Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(O)(O)[C@H:2]1N(C([C@@H](N)C(C)C)=O)CCC1.CS(O)(=O)=O.[S:21]1[CH:25]=[CH:24][C:23]2[C:26]([O:30][CH2:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C:37]=3[CH3:38])=[CH:27][CH:28]=[CH:29][C:22]1=2.[BrH:45].O1CCCOO1>ClCCl>[Br:45][CH2:2][C:29]1[C:22]2[S:21][CH:25]=[CH:24][C:23]=2[C:26]([O:30][CH2:31][CH2:32][C:33]2[N:34]=[C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[O:36][C:37]=2[CH3:38])=[CH:27][CH:28]=1
Reactant: Br
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1cccc2sccc12
Agent: C1COOOC1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CBr)c2sccc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A 500-ml 4-necked jacketed reactor equipped with a mechanical stirrer, a thermo-meter, a 50-ml dropping funnel, an argon inlet, a PT100 temperature sensor and a thermostat was charged with 33.54 g of 4-[2-(Benzo[b]thiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole (0.100 mol) and 400 ml of dichloromethane. After cooling the solution to 0° C., 30.3 ml of hydrobromic acid 62% (0.400 mol) were added dropwise within 9 min at a temperature of 0°-4° C. To the yellow biphasic mixture a solution of 3.30 g of trioxane (0.110 mol) in 40 ml of dichloromethane was added at 0-1° C. After 3 h 15.1 ml of hydrobromic acid 62% (0.200 mol) were added within 7 min at 0-1° C. After 4 h additional 15.1 ml of hydrobromic acid 62% (0.200 mol) were added and the mixture was stirred over night at 0° C. After a total of 24 h the colorless bottom HBr-phase was removed through the bottom valve and extracted with 100 ml of dichloromethane. To the combined organic phases in the reactor 300 ml of sat. aqueous sodium bicarbonate solution were added at ca. 0° within 30 min. The resulting biphasic mixture was stirred for 5 min and the aqueous phase was extracted twice with 100 ml, a total of 200 ml of dichloromethane. The combined organic phases were dried (Na2SO4), rotary evaporated (45°, 600 mbar) and shortly dried (45° C., 20 mbar, 15 min). The resulting light brown residue was suspended in 200 ml of acetone and the suspension stirred for 1 h at reflux, 1 h at rt and 1 h in an ice bath. The crystals were filtered off with suction, washed with 50 ml of cold (−20° C.) acetone and dried to constant weight at 55° C. and 10 mbar for 4 h, affording 24.88 g of 4-[2-(7-Bromomethyl-benzo[b]thiophen-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole as off-white crystals with m.p of 143-144° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[CH:2]=1.[N:12]([O-])=O.[Na+].O.O.[Cl:18][Sn]Cl>Cl>[ClH:18].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][NH2:12])[CH:2]=1
Reactant: Cl[Sn]Cl
Reactant: Nc1cnc2ccccc2c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cnc2ccccc2c1
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution of quinolin-3-ylamine (5 g, 35 mmol) in conc. HCl (12 mL) was added dropwise an aqueous solution (4 mL) of NaNO2 (2.42 g, 35 mmol) at 0° C. The resulting mixture was stirred for 1 h, and then treated with a solution of SnCl2.2H2O (15.8 g, 70 mmol) in conc. HCl (15 mL). The reaction solution was stirred for an additional 2 h at RT. The precipitate was filtered and washed with EtOH and ether to yield 1-(quinolin-3-yl)hydrazine hydrochloride (4.5 g, 81% yield), which was used in the next reaction without further purification.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=1)(=[O:3])[CH3:2].C(O[CH:27](OCC(C)(C)C)[N:28]([CH3:30])[CH3:29])C(C)(C)C>>[CH3:27][N:28]([CH3:30])[CH:29]=[CH:2][C:1]([C:4]1[C:9](=[O:10])[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1cc(C(C)=O)c(=O)[nH]c1C(=O)OCC
Reactant: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Product: CCOC(=O)c1cc(C(=O)C=CN(C)C)c(=O)[nH]c1C(=O)OCC
Temperature: 25 °C
Yield: 70 %

