Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:18][CH2:19][Cl:20])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)=[O:5])[CH3:2].Cl.[F:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[CH:26]=[C:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C(O)C>[ClH:20].[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:18][CH2:19][N:30]2[CH2:31][CH2:32][C:27](=[CH:26][C:25]3[CH:33]=[CH:34][CH:35]=[C:23]([F:22])[CH:24]=3)[CH2:28][CH2:29]2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)=[O:5])[CH3:2]
Reactant: Fc1cccc(C=C2CCNCC2)c1
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2)c(CCCl)s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1nc(-c2ccc(F)cc2)c(CCN2CCC(=Cc3cccc(F)c3)CC2)s1
Yield: 47.2 %

Procedure:
1.50 g of 2-ethoxycarbonyl-4-(4-fluorophenyl)-5-(2-chloroethyl)thiazole, 1.10 g of 4-(3-fluorobenzylidene)piperidine hydrochloride and 2.50 g of N,N-diisopropylethylamine were stirred in 3 ml of ethanol at 80° C. for 40 hours. The reaction solution was concentrated under reduced pressure, and the residue was treated with ethyl acetate and saturated aqueous sodium bicarbonate to effect separation of layers. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the drying agent was removed by filtration. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by a flash column chromatography (Wako Gel C200 (manufactured by Wako Pure Chemical Industries), eluant: hexane-ethyl acetate-5.1) and then Chromatolex NH NHDM1020 (manufactured by Fuji Division Chemical), eluant: hexane-ethyl acetate=10.1). This product was treated with 4 N hydrogen chloride/1.4-dioxane solution and then recrystallized from ethanol to obtain 1.14 g of 2-ethoxycarbonyl-4-(4-fluorophenyl)-5-[2-[4-(3-fluorobenzylidene)piperidin-1-yl]ethyl]thiazole hydrochloride
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:29](OC)(OC)(OC)[CH3:30]>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]4[O:24][C:29]([CH3:30])=[N:26][N:25]=4)=[CH:27][CH:28]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)NN)cc3)CC2)CC1
Reactant: COC(C)(OC)OC
Product: Cc1nnc(-c2ccc(O[C@H]3CC[C@H](C(=O)N4CCN(C(C)C)CC4)CC3)cc2)o1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of 100 mg (0.26 mmol) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid hydrazide and 4 ml of trimethyl orthoacetate was stirred for 10 min at 120° C. using microwave reactor. After evaporation, the mixture was diluted with AcOEt, washed with saturated NaHCO3 solution, water and brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica eluting with dichloromethane and methanol=from 98:2 to 19:1. The combined product fractions were evaporated to dryness to yield 15 mg (14%) of the title compound. MS (m/e): 413.4 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=C1Cc2ccccc2N1
Agent: O=S(=O)(O)O
Product: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
2-Oxindole (6.5 g) was dissolved in 25 mL concentrated sulfuric acid and the mixture maintained at -10 to -15° C. while 2.1 mL of fuming nitric acid was added dropwise. After the addition of the nitric acid the reaction mixture was stirred at 0° C. for 0.5 hr and poured into ice-water. The precipitate was collected by filtration, washed with water and crystallized from 50% acetic acid. The crystalline product was then filtered, washed with water and dried under vacuum to give 6.3 g (70%) of 5-nitro-2-oxindole.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]1[C:31]2[CH:30]=[C:29]([CH:32]=O)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+]>>[O:22]1[C:31]2[CH:30]=[C:29]([CH2:32][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:15]5[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=5[O:13][CH2:12][C:11]4=[O:21])[CH2:6][CH2:7]3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: NC1CCN(CCN2C(=O)COc3ccc(F)cc32)CC1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(F)cc2N1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Yield: 32.3 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-fluoro-2H-1,4-benzoxazin-3(4H)-one (Intermediate 54) (0.7 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (140 mg, 0.84 mmol), and sodium cyanoborohydride (90 mg, 1.4 mmol) were reacted as described under Example 21 to give 100 mg (32%) product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]([Cl:19])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(C(=O)O)s2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C(=O)Cl)s2)cc1
Temperature: 100 °C

