Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](N)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[N:6]2[CH3:12].[I:20]CI.N(OCCC(C)C)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]([I:20])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[N:6]2[CH3:12]
Reactant: Cn1c(-c2cccc(F)c2)nc2c(Cl)nc(N)nc21
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(-c2cccc(F)c2)nc2c(Cl)nc(I)nc21
Yield: 75 %

Procedure:
6-Chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl-amine (960 g) was dissolved in 9.6 liters of tetrahydrofuran and then 774.3 g of cuprous iodide and 1.49 liters of diiodomethane were added thereto. Isoamyl nitrite (1.49 liters) was added dropwise during 1 hour into the mixture with heating under reflux. The reaction solution was heated under reflux for 15 minutes, cooled, diluted with 4 liters of ethyl acetate and then filtered through Celite followed by washing with ethyl acetate three times (3×2 liters). The filtrate and the washings were combined and washed with 8 liters of water and 8 liters of brine. The organic layer was dried over 2 kg of anhydrous sodium sulfate and concentrated to about 3 liters. The concentrated solution was diluted with 10 liters of hexane and the resulting crystals were filtered and washed with 1 liter of hexane. The crystals were then dried at 50° C. for 4 hours to give 1076 g of 6-chloro-8-(3-fluorophenyl)-2-iodo-9-methyl-9H-purine. The yield was 75%.
Reaction SMILES: [CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C@@H:10]([OH:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]3)=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:7]=2[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[O:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])(=O)=O.Cl>C1(C)C=CC=CC=1>[Si:52]([O:18][C@@H:10]1[C:9]2[C:14](=[CH:15][C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[C:7]([C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=3)=[O:27])[C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:13][C:12]([CH3:16])([CH3:17])[CH2:11]1)([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]
Reactant: CC1(C)C[C@H](O)c2c(cc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)cc2)O1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: CC1(C)C[C@H](O[Si](C)(C)C(C)(C)C)c2c(cc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)cc2)O1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
Under argon, 200 mg (0.39 mmol) of [(4S)-7-cyclopentyl-5-(4-fluorophenyl)-4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl][4-(trifluoromethyl)phenyl]methanone (Example 12A) and 180 μl (1.56 mmol) of 2,6-dimethylpyridine are dissolved in 1.25 ml of toluene and cooled to −20° C. A solution of 0.18 ml (0.78 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate in 1.25 ml of toluene is added dropwise, and the mixture is stirred at −20° C. for 15 min, then warmed to 0° C. and stirred for 1 hour. Another 18 μl (0.078 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate are added, and stirring is continued for another 1.5 h. 5 ml of 0.1 N hydrochloric acid are added, and the mixture is extracted repeatedly with ethyl acetate. The organic phases are washed with a 1:1 mixture of saturated sodium bicarbonate solution and saturated sodium chloride solution and with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 15:1). This gives 227 mg (93% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[O:20]1[CH2:22][C@H:21]1[CH2:23][O:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2>CO.CS(C)=O>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]3[CH2:13][CH2:14][N:15]([CH2:22][C@H:21]([OH:20])[CH2:23][O:24][C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)[CH2:16][CH2:17]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: FC(F)(F)c1ccc2c(C3CCNCC3)c[nH]c2c1
Solvent: CO
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3cc(C(F)(F)F)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-trifluoromethyl-3-(piperidin-4-yl)-1H-indole (0.50 g, 1.9 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.35 g, 1.9 mmol). The product was isolated as a white foam. Yield 250 mg (29%). mp 100-105° C. FDMS m/e=457 (M+ of free base). α[D]589=+8.13 (c=1.01, methanol/dimethylsulfoxide).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:31]>CCOCC>[ClH:31].[C:1]1([C:7]2[CH:8]=[N:9][NH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Agent: Cl
Solvent: CCOCC
Product: c1ccc(-c2cn[nH]c2)cc1
Yield: 93.61 %

Procedure:
A solution of 4-phenyl-1-trityl-1H-pyrazole (120 mg, 0.33 mmol) in Ether.HCl (10 mL) was stirred for 1 hr. The reaction mixture was then concentrated under reduced pressure to afford the residue. The residue obtained was washed with hexane to afford 44 mg (93.61%) of 4-phenyl-1H-pyrazole hydrochloride salt. 1H NMR (DMSO-d6): δ 8.1-8.08 (s, 2H), 7.64 (d, 2H), 7.38 (t, 2H), 7.22 (t, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23][O:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[CH2:33][OH:34])=[CH:27][CH:26]=1>ClCCl>[S:2]([O:34][CH2:33][C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([CH2:29][C:28]2[CH:38]=[CH:39][C:25]([O:24][CH2:23][C:14]3[CH:15]=[CH:16][C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:13]=3)=[CH:26][CH:27]=2)[CH:31]=1)(=[O:4])(=[O:3])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Reaction time: 24 h

