Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:10]([CH:12]=O)[N:11]=1)=[O:5].[N+](=[C:31](P(=O)(OC)OC)C(=O)C)=[N-].C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[C:12]([C:10]1[N:11]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:27][CH:26]=[CH:25][C:24]=2[F:28])[S:8][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)#[CH:31]
Reactant: O=Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
Into a solution of Compound 67 (50.0 mg, 0.12 mmol) and dimethyl 1-diazo-2-oxopropylphosphonate (46.0 mg, 0.24 mmol) in MeOH (1.00 mL) was added K2CO3 (50.0 mg, 0.36 mmol) was added. The mixture was stirred at room temperature overnight, diluted with CH2Cl2, washed with water, dried (Na2SO4), filtered and concentrated. The residue was purified on silica to give Compound 104 (10.0 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:25])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(=O)([O-])O.[Na+]>ClCCl>[CH2:18]([CH:15]1[CH2:16][CH2:17][N:12]([C:10](=[O:11])[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:3]=2)=[O:25])[CH2:13][CH2:14]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 30 %

Procedure:
To a stirred solution of 0.34 g (1 mmol) of N-(3-amino-phenyl)-2-(4-benzyl-piperidin-1-yl)-2-oxo-acetamide (Example 11) and 0.16 ml (2 mmol) of pyridine in 10 ml of dichloromethane 0.16 ml (2 mmol) of methanesulfonyl chloride in 2 ml of dichloromethane is added dropwise below 10° C., and the reaction mixture is stirred at room temperature for 10 hours. Then 50 ml of 8% sodium hydrogencarbonate solution is added to the mixture, the organic layer is separated and the water phase is extracted three times with 10 ml of dichloromethane. The combined organic layers are dried over sodium sulfate, concentrated, the residue is treated with diethylether and the crystals are filtered to yield 0.25 g (30%) of the title compound. Melting Point: 128-130° C. (diethylether)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH:15][CH2:16][CH2:17][NH:18][NH2:19]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:18]([CH2:17][CH2:16][OH:15])[NH2:19])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: NNCCO
Solvent: CCCCO
Product: NN(CCO)c1ccc(-c2ccc(Cl)cc2)nn1

Procedure:
A mixture of 5.0 g. of 6-(p-chlorophenyl)-3-chloropyridazine and 5.02 g. of 2-hydroxyethylhydrazine in 75 ml. of butanol is heated at reflux overnight and then cooled in an ice bath. The precipitate is collected by filtration, washed with butanol, water and then dried. Recrystallization from ethanol gives crystals, m.p. 172°-174° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.CN(C)C=O>O>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccnc1Nc1ccc(O)cc1
Temperature: 50 °C

Procedure:
A mixture of 2-chloro-3-nitropyridine (2C3NP, 138.1 Kg), 4-aminophenol (2.5-3 equivalents) and N,N-dimethylformamide (DMF, 4.8 mL/g 2C3NP) was stirred until homogeneous, heated at 50° C. during which an exotherm raised the solution temperature to 70° C., warmed to 80-85° C., stirred until no 2-chloro-3-nitropyridine remained, cooled to 30° C., treated with water (10.6 mL/g 2C3NP) to precipitate product, then with acetic acid (1.2 mL/g 2C3NP), then with ethyl acetate (0.5 mL/g 2C3NP), cooled to 5° C., stirred for 2 hours and filtered. The filtrant was washed sequentially with distilled water (1.6 mL/g 2C3NP), cold ethanol (1.2 mL/g 2C3NP) and cold isopropyl ether (1.2 mL/g 2C3NP), and dried under vacuum.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH4+:12].[OH-]>C1COCC1.C(Cl)Cl.Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH2:12])[C:5]2=[N:4][CH:3]=1
Reactant: [NH4+]
Reactant: Brc1cncc2ncc(Br)n12
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1nccn2c(Br)cnc12
Temperature: 50 °C
Yield: 50 %