Procedure:
To a solution of 5-(4-methoxyphenyl)thiophene-2-carboxylic acid (0.60 g, 2.5 mmol) in toluene (4 mL) was added thionylchloride (560 mL, 7.7 mmol) and the reaction mixture was heated at 100° C. for 18 h. The reaction mixture was cooled to room temperature and concentrated to afford the desire product (642 mg, crude): ESI MS m/z 253 [C12H9ClO2S+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:24][C:16]=2[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:10][CH:9]=1>ClCCl>[C:8]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:24][C:16]=2[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1Nc1ccc(-c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2ccccc2)cc1Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
Trifluoroacetic acid 2.5 mL was added to dichloromethane 2.5 mL solution of tert-butyl 2-((biphenyl-4-yl)amino)-4-phenylbenzoate 84 mg, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 2-((biphenyl-4-yl)amino)-4-phenylbenzoic acid 52 mg of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)#[CH:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:23]#[C:22][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Reactant: C#Cc1cccnc1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3cccnc3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-iodo-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.4) (420 mg, 1.0 mmol) and commercially available 3-Ethynylpyridine (102 mg, 0.9 mmol) according to general procedure II. Obtained as an orange solid (230 mg, 58%). MS (ISP) 398.9 [(M+H)+]; mp 214-215° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21](=O)[CH3:22])=[C:6]([CH3:20])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[C:8]=1[CH3:9])(=O)[CH3:2].[NH2:24][NH2:25]>>[CH3:2][C:1]1[C:4]2=[C:8]([CH3:9])[N:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=3)[C:6]([CH3:20])=[C:5]2[C:21]([CH3:22])=[N:25][N:24]=1
Reactant: NN
Reactant: CCCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)cc1
Product: CCCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)cc1

Procedure:
As outlined in Example 65, 1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (Example 52, 20 mg) reacted with 1-bromo-propane (100 μL), in the presence of K2CO3 powder (50 mg), to afford 1-[4-acetyl-2,5-dimethyl-1-(4-propoxy-phenyl)-1H-pyrrol-3-yl]-ethanone: MS (ESI) 328 (M+H)+. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-2,5-dimethyl-1-(4-propoxy-phenyl)-1H-pyrrol-3-yl]-ethanone and hydrazine reacted to give 1,4,5,7-Tetramethyl-6-(4-propoxy-phenyl)-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.04 (d, 1H), 6.95 (br s, 1H), 6.91 (d, 1H), 4.03 (t, 2H), 2.85 (s, 6H), 2.42 (s, 6H), 1.86 (q, 2H), 1.79 (s, 3H), 1.09 (t, 3H); MS (ESI) 328 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=1.[CH3:19][N:20](C=O)C.CN>C(Cl)Cl.C1COCC1.O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([NH:20][CH3:19])=[O:18])=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CNC(=O)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
