Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](O)=[O:15])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.C1COCC1.CO>C1COCC1>[OH:15][CH2:14][C:13]1[CH:12]=[C:11]([S:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2ccccc2)c1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(Nc1ccccc1)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To solution of 3-Phenylsulfamoyl-benzoic acid (380 mg, 1.36 mmol) in THF (10 ml) was added BH3.THF (1M, 5.4 ml, 5.4 mmol) dropwise. After the addition, the reaction mixture was allowed to stir for 3 d at room temperature. Methanol was added to the reaction and the mixture concentrated in vacuo (5×). This compound was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH3:18])[N:17]=1>>[CH3:18][C:16]1[N:17]=[C:13]([NH:12][C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[S:14][CH:15]=1
Reactant: Cc1csc(N)n1
Reactant: Clc1nccc2cccnc12
Product: Cc1csc(Nc2nccc3cccnc23)n1

Procedure:
The title compound, MS: m/e=243.3 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-[1,7]naphthyridine and 2-amino-4-methylthiazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[NH:17][N:18]=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH3:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:15][C:16]3[NH:17][N:18]=[C:19]([CH3:21])[CH:20]=3)[N:7]=2)[CH2:9][CH2:10]1
Reactant: CC1CCN(c2ccnc(Cl)n2)CC1
Reactant: Cc1cc(N)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Cc1cc(Nc2nccc(N3CCC(C)CC3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of 2-chloro-4-(4-methylpiperidin-1-yl)-pyrimidine (prepared using a procedure similar to the one reported in Eur. J. Med. Chem., 26(7) 729(1991))(222 mg, 1.05 mmol) in BuOH (5 mL) was added 3-amino-5-methyl-2H-pyrazole (305 mg, 3.15 mmol) and the reaction mixture was then heated under reflux overnight. The solvent was evaporated and the residue dissolved in a mixture ethanol/water (1/3, 4 mL). Potassium carbonate (57 mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water twice and rinsed with ether twice to give the title compound as a white solid (143 mg, 50%): mp 193–195° C.; 1H NMR (DMSO) δ 0.91 (3H, d), 1.04 (2H, m), 1.67 (3H, m), 2.16 (3H, s), 2.83 (2H, t), 4.31 (2H, m), 6.19 (2H, m), 7.87 (1H, d), 8.80 (1H, br s), 11.71 (1H, s); IR (solid) 1627, 1579, 1541, 1498, 1417, 1388, 1322, 1246; MS 273.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]([CH3:14])=[CH2:13])[C:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)=[C:7]([CH3:27])[C:6]=2[C:5]([OH:28])=[CH:4][CH:3]=1.C(OCC)(=O)C>[OH-].[Pd+2].[OH-].CO>[Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH:12]([CH3:13])[CH3:14])[C:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)=[C:7]([CH3:27])[C:6]=2[C:5]([OH:28])=[CH:4][CH:3]=1
Reactant: C=C(C)c1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(-n2cccn2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C(C)C)nc2c(Cl)ccc(O)c12
Temperature: 25 °C
Reaction time: 27 h
Yield: 80.4 %

Procedure:
A mixture of 8-chloro-2-isopropenyl-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.26 g), ethyl acetate (10 mL), methanol (5.0 mL) and palladium hydroxide (0.05 g) was stirred at room temperature for 27 hours under an atmosphere of hydrogen. The mixture was filtered through Celite and the filtrated concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 0:1 by volume) gave title compound as a yellow oil (0.21 g),
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([NH:15][C:16]2[S:17][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:19][N:20]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[I-].[K+]>CN(C)C=O>[CH:21]([C:18]1[S:17][C:16]([NH:15][C:13](=[O:14])[CH2:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:7]=2)=[N:20][CH:19]=1)([CH3:23])[CH3:22]
Reactant: C1COCCN1
Reactant: CC(C)c1cnc(NC(=O)Cc2cccc(OCCCCl)c2)s1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1cnc(NC(=O)Cc2cccc(OCCCN3CCOCC3)c2)s1
Temperature: 100 °C
Yield: 87 %

Procedure:
A mixture of 2-[3-(3-chloropropoxy)phenyl]-N-(5-isopropyl-1,3-thiazol-2-yl)acetamide (1.00 g, 2.8 mmoles), morpholine (1.24 ml, 14.2 mmoles), potassium iodide (0.24 g, 1.4 mmoles) in anhydrous dimethylformamide (3.5 ml) was heated at 100° C. for 6 hours. The solution was acidified and extracted with ether to eliminate unreacted products; then the solution was basified and extracted with ether. The solvent was evaporated to dryness to give the product as an oily semisolid which was purified by flash chromatography with dichloromethane:methanol (97:3) as eluent (1.0 g, 87% yield)
Reaction SMILES: C(=[C:5]1[C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=[CH:7][NH:6]1)C(C)C.[CH3:13][C:14]([O-])([CH3:16])[CH3:15].[K+]>C1(C)C=CC=CC=1>[N:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=[N:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:5]=1
Reactant: CC(C)C=C1NC=CC=C1CN
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)CN=Cc1cccnc1
Yield: 2062.8 %

Procedure:
The procedure is carried out as in Example 1 (b) but with the use of 80.1 g (0.495 mol) of isobutylidene-3-aminomethylpyridine, 2.5 g (0.0223 mol) of potassium tert-butylate and 75 ml of toluene. After a reaction time of 1 hour at 30°-35° C., distillation yields 74.5 g (0.46 mol) of 3-pyridylmethylidene-isobutylamine; yield 93% of theory; b.p. 108° C./2×103Pa; nD20 =1.5198.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1.[Br:18]N1C(=O)CCC1=O.O>O1CCCC1>[Br:18][C:10]1[NH:11][C:5]2[CH:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:3][N:2]([CH3:1])[CH2:8][CH2:7][C:6]=2[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCc2cc[nH]c2C(c2ccccc2)C1
Solvent: C1CCOC1
Solvent: O
Product: CN1CCc2cc(Br)[nH]c2C(c2ccccc2)C1
Reaction time: 0.67 h

Procedure:
A solution of 1,4,5,6,7,8-hexahydro-6-methyl-8-phenylpyrrolo[2,3-d]azepine (0.238 g) in tetrahydrofuran (30 ml) was cooled to -70° C. N-Bromosuccinimide (0.188 g) in tetrahydrofuran (3 ml) was added dropwise over 10 minutes, allowing the temperature to reach -10° C. over 40 minutes. Water was added and the product was extracted into ethyl acetate. The extracts were washed with water, dried and evaporated to give the title product as a solid, m.p. 132°-133° C. (acetonitrile).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][F:16])[CH:14]=1)[C:8](OC)=[O:9])=[N+:2]=[N-:3].[BH4-].[Na+].CO>C1COCC1>[N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][F:16])[CH:14]=1)[CH2:8][OH:9])=[N+:2]=[N-:3]
Reactant: COC(=O)c1cc(CF)cc(CN=[N+]=[N-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: [N-]=[N+]=NCc1cc(CO)cc(CF)c1
Yield: 36.3 %

Procedure:
Methyl 3-azidomethyl-5-fluoromethylbenzoate (35) (468 mg, 2.10 mmol) was dissolved in THF (1.5 mL). The air was evacuated from the reaction system, and then Ar was charged therein. To the solution were added NaBH4 (97.5 mg, 2.58 mmol), and then a mixed solution of THF:MeOH (1.3 mL:0.4 mL) slowly dropwise. The reaction mixture was refluxed for 20 hour. TLC was used to confirm the progress of the reaction. Then, the reaction was quenched with 1N hydrochloric acid (2.5 mL). The mixture was extracted with EtOAc. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue was purified by neutral silica gel column chromatography (hexane:EtOAc=5:1, then EtOAc) to isolate 3-azidomethyl-5-fluoromethylbenzylalcohol (36) (149 mg, 36%) as a colorless oil. In addition, the aqueous layer of the extraction was basified with a saturated sodium hydrogen carbonate aqueous solution and extracted with EtOAc. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give methyl 3-aminomethyl-5-fluoromethylbenzoate (37) (33.1 mg, 8%) as a yellow clear oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH2:27][C:28](=[O:30])[CH3:29])[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH2:27][C:28]([OH:30])([CH3:31])[CH3:29])[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cn1c(COCc2ccccc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1nc(COCc2ccccc2)n(CC(C)(C)O)c1Sc1cc(Cl)cc(Cl)c1
Yield: 73 %

