Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH:22]4[CH2:27][CH2:26][CH:25]([C:28]([CH3:32])([CH3:31])[CH2:29][CH3:30])[CH2:24][CH2:23]4)[CH:17]=3)[N:12]=2)[CH2:6]1)=[O:4].CO.O1CCCC1.[OH-].[Li+].O>>[CH3:32][C:28]([CH:25]1[CH2:24][CH2:23][CH:22]([O:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([CH2:10][N:7]2[CH2:8][CH2:9][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]2)[N:20]=[CH:19]3)[CH2:27][CH2:26]1)([CH3:31])[CH2:29][CH3:30]
Reactant: CCC(C)(C)C1CCC(Oc2ccc3nc(CN4CCC(C(=O)OC)C4)ncc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCC(C)(C)C1CCC(Oc2ccc3nc(CN4CCC(C(=O)O)C4)ncc3c2)CC1
Yield: 90 %

Procedure:
1-{6-[4-(1,1-Dimethyl-propyl)-cyclohexyloxy]-quinazolin-2-ylmethyl}-pyrrolidine-3-carboxylic acid methyl ester (229.50 mg, 5.2208E-4 mol) was dissolved in Methanol (5 mL, 0.1 mol) and Tetrahydrofuran (5 mL, 0.06 mol), followed by 2 M of Lithium hydroxide in Water (2 mL, 0.004 mol) at at 23° C. for 10 minutes. Excess of solvents were removed under vacuum, and the solid residue was treated with HCl (2N, 3 mL), and extracted with DCM (20×3 mL). The organic layers were dried over Na2SO4. Removal of solvent gave a pure product (200 mg, 90%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.69-0.94 (m, 12H) 1.13-1.37 (m, 10H) 1.39-1.59 (m, 2H) 1.76-1.96 (m, 3H) 2.18-2.37 (m, 2H) 4.84 (br. s., 1H) 7.16-7.38 (m, 2H) 7.55-7.71 (m, 1H) 7.99 (br. s., 1H) MS (ESI, M+1): 426.30.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C:8]([NH:22]S(C(C)(C)C)=O)([C:10]([F:21])([F:20])[CH2:11][O:12][Si](C(C)(C)C)(C)C)[CH3:9])[CH:7]=1>CO.Cl>[NH2:22][C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:29])([CH3:9])[C:10]([F:20])([F:21])[CH2:11][OH:12]
Reactant: CC(C)(C)S(=O)NC(C)(c1cc(Br)ccc1F)C(F)(F)CO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(N)(c1cc(Br)ccc1F)C(F)(F)CO

Procedure:
To a solution of N-(2-(5-bromo-2-fluorophenyl)-4-(tert-butyldimethylsilyloxy)-3,3-difluorobutan-2-yl)-2-methylpropane-2-sulfinamide (8.8 g, 17.08 mmol) in dry MeOH (60 mL), dry HCl gas was purged for 30 min at −22° C. Reaction mixture was concentrated under reduced pressure and basified with NH4OH solution under cooling. Product was extracted with dichloromethane, washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to furnish title compound as a color less thick liquid. Yield=4.4 g (88%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([S:16][C:17]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[S:19][C:18]=1[C:26](O)=O)[CH3:15].CCN=C=NCCCN(C)C.Cl.N1C=CC=CC=1>C1C=CC2N(O)N=NC=2C=1.O>[CH2:14]([S:16][C:17]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[S:19][C:18]=1[C:26]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1)[CH3:15]
Reactant: CCSc1cc(C(F)(F)F)sc1C(=O)O
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CCSc1cc(C(F)(F)F)sc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 80 °C
Reaction time: 6 h
Yield: 116.2 %

