9]2[CH2:20][CH2:21][CH2:22][CH2:23][CH:8]12>O1CCCC1>[CH2:7]1[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[CH2:11][CH2:10][N:9]2[CH2:20][CH2:21][CH2:22][CH2:23][CH:8]12
Reactant: CCOC(=O)CCN1CCN2CCCCC2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCN1CCN2CCCCC2C1
Reaction time: 8 h

Procedure:
1 g of LiAlH4 is added in portions to a solution of 3 g of the compound obtained in Step A, in 100 ml of tetrahydrofuran, and then the reaction mixture is stirred for 8 hours, subsequently hydrolysed, filtered and finally evaporated to dryness.
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:6][N:7]([C:32]1[N:33]=[N:34][N:35]([CH3:37])[N:36]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([O:24]C)=[O:23])[CH2:18][CH2:17]2)[C:10]2[C:26]([CH3:31])=[CH:27][C:28]([CH3:30])=[CH:29][C:9]1=2.[OH-].[Na+]>CO>[F:44][C:41]([F:42])([F:43])[C:39]1[CH:38]=[C:5]([CH2:6][N:7]([C:32]2[N:33]=[N:34][N:35]([CH3:37])[N:36]=2)[C@@H:8]2[C:9]3[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:10]=3[N:11]([CH2:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14]2)[CH:4]=[C:3]([C:2]([F:1])([F:46])[F:45])[CH:40]=1
Reactant: COC(=O)[C@H]1CC[C@H](CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)cc(C)c32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)c2c(c1)[C@@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)CCCN2C[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 60 °C
Reaction time: 7 h

Procedure:
Charge a flask with (trans)-methyl 4-(((S)-5-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)cyclohexanecarboxylate (149 mg). Add MeOH (6 mL) and 1.0 N NaOH (3.0 mL). Heat the resulting mixture to about 60° C. Monitor the reaction via TLC. After about 7 hrs or when the starting ester has reacted, cool the mixture to about 0° C. and quench with 1 N HCl. Dilute the mixture with EtOAc (60 mL). Sequentially wash the mixture with water (20 mL), brine (20 mL) and dry over Na2SO4. Filter and concentrate the filtrate. Purify via flash chromatography with CH2Cl2. Remove the solvent to provide the title compound (125 mg) as a white solid.
Reaction SMILES: [CH:1]1([NH:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH2:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:13][S:14][C:15]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[C:16]=1[C:17](O)=[O:18]>>[CH:1]1([NH:6][C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][C:17](=[O:18])[C:16]2[C:20]([C:28]([F:29])([F:30])[F:31])=[CH:21][C:22]([C:24]([F:25])([F:26])[F:27])=[CH:23][C:15]=2[S:14][CH3:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1NC1CCCC1
Reactant: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Product: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCC[C@@H]1NC1CCCC1

Procedure:
The title compound, light pink solid, MS: m/e=455.3 [(M+H)+], was prepared in accordance with the general method of example 5 from (1RS,2SR)—N-Cyclopentyl-cyclopentane-1,2-diamine (intermediate AE) and 2-methylthio-4,6-bis(trifluoromethyl)benzoic acid (CAS 896120-49-3).
Reaction SMILES: [NH:1]1[C:46](=[O:47])[C@H:41]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:40][C:38](=[O:39])[C@@H:34]([CH:35]([CH3:37])[CH3:36])[NH:33][C:31](=[O:32])[C@H:26]([CH2:27][CH2:28][S:29][CH3:30])[NH:25][C:23](=[O:24])[C@@H:18]([CH2:19][C:20](=[O:22])[OH:21])[NH:17][C:15](=[O:16])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1.[OH:48]O>C(O)(=O)C>[NH:1]1[C:46](=[O:47])[C@H:41]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:40][C:38](=[O:39])[C@@H:34]([CH:35]([CH3:37])[CH3:36])[NH:33][C:31](=[O:32])[C@H:26]([CH2:27][CH2:28][S:29]([CH3:30])=[O:48])[NH:25][C:23](=[O:24])[C@@H:18]([CH2:19][C:20](=[O:21])[OH:22])[NH:17][C:15](=[O:16])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1
Reactant: CSCC[C@@H]1NC(=O)[C@@H](CC(=O)O)NC(=O)[C@@H](Cc2cn(C=O)c3ccccc23)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C(C)C)NC1=O
Reactant: OO
Solvent: CC(=O)O
Product: CC(C)C[C@@H]1NC(=O)[C@@H](C(C)C)NC(=O)[C@H](CCS(C)=O)NC(=O)[C@@H](CC(=O)O)NC(=O)[C@@H](Cc2cn(C=O)c3ccccc23)NC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of cyclo(-DTrp(CHO)-DAsp-Met-DVal-Leu-) (12.9 mg) which was prepared in Example 55 in acetic acid(2.0 ml) was added 35% H2O2 (5 μl). The reaction mixture was stirred at room temperature for 3 h and concentrated under reduced pressure till the volume of the mixture was reduced to ca. 1 ml. The residue was triturated with water(3 ml) to give the title compound (7.6 mg) as a pale yellow powder.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:12][CH:11]([C:13]2[O:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:10]2=[C:19]3[N:32]([CH3:33])[C:31](=[O:34])[N:30]([CH3:35])[C:29](=[O:36])[C:20]3=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[N:9]2[CH2:8]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:43]1[CH:47]=[CH:46][N:45]=[CH:44]1>C(#N)C.O>[N:43]1([CH2:6][C@@H:7]2[O:12][C@@H:11]([C:13]3[O:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[C:10]3=[C:19]4[N:32]([CH3:33])[C:31](=[O:34])[N:30]([CH3:35])[C:29](=[O:36])[C:20]4=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[N:9]3[CH2:8]2)[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: c1c[nH]cn1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)O[C@@H](COS(C)(=O)=O)C3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)[C@H](c1ccc(Cl)o1)O[C@@H](Cn1ccnc1)C3
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A mixture of ((8R)-10-(5-chlorofuran-2-yl)-5-(3-fluorophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,7,8,10-hexahydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]oxazin-8-yl)methyl methanesulfonate (117 mg, 0.217 mmol), cesium carbonate (142 mg, 0.435 mmol) and imidazole (22.51 mg, 0.331 mmol) in acetonitrile (6 mL) was heated at 80° C. for 16 hours, then at 85° C. for 3.5 hours. Further portions of imidazole (22.51 mg, 0.331 mmol) and cesium carbonate (142 mg, 0.435 mmol) were added and the mixture heated for a further 2 hours. The mixture was cooled to room temperature, diluted with water (30 ml) and extracted with DCM (2×30 ml). The combined organic extracts were washed with brine (30 ml) passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-100% EtOAc/hexane then with 0-10% MeOH/DCM, afforded the title compound as a mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.[CH2:18](Br)[C:19](=[CH2:21])[CH3:20].NC1C(C(N)=O)=CC2C3C(=CC=CC=3)N(C(C)C)C=2N=1>>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:20][C:19]([CH3:21])=[CH2:18])[C:6]=2[N:14]=1
Reactant: C=C(C)CBr
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: CC(C)n1c2ccccc2c2cc(C(N)=O)c(N)nc21
Product: C=C(C)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Yield: 58.9 %

Procedure:
2-Amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 196 mg, 0.866 mmol) was alkylated with methallyl bromide (0.131 mL, 1.30 mmol) according to the procedure detailed in the synthesis of 13 to afford 2-amino-9-(2-methylprop-2-en-1-yl)-9H-pyrido[2,3-b]indole-3-carboxamide (xii-a, 143 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]([C:21](OCC)=[O:22])=[C:13](O)[CH2:12][S:11]2(=[O:28])=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][CH2:35][NH2:36])=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][CH2:35][NH:36][C:21]([C:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:10]([CH2:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[S:11](=[O:27])(=[O:28])[CH2:12][C:13]=2[NH:36][CH2:35][CH2:34][C:33]2[CH:37]=[CH:38][C:30]([Cl:29])=[CH:31][CH:32]=2)=[O:22])=[CH:32][CH:31]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: CCOC(=O)C1=C(O)CS(=O)(=O)N(Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Solvent: Cc1ccccc1
Product: O=C(NCCc1ccc(Cl)cc1)C1=C(NCCc2ccc(Cl)cc2)CS(=O)(=O)N(Cc2ccc(Cl)c(Cl)c2)c2ccccc21

