Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]O.[C:3]1([CH:9]([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C(Cl)=CC=C(Cl)C=1.C(OCC1OC1)(=O)C(C)=C.[C:30]1([C:36]([CH2:38]C(C2C=CC=CC=2)(C)C)=[CH2:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:11][C:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[CH2:10].[CH3:38][C:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH2:37]
Reactant: C=C(CC(C)(C)c1ccccc1)c1ccccc1
Reactant: CC(C)c1ccccc1
Agent: C=C(C)C(=O)OCC1CO1
Agent: [O-]O
Solvent: Clc1ccc(Cl)cc1
Product: C=C(C)c1ccccc1
Temperature: 90 °C
Reaction time: 0.71 h

Procedure:
A high temperature initiator, cumene hydroperoxide, was included in this run to drive the polymerization further towards completion and to reduce residual monomer. The flask was charged with brominated styrene monomer (1002.6), dichlorobenzene (497 g), glycidyl methacrylate (5.13 g, 0.0360 mol), 2,4-diphenyl-4-methyl-1-pentene (20.26 g, 0.08571 mol), VAZO-52™ azo type initiator (1.05 g, 4.22 mmol) and cumene hydroperoxide (1.06 g, 6.96 mmol). The solution was then heated to about 90° C. until exotherm. Peak temperature reached was 163° C. after which the mixture was heated to 190° C. over 5-10 min and held at 190° C. for 40-45 min. Heating was halted; the solution (1513.7 g) was transferred to a 2-liter bottle, and cooled to room temperature. The material was split into four parts. Each part was precipitated into a 5-liter flask of 3400 mL acetone and 400 mL methanol. The precipitate was filtered over frit, dried at ambient temperature for about 14 h and oven dried at 110° C. for 8 h. A white powder (883 g) was isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5]([Cl:23])=[CH:4][N:3]=1.Br[C:25]1[N:26]=[CH:27][C:28]([C:31]#[N:32])=[N:29][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:23][C:5]1[C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]2)=[CH:7][C:2]([NH:1][C:25]2[CH:30]=[N:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(N)ncc2Cl)CC1
Reactant: N#Cc1cnc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2Cl)CC1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 60.1 %

Procedure:
Dry dioxane (0.45 mL) was added to a microwave reaction vial containing tert-butyl 4-((2-amino-5-chloropyridin-4-ylamino)methyl)piperidine-1-carboxylate (23 mg, 0.067 mmol), 5-bromopyrazine-2-carbonitrile (8.3 mg, 0.045 mmol), tris(dibenzylideneacetone)-dipalladium chloroform complex (1.9 mg, 4 mol %), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (2.2 mg, 8 mol %) and sodium tert-butoxide (6.1 mg, 1.4 eq.) under nitrogen. The vial was sealed and nitrogen gas was bubbled through the suspension with stirring for 5 min. The mixture was heated at 90° C. for 30 min under microwave irradiation. The mixture was diluted with methanol and adsorbed onto Isolute SCX-II acidic resin (2 g). The resin was washed with methanol, then 2M ammonia in methanol. The basic fractions were concentrated and the residue was further purified by preparative thin layer chromatography, eluting with 5% MeOH in dichloromethane, to give tert-butyl 4-((5-chloro-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (12 mg, 60%) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5C(OC)=CC=C2[C@]5(C=34)CC1.[O-]C(C(C(C(O)=O)O)O)=O.CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5C(C=C[C@@H]2[C@]5(C=34)CC1)=O.OO.C(OO)(=O)C>C(O)=O.C(O)(C)C>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][CH:13]5[C:14]([CH:16]=[CH:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: CC(=O)OO
Agent: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Solvent: O=CO
Solvent: CC(C)O
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314

Procedure:
Oxycodone has also been prepared from thebaine bitartrate and codeinone ethyldienol ether by oxidation with hydrogen peroxide in formic acid and isopropanol, followed by catalytic hydrogenation5. Oxycodone has also been prepared by the oxidation with peracetic acid of codeinone dienol silylether in organic solvents to give 14-hydroxycodeinone, followed by catalytic hydrogenation in acetic acid solution15.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:14]=[CH:15]/[C:16]([O:18]CC)=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: CCOC(=O)/C=C/c1ccc(Cn2ccnc2)c(Cl)c1
Agent: Cl
Product: O=C(O)/C=C/c1ccc(Cn2ccnc2)c(Cl)c1
Reaction time: 2 h

