Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3](O)[OH:4].[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][N:16]([C:18]([NH:23][CH3:24])=[CH:19][N+:20]([O-:22])=[O:21])[CH3:17])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]([OH:4])[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([N:16]([CH2:15][C:12]1[CH:13]=[N:14][C:9]([Cl:8])=[CH:10][CH:11]=1)[CH3:17])[NH:23][CH3:24]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: CNC(=C[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC(=C(C(O)C(Cl)(Cl)Cl)[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Chloral hydrate (0.40 g) was added slowly in 40 minutes to a mixture of 1-[N-(6-chloro-3-pyridylmethyl)-N-methylamino]-1-methylamino-2-nitroethylene (0.26 g), triethylamine (0.1 g) and acetonitrile (3 ml). The mixture was stirred at room temperature for 21 hours and under refluxing for 9 hours. The resultant crystals were collected by filtration to give 1,1,1-trichloro-4-[N-(6-chloro-3-pyridylmethyl)-N-methylamino]-4-methylamino-3-nitro-3-buten-2-ol (Compound No. 11) (0.23 g) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][O:49][C:50]2[CH:59]=[CH:58][C:57]([C:60]3[CH:61]=[N:62][N:63]([CH2:65][CH2:66][O:67][CH3:68])[CH:64]=3)=[CH:56][C:51]=2[C:52](OC)=[O:53])=[CH:44][CH:43]=1>CN(C)C=O>[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][O:49][C:50]2[CH:59]=[CH:58][C:57]([C:60]3[CH:61]=[N:62][N:63]([CH2:65][CH2:66][O:67][CH3:68])[CH:64]=3)=[CH:56][C:51]=2[C:52]([NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:53])=[CH:44][CH:43]=1
Reactant: Nc1cccnc1
Reactant: COCCn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)OC)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)Nc3cccnc3)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Pyridinamine (49.0 mg, 0.52 mmol), HATU (148 mg, 0.39 mmol) and diisopropylethylamine (0.11 ml, 0.65 mmol) were added to a solution of methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-{1-[2-(methyloxy)ethyl]-1H-pyrazol-4-yl}benzoate (may be prepared as described in Description 116; 100 mg, 0.26 mmol) in N,N-dimethylformamide (5 ml) and the mixture was stirred at room temperature overnight. The DMF was evaporated under reduced pressure on a buchi. Water (5 ml) and ethyl acetate (10 ml) were added to the residue. The organics were separated and the aqueous layer was further extracted with ethyl acetate (3×10 ml). The organics were combined and evaporated. The residue was purified using MDAP to yield the title compound. 36 mg.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C1(S([Cl:28])(=O)=O)C=CC=CC=1>C(OCC)C.CCOC(C)=O>[C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([Cl:28])=[CH:12][N:13]=1)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)NS(=O)(=O)c1nccs1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)NS(=O)(=O)c1ncc(Cl)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a solution of (tert-butyl)(1,3-thiazol-2-ylsulfonyl)amine (0.15 g, 0.7 mmol) in ethyl ether (3 mL) at −78° C. was added a 1.6M solution of n-butyllithium (0.875 mL, 1.4 mmol) in hexanes via syringe under argon: The reaction mixture was stirred at −78° C. for 1 hr, then neat benzenesulfonyl chloride (90 μL, 0.7 mmol) was added. The resulting suspension was stirred at room temp for 2 hr. The reaction was diluted with EtOAc, washed with water and brine, dried, concentrated in vacuo and chromatographed (15% EtOAc/hexane) to give pure desired compound (58 mg, 33%). ES-MS (M+Na)+=277, 279 (Cl), (M−tBu+H)+=199, 201 (Cl).