Procedure:
To methanesulfonyl chloride (0.002 mol) and triethylamine (0.002 mol) in dichloromethane (40 ml) at 0° C. is added 3-(4-(2-quinolinylmethyloxy)benzyl)benzyl alcohol (0.0018 mol) in dichloromethane (40 ml) dropwise. After 24 hours, the reaction mixture is washed with water, dried and evaporated to give 3-(4-(2-quinolinylmethyloxy)benzyl)benzyl alcohol mesylate.
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:5]=1.[Mg].[Cl-].[NH4+:17]>C1COCC1.CCC(=O)CC>[CH:12]1([CH2:11][O:10][C:6]2[CH:5]=[C:4]([C:4]([NH2:17])([CH2:9][CH3:8])[CH2:5][CH3:6])[CH:9]=[CH:8][CH:7]=2)[CH2:14][CH2:13]1
Reactant: [NH4+]
Reactant: Brc1cccc(OCC2CC2)c1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCC(=O)CC
Solvent: C1CCOC1
Product: CCC(N)(CC)c1cccc(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of magnesium (280 mg) in THF (2.5 mL), iodine (10 mg) was added at room temperature. Then, a small amount of a solution of 1-bromo-3-(cyclopropylmethoxy)benzene (2.27 g) obtained according to a method described in the document (Izvestiya akademi Nauk SSSR, Seriya Khimicheskaya, 12, 2752-2755 (1989)) in THF (3.5 mL) was added thereto, and the mixture was stirred at room temperature for 10 minutes until the iodine color disappeared. The remaining amount of the solution of 1-bromo-3-(cyclopropylmethoxy)benzene in THF was added thereto, and the mixture was stirred at room temperature for 1 hour until the magnesium disappeared. To the reaction mixture, a solution of 3-pentanone (1.02 g) in THF (3.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, an aqueous saturated ammonium chloride solution (10 ml) was added at 0° C., and the aqueous layer was extracted with ethyl acetate (20 mL×2). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane). The obtained compound was dissolved in chloroform (20 mL). To the solution, sodium azide (1.7 g) was added. To the reaction mixture, trifluoroacetic acid (3.2 mL) was added dropwise at 0° C., and the mixture was then stirred at room temperature for 1 hour. To the reaction mixture, water (20 mL) was added, and the resultant mixture was then extracted with chloroform (20 mL). The organic layer was washed with an aqueous saturated sodium bicarbonate solution (20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane). The obtained compound was dissolved in methanol (10 mL). To the solution, 10% palladium-carbon (260 mg) was added, and the reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The precipitate was removed by filtration through a pad of Celite and washed with methanol (100 mL). Then, the combined filtrate was concentrated under reduced pressure to obtain the title compound (1.70 g) as a crude product.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[OH:29][C:26]([CH:24]1[CH2:25][N:22]([C:3]2[C:2]([C:34]3[CH:35]=[N:36][C:31]([CH3:30])=[CH:32][CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1)([CH3:28])[CH3:27]
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CC(C)(O)C1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC(C(C)(C)O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 142.1) and (6-methylpyridin-3-yl)boronic acid to afford an off-white foam. HPLC (Condition 4) tR=4.37 min, UPLC-MS (Condition 7) m/z=487.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.93 (s, 6H) 2.49 (s, 3H) 3.31 (br. s, 1H) 3.54-3.66 (m, 4H) 4.36 (d, J=0.78 Hz, 1H) 7.22-7.43 (m, 3H) 7.73 (dd, J=7.82, 2.35 Hz, 1H) 7.79-7.88 (m, 2H) 7.95 (d, J=2.35 Hz, 1H) 8.51 (d, J=1.96 Hz, 1H) 8.72 (d, J=2.35 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].Br[C:13]1[CH:14]=[C:15]([Cl:19])[CH:16]=[CH:17][CH:18]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)C>[Cl:19][C:15]1[CH:14]=[C:13]([NH:11][C:10]2[CH:9]=[CH:8][NH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: Clc1cccc(Br)c1
Reactant: CCOC(=O)c1[nH]ccc1N
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)c1[nH]ccc1Nc1cccc(Cl)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
A mixture of 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.20 g, 1.3 mmol), 3-bromochlorobenzene (0.30 g, 1.6 mmol), Pd2(dba)3 (0.048 g, 0.052 mmol), rac-BINAP (0.048 g, 0.078 mmol) and cesium carbonate (0.59 g, 1.8 mmol) was heated at 100° C. in a sealed microwave vial under nitrogen atmosphere overnight. Additional Pd2(dba)3 (0.10 g, 0.11 mmol) and R,S-BINAP (0.11 g, 0.18 mmol) were added and the reaction was continued stirring at 100° C. overnight. Additional 3-bromochlorobenzene (0.15 g), Pd2(dba)3 (0.098 g) and R,S-BINAP (0.098 g) were added and the reaction was continued stirring at 100° C. for three more days. The reaction mixture was poured into ethanol and the resulting solution was filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 30% ethyl acetate), obtaining 0.052 g (15%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[C:12]([CH2:14][C:15]([O:17]CC)=[O:16])[N:13]=2)=[CH:5][CH:4]=1.CO.[OH-].[K+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[N:13]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(OC)cc2)oc1-c1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2nc(CC(=O)O)c(-c3ccco3)o2)cc1
Yield: 82 %

