Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:18][C:19]([O:21]CC)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1>CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:18][C:19]([OH:21])=[O:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(CCCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC(CCCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.7 g of ethyl 8-(p-chlorophenyl- sulfonamido)-3-[4-(3-pyridyl)-butyl]-octanoate, in a mixture of 50 mL of methanol and 100 mL of 1N aqueous NaOH is stirred at room temperature for 18 hours. The reaction mixture is then concentrated to remove the methanol. The product is neutralized with dilute aqueous hydrochloric acid, and the aqueous solution extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate, filtered and concentrated to give 8-(p-chlorophenylsulfonamido)-3-[4-(3-pyridyl)-butyl]-octanoic acid, NMR (CDCl3): delta 7.77 (d,2H), 7.43 (d,2H), 2.9 (t,2H), 2.6 (t,2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:18])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[Cl:17])[C:6]=1[CH:7]=O.C1(P(=[CH:38][C:39]([O:41][CH3:42])=[O:40])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:18])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[Cl:17])[C:6]=1/[CH:7]=[CH:38]/[C:39]([O:41][CH3:42])=[O:40]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(Cl)c(C=O)n1Cc1ccc(I)cc1Cl
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1c(Cl)nc(C)n1Cc1ccc(I)cc1Cl
Yield: 84.5 %

Procedure:
To a solution of 4-chloro-1-(2-chloro-4-iodobenzyl)-2-methylimidazole 5-carbaldehyde (1.01 g) in tetrahydrofuran (10 ml) was added methyl (triphenylphosphoranylidene)acetate (1.27 g) and the mixture was refluxed under heating for 4 hr. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give methyl (E)-3-(4-chloro-1-(2-chloro-4-iodobenzyl)-2-methylimidazol-5-yl)-2-propenate (974 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:18]([O:20]C)=[O:19])=[N:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH3:16])[C:8](=[O:17])[C:7]=12.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[C:4]([C:18]([OH:20])=[O:19])=[N:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH3:16])[C:8](=[O:17])[C:7]=12
Reactant: COC(=O)c1nn2c(c1OC)c(=O)n(C)c1ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C(=O)O)nn2c1c(=O)n(C)c1ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-methoxy-5-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-2-carboxylate (220 mg, 0.7 mmol) in MeOH (5 mL) was added aqueous NaOH (0.91 mL of a 1.0 N solution, 0.91 mmol). The mixture was stirred at ambient temperature for 18 hours. Aqueous HCl (0.16 mL of a 6.0 N solution, 0.96 mmol) was added to the mixture and the solvents were removed under reduced pressure. The residue was triturated in 1:1 MeOH:water and filtered to give the product as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 13.31 (s, 1H), 8.20 (d, J=8.1 Hz, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.55 (t, f=8.0 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 3.99 (s, 3H), 3.60 (s, 3H); ES MS (M+1)=274.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[C:11]2[S:15][C:14](=[S:16])[N:13]([CH2:17][C:18]([OH:20])=[O:19])[C:12]2=[O:21])[C:8]([OH:10])=[O:9])[N:6]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)P(=O)(N(C)C)N(C)C>[C:8]([C:7](=[C:11]1[S:15][C:14](=[S:16])[N:13]([CH2:17][C:18]([OH:20])=[O:19])[C:12]1=[O:21])[C:5]1[N:6]=[C:2]([NH:1][C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[S:3][CH:4]=1)([OH:10])=[O:9]
Reactant: O=C=Nc1ccccc1
Reactant: Nc1nc(C(C(=O)O)=C2SC(=S)N(CC(=O)O)C2=O)cs1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)CN1C(=O)C(=C(C(=O)O)c2csc(NC(=O)Nc3ccccc3)n2)SC1=S

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 1 g of 5-[1-(2-aminothiazol-4-yl)-1-carboxymethylene]rhodanine-3-acetic acid, 3.9 g of phenyl isocyanate and 10 ml of hexamethylphosphoric triamide. The resulting product was a ellow powder having the following physical properties.
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[CH3:24]>>[CH3:24][C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[NH:13][CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Cc1cc(C(F)(F)F)ccc1N
Product: Cc1cc(C(F)(F)F)ccc1NC1CN(C(=O)OC(C)(C)C)C1
Yield: 21.4 %

