Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Mg].[C:13]([CH:15]1[CH2:17][CH:16]1[C:18](N(OC)C)=[O:19])#[N:14].[Cl-].[NH4+]>BrC(Br)C.C(OCC)C.C1COCC1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:18]([CH:16]2[CH2:17][CH:15]2[C:13]#[N:14])=[O:19])=[CH:3][CH:4]=1
Reactant: CON(C)C(=O)C1CC1C#N
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CC1CC1C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, a few drops of dibromoethane and a solution of 4.00 g (14.7 mmol) of 1-iodo-4-(trifluoromethyl)benzene in 10 ml of dry diethyl ether were added to 375 mg (15.4 mmol) of magnesium in 40 ml of dry diethyl ether, and the mixture was heated under reflux for 2 h. After cooling, the supernatant reaction solution was added dropwise under argon to 2.00 g (13.0 mmol) of the compound from Example 73A in 50 ml of THF, and the mixture was stirred at RT overnight. The reaction solution was then added to saturated aqueous ammonium chloride solution, the phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. Purification of the residue by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) resulted in 1.42 g (46% of theory) of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:8]([F:10])([F:9])[C:7]([F:12])([F:11])[C:6]=1Cl)([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl-].[Ca+2].[Cl-]>[C].[Pd].CCOCC>[CH:1]([O:4][CH:5]1[CH2:6][C:7]([F:11])([F:12])[C:8]1([F:9])[F:10])([CH3:3])[CH3:2]
Reactant: CC(C)OC1=C(Cl)C(F)(F)C1(F)F
Agent: [Pd]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)OC1CC(F)(F)C1(F)F

Procedure:
To 40 g of 10% strength palladium-carbon under nitrogen a solution of 274 g (1.26 mol) of 2-chloro-3,3,4,4-tetrafluorocyclobutenyl isopropyl ether, 252 g (2.50 mol) of triethylamine, and 1200 ml of ether dried over calcium chloride is added, and the mixture is hydrogenated in a 3 l VA autoclave at 100° C. until the pressure is constant (about 5 hours). The solid is filtered off with suction and washed well with ether, and the filtrate is washed with dilute hydrochloric acid. After drying, the organic phase is distilled.
Reaction SMILES: [CH3:1][CH:2]([CH2:17]S(C1C=CC=CC=1)(=O)=O)[CH2:3][CH:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O.[OH-].[K+].O.CS(C)=O>C1(C)C=CC=CC=1>[CH3:17][CH:2]1[CH2:3][C:4]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=2)=[CH:1]1
Reactant: CC(CC1CCCCCCCCCCC1=O)CS(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1C=C2CCCCCCCCCC=C2C1
Yield: 85.6 %

Procedure:
11.35 g (0.03 mole) of 2-(2-methyl-3-phenylsulfonyl-prop-1-yl)-cyclododecanone and 11.0 g (0.197 mole) of powdered KOH in 30 ml of toluene were first heated to reflux during 30 min., in a reaction vessel fitted with a water separator. After addition of 6 ml of DMSO, the reaction mixture was further heated at 110°, for 12 hours. After the treatments of extraction, washing, drying and distillation (0.05 Torr--bath temperature: 150°) described in Example 1, there were isolated 5.61 g (86% yield) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:22][C@@H:23]1[C@@H:30]2[C@@H:26]([O:27][C:28]([CH3:32])([CH3:31])[O:29]2)[C@H:25]([N:33]2[C:37]3[N:38]=[CH:39][N:40]=[C:41]([NH:42][CH2:43][C:44]4[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][C:45]=4[O:52][CH3:53])[C:36]=3[CH:35]=[CH:34]2)[O:24]1)[CH:19]([CH3:21])[CH3:20]>C(O)(=O)C>[C:8]([C:6]1[CH:5]=[CH:4][C:3]2[NH:12][C:13]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:22][C@@H:23]3[C@H:30]4[O:29][C:28]([CH3:31])([CH3:32])[O:27][C@H:26]4[C@H:25]([N:33]4[C:37]5[N:38]=[CH:39][N:40]=[C:41]([NH:42][CH2:43][C:44]6[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][C:45]=6[O:52][CH3:53])[C:36]=5[CH:35]=[CH:34]4)[O:24]3)[CH:19]([CH3:21])[CH3:20])=[N:1][C:2]=2[CH:7]=1)([CH3:9])([CH3:11])[CH3:10]
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCCC(=O)Nc3ccc(C(C)(C)C)cc3N)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCCc3nc4cc(C(C)(C)C)ccc4[nH]3)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 65 °C
Yield: 87.8 %

