Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:28])[C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:16][CH:15]=2)[CH:8]=[CH:9][C:10]=1[CH3:11])[C:2]([NH2:4])=[NH:3].[CH3:29][NH:30][CH3:31]>C(O)CCC>[CH3:27][N:24]1[CH2:25][CH2:26][N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:7]3[CH:8]=[CH:9][C:10]([CH3:11])=[C:5]([NH:1][C:2]4[N:4]=[C:5]([C:10]5[CH:29]=[N:30][CH:31]=[CH:8][CH:9]=5)[CH:6]=[CH:7][N:3]=4)[CH:6]=3)=[O:28])=[CH:19][CH:18]=2)[CH2:22][CH2:23]1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1NC(=N)N
Reactant: CNC
Solvent: CCCCO
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
A suspension of N-(3-guanidino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide (30 g, 79 mmol) in n-butanol (150 ml) at 120° C. under an atmosphere of nitrogen is treated with 3-dimethylamino-1-pyridin-3-yl-propenone (15.3 g, 87 mmol). The resulting suspension is heated at 150° C. for 5 hrs. The reaction mixtures becomes a homogeneous deep orange solution and dimethylamine is removed by the distillation of n-butanol (130 ml). n-Butanol (20 ml) is added during the distillation. Butyl acetate (60 ml) is added dropwise at 100° C. and the solution is cooled to 0° C. within 1 hr and stirred at 0° C. for 16 hrs. The resulting deep orange suspension is filtered off with suction, the isolated solid is washed with n-butanol (2×50 ml) and water (2×50 ml) and dried in vacuo at 60° C. Yield: 36.4 g of the title compound, 93% based on theory, as off-white crystals. (99.6% area by HPLC).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:18][CH2:17][C@@H:16]2[CH2:19][C@H:13]1[C:14](=[O:27])[N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[BH4-].[Na+].[OH-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:18][CH2:17][C@@H:16]([NH:15][C:20](=[O:21])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:19][C@H:13]1[CH2:14][OH:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.2 %

Procedure:
A solution of (1R,2S,5R)-tert-butyl 2-(benzyloxycarbonylamino)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (2.0 g, 5.34 mmol) in tetrahydrofuran (40 mL) was treated with water (8 mL) and then with NaBH4 (1.01 g, 26.7 mmol). The mixture was stirred at rt for 5 h, then was treated with aqueous NaOH (1.0 M, 100 mL) and stirred for 60 min. The mixture was extracted four times with ethyl acetate. The combined extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated under vacuum. The residue was recrystallized from ethyl acetate-hexane to provide tert-butyl (1R,3R,4S)-4-benzyloxycarbonylamino-3-(hydroxymethyl)cyclohexylcarbamate as a white solid (1.438 g). MS found: (M+H)+=379.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:37])[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:22]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:37])[C:21]3[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)[CH:22]=3)[CH:15]=[CH:16][C:17]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1ccc(NC(=O)c2cc(N3CCOCC3)cc(C(F)(F)F)c2)cc1N
Product: Cc1ccc(NC(=O)c2cc(N3CCOCC3)cc(C(F)(F)F)c2)cc1NC(=O)c1ccc(Cl)nc1
Temperature: 100 °C
Yield: 63 %