Procedure:
Diethyl 5-acetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate, (25 g, 0,089 mol) and N,N-dimethylformamide dineopentyl acetal (50 mL, 98%, 40.62 g, 0.176 mol) are heated for 30 minutes at 80°-100° C. After cooling to room temperature, the product is obtained as a precipitate and is filtered and washed with hexane to yield 23.4 g, 70% yield, of solid which is recrystallized from isopropanol to give a pure product, melting point 182°-183° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][C:3]=1[N+:17]([O-])=O>C(O)C.C1COCC1.[Pd]>[NH2:17][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc(F)c(N)c1

Procedure:
535 mg (2.00 mmol) of tert-butyl(2E)-3-(4-fluoro-3-nitrophenyl)prop-2-enoate were dissolved in 1 ml of ethanol and 1 ml of THF, and 21.3 mg of palladium (10% on carbon) were added. At RT, the mixture was hydrogenated under a hydrogen atmosphere at atmospheric pressure overnight. The reaction mixture was filtered off with suction through kieselguhr, the residue was washed with THF and the filtrate was concentrated. This gave 479 mg (100% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[CH2:27]([O:29][C:30](=[O:49])[C:31]([CH3:48])([C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:32])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:49])[C:31]([C:33]1[CH:38]=[CH:37][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:25])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:26])=[CH:19][CH:20]=2)=[CH:35][CH:34]=1)([CH3:48])[CH3:32])[CH3:28]
Reactant: CCOC(=O)C(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Product: CCOC(=O)C(C)(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3Cl)cc2)cc1

Procedure:
Prepared as described in Example 36, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and 2-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester.
Reaction SMILES: [N:1]1([C:6]2[C:7]([C:12]#[N:13])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1>[Pd].C(O)C>[N:1]1([C:6]2[C:7]([CH2:12][NH2:13])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: N#Cc1ncccc1-n1cnnn1
Agent: [Pd]
Solvent: CCO
Product: NCc1ncccc1-n1cnnn1

