Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11]2)=[CH:5][CH:4]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C@@H:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:8][CH:7]=2)[N:10]2[CH2:11][C:12](=[C:14]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[S:15]([CH3:18])(=[O:16])=[O:17])[CH2:13]2)=[CH:28][CH:29]=1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1)c1cc(F)cc(F)c1
Solvent: ClCCl
Product: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CN3CCCCC3)cc2)C1)c1cc(F)cc(F)c1
Yield: 63.9 %

Procedure:
The operation is carried out as described in Example 87, starting with 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm3 of dichloromethane, and 0.017 g of piperidine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm3 fractions immediately after using this eluent mixture. Fractions 5 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.035 g of 1-{(R*)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): from 1.35 to 1.65 (mt, 6H), 2.35 (unresolved complex, 4H), 2.80 (s, 3H), 3.41 (broad s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N+:19]([O-])=O.[NH4+].[Cl-]>[Fe].CCO>[NH2:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:2]=1[F:1])[CH2:6][NH:7][C:8]([C:10]1([C:13]([F:14])([F:15])[F:16])[CH2:11][CH2:12]1)=[O:9]
Reactant: O=C(NCc1ccc(F)c([N+](=O)[O-])c1)C1(C(F)(F)F)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cc(CNC(=O)C2(C(F)(F)F)CC2)ccc1F

Procedure:
The sub-title compound was prepared in analogy to the procedure in Example 93, step (c) using N-(4-fluoro-3-nitrobenzyl)-1-(trifluoromethyl)-cyclopropanecarboxamide (3.77 g; 12.3 mmol), Fe (3.45 g; 61.6 mmol), NH4Cl (aq, sat, 30 mL) and EtOH (30 mL).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[NH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25].C1(C)C=CC=CC=1>ClCCl>[CH3:1][C:2]1[C:3]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][NH:22][C:21]2=[O:25])=[N:6][CH:7]=1
Reactant: Cc1cnc(S(C)(=O)=O)nc1-c1cccs1
Reactant: NCCN1CCNC1=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cnc(NCCN2CCNC2=O)nc1-c1cccs1
Temperature: 200 °C

Procedure:
5-Methyl-2-(methylsulfonyl)-4-(thiophen-2-yl)pyrimidine (0.1 g, 0.39 mmol) and 1-(2-aminoethyl)imidazolidin-2-one (0.06 g, 047 mmol) were added to a microwave tube along with toluene (1 mL). The tube was capped and heated to 200° C. for 10 min in a Personal Chemistry microwave. The mixture was diluted with dichloromethane and purified by flash chromatography using a gradient of 2 to 10% methanol in dichloromethane to obtain an off-white solid. Yield=0.03 g. MS (M+H)+ 304.
Reaction SMILES: [C:1]([C:4]1[N:12]2[C:7]([C:8]([NH2:13])=[N:9][CH:10]=[N:11]2)=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=3[F:34])=[O:22])=[CH:16][CH:15]=2)[CH:5]=1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[Br:56]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[Br:56][CH2:2][C:1]([C:4]1[N:12]2[C:7]([C:8]([NH2:13])=[N:9][CH:10]=[N:11]2)=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=3[F:34])=[O:22])=[CH:16][CH:15]=2)[CH:5]=1)=[O:3]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(=O)c1cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1ncnn2c(C(=O)CBr)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A suspension of Example 100 in THF (5 mL) was cooled to −78° C. and treated with diisopropylethyl amine (0.424 mL, 2.57 mmol) followed by trimethylsilyltriflate (0.421 mL, 2.177 mmol). The reaction was allowed to warm to rt over 30 min, then cooled again to −78° C. and treated with 1,3-dibromo-5,5-dimethylhydantoin (62 mg, 0.218 mmol). The reaction was allowed to stir for 1 h at −78 C, then warmed to rt and quenched with methanol (200 uL) and diluted with ethyl acetate and 1N sodium sulfite solution. The organic layer was separated, washed with 1 N bisulfate buffer (pH 2), dried with sodium sulfate and passed thru a silica plug. Evaporation of the solvent gave a yellow solid which was triturated with Et2O:hexanes (1:1) to provide the title compound as a yellow solid (154 mg, 70% Yield). 1H-NMR (DMSO-d6) δ 9.18 (s, 1H), 8.45 to 8.48 (m, 1H), 8.02 (s, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.27 (s, 1H), 7.20 to 7.37 (m, 4H), 4.77 (s, 2H). MS [M+H]+=551.2; LCMS RT=3.63.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][OH:12])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>>[CH2:1]([N:8]([CH2:10][CH2:11][O:12][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(CCO)Cc1ccccc1
Product: CN(CCOc1ccc(C=O)cc1)Cc1ccccc1

Procedure:
The title compound was prepared from 2-(N-benzyl-N-methylamino)ethanol (2.5 g) obtained in example 8 and 4-fluorobenzaldehyde (2 ml) by an analogous procedure to that described in preparation 23.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)[CH2:4][NH2:5].[C:13]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:20]=1)([O:15][CH3:16])=[O:14].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[C:13]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][NH:5][CH2:4][CH:3]([O:2][CH3:1])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=2)=[CH:23][CH:24]=1)([O:15][CH3:16])=[O:14]
Reactant: COC(CN)c1cccc(Cl)c1
Reactant: COC(=O)COc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)COc1ccc(CCNCC(OC)c2cccc(Cl)c2)cc1
Temperature: 55 °C

Procedure:
A mixture of 2-methoxy-2-(3-chlorophenyl)ethanamine (1.81 g), 2-(4-carbomethoxymethoxyphenyl)-1-(p-toluenesulphonyloxy)ethane (4.0 g) and triethylamine (4 ml) in dimethyl sulphoxide (50 ml) was heated at 55° C. After 24 h the solution was poured into saturated sodium carbonate solution and the aqueous layer extracted with dichloromethane. The organic extract was separated, dried and evaporated. Chromatography over silica gel (eluting with 2% methanol-dichloromethane) gave N-[2-(4-carbomethoxymethoxyphenyl)ethyl]-2-methoxy-2-(3-chlorophenyl)ethanamine which was converted into the title compound, mp 167°-169° C. (ethyl acetate-hexane) by an analogous procedure to that described in Example 4.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:23][CH2:24][N:25]([C:4]([C:3]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=2[CH3:1])=[O:6])[CH2:26][CH2:27]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(C(=O)c3ccc([N+](=O)[O-])cc3C)CC2)c(C)c1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
2-Methyl-4-nitrobenzoic acid (500 mg), 1-(2,4-dimethylphenyl)piperazine (523 mg) and 1-hydroxybenzotriazole 1 hydrate (373 mg) were dissolved in N,N-dimethylformamide (13 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (531 mg) was added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give [4-(2,4-dimethylphenyl)piperazin-1-yl](2-methyl-4-nitrophenyl)methanone (771 mg). Then, to a mixed solution of ethanol (11 mL) and water (3 mL) were added ammonium chloride (660 mg) and iron (480 mg), and the obtained [4-(2,4-dimethylphenyl)piperazin-1-yl](2-methyl-4-nitrophenyl)methanone (771 mg) was added while stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (833 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C([O:12][C:13](=O)[CH:14]([N:16]=[C:17]=[O:18])[CH3:15])C>>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]2[C:13](=[O:12])[CH:14]([CH3:15])[NH:16][C:17]2=[O:18])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C(C)N=C=O
Product: CC1NC(=O)N(c2ccc(F)c(Cl)c2)C1=O

Procedure:
A mixture of 2.91 g (20 mmol) of 3-chloro-4-fluoroaniline and 3.01 g (21 mmol) of 2-isocyanato-propionic acid ethyl ester was maintained at 130°-140° C. for 91/2 hours. The resulting product was crystallized from chloroform/methanol to yield 3-(3-chloro-4-fluorophenyl)-5-methyl-hydantoin, m.p. 174°-175.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][NH:30][CH3:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].C(N(CC)CC)C.[C:39]([CH2:43][C:44](Cl)=[O:45])([CH3:42])([CH3:41])[CH3:40].OS([O-])(=O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:20][C:19]=2[CH2:29][N:30]([CH3:31])[C:44](=[O:45])[CH2:43][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1noc(C)c1C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1onc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)CC(C)(C)C)c1C
Reaction time: 0.08 h