Procedure:
Using an analogous procedure to that described in Example 2 except that the reaction mixture was heated to 100° C. for 2 hours, 6-chloropyridine-3-carbonyl chloride was reacted with N-(3-amino4-methylphenyl)-3-morpholino-5-trifluoromethylbenzamide. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulphate and evaporated. The residue was triturated under a mixture of isohexane and diethyl ether. There was thus obtained the title compound in 63% yield; NMR Spectrum: (DMSOd6): 2.2 (s, 3H), 3.3 (m, 4H) 3.75 (t, 4H), 7.25 (d, 1H), 7.35 (s, 1H), 755-7.65 (m, 1H), 7.65 (s, 1H), 7.7-7.75 (m, 2H), 7.8 (d, 1H), 8.35-8.4 (m, 1H), 8.95 (d, 1H), 10.15 (s, 1H), 10.33 (s, 1H); Mass Spectrum M+H+ 519 and 521.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:29][Mg]Br>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:18]([CH3:22])([CH3:21])[CH:19]([OH:20])[CH3:29])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C=O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Solvent: C1CCOC1
Product: CC(O)C(C)(C)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanal (from Ex 116(b), 25 mg, 0.067 mmol) in THF (1 ml) at 0° C. was added a solution of 1.4 M methylmagnesium bromide in 1 ml of THF (1.4 M) dropwise. After 1 hr, the reaction was quenched with sat. NH4Cl and was extracted with ethyl acetate. The organic phase was washed, dried over MgSO4, filtered, and concentrated to give 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-4-phenylbutan-2-ol as a white solid (24 mg, 92% yield). It is a mixture of diastereomers in a 1:1 ratio. 1H NMR (400 MHz, MeOD) δ ppm 8.20 (1 H, d, J=5.09 Hz) 7.96 (1 H, d, J=9.16 Hz) 7.68-7.75 (2 H, m) 7.59-7.67 (2 H, m) 7.53 (2 H, dd, J=7.63, 2.54 Hz) 7.23-7.35 (4 H, m) 7.14-7.20 (1 H, m) 4.40 (1 H, s) 3.50-3.60 (1 H, m) 1.10 (3 H, 2 singlets,) 1.05 (3 H, s) 0.99 (3 H, 2 singlets). LC/MS (m/z) 389.3 [(M+1)+]; HPLC Rt: 3.96 min.
Reaction SMILES: [O:1]=[C:2]([CH3:6])[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].O.[C:13](=[O:20])([S:17][CH2:18][CH3:19])[O:14][CH2:15]I>C(Cl)Cl>[C:13](=[O:20])([S:17][CH2:18][CH3:19])[O:14][CH2:15][O:4][C:3](=[O:5])[C:2](=[O:1])[CH3:6]
Reactant: CCSC(=O)OCI
Reactant: CC(=O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCSC(=O)OCOC(=O)C(C)=O

Procedure:
Redistilled 2-oxopropanoic acid (12.6 ml, 0.18 mol) is added to a vigorously stirred mixture of NaHCO3 (30.6 g, 0.36 mol), TBA HSO4 (61.2 g, 0.18 mol), H2O (360 mL), and CH2Cl2 (360 mL) in an open Erlenmeyer flask. Following stirring for 10 min 5b (44.0 g, 0.18 mol) in CH2Cl2 (400 mL) is added during 3 h at 25° C. together with CH2Cl2 (500 mL) in portions to compensate for the evaporation. In this way the formation of sulfurous by-products is minimized. The mixture is extracted with CH2Cl2 (300-200 mL). The combined organic phases are washed with H2O (2×200 mL); dried (MgSO4) and evaporated. The residue is triturated with Et2O (600 mL). After filtration the filtrate is treated with charcoal, evaporated, and the residue crystallized from pentane at -70° C. to yield 6ob, melting below room temperature.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:27])([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[NH2:21]>>[CH3:19][C:20]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]([F:18])([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[CH3:27]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Reactant: CC(C)(N)c1ncco1
Product: CC(C)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)c1ncco1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113 d) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=370.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.[N+:23]([C:26]1[CH:32]=[C:31]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH:30]=[CH:29][C:27]=1[NH2:28])([O-:25])=[O:24]>O1CCCC1>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([NH:28][C:27]1[CH:29]=[CH:30][C:31]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])=[CH:32][C:26]=1[N+:23]([O-:25])=[O:24])=[O:5]
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1[N+](=O)[O-])C(F)(F)F
Temperature: 45 °C
Yield: 114.4 %

Procedure:
A mixture of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.00 g), 1,1'-carbonyldiimidazole (1.03 g) and dry tetrahydrofuran (25 mL) was heated, under N2, at 45° C. in an ultrasound bath for 0.5 hours. 2-Nitro-4-(phenylsulfonyl)aniline (1.75 g) was added, the mixture was heated at 45° C. for 18 hours, poured onto water (350 mL) and extracted with Et2O. The combined extracts were washed (brine), dried and evaporated to give an orange solid (3.01 g) that was purified by chromatographed, with chloroform as the eluent, to yield the title compound as a pale yellow solid (0.46 g); mp 191-192.5° C.; MS: m/z=419(M+1); NMR: 1.58 (s,3), 7.63-7.76 (m,3), 8.02-8.07 (d,3), 8.34 (dd,1, J=2.2, 8.6), 8.59 (s,1), 8.61 (d,1, J=2.3). Analysis for C16H13F3N2O6S: Calculated: C, 45.94; H, 3.13; N, 6.70; Found: C, 45.95; H, 3.19; N, 6.53.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:12][C:4]2[CH:5]=[C:6]([CH3:11])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OCc2ccc(F)cc2)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 3,5-dimethyl-4-nitrophenol (0.97 g, 5.79 mmol), 4-fluorobenzyl chloride (1.26 g, 8.69 mmol) and anhydrous potassium carbonate (1.24 g, 9.0 mmol) in 50 ml of acetone was stirred under reflux for 22 hours. TLC showed this reaction is complete. The reaction mixture was cooled to room temperature and filtered and washed with acetone. The filtrate was evaporated to dryness to give the crude product, which was used for next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=1)[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[N:22]2[CH2:27][CH2:26][N:25]([C@@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:29])[CH2:24][CH2:23]2)[C:13]1=[O:36])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][CH2:9][CH2:10][CH:11]([N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[N:22]2[CH2:27][CH2:26][N:25]([C@@H:28]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH3:29])[CH2:24][CH2:23]2)[C:13]1=[O:36])[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=1
Reactant: COc1ccc(C(CCCNC(=O)OC(C)(C)C)N2C(=O)c3cccc(N4CCN([C@H](C)c5ccccc5)CC4)c3C2=O)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(CCCN)N2C(=O)c3cccc(N4CCN([C@H](C)c5ccccc5)CC4)c3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.4 %

Procedure:
A 10-mL round bottom flask was charge with Compound 65 (0.15 g, 2.0 mmol) and dichloromethane (2.0 mL). Trifluoroacetic acid (0.5 mL) was added and the mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo to give Compound 66 (113 mg) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.63-7.69 (m, 1 H), 7.50-7.56 (m, 5H), 7.40-7.42 (m, 1 H), 7.26-7.29 (m, 1H), 7.13-7.18 (m, 1 H), 7.02-7.06 (m, 1 H), 6.88-6.92 (m, 1 H), 5.25 (q, J=7.0 Hz, 1 H), 4.47 (q, J=6.8 Hz, 1 H), 3.85 (s, 3 H), 3.80 (s, 3 H), 3.47-3.60 (m, 3 H), 3.32-3.36 (m, 4 H), 2.96-3.07 (m, 3 H), 2.54-2.67 (m, 1 H), 2.32-2.42 (m, 1 H), 1.80 (d, J=6.8 Hz, 3 H), and 1.64-1.69 (s, 2 H); MS (ES+) 543 (M+1).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:32])[CH2:7][N:8]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:11][CH:10]([N:28]=[N+]=[N-])[C:9]1=[O:31])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(Cl)Cl.[Pd]>[C:1]([NH:5][C:6](=[O:32])[CH2:7][N:8]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:11][CH:10]([NH2:28])[C:9]1=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1C1CC(N=[N+]=[N-])C(=O)N(CC(=O)NC(C)(C)C)C(c2ccccc2)C1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccccc1C1CC(N)C(=O)N(CC(=O)NC(C)(C)C)C(c2ccccc2)C1
Yield: 94.7 %

Procedure:
A solution of 13.7 grams (31.6 mmol) N-(t-Butyl)-2-oxo-3-azido-5-(2-methylphenyl)-7-phenyl-2,3,4,5,6,7-hexahydroazepin-1-yl ethanoic amide in 120 mL ethanol and 60 mL methylene chloride was hydrogenated at 42 p.s.i. in the presence of 3.9 grams 10% palladium-on-carbon for 36 hours. It was then filtered through celite with ethanol and methylene chloride, evaporated, and chromatographed on silica gel using 15% and 30% methanol in ethyl acetate as eluent to afford 12.2 grams (95%) of a foam.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])=[CH:5][CH:4]=1)#[CH:2].Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([CH:38]=1)[C:26]([N:28]=[S@@:29]([CH3:37])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[F:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([F:18])[C:11]=1[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:38]=2)[C:26]([N:28]=[S@@:29]([CH3:37])(=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[CH:8][CH:7]=1)=[O:19]
Reactant: C#Cc1ccc(NC(=O)c2c(F)cccc2F)cc1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(NC(=O)c3c(F)cccc3F)cc2)c1)c1ccccc1
Yield: 74.3 %