Procedure:
The title compound (D32) (330 mg) was prepared according to the experimental procedure described in Description 30 starting from 1-Boc-3-azetidinone (800 mg, 4.67 mmol) and 4-Amino-3-methylbenzotrifluoride (818.4 mg, 4.67 mmol).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([Br:9])[C:5]([Br:10])=[C:4]([Br:11])[C:3]=1[Br:12].C1([O-])C=CC=CC=1.[Br:20][C:21]1[C:26]([O:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35]Cl)=[C:25]([Br:38])[C:24]([Br:39])=[C:23]([Br:40])[C:22]=1[Br:41]>[OH-].[K+].COCCO>[Br:20][C:21]1[C:26]([O:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][O:8][C:7]2[C:6]([Br:9])=[C:5]([Br:10])[C:4]([Br:11])=[C:3]([Br:12])[C:2]=2[Br:1])=[C:25]([Br:38])[C:24]([Br:39])=[C:23]([Br:40])[C:22]=1[Br:41]
Reactant: Oc1c(Br)c(Br)c(Br)c(Br)c1Br
Reactant: O=C(Oc1c(Br)c(Br)c(Br)c(Br)c1Br)c1ccccc1CCl
Agent: [K+]
Agent: [O-]c1ccccc1
Agent: [OH-]
Solvent: COCCO
Product: O=C(Oc1c(Br)c(Br)c(Br)c(Br)c1Br)c1ccccc1COc1c(Br)c(Br)c(Br)c(Br)c1Br

Procedure:
In a two-liter flask, 5.6 of potassium hydroxide was dissolved at 75° C in 800 ml of methyl glycol; then 48.9 g (= 0.1 mole) of pentabromphenol was stirred in. To this phenolate solution, at 75° C, 64.15 g was added of the o-chloromethylbenzoic acid pentabromophenyl ester, prepared as in Example 9a, and the mixture was heated with stirring to ebullition. It was refluxed for an hour, then cooled, and the solids were isolated and worked up as described in the preceding examples.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.C([O:22][C@@H:23]1[C@@H:26]([C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH3:28])[C:25](=O)[NH:24]1)(=O)C.S([O-])(O)(=O)=O.[K+]>ClCCl.[I-].[Zn+2].[I-]>[Si:30]([O:29][C@@H:27]([C@@H:26]1[C@@H:25]([CH2:10][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:11])[NH:24][C:23]1=[O:22])[CH3:28])([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:32])[CH3:31]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: COc1cccc(C(C)=O)c1
Agent: O=S(=O)([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)C[C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To m-methoxyacetophenone (7.5 g, 50 mmol) and triethylamine (10.5 ml, 75 mmol) in dichloromethane (200 ml) was dropped at 0° C. under stirring trifluoromethanesulfonic acid trimethylsilyl ester (10.9 ml, 60 mmol) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added at room temperature (2R,3R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxo-2-azetidinyl acetate (14.4 g, 50 mmol) and zinc iodide (9.6 g, 30 mmol), and the mixture was stirred for 2 hours. To the reaction mixture was added a 5% aqueous potassium hydrogensulfate solution (250 ml), and an organic layer was separated by a separatory funnel. An aqueous layer was extracted with chloroform (100 ml×twice). The extract was combined with the organic layer, dried over magnesium sulfate, filtered and concentrated. The residue was purified with silica gel chromatography (silica gel 400 g, hexane:ethyl acetate=2:1˜0:1) to give (3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-[2-(3-methoxyphenyl)-2-oxoethyl]azetidin-2-one (15.91 g, yield 84%) as a pale yellowish solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][N:8]=2)[N:6]=1.[Cl:17][C:18]1[CH:19]=[C:20]([C:24]([NH:26][C@H:27]2[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]2[O:33][CH2:34][CH2:35][CH3:36])=[O:25])[NH:21][C:22]=1[CH3:23].CCN(C(C)C)C(C)C.O>CN1CCCC1=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][N:30]([C:2]3[S:3][C:4]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([C:7]4[N:11]([CH3:12])[N:10]=[CH:9][N:8]=4)[N:6]=3)[CH2:29][C@@H:28]2[O:33][CH2:34][CH2:35][CH3:36])=[O:25])[NH:21][C:22]=1[CH3:23]
Reactant: CCCO[C@@H]1CNCC[C@@H]1NC(=O)c1cc(Cl)c(C)[nH]1
Reactant: COC(=O)c1sc(Cl)nc1-c1ncnn1C
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCO[C@H]1CN(c2nc(-c3ncnn3C)c(C(=O)OC)s2)CC[C@H]1NC(=O)c1cc(Cl)c(C)[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Methyl 2-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate (Intermediate 2, 68 mg, 0.267 mmol) was added to a solution of 4-chloro-5-methyl-N-[(3R,4S)-3-propoxypiperidin-4-yl]-1H-pyrrole-2-carboxamide (Intermediate 74, 80 mg, 0.267 mmol) and DIPEA (0.04 mL, 0.8025 mmol) in N-methyl 2-pyrrolidinone (1.0 mL) and the resulting reaction mixture was stirred overnight at 80° C. The reaction mixture was cooled to room temperature and poured into water (30 mL). The solid that formed was collected by filtration, washed well with diethyl ether (30 mL) and dried to afford methyl 2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate 80 mg (57.1%) as solid.
Reaction SMILES: [O:1]=[C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].I[CH3:18]>O1CCCC1>[CH3:18][CH:9]([C:2](=[O:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(C)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
To a solution of diethyl 3-oxopentanedioate (23.2 g, 114.8 mmol) in tetrahydrofuran (100 mL) was added sodium hydride (60%, 4.8 g, 120.5 mmol) at 0° C., and the reaction mixture was stirred at RT for 30 mins, followed by the addition of iodomethane (7.15 ml, 114.8 mmol). The reaction mixture was stirred at RT for 48 h, quenched with water (500 mL) and extracted with ethyl acetate (500 mL×3). The organic layers were separated, combined, washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate=20:1) to get the title compound as a colorless oil (9 g, 36%). MS (ES+) C10H16O5 requires: 216. Found: 217 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:9]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:17]3[C@H:13]([CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16]3)[C:12](=[O:25])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>CO>[C:3]1([C:9]2([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C@H:17]3[C@H:13]([CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16]3)[C@@H:12]([OH:25])[CH2:11][CH2:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Reaction time: 3 h
Yield: 46.9 %

