Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O.[C:22]([O-])(=O)[CH3:23].[Na+]>C(OC(=O)C)(=O)C>[CH2:22]([O:13][C:12]([C:11]1[C:2]([CH3:1])=[N:3][C:4]2[C:5](=[CH:20][C:16]3[O:15][CH:19]=[CH:18][CH:17]=3)[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1)=[O:14])[CH3:23]
Reactant: CC(=O)[O-]
Reactant: O=Cc1ccco1
Reactant: Cc1nc2c(cc1C(=O)O)CCCC2
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2c(nc1C)C(=Cc1ccco1)CCC2

Procedure:
A solution of 5,6,7,8-tetrahydro-2-methyl-3-quinolinecarboxylic acid (2.19 g) in acetic anhydride (10 ml) is treated with 2-furaldehyde (1.0 ml) and sodium acetate (0.82 g). The solution is treated at reflux temperature for 24 hours. The residue from the solvent evaporation is dissolved in ethyl acetate, washed with brine solution, dried and evaporated to a semi-crystalline residue (30 g). Filtration through silica gel (150 g) with 9:1 Skelly B:ethyl acetate gives 8-(2-furanylmethylene)-5,6,7,8-tetrahydro-2-methyl-3-quinolinecarboxylic acid ethyl ester (1.40 g), m.p. 119° C.-120° C. after hexane crystallization.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:18][C:17]=1[F:27])=[CH:5]/[O:6][CH3:7].[BH-](OC(C)=O)(OC(C)=O)O[C:31](C)=O.[Na+].C=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:31])=[CH:18][C:17]=1[F:27])=[CH:5]/[O:6][CH3:7]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1ccc(NCC(C)C)cc1F
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1ccc(N(C)CC(C)C)cc1F
Temperature: 25 °C
Reaction time: 22 h
Yield: 69.2 %

Procedure:
70 mg (0.18 mmol) of the compound obtained in Step 3 was dissolved in 1.5 ml of methylene chloride, and 57 mg (0.27 mmol) of NaBH(OAc)3 and 30 μl (0.40 mmol) of formaldehyde were added thereto. After stirring at room temperature for 22 hours, the reaction mixture was treated with a saturated sodium bicarbonate aqueous solution, and the water layer was separated and extracted twice with 10 ml of methylene chloride. The organic layers were combined, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The residue was subjected to column chromatography using 20% ethyl acetate/hexane as an eluent to obtain 50 mg (yield 73%) of (E)-methyl-2-[2-((4-(N-isobutyl-N-methylamino)-2-fluorophenoxy)methyl)phenyl]-3-methoxyacrylate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[O:6])=[CH:18][CH:17]=1
Reactant: Clc1ccccc1
Reactant: O=C(O)c1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 2-fluorobenzoic acid (1.00 g, 7.14 mmol), thionyl chloride (3 mL, 41.1 mmol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed on the pump. Chlorobenzene (5 mL, 50 mmol) and aluminum trichloride (1.050 g, 7.85 mmol) were added to the reaction mixture. The reaction mixture turned yellow in color on addition of AlCl3. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc. HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+].[ClH:38]>CO>[ClH:38].[NH2:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:6][OH:7])[CH2:11][OH:12]
Reactant: CCCCCCCCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCCC(N)(CO)CO