Procedure:
To a solution of 3,5-dibromo-imidazo[1,2-a]pyrazine (D) (500 mg, 1.8 mmol) in THF (4 ml) was added NH4OH (4 ml). The mixture was heated at 50° C. in sealed tube overnight. Additional NH4OH (4 ml) was added to the reaction mixture and was heated at 50° C. in sealed tube overnight. The mixture was then cooled to rt, diluted with DCM (200 ml) and 1N HCl (50 ml). The organic layer was washed with 10N NaOH, brine, dried and concentrated. The residue was purified on a silica gel column to afford 190 mg (yield 50%) of 3-bromo-imidazo[1,2-a]pyrazin-8-ylamine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Cl:19][C:20]1[CH:25]=[C:24](/[C:26](/[C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:42][CH2:41]3)=[C:36]([O:43][CH3:44])[N:35]=2)=[CH:27]\[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:23]=[CH:22][C:21]=1[OH:45].O>CN(C)C=O>[Si:12]([O:11][CH2:10][CH2:9][CH2:8][O:45][C:21]1[CH:22]=[CH:23][C:24](/[C:26](/[C:34]2[N:35]=[C:36]([O:43][CH3:44])[C:37]([CH:40]3[CH2:41][CH2:42]3)=[CH:38][CH:39]=2)=[CH:27]\[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:25][C:20]=1[Cl:19])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: COc1nc(/C(=C/C2CCOCC2)c2ccc(O)c(Cl)c2)ccc1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(/C(=C/C2CCOCC2)c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(Cl)c2)ccc1C1CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Potassium carbonate (214 mg) and (3-bromopropoxy)(tert-butyl)dimethylsilane (240 μL) were added to a solution of 2-chloro-4-[(E)-1-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethenyl]phenol obtained in Example 1-53(2) (200 mg) in N,N-dimethylformamide (4 mL), and the mixture was stirred at 65° C. for 1.5 hours and at room temperature overnight. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give 6-{(E)-1-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-3-chlorophenyl]-2-(tetrahydro-2H-pyran-4-yl)ethenyl}-3-cyclopropyl-2-methoxypyridine as a colorless oil (245 mg, 80%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:14]([F:17])([F:16])[F:15])=[CH:8][C:9]=2[N+]([O-])=O)[N:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:3]=1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:31](OCC)(=[O:33])[CH3:32]>>[C:31]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:14]([F:15])([F:16])[F:17])=[CH:8][CH:9]=2)[N:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:3]=1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:33])[CH3:32]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2c([N+](=O)[O-])cc(C(F)(F)F)cc21
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2ccc(C(F)(F)F)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-2-benzoyl-1-(ethoxycarbonyl)-6-trifluoromethylnitroindole (step 2). tlc: Rf=0.6 (50% ethyl acetate in hexanes)
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH:11]1[N:16](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:15][CH2:14][N:13]([CH:29]([CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)[C:30]([NH:32][CH3:33])=[O:31])[C:12]1=[O:45])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[Si:1]([O:8][CH2:9][CH2:10][CH:11]1[NH:16][CH2:15][CH2:14][N:13]([CH:29]([CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)[C:30]([NH:32][CH3:33])=[O:31])[C:12]1=[O:45])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CCO[Si](C)(C)C(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCNC(CCO[Si](C)(C)C(C)(C)C)C1=O

Procedure:
2-[3-[2-(tert-butyldimethylsilanyloxy)ethyl]-4-(2-nitrobenzene-sulfonyl)-2-oxo-piperazin-1-yl]-N-methyl-3-naphthalen-2-yl propionamide, 57, (6.5 g, 10 mmol), trifluoroacetic acid (5 mL), and dichloromethane (50 mL) is stirred at room temperature for 2 hours and then concentrated in vacuo. The crude product is dissolved in dichloromethane and the organic layer washed with saturated sodium bicarbonate, dried, and concentrated in vacuo to afford the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH2:7][CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[C:13](Cl)=[N:14][CH:15]=[C:16]([CH:19]=1)[C:17]#[N:18]>>[Cl:11][C:12]1[C:13]([NH:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:10])=[N:14][CH:15]=[C:16]([C:17]#[N:18])[CH:19]=1
Reactant: N#Cc1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CCN
Product: CC(C)(C)OC(=O)CCNc1ncc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of beta-alanine tert-butyl ester (5.88 g, 40.4 mmol), TEA (5.6 mL, 40.4 mmol) and 5,6-dichloronicotinonitrile (Bionet GC-0755, 7.0 g, 40.4 mmol) was prepared and stirred at RT for 24 hours. The reaction mixture was filtered to remove inorganic solids and filtrate was concentrated under reduced pressure. The residue taken up with EtOAc (100 mL) and washed with water (2×100 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, pet ether/EtOAc), the title compound was obtained as a white powder (8.3 g, 72%). 1H NMR (DMSO-d6, 400 MHz) δ 8.44 (1H, d), 8.08 (1H, d), 7.52 (1H, t), 3.62 (2H, m), 2.50 (2H, m), 1.35 (9H, s).
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[CH2:10][CH2:9][N:8]=2)C=CC=CC=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[CH3:21][N:22]([CH:24]=[C:10]1[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:7]=[N:8][CH2:9]1)[CH3:23]
Reactant: O=C1CCN=C(c2ccccc2)c2ccccc21
Reactant: COC(OC)N(C)C
Product: CN(C)C=C1CN=Cc2ccccc2C1=O

Procedure:
A mixture of 5.2 g (22 mmole) of 3,4-dihydro-1-phenyl-5H-2-benzazepin-5-one and 43 ml of dimethylformamide dimethyl acetal was refluxed for 4 hr. The mixture was concentrated at reduced pressure to dryness. The residue was crystallized with ether to give a yellow solid, mp 131°-133° C. Recrystallization from ether gave yellow prisms, mp 131°-132° C.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].O=[C:36]1[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]1>C1COCC1.O>[F:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:40]2[CH2:41][CH2:36][CH2:37][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39]2)[CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: Fc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(=Cc2cccc(F)c2)C1
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
(3-Fluorobenzyltriphenylphosphonium bromide (Intermediate 228, 5.3 g) was added in portions to a solution of sodium tert-butoxide (1.06 g) in anhydrous THF (20 mL) at room temperature and the mixture was stirred for 30 minutes. A solution of tert-butyl 3-oxopiperidine-1-carboxylate (2 g) in anhydrous THF (10 mL) was added dropwise at room temperature and the mixture was stirred for 24 hours. The mixture was diluted with water (100 mL) and extracted with ether (100 mL), washed with brine, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexxane with a gradient of 0-20% to give tert-butyl 3-[1-(3-fluorophenyl)-methylidene]piperidine-1-carboxylate (1.42 g).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.[P:12]([OH:15])([OH:14])[OH:13].P(Cl)(Cl)Cl>S1(CCCC1)(=O)=O>[CH:6]1[CH:7]=[N:2][CH:3]=[C:4]([CH2:8][C:9]([P:12]([OH:15])([OH:14])=[O:13])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH:5]=1
Reactant: OP(O)O
Reactant: O=C(O)Cc1cccnc1
Agent: Cl
Solvent: ClP(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A suspension of 3-pyridylacetic acid hydrochloride (50 g, 0.288 mol) and phosphorous acid (35.4 g, 0.432 mol) in sulfolane (180 ml) is heated to 75° C. for 30 min. The mixture is cooled to 35-40° C. and then gradually introduced phosphorous trichloride (85.6 ml, 0.98 mol) while maintaining the temperature between 35-45° C. The mixture is heated to 63-67° C. for 3 hours whereby a thick white mass results. It is then cooled to 0-5° C. and quenched by slow addition of water (500 ml) at 0-5° C. over a period of 1 hour. The resulting clear solution is charcoalized and heated at 100° C. for 3 hrs, cooled to ambient temperature and then cooled 0-5° C. After stirring for 2 hrs at 0-5° C. the crystallized product is filtered, washed sequentially with chilled water (100 ml), rectified spirit (75 ml) and dried in air oven at 55-60° C. until loss on drying is less than 0.5% w/w. Yield 60.4 g, (70.47%), appearance: white crystalline solid, purity >99.0%.
Reaction SMILES: [F:1][C:2]1[CH:45]=[CH:44][C:5]([CH2:6][N:7]([CH:27]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[C:8](=[O:26])[C@@H:9]([NH:17][C:18](=O)N(C)C(C)(C)C)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:27]([CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)[CH2:36][CH2:37][C:38]2[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=2)[C:8](=[O:26])[C@@H:9]([NH:17][CH3:18])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:44][CH:45]=1
Reactant: CN(C(=O)N[C@@H](Cc1ccccc1)C(=O)N(Cc1ccc(F)cc1)C(CCc1ccncc1)CCc1ccncc1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](Cc1ccccc1)C(=O)N(Cc1ccc(F)cc1)C(CCc1ccncc1)CCc1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Compound 4 was dissolved in methylene chloride (10 mL) and treated with trifluoroacetic acid (4.0 mL). After stirring at room temperature for 1.5 h, the reaction was concentrated in vacuo. The residue was neutralized with saturated potassium carbonate and extracted with ethyl acetate (2×). The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to provide Compound 5.
Reaction SMILES: CC([O-])=O.[Na+].[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=O)[CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1.Cl.[OH:19][NH2:20]>O.CCO>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[N:20][OH:19])[CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1
Reactant: O=C1CCOc2cc(Br)ccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCOc2cc(Br)ccc21
Temperature: 25 °C

