Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[N:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[C:8]([CH:9]=[CH2:1])=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: O=Cc1cccnc1Br
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cccnc1Br
Temperature: 0 °C

Procedure:
See Spivey, A. C.; Shukla, L.; Hayler, J. F. Org. Lett. 2007, 9, 891-894. Butyllithium (22.75 mL, 59.1 mmol) was added to the THF (450 mL) suspension of methyltriphenylphosphonium bromide (21.13 g, 59.1 mmol) at 0° C. The solution turned to orange and the reaction was lift to room temperature for 30 min before cooled it back to 0° C. 2-bromonicotinaldehyde (10 g, 53.8 mmol) in 50 mL THF was added through canula to the reaction solution. The precipitate was formed and the reaction was lift to room temperature. The color of the reaction turned to green, gray. After a while, the color of to reaction became orange again. The reaction was stirred at room temperature over weekend. The solvent was removed mostly via vacuum and the crude was partitioned between water and diethyl ether. The organic layer was separated and the aqueous layer was extract twice with diethyl ether. The diethyl ether layer was combined, dried (Na2SO4), filtered and concentrated. The product was obtained by flash column eluted with ethyl acetate in hexane (10%) as yellow oil (8.78 g, 89%). MS (ESI)[M+H+]=184.04; 1H NMR δ ppm (400 MHz, CHLOROFORM-d) 8.21-8.29 (m, 1H) 7.78 (dd, J=7.68, 1.89 Hz, 1H) 7.20-7.28 (m, 1H) 6.96 (dd, J=17.37, 11.08 Hz, 1H) 5.72 (d, J=17.37 Hz, 1H) 5.46 (d, J=11.08 Hz, 1H).
Reaction SMILES: [CH:1]1[C:14]2[C:5]([S:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[Cl:27]Cl.O>C(O)(=O)C>[Cl:27][C:4]1[C:3](=[O:15])[CH:2]=[CH:1][C:14]2[C:5]=1[S:6][C:7]1[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=1)[N:13]=2
Reactant: ClCl
Reactant: O=c1ccc2nc3ccccc3sc-2c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc2nc3ccccc3sc-2c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 500 g (2.34 mol) of 3H-phenothiazin-3-one in 12.5 liters of glacial acetic acid was added 1.25 kg of potassium dichromate. The mixture was stirred at room temperature for 1/2 hour. To this resulting mixture was then added 2.34 mol of a 1M solution of chlorine in glacial acetic acid dropwise over a period of 4 hours. The progress of the reaction was monitored by tlc to ensure no excess chlorine was added. After addition of chlorine was completed the mixture was stirred at room temperature for another 1/2 hour and was then poured into 120 liters of H2O with vigorous stirring. The 4-chloro-3H-phenothiazin-3-one which precipitated was allowed to settle overnight. The majority of the aqueous solution was siphoned off and discarded and the rest was filtered. The filtered precipitate was washed thoroughly with water and then rinsed with methanol and was allowed to dry to give 504 g crude 4-chloro-3H-phenothiazin-3-one which was recrystallized from toluene. m.p.: 221° C.
Reaction SMILES: S(=O)(=O)(O)O.C(O[CH:9]=[CH:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:12])C>O>[CH3:25][O:24][C:22]1[CH:21]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:15]2[CH:9]=[CH:10][C:11](=[O:12])[NH:13][C:14]=2[CH:23]=1
Reactant: CCOC=CC(=O)Nc1cc(OC)cc(C(=O)OC)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc(OC)cc2[nH]c(=O)ccc12
Reaction time: 1 h
Yield: 22.3 %

Procedure:
To 5 mL of concentrated sulfuric acid cooled with ice, 1.86 g of methyl 3-((3-ethoxyacryloyl)amino)-5-methoxybenzoate was added little by little, and the mixture was stirred for 1 hour under cooling with ice. The reaction mixture was fed into water cooled with ice, the insoluble material was collected by filtration, and the insoluble material thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60 manufactured by Kanto Chemical Co., Inc., eluent; chloroform:methanol=50:1] to obtain 346 mg of methyl 7-methoxy-2-oxo-1,2-dihydroquinoline-5-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[C:20]([F:27])=[C:21]([OH:26])[C:22]([F:25])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:28]([O:33][CH3:34])(=[O:32])[C@H:29]([CH3:31])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[C:20]([F:27])=[C:21]([C:22]([F:25])=[CH:23][CH:24]=2)[O:26][C@H:29]([CH3:31])[C:28]([O:33][CH3:34])=[O:32])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: COC(=O)[C@H](C)O
Reactant: Oc1c(F)ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: COC(=O)[C@@H](C)Oc1c(F)ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 86 %

