Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]2([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])OCC[O:43]2)[C@:22]([CH2:31][CH2:32][F:33])([OH:30])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].S(=O)(=O)(O)O.C(O)=O>C(#N)C.O.C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:43])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C@:22]([CH2:31][CH2:32][F:33])([OH:30])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCF)C(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: O
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCF)C(=O)O)C(=O)OC)cc1
Reaction time: 18.5 h
Yield: 28.8 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-(2-fluoro-ethyl)-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-undec-4-enoate (64.0 mg, 0.0855 mmol) was dissolved in acetonitrile (0.96 mL), and water (0.03 mL, 1.67 mmol) and sulfuric acid (0.016 mL, 0.300 mmol) were then added at room temperature. After stirring for 18.5 hours, ethyl acetate (10 mL) and water (10 mL) were added, and the mixture was separated. The ethyl acetate layer was washed with a saturated aqueous solution (10 mL) of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure. Formic acid (0.016 mL, 0.424 mmol) was added to the obtained residue (41.0 mg) at room temperature, and the mixture was then stirred for 21 hours. Formic acid was distilled off under reduced pressure. The residue was then purified by preparative HPLC and preparative TLC (diol, n-hexane/acetone=2/1) to obtain 15.9 mg of the title compound (0.0246 mmol, yield 29%).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)(Cl)Cl>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:16](=[O:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc(I)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)NCc1ccc(I)cc1
Reaction time: 4 h

Procedure:
4-Iodobenzylamine (5.32 g) was dissolved in chloroform (50 ml), and, under ice-cooling, pyridine (2.76 ml) and acetic anhydride (2.58 ml) were added and the mixture was stirred for 4 hr. The reaction mixture was washed successively with water, 1N-hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2-1:3) to give the title compound (5.18 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[O:8][CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.BrC1C=C2OC=NC2=NC=1.[CH3:21][N:22](C(OC(C)(C)C)=O)[CH:23]([CH2:25][CH:26]=[CH2:27])[CH3:24]>>[CH3:21][NH:22][CH:23]([CH2:25]/[CH:26]=[CH:27]/[C:2]1[N:7]=[C:6]2[O:8][CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1)[CH3:24]
Reactant: Brc1ccc2ncoc2n1
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Agent: Brc1cnc2ncoc2c1
Product: CNC(C)C/C=C/c1ccc2ncoc2n1

Procedure:
5-Bromooxazolo[5,4-b]pyridine, isomeric by orientation of ring fusion to the previously described 6-bromooxazolo[4,5-b]pyridine, can also be used in the Heck coupling with N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine. Subsequent removal of the tert-butoxycarbonyl protecting group provides (4E)-N-methyl-5-(5-oxazolo[5,4-b]pyridinyl)-4-penten-2-amine. The 5-bromooxazolo[5,4-b]pyridine can be synthesized from 3-amino-5-bromo-2-pyridinol (3-amino-5-bromo-2-pyridone) by condensation with formic acid (or a derivative thereof) as described above. 3-Amino-5-bromo-2-pyridinol can be made by bromination (using techniques described by T. Batkowski, Rocz. Chem. 41: 729-741 (1967)) and subsequent tin(II) chloride reduction (according to the method described by S. X. Cai et al., J. Med. Chem. 40(22): 3679-3686 (1997)) of commercially available 3-nitro-2-pyridinol (Aldrich Chemical Company).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])([O-:15])=[O:14]>ClCCCl>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:19]([C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)=[O:20])=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a cold (0° C.) mixture of anisole (17.7 mL, 0.162 mol, 1.0 eq.) and aluminium trichloride (26.9 g, 0.202 mol, 1.25 eq.) in 1,2-dichloroethane (140 mL) was slowly added 3-nitrobenzoylchloride (30 g, 0.162 mol). The cooling bath was removed, and the reaction mixture was stirred 2 h at 20° C. The reaction mixture was poured into ice water. Concentrated hydrochloric acid (5 mL) was added. The aqueous layer was extracted with dichloromethane (2 times). The combined organic layers were dried over sodium sulfate, filtered and the volatiles were removed in vacuo. Purification by flash chromatography afforded the title compound (35.1 g, 84%) as an orange solid, m.p.: 88-89° C.
Reaction SMILES: NCC([O-])=O.[Na+].C(OC(=O)C)(=O)C.C([N:17]1[CH:21]=[C:20]2[CH2:22][CH:23]([NH:26]C(=O)C)[CH2:24][CH2:25][C:19]2=[CH:18]1)(=O)C>>[CH2:24]1[CH:23]([NH2:26])[CH2:22][C:20]2[C:19](=[CH:18][NH:17][CH:21]=2)[CH2:25]1
Reactant: CC(=O)NC1CCc2cn(C(C)=O)cc2C1
Agent: NCC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: NC1CCc2c[nH]cc2C1