Procedure:
To the title product of Step F in 300 ml of CH2Cl2 at 0° C., triethylamine (6.17 g, 60.96 mmol) was added and stirred for 5 minutes. To the mixture, t-butylacetyl chloride (3.98 g, 29.57 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred at 0° C. for 10 minutes and at room temperature for 1 hr. 100 ml 10% aqueous NaHSO4 was added. The aqueous layer was extracted with 100 ml CH2Cl2. The combined organic extracts were washed with 100 ml H2O, 50 ml brine, dried and concentrated. The residue was chromatographed on silica gel using 60:40:1 hexane/EtOAc/AcOH to provide the title product of this Example (13.10 g, 80% for two steps) as a white solid. melting point=120-128° C. (amorphous).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9]/[C:10](/SC)=[CH:11]/[C:12]([C:14]2[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:26]([O:28][C:29](=[O:33])[CH2:30][NH:31][NH2:32])[CH3:27].Cl.C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[CH2:26]([O:28][C:29](=[O:33])[CH2:30][N:31]1[C:12]([C:14]2[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)=[CH:11][C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[N:32]1)[CH3:27]
Reactant: CS/C(=C\C(=O)c1ccc2c(c1)OCCO2)Nc1ccc(F)c(F)c1
Reactant: CCOC(=O)CNN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)Cn1nc(Nc2ccc(F)c(F)c2)cc1-c1ccc2c(c1)OCCO2

Procedure:
A mixture of D16 (0.00138 mol), 2-hydrazinyl-acetic acid ethyl ester.monohydrochloride (1:1) (0.00276 mol) and K2CO3 (0.00206 mol) in t-BuOH (100 ml) was stirred at 85° C. overnight in a sealed reaction vessel. The reaction mixture was cooled, filtered and the filtrate's solvent evaporated in vacuo. Yield: 0.55 g of E10 (96.5%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][C:15]([CH3:19])=[CH:16][CH:17]=O.N1C=CC=CC=1>>[OH:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]2[C:9]=1[CH:17]=[CH:16][C:15]([CH3:19])([CH3:14])[O:10]2
Reactant: O=Cc1cc([N+](=O)[O-])c(O)cc1O
Reactant: CC(C)=CC=O
Solvent: c1ccncc1
Product: CC1(C)C=Cc2c(O)c(C=O)cc([N+](=O)[O-])c2O1
Reaction time: 18 h

Procedure:
A solution of 2,4-dihydroxy-5-nitro-benzaldehyde (10.61 g, 58 mmol) in Me2CO (6 mL) is added during a 5.5 h period to a stirring solution of 3-methyl-but-2-enal (4.00 g, 29 mmol) in pyridine (2.29 g, 2.34 mL, 29 mmol) at 120° C. After completion of addition heating is continued for an additional 18 h. The Me2CO is evaporated and the pyridine is removed by azeotrope distillation with toluene to afford a crude product. The crude product is purified using silica gel chromatography with 1% ethyl acetate in hexanes to afford 5-hydroxy-2,2-dimethyl-8-nitro-2H-chromene-6-carbaldehyde.
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4][CH2:5][CH:6]([S:10][C:11](CC1C=CC=CC=1)=S)[C:7]([OH:9])=[O:8].Cl>C(O)C>[O:1]=[C:11]1[NH:4][CH2:5][CH:6]([C:7]([OH:9])=[O:8])[S:10]1
Reactant: NCC(SC(=S)Cc1ccccc1)C(=O)O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1NCC(C(=O)O)S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
12.0 ml of a 1 N aqueous solution of sodium hydroxide were added to a suspension of 1.2 g of 3-amino-2-(benzylthiocarbonylthio)propionic acid hydrochloride in 35 ml of ethanol, and the resulting mixture was stirred at room temperature for 30 minutes, after which 12.0 ml of 1 N aqueous hydrochloric acid were added, whilst ice-cooling. The solvent was then removed by distillation under reduced pressure, the resulting residue was dissolved in diethyl ether and the solution was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 0.50 g of a colorless powder. This powder was recrystallized from ethyl acetate, to give 0.25 g of the title compound as colorless columnar crystals, melting at 148°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]2[O:10][CH:9]([C:11]([F:13])([F:12])[F:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(-c3ccccc3)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2cc(Cl)cc(-c3ccccc3)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.5 %