Procedure:
To a solution of 3-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-2,6 difluoro-phenol (0.570 g, 1.29 mmol), commercially available (S)-lactic acid, methyl ester. (0.246 mL, 2.58 mmol) and triphenylphosphine (0.677g, 2.58 mmol) in dry benzene (7 mL) was added diethylazodicarboxylate (0.406 mL, 2.58 mmol) dropwise at room temperature under a dry nitrogen atmosphere. The reaction mixture was sealed in a pressure bottle and immersed in a pre-heated oil bath at 105° C. After heating for 2.5 hours the mixture was stirred at ambient temperature for about 14 hours. The reaction mixture was then diluted with methylene chloride and combined with silica gel. The solvents were removed and the adsorbate was flash chromatographed (90/10 petroleum ether/ethyl acetate) to give (R)-2-[3-(6-bromo-benzo[b]naphtho[2,3-d ]thiophen-11-yl)-2,6-difluoro-phenoxy]-propionic acid, methyl ester as a white solid (0.59 g, 86%). To a solution of this methyl ester (0.46 g, 0.929 mmol) in tetrahydrofuran (18 mL) and methanol (6 mL) was added a 1 N aqueous solution of potassuim hydroxide (1.39 mL, 1.39 mmol) dropwise at room temperature. After stirring for 2 hours the solvents were removed and the residue was combined with water (50 mL) and acidified with 10% HCl. The solid was extracted into ether. The layers were shaken together well, separated, and the organic layer was washed with water and concentrated to give the title compound as a white solid (0.396 g, 88%): [a]D25=+13.22 (9.383 mg/mL methanol); NMR (400 MHz, DMSO-d6): δ13.11 (s, 1 H), 8.31 (d, J=8 Hz, 1H), 8.10-8.08 (m, 1H), 7.83-7.78 (m, 1H), 7.65-7.46 (m, 4 H), 7.32-7.19 (m, 2 H), 6.82-6.75 (m, 1 H), 4.98-4.93 (m, 1 H), 1.53-1.50 (m, 3 H); MS (-FAB): (M-H): one bromine pattern observed: 511/513 (2%); Anal. Calc. for C25H15BrF2O3S: C, 58.49, H, 2.95, N, 0.00. Found: C, 58.41, H, 3.44, N, 0.02.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[S:6][CH:7]=[C:8]([CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:11]3=[O:19])[C:4]=2[CH:3]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([O:26][C:22](=[O:25])[CH2:23][CH2:24][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH2:9][C:8]2[C:4]3[CH:3]=[C:2]([Cl:1])[CH:21]=[CH:20][C:5]=3[S:6][CH:7]=2)[C:11]1=[O:19])[CH3:28]
Reactant: C=CC(=O)OCC
Reactant: O=c1[nH]c2ccccc2n1Cc1csc2ccc(Cl)cc12
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1c(=O)n(Cc2csc3ccc(Cl)cc23)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(5-Chloro-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (50 mg, 0.16 mmol) in DMF (2 mL) were added ethyl acrylate (0.02 mL) and benzyltrimethyl ammonium hydroxide (20 mg, 0.01 mmol). The resulting mixture was stirred at room temperature overnight. When the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 50 mg of the desired product as a colorless oil. LCMS (ESMS): m/z 415.78 (M+H+).
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].C(N(CC)CC)C.[Cl:17][C:18]([Cl:23])([Cl:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:1][CH:2]=[CH:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[C:19](=[O:20])[C:18]([Cl:23])([Cl:22])[Cl:17]
Reactant: COCCNCC=CCl
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(CC=CCl)C(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.7 %

Procedure:
N-(3-chloro)allyl-N-methoxyethylamine (2.25 g, 0.015 mol) and 1.52 g (0.015 mol) triethylamine were stirred in 70 ml dichloromethane. The reaction was kept at approximately 5° C. with an ice-water bath. Trichloroacetyl chloride (2.73 g, 0.015 mol) in 10 ml dichloromethane was added dropwise to the cooled solution. Upon completion of the addition, the mixture was stirred at room temperature for 6 hours. The reaction mixture was then washed twice with saturated brine and dried with sodium sulfate. Rotary evaporation yielded 4.1 g of the above-named product.
Reaction SMILES: Cl[C:2]1[C:3]2[S:22][CH2:21][CH2:20][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[C:23]1([NH2:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[C:23]1([NH:29][C:2]2[C:3]3[S:22][CH2:21][CH2:20][C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:10][CH2:9]3)[N:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Clc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Reactant: Nc1ccccc1
Solvent: O
Product: c1ccc(Nc2nc(N3CCN(c4ccccc4)CC3)nc3c2SCC3)cc1
Yield: 51 %