Reaction SMILES: [CH3:1][Si:2]([CH3:41])([C:35]([CH3:40])([CH3:39])[CH:36]([CH3:38])[CH3:37])[O:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[O:28])[CH2:14][CH2:13][C@H:12]([CH2:29]O)[CH2:11][O:10][C:9](=[O:31])[C:8]=2[C:7]([CH3:32])=[C:6]([O:33][CH3:34])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:87]=[N+:88]=[N-:89])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:87]([CH2:29][C@@H:12]1[CH2:11][O:10][C:9](=[O:31])[C:8]2[C:7]([CH3:32])=[C:6]([O:33][CH3:34])[CH:5]=[C:4]([O:3][Si:2]([CH3:1])([CH3:41])[C:35]([CH3:40])([CH3:39])[CH:36]([CH3:37])[CH3:38])[C:21]=2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]2[O:26][N:25]=[C:24]([CH3:27])[N:23]=2)[NH:16][C:15](=[O:28])[CH2:14][CH2:13]1)=[N+:88]=[N-:89]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@@H](CO)CCC(=O)N[C@H](c1nc(C)no1)CSC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@@H](CN=[N+]=[N-])CCC(=O)N[C@H](c1nc(C)no1)CSC2
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a solution of 140 mg of (4R,9R)-16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-9-hydroxymethyl-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-6,12-dione and 121 mg of triphenyl-phosphine in 2 ml of tetrahydrofuran were added at 0° C. 80 mg of diethyl azodicarboxylate and 127 mg of diphenylphosphoryl azide. The mixture was stirred at 0° C. for 35 min and then evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent, to yield (4R,9R)-9-azidomethyl-16-[dimethyl-(1,1,2-trimethyl-propyl)silanyloxy]-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-6,12-dione as a foam
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]([NH:11][NH:12][CH:13]=O)=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CN(C=O)C>[N:11]1[N:12]=[CH:13][N:1]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:9]=1
Reactant: O=CNNC=O
Reactant: Nc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Oc1ccc(-n2cnnc2)cc1

Procedure:
4-aminophenol (1 g, 9.16 mmol) and bisformyl hydrazine (888 mg, 10.08 mmol) were dissolved in a mixture of toluene (30 mL) and DMF (3 mL), followed by addition of pTSA (1.92 g, 10.08 mmol). The mixture was heated under reflux for 3 hours. Upon cooling, the mixture separated to two layers. The upper toluene layer was discarded. The lower dark DMF layer was directly purified by column chromatography using a 115 gram biotage silica gel cartridge eluting with 20-40 ethyl acetate/hexanes (gradient) to give the product as pale yellow solid. LRMS tale: 161.1; obs: 162.4 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:10]2[CH:11]=[CH:12][C:13]3[C:18]([C:9]2=[N:8][C:7]=1[CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19].C(N(CC)CC)C.Cl[C:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[S:31](=[O:39])(=[O:38])[N:30]=1>C(O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][N:10]1[C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[S:31](=[O:38])(=[O:39])[N:30]=3)=[C:7]([CH3:20])[N:8]=[C:9]12
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1CSCCN
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc2c3cccc(Cl)c3ccn2c1CSCCNC1=NS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a mixture of 3-(2-aminoethyl)thiomethyl-7-chloro-2-methylimidazo[2,1-a]isoquinoline (1.5 g) and triethylamine (0.5 g) in ethyl alcohol (35 ml) was added portionwise 3-chloro-1,2-benzisothiazole-1,1dioxide (1.0 g). After being stirred at ambient temperature for 1 hour, the resulting precipitate was collected by filtration and washed several times with ethyl alcohol to give 3-[2-[(7-chloro-2-methylimidazo[2,1-a]isoquinolin-3-yl)methylthio]ethylamino]-1,2-benzisothiazole-1,1-dioxide (2.2 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([C:33]3[S:37][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:34]=3)=[N:11][N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)O1.Br[C:44]1[CH:45]=[CH:46][C:47]2[N:48]([C:50]([C:53]3[S:54][CH:55]=[CH:56][N:57]=3)=[CH:51][N:52]=2)[CH:49]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[S:54]1[CH:55]=[CH:56][N:57]=[C:53]1[C:50]1[N:48]2[CH:49]=[C:44]([C:9]3[C:10]([C:33]4[S:37][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:34]=4)=[N:11][N:12]([C:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:13]=3)[CH:45]=[CH:46][C:47]2=[N:52][CH:51]=1