Procedure:
In a manner similar to that described in Example 449, N-(4-ethynyl-phenyl)-2,6-difluoro-benzamide (0.114 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (113 mg, 74%)
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH2:6]([S:8]([C:11]1[CH:40]=[CH:39][C:14]([O:15][C:16]2[C:17]([CH:31]([O:34][Si](C)(C)C)[C:32]#[N:33])=[CH:18][C:19]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[NH:21][C:20]=3[CH:30]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:7]>>[CH2:6]([S:8]([C:11]1[CH:40]=[CH:39][C:14]([O:15][C:16]2[C:17]([CH:31]([OH:34])[C:32]([NH2:33])=[O:2])=[CH:18][C:19]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[NH:21][C:20]=3[CH:30]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:7]
Reactant: O=S(=O)(O)O
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2C(C#N)O[Si](C)(C)C)cc1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2C(O)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
80% sulfuric acid (0.2 ml) was added to (6-(4-(ethylsulfonyl)phenoxy)-2-pyridin-2-yl-1H-benzimidazol-5-yl)((trimethylsilyl(oxy)acetonitrile (25 mg) obtained in Example 31 (step 1), and the reaction liquid was stirred at room temperature for 3 hours. The reaction mixture was purified through reversed-phase middle-pressure liquid chromatography (ODS-AS-360-CC (by YMC), mobile phase: water/acetonitrile/0.1% trifluoroacetic acid), and the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline water in that order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([C:11]([OH:13])=O)=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3].[CH2:14]([O:16][C:17]([CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CC[N:30](C(C)C)C(C)C.CC(O)C.C(Cl)Cl>C(Cl)Cl>[CH2:14]([O:16][C:17]([C:19]1([NH:30][C:11]([C:6]2[C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1Cc2ccccc2C1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCOc1cccnc1C(=O)O
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCOc1cccnc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Reaction time: 0.03 h
Yield: 99 %

Procedure:
A 40 mL reaction vial which contains a stirring bar is charged with 3-n-propoxypicolinic acid (397 mg, 2.19 mmol) and dry DCM (6 mL). Stirring is initiated. After 2 min, the HTBU (831 mg, 2.195 mmol) is added. After 5 min, the 2-amino)-indane-2-carboxylic acid ethyl ester (450 mg, 2.19 mmol is added followed by DIPEA (0.96 mL, 5.48 mmol). The reaction is allowed to stir at ambient temperature. After 20 days, analysis by tlc of the reaction mixture (silica, 5% iPrOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are transferred to a separatory funnel and diluted with EtOAc (50 mL). This is washed consecutively with dilute aqueous HCl (3%, 25 mL), saturated aqueous NaHCO3 (25 mL) and brine (25 mL), and dried over MgSO4, filtered and evaporated in vacuo to give 1.23 g of light orange solid. This material is dissolved in 10 mL of DCM. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAc in heptanes over 3 column volumes followed by a linear gradient to 60% EtOAc in heptanes over 10 column volumes. 17 mL fractions eluent are collected. Fractions 57 through 67 are combined and evaporated in vacuo by pumping to constant weight to give white solid (0.8 g, 99%).
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][CH:8]([Cl:13])[C:9]([F:12])([F:11])[F:10].[CH3:14][CH:15]([CH3:19])[CH:16]=[C:17]=[O:18].O1CCCC1>CN(C)C=O>[Br:7][C:8]([Cl:13])([C:9]([F:12])([F:11])[F:10])[CH:17]([OH:18])[CH:16]=[C:15]([CH3:19])[CH3:14]
Reactant: CC(C)C=C=O
Reactant: FC(F)(F)C(Cl)Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)=CC(O)C(Cl)(Br)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Sodium t-butoxide (1.39 g of a 42% solution in dry dimethyl formamide was added dropwise over a period of 5 minutes to a stirred mixture of 1-bromo-1-chloro-2,2,2-trifluoroethane (0.535 ml), 3-methylbut-1-en-1-al (0.538 ml) and dry tetrahydrofuran (10 ml) maintained at a temperature of -78° C. by external cooling under a nitrogen atmosphere. The mixture was then stirred for a further 40 minutes at the temperature after which the external cooling was removed and the reaction quenched by the dropwise addition of saturated aqueous ammonium chloride solution. The mixture was then partitioned between water and diisopropyl ether and the aqueous phase separated, washed with diisopropyl ether (3×25 ml), and the washings combined with the organic phase. The organic phase was washed with brine and dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure. After purification by a procedure similar to that set out in the previous Example there was obtained 5-bromo-5-chloro-4-hydroxy-2-methyl-6,6,6-trifluorohex-2-ene (1.39 g), identified by nuclear magnetic resonance and infra-red spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[Mg].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19][Cl:20])=[CH:14][CH:13]=1.[Cl-].[NH4+]>CCOCC.C1(C)C=CC=CC=1>[Cl:20][CH2:19][C:18]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)([OH:21])[CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1]
Reactant: ClCc1ccccc1Cl
Reactant: O=C(CCl)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: OC(CCl)(Cc1ccccc1Cl)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 949.5 %