Add oxalyl chloride (1.75 mL, 2.54 g, 4 eq.) to a solution of 3-(4-bromo-phenyl)-propionic acid in methylene chloride (100 mL), which contains 0.1 mL DMF at 0° C. and allow the reaction mixture to warm to room temperature and stir 1 hour. Evaporate solvent and dissolve it in 10 mL THF. Add half of the THF solution to 20 mL of methylamine (2M) and stir another hour. Add water to the solution to dissolve solid and wash organic layer with 2N HCl, water and saturated aq. sodium chloride and dry it over MgSO4. Evaporate solvent to afford the title compound 500 mg, 41%. MS 246.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=4)[O:22][CH2:23][C:24]([OH:26])=[O:25])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:5][CH:4]=1.[CH3:36][OH:37]>ClCCl>[CH2:36]([CH2:12][NH2:13])[OH:37].[CH2:36]([CH2:12][NH2:13])[OH:37].[CH2:36]([CH2:12][NH2:13])[OH:37].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=4)[O:22][CH2:23][C:24]([OH:26])=[O:25])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:7][CH:8]=1
Reactant: CO
Agent: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(OCC(=O)O)c4)c23)cc1
Solvent: ClCCl
Product: NCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Initially charge 50 mg (0.107 mmol) of 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenoxyacetic acid in 2 ml of a 1:1 mixture of methanol and dichloromethane, add 13 mg (0.107 mmol) of 2-amino-2-hydroxymethyl-1,3-propanediol(trisethanolamine) and stir at RT overnight. Then concentrate the mixture under reduced pressure. 60.3 mg of the target compound are obtained as a colourless glass.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH:22]=[C:21]([O:26][CH:27]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28]([O:30]C)=[O:29])[CH:20]=[CH:19]4)=[CH:14][N:15]=2)=[CH:3]1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH:22]=[C:21]([O:26][CH:27]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28]([OH:30])=[O:29])[CH:20]=[CH:19]4)=[CH:14][N:15]=2)=[CH:3]1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3cnc(-c4cn(C)c5ccccc45)o3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1cc(-c2ncc(-c3ccc4cc(OC(Cc5ccccc5)C(=O)O)ccc4c3)o2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A mixture of methyl 2-({6-[2-(1-methyl-1H-indol-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)-3-phenylpropanoate (185 mg, 0.369 mmol), prepared in the previous step, and 1 N NaOH (550 μL, 0.55 mmol) in 10 mL of THF, 10 mL of methanol and 5 mL of H2O was stirred at room temperature for 18 h (overnight). The reaction was acidified by the addition of 600μL of 1N HCl and then concentrated under reduced pressure to remove the THF and the methanol. The white solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (102 mg, 90%) as a white solid, mp 149-151° C. Elemental Analysis for C31H24N2O4+0.36 H2O Calc'd: C, 75.22; H, 5.03; N, 5.66. Found: C, 75.28 ;H, 5.22; N, 5.39.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][CH:8]([C:16]#[N:17])[CH:9]([CH:13]([CH3:15])[CH3:14])[CH2:10][CH2:11][CH3:12])(C)(C)C>CO.[Ni]>[CH:13]([CH:9]([CH:8]1[CH2:16][NH:17][C:6](=[O:5])[CH2:7]1)[CH2:10][CH2:11][CH3:12])([CH3:15])[CH3:14]
Reactant: CCCC(C(C)C)C(C#N)CC(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CO
Product: CCCC(C(C)C)C1CNC(=O)C1
Yield: 102.3 %