Procedure:
N-(2-amino-4-(tert-butyl)phenyl)-5-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)pentanamide (140 mg, mmol) was taken up in acetic acid (3.5 mL) and the solution was heated at 65° C. for 2 h, whereupon HPLC indicated the starting material had been consumed. The reaction mixture was cooled to room temperature and the solvent was removed under high vac. The residue was taken up in 30 mL CH2Cl2 and washed with 20 mL portions of sat NaHCO3 and 2% Na2CO3 solution. The organic phase was dried over Na2SO4, filtered and concentrated to yield a light tan glass/stiff foam. The crude material was purified by flash chromatography (25 g silica gel; 3% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (120 mg, 88%) as a slightly tan glass: MS (ESI+) for C41H55N7O5 m/z 726.5 (M+H)+; MS (ESI−) for C41H55N7O5 m/z 724.6 (M−H)−; HPLC purity 90% (ret. time, 3.14 min).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[C:19]2[C:10](=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][CH:7]=1.[C:20](Cl)(=[O:24])[C:21](Cl)=[O:22].Cl>C(=S)=S>[Cl:5][C:6]1[C:19]2[C:10]3[C:9]([C:20](=[O:24])[C:21](=[O:22])[C:11]=3[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=1
Reactant: Clc1cccc2cc3ccccc3cc12
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1C(=O)c2c3ccccc3cc3c(Cl)ccc1c23
Temperature: 0 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
Anhydrous aluminum chloride (3.5 g, 26.2 mmol) was added to a cold (0° C.) mixture of 1-chloroanthracene (3 g, 14.1 mmol) and oxalyl chloride (10 g, 78.8 mmol) in 30 ml of dry carbon disulfide. After stirring the reaction mixture under an argon atmosphere for two hours at 0° C., additional portions of anhydrous carbon disulfide (30 ml) and dry aluminum chloride (2.25 g, 18.7 mmol) were added. Stirring at 0° C. was continued for an additional two hours. Thereafter, an additional portion of anhydrous carbon disulfide (10 ml) was added, and stirring was continued overnight at room temperature. At the end of the reaction, the mixture was cooled to 0° C. and dilute hydrochloric acid was slowly added. An orange precipitate was collected, washed with water, and treated with 5% sodium hydroxide solution (150 ml). The insoluble solid was collected, washed with water, and air-dried. The crude material was purified by short-column filtration using silica gel and chloroform. Yield was 53%.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][CH2:29][CH:30]([PH:32](=[O:34])[OH:33])[CH3:31])=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1.[CH3:39][C:40]1([CH3:56])[C:44]([CH3:46])([CH3:45])[O:43][B:42]([C:47]2[CH:48]=[N:49][N:50]([CH2:52][CH2:53][CH2:54]O)[CH:51]=2)[O:41]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][CH2:29][CH:30]([PH:32](=[O:33])[O:34][CH2:54][CH2:53][CH2:52][N:50]4[CH:51]=[C:47]([B:42]5[O:43][C:44]([CH3:46])([CH3:45])[C:40]([CH3:39])([CH3:56])[O:41]5)[CH:48]=[N:49]4)[CH3:31])=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC(C)[PH](=O)O)cc2OC)ncc1C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC(C)[PH](=O)OCCCn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A suspension of (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)propan-2-ylphosphinic acid (Compound 68B, 0.240 g, 0.389 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E, 97.9 g, 0.388 mmol) in 1,2-dichloroethane (8.53 mL) and DIPEA (0.812 mL, 4.66 mmol) was charged with (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (1.21 g, 2.33 mmol). The reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with DCM (20 mL). The organic layer was washed with NaHCO3 (10 mL), washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a brown oil. The crude material was purified using a Teledyne ISCO Combiflash® Rf system using 1:1 DCM-EtOAc/MeOH (100:0→90:10) as eluent to afford the title compound as an off-white foam. MS (ESI): m/z 851.84/853.82 [M+H]+. UPLC: tR=1.57 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][C:3]=1[NH:15][C:16](=O)[CH2:17][CH2:18][C:19]1[NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]=1.O>C(O)(=O)C>[NH:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[CH2:18][CH2:17][C:16]1[NH:15][C:3]2=[CH:4][C:5]3[C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]([CH3:11])[C:9]=3[CH:10]=[C:2]2[N:1]=1
Reactant: CN1C(=O)C(C)(C)c2cc(NC(=O)CCc3nc4ccccc4[nH]3)c(N)cc21
Solvent: CC(=O)O
Solvent: O
Product: CN1C(=O)C(C)(C)c2cc3[nH]c(CCc4nc5ccccc5[nH]4)nc3cc21
Yield: 43.4 %

Procedure:
A solution of N-(6-amino-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-(1H-benzoimidazol-2-yl)-propionamide (218 mg) in acetic acid (6 ml) is heated under reflux for 3 h. After re-cooling, water is added and the mixture is extracted with EtOAc (3×30 ml). The combined organic layer is washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo to give the desired compound (90 mg).
Reaction SMILES: CN.O=C1C2C(=CC=CC=2)C(=O)[N:5]1[CH2:14][C:15]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([O:24][C:25]2[C:26]([CH3:34])=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][N:29]=[CH:28]3)[CH2:19]1)=[O:16].[ClH:35].CC1C(O[C@@H]2CCC[C@H](NCC(N)=O)C2)=CC=C2C=1C=NN2>>[ClH:35].[CH3:34][C:26]1[C:25]([O:24][C@@H:20]2[CH2:21][CH2:22][CH2:23][C@H:18]([NH:17][C:15](=[O:16])[CH2:14][NH2:5])[CH2:19]2)=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[N:29][NH:30]2
Reactant: Cc1c(O[C@@H]2CCC[C@H](NC(=O)CN3C(=O)c4ccccc4C3=O)C2)ccc2[nH]ncc12
Agent: CN
Agent: Cc1c(O[C@@H]2CCC[C@H](NCC(N)=O)C2)ccc2[nH]ncc12
Agent: Cl
Product: Cc1c(O[C@@H]2CCC[C@H](NC(=O)CN)C2)ccc2[nH]ncc12
Reaction time: 8 h

Procedure:
A 40% methylamine methanolic solution (5 mL) was added to the 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide (70 mg, 0.16 mmol) obtained in Example 825, and the resulting mixture was stirred overnight. The reaction solution was distilled under reduced pressure to remove the solvent and then the residue was purified by a silica gel chromatography. To a solution of the purified residue in 2-propanol was added a hydrochloric acid-diethyl ether solution, and stirred for 30 minutes. After the solvent was distilled off under reduced pressure, the residue was crystallized from 2-propanol-diisopropyl ether-diethyl ether to obtain N˜1˜(identification is required)-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}glycinamide monohydrochloride (39 mg, 79%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:6][C:5](=[O:7])[C:4]([O:8][CH:9]([CH3:14])[C:10](OC)=[O:11])=[C:3]1[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.[Li+].[BH4-]>C(Cl)Cl.CCOCC>[OH:11][CH2:10][CH:9]([CH3:14])[O:8][C:4]1[C:5](=[O:7])[O:6][C:2]([CH3:1])([CH3:25])[C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=1
Reactant: COC(=O)C(C)OC1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(CO)OC1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Temperature: 25 °C
Yield: 26.3 %