Reactant: Brc1ccc2ncc(-c3nccs3)n2c1
Reactant: COC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2B2OC(C)(C)C(C)(C)O2)s1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4nccs4)n3c2)s1
Yield: 86.2 %

Procedure:
1.6 g methyl 5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-3-pyrazolyl]-2-thiophene carboxylate (compound in Production Example 117), 0.6 g 2-(6-bromoimidazo[1,2-a]pyridin-3-yl)-1,3-thiazole (compound in Production Example 57), 0.68 g tripotassium phosphate, 0.12 g tetrakis (triphenylphosphine)palladium and 30 mL N,N-dimethylformamide were heated at 85° C. for 2.5 hours under nitrogen atmosphere. After the solvent was removed, the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give 1.2 g of the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1.C(N(CC)CC)C.[Cl:33][CH2:34][C:35](Cl)=[O:36]>C1COCC1>[Cl:33][CH2:34][C:35]([NH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1)=[O:36]
Reactant: O=C(Cl)CCl
Reactant: Cc1c(-c2ccc(C(=O)N3CCC[C@H](N)C3)s2)noc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](NC(=O)CCl)C3)s2)noc1C(F)(F)F
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of ((S)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone, hydrochloride (Example 26, 79 mg, 0.20 mmol) and triethylamine (69 μL, 0.42 mmol) in THF (3 mL) was treated with chloroacetyl chloride (18 μL, 0.22 mmol), stirred for 1 hr and evaporated to a solid. The solid was triturated and filtered with the aid of water, then air dried to provide the 2-Chloro-N-{(S)-1-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-yl}-acetamide intermediate as a colorless solid (75 mg, 86%). LC/MS 6.13 min, [M+1]+ 436. The chloroacetyl intermediate (35 mg, 0.08 mmol) was dissolved in acetonitrile (3 mL) containing anhydrous K2CO3, treated with morpholine (14 μL, 0.16 mmol), and stirred for 3 days. The reaction mixture was then evaporated and treated with water to provide an oil which was then triturated with water (3×2 mL), dissolved in EtOAc (4 mL), dried over MgSO4, filtered, and evaporated to afford product as an oil (34 mg, 87%). 1H NMR (CDCl3) 1.62-1.76 (m, 3 H), 1.88-1.98 (m, 1 H), 2.29 (d, J=1.3, 3 H), 2.45-2.48 (m, 4 H), 2.93 (s, 2 H), 3.52 (br s, 1 H), 3.63-3.67 (m, 4 H), 3.72-3.92 (m, 2 H), 3.98-4.08 (m, 1 H), 7.32 (br s, 1 H), 7.41 (s, 2 H). 19F NMR −63.1. LC/MS 4.68 min, [M+1]+ 487.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[CH2:15][CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:21])[CH2:5][CH2:4]2.[BH4-].[K+].O.C(O)(=[O:27])C>C(O)C>[OH:27][C@H:15]1[CH2:14][CH2:13][C@H:12]2[C@H:11]3[C@H:20]([CH2:19][CH2:18][C@:16]12[CH3:17])[C@:3]1([CH2:2][OH:1])[C:8](=[CH:7][C:6](=[O:21])[CH2:5][CH2:4]1)[CH2:9][CH2:10]3
Reactant: C[C@@]12CCC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(CO)[C@H]1CC2
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 150 g of 19-hydroxyandrost-4-en-3-one in 6 liters of ethanol is cooled in an ice bath. To this cold solution is added 13.5 g of potassium borohydride, and the reaction mixture is stirred for two hours at about 0° C after which a second 13.5 g or potassium borohydride is added. Two hours later a third 13.5 g portion of potassium borohydride is added to the reaction mixture which is stirred for an additional 1 hour then poured into 11 liters of water to which 70 ml of acetic acid is added. The ethanol is distilled off under reduced pressure and the aqueous residue cooled to 0° C. The solid which separates is filtered off, dried and dissolved in 25 liters of hot chloroform after which the temperature is adjusted to 25° C. To the chloroform solution is added 250 g of manganese dioxide, and the mixture is stirred for 2 hours then filtered and the solvents removed under reduced pressure. The solid residue is recrystallized from acetonitrile to give 17β,19-dihydroxyandrost-4-en-3-one. M.P. 205°-207° C.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([CH2:12][NH2:13])[O:8][C:7]=2[CH:14]=1.Br[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24](=[O:30])[CH:25]=[CH:26][O:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([CH2:12][NH:13][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24](=[O:30])[CH:25]=[CH:26][O:27]4)=[CH:22][CH:21]=3)[O:8][C:7]=2[CH:14]=1
