Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Br[C:20]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:23]=[C:22]([NH:32][C:33]2[CH:34]=[N:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[NH2:1][C:2]1[CH:7]=[C:6]([C:5]([C:20]2[CH:21]=[C:22]([NH:32][C:33]3[CH:34]=[N:35][C:36]4[C:41]([CH:42]=3)=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:23]=[C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[N:25]=2)=[CH:4][N:3]=1)[C:8]#[N:9]
Reactant: Brc1cc(Nc2cnc3ccccc3c2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2cnc(N)cc2C#N)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1cc(N)ncc1-c1cc(Nc2cnc3ccccc3c2)nc(N2CCOCC2)n1
Temperature: 120 °C
Yield: 20.7 %

Procedure:
To the crude 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-4-carbonitrile (prepared as in Method 11) (25 mg, 0.13 mmol) solution in dioxane (1.8 mL) in a pressure vessel, was added (6-bromo-2-morpholin-4-yl-pyrimidin-4-yl)-quinolin-3-yl-amine (19.4 mg, 0.05 mmol) and aq. Na2CO3 (2 M, 0.6 mL, 1.2 mmol). After purging the reaction mixture with argon, dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (10.3 mg, 0.01 mmol) was added in one portion. The pressure vessel was sealed and the mixture was heated in a microwave at 120° C. for 900 seconds. The crude mixture was filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to give 2-amino-5-[2-morpholin-4-yl-6-(quinolin-3-ylamino)-pyrimidin-4-yl]-isonicotinonitrile (4.4 mg, 20%). LC/MS (m/z): 425.0 (MH+), Rt 2.03 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[N:13]=[N:14][S:15][C:16]=2[CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=O)[CH:5]=[CH:6][C:7]=1[F:8].COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:38]2)=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[N:13]=[N:14][S:15][C:16]=2[CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[S:38])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)[Si](OCc1snnc1C(=O)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1snnc1C(=S)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 160 °C
Yield: 75.2 %

Procedure:
A solution of N-(3-chloro-4-fluorophenyl)-5-[(triisopropylsilyl)oxy]methyl-1,2,3-thiadiazole-4-carboxamide (2.3 g, 0.0052 mol) in anhydrous THF (10 mL) was distributed equally into 2 microwave vials. 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (4.2 g, 0.010 mol) (Lawesson's reagent) was added to each vial. The reactions were each heated at 160° C. in a microwave for 15 minutes. The solutions were combined, concentrated and purified by flash chromatography to give the desired product (1.80 g, 76%). MF═C19H27ClFN3OS2Si; LCMS calculated for C19H28ClFN3OS2Si (M+H)+: m/z=460.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2.CCN(C(C)C)C(C)C.Cl>CCCCO.C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[NH:30][CH:29]=[CH:28]5)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: Nc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc5[nH]ccc5c4)ncnc3[nH]2)CC1
Temperature: 120 °C
Reaction time: 23 h

Procedure:
A suspension of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (606.0 mg, 1.810 mmol, 1 eq) and 5-aminoindole (548.9 mg, 4.153 mmol, 2.3 eq) in n-BuOH (30 mL) was stirred at 120° C. for 23 h, after which it was concentrated in vacuo, to a dark brown foam. The crude material (1.2974 g) was dissolved in mixtures of DCM and MeOH (DCM alone was insufficient), to which DiPEA (0.4 mL, 2 mmol, 1 eq) was added to ensure that material was free base and not HCl salt. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with MeOH:DCM 1%→5% →10%]. Trituration of combined and concentrated product fractions in DCM/sonication gave the title compound as white solid. 1H NMR (400 MHz, DMSOd6): δ=1.43 (s, 9H), 2.44 (s, br, 2H), 3.55 (t, J=5.6 Hz, 2H), 4.03 (s, br, 2H), 6.35 (s, br, 1H), 6.40 (t, J=2.0 Hz, 1H), 6.67 (s, br, 1H), 7.29-7.41 (m, 3H), 8.03 (s, br, 1H), 8.19 (s, 1H), 9.14 (s, —NH), 10.99 (s, —NH), 11.81 (d, J=1.6 Hz, —NH). MS (ES+): m/z 431.04 (100) [MH+]. HPLC: tR=2.42 min (ZQ2000, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]Br)=[N:6][CH:7]=1.[CH3:10][NH:11][CH3:12]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:11]([CH3:12])[CH3:10])=[N:6][CH:7]=1
Reactant: BrCc1ccc(Br)cn1
Reactant: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)Cc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Place 5-bromo-2-bromomethyl-pyridine (1.7 g, 6.7 mmol, 1 eq) (Bioorg. Med. Chem. Lett. 1994, 4(1), 99) in a 250 mL round bottom short neck flask, dissolve in 100 mL of THF, cool to 0° C. and treat with a 2 M N,N-dimethylamine solution in THF (9 mL, 18 mmol, 2.7 eq). After 2 hours, concentrate the reaction, dilute with 50 mL of CH2Cl2, and wash with 20 mL of water. Dry the organics and concentrate to give 0.90 g (64%) of the title compound as a brown oil. MS (ES), m/z 217 (M+1).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:27]2[CH:28]=[N:29][C:30]([O:34][CH2:35][C:36]3([C:40]([O:42]CC)=[O:41])[CH2:39][CH2:38][CH2:37]3)=[CH:31][C:32]=2[CH3:33])[CH:7]=[N:8][C:9]=1[C:10]1[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1>CO>[Cl:3][C:4]1[CH:5]=[C:6]([C:27]2[CH:28]=[N:29][C:30]([O:34][CH2:35][C:36]3([C:40]([OH:42])=[O:41])[CH2:37][CH2:38][CH2:39]3)=[CH:31][C:32]=2[CH3:33])[CH:7]=[N:8][C:9]=1[C:10]1[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:24])[CH3:25])[CH:12]=[C:13]([C:15]([F:17])([F:16])[F:18])[N:14]=1
Reactant: CCOC(=O)C1(COc2cc(C)c(-c3cnc(-c4nc(C(F)(F)F)cn4COCC[Si](C)(C)C)c(Cl)c3)cn2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1cnc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(Cl)c1

Procedure:
Methanol (7 mL) and 1N aqueous sodium hydroxide solution (2.6 mL) were added to ethyl 1-[({5′-chloro-4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylate (327 mg), and the mixture was refluxed for 1 hour. Methanol was distilled off under reduced pressure, and the residue was neutralized by 1N hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure to obtain 1-[({5′-chloro-4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]-cyclobutanecarboxylic acid.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]([NH2:7])=[CH:5][CH:6]=1.C1C2C3C=CC(C2C=C1)C3.[CH3:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH:22]1([C:5]2[CH:6]=[C:1]([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]=2[NH2:7])[CH2:23][CH2:24][CH:20]=[CH:21]1
Reactant: Cc1ccc(N)cc1N
Reactant: CCCCC
Solvent: C1=CC2C3C=CC(C3)C2C1
Product: Cc1cc(C2C=CCC2)c(N)cc1N
Temperature: 205 °C

Procedure:
A 200 g (1.64 mol) portion of 2,4-toluenediamine, 162 g (1.23 mol, 2.45 equiv) of dicyclopentadiene, 200 g (2.78 mol) of pentane, and 20.0 g of an amorphous alumina-silica catalyst comprised of 13% alumina and 87% silica were charged to a 1000 cc pressure vessel equipped with a mechanical stirrer. The vessel was sealed and purged with nitrogen leaving a 32 psig nitrogen blanket. The vessel contents were heated to 205° C. with stirring and were maintained at that temperature for 22 hr. The contents were cooled to 150° C. and isoIated catalyst free by hot filtration. Selective removal of residual hydrocarbons by vacuum distillation and analysis by gas chromatography (GC) revealed the following product mixture:
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]=[CH2:11]>>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:10][CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)c1ccccc1
Reactant: C=C
Product: CCC(C)(C)c1ccccc1
Temperature: 160 °C

Procedure:
In a 600 ml autoclave equipped with a magnetic stirrer, Solid Base A (0.45 g) and cumene (240 g) were charged under nitrogen, heated to 160° C. while stirring at 1,000 rpm and then reacted at the same temperature for 3 hours while supplying ethylene gas under pressure of 10 kg/cm2G. to produce tert.-amylbenzene (hereinafter referred to as "TAB").
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:25][C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[Cl:22])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: Clc1ccccc1CBr
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Product: COC(=O)c1nc2n(c1Cc1ccccc1Cl)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (0.3 g) was reacted with 2-Chlorobenzyl bromide similar to as described in example 8 with non-critical modifications to produce methyl 10-bromo-3-(2-chlorobenzyl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. This crude intermediate was reacted via General Procedure L to provide 10-bromo-3-(2-chlorobenzyl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was reacted as a crude with 2-Methyl-3-butyne-ol via General Procedure E to afford 13 mg (3%) of 3-[(2-chlorophenyl)methyl]-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[N:48]1([CH2:53][C:54]2[CH:55]=[C:56]3[C:61](=[CH:62][CH:63]=2)[CH2:60][C@@H:59]([NH2:64])[CH2:58][CH2:57]3)[CH2:52][CH2:51][CH2:50][CH2:49]1>CN1C(=O)CCC1.C(OCC)(=O)C>[N:48]1([CH2:53][C:54]2[CH:55]=[C:56]3[C:61](=[CH:62][CH:63]=2)[CH2:60][C@@H:59]([NH:64][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][C@@H:2]4[CH2:3][CH2:4][CH2:5][O:1]4)=[CH:16][CH:15]=2)[CH2:58][CH2:57]3)[CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: O=C(O)c1ccc(OC[C@@H]2CCCO2)cc1
Reactant: N[C@H]1CCc2cc(CN3CCCC3)ccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CCc2cc(CN3CCCC3)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cc1
Reaction time: 12 h

