Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([CH2:13][C:14](Cl)=[O:15])=[N:9]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH:25]([C:28]1[N:29]=[C:30]([CH2:33][CH2:34][C:35]2[CH:51]=[CH:50][N:38]3[C:39](=[O:49])[CH:40]=[C:41]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[N:42]=[C:37]3[CH:36]=2)[S:31][CH:32]=1)([CH3:27])[CH3:26]>C(Cl)Cl>[CH:25]([C:28]1[N:29]=[C:30]([CH2:33][CH2:34][C:35]2[CH:51]=[CH:50][N:38]3[C:39](=[O:49])[C:40]([C:14](=[O:15])[CH2:13][C:10]4[N:11]=[N:12][N:8]([CH2:7][C:6]5[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[N:9]=4)=[C:41]([N:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)[N:42]=[C:37]3[CH:36]=2)[S:31][CH:32]=1)([CH3:27])[CH3:26]
Reactant: COc1ccc(Cn2nnc(CC(=O)Cl)n2)cc1
Reactant: CC(C)c1csc(CCc2ccn3c(=O)cc(N4CCOCC4)nc3c2)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Cn2nnc(CC(=O)c3c(N4CCOCC4)nc4cc(CCc5nc(C(C)C)cs5)ccn4c3=O)n2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 7.8 %

Procedure:
The 2-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]ethanoyl chloride (0.27 g, 1.05 mmol) obtained in (C) was dissolved in methylene chloride (3 ml), added dropwise with pyridine (170.2 μl, 2.10 mmol) under ice cooling, and added dropwise with a solution of 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4 H-pyrido-[1,2-a]pyrimidin-4-one (80.9 mg, 0.21 mmol) in methylene chloride (3 ml). The reaction solution was stirred at room temperature for 23 hours, then further added with a solution of 2-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]ethanoyl chloride (0.27 g, 1.05 mmol) in methylene chloride (2 ml) and pyridine (170.2 μl, 2.10 mmol) under ice cooling. Further, the reaction solution was added with the same amounts of the acid chloride and pyridine twice every 24 hours, and stirred at room temperature. The solvent was evaporated, and the residue was added with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by preparative TLC (hexane:ethyl acetate=1:1, v/v and chloroform:methanol=30:1, v/v) to obtain the title compound (10.1 mg, 7.8%) as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](Cl)=[O:20].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([NH:11][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)=[O:20])[CH:3]=1
Reactant: Nc1cc(Br)cc2[nH]ncc12
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(Br)cc2[nH]ncc12)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-bromo-1H-indazol-4-amine (available from Sinova, 100 mg, 0.47 mmol), 2-pyridinecarbonyl chloride hydrochloride (available from Apollo, 100 mg, 0.71 mmol), DIPEA (0.164 ml) in DCM (10 ml) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. Purification by Mass Directed Automated Preparative HPLC (Method B) gave after evaporation of solvents the title compound (38 mg) as a white solid. LCMS (Method B) Rt=0.97 mins, MH+=318.
Reaction SMILES: [OH:1][N:2]=[C:3]([Br:5])Br.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[CH:7]=[CH2:8].O>CN(C=O)C>[Br:5][C:3]1[CH2:8][CH:7]([C:6]([O:10][CH2:11][CH3:12])=[O:9])[O:1][N:2]=1
Reactant: C=CC(=O)OCC
Reactant: ON=C(Br)Br
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC(Br)=NO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a vigorously stirred mixture of hydroxycarbonimidic dibromide (15.5 g, 76.4 mmol) and ethyl acrylate (15.3 g, 153 mmol) in DMF (200 mL) was added a solution of 15 wt % aqueous KHCO3 (102 mL, 153 mmol). The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted twice with methyl tert-butyl ether. The combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH:9]=[C:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:13]([N:16]1[C:24]2[C:19](=[CH:20][C:21](O)=[C:22]([Br:25])[CH:23]=2)[CH2:18][CH2:17]1)(=[O:15])[CH3:14]>>[C:13]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:12][CH2:11][C:8]3[CH2:9][CH2:10][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH:7]=3)=[C:22]([Br:25])[CH:23]=2)[CH2:18][CH2:17]1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Reactant: CC(C)(C)N1CC=C(CO)CC1
Product: CC(=O)N1CCc2cc(OCC3=CCN(C(C)(C)C)CC3)c(Br)cc21

