Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25].[OH-].[Na+].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([NH:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCC(=O)O
Reactant: COc1ccc(C(=O)Cl)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCCCC(=O)O)cc1OCc1ccccc1
Reaction time: 2 h

Procedure:
14.0 g of 3-benzyloxy-4-methoxybenzoyl chloride are added in one portion at 26° C. to 15.6 g of 4-aminobutyric acid, 12.1 g of sodium hydroxide and 160 ml of ion-free water and subsequently 30 ml of tetrahydrofuran are added dropwise within 10 minutes. After 2 hours, the mixture is acidified with concentrated hydrochloric acid at a temperature below 10° C. The precipitate is separated and stirred with ethyl acetate. The mixture is filtered and the filter cake is washed with ethyl acetate. There is obtained 4-[(3-benzyloxy-4-methoxybenzoyl)amino]butyric acid which, after recrystallisation from ethyl acetate, melts at 156°-158° C.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH:8]1([NH2:11])[CH2:10][CH2:9]1>CO>[OH:7][C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[NH:11][CH:8]1[CH2:10][CH2:9]1
Reactant: C1CCC2OC2C1
Reactant: NC1CC1
Solvent: CO
Product: O[C@@H]1CCCC[C@H]1NC1CC1

Procedure:
Cyclohexene oxide (143 ml) and cyclopropylamine (82 g) are dissolved in methanol (1 liter), and the mixture is refluxed for 5 hours. The mixture is concentrated under reduced pressure to remove the solvent, and the resulting residue is distilled under reduced pressure to give trans-N-(2-hydroxycyclohexyl)-N-cyclopropylamine (126 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[C:13](=[O:27])[NH:12][C:11]([CH3:28])=[C:10]2[C:29]([O:31][CH3:32])=[O:30])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:33][CH2:34][CH2:35][CH2:36][N:37]1[CH:41]=[CH:40][N:39]=[CH:38]1>C(Cl)Cl>[CH3:32][O:31][C:29]([C:10]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[N:14]([C:15](=[O:16])[NH:33][CH2:34][CH2:35][CH2:36][N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[C:13](=[O:27])[NH:12][C:11]=1[CH3:28])=[O:30]
Reactant: COC(=O)C1=C(C)NC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Reactant: NCCCn1ccnc1
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCn2ccnc2)C1c1ccc(F)c(F)c1
Yield: 83.9 %

Procedure:
A solution of 6-(3,4-difluorophenyl)-4-methyl-5-methoxycarbonyl-1-(4-nitrophenoxy)carbonyl-2-oxo-1,2,3,6-tetrahydro-pyrimidine (100 mg, 0.22 mmol) and 1-(3-aminopropyl)imidazole (40 ml, 0.34 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 3 hours. The solvent was removed in vacuum. The residue was separated on preparative TLC (CHCl3/MeOH=100/15) to get the title compound (80 mg, 84% yield) as a white solid. Hydrochloride of title compound was made with HCl in ether. Calcd for C20H21N5O4F2+0.3 H2O: C, 54.74%; H, 4.99%; N, 15.89%. Found: C, 54.92%; H, 4.65%; N, 15.77%. M.P. of the salt: 221-224° C.
Reaction SMILES: [C-]#N.[K+].CN([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[NH:10][CH:9]=1)C.[CH3:18][N:19](C=O)C>O.C1(C)C=CC=CC=1>[F:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]([CH2:7][C:18]#[N:19])=[CH:9][NH:10]2)=[CH:15][CH:14]=1
Reactant: CN(C)C=O
Reactant: CN(C)Cc1c[nH]c2cc(F)ccc12
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CCc1c[nH]c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Combine KCN (50.8 g, 0.78 mol), 3-(N,N-dimethylaminomethyl)-6-fluoroindole (100 g, 0.52 mol), DMF (400 mL) and water (200 mL). Heat to reflux. Evolution of gas begins at about 70° C. Maintain the reflux for 4 hours. Cool the reaction mixture to room temperature, dilute with water and toluene and stir for 10 minutes. Decant the organic layer and wash successively with of saturated aqueous sodium bicarbonate and of 2M aqueous hydrochloric acid. Concentrate to dryness the organic layer to give 2-(6-fluoro-1H-indol-3-yl)acetonitrile.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[S:12][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:22].[OH-].[Na+]>C1COCC1.O>[C:3]([O:7][C:8]([N:10]([CH3:22])[C:11]1[S:12][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(N(C)C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Yield: 45 %