Procedure:
2-Acetamido-1,3-diacetoxy-2-icosylpropane (1.5 g) was dissolved in 40 ml of methanol and 9.6 ml of a 1N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 6 hours. The mixture was neutralized with a 1N aqueous hydrochloric acid solution and the reaction mixture was concentrated under reduced pressure. The concentrate was washed with water and ethyl acetate:hexane =1:1 in order to give 817 mg of 2-amino-2-icosyl-1,3-propanediol hydrochloride.
Reaction SMILES: CN1CCOCC1.[CH3:8][C:9]1[C:17]([OH:18])=[C:16]2[C:12]([CH:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[O:14][CH2:15]2)=[CH:11][N:10]=1.[N+:26]([O:29][CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])([O-:28])=[O:27].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[N+:26]([O:29][CH2:30][CH2:31][CH2:32][C:33]([O:18][C:17]1[C:16]2[CH2:15][O:14][C@H:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:12]=2[CH:11]=[N:10][C:9]=1[CH3:8])=[O:34])([O-:28])=[O:27]
Reactant: Cc1ncc2c(c1O)COC2c1ccc(Cl)cc1
Reactant: O=C(O)CCCO[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1ncc2c(c1OC(=O)CCCO[N+](=O)[O-])CO[C@@H]2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methylmorpholine (90 μL, 0.82 mmol) was added to a stirred solution of (R)-(−)-cicletanine (48 mg, 0.18 mmol), 4-(nitrooxy)butanoic acid (27 mg, 0.18 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (42 mg, 0.22 mmol), and 4-dimethylaminopyridine (9 mg, 0.07 mmol) in dichloromethane (1.8 mL). The solution was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by HPLC reverse phase (C-18) cluting with acetonitrile/water with 0.05% TFA to afford the title compound as a colorless oil. LC-MS: m/z 392.9 (M+H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]([O:14][C@H:15]1[C@@H:28]([OH:29])[C@@H:27]([CH2:30][O:31][CH2:32][CH:33]=[CH2:34])[O:26][C@@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16]1O)[CH:12]=[CH2:13].CN(C)[CH:38]=[O:39]>CO>[CH2:11]([O:14][C@H:15]1[C@@H:28]([O:29][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:27]([CH2:30][O:31][CH2:32][CH:33]=[CH2:34])[O:26][C@@H:17]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@@H:16]1[O:39][CH2:38][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:12]=[CH2:13]
Reactant: BrCc1ccccc1
Reactant: CN(C)C=O
Reactant: C=CCOC[C@H]1O[C@@H](OCc2ccccc2)[C@H](O)[C@@H](OCC=C)[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: C=CCOC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCC=C)[C@H]1OCc1ccccc1
Reaction time: 18 h
Yield: 90 %

Procedure:
Under nitrogen gas atmosphere and ice cooling, benzyl bromide (11.4 ml, 95.5 mmol) was added to a mixture of 60% sodium hydride (3.8 g, 95.5 mmol), Compound 11 (6.7 g, 19.1 mmol) and dimethylformamide (20 ml), and the mixture was stirred for 18 hours. Methanol was added to the reaction mixture under ice cooling and stirred for 1 hour, and the solvent was evaporated under reduced pressure. The residue was diluted with diethyl ether, washed successively with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1-9:1) to obtain Compound 12 (9.1 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(N)c1C(=O)O
Product: Cc1cccc(NC(=O)CCl)c1C(=O)O

Procedure:
2-amino-6-methylbenzoic acid is reacted with 2-chloroacetyl chloride to produce the 2-(-2-chloroacetamido)-6-methylbenzoic acid. Reaction with o-toluidine and phosphoryl trichloride yields the cyclized intermediate. Further reaction with diBOC-protected adenine give the BOC protected product, which is deprotected resulting in 2-((6-amino-9H-purin-9-yl) methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one (2c).
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[CH2:5]([N:7]([CH2:11][CH3:12])[C:8](Cl)=[O:9])[CH3:6]>C(#N)C>[CH2:5]([N:7]([CH2:11][CH3:12])[C:8]([S:1][C:2]#[N:3])=[O:9])[CH3:6]
Reactant: CCN(CC)C(=O)Cl
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CC#N
Product: CCN(CC)C(=O)SC#N
Temperature: 80 °C
Reaction time: 0.83 h

Procedure:
A suspension of sodium thiocyanate (3.30 g, 40.7 mmol) in dry acetonitrile (25 mL) at 80° C. was treated dropwise with a solution of N,N-diethyl carbamoyl chloride (5.0 g, 36.9 mmol) in dry acetonitrile (15 mL). The reaction mixture was stirred at 80° C. for 50 min, cooled to room temperature, then filtered through a fme glass frit. The resulting filtrate was used as a 0.9 M solution of N,N-diethyl carbamoyl thiocyanate in acetonitrile.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:76]=[CH:75][C:67]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])=[C:66]([F:77])[CH:65]=1>C(Cl)Cl>[C:71]([O:70][C:68](=[O:69])[C:67]1[CH:75]=[CH:76][C:64]([NH:63][C:35]([C@H:16]2[C@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:33])([CH3:32])[CH3:34])[NH:17]2)=[O:36])=[CH:65][C:66]=1[F:77])([CH3:74])([CH3:72])[CH3:73]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)OC(C)(C)C)c(F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid compound with 2,2,2-trifluoroacetic acid (1:1) (200 mg, 344 μmol, Eq: 1.00), was combined with CH2Cl2 (4.5 ml) to give a yellow solution. DIPEA (178 mg, 1.38 mmol, Eq: 4) and diphenylphosphinic chloride (244 mg, 1.03 mmol, Eq: 3) were added and the reaction was stirred at RT for 20 minutes. Tert-butyl 4-amino-2-fluorobenzoate (72.7 mg, 344 μmol, Eq: 1.00) was added and the reaction mixture was stirred at RT overnight. The crude reaction mixture was concentrated under vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 20% EtOAc in hexanes) to give a white solid as the product. 215 mg. MS (ES+) m/z Calcd: [(M+H)+]: 660, fund: 660.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].[NH2:23][CH2:24][CH2:25][CH2:26][NH2:27].O>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[N:23]3[CH2:24][CH2:25][CH2:26][NH:27][C:8]3([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: NCCCN
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2C2(c3ccccc3)NCCCN12
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a solution of 1.89 g of 2-trichloroacetamido-5-chlorobenzophenone in 50 ml of ethanol was added 2.22 g of 1,3-diaminopropane, and the resultant mixture was allowed to stand at room temperature overnight. Then, the reaction mixture was poured into 300 ml of water, and the precipitate thus formed was separated by filtration, washed with ether and dried to give 1.25 g of 10-chloro-1,2,3,4,7,11b-hexahydro-11b-phenyl-6H-pyrimido[1,2-C]quinazolin-6-one, having a melting point of 275° - 276°C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]=[C:4]2[N:14](S(C3C=CC=CC=3)(=O)=O)[CH:15]=[CH:16][C:3]=12.C1COCC1.O.[Li+].[OH-]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]=[C:4]2[NH:14][CH:15]=[CH:16][C:3]=12
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(-c3ccccc3)cnc21
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Clc1c(-c2ccccc2)cnc2[nH]ccc12
Temperature: 65 °C
Yield: 95.8 %

Procedure:
4-Chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.70 g, 4.61 mmol) was placed in 1:1 THF:water (30 mL). 3M LiOH (aq., 15.4 mL, 46.1 mmol) was then added, and the reaction was heated to 65° C. for 18 hours. The reaction was cooled to room temperature, diluted with DCM (50 mL) and poured into water. The organic fraction was dried, filtered, and concentrated to give the crude product 4-chloro-5-phenyl-1H-pyrrolo[2,3-b]pyridine (1.01 g, 95.8% yield), which was used without further purification.
Reaction SMILES: C(CN)O.[CH2:5]([NH2:8])[CH2:6][NH2:7].P(=O)(O)(O)O.[NH2:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][NH2:20].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.NCCNCCO>>[NH2:7][CH2:6][CH2:5][NH:8][CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH2:14].[NH2:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][NH:20][CH2:25][CH2:26][NH:21][CH2:22][CH2:23][NH2:24]
Reactant: NCCNCCN
Reactant: NCCN
Reactant: C1CNCCN1
Agent: O=P(O)(O)O
Solvent: NCCNCCO
Solvent: NCCO
Product: NCCNCCNCCN
Product: NCCNCCNCCNCCN

Procedure:
Employing the reaction equipment and general procedures described in Example I, a solution of 229.0 g. (3.75 moles) monoethanolamine and 225.0 g. (3.75 moles) ethylenediamine was admixed with 6.25 g. (0.054 mole; 2.3wt.% and 1.44 mole%, basis MEA) 85% phosphoric acid and heated at 250° C. under 225 - 225 psig pressure for 2.0 hours. Analysis of the reaction product by gas-liquid chromatography (GLC Area %) showed a total conversion of reactants of only 4.7% was obtained. The reaction products were 95.0 diethylenetriamine, 2.5 piperazine and 2.5 Area % N-(2-aminoethyl)-ethanolamine. No higher polyethylene polyamines, e.g., triethylenetetramine, tetraethylenepentamine, etc. were formed.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([N:21]([CH3:23])[CH3:22])=[C:14]([NH:16][C:17](=[O:20])[CH2:18]Cl)[CH:15]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:3]=1.[NH2:40][CH2:41][CH:42]1[CH2:44][CH2:43]1>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([N:21]([CH3:23])[CH3:22])=[C:14]([NH:16][C:17](=[O:20])[CH2:18][NH:40][CH2:41][CH:42]3[CH2:44][CH2:43]3)[CH:15]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:3]=1
Reactant: COc1ccc(COc2ccccc2-c2cc(-c3ccc(N(C)C)c(NC(=O)CCl)c3)c(C#N)c(N)n2)cc1
Reactant: NCC1CC1
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccccc2-c2cc(-c3ccc(N(C)C)c(NC(=O)CNCC4CC4)c3)c(C#N)c(N)n2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
To a stirred solution of N-[5-(2-amino-3-cyano-6-{2-[(4-methoxybenzyl)oxy]phenyl}-4-pyridinyl)-2-(dimethylamino)phenyl]-2-chloroacetamide (0.400 g, 0.738 mmol) in DMF (5 mL) was added aminomethylcyclopropane (0.192 mL, 2.214 mmol). The mixture was stirred at 60° C. for 2 hrs. After cooled to room temperature, the mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification was carried out by column chromatography on silica gel (chloroform:methanol=100:2, hexane:ethyl acetate=1:2-1:3-1:5, 2 times) to give N1-[5-(2-amino-3-cyano-6-{2-[(4-methoxybenzyl)oxy]phenyl}-4-pyridinyl)-2-(dimethylamino)phenyl]-N2-(cyclopropylmethyl)-glycinamide as a yellow oil (0.130 g, yield 30%).
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.[Cl:13][CH2:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=1>>[ClH:13].[NH2:2][O:1][CH2:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCc1ccc(CCl)cc1
Product: Cl
Product: NOCc1ccc(CO)cc1

Procedure:
Prepared by a similar procedure as described for preparation 18, starting from N-hydroxyphthalimide and 4-(chloromethyl)benzyl alcohol (Aldrich). 13C-NMR (DMSO-d6) δ 143.6, 131.8, 129.0, 126.4, 75.5, 62.4.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N:34]([C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=1[O:47][CH3:48])=[C:35]=O.[F:49][C:50]1[CH:58]=[CH:57][C:56]2[N:55]3[CH2:59][CH2:60][NH:61][CH2:62][C:54]3=[CH:53][C:52]=2[CH:51]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:35]([N:61]1[CH2:60][CH2:59][N:55]3[C:56]4[CH:57]=[CH:58][C:50]([F:49])=[CH:51][C:52]=4[CH:53]=[C:54]3[CH2:62]1)[N:34]([C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=1[O:47][CH3:48])[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: Fc1ccc2c(c1)cc1n2CCNC1
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Reactant: COC(=O)/C=C/c1cccc(F)c1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCn3c(cc4cc(F)ccc43)C2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
Starting with 182 mg (0.4 mmol) of the irninophosphorane from Example 12A, 86 mg of 2-isocyanato-1-methoxy-4-(trifluoromethyl)benzene and 130 mg (0.4 mmol) of 8-fluoro-1,2,3,4-tetrahydropyrazino[1,2-a]indole from Example 36A, the general procedure [M] gives 95 mg (35% of theory) of product.
Reaction SMILES: O[CH:2]=[C:3]1[C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.[NH2:29][NH2:30]>CCO>[N:15]1([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:16][CH2:17][C:12]2([C:3]3[CH:2]=[N:30][NH:29][C:4]=3[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:11]2)[CH2:13][CH2:14]1
Reactant: NN
Reactant: O=C1C(=CO)C2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC2(CC1)Oc1ccccc1-c1[nH]ncc12
Reaction time: 3 h
Yield: 58 %

Procedure:
A solution of benzyl 3-(hydroxymethylene)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (1.95 g, 5.10 mmol) and hydrazine (161 μL, 5.10 mmol) in EtOH (39 mL) was stirred at room temperature for 1 hour and then at 50° C. for 3 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (10-100% ethyl acetate in hexane) to afford benzyl 1H-spiro[chromeno-[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (1.11 g, 58%). ESI-MS m/z calc. 375.2. found 376.3 (M+1)+; Retention time: 1.71 minutes (3 min run).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([O:19][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[C:15]([F:18])([F:16])[F:17])[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](O)C(F)(F)F)COC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](Oc2ccc([N+](=O)[O-])cc2)C(F)(F)F)COC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a cooled, stirred solution of (S)-2,2-dimethyl-4-((R)-3,3,3-trifluoro-2-hydroxy-propyl)-oxazolidine-3-carboxylic acid tert-butyl ester (1.99 g) and 1-fluoro-4-nitrobenzene (0.69 ml) in THF (20 ml) at 0° C. was added dropwise potassium bis(trimethylsilyl)amide solution (7.7 ml, 1 M solution in THF). The reaction mixture was stirred for 30 min at 0° C., then allowed to warm to room temperature and stirred for a further 1 h. The mixture was then diluted with dichloromethane and washed with sat. aq. ammonium chloride solution. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-2,2-dimethyl-4-[(R)-3,3,3-trifluoro-2-(4-nitro-phenoxy)-propyl]-oxazolidine-3-carboxylic acid tert-butyl ester as a yellow viscous oil (2.7 g, 97%). MS (ISP): 435.3 ([M+H]+), 379.3 ([M+H—C4H8]+), 335.4 ([M+H—C4H8—CO2]+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[S:10]1[CH:11]=[CH:12][N:13]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1
Reactant: COc1ccc(-c2nccs2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2nccs2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of the product of step 1 (1.0 g, 5.23 mmol) in methylene chloride (25 ml) was slowly added boron tribromide (2.00 ml, 15.7 mmol) at −78° C., and stirred at −78° C. for 1 h. After it was stirred at room temperature for 16 h, the reaction mixture was poured into ice-water. The product was collected on a filter, washed with ether to yield the title product (0.84 g, 84%); 1HNMR (400 MHz, CDCl3) δ 7.85 (d, J=3.2 Hz, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.67 (d, J=3.2 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H); MS (ESI−) 176 (M−1, 100).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[CH:28][C:29]([F:43])=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([C:38]([O:40]C)=[O:39])=[CH:34][C:33]=5[CH3:42])[CH:31]=4)=[CH:24][N:23]=[C:22]([S:44][CH3:45])[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[OH-:50].[OH2:51].C1C=C(Cl)C=C(C(OO)=O)C=1>O1CCOCC1>[F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[CH:28][C:29]([F:43])=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([C:38]([OH:40])=[O:39])=[CH:34][C:33]=5[CH3:42])[CH:31]=4)=[CH:24][N:23]=[C:22]([S:44]([CH3:45])(=[O:51])=[O:50])[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: [OH-]
Reactant: COC(=O)c1ccc(-c2cc(-c3cnc(SC)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)ccc2F)c(C)c1
Reactant: O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Li+]
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1-c1cc(-c2cnc(S(C)(=O)=O)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the title compound from Step C (150 mg, 0.216 mmol) and LiOH (51.8 mg, 2.16 mmol) was stirred in dioxane and water overnight. The solvent was removed and water was added. A few drops of 1 N HCl were added. The organic material was extracted with EtOAc (3×10 mL). The combined EtOAc layers were dried over Na2SO4. The solvent was removed. The residue was dissolved in CH2Cl2 (5 mL) at 25° C. and mCPBA (82 mg, 0.476 mmol) was added. The solution was stirred at 25° C. for 3 h. The solution was washed with Na2S2O3 and dried over Na2SO4. The residue was purified by reverse phase HPLC to give the title compound as a colorless solid. LCMS=712.6 (M+H)+