Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([C:13]([OH:15])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(OC([N:23]1[CH2:28][CH2:27][NH:26][C:25]([CH3:30])([CH3:29])[CH2:24]1)=O)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].CC1(C)CNCCN1C(C1N=CN(C2C=CC=CC=2)N=1)=O>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([C:13]([N:26]3[CH2:27][CH2:28][NH:23][CH2:24][C:25]3([CH3:30])[CH3:29])=[O:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Agent: CC1(C)CNCCN1C(=O)c1ncn(-c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCCN1C(=O)c1ncn(-c2cccc(Cl)c2)n1

Procedure:
This intermediate was prepared from 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid and 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in two steps according to the preparation of (2,2-dimethyl-piperazin-1-yl)-(1-phenyl-1-H-[1,2,4]triazol-3-yl)-methanone trifluoroacetate and purified using HPLC.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[CH:9][N:8]([CH2:11]Cl)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH2:13]([CH:16]([C:19]#[N:20])[C:17]#[N:18])[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([C:16]([CH2:11][N:8]1[CH:9]=[CH:10][C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])=[N:7]1)([C:19]#[N:20])[C:17]#[N:18])[CH:14]=[CH2:15]
Reactant: C=CCC(C#N)C#N
Reactant: CC(C)(C)c1ccn(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(C#N)(C#N)Cn1ccc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.4 %

Procedure:
1.24 g of 3-t-butyl-1-(chloromethyl)-1H-pyrazole hydrochloride and 0.63 g of allyl malononitrile were dissolved in 18 ml of N,N-dimethylformamide. 1.63 g of potassium carbonate was added to the solution, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.38 g of allyl [(3-t-butyl-1H-pyrazole-1-yl)methyl]malononitrile (referred as the compound of the present invention (4), hereinafter) shown by below formula.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C>CS(C)=O.CCOC(C)=O>[C:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:2]2[CH:3]=[C:4]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:21][CH2:22]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of tert-butyl 2-chloro-6-(trifluoromethyl)isonicotinate (3.0 g, 11 mmol, Example 21, Step 1), tert-butyl 4-aminopiperidine-1-carboxylate (4.3 g, 21 mmol, Aldrich) and N,N-diisopropylethylamine (3.7 mL, 21 mmol) in dimethyl sulfoxide (9.2 mL) was heated to 100° C. for 20 hours. The mixture was cooled to room temperature and diluted with EtOAc. The combined organic extracts were washed with water (3 times) and brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography using a 120 g silica gel cartridge and eluting with a gradient from 0-15% EtOAc in hexanes afforded product as a white solid (3.4 g, 72%). LCMS (M+Na)+: 468.2.
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=[C:7]([CH3:16])[C:6]=1[N:17]([CH3:19])[CH3:18])([CH3:4])([CH3:3])[CH3:2].[B:20](O)([OH:22])[OH:21].C1C=CC=CC=1>O>[B:20]([O:11][C:10]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:6]([N:17]([CH3:19])[CH3:18])[C:7]([CH3:16])=[CH:8][C:9]=1[C:12]([CH3:13])([CH3:15])[CH3:14])([OH:22])[OH:21]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1N(C)C
Reactant: OB(O)O
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(C(C)(C)C)c(OB(O)O)c(C(C)(C)C)c1N(C)C
Temperature: 85 °C
Yield: 84.3 %

Procedure:
A mixture of 2,6-di-tertiary-butyl-dimethylamino- p-cresol (131.5 gm, 0.5 mole), boric acid (31.0 gm, 0.5 mole), and benzene (450 ml.) was heated while stirring vigorously at 85° C. for twenty-two hours. Water (5.5 ml.) formed during reaction was collected by azeotropic distillation.At the end of the reaction, the unreacted, insoluble material was removed by filtration, and the benzene was removed under reduced pressure using a rotary evaporator. This gave a golden orange solid (129.5 gm) with a melting point of 75°-80° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1.[F:16][C:17]1[CH:18]=[C:19]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]1[CH2:24][CH2:23][CH:22]([CH:30]=O)[CH2:21][C:20]2=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:16][C:17]1[CH:18]=[C:19]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]1[CH2:24][CH2:23][CH:22]([CH2:30][NH:1][CH:2]3[CH2:14][O:13][C:12]4[CH:11]=[CH:10][C:9]5[CH2:8][NH:7][C:6](=[O:15])[C:5]=5[C:4]=4[CH2:3]3)[CH2:21][C:20]2=1
Reactant: O=CC1CCc2[nH]c3ccc(F)cc3c2C1
Reactant: NC1COc2ccc3c(c2C1)C(=O)NC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NCc2ccc3c(c21)CC(NCC1CCc2[nH]c4ccc(F)cc4c2C1)CO3
Reaction time: 0.67 h

Procedure:
To a mixture of (1) (60 mg, 0.294 mmol), 6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carbaldehyde ((28), 64 mg, 0.294 mmol) in acetic acid (38 mg, 0.588 mmol) and methanol (3 ml) was added NaBH3CN (37 mg, 0.588 mmol) in portions. The resulting mixture was stirred for 40 min. The solvent was removed in vacuo and the residue was dissolved in methylene chloride. The organic solution was washed with 1N NaOH and saturated NaCl before being dried over with Na2SO4. The concentration of organic solution in vacuo gave crude (27), which was purified on silica gel eluting with 80% EtOAc/Hexane to give a white solid (71 mg, 60%). MS (ES) m/z 406.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[O:26]=[C:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:32][CH2:33][C:34](O)=[O:35]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:34](=[O:35])[CH2:33][CH2:32][N:28]3[CH2:29][CH2:30][CH2:31][C:27]3=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)CCN1CCCC1=O
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)CCN2CCCC2=O)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound rac-{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[3-(2-oxo-pyrrolidin-1-yl)-propionyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 3-(2-oxo-pyrrolidin-1-yl)-propionic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a colorless oil. MS m/e: 522.2 [M]+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1F)([O-:18])=[O:17]>CN(C)C=O>[CH2:1]([NH:8][C:20]1[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of 2.68 g (25.0 mmol) benzylamine in 100 ml dry dimethylformamide was added 2.55 g (25.2 mmol) dry triethylamine. A solution of 4.65 g (25.0 mmol) 2,4-dinitro-1-fluorbenzen in 20 ml dry dimethylformamide was added dropwise, and the reaction mixture was stirred at 25° C. for 1 h. The mixture was evaporated, then dissolved in 50 ml ethylacetate and washed with 100 ml water. The ethyl acetate was evaporated to give 6.1 g (89%) N-benzyl-2,4-dinitroaniline. M.p. 106.2° C. 1H-NMR (CDCl3): 9.1 (1H, d), 8.9 (1H, broad s), 8.2 (1H, dd), 7.3 (5H, s), 6.9 (1H, d), 4.2 (2H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19](=O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:17])=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:17][C:16]1[N:18]=[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]2[C:13]=1[CH:14]=[N:15][C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[N:11]2
Reactant: COc1cccc(Nc2ncc(C(C)NC(=O)c3ccccc3)nn2)c1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(Nc2ncc3c(C)nc(-c4ccccc4)n3n2)c1
Yield: 5.7 %

Procedure:
Applying the Cyclization Procedure 1, using N-[1-(3-{[3-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (Intermediate 74) (55 mg, 0.16 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.20 mL, 2.14 mmol), to afford 5-methyl-N-[3-(methyloxy)phenyl]-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (3 mg) as a yellow solid. MS m/z 332 (M+1).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[NH2:17])(=O)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]1[CH:40]=[CH:39][C:28]([CH2:29][O:30][C:31]2[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=2)=[CH:27][CH:26]=1.C(OCC)(=O)C>O>[CH2:13]([O:12][C:10]([C:9]1[CH:15]=[CH:16][C:6]2[N:5]=[C:1]([CH2:2][CH3:3])[N:17]([CH2:35][C:34]3[CH:37]=[CH:38][C:31]([O:30][CH2:29][C:28]4[CH:39]=[CH:40][C:25]([F:24])=[CH:26][CH:27]=4)=[CH:32][CH:33]=3)[C:7]=2[CH:8]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)c1ccc(NC(=O)CC)c(N)c1
Reactant: Fc1ccc(COc2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc2nc(CC)n(Cc3ccc(OCc4ccc(F)cc4)cc3)c2c1
Temperature: 75 °C
Reaction time: 16 h
Yield: 23.3 %

Procedure:
A mixture of 0.534 g of ethyl 4-propionylamino-3-aminobenzoate, 0.374 g of potassium carbonate, 0.800 g of 4-(4-fluorobenzyloxy)benzyl bromide, 5 ml of ethyl acetate and 3 ml of water was stirred at 75° C. for 16 hours. The organic layer was concentrated, and ethanol and 0.46 g of 36% hydrochloric acid were added to the residue. The mixture was stirred for 2 hours while being heat-refluxed. The reaction mixture was neutralized with potassium carbonate, and the solvent was then concentrated under reduced pressure. The residue was extracted with ethyl acetate and with water. The organic layer was concentrated under reduced pressure, and was purified through silica-gel column chromatography (eluent: a mixture of hexane and ethyl acetate at a ratio of 1:1) to give 0.228 g of 6-ethoxycarbonyl-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole (325).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(OC([N:70]1[CH2:74][CH2:73][CH2:72][NH:71]1)=O)(C)(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:70]1[CH2:74][CH2:73][CH2:72][NH:71]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCN3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-tert.-butyloxycarbonyl-pyrazolidine in DMSO at ambient temperature.
Reaction SMILES: [N:1]#[C:2][SH:3].[C:4]1([CH:10]([OH:15])[CH2:11][N:12]2[CH2:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1CC1.[ClH:19]>C(O)C>[ClH:19].[OH:15][CH:10]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:11][N:12]1[CH2:14][CH2:13][S:3][C:2]1=[NH:1]
Reactant: OC(CN1CC1)c1ccccc1
Reactant: N#CS
Agent: C1CN1
Agent: Cl
Solvent: CCO
Product: N=C1SCCN1CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To the stirred solution of thiocyanic acid is added a solution of the crude dl-α-phenyl-1-aziridineethanol in 250 ml. of ethanol at a rate sufficient to keep the reaction temperature at 30°-35° C. After the aziridine addition is complete, 72 g. of a methanolic solution of hydrogen chloride (0.35 mole) is added and the solution stirred for 1.5 hours at room temperature. An additional 0.05 mole of hydrogen chloride in 10 g. of ethanol is added, and the reaction heated at 35°-40° C. for 0.5 hour. It is then allowed to proceed at room temperature for 2.5 days. The mixture is concentrated under reduced pressure to about 100 ml., filtered, washed with ethanol and dried to give 27.1 g. of white crystals, melting point 198°-200° C. The yield is 42% (based on styrene oxide) or 71% (based on dl-α-phenyl-1-aziridineethanol).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:24]>C1COCC1.CN1CCCN(C)C1=O>[CH3:24][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]([C:14]=23)=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: Cn1c(-c2ccccc2)c2c3c(cccc31)C(=O)NCC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of compound 12 (51.3 mg, 0.20 mmol) in THF (1 mL) and 0.1 mL 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) was cooled with an ice/water bath and treated dropwise with a suspension of NaH (0.45 mmol) in THF (0.5 mL). The yellow mixture was allowed to stir at 0° C. for 10 min., and was treated dropwise with a 1M solution of iodomethane in THF (0.22 mL, 0.22 mmol). The mixture was allowed to warm to ambient temperature and stirred for 30 min. The reaction was quenched at 0° C. with saturated aqueous NH4Cl, and extracted with EtOAc (5 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by radial chromatography (2 mm SiO2; 1-5% MeOH in CH2Cl2) to yield 18 as a white solid, 44.9 mg (81%). mp 254-256° C. (dec.); 1H NMR (DMSO-d6) δ 2.88 (m, 2H), 3.40 (m, 2H), 3.74 (s, 3H), 7.34 (t, 1H, J=7.7 Hz), 7.56 (m, 5H), 7.73 (d, 1H, J=7.7 Hz), 7.80 (d, 1H, J=7.7 Hz), 8.15 (bt, 1H); Anal. (C18H16N2O.0.75 H2O) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[CH:17][N:16]=[C:15]3[C:10]=2[C:11]2[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=2[C:13](=[O:19])[NH:14]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:33]([CH3:36])=[C:34]=[O:35]>CS(C)=O>[CH3:36][NH:33][C:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:18]=[CH:17][N:16]=[C:15]3[C:10]=2[C:11]2[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=2[C:13](=[O:19])[NH:14]3)=[CH:6][CH:7]=1)=[O:35]
Reactant: CN=C=O
Reactant: Nc1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)Nc1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.2 %

Procedure:
340 (40 mg, 0.13 mmol), DIEA (34 mg, 0.26 mmol), and isocyanatomethane (11 mg, 0.18 mmol) were suspended in DMSO (1 mL), and stirred for 4 h at room temperature. The reaction mixture was quenched with H2O, filtered, washed with H2O and MeOH, and dried under vacuum to provide 342 (23 mg, 46% yield) as a solid. LC-MS (M+H=361, obsd.=361).
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[C:7]([CH3:44])([O:9][C:10]1[CH:43]=[CH:42][C:13]([CH2:14][N:15]2[C:19](=[O:20])[C:18]3([CH2:25][CH2:24][N:23](C(OCC4C=CC=CC=4)=O)[CH2:22][CH2:21]3)[N:17]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:16]2)=[CH:12][CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C.CO>[CH3:44][C:7]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[C:19](=[O:20])[C:18]3([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:17]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:16]2)=[CH:42][CH:43]=1)([CH3:8])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:45]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a solution of benzyl 3-(4-(1-tert-butoxy-2-methyl-1-oxopropan-2-yloxy)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.69 g, 1.12 mmol) in 1:1 solution of ethyl acetate/methanol (20 mL), was added 10 wt % palladium on carbon (0.2 g). After stirring under hydrogen at room temperature and atmospheric pressure for 2 hours, the reaction mixture was filtered, washed with methanol, concentrated in vacuo to obtain tert-butyl 2-methyl-2-(4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenoxy)propanoate (0.5 g, 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][C:9]=1[NH2:10])([O-])=O>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: Nc1ccc(CC(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1ccc(CC(=O)O)cc1N

Procedure:
2-(3,4-Diaminophenyl)acetic acid can be prepared by acetylation of 2-(4-aminophenylacetonitrile with acetic anhydride in pyridine. The 2-(4-acetamidophenyl)acetonitrile product is nitrated in acetic anhydride to provide 2-(3-nitrile-4-acetamidophenyl)acetonitrile. The nitrile is hydrolyzed with concentrated hydrochloric acid to give 2-(3-nitro-4-aminophenyl)acetic acid after neutralization. The nitro acid is then hydrogenated at 60 psi at room temperature over palladium-on-carbon to yield 2-(3,4-diaminophenyl)acetic acid. The acid can be esterified with C1 -C8 carbinols in the presence of acid catalysts to yield starting materials according to II in which R3 is an ester group. Similarly, the preparation of 2-(3,4-diaminophenyl)propionic acid begins with 2-(4-aminophenyl)propionitrile as described above for the preparation of the diaminophenylacetic acid.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([NH2:13])[CH2:5][CH2:4]1.[O-:14][C:15]#[N:16].[K+]>O>[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([NH:13][C:15]([NH2:16])=[O:14])[CH2:5][CH2:4]1
Reactant: N#C[O-]
Reactant: NC1CCC(=O)c2ccccc21
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NC1CCC(=O)c2ccccc21
Reaction time: 72 h

Procedure:
A sample of 26.55 g. of 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine hydrochloride is dissolved in 250 ml. water and a solution of 21.8 g. of potassium cyanate in 75 ml. of water added. The reaction mixture is stirred for 72 hours, the precipitate formed in the reaction is collected by filtration and dried to afford 21.45 g. of the title compound, m.p. 225° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18]O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>COCCOC.[Fe](Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[N:11]([C:12]([S:16][CH3:17])=[N:13][CH:14]=[CH:15]3)[N:18]=2)=[CH:4][CH:3]=1
Reactant: CSc1nccc(CC(=NO)c2ccc(F)cc2)n1
Agent: Cl[Fe]Cl
Solvent: COCCOC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CSc1nccc2cc(-c3ccc(F)cc3)nn12
Temperature: 20 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a 0° C. solution of 1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone oxime (4.0 g, 14 mmol) in ethylene glycol dimethyl ether (40 mL) was added trifluoroacetic anhydride (3.0 g, 14 mmol) dropwise. The reaction was allowed to warm to 20° C., then re-cooled to 0° C. Triethylamine (2.9 g, 29 mmol) was added dropwise so that the internal reaction temperature did not exceed 10° C. The reaction was allowed to warm to room temperature and was stirred for 2 hours. Iron (II) chloride (18 mg, 0.14 mmol) was added and the mixture heated to 80° C. for 2 hours. An additional portion of iron (II) chloride (18 mg, 0.14 mmol) was added and the mixture heated at 80° C. for 2 hours. An additional portion of iron (II) chloride (18 mg, 0.14 mmol) was added and the mixture heated at 80° C. for 4 hours. The reaction was allowed to cool to room temperature and stirred overnight. The mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×20 mL) and the organic layers combined. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica chromatography eluting with 1% acetone in dichloromethane to yield 2.54 g (68%) of 2-(4fluorophenyl)-7-(methylsulfanyl)-pyrazolo[1,5-c]pyrimidine. 1H NMR (CDCl3): δ 8.04 (dd, 2H),7.80 (d, 1H), 7.20 (m, 3H), 6.79 (s, 1H), 2.76 (s, 3H). MS m/z 260 (M+1).
Reaction SMILES: C([C:3](=[C:9]([O:15][CH2:16][CH3:17])/[CH:10]=[CH:11]/[N:12](C)[CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#N.C(O)(=[O:20])C>>[CH2:16]([O:15][C:9]1[CH:10]=[CH:11][NH:12][C:13](=[O:20])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:17]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(C#N)=C(/C=C/N(C)C)OCC
Product: CCOC(=O)c1c(OCC)cc[nH]c1=O
Temperature: 100 °C
Yield: 58.5 %

Procedure:
(4E)-Ethyl 2-cyano-5-(dimethylamino)-3-ethoxypenta-2,4-dienoate (20 kg) and acetic acid (126 L) were charged to a reactor and heated to 100° C. for 3 hrs until the reaction was complete as characterized by HPLC. The reaction mass was cooled to 55° C. and acetic acid was removed by vacuum distillation at 65-75° C. After distillation, the mixture was cooled to room temperature and water (3 L) was added. The pH of the mixture was adjusted to 8 by addition of 100 L of a 30% sodium carbonate solution. The solids were filtered off and washed with 10 L of water. The combined aqueous layers were extracted three times with DCM (100 L). The combined DCM layers were washed with brine, then dried over sodium sulfate and concentrated to dryness. Ethyl acetate was added to the concentrate. The mixture was heated to 40° C. and then cooled to 25° C. The solids were filtered off, washed with petroleum ether and dried at room temperature for 12 hrs to yield ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (10.3 kg; 58.5% yield).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[N:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH:20]=[N:19][C:18]([NH:22][CH:23]=O)=[CH:17]2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[N+:22]([C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][N:19]=1)[C:12]([N:3]1[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]1=[O:11])=[N:13][CH:14]=[CH:15]2)#[C-:23]
Reactant: O=CNc1cc2ccnc(N3C(=O)c4ccccc4C3=O)c2cn1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [C-]#[N+]c1cc2ccnc(N3C(=O)c4ccccc4C3=O)c2cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
4-8 (90.0 mg, 0.280 mmol) was suspended in CH2Cl2 (10 mL) and cooled to 0° C. To the mixture were added triphosgene (252 mg, 0.85 mmol) followed by Et3N (0.240 mL, 1.69 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with CH2Cl2, washed with saturated aqueous NaHCO3, brine, and dried over Na2SO4. The residue was purified by silica gel chromatography (0-5% EtOAc in CH2Cl2) to give 73.3 mg (41%) of 4-9 as a pale white solid: 1H NMR (300 MHz, CDCl3) δ 9.18 (1H, br s), 8.86 (1H, d, J=5.7 Hz), 8.06 (2H, m), 7.90 (2H, m), 7.85 (1H, br s), 7.84 (1H, d, J=5.7 Hz); ESI-MS m/z 301 [C17H8N4O2+H]+.