Procedure:
2.0 g of ethyl 2-[2-(4-methoxyphenyl)-5-(2-furyl)-4-oxazolyl]acetate, 30 ml of methanol, 3 ml of water and 0.85 g of potassium hydroxide are treated in the same manner as described in Example 16. 1.5 g of 2-[2-(4-methoxyphenyl)-5-(2-furyl)-4-oxazolyl]acetic acid are thereby obtained. Yield: 82.0%
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].Br[CH2:36][CH2:37][O:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][O:40]1>C(#N)C>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:36][CH2:37][O:38][CH:39]5[CH2:44][CH2:43][CH2:42][CH2:41][O:40]5)[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ncc2c(c1OC1CCNCC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Reactant: BrCCOC1CCCCO1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ncc2c(c1OC1CCN(CCOC3CCCCO3)CC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 50 °C
Yield: 33.5 %

Procedure:
To a suspension of 9-benzenesulfonyl-3-bromo-5-(piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (789 mg, 1.54 mmol) in acetonitrile (50 mL) was added sodium iodide (46 mg, 0.31 mmol) and the resultant suspension sonicated for 5 minutes. 2-(2-Bromoethoxy)tetrahydropyran (483 mg, 2.31 mmol) was added and the reaction mixture was heated to 50° C. for 48 hours. The resultant residue was concentrated in-vacuo then dissolved in dichloromethane, diluted with 1N aqueous sodium carbonate (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layer was dried (Na2SO4), filtered, evaporated in-vacuo and the resultant residue purified by flash chromatography (silica, 40 g column, ISCO, 0-30% ethyl acetate in dichloromethane) to afford the title compound as a pale yellow solid (330 mg, 33%). 1H NMR (300 MHz, CDCl3): 9.54 (s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.65 (d, J=2.3 Hz, 1H), 8.23-8.22 (m, 2H), 7.64-7.64 (m, 1H), 7.53-7.50 (m, 2H), 5.13-5.11 (m, 1H), 4.59 (t, J=3.5 Hz, 1H), 3.87-3.86 (m, 2H), 3.54-3.52 (m, 2H), 2.99 (d, J=11.6 Hz, 2H), 2.67 (t, J=6.0 Hz, 2H), 2.35 (t, J=11.3 Hz, 2H), 2.22 (d, J=12.3 Hz, 2H), 2.03-1.99 (m, 2H), 1.87-1.47 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH:21]=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1.[OH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C>O1CCOCC1.CC(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH2:21][CH2:22][N:27]3[CH2:28][CH2:29][CH:24]([OH:23])[CH2:25][CH2:26]3)=[CH:18][CH:19]=2)[CH2:14][O:13]1
Reactant: C=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Reactant: OC1CCNCC1
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CCN3CCC(O)CC3)ccc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A solution of 5-fluoro-3-(2-vinyl-7H-furo[3,4-b]pyridin-5-ylidene)-1,3-dihydro-indol-2-one (50 mg, 0.17 mmol) in dioxane (10 mL) is treated with 4-hydroxypiperidine (260 mg, 2.57 mmol) and 10 drops of glacial AcOH. The reaction is stirred at 100° C. for 1 h and then cooled to room temperature. The reaction mixture is treated with triethylamine (2 mL) and is loaded onto silica gel. Purification by chromatography (silica gel) gave the title compound (57 mg, 85%).
Reaction SMILES: BrC1C=CC2C(=CC=C(OCF)C=2)C=1.[F:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C:28]([C:33]1[N:34]=[CH:35][N:36](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:37]=1)([OH:32])[CH:29]([CH3:31])[CH3:30])[CH:22]=[CH:21]2.C([Li])CCC.C(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)=O.O>CCOCC.CCCCCC.C1COCC1>[F:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C:28]([C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)([OH:32])[CH:29]([CH3:31])[CH3:30])[CH:22]=[CH:21]2
Reactant: CC(C)C(O)(c1ccc2cc(OCF)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: FCOc1ccc2cc(Br)ccc2c1
Agent: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccc2cc(OCF)ccc2c1)c1c[nH]cn1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 212.7 %