Procedure:
According to Reaction Scheme I, 4-acetamido cyclohexanone, prepared by the procedure of Fraser and Swingle, Can. J. Chem., 48, 2065 (1970) is reacted with the dimethylacetal of dimethylformamide to yield 2-dimethylaminomethylene-4-acetamidocyclohexanone (III). Reacting this compound with sodium glycinate followed by a ring closure reaction in the presence of acetic anhydride yields, when R3 is methyl, dl-2-acetyl-5-acetamido-4,5,6,7-tetrahydro-2H-benzo[c]-pyrrole (IV). Treatment of this latter compound with base gives dl-5-amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole (V). This latter compound can be preferentially alkylated on the amino group at C-5 using a reductive alkylation procedure; i.e., reaction with an aldehyde (formaldehyde, acetaldehyde, acrolein, or propionaldehyde) in the presence of a strong organometallic reducing agent such as sodium cyanoborohydride. The dialkylated compound, for instance, dl-5-di(n-propyl)amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole (VI) can also be alkylated on the pyrrole ring nitrogen under basic conditions using an alkyl halide R2X (methyl iodide, allyl chloride, ethyl bromide, or the like) to yield a dl-2-(C1 -C3 alkyl or allyl)-5 -disubstituted-amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole of Formula VII.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][CH2:26][CH3:27])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH2:26][CH3:27])[C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[N:3]=2)[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)nc1F
Reactant: CCNC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN(c1nc(F)ccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
2,6-Difluoro-3-nitropyridine (5.00 g) is dissolved in acetonitrile (10 ml) and 1-benzyl-4-ethylaminopiperidine (EXAMPLE 11, 6.81 g) dissolved in 10 ml of acetonitrile is added via cannula. Then an additional 58 ml of acetonitrile is added and the reaction is cooled to 0°. Then 5.1 g of potassium carbonate is added and the reaction is stirred 10 min and allowed to warm to 20°-25°. After 6 hrs, the reaction is poured into water, extracted with ethyl acetate, washed with saline and dried over sodium sulfate. Flash column chromatography (silica gel; 5% ethyl acetate/hexane to 10% ethyl acetate/hexane) gives the title compound, NMR (300 MHz, CDCl3) 8.22, 7.37-7.23, 6.25, 3.66, 3.55, 3.50, 3.01, 2.10, 1.95, 1.83 and 1.09δ.
Reaction SMILES: CN1C=CN=C1.Cl[P:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][P:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:22]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CCO
Agent: Cn1ccnc1
Product: CCOP(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
The following feed streams were mixed continuously in a reaction mixing pump: 1) mixture of 156.7 g of 1-methylimidazole and 84.1 g of ethanol and 2) 370.0 g of chlorodiphenylphosphine (99.1% strength). Stream 1) was added at 167.5 g/h and stream 2) was added at 257.4 g/h. The volume of the mixing chamber was 3.3 ml. The top of the reaction mixing pump was thermostated to 80° C. The system was brought to equilibrium over a period of 60 minutes. The output was subsequently collected for 87 minutes in order to carry out a mass balance. During the mass balance run, the amount of starting materials was determined by weighing the reservoirs. 370.0 g of chlorodiphenylphosphine were added. The output consisted of two liquid phases. During the 87 minutes, 389.3 g of upper phase and 219.2 g of lower phase were collected. The upper phase comprised 96.8% of EODPP, so that the yield determined by gas chromatography was 98.5%. The residence time of the reactants in the mixing chamber was 30 s.
Reaction SMILES: [C:1]1([P:7](Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([OH:17])[CH3:16].N1C=CC=CC=1>CCOCC>[C:1]1([P:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:17][CH2:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOP(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of diphenylphosphinous chloride (135 mmol) in dry ether (120 mL) was treated dropwise at 5° C. with a solution of ethanol (200 mmol) and pyridine (134 mmol) in ether (120 mL). After addition was complete, the mixture was warmed to room temperature, filtered under argon, and the solid hydrochloride washed with ether. Evaporation of the solvent gave an oil which was purified by Kugelrohr distillation at 95° C. (0.1 mmHg). Yield: 119 mmol (88%); 1H NMR (CDCl3) δ 7.6-7.2 (m, 10 H), 3.95 (doublet of quartets, JH-H =7 Hz, JP-H =10 Hz, 2 H), 1.30 (t, J=7 Hz, 3 H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:8]([CH:9]=[C:10]([Br:12])[Br:11])[C:7]1([CH3:14])[CH3:13])=[O:5])C.[OH-].[Na+]>>[CH3:13][C:7]1([CH3:14])[CH:8]([CH:9]=[C:10]([Br:12])[Br:11])[CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1C(C=C(Br)Br)C1(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)C(C=C(Br)Br)C1C(=O)O
Temperature: 20 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
36.2 g. of 2,2-dimethyl-3-(2,2-dibromovinyl)-cyclopropane-1-carboxylic acid ethylester (purity: 90%, cis) trans ratio: 45:65/, 4 g. of a 25% aqueous sodium hydroxide solution and 0.2 g. of tricaprylmethyl ammonium chloride are stirred at 100° C. for 30 minutes, whereupon three 4-g. portions of the sodium hydroxide solution are added in 30 minutes intervals and stirring is continued for altogether 240 minutes. The mixture is cooled to 20° C., diluted with 100 ml. of water and extracted with 10 ml. of benzene. The aqueous solution is admixed with 12 g. of a 36% aqueous hydrochloric acid solution at 70° C. and cooled to room temperature with stirring. The precipitated acid is dissolved in 60 ml. of benzene, the solution is separated and the solvent is evaporated. 30.0 g (92%) of 2,2-dimethyl-3-(2,2-dibromovinyl)-cyclopropanecarboxylic acid are obtained. Cis/trans ratio: 40:60.
Reaction SMILES: [BH4-].[Na+].[Cl-].[Ca+2].[Cl-].[OH:6][C@@:7]([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:50]([NH:52][CH3:53])=[O:51])[CH:46]=2)[CH:41]=1)([C:16]1[N:17]=[CH:18][N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1)[CH2:8][C:9](OC(C)(C)C)=[O:10].Cl>C(OCC)(=O)C.O.C1COCC1.C(O)C>[OH:6][C@@:7]([C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[CH:46]=[C:45]([C:50]([NH:52][CH3:53])=[O:51])[CH:44]=[CH:43]2)([C:16]1[N:17]=[CH:18][N:19]([C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1)[CH2:8][CH2:9][OH:10]
Reactant: CNC(=O)c1ccc2cc([C@@](O)(CC(=O)OC(C)(C)C)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CNC(=O)c1ccc2cc([C@@](O)(CCO)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reaction time: 0.58 h
Yield: 56.1 %

