Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([O:30][CH3:31])[CH:21]=1.[C:32]([NH:36][C:37](=[O:51])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH:39]=1)([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>ClCCl>[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24]([N:48]2[CH2:47][CH2:46][N:45]([CH2:44][C:40]3[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=3)[C:37]([NH:36][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:51])[CH2:50][CH2:49]2)=[O:26])=[C:22]([O:30][CH3:31])[CH:21]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (6.31 g, 9.92 mmol, 5.91 ml) was added dropwise to a solution of 4-amino-5-chloro-2-methoxybenzoic acid (1 g, 5 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (1.5150 g, 5,5 mol) and triethylamine (1.508 g, 14.88 mmol, 2.068 mL) in dichloromethane. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was taken up with ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic phase was concentrated under vacuum to afford the title compound (1.71 g). MS (ESI) m/z 459.7 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][NH2:24].[OH:25][CH2:26][CH:27]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][N:24]=[CH:27][CH2:26][OH:25]
Reactant: O=CCO
Reactant: CSc1ccc(/C=C2/C(C)=C(CCON)c3cc(F)ccc32)cc1
Product: CSc1ccc(/C=C2/C(C)=C(CCON=CCO)c3cc(F)ccc32)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylthiophenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with hydroxyacetaldehyde by the method of Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(N(CC)C(C)C)(C)C.Cl[CH2:23][O:24][CH3:25]>ClCCl>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:23][O:24][CH3:25])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCl
Reactant: COC(=O)c1cc(O)cc(O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cc(O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.8 %

Procedure:
With ice cooling, to a solution of methyl 3,5-dihydroxybenzoate (14.0 g, 83.3 mmol) and N,N-diisopropylethylamine (11.0 g, 85.0 mmol) in dichloromethane (100 mL) was added dropwise chloromethylmethyl ether (6.84 g, 85.0 mmol), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with dichloromethane (300 mL), and the organic layer was washed successively with a 3% aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution and saturated brine, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=4:6) to give the title compound (7.74 g, yield 44%) as an oily matter.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([O:9][C:21]([C:20]1[CH:19]=[CH:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=2)=[CH:25][CH:24]=1)=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 87.5 %

Procedure:
Fifteen grams of n-octanol, 7.5 g of 4-(4'-hydroxyphenyl)benzoic acid and 7.0 g of p-toluenesulfonic acid were dissolved with 100 ml of toluene in a three necked flask with a dehydration apparatus, and the mixture was refluxed for 15 hours. Water was added to the mixture to separate a toluene layer. Ten grams of 4-(4'-octyloxycarbonylphenyl)phenol (AB) were obtained by removing the toluene layer under reduced pressure followed concentration. (s)-4-(1-chloro-2-methylpropylcarbonyloxy)benzoic acid dispersed in 20 ml of carbon tetrachloride was reacted with 5 ml of thionyl chloride by refluxing for 3 hours. After removing the solvent (s)-4-(1-chloro-2-methylpropylcarbonyloxy)benzoic chloride (AC) was obtained. 1.5 g of (AC) was dissolved with mixed solvent of 80 ml of carbon tetrachloride and 10 ml of pyridine, and then 1.7 g of (AB) was added to the mixed solution with cooling and the mixture was allowed to stand overnight to obtain crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH2:15][CH3:16])=[C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:7]=1.[CH:17]([NH:20][NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH2:15][CH3:16])=[C:6]([CH2:8][CH2:9][C:10]([N:20]([CH:17]([CH3:19])[CH3:18])[NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:12])[CH:7]=1
Reactant: CCCOc1ccc(F)cc1CCC(=O)O
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCOc1ccc(F)cc1CCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 36.2 %