Procedure:
To the ester of Step 1 (1.13 g, 3.07 mmol) in CH2Cl2 (30 mL) and Et2O 50 mL was added at 0∞C. LiBH4 (80 mg, 3.68 mmol). The reaction mixture was stirred at room temperature until completion. The reaction mixture was partitioned between 25% NH4OAc and EtOAc. The organic phase was separated, dried over Na2SO4 and evaporated. The title compound (275 mg) was obtained as a white solid after purification by flash chromatography.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[CH3:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[NH:33][C:34]([C:36]2[N:40]3[CH:41]=[CH:42][C:43](F)=[CH:44][C:39]3=[N:38][CH:37]=2)=[O:35])[N:26]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=2)[N:25]=1>C(O)(C)(C)C>[CH3:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[NH:33][C:34]([C:36]2[N:40]3[CH:41]=[CH:42][C:43]([O:7][CH2:8][CH2:9][N:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[CH:44][C:39]3=[N:38][CH:37]=2)=[O:35])[N:26]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=2)[N:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(F)ccn45)cccc32)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C(=O)OC(C)(C)C)CC6)ccn45)cccc32)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A flask was charged with solid potassium tert-butoxide (0.07 g, 0.64 mmol), tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.17 g, 0.74 mmol), and tert-butanol (0.6 mL). The mixture was heated to 60° C. for 20 minutes before adding N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (0.045 g, 0.105 mmol) in one portion. The mixture was heated in a sand bath at 80° C. with stirring overnight. The reaction mixture was quenched with water and concentrated before purifying by reverse phase chromatography on a Biotage 25+C18 column, eluting with a gradient from 0-65% acetonitrile/water over 12 column volumes, to give tert-butyl 4-(2-(3-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridin-7-yloxy)ethyl)piperazine-1-carboxylate (40 mg) as a beige solid. MS (APCI), positive scan, m/z=639.1 (M+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[OH-].[Na+]>CO>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)=[O:3])=[CH:14][CH:13]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C=CC(=O)c2ccccn2)cc1
Reaction time: 14 h

Procedure:
7.4 g 2-acetylpyridine is added to a solution of 8.3 g 4-methoxybenzaldehyde in 100 ml methanol at 0° C. 100 ml of a 2 N sodium hydroxide solution is added with strong agitation. After 14 hours of agitation at room temperature, the yellow precipitate is filtered off, washed with 10 ml methanol and washed three times with 50 ml water, and dried in a vacuum.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:10]2=[N:11][O:12][N:13]=[C:9]2[C:8]=1[CH3:16])(=O)=O.[CH:19]([B-](F)(F)F)=[CH2:20].[K+]>CCO>[CH:19]([C:7]1[CH:15]=[CH:14][C:10]2=[N:11][O:12][N:13]=[C:9]2[C:8]=1[CH3:16])=[CH2:20]
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)ccc2nonc12
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCO
Product: C=Cc1ccc2nonc2c1C

Procedure:
The mixture of 4-methyl-2,1,3-benzoxadiazol-5-yl trifluoromethanesulfonate (3.90 g, 13.8 mmol), potassium vinyltrifluoroborate (2.22 g, 16.6 mmol) and Pd (dppf)2Cl2 (0.5 g) in 50 mL of EtOH and 15 mL of TEA was refluxed under Ar for 4 hours. Concentrated, the residue was purified by silica column chromatography (PE:EtOAc=20:1) to afford 5-ethenyl-4-methyl-2,1,3-benzoxadiazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]([NH2:9])[CH3:8].C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[CH3:43][C:31]1[N:30]([CH2:29][C:26]2[CH:27]=[CH:28][C:23]([C:18]3[C:17]([C:15]([OH:16])=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:24][CH:25]=2)[C:38]2[C:33]([C:32]=1[CH3:42])=[CH:34][C:35]([C:39](=[O:40])[NH:9][C@H:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:8])=[CH:36][CH:37]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1ccccn1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccccn3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(pyridin-2-yl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 504 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[N:5](COCCOC)[C:6]([C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:17]=[N:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)[CH:12]=[CH:11][N:10]=2)=[CH:7][N:8]=1)([CH3:3])[CH3:2].Cl>O1CCOCC1>[CH:1]([C:4]1[NH:5][C:6]([C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:17]=[N:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)[CH:12]=[CH:11][N:10]=2)=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: COCCOCn1c(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)cnc1C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1ncc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)[nH]1
Temperature: 50 °C
Yield: 99.3 %