Procedure:
NaOAc (3.78 g, 46.2 mmol) in H2O (30 mL) was added to a soln of 7-bromo 4-chromanone (3.5 g, 15.4 mmol) and hydroxyl-amine hydrochloride (1.75 g, 23.1 mmol) in EtOH (70 ml). The reaction was heated at reflux for 2 h, cooled to room temperature, and concentrated. The residue was diluted with H2O and a precipitate was filtered to give 7-bromochroman-4-one oxime obtained as the needle like crystals 3.5 g (98%). LCMS 244 (M+2H) RT=1.7 min (Condition 2); 1H NMR (DMSO-d6) 11.37 (s, OH, 1H), 7.76-7.70 (d, 1H), 7.09-7.13 (d, 2H), 4.16-4.20 (t, 2H), 2.79-2.83 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27]=[O:28].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:27]([NH:26][CH3:25])=[O:28])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CN=C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Yield: 51 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine is reacted with 1.1 eq of methyl isocyanate in dioxane/water (2:1) in the absence of sodium acetate. The crude product is purified by column chromatography (silica gel) eluting with a gradient of acetone/hexane to give pure 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-[(methylamino)carbonyl]-1H-indole-3-methanamine (51%) as an amorphous solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[N:18]1([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(O)CCC>[N:26]1([CH2:25][CH2:24][N:18]2[CH2:19][CH2:20][N:21]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=3)[CH2:22][CH2:23]2)[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: C1CN(CCN2CCOCC2)CCN1
Reactant: Nc1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(CCN3CCOCC3)CC2)ncn1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
6-chloropyrimidin-4-amine 7-2 (3.09 g, 23.9 mmol) and diisopropylethylamine (3.08 g, 23.9 mmol) were suspended in n-butanol and then 4-(2-piperazin-1-ylethyl)morpholine 7-3 (4.75 g, 23.9 mmol) was added. The reaction was stirred at 125° C. for 18 hours and then the product was filtered off, washed with n-butanol and ethyl ether and then air dried. Hi-Res MS: calc: 293.2084 found: 293.2078. 1H-NMR (DMSO): 7.94 ppm (s, 1H); 6.18 ppm (s, 2H); 5.57 ppm (s, 1H); 3.56 ppm (m, 6H); 3.39 ppm (m, 8H); 2.47 ppm (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([NH:8][O:9][CH3:10])=[NH:7])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[O:19][C:20]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:22]=1)CCC>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:10][O:9][NH:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([C:20]2[O:19][C:18]([C:2]3[CH:12]=[CH:11][C:5]([C:6](=[NH:7])[NH:8][O:9][CH3:10])=[CH:4][N:3]=3)=[CH:22][CH:21]=2)=[N:3][CH:4]=1)=[NH:7]
Reactant: CONC(=N)c1ccc(Cl)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc([Sn](CCCC)(CCCC)CCCC)o1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CONC(=N)c1ccc(-c2ccc(-c3ccc(C(=N)NOC)cn3)o2)nc1
Yield: 35 %