Procedure:
A flask is charged with a suspension of sodium hydride (60% in mineral oil) (0.109 g, 2.72 mmol) in THF (5 mL). The ethyl 2-[(tert-butoxycarbonyl)amino]-1,3-thiazole-5-carboxylate (0.735 g, 2.70 mmol) is added, followed by iodomethane (175 μL, 2.70 mmol) and the resulting suspension is heated to reflux for 3 hours, then cooled to room temperature. Water is added, followed by 1.0 N NaOH. The basic phase is extracted with 3 portions of EtOAc. The combined organic phases are washed with brine, dried over Na2SO4, filtered, and concentrated to give a clear oil purified with flash chromatography. Yield 45%. HRMS (FAB) calculated for C12H18N2O4S+H 287.1065, found 287.1068.
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]2[C:4](=[C:5]([C:22]#[N:23])[N:6]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N+:7]=2[O-])[CH:3]=1.P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]2[C:4](=[C:5]([C:22]#[N:23])[N:6]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[N:7]=2)[CH:3]=1
Reactant: N#Cc1c2cc(Br)c([N+](=O)[O-])cc2[n+]([O-])n1-c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: ClP(Cl)Cl
Product: N#Cc1c2cc(Br)c([N+](=O)[O-])cc2nn1-c1ccc(F)cc1
Temperature: 60 °C

Procedure:
To a stirred solution of 5-bromo-3-cyano-2-(4-fluorophenyl)-6-nitro-2H-indazole 1-oxide (5.0 g, 0.013 mol) in chloroform (50 mL) was added phosphorus trichloride (5.0 mL, 0.057 mol) dropwise and the reaction mixture was heated to 60° C. for 1 h. Then the reaction mixture was poured into ice water and extracted into DCM (2×80 mL). The organic layer was concentrated, and ethanol was added to the residue. After filtration, 5-bromo-2-(4-fluorophenyl)-6-nitro-2H-indazole-3-carbonitrile was collected as solid (4.3 g, 91%). 1H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.25 (s, 1H), 7.89˜7.91 (m, 2H), 7.33˜7.37 (m, 2H). MS (M+H)+: 361/363.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]1([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[CH3:21][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]([OH:20])=[O:19]
Reactant: CC(C(=O)O)c1ccccc1
Reactant: CC(C)(C)CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)CCC(C)(C(=O)O)c1ccccc1
Reaction time: 17 h
Yield: 95.5 %

Procedure:
Lithium bis(trimethylsilyl)amide (32.3 g, 193 mmol) was added to 80 mL of tetrahydrofuran and the resulting solution was cooled in an ice bath. Addition of a solution of 2-phenyl-propionic acid (11.6 g, 77.3 mmol) in 10 mL of tetrahydrofuran to the reaction solution was followed by addition of 1-bromo-3,3-dimethyl-butane (20.4 g, 124 mmol). The reaction vessel was removed from the cooling bath, placed in a 50° C. oil bath, and the reaction solution was stirred for 17 hours. After concentration, the resulting residue was dissolved in 250 mL of 1 N NaOH, washed with 250 mL of 2:1 hexane/iso-propyl acetate, acidified to pH 1 with 6 N HCl, and extracted with ethyl acetate (3×300 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 17.3 g (96%) of clear oil. 1H NMR (300 MHz, CDCl3): δ ppm 0.86 (s, 9 H) 1.09 m, 2 H) 1.56 (s, 3 H) 1.99 m, 2 H) 7.33 m, 5 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([O:18]C)=[O:17])[CH:10]=2)=[CH:5][CH:4]=1>Cl.C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([OH:18])=[O:17])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccccc1-c1cc(-c2ccc(OC)cc2)on1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2cc(-c3ccccc3C(=O)O)no2)cc1
Yield: 99 %