Procedure:
A solution of the ester from step 1 (1.0 g, 2.6 mmol) was dissolved in THF (5 mL) and methanol (5 mL) was treated with a 2.5 N NaOH solution (4.0 mL, 10.4 mmol). The resulting mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo, and the residue taken up in ethyl acetate and acidified with 3 N HCl. The solution was extracted with ethyl acetate. The extracts were combined, dried over MgSO4, filtered, and concentrated in vacuo yielding a yellow solid. Recrystallization from ethyl acetate-hexanes afforded the title compound as a pale yellow solid (0.42 g, 46%): mp 196.3–197.7° C. 1H NMR (CDCl3/300 MHz) d 7.65 (s, 1H), 7.40–7.23 (m, 6H), 7.15 (s, 1H), 5.63 (q, 1H, J=6.5 Hz), 3.35 (broad s, 1H). 19F NMR (CDCl3/282 MHz)d −78.71 (d, J=5.8 Hz). FABLRMS m/z 355 (M+H). ESHRMS m/z 353.0198 (M−H, Calc'd 353.0192).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[O:4].[CH3:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]([N:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3](=[O:4])[CH2:2][NH:1][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=2)=[O:31])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: COc1cccc(N(CC(=O)OC(C)(C)C)C(=O)CN)c1
Product: COc1cccc(N(CC(=O)OC(C)(C)C)C(=O)CNC(=O)Nc2cccc(C)c2)c1
Yield: 65.9 %

Procedure:
The procedure used is similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(3-methoxyphenyl)acetamido]acetate (2.3 g) and 3-methylphenyl isocyanate (1.1 g). The product obtained is purified by chromatography on silica (0.04-0.063 mm) (150 g) contained in a column 3.5 cm in diameter [eluent: cyclohexane/ethyl acetate (70:30 by volume)], using an excess pressure of nitrogen of 40 kPa and collecting 20-cc fractions. Fractions 10 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallisation in diisopropyl ether, tert-butyl 2-{N-(3-methoxyphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (2.2 g), m.p. approximately 60° C., is obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1.[CH:19]1([CH:22]=O)[CH2:21][CH2:20]1.CCN(CC)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][N:10]([CH2:22][CH:19]3[CH2:21][CH2:20]3)[CH2:9][C:7]=2[N:8]=1
Reactant: O=CC1CC1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(CC1CC1)C2
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 94.9 %

Procedure:
To a stirring solution of (S)-4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine hydrochloride (intermediate 6) (870 mg, 3.01 mmol) in dichloroethane, was added cyclopropanecarboxaldehyde (450 uL, 6.02 mmol) and Et3N (840 uL, 6.02 mmol). The reaction mixture was stirred at room temperature (20° C.) for 45 minutes, before adding sodium triacetoxy borohydride (1.28 g, 6.02 mmol). The reaction mixture was then stirred for a further 2 h at room temperature (20° C.) before partitioning between saturated NaHCO3 solution and DCM. The organic layer was recovered, dried over MgSO4, filtered and the solvent removed in vacuo, affording the title compound as a colourless oil (882 mg, 92% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[C:22]([CH3:24])[C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[C:22]([CH3:24])[C:18]([C:19]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[O:20])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(-n2ncc(-c3ccc(C#N)cc3)c2O)ncc1C(=O)O
Product: Cc1cc(-n2ncc(-c3ccc(C#N)cc3)c2O)ncc1C(=O)N1CCN(C)CC1

Procedure:
The title compound was prepared in a manner similar to Example 412 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)-4-methylnicotinic acid and 1-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.39 (s, 3 H) 2.82 (s, 3 H) 4.02 (br. s., 4 H) 4.56 (br. s., 4 H) 7.79 (d, J=8.59 Hz, 2 H) 8.12 (br. s., 2 H) 8.37 (s, 1 H) 8.59 (br. s., 2 H); ESI-MS m/z (M+H)+ calc'd for C22H22N6O2, 403.18; found 403.3.
Reaction SMILES: [C:1]([NH:4]/[C:5](=[CH:9]\[CH2:10][PH:11]([CH2:13][OH:14])=[O:12])/[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[H][H]>CO>[C:1]([NH:4][C@@H:5]([CH2:9][CH2:10][PH:11]([CH2:13][OH:14])=[O:12])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N/C(=C\C[PH](=O)CO)C(=O)O
Reactant: [H][H]
Solvent: CO
Product: CC(=O)N[C@@H](CC[PH](=O)CO)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 612.4 %

