Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]1[C:14]([C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[CH:27]=[C:28]5[C:32](=[CH:33][CH:34]=4)[NH:31][N:30]=[CH:29]5)[CH:24]=3)[NH:19][CH:18]=2)=[O:16])=[C:13]([F:35])[CH:12]=[CH:11][C:10]=1[NH:36][S:37]([C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=1[F:47])(=[O:39])=[O:38]>O.C(OCC)(=O)C>[C:1]([N:31]1[C:32]2[C:28](=[CH:27][C:26]([C:23]3[CH:24]=[C:25]4[C:17]([C:15]([C:14]5[C:9]([F:8])=[C:10]([NH:36][S:37]([C:40]6[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=6[F:47])(=[O:39])=[O:38])[CH:11]=[CH:12][C:13]=5[F:35])=[O:16])=[CH:18][NH:19][C:20]4=[N:21][CH:22]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1)(=[O:3])[CH3:2]
Reactant: O=C(c1c(F)ccc(NS(=O)(=O)c2cc(F)ccc2F)c1F)c1c[nH]c2ncc(-c3ccc4[nH]ncc4c3)cc12
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)n1ncc2cc(-c3cnc4[nH]cc(C(=O)c5c(F)ccc(NS(=O)(=O)c6cc(F)ccc6F)c5F)c4c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
Into a reaction flask, a mixture of acetic anhydride (12 mg, 0.11 mmol) and N-{2,4-difluoro-3-[5-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-0002, 22 mg, 0.031 mmol) is stirred at room temperature overnight, then diluted with water and ethyl acetate. The organic layer is washed with saturated sodium bicarbonate, then brine and dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with methanol and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-0005, 3 mg, 20%). MS (ESI) [M+H+]+=607.8.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH3:20])=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][NH:19][C:17]([C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)[CH:3]=3)[CH:9]=[N:10][C:11]=2[CH:16]=1)=[O:18]
Reactant: CNC(=O)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc2c(c1)ncn2-c1cccc(-c2cccs2)c1

Procedure:
To a solution of 1-(3-bromophenyl)-N-methyl-1H-benzimidazole-5-carboxamide (20 mg, 0.06 mmol) and thiophene-2-boronic acid (9.0 mg. 0.073 mmol) in anhydrous DMF (0.6 mL) was added Pd(PPh3)4 (3.5 mg, 0.003 mmol) followed by a solution of Na2CO3 (19 mg, 0.18 mmol) in water (0.16 mL). The reaction was irradiated in the microwave for 10 min (200 W, 150° C.). After cooling, the reaction mixture was filtered through Celite and washed with EtOAc (15 mL). The combined organic layer was washed with saturated aqueous NaHCO3 solution (10 mL) followed by saturated aqueous solution brine (3×10 mL), dried (MgSO4) and evaporated to dryness. The crude product was purified by solid-phase extraction (Isolute SAX, followed by Isolute SCX), giving N-methyl-1-(3-thien-2-ylphenyl)-1H-benzimidazole-5-carboxamide as an off-white solid; 1H NMR (400 MHz, MeOH-d4): δ 8.57 (s, 1H), 8.27 (d, J=2 Hz, 1H), 7.89-7.86 (m, 2H), 7.78 (d, J=7.8 Hz, 1H), 7.66-7.62 (m, 2H), 7.52-7.54 (m, 2H), 7.45 (d, J=5.1 Hz, 1H), 7.12 (dd, J=3.5 Hz, 1.5 Hz, 1H), 2.97 (s, 3H); MS (ES+): m/z 333.9 (100%) [MH+].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:21]=[CH:20][C:11]2[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[C:13]([CH3:15])[O:14][C:10]=2[CH:9]=1.[Cl:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1.O>CN(C=O)C>[Cl:22][C:23]1[N:28]=[C:27]([O:7][C:8]2[CH:21]=[CH:20][C:11]3[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CNC(=O)c1c(C)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc(Cl)n3)ccc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Potassium carbonate (1.5 mmol) was added to a solution of 6-hydroxy-N,2-dimethylbenzofuran-3-carboxamide (1 mmol) in 5 ml DMF. After 30 mins, 2,4-dichloropyrimidine (1 mmol) was added and the reaction mixture was stirred overnight at 60° C. Water was added. The resultant solid was filtered, washed with water, and dried to give 6-(2-chloropyrimidin-4-yloxy)-N,2-dimethylbenzofuran-3-carboxamide in a yield of 82%, as a solid, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH:11]([CH3:13])[CH3:12])[C:5]([CH3:14])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH:18]([NH2:21])([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[CH:18]([NH:21][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH:11]([CH3:13])[CH3:12])[C:5]([CH3:14])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)N
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(C)C
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(NC(C)C)c([N+](=O)[O-])c1C(C)C
Temperature: 100 °C
Yield: 73.4 %

Procedure:
A mixture of 5-chloro-4,6-dinitro-o-cymene (4.0 g, 0.0155 mole) and isopropylamine (3.2g, 0.054 mole) in toluene is heated in a bomb at 100° C. for 4 hours. The cooled mixture is washed with aqueous bicarbonate solution, dried over magnesium sulfate, and concentrated to leave the crude product which is purified by dry column chromatography to yield 3.2 g of product with mp 54°-55° C. By using one of the aforementioned procedures for the dinitration of the appropirate N-alkyl-4-alkyl-m-toluidines or by reacting the appropriate amine with the desired 3-chloro-2,4-dinitro-6-alkyltoluene the following compounds are prepared.
Reaction SMILES: [N:1]1[N:2]2[CH:10]=[CH:9][CH:8]=[C:3]2[C:4]([NH2:7])=[N:5][CH:6]=1.[Br:11]N1C(C)(C)C(=O)N(Br)C1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:11][C:8]1[CH:9]=[CH:10][N:2]2[C:3]=1[C:4]([NH2:7])=[N:5][CH:6]=[N:1]2
Reactant: Nc1ncnn2cccc12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ncnn2ccc(Br)c12
Reaction time: 4 h

Procedure:
A suspension of pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.5 g, 0.004 mol) in dichloromethane (100 mL) was stirred and cooled between −10° C. and −14° C. under nitrogen atmosphere. A solution of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (544 mg, 0.002 mol) in dichloromethane (100 mL) added dropwise over a 1 h. After 4 h, 100 mL of 10% aqueous sodium thiosulfate solution was added, and the mixture was stirred vigorously for a few minutes. The phases were separated, the dichloromethane phase washed with water, then brine, dried (anhydrous sodium sulfate), filtered and concentrated in vacuo. The residue was purified by MPLC (dichloromethane/ethyl acetate gradient). Purified material was triturated with dichloromethane, filtered, washed and dried under vacuum to afford 289 mg (36%) of colorless, fluffy solid. 1H-NMR (DMSO-d6): δ 8.01 (br s, 1 H), 7.82 (s, 1 H), 7.70 (d, 1 H), 6.78 (d, br s, 2 H). MS: LC/MS (+esi), m/z=212.5, 213.1 [M+H]. RT=1.34 min. Calc. for C6H5BrN4: C, 33.83; H, 2.37; Br, 37.50; N, 26.3. Found: C, 33.85; H, 2.24; Br, 38.24; N, 26.21.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38](OC)=[O:39])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:48][CH:47]([F:49])[CH2:46]4)[N:21]=3)[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:53][NH2:54]>C(O)C>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([NH:53][NH2:54])=[O:39])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:48][CH:47]([F:49])[CH2:46]4)[N:21]=3)[C@H:14]2[CH3:50])[CH:4]=[C:3]([C:2]([F:1])([F:52])[F:51])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reactant: NN
Solvent: CCO
Product: COc1ncc(-c2ccc(C(=O)NN)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C

