Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([OH:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>ClCCl.CCOCC>[CH:12](=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCC=O
Reaction time: 2 h

Procedure:
21.5 g (100 mmol) of pyridinium chlorochromate are suspended in 200 ml of anhydrous dichloromethane. 16 g (66 mmol) of hexadecanol in 50 ml of anhydrous dichloromethane are added dropwise. After 2 hours, the mixture is diluted with 300 ml of anhydrous ether, and the solution is decanted off from the black residue. The residue is washed three times with about 50 ml of anhydrous ether. The organic phases are combined and the ether is evaporated off to dryness. The residue is chromatographed on silica gel using petroleum ether/ethyl acetate 9:1. Yield: 15 g (95%), melting point 33°-34° C.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[H-].[Na+].Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1>O>[F:6][C:7]1[CH:14]=[C:13]([O:15][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: Fc1ccc(CCl)nc1
Reactant: O=Cc1ccc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccc(F)cn2)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.2 %

Procedure:
To an N,N-dimethylformamide (20.0 mL) solution of 2-fluoro-4-hydroxy-benzaldehyde (1.48 g, 10.2 mmol) was added sodium hydride (411 mg, 10.3 mmol, 60% in oil) under nitrogen atmosphere at 0° C., which was stirred for 20 minutes at room temperature. 2-Chloromethyl-5-fluoro-pyridine (1.20 g, 8.56 mmol) described in Manufacturing Example 41-1-2 was then added at room temperature, and stirred for 30 minutes at 80° C. Water was added at room temperature to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:5→1:2) to obtain the title compound (901 mg, 42.2%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)([CH3:22])[CH3:21].[Cl:30][C:31]1[C:36]([CH2:37]O)=[CH:35][CH:34]=[CH:33][N:32]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:30][C:31]1[C:36]([CH2:37][O:29][C:26]2[CH:27]=[CH:28][C:23]([CH:20]([CH3:22])[CH3:21])=[CH:24][CH:25]=2)=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: OCc1cccnc1Cl
Reactant: CC(C)c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1ccc(OCc2cccnc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a mixture of triphenylphosphine (2740 mg), 4-isopropylphenol (1138 mg), (2-chloropyridin-3-yl)methanol (1000 mg) and dehydrated THF (20 mL) was added DEAD (40% toluene solution, 4549 mg) at room temperature over 30 min. The reaction mixture was stirred at room temperature for 2 hr, DEAD (40% toluene solution, 919 mg) was added at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1623 mg) as an orange oil.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]=O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.[H][H]>CO.[Pd]>[CH3:11][C:10]1[CH:9]=[CH:8][C:7]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:2]=1[OH:1]
Reactant: [H][H]
Reactant: O=Cc1ccc2c(c1O)CCC2
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(c1O)CCC2
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of 4-Hydroxy-indan-5-carbaldehyde (5 gm) in Methanol (80 ml), 10% wt/wt Palladium-charcoal (500 mg) was added. The hydrogenation was carried out for 8 hours at 55-60° C. in an autoclave at 240-250 psi using Hydrogen gas. The reaction mixture was filtered through hyflow bed and distilled under vacuum to give 4.0 gm of title compound as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[O:13][C:12](=[O:14])[NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].I[CH2:18][CH3:19].CN(C)C=O.[H-].[Na+]>O>[CH2:18]([N:11]1[N:10]=[C:9]([CH2:8][C:7]2[CH:15]=[CH:16][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:13][C:12]1=[O:14])[CH3:19]
Reactant: O=c1[nH]nc(Cc2ccc([N+](=O)[O-])cc2)o1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(Cc2ccc([N+](=O)[O-])cc2)oc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
