Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:17]1([C:23]#[C:24][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[S:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1ccc(-c2nc3ccccc3s2)cc1
Reactant: C#Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C(#Cc1ccc(-c2nc3ccccc3s2)cc1)c1ccccc1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To a solution containing 2-(4-bromophenyl)benzthiazole (43.5 g 0.15 mol) and phenylacetylene (20 g, 0.19 mol) in 0.8 L of triethylamine was added the catalyst system consisting of dichlorobis-(triphenylphosphine)palladiumII (1 g), triphenylphosphine (0.3 g) and cuprous iodide (0.1 g). The reaction mixture was refluxed under a nitrogen atmosphere for 19 h. After cooling to 25° C., the reaction mixture was filtered and the filtrate poured into 3 L of water. The resulting light gray solid was isolated by filtration and dried in an oven at 110° C. Recrystallization from heptane using activated charcoal gave 37 g (78.9%) of a white crystalline product: m.p. 172°-173° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][N:3]=1.[Br:14]Br>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]([Br:14])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: CCOC(=O)Cc1ccnc(N)c1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cc(N)ncc1Br
Reaction time: 3 h
Yield: 45.5 %

Procedure:
A flask was charged with ethyl 2-(2-aminopyridin-4-yl)acetate (12.45 g, 69.09 mmol) and acetic acid (100 mL). Bromine (3.550 ml, 69.09 mmol) was added, and the reaction mixture was stirred for 3 hours. The solvent was evaporated in vacuo and the residue was mixed with ice, basified with ammonium hydroxide, and extracted with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residual brown oil was purified by silica gel chromatography, eluting with 1-2% methanol/dichloromethane to provide the desired product (8.15 g, 45.53% yield) as pale yellow solid.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:16](B2OC(C)(C)C(C)(C)O2)=[C:15]([CH3:26])[S:14][C:13]=1[CH3:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[C:34]1[CH:43]=[CH:42][C:41]2[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=2[CH:35]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][CH:6]([C:12]1[C:16]([C:34]2[CH:43]=[CH:42][C:41]3[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=3[CH:35]=2)=[C:15]([CH3:26])[S:14][C:13]=1[CH3:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Oc1ccc2c(c1)CCCC2)C(F)(F)F
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1-c1ccc2c(c1)CCCC2
Temperature: 100 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
Under argon atmosphere, ethyl 2-(tert-butoxy)-2-[2,5-dimethyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl]acetate (28f) (50 mg, 0.12 mmol), 5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (39a) (41.4 mg, 0.15 mmol) and sodium carbonate (13.7 mg, 0.13 mmol) were dissolved in dimethylformamide (2.5 mL) and water (0.85 mL). The solution was degassed under argon for 10 minutes and Tetrakis(triphenylphosphine)palladium (28.5 mg, 0.02 mmol) was added. The reaction was heated and shaken at 100° C. for 4 hours. After cooling at room temperature, water was added and the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by preparative TLC (cyclohexane/ethyl acetate: 9/1) to provide the desired product (39b) (40 mg, 0.1 mmol, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.C[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:36][CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[NH:10]1)=[O:28]
Reactant: CNCCCCO
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCCCCO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 43.4 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example 1d was reacted with 4-methylamino-butan-1-ol (44.5 mg, 0.50 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydroxy-butyl)-amide (30.5 mg, 43.4%). HRMS (ES+) m/z Calcd for C27H33Cl2N3O2+H [(M+H)+]: 502,2023. found: 502.2020.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:44][C:45]1[N:50]=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:51][C:48]3[CH:49]=[N:50][C:45]([CH3:44])=[CH:46][CH:47]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: Cc1ccc(N)cn1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: Cc1ccc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)cn1

