Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].C([O-])([O-])=O.[K+].[K+]>CO.CCCCC>[CH2:13]([O:12][C:5]([O:6][CH2:7][CH3:8])([O:9][CH2:10][CH3:11])[C:4]#[CH:3])[CH3:14]
Reactant: CCOC(C#C[Si](C)(C)C)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCC
Solvent: CO
Product: C#CC(OCC)(OCC)OCC
Temperature: 23 °C
Reaction time: 15 h
Yield: 75.4 %

Procedure:
A solution of trimethyl(3,3,3-triethoxyprop-1-ynyl)silane (25 g, 102 mmol) in MeOH (400 mL), was treated with K2CO3 (14 g, 102 mmol). The reaction was stirred at 23° C. After 15 hours, the reaction was diluted with pentane (500 mL). The pentane layer was separated, and the MeOH layer was extracted with pentane (2×250 mL). The combined pentane layers were washed with water (200 mL), dried over MgSO4, and concentrated (at 220 torr on rotary evaporator). The crude product was filtered through a silica gel plug using 10% diethyl ether/pentane as the eluant and concentrated (at 220 torr on rotary evaporator) affording 13.25 g of 3,3,3-triethoxyprop-1-yne.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:6](=[O:23])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:35][C:36]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:37]=1[CH2:38]Br.N1CCOCC1>CN(C=O)C.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:22]=[N:21][N:20]([CH2:38][C:37]4[CH:40]=[CH:41][C:42]([F:44])=[CH:43][C:36]=4[F:35])[CH:19]=3)[C:6](=[O:23])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCc1cn[nH]c1)c(=O)n2CCCCC
Reactant: Fc1ccc(CBr)c(F)c1
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: CN(C)C=O
Solvent: C1COCCN1
Product: CCCCCn1c(=O)n(CCCc2cnn(Cc3ccc(F)cc3F)c2)c(=O)c2[nH]c(Cl)nc21
Yield: 38.4 %

Procedure:
8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione (81 mg, 0.2 mmol) and sodium carbonate (85 mg, 0.8 mmol) were stirred in dry DMF (2 ml) with 2,4-difluorobenzyl bromide (166 mg, 0.8 mmol) at 45° C. for 18 h. The mixture was degassed and stirred with tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.04 mmol) and morpholine (176 mg, 2 mmol) at rt for 6 h. The reaction was worked up and purified by aminopropyl SPE (5 g, washing with THF-MeOH (1:1) then neat MeOH, eluting with DCM-MeOH (1:1) with 5% added AcOH) to yield the title compound (37.7 mg) as a solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([F:26])([F:25])[F:24])[CH:8]=2)[N:3]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C.Cl>CC(N(C)C)=O>[C:17]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:23]([F:26])([F:25])[F:24])[CH:8]=3)[N:3]=[C:2]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:11]=2[C:12]2[NH:16][N:15]=[N:14][N:13]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C1CCNCC1
Reactant: FC(F)(F)c1ccc2nc(Cl)c(-c3nnn[nH]3)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1ccc2nc(N3CCCCC3)c(-c3nnn[nH]3)c(-c3ccccc3)c2c1
Temperature: 100 °C
Yield: 18.6 %