Procedure:
0.300 g (0.90 mmol) of 4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (V) and 3 mL of phenylamine are combined, then reacted for 0.3 hours at 130° C. in the microwave. Then the reaction mixture is combined with water and extracted with ethyl acetate. The organic phase is dried and evaporated to dryness. The residue is triturated with diethyl ether and suction filtered. 0.18 g of product I (51%) is obtained (m.p. 174° C.-175° C.). 1H-NMR (400 MHz, DMSO): 8.59 (1H, s); 7.63 (2H, d); 7.31 (2H, t); 7.22 (2H, t); 7.03 (1H, t); 6.99 (2H, d); 6.80 (1H, t); 3.83-3.73 (4H, m); 3.31 (2H, t); 3.23 (4H, m); 3.12 (2H, t).
Reaction SMILES: [CH2:1]([C:5]1([CH2:21][CH2:22][CH2:23][CH3:24])[C:17]2[CH:16]=[C:15]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:29](Cl)(=[O:31])[CH3:30].O>[N+](C1C=CC=CC=1)([O-])=O>[CH2:1]([C:5]1([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]2[CH:7]=[C:8]([C:29](=[O:31])[CH3:30])[CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)c2ccccc2-c2ccc([N+](=O)[O-])cc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCC1(CCCC)c2cc(C(C)=O)ccc2-c2ccc([N+](=O)[O-])cc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
After 7.0 g of 9,9-di-n-butyl-2-nitrofluorene (5) (21.7 mmol) was dissolved in 200 ml of anhydrous nitrobenzene and 5.77 g of anhydrous aluminum chloride (43.4 mmol) was added thereto, the reaction mixture was heated to 45° C., and a solution in which 3.40 g of acetyl chloride (43.3 mmol) was dissolved in 40 ml of anhydrous nitrobenzene was slowly added thereto for 1 hour, followed by stirring at 65° C. for 1 hour. Thereafter, the reaction mixture was cooled to room temperature, 100 ml of distilled water was added thereto and stirred for about 30 minutes, followed by extracting the product with 200 ml of dichloromethane. The extracted organic layer was sequentially washed with 100 ml of saturated aqueous sodium bicarbonate solution and 100 ml of distilled water. Then, a solid product obtained by drying the recovered organic layer over anhydrous magnesium sulfate and distilling a solvent under reduced pressure was dispersed in a small amount of ether and stirred at room temperature for 30 minutes, followed by filtering and drying, thereby obtaining 5.44 g of 1-(9,9-di-n-butyl-7-nitrofluorene-2-yl)-ethanone (6) (68.7%) as a light yellow product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[O:18])[S:10][N:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:34]1([CH3:43])[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1>CN(C)C=O.CCOC(C)=O>[CH3:43][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])=[O:18])[S:10][N:9]=3)=[CH:6][CH:7]=2)=[O:42])=[CH:36][CH:35]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)N1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)Nc2ccc(-c3nsc(NC(=O)N4CCCC4=O)c3C(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A solution of 3-(4-aminophenyl)-5-{[(2-oxopyrrolidin-1-yl)carbonyl]amino}isothiazole-4-carboxamide (9.6 g, 0.027 mol), diisopropylethylamine (5.3 g, 0.046 mol) in dimethylformamide (150 mL) at ambient temperature was treated with para-Tolyl isocyanate (4.0 g 0.03 mol) over 20 minute period. The resulting mixture was stirred at ambient temperature for 2 hr. The reaction mixture was concentrated in vacuo to give an off white solid, which was stirred in EtOAc (150 mL), filtered the solid and washed with EtOAc to give the title compound