Procedure:
A solution of 3-(5-fluoro-2-propoxy-phenyl)-propionic acid (160 mg, 0.71 mmoles) and benzoic acid N′-isopropyl-hydrazide (106 mg, 0.60 mmoles) in DMF (3 mL) was treated with diisopropylethylamine (0.26 mL, 1.49 mmoles), and PyBroP (416 mg, 0.89 mmoles) at room temperature for 16 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (84 mg, 30%). LC-MS m/e 387.26 (M+H+)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:43][C:44]1[C:45](F)=[CH:46][C:47]([F:70])=[C:48]([S:50]([N:53]([CH2:59][C:60]2[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][C:61]=2[O:68][CH3:69])[C:54]2[S:55][CH:56]=[N:57][N:58]=2)(=[O:52])=[O:51])[CH:49]=1>CS(C)=O>[Cl:43][C:44]1[CH:49]=[C:48]([S:50]([N:53]([CH2:59][C:60]2[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][C:61]=2[O:68][CH3:69])[C:54]2[S:55][CH:56]=[N:57][N:58]=2)(=[O:51])=[O:52])[C:47]([F:70])=[CH:46][C:45]=1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:19]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cc(-c4ccc(C(F)(F)F)cc4)ccc3O)ccn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
tert-Butyl 4-(4-(4-hydroxy-4′-(trifluoromethyl)biphenyl-3-yl)pyridin-2-yl)piperazine-1-carboxylate (Preparation 114, 200 mg, 0.400 mmol) was dissolved in dimethyl sulfoxide (3 mL) and potassium carbonate (110 mg, 0.800 mmol) was added followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 185 mg, 0.400 mmol). The reaction was stirred at room temperature for 18 hours and then partitioned between ethyl acetate (10 mL) and water (5 mL). The organic layer was separated and washed with brine (5 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified on silica gel by Biotage™ (7% to 60% ethyl acetate in heptane over 20 CV) to give the title product (340 mg, 90%) as a yellow foam.
Reaction SMILES: I[C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>[Cu]I.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.CN1CCCC1=O>[CH3:10][Si:11]([C:14]#[C:15][C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1)([CH3:13])[CH3:12]
Reactant: Nc1ccc(I)c(N)n1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)C#Cc1ccc(N)nc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a mixture of 3-iodo-pyridin-2,6-diamine (20.0 g, 85.2 mmol) described in Manufacturing Example 13-1-1, trimethylsilyl acetylene (24.2 mL, 170 mmol), copper (I) iodide (3.25 g, 17.0 mmol) N,N-diisopropylethylamine (19.1 g, 148 mmol) and N-methylpyrrolidinone (286 mL) was added tetrakis(triphenylphosphine)palladium (0) (9.81 g, 8.52 mmol) under argon atmosphere, which was stirred for 30 minutes at room temperature. The reaction solution was partitioned into water and ethyl acetate. The ethyl acetate layer was washed with water 4 times and dried over sodium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel chromatography (heptane:ethyl acetate=4:1 then 1:1). The solids obtained by concentrating the eluate under a reduced pressure were washed with heptane containing a small amount of ethyl acetate to obtain the title compound (10.5 g, 60.0%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)=[O:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([CH:31]=[O:32])[CH:38]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2cccc(C=O)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 64.1 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (400 mg, 0.84 mmol) and (3-formylphenyl)boronic acid (189 mg, 1.26 mmol) in dioxane (2 mL), aqueous 2M Na2CO3 solution (1.5 mL, 3.03 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (97 mg, 0.08 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (270 mg, 64%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.[H-].[Na+].[I:23][C:24]1[C:32]2[C:27](=[N:28][CH:29]=[N:30][C:31]=2N)[NH:26][N:25]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][N:19]2[C:31]3=[N:30][CH:29]=[N:28][C:27]([NH2:26])=[C:32]3[C:24]([I:23])=[N:25]2)=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: Cc1cccc2cc(CN)c(-c3ccccc3F)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2cc(Cn3nc(I)c4c(N)ncnc43)c(-c3ccccc3F)nc12

Procedure:
Prepared according to Procedure I using (2-(2-fluorophenyl)-8-methylquinolin-3-yl)methanamine (0.200 g, 0.7 mmol), NaH (0.031 g, 60% in oil, 0.77 mmol, 1.1 eq) and 3-iodo-1H-pyrazolo{3,4-d}pyrimidin-4-amine (0.201 g, 0.77 mmol, 1.1 eq) in DMF. 1-((2-(2-fluorophenyl)-8-methylquinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine [PI3Kδ IC50=4 nM] was obtained after purification as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.09 (1 H, s), 8.00 (1 H, s), 7.96 (1 H, s), 7.80 (1 H, d, J=7.9 Hz), 7.63 (1 H, d, J=7.3 Hz), 7.46-7.53 (1 H, m), 7.30 (1 H, dt), 7.08 (1 H, dd, J=7.6, 1.5 Hz), 7.02 (1 H, d, J=7.9 Hz), 6.91 (1 H, t, J=7.3 Hz), 5.46-5.54 (2 H, m), 2.90 (3 H, s) Mass Spectrum (ESI) m/e=511.0 (M+1)
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH:10]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:25].[OH-].[Na+]>>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH:10]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11]2)[C:8]([NH2:9])=[O:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)N1CCC(C(C#N)(c2ccccc2)c2ccccc2)C1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)N1CCC(C(C(N)=O)(c2ccccc2)c2ccccc2)C1

