Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]=2[CH:8]=[C:7]([C:16](=[O:18])[CH3:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:19]Br>C(O)(=O)C.C1(C)C=CC=CC=1>[Br:19][CH2:17][C:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:14]2[O:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]=2[CH:8]=1)=[O:18]
Reactant: BrBr
Reactant: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CN1CCOc2c1cc(C(=O)CBr)cc2C(C)(C)C
Reaction time: 2.5 h
Yield: 13 %

Procedure:
1-(8-tert-Butyl-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)ethanone (250 mg, purchased from Chembiotek, India) was warmed to 50° C. to 55° C. in a mixture of acetic acid (4 ml) and toluene (8 ml). Bromine (200 mg dissolved in acetic acid) was carefully added dropwise at this temperature. After 2.5 h, the heating was removed, and the mixture was treated with ice water at RT and extracted three times with toluene. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified on silica gel, so that 65 mg of the desired compound were obtained, in addition to a further 43 mg of product, which were slightly contaminated, and 37 mg of starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C[I:14].[CH2:15](OCC)C>CC#N>[I-:14].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:12])=[CH:7][CH:8]=[N+:9]2[CH3:15])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1ccnc2cc(Cl)ccc12
Reactant: CCOCC
Solvent: CC#N
Product: Cc1cc[n+](C)c2cc(Cl)ccc12
Product: [I-]

Procedure:
A portion of the 7-chlorolepidine (80 mg) prepared as above was methylated by heating with CH3I (0.5 ml) in CH3CN (1 ml) at reflux for two hours. The mixture was treated with diethyl ether, followed by centrifugation, to give a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[CH:3]=1.[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[C:27](OC)=[O:28].CO[Na].CO.Cl>O.C(#N)C>[C:19]([C:4]1[CH:3]=[C:2]([NH:1][C:27]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][N:21]=2)=[O:28])[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=1)#[N:20]
Reactant: COC(=O)c1cnccn1
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Agent: CO[Na]
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CC#N
Product: N#Cc1cc(NC(=O)c2cnccn2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
Into a mixture of 0.5 g (1.6 mmol) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole-3-carbonitrile, 0.24 g (1.7 mmol) of methyl pyrazinecarboxylate, and 0.5 ml of acetonitrile was gradually added 0.3 g (1.6 mmol) of 28% CH3ONa/CH3OH at room temperature. After 2 hours of stirring at room temperature, 5 ml of water and then concentrated hydrochloric acid were added thereto to make the mixture pH 2, whereby crystals were precipitated. Thereto was added 10 ml of ethyl acetate, followed by extraction. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After removal of the sodium sulfate by filtration, the layer was concentrated and the resulting crystals were filtrated. The crystals were washed with a small amount of hexane and ethyl acetate and the dried to obtain 0.5 g (yield 77%) of N-[3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole-5-yl]pyrazine-2-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](C#N)=[O:7])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[CH3:12][N:13]1[C:17]([C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=[C:14]1[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: Cc1ccc(C(=O)C#N)cc1
Reactant: COC(=O)Cc1cccn1C
Product: COC(=O)Cc1ccc(C(=O)c2ccc(C)cc2)n1C
Yield: 398.8 %

Procedure:
A mixture of 5.0 g (0.034 mole) of 4-methylbenzoylcyanide and 0.8 g (0.005 mole) of methyl 1-methyl-pyrrole-2-acetate was added over 4 hours from a heated addition funnel to a sample of 3.8 g (0.025 mole) of methyl 1-methylpyrrole-2-acetate at 180° through which nitrogen was bubbled. The mixture was heated for six more hours after the addition was complete. The reaction was cooled and dissolved in methylene chloride-toluene. The organic solution was washed with 10 percent sodium hydroxide solution and saturated brine and dried (MgSO4). The solvent was evaporated in vacuo and the residue recrystallized twice from methanol to give 5.41 g (69 percent yield) of white crystalline methyl 1-methyl-5-(4-methyl-benzoyl)-pyrrole-2-acetate, mp 118°-120° C. The solid state IR spectrum was identical to authentic material.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:21][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:7][NH:6][CH2:5]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30](=[O:32])[CH3:31]>C(#N)C.ClCCl>[CH3:1][O:2][CH2:3][CH:4]1[CH2:5][N:6]([CH2:29][C:30](=[O:32])[CH3:31])[CH2:7][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[O:21]1
Reactant: CC(=O)CBr
Reactant: COCC1CNCC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: COCC1CN(CC(C)=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1

Procedure:
To a mixture of tert-butyl 10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate and K2CO3 (115 mg, 0.832 mmol) in acetonitrile (1.4 mL) was added 1-bromopropan-2-one (304 mg, 2.00 mmol). The reaction mixture was heated under argon in a sealed tube for 16 h. The mixture was cooled, diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to provide tert-butyl 2-(methoxymethyl)-4-(2-oxopropyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate. ESI-MS m/z calc. 356.2. found 357.3 (M+1)+; Retention time: 0.98 minutes (3 min run).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][C:31]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:32])[CH:34]=[CH:35][CH:36]=1
Reactant: O=C(O)C=Cc1cccc(F)c1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1cccc(F)c1
Yield: 73 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (4.0 g), triethylamine (2.3 mL), 3-fluorocinnamic acid (2.7 g), WSC.HCl (3.2 g), and methylene chloride (100 mL), to give the captioned compound (4.2 g, 74%) as an oily product.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[F:28][C:29]([F:36])([F:35])[CH:30]([OH:34])[C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH:30]([OH:34])[C:29]([F:36])([F:35])[F:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)C(O)C(F)(F)F
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C(O)C(F)(F)F

Procedure:
The title compound, yellow solid (110 mg, 96%), MS (ISP) m/z=457.4 [(M+H)+], mp 185° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (RS)-3,3,3-trifluoro-2-hydroxy-propionic acid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]([NH:11][S:12](Cl)(=[O:14])=[O:13])([CH3:10])[CH3:9].C(N)(C)C.S(Cl)(Cl)(=O)=O.[Sb](Cl)(Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[C:1]1([O:7][S:12](=[O:14])(=[O:13])[NH:11][CH:8]([CH3:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC(C)NS(=O)(=O)Cl
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O=S(=O)(Cl)Cl
Solvent: CC(C)N
Product: CC(C)NS(=O)(=O)Oc1ccccc1
Yield: 32 %

Procedure:
This compound was prepared according to the procedure of Example 37. Thus a solution of 16.2 g (0.17 mole) of phenol and 33.0 g (0.21 mole) of N-isopropylsulfamoyl chloride (prepared from isopropylamine, sulfuryl chloride and antimony pentachloride by the procedure of Example 2, part a) in 150 ml of toluene gave a dark oil which was purified by column chromatography on silica gel using ethyl acetate-hexanes (1:16) to elute the product. Desired fractions were combined and concentrated to yield 11.7 g (32%) of the title compound as a light-yellow oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C@H:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:1]([NH:17][C@@H:10]([CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@H](N)c1ccccc1
Product: C[C@H](NCc1ccccc1)c1ccccc1
Yield: 96.1 %

Procedure:
Benzaldehyde (3.94 mL, 38.8 mmol) and (S)-α-methylbenzylamine (5.0 mL, 38.8 mmol, 96% ee.) were allowed to react according to the procedure of Example 86 to yield 7.88 g (96%) of N-benzyl-(S)-α-methylbenzylamine as an oil contaminated with ~5% of benzyl alcohol and (S)-α-methylbenzylamine: 1H NMR (DMSO-6, 250 MHz) δ7.15-7.45 (m, 10H, Ar), 3.69 (q, 1H, J=6.5 Hz), 3.48 (dd, 2H, J1 =13.6 Hz, J2 =20.9 Hz), 2.45 (br s, 1H, NH), 1.26 (d, 3H, J=6.5 Hz, CH3); 13C NMR (DMSO-d6) δ146.0, 141.0, 128.1, 128.0, 127.8, 126.4, 126.3, 56.7, 50.6, 24.5. This mixture was directly used in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:12])[CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:12])[CH2:9][CH2:10][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][CH:3]=1
Reactant: CC1=CCC(C(C)CC=O)CC1
Reactant: C1CCNC1
Product: CC1=CCC(C(C)CCN2CCCC2)CC1