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 6-methyl-pyridin-3-ylamine according to procedure B followed by deprotection yielded the title compound as an off-white foam. MS (ESI): m/z=370.2 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([O:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([Cl:32])=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=3)=[O:20])=[CH:16][CH:17]=2)[CH:8]=[CH:9][N:10]=1)=[O:4].[S:33](=[O:37])(=[O:36])([OH:35])[OH:34]>C(O)C>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([Cl:32])=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=3)=[O:20])=[CH:14][CH:13]=2)[CH:8]=[CH:9][N:10]=1)=[O:4].[S:33]([O-:37])([O-:36])(=[O:35])=[O:34]
Reactant: O=S(=O)(O)O
Agent: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Solvent: CCO
Product: O=S(=O)([O-])[O-]
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
Ethanol (25 mL) was added to a reaction vessel containing sorafenib free base (5 g). The reaction mixture was stirred for about 5 minutes. The temperature was raised to about 60° C. The reaction mixture was stirred for about 30 minutes. A sulphuric acid solution (sulphuric acid:ethanol:water: 0.57 mL:6 mL:19 mL) was added drop-wise. The reaction mixture was cooled to room temperature and stirred for about 12 hours. The reaction mixture was concentrated. The solid was filtered and dried under reduced pressure at about 50° C. for about 12 hours to obtain sorafenib sulphate.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:17]1[C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=[C:18]1[C:25]([OH:27])=O>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:22]([C:21]1[O:17][C:18]([C:25]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:27])=[CH:19][CH:20]=1)=[O:24])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)c1ccc(C(=O)O)o1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)c1ccc(C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)o1
Yield: 78.1 %

Procedure:
Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzyl ester hydrochloride and 640 mg (4.1 mmol) furan-2,5-dicarboxylic acid afforded, after flash chromatography (EtOAc), 1.7 g (78%) of the title compound as a yellow oil. MS m/e
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH:10]=[N:11]O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C([O-])(O)=O.[Na+]>O>[Br:8][C:5]1[N:4]2[N:11]=[CH:10][N:9]=[C:3]2[C:2]([Br:1])=[N:7][CH:6]=1
Reactant: ON=CNc1nc(Br)cnc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Brc1ncc(Br)n2ncnc12
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 62.1 %

Procedure:
N-(3,6-dibromo-pyrazin-2-yl)-N′-hydroxyformamidine (17.4 mg, 58.80 mmol) is treated with polyphosphoric acid (150 g) for one hour at 50° C. and then for 1.75 hours at 70° C. After cooling to room temperature, water is added to the reaction mixture. The resultant suspension is brought to pH 8 by careful addition of solid NaHCO3 in small portions. The precipitate formed is collected by filtration, washed once with 1N NaOH, three times with water and dried in vacuo. The residue is partitioned between ethyl acetate and 1N NaOH and the organic phase is washed one more time with 1N NaOH and once with brine. The organic phase is dried over MgSO4, filtered and evaporated to give the title compound (10.15 g) as a white solid. 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 8.43 (s, 1H), 8.92 (s, 1H). LCMS: Rt 2.73 min (94.2%), m/z (APCI) 277 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]1[CH2:35][NH:34][CH2:33][CH2:32][NH:31]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:34]4[CH2:33][CH2:32][NH:31][CH:30]([C:26]5[O:25][CH:29]=[CH:28][CH:27]=5)[CH2:35]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: c1coc(C2CNCCN2)c1
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(c5ccco5)C4)c(F)cc3cc2c1=O
Yield: 66.7 %

Procedure:
(RS)-3-Ethoxycarbonyl-7,9-difluoro-8-[3-(2-furyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.85 g) and (RS)-2-(2-furyl)piperazine (1 g). After concentration of the combined organic extracts under reduced pressure (20 kPa, approximately 40° C.), the residual solid is recrystallized in ethanol (100 cc). (RS)-3-Ethoxycarbonyl-7,9-difluoro-8-[3-(2-furyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.72 g) is obtained in the form of a yellow solid, m.p. 208°-210° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O=C(C1C=CC=CN=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CCOC(=O)CC(=O)c1ccccn1
Product: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
N-Boc-4-(2-Ethoxycarbonyl-acetyl)-piperidine was prepared from N-Boc-piperidine-4-carboxylic acid in the same manner as ethyl 3-oxo-3-pyridin-2-yl-propionate (Example 94).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15]>>[CH3:11][O:12][CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1
Reactant: Clc1ccn2nccc2n1
Reactant: COCCN
Product: COCCNc1ccn2nccc2n1
Temperature: 65 °C
Yield: 108.1 %