Procedure:
A solution of 29.0 g. of α,α-diphenyl-α-(1-isopropyl-3-pyrrolidinyl)acetonitrile in 100 ml. of conc. sulfuric acid was heated at 80° C. for 18 hours. The reaction mixture was poured onto ice, the resulting cold acidic solution made basic using sodium hydroxide and the basic solution extracted with chloroform. The dried chloroform extract was concentrated and the residue crystallized from isooctane. The solid was recrystallized from isopropyl ether to give 13.2 g. (43%) of product which melted at 110.5°-112.5° C.
Reaction SMILES: ClC(OCC(C)C)=O.[OH:9][C:10]1[CH:11]=[CH:12][C:13]2[C:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=O)=[C:16]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)[S:15][C:14]=2[CH:36]=1.CN1CCOCC1.[CH2:44]([NH2:51])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>C(Cl)Cl>[CH2:44]([NH:51][C:26](=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]1[C:13]2[CH:12]=[CH:11][C:10]([OH:9])=[CH:36][C:14]=2[S:15][C:16]=1[C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: O=C(O)CCCCCCCCc1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Reactant: CCCCCCCN
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCCCCNC(=O)CCCCCCCCc1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of isobutyl chloroformate (0.117 g.) in methylene chloride (5 ml.) was added to a stirred solution of 9-(6-hydroxy-2-p-hydroxyphenylbenzo[b]thien-3-yl)nonanoic acid (0.1 g.) and N-methylmorpholine (0.145 g.) in methylene chloride (10 ml.) which was cooled to -30° C., and the mixture was allowed to warm up to laboratory temperature. A solution of n-heptylamine (0.098 g.) in methylene chloride (5 ml.) was added and the mixture was stirred at laboratory temperature for 1 hour and then evaporated to dryness. The residue was dissolved in methanol (5 ml.), aqueous 40% sodium hydroxide solution (2 ml.) was added and the mixture was stirred for 5 minutes and then acidified with concentrated aqueous hydrochloric acid and extracted three times with diethyl ether (20 ml. each time). The combined extracts were washed with water, dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 100:3 v/v mixture of methylene chloride and methanol as eluant. There was thus obtained as an oil N-n-heptyl-9-(6-hydroxy-2-p-hydroxyphenylbenzo[b]thien-3-yl)nonanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[CH:12]=1.CCN(CC)CC.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C1COCC1>[C:20]([CH:9]1[NH:8][CH2:7][C:6]2[CH:12]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[NH:11][CH2:10]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc2c(c1)CNCCN2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)C1CNc2ccc(Cl)cc2CN1
Temperature: 25 °C
Yield: 22.6 %

Procedure:
7-chloro-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (12.5 mmol) was dissolved in a mixture of THF (100 mL), Et3N (19.1 mmol) and acetic anhydride (12.4 mmol). The reaction mixture was heated under reflux for 18 h, cooled to room temperature and partitioned between H2O and EtOAc. The aqueous phase was extracted again 2× with EtOAc and the combined organic layers were dried over MgSO4, filtered and concentrated to a yellow, oily solid. The crude material was purified by column chromatography on silia eluting with EtOAc to yield 3-acetyl-7-chloro-1,2,3,5-tetrahydro-4H-[1,4]benzodiazepine (2.8 mmol, 22%) as a clear oil.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][CH2:12][N:7]2[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N[C@@H]1C(=[O:39])N2[C@H](C(OC(C)(C)C)=O)CCCN2CCC1>>[O:39]=[C:6]1[CH2:5][CH2:4][C@H:3]([NH:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:2](=[O:1])[N:8]2[C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][CH2:12][N:7]12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2CCC[C@H](N)C(=O)N12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2CCC[C@H](NC(=O)CCc3ccccc3)C(=O)N12
Product: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)CCc3ccccc3)C(=O)N12