Procedure:
A solution of 2-(2-isopropyl-1-((2-methoxyethoxy)methyl)-1H-imidazol-5-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (783 mg, 1.894 mmol) in dioxane (15 mL) was treated with 6N HCl (9.0 mL), heated at 50° C. for 16 h, then cooled to RT and evaporated to remove most of the organics. The aqueous residue was treated with EtOAc, made basic with 1N NaOH, the layers separated and the aqueous layer extracted with additional EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 2-(2-isopropyl-1H-imidazol-5-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (612 mg, 99%). 1H NMR (400 MHz, DMSO-d6): δ 12.01 (s, 1H), 8.58 (d, J=2.8 Hz, 1H), 8.47 (d, J=5.6 Hz, 1H), 8.41 (d, J=8.9 Hz, 1H), 7.95 (dd, J=8.9, 2.8 Hz, 1H), 7.61 (d, J=2.1 Hz, 1H), 7.45 (d, J=2.5 Hz, 1H), 6.97 (dd, J=5.4, 2.7 Hz, 1H), 2.95-2.94 (m, 1H), 1.23 (t, J=6.9 Hz, 6H); MS (ESI) m/z: 326.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(OC)cc2)C1
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)c2ccc(OC)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4′-fluoro-biphenyl-4-ol and 3-iodomethyl-1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 14) to afford the racemate as a white solid (162 mg, 73.2%)
Reaction SMILES: [CH2:1]([N:3]1[C:7]([F:8])=[C:6]([CH2:9]O)[C:5]([C:11]([F:14])([F:13])[F:12])=[N:4]1)[CH3:2].P(Br)(Br)[Br:16]>C(OCC)C>[Br:16][CH2:9][C:6]1[C:5]([C:11]([F:14])([F:13])[F:12])=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[F:8]
Reactant: CCn1nc(C(F)(F)F)c(CO)c1F
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CCn1nc(C(F)(F)F)c(CBr)c1F
Temperature: -10 °C
Reaction time: 8 h

Procedure:
A solution of 9.1 g (42.9 mmoles) of (1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolved in 100 ml of diethyl ether was cooled to −10° C. Thereto was added 12.2 g (45.0 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into ice water and extraction with diethyl ether was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain a crude product of 4-bromomethyl-1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Ca+2].[I:14](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[NH2:1][C:2]1[C:7]([I:14])=[N:6][C:5]([Cl:8])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(Cl)nc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.1 %

Procedure:
23.2 g (180.5 mM) of 5-amino-2-chloropyridine are mixed in 70 ml of dichloro-methane (DCM) and 180 ml of methanol, and 21.6 g (216 mM) of calcium carbonate and 75.3 g (226 mM) of benzyltrimethylammonium dichloroiodate are added. The reaction mixture is stirred at room temperature for 16 hours, and then filtered to remove the mineral salts. The filtrate is diluted with water and extracted with DCM. The organic phase obtained is washed with sodium chloride solution, and then with saturated sodium thiosulfate solution, dried over magnesium sulfate and concentrated under reduced pressure. An oil is obtained, which is purified by chromatography on silica gel, eluting with a cyclohexane/ethyl acetate mixture (80/20 and then 70/30; v/v). 13.9 g of the expected product are thus obtained in the form of an orange-colored solid (yield=30%).
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1[C:30]([O:50][CH3:51])=[C:31]([C:36]([CH2:39][S:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[OH:49])(=[O:42])=[O:41])=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33]>>[O:25]1[CH:26]=[CH:27][C:23]([C:29]2[C:30]([O:50][CH3:51])=[C:31]([C:36]([CH2:39][S:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[OH:49])(=[O:42])=[O:41])=[CH:37][CH:38]=2)[C:32]([O:34][CH3:35])=[O:33])=[CH:24]1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2O)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2O)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-6-(2-hydroxybenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 138).
Reaction SMILES: [OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([C:24]4[CH2:28][CH2:27][C:26](=[O:29])[CH:25]=4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1.C([SiH](CC)CC)C>[Pd]>[OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][C:26](=[O:29])[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(C4=CC(=O)CC4)ccc23)C1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Product: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(C4CCC(=O)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 126 using 6-chloro-2-(3-oxo-cyclopent-1-enyl)-quinoline-5-carboxylic acid (1-hydroxy-3-methylcyclo hexyl methyl)-amide, palladium on carbon and triethylsilane.