Procedure:
A mixture of ethyl (E)-3-[3-chloro-4-(imidazol-1-ylmethyl)phenyl]prop-2-enoate (0.1 g, 0.31 mmol) and hydrochloric acid (6M, 2.0 ml) was stirred and boiled for 2 h. The reaction mixture was then concentrated under reduced pressure, when ethanol (4.0 ml) was added and the reaction mixture was again concentrated.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10](O)=[O:11].CO.Cl>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[CH2:10][OH:11]
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: OC[C@@H]1Cc2ccccc2N1
Reaction time: 2 h
Yield: 87 %

Procedure:
BH3-DMS solution (18.4 mmol, 2 eq) was added dropwise to a solution of (S)-indoline-2-carboxylic acid (9.2 mmol, 1.0 eq) in THF (18 ml) and the mixture was refluxed for 12 h. Methanol (7.5 ml) and concentrated HCl (2.5 ml) were added to the reaction mixture with cooling, then refluxing was continued for a further 2 hours. The solvent was removed under vacuum and the residue made alkaline with 40% NaOH solution and extracted with DCM. The organic phase was washed with saturated sodium chloride solution, dried (Na2SO4) and concentrated to small volume under vacuum. The crude product was processed by column chromatography. Yield: 87%
Reaction SMILES: C1(COC2C(C3N([CH2:17][C:18]4[CH:23]=[CH:22][C:21](CCC(O)=O)=[CH:20][CH:19]=4)C4C=C(F)C(F)=CC=4N=3)=CC=CN=2)CC1.[F:35][C:36]1[C:61]([F:62])=[CH:60][C:39]2[NH:40][C:41]([C:43]3[CH:59]=[CH:58][CH:57]=[CH:56][C:44]=3[CH2:45][O:46][C:47]3[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][C:48]=3[F:55])=[N:42][C:38]=2[CH:37]=1.BrCC1CCCCC1>>[CH:18]1([CH2:17][N:42]2[C:38]3[CH:37]=[C:36]([F:35])[C:61]([F:62])=[CH:60][C:39]=3[N:40]=[C:41]2[C:43]2[CH:59]=[CH:58][CH:57]=[CH:56][C:44]=2[CH2:45][O:46][C:47]2[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][C:48]=2[F:55])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: N#Cc1ccc(OCc2ccccc2-c2nc3cc(F)c(F)cc3[nH]2)c(F)c1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Agent: BrCC1CCCCC1
Product: N#Cc1ccc(OCc2ccccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)c(F)c1

Procedure:
The compound was prepared in analogy to Example 19, intermediate b, from 4-[2-(5,6-difluoro-1H-benzoimidazol-2-yl)-benzyloxy]-3-fluoro-benzonitrile and bromomethyl-cyclohexane (CAS Reg. No. 2550-36-9). Yellow powder (69%). MS (Turbo Spray): m/z=476.4 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1.[Na+].[I-:29]>CC(=O)CC>[I:29][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1
Reactant: [I-]
Reactant: CN([C@H]1CC[C@H](C#CCCCCl)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: CN([C@H]1CC[C@H](C#CCCCI)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C

Procedure:
A solution of 250 mg (0.59 mmol) of trans-N-[4-(5-Chloro-pent-1-ynyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide in 10 ml butan-2-one was treated with 136 mg of NaI (0.91 mmol) and heated at 80° C. for 48 h. Evaporation gave 330 mg of crude trans-N-[4-(5-Iodo-pent-1-ynyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide which was used directly for the next step, MS: 514 (MH+).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:30][C:31](=[O:34])[CH:32]=[CH2:33]>C1C=CC=CC=1>[O:34]=[C:31]1[CH2:32][CH2:33][C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH:1]=[CH:30]1
Reactant: C=CC(C)=O
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Temperature: 70 °C
Yield: 62.5 %