Procedure:
In 5 ml of tetrahydrofuran was dissolved 464 mg (1 mmol) of the ketone (139), followed by addition dropwise of 134 mg (1.1 mmol) of methylmagnesium bromide (tetrahydrofuran;2 ml) under ice-cooling and stirring, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added an aqueous solution of ammonium chloride, the mixture was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate:methylene chloride=1:1) to provide 350 mg (yield 73%) of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-1-(2-hydroxy-2-methylpropyl)-4-isopropyl-1H-imidazole (140b) as oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH:16]=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([CH2:31][N+:32]#[C-:33])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH:33]=[N:32][CH:31]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3cnco3)c2[C@@H]2CCCN12

Procedure:
A mixture of 1.51 g (5 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxaldehyde, 1.07 g (5.5 mmol) of toluene-4-sulphonylmethyl isocyanide, 1 g of powdered potassium carbonate and 20 ml of methanol is heated to boiling under reflux for 2 hours. The mixture is then evaporated to a volume of 5 ml and the material obtained is chromatographed on silica gel while eluting with ethyl acetate/methanol (9:1). After recrystallization from ethyl acetate there is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-1-(5-oxazolyl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 201°-202°.
Reaction SMILES: [CH2:1]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>ClCCl>[C:22]([O:21][C:19](=[O:18])[N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[CH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Oc1ccc(CNCCc2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCc1ccccc1)Cc1ccc(O)cc1
Yield: 52.8 %

Procedure:
Suspend 4-(phenethylaminomethyl)phenol (0.750 g, 3.30 mmol) in dichloromethane (10 mL). Add a solution of (BOC)2O (1.08 g, 4.95 mmol) in dichloromethane (6.5 mL). Quench with 1.0 N NaOH (75 mL) after 19 hours. Extract with dichloromethane (2×200 mL). Wash the organic layer with brine (1×75 mL), dry over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 20-30% ethyl acetate in hexanes to give the title compound (0.570 g, 52.8%): MS ES+ 328.3 (M+H)+, base peak ES+ 272.1 (M+2H—C(CH3)3)+, ES− 326.3 (M−H)−; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=14.7 min, 100% purity.
Reaction SMILES: Cl[CH:2]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:3]1[O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=1>>[CH:13]1([CH:2]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:3]2[O:4][C:5]3[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=3[C:7]=2[CH3:8])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1c(C(Cl)C2CCCCC2)oc2ccccc12
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccccc12

Procedure:
Using 2-[chloro(cyclohexyl)methyl]-3-methyl-1-benzofuran (429 mg) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (408 mg) synthesized in Example 2(2) and in the same manner as in Example A7(3), the title object compound (247 mg, 34%) was obtained as a white solid.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34]1([CH2:40][C:41](Cl)=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41](=[O:42])[CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccccc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 54.7 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 4.26 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, phenylacetyl chloride (0.35 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: EtOAc 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-phenylacetamide (0.41 g, 55%) as a white solid: mp 128-130° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 8.67 (t, J=5.5 Hz, 1H), 7.80-7.61 (m, 3H), 7.29 (s, 5H), 5.19-5.12 (dd, J=5.1 and 12.4 Hz, 1H), 4.71 (d, J=5.5 Hz, 2H), 3.53 (s, 2H), 2.96-2.83 (m, 1H), 2.63-2.50 (m, 2H), 2.08-2.03 (m, 1H); 13HNMR (DMSO-d6) δ 172.77, 170.65, 169.82, 167.45, 166.93, 139.19, 136.15, 134.68, 133.18, 131.53, 129.05, 128.25, 127.13, 126.43, 121.90, 48.85, 42.24, 37.85, 30.93, 21.98; Anal. Calcd. For C22H19N3O5: C, 65.18; H, 4.72; N, 10.36. Found: C, 65.16; H, 4.75; N, 10.11.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([Cl:38])=[C:7]([NH:13][C:14]3[N:19]=[C:18]([N:20]([CH:30]4[CH2:32][CH2:31]4)CC4C=CC(OC)=CC=4)[C:17]4=[N:33][CH:34]=[C:35]([C:36]#[N:37])[N:16]4[N:15]=3)[CH:8]=[C:9]([C:11]#[N:12])[CH:10]=2)[CH2:2]1.[O:39]1[CH2:42][C:41](=O)[CH2:40]1>>[Cl:38][C:6]1[C:5]([CH:3]2[CH2:2][N:1]([CH:41]3[CH2:42][O:39][CH2:40]3)[CH2:4]2)=[CH:10][C:9]([C:11]#[N:12])=[CH:8][C:7]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH:30]2[CH2:32][CH2:31]2)[C:17]2=[N:33][CH:34]=[C:35]([C:36]#[N:37])[N:16]2[N:15]=1
Reactant: O=C1COC1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C4CNC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CN(C3COC3)C2)c1

Procedure:
The title compound, was prepared from 2-((3-(azetidin-3-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 357E) and oxetan-3-one using a method analogous to that used to prepare Example 301.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][C:4]([CH3:7])([NH2:6])[CH3:5].[C:9](ON1C(=O)CCC1=O)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>C(O)(C)C.O>[CH3:1][N:2]([CH3:8])[CH2:3][C:4]([NH:6][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:7])[CH3:5]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CN(C)CC(C)(C)N
Solvent: CC(C)O
Solvent: O
Product: CN(C)CC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.3 %

Procedure:
N1,N1,2-Trimethylpropane-1,2-diamine (5.68 g, 48.8 mmol) was dissolved into isopropanol/water (1:1, 150 mL). To this solution was added CbzOSu (12.2 g, 1 equiv, 48.8 mmol) in one portion. The reaction was left to stir at room temperature overnight for 17 h. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (300 mL) and water (100 mL). The layers were separated and the organic layer extracted with water (2×100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to an oil. The crude oil was purified on an ISCO purification system with gradient elution from 2% methanol in DCM to 30% methanol in DCM. The desired fraction was collected and concentrated to give a colorless oil (8.95 g, yield: 73.2%). 1H NMR (CDCl3, 400 MHz): δ 1.41 (s, 6H), 2.51 (s, 2H), 2.98 (s, 2 H). LRMS (ESI+) for C14H22N2O2 (250.2); Found: 251 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Yield: 99.9 %

Procedure:
A solution of t-butyl 3-methoxy-4-o-tolylureidophenylacetate (0.016 g, 0.043 mmol) in trifluoroacetic acid (1.0 mL) was stirred for 1 h. The reaction was concentrated and the residue coevaporated with methylene chloride (2×) then ether to afford 3-methoxy-4-o-tolylureidophenylacetic acid (0.0135 g, 100%) as a white residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([OH:27])=O)[CH:19]=3)[NH:14]2)[CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:27])[CH:19]=3)[NH:14]2)[CH:5]=[C:6]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:7]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(N2CCCC2)c1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cc(F)cc(N2CCCC2)c1
Temperature: 60 °C
Yield: 35.3 %