as a white solid (11.8 g, 88%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:14][C:15]([C:17]1([C:48]([OH:50])=[O:49])[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:34]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[C:37]([F:47])[CH:36]=4)[O:32][N:31]=3)=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:51]([O:57][CH2:58]Cl)(=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53].O>CN(C)C(=O)C>[CH3:53][C:52]([CH3:55])([CH3:54])[C:51]([O:57][CH2:58][O:49][C:48]([C:17]1([C:15]([O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:16])[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[N:34]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=5)=[C:37]([F:47])[CH:36]=4)[O:32][N:31]=3)=[CH:28][CH:29]=2)[CH2:19][CH2:18]1)=[O:50])=[O:56]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)C(=O)OCOC(=O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium carbonate (0.125 g, 0.0012 mol) is added to a solution of 1-{4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole-3-yl]benzyl}piperidine-4,4-dicarboxylic acid mono benzyl ester (0.35 g, 0.00059 mol) in N,N-dimethylacetamide (3.5 mL). The reaction mixture is stirred for 30 minutes at room temperature. Chloromethyl pivalate (0.187 g, 0.0012 mol) is added to the reaction mixture which is then heated at 65° C. for 4 hrs. The reaction mixture is treated with demineralized water (5 mL) and extracted in ethyl acetate (2×5 mL). Sodium chloride (0.25 g) is added to the ethyl acetate layer and stirred for 15 minutes. Demineralized water (5 mL) is added to the ethyl acetate layer and the layers are separated. The ethyl acetate layer is dried over sodium sulphate. Removal of solvent under reduced pressure gives a viscous liquid, which is purified by column chromatography (silica gel 230-400 mesh, n-hexane:ethyl acetate 70:30) to furnish 1-{4-[5-(2-fluorobiphenyl-4-yl)-1,2,4oxadiazol-3-yl]benzyl}-piperidine-4,4-dicarboxylic acid benzyl ester (2,2-dimethylpropanoyloxymethyl) ester.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1COCC1.CCO.O>[N:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])[CH:25]=[N:24][CH:23]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(I)c1
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(-c2cncnc2)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 3-iodo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.1, 550 mg, 1.351 mmol), pyrimidin-5-ylboronic acid (418 mg, 3.38 mmol), Na2CO3 (716 mg, 6.75 mmol), DME (6304 μL), water (1801 μL) and EtOH (901 μL) was stirred at 80° C. for 1 h. THF (5 mL) was added and the mixture was treated with Si-Thiol (938 mg, 1.351 mmol), stirred for 2 h and filtered through Florisil®. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by flash chromatography (Biotage Silica gel column, 25 g, cyclohexane/EtOAc, from 20% to 75% EtOAc) to yield the title compound as a white solid. UPLC-MS (Condition 1) tR=360.0 [M+H]+, m/z=358.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.40 (m, J=8.3 Hz, 2H) 7.72 (t, 1H) 7.91 (m, J=8.6 Hz, 2H) 7.98-8.11 (m, 2H) 8.36 (br. s, br. s, 1H) 9.19-9.31 (m, 3H) 10.52 (br. s, br. s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1>Cl.O1CCOCC1>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][CH:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC2CCN(CC3CC3)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C1CC(CC2CCN(CC3CC3)CC2)CCN1
Yield: 71.2 %