Procedure:
A solution of 1.81 g of methyl 2-[5-(4-methoxyphenyl)-3-isoxazolyl]benzoate in 8 ml concentrated HCl and 8 ml of acetic acid was held at reflux for 4 hours, cooled, diluted with water, and filtered to give 1.71 g (99%) of white solid, mp 182°-185° C. Recrystallization of the solid from CH3CN gave 1.27 g (73%) of solid, mp 186°-187.5° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[O:13]1[C:23]23[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]2)[O:17][CH2:16][CH2:15][C@H:14]13.[OH-].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C@H:14]2[C@:23]3([OH:13])[C@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)[O:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: C1CCC23O[C@H]2CCO[C@@H]3C1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O[C@]12CCCC[C@@H]1OCC[C@H]2Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-Fluoroaniline (0.173 g, 1.56 mmol) in CH2Cl2 (3 mL) at 0° C. was added trimethylaluminum (2M in toluene, 0.778 mL) dropwise. The mixture was warmed to rt and stirred for 30 min. Trans hexahydro-1aH,4aH-oxireno[d]chromene (0.200 g, 1.30 mmol) in CH2Cl2 (2 mL) was then added and the mixture was stirred at rt overnight. The reaction was cooled to 0° C. and treated with 50% NaOH (1 mL) then water (1 mL). The reaction mixture was extracted 3× with CH2Cl2. The combined organics were dried, filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 6.90 (t, 2H, J=8.8 Hz), 6.60 (dd, 2H, J=4.2 Hz, 8.8 Hz), 3.88 (dd, 1H, J=5.4 Hz, 12.0 Hz), 3.68-3.74 (m, 1H), 3.47 (dd, 1H, J=4.8 Hz, 11.5 Hz), 3.40 (t, 1H, J=3.2 Hz), 2.30-2.40 (m, 1H), 1.69-1.78 (m, 2H), 1.54-1.68 (m, 5H), 1.45-1.48 (m, 1H), 1.20-1.30 (m, 1H), HRMS (ES) m/z M+H calc'd.: 266.1551. found: 266.1556
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)[C:11]#[C:12][CH3:13].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29].[Cl-].[NH4+]>C(Cl)(Cl)Cl>[CH2:10]([O:14][C:15]1[CH:20]=[C:19]([S:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[F:22])[N:18]=[CH:17][N:16]=1)[C:11]#[C:12][CH3:13]
Reactant: Fc1ccccc1S
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC#CCOc1cc(Sc2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 23.3 %

Procedure:
To 2.2 ml of chloroform were added 0.29 ml of diisopropylethylamine, 0.2 g of 4-(2-butynyloxy)-6-chloropyrimidine, and 0.17 g of 2-fluorothiophenol, followed by stirring at room temperature for 7 hours. Then, a saturated aqueous ammonium chloride solution was poured into the reaction mixture, which was extracted three times with t-butyl methyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.07 g of 4-(2-butynyloxy)-6-(2-fluorophenylthio)pyrimidine (the present compound (146)).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]([NH:16][NH2:17])=[O:15])[CH:8]=2)[NH:3]1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:22](O)=O.C(N(CC)CC)C.CCCP(=O)=O>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([C:22]2[O:15][C:14]([CH2:13][O:12][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2](=[O:1])[CH:11]=[CH:10]4)=[N:16][N:17]=2)[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: NNC(=O)COc1ccc2[nH]c(=O)ccc2c1
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Agent: CCCP(=O)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1ccc2cc(OCc3nnc(-c4ccc(Cl)c(Cl)c4)o3)ccc2[nH]1
Temperature: 100 °C
Yield: 4.8 %