Procedure:
A stirred mixture of 5-chloro-pyrazolo[1,5-a]pyrimidine [29274-24-6], (525.5 mg, 3.4 mmol) and 2-methoxy-ethylamine (3.0 mL, 34.5 mmol) was heated to 65° C. for 17 h, cooled and partitioned between brine (pH adjusted to 8 with saturated aqueous sodium bicarbonate) and ethyl acetate. Extract was dried (MgSO4) and evaporated to yield 706.4 mg of light yellow solid. LRMS (ESI) m/z 193.1 [(M+H)]+, calc'd for C9H12N4O: 192.22.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[CH:13][C:12]=2[N:20]2[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21]2)[CH2:5][CH2:4]1.[Cl:30][C:31]1[C:44]([N:45]=[C:46]=S)=[C:43]([Cl:48])[CH:42]=[CH:41][C:32]=1[CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].CC(C)N=C=NC(C)C>CC#N>[F:29][C:2]([F:1])([F:28])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([N:20]3[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21]3)=[CH:13][C:14]3[N:18]([CH3:19])[C:46]([NH:45][C:44]4[C:43]([Cl:48])=[CH:42][CH:41]=[C:32]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:31]=4[Cl:30])=[N:17][C:15]=3[CH:16]=2)=[O:27])[CH2:5][CH2:4]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CNc1cc(N2CCC(F)(F)C2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(N3CCC(F)(F)C3)cc21

Procedure:
The title compound is prepared in analogy to 6c from N-(trans-4-trifluoromethyl-cyclohexyl)-2-[3,3-difluoro-pyrrolidinyl]-4-methylamino-5-amino-benzoic acid amide (140 mg, 0.33 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (93 mg, 0.29 mmol), DIC (63 μL) and MeCN (3.0 mL).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)=O.C([O-])(=O)C.[NH4+].C([BH3-])#[N:23].[Na+].Cl>CO>[O:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:2]([NH2:23])[CH3:1])=[CH:5][CH:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CC(N)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
Mix 4-phenoxyacetophenone (5.3 g, 25 mmol), ammonium acetate (14.5 g, 187.5 mmol) and sodium cyanoborohydride (3.2 g, 50 mmol) in anhydrous methanol (200 mL). Stir for 18 h at ambient temperature. Acidify with 1N aqueous HCl (10 mL), dilute, extract with ethyl ether (3×150 mL), dry over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting sequentially with hexane/EtOAc (4:1, 1:1 and 0:1) and EtOAc/methanol (1:1) to give (±)-1-(4-phenoxyphenyl)-ethylamine (1.6 g, 30%). Dissolve the racemate (1.1 g, 5.2 mmol) in DCM (100 mL), add triethylamine (1.6 mL, 11.4 mmol) followed by di-tert-butyl-dicarbonate (1.7 g, 7.8 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give [α-methyl-(4′-phenoxy)-benzylamino]carbamic acid tert-butyl ester as an off-white solid (1.3 mg, 81%). Separate via chiral chromatography (heptane/isopropanol/DMEA 95:5:0.2, 4.6×250 mm Chiralpak AD, 1 mL/min, UV detector at 260 nm) to give [α-methyl-(4′-phenoxy)benzylamino]carbamic acid tert-butyl ester, isomer 1 (315 mg, chiral HPLC: tR=7.35 min; 99.1% ee) and [α-methyl-(4′-phenoxy)benzyl-aminocarbamic acid tert-butyl ester, isomer 2 (400 mg, chiral HPLC: tR=8.7 min; 97.2% ee). Dissolve [α-methyl-(4′-phenoxy)benzylamino]carbamic acid tert-butyl ester isomer 1 or isomer 2 in DCM/trifluoroacetic acid (1:1, 20 mL) to give, after solvent evaporation and chromatography over SCX column, 1-(4-phenoxyphenyl)-ethylamine, isomer 1 (Preparation 146) and 1-(4-phenoxyphenyl)-ethylamine, isomer 2 (Preparation 147). MS (ES+) m/z: 214 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[N:5][OH:6])[CH2:3][CH3:4].[CH:7]1([N:13]=[C:14]=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C1COCC1.[OH-].[Na+]>[CH:16]1([NH:15][C:14](=[N:13][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[O:6][N:5]=[C:2]([CH2:3][CH3:4])[CH3:1])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCC(C)=NO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(C)=NOC(=NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.6 %