Procedure:
1,1-Dimethylethyl 4-{[1-(cyclopropylmethyl)-4-piperidinyl]methyl}-1-piperidinecarboxylate (may be prepared as described in Description 9) (2.0 g) was stirred in a solution of HCl-Dioxane (700 ml, 4M) for 2 h. The solvent was evaporated and the resultant yellow solid was dissolved in saturated potassium carbonate (25 ml). The solution was extracted into dichloromethane (3×50 ml) and the combined organics dried (MgSO4) and evaporated to give the title compound (D10) (1.0 g).
Reaction SMILES: Cl.N[C@@H](C)[C@@H:4](C1C=CC(OC)=CC=1)[OH:5].[O:15]=[C:16]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:17]([NH:20]C(=O)OC(C)(C)C)[CH2:18][CH3:19]>>[NH2:20][C@@H:17]([CH2:18][CH3:19])[C@@H:16]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([O:5][CH3:4])[CH:33]=1)[OH:15]
Reactant: COc1ccc([C@@H](O)[C@H](C)N)cc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Agent: Cl
Product: CC[C@H](N)[C@H](O)c1cccc(OC)c1

Procedure:
was synthesised in the same way as 90b from (S)-tert-butyl 1-oxo-1-phenylbutan-2-ylcarbamate (97c, 225 mg, 0.768 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]CC)=[O:12])[CH:10]=1)[N:7](C(OC(C)(C)C)=O)[CH:6]=[C:5]2[CH:23]1[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[C:25]([CH3:32])([CH3:31])[CH2:24]1.[OH-].[Na+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:23]1[CH2:28][CH2:27][S:26](=[O:29])(=[O:30])[C:25]([CH3:32])([CH3:31])[CH2:24]1
Reactant: CCOC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C(C)(C)C3)cn(C(=O)OC(C)(C)C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CC(c2c[nH]c3c(C(=O)O)cc(Br)cc23)CCS1(=O)=O
Temperature: 80 °C
Yield: 94.5 %

Procedure:
1-(1,1-dimethylethyl) 7-ethyl 5-bromo-3-(2,2-dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-1,7-dicarboxylate (685 mg, 1.296 mmol) was placed in a flask and dissolved in methanol (6 mL) and water (3 mL). An aqueous solution of sodium hydroxide 6N in water (3.24 mL, 19.44 mmol) was added. The mixture was heated in a microwave for 30 mins at 80° C. The mixture was acidified with aqueous HCl 1N until pH=1, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4) and the solvent removed under vacuum to afford 490 mg of the title compound as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[C:18]([CH2:19][OH:20])=[CH:17][N:16]=[C:15]([S:21][CH3:22])[N:14]=1)[CH2:9][CH2:8]2>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[C:18]([CH:19]=[O:20])=[CH:17][N:16]=[C:15]([S:21][CH3:22])[N:14]=1)[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(Nc1nc(SC)ncc1CO)CC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cccc2c1C(Nc1nc(SC)ncc1C=O)CC2
Reaction time: 18 h
Yield: 80.6 %

Procedure:
To a solution of (4-(7-methoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(methylthio)pyrimidin-5-yl)methanol (2.36 g, 7.43 mmol) in dichloromethane (80 mL) was added manganese dioxide (90%, 3.87 g, 40 mmol) in small portions. The resulting suspension was stirred for 18 h. Additional manganese dioxide (90%, 3.87 g, 40 mmol) was added and the mixture was stirred for an additional 18 h. The mixture was filtered through Celite and washed with dichloromethane (5×10 mL). The combined filtrates were evaporated in vacuo to give 4-(7-methoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(methylthio)pyrimidine-5-carbaldehyde as a light brown solid (1.89 g, 5.99 mmol, 80%). ESMS m/z 316 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1)(=O)=O.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>>[N:17]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(CCCOS(C)(=O)=O)cn1
Product: COc1ccc(CCCn2ccnc2)cn1
Yield: 94 %

Procedure:
In substantially the same manner as in Reference Example 88, 3-(2-methoxy-5-pyridyl)propyl methanesulfonate was reacted with imidazole to give 5-[3-(1-imidazolyl)propyl]-2-methoxypyridine. The yield was 94%. Oily substance.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].[CH3:10][C:11]1([CH3:18])[C:15]([CH3:17])([CH3:16])[O:14][BH:13][O:12]1.C(N(CC)CC)C>O1CCCC1.[H-].[Cl-].C1([Zr+2]C2C=CC=C2)C=CC=C1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])/[CH:5]=[CH:6]/[B:13]1[O:14][C:15]([CH3:17])([CH3:16])[C:11]([CH3:18])([CH3:10])[O:12]1)[CH3:2]
Reactant: CC1(C)OBOC1(C)C
Reactant: C#CC(OCC)OCC
Agent: C1=CC([Zr+2]C2C=CC=C2)C=C1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(/C=C/B1OC(C)(C)C(C)(C)O1)OCC
Temperature: 50 °C
Yield: 43.1 %

Procedure:
A mixture of 3,3-diethoxy-1-propyne (18.5 g, 0.144 mol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27.6 g, 0.216 mol) and bis(cyclopentadienyl)zirconium chloride hydride (1.9 g, 0.007 mol) in tetrahydrofuran (75 mL) was heated at 50° C. for 2 days. Triethylamine (2 mL) was added and the solvent was removed in vacuo. The residue was distilled at 90° C. at 10 torr. The residue was purified by column chromatography on neutral alumina using 89:10:1 dichloromethane:ethyl acetate:triethylamine as an eluent. The solvent was removed in vacuo to give the title compound (15.9 g, 53%) as a brown oil. 1H NMR (DMSO-d6, 400 MHz) δ 6.48 (dd, 1H), 5.75 (d, 1H), 4.85 (d, 1H), 3.55–3.67 (m, 2H), 3.40–3.52 (m, 2H), 1.22 (s, 12H), 1.17 (t, 6H).