Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@@H:25]([N:29]([CH:37]=[O:38])[O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:26][CH2:27][CH3:28])[C:11]([O:13]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:39]1[CH:43]=[N:42][N:41]=[C:40]1[NH:44][C:45](=[O:63])[C@@H:46]([NH2:62])[CH2:47][CH2:48][CH2:49][CH2:50][NH:51][C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:55]([O:54][C:52]([NH:51][CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]([NH:62][C:11](=[O:13])[C@H:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@@H:25]([N:29]([CH:37]=[O:38])[O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[CH2:26][CH2:27][CH3:28])[C:45](=[O:63])[NH:44][C:40]1[S:39][CH:43]=[N:42][N:41]=1)=[O:53])[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: CCC[C@@H]([C@@H](CCCc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)N(C=O)OC1CCCCO1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCC[C@@H]([C@@H](CCCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Nc1nncs1)N(C=O)OC1CCCCO1
Temperature: 50 °C
Reaction time: 18 h
Yield: 20.1 %

Procedure:
To a solution of pentafluorophenyl (2R,3S)-2-(3-phenyl-1-propyl)-3-(formyl-2-tetrahydropyranyloxyamino)hexanoate (90 mg, 0.166 mmol) in DMF (0.5 mL) is added (2S)-6-benzyloxycarbonylamino-2-aminohexanoic acid 1,3,4-thiadiazol-2-ylamide (78 mg, 0.215 mmol) and HOBt ( 2.2 mg, 0.017 mmol). The resulting solution is heated to 50° C. and is stirred for 18 h. The reaction mixture is cooled to 25° C., concentrated in vacuo, diluted with 20 mL of EtOAc, and washed with 1 M aqueous sodium carbonate solution. The organic layer is dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 2:1 EtOAc-hexane) to provide (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(3-phenyl-1-propyl)hexanoic acid [(1S)-5-benzyloxycarbonylamino-1-(1,3,4-thiadiazol-2-ylcarbamoyl)-1-pentyl]amide as an oil (24.1 mg, 25% yield). APCI-MS m/z 745 (M+Na)+.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:42])[C:6]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[N:24][N:23]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:20]3=[N:21][CH:22]=2)[CH:14]=[C:8]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:7]=1.O>O.CO>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]1[C:19]2[C:20](=[N:21][CH:22]=[C:17]([C:15]3[CH:14]=[C:8]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:7]=[C:6]([CH:16]=3)[C:5]([OH:42])=[O:4])[CH:18]=2)[N:23]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:39])[CH3:40])[N:24]=1
Reactant: COC(=O)c1cc(C(=O)N(C)C)cc(-c2cnc3c(c2)c(-c2ccccc2OC)nn3COCC[Si](C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(C(=O)O)cc(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
4 N aqueous lithium hydroxide (0.43 ml, 1.71 mmol) was added to 5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-isophthalamic acid methyl ester (0.80 g, 1.43 mmol) in water/methanol (3:1) and stirred at room temperature for 16 hours, water was added and the mixture was extracted with ethyl acetate (3×), the combined organic layers were dried over magnesium sulfate and purified by silica gel chromatography to give 5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-isophthalamic acid (717 mg, 92% yield) of an off white powder. MS: m/z 546.7 (M+H+).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([NH:14][CH:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16](=O)[CH:17]([CH3:19])[CH3:18])=[O:13])[CH2:8]2.Cl.[Na+].[Cl-]>C1COCC1>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:16]([CH:17]([CH3:19])[CH3:18])=[C:15]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:14][C:12]1=[O:13])[CH2:8]2
Reactant: CC(C)C(=O)C(Cc1ccccc1)NC(=O)NC1C2CC3CC(C2)CC1C3
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1c(Cc2ccccc2)[nH]c(=O)n1C1C2CC3CC(C2)CC1C3
Temperature: 0 °C
Yield: 18.9 %

