Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)[CH:2]=[CH2:3].ClC(N(C)C)=C(C)C.C(N(CC)CC)C>ClCCl>[CH2:3]1[CH:2]2[CH2:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH:10]2[C:11]1=[O:13]
Reactant: C=CCc1ccccc1CC(=O)O
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC2Cc3ccccc3C12
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution of 2-allyl phenyl acetic acid (Example I2, Step 2, 0.095 g, 0.539 mmol) in dichloromethane (25 mL) was added at 0° C. 1-chloro-N,N,2-trimethyl-1-propenylamine (0.078 mL, 0.593 mmol). The solution was stirred for 1 h and then heated to reflux. Then, a solution of triethylamine (0.082 mL, 0.593 mmol) in dichloromethane (4 mL) was added slowly over two hours to the solution of the acid chloride at reflux. The reaction mixture was stirred for another 2 h and then cooled down. The solvents were removed in vacuo and the residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (20/1) to give 1,2a,7,7a-tetrahydro-2H-Cyclobut[a]inden-2-one (colourless oil, 56 mg, 66%) The analytical data were identical to the product obtained with the method A.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([CH2:14][NH2:15])[OH:13].[BH4-].[Na+].O>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH:15][CH2:14][CH2:12][OH:13])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: NCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccc(CNCCO)c1
Temperature: 80 °C
Yield: 91.5 %

Procedure:
500 mg of 3-nitrobenzaldehyde and 202 mg of ethanol amine were dissolved in 10 mL of ethanol, followed by stirring at 80° C. To this was added 125 mg of sodium borohydride, followed by stirring for 3 hours. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was then washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 594 mg (yield 92%) of a title compound as a yellow solidified product.
Reaction SMILES: O=O.[CH2:3]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)=[C:14]([F:25])[CH:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[Li+].CC([N-]C(C)C)C>C1COCC1.CN1C(=O)N(C)CCC1>[CH2:3]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:20][N:19]=2)=[C:14]([F:25])[CH:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C)cn2)c(F)c1
Reactant: CCCCCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: O=O
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCCCCCCCCc1ccc(-c2ccc(OCCCCCCCC)cc2F)nc1
Temperature: 25 °C

Procedure:
With atmospheric oxygen and moisture being excluded, 7.9 mmol of 2-(4-octyloxy-2-fluorophenyl)-5-methylpyridine dissolved in THF and, about 15 minutes later, 8.7 mmol of 1-bromooctane are added at -70° C. to a solution of 8.7 mmol LDA (prepared from BuLi and diisopropylamine) in THF in the presence of 1.04 ml of DMPU. The reaction mixture is allowed to heat up to room temperature, stirring is continued for a further hour and working up is carried out as usual.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].Cl.[O:33]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34]1.C(N(CC)CC)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:38][CH:35]3[CH2:36][CH2:37][O:33][CH2:34]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: NC1CCOC1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(NC2CCOC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 30 %