Procedure:
The title compound was prepared from 1-tert-butyl-1,2,3,6-tetrahydropyridine-4-methanol (D58) and 1-acetyl-6-bromo-2,3-dihydroindol-5-ol (Tetrahedron, 1973, 29 (8), 1115) using the method outlined in Description 8a in WO 96/19477 (68%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.I.[NH2:37][C:38]1[C:39]([C:46]([NH:48][C:49](=[NH:52])SC)=[O:47])=[N:40][C:41]([Cl:45])=[C:42]([NH2:44])[N:43]=1>C(O)C>[C:23]([O:22][C:20]([NH:19][C@H:15]([CH2:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:49]([NH2:52])=[N:48][C:46]([C:39]2[C:38]([NH2:37])=[N:43][C:42]([NH2:44])=[C:41]([Cl:45])[N:40]=2)=[O:47])=[CH:7][CH:8]=1)[C:16]([OH:18])=[O:17])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)(C)OC(=O)N[C@H](CCCc1ccc(CCCCN)cc1)C(=O)O
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CCCc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1)C(=O)O
Temperature: 65 °C
Yield: 74.7 %

Procedure:
The compound 280 (0.077 g, 0.211 mmol) was mixed with ethanol (5 mL). The mixture was heated at 65° C. for 15 min to achieve complete dissolution. To the clear solution were sequentially added diisopropylethylamine (0.184 mL, 1.056 mmol) and 1-(3,5-diamino-6-chloropyrazinoyl)-2-methylisothiourea hydriodide (0.99 g, 0.254 mmol). The mixture was heated at 65° C. for an additional three hours. It was then concentrated under vacuum. The residue was chromatographed over silica gel, eluting with a mixture of concentrated ammonium hydroxide (0-2.2%), methanol (0-22%) and dichloromethane (100-75.8%) to afford the product 290 (0.091 g, 75%) as a yellow solid. 1H NMR (300 MHz, CD6OD): δ 1.44 (s, 9H), 1.58-1.84 (m, 8H), 2.54-2.68 (m, 4H), 3.34-3.42 (m, 2H), 4.02 (m, 1H), 7.08 (s, 4H). m/z (APCI) 577 [C26H37ClN8O5+H]+.
Reaction SMILES: [Mg].II.Br[CH2:5][CH:6]([CH3:8])[CH3:7].[C:9]([OH:12])(=[O:11])[CH3:10].[C:13]([OH:16])(=[O:15])[CH3:14].[C:17]([OH:20])(=[O:19])[CH3:18].[C:21]([OH:24])(=[O:23])[CH3:22].Br[C@@:26]1([O:35][C@H:34]([CH2:36][OH:37])[C@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]1[OH:29])[OH:27]>C(OCC)C.CC(O)=O.O>[C:9]([OH:12])(=[O:11])[CH3:10].[C:13]([OH:16])(=[O:15])[CH3:14].[C:17]([OH:20])(=[O:19])[CH3:18].[C:21]([OH:24])(=[O:23])[CH3:22].[CH2:5]([C@:26]1([O:35][C@H:34]([CH2:36][OH:37])[C@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]1[OH:29])[OH:27])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CBr
Reactant: OC[C@H]1O[C@@](O)(Br)[C@H](O)[C@@H](O)[C@H]1O
Agent: II
Agent: [Mg]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: CC(C)C[C@@]1(O)O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 69 %