Procedure:
Adamantan-2-yl-3-(1-benzyl-3-methyl-2-oxo-butyl)-urea (100 mg) was dissolved in dry THF (2 mL) and treated with 25% HCl (5 mL) at 60° C. for 3.5 hours. The mixture was cooled, poured into ice cold 3M NaOH, saturated with NaCl. The mixture was extracted with ethyl acetate and the organic layer was separated, washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography using a gradient of 10 to 40% ethyl acetate in heptane as an eluent. Fractions containing the desired material were combined and evaporated to give 1-adamantan-2-yl-4-benzyl-5-isopropyl-1,3-dihydro-imidazol-2-one as a white foam (18 mg). MS (EI): 350.3 (M+).
Reaction SMILES: C(OC1C=C(C=C(OCC2C=CC=CC=2)C=1)C=O)C1C=CC=CC=1.NCC(OCC)OCC.[CH2:34]([O:41][C:42]1[CH:43]=[C:44]([CH:55]=[C:56]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:57]=1)[CH:45]=[N:46][CH2:47][CH:48]([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[BH4-].[Na+]>C(O)C>[CH2:34]([O:41][C:42]1[CH:43]=[C:44]([CH:55]=[C:56]([O:58][CH2:59][C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:57]=1)[CH2:45][NH:46][CH2:47][CH:48]([O:49][CH2:50][CH3:51])[O:52][CH2:53][CH3:54])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(CN=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1)OCC
Agent: CCOC(CN)OCC
Agent: O=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: [BH4-]
Solvent: CCO
Product: CCOC(CNCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1)OCC

Procedure:
1-[N-(3,5-dibenzyloxybenzyl)-N-p-tosyl-amino]-2,2-diethoxyethane (VI) is readily obtainable. For example, said compound (VI) is prepared by condensing 3,5-dibenzyloxybenzaldehyde with 1-amino-2,2-diethoxyethane at 60° to 100° C, reducing the resultant 1-[N-(3,5-dibenzyloxybenzylidene)amino]-2,2-diethoxyethane with sodium borohydride in ethanol under refluxing to give 1-[N-(3,5-dibenzyloxybenzyl)amino]-2,2-diethoxyethane, and then reacting said product with p-tosyl chloride in pyridine under ice-cooling.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([OH:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1>>[C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([O:19][CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1cc(-c2ccccc2)nc(-c2ccncc2)n1
Product: O=C(O)c1ccc(COc2cc(-c3ccccc3)nc(-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared from 6-phenyl-2-pyridin-4-yl-pyrimidin-4-ol (which was obtained in Intermediate 3) and methyl 4-(bromomethyl)benzoate according to Method A and Method B; 1H NMR (DMSO-d6, 300 MHz) δ 5.65 (s, 2H), 7.26 (t, J=8.8 Hz, 2H), 7.50-7.70 (m, 4H), 8.30-8.40 (m, 2H), 8.57 (d, J=4.9 Hz, 2H), 8.90 (d, J=4.9 Hz, 2H); LC retention time 2.79 min; MS: m/z (ESI) 382 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]#[CH:33])[CH2:27][CH2:26]1.CO>C(N(CC)CC)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:33]#[C:32][CH2:31][N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: C#CCN1CCN(C)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(Nc2c(C#N)cnc3cc(C#CCN4CCN(C)CC4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 0.42 mmol), 1-methyl-4-prop-2-ynyl-piperazine (87.0 mg, 0.65 mmol), 9.7 mg of tetrakis(triphenylphosphine)palladium(0) and 2.0 mg of copper(I) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux for 5 hours. The mixture is cooled to room temperature and 2 mL of methanol are added. The solvents are removed in vacuo and the residue is purified by preparative thin layer chromatography developing with 12% methanol in dichloromethane to give a solid which is triturated with ether containing several drops of dichloromethane, to provide 89.6 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]thieno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp 172–173° C.; 1H NMR (DMSO-d6) δ 2.18 (s, 3H), 2.37 (s, 4H), 2.49 (s, 4H), 3.59 (s, 2H), 3.85 (s, 3H), 7.37 (s, 1H), 7.62 (s, 1H), 7.78 (s, 1H), 8.62 (s, 1H), 9.82 (s 1H); MS 486.1, 488.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[N:7]=[N:8][C:4]=2[C:3]=1[OH:20].F[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[C:25]#[N:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[Cl:30][C:28]1[CH:27]=[C:24]([CH:23]=[C:22]([O:20][C:3]2[C:4]3[N:8]=[N:7][N:6]([CH2:9][C:10]4[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=4)[C:5]=3[CH:18]=[CH:19][C:2]=2[Cl:1])[CH:29]=1)[C:25]#[N:26]
Reactant: COc1ccc(Cn2nnc3c(O)c(Cl)ccc32)cc1
Reactant: N#Cc1cc(F)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Cn2nnc3c(Oc4cc(Cl)cc(C#N)c4)c(Cl)ccc32)cc1
Temperature: 140 °C