Procedure:
To a benzene (700 mL) solution of benzyl 4-formylpiperidine-1-carboxylate (90.0 g, 364 mmol) in a 2 L 3-neck flask fitted with a Dean-Stark trap was added p-toluenesulfonic acid (6.92 g, 36.4 mmol) with stirring. The reaction was heated to 70° C., and 3-buten-2-one (61.8 mL, 753 mmol) was added. The mixture was heated at reflux for 24 hours collecting expelled water in the trap. The reaction was cooled to room temperature and washed with 500 mL saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated. The resultant dark brown oil was taken up in 200 mL dichloromethane and filtered through a silica pad (600 mL silica), eluting with 2 L heptane followed by 3 L 50% ethyl acetate/heptane and then 3 L ethyl acetate. Fractions containing clean product were combined and concentrated to yield 68.1 g of the title compound as a thick brown oil. The fractions containing impure product were combined and concentrated and purified by flash column chromatography (10-80% ethyl acetate/heptanes) to yield an additional 23.6 g of the title compound as a thick brown oil. A combined yield of 91.7 g, (94.1%) was realized. 1H NMR (400 MHz, CDCl3, δ): 7.27-7.43 (m, 5 H), 6.79 (d, J=10.3 Hz, 1 H), 5.95 (d, J=10.3 Hz, 1 H), 5.13 (s, 2 H), 3.56-3.71 (m, 2 H), 3.39-3.55 (m, 2 H), 2.38-2.50 (m, 2 H), 1.96 (t, J=6.7 Hz, 2 H), 1.52-1.70 (m, 4 H).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([CH3:32])[C:24]=1[S:25]([CH2:28][N+:29]([O-:31])=[O:30])(=[O:27])=[O:26])[NH2:21].O>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:21][C:20]2[CH:19]=[C:18]([CH3:17])[C:24]([S:25]([CH2:28][N+:29]([O-:31])=[O:30])(=[O:27])=[O:26])=[C:23]([CH3:32])[CH:22]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2ccc(Cl)cc2)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 27 h
Yield: 14.3 %

Procedure:
1.45 g (14.5 mmol) of calcium carbonate and then 2.3 g (10.9 mmol) of 4-chlorobenzenesulphonyl chloride are successively added to a mixture of 1.8 g (7.37 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 45 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for 27 h at room temperature and then poured into 200 ml of water. This mixture is extracted 3 times with methylene chloride. The combined organic extracts are washed with water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The residue obtained is purified by chromatography on a column of silica (eluent: methylene chloride) and then by recrystallization from chloroform, to give 0.44 g (14%) of 4-chloro-N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]benzenesulphonamide.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH:10]=[C:9]([CH:11](O)[C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[N:8]=[CH:7]1)(=[O:5])=[O:4].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH3:18][N:2]([CH3:1])[S:3]([N:6]1[CH:10]=[C:9]([CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[N:8]=[CH:7]1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)n1cnc(C(O)c2cccs2)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)S(=O)(=O)n1cnc(Cc2cccs2)c1
Yield: 93.2 %

Procedure:
2-(tert-butyl-dimethyl-silanyl)-4-(hydroxy-thiophen-2-yl-methyl)-imidazole-1-sulfonic acid dimethylamide (Intermediate-E1) (2.5 g, 6.2 mmol) in THF (60 mL) was treated with tetrabutylammonium fluoride (TBAF) (6.9 mL of a 1M soln) at 0° C. for 1 h and at rt for 3 h. The reaction mixture was subjected to an aqueous work-up and the product was purified by chromatography on silica gel with EtOAc to give 4-(hydroxy-thiophen-2-yl-methyl)-imidazole-1-sulfonic acid dimethylamide as a white solid, 1.43 g. 4-(Hydroxy-thiophen-2-yl-methyl)-imidazole-1-sulfonic acid dimethylamide (0.5 g, 1.74 mmol) in dichloromethane (25 mL) was reacted with trifluoroacetic acid (4.3 mL, 56 mmol) and triethylsilane (TES) (2.2 mL, 14 mmol) at rt for 18 h. The mixture was quenched with water and solid NaHCO3. This material was subjected to an aqueous work-up and the residue was purified by chromatography on silica gel with 50% EtOAc: hexane to yield 4-thiophen-2-ylmethyl-imidazole-1-sulfonic acid dimethylamide (Intermediate-E2) 0.44 g.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[N-:10]=[N+]=[N-].[Na+].C(=O)([O-])[O-].[K+].[K+]>Cl>[CH3:1][CH:2]1[NH:10][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC1CCCCCC1=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1CCCCCC(=O)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Cool a solution of 17 g 2-methylcycloheptanone in 75 ml concentrated hydrochloric acid and add protionwise 13.2 g sodium azide. Stir the reaction of 0° for 1 hour then at room temperature for 2 hours. Add the reaction to 150 ml ice water, bring to pH 7 with potassium carbonate and extract with chloroform. Treat the extracts with charcoal, dry over MgSO4, filter and concentrate to obtain crude 8-methylperhydroazocin-2-one. Obtain a pure product by recrystallization from hexane (m.p. 70-73).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([O-])(O)=[O:19].[Na+].O=C(Cl)OC(Cl)(Cl)Cl>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([N:10]=[C:18]=[O:19])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Temperature: 0 °C
Yield: 90 %