Procedure:
The procedure of Example 1 was followed using 50g (0.3 mole) of 3-(4-methyl-3-cyclohexenyl)butyraldehyde and 24g (0.33 mole) of pyrrolidine. Obtained following distillation was 48.5g of pure N-[3 . . . butyl]pyrrolidine as a clear, colorless liquid: bp 106°-108° (0.2mm) ir (τ max. film 3.5 (s), 6.9 (s), 7.3 (s), 8.7 (s), 12.5 (m) microns; nmr (δ, CDCl3) 5.36 (m, 1H), 2.45 (m, 6H), 2.1 to 0.8 (m, 20H) ppm; ms (molecular ion) 221.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH:7]1[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][CH2:8]1.O>ClCC(Cl)(Cl)Cl>[Br:2][CH2:6][CH:7]1[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][CH2:8]1
Reactant: OCC1COc2ccccc2O1
Reactant: BrP(Br)Br
Agent: ClCC(Cl)(Cl)Cl
Solvent: O
Product: BrCC1COc2ccccc2O1

Procedure:
0.11 mole of phosphorus tribromide in 500 ml of tetrachloroethane was slowly added to 0.3 mole of 2-hydroxymethyl-1,4-benzodioxane and the mixture was warmed at 80°-90° C. for 2 hours. After the mixture had been cooled, it was poured into water, the organic layer was separated off, washed with dilute sodium hydroxide solution and water, dried and concentrated and the residue was distilled. Boiling point: 102°-103° C. (1.3 mbar).
Reaction SMILES: C1(C2C=CC3C(=C(N)C=CC=3)N=2)C=CC=CC=1.C(OC(N1CCC(C(O)=O)CC1)=O)(C)(C)C.[C:34]1([C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[C:43]([NH:50][C:51]([CH:53]4[CH2:58][CH2:57][N:56](C(OC(C)(C)C)=O)[CH2:55][CH2:54]4)=[O:52])[CH:44]=[CH:45][CH:46]=3)[N:41]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:34]1([C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[C:43]([NH:50][C:51]([CH:53]4[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]4)=[O:52])[CH:44]=[CH:45][CH:46]=3)[N:41]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc3ccc(-c4ccccc4)nc23)CC1
Agent: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Nc1cccc2ccc(-c3ccccc3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc2ccc(-c3ccccc3)nc12)C1CCNCC1

Procedure:
2-Phenylquinolin-8-amine (60 mg, 0.27 mmol) was subjected to the same general amide coupling procedure outlined above using 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. The resulting intermediate, namely tert-butyl 4-(2-phenylquinolin-8-ylcarbamoyl)piperidine-1-carboxylate, was further treated with 2 mL of 25% TFA in CH2Cl2 for 6 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (using aqueous CH3CN that has been buffered with 0.1% TFA) to afford 25 mg of the product. MS (ESI) calcd for C21H21N3O (m/z): 331.17. found: 332 [M+1].
Reaction SMILES: C1(C)C=CC(S(N[C@H](C(O)=O)C)(=O)=[O:8])=CC=1.ON1C2C=CC=CC=2N=N1.[CH:27]1([N:33]=[C:34]=[N:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.COC1C=C(O)C=C(OC)C=1.C(N(CC)CC)C>C(OCC)(=O)C>[CH:36]1([NH:35][C:34]([NH:33][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[O:8])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COc1cc(O)cc(OC)c1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 2 h

Procedure:
For reaction by the active ester process, 14.6 g. (0.06 mol) N-(toluene-4-sulphonyl)-L-alanine and 12.2 g. (0.09 mol) N-hydroxybenzotriazole are dissolved in 300 ml. anhydrous ethyl acetate, cooled to 0° C. and mixed with 12.4 g. (0.06 mol) dicyclohexylcarbodiimide. For the formation of the active ester, the reaction mixture is stirred for 2 hours at 0° C. and then for a further 2 hours at ambient temperature. After the addition of 6.2 g. (0.04 mol) 3,5-dimethoxyphenol and 5.5 ml. (0.04 mol) triethylamine, the reaction mixture is stirred for 15 hours at ambient temperature. The N,N'-dicyclohexylurea formed is filtered off with suction and the filtrate is evaporated in a vacuum at a maximum bath temperature of 50° C. The residue is taken up in 200 ml. ethyl acetate and successively washed, in each case three times, with 100 ml. amounts of 5% citric acid and then with 100 ml. amounts of 5% sodium bicarbonate solution. After drying with anhydrous sodium sulphate, the organic phase is evaporated in a vacuum. The oily crude product obtained is purified column chromatographically with a silica gel column, using toluene-ethyl acetate (4:1 v/v) as elution agent. After evaporating the appropriately collected fractions, the residue is dissolved in a little methylene chloride and the product precipitated out by the addition of diethyl ether, there being obtained 5.8 g. (38% of theory) 1-[N-(toluene-4'-sulphonyl)-L-alanyloxy]-3,5-dimethoxybenzene in the form of colorless crystals; m.p. 110° C.; αD20 : -52.5° (c=1% in acetone).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.[C:49](Cl)(=[O:53])[CH2:50][CH2:51][CH3:52]>C(OCC)(=O)C>[C:33]([C:31]1[CH:30]=[CH:29][C:28]2[N:24]([CH2:23][CH2:22][O:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][CH:9]([NH:8][C:49](=[O:53])[CH2:50][CH2:51][CH3:52])[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:19]=3)[C:25](=[O:41])[S:26][C:27]=2[CH:32]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)C(N)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Reactant: CCCC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCC(=O)NC(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)OC
Reaction time: 8 h

Procedure:
500 mg of the compound obtained in Step A of Example 12 are dissolved in 10 ml of ethyl acetate; 0.353 ml of triethylamine is then added and the temperature is lowered to 0° C. 0.177 ml of butyryl chloride is added and the mixture is allowed to return to ambient temperature and is stirred overnight.
Reaction SMILES: C1(C2C=CC(C[NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=CC=2)CC1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[C:34]([O:37][CH3:38])([CH3:36])[CH3:35])[CH:29]=O.FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[C:34]([O:37][CH3:38])([CH3:36])[CH3:35])[CH2:29][NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:13]=1
Reactant: COC(C)(C)c1ccc(C=O)cc1Cl
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: COC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1Cl

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 77 mg of 3-chloro-4-(1-methoxy-1-methyl-ethyl)-benzaldehyde (0.36 mmol), 68 mg of 2-(3-trifluoromethylphenyl)-ethylamine (0.36 mmol) and 21 mg of sodium borohydride (0.54 mmol). The isolated colorless liquid (113 mg, 81%) was used in the following step without further purification. MS (ISP) 386.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([N:6]1[C@@H:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][O:8][C:7]1=[O:14])[CH2:3][CH2:4][CH3:5].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.Br[CH2:36][S:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[O:1]=[C:2]([N:6]1[C@@H:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][O:8][C:7]1=[O:14])[C@@H:3]([CH2:36][S:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:4][CH3:5]
Reactant: BrCSCc1ccccc1
Reactant: CCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC[C@H](CSCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1C(C)C
Yield: 123.3 %