Procedure:
A stirred suspension of 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-benzotriazol-4-ol (0.050 g, 0.173 mmol), 3-fluoro-5-chloro-benzonitrile (0.081 g, 0.518 mmol) and cesium carbonate (0.068 g, 0.207 mmol) in NMP (1.5 mL) was heated at 140° C. for 72 hours. The reaction mixture was then quenched with aqueous ammonium chloride (25 mL) and extracted with dichloromethane (2×100 mL). The combined extracts were concentrated under reduced pressure. The resulting residue was subjected to reverse phase chromatography (5-95% MeCN/H2O, 0.1% TFA). The product fractions were combined and extracted with dichloromethane (2×100 mL). The combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to yield the title product. 1H NMR (DMSO d6) δ 7.90-7.88 (m, 1H), 7.80 (s, 1H), 7.79-7.75 (m, 1H), 7.60-7.55 (m, 2H), 7.40-7.35 (d, J=6.9 Hz, 2H), 6.95-6.88 (m, 2H), 5.80 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([NH:23][C:24](=O)[C:25]([F:28])([F:27])[F:26])=[C:12]([CH:22]=1)[CH:13]([OH:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].O>C(OCC)C.O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([NH:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[C:12]([CH:22]=1)[CH:13]([OH:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: O=C(Nc1ccc(Cl)cc1C(O)c1ccccc1Cl)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccccc1Cl)c1cc(Cl)ccc1NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a suspension of 0.25 g of lithium aluminum hydride in 20 ml of absolute ethyl ether, a solution of 1.2 g of 5-chloro-α-(2-chlorophenyl)-2-(trifluoroacetylamino)benzyl alcohol in 5 ml of tetrahydrofuran was added dropwise. After mixture stirring at room temperature for 1 hour, water was added, and the organic layer was dried, after which the solvent was removed and the residue was subjected to silica gel column chromatography to yield 1.0 g of an oily compound.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)([C:8]#[N:9])[C:6]#[N:7].C(N(S(F)(F)[F:27])CC)C>ClCCl>[F:27][CH2:2][CH2:3][CH2:4][C:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)([C:8]#[N:9])[C:6]#[N:7]
Reactant: CCN(CC)S(F)(F)F
Reactant: N#CC(C#N)(CCCO)Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: N#CC(C#N)(CCCF)Cc1ccc(C(F)(F)F)cc1
Yield: 5 %

Procedure:
Using 0.80 g of 2-(3-hydroxypropyl)-2-(4-(trifluoromethyl)benzyl)malononitrile, 8 ml of dichloromethane and 0.3 ml of Diethylaminosulfur trifluoride, and according to the process described in the Production Example 11, there was obtained 0.05 g of 2-(3-fluoropropyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (14)).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([N:16]1[C@H:24]([C:25]([OH:27])=[O:26])[CH2:23][C:18]2([S:22][CH2:21][CH2:20][S:19]2)[CH2:17]1)=[O:15])[CH3:13])=O)C1C=CC=CC=1.C(OCC)C.[BrH:33]>C(O)(=O)C>[BrH:33].[NH2:11][C@H:12]([C:14]([N:16]1[C@H:24]([C:25]([OH:27])=[O:26])[CH2:23][C:18]2([S:22][CH2:21][CH2:20][S:19]2)[CH2:17]1)=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: C[C@H](N)C(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 1.4 g of 7-[N-benzyloxycarbonyl-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid in 20 ml of 20% hydrobromic acid in glacial acetic acid and stir the mixture at room temperature for two hours. Add the mixture dropwise to diethyl ether at 0°-5° C. to give 7-[(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid hydrobromide which is used immediately in the process described in paragraph F below.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([CH:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:27]2[CH2:30][CH:29]([OH:31])[CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:38]([C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)([CH3:41])([CH3:40])[CH3:39].N(C(OCC)=O)=NC(OCC)=O>C(#N)C.O>[C:38]([C:42]1[CH:47]=[CH:46][C:45]([O:31][CH:29]2[CH2:30][N:27]([CH:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:28]2)=[CH:44][CH:43]=1)([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reaction time: 8 h
Yield: 50.5 %