Procedure:
To a solution of methylethylketone oxime (4.6 g, 0.053 mol) in dry THF (30 ml) is added finely powdered NaOH (0.15 g) and dicyclohexylcarbodiimide (10.3 g, 0.05 mol). The mixture is then stirred 5 h at room temperature under argon. The turbid mixture is thereafter filtered and evaporated under reduced pressure. The residue is stirred 10 minutes with acetonitrile (30 ml), the acetonitrile phase is then discarded, the oily residue is dissolved in dichloromethane (30 ml), filtered and evaporated to afford 11.24 g of the title compound as a slightly yellow liquid.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH2:6][C:5]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:4]2)[O:2]1.Cl.C(=O)(O)[O-].[Na+].ClCCl>CC(C)=O>[F:25][C:24]([F:26])([F:27])[C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:21]=1)[CH2:17][O:16][CH2:15][C:5]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7][CH2:8][C:3](=[O:2])[CH2:4]1
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCC3(C2)OCCO3)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C1CCCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Yield: 92.3 %

Procedure:
To a solution of 1-(((3,3-ethylenedioxy-1-phenylcyclohexyl)methoxy)methyl)-3,5-bis(trifluoromethyl)benzene (990 mg, 2.09 mmol) in acetone (4 mL) at room temperature were added 1N HCl solution (3.13 mL) and the resulting mixture was stirred at reflux for 2 hr. After cooling down, saturated sodium bicarbonate and dichloromethane were added and the organic layer was separated. The aqueous layer was extracted with dichloromethane 2 times and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum to give the title compound as clear pale yellow sticky oil (830 mg, 92% yield). 1H NMR (400 MHz, CDCl3) δ 1.60 (1H, m), 1.88 (1H, m), 2.19-2.24 (2H, m), 2.29-2.32 (2H, m), 2.85 (2H, dd, J=12, 68 Hz), 3.51 (2H, dd, J=12, 56 Hz), 4.52 (2H, dd, J=16, 18 Hz), 7.22-7.25 (1H, m), 7.32 (4H, d, J=4 Hz), 7.63 (2H, s), 7.77 (1H, s). HPLC purity (retention time): 90% (2.32 min, method C). MS: 453.37 (M+Na+).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][S:5][C:4]1=[C:8]1[C:13](=[O:14])[CH2:12][CH2:11][NH:10][C:9]1=[O:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([N:10]1[CH2:11][CH2:12][C:13](=[O:14])[C:8](=[C:4]2[S:5][CH:6]=[CH:7][S:3]2)[C:9]1=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCNC(=O)C1=C1SC=CS1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCN(Cc2ccccc2)C(=O)C1=C1SC=CS1
Reaction time: 0.17 h
Yield: 62 %

Procedure:
Sodium hydride (60% dispersion in oil) (47 mg) is suspended in N,N-dimethylformamide (2 ml), and to the suspension is added dropwise a solution of 3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine (200 mg) in N,N-dimethylformamide (16 ml). The mixture is stirred for 10 minutes and thereto is added benzyl bromide (0.12 ml), and the mixture is further stirred for 1 hour. After the reaction, the reaction mixture is distilled to remove the solvent under reduced pressure and the residue is dissolved in chloroform. The chloroform solution is washed with an aqueous saturated sodium chloride solution, dried and then distilled to remove the solvent. The residue is recrystallized from isopropyl alcohol to give 1-benzyl-3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine (176 mg, 62%) as pale yellow needles. m.p. 122°-124° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2].[C:22]([O:26][C:27](=[O:33])[NH:28][CH2:29][CH2:30][CH2:31]Br)([CH3:25])([CH3:24])[CH3:23]>>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:6]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:8]=[C:9]([O:11][CH2:31][CH2:30][CH2:29][NH:28][C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:33])[CH:10]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CCOC(=O)c1cc(O)cc(Oc2ccc(C#N)cc2)c1
Product: CCOC(=O)c1cc(OCCCNC(=O)OC(C)(C)C)cc(Oc2ccc(C#N)cc2)c1
Yield: 68 %