Procedure:
A mixture of 0.12 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 0.2 g of 3-ethylthio-5-trifluoromethylthiophene-2-carboxylic acid, 0.15 g of EDCI hydrochloride, 9 mg of HOBt and 3 ml of pyridine was stirred at 80° C. for 6 hours. Water was poured into the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure and applied to a silica gel column chromatography to obtain 0.3 g of 2-(3-ethylthio-5-trifluoromethylthiophen-2-yl)-3-methyl-6-t rifluoromethyl-3H-imidazo[4,5,b]pyridine (Compound of Present Invention (5)).
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][N:26]=2)=[N:20][C:19]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][C:38]=2[C:39]#[N:40])=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:16]1[N:17]=[CH:18][C:19]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][C:38]=2[C:39]#[N:40])=[N:20][C:21]=1[C:22]1[O:23][C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:25][N:26]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnccc2C#N)nc1-c1nnc(-c2ccccc2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccncc1-c1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
tert-Butyl N-tert-butoxycarbonyl-N-[5-(4-cyano-3-pyridyl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]carbamate (140 mg, 0.2585 mmol) in dichloromethane (2 mL) was treated with TFA (2 mL, 25.96 mmol) and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, re-dissolved in MeOH/DCM and concentrated (2×), dissolved MeOH/DCM and passed through bicarbonate cartridge, concentrated under reduced pressure to give a yellow solid. The solid was triturated with acetonitrile and filtered to give yellow solid (83 mg, 94%); 1H NMR (400.0 MHz, DMSO) d 7.69-7.77 (m, 3H), 8.07 (d, 1H), 8.24-8.26 (m, 2H), 7.80-8.40 (br s, 2H), 8.90 (d, 1H), 9.09 (s, 1H) and 9.47 (s, 1H) ppm; MS (ES+) 342.16
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:49][O:50][CH2:51][CH2:52][NH2:53]>>[F:1][C:2]1[CH:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:3]=1[C:4]([NH:53][CH2:52][CH2:51][O:50][CH3:49])=[O:6]
Reactant: CNc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(F)c(C(=O)NCCOC)cc1[N+](=O)[O-]

Procedure:
2-Fluoro-N-(2-methoxy-ethyl)-4-methylamino-5-nitro-benzamide was prepared by following General Procedure F starting from 2-fluoro-4-methylamino-5-nitro-benzoic acid (75 mg), HBTU (159 mg), DIEA (92 uL), and 2-methoxyethylamine (26 mg). The crude product was used directly in the next step without further purification.
Reaction SMILES: [N+]([O-])(O)=[O:2].[CH3:5][C:6]1([CH3:15])[CH2:11][CH2:10][CH2:9][CH:8]([CH3:12])[CH:7]1[CH:13]=[O:14].C1(C)C=CC=CC=1>O>[CH3:15][C:6]1([CH3:5])[CH2:11][CH2:10][CH2:9][CH:8]([CH3:12])[CH:7]1[C:13]([OH:2])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CC1CCCC(C)(C)C1C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CCCC(C)(C)C1C(=O)O
Temperature: 55 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
In a 300-ml 4-necked flask equipped with a condenser, a thermometer, a dropping funnel, and a stirrer was placed 39 g of nitric acid (60% aqueous solution) and heated to 55° C. To the solution was added dropwise 93 g (0.60 mole) of 2,2,6-trimethylcyclohexanecarbaldehyde (4) composed of 35% of the trans-form and 65% of the cis-form synthesized in Synthesis Example 1-A) described above over a period of 2 hours. Thereafter, the reaction was carried out for 3 hours at the same temperature. Then, 100 g of toluene and 100 g of water were added to the reaction mixture at room temperature to wash with water and form an organic layer and an aqueous layer separately. The organic layer was washed thrice with 100 g of a saturated aqueous sodium chloride solution, and the toluene was distilled off under reduced pressure by means of an evaporator, to provide 101 g of crude 2,2,6-trimethylcyclohexanecarboxylic acid (5) composed of 35% of the trans-form and 65% of the cis-form.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20].C(O)C>CC(C)=O>[I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C=O)cc(I)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(I)cc(C=O)cc1OC
Yield: 48.8 %

Procedure:
The compound was prepared according to general procedure E with 5-iodovanillin (1.8 mmol) in dry acetone (25 ml), anhydrous K2CO3 (2.4 mmol), and ethylbromoacetate (2.7 mmol) at reflux for 1 h15. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate. 673 mg of crude product were obtained and purified by silica gel chromatography (eluent dichloromethane). 320 mg of purified compound were obtained (49% yield). 1H NMR (250 MHz, CD3COCD3): δ 1.28 (t, J=7.2 Hz, 3H), 3.97 (s, 3H), 4.23 (q, J=7.2 Hz, 2H), 4.85 (s, 2H), 7.55 (s, 1H), 7.95 (s, 1H), 9.90 (s, 1H) 13C NMR (126 MHz, CD3COCD3): δ 15.2, 57.4, 62.1, 70.5, 92.4, 113.9, 135.1, 135.5, 153.1, 169.4, 191.1. MS (ESI): m/z 364.9 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>O1CCCC1.O>[O:29]1[CH2:30][CH2:31][N:26]([CH2:2][C:3](=[O:25])[C@@H:4]2[C@:21]3([CH3:22])[C@H:7]([C@H:8]4[C@H:18]([C:19](=[O:23])[CH2:20]3)[C@:16]3([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]3)[CH2:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:27][CH2:28]1
Reactant: C1COCCN1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCl)[C@@]3(C)CC(=O)[C@@H]12
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 72 h