Procedure:
A solution of the N-acylated product of Step 6 (36.9 g, 185 mmol) in anhydrous THF (70 mL) was added to a magnetically stirred, cooled (-78° C.) solution of LDA (lithium diisopropylamide) (prepared from 28.6 mL (20.6 g, 204 mmol) of diisopropylamine and 127.5 mL (1.6M in hexane, 204 mmol) of n-butyllithium) in anhydrous THF (240 mL). After stirring for 0.5 h at -78° C. the resultant lithium enolate was treated with benzyl bromomethyl sulfide (52.3 g, 241 mmol) for 2 h at -20° C. The reaction was quenched by the addition of half-saturated aq NH4Cl (200 mL). Volatiles were removed in vacuo and the product was extracted into CH2Cl2 (3×). The combined organic extracts were successively washed with 1 M aqueous sodium bisulfate (2×), 1M aqueous KHCO3 (2×) and brine, dried over MgSO4 and concentrated in vacuo to give 76.5 g of a yellow liquid. This crude material was roughly purified by flash chromatography on silica with EtOAc:hexane 1:99, 2:98, 5:95, 10:90 and 15:85 to give the title compound as a colorless liquid (48.9 g), which was used as such for the next step.
Reaction SMILES: [CH2:1]([NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:21])=O>>[CH2:1]([N:9]=[C:10]([Cl:21])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(=O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCN=C(Cl)c1ccc(Cl)cc1
Yield: 76.2 %

Procedure:
N-Octyl 4-chlorobenzamide (17.2 g, 64.2 mmole) and thionyl chloride (42.59 g, 358 mmole) were stirred and heated at reflux for one hour. The product was isolated by fractional distillation at reduced pressure (b.p. 70°-90° C. at 15 mm Hg) to yield 14.0 g (77%) of impure title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc2c1cnn2Cc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c1cnn2Cc1ccccc1

Procedure:
A mixture of 1-benzyl-4-nitro-1H-indazole (150 mg; 0.592 mmol), iron powder (331 mg; 5.92 mmol) and ammonium chloride (16 mg; 0.296 mmol) in ethanol/water (4:1; 5 mL) was heated at reflux for 5 hours. The solvent was removed under vacuum and the residue was mixed with ethyl acetate/triethylamine (4:1; 5 mL) and heated at reflux for 1 hour. The mixture was allowed to cool and then filtered through a pad of silica, washing with ethyl acetate. The solvent was removed under vacuum to give the desired product that was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.Br[CH:17]([CH3:20])[CH:18]=[CH2:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH:18]([CH3:19])[CH:17]=[CH2:20])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: C=CC(C)Br
Product: C=CC(C)C(O)c1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 63, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 3-bromo-but-1-ene.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])[O:7][CH2:6]2)#[N:2].[NH2:13][OH:14]>CCO>[OH:14][N:13]=[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])[O:7][CH2:6]2)[NH2:2]
Reactant: NO
Reactant: N#Cc1ccc2c(c1)COC2=O
Solvent: CCO
Product: NC(=NO)c1ccc2c(c1)COC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A solution of 5-cyanophthalide (1 g, 6.28 mmol) and hydroxylamine (50% in water, 0.77 cm3, 0.83 g, 12.6 mmol, 2 eq) in EtOH (50 cm3) was stirred at room temperature for 60 hours and then under reflux for 3 hours. After cooling to room temperature and standing overnight, the solid formed was collected by filtration and dried in high vacuum line to give the product N′-hydroxy-1-oxo-1,3-dihydroisobenzofuran-5-carboximidamide (1.04 g, 86.2%) as a white solid, mp 223-226° C. (decomposed).
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH3:35])=[O:33]>ClCCl>[CH3:35][O:34][C:32]([N:21]1[CH2:20][CH2:19][CH:18]([C:16]2[S:15][CH:14]=[C:13]([C:11]([N:1]3[C@@H:10]4[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]4)[CH2:4][CH2:3][CH2:2]3)=[O:12])[CH:17]=2)[CH2:23][CH2:22]1)=[O:33]
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Reaction time: 2 h
Yield: 49.1 %

Procedure:
cis-(Octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (CC-033) (0.04 g, 0.12 mmol) was dissolved in dichloromethane (2 mL) and triethylamine (0.37 mmol). Methyl chloroformate (0.25 mmol) was added and the mixture stirred for 2 hours and then the solvent removed by evaporation. The residue was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.023 g). LCMS m/z 391.15 min [M+H]+ RT=11.55 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.2 (s, 1H), 6.9 (s, 1H), 4.6 (m, 1H), 4.3 (m, 2H), 3.8 (m, 1H), 3.7 (s, 3H), 3.1-2.7 (m, 4H), 2.1-1.1 (m, 17H).