Procedure:
Following the general procedure outlined in Example 195, the product of Example 48 (125 mg, 0.28 mmol), the crude tetrahydro-furan-3-ylamine hydrochloride (240 mg) and triethylamine (0.27 mL, 1.9 mmol) were reacted to give the crude material. Purification by flash chromatography, eluting with EtOAc/hexane/triethylamine (50/50/2, v/v/v), gave the desired product (38 mg, 30%). LC-MS: 453.2 (MH+, m/z), 2.20 (Rt, min).
Reaction SMILES: Cl.[OH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:12])[CH2:6][CH2:5]1.[Cl:19][C:20]1[C:21]([CH3:30])=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C>C(#N)C>[Cl:19][C:20]1[C:21]([CH3:30])=[C:22]([S:26]([N:15]2[CH2:16][CH2:17][CH2:18][C@H:13]([C:11]([NH:10][C@H:7]3[CH2:6][CH2:5][C@H:4]([CH2:3][OH:2])[CH2:9][CH2:8]3)=[O:12])[CH2:14]2)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(N[C@H]1CC[C@H](CO)CC1)[C@H]1CCCNC1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](C(=O)N[C@H]2CC[C@H](CO)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3S)-N-[trans-4-(hydroxymethyl)cyclohexyl]piperidine-3-carboxamide hydrochloride (170 mg, 0.61 mmol), 3-chloro-2-methylbenzenesulfonyl chloride (138 mg, 0.61 mmol), and triethylamine (0.21 mL, 1.54 mmol) in acetonitrile (3 mL) was stirred at r.t. for 2 hours. After removal of solvent, the residue was loaded on flash column with methylene chloride and eluted with ethyl acetate-hexane. 110 mg final product was obtained. (Yield: 41%). LCMS: m/z 429.0 (M+H)+; 879.2 (2M+Na)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([C:18]([NH2:21])=[CH:19][CH:20]=1)[CH:16]=O.Cl>CO>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[C:18]([NH2:21])=[CH:19][CH:20]=1
Reactant: Nc1ccc(Cl)cc1C=O
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: Nc1ccc(Cl)cc1C=C1Oc2cc(O)ccc2C1=O
Temperature: 25 °C
Yield: 74.1 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-chloro-6-aminobenzaldehyde 1.24 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 1.42 g.
Reaction SMILES: [CH2:1]([C:4]1[C:5]2[CH:6]=[CH:7][C:8]([O:27][CH3:28])=[C:9]([O:25][CH3:26])[C:10]=2[CH2:11][NH+:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]4[O:24][CH2:23][O:22][C:17]=4[CH:18]=3)[C:13]=12)[CH:2]=[CH2:3].[Br-].[C:30]([Mg]Br)([CH3:32])=[CH2:31].O1CCCC1>C(OCC)C>[CH2:1]([C:4]1[C:5]2[CH:6]=[CH:7][C:8]([O:27][CH3:28])=[C:9]([O:25][CH3:26])[C:10]=2[CH:11]([C:30]([CH3:32])=[CH2:31])[N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]4[O:24][CH2:23][O:22][C:17]=4[CH:18]=3)[C:13]=12)[CH:2]=[CH2:3]
Reactant: C=CCC1=C2c3cc4c(cc3CC[NH+]2Cc2c1ccc(OC)c2OC)OCO4
Reactant: C=C(C)[Mg]Br
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC1=C2c3cc4c(cc3CCN2C(C(=C)C)c2c1ccc(OC)c2OC)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a suspension of 13-allyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; bromide (300 mg, 0.66 mmol) in anhydrous diethyl ether (20 mL) at 0° C. was added a solution of isopropenylmagnesium bromide in tetrahydrofuran (0.5 M, 20 mL, 10 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (50 mL). The mixture was extracted with diethyl ether (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 13-allyl-8-isopropenyl-9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (75 mg, 27%). LC/MS m/e calcd for C26H27NO4 (M+H)+: 418.51, observed: 418.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3 H) 2.64-2.80 (m, 2 H) 2.97-3.06 (m, 1 H) 3.18-3.25 (m, 1 H) 3.72 (s, 3 H) 3.79 (s, 3 H) 4.63 (s, 1 H) 4.73 (s, 1 H) 5.06-5.18 (m, 3 H) 6.02 (s, 2 H) 6.05-6.15 (m, 1 H) 6.81 (m, 1 H) 6.86 (s, 1 H) 6.91 (m, 1 H) 6.98 (s, 1 H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 427 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][N:22]([CH3:35])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][NH:33][CH3:34])=[CH:25][CH:24]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:33]([CH3:34])[CH2:32][CH2:31][CH2:30][O:29][C:26]3[CH:25]=[CH:24][C:23]([N:22]([CH3:21])[CH3:35])=[CH:28][CH:27]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNCCCOc1ccc(N(C)C)cc1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCOc1ccc(N(C)C)cc1)CC2

Procedure:
The title compound is prepared from [3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane, N-[3-(4-dimethylaminophenyloxy)-propyl]-methylamine and triethylamine analogously to Example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[CH:17]=C)=[O:5].I([O-])(=O)(=O)=[O:25].[Na+].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[CH:17]=[O:25])=[O:5]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reaction time: 0.08 h
Yield: 56.3 %