Procedure:
Production of 1-(6-Fluoromethyloxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol 2-Bromo-6-fluoromethyloxynaphthalene (2.10 g) was dissolved in ether (100 ml), and the solution was cooled to −70° C. To the solution was slowly added a solution of n-butyllithium in hexane (1.6 M, 5.7 ml), and the mixture was stirred at −70° C. for 20 min. To the mixture was added dropwise a solution of 4-formyl-1-trityl-1H-imidazole (1.58 g) in THF (10 ml). The mixture was stirred for 20 min at −70° C. To the mixture was added water, and the mixture was extracted with ethyl acetate and dried. The solvent was distilled off and the residue was purified by silica gel chromatography (eluent, hexane:ethyl acetate=1:1) followed by recrystallization from diisopropyl ether to give the titled compound (1.73 g) as colorless needles.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[O:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[C:52](Cl)=[O:53]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:52]([C:48]2[O:47][CH:51]=[CH:50][CH:49]=2)=[O:53])[CH2:42][CH2:41]1)=[O:39]
Reactant: O=C(Cl)c1ccco1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCN(C(=O)c2ccco2)CC1
Yield: 16 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 2-furancarbonyl chloride as starting materials in 16% yield. LCMS for C29H28ClN6O3 (M+H)+: m/z=543.2.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].Br[CH2:12][C:13]1[C:18]2[N:19]=[C:20]([N:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[S:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH:7][CH2:12][C:13]1[C:18]2[N:19]=[C:20]([NH:22][C:23](=[O:24])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[S:21][C:17]=2[CH:16]=[CH:15][CH:14]=1)[CH3:6])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2c(CBr)cccc2s1
Reactant: CCOC(OCC)[C@H](C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(OCC)[C@H](C)NCc1cccc2sc(NC(=O)OC(C)(C)C)nc12
Temperature: 65 °C
Reaction time: 2 h
Yield: 140.8 %

Procedure:
To the solution of (S)-1,1-diethoxypropan-2-amine (Compound XIX-1) 442 mg (3.00 mmol) in acetonitrile 5 ml, 4-bromomethyl-2-bis(tert-butoxycarbonyl)aminobenzothiazole (Compound XXI-1) 133 mg (0.30 mmol) and potassium carbonate 62 mg (0.45 mmol) were added and stirred at 65° C. for 2 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate 100 ml and washed with water 100 ml and brine 100 ml. The organic phase was dried with magnesium sulfate 1 g and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain the title compound 173 mg (yield 71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:24])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([O:17]C)=[O:16])[S:14][C:7]=12.[OH-].[Na+].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:24])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[S:14][C:7]=12
Reactant: COC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 7-(3-fluoro-4-(3-(2-fluoro-5-methylphenyl)ureido)phenoxy)thieno[3,2-b]pyridine-2-carboxylate (1.84 g, 3.92 mmol) was taken up in 100 mL THF followed by the dropwise addition of 1N sodium hydroxide (4.8 mL, 4.8 mmol). The solution was stirred at room temperature for 3 hours, at which time an additional 2.4 mL of 1N sodium hydroxide was added. The solution was stirred at room temperature for overnight and the resulting mixture was diluted with 75 mL of water and acidified using 1N HCl. The insoluble material was separated by filtration and the filter cake was suspended in ethyl acetate and stirred for several minutes before filtering. The filter cake was washed several times with ethyl acetate and dried under high vacuum to give 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid as an off white solid. Yield: 1.6 g (90%); MS [M+H]+456.1; 1HNMR (DMSO-d6) δ: 13.9 (bs, 1H), 9.2 (s, 1H), 9.0 (s, 1H), 8.6 (d, 1H), 8.3 (t, 1H), 8.1 (s, 1H), 8.0 (d, 1H), 7.5 (d, 1H), 7.2 (m, 2H), 6.8 (m, 2H), 2.1 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:20]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([O:13][CH3:20])=[O:12])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)CCC(=O)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(=O)c1ccc(Br)cc1
Yield: 89 %

Procedure:
To a solution of 4-(4-bromophenyl)-4-oxobutanoic acid (16.0 g, 62.0 mmol) in MeOH (200 mL) was added concentrated H2SO4 (0.2 mL). The mixture was heated at reflux overnight. The solvent was evaporated and then water (250 mL) was added to the residue. The mixture was neutralized with sat. NaHCO3 solution until pH 7-8. The mixture was extracted with ethyl acetate (100 mL×2). The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to afford methyl 4-(4-bromophenyl)-4-oxobutanoate (15.0 g, 89%). 1H NMR (CDCl3, 300 MHz) δ 7.85 (d, J=8.1, 1H), 7.61 (d, J=8.1, 2H), 3.71 (s, 3H), 3.28 (t, J=6.6, 2H), 2.77 (t, J=6.6, 2H).