Procedure:
Magnesium turnings (4.2 g) were suspended in diethyl ether (45 mL) and then initiated with a crystal of I2. 1-Bromo-2-methylpropane (1.37 mL, 12 mmol) was then added to the magnesium suspension. The mixture turned a cloudy white after the flask was heated with α heat gun. A solution of 1-bromo-α-D-galactose tetraacetate 4 (4.307 g, 10.5 mmol) in diethyl ether (10 mL) was added dropwise into the Grignard reaction mixture. The reaction went to completion after the mixture was heated at reflux for 4 h. The mixture was slowly poured into water (300 mL). Glacial AcOH (11 mL) was added. The mixture was separated and the aqueous layer was concentrated. The residue was treated with acetic anhydride (150 ML) and pyridine (150 mL) overnight. The resulting mixture was diluted with water (300 mL), extracted with diethyl ether (3×250 mL), washed with water (2×150 mL), and dried with magnesium sulfate. The solvent was removed under reduced pressure. The product was purified by flash chromatography (silica gel, 2:3 ethyl acetate/hexane) to afford 5 as a white solid (2.80 g, 7.24 mmol, 69%).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:40]([OH:42])=O)([N:34](C)[C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[C:47](N1C=CN=C1)(N1C=CN=C1)=O.[CH3:59][C:60]1([S:63]([NH2:66])(=[O:65])=[O:64])[CH2:62][CH2:61]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:47])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:40]([NH:66][S:63]([C:60]6([CH3:59])[CH2:62][CH2:61]6)(=[O:65])=[O:64])=[O:42])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NCCCCC=CC5CC5(C(=O)O)N(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6(C)CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Temperature: 25 °C
Yield: 58 %

Procedure:
A solution of carboxylic acid 46 (240 mg, 0.38 mmol) and carbonyldiimidazole (2 eq) in dry THF (5 mL) was stirred at reflux under nitrogen for 2 h. The reaction mixture was cooled to room temperature and 1-methylcyclopropylsulfonamide (2 eq) and DBU (2 eq) were added. This solution was heated at 50° C. for 15 h. Then, the reaction mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and HCl 1N, the organic layer was washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2Cl2) afforded 170 mg (58%) of the title compound 48 as an off-white solid which was further washed with water, then isopropylether, and dried in the vacuum oven: m/z=764 (M+H)+. 1H NMR (acetone-d6): 0.86 (m, 2H), 1.15-1.78 (m, 19H), 1.87 (m, 2H), 2.13-2.54 (m, 3H), 2.57-2.71 (m, 4H), 2.96-3.25 (m, 4H), 3.54 (m, 2H), 4.02 (s, 3H), 4.58 (t, J=13 Hz, 1H), 5.04 (m, 1H), 5.46 (m, 1H), 5.62 (m, 1H), 7.31 (s, 1H), 7.43 (d, J=9 Hz, 1H), 7.58 (s, 1H), 8.07 (d, J=13 Hz, 1H), 8.19 (broad s, 1H), 11.44 (broad s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15](B4OC(C)(C)C(C)(C)O4)[CH:16]=[C:11]3[CH:10]=[CH:9]2)=[CH:5][CH:4]=1.Br[C:29]1[CH:42]=[CH:41][C:32]([CH2:33][N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)Cl.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>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:42]4[CH:29]=[CH:30][CH:31]=[C:32]([CH2:33][N:34]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]5)[CH:41]=4)[CH:16]=[C:11]3[CH:10]=[CH:9]2)=[CH:26][CH:27]=1
Reactant: COc1ccc(Cn2ccc3cc(B4OC(C)(C)C(C)(C)O4)cnc32)cc1
Reactant: CN1CCN(Cc2ccc(Br)cc2)CC1
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: [Cs+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccc(Cn2ccc3cc(-c4cccc(CN5CCN(C)CC5)c4)cnc32)cc1
Temperature: 90 °C