Procedure:
To a suspension of 8-(2,6-dichlorobenzoylamino)-4-vinylquinoline (150 mg) in dioxane and water was added catalytic amount of osmium tetroxide in tert-butanol under ice-cooling, and the mixture was stirred for 5 minutes. To the mixture was added sodium periodate (206 mg) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature and for 6 hours at ambient temperature. To the mixture was added saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (dichloromethane-n-hexane) to give 8-(2,6-dichlorobenzoylamino)-4-formylquinoline (85 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.O1CC1C[CH:16]([O:25][CH:26]([CH2:35][CH:36]1OC1)C1C=CC(OC)=CC=1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.[O:40]1CCCC1>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH2:36][CH:35]([OH:40])[CH2:26][O:25][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH:3]=1
Reactant: C1CCOC1
Reactant: COc1ccc(C(CC2CO2)OC(CC2CO2)c2ccc(OC)cc2)cc1
Reactant: Brc1cccnc1
Agent: [Li]C(C)(C)C
Product: COc1ccc(COCC(O)Cc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Bromopyridine (3.5 g, 0.022 mol) in dry tetrahydrofuran (5 ml) was added dropwise to a stirred solution of t-butyllithium (1.4M, 15.7 ml, 0.022 mol) in dry tetrahydrofuran (100 ml) at -100° C. under nitrogen atmosphere. The resultant solution was stirred for 20 min and cuprous iodide-trimethyl phosphite complex (6.9 g, 0.022 mol) in dry tetrahydrofuran (15 ml) added. After a further 10 min, 2,3-epoxypropyl-4-methoxybenzyl ether (4.27 g, 0.022 mol) in dry tetrahydrofuran (10 ml) was added and the mixture allowed to warm up from -100° to 20° C. over 3 hours and left to stir overnight at room temperature. The mixture was quenched with saturated aqueous ammonium chloride and evaporated in vacuo. The solid was extracted with ethyl acetate (300 ml), washed with water and dried (MgSO4). Filtration and evaporation of solvent in vacuo gave a crude oil which was purified by column chromatography (silica gel/chloroform). Recrystallisation from ether/pentane gave pure 1-(3-pyridyl)-3-[(4-methoxyphenyl)methoxy]propan-2-ol as a colourless crystalline solid, m.p. 55°-56°.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6](F)=[C:5]([CH:18]=[CH2:19])[C:4]=1[CH3:20])#[N:2].C(N(CC)CC)C.[CH3:28][N:29]([CH3:35])[C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6]([N:32]2[CH2:33][CH2:34][C@H:30]([N:29]([CH3:35])[CH3:28])[CH2:31]2)=[C:5]([CH:18]=[CH2:19])[C:4]=1[CH3:20])#[N:2]
Reactant: C=Cc1c(C)c(C#N)c2nc(C(=O)N(C)C)oc2c1F
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C=Cc1c(C)c(C#N)c2nc(C(=O)N(C)C)oc2c1N1CC[C@H](N(C)C)C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 70.3 %

Procedure:
4-Cyano-7-fluoro-N,N,5-trimethyl-6-vinyl-1,3-benzoxazole-2-carboxamide (I-185) (130 mg, 0.48 mmol) was dissolved in dimethyl sulfoxide (8 ml), then at room temperature, triethylamine (100 μl, 0.48 mmol) was added. The solution was gradually heated from room temperature up to 150° C. under nitrogen atmosphere, a solution of (3S)-3-(dimethylamino)pyrrolidine (79 μl, 0.62 mmol) dissolved in dimethyl sulfoxide (1 ml) was added all at a time. The solution was stirred at the same temperature for 1.25 hours, and the cooled to room temperature. This was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=93:7) to obtain a roughly-purified product (124 mg). This was washed with diisopropyl ether to obtain the entitled compound (87 mg, 50%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[C:18]1(O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[O:17]([CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[CH:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccccc1
Reactant: Nc1nc2ccccc2c2c1ncn2CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2c2c1ncn2CCOc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (25 mg, 0.108 mmol) and N,N-dimethylformamide (1 mL) were combined. Phenol (12 mg, 0.130 mmol) and triphenylphosphine (34 mg, 0.130 mmol) were added and the resulting slurry was sonicated for about 1 minute. Diethyl azodicarboxylate (23 mg, 0.130 mmol) was added and the reaction mixture was shaken at ambient temperature for 24 hours. Analysis by LC-MS showed that a major amount of starting material remained. An additional equivalent each of phenol, triphenylphosphine and diethyl azodicarboxylate were added. The reaction mixture was sonicated for 30 minutes. After 1 hour analysis by LC-MS showed product. The solvent was removed and the residue was purified by semi-preparative HPLC using Method A. Mass Measurement: TM=304, NM[M+H]+1=305.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH3:27])[C:13]=3[NH:17][C:18](=[O:26])[CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:8]=2)[CH2:3]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[CH3:27][C:12]1[C:13]([NH:17][C:18](=[O:26])[CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([O:1][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:3]1)[CH:16]=[CH:15]2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2nc(N3CC[C@@H](O)C3)ccc2c1NC(=O)CC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2nc(N3CC[C@@H](OS(C)(=O)=O)C3)ccc2c1NC(=O)CC1CCCCC1