Procedure:
Methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3-fluoroazetidin-1-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (EXAMPLE 36 Step A, 0.091 g, 0.122 mmol) was dissolved in ethanol (0.83 mL). Added hydrazine (0.117 mL, 3.65 mmol) and stirred at 85° C. in a screw cap vial (with a pressure relief cap) under a nitrogen blanket. The reaction was monitored by LCMS. Once complete, the reaction was cooled to room temperature. The solvent was removed by rotary evaporation, and the crude isolate was partitioned between ethyl acetate and water. Washed the organic twice more with water, then once with brine, dried over sodium sulfate, filtered and evaporated to give an off-white foam as the product. The compound was used without further purification. 1H NMR (CDCl3, 500 MHz): δ 8.19 (d, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 7.74 (s, 2H), 7.71 (s, 1H), 7.61 (dd, 1H), 7.46 (d, 1H), 7.36 (s, 1H), 7.32 (d, 1H), 5.67 (d, 1H), 5.51 (m, 0.5H), 5.40 (m, 0.5H), 4.71 (d, 1H), 4.44 (m, 3H), 4.31 (m, 2H), 4.00 (m, s, 4H), 2.37 (s, 3H), 1.59 (br, 2H+water), 0.74 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([N:18]4[CH:22]=[CH:21][N:20]=[CH:19]4)[CH:15]=[C:16]([CH3:17])[C:10]=3[N:9]=2)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH2:24][C@@H:25]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:26][OH:27].C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH:24][C@@H:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:26][OH:27])[C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:15]=[C:16]([CH3:17])[C:10]=2[N:9]=1
Reactant: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(Cl)ncnc3Cl)nc12
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(Cl)ncnc3N[C@H](CO)Cc3ccccc3)nc12
Temperature: 80 °C

Procedure:
To a solution of 2-(4,6-dichloro-pyrimidin-5-yl)-6-imidazol-1-yl-4-methyl-1H-benzimidazole (40 mg, 0.16 mmol) in isopropanol (5 mL) was added (S)-(−)-2-amino-3-phenyl-propanol (35 mg, 0.23 mmol) and triethylamine (0.5 mL). The reaction mixture was heated to 80° C. for 4 h, cooled to room temperature and concentrated with high vacuum. The crude product was used for the next step without purification. LCMS (M+H)+ m/z 460 (t=2.13 min.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:21](I)[CH3:22]>CN(C=O)C>[CH2:21]([O:1][C:2]1[CH:9]=[C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:22]
Reactant: CCI
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(N(CC)CC)ccc1C=O
Reaction time: 48 h

Procedure:
To a mixture of 2-hydroxy-4-(diethylamino)benzaldehyde (10.0 g, 51.75 mmol), K2CO3 (14.3 g) and DMF (150 ml) at room temperature was added ethyl iodide (4.1 ml). The reaction mixture was stirred for about two days, filtered and the filtrate was concentrated in vacuo. The residue was partitioned between ether and saturated Na2CO3, and the organic layer was separated, dried over MgSO4, treated with charcoal, filtered and concentrated in vacuo. The solid product was recrystallized from hexane to afford, as a pink crystalline solid, 9.8 g of 2-ethoxy-4-(diethylamino)benzaldehyde, m.p. 58°-59° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:25]4[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:24]=4[CH3:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: Cc1cccc(C)c1B(O)O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4c(C)cccc4C)c3O2)cc1
Yield: 18 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.00 g, 2.61 mmol) with 2,6-dimethylphenylboronic acid (0.783 g, 5.22 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.103 g, 0.135 mmol), and potassium carbonate (0.90 g, 6.52 mmol) generally according to the procedure described for Intermediate 37 provided 0.192 g (18%) of (±)-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Anal. calcd. for C24H24O4S: C, 70.56; H, 5.92. Found: C, 68.01; H, 5.6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][N:18]3[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25]N1C(=O)CCC1=O.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]=[C:17]([Cl:25])[N:18]3[CH3:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cnc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(Cl)nc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(Cl)nc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 107.3 %

Procedure:
4-(2-Chloro-9-methyl-9H-purin-6-yl)piperazine-1-carboxylic acid t-butyl ester (7.3 g) was dissolved in N,N-dimethylformamide (70 mL), and then N-chlorosuccinimide (2.9 g) was added to this solution. The reaction solution was stirred at room temperature for 23 hours. Water (260 mL) was added to the reaction solution, and this was stirred at room temperature for one hour. A white precipitate was then collected by filtration. The white solid obtained was washed with water and hexane to give the title compound (8.6 g).
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[N:29]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:28]=[N:27][N:26]=2)=[CH:15][CH:14]=1>>[CH2:1]([C:4]1[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[N:29]([C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:28]=[N:27][N:26]=3)=[CH:17][CH:18]=2)[C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C=O)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCc1ccc(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 78 %

Procedure:
This compound was prepared using the same procedure as in Example 1. 3.9 g of 5-n-propyl-2-pyrrolaldehyde (0.031 moles) and 15 g of 4′-bromomethyl-2-(1-triphenylmethyltetrazol-5-yl)-biphenyl (0.031 moles) yield 15 g of product which are used in the subsequent step. Formula: C41H35N5O (m.w. 613.76). Yield 78%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18]N)=O)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[N:8]=[C:16]([C:15]3[CH:20]=[CH:21][C:12]([F:11])=[CH:13][CH:14]=3)[NH:18][N:7]=2)=[CH:4][CH:3]=1
Reactant: N=C(N)c1ccc(F)cc1
Reactant: NNC(=O)c1ccc(F)cc1
Product: Fc1ccc(-c2n[nH]c(-c3ccc(F)cc3)n2)cc1
Yield: 71.2 %

Procedure:
4 g 4-fluoro-benzamidine was added to 4.5 g 4-fluoro-benzoic acid hydrazide and this mixture was melted. This mixture was crystallized with ethyl acetate to give 5.3 g of the desired compound. Rt: 1.55 min (method A), (M+H)+: 258
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[CH3:22][S:23]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.8 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.0 g, 36 mmol) and triethyl amine (6.0 ml, 43 mmol) in 50 ml of THF at 0° C. under an atmosphere of nitrogen was added MsCl (3.4 ml, 43 mmol). The mixture was stirred at 0° C. for 3 h and quenched with aqueous sodium hydrogen carbonate (saturated, 100 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with brine (1×100 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40M, eluting with EtOAc/isohexane to hexanes to afford the title compound as a colorless solid (4.2 g, 42%). 1H-NMR (500 MHz, CDCl3) δ 4.90 (s, 1H), 3.70 (m, 2H), 3.30 (m, 2H), 3.05 (s, 3H), 1.95 (m, 2H), 1.82 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH:20][C:21]1C=C2C(C(C3C=CC=CC=3)CC2=O)=C[CH:22]=1>>[C:21]([O:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)[CH2:10][C:11]2=[O:19])(=[O:20])[CH3:22]
Reactant: O=C1CC(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: O=C1CC(c2ccccc2)c2ccc(O)cc21
Product: CC(=O)Oc1ccc2c(c1)C(=O)CC2c1cc(F)cc(F)c1
Reaction time: 2 h
Yield: 83 %

Procedure:
The procedure of Step 3 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-2,3-dihydro-6-hydroxyinden-1-one obtained in Step 2 as a starting material instead of 2,3-dihydro-6-hydroxy-3-phenylinden-1-one and being stirred for 2 h to obtain the title compound (83%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]2[CH2:19][CH2:18][CH:17]([C:20](N)=[O:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1.[OH-:23].[K+].O.Cl>C(O)CO>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:21])=[O:23])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1
Reactant: [OH-]
Reactant: NC(=O)C1CCC([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Agent: Cl
Agent: [K+]
Solvent: OCCO
Solvent: O
Product: O=C(O)[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Temperature: 180 °C