Procedure:
A mixture of 1.7 g of ethyl 1-(3,4-dichlorophenylmethyl)-1,3-dihydro-4-hydroxy-2,1-benzothiazepine-5-carboxylate-2,2-dioxide, 0.6 g of 4-chlorophenethylamine in 100 ml of toluene is heated at reflux for 2 days. The reaction mixture is evaporated to dryness. The residue is crystallized from ether - hexane (charcoal) to yield N-(4-chlorophenethyl)-1-(3,4-dichlorophenylmethyl)-1,3-dihydro-4-(4-chlorophenethylamino)-2,1-benzothiazepine-5-carboxamide-2,2-dioxide; m.p. 119°-121°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[C:60]([O:66][CH3:67])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:25]([CH:28](/[CH:46]=[CH:47]/[C:48]1[C:53]([O:54][CH3:55])=[CH:52][C:51]([O:56][CH3:57])=[CH:50][C:49]=1[O:58][CH3:59])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH:37][C:38](=[O:45])[CH:39]([O:41]C(=O)C)[CH3:40])[CH:30]=1)(=[O:27])=[O:26])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:24])[CH:18]([O:20]C(=O)C)[CH3:19])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH3:55][O:54][C:53]1[CH:52]=[C:51]([O:56][CH3:57])[CH:50]=[C:49]([O:58][CH3:59])[C:48]=1/[CH:47]=[CH:46]/[CH:28]([S:25]([CH:7](/[CH:6]=[CH:5]/[C:4]1[C:3]([O:2][CH3:1])=[CH:63][C:62]([O:64][CH3:65])=[CH:61][C:60]=1[O:66][CH3:67])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:24])[CH:18]([CH3:19])[OH:20])[CH:9]=1)(=[O:26])=[O:27])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH:37][C:38](=[O:45])[CH:39]([OH:41])[CH3:40])[CH:30]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)C(C)OC(C)=O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)C(C)OC(C)=O)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)C(C)O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)C(C)O)c2)c(OC)c1

Procedure:
A solution of (E)-2,4,6-trimethoxystyryl-3-(2-acetoxypropionamido)-4-methoxybenzylsulfone (10 mmol) was hydrolyzed with potassium carbonate (70 mmol) in 1:1 ethanol/water (25 mL) to give (E)-2,4,6-trimethoxystyryl-3-(2-hydroxy-2-methylacetamido)-4-methoxy benzylsulfone. (m.p. 174-1 76° C.)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]1[CH:59]=[CH:58][N:57]=[CH:56][C:55]=1[C:60](Cl)=[O:61]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:60]([C:55]2[CH:56]=[N:57][CH:58]=[CH:59][N:54]=2)=[O:61])[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: O=C(Cl)c1cnccn1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cnccn1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and pyrazine-2-carbonyl chloride as the starting materials in 50% yield. LCMS for C29H30ClN8O2 (M+H)+: m/z=557.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)([C:27]#[CH:28])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O=[Pt]=O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)([CH2:27][CH3:28])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C#CC(CC(=O)OC(C)(C)C)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: O=[Pt]=O
Solvent: CCO
Product: CCC(CC(=O)OC(C)(C)C)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21

Procedure:
To a solution of the product of Step E (150 mg, 0.3 mmol) in ethanol (3 mL) was added PtO2 (6.8 mg, 0.03 mmol) at room temperature under H2 atmosphere for 2 h. The solid was filtered off and the filtrate was concentrated in vacuo to give the title compound as colorless oil. LC/MS m/z=499.2[M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:25][C:26]1[C:31]([SH:32])=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:5]2[N:6]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=3)[CH:7]=[C:3]([CH2:2][S:32][C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:25])[N:4]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccccc1S
Reactant: CS(=O)(=O)c1ccc(-n2cc(CCl)nc2-c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1SCc1cn(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloromethyl-2-(4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl]-1H-imidazole (Example 159, Step 1) (250 mg, 0.656 mmol) and o-thiocresol (163 mg, 1.31 mmol) in 5 ml of dry dimethylformamide was added anhydrous potassium carbonate (226 mg, 1.64 mmol). The mixture was stirred rapidly overnight at room temperature. The mixture was then partitioned between ethyl acetate and water. The aqueous layer was further extracted with ethyl acetate, the combined organic extracts washed with brine, and dried over sodium sulfate. The solution was filtered and concentrated. Chromatography of the residue over silica gel using 40% ethyl acetate in hexane gave the title compound as a very pale yellow solid (210 mg): mp (DSC) 51° C. Anal. Calc'd. for C24H21ClN2O2S2 (MW 469.03): C, 61.46; H, 4.51; N, 5.97. Found: C, 61.16; H, 4.50; N, 5.86.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[C:9]([F:15])=[N:10][CH:11]=[CH:12][C:13]=2I)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C([O-])(=O)C.[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CCCCCC.C(OCC)(=O)C>[F:15][C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[C:6](=[O:7])[CH:1]1[CH2:5][CH:4]2[CH:3]=[CH:2]1
Reactant: O=C(c1c(I)ccnc1F)C1CC=CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1c2c(ccnc2F)C2C=CC1C2
Temperature: 100 °C
Reaction time: 0.12 h