Procedure:
6.5 mL of ethanol and 6.5 mL of THF were added to 0.47 g (12.5 mmol, 8 eq) of sodium borohydride. 0.7 g (6.27 mmol, 4 eq) of calcium chloride was added at 4˜5° C., and the mixture was stirred at 4˜5° C. for 35 minutes. 1 g (1.57 mmol) of tert-butyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate was added at 5° C. The mixture was stirred at 23˜29° C. for 6 hours. 35 mL of water was added dropwise. 12.5 mL of 1N hydrochloric acid was added dropwise, diluted with 20 mL of ethyl acetate, and the layers were separated. The aqueous layer was re-extracted with 20 mL of ethyl acetate. The organic layers were combined, and washed successively with 10 mL of water and 10 mL of an aqueous saturated sodium chloride solution. After concentrated under reduced pressure, the concentration residue was dissolved in 1 mL of ethanol, and allowed to stand overnight. Crystals were filtered, and washed with 0.2 mL of ethanol. The filtrate was concentrated under reduced pressure, 0.5 mL of ethyl acetate and 1 mL of IPE were added to the concentration residue, crystals were loosened, filtered, and washed with 0.75 mL of ethyl acetate/IPE=1/10.75 ml. Vacuum drying (40° C.) to a constant weight afforded 0.5 g of 6-[(1S)-1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide (yield 61%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1.[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13]Cl.C([O-])([O-])=O.[K+].[K+].CC(C)=O>C(OCC)(=O)C>[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13][N:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1
Reactant: N#Cc1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(C#N)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.9 %