Procedure:
Following the procedure of Example 69(b) 3-(4-cyano-phenoxy)-5-hydroxy-benzoic acid ethyl ester 0.9 g (3.17 mmol) and (3-bromo-propyl)-carbamic acid tert-butyl ester (1.5 g, 6.34 mmol) were used to afford 0.95 g of the required product. 1H NMR (DMSO-d6): δ 2.05 (4H, m), 3.35 (2H, m), 3.90 (3H, s), 4.08 (211, t), 4.72 (1H, brs), 6.78 (1H, t), 7.02 (2H, d), 7.28 (1H, s), 7.41 (1H, s), 7.62 (2H, d), 8.05 (1H, brs).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([O-:7])=[CH:5][CH:4]=1.[Li+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([O:7][CH:3]([CH2:9][CH2:8][CH3:6])[CH:4]=[CH2:5])=[CH:5][CH:4]=1
Reactant: COc1ccc([O-])cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(CCC)Oc1ccc(OC)cc1
Reaction time: 14 h
Yield: 75.1 %

Procedure:
The general procedure was followed with lithium 4-methoxyphenoxide (260 mg, 2.0 mmol) and 2-hexenyl methylcarbonate (160 mg, 1.0 mmol) in THF (2 mL). The reaction was conducted at 50° C. for 14 h. 1H NMR analysis of the mixture indicated the ratio of regioisomers to be 90/10. The residue was purified by flash chromatography on silica gel (1% Et2O/Hexanes) to afford 155 mg of the title compound as an oil. [73%, Rf 0.82 (5% Et2O/Hexanes)].[α]D20−8.2 (c 0.6, CHCl3). 1H NMR (500 MHz, CDCl3) δ 6.88 (d, J=9.3 Hz, 2H), 6.84 (d, J=9.2 Hz, 2H), 5.87 (ddd, J=17.3, 10.6, 6.3 Hz, 1H), 5.25 (d, J=17.3 Hz, 1H), 5.21 (d, J=10.6 Hz, 1H), 4.51 (q, J=6.4 Hz, 1H), 3.80 (s, 3H), 1.81 (m, 1H), 1.66 (m, 1H), 1.56-1.46 (m. 2H), 1.00 (t, J=7.3 Hz, 3H); 13C NMR (125.77 MHz, CDCl3) δ 153.8 (C), 152.5 (C), 138.5 (CH), 117.3 (CH), 116.2 (CH2), 114.4 (CH), 79.9 (CH), 55.6 (CH3), 37.7 (CH2), 18.5 (CH2), 13.9 (CH3); Anal. Calc. for C13H8O2: C, 75.69; H, 8.80. Found: C, 75.90, H, 9.07. HPLC analysis indicated an enantiomeric excess of 85% [Chiralcel® OD-H column, eluting with 99.9:0.1 hexane/i-PrOH, 0.6 mL/min, 220 nm; major enantiomer tR, 24.5, minor enantiomer tR 27.6 min].
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]([Cl:9])=[C:6]([CH3:8])[N:7]=1.[NH3:10]>>[NH2:10][C:2]1[CH:3]=[N:4][C:5]([Cl:9])=[C:6]([CH3:8])[N:7]=1
Reactant: N
Reactant: Cc1nc(Cl)cnc1Cl
Product: Cc1nc(N)cnc1Cl
Temperature: 135 °C

Procedure:
A mixture of 3,6-dichloro-5-methylpyrazine (5 g, 30.7 mmol) in ethanolic ammonia solution (50 ml) was heated for 8 hours in a high-pressure cell at 135° C. The solvent was then removed by evaporation and the residue dissolved in chloroform (40 ml). The organic solution was washed with water (2×25 ml) dried (MgSO4) and the volatiles removed by evaporation. The crude solid was semi-purified by column chromatography on silica gel eluting with dichloromethane/methanol (95:5) to the title compound (1.3 g, 31%) as a 10:17 mixture with its regioisomer. NMR: 2.06 (s, 3H), 2.18 (s, 3H), 6.2 (br s, 4H), 6.74 (s, 1H), 7.26 (s, 1H); m/z: 143 [MH]+.