Procedure:
A mixture of 2-chloro-4-phenyl-3-(1H-tetrazol-5-yl)-6-trifluoromethyl-quinoline (105 mg, 279 μmol), piperidine (47.6 mg, 55.3 μl, 559 μmol) and triethylamine (84.8 mg, 117 μl, 838 μmol) in DMA (2 ml) was heated to 100° C. in a sealed tube. After 4 h 0.1N HCl was added at room temperature and the mixture was extracted with EtOAc. The combined organic layers were washed with 0.1N HCl and brine and dried with Na2SO4. The remaining brown oil was purified by chromatography (silica gel, DCM/MeOH 98:2 to 95:5). The product fractions were concentrated and the remaining solid was dissolved in EtOAc, filtered through silica gel and evaporated. The remaining residue was finally purified by preparative thin-layer chromatography (DCM/MeOH 95:5) to obtain the title compound (22 mg, 18%) as light yellow solid. MS (ESI): 425.4 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])[N:6]=[CH:5][N:4]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]([CH2:30][C@H:31]([OH:36])[C:32]([F:35])([F:34])[F:33])[C:26](=[O:29])[NH:27][N:28]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]([CH2:30][C@H:31]([OH:36])[C:32]([F:34])([F:35])[F:33])[C:26](=[O:29])[N:27]([CH2:2][C:3]3[CH:8]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=4[Cl:16])[N:6]=[CH:5][N:4]=3)[N:28]=2)=[CH:20][CH:19]=1
Reactant: Clc1cccc(-c2cc(CBr)ncn2)c1Cl
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Product: O=c1n(Cc2cc(-c3cccc(Cl)c3Cl)ncn2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of the compound in Example 94, 23 mg (0.07 mmol) of the compound from Example 84A and 24 mg (0.08 mmol) of the compound from Example 5A were reacted with one another. This gave 29 mg (66% of theory) of the target compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[N:14][CH:13]=2)[N:3]=1.[F:18][C:19]1[CH:20]=[C:21]([NH2:26])[CH:22]=[CH:23][C:24]=1[F:25]>CC(O)C>[F:18][C:19]1[CH:20]=[C:21]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][N:15]=[N:14][CH:13]=3)[N:3]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Nc1ccc(F)c(F)c1
Reactant: Clc1nc(-c2ccnnc2)nc2ccccc12
Solvent: CC(C)O
Product: Fc1ccc(Nc2nc(-c3ccnnc3)nc3ccccc23)cc1F
Temperature: 85 °C
Yield: 53.1 %

Procedure:
(This method is representative of method G1, G2, and G3. These three methods can be implemented in a similar way except for substitution of the appropriate solvent and temperature) The mixture of 4-chloro-2-(pyridazin-4-yl)quinazoline (10 mg, 0.041 mmol, 1 eq.) and 3,4-difluorobenzenamine (11 mg, 0.082 mmol, 2 eq.) was suspended in i-PrOH. The mixture was heated at 85° C. overnight. After cooling, the resulting precipitate was filtered and purified on HPLC (Condition C). 7.3 mg of N-(3,4-difluorophenyl)-2-(pyridazin-4-yl)quinazolin-4-amine was obtained (yield 53%). LCMS m/z=336.0 (M+1) (Method B) (retention time=1.731 min). 1H-NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 10.00 (dd, J=2.2, 1.3 Hz, 1H), 9.44 (dd, J=5.4, 1.2 Hz, 1H), 8.59 (d, J=8.1 Hz, 1H), 8.39 (dd, J=5.4, 2.4 Hz, 1H), 8.05-8.13 (m, 1H), 7.99 (s, 1H), 7.97 (d, J=3.6 Hz, 1H), 7.72-7.79 (m, 2H), 7.51-7.61 (m, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]>CC(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]
Reactant: ClCCCCBr
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCCOc1ccc2ccccc2c1

Procedure:
A mixture of β-naphthol (1gm, 0.006 mole), anhydrous K2CO3 (10 gm, in excess) and 1-bromo 4-chlorobutane (0.8 ml, 0.006 mole) was refluxed in dry acetone (50 ml) for 6 hours. Reaction mixture was filtered and filtrate was concentrated to get oily compound, which was crystallized with benzene-hexane to give the colorless crystals of pure desired compound, m.p. 112° C., (yield 1.6 gm, 98%).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[C:15]1([CH3:29])[CH:20]=[CH:19][C:18]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[C:26](O)=[O:27])=[CH:17][CH:16]=1>>[F:13][C:10]([F:12])([F:11])[C:9]([NH:8][CH2:7][C@H:2]1[N:3]([C:26]([C:25]2[CH:24]=[CH:23][S:22][C:21]=2[C:18]2[CH:19]=[CH:20][C:15]([CH3:29])=[CH:16][CH:17]=2)=[O:27])[CH2:4][C@H:5]2[C@@H:1]1[CH2:6]2)=[O:14]
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)C(F)(F)F
Reactant: Cc1ccc(-c2sccc2C(=O)O)cc1
Product: Cc1ccc(-c2sccc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)C(F)(F)F)cc1

Procedure:
prepared by reaction of N-[(1S,2S,5R)-1-(3-Aza-bicyclo[3.1.0]hex-2-yl)methyl]-2,2,2-trifluoro-acetamide with 2-p-tolyl-thiophene-3-carboxylic acid.
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[C:12]([F:30])=[C:13]([NH:18][S:19]([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])(=[O:21])=[O:20])[CH:14]=[CH:15][C:16]=2[F:17])=[N:4][N:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH:6]=1.CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[CH2:7]([N:5]1[CH:6]=[C:2]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[C:3]([C:11]2[C:12]([F:30])=[C:13]([NH:18][S:19]([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])(=[O:21])=[O:20])[CH:14]=[CH:15][C:16]=2[F:17])=[N:4]1)[CH:8]([CH3:9])[CH3:10]
Reactant: CC(C)Cn1cc(Br)c(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
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: COCCOC
Product: CC(C)Cn1cc(-c2ccncc2)c(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 110 °C
Reaction time: 0.08 h

Procedure:
To a solution of tetrakis(triphenylphosphine)palladium(0) (0.035 g, 0.03 mmol) in dimethoxyethane (1 mL), N-{3-[4-bromo-1-(2-methylpropyl)-1H-pyrazol-3-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide (0.09 g, 0.18 mmol) in dimethoxyethane (1 mL) was added and the mixture was insufflated with nitrogen for 5 min. A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.08 g, 0.4 mmol)) in dimethoxyethane (1 mL) was added and the mixture was insufflated with nitrogen for 10 min, then 2 M sodium carbonate solution (1 mL) was added and the mixture was heated at 110° C. in a microwave cavity for 1 h. More tetrakis(triphenylphosphine)palladium(0) (0.012 g, 0.01 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.016 g, 0.08 mmol) were added and the process was resumed for 0.5 h. The mixture was cooled and the organic phase was concentrated. The crude oil was purified by flash chromatography (eluant: dichloromethane/methanol 30:1). The title compound was obtained as a white solid (0.025 g, 28%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C@@:11]2([CH2:17][OH:18])[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[C:21]([F:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:16])[NH:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([Cl:19])[C:21]=2[F:28])[CH2:12][C@@:11]2([CH2:17][OH:18])[C@@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@H]2C[C@@]2(CO)C[C@H]1C(=O)O
Reactant: NCc1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H]2C[C@@]2(CO)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a diastreoisomeric mixture of (1R,3S,5S) and (1S,3S,5R)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (312 mg, 1.21 mmol), 3-chloro-2-fluorobenzylamine (232 mg, 1.46 mmol), HBTU (690 mg, 1.82 mmol) in CH2Cl2 (6 mL) was added DIPEA (0.623 mL, 3.64 mmol). The resulting solution was stirred at RT under nitrogen overnight. DIPEA (0.21 mL, 1.21 mmol), HBTU (230 mg, 0.6 mmol) and 3-chloro-2-fluorobenzylamine (97 mg, 0.606 mmol) were added and the mixture was further stirred overnight at RT under N2. The mixture was poured into an aqueous solution of HCl 1N (pH-1) and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 40:60) to give (1S,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester: TLC, Rf (EtOAc)=0.55 (stained with ninhydrine); MS (UPLC-MS): 399.2/401.2 [M+H]+, 299.2/301.2 [MH−Boc]+, 343.2/345.2 [MH−tBu]+, 443.2/445.3 [M+HCOO]−; tR (HPLC conditions f): 1.95 min, and (1R,3S,5S)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester: TLC, Rf (EtOAc)=0.45 (stained with ninhydrine); MS (UPLC-MS): 399.2/401.2 [M+H]+, 299.2/301.2 [MH−Boc]+, 343.2/345.2 [MH−tBu]+, 443.2/445.3 [M+HCOO]−; tR (HPLC conditions f): 1.89 min.
Reaction SMILES: [OH:1][CH:2]([CH:16]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[N:23]1([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]([O:1][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:3][O:4][C:5](=[O:15])[C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCC(O)C(c1ccccc1)n1ccc2ccccc21)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(COC(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)n1ccc2ccccc21