Procedure:
A flask charged with imidazole-4-carbonitrile (0.50 g, 5.2 mmol) (Synthesis, 677, 2003), 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) (0.95 mL, 5.3 mmol), K2CO3 (1.40 g, 10.4 mmol), and acetone (5 mL) was stirred for 10 h at RT. The mixture was diluted with ethyl acetate (EtOAc) (20 mL) and washed with water (20 mL) and brine (20 mL) and the organic layer was dried over MgSO4. The crude product was eluted from a 20-g SPE cartridge (silica) with 30% EtOAc/hexane to give 0.80 g (70%) of the title compound as a colorless oil. Mass spectrum (CI (CH4), m/z) Calcd. for C10H17N3OSi, 224.1 (M+H). found 224.1.
Reaction SMILES: [C:1]([C@@:9]([C:24]([OH:26])=[O:25])([OH:23])[C@@:10]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:14])[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:40]=[CH:39][C:31]([CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][N:34]2[CH3:38])=[CH:30][CH:29]=1>CC(C)=O>[C:15]([C:10]([C:11]([OH:13])=[O:12])([OH:14])[C:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:23])[C:24]([OH:26])=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl:27][C:28]1[CH:40]=[CH:39][C:31]([CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][N:34]2[CH3:38])=[CH:30][CH:29]=1
Reactant: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Agent: CN1CCCC1Cc1ccc(Cl)cc1
Solvent: CC(C)=O
Product: O=C(O)C(O)(C(=O)c1ccccc1)C(O)(C(=O)O)C(=O)c1ccccc1
Reaction time: 96 h
Yield: 24.4 %

Procedure:
Add a solution of 27 g of dibenzoyl-L-tartaric acid in 200 ml of acetone to 15 g of 2-(4-chlorobenzyl)-1-methylpyrrolidine dissolved in 100 ml of acetone. Allow the resulting mixture to stand for 6 hours at room temperature and for 4 days at 0°. Filter off the precipitated crystals (8.5 g). Concentrate the filtrate somewhat and then allow the mixture to stand for a further 12 hours at 0°. Collect the further-precipitated crystals (4.53 g). Recrystallize the collected crystalline products from 100 ml of acetone and filter to obtain a total yield of 9.9 g of (+)-2-(4-chlorobenzyl)-1-methylpyrrolidine dibenzoyl tartrate, m.p. 117° to 120°, [α]58920 =-64° (25 mg/ml in methanol). Shake 9.4 g of this salt with diethyl ether/sodium hydroxide solution until solution is complete. Dry the ether phase, evaporate off the solvent and distill the residue to obtain 2.73 g of the base, the title compound, b.p. 70° at 0.005 mm of Hg, [α]58920 =+78.9° (25 mg/ml in methanol).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]([NH:9]C(=O)OC(C)(C)C)[C:3]1=[O:17].Cl>O1CCOCC1>[NH2:9][C@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[C:3]1=[O:17]
Reactant: CN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCCC[C@H](N)C1=O
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl [(3S)-1-methyl-2-oxohexahydro-1H-azepin-3-yl]carbamate (470 mg, 1.9 mmol) in dioxane (5 mL) was added HCl (4.8 mL, 19 mmol, 4M in dioxane), and the reaction was stirred overnight. Evaporation of the solvent gave a quantitative yield of (3S)-3-amino-1-methylhexahydro-2H-azepin-2-one. LCMS: (M+H)+: 143.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:13])[CH2:11][OH:12])([O-:3])=[O:2].CN1CCOCC1.O=C(Cl)[O:23][C:24](Cl)(Cl)[Cl:25]>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:13])[CH2:11][O:12][C:24]([Cl:25])=[O:23])([O-:3])=[O:2]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(CO)c1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(COC(=O)Cl)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
A solution consisting of 7.2 g 2-(2-nitrophenyl)propanol (39.7 mmol) and 4.4 ml N-methylmorpholine (39.7 mmol) in 15 ml absolute THF are slowly added to 5 ml diphosgene (41.4 mmol) in 10 ml absolute THF at 0° C. in a nitrogen atmosphere through a needle. Having stirred for 1 hour at 0° C., some of the precipitate is sucked off and the filtrate is withdrawn at the high vacuum. 6.91 g of (1) is obtained in the form of a brown oil (71%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1.S(Cl)([Cl:17])=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([Cl:17])=[O:14])=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-c2ccccn2)s1

Procedure:
A mixture of 1.0 g of 5-(2-pyridinyl)thiophene-2-carboxylic acid and 5 ml of thionyl chloride is refluxed for 2.5 hours. The mixture is concentrated to dryness under vacuum. Toluene is added (2 times) and the solvent removed under vacuum to give the product as an off-white solid.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([NH2:21])[C:19]#[CH:20]>CO>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])=[N:21][CH2:18][C:19]#[CH:20])#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: C#CCN
Solvent: CO
Product: C#CCN=C(NC#N)NCCSCc1[nH]cnc1C