Procedure:
A solution of 3-(tetrazol-1-yl)cyanopyridine (250 mg, 1.45 mmol) and 45% by weight of palladium on carbon, 10% catalyst (110 mg) in ethanol (75 ml) was placed on a PARR hydrogenation Apparatus under a hydrogen atmosphere at 55 psi. overnight. The mixture was filtered through celite and concentrated to give 3-(tetrazol-1-yl)-2-aminomethylpyridine; 1H NMR (CD3OD) δ 9.60 (s, 1H), 8.83–8.81 (m, 1H), 7.99–7.97 (m, 1H), 7.59–7.56 (m, 1H), 3.77 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21](SC)[CH:20]=3)[C:7]([CH:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[N:8][C:4]=2[CH:3]=1.O[O:30][S:31]([O-:33])=O.[K+].[CH2:35]1COCC1>O>[F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]([S:31]([CH3:35])(=[O:33])=[O:30])[CH:24]=3)[C:7]([CH:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Reactant: CSc1cccc(-n2c(C(C)NC(=O)OC(C)(C)C)nc3cc(F)ccc32)c1
Agent: [K+]
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1nc2cc(F)ccc2n1-c1cccc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl 1-(5-fluoro-1-(3-(methylthio)phenyl)-1H-benzo[d]-imidazol-2-yl)ethylcarbamate (0.7397 g, 1.842 mmol) in THF (13.82 mL) and water (4.61 mL) was added oxone (2.83 g, 4.61 mmol) and the mixture was stirred at rt. After 3 h, water (50 mL) was added to the mixture, and extracted with DCM (50 mL×2). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure to give a white solid, which was purified by column chromatography on a 24 g of Redi-Sep™ Gold column using 0 to 50% gradient of EtOAc in hexane over 5 min and then 50% isocratic of EtOAC for 20 min as eluent to give tert-butyl 1-(5-fluoro-1-(3-(methylsulfonyl)phenyl)-1H-benzo[d]imidazol-2-yl)ethylcarbamate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.05-8.15 (2H, m), 7.90 (2H, d, J=4.9 Hz), 7.56 (1H, dd, J=9.5, 2.2 Hz), 7.35 (1H, d, J=8.0 Hz), 7.06-7.18 (2H, m), 4.82-4.95 (1H, m), 3.33 (3H, s), 1.44 (3H, d, J=6.8 Hz), 1.23 (9H, s); LC-MS (ESI) m/z 434.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([C:8]1[CH:22]=[CH:21][C:11]([CH2:12]P(=O)(OCC)OCC)=[CH:10][CH:9]=1)([O:5][CH2:6][CH3:7])=[O:4].[Si:23]([O:30][CH:31]1[C:36]2([CH3:53])[C:37]3[CH:42]=[C:41]([CH:43]=O)[C:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:39][C:38]=3[C:32]1([CH3:54])[CH2:33][CH2:34][CH2:35]2)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C>[Si:23]([O:30][CH:31]1[C:36]2([CH3:53])[C:37]3[CH:42]=[C:41](/[CH:43]=[CH:12]/[C:11]4[CH:10]=[CH:9][C:8]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:21]=4)[C:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:39][C:38]=3[C:32]1([CH3:54])[CH2:33][CH2:34][CH2:35]2)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1ccc(CP(=O)(OCC)OCC)cc1
Reactant: CCCCCCCOc1cc2c(cc1C=O)C1(C)CCCC2(C)C1O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCOc1cc2c(cc1/C=C/c1ccc(C(=O)OCC)cc1)C1(C)CCCC2(C)C1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
248 mg of NaH (about 50% in oil) were placed in 12 ml of abs. DMF under argon. 2.45 g of diethyl (4-carbethoxybenzyl)phosphonate were added thereto at 0° and the mixture was subsequently stirred at room temperature for about 2 hours until the H2 evolution had finished. The mixture was cooled to −10° C. and 2.20 g of (5RS,9SR,10RS)-10-t-butyldimethylsilyloxy-2-formyl-3-heptyloxy-5,9-dimethyl-6,7,8,9-tetrahydro-5,9-methano-5H-benzocycloheptene dissolved in 10 ml of abs. DMF were slowly added dropwise thereto. Then, the cooling bath was removed and the mixture was left to react at room temperature for 2 hours. It was then poured into ice/NH4Cl solution, extracted with diethyl ether, washed with NaCl solution, dried over Na2SO4 and concentrated. Flash chromatography on SiO2 (hexane/ethyl acetate 98/2) gave 2.32 g of ethyl (E)-4-[2-[(5RS,9SR,10RS)-10-t-butyldimethylsilyloxy-3-heptyloxy-5,9-dimethyl-6,7,8,9-tetrahydro-5,9-methano-5H-benzocyclohepten-2-yl]vinyl]benzoate as a yellowish oil.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][OH:16].[F:23][C:24]1[C:29]([F:30])=[C:28]([CH2:31][CH2:32][C@H:33]2[CH2:38][CH2:37][C@H:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:35][CH2:34]2)[CH:27]=[CH:26][C:25]=1[C:44]1[N:49]=[CH:48][C:47](O)=[CH:46][N:45]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC1C(F)=C(CCCCC)C=CC=1C1N=CC(OC[C@H](F)CCCCCC)=CN=1>C1COCC1>[F:23][C:24]1[C:29]([F:30])=[C:28]([CH2:31][CH2:32][C@H:33]2[CH2:34][CH2:35][C@H:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:37][CH2:38]2)[CH:27]=[CH:26][C:25]=1[C:44]1[N:45]=[CH:46][C:47]([O:16][CH2:15][C@H:14]([F:13])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:48][N:49]=1
Reactant: CCCCCC[C@@H](F)CO
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(-c3ncc(O)cn3)c(F)c2F)CC1
Agent: CCCCCC[C@@H](F)COc1cnc(-c2ccc(CCCCC)c(F)c2F)nc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCC[C@@H](F)COc1cnc(-c2ccc(CC[C@H]3CC[C@H](CCCCC)CC3)c(F)c2F)nc1
Yield: 61.3 %

Procedure:
--Quantities: DEAD (448 mg, 2.58 mmol) in THF (3 ml), (R)-(+)-2-fluorooctanol (379 mg, 2.58 mmol), hydroxypyrimidine 48 (1.0 g, 2.58 mmol), triphenylphosphine (676 mg, 2.58 mmol). The experimental procedure was as described for compound 34. The crude product was purified by flash chromatography (5 to 7% ethyl acetate-light petroleum) to give the 2-fluorooctyloxypyrimidine 49 (820 mg, 61%) (from EtOH), transitions/° C. K 102.2 N* 128.3 I; [α]D26 -2.4° (c 2.0 in CHCl3); νmax /cm-1 (KBr) 2920, 2845, 1540, 1460, 1435s, 1285 1085, and 900; δ 0.80-1.03 (10H, m), 1.06-1.45 (16H, m), 1.55 (4H, m), 1.82 (6H, m), 2.71 (2H, t J 8, ArCH2), 4.22 (2H, dd, 3JHF 22 and J 4, OCH2), 4.86 (1H, d of sext, 2JHF 48 and J 4, CHF), 7.01 (1H, ddd, J 7.5, 7 and 1.5, 5'-H), 7.67 (1H, ddd, J 7.5, 7 and 1.5, 5'-H) and 8.53 (2H, s, 4- and 6-H); m/z 518 (M+), 489, 475, 461, 447, 365 and 353.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][N:6]=1.[Br:13]Br>O.[K+].[Br-]>[Br:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:5]([O:4][CH3:3])=[N:6][CH:7]=1
Reactant: COc1ccnc(OC)c1
Reactant: BrBr
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cc(OC)c(Br)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
According to Scheme 23 Step 2: To a solution of KOH (0.5 eq, 0.8 mmol, 40 mg) in water (75 mL) was added 2,4-dimethoxypyridine (1 eq, 2.00 mmol, 0.21 g) followed by the dropwise addition of Br2 (1 eq, 2.00 mmol, 0.20 g) in 1M aqueous KBr solution (75 mL). The reaction was stirred at room temperature for 5 hours and then poured onto water (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated under reduced pressure to afford 5-bromo-2,4-dimethoxypyridine (1.40 mmol, 0.30 g, 70%) as a colorless oil. The crude product was reacted on.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:7]=1.[NH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][OH:31]>CO.CCOC(C)=O>[OH:32][C@H:29]([CH2:30][OH:31])[CH2:28][NH:27][C:22]([C:21]1[CH:20]=[N:19][N:16]2[CH:17]=[CH:18][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:25][CH3:26])=[N:14][C:15]=12)=[O:24]
Reactant: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: NC[C@H](O)CO
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NC[C@H](O)CO)c2n1
Yield: 53 %

Procedure:
Prepared by the method of Example 1, using (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation G) and (S)-3-aminopropane-1,2-diol (2.0 equiv). The crude material was purified by SiO2 column chromatography, eluting with EtOAc then 10% MeOH-EtOAc to afford the title compound as a white solid (53% yield). MS (apci) m/z=430.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5](C(OC)=O)=[N:6][CH:7]=1.[CH3:12][Mg]Br.C([O:17][CH2:18][CH3:19])C.Cl>O1CCCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:18]([OH:17])([CH3:19])[CH3:12])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Br)cn1
Reactant: CCOCC
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1cnc(Br)cn1
Reaction time: 1 h

Procedure:
To a solution of methyl 5-bromopyrazine-2-carboxylate (0.250 g, 1.152 mmol) in Tetrahydrofuran (THF) (6.53 ml) at 0° C. under nitrogen was added methylmagnesium bromide, 3 M in diethyl ether (1.152 ml, 3.46 mmol) slowly. After 1 hour at 0° C., 2N HCl (15 mL) was added slowly. The mixture was extracted with ethyl acetate (2×15 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. The residue was purified using silica gel chromatography CISCO): 10-30% ethyl acetate/hexanes (20 min), 12 gram silica gel column. Obtained 2-(5-bromopyrazin-2-yl)propan-2-ol as an orange oil (71 mg, 24%). MS (m/z) 216.9 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34](O)=[O:35].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>N1C=CC=CC=1.C(OCC)(=O)C>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:34](=[O:35])[CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]([F:37])([F:25])[F:38]
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1C(F)(F)F)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.29 mmol) produced in Example 16(vi) was dissolved in pyridine (2.0 mL), [2-(trifluoromethyl)phenyl]acetic acid (120 mg, 0.58 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (220 mg, 0.58 mmol) were added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed successively with 5% aqueous ammonium chloride solution (5 mL), saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and the obtained solid was washed with ethyl acetate/heptane to give the title compound (120 mg, 79%) as a colorless powder.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:6].CCO[CH2:10][CH3:11].[CH3:12]COC(C)=O>>[CH2:2]([Cl:6])[C:3]1[CH:11]=[CH:10][CH:12]=[CH:5][CH:4]=1.[NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl
Reactant: CCOCC
Reactant: CCOC(C)=O
Solvent: C1CCNC1
Product: ClCc1ccccc1
Reaction time: 1 h