Procedure:
3-Cyano-4-isopropyl-heptanoic acid t-butyl ester (0.8 g, 3.2 mmol) is reduced under 50 psi of H2 in MeOH containing TEA and Ra Ni. When the theoretical amount of H2 is taken up, the catalyst is removed by filtration, and the solvent is evaporated to give 0.6 g (100% yield) of 4-(1-isopropyl-butyl)-2-pyrrolidone as an oil.
Reaction SMILES: [CH:1]1([CH2:9][OH:10])[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.CC[O:13]CC.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1.S(=O)(=O)(O)O>CCCCC.O.N1C=CC=CC=1>[CH:1]1([C:9]([OH:10])=[O:13])[CH2:6][CH2:5]1.[CH:16]1([C:19]([OH:20])=[O:8])[CH2:18][CH2:17]1.[CH2:9]=[C:1]1[CH2:6][CH2:5][C:4](=[CH2:7])[CH2:3][CH2:2]1
Reactant: CCOCC
Reactant: O=C(Cl)C1CC1
Reactant: OCC1CCC(CO)CC1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: O
Solvent: CCCCC
Product: C=C1CCC(=C)CC1
Product: O=C(O)C1CC1
Reaction time: 1 h

Procedure:
To a solution of 2.88 g. of 1,4-cyclohexanedimethanol in 100 ml. ether is added 5.3 g, of cyclopropanecarboxylic acid chloride. Upon the addition of 4.8 g. of pyridine, a precipitate forms immediately, accompanied by the evolution of a small amount of heat. The reaction mixture is stirred for one hour, water and pentane are added, the mixture is acidified with 3 N sulfuric acid, the organic phase is separated and then washed with water, potassium carbonate, saturated aqueous copper sulfate, water and brine. The solution is then dried and solvent removed to yield 1,4-dimethylenecyclohexane bis(cyclopropanecarboxylate). The above product can also be named as (1,4-bis(cyclopropylcarbonyloxymethyl)cyclohexane) ##SPC2##
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:23])=[C:12]3[CH:18]=[C:17]([C:19]#[C:20][CH2:21][OH:22])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH2:34][OH:35]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[CH:18]=[C:17]([C:19]#[C:20][CH2:21][OH:22])[S:16][C:13]=3[N:14]([CH2:33][CH2:34][OH:35])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: OCCBr
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(C#CCO)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCO)c2sc(C#CCO)cc2c1=O
Temperature: 100 °C
Reaction time: 18 h
Yield: 36 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(3-hydroxy-1-propynyl)thieno[2,3-b]pyridine-5-carboxamide (Example No. 5) (0.250 g) in DMF (3 mL) is added K2CO3 (0.278 g) and 2-bromoethanol (0.14 mL). The reaction is heated to 100° C. and stirred for 18 h. The reaction mixture is concentrated in vacuo, and the resulting residue is partitioned between H2O (50 mL) and CH2Cl2 (50 mL). The aqueous layer is extracted with CH2Cl2 (3×50 mL). The combined organic layers are dried with MgSO4, filtered, and concentrated in vacuo to give a small amount of starting material. The desired product precipitates out of the aqueous layer as a tan solid. This material is recrystallized from methanol to yield 0.100 g (36%) of the title compound as a tan, crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:28][C:27]3[CH:29]=[CH:30][C:24]([C:21](=[O:23])[CH3:22])=[CH:25][CH:26]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: CC(=O)c1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 39.4 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and p-acetylaniline (80 mg, 0.59 retool) to give 90 mg of the title compound (38%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (s, 1H), 10.35 (s, 1H), 7.93 (d, 2H, J=9 Hz), 7.70 (d, 1H, J=9 Hz), 7.24 (d, 1H, J=2 Hz), 7.17 (d, 2H, J=9 Hz), 5.17~5.27 (m, 1H), 3.05 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=16.8 Hz), 2.65 (d, 2H, J=6.9 Hz), 2.53 (s, 3H), 2.12 (dm, 1H, J=13.5 Hz), 1.80~1.97 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:14][CH2:15][CH3:16])([CH3:13])[PH2:11]=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+]>C1COCC1.CO.O>[CH2:15]([O:14][C:10]([CH3:13])([PH2:11]=[O:12])[C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[CH:5][CH:6]=1)[CH3:16]
Reactant: CCOC(C)([PH2]=O)c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC(C)([PH2]=O)c1ccc(C(=O)O)cc1
Reaction time: 18 h

Procedure:
To a solution of 4-(ethoxy-methyl-phosphinoylmethyl)-benzoic acid methyl ester (660 mg, 2.58 mmol) in THF (5 mL) and MeOH (3 mL) was added 1N NaOH (2.58 mL, 2.58 mmol), and the mixture was stirred for 18 h. The mixture was diluted with H2O and washed with EtOAc. The aqueous layer was acidified with 1 N HCl, saturated with NaCl and extracted with a mixture of CHCl3 and MeOH, dried (MgSO4), and filtered. The solvent was evaporated under reduced pressure and the material was used without further purification. 1H NMR (CDCl3, 600 MHz) δ 7.98 (d, J=7.9 Hz, 2H), 7.34 (dd, J=7.9, 2.0 Hz, 2H), 4.12-4.03 (m, 2H), 3.26 (dd, J=25.2, 14.2 Hz, 1H), 3.23 (dd, J=25.2, 14.2 Hz, 1H), 1.44 (d, J=13.8 Hz, 3H), 1.30 (t, J=7.0 Hz, 3H). MS: cal'd 243 (MH+), exp 243 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][N:4]=1.[Li]C.[CH:15](N1CCCCC1)=[O:16]>C1COCC1.C(NC(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][N:4]=1)[CH:15]=[O:16]
Reactant: COCOc1ccc(OC)nc1
Reactant: O=CN1CCCCC1
Agent: [Li]C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCOc1cnc(OC)cc1C=O
Temperature: -40 °C
Reaction time: 3 h
Yield: 42.3 %