Procedure:
A stirred solution of 1-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (147PG) (50 mg, 0.137 mmol) and 1-(4-bromobenzyl)-4-methylpiperazine (121) (37 mg, 0.137 mmol, 1.1 eq) in DME (10 mL) was degassed and purged with N2 for 10 min and Cs2CO3 (2.0 eq) was added and the reaction mixture purged and degassed again. To this reaction mixture was added Pd(PPh3)4 (0.04 eq) and the resulting reaction was heated at 90° C. for 12 hrs in sealed tube condition. After completion of the reaction the contents were was cooled and diluted with CH2Cl2 and filtered through Celite bed. The CH2Cl2 layer was completely distilled off to get the crude product. The crude was passed through 100-200 mesh silica gel, eluting the pure compound 1-(4-methoxybenzyl)-5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine 151 obtained with 5% MeOH in CH2Cl2 as an off-white coloured solid in 30 mg quantity.
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[C:36]1[CH:41]=[C:40]([CH:42]([CH3:44])[CH3:43])[CH:39]=[CH:38][C:37]=1[O:45][CH3:46])[C:8]1[N:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[O:15])=[CH:10][N:9]=1.[OH-].[Na+].Cl>C(O)C>[F:55][C:2]([F:1])([F:54])[C:3]1[CH:4]=[C:5]([CH:47]=[C:48]([C:50]([F:51])([F:52])[F:53])[CH:49]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[C:36]1[CH:41]=[C:40]([CH:42]([CH3:44])[CH3:43])[CH:39]=[CH:38][C:37]=1[O:45][CH3:46])[C:8]1[N:9]=[CH:10][C:11]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:15])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCNC(=O)c1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(C(=O)NCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
Ethyl 4-({2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidine-5-carbonyl}-amino)-butyrate (230 mg) is dissolved in ethanol (5 ml) and thereto is added a 2M-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 1 hour and a half. To reaction mixture is added a 2N-hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=25:1) to give 4-({2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidine-5-carbonyl}-amino)-butyric acid (220 mg). MS (m/z): 757 [M+H]+
Reaction SMILES: [CH3:1][C:2]([CH3:38])([CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[CH:20]=[N:19][C:18]([C:21]3[N:22](COCC[Si](C)(C)C)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=3)=[CH:17][N:16]=2)=[CH:10][N:9]=1)[C:3]([OH:5])=[O:4].CC(C)(COC1C=C(C)C(C2C=NC(C3N(COCC[Si](C)(C)C)C(C(F)(F)F)=CN=3)=CN=2)=CN=1)C(O)=O.C(O)(=O)C>FC(F)(F)C(O)=O.O>[CH3:1][C:2]([CH3:38])([CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[CH:20]=[N:19][C:18]([C:21]3[NH:25][C:24]([C:26]([F:28])([F:27])[F:29])=[CH:23][N:22]=3)=[CH:17][N:16]=2)=[CH:10][N:9]=1)[C:3]([OH:5])=[O:4]
Reactant: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1cnc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)cn1
Agent: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1cnc(-c2ncc(C(F)(F)F)n2COCC[Si](C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1cnc(-c2ncc(C(F)(F)F)[nH]2)cn1
Temperature: 25 °C

Procedure:
In trifluoroacetic acid (3.1 mL) and water (0.31 mL) was dissolved the mixture of 2,2-dimethyl-3-[(4-methyl-5-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]propanoic acid and 2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]-propanoic acid obtained in the above-mentioned 5), and the solution was stirred at room temperature. Acetic acid was added to the residue obtained by concentrating the solution under reduced pressure, and the resulting mixture was concentrated under reduced pressure. Isopropyl ether was added to the solid residue to pulverize the same, and the pulverized material was dried to obtain 2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]propanoic acid (197 mg).
Reaction SMILES: O[CH2:2][C:3]1[C:4]2[N:5]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Cl:19][CH2:2][C:3]1[C:4]2[N:5]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cn2cccc(CO)c2n1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn2cccc(CCl)c2n1
Yield: 90.5 %

Procedure:
The product from Example 20 (5.0 g, 23 mmol) was dissolved in CHCl3 (50 mL) and placed in a 100 mL flask. Thionylchloride (2.97 g, 25 mmol) was added dropwise to the reaction. The reaction was heated to reflux for 1 h. After cooling the reaction to room temperature, aq KHCO3 was added to the solution, and product was extracted with CHCl3. The organic extracts were dried (MgSO4), treated with activated charcoal, filtered and stripped in vacuo to leave the title compound as a tan solid (4.97 g, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.S(Cl)([Cl:18])=O>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][Cl:18])[CH:9]=2)=[N:6][CH:7]=1
Reactant: OCc1cccc(-c2ncc(Br)cn2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cccc(-c2ncc(Br)cn2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
80 g (302 mmol) of [3-(5-bromopyrimidin-2-yl)phenyl]methanol are suspended in 300 ml of dichloromethane, and 33 ml (453 mmol) of thionyl chloride are slowly added with cooling. The reaction mixture is stirred at room temperature for 3 h. The solvent is distilled off, co-evaporated 3 times with toluene and stirred with diethyl ether;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:5]2.[H-].[Na+].I[CH3:21].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:21])[C:6]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:5]2
Reactant: Fc1cc(Cl)cc2cc(-c3cccnc3)[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(-c2cccnc2)cc2cc(Cl)cc(F)c21
Reaction time: 0.5 h