Procedure:
NR2=Pyrrolidine (11f). The HCl salt of 11f was prepared by suspending the free base in EtOAc and adding 1.1 eq HCl/Et2O and stirring for 1 h. Filtration of the resulting solid led to a hygroscopic solid. Yield=72%; 1H NMR (CDCl3) δ 7.93 (d, 1H), 7.79 (d, 1H), 7.49 (t, 1H), 7.22 (d, 2H), 7.11 (d, 2H), 4.50 (m, 5H), 4.17 (s, 2H), 3.40 (m, 2H), 3.25 (m, 4H), 3.13 (m, 2H), 2.99 (m, 2H), 2.00 (m, 2H), 1.83 (m, 2H); MS (ES+=375.38). Anal Calcd. for C23H27ClN4O1 (4 H2O): C, 57.19; H, 7.30; N, 11.60. Found: C, 56.93; H, 7.46; N, 11.74.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[S:7][CH:8]=[C:9]([CH:13]([CH3:15])[CH3:14])[C:10]=1[C:11]#[N:12]>C1(C)C=CC=CC=1>[C:11]([C:10]1[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][S:7][C:6]=1[NH:5][C:3]([NH:2][CH3:1])=[O:4])#[N:12]
Reactant: CN=C=O
Reactant: CC(C)c1csc(N)c1C#N
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1scc(C(C)C)c1C#N
Yield: 56 %

Procedure:
11.8 ml (0.2 mole) of methyl isocyanate were added to a solution of 33.2 g (0.2 mole) of 2-amino-3-cyano-4-isopropyl-thiophene in 200 ml of toluene. After the exothermic reaction had subsided, the product which precipitated in the solid form was filtered off. Further portions of reaction product were obtained by concentrating the mother liquor. 25 g of 1-(3-cyano-4-isopropyl-thien-2-yl)-3-methyl-urea of melting point 179°-181° C. were obtained in this manner.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18][CH3:19])=[N:9]2)=[CH:4][CH:3]=1.CC(C)=[O:32].C[N+]1([O-])CCOCC1.[OH2:42]>O=[Os](=O)(=O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:19])(=[O:32])=[O:42])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: CSc1ccccc1-c1nc2cc(F)ccc2cc1[C@H](C)NC(=O)OC(C)(C)C
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1cc2ccc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Under an N2 atmosphere, (S)-tert-butyl (1-(7-fluoro-2-(2-(methylthio)phenyl)-quinolin-3-yl)ethyl)carbamate (412 mg, 999 μmol) was dissolved in acetone (3.00 ml, 40.8 mmol) and water (3 mL), and NMO (351 mg, 3.00 mmol) was added followed by OsO4 (12.7 mg, 0.05 mmol). The reaction was allowed to stir at rt overnight. LC-MS showed the reaction not to be complete. The reaction was treated with OsO4 (12.7 mg, 0.05 mmol) again and stirred overnight. LC-MS showed only a trace of the starting reagent. The reaction was quenched by the addition of 5 mL of a saturated sodium thiosulfate solution. The reaction was diluted with EtOAc and washed with 5% Na2CO3. The organic layer was then washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified eluting with 30% to 60% EtOAc in hexanes to provide a white solid (S)-tert-butyl (1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)quinolin-3-yl)-ethyl)carbamate (440 mg, 99%). Mass Spectrum (ESI) m/e=445 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([CH:18]=O)=[CH:13][C:12]=3[CH:20]=2)=[CH:4][CH:3]=1.[CH3:21][N:22]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:21][N:22]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34][CH2:18][C:14]2[CH2:15][CH2:16][O:17][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:20][C:12]=3[CH:13]=2)=[CH:35][CH:36]=1)[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C=O)CCO3)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(CNc2ccc(CN(C)C4CCOCC4)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 26 %

Procedure:
Into a solution of 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carbaldehyde (191 mg)) and 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (159 mg) in 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (168 mg). The resulting mixture was stirred at room temperature for 4.5 hours, additional sodium triacetoxyborohydride (76 mg) was added thereto and the resulting mixture was stirred further for 4 days. The reaction mixture was mixed with an aqueous solution of sodium bicarbonate under ice cooling and was extracted with dichloromethane, and the extract was washed with an aqueous solution of sodium chloride. The extract was dried (anhydrous magnesium sulfate) and was then concentrated under reduced pressure. The residue was subjected to purification using silica gel column chromatography (ethyl acetate/methanol=10/1), 4 N hydrochloric acid was added to the resulting product and the precipitate was collected by filtration and was washed with ethyl acetate to obtain N-[4-[(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)]phenyl]-N-[7-(4-methylphenyl)-2,3-dihydro-1-benzooxepin-4-yl]methylamine (compound 34) (88 mg) as a light yellow powder.