Procedure:
Triphenylphosphine (13.11 g, 50.0 mmol) was added to a stirred solution of 1-(diphenylmethyl)-3-azetidinol (11.97 g, 50.0 mmol) and 4-tert-butylphenol (7.50 g, 50.0 mmol) in acetonitrile (200 mL). Diethyl azodicarboxylate (7.9 mL, 8.7 g, 50.0 mmol) was added dropwise to the solution with water cooling. The suspension was heated under reflux for 4 h, the solution allowed to cool and concentrated in vacuo. The gum was suspended in ether (200 mL), and the suspension was refrigerated overnight. The precipitated triphenylphosphine oxide was filtered off and washed with ether, and the combined filtrate and washings were concentrated. The solid residue was dissolved in dichloromethane (200 mL), and the solution was washed with 1-N sodium hydroxide (50 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by chromatography [SiO2; ethyl acetate-hexane (1:4)] and triturated with cyclohexane to give the title compound (9.39 g, 51%) as a white solid, m.p. 126-127° C. Found: C, 83.9; H, 7.9; N, 3.75. C26H29NO require C, 84.1; H, 7.9; N, 3.8%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][N:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:28](=O)([O-])[O-].[Na+].[Na+].IC.O>CN(C)C=O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:13]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[N:17]([CH3:28])[C:16]3=[O:21])=[CH:12][N:11]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:10]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1NC(=O)C(=Cc2cn(-c3ccccc3)nc2-c2cc(F)cc(F)c2)S1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN1C(=O)SC(=Cc2cn(-c3ccccc3)nc2-c2cc(F)cc(F)c2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.8 %

Procedure:
5-[3-(3,5-Difluoro-phenyl)-1-phenyl-1H-pyrazol-4-ylmethylene]-thiazolidine-2,4-dione (Compound No. 58, 0.10 g, 0.21 mmol) was dissolved in 1.0 mL of anhydrous dimethylformamide. Sodium carbonate (26.50 mg, 0.25 mmol) was added under nitrogen atmosphere and iodomethane (20.00 μL, 0.32 mmol) was added 10 minutes later. The mixture was stirred for 2 hours at room temperature. Water was added after the reaction was completed. The resultant solid was washed with water (10 mL×3 times). The solid was dried to obtain 90.0 mg (87%) of the target product.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:31](O)=[O:32].C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:31]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20])=[O:32]
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: Cn1c(C(=O)O)cc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cn1c(C(=O)NC2N=C(c3ccccc3F)c3ccccc3NC2=O)cc2ccccc21
Reaction time: 4 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (50 mg, 0.186 mmol) was suspended in 1 ml of methylene chloride. 1-Methylindole-2-carboxylic acid (36.2 mg, 0.2 mmol) was added to the solution followed by the addition of 38.5 mg (0.2 mmol) of EDC. The pH of the solution was brought to 8 with 60 μl of triethylamine. After stirring for 4 hours the product was purified by preparative TLC on a 2000 μ silica gel plate with a 95:5:0.5 chloroform/methanol/water solvent system. The product band was collected and isolated by washing the silica with 90:10:1 CMW. yield 16.5 mg.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[NH:5])C.[NH2:22][NH:23][C:24](=O)[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C[O-].[Na+]>CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([C:4]4[NH:22][N:23]=[C:24]([CH2:25][O:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:5]=4)[CH:7]=3)[NH:11][N:10]=2)=[CH:20][CH:19]=1
Reactant: NNC(=O)COCc1ccccc1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(-c2n[nH]c3ccc(-c4nc(COCc5ccccc5)n[nH]4)cc23)cc1
Temperature: 90 °C