Procedure:
To a stirred solution of 2-((2-oxo-1,2-dihydroquinolin-6-yl)oxy)acetohydrazide (0.2 g, 0.858 mmol) and 3,4-dichlorobenzoic acid (0.163 g, 0.858 mmol)) in DMF (8 mL) was added triethylamine (0.598 mL, 4.29 mmol) and propylphosphonic anhydride (T3P) (0.819 g, 2.57 mmol). The reaction mixture was heated at 100° C. overnight under N2 atm. The reaction mixture was concentrated to remove solvent and ice-cold water was added. The precipitate was filtered and washed with water to afford a brown solid. The crude product was purified by preparative HPLC on a C18 reverse phase column (ACN-NH4OAc method) to give 6-((5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-2(1H)-one as a white solid (0.016 g, 4.81%). 1H NMR: 400 MHZ, DMSO-d6: δ 5.51 (s, 1H), 6.52 (d, J=9.60 Hz, 1H), 7.27-7.31 (m, 2H), 7.43 (d, J=2.40 Hz, 1H), 7.83-7.92 (m, 2H), 8.00 (dd, J=1.60, 8.40 Hz, 1H), 8.21 (d, J=1.60 Hz, 1H), 11.68 (s, 1H). LCMS: RT 1.92 min. LCMS (ES-API), m/z 390.0 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH2:24]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27]>>[CH2:24]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:2]([CH2:3][C:4]2[CH:5]=[C:6]([C:10]3[CH:11]=[CH:12][C:13]([CH2:16][CH:17]4[S:21][C:20](=[O:22])[NH:19][C:18]4=[O:23])=[CH:14][CH:15]=3)[CH:7]=[CH:8][CH:9]=2)[CH3:1])=[O:34])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Product: CCCCOc1ccc(C(=O)N(C)Cc2cccc(-c3ccc(CC4SC(=O)NC4=O)cc3)c2)cc1

Procedure:
In a manner similar to that of Example 37(e), by reacting 500 mg (1.5 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione with 290 μl (1.5 mmol) of 4-butoxybenzoyl chloride, and after purification, 550 mg (83%) of 4-20 butoxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbenzamide are obtained in the form of a white solid with a melting point of 116° C.
Reaction SMILES: C(OC(N[C@@H:9]([CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])[C:10]([OH:12])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=[O:30]>ClC(Cl)C>[O:26]=[C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24](=[O:25])[N:16]1[CH2:15][CH2:14][CH2:13][C@H:9]([OH:30])[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN1C(=O)c2ccccc2C1=O)C(=O)O
Reactant: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: O=C(O)[C@@H](O)CCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (S)-2-(tert-butoxycarbonylamino)-5-(1,3-dioxoisoindolin-2-yl)pentanoic acid L (1.45 g, 4.0 mmol) in dichloroethane (25 mL) was cooled to 0° C. Trifluoroacetic acid was added in one portion and the mixture was allowed to warm to room temperature and stir for 2 h. The mixture was concentrated to dryness mixed with water (18.5 mL), HOAc (9.5 mL) and aqueous NaNO2 (1.2 g in 25 mL H2O). After 15 min another portion of HOAc (14 mL) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated to dryness. The residue was dissolved in water (100 mL), the pH was adjusted to 1 by addition of 10% aqueous HCl, and the solution was extracted with diethyl ether (5×100 mL). The organic phase was dried over Na2SO4 and concentrated to dryness under reduced pressure afford (S)-5-(1,3-dioxoisoindolin-2-yl)-2-hydroxypentanoic acid LI (0.98 g, 3.73 mmol, 93%). ESIMS found for C13H13NO5 m/z 262 (M−H)−.
Reaction SMILES: [H-].[Na+].CN(C)P(N(C)C)(N(C)C)=O.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[OH:24].Cl[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32]>O>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[O:24][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32]
Reactant: Oc1ccc2ccccc2c1
Reactant: OCCCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: OCCCCCCOc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled round bottom flask is added, 4.2 g of 57% sodium hydride in oil, 50 ml of hexamethylphosphoramide and 15.8 g. of 2-naphthol. After 1/2 hour the mixture is allowed to warm to room temperature and 13.6 g. of 6-chlorohexan-1-ol is added. The mixture is heated at 110° C. overnight, cooled, diluted with water and extracted with ether. The ether extract is washed with sodium hydroxide solution, then with water, dried (magnesium sulfate) and the solvent removed under vacuum. The solid is dissolved in ether and the solution washed with sodium hydroxide solution. The ether layer is dried (magnesium sulfate) and the solvent removed under vacuum to give 15.9 g. of product, as crystals, mp 53°-56° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([CH:11]=[CH:12]N(C)C)[C:8]([N+:16]([O-])=O)=[CH:7][C:6]=1[N+:19]([O-])=O)[CH3:2]>CCO.[Ni]>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][C:6]=1[NH2:19])[NH:16][CH:12]=[CH:11]2)=[O:22])[CH3:2]
Reactant: CCOC(=O)c1cc(C=CN(C)C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1cc2cc[nH]c2cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A mixture of 5-(2-dimethylamino-vinyl)-2,4-dinitro-benzoic acid ethyl ester (15 g, 0.05 mol) and Raney Ni (5 g) in EtOH (500 mL) was stirred under H2 (50 psi) at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to give 6-amino-1H-indole-5-carboxylic acid ethyl ester (B-25) (3 g, 30%). 1H NMR (DMSO-d6) δ 10.68 (s, 1H), 7.99 (s, 1H), 7.01-7.06 (m, 1H), 6.62 (s, 1H), 6.27-6.28 (m, 1H), 6.16 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 1.32-1.27 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:27][Si](C)(C)C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:27])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-propionic acid (105 mg, 0.37 mmol) in methylene chloride (10 mL) and 1 drop of N,N-dimethylformamide was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.18 mL, 0.37 mmol). The reaction was stirred for 30 min at 0° C., at which time, 1,1,1,3,3,3-hexamethyldisilazane (0.25 mL, 1.17 mmol) was added to the reaction mixture. The reaction was then allowed to slowly warm to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was then washed with a 5% aqueous sulfuric acid solution (2×10 mL). The combined aqueous layers were extracted with methylene chloride (3×10 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide (60 mg, 58%) as a white solid: [α]23589=−67.6° (c=0.106, chloroform); EI-HRMS m/e calcd for C14H17Cl2N1O1(M+) 285.0687, found 285.0685.
Reaction SMILES: Br[C:2]1(Br)[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C)C1C=CC=CC=1>CS(C)=O>[C:18]1([NH:24][N:25]=[C:2]2[C:7]3=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]3[CH:5]([CH3:16])[CH2:4][CH2:3]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1CCC(Br)(Br)c2ncc(C(=O)O)c(=O)n21
Reactant: NNc1ccccc1
Solvent: CS(C)=O
Solvent: CN(C)c1ccccc1
Product: CC1CCC(=NNc2ccccc2)c2ncc(C(=O)O)c(=O)n21
Reaction time: 72 h
Yield: 64 %