Procedure:
To a solution of 2-methoxy-5-(methoxymethoxy)pyridine (20 g, 0.12 mol) in THF was added diisopropylamine (0.24 g, 2.4 mmol). The solution was cooled to −40° C. followed by addition of MeLi (3M/THF, 72 mL, 0.216 mol) slowly. The resulting mixture was warmed to 0° C., stirred at 0° C. for 3 h, cooled back down to −40° C. and added N-formylpiperidine (24 mL, 0.216 mol). After stirring at −40° C. for 2 h, the mixture was quenched with a mixed solution of HCl (37%, 120 mL) and THF (250 mL). The temperature was then raised to rt and diluted with water (200 mL) and EtOAc (200 mL). The pH of the mixture was adjusted to 8-9 with solid K2CO3 and extracted with EtOAc (300 mL) twice. The organic layer was combined, dried over Na2SO4, and concentrated. The residue was purified on silica gel with 25% EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (10 g, 42%) as a pale yellow oil. 1H NMR (400 MHz; CD3OD) 7.90 (s, 1H), 6.92 (s, 1H), 5.64 (s, 1H), 5.20 (s, 2H), 3.84 (s, 3H), 3.48 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]([NH:19][CH3:20])=[O:18])[C:6]=2[CH:21]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Cl)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:22]([CH2:34][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)[S:23]([CH3:26])(=[O:24])=[O:25])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)=[C:7]([C:17]([NH:19][CH3:20])=[O:18])[C:6]=2[CH:21]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(Cc3ccc(Cl)cc3)S(C)(=O)=O)c(Br)cc12

Procedure:
A solution of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (0.55 g, 1.25 mmol), 1-chloro-4-(chloromethyl)benzene (0.24 g, 1.5 mmol), K2CO3 (0.35 g, 2.5 mmol) and KI (0.25 g, 0.15 mmol) in DMF (10 mL) was stirred at 80° C. for 2 hours. The mixture was concentrated in vacuo and the resulting residue was washed by H2O and filtered to provide the white solid 5-bromo-6-(N-(4-chlorobenzyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide without further purification. 1H-NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 7.81˜7.84 (m, 2H), 7.15˜7.25 (m, 7H), 5.79 (br s, 1H), 5.15 (d, J=7.4 Hz, 1H), 4.55 (d, J=7.4 Hz, 1H), 3.10 (s, 3H), 2.96 (d, J=4.8 Hz, 3H). MS (M+H)+: 565/567.
Reaction SMILES: O1CC1COC1C=CC=C2C=1CCC2=O.Cl.[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH:18]1[NH:27]CC(O)COC1C=CC=C2C=1CCC2=O>C(O)C>[NH2:27][CH:18]1[CH2:19][CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17]1
Reactant: O=C1CCc2c(OCC(O)CNC3CCc4ccccc4C3)cccc21
Agent: Cl
Agent: O=C1CCc2c(OCC3CO3)cccc21
Solvent: CCO
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure of Example 27, but starting from 4-(2,3-epoxypropoxy)-1-oxoindane (18.8 g, see JP 49-048649) and 2-aminotetralin (14.81 g) in absolute ethanol (120 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-oxoindan-4-yloxy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 35, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[C:5]2[CH:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:4]=2[N:3]=1.[C:25](OC)(=[O:28])[C:26]#[CH:27]>CO>[C:23]([C:20]1[CH:21]=[CH:22][C:4]2[N:3]3[CH:27]=[CH:26][C:25](=[O:28])[N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=3)[C:5]=2[CH:19]=1)#[N:24]
Reactant: CS(=O)(=O)c1ccc(C2=NCC(N)=Nc3ccc(C#N)cc32)cc1
Reactant: C#CC(=O)OC
Solvent: CO
Product: CS(=O)(=O)c1ccc(C2=NCc3nc(=O)ccn3-c3ccc(C#N)cc32)cc1

Procedure:
In the manner given in Example 1, 2-amino-7-cyano-5-(p-methylsulfonylphenyl)-3H-1,4-benzodiazepine, methyl propiolate and methanol were refluxed. The mixture was chromatographed to give 9-cyano-7-(p-methylsulfonylphenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.