To a mixture of 5-(4-nitrobenzyl)-1,3,4-oxadiazol-2(3H)-one (1.50 g), iodoethane (1.59 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.30 g) at room temperature. The reaction mixture was stirred at room temperature for 3 hrs. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-ethyl-5-(4-nitrobenzyl)-1,3,4-oxadiazol-2(3H)-one as colorless crystals (0.99 g, yield 59%) from a fraction eluted with hexane-ethyl acetate (3:1-2:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 108-109° C.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:21])([CH3:20])[CH2:9][C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I[CH2:24][CH2:25][CH2:26]CCCCCC>>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:21])([CH3:20])[CH2:9][C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21
Reactant: CCCCCCCCCI
Product: CCCCCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21

Procedure:
Following a procedure similar to that used for the preparation of Intermediate 6a but using 1-iodo-n-nonane as the alkylating reagent the title compound was obtained as a colorless oil (70% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.CN(C=O)C.CS(O[CH2:19][C:20]1[C:21]2[CH:29]=[C:28]([CH:30]3[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[CH2:32][CH2:31]3)[S:27][C:22]=2[N:23]=[C:24]([CH3:26])[N:25]=1)(=O)=O>O>[CH3:36][C:33]1([CH3:37])[CH2:34][CH2:35][CH:30]([C:28]2[S:27][C:22]3[N:23]=[C:24]([CH3:26])[N:25]=[C:20]([CH2:19][N:1]4[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]4)[C:21]=3[CH:29]=2)[CH2:31][CH2:32]1
Reactant: Cc1nc(COS(C)(=O)=O)c2cc(C3CCC(C)(C)CC3)sc2n1
Reactant: O=S1(=O)CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(CN2CCS(=O)(=O)CC2)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a mixture of thiomorpholine-1,1-dioxide (70 mg) and DMF (4 mL) were added [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl methanesulfonate (120 mg) and TEA (150 μL), followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) to obtain 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine (102 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9][CH:8]=[C:7]([Br:24])[CH:6]=2.[C:25](N1C=CN=C1)(N1C=CN=C1)=[S:26]>C1COCC1>[Br:24][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:25](=[S:26])[NH:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2cc(Br)ccc12
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCn1c(=S)[nH]c2cnc3cc(Br)ccc3c21
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A solution of tert-butyl 3-[(3-amino-7-bromoquinolin-4-yl)amino]propylcarbamate (9.3 g, 23.5 mmol) and 1,1′-thiocarbonyldiimidazole (4.6 g, 26 mmol) in THF (250 mL), and the reaction mixture was heated at reflux for two hours. An analysis by liquid chromatography/mass spectrometry (LC/MS) indicated the reaction was incomplete, and additional 1,1′-thiocarbonyldiimidazole (1 g) was added. The reaction was heated at reflux for an additional hour, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was dissolved in water, and the resulting solution was extracted with tert-butyl methyl ether. The combined organic fractions were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with a gradient of 2% ammonium hydroxide/methanol in dichloromethane) to provide 4 g of tert-butyl 3-(7-bromo-2-thioxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate.
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:18]=1[NH2:24]>CO.C(O)(=O)C>[C:1]1([C:7]2[N:23]=[C:19]3[CH:20]=[CH:21][CH:22]=[N:17][C:18]3=[N:24][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccnc1N