Procedure:
0.73 g. (0.002 moles) of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid are dissolved in 2 ml. of dimethyl sulfoxide. To the solution 0.2 ml. (0.002 moles) of phenyl hydrazine and 0.5 ml. (0.004 moles) of N,N-dimethylaniline are added. Thereafter the reaction mixture is allowed to stand for three days. The precipitated crystals are filtered off and washed with methanol. The product is purified by alkaline/acidic precipitation. 0.4 g. (64.0%) of 9-(phenylhydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid are obtained, melting at 254° to 255° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=1[Cl:34])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][C:25]=1[Cl:34])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: CCC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(=O)OC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Solvent: O
Solvent: C1COCCO1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(S(C)(=O)=O)cc1Cl
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (1.0 g), 2-(2-chloro-4-methanesulfonylbenzyl)-3-oxopentanoic acid methyl ester (2.1 g), polyphosphoric acid (10 g) and dioxane (10 mL) was heated at 130° C. for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (19:1 by volume) to afford title compound, 1.6 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:48])[C:32]([C:46]#[N:47])=[CH:33][C@@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3C(OC(C)(C)C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[ClH:49]>O1CCOCC1>[ClH:49].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:33][C@@H:34]3[CH2:38][CH2:37][CH2:36][NH:35]3)[C:46]#[N:47])=[O:48])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Agent: Cl
Solvent: C1COCCO1
Product: N#CC(=C[C@@H]1CCCN1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
To a solution of tert-butyl (2S)-2-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]pyrrolidine-1-carboxylate (84 mg, 0.13 mmol) in 1,4-dioxane (2 mL) and added 4N HCl in dioxane (0.16 mL). The solution was stirred for 16 hr at room temperature then concentrated. The residue was dissolved in methanol (−1 mL) and added dropwise to ethyl ether (20 mL) while stirring. The resulting solid was collected by filtration to provide 42 mg (59%) of the title compound as an HCl salt. MS (pos. ion) m/z: 553 (M+1).