Procedure:
Cyclopent-3-enyl-(2-fluoro-4-iodo-pyridin-3-yl)-methanone (110 mg, 0.35 mmol) as prepared above, was combined with tetrabutylammonium bromide (112 mg, 0.35 mmol), potassium acetate (102 mg, 1.04 mmol), triphenylphosphine (2 mg, 0.009 mmol) and DMF (4 ml). The reaction mixture was deoxygenated with nitrogen and then palladium acetate (2 mg, 0.008 mmol) was introduced. The reaction mixture was heated in a 100° C. oil bath for 20 min. A black precipitate was observed after 7 min. The reaction mixture was cooled to room temperature and was then added to a mixture of 1:1:1:1 ethyl acetate, hexane, brine and water. The organic layer was separated and washed with brine and then dried and evaporated. The residue (60 mg) was used directly in the next step. 1H NMR (CDCl3, 400 MHz) δ 8.15 (d, 1H, J=5 Hz), 7.03 (d, 1H, J=5 Hz), 6.65 (m, 1H), 6.19(m, 1H), 3.69 (br s, 1H), 3.51 (m, 1H), 2.68 (m, 1H), 2.63 (d, 1H, J=11 Hz); APCl MS m/z 190 (M+1)+; HRMS (m/z): (M+H)+ calc'd. for C11H8FNO2: 190.0668; found, 190.0654.
Reaction SMILES: C[S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].ClC1C=CC(S(=O)(=O)[NH2:30])=CC=1C(O)=O.N1CCCC1>>[N:14]1([C:8]2[CH:7]=[CH:6][C:5]([S:2](=[O:4])(=[O:3])[NH2:30])=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCNC1
Product: NS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Yield: 19 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example S) from 2-Chloro-5-sulfamoyl-benzoic acid (CAS: 97-04-1; Basu; D.-G.; J.Indian Chem.Soc.; 16; 1939; 100, 106) and pyrrolidine and obtained in 19% yield. MS (m/e): 269.4 (MH− 100%).
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C@@H:10]([OH:14])[C:11](O)=[O:12].[H]1[BH2][H][BH2]1.C1COCC1>CO>[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:10]([OH:14])[CH2:11][OH:12])[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)[C@H](O)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CO
Product: OC[C@H](O)c1cccc(Cl)c1
Reaction time: 12 h

