Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[NH:2][NH2:3].[N:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1>C(O)C>[N:19]1[CH:24]=[CH:23][C:22]([CH:25]=[N:3][NH:2][C:1]([O:5][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:4])=[CH:21][CH:20]=1
Reactant: O=Cc1ccncc1
Reactant: NNC(=O)OC(c1ccccc1)c1ccccc1
Solvent: CCO
Product: O=C(NN=Cc1ccncc1)OC(c1ccccc1)c1ccccc1
Yield: 78.6 %

Procedure:
To 24.11 gm (0.1 mole) of benzhydryl carbazate in 200 ml of warm absolute ethanol is added 10.66 gm (0.1 mole) of 4-pyridinecarboxaldehyde in 75 ml of absolute ethanol. The mixture is refluxed 7 hr and cooled. The solvent is removed in vacuo. Recrystallization from ethanol/Skellysolve B yields 26.03 gm (78.5%) of the title compound having a melting point of 159°-160° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][NH:7][CH3:8])[CH3:3].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[C:18][C:19]([OH:21])=O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[C:18][C:19]([N:7]([CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9])[CH3:8])=[O:21]
Reactant: CCOC(=O)CNC
Reactant: O=C(O)C#Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)CN(C)C(=O)C#Cc1ccccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.6 %

Procedure:
To a solution of sarcosine ethyl ester hydrochloride (1.14 g, 7.44 mmol) and 3-(2-fluorophenyl)prop-2-ynoic acid (1.22 g, 7.44 mmol) in anhyd. CH2Cl2 was added NMM (10 mL, 8.93 mmol), followed by EDCI.HCl (1.86 g, 9.67 mmol) and DMAP (0.99 g, 8.2 mmol). The reaction mixture was stirred for 5 h at room temperature and diluted with CH2Cl2. The resulting solution was washed with a 0.5N HCl solution (2×25 mL), a 0.5N NaOH solution (2×25 mL) and a saturated NaCl solution. The organic layer was dried (MgSO4), concentrated onto silica gel under reduced pressure and purified by flash chromatography (30% EtOAc/hex) to yield ethyl 2-[3-(2-fluorophenyl)-N-methylprop-2-ynoylamino]acetate (1.50 g, 77%) as a yellow oil: TLC (50% EtOAc/hex) Rf 0.54; HPLC ES-MS m/z (rel abundance) 264 (100%).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[C:6]1([CH:16]=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+].Cl>C(O)C.O>[C:6]1([CH2:16][CH:2]([C:1]#[N:5])[C:3]#[N:4])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: N#CCC#N
Reactant: O=Cc1cccc2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CC(C#N)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 168 h
Yield: 80 %

Procedure:
To a mixture of malononitrile (1.32 g, 20 mmol) in Ethanol (50 mL) and Water (2.50 mL) was added 1-naphthalenecarbaldehyde (3.12 g, 20 mmol). The reaction was stirred at rt for 7 days. The mixture was cooled to 0° C. in an ice bath. Sodium borohydride (0.204 g, 5.40 mmol) was introduced to the vigorously stirred mixture and the reduction was complete in about 10 min. To the reaction mixture was added water (20 mL). 1N HCl was added in to quench the excess hydride. More water was added in until precipitation was complete. Filtration gave (1-naphthalenylmethyl)propanedinitrile (3.3 g, 80%). To a solution of (1-naphthalenylmethyl)propanedinitrile (3.3 g, 16 mmol) in Ethanol (80 mL) was added hydrazine hydrate (0.785 mL, 16.00 mmol). The mixture was heated at reflux temperature for 8 h. The reaction mixture was concentrated. The crude material was purified on a silica column (MeOH/DCM: 0˜10%) to give the product (2.18 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.96 (s, 2H) 7.26 (d, J=7.07 Hz, 1H) 7.31-7.44 (m, 1H) 7.45-7.58 (m, 2H) 7.74 (d, J=8.08 Hz, 1H) 7.85-7.97 (m, 1H) 8.12-8.26 (m, 1H) 10.05 (bs, 1H). LC/MS: MS (ES+) m/e 239.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]3)[CH:8]=2)[NH:3]1.O.[C:19]1(C)C=CC(S(O)(=O)=O)=C[CH:20]=1>C(O)C>[O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3([C:15]([O:17][CH2:19][CH3:20])=[O:16])[CH2:14][CH2:13]3)[CH:8]=2)[NH:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1Nc2ccc(C3(C(=O)O)CC3)cc2C1=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(c2ccc3c(c2)C(=O)C(=O)N3)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 983.2 %