Procedure:
A mixture of 2-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (50 mg, 0.14 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (39 mg, 0.20 mmol), 4-dimethylaminopyridine (24.4 mg, 0.20 mmol), methane sulfonamide (40 mg, 0.42 mmol) in dichloromethane (3 mL) was heated for 12 hours at 60° C. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[2-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (22 mg, 35%) as a light yellow solid: LC/MS m/e calcd for C23H28FN3O3S (M+H)+: 446.6, observed: 446.2.
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH2:12][C:13](=[N:15][O:16][CH2:17][CH3:18])[CH3:14])=[C:9]([Br:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:20]1(=O)[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH2:21]1.Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Br:1][C:2]1[C:10]([O:11][CH2:12][C:13](=[N:15][O:16][CH2:17][CH3:18])[CH3:14])=[C:9]([Br:19])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH:21]=1)=[O:5]
Reactant: CCON=C(C)COc1c(Br)ccc(C(=O)O)c1Br
Reactant: O=C1CCCC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CCON=C(C)COc1c(Br)ccc(C(=O)OC2=CC(=O)CCC2)c1Br

Procedure:
0.280 g (0.70 mmol) of 2,4-dibromo-3-(2-ethoxyiminopropyloxy)benzoic acid, 0.087 g (0.80 mmol) of cyclohexane-1,3-dione, 0.139 g (0.70 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 0.001 g of dimethylaminopyridine were stirred in 15 ml of CH2Cl2 at RT for 3 h. The mixture was then diluted with CH2Cl2 and washed with 0.5 N HCl, water, saturated NaHCO3 solution and again with water. The combined organic phases were dried over Na2SO4 and evaporated to dryness, giving 3-oxo-1-cyclohexenyl 2,4-dibromo-3-(2-ethoxyiminopropyloxy)-benzoate in the form of a yellow resin of sufficient purity.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[CH:10]=[C:11]([C:16]2[C:17](=[O:38])[N:18]([CH2:36][CH3:37])[C:19]3[C:24]([CH:25]=2)=[CH:23][N:22]=[C:21]([NH:26]CC2C=CC(OC)=CC=2)[CH:20]=3)[CH:12]=[CH:13][C:14]=1[F:15].C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:26][C:21]1[CH:20]=[C:19]2[C:24]([CH:25]=[C:16]([C:11]3[CH:12]=[CH:13][C:14]([F:15])=[C:9]([NH2:8])[CH:10]=3)[C:17](=[O:38])[N:18]2[CH2:36][CH3:37])=[CH:23][N:22]=1
Reactant: CCn1c(=O)c(-c2ccc(F)c(N)c2)cc2cnc(NCc3ccc(OC)cc3)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(-c2ccc(F)c(N)c2)cc2cnc(N)cc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To a solution of TFA in CH2Cl2 (10%, 50 mL) was added 3-(3-amino-4-fluoro-phenyl)-1-ethyl-7-(4-methoxy-benzylamino)-1H-[1,6]naphthyridin-2-one (2.0 g, 4.78 mmol). The resulting mixture was stirred at 50° C. overnight. The reaction mixture was poured saturated aq NaHCO3 solution (100 mL), and was extracted with CH2Cl2 (3×75 mL). The combined organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 7-amino-3-(3-amino-4-fluorophenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (0.45 g, 32% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.35 (s, 1 H), 7.76 (s, 1 H), 7.09 (dd, J=9.0, 2.1 Hz, 1 H), 6.97 (dd, J=11.4, 8.4 Hz, 1 H), 6.75 (m, 1 H), 6.44 (s, 2 H), 6.31 (s, 1 H), 5.09 (s, 2 H), 4.08 (q, J=7.2 Hz, 2 H), 1.20 (t, J=7.2 Hz, 3 H), MS (ESI) m/z (M+H+): 299.3.
Reaction SMILES: [S:1]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:14](C(O)C([O-])=O)C>>[S:1]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([C:4]([F:6])([F:7])[F:5])(=[O:3])=[O:2]
Reactant: COC(=O)COS(=O)(=O)C(F)(F)F
Reactant: CCC(O)C(=O)[O-]
Product: CCOC(=O)COS(=O)(=O)C(F)(F)F

Procedure:
Prepared in the same way as described for TfO-CH2COOMe starting with ethylglycolate.