Procedure:
Continuing with Scheme 5, a mixture of 26 (6, mmol), 2,5-bis(tri-n-butylstannyl)furan (3 mmol) and tetrakis(triphenylphosphine)-palladium(0) (150 mg) in dry 1,4-dioxane (20 mL) was heated under nitrogen at reflux (100–110° C.) for 24 h. The solvent was evaporated under reduced pressure, dissolved in methylene chloride, and the solution was passed through celite to remove Pd. The solution was evaporated, the solid was filtered and washed with hexanes to afford 27 (SiO2, hexanes/EtOAc, 1:1), yield 35%, mp 228–230° C. 1H nmr (DMSO-d6); δ 3.80 (s, 6H), 6.31 (s, 4H), 7.34 (s, 2H), 7.98 (d, J=8.4 Hz, 2H), 8.13 (dd, J=8.4, 2.4 Hz, 2H). 8.88 (d, J=2.4 Hz, 2H). 13C nmr; δ 153.5, 148.9, 148.3, 147.0, 134.1, 126.8, 118.1, 112.0, 60.7. MS (m/z, rel.int.); 366 (M+, 100), 335 (25), 319 (30), 288 (40). High resolution mass calcd. for C18H18N6O3: 366.14404. Observed: 366.14012.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9].[NH2:15]C1C=CC(F)=CC=1C(N)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8]([NH2:15])=[O:9]
Reactant: NC(=O)c1cc(F)ccc1N
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Product: COc1ccc([N+](=O)[O-])c(C(N)=O)c1

Procedure:
5-Methoxy-2-nitrobenzoic acid (4) (1.0 g, 5.1 mmol) was treated as described for the preparation of compound 3 to give 5-methoxy-2-nitrobenzamide (8). The intermediate was then dissolved in MeOH and hydrogenated over 10% Pd/C for 6 h. The catalyst was removed by filtration, and the solution was evaporated to afford 10 (0.8 g) as brown powder; MS m/z 166 (M+).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:8]1[CH:31]=[C:30]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:29]=[CH:28][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH:18](O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:6][CH3:7].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][CH:18]([C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:28]=[CH:29][C:30]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:31][C:8]=2[CH2:5][CH2:6][CH3:7])[CH:16]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCCc1cc(C2CCCCC2)ccc1OCCCOc1cccc(C(O)C(=O)OCC)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1cc(C2CCCCC2)ccc1OCCCOc1cccc(C(Cl)C(=O)OCC)c1
Reaction time: 6.5 h

Procedure:
Thionyl chloride (0.15 mL) was added to a solution of ethyl 4-(3-(2-propyl-4-cyclohexylphenoxy)propoxy) mandelate of Step C (0.71 g), pyridine (0.19 mL), and toluene (15 mL). The reaction mixture was stirred 6-7 h and then partitioned between ethyl acetate and water. The organic layer was washed twice with water, once with brine, dried over sodium sulfate, and filtered. The solvent was removed in vacuo and the resulting oil was used as such for the next step.
Reaction SMILES: [NH2:1][C:2]1[C:17]([N+:18]([O-])=O)=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][N:10]=2)=[O:7])=[C:4]([F:21])[CH:3]=1.[H][H]>C1COCC1.[Ni]>[NH2:1][C:2]1[C:17]([NH2:18])=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][N:10]=2)=[O:7])=[C:4]([F:21])[CH:3]=1
Reactant: Nc1cc(F)c(C(=O)Nc2cc(Cl)ccn2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(F)c(C(=O)Nc2cc(Cl)ccn2)cc1N

Procedure:
A solution of the product obtained at 142f (320 mg, 1.0 mmol) in 20 mL THF was combined with Raney nickel (70 mg) and hydrogenated in a Parr apparatus at ambient temperature for 1.5 days at 3 bar hydrogen pressure. Then the mixture is filtered and concentrated i.vac. The residue is purified by chromatography on RP-HPLC (stable bond C18, 5 μm). The mixture was concentrated i.vac., taken up in water and treated with K2CO3. The aq. phase is diluted with ethyl acetate. The organic phase is dried, filtered and concentrated i.vac.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([NH:21][OH:22])([CH3:20])([CH3:19])[CH3:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N+:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[O-:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)NO
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)[N+]([O-])=Cc1ccc(OCc2ccccc2)cc1
Yield: 89.3 %

Procedure:
A mixture of 4-benzyloxybenzaldehyde, N-tert-butylhydroxylamine and catalytic amount of p-toluenesulfonic acid monohydrate in benzene was refluxed under argon atmosphere with a Dean-Stark trap to remove generated water. The mixture was then rotary evaporated to give a residue which was purified by recrystallization. The title compound was obtained in 89.3% yield as a white powder, m.p. 111.0° C. (Rf=0.66 on a silica gel plate using EtOAc as an eluant).