Procedure:
To a solution of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (4) (WO 2000043384) (1.00 g, 4.36 mmol) in DCM (90 mL) was added a saturated aq solution of NaHCO3 (60 mL). The mixture was stirred vigorously, cooled to 0° C. and diphosgene (2.1 mL, 17.4 mmol) was added in a single portion. After stirring for 1 hr at RT, the layers were separated and the organics dried and evaporated to give a brown oil. The oil was triturated with iso-hexane (5.0 mL) and the solid filtered. The filtrate was concentrated in vacuo to give 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole (19) as a light brown oil (1.00 g, 3.92 mmol, 90%). m/z 288 (in MeOH) (M+H+MeOH)+ (ES+).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][NH:7][C:8](=O)[CH3:9].[CH3:11][S:12]([C:15]1[CH:46]=[CH:45][C:18]([CH2:19][NH:20][C:21]([C:23]2[C:24](=[O:44])[N:25]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=3)[C:26]([CH3:33])=[C:27]([C:29]([NH:31][NH2:32])=O)[CH:28]=2)=[O:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][NH:20][C:21]([C:23]2[C:24](=[O:44])[N:25]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:41])[F:42])[CH:35]=3)[C:26]([CH3:33])=[C:27]([C:29]3[N:7]([CH3:6])[C:8]([CH3:9])=[N:32][N:31]=3)[CH:28]=2)=[O:22])=[CH:45][CH:46]=1)(=[O:14])=[O:13]
Reactant: Cc1c(C(=O)NN)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CNC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nnc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)n1C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
A solution of POCl3 (0.030 g, 0.2 mmol) in CHCl3 (1 ml) and pyridine (1 ml) was added to N-methylacetamide (0.015 g, 0.2 mmol) and the mixture was cooled in an ice-water bath and stirred for 90 minutes. To this solution was added a solution of 5-hydrazinocarbonyl-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (Example 38 (a), 0.040 g, 0.076 mmol) in CHCl3 (2 ml) and the mixture was stirred overnight at room temperature. Purification by preparative HPLC gave the linear intermediate (0.020 g). This material was suspended in EtOAc (2 ml) and was heated (90° C.) with stirring for 4 h, giving rise to a mixture of three components. This mixture was purified on preparative HPLC giving the title compound (0.003 g, 7%) after freeze-drying the pure fractions.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C)(C)C)(=O)[NH:16][NH2:17].CO.C([BH3-])#N.[Na+].[OH-].[Na+]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:16][NH2:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NNC1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzylpiperidin-3-one (2.0 g, 0.0089 mol), and tert-Butyl carbazate (1.17 g, 0.00886 mol) in Methanol (31 mL, 0.78 mol) was added Sodium cyanoborohydride (1.11 g, 0.0177 mol) portionwise at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was basified with 1N NaOH solution and a white precipitate crashed out of solution. The reaction mixture was filtered and the white solid was allowed to air dry to give 1-benzyl-3-hydrazinylpiperidine.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])[C:4]#[N:5].N>CO.[Ni]>[OH:1][CH2:2][CH:3]([C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])[CH2:4][NH2:5]
Reactant: Cc1cccc(C)c1C(C#N)CO
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1cccc(C)c1C(CN)CO