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(-c2nc3cccnc3nc2-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of benzil (45.7 g, 217 mmol) and pyridine-2,3-diamine (23.7 g, 217 mmol) in methanol (514 ml) and acetic acid (57 ml) was heated at 160° C. for 10 mins using microwave radiation. The reaction mixture was concentrated in vacuo. To the crude residue in methanol (510 ml) was added activated charcoal (25 g) and the suspension was stirred at 60° C. for 1 h. The suspension was filtered hot, cooled and then was stirred in an ice bath. The solid was filtered, washed with cold methanol (50 ml) and dried in vacuo at 40° C. overnight to afford the title compound as pale brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:43][C:44]1[CH:45]=[C:46]([O:59][CH3:60])[CH:47]=[C:48]2[C:53]=1[O:52][C:51]([C:54]([O:56][CH3:57])=[O:55])=[CH:50][C:49]2=[O:58]>ClCCl>[CH3:60][O:59][C:46]1[CH:47]=[C:48]2[C:53](=[C:44]([NH:43][C:19]([CH2:18][CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][CH:10]([O:9][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:11][CH2:12]3)=[O:20])[CH:45]=1)[O:52][C:51]([C:54]([O:56][CH3:57])=[O:55])=[CH:50][C:49]2=[O:58]
Reactant: O=C(O)CCCN1CCC(OC(c2ccc(Cl)cc2)c2ccccn2)CC1
Reactant: COC(=O)c1cc(=O)c2cc(OC)cc(N)c2o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)c1cc(=O)c2cc(OC)cc(NC(=O)CCCN3CCC(OC(c4ccc(Cl)cc4)c4ccccn4)CC3)c2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
To 2.0 g (5.14 mmol) of 4-(4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidinyl)butanoic acid dissolved in 20 ml of dichloromethane was added 1.27 g (6.17 mmol) of dicyclohexylcarbodiimide, and the mixture was stirred at 0° C. for 30 minutes. To the reaction mixture was added 1.54 g (6.18 mmol) of 8-amino-6-methoxy-2-methoxycarbonylchromone, and the mixture was further stirred at 0° C. for 3 hours. The reaction mixture was allowed to stand at room temperature overnight and then concentrated under reduced pressure. To the residue was added ethyl acetate, and the insolubles were filtered off. The filtrate was concentrated under reduced pressure, and the residue was applied to silica gel column chromatography using a mixed solvent of chloroform and methanol in a volume ratio of 20:1 as an eluent to obtain 0.50 g (yield: 17%) of 1-(3-[N-(6-methoxy-2-methoxycarbonylchromon-8-yl)carbamoyl]propyl)-4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine as a brown foamy product.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]#[N:18])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH:20]=1)[CH:6]([CH3:8])[CH3:7].O>C(Cl)Cl>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([C:10]2[CH:11]=[CH:12][C:13]([CH2:15][CH2:16][C:17]#[N:18])=[CH:14][C:9]=2[CH2:5][CH:6]([CH3:7])[CH3:8])=[CH:20][C:21]=1[CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: COc1ccc(-c2ccc(CCC#N)cc2CC(C)C)cc1CC(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1cc(-c2ccc(CCC#N)cc2CC(C)C)ccc1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
2.37 ml (2.37 mmol, 3.00 eq.) of a 1 M solution of BBr3 in CH2Cl2 was added to a solution of 275.6 mg (0.79 mmol) 3-(2,3′-Diisobutyl-4′-methoxy-biphenyl-4-yl)propionitrile (73) in 25 ml dry CH2Cl2 at 0° C. via syringe. After that the solution was stirred for 3 h at 0° C. and then for 10 h at r.t. The reaction mixture was then added to water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (hexanes/EtOAc (2+1)) yielded 174.9 mg (0.52 mmol, 65.99%) 3-(4′-Hydroxy-2,3′-diisobutyl-biphenyl-4-yl)-propionitrile (74) as an oily white solid. Rf (hexanes/EtOAc (2+1))=0.38. 1H-NMR (500 MHz, CDCl3): δ=0.69 (d, 6H, J=6.62 Hz, 2*CH3), 0.92 (d, 6H, J=6.62 Hz, 2*CH3), 1.63 (m, 1H, CH), 1.93 (m, 1H, CH), 2.45 (d, 2H, J=7.25 Hz, CH2), 2.47 (d, 2H, J=7.25 Hz, CH2), 2.62 (t, 2H, J=7.41 Hz, CH2CH2CN), 2.94 (t, 2H, J=7.41 Hz, CH2CH2CN), 4.60 (s, br 6.75 (d, 1H, J=8.36 Hz), 6.92-6.96 (m, 2H), 7.01-7.06 (m, 2H), 7.11 (d, 1H, J=7.57 Hz). MS (EI): m/z=336 (24), 335 (100), 292 (18), 251 (10), 236 (35), 209 (12), 196 (10), 195 (48), 178 (10), 165 (10). HR-MS (EI): Calcd. for C23H29NO: 335.224914. Found: 335.225330.