Procedure:
(Z)-2-acetylamino-4-hydroxymethylphosphinyl-2-butenoic acid (4.0 g, 18 mmol), (RuCl(p-cymene)((S)-binap)Cl (8.4 mg, 0.009 mmol), and methanol (20 ml) were added to a 200 ml autoclave, and a nitrogen substitution and a hydrogen substitution were performed. The temperature in the autoclave was set to 70° C., hydrogen gas was charged to 1 MPa, and the reaction solution was stirred at the same temperature for 5 hours. A part of the reaction solution was taken as a sample. After completion of the reaction was confirmed with high performance liquid chromatography (HPLC) analysis on the sample, reaction solution was cooled to room temperature, hydrogen was purged, and then the reaction solution was moved to a 100 ml flask. After methanol was removed in vacuo and water (20 ml) was added, the water phase was washed with toluene (10 ml) twice and 24.6 g of (S)-2-acetylamino-4-hydroxymethylphosphinylbutanoic acid was obtained as a solution. The optical purity of the obtained (S)-2-acetylamino-4-hydroxymethylphosphinylbutanoic acid was 90.8% ee.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>>[F:1][C:2]1[CH:16]=[CH:15][C:5](/[C:6](/[Cl:19])=[N:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Product: Fc1ccc(/C(Cl)=N/c2ccccc2)cc1

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed 4-fluoro-N-phenylbenzamide (50 g; 233 mmol) and thionyl chloride (200 mL). The mixture was stirred at refluxed for 3 h and then the solvent was evaporated to dryness to afford (Z)-4-fluoro-N-phenylbenzimidoyl chloride as white solid. The solid was dissolved into chlorobenzene and SnCl4 (39.0 mmol) and ethyl cyanoformate (39.0 mmol) were added. The reaction mixture was heated at 140° C. for 1 hour and concentrated to get black oil. The black oil was added into water, made alkaline with 20% NaOH, and extracted with 2×300 mL of dichloromethane. The organic layer was washed with 1×100 mL of brine and dried over sodium sulphate and concentrated to get the crude product, which was purified by flash chromatography on silica gel, eluting with hexane/ethyl acetate (10:1) to afford ethyl 2-(4-fluorophenyl)quinazoline-4-carboxylate as white solid (8.1 g, 11.7%, 2 steps). MS (ESI) m/z 297 ([M+H]+).
Reaction SMILES: COC1C=CC(C[O:10][C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH2:33][C:34]([F:37])([F:36])[F:35])[C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=3)=[CH:13][CH:12]=2)=CC=1>[Pd]>[O:10]=[C:11]1[NH:16][CH:15]=[C:14]([O:17][CH2:18][CH2:19][N:20]([CH2:33][C:34]([F:37])([F:35])[F:36])[C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:30])([F:31])[F:32])[CH:22]=2)[CH:13]=[CH:12]1
Reactant: COc1ccc(COc2ccc(OCCN(CC(F)(F)F)c3ccc(C#N)c(C(F)(F)F)c3)cn2)cc1
Agent: [Pd]
Product: N#Cc1ccc(N(CCOc2ccc(=O)[nH]c2)CC(F)(F)F)cc1C(F)(F)F
Reaction time: 0.75 h
Yield: 77.4 %

Procedure:
A mixture of 4-[(2-{[6-({[4-(methyloxy)phenyl]methyl}oxy)-3-pyridinyl]oxy}ethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.270 g, 0.51 mmol; step C above) and Pd—C (0.027 g of 10 wt % on activated carbon (dry basis), ca. 50 wt % H2O, ca. 0.013 mmol Pd) was stirred under an atmosphere of H2 for 45 min and filtered through Celite. The filtrate was adsorbed onto a small amount of silica gel and purified by flash chromatography (MeOH/CH2Cl2), affording 0.160 g of the title compound as a colorless solid: MS (ESI) 406 (M+1).