Procedure:
The mixture of N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-S-methylisothiourea (10.0 g; 0.0371 mole) and distilled propargylamine (20 ml; 0.325 mole) in methanol (50 ml) was stirred at reflux, under a positive pressure nitrogen atmosphere (nitrogen sweep), for 20.5 hours. The solvent and excess amine were then removed by evaporation to leave a yellow-brown oil that readily crystallized. Trituration of the crude product under isopropanol (30 ml) gave the title compound as an off-white, friable solid (8.11 g, 79%); m.p. 146°-148.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][C:11](=O)[CH3:12].Cl.[CH3:15][O:16][NH2:17].O.[OH-].[Na+]>CO>[CH3:15][O:16][N:17]=[C:11]([CH3:12])[CH2:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[Cl:9]
Reactant: CON
Reactant: CC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CON=C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 50 °C

Procedure:
1-(2,4,6-trichloro-phenyl)-propan-2-one (273 g, 1.118 mol) was suspended in methanol (544 g) at ambient temperature. The resulting suspension was then heated under stirring to a temperature of 50° C. (most of the solid is dissolved). Then O-methyl-hydroxylamine hydrochloride as a 30% solution in water (358 g, 1.286 mol) was fed within 30-60 min. maintaining the temperature between 50-52° C. During the course of O-methyl-hydroxylamine hydrochloride addition the reaction mass turned into a two-phase system (liquid-liquid). At the end of O-methyl-hydroxylamine hydrochloride feed the pH was adjusted to 4-5 by slow addition of NaOH 30% (264 g 1.981 mol). The mixture was then stirred for 1-2 hours at 50-52° C. to allow the reaction to go to completion. Subsequently the pH was adjusted to 7-8 by adding NaOH 30% (8.5 g, 0.064 mol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.[C-:14]#[N:15]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:14]#[N:15])=[CH:8][CH2:7][CH2:6]2
Reactant: [C-]#N
Reactant: COc1ccc2c(c1)CCCC2=O
Product: COc1ccc2c(c1)CCC=C2C#N

Procedure:
The process of claim 1 wherein (1) 6-methoxytetralone is reacted with cyanide ion and a Lewis acid so as to form 6-methoxy-1-cyano-3,4-dihydronaphthalene, (2) the 6-methoxy-1-cyano3,4-dihydronaphthalene is dehydrogenated to 6-methoxy-1-cyanonaphthalene, (3) the 6-methoxy-1-cyanonaphthalene is halogenated so as to form a 6-methoxy-5-halo-1-cyanonaphthalene and then trifluoromethylated to replace the halo substituent with a trifluoromethyl group, and (4) the resultant 6-methoxy-5-trifluoromethyl-1-cyanonaphthalene is hydrolyzed to 6-methoxy-5-trifluoromethyl-1-naphthoic acid.
Reaction SMILES: C1(C)C=CC(S([Cl:10])(=O)=O)=CC=1.[CH3:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N+:14]=1[O-]>O1CCOCC1>[Cl:10][CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccc(C)[n+]([O-])c1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CCl)nc1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
p-Toluenesulfonyl chloride (10.7 g, 56.1 mmol) was combined with 13 (7.8 g, 51.0 mmol) in dioxane (100 ml) under an Argon atmosphere. The reaction mixture was heated under reflux for 1 night. After cooling to room temperature the solvent was evaporated and the residue dissolved in dichloromethane (200 ml). The solution was washed with saturated Na2CO3 (aq) (2×100 ml), brine (50 ml) and dried (Na2SO4). After evaporation of the solvent the product was purified by column chromatography (SiO2, hexane/ethyl acetate 10:2.5) to give 14 (5.71 g, 30.8 mmol, 60%) as a slightly yellow solid. An analytically pure sample could be obtained by recrystallization from n-hexane, mp 63.5-63.8° C.; 1H-NMR (CDCl3) δ3.94 (s, 3H), 4.70 (s, 2H), 7.58 (d, 1H, J=8.4 Hz), 8.30 (dd, 1H, J 8.1 Hz, J=2.2 Hz), 9.08 (d, 1H, J=1.5 Hz); Anal. Calcd. for C8H8ClNO2: C 51.77, H 4.34, N 7.55; found: C 51.50, H 4.23, N 7.46.