Reaction SMILES: [C:1]([C:3]([CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[CH2:22]1[O:32][C:31]2[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][C:24]=2[O:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:27][C:26]2[CH:29]=[CH:30][C:31]3[O:32][CH2:22][O:23][C:24]=3[CH:25]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)C1CCCN(Cc2ccc3c(c2)OCO3)C1

Procedure:
A mixture containing 3-(R,S)-(1-cyano-1,1-diphenylmethyl)piperidine (0.27 g), 3,4-methylenedioxybenzyl chloride (0.18 g), anhydrous potassium carbonate (0.3 g) and acetonitrile (10 ml) was heated under reflux for 16 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 2%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless solid, yield 0.2 g, m.p. 127°-130° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([C:19]2[S:20][C:21]([CH2:25][O:26][CH3:27])=[CH:22][C:23]=2[Br:24])=O)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].Cl>N1C=CC=CC=1>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([C:19]2[S:20][C:21]([CH2:25][O:26][CH3:27])=[CH:22][C:23]=2[Br:24])=[N:2][OH:3])[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: COCc1cc(Br)c(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COCc1cc(Br)c(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
Add hydroxylamine hydrochloride (2.29 g, 45.27 mmol, 2.00 equivalents) to a stirred solution of 4-[1-(3-bromo-5-methoxymethyl-thiophen-2-yl)-methanoyl]-piperidine-1-carboxylic acid tert-butyl ester (9.47 g, 22.64 mmol, 1.00 equivalents) in pyridine (42.40 mL). Stir the resulting solution at room temperature overnight and then at 70° C. for 4 hours. Cool the reaction mixture slightly, add hydrochloric acid (3N, 100 mL) and extract the resulting mixture with dichloromethane (100 mL). Wash the extract with water (100 mL), dry over magnesium sulfate, filter and evaporate to yield the desired product as a yellow oil (9.48 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[Cl:10][CH2:11][S:12]([NH:15][C:16]1[CH:21]=[C:20]([N:22]=[C:23]=[O:24])[C:19]([F:25])=[CH:18][C:17]=1[Cl:26])(=[O:14])=[O:13].Cl>[OH-].[Na+].C(C(C)=O)C(C)C>[Cl:26][C:17]1[C:16]([NH:15][S:12]([CH2:11][Cl:10])(=[O:14])=[O:13])=[CH:21][C:20]([NH:22][C:23]([N:5]2[CH2:6][C@H:2]([OH:1])[CH2:3][C@@H:4]2[C:7]([OH:9])=[O:8])=[O:24])=[C:19]([F:25])[CH:18]=1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: O=C=Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: O=C(O)[C@H]1C[C@@H](O)CN1C(=O)Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Yield: 90 %

Procedure:
To a stirred solution of cis-4-hydroxy-D-proline (262 g, 2 mol) in 2 L of 1 N NaOH at 0° C. was added dropwise 1950 mL of a solution of 1-chloro-N-(2-chloro-4-fluoro-5-isocyanatophenyl)methanesulfonamide in methyl isobutyl ketone over 90 minutes. The temperature was kept between −3° C. and 5° C. The pH wag maintained at 8-9 by the addition of 550 mL of 10% NaOH. Stirring was continued at this temperature for another hour at pH 8 and then the two-phase mixture was allowed to come to room temperature. 70 mL of concentrated HCl was added in order to lower the pH to 6.5. After stirring for 20 minutes, the phases were separated. Methyl isobutyl ketone was added to the aqueous phase and the solution was acidified with concentrated hydrochloric acid to pH 2. After addition of solid sodium chloride and vigorous stirring the organic layer was separated. The solvent was removed to yield 775 g (90%) of the title compound (purity: 95-97% by HPLC). 1H NMR (Me2SO-d6) δ 12.4 (br s, 1H), 10.1 (br s, 1H), 8.2 (s, 1H), 7.7 (d, 1H), 7.5 (d, 1H), 5.1-5.0 (br s, 1H), 5.0-4.9 (s, 2H), 4.4 (m, 1H), 4.3 (m, 1H), 3.7-3.6 (m, 1H); 3.4-3.3 (m, 2H), 2.4-2.3 (m, 1H).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH2:9][CH2:8][C:7](=[C:10]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH2:16][C:15]3[CH:14]=[CH:13][S:12][C:11]2=3)[CH2:6][CH2:5]1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:13]1[S:12][C:11]2[C:10](=[C:7]3[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH2:16][C:15]=2[CH:14]=1
Reactant: CN1CCC(=C2c3ccccc3OCc3ccsc32)CC1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1CCC(=C2c3ccccc3OCc3cc(Br)sc32)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
Bromine (5 mL, 98 mmol) was added dropwise to a chloroform (300 mL) solution of 1-methyl-4-(10H-9-oxa-3-thiabenzo[f]azulen-4-ylidene)piperidine (19.3 g, 65.0 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hours, and a saturated aqueous sodium hydrogencarbonate solution was then added thereto to allow the separation of an organic layer. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate, the solvents were then distilled off under a reduced pressure, and the residue was purified by column chromatography (chloroform:methanol=9:1). The crystals were formed from a petroleum ether, to give 11.2 g (46%) of the captioned compound.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:22][N:23]([CH3:39])[CH:24]1[CH2:28][CH2:27][N:26]([C:29]2[S:30][C:31]3[CH:37]=[C:36]([NH2:38])[CH:35]=[CH:34][C:32]=3[N:33]=2)[CH2:25]1>CN(C=O)C.C(Cl)Cl>[CH3:22][N:23]([CH3:39])[CH:24]1[CH2:28][CH2:27][N:26]([C:29]2[S:30][C:31]3[CH:37]=[C:36]([NH:38][C:7]([C:4]4[CH:3]=[CH:2][C:1]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)=[CH:6][CH:5]=4)=[O:9])[CH:35]=[CH:34][C:32]=3[N:33]=2)[CH2:25]1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)c4ccc(-c5ccccc5)cc4)cc3s2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
Combine 4-biphenylcarboxylic acid (0.124 g, 0.623 mmol), dichloromethane (5.0 mL), and DMF (3 drops) with stirring. Add oxalyl chloride (0.11 mL, 1.25 mmol) and stir the mixture for 2 h at room temperature. Concentrate the mixture in vacuo, add hexane (approximately 10 mL), re-concentrate in vacuo, and re-dissolve in CH2Cl2 (4.0 mL). Transfer the mixture to a 40 mL reaction vial and add a mixture of 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (0.109 g, 0.415 mmol) (Example 1, step 3) in CH2Cl2 (2.0 mL). Stir the mixture overnight at room temperature. Dilute the reaction mixture with CH2Cl2 (25 mL), wash with saturated NaHCO3 (aqueous) (25 mL), and extract the aqueous phase with CH2Cl2 (25 mL). Wash the combined organic phases with saturated NaHCO3 (aqueous) (2×25 mL), dry over sodium sulfate, filter, and concentrate in vacuo to yield a yellow solid. Purify the crude product using silica gel chromatography (40 g column, 5% MeOH/CH2Cl2) to afford the title compound (53 mg, 29%). mass spectrum (m/e): 443.4 [M+1], 441.3 [M−1]. 1H NMR (400 MHz, CDCl3): δ 8.69-8.58 (m, 1H), 8.26 (s, 1H), 7.93 (d, 2H, J=8.0 Hz), 7.67 (d, 2H, J=7.6 Hz), 7.59 (d, 2H, J=7.2 Hz), 7.50-7.26 (m, 5H), 3.81 (t, 1H, J=10.4 Hz), 3.72 (t, 1H, J=8.8 Hz), 3.52 (m, 1H), 3.43 (m, 1H), 3.01 (m, 1H), 2.35 (s, 6H), 2.29 (m, 1H), 2.04 (m, 1H).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[C:8]1(O)[CH:13]=CC=[CH:10][CH:9]=1>C(O)(=O)C>[C:5]([O:4][C:1]1[CH:10]=[CH:9][CH:8]=[CH:13][CH:2]=1)(=[O:7])[CH3:6]
Reactant: Oc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Oc1ccccc1

Procedure:
reacting acetic anhydride with a phenol to produce a phenyl acetate and acetic acid;
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.[C:12]1([C:18]#[C:19][CH:20]2[CH:25]=[CH:24][NH:23][CH2:22][CH2:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:10][C:7]1[N:6]=[C:5]([NH2:11])[C:4]([CH2:3][N:23]2[CH2:22][CH:21]=[C:20]([C:19]#[C:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:25][CH2:24]2)=[CH:9][N:8]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: C(#CC1C=CNCC1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CC=C(C#Cc3ccccc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.19 g (0.00098 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 20 ml of dimethyl-formamide was treated with 0.15 g (0.82 mol) of 4-phenylethynyl-1,2,3,4-tetrahydro-pyridine and 0.34 ml (0.0024 mol) of triethylamine and the mixture was stirred at room temperature under argon for 16 hours. The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water, extracted, chromatographed over silica gel with acetonitrile/ethanol 8:1 as the eluent and digested in diethyl ether. 0.10 g (34%) of 2-methyl-5-(4-phenylethynyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-pyrimidin-4-ylamine as white crystals; m.p. 187°-188°.