Procedure:
52.4 g (0.3 mol) of 3-hydroxy-2-(2,6-dimethylphenyl)-propionitrile are dissolved in 400 ml methanol and combined with 50 9 of NH3. The reaction mixture is hydrogenated under a pressure of 70 bar and at a reaction temperature of 70° C. in the presence of 60 g Raney nickel. After 4 h the mixture is cooled, filtered over silica gel and the solvent is eliminated in vacuo. The residue is distilled under high vacuum. Yield: 40.6 g (76%), boiling point: 135-140° C. (0.02 mbar); melting point of the hydrochloride: 166° C.
Reaction SMILES: [CH2:1]1[O:20][C:4]2([CH2:9][CH2:8][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16](F)[CH:17]=4)[NH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:21]C1C=C2C(C(C3CCCCC=3)=CN2)=CC=1>>[CH2:1]1[O:20][C:4]2([CH2:9][CH2:8][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([F:21])=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: Fc1ccc2[nH]cc(C3CCC4(CC3)OCCO4)c2c1
Reactant: Fc1ccc2c(C3=CCCCC3)c[nH]c2c1
Product: Fc1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Yield: 60 %

Procedure:
This compound was prepared in the manner as described above for (2a) by replacing 4-(5-fluoro-1H-3-indolyl)-cyclohex-3-en-ethylene ketal with 4-(6-fluoro-1H-3-indolyl)-cyclohex-3-en-isomer ethylene ketal (9.54 g) in 60% yield (5.83 g) as a white solid: mp 158-159° C.
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[C:9]([CH2:12][CH2:13][CH3:14])[NH:10][CH:11]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:12]([C:9]1[N:8]2[C:3](=[S:2])[NH:4][N:5]=[CH:6][C:7]2=[CH:11][N:10]=1)[CH2:13][CH3:14]
Reactant: CCCc1nc(C=NNC(=S)SC)c[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCc1ncc2cn[nH]c(=S)n12

Procedure:
A 102.2 gm. portion of 3-(2-n-propyl-4-imidazolylmethylene) dithiocarbazic acid methyl ester in 500 ml. of diphenyl ether is reacted as described in Example 58 giving the desired product as a white solid, m.p. 201.5°-203.5° C.
Reaction SMILES: NC1C=CC(C(F)(F)F)=CN=1.[Cl:12][NH:13][C:14]1[C:19](Cl)=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1>>[Cl:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:21]([F:23])([F:22])[F:24])=[CH:16][N:15]=1
Reactant: FC(F)(F)c1cnc(NCl)c(Cl)c1
Agent: Nc1ccc(C(F)(F)F)cn1
Product: FC(F)(F)c1ccc(NCl)nc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Then, 16.2 g (0.1 mol) of 2-amino-5-trifluoromethylpyridine was added to the reaction product, and the mixture was heated to 20° C. and stirred at the same temperature for two hours. The reaction product was analyzed by liquid chromatography, whereby 2-chloroamino-3-chloro-5-trifluoromethylpyridine was found to have decreased to 1%, and 2-chloroamino-5-trifluoromethylpyridine was formed afresh in an amount of 31%, and 2-amino-3-chloro-5-trifluoromethylpyridine was formed in an amount of 30%. The rest was the hydrochloride of 2-amino-3-chloro-5-trimethylpyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:44]=[CH:43][C:7]([CH2:8][O:9][C:10](=[O:42])[CH:11]([N:15]2[CH:18]([S:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:17]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:16]2=[O:41])[C:12](=[CH2:14])C)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(O)[O-:46].[Na+].[I-].[K+]>C(OC)(=O)C.O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:44]=[CH:43][C:7]([CH2:8][O:9][C:10](=[O:42])/[C:11](/[N:15]2[CH:18]([S:19][S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:21])=[O:22])[CH:17]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:16]2=[O:41])=[C:12](\[OH:46])/[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S([O-])O
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COC(C)=O
Product: C/C(O)=C(/C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1

Procedure:
(di) The crude 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid p-nitrobenzyl ester obtained according to Example 1.cvii) is dissolved in 20 ml of methyl acetate and ozonised at -70° C. until starting material is no longer present, according to a thin layer chromatogram. A stream of nitrogen is then passed through the solution and the latter is warmed to 0°-5° C. A solution of 300 mg of sodium bisulphite in 5 ml of water is added and the mixture is stirred for about 5 minutes until no further ozonide is detectable by means of potassium iodide/-starch paper. The mixture is diluted with ethyl acetate, the aqueous phase is separated off and the organic phase is washed with water, dried over magnesium sulphate and freed from the solvent in vacuo. The crude product is dissolved in 3 ml of methylene chloride and 15 ml of toluene are added. The precipitate is filtered off and the filtrate is concentrated by evaporation in vacuo. The residue is recrystallised from methanol and gives 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid p-nitrobenzyl ester of melting point 159°-160° C. 155°-