Procedure:
21-Chloro-5α-pregnane-3,11,20-trione (200 mg.) in dry tetrahydrofuran (4 ml.) was treated with morpholine (0.20 ml.), and the solution was refluxed for 21/2 hours, and then left at room temperature for 3 days. The solution was diluted with water and extracted with chloroform. The organic solution was washed with water, dried over sodium sulphate and evaporated to a white foam (210 mg.), which was purified by preparative TLC in ethyl acetate to give 21-morpholino-5α-pregnane-3,11,20-trione (88 mg.) as a white foam, [α]D + 99°, (c 0.59). Treatment of this product in similar manner to that described in Example 50 gave title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[CH:24]1([NH:23][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:6]4[O:7][C:3]([CH2:2][NH:1][S:28]([CH3:27])(=[O:30])=[O:29])=[N:4][N:5]=4)=[CH:13][CH:12]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNS(C)(=O)=O)o2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4′-[5-Aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg) was mixed with methanesulphonyl chloride (0.02 ml) and pyridine (0.034 ml) in DCm (3 ml) and the reaction stirred at room temperature for 18 hours. The reaction was washed with water (4×4 ml) and then hydrochloric acid (2N, 5 ml). The organic phase was reduced to dryness under vacuum and the residue purified by HPLC to give after evaporation of the solvents N-cyclopropyl-6-methyl-4′-5-{[(methylsulfonyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5](=[O:30])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)=[O:8])C.[Li+].[OH-]>C1COCC1>[CH2:23]([N:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:10]=[C:9]([C:7](=[O:8])[CH2:6][C:5](=[O:30])[C:4]([OH:31])=[O:3])[CH:14]=[CH:13][CH:12]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(N(Cc2ccccc2)Cc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(=O)CC(=O)c1cccc(N(Cc2ccccc2)Cc2ccccc2)c1

Procedure:
In a similar manner to example AI-2-1, 4-(3-dibenzylaminophenyl)-2,4-dioxobutanoic acid ethyl ester (0.489 g, 1.1 mmol) was reacted with 3 ml 1N LiOH in 10 ml THF to yield 0.4 g (94%) of AV-3-1 as an orange resin. 1H NMR (400 MHz, CDCl3) δ4.71 (s, 4H), 6.96 (dt, 1H, J=7.33, 2.20 Hz).
Reaction SMILES: [C:1](=[O:25])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:24])[CH:8]=[C:9]([CH:20]=[N:21][O:22][CH3:23])[CH:10]=2)[NH2:2]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:4]([O:24][C:7]1[CH:8]=[C:9]([CH:20]=[N:21][O:22][CH3:23])[CH:10]=[C:11]2[C:6]=1[CH:5]([CH2:4][O:3][C:1](=[O:25])[NH2:2])[C:17]1([O:19][C:17](=[O:18])[CH3:16])[O:18][N:12]2[CH2:13][CH:14]2[CH:16]1[N:15]2[C:7](=[O:24])[CH3:6])(=[O:3])[CH3:5]
Reactant: CON=Cc1cc(O)c2c(c1)N1CC3NC3C(O)(O1)C2COC(N)=O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CON=Cc1cc(OC(C)=O)c2c(c1)N1CC3C(N3C(C)=O)C(OC(C)=O)(O1)C2COC(N)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 165.8 %

Procedure:
6,9-Dihydroxy-4-methoxyiminomethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (55 mg) was dissolved in a mixture of pyridine (3 ml) and acetic anhydride (1.5 ml) and stirred for 12 hours at ambient temperature. The mixture was evaporated in vacuo and subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (20:1, v/v) to afford 11-acetyl-8-carbamoyloxymethyl-4-methoxyiminomethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (62 mg).
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[Br-].[C:22]12([Zn+])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2.N>O1CCCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].[Cu]I>[C:22]12([C:2]3[C:3](=[O:20])[N:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:7]=3)[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2
Reactant: [Zn+]C12CC3CC(CC(C3)C1)C2
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe]
Solvent: C1CCOC1
Product: O=c1c(C23CC4CC(CC(C4)C2)C3)cc(-c2ccccn2)cn1-c1ccccc1
Reaction time: 8 h