Procedure:
Into THF (70 ml) were added (R)-3-chloromandelic acid (10 g) and further, under ice-cooling and dropwise, a 1M-diborane THF solution (81.5 ml) over 2 hours, and then stirring was continued at 25° C. for 12 hours. The reaction mixture was cooled, methanol (20 ml) was added thereto over 30 minutes and then stirring was further continued for 3 hours. The resulting reaction mixture was concentrated and then the residue was recrystallized from diethyl ether to obtain a colorless oily compound mentioned above (7.3 g, 78.9%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N1CC[C@@H](N)C1)(OC(C)(C)C)=O.Br[C:21]1[CH:22]=[CH:23][C:24]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]3([C:48]4[C:39](=[CH:40][C:41]5[O:46][CH2:45][CH2:44][O:43][C:42]=5[CH:47]=4)[O:38][CH2:37]3)[C:29]2=[O:49])=[N:25][CH:26]=1.BrC1C=CC(CN2C3C(=CC=CC=3)C3(C4C=C(F)C(F)=CC=4OC3)C2=O)=CC=1>>[N:1]1([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][N:28]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]4([C:48]5[C:39](=[CH:40][C:41]6[O:46][CH2:45][CH2:44][O:43][C:42]=6[CH:47]=5)[O:38][CH2:37]4)[C:29]3=[O:49])=[N:25][CH:26]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C1N(Cc2ccc(Br)cn2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: O=C1N(Cc2ccc(Br)cc2)c2ccccc2C12COc1cc(F)c(F)cc12
Product: O=C1N(Cc2ccc(N3CCOCC3)cn2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 33.1 and making non-critical variations using morpholine to replace (R)-(+)-1-Boc-3-aminopyrrolidine, and 1′-[(5-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 1′-(4-bromobenzyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 1′-[(5-morpholin-4-ylpyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (60%) as a pale yellow solid: mp 204-206° C.; 1H NMR (300 MHz, CDCl3) δ8.23 (d, J=2.4 Hz, 1H), 7.23-7.11 (m, 4H), 7.01 (dd, J=7.5, 7.5 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.27 (s, 1H), 5.13 (d, J=15.3 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.89 (d, J=15.6 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.21-4.11 (m, 4H), 3.87 (t, J=4.8 Hz, 4H), 3.17 (t, J=5.0 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 177.4, 155.3, 146.3, 146.2, 144.6, 142.2, 138.3, 137.3, 132.2, 128.8, 123.7, 123.4, 123.2, 122.0, 121.1, 111.7, 109.7, 99.4, 80.2, 66.6, 64.5, 63.9, 58.1, 48.5, 45.6; MS (ES+) m/z 472.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:26][P:27](=[O:34])([O:31]CC)[O:28]CC)[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22](=[O:25])[NH:23][CH3:24])[CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C[Si](Br)(C)C.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:26][P:27](=[O:28])([OH:34])[OH:31])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22](=[O:25])[NH:23][CH3:24])[CH2:17][CH2:16]3)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOP(=O)(CN(c1ccc2c(c1)CCN2C(=O)NC)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)N1CCc2cc(N(CP(=O)(O)O)S(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Temperature: 25 °C

Procedure:
1.2 g diethyl {[(3,5-dichloro-phenylsulphonyl)-(1-methylcarbamoyl-2,3-dihydro-1H-indol-5-yl)-amino]-methyl}-phosphonate are dissolved in 30 ml dichloromethane. 1.2 ml of trimethylsilylbromide are added with stirring. Then the mixture is refluxed for 2 hours and after cooling to ambient temperature combined with 30 ml of methanol. The mixture is stirred for 1 hour, the solvents are eliminated in vacuo, another 30 ml of methanol are added and the mixture is stirred for a further 10 minutes. Then the solvent is eliminated in vacuo and the residue is dried in vacuo at 80° C. Then it is extracted from diethyl ether, the solid is suction filtered and dried in vacuo.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]([CH3:12])[CH3:11].C(O)(C)C.C(=O)=O.C([Li])CCC.[B:25](OC)([O:28][CH3:29])[O:26][CH3:27]>O1CCCC1>[CH3:11][N:10]([CH3:12])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:25]([O:28][CH3:29])[O:26][CH3:27]
Reactant: CN(C)CCc1ccccc1Br
Reactant: COB(OC)OC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COB(OC)c1ccccc1CCN(C)C
Temperature: -70 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
19.0 g (83.2 mmol) of the [2-(2-bromophenyl)ethyl]dimethylamine prepared according to example 10 (2nd stage) were dissolved in 300 ml tetrahydrofuran and the solution was cooled to −70° C. in a cooling bath (isopropanol/dry ice). 60 ml (95.7 mmol) butyllithium solution (1.6 M in hexane) were added dropwise under nitrogen such that the temperature did not rise above −60° C. After the mixture had been stirred at −70° C. for two hours, 28 ml (250 mmol) trimethyl borate were also added dropwise such that the temperature did not rise above −60° C. The mixture was warmed to 25° C. in the course of 15 hours and the solution was concentrated on a rotary evaporator (500-10 mbar) without heat being supplied. The residue was taken up in 200 ml n-hexane, the mixture was stirred for one hour and filtered over an inert gas frit under nitrogen and the filtrated was concentrated on a rotary evaporator (500-10 mbar) without heat being supplied. 14.1 g dimethyl 2-(2-dimethylaminoethyl)benzeneboronate (76.5% of theory) were obtained in this manner.