Procedure:
To a solution of 4-[(S)-1-(TETRAHYDROFURAN-2-YL)METHOXY]BENZOIC ACID (3.38 g) in NMP (30 ml) were added HATU (O-(7-AZABENZOTRIAZOL-1-YL)-N,N,N′,N′-TETRAMETHYLURONIUM HEXAFLUOROPHOSPHATE; 5.78 g) and then triethylamine (2.12 ml). A solution of (S)-6-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydronaphthalen-2-ylamine (3.5 g) in NMP (20 ml) was added dropwise. After 12 hours, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium carbonate solution and concentrated. The residue was purified by chromatography on silica gel (eluent: 10:1 DCM/MeOH). The product was thus obtained with the molecular weight of 434.58 (C27H34N2O3); MS (ESI): 435 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=2)[N:5]=1)[CH3:2].[H-].[Na+].Cl[CH2:29][C:30]1[N:31]=[C:32]([C:36]2[O:37][CH:38]=[CH:39][CH:40]=2)[O:33][C:34]=1[CH3:35].O>CN(C)C=O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[O:37][CH:38]=[CH:39][CH:40]=4)[O:33][C:34]=3[CH3:35])=[C:19]([O:24][CH3:25])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)c(OC)c2)nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a solution of ethyl 3-[3-ethoxy-1-(4-hydroxy-3-methoxybenzyl)-1H-pyrazol-4-yl]propionate (505 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 58.0 mg) was added at 0° C., and then the solution was stirred at room temperature for 30 minutes. 4-Chloromethyl-2-(2-furyl)-5-methyloxazole (573 mg) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyl]-1H-pyrazol-4-yl]propionate (564 mg, yield: 76%) was obtained as a yellow oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH:6]([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:4].C([O-])([O-])=O.[Ca+2].[I:24]Cl>CO>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][CH:6]([CH3:16])[CH2:7][C:8]1[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][C:13]=1[I:24])=[O:4]
Reactant: ClI
Reactant: COc1cccc(CC(C)NC(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: COc1ccc(I)c(CC(C)NC(=O)C(F)(F)F)c1
Reaction time: 8 h
Yield: 110.6 %

Procedure:
A solution of N-trifluoroacetyl-1-(3-methoxyphenyl)-2-propylamine (4.29 g, 15.7 mmol) in methanol (100 mL) was cooled to −78 C and treated with CaCO3 (3.17 g, 31.4 mmol), followed by a solution of ICl (6.37 g, 39.3 mmol) in methanol (50 mL). The reaction was allowed to warm to 20 C while stirring overnight. The product mixture was filtered, concentrated, dissolved in EtOAc (200 mL), washed twice with 5% aqueous sodium bisulfite (100 mL), once with brine (100 mL), dried with Na2SO4 and concentrated to give 6.72 g of a white solid powder. MS calculated for C12H13F3INO2+H: 388, observed: 388.
Reaction SMILES: B.C1COCC1.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH2:22][Br:23])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO>C1(C)C=CC=CC=1.C1COCC1>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]([OH:24])[CH2:22][Br:23])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: B
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of BH3.THF in THF (1 M, 3.70 mL, 3.70 mmol) was added to a solution of 1-(4-benzyloxy-3-nitrophenyl)-2-bromoethanone (3) (1.08 g, 3.08 mmol) and R-methyl-CBS-oxazoborolidine (1 M in toluene, 0.61 mL, 0.61 mmol) in anhydrous THF (15 mL). The resulting reaction mixture was stirred at rt for 16 h. Methanol (5 mL) was slowly added to quench the reaction. After removal of solvent by rotary evaporation, the resulting residue was purified by Biotage silica gel column chromatography eluting with dichloromethane to give the desired bromo alcohol 4 as a yellow, viscous oil (0.72 g, 66%): 1H NMR (500 MHz, CDCl3) δ 2.82 (d, 1H), 3.48 (dd, 1H), 3.59 (dd, 1H), 4.89 (m, 1H), 5.21 (s, 2H), (d, 1H), 7.39 (m, 5H), 7.50 (dd, 1H), 7.87 (d, 1H).
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Ti:6].[S:7](=[O:11])(=[O:10])([OH:9])[OH:8]>>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Ti+4:6].[S:7]([O-:11])([O-:10])(=[O:9])=[O:8]
Reactant: [Ti]
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: [Ti+4]