Procedure:
40 mg of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 10 ml of tetrahydrofuran. To the mixture were added 5 mg of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and 1.2 mg of copper(I) iodide. While stirring the mixture at room temperature in nitrogen atmosphere overnight, 0.4 ml of 1-adamantyl zinc bromide (0.5M tetrahydrofuran solution) was added dropwise thereinto. After stirring in nitrogen atmosphere overnight, an aqueous ammonia was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 12 mg of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Cl:21][CH2:22][C:23](Cl)=[O:24]>CC(C)=O.O.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:23](=[O:24])[CH2:22][Cl:21])[CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: OCC1CN(Cc2ccccc2)CCN1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(CCl)N1CCN(Cc2ccccc2)CC1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a stirred solution of (4-benzyl-piperazin-2-yl)methanol (500 mg, 2.42 mmol) and sodium acetate (397.6 mg, 4.85 mmol, 2.0 eq) in acetone (9.7 mL) and water (24.2 mL) under N2 at 0° C. was added dropwise chloroacetyl chloride (0.20 mL, 2.54 mmol, 1.05 eq) over 5 minutes. The mixture was stirred at 0° C. for 5 min and at rt for 1 h. The mixture was diluted with EtOAc (150 mL) and the organic phase was washed with water, aqueous saturated NaHCO3 solution, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 680 mg (99%) of the desired product as an oil. 1H-NMR (300 MHz, CD3OD) δ 7.32 to 7.23 (m, 5H), 4.51 (d, 1H), 4.32 to 3.98 (m, 4H), 3.82 to 3.73 (m, 1H), 3.62 to 3.42 (m, 3H), 3.06 to 3.00 (m, 1H), 2.91 to 2.82 (m, 2H), 2.25 to 1.98 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C@@H:10]2[CH2:18][N:13]3[CH2:14][CH2:15][NH:16][CH2:17][C@@H:12]3[CH2:11]2)[N:4]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1>CS(C)=O>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([N:16]2[CH2:15][CH2:14][N:13]3[CH2:18][C@@H:10]([NH:9][C:5]4[N:4]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:8]=[CH:7][N:6]=4)[CH2:11][C@H:12]3[CH2:17]2)=[N:29][CH:30]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: FC(F)(F)c1ccnc(N[C@H]2C[C@H]3CNCCN3C2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: FC(F)(F)c1ccnc(N[C@H]2C[C@H]3CN(c4ccc(Cl)cn4)CCN3C2)n1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a solution of Example 33 (115 mg, 0.4 mmol) and sodium carbonate (72 mg, 0.68 mmol) in dimethyl sulfoxide (0.5 mL) was added 2,5-dichloropyridine (95 mg, 0.64 mmol). The mixture was stirred at 100° C. for 2 days. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=15:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (m, 1H), 2.00-2.15 (m, 2H), 2.30-2.40 (m, 2H), 2.60 (m, 1H), 2.88-3.00 (m, 3H), 4.20-4.40 (m, 3H), 6.89 (d, 1H, J=7 Hz), 6.98 (m, 1H), 7.58 (d, 1H, J=7 Hz), 8.04 (m, 1H), 8.06 (s, 1H), 8.60 (m, 1H); MS (ESI) m/z 399 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)(=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][O:17][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:4]=1[Cl:16])(=[O:20])[CH3:19]
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: CC(=O)OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Yield: 92.9 %

Procedure:
This compound was prepared in a manner analogous to that set forth in Step B of Example 1, using 25 grams (0.093 mole) of 2,6-dichloro-4-phenylmethoxyphenol (known compound), 19.5 grams (0.10 mole) of 4-bromobutyl acetate and 19.4 grams (0.14 mole) of potassium carbonate in 400 mL of DMF, differing in that the reaction mixture was warmed to 80 C., where it was maintained prior to work-up. The crude reaction product was purified with column chromatography on silica gel using 1:1 methylene chloride:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 33.1 grams of compound the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH:11][C:12]2[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:3][CH2:2]1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>>[Cl:23][CH2:24][C:25]([NH:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:12]([NH:11][CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[O:1][CH2:2][CH2:3]3)[O:13][CH2:14][C:15]=2[CH:21]=1)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc2c(c1)COC(NC1CCOc3ccccc31)=N2
Product: O=C(CCl)Nc1ccc2c(c1)COC(NC1CCOc3ccccc31)=N2
Yield: 83.1 %

Procedure:
Prepared from rac-N2-chroman-4-yl-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 75) (591 mg, 2.0 mmol) and chloroacetyl chloride (167 ul, 2.1 mmol) according to the procedure described for Example 3 step A. Obtained the title compound as an off-white solid (618 mg, 83%), MS (ISP) m/e=372.1 [(M+H)+] and 374 [(M+2+H)+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([CH2:21][CH2:22][CH3:23])([CH3:20])[NH:5][S:6]([NH:9]C(OCC1C=CC=CC=1)=O)(=[O:8])=[O:7]>[Pd].CO>[CH3:1][O:2][C:3](=[O:24])[C:4]([CH2:21][CH2:22][CH3:23])([CH3:20])[NH:5][S:6]([NH2:9])(=[O:7])=[O:8]
Reactant: CCCC(C)(NS(=O)(=O)NC(=O)OCc1ccccc1)C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCCC(C)(NS(N)(=O)=O)C(=O)OC
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
A mixture of N-(carbobenzyloxyaminosulfonyl)-2-propyl-DL-alanine methyl ester (22.35 g, 62.36 mmol), methanol (200 mL) and 10% palladium on Carbon (1.0 g) was placed on a Parr hydrogenator at 60 psi for 1.5 hours. The reaction mixture was passed through a pad of CELITE®, and the filtrate was concentrated in vacuo to afford 11.16 g (79.8%) of N-aminosulfonyl-2-propyl-DL-alanine methyl ester (Formula VII: R=CH3 ; R1 =propyl; R2 =CH3; R3 =H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:12]([O:15][C:16](=O)[CH3:17])(=O)C>>[CH3:12][O:15][CH2:16][C:17]1[N:10]([CH3:11])[C:8](=[O:9])[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=1
Reactant: CNC(=O)c1nccnc1N
Reactant: CC(=O)OC(C)=O
Product: COCc1nc2nccnc2c(=O)n1C

Procedure:
A mixture of 7.8 g (0.0513 mole) of 3-amino-N-methyl-2-pyrazinecarboxamide [prepared according to W. F. Keir et al., J. Chem. Soc., Perkin Trans 1, 1978, 1002], 39.4 g (0.205 mole) of triethyl orthomethoxyacetate and 45.3 ml of acetic anhydride is refluxed under a nitrogen atmosphere for 3 days. The temperature of this reflux falls with the passage of time from 114° to 90° C. and then remains constant at the latter temperature. After cooling, the reaction mixture is concentrated to dryness under reduced pressure. The residue obtained is purified by chromatography on a silica column (eluant: chloroform/methanol, 95:5 and then 90:10), and is then recrystallized from ethyl acetate. Yld: 5.0 g (47%), m.p. 130.5°-132.5° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:32])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH2:23][O:24][CH3:25])[CH:17]=[C:16]([C:26]([O:28]CC)=[O:27])[C:15]3=[O:31])=[CH:8][CH:7]=1)[CH3:2].[OH-].[Na+].C(O)C>O1CCCC1>[CH2:1]([NH:3][C:4](=[O:32])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH2:23][O:24][CH3:25])[CH:17]=[C:16]([C:26]([OH:28])=[O:27])[C:15]3=[O:31])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CCOC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCNC(=O)Nc1ccc(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3CCOC)cn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A suspension of ethyl 6-(6-(3-ethylureido)pyridin-3-yl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 42, 59 mg, 0.13 mmol) and sodium hydroxide (0.202 mL, 0.40 mmol) in tetrahydrofuran (1 mL) was heated to 60° C. After 2 h, the reaction was not yet complete. Ethanol (2 mL) was added and the reaction was heated for another 1 h, then cooled to room temperature and concentrated under reduced pressure. The resulting solid was dissolved in water and acidified to pH 4 with 10% HCl. The solid that formed was collected by filtration and placed under high vacuum to remove residual water. MS (ESP): 411 (M+H+) for C21H22N4O5; NMR: 1.11 (t, J=6 Hz, 3H), 3.20 (m, 2H), 3.23 (s, 3H), 3.74 (m, 2H), 4.83 (m, 2H), 7.50 (m, 1H), 8.01 (br s, 1H), 8.21 (m, 1H), 8.31 (m, 1H), 8.58 (m, 1H), 8.69 (m, 1H), 8.94 (s, 1H), 9.38 (s, 1H), 15.20 (s, 1H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=O.[BH4-].[Na+]>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[CH2:6][CH:5]([CH2:3][OH:2])[CH2:9][C:8]2=[O:10])=[CH:12][CH:13]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3ccccc3)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CC(CO)CN1c1ccc(OCc2ccccc2)cc1

Procedure:
The title compound is prepared in analogy to Example 33a) from (RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester and sodium borohydride. Yield: 82% of a colorless solid. MS: m/e=298.3 (M+H)+.