Procedure:
A solution of 1 g of sodium borohydride in 200 cm3 of methanol is added dropwise over 40 minutes to a solution, cooled to +4° C., of 17.8 g of (3aR, 7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindolone in one litre of methanol, followed by 10 drops of lye. The reaction mixture is stirred for 3 hours at +4° C. and then 2 cm3 of a 0.1N aqueous solution of hydrochloric acid are added and the mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in 350 cm3 of dichloromethane, washed with 100 cm3 of water and then with 50 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 40 cm3 of ethyl ether. The crystals obtained are drained and dried. 8.4 g of (3aR, 4S, 7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindolol are obtained in the form of white crystals; melting point 190° C. The crystallization mother liquors are concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 33 cm), eluting under a nitrogen pressure of 0.4 bar with a dichloromethane and methanol mixture (96/4 by volume) and collecting fractions of 20 cm3. Fractions 18 to 21 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 1.88 g of (3aR, 4R,7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindolol are obtained in the form of a white meringue. Fractions 26 to 31 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 5 cm3 of ethyl ether. 2.88 g of (3aR, 4S, 7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindolol are additionally obtained in the form of white crystals; melting point 190° C.
Reaction SMILES: C1C=CC2N(O)[N:8]=[N:7]C=2C=1.CCN=C=NCCCN(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][N:31]=1)[C:26](O)=[O:27].O.NN>C(#N)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][N:31]=1)[C:26]([NH:7][NH2:8])=[O:27]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: O
Solvent: CC#N
Product: NNC(=O)c1ccnc(Cl)c1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
HOBt (823 mg, 6.09 mmol), and EDCI (1.2 g, 6.09 mmol) were added to a suspension of 2-chloro-isonicotinic acid (800 mg, 5.08 mmol) in acetonitrile (10.3 ml) at room temperature. After two h a solution of hydrazine monohydrate (0.493 ml, 10.2 mmol) in acetonitrile (5.0 ml) was added drop-wise at 0° C. After 30 min, the solvent was removed using a roto-evaporator and the residue was diluted with ethyl acetate, quenched with water, dried over sodium sulfate, filtered and concentrated to afford 2-chloro-isonicotinic acid hydrazide (493 mg, 57%, yellow solid). 1H NMR (DMSO) d (ppm): 10.21 (bs, 1H), 8.55 (d, 1H), 7.82 (s, 1H), 7.75 (d, 1H), 4.69 (bs, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[C:17]([O:22][CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14]=2[C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]1[CH2:32][OH:33].C([O-])([O-])=O.[Na+].[Na+]>O.C(O)(=O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:11]2[O:12][C:13]3[C:18]([C:19](=[O:21])[CH:20]=2)=[C:17]([O:22][CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14]=3[C@@H:26]2[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]2[CH2:32][OH:33])=[C:2]([Br:1])[CH:7]=1
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccc([N+](=O)[O-])cc3Br)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(OC)c2c(=O)cc(-c3ccc(N)cc3Br)oc2c1[C@@H]1CCN(C)[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound of example 41 (0.3 g, 0.6 mmol) was treated with iron dust (0.3 g) in water (1.2 mL) and glacial acetic acid (1.2 mL). The reaction mixture was stirred vigorously at room temperature for 1 h. It was poured into water (25 mL), basified using saturated aqueous Na2CO3 solution and extracted with EtOAc (3×25 mL). The organic extract was washed, dried (anhydrous Na2SO4) and concentrated to obtain the title compound.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:8]1[C:21]2NC3C(=CC=CC=3)SC=2C=C[CH:9]=1>C(O)CCC>[C:1]([O:6][CH2:7][CH2:9][CH2:8][CH3:21])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCCCO
Product: C=C(C)C(=O)OCCCC
Reaction time: 6 h