Procedure:
Prepared according to the method of example 33(a), using N-[2-[(3R)-3-hydroxy-1-pyrrolidinyl]-6-methyl-5-quinolinyl]-cyclohexaneacetamide (Example 84) (0.545 g), methanesulfonyl chloride (0.23 mL), triethylamine (0.62 mL) and dichloromethane (20 mL) to afford the sub-title compound (0.4 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:23][C:24]([NH2:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([S:30](Cl)(=[O:32])=[O:31])[CH2:28][CH3:29].C(N(CC)CC)C.O.N>ClCCl>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][S:30]([CH2:27][CH2:28][CH3:29])(=[O:32])=[O:31])=[CH:20][CH:21]=2)[N:12]=[CH:11][C:10]=1[CH2:23][C:24]([NH2:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: NC(=O)Cc1cnc(Nc2ccc(N)cc2)cc1NCc1ccccc1
Agent: N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(Nc2cc(NCc3ccccc3)c(CC(N)=O)cn2)cc1
Reaction time: 0.08 h
Yield: 23.6 %

Procedure:
39 mg of 4-(benzylamino)-6-{(4-aminophenyl)amino) pyridine-3-carboxyamide (the compound of Example 65), 83 mg of 1-propanesulfonyl chloride and 67 mg of triethylamine in 1.5 mL of dichloromethane were stirred at room temperature for 1 hour. Under ice cooling, ammonia water was added to the reaction mixture, and stirred for 5 minutes. The reaction mixture was extracted with chloroform, and the extract was dried on anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (chloroform:ammonia methanol=10:1) to obtain 12 mg (19%) of the title compound as a light brown crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH:63][N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][N:64]([OH:63])[CH2:65][CH2:66]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: ON1CCNCC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCN(O)CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4-hydroxy-piperazine in DMSO at ambient temperature.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]=O.CCCCCC>O1CCCC1>[CH3:2][O:3]/[CH:4]=[CH:36]\[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CO/C=C\c1ccccn1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 24 %

Procedure:
A stirred suspension of methoxymethyltriphenyl phosphonium chloride (12.48 g) in tetrahydrofuran (60 ml) under argon was cooled in an ice-bath. Potassium tert-butoxide (36.41 ml, 1M solution in tetrahydrofuran) was then added dropwise over 30 minutes to give a deep orange-red colour. Stirring was continued at 0-5° C. for 50 minutes then the mixture was cooled to −78° C. 2-Pyridinecarboxaldehyde was added dropwise and stirring continued at −78° C. for a further 2 h then allowed to warm to room temperature and stirred for 2 h. Hexane (100 ml) was added, the mixture filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting, with 10% ethyl acetate in hexane to give the pure cis-2-(2-methoxyvinyl)pyridine (0.91 g, 24%):
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[C:6]([C:14]([OH:16])=O)(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+].[CH3:19]I>O.CO>[CH3:19][S:4][C:3]1[NH:5][C:14](=[O:16])[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:1][N:2]=1
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: CI
Reactant: NNC(N)=S
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1nnc(-c2ccccc2)c(=O)[nH]1
Temperature: 80 °C
Yield: 98.1 %

Procedure:
A mixture of thiosemicarbazide (1.8 g, 0.020 mol) and benzoylformic acid (3.0 g, 0.020 mol) in water (50 mL) was heated under reflux for 15 min. Then potassium hydroxide (1.5 g, 0.027 mol) in methanol (50 mL) was added at 80° C. The reaction mixture was stirred and heated at 80° C. for 2 days. After cooling to 35° C., methyl iodide (1.4 mL, 0.022 mol) was added. The reaction mixture was stirred at 40° C. for 30 min. The mixture was concentrated. The precipitate formed was collected by filtration, washed with water, and dried under vacuum to afford the desired product (4.3 g, 97.7%). Analytical LCMS: (M+H)+=220.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1.C(N(CC)CC)C>CS(C)=O>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2)=[N:14][CH:15]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)C1CCN(c2ccc(C(F)(F)F)cn2)CC1

Procedure:
0.500 g (3.18 mmol) of ethyl piperidine-4-carboxylate, 0.866 g (4.77 mmol) of 2-chloro-5-trifluoromethylpyridine and 0.483 g (4.77 mmol) of triethylamine were reacted in dimethyl sulfoxide at 60° C. overnight. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to dryness to yield crude ethyl 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylate.