Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[CH:25]=[C:26]([N:30]([CH3:39])[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=O)[CH:27]=[CH:28][CH:29]=1>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:25]=[C:26]([N:30]([CH3:39])[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[S:10])[CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN(C(=O)c1ccccn1)c1cccc(F)c1
Solvent: Cc1ccccc1
Product: CN(C(=S)c1ccccn1)c1cccc(F)c1

Procedure:
Lawesson's reagent (3.20 g, 7.9 mmol) and N-(3-fluorophenyl)-N-methyl-2-pyridinecarboxamide (3.51 g, 15.2 mmol) were heated to reflux in toluene (45 mL) under nitrogen for 2 hours. The residue, after evaporation of the solvent, was dissolved in dichloromethane, preadsorbed onto silica gel, and flash chromatographed (250 g of silica gel eluted with 10% ethyl acetate in petroleum ether) to yield N-(3-fluorophenyl)-N-methyl-2-pyridinecarbothioamide, as a yellow solid (1.70 g, 45%), m.p. 100°-103° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C(N(CC)CC)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CN(C1C=CC=CN=1)C>ClCCl>[C:36]([N:18]1[CH2:19][CH2:20][CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:15]([S:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH2:16][CH2:17]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCNCCC2C(=O)OC(C)(C)C)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccccc3)CCC2C(=O)OC(C)(C)C)cc1

Procedure:
tert-Butyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylate (0.425 g, 0.96 mmol) in dichloromethane at 25° C. (10 mL) was treated with triethylamine (0.28 mL, 2.02 mmol) followed by benzoyl chloride (0.12 mL, 1.06 mmol) and dimethylaminopyridine (10 mg). After 18 hours aqueous workup gave tert-butyl 1-benzoyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylate. 1H NMR (dmso-d6, 300 MHz): 1.24 (s, 9H, t-bu), 1.82 (s, 3H, CH3), 2.0-4.0 (m, 8H, CH2), 4.65 (s, 1H, CH), 4.85 (s. 2H, CH2), 7.0-7.9 (m, 9H, ArH). Treatment with trifluoroacetic acid (4 mL) in dichloromethane (10 mL) for 6 hours gave, after concentration in vacuo followed by chromatography on silica gel eluting with dichloromethane/methanol, 1-benzoyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylic acid as a foam (0.328 g).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][CH2:7][N:8]([C:11]([CH:13]3[CH2:18][O:17][CH2:16][CH2:15][O:14]3)=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.O1CCOCC1C=O.Cl[C:30]1[N:35]=[C:34]([NH:36][C:37]2[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:38]=2[C:39]([NH:41][CH3:42])=[O:40])[C:33]([Cl:48])=[CH:32][N:31]=1>>[Cl:48][C:33]1[C:34]([NH:36][C:37]2[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:38]=2[C:39]([NH:41][CH3:42])=[O:40])=[N:35][C:30]([NH:1][C:2]2[CH:20]=[CH:19][C:5]3[CH2:6][CH2:7][N:8]([C:11]([CH:13]4[CH2:18][O:17][CH2:16][CH2:15][O:14]4)=[O:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:31][CH:32]=1
Reactant: Nc1ccc2c(c1)CCN(C(=O)C1COCCO1)CC2
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: O=CC1COCCO1
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(C(=O)C2COCCO2)CC3)ncc1Cl

Procedure:
(7-Amino-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1,4-dioxinan-2-yl-methanone, prepared in a similar manner as 7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1,4-dioxinan-2-yl-methanone of Example 633b, was reacted with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide, in a similar manner as Example 601b, to yield desired product 2-{5-Chloro-2-[3-([1,4]dioxane-2-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide as a lyophylate (31%); 1H NMR (400 MHz, DMSO-d6) δ 9.39 (d, J=9.23 Hz, 1H), 9.33 (s, 1H), 8.55 (m, 1H), 8.18 (s, 1H), 7.51-7.43 (m, 3H), 7.26 (s, 1H), 7.17 (m, 1H), 6.89 (m, 1H), 4.39 (m, 1H), 3.74-3.4 (bm, H2O+11H), 2.81 (m, 1H), 2.74 (d, J=4.55 Hz, 3H), 2.67 (m, 2H); MS (m/e) 555.14 (M+H).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH2:8][C:9]([F:12])([F:11])[F:10])[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O>C1COCC1.O>[C:23]([O:22][C:20]([NH:2][CH:3]([CH2:7][CH2:8][C:9]([F:10])([F:11])[F:12])[C:4]([OH:6])=[O:5])=[O:19])([CH3:26])([CH3:25])[CH3:24]
Reactant: NC(CCC(F)(F)F)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CCC(F)(F)F)C(=O)O
Reaction time: 0.17 h
Yield: 122.4 %

Procedure:
To a stirred solution of 2-amino-5,5,5-trifluoropentanoic acid hydrochloride (400 mg, 1.503 mmol) in THF (8 mL) and water (8 mL) was added K2CO3 (831 mg, 6.01 mmol) at rt and the solution was stirred for 10 min. To this mixture was added BOC2O (656 mg, 3.01 mmol). The reaction mixture was stirred for 8 h at rt. The reaction mixture was concentrated under reduced pressure. The aq. layer was washed with ethyl acetate (3×5 mL). The aqueous layer was acidified with saturated citric acid solution (5 mL) and then extracted with ethyl acetate (3×8 mL). The combined organic layers were washed with water (3×5 mL) followed by brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 2-((tert-butoxycarbonyl)amino)-5,5,5-trifluoropentanoic acid (500 mg, 1.84 mmol) quantitatively as a colorless oil. The crude material was taken as such to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 5.04 (s, 1H), 4.38 (s, 1H), 2.15-2.28 (m, 2H), 1.91-1.95 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]([OH:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH:28]=[CH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:23][CH2:22]1.O>C1(C)C(C)=CC=CC=1>[CH3:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:15][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH:28]=[CH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)=[CH:6][CH:5]=1
Reactant: ClCCN1CCN(CC=Cc2ccccc2)CC1
Reactant: Cc1ccc(C(O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1ccc(C(OCCN2CCN(CC=Cc3ccccc3)CC2)c2ccccc2)cc1

Procedure:
2 g of 60% sodium hydride in paraffin oil were added to a solution of 10 g (0.05 mol) of 4-methylbenzhydrol in 100 ml of anhydrous xylene. The reaction mixture was refluxed for half an hour and then 12.7 g (0.05 mol) of 1-(2-chloroethyl)-4-(3-phenyl-2-propenyl)piperazine (German pat.appl.2.431.178) in 50 ml of xylene were added dropwise. The reaction mixture was refluxed for another three hours and then cooled and poured into water. The organic layer was separated off, washed with water and concentrated. The residue was purified by column chromatography (Silicagel) with chloroform/ethylacetate/methanol/ammonia (25:25:1:0.5) as the eluent which yielded 1-[2-[(4-Methylphenyl)phenylmethoxy]ethyl]-4-(3-phenyl-2-propenyl)piperazine.
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Br:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrP(Br)Br
Reactant: OCCCCCc1ccccc1
Solvent: ClC(Cl)Cl
Product: BrCCCCCc1ccccc1

Procedure:
A 1.8 g (6.7 mmol) amount of phosphorus tribromide was added to a chloroform solution (20 ml) of 3.3 g (20 mmol) of 5-phenyl-1-pentanol and the resulting solution was heated at reflux for 4 hours. When the reaction was traced by TLC, the starting materials were found to still remain in the reaction mixture, and so 0.2 g of phosphorus tribromide was further added and heated at reflux. Afterwards, the reaction solution was washed with water and dried with anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. Thus, 4.30 g of a crude 5-phenylpentyl bromide was obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[O-]CC.[Na+].[F:13][C:14]1[CH:26]=[CH:25][C:17]([CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1>C(O)C>[C:1]([CH:3]([CH:18]([C:17]1[CH:16]=[CH:15][C:14]([F:13])=[CH:26][CH:25]=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C=Cc1ccc(F)cc1
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(F)cc1)C(C#N)C(=O)OCC
Yield: 47.4 %

Procedure:
To 12 g of ethyl cyanoacetate dissolved in 20 mL of ethanol, 8 g of sodium ethoxide and 40 mL of ethanol were added under cooling with ice, and then 20 g of ethyl p-fluorocinnamate and 40 mL of ethanol were added. The reaction mixture was heated under reflux for 20 hours and then filtered. The filtrate was poured into a mixture of 200 g of ice and 10 mL of concentrated hydrochloric acid and extracted with chloroform. The extract was concentrated and separated by silica gel column chromatography (hexane: ethyl acetate=9:1) to obtain 15 g of diethyl 2-cyano-3-(p-fluorophenyl)glutarate as a diastereomer mixture.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccccc4F)CC3)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccccc4F)CC3)cnc12
Yield: 27 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(2-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.035 g, 0.074 mmol) obtained in step 2 and methanesulfonamide (0.038 g, 0.375 mmol), the title compound (0.011 g, 27%) was obtained.
Reaction SMILES: [CH:1]([C:3]([CH3:5])=O)=[CH2:2].[Si:6]([O:13][NH2:14])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>C(Cl)Cl>[Si:6]([O:13][N:14]=[C:3]([CH3:5])[CH:1]=[CH2:2])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)ON
Reactant: C=CC(C)=O
Solvent: ClCCl
Product: C=CC(C)=NO[Si](C)(C)C(C)(C)C
Temperature: 5 °C
Reaction time: 18 h

Procedure:
The procedure followed was that described by Behforouz et al., J. Org. Chem. 58:7089-7091 (1993). In a 50 mL round bottom flask, dry 4 Å molecular sieves (Fisher, 3.4 g) were added to dry CH2Cl2 (distilled from CaH2, 10 mL) and cooled to 5° C. with an ice bath. Methyl vinyl ketone (Aldrich, new bottle, used without purification, 0.725 mL, 0.618 g, 3.84 mmol) was added. A solution of O-(tert-butyldimethylsilyl)hydroxylamine (Aldrich, used without purification, 1.0 g, 6.80 mmol) in dry CH2Cl2 (distilled from CaH2, 3 mL) was added dropwise over a period of 5 min. The ice bath was removed and the mixture was stirred at rt under N2 for 18 h. The sieves were removed by filtration and the CH2Cl2 was evaporated to dryness (roto-vap). Column chromatography with silica gel and CHCl3 as eluent afforded 1-(tert-butyldimethylsilyloxy)-2-methyl-1-aza-1,3-butadiene as a light oil (1.2 g, 81%, interpretation of the 1H NMR showed a 1:1 anti/syn mixture): 1H NMR (CDCl3) δ (anti) 0.17 (s, 6H), 0.94 (s, 9H), 1.97 (s, 3H), 5.35-5.75 (m, 2H), 6.41-6.53 (m, 1H); (syn) 0.17 (s, 6H), 0.94 (s, 9H), 1.99 (s, 3H), 5.35-5.75 (m, 2H), 7.15-7.25 (m, 1H).
Reaction SMILES: [O:1]1[CH2:5][C:4](=[O:6])[CH2:3][C:2]1=[O:7].[F:8][C:9]([F:15])([F:14])[CH2:10][C:11](O)=[O:12].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CC#N>[OH:6][C:4]1[CH2:5][O:1][C:2](=[O:7])[C:3]=1[C:11](=[O:12])[CH2:10][C:9]([F:15])([F:14])[F:8]
Reactant: O=C1COC(=O)C1
Reactant: O=C(O)CC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: ClCCl
Product: O=C(CC(F)(F)F)C1=C(O)COC1=O
Temperature: 0 °C

Procedure:
To a cool (0° C.), stirred suspension of furan-2,4(3H,5H)-dione (16.46 g, 164 mmol) in DCM (650 mL) was added TEA (23.0 mL, 165 mmol), DMAP (6.04 g, 49.4 mmol), 3,3,3-trifluoropropanoic acid (16.0 mL, 181 mmol) and DCC (40.70 g, 197 mmol) resulting in a yellow homogenous solution. The solution was stirred at 0° C., and then was allowed to warm to room temperature as the bath warmed while stirring overnight. The suspension was filtered and the solid was washed with DCM. The deep red filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc and 1M HCl (400 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford an amber solid. This was dissolved in a minimum amount of CH3CN, to which DCM was added to form a precipitate. The suspension was allowed to stand in the freezer overnight. It was sonicated then cooled and filtered, the solid was washed with cold DCM and then dried to provide Preparation 1A (31.62 g, 91%) as a cream solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 13.07 (1H, br. s.), 4.29 (2H, s), 3.80 (2H, q, J=11.67 Hz).
Reaction SMILES: C(=O)([O-])O.[Na+].[C:6](OC(=O)C)(=[O:8])[CH3:7].[NH2:13][CH:14](/[CH:18]=[CH:19]/[CH2:20][P:21]([OH:24])([OH:23])=[O:22])[C:15]([OH:17])=[O:16]>O1CCOCC1.O>[NH:13]([CH:14](/[CH:18]=[CH:19]/[CH2:20][P:21]([OH:24])([OH:23])=[O:22])[C:15]([OH:17])=[O:16])[C:6]([CH3:7])=[O:8]
Reactant: NC(/C=C/CP(=O)(O)O)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NC(/C=C/CP(=O)(O)O)C(=O)O
Reaction time: 0.5 h

Procedure:
At 0°, 170 mg of sodium hydrogen carbonate and, within a period of 5minutes, 50 microliters of acetic anhydride are added to a solution of 100 mg of E-2-amino-5-phosphono-3-pentenoic acid in 6 ml of dioxan/water (1:1). The whole is stirred for 30 minutes at 0°, approximately 2 ml of Dowex 50 H+ are added and filtration is carried out. The filtrate is concentrated by evaporation and purified by ion exchange chromatography (Dowex 50 H+). Lyophilisation of the pure fractions yields 110 mg of E-2-acetamino-5-phosphono-3-pentenoic acid, m.p. 155°.
Reaction SMILES: ClCCCl.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13].[Cl-].[Cl-].[Cl-].[Al+3]>CCO>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:19]([C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=2)=[O:20])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: ClCCCl
Product: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 40 °C

Procedure:
A 2-L 4-neck flask equipped with a thermocouple controller, a mechanical stirrer, a condenser, and a nitrogen inlet/outlet adapter was charged with DCE (480.8 mL), chlorobenzene (1) (90.4 mL, 888.5 mmol) and 4-nitrobenzoylchloride (111.4 g, 600.3 mmol), and the resulting mixture stirred and warmed to 40° C. Aluminum trichloride (97.0 g, 720.4 mmol) was added portionwise over 1 h and then the reaction was heated to 60° C. and stirred for 10 h. The reaction was cooled to 20° C., poured into ice-water (2 L) and stirred for 10 min. The resulting aqueous mixture was extracted with DCM (600 mL×2). The combined organic extracts were was washed with deionized water (1 L×3). The solvent was concentrated at 40° C. to remove DCM and then at 66° C. to yield a pale to slight yellowish solid, which was dissolved in hot EtOH (500 mL) at 76° C., stirred for 30 min, and then gradually cooled to 4° C. over 1 h. The resulting solid was collected by filtration to yield (4-chlorophenyl)(4-nitrophenyl)methanone as a slightly yellowish crystalline solid. (ES, m/z) 262 (M+H)+, 284, 286 (M+Na)+
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3]/[CH:4]=[CH:5]/[C:6]([O:8]C)=[O:7].[OH-].[Na+].[ClH:13]>CO.O>[ClH:13].[CH3:1][N:2]([CH3:10])[CH2:3]/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7]
Reactant: COC(=O)/C=C/CN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)C/C=C/C(=O)O
Temperature: 50 °C
Yield: 51 %

Procedure:
Methyl (2E)-4-(dimethylamino)but-2-enoate (3.4 g, 23.7 mmol) was dissolved in methanol (25 mL). A solution of sodium hydroxide (0.95 g, 23.7 mmol) in water (7 mL) was added, and the mixture was heated to 50° C. for 1 h. The pH was then adjusted to 2 with conc. hydrochloric acid. The solution was concentrated to dryness, and the residue was triturated with ethanol (30 mL). It was filtered, and the solution was concentrated in vacuo. The residue was triturated with 2-propanol, and the precipitate was collected by suction filtration and dried to yield 2.00 g (51%) of the title compound.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1)[CH3:4].[N:15]#[C:16][NH2:17].[O-]Cl.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(#N)C.O>[F:12][C:11]([F:14])([F:13])[C:8]1[N:7]=[CH:6][C:5]([CH:3]([S:2]([CH3:1])=[N:17][C:16]#[N:15])[CH3:4])=[CH:10][CH:9]=1
Reactant: CSC(C)c1ccc(C(F)(F)F)nc1
Reactant: N#CN
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CC#N
Product: CC(c1ccc(C(F)(F)F)nc1)S(C)=NC#N
Temperature: -1 °C
Reaction time: 0.5 h

Procedure:
solution of 110.6 g (0.475 mol, 95% assay) of 3-[1-(methylthio)ethyl]-6-(trifluoromethyl)pyridine and 25.2 g (0.6 mol) of cyanamide in 600 mL of acetonitrile was cooled to −5° C. To this solution was added 750 g (0.575 mol, Clorox™ 5.7% wt) of aqueous NaOCl dropwise over 45 min with the temperature kept below 0° C. The reaction mixture was allowed to stir at −1° C. for 30 min To the mixture was added 9.5 g (0.05 mol) of sodium metabisulfite in 25 mL of water and the two phase mixture was allowed to settle. The aqueous phase was re-extracted 2×'s with 50 mL of acetonitrile. The organics were combined and this acetonitrile/sulfilimine solution was used directly in the following oxidation. LC analysis indicated a 40:54 (area) ratio of two isomers.
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([O:19]C)=O)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:21]>O1CCOCC1>[CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([NH2:21])=[O:19])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Reactant: N
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Temperature: 100 °C

Procedure:
Methyl (2S)-1-[(cyclohexylmethyl)sulfonyl]-2-piperidinecarboxylate (3.0 g) [see Preparation 25) was dissolved in 1,4-dioxane (30 ml) and 0.88 aqueous ammonia solution (25 ml) was added. Ammonia gas was bubbled through the mixture for 20 mins. and the reaction mixture was heated to 100° C. in a sealed vessel for 56 hours. After this time the mixture was cooled and the solvent removed under reduced pressure. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, brine, dried over magnesium sulphate and the solvent was removed under reduced pressure to afford (2S)-1-[(cyclohexylmethyl)sulfonyl]-2-piperidinecarboxamide (1.77 g) as a colourless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[C:17](Cl)=[O:18])[O:10][CH2:9][CH2:8]1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[O:7]1[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[C:17]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:18])[O:10][CH2:9][CH2:8]1
Reactant: O=C(Cl)C1CCCCC12OCCO2
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(C1CCCCC12OCCO2)N1CCOCC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
Morpholine (0.22 mL, 2.5 mmol) was added at 0° C. to a 1 M solution of 1,4-dioxa-spiro[4.5]decane-6-carbonyl chloride in toluene (1 mL, 1 mmol). The mixture was stirred at 20° C. for 1 h, then diluted with ethyl acetate (40 mL), and washed successively with water (10 mL), saturated aqueous sodium carbonate solution (10 mL), 1 N hydrochloric acid, and with brine (10 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the title compound (59 mg, 23%) as white solid. MS ISP (m/e): 256.3 (100) [(M+H)+].
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.N([O-])=O.[Na+].[Br-:15]>Br>[Br:15][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: [Br-]
Reactant: Nc1ccc2c(c1)CCC2
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Product: Brc1ccc2c(c1)CCC2
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
5-Aminoindane was treated with concentrated hydrobromic acid. The suspension was cooled to −5° C., and 5 M sodium nitrite solution was added at a temperature between 0° C. to 5° C. in period of 30 minutes through an addition funnel. Stirring was continued for 20 minutes at 0° C. to 5° C. The reaction mixture was now very dark fluid slurry. In a second reaction vessel, a solution of cupper (I) bromide in concentrated hydrobromic acid had been prepared and preheated to 40° C. When the diazonium salt slurry was added in portions, a very slow gas evolution was observed which became vehement when heating to 60° C. After stirring at 60° C. for 40 min, the gas evolution ceased. The mixture was poured onto water. The product was extracted twice with ethyl acetate. Some of the precipitated copper bromide was removed by filtration to facilitate phase separation. The organic extracts were washed twice with water and one time with brine. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. After flash chromatography, the title compound was obtained as pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>CCOCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reaction time: 24 h
Yield: 52.6 %

Procedure:
A mixture of 100.0 g of methyl 2-methyl-3-nitrobenzoate, 100.0 g of N-bromosuccinimide, 3.0 g of dibenzoyl peroxide and 1000 ml of carbon tetrachloride was refluxed for 24 hours. The reaction mixture was cooled, 3.0 g of dibenzoyl peroxide added, and refluxing continued an additional 24 hours. The reaction mixture was cooled, filtered and the filtrate concentrated in vacuo. The crude reaction product was dissolved in ether and the organic solution washed sequentially with saturated sodium sulfite (500 ml), water (2×500 ml), 2.5% sodium hydroxide (500 ml), water (2×500 ml) and saturated brine (500 ml). The organic solution was dried over magnesium sulfate, filtered and the solvent evaporated in vacuo giving a pale yellow oily solid. Recrystallization from 350 ml of 1-chlorobutane/cyclohexane (2:1) gave 73.9 g of methyl 2-bromomethyl-3-nitrobenzoate, m.p. 67°-70°.