Procedure:
Two hundred six grams of a reaction mix containing a 5:1 mole ratio of methyl methacrylate, 1-butanol, and 100 ppm phenothiazine as inhibitor were added to a 500 ml flask equipped with an agitatior, thermocouple, and a 10-tray Oldershaw fractional distillation column. Thirty grams of the heterogeneous zirconium vinylbenzyl acetylacetonate/styrene/divinylbenzene catalyst was added. The mixture was heated to reflux at atmospheric pressure while an azeotropic mixture of methyl methacrylate and methanol was removed from the upper portion of the fractionating column. The reaction was continued in this manner for 6 hours while the temperature at the column was 64°-67° C. and the temperature in the pot was 101°-107° C. Gas liquid chromatography (GLC) analysis showed 60% conversion of 1-butanol with a selectivity to butyl methacrylate of 99%.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[O:15])[CH2:10][CH2:9]2)C=CC=CC=1.[C:21](Cl)(=[O:25])[O:22][CH2:23][CH3:24]>C1C=CC=CC=1>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:21]([O:22][CH2:23][CH3:24])=[O:25])[CH2:13][CH2:12]1)=[O:15]
Reactant: CCOC(=O)Cl
Reactant: O=C(c1cccs1)C1CCN(Cc2ccccc2)CC1
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(C(=O)c2cccs2)CC1
Reaction time: 6 h

Procedure:
To a stirred mixture of 15 parts of [1-(phenylmethyl)-4-piperidinyl](2-thienyl)methanone in 120 parts of benzene are added dropwise 8 parts of ethyl carbonochloridate. Upon completion, the whole is heated to reflux and stirred for 6 hours at reflux temperature. The reaction mixture is cooled, filtered and evaporated, yielding 13 parts of ethyl 4-(2-thienylcarbonyl)-1-piperidinecarboxylate as a residue.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@:21](Br)([C@@H:22]([F:24])[CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].C([SnH](CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([C@@H:22]([F:24])[CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(Br)[C@@H](F)C[C@]12C
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@]12C