Procedure:
(1S,9S) t-Butyl octahydro-10-oxo-9-(3-phenylpropionylamino)-6H-pyridazino-[1,2-a] [1,2]diazepine-1-carboxylate (44b), was prepared from (1S,9S) t-butyl 9-amino-octahydro-10-oxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (Attwood et al., J. Chem. Soc. Perkin 1, pp. 1011-19 (1986)) as for 44a, to afford 810 mg (81%) of a colorless oil: [α]D23 −33.5° (C 0.545, CH2Cl2); IR (film) 3334, 2935, 1737, 1728, 1659, 1642; 1H NMR (CDCl3) δ 7.24 (5H, m), 6.75 (1H, d, J=6.7), 5.27 (1H, m), 4.92 (1H, m), 3.39 (1H, m), 3.03 (4H, m), 2.55 (3H, m), 2.33 (1H, m), 2.17 (1H, m), 1.80 (5H, m), 1.47 (9H, s), 1.39 (1H, m). MS(FAB, m/z): 416 (M++1), 360, 211, 143, 97.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:19])=O)[N:12]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([NH:24][C:17]([C:13]1[N:12]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:16]=[CH:15][CH:14]=1)=[O:19])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN
Reactant: CCc1cc(-c2cccc(C(=O)O)n2)c(C)[nH]c1=O
Product: CCCCNC(=O)c1cccc(-c2cc(CC)c(=O)[nH]c2C)n1

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-6-carboxylic acid and n-butyl amine to afford the title compound. MS: m/e=314 (M+H).
Reaction SMILES: CO.[C:3]([NH:11][C:12]1[CH:20]=[C:19](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[C:3]([NH:11][C:12]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Nc1cc(/C=C/c2cccc(Cl)c2)ccc1C(=O)O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1cc(CCc2cccc(Cl)c2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9 mg of 5% palladium-carbon was added to a mixed solution of 2.7 mL of methanol and 2.7 mL of ethyl acetate containing 30 mg of 2-benzamido-4-((E)-2-(3-chlorophenyl)vinyl)benzoic acid and stirred under hydrogen atmosphere at room temperature for 3 hours. Insoluble were removed by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 60-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to obtain 2.0 mg of 2-(benzamido)-4-(2-(3-chlorophenyl)ethyl)benzoic acid as white solid.
Reaction SMILES: [C:1]1([CH2:13][C:14]([NH2:16])=[O:15])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[O:17]1CCOCC1>O.[Pd]>[C:1]1([C:13](=[O:17])[C:14]([NH2:16])=[O:15])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: C1COCCO1
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Agent: [Pd]
Solvent: O
Product: NC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Yield: 96 %

Procedure:
To a solution of (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide (0.30 g, 1.31 mmol) in dioxane (6 mL) and water (2 mL) was added 10% palladium on carbon (0.060 g), followed by the careful addition of NaH2PO2.H2O (0.60 g, 5.67 mmol) and the reaction was brought to reflux under nitrogen. After 3 hours an additional 0.60 g of NaH2PO2.H2O was added and the reaction was heated at reflux for another 6 hrs. The mixture was cooled, filtered through a pad of Celite, and washed well with ethyl acetate (100 mL). The solution was concentrated under reduced pressure and the residue triturated with water (20 mL). The resulting suspension was filtered and the recovered solid dried under reduced pressure to provide 0.27 g (96%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[NH:14]2)=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[NH:14]2)=[C:7]([S:9]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: C1COCCN1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)NC(=O)N1c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)N2CCOCC2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (20 mg, 42 μmol) was dissolved in absolute dichloromethane (2.5 ml), morpholine (7.3 μl, 83 μmol; 2 eq.) was added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (8.6 mg, 35% of theory).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([C:10]([OH:12])=O)=[N:3]1.Cl.[CH3:14][NH2:15]>>[CH3:14][NH:15][C:10]([C:4]1[C:5]([N+:7]([O-:9])=[O:8])=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:12]
Reactant: CN
Reactant: Cn1cc([N+](=O)[O-])c(C(=O)O)n1
Agent: Cl
Product: CNC(=O)c1nn(C)cc1[N+](=O)[O-]

Procedure:
The product was obtained according to the method described in example 1, step 1 starting from 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid and methylamine hydrochloride as light yellow solid (250 mg, 64%).