Procedure:
To a solution of 5-chloro-7-fluoro-2-pyridin-3-yl-1H-indole (Example 86, 276 mg, 1.12 mmol) in DMF (4 mL) is added 60% sodium hydride in mineral oil (120 mg, 3.0 mmol) and the suspension is stirred for 30 min. Iodomethane (213 mg, 1.5 mmol) is then added to the reaction mixture and stirred at ambient temperature for 1 h. Water (2 mL) is added to quench the reaction. The mixture is filtered and purified by HPLC using Xbridge C18 with a gradient of acetonitrile in 0.1% NH4OH to afford 5-chloro-7-fluoro-1-methyl-2-pyridin-3-yl-1H-indole. MS (ESI) m/z 261 (M+H)+.
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[CH2:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([S:46]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:47])=[CH:42][C:41]=1[N+:54]([O-])=O)[CH3:38]>>[NH2:54][C:41]1[CH:42]=[C:43]([S:46]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:47])[CH:44]=[CH:45][C:40]=1[NH:39][CH2:37][CH3:38]
Reactant: CCNc1ccc(S(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: CCNc1ccc(S(=O)c2ccccc2)cc1N
Yield: 93 %

Procedure:
Following the procedure described in Example 40 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of (4-ethylamino-3-nitrophenyl)-phenyl sulfoxide, the title compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].CC(C)([O-])C.[K+].Cl[CH:21]([C:27]([CH3:29])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C=O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([O:13][CH:21]([C:27]([CH3:29])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: COc1cc(O)cc(OC)c1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1cc(OC)c(OC)c(OC)c1)C(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,4,5-Trimethoxyphenol (5,83 g) was dissolved in DMF (60 mL), and potassium tert-butoxide (3.55 g) was added to the solution under ice cooling. Ethyl 2-chloroaceto-acetate (4.46 mL) was then added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was heated to 80° C. and stirred for 2 hours. After allowing the reaction mixture to cool, water was added to the reaction mixture to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane 1:3) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16](OC)=[O:17])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][CH2:16][OH:17])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)CNc1ccn(-c2ccc(OC)cc2)n1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-n2ccc(NCCO)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-[N-glycyl]-1H-pyrazole-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)carboxyamide (0.14 g, 0.27 mmol) in tetrahydrofuran at -20° C. was added triethylamine (0.038 mL, 0.27 mmol) and ethyl chloroformate (0.026 mL, 0.27 mmol). This mixture was stirred for 30 min and then there was added sodium borohydride (20 mg, 0.54 mmol) in a minimal amount of water. The reaction mixture was stirred with slow warming to room temperature for 1 h and then was quenched with 10% aq HCl. After diluting with ethyl acetate, the organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford 35 mg (26%) of the title compound as a white powder. LRMS (ES+): 507.9 (M+H)+.
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12].C(OCC)(=O)C>CCCCCC>[CH3:4][NH:6][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CNC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a mixture of 40% aqueous solution of Methylamine hydrochloride (2.175 g, 33.2 mmol) and Triethyl amine (3.75 g, 37.18 mmol) at 0° C., added 4-Nitro-benzoyl chloride (4.6 g, 24.78 mmol) and stirred for 30 mins. The reaction was monitored by TLC (50% Ethyl acetate in Hexane). The solid precipitate so obtained was filtered, washed with ice cold water and dried to afford 4 g (89%) of N-Methyl-4-nitro-benzamide. 1H NMR: (DMSO-d6): δ 8.78 (s, 1H), 8.32 (d, 2H), 8.06 (d, 2H), 2.8 (s, 3H).