Procedure:
5.0 g (0.031 mol) of 2-chlorobenzyl chloride are added within 5 minutes at from 24° to 36° C. to 9.7 g (0.404 mol) of magnesium turnings in 20 ml of absolute ether. After the reaction has commenced, a solution of 200 ml of absolute ether and 50.2 g (0.31 mol) of 2-chlorobenzyl chloride is added dropwise. The mixture is subsequently refluxed for about a further 10 minutes, the excess magnesium is decanted off under nitrogen, and the Grignard solution is cooled to 0° C. 55.7 g (0.3 mol) of para-chloro-ω-chloroacetophenone dissolved in 350 ml of toluene are then added dropwise, and the reaction mixture is stirred at 0° C. for 1.5 hours and added dropwise at from about 2° to 6° C. to 1.5 l of concentrated ammonium chloride solution. Extraction with methyl tert.-butyl ether and subsequent conventional work-up gives 92.9 g (yield 99%, purity according to HPLC: 68.2%) of 1-chloro-2-(4-chlorophenyl)-3-(2-chlorophenyl)propan-2-ol as a crude oil, which can be further reacted directly. For characterization, the product was recrystallized from n-hexane.
Reaction SMILES: [CH3:1][C:2]1(C)[CH2:9][CH:8]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:7][CH2:6][O:5][C:3]1=O.[CH3:23][O-:24].[Na+].[CH3:26][OH:27]>>[CH3:1][C:2]([CH3:3])([CH2:9][CH:8]([CH2:7][CH2:6][OH:5])[CH2:10][CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17])[C:23]([O:27][CH3:26])=[O:24]
Reactant: CC1(C)CC(CCCCO[Si](C)(C)C(C)(C)C)CCOC1=O
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: COC(=O)C(C)(C)CC(CCO)CCCCO[Si](C)(C)C(C)(C)C
Reaction time: 2.5 h

Procedure:
To a solution of 2.35 g (7.2 mmol) of 2,2-dimethyl-4-(4-t-butyldimethylsilyloxybutyl)epsilon-caprolactone in 22 ml methanol is added 0.386 g (7.2 mmol) sodium methoxide and the mixture is stirred for 2.5 h. The reaction is quenched with saturated aqueous ammonium chloride and extracted twice with methylene chloride. The combined organic extracts are washed with water and brine, dried, filtered and evaporated to yield methyl 2,2-dimethyl-4-(2-hydroxyethyl)-8-(t-butyldimethylsilyloxy)-octanoate as an oil; NMR (CDCl3): delta 3.67 (s,3H), 3.55-3.65 (m,4H), 1.18 (s,6H), 0.89 (s,9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Cl:15][CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1.O.Cl.[Cl-].[Na+].O>[Cl:15][CH2:16][CH2:17][CH2:18][S:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)(=[O:21])=[O:20]
Reactant: COC(=O)C(OC)c1ccc(N)cc1
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C(OC)c1ccc(NS(=O)(=O)CCCCl)cc1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-2-methoxyacetate (0.6 g, 3.07 mmol) in anhydrous pyridine (6 mL) under argon was added 3-chloropropane-1-sulfonyl chloride (0.5 mL, 4.11 mmol) dropwise. The exothermic reaction was cooled briefly over a cold H2O bath. After stirring for 1 hr, the reaction was diluted with H2O, 1 M HCl and brine and extracted with EtOAc. The combined organics were washed with 1 M HCl, H2O and brine then dried over Na2SO4 and concentrated in vacuo to give methyl 2-(4-(3-chloropropylsulfonamido)phenyl)-2-methoxyacetate as an orange oil (1.03 g, quant. yield). The product was used without further purification.