Procedure:
To a solution of (2RS, 3RS)-4-nitro-benzoic acid 2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester and triethylamine (1.4 mL, 10.5 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.59 mL, 7.6 mmol) dropwise at 0-5° C. with stirring. After stirring for 30 minutes, the mixture was washed with a 1N aqueous solution of hydrochloric acid, 5% aqueous sodium bicarbonate, and water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a light yellow fluffy solid. The crude product was recrystallized from dichloromethane with a minimum amount of diethyl ether to give (2RS,3RS)-4-nitro-benzoic acid-3-indol-1-yl-2-methanesulfonyloxy-3-phenyl-propyl ester as a yellow solid. MS (ESI) m/z 495 ([M+H]+).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](=[O:7])[CH3:6].[CH2:15]([O:17][C:18](=[O:24])[C:19](OCC)=[O:20])[CH3:16].CC[O-].[Na+]>CCO>[CH2:15]([O:17][C:18](=[O:24])[C:19](=[O:20])[CH2:6][C:5](=[O:7])[CH:4]([CH3:3])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:16]
Reactant: CC(=O)C(C)Cc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)C(C)Cc1ccccc1
Temperature: 25 °C

Procedure:
Sodium hydride (0.3965 g, 16.52 mmol) was added slowly to a NaCl ice bath containing EtOH (5.6 mL, 2.6 M) stirring under N2. 59 (2.2727 g, 14.01 mmol) and diethyloxalate (2.0649 g, 14.13 mmol) were mixed together, and then added to the chilled NaOEt solution. After stirring for 5 minutes, the reaction was warmed to room temperature. After stirring for 5 h, the reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 67:30:3 Hexanes:CH2Cl2:2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 60. 1H (CDCl3, 400 MHz): δ 14.55 (1H, broad s), 7.32-7.12 (5H, m), 6.36 (1H, s), 4.33 (2H, q, J=7.0 Hz), 3.05 (1H, dd, J=13.5, 6.8 Hz), 2.84 (1H, app sex, J=7.0 Hz), 2.67 (1H, dd, J=13.5, 7.8 Hz), 1.36 (3H, t, J=7.1 Hz), 2.33 (3H, d, J=7.0 Hz) ppm. 13C (CDCl3, 100 MHz): δ 205.78, 166.96, 161.88, 138.75, 128.80, 128.30, 126.29, 100.75, 62.32, 46.35, 39.10, 16.51, 13.88 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 16.51, 13.88; CH2 carbons: 62.32, 39.10; CH carbons: 128.80, 128.30, 126.29, 100.75, 46.35 ppm. HPLC: 11.084 min.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.C[N:18](C)C=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 72 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 10 g of 2,6-dichloro-5-fluoronicotinic acid in 30 mL of toluene, 8.5 g of thionyl chloride and 0.10 mL of N,N-dimethylformamide were added, and the mixture was stirred at 72° C. for 1 hour 30 minutes. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The resultant residue was dropped to 30 mL of 25% ammonium water at −20° C. The temperature was increased to 5 C.°, and the mixture was stirred for 30 minutes. The solid was filtered off to obtain 9.9 g of 2,6-dichloro-5-fluoronicotinamide as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(OCC)(=O)C>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:4]([CH2:5][CH2:6][NH:7][C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1)(=[O:23])[CH3:22]
Reactant: O=C(/C=C/c1cccnc1)NCCc1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cccc(CCNC(=O)/C=C/c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
(E)-N-(3-hydroxyphenethyl)-3-(3-pyridyl)-2-propenoic acid amide (600 mg, 2.24 mmol) obtained in Example 81 was dissolved in pyridine (4.0 ml) and acetic anhydride (0.40 ml, 4.24 mmol) was added under ice-cooling and stirred at room temperature for 1.5 hours. Ethyl acetate was added to the reaction mixture and the mixture was washed with water and dried over magnesium sulfate. The solvent was distilled out under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane=1:30) and recrystallized to yield the titled compound (574 mg, 82%).
Reaction SMILES: [P:1](Cl)([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)([O:3][CH3:4])=[O:2].[OH:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[C:24](=[O:26])[CH2:23][CH2:22]2.C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[C:24](=[O:26])[CH2:23][CH2:22]2)([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C1CCc2cccc(O)c21
Reactant: COP(=O)(Cl)Sc1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COP(=O)(Oc1cccc2c1C(=O)CC2)Sc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
O-Methyl S-(3-nitrophenyl) chlorothiophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 7-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product O-methyl S-(3-nitrophenyl) O-indan-1-on-7-yl thiophosphate.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[O:27]1[C:31]2=[CH:32][CH:33]=[CH:34][C:35]([C:36](O)=[O:37])=[C:30]2[CH:29]=[CH:28]1>>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:36]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]3[O:27][CH:28]=[CH:29][C:30]=23)=[O:37])[CH2:7]1
Reactant: O=C(O)c1cccc2occc12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc3occc23)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with benzofuran-4-carboxylic acid (M. A. Eissenstat et al. J. Med. Chem. 1995, 38, 3094-3105).
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH:18]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([C:45](=[O:48])[NH:46][CH3:47])=[CH:41][CH:40]=3)[C:19](=[O:37])[N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[C:26]3[NH:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:30]=3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)(Cl)Cl>[NH2:17][CH:18]([C:19](=[O:37])[N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[C:26]1[NH:27][CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:30]=1)[CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]([NH:46][CH3:47])=[O:48])=[CH:43][CH:44]=1
Reactant: CNC(=O)c1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCCC2c2nc(-c3ccccc3)c[nH]2)cc1
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1ccc(CC(N)C(=O)N2CCCCC2c2nc(-c3ccccc3)c[nH]2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 38.1 %