Procedure:
The sulfate process generally comprises the steps of (1) dissolving a titanium slag or raw ilmenite ore into sulfuric acid to obtain a titanium sulfate solution, (2) adding waste iron or waste aluminum to the titanium sulfate solution to chemically reduce ferric ion contained as an impurity in the solution to the divalent (ferrous) state in order to prevent precipitation of iron and to increase the degree of whiteness of the titanium oxide product, followed by cooling the solution to precipitate and remove ferrous sulfate, (3) heat-hydrolyzing the titanium sulfate solution from which ferrous sulfate had been removed, followed by precipitating hydrous titanium oxide, which is then filtered and washed, and (4) then calcining the washed hydrous titanium oxide at 800 to 1,100° C. to obtain anhydrous titanium oxide.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:13]([O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:13]([O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:22][CH2:21]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To 20 mL of a chloroform solution containing 2.17 g of 1,4-benzodioxane-6-carbaldehyde and 2.67 g of tert-butyl(piperidin-4-yl)carbamate, 0.76 mL of acetic acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with 4.27 g of sodium triacetoxyborohydride, and stirred overnight. Thereto was added an aqueous saturated sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60 manufactured by Kanto Chemical Co., Inc., eluent; ethyl acetate:hexane=5:1] to obtain 2.96 g of tert-butyl(1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-piperidin-4-yl)carbamate.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:26])=[C:8](C(O)=O)[NH:9][C:10]=1[CH:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[CH3:21])[NH:14][C:13]1=[O:22])([OH:3])=[O:2].[OH-].[K+].O.Cl>C(O)CO>[CH3:21][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[C:12](=[CH:11][C:10]1[NH:9][CH:8]=[C:7]([CH3:26])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:13](=[O:22])[NH:14]2
Reactant: Cc1cccc2c1C(=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O)C(=O)N2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1c[nH]c(C=C2C(=O)Nc3cccc(C)c32)c1CCC(=O)O
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
4-(2-carboxyethyl)-3-methyl-5-(4-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (300 mg) suspended in ethylene glycol (5 mL) was heated in a sealed tube in a pre-heated oil bath at 200° C. for 2 hours. The reaction mixture was cooled to 90° C. and potassium hydroxide (1 pellet) was added. It was then stirred at 90° C. for 30 minutes. The reaction mixture was cooled, poured into water, and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and purified on a silica gel column to give 115 mg (44% yield) of 3-[2-(4-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Br:11])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:6]=1)=[O:4].[OH-].[Li+]>O1CCCC1.O>[Br:11][C:8]1[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1
Reactant: COC(=O)c1cnc(Br)c(-c2ccc(F)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(Br)c(-c2ccc(F)cc2)n1
Reaction time: 0.25 h
Yield: 100.8 %

Procedure:
To a solution of 0.81 g 5-bromo-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid methyl ester in 10 ml tetrahydrofuran was added at room temperature 2.6 ml of a 1M solution of lithium hydroxide in water and the mixture was stirred for 15 minutes. The resulting solution was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic layer washed with water and brine. The organic phase was dried over magnesium sulfate and evaporated to yield 0.78 g of the title compound as white crystals. MS (ISP) (M+H+)=297.2 and 299.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([C:19]([O:21]C)=[O:20])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:8]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([C:19]([OH:21])=[O:20])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[CH:8]=1
Reactant: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(OC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a suspension of methyl 5-methoxy-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (10.0 g, 30.5 mmol) in MeOH (100 mL) was added 1 M NaOH aqueous solution (61 mL) at 0° C. The mixture was stirred at room temperature for 30 min. To the solution was added 1 M HCl aqueous solution (61 mL) at 0° C. The mixture was concentrated in vacuo. The precipitates were collected by filtration, washed with water and dried in vacuo at 60° C. to yield the title compound (8.78 g, 92% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.98 (3H, s), 7.82-8.01 (2H, m), 8.11-8.34 (2H, m), 8.97 (1H, s), 15.00 (1H, brs).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]OS(C)(=O)=O)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][S:16][C:13]3[CH:14]=[CH:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: COc1ccc(F)c(-c2ccc(S)cc2CC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1cccc(COS(C)(=O)=O)c1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1cccc(CSc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-thiol (161 mg) in DMF (2.6 mL) were added ethyl 3-cyclopropyl-3-(3-(((methylsulfonyl)oxy)methyl)phenyl)propanoate (207 mg) and potassium carbonate (146 mg) at room temperature, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (267 mg) as a colorless oil.