Procedure:
8 g. of 17β-acetoxy-9-bromo-11β-fluoro-4-androsten-3-one is agitated at room temperature for 5 hours in 160 ml. of tetrahydrofuran with 20 ml. of tributyltin hydride with the addition of 10 mg. of α ,α'-azoisobutyrodinitrile. The solution is evaporated under vacuum; the residue is crystallized with hexane. The crystalline product is vacuum-filtered and chromatographed on silica gel for further purification. With ethyl acetate/hexane, 3.4 g. of 17β-acetoxy-11β-fluoro-4-androsten-3-one is obtained as the elution product; m.p. 165°-167° (decomposition). UV: ε239 = 16,400 (methanol).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:4]=1.[B-](F)(F)(F)[C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=1.[K+].C([O-])([O-])=O.[Cs+].[Cs+]>COC1CCCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=2)=[CH:4][C:5]=1[C:10]([F:13])([F:12])[F:11]
Reactant: O=Cc1ccc([B-](F)(F)F)cc1
Reactant: FC(F)(F)c1cc(CBr)ccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COC1CCCC1
Product: O=Cc1ccc(Cc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
To a suspension of 4-(bromomethyl)-1-chloro-2-(trifluoromethyl)benzene (4.5 g, 16.45 mmol), potassium trifluoro(4-formylphenyl)borate (3.52 g, 16.62 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.672 g, 0.823 mmol) and Cs2CO3 (16.08 g, 49.4 mmol) in cyclopentyl methyl ether (100 mL) and water (100 mL). The mixture was charged with Argon and stirred for overnight at 80° C. The result mixture was cooled to room temperature and partitioned with water 100 mL and ethyl acetate 100 mL. The organic phase was washed by water, brine and dried over sodium sulfate, the solvent was removed and the residue was purified via flash column chromatography. Removed the solvent afforded the title compound (2.55 g). LC-MS (ESI): m/z 299 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:17][C:18]3[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Reactant: CCOC(=O)c1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1CN1CCOc2cc([N+](=O)[O-])ccc21
Yield: 237.2 %

Procedure:
The same operation as in Example (90a) was performed using 7-nitro-2,3-dihydro-4H-1,4-benzoxazine (described in Higuchi, Robert I.; Arienti, Kristen L.; Lopez, Francisco J.; Mani, Neelakhanda S.; Mais, Dale E.; Caferro, Thomas R.; Long, Yun Oliver; Jones, Todd K.; Edwards, James P.; Zhi, Lin; Schrader, William T.; et al.; J. Med. Chem.; 50; 10; 2007; 2486-2496, 0.6 g, 3.3 mmol), sodium hydride (55% content, 145 mg, 3.3 mmol), ethyl 2-chloromethyl-benzoate (1.95 g, 10.8 mmol) and DMF (30 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/3, 2/3, 3/2, 3/1) to obtain 2.68 g of the title compound as a yellow solid (72%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Ni].C1(C)C(C)=CC=CC=1>[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: OCCc1ccccc1
Agent: [Ni]
Solvent: Cc1ccccc1C
Product: O=C(NC1CCN(CCc2ccccc2)CC1)c1ccccc1

Procedure:
2-Phenylethanol (0.61 g., 0.005 mole), 4-benzamidopiperidine (1.02 g., 0.005 mole) and Raney Nickel (W7, ca. 2 g.) were stirred in xylene (50 ml.) and the mixture boiled under reflux for 16 hours. Liberated water was removed by means of a Dean and Stark apparatus. Filtration of the hot mixture provided a yellow solution which was stored at room temperature until crystallisation was complete. The title compound was obtained as cream needles (0.85 g.), m.p. 164°-7° C.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=[C:9]([Cl:18])[CH:8]=2>CN(C=O)C.O>[Cl:18][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[NH:14][CH2:15][CH2:16][O:17][C:4]=3[CH:5]=[N:6][C:7]=2[CH:8]=1
Reactant: OCCNc1c(Br)cnc2cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2c3c(cnc2c1)OCCN3
Reaction time: 2 h

Procedure:
Sodium hydride (obtained from 3 g of 50% suspension in mineral oil) was added to a solution of 3-bromo-7-chloro-N-(2-hydroxyethyl)-4-quinolinamine (15 g) in 30 ml of DMF and the mixture stirred at 80°-90° C. for 2 hours. After cooling, it was diluted with 300 ml of water and the product extracted with ethyl acetate. The extract was dried over sodium sulfate, the solvent was evaporated and the oily residue purified by high pressure liquid chromatography (HPLC) (hexane:ethyl acetate=1:1). The desired fractions were combined, concentrated and recrystallized from isopropanol. The yield was 2.0 g, mp 219°-220° C.