Procedure:
6.5 g of (2,3-dioxo-2,3-dihydro-1H-indol-5-yl)cyclopropanecarboxylic acid are dissolved in 100 ml of ethanol, and 500 mg of toluene-4-sulfonic acid monohydrate are added. The mixture is heated at 80° C. for 1 h and subsequently evaporated in vacuo. The residue is taken up in 100 ml of water and 100 ml of ethyl acetate and stirred at 60° C. for a further 12 h. The mixture is neutralised using sodium hydrogencarbonate, and the organic phase is separated off. The aqueous phase is washed a further twice with 100 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness in vacuo, giving 6.7 g (92%) of ethyl 1-(2,3-dioxoindolin-5-yl)cyclopropanecarboxylate; LC-MS retention time: 1.30 min.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([O:32][C:33]([O:35][CH2:36]I)=[O:34])[CH2:28][CH2:29][CH2:30][CH3:31]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:36][O:35][C:33]([O:32][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:34])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CCCCCOC(=O)OCI
Agent: [Na+]
Product: CCCCCOC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 86 %

Procedure:
In the same manner as in Example 81, 168 mg of the title compound was prepared from 150 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 162 mg of (pentan-1-yl)oxycarbonyloxymethyl iodide.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH:14]2[CH2:17]C[CH2:15]2)[C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[C:11]([NH:13][CH:14]([CH3:17])[CH3:15])[CH:12]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1NC1CCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)Nc1cc(Cl)ncc1CO
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of ethyl 6-chloro-4-(isopropylamino)nicotinate (2) (1 g, 4.12 mmol) in dry DCM (30 mL), DIBAL-H (8.24 mmol, 2 equiv.) (1.0 M in DCM) was added dropwise at −78° C. The reaction mixture was stirred at −78° C. for 2 h, gradually, the reaction was allowed to warm up to −10° C. over 1 h. The reaction mixture was quenched with saturated solution of sodium potassium tarterate and allowed to stir at room temperature. The reaction mixture was filtered through a small pad of celite. The filtrate was washed with brine solution, dried over Na2SO4, filtered and concentrated to give crude alcohol. The crude material obtained was purified by flash column chromatography through silica gel and MeOH: CHCl3 as eluent to afford (6-chloro-4-(isopropylamino)pyridin-3-yl)methanol. LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 0.806 min; LCMS (ES-API), m/z 201.0 (M+H).
Reaction SMILES: [CH2:1]([N:19]1[C:27](=O)[CH:26]2C(C[CH:23]=[CH:24][CH2:25]2)[C:20]1=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C[CH:31]([OH:33])[CH3:32].[BH4-].[Na+].Cl>O>[OH:33][CH2:31][CH:32]1[CH:27]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:20]=[O:29])[CH2:26][CH:25]=[CH:24][CH2:23]1
Reactant: CCCCCCCCCCCCCCCCCCN1C(=O)C2CC=CCC2C1=O
Reactant: CC(C)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCN(C=O)C1CC=CCC1CO
Temperature: 25 °C
Reaction time: 46 h

Procedure:
2-Octadecyl-4,7,3a,7a-tetrahydroisoindole-1,3-dione (5.00 g) was suspended into a mixture of 2-propanol (90 ml) and water (15 ml) and then sodium borohydride (2.34 g) was added thereto. After being stirred for 46 hours at room temperature, the reaction mixture was acidified with dilute hydrochloric acid and then concentrated. The residue was, with chloroform added thereto, washed with dilute hydrochloric acid, water and saturated sodium hydrogencarbonate aqueous solution successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 80 g, chloroform:methanol=50:1-10:1), thereby yielding the entitled compound (4.32 g) as white crystals.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:27])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:27])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reaction time: 0.75 h