Procedure:
To a suspension of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine.2HCl (307 mg, 0.96 mmol) and N-amino-2-(phenylmethoxy)acetamide (259 mg, 1.44 mmol) in anhydrous methanol (3.0 mL) in a screw-top pressure tube was added freshly prepared sodium methoxide (615 μL of a 3.12 M solution in methanol). The tube was sealed and heated in a 90° C. oil bath for 17 h. The reaction was cooled, evaporated to dryness and partitioned between ethyl acetate and satd. NH4Cl. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo to give an oily brown residue. Purification by flash chromatography on silica gel eluting with 5% methanol in dichloromethane (Rf=0.43) gave a pale solid (155 mg) which was re-chromatographed using 30% hexanes in ethyl acetate to remove traces of color.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[O:10][C:9]2[C:11]([C:16]([O:18]CC)=[O:17])=[CH:12][C:13]([CH3:15])=[CH:14][C:8]=2[C:7]=1[CH3:21])=O.O.NN.[K].Cl>C(O)CO>[C:16]([C:11]1[C:9]2[O:10][C:6]([CH2:4][C:3]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:2]=3[Cl:1])=[C:7]([CH3:21])[C:8]=2[CH:14]=[C:13]([CH3:15])[CH:12]=1)([OH:18])=[O:17]
Reactant: CCOC(=O)c1cc(C)cc2c(C)c(C(=O)c3ccc(Cl)cc3Cl)oc12
Agent: Cl
Agent: NN
Agent: [K]
Solvent: O
Solvent: OCCO
Product: Cc1cc(C(=O)O)c2oc(Cc3ccc(Cl)cc3Cl)c(C)c2c1
Temperature: 150 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
2-(2,4-Dichlorobenzoyl)-7-(ethoxycarbonyl)-3,5-dimethylbenzo[b]furan (0.78 g) and hydrazine monohydrate (0.70 g) were stirred in ethylene glycol (6.5 ml) at 140° C. for 2 hr. After cooling, potassium hydoroxide (0.75 g) was added and the mixture was stirred at 150° C. for 4 hr. After cooling, ice and concentrated hydrochloric acid were added and precipitate was collected by filtration. The precipitate was washed with water and diisopropyl ether and dried to give the objective compound (0.66 g) as white crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[N:7]=1)[CH3:4].[Cl:26][C:27]1[C:28]([CH2:39]Cl)=[N:29][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:31][CH:32]=1.O>CN(C)C=O>[Cl:26][C:27]1[C:28]([CH2:39][O:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:8]3[CH:9]=[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([O:5][CH2:3][CH3:4])=[N:7]3)=[CH:24][CH:23]=2)=[N:29][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:31][CH:32]=1
Reactant: ClCc1nc(-c2ccccc2)ccc1Cl
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)ccc3Cl)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (478 mg) and 3-chloro-2-chloromethyl-6-phenylpyridine (357 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[4-(3-chloro-6-phenyl-2-pyridylmethoxy)benzyl]-3-ethoxy-1H-pyrazol-4-yl]propionate (740 mg, yield: 95%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH3:6])[CH2:3][OH:4].[C:7]1(=O)[O:12][C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12>C(O)(C)C>[C:7]1(=[O:12])[N:1]([CH:2]([CH2:5][CH3:6])[CH2:3][OH:4])[C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCC(N)CO
Solvent: CC(C)O
Product: CCC(CO)N1C(=O)c2ccccc2C1=O
Yield: 87 %

Procedure:
17.83 Gms. (0.2 mole) of 2-aminobutan-1-ol was added, with stirring, to a suspension of 29.62 gms. (0.2 mole) of phthalic anhydride in 90 mls. of isopropanol. The resulting mixture was refluxed for 18 hours. Thereafter, the isopropanol was distilled off under reduced pressure and the residue was distilled to give 38.1 gms. (yield 87%) of 2-phthalimidobutan-1-ol as a colourless viscous oil. (boiling point = 170° to 172°C./1 mm. Hg.)
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]([CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]1=O)(=O)[CH3:5]>CO>[CH3:1][N:2]1[C:8]2[CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:7]=2[C:4]([CH3:5])=[N:3]1
Reactant: CC(=O)C1C(=O)CCCC1=O
Reactant: CNN
Solvent: CO
Product: Cc1nn(C)c2c1C(=O)CCC2
Temperature: 0 °C

Procedure:
A solution of 11 ml of methylhydrazine in 50 ml of methanol was added dropwise to an ice-cold solution of 30 grams of 2-acetyl-1,3-cyclohexanedione in 200 ml of methanol and the reaction mixture was heated at reflux for 90 minutes. The solvent was removed under reduced pressure and the residue was triturated in hexane and cooled to give a clammy tan solid. This crude product was recrystallized from a mixture of toluene and hexane to give 1,5,6,7-tetrahydro-1,3-dimethyl-4H-indazol-4-one as a yellow crystalline solid melting at about 82.5°-84° C.