Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>CN(C=O)C>[C:35]([O:34][C:32](=[O:33])[CH2:31][N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([CH2:14][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([O:12][CH3:13])=[O:11])=[CH:16]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1cn(CC(=O)OC(C)(C)C)c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
To a 0° C. solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(1H-indol-3-yl)propanoate (4 g, 12.56 mmol) and cesium carbonate (4.50 g, 13.82 mmol) in DMF (40 mL) was added tert-butyl 2-bromoacetate (2.015 mL, 13.82 mmol) and was allowed to warm up to RT by removing from ice bath and stirred for 18 hrs. The reaction was poured into 1:1 ice water:1N HCl and extracted with EtOAc. The organic layer washed with brine, collected, dried over MgSO4, filtered and evaporated to give the crude product. The crude product was purified via silica gel chromatography (80 g column, 0-50% EtOAc:Hexanes over 20 CV) to get the product (S)-methyl 3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate (4.69 g, 86% yield). 1H NMR (400 MHz, chloroform-d) d 7.56 (d, J=7.8 Hz, 1H), 7.26-7.18 (m, 2H), 7.17-7.12 (m, 1H), 6.92 (s, 1H), 5.09 (d, J=7.6 Hz, 1H), 4.71 (s, 2H), 3.73-3.59 (m, 3H), 3.30 (d, J=5.1 Hz, 2H), 1.45 (s, 18H). ESI-MS(+) m/z=433 (M+H).
Reaction SMILES: C(O)(=O)CCