Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH2:37][C:38]([NH:40][CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=[O:39]>C(Cl)Cl>[CH2:8]([NH:26][C:27](=[O:28])[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH2:37][C:38]([NH:40][CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=[O:39])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: O=C(CCc1ccccc1O)NCCCN1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)Oc1ccccc1CCC(=O)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.56 ml) and octadecyl isocyanate (1.26 ml) were added to a solution containing 3-(2-hydroxyphenyl)-N-(3-morpholinopropyl)propanamide (1.05 g) in methylene chloride (11 ml) and stirred for 3 hours at room temperature. The insoluble matters were filtrated out and washed with chloroform. The filtrate and washings were combined and the mixture was washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=60:1 to 50:1), thereby yielding the entitled compound (1.78 g) as white solid.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26](=O)[CH2:27][C:28]([CH3:30])=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl.[F:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][NH2:42])=[CH:37][CH:36]=1.C([O-])(=O)C.[Na+]>>[F:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[C:26]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:32])[S:12][CH:13]=3)=[CH:27][C:28]([CH3:30])=[N:42]2)=[CH:37][CH:36]=1
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=O)CC(C)=O
Reactant: NNc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1cc(C)nn1-c1ccc(F)cc1

Procedure:
A compound obtained using 2-[(4-{2-[acetoacetyl(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 446-1, and (4-fluorophenyl)hydrazine hydrochloride and sodium acetate for neutralization, and by an operation similar to that of Example 446 was purified by silica gel chromatography (elution solvent; chloroform:methanol=10:1) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([N+:21]([O-])=O)=[C:16]([NH2:24])[N:15]=2)[N:6]=1>N1C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[C:16]([NH2:24])[N:15]=2)[N:6]=1
Reactant: Nc1nc(-n2nc(Cc3ccccc3F)c3ncccc32)nc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: c1ccncc1
Product: Nc1nc(-n2nc(Cc3ccccc3F)c3ncccc32)nc(N)c1N
Temperature: 50 °C

Procedure:
690 mg (1.42 mmol) of 2-[3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]-5-nitropyrimidine-4,6-diamine from example 15A are dissolved in 120 ml of pyridine. 270 mg of 10% palladium on activated carbon are added, and hydrogenation is carried out under a hydrogen pressure of 3.5 bar for 15 h. The catalyst is then filtered off and washed with ethanol. The residue after concentration to dryness is stirred with ethanol at 50° C. and filtered off with suction. 378 mg (76% of theory) of the desired product are obtained. A further 92 mg (18% of theory) of the target compound can be obtained from the filtrate by purifying by preparative HPLC.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[O:12][CH2:13][CH2:14][OH:15])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:11]([O:12][CH2:13][CH2:14][OH:15])[CH:10]=2)=[N:7][C:2]([NH:20][C:21]2[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(O)c1
Reactant: OCCOc1cccc(Nc2nc(Cl)ncc2Cl)c1
Product: OCCOc1cccc(Nc2nc(Nc3cccc(O)c3)ncc2Cl)c1
Yield: 34 %

Procedure:
The desired compound was prepared according to the procedure of Example D5, step B, using 2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenoxy}ethanol and 3-aminophenol as the starting materials in 34% yield. LCMS for C18H18ClN4O3 (M+H)+: m/z=373.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])/[C:7](/[CH3:18])=[CH:8]/[C:9]1[O:10][C:11]([C:14]([O:16]C)=[O:15])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([CH:7]([CH3:18])[CH2:8][C:9]1[O:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][CH:13]=1)=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(/C=C(\C)C(=O)OC(C)(C)C)o1
Agent: [Pd]
Solvent: CO
Product: CC(Cc1ccc(C(=O)O)o1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
(2E)-(5-Methoxycarbonylfuran-2-yl)-2-methylpropenoic acid tert-butyl ester (2.96 g, 11.1 mmol) was dissolved in methanol (100 ml), 10% palladium/carbon (0.3 g) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After completion of the reaction, palladium/carbon was removed by celite filtration, and the solvent was evaporated under reduced pressure to give the title compound (2.72 g).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[N:12]=[C:13](Cl)[C:14]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)=[CH:15][C:10]3=[N:9]2)=[CH:5][CH:4]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O.C1(C)C=CC=CC=1.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>[F:28][C:2]([F:29])([F:1])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[N:12]=[C:13]([C:34]4[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=4)[C:14]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)=[CH:15][C:10]3=[N:9]2)=[CH:5][CH:4]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Reactant: OB(O)c1ccc(Cl)cc1
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: Cc1ccccc1
Solvent: O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nn12
Temperature: 125 °C
Reaction time: 10 h
Yield: 12.6 %

Procedure:
To a suspension of 2-(4-(trifluoromethyl)benzyl)-6-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (150 mg, 0.34 mmol), 4-chlorophenylboronic acid (60 mg, 0.38 mmol), Na2CO3 (90 mg, 0.85 mmol) dissolved in water (0.2 mL) in toluene (3 mL) was added Pd(PPh3)4 (25 mg, 0.02 mmol). The resulting reaction mixture was bubbled with argon for 10 min before the flask was placed in an oil bath preheated at 125° C. After stirring at 125° C. for 10 h, the reaction was then allowed to cool to room temperature. To the reaction was added water (10 mL), the aqueous mixture extracted with EtOAc (10 mL×3). The combined EtOAc extracts were washed with water (10 mL×2), followed by saturated aqueous NaCl (10 mL×2) and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 17% to 100% B, 25 min gradient, hold at 100% B for 5 min (A=90% H2O, 10% acetonitrile and B=10% H2O, 90% acetonitrile); Flow rate at 20 mL/min, UV detection at 220 nm) to obtain 22 mg (13%) the title compound as a yellow solid. LC/MS (Method C): retention time=4.26 min; (M+H)+=515. 1H NMR (CDCl3, 500 MHz): δ 7.61 (d,J=5.0 Hz, 2H), 7.56 (d,J=5.0 Hz, 2H), 7.41(s, 1H), 7.24-7.30 (m, 4H), 7.21 (d,J=5.0 Hz, 2H,), 7.01 (d,J=5.0 Hz, 2H), 5.29 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.[CH2:10](O)[C@@H:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]CC>>[CH2:21]([CH:1]1[O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CCCCCCCCCCCC[C@H](O)CO
Reactant: COc1cscc1OC
Product: CCCCCCCCCCCCC1COc2cscc2O1

Procedure:
Chiral 2-n-dodecyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine was synthesized by transetherification of 3,4-dimethoxythiophene with (S)-1,2-tetradecanediol and purified to a purity of 98.01% as described in INVENTION EXAMPLE 1. It was characterized by GC-MS and 1H-NMR-spectroscopy, and exhibited a specific rotation of −65° at 25° C. and 436 nm in hexane.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH:7][CH:8]([C:11]1[N:16]=[C:15]([CH2:17][N:18]2[C:26]3[C:21](=[C:22]([NH:27][C:28]([C:30]4[N:34]5[CH:35]=[CH:36][CH:37]=[CH:38][C:33]5=[N:32][CH:31]=4)=[O:29])[CH:23]=[CH:24][CH:25]=3)[C:20]([CH2:39][CH3:40])=[N:19]2)[CH:14]=[CH:13][CH:12]=1)CO>ClCCl>[CH2:39]([C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][C:22]=2[NH:27][C:28]([C:30]2[N:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]3=[N:32][CH:31]=2)=[O:29])[N:18]([CH2:17][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:8]=[O:7])[N:16]=2)[N:19]=1)[CH3:40]
Reactant: CCc1nn(Cc2cccc(C(O)CO)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CCc1nn(Cc2cccc(C=O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To a slurry of silica gel (200 mg) in dichloromethane (1 mL) was added, drop wise, sodium periodate solution (202 μL, 0.13 mmol; 0.65M in water). The slurry was stirred for 10 minutes and broken up into a fine slurry with a spatula. To this was slowly added N-(1-((6-(1,2-dihydroxyethyl)pyridin-2-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (40 mg, 0.088 mmol) in dichloromethane (1 mL). The slurry was stirred for 30 minutes, then filtered and washed with dichloromethane (5 mL). The solution was concentrated under reduced pressure to provide the desired product (28 mg).
Reaction SMILES: Br[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ncccc1Br
Reactant: OB(O)c1cccs1
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: C1CCOC1
Solvent: COCCOC
Product: O=Cc1ncccc1-c1cccs1
Temperature: 90 °C
Yield: 63.4 %

Procedure:
A stirred solution of 3-bromo-pyridine-2-carbaldehyde (126 mg, 0.675 mmol) and 2-thiopheneboronic acid (91.6 mg, 0.716 mmol) in a mixture of THF (0.75 mL), DME (2.0 mL) and 2M Na2CO3 (0.75 mL) was degassed with Ar for 15 minutes, after which Pd(PPh3)4 (39 mg, 0.034 mmol) was added and the heterogeneous mixture heated to 90° C. for 4 h. The reaction was quenched with brine (15 mL) and diluted with EtOAc (40 mL). The organic layer was separated, washed with brine (2×15 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 80:20) gave 3-thiophen-2-yl-pyridine-2-carbaldehyde (81 mg, 63%) as a yellow oil. 1H NMR (CDCl3) δ 7.13-7.22 (m, 2H), 7.48-7.57 (m, 2H), 7.92 (dd, 1H, J=7.9, 1.9 Hz), 8.82 (dd, 1H, J=6.0, 1.5 Hz), 10.23 (s, 1H).
Reaction SMILES: [ClH:1].[CH2:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH:6]1[CH3:30])[CH:3]=[CH2:4].C>C(OCC)(=O)C.[Pd]>[ClH:1].[CH:27]([C:24]1[CH:25]=[CH:26][C:21]([S:18]([NH:17][C:14]2[CH:15]=[N:16][C:11]([N:8]3[CH2:9][CH2:10][N:5]([CH2:2][CH2:3][CH3:4])[CH:6]([CH3:30])[CH2:7]3)=[CH:12][CH:13]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1)([CH3:29])[CH3:28]
Reactant: C=CCN1CCN(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cn2)CC1C
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCN1CCN(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cn2)CC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.24 mmol) of N-[6-(4-allyl-3-methylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide hydrochloride from Example 13.4 were dissolved in 10 ml of ethyl acetate, after which 10 mg of palladium on active charcoal (10%) were added and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After that, the catalyst was filtered off and the filtrate was evaporated down to dryness. After 1 ml of dichloromethane had been added to the resulting residue, diethyl ether was slowly added dropwise until the solution became cloudy. The reaction mixture was stirred for 30 minutes and the precipitate which had formed was filtered off with suction. The filtrate was evaporated down to dryness, after which the residue was dissolved in a 1:1 mixture of dichloromethane and diethyl ether and converted into the hydrochloride by adding ethereal hydrochloric acid. 71 mg (63% of theory) of the title compound were obtained.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[N:24]1>>[N:23]1([CH2:22][N:8]2[C:9]([O:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[N:24]1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: ClCn1nnc2ccccc21
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cn2nnc3ccccc32)c1
Yield: 26.6 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 1-chloromethyl-1H-benzotriazole were reacted by the same way with the example 1 to obtain the titled compound (108 mg, yield: 26.6%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[N+:4]([O-])[C:3]=1[CH3:11].C(OC(=O)C)(=[O:14])C.CO>C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH2:11][OH:14])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc[n+]([O-])c(C)c1Cl
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccnc(CO)c1Cl
Temperature: 90 °C

Procedure:
5.8 g of 3-chloro-4-methoxy-2-picoline-N-oxide were dissolved in 8 ml of glacial acetic acid and, while stirring at 90° C., 14 ml of acetic anhydride were added. The mixture was heated at 110°-115° C. for 2 hours and then cooled to 80° C. and 25 ml of methanol were added dropwise. The solvent was then removed by distillation under reduced pressure, and subsequently 20 ml of water and 8 g of sodium hydroxide were added in small portions to the residue, and this mixture was heated to reflux for 2 hours. After cooling, the mixture was extracted with dichloromethane, the solvent was evaporated off, and the residue is induced to crystallize with diethyl ether. Solid, melting point 103°-105° C.
Reaction SMILES: C[O:2][C:3]1[NH:4][CH2:5][CH2:6][CH:7]=1.[CH3:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1>C1C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:4]2[CH2:5][CH2:6][CH2:7][C:3]2=[O:2])=[O:15])=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC1=CCCN1
Solvent: c1ccccc1
Product: COc1ccc(C(=O)N2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.2 g. of 2-methoxypyrroline are dissolved in 25 ml. of benzene and treated at room temperature with 6.6 g. of p-methoxybenzoyl chloride dissolved in 30 ml. of benzene. The mixture is stirred at room temperature for 60 minutes and at reflux for 4 hours. 30 ml. of benzene are then added and the mixture is boiled at reflux for a further 24 hours. The volatile constituents are distilled off, the residue is taken up in ethanol, the mixture is concentrated, the residue is triturated with diethyl ether, filtered and the filter cake is taken up in ethyl acetate. The ethyl acetate solution is washed with sodium bicarbonate solution and water, dried over sodium sulfate and concentrated. The residue is sublimed in vacuo and there is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 119°-120° C.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][NH:26][S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3].[H-].[Na+].I[CH3:41].O>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]([CH3:41])[S:27]([C:30]([CH3:31])([CH3:33])[CH3:32])(=[O:28])=[O:29])[C:5]1=[O:36])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C(C)(C)C)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-2-methylpropane-2-sulfonamide (100 mg, 0.177 mmol; Example 181, Step A) was dissolved in DMF (2.5 mL), and sodium hydride (60% dispersion in mineral oil, 19 mg, 0.45 mmol) was added in a single portion. After 25 minutes, this mixture was cooled to 0° C. in an ice-water bath, and iodomethane (0.04 mL, 0.643 mmol) was added dropwise by syringe. The mixture was allowed to gradually warm to ambient temperature, gradually becoming a pale yellow suspension. After 2 h water (2 mL) was added very carefully. The resulting mixture was partitioned between ethyl acetate and saturated aq. NH4Cl solution. The aqueous phase was back-extracted (2×) and the combined organics were washed with sat. aq. NaCl solution (2×), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to an oily residue that was chromatographed on a 12 g silica column, eluting with a gradient of 0 to 35% EtOAc in hexanes. Fractions containing the sulfonamide product were pooled and concentrated to give the title compound. MS (ESI) m/z=579 [M+H]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1/[C:10](=[N:21]/[O:22][CH3:23])/[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1.[C:24]([CH:26]([C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[CH2:27][C:28]([O:30]C)=[O:29])#[N:25]>>[C:24]([CH:26]([C:32]1[CH:37]=[CH:36][C:35]([O:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11]/[C:10](/[C:2]3[CH2:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)=[N:21]\[O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:34][CH:33]=1)[CH2:27][C:28]([OH:30])=[O:29])#[N:25]
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)C1=Cc2ccccc2C1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)C1=Cc2ccccc2C1
Yield: 20.5 %

Procedure:
Compound 101 was synthesized from (4-{[(2Z)-2-(1H-inden-2-yl)-2-(methoxyimino)ethyl]oxy}phenyl)methanol (0.079 g, 0.4 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.11 g, 0.4 mmol) by following the procedure described in scheme 5 (0.008 g, yield: 20.5%); Purity: 97.17%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19]([O:21]CC)=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:24]=1.[Li+].[OH-].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19]([OH:21])=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:24]=1
Reactant: CCOC(=O)C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: 80 °C
Reaction time: 2 h
Yield: 105.8 %

Procedure:
A mixture of ethyl 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylate (606 mg, 1.75 mmol) and LiOH (168 mg, 7.00 mmol) in dioxane/H2O (6 mL/5 mL) was stirred at 80° C. for 2 hours. The reaction was monitored using TLC. When the reaction was completed, the mixture was adjusted to pH 4-5 with 1 N HCl aqueous. The mixture was extracted with EtOAc (10 mL*3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under reduce pressure, afforded the desired product of 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylic acid (crude: 590 mg, yield: 99%). 1H-NMR (400 MHz, DMSO-d6) δ 7.74 (d, J=8.6 Hz, 1H), 7.56˜7.43 (m, 2H), 7.37 (s, 1H), 7.34˜7.25 (m, 1H), 7.15 (s, 1H), 7.02˜6.92 (m, 1H). MS (M+H)+: 319.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12](F)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[N-:17]=[N+]=[N-].[Na+].O>CS(C)=O>[NH2:17][C:12]1[CH:13]=[CH:14][C:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[OH:16])=[CH:10][CH:11]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Cl)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(C(O)c2ccc(Cl)cn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30.1 %

Procedure:
A solution of 5-chloro-2-(4-fluorobenzoyl)pyridine (3.0 g) and sodium azide (0.84 g) in DMSO (60 ml) was stirred for 20 hours at 90° C. To the reaction mixture was added water, and the mixture was extracted with diethylether. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and a solution of the residue (3.19 g) in. THF (60 ml) was added dropwise to a suspension of aluminum lithium hydride (0.97 g) in THF (10 ml) at 0° C. The mixture was stirred at 0° C. for 10 minutes, and water (0.97 ml), 15% aqueous solution of sodium hydroxide (0.97 ml) and water (2.9 ml) were sequentially and slowly added dropwise to the solution. The mixture was stirred at room temperature for 18 hours, magnesium sulfate was added to the mixture, and the precipitates were removed by filtration (Celite). The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:hexane 1:1→2:1), to give (4-aminophenyl)(5-chloropyridin-2-yl)methanol (0.90 g) as pale yellow crystals.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH2:12])[C:8]=1[C:9]([OH:11])=[O:10].[CH2:13]=O.[BH4-].[Na+].[OH-].[K+].Cl>CO>[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH:12][CH3:13])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: C=O
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: CNc1cccc(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.9 %

Procedure:
Sodium (3.35 g, 146 mmol) was slowly added to stirred MeOH (45 mL). Upon completion of gas evolution, 6-chloroanthranilic acid (5 g, 29 mmol) was added forming a suspension. This mixture was added to a separate flask containing a suspension of paraformaldehyde (1.22 g, 43.5 mmol) in MeOH (35 mL), and the resulting solution was stirred for 5 h at room temperature. Sodium borohydride (1.1 g, 29 mmol) was added and the mixture refluxed for 3 h. The cooled mixture was hydrolyzed with 1 M potassium hydroxide then neutralized to pH 3 using 2 M HCl. The precipitate was filtered to yield 2-chloro-6-methylamino benzoic acid (2.2 g, 41%).