Procedure:
A solution of tert-butyl{1-[2-(7-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 141, 240 mg, 0.62 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (15 mL). After 45 minutes, the reaction was concentrated to dryness, the residue taken up in methanol/chloroform (15:85, 30 mL) and washed with saturated sodium bicarbonate solution. The aqueous layer was re-extracted with methanol/chloroform (15:85, 3×30 mL. The combined organic phases were dried over magnesium sulfate and concentrated to dryness to give 170 mg (quantitative) of the crude product as an oil.
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:33])([CH3:32])[C@H:10]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[NH2:31])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[Cl:35][CH2:36][C:37](=N)OCC>ClCCCl>[Si:1]([O:8][C:9]([CH3:33])([CH3:32])[C@H:10]([N:20]1[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:31]=[C:37]1[CH2:36][Cl:35])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c(N)cnc2ccccc12
Reactant: CCOC(=N)CCl
Agent: Cl
Solvent: ClCCCl
Product: CC(C)(O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 70 °C
Yield: 25.4 %

Procedure:
N4-[(1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylpropyl]quinoline-3,4-diamine (6.12 g, 12.5 mmol) was dissolved in 100 mL of dry 1,2-dichloroethane and the solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (2.77 g, 17.5 mmol) was then added and the reaction mixture was heated to 70° C. After stirring for 3 days, the reaction mixture was treated with an additional 1.00 g of ethyl 2-chloroethanimidoate hydrochloride and the reaction temperature was increased to 85° C. After stirring for 2 days, the reaction was cooled and the 1,2-dichloroethane was removed under reduced pressure. The resulting material was partitioned between 200 mL of saturated NaHCO3 solution and 200 mL of ethyl acetate. The layers were separated and the organic portion was washed with H2O and brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 25%-50% ethyl acetate/hexanes) gave 1-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylpropyl]-2-(chloromethyl)-1H-imidazo[4,5-c]quinoline (1.74 g) as a golden syrup.
Reaction SMILES: C1C2NC3C(=CC=CC=3)SC=2C=CC=1C(O)=[O:16].[C:18]([N:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][CH2:24][C:23]2[CH:32]=[CH:33][C:34]([C:36](=[O:38])C)=[CH:35][C:22]1=2)(=[O:20])[CH3:19]>>[C:18]([N:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][CH2:24][C:23]2[CH:32]=[CH:33][C:34]([C:36]([OH:16])=[O:38])=[CH:35][C:22]1=2)(=[O:20])[CH3:19]
Reactant: O=C(O)c1ccc2c(c1)Nc1ccccc1S2
Reactant: CC(=O)c1ccc2c(c1)N(C(C)=O)c1ccccc1CC2
Product: CC(=O)N1c2ccccc2CCc2ccc(C(=O)O)cc21
Yield: 62 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of intermediate 1.10, using 1-(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)ethanone (J. Chem. Soc. 1973, 859-863) as starting product. A pale yellow solid is obtained with a yield of 62%. Melting point: 189-189.5° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[S:47](Cl)(=[O:49])=[O:48])#[N:40]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][S:47]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[C:39]#[N:40])(=[O:49])=[O:48])[CH:29]=3
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1S(=O)(=O)Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Yield: 27 %

Procedure:
The desired compound was prepared according to the procedure of Example B136, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and -cyanobenzenesulfonyl chloride as the starting materials in 27% yield. LCMS for C25H20ClN6O2S (M+H)+: m/z=503.1.
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.[C:12]1([C@@H:18]([NH:20][C:21]2[N:26]=[C:25](Cl)[CH:24]=[C:23]([Cl:28])[N:22]=2)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[C:12]1([C@@H:18]([NH:20][C:21]2[N:26]=[C:25]([N:3]3[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[N:5]=[CH:4]3)[CH:24]=[C:23]([Cl:28])[N:22]=2)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccccc1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Nc1nc(Cl)cc(-n2cnc3ccccc32)n1)c1ccccc1
Temperature: 0 °C
Yield: 61.4 %

