Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[C:30]([F:31])=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[OH:35]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:35][C:26]3[C:27]([F:34])=[C:28]([F:33])[C:29]([F:32])=[C:30]([F:31])[C:25]=3[F:24])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(Oc3c(F)c(F)c(F)c(F)c3F)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0.613 mmol) and 2,3,4,5,6-pentafluorophenol were reacted as starting materials at 150° C. for 24 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless amorphous solid (175.6 mg, 60.5%).
Reaction SMILES: C([N:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)[C:9](=[O:11])[O-:10])C1C=CC=CC=1.[CH3:21][O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[C:27]([CH3:34])[CH:26]=1)=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([O:10][C:9]([NH:8][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:28]2[CH:29]=[CH:30][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:26][C:27]=2[CH3:34])=[CH:18][CH:19]=1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C([O-])N(CCc1ccc(Br)cc1)Cc1ccccc1
Reactant: COC(=O)c1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccc(CCNC(=O)OCc3ccccc3)cc2)c(C)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a solution of N-benzyl-N-[2-(4-bromophenyl)ethyl]-carbamate (1.3 g) in 1,2-dimethoxyethane (20 ml) was added [4-(methoxycarbonyl)-2-methylphenyl]boronic acid (792 mg), tetrakis(triphenylphosphine)palladium (360 mg) and aqueous solution of sodium carbonate (2M, 4.1 ml), and the mixture was stirred at 80° C. for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 4′-[2-[[(benzyloxy)carbonyl]amino]ethyl]-2-methyl-1,1′-biphenyl-4-carboxylate (660 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:14])[CH2:7][C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])[CH3:4].C([Li])CCC.[CH:20]1([C:23]2[C:32]([CH:33]=[O:34])=[C:31]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH2:22][CH2:21]1>C(OCC)(=O)C.CCCCCC.C1(C)C=CC=CC=1.C(O)(=O)C.O1CCCC1>[CH2:3]([O:5][C:6](=[O:14])[CH2:7][C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH2:11][CH:33]([C:32]1[C:23]([CH:20]2[CH2:21][CH2:22]2)=[N:24][C:25]2[C:30]([C:31]=1[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:34])[CH3:4]
Reactant: CCOC(=O)CC(=O)CC(C)=O
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)CC(=O)CC(O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Yield: 89.2 %

Procedure:
In a mixture solution of 2.40 g of an oily 60% sodium hydride and 200 ml of tetrahydrofuran, a mixture solution of 10.3 g of 3,5-dioxohexanoic acid ethyl ester and 40 ml of tetrahydrofuran was dropped in 20 minutes while keeping an inner temperature at 2° C. or less. After allowing a reaction for 50 minutes at −10° C., 75 ml of a hexane solution of 1.6 M n-butyl lithium was dropped in 40 minutes with the inner temperature kept at −20 to −15° C., while allowing a reaction for 40 minutes at an inner temperature of 2° C. or less. In this case, furthermore, while keeping an inner temperature of −15° C. or less, a mixture of 11.7 g of 2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-carbaldehyde and 80 ml of tetrahydrofuran was dropped in 40 minutes and was then reacted at 10° C. or less for 1 hour. Furthermore, while keeping an inner temperature of 5° C. or less, 14.4 ml of acetic acid and 40 ml of toluene were added in a reaction system, followed by washing with 100 ml of water and 100 ml of saturated brine in that order. After the solvent is distilled off, the residue thus obtained was added with 100 ml of hexane and 5 ml of ethyl acetate so as to be crystallized, followed by filtrating and drying it to obtain 16.6 g (yield: 89%) of 7-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-7-hydroxy-3,5-dioxoheptanoic acid ethyl ester was obtained.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Cl:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1>>[Cl:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N+:6]([O-:9])=[O:7])[N:12]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
69 ml of 96% sulfuric acid is carefully added in drops to 84 ml of 100% nitric acid. While being cooled with ice, 25 g (152 mmol) of 2-chloroquinoline is added thereto, and the batch is heated for 1 hour to 60° C. After cooling to room temperature, the batch is carefully incorporated into an ice/water mixture. After 15 minutes of stirring, the solid is washed with water and dried in a vacuum at 40° C. Column chromatography on silica gel with hexane-ethyl acetate yields 10.7 g of a white solid.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1.[OH-].[Li+]>O1CCCC1>[CH3:18][S:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:19])=[O:2])=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccnc1Oc1ccc(SC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSc1ccc(Oc2ncccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
2-(4-methylsulfanyl-phenoxy)-nicotinic acid methyl ester (10.36 g, 37.6 mmol) was dissolved in tetrahydrofuran (140 ml) and 1M aqueous lithium hydroxide solution (94 ml, 94 mmol) was added. The reaction was stirred at room temperature for 18 h and the tetrahydrofuran was removed under reduced pressure. The residue was acidified to pH1 with concentrated hydrochloric acid and the resulting precipitate was filtered, washed with water (2×10 ml), diethyether (3×10 ml) and dried in vacuo to give 2-(4-methylsulfanyl-phenoxy)-nicotinic acid (9.3 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[NH:12][C:13]([NH:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)=[O:14].CC1(C)C(C)(C)OB([C:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32]C=2)O1.CC1(C)C(C)(C)OB(C2CN(C(OC(C)(C)C)=O)CC=2)O1>>[C:39]([O:38][C:36]([N:33]1[CH2:32][CH:30]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[C:5]3[NH:12][C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH2:34]1)=[O:37])([CH3:40])([CH3:41])[CH3:42]
Reactant: O=C(Nc1cnccn1)Nc1ccnc2ccc(Br)cc12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)C1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3nccc(NC(=O)Nc4cnccn4)c3c2)C1

Procedure:
The title compound was prepared as described in example 27 step 2, substituting 1-(6-bromo-quinolin-4-yl)-3-(6-trifluoromethyl-pyridin-2-yl)-urea by 1-(6-bromoquinolin-4-yl)-3-(pyrazin-2-yl)urea (example 9, step 1) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate by tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate.
Reaction SMILES: C([BH3-])#N.[Na+].O=[C:6]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH2:22]([O:29][C:30]([CH:32]([N:34]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]([NH:41]C(C(OCC)=O)CCC2C=CC=CC=2)[C:35]1=[O:56])[CH3:33])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C.[Na+]>C(O)C>[CH2:22]([O:29][C:30]([CH:32]([N:34]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]([NH:41][CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:35]1=[O:56])[CH3:33])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)C(=O)CCc1ccccc1
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@H]1CCCCN(C(C)C(=O)OCc2ccccc2)C1=O
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C(=O)OCc1ccccc1)N1CCCC[C@H](NC(CCc2ccccc2)C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 490 mg sodium cyanoborohydride in 3 ml ethanol is added over 2.5 hrs to a solution of 2.43 g t-butyl 2-oxo-4-phenylbutyrate, 850 mg 1-(1-benzyloxycarbonylethyl)-3-(S)-aminoperhydroazepin-2-one hydrochloride (from Isomer A, Example 24) and 267 mg sodium acetate in 10 ml ethanol. The reaction is stirred at room temperature overnight, filtered and concentrated. The residue is partitioned between ethyl acetate and 5% sodium bicarbonate. After drying, concentration of the organic phase affords a residue which is chromatographed over silica gel with hexane-ethyl acetate (7:3) giving the pure diastereomers of 1-(1-benzyloxycarbonylethyl)-3-(S)-(1-t-butoxycarbonyl-3-phenylpropyl)aminoperhydroazepin-2-one.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Cl:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[C:20]2[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]([OH:38])=O)[CH2:32][CH2:31]2)=[O:29])=[CH:16][CH:15]=1.N1(O)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[N:60]1[CH:65]=[CH:64][C:63]([CH:66]([NH2:68])[CH3:67])=[CH:62][CH:61]=1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[C:20]2[C:28]([N:30]2[CH2:31][CH2:32][CH:33]([C:36]([NH:68][CH:66]([C:63]3[CH:64]=[CH:65][N:60]=[CH:61][CH:62]=3)[CH3:67])=[O:38])[CH2:34][CH2:35]2)=[O:29])=[CH:16][CH:15]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: CC(N)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(NC(=O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (259 mg, 1.350 mmol), 1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (428 mg, 1.080 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol (182 mg, 1.350 mmol) were dissolved in 4.0 mL of DCM. The reaction was stirred at room temperature for ten minutes before Hunig's Base (0.236 ml, 1.350 mmol) and 1-(4-pyridinyl)ethanamine as a 1.0 mL DCM solution was added. The reaction was allowed to stir at room temperature overnight. The reaction was diluted with water and ethyl acetate. The organic phase was washed with water, saturated sodium bicarbonate (twice), and saturated sodium chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated. The crude material was triturated with ether and ethyl acetate and filtered to obtain white solid as a product. (Yield: 37.9 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 8.52-8.45, 8.35, 7.62, 7.53, 7.36-7.30, 7.30-7.25, 7.24-7.18, 7.13-7.06, 6.72, 5.48, 4.87, 4.57-3.84, 2.93, 2.48-2.42, 1.71, 1.58-1.26
Reaction SMILES: [SH:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[C:5]([CH3:12])[C:3]=1[OH:4].[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1>CC(C)=O>[OH:10][C:7]1[C:6]([CH3:11])=[C:5]([CH3:12])[C:3]2[O:4][C:13]([CH3:18])([CH3:14])[S:1][C:2]=2[C:8]=1[CH3:9]
Reactant: Cc1c(C)c(O)c(S)c(C)c1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)SC(C)(C)O2
Yield: 7.7 %

Procedure:
A mixture of 4.8 g of 2-mercapto-3,5,6-trimethylhydroquinone, 1 g of p-toluenesulfonic acid, 10 g of molecular sieve 4A and 100 ml of acetone was heated under reflux for 5 hours under a stream of nitrogen. At the end of this time, the acetone was distilled off, and an aqueous solution of sodium bicarbonate was added to the residue. This mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled from the extract. Benzene was added to the resulting residue. Substances which were not soluble in benzene were filtered off, and crystals precipitating from the benzene solution were removed. The portion which was readily soluble in benzene was separated by silica gel column chromatography. The portion eluted with benzene was recrystallized from petroleum ether to yield 0.1 g of the title compound, melting at 62°-64.5° C. Mass spectrum (m/e): 224 (M+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:28]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:29]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:29][CH2:28][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:19]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCNC3)c2n1
Reactant: CC(I)C1CCCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCN(CCC4CCCCC4)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(3-piperidinyl)propyl]-9H-purin-6-amine and (1-iodoethyl)cyclohexane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12][CH2:11][N:10]1[C:18]([O:20][CH3:21])=[O:19].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:34]([O:36][C:37](=[O:42])[CH2:38]C([O-])=O)[CH3:35].[K+].[Cl-].[Mg+2].[Cl-].Cl>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.CCCCCCC.CCOC(C)=O.O.CC(OC)(C)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][C@@H:13]([C:15](=[O:17])[CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:42])[CH2:12][CH2:11][N:10]1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COC(=O)N1CCC(C(=O)O)CC1c1ccc(F)cc1F
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: COC(C)(C)C
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32 %

Procedure:
2-(2,4-Difluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.20 g, 7.35 mmol) (reference compound 19) was dissolved in methyl THF (70 mL), then di(1H-imidazol-1-yl)methanone (2.146 g, 13.23 mmol) was added. The mixture was stirred at room temperature under nitrogen for 5 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (2.252 g, 13.23 mmol) was suspended in methyl THF (70.0 mL), then magnesium chloride (1.260 g, 13.23 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 5 h using a large magnetic stirring bar (flask 2). After the 3 h, the contents of flask 1 was transferred into flask 2. The resulting white suspension was stirred under nitrogen at room temperature overnight. The mixture was acidified to pH 1 with 3.8 M HCl, then MTBE (50 mL) and water (50 mL) was added. The phases were separated and the organic layer was washed with water, satd NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated leaving a slightly yellow oil. The product was flashed on Biotage (340 g) with 1 CV EtOAc in heptane (20%) followed by a gradient of 20-60% EtOAc in n-heptane (8 CV). The column was conditioned at 20% EtOAc in -n-heptane (1 CV). Cis-methyl 2-(2,4-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (870 mg, 32%) was isolated. MS m/z 370 (M+H)+
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[OH:28].Br[CH2:31][CH2:32][CH3:33]>>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[O:28][CH2:31][CH2:32][CH3:33]
Reactant: CCCBr
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Product: CCCOc1cc(-c2nc(CNC(=O)c3ccccc3OCC)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 347 and 1-bromopropane, white powdery N-[2-(4-difluoromethoxy-3-propoxy phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 348.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]1)=[O:9].[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:35][C@@H:36]([C:45]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[C:51]2[C:46]=1[CH:47]=[CH:48][C:49](=[O:63])[NH:50]2)[O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl>O.CN(C)C=O>[CH2:64]([N:34]([CH2:35][C@@H:36]([C:45]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[C:51]2[C:46]=1[CH:47]=[CH:48][C:49](=[O:63])[NH:50]2)[O:37][Si:38]([C:41]([CH3:42])([CH3:43])[CH3:44])([CH3:40])[CH3:39])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:19]([CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][CH:11]([O:10][C:8](=[O:9])[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:16][CH2:15]1)=[O:20])[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCCCCN)Cc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCCCCNC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)Cc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
A mixture of the product of step (e) (3.68 g, 10 mmol) and N,N-dimethylformamide (50 mL) was heated at 60° C. until the solid completely dissolved and then cooled to room temperature. The product of step (d) (6 g, 10 mmol) and diisopropylethylamine (3.5 mL) was added and the reaction mixture was cooled to 0° C. PyBOP (6.25 g, 12 mmol) was added in one portion and the reaction mixture was stirred at 0° C. to room temperature for 2 hours. The reaction mixture was then poured into cold water (500 mL) with stirring and the pH of the resulting mixture was adjusted to about 2 using aqueous 1 M hydrochloric acid. This mixture was stirred for 15 min and then filtered to collect the solid, which was washed with water (100 mL) and dried to afford the title compound (8.7 g, HPLC purity >95%) as an off- white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([CH:25]=C)=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1.I([O-])(=O)(=O)=[O:29].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([CH:25]=[O:29])=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: C=Cc1nc2ccc(-c3c(C)noc3C)c3c2n1[C@@H](c1ccccn1)CO3
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(C)c1-c1ccc2nc(C=O)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 147.1 %

Procedure:
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-vinyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (0.05 g, 0.1 mmol) was dissolved in tetrahydrofuran (1.7 mL). The resulting solution was cooled to 0° C., then a solution of 0.16 M osmium tetraoxide in water (0.3 mL, 0.04 mmol) [Aldrich, cat. #251755] and sodium metaperiodate (140 mg, 0.66 mmol) [Aldrich, cat. #S1878] in water (0.1 mL) were added. The reaction was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with saturated aqueous sodium sulfite (10 mL) for 10 min at room temperature. The mixture was filtered through a Celite plug and the plug was rinsed with dichloromethane. The organic layer was concentrated under vacuum. The resulting residue was purified by flash chromatography elucting ethyl acetate in hexanes (75-100%, ethyl acetate containing 20% MeOH) to afford the desired product (0.053 g, 100%). LCMS for C20H17O3N4 (M+H)+: calculated m/z=361.1. found 361.2.
Reaction SMILES: O.[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([N+:13]([O-])=O)=[C:6]2[NH:16][C:17]1([CH3:23])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.Cl.N>CCO.[Fe]>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([NH2:13])=[C:6]2[NH:16][C:17]1([CH3:23])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CC1(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)CCOCC1
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Product: CC1(Nc2c(N)cnc3ccc(Br)cc23)CCOCC1
Temperature: 105 °C
Yield: 86.6 %

Procedure:
Water (8.35 mL) was added to a stirred mixture of 6-bromo-N-(4-methyloxan-4-yl)-3-nitroquinolin-4-amine (1.07 g, 2.92 mmol), iron (0.979 g, 17.53 mmol) and ammonia hydrochloride (0.109 g, 2.05 mmol) in EtOH (50.1 mL) and the resulting slurry heated to 105° C. for 2 h. The reaction was filtered warm through a pad of celite, washing with MeOH, and the filtrate evaporated to dryness. The crude solid was dissolved in DCM (10 mL) and washed with a sat. aqueous solution of NaHCO3 (10 mL) and sat. brine (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford the desired material (0.850 g, 87%) as a pale orange solid. This was used without further purification. NMR Spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.19 (3H, s), 1.51 (2H, d), 1.76 (2H, td), 3.43 (2H, td), 3.73 (2H, dt), 4.15 (1H, s), 5.45 (2H, s), 7.39 (1H, dd), 7.67 (1H, d), 8.22 (1H, d), 8.51 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=336, 338.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].[NH2:9][C:10]1[C:11]([C:22]([O:24]C)=[O:23])=[N:12][C:13]([S:17][C:18]([F:21])([F:20])[F:19])=[C:14]([NH2:16])[N:15]=1.O>CO>[OH2:23].[C:3]([NH:5][C:22]([C:11]1[C:10]([NH2:9])=[N:15][C:14]([NH2:16])=[C:13]([S:17][C:18]([F:19])([F:20])[F:21])[N:12]=1)=[O:24])(=[NH:2])[NH2:4]
Reactant: N=C(N)N
Reactant: COC(=O)c1nc(SC(F)(F)F)c(N)nc1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N=C(N)NC(=O)c1nc(SC(F)(F)F)c(N)nc1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Guanidine hydrochloride (3.34 g., 0.035 mole) is added to a solution of sodium methoxide (1.67 g., 0.032 mole) in methanol (20 ml.) with stirring at 25° C. After 15 minutes, methyl 3,5-diamino-6-trifluoromethylthio-2-pyrazinoate (1.85 g., 0.007 mole) is added, and the mixture is heated on a steam bath for 15 min. Crushed ice--H2O (20 ml.) is added to the reaction mixture to precipitate 390 mg. of N-amidino-3,5-diamino-6-trifluoromethylthio-2-pyrazinecarboxamide, m.p. 195° C.