Procedure:
42 g of crude 4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanecarboxamide were suspended in 500 ml of ethylene glycol while gassing with argon and then treated with 19 g of solid potassium hydroxide. The mixture was heated to 180° C. (bath temperature) for 5 hours while stirring. After cooling the reaction mixture was poured into 500 ml of water, acidified to pH about 3 with 10 percent hydrochloric acid and extracted three times with 300 ml of methylene chloride each time. The combined organic phases were washed once with 500 ml of 1 percent hydrochloric acid and twice with 500 ml of water each time, dried over magnesium sulfate, filtered and evaporated. The dark brown crude product (41 g) was purified by chromatography on silica gel with ethyl acetate. Crystallization of the product obtained (36 g) from acetone gave 13.8 g of pure trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanecarboxylic acid. Working-up of the mother liquor gave a further 2.5 g of pure product.
Reaction SMILES: [CH:1]1([C:7]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:8])CCCC[CH2:2]1.N1C2C(=CC(S(N)(=O)=O)=CC=2)CC1.[Cl:35]CCC(Cl)=O>>[Cl:35][CH2:2][CH2:1][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:8]
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)C1CCCCC1
Reactant: O=C(Cl)CCCl
Agent: NS(=O)(=O)c1ccc2c(c1)CCN2
Product: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)CCCl
Yield: 98 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 55, indoline-5-sulfonamide (Intermediate 54A, 300 mg, 1.51 mmol) and 3-chloropropanoyl chloride (189 μL, 1.97 mmol) were converted to the title compound (430 mg, 98%). 1H NMR (DMSO-d6) δ 8.16 (d, J=8.1 Hz, 1H), 7.66-7.63 (m, 2H), 7.22 (s, 2H), 4.18 (t, J=8.6 Hz, 2H), 3.89-3.86 (m, 2H), 3.21 (t, J=8.5 Hz, 2H), 3.03 (t, J=6.4 Hz, 2H); MS (ESI+) m/z 289.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:37](Cl)(=[O:39])[CH3:38]>C1COCC1>[C:37]([NH:30][S:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:8]([CH2:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:34][CH:33]=2)[CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[CH:28][CH:27]=1)(=[O:32])=[O:31])(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N(CCc2ccc(Br)cc2)Cc2ccc(S(N)(=O)=O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccc(CN(CCc2ccc(Br)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
tert-Butyl 4-((4-bromophenethyl)(4-sulfamoylbenzyl)amino)piperidine-1-carboxylate (see Example 15, step 1) was dissolved in anhydrous THF (5 mL/mmol) under atmosphere of argon and the solution was cooled to 0° C. Sodium hydride (2 equiv) was then added in one portion and after 10 minutes acetyl chloride (2 equiv) was added dropwise by syringe over 10 minutes. The cooling batch was removed and the reaction mixture was allowed to stir for two days after which time the starting material could no longer be detected. The reaction mixture was then diluted with EtOAc (12 mL/mmol of starting material), washed with 1 M NaOH (2×), water (2×) and brine (2×) and dried over anhydrous MgSO4. After filtration of the drying agent the solvent was stripped off and the crude product was purified by column chromatography (yield 65%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)=[CH:10][CH:9]=1.Cl.[CH2:20]([NH2:22])[CH3:21].O>C(Cl)Cl>[CH2:20]([NH:22][C:15](=[O:17])[CH:14]([C:11]1[CH:10]=[CH:9][C:8]([Br:7])=[CH:13][CH:12]=1)[CH3:18])[CH3:21]
Reactant: CCN
Reactant: CC(C(=O)O)c1ccc(Br)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)C(C)c1ccc(Br)cc1
Reaction time: 2 h

Procedure:
16.6 g (130 mmol) oxalyl chloride are added to 15.0 g (65 mmol) 2-(4-bromo-phenyl)-propionic acid (Bioorg. Med. Chem. Lett. 2010, 20, 887) in 75 mL DCM at 0° C. The cooling is removed and the mixture is stirred for 2 h under reflux. After that time, the solvent is evaporated and the residue is taken up in 70 mL THF. 3.20 g (39 mmol) ethylamine hydrochloride and 66.0 g (655 mmol) TEA are added and the mixture is stirred for 16 h at rt. After that time, iced water is added, the mixture is extracted with EtOAc and the organic layer is dried over sodium sulphate. The solvent is evaporated and the residue is purified by column chromatography (silica gel).