Procedure:
To a solution of 148 mg (0.21 mmol) of the product from step C in 2 mL of chloroform was added 2 ml of piperidine. The resulting mixture was allowed to stir at room temperature under argon for 3.5 hours. The reaction mixture was then concentrated and the residue purified on a Gilson prep LC system. The product was lophilized to obtain 47 mg (0.08 mmol, 48% yield) of the desired product as a white powder assumed to be a TFA salt. 1H NMR (300 MHz, CD3OD): δ 1.20–1.45 (2H, m), 1.50–1.80 (4H, m), 1.90–2.40 (2H, m), 2.90 (3H, d), 2.95–3.21 (2H, m), 3.78 (1H, m), 4.54 (1H, d), 5.12 (1H, s), 5.92 (1H, t), 7.28 (1H, d), 7.33–7.88 (10H, m). TLC (90:9:9, CHCl3:MeOH:NH4OH) Rf=0.33
Reaction SMILES: [C:1]1([NH:7]/[CH:8]=[CH:9]/[CH:10]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:12](OC)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C(O)(=O)C>CO>[O:13]=[C:12]1[C:11]([C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=[CH:8][N:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(=C/C=C/Nc1ccccc1)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cccn(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To a solution of (E)-dimethyl 2-(3-(phenylamino)allylidene)malonate (130 mg, 0.50 mrnol) in methanol (8 mL) at rt was added NaH (50 mg of the 60% NaH in oil, 1.2 mmol) and the mixture was stirred at rt for 3 h. Acetic acid (0.3 mL) was added to the mixture, concentrated to a volume of 4 mL, and purificationof the reaction mixture by preparative HPLC provided the desired product (105 mg, 92%) as a yellow solid. 1H NMR (CD3OD) δ 8.30 (dd, 1H, J=7.2, 2.2 Hz), 7.87 (dd, 1H, J=6.6, 1.7 ), 7.57-7.38 (m, 5H), 6.53 (t, 1H, J=7.0 Hz), 3.84 (s, 3H); MS(ESI+) m/z 230.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N+:18]([O-:20])=[O:19])=[C:13](F)[C:12]=1[F:22]>>[F:22][C:12]1[C:11]([F:10])=[CH:16][C:15]([CH3:17])=[C:14]([N+:18]([O-:20])=[O:19])[C:13]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1]
Reactant: Cc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Reactant: Nc1ccc(I)cc1F
Product: Cc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]

Procedure:
2-Fluoro-4-iodoaniline and 1,2,3-trifluoro-5-methyl-4-nitrobenzene were reacted using the condition described in Example 1 (Step A) to form the title compound. M−H+: 407.9