Procedure:
To a suspension of NaH (74 mg) in DMF (5 mL) at 0° C. was added benzimidazole (204 mg). The reaction mixture was stirred at 0° C. until gas evolution ceased, then stirred at room temperature until the mixture became homogeneous (ca. 10 min.). A solution of 2-[(S)-1-phenylethylamino]-4,6-dichloropyrimidine (412 mg) in DMF (2 mL) was added to the mixture, which was then placed in 100° C. oil bath for 1 h. The reaction mixture was cooled and carefully quenched with water. The layers were separated, and the aqueous layer was extracted CH2Cl2 (2×15 mL). Combined organic layers was washed with water and brine and dried over anhydrous Na2SO4. The solvent was concentrated under reduced pressure, and the crude product was purified by flash chromatography (1:5 EtOAc:hexanes) to give 330 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.21 (br s, 1H); 7.82 (d, J=7.5 Hz, 1H); 7.75 (br s, 1H); 7.45-7.28 (m, 7H); 6.8 (s, 1H); 5.92 (br s, 1H); 5.2 (br s, 1H); 1.62 (d, J=7.1 Hz, 3H). Mass spectrum (CI) 350.2 (M+1).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:14]([F:13])([F:22])[F:23])=[CH:16][CH:17]=1)=[O:11]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a solution of 1H-benzo[d][1,3]oxazine-2,4-dione (1.63 g, 10.0 mmol) in anhydrous DMF (20 mL) was added 4-trifluoromethyl-aniline (1.61 g, 10.0 mmol) and the reaction mixture was stirred at 115° C. for 16 hours. It was then cooled to room temperature, diluted with ethyl acetate (150 mL), and the organic phase was washed with water (100 mL), 10% aq. NaOH solution (100 mL), water (150 mL), brine (150 mL), and dried over anhydrous Na2SO4. Solvent was evaporated and the crude compound was purified by the Simpliflash system (20% ethyl acetate in hexanes as eluent) to give 2-amino-N-(4-trifluoromethyl-phenyl)-benzamide as an off-white solid. Yield: 0.2 g (7%).
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[C:33]([F:36])([F:35])[F:34])[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].[F:37][C:38]1[CH:47]=[CH:46][C:41]([C:42](=O)[CH2:43]Br)=[CH:40][CH:39]=1>>[F:35][C:33]([F:34])([F:36])[C:24]1[CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=[CH:28][C:23]=1[CH2:22][N:4]([C:2]1[S:3][CH:43]=[C:42]([C:41]2[CH:46]=[CH:47][C:38]([F:37])=[CH:39][CH:40]=2)[N:1]=1)[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([OH:15])=[O:14])=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(N)=S)cc1
Reactant: O=C(CBr)c1ccc(F)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2nc(-c3ccc(F)cc3)cs2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 4-fluorophenacyl bromide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[CH:14][C:15](OCC)=[O:16])[C:8]=1[N+:20]([O-])=O)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:8]=1[NH:20][C:15](=[O:16])[CH2:14][CH2:13]2)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(C=CC(=O)OCC)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cccc2c1NC(=O)CC2

Procedure:
A solution of 2-nitro-1,3-benzenediacrylic acid diethyl ester (3.5 g, 0.011 mole) in absolute ethanol (100 ml) is treated with hydrogen at 1 atmosphere pressure for 12 hours in the presence of 20% Pd/C. The mixture is filtered and concentrated at reduced pressure to yield 1,2,3,4-tetrahydro-2-oxo-8-quinolinepropanoic acid ethyl ester, mp 102°-103° C.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:15]([CH3:16])[C@@H:14]2[C@:5]3([CH2:19][CH2:18][NH:17][C@@H:13]2[CH2:12][C:11]2[CH:10]=[CH:9][C:8]([O:20][CH3:21])=[C:7]([OH:22])[C:6]3=2)[CH2:4][C:3]1=[O:23].C([O-])(O)=O.[Na+].[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1.[ClH:34]>CN(C=O)C.C(O)C>[ClH:34].[CH:29]1([CH2:32][N:17]2[CH2:18][CH2:19][C@@:5]34[C:6]5[C:7]([OH:22])=[C:8]([O:20][CH3:21])[CH:9]=[CH:10][C:11]=5[CH2:12][C@@H:13]2[C@@H:14]3[C@@H:15]([CH3:16])[C@H:2]([CH3:1])[C:3](=[O:23])[CH2:4]4)[CH2:31][CH2:30]1
Reactant: COc1ccc2c(c1O)[C@]13CCN[C@H](C2)[C@@H]1[C@@H](C)[C@H](C)C(=O)C3
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc2c(c1O)[C@]13CCN(CC4CC4)[C@H](C2)[C@@H]1[C@@H](C)[C@H](C)C(=O)C3
Yield: 90 %

Procedure:
A mixture of 18b (7.20 g, 22.8 mmole), NaHCO3 (3.84 g, 45.7 mmole) and cyclopropylmethyl bromide (3.70 g, 27.4 mmole) in DMF (100 ml) was heated at 100° under argon for 2.5 hours. The mixture was processed as described for 19a-CPM to give 8.31 g (99%) of 19b-CPM as a foam. NMR: δ 6.90 (aromatic); 6.35, broad s, 1H (hydroxyl proton); 4.23 (H-5α); 3.78 (CH3O--); 1.10, unsymmetrical d, (8β-CH3, J=5 Hz); 0.92 symmetrical d, (7α-CH3, J=6 Hz). The foam was converted to the HCl salt by dissolving the free base in ethanol, adding an excess of concentrated HCl followed by evaporation to dryness. The residue was azeotroped with 1:1 ethanol-toluene, then toluene and finally crystallized from acetone to give 8.24 g (90%) of 19b-CPM.HCl, mp 194°-195°. Recrystallization from acetone gave an analytical sample of 19b-CPM.HCl as the hemi-acetone solvate. The presence of acetone was confirmed by the nmr of 19b-CMP.HCl taken in DMSO-d6.
Reaction SMILES: Cl.Cl.[CH2:3]([NH2:8])[CH2:4][CH2:5][CH2:6][NH2:7].CN(C=O)C.[C:14](Cl)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[OH-].[Na+]>O>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:8][C:14](=[O:15])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: NCCCCNC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 46.3 %

Procedure:
1,4-butanediamine dihydrochloride (5.96 g, 37 mmol) was dissolved in water (15 mL), and DMF (50 mL) was added. With rapid stirring, CBZ-Cl (1.0 mL, 7.0 mmol) was added dropwise over 2 minutes. The cloudy solution had pH~2.8. The pH was adjusted to 9.0 with 5 N NaOH, (clear solution) and stirred for 2 hr. 10 The reaction mixture was acidified to pH=1.25, extracted with ether (2 X), made basic (pH>10) with 5 N NaOH, and extracted with dichloromethane (2 X). The dichloromethane fractions were combined and washed with water (2 X), dried and evaporated in vacuo to provide the crude mono-CBZ amine (0.72 g, 3.24 mmol, 46%) which was used as is in the next step.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[NH:17]1[CH:21]=[CH:20][CH:19]=[N:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:2][C:11]2[CH:6]=[CH:7][C:8]([N:17]3[CH:21]=[CH:20][CH:19]=[N:18]3)=[CH:9][CH:10]=2)[N:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1n[nH]c2ccccc2c1=O
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 4-oxo-1,4-dihydrocinnoline-3-carboxylate (427 mg, 1.96 mmol) was dissolved in degassed N,N-dimethylformamide (5 mL) and treated with 1-[4-bromomethyl)phenyl]-1H-pyrazole (510 mg, 2.15 mmol, 1.1 equiv) and potassium carbonate (325 mg, 2.35 mmol, 1.2 equiv). The mixture was stirred under nitrogen at ambient temperature for 18 hours and then partitioned between water and ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gradient gel chromatography (100:0 to 90:10; chloroform:methanol), providing the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:11]([NH:15][C:8]([C:5]1[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:10])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccc(Cl)nn1
Reactant: CC(C)(C)N
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(Cl)nn1
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a solution of 6-chloro-3-pyridazinecarboxylic acid (0.12 g, 0.76 mmol) in methylene chloride (15 ml) were added t-butylamine (0.21 ml, 2.0 mmol) and N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.24 g, 0.93 mmol), and stirred overnight. The reaction mixture was added to saturated aqueous NaHCO3 and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (0.080 g; 49%).