Reactant: O=c1ccoc2cc(OCCCBr)ccc12
Reactant: NCC1COc2ccc(O)cc2O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccoc2cc(OCCCNCC3COc4ccc(O)cc4O3)ccc12
Temperature: 80 °C
Yield: 10.1 %

Procedure:
2,3-Dihydro-7-hydroxy-1,4-benzodioxin-2-methanamine hydrochloride (4.7 g, 22 mmole), 7-(3-bromopropoxy)chromen-4-one (6.1 g, 22 mmole) and diisopropylethylamine (18.8 ml, 108 mmole) were combined in 200 ml of DMF and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. The residue was chromatographed on a silica gel column using first dichloromethane and then 5% methanol/dichloromethane as eluents. The fractions containing material with Rf=0.37 on silica gel tlc (chloroform/methanol/ammonia=95/5/1) were combined, concentrated, and the residual solid was recrystallized from ethanol with the addition of 4N isopropanolic HCl and ether to give 0.85 g of title compound as a light brown solid hydrochloride, quarter hydrate, m.p. 186°-189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: Clc1ccccc1N1CCNCC1
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccccc2Cl)CC1
Yield: 91 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 3.15 (s, 4H), 3.79 (s, 4H), 4.15 (s, 3H), 6.99-7.06 (m, 2H), 7.23-7.45 (m, 4H), 7.74-7.79 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>CO.C(Cl)Cl>[C:16]1([S:15][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:1][NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=4)[CH:4]=3)[NH:8][C:7]=2[C:12]([NH2:14])=[O:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1[nH]c2ccc(CNc3cccc(C(F)(F)F)c3)cc2c1Sc1ccccc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with 3-trifluoromethylaniline (80 mg, 0.50 mmol) as described in General Procedure X to afford Iac (36 mg, 48.3%) as an ivory colored solid, tlc Rf=0.5 (5% MeOH/CH2Cl2), m/z obs=442 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24](=[CH2:27])[CH2:25][CH3:26])[C:5]2=[CH:4][CH:3]=1.[CH3:29][O:30][CH:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])[CH3:32].Br[CH2:38][C:39]([NH2:41])=[O:40].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:41][C:39]([CH2:38][N:12]1[C:13](=[O:23])[CH2:14][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:28])[CH:11]1[C:24](=[CH2:27])[CH2:25][CH3:26])=[O:40].[CH3:29][O:30][CH:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])[CH3:32]
Reactant: C=C(CC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Reactant: NC(=O)CBr
Agent: COC(C)[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=C(CC)C1N(CC(N)=O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Reaction time: 8 h
Yield: 36.2 %

Procedure:
Racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (2 g, 3.4 mmol) prepared in Example 161b, 2-bromo-acetamide (1.4 g, 10.2 mmol) and cesium carbonate (6.6 g, 20.4 mmol) were mixed in DMF (10 mL). The mixture was stirred overnight. Then the solution was concentrated and the residue was purified by Prep-TLC to give product (800 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH2:24].CCOC(C)=O>CS(C)=O>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH:24][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1ccc2nc(Cl)cnc2c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(CNc2cnc3cc(C)ccc3n2)c(OC)c1
Yield: 95.8 %

Procedure:
2-Chloro-6-methylquinoxaline (0.51 g, 2.86 mmol), prepared according to J. Chem. Soc. 1948, 1310-1313, and (2,4-dimethoxyphenyl)methanamine (1.29 mL, 8.57 mmol) were microwaved in DMSO (2.5 mL) for 30 min at 150° C. This was diluted into 150 mL EtOAc and extracted three times with 100 mL brine. The crude product was purified by flash chromatography on a 90 g silica gel cartridge with 20 to 60% EtOAc in hexane, 50 min, at 40 mL/min to afford N-(2,4-dimethoxybenzyl)-6-methylquinoxalin-2-amine (848 mg, 2.74 mmol, 96% yield).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:29][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2cccc(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cccc(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 35.4 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluorobenzyl)piperidine-1-carboxylate (0.663 g, 1.81 mmol) (from example 99, step 1) was dissolved in MeOH (8 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.073 g, 1.81 mmol) dissolved in water (1 mL) was added during 20 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.111 mL, 1.81 mmol) was added during 5 min. The resulting solution was stirred at −40° C. for 4 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (9 mL, 54.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a brown semi-solid. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(3-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (214 mg, 35%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.47-1.77 (m, 2H), 1.82-2.15 (m, 2H), 2.75-3.00 (m, 2H), 3.00-3.15 (m, 2H), 3.40-3.80 (m, 3H), 4.00-4.42 (m, 1H), 4.42-4.80 (m, 1H), 5.64 (s, 1H), 6.83-7.05 (m, 3H), 7.22-7.31 (m, 1H). MS m/z 335 (M+H)+
Reaction SMILES: OC1C=C(C[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[OH:19])C=C(O)C=1.C[O:21][C:22]1[C:29]([CH3:30])=[C:28]([O:31]C)[CH:27]=[CH:26][C:23]=1[CH:24]=O>>[OH:19][C:13]1[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][CH2:24][C:23]1[CH:26]=[CH:27][C:28]([OH:31])=[C:29]([CH3:30])[C:22]=1[OH:21]
Reactant: COc1ccc(C=O)c(OC)c1C
Reactant: Oc1cc(O)cc(CCCc2ccc(O)cc2O)c1
Product: Cc1c(O)ccc(CCCc2ccc(O)cc2O)c1O

Procedure:
Compound 32 was synthesized following a similar procedure as described for compound 30 using as starting materials 2,4-dibenzyloxyacetophenone and 2,4-dimethoxy-3-methylbenzaldehyde. 1H-NMR (MeOD, 500 MHz): δ 6.879 (d, 1H, J=8.5 Hz), 6.747(d, 1H, J=8.0 Hz), 6.352(d, 1H, J=1.5 Hz), 6.341(d, 1H, J=4.0 Hz), 6.285(dd, 1H, J=8.0 Hz & 2.5 Hz), 2.567(dd, 4H, J=8.0 & 7.5 Hz), 2.133(s, 3H), 1.786-1.817 (m, 2H). 13C-NMR (MeOD, 125 MHz): δ 155.486(C), 155.316(C), 153.428(C), 152.906(C), 130.295(CH), 126.523(CH), 120.933(C), 120.518(C), 111.556(C), 106.788(CH), 106.377(CH), 102.283 (CH), 30.767(CH2), 29.649(CH2), 29.127(CH2), 7.833(CH3).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=O.[OH-].[Na+].[CH3:14][C:15]([CH3:17])=[O:16]>O>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1/[CH:4]=[CH:14]/[C:15](=[O:16])[CH3:17]
Reactant: O=Cc1c(Cl)ccc(Cl)c1Cl
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1c(Cl)ccc(Cl)c1Cl
Reaction time: 4 h
Yield: 92.3 %

Procedure:
Using the method of Example 1 step 1: To 5.0 g (23.9 mmole) of 2,3,6-trichloro benzaldehyde in 20 ml acetone, was added 2.3 g 50% aqueous NaOH (28.7 mmole) in 100 ml water; After 4 hours the reaction mixture was worked u to give 5.5 g of the trans-4-(2,3,6-trichlorophenyl)-3-buten-2-one as a yellow oil with solid in a 92.3% yield (99% purity by GLC).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:15][CH2:16][NH2:17])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[CH2:2][CH3:3].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:30][C:31](OCC)=[O:32])[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:19]>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:15][CH2:16][NH:17][C:31](=[O:32])[CH2:30][C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH3:29])=[C:21]([O:20][CH2:18][CH3:19])[CH:22]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[CH2:2][CH3:3]
Reactant: CCOC(=O)Cc1ccc(OCC)c(OCC)c1
Reactant: CCCOc1ccc(CCN)cc1OCCC
Product: CCCOc1ccc(CCNC(=O)Cc2ccc(OCC)c(OCC)c2)cc1OCCC

Procedure:
N-[2-(3,4-di-n-propoxyphenyl)ethyl]-3,4-diethoxy-phenylacetamide was prepared from 2-(3,4-di-n-propoxyphenyl)ethylamine and ethyl 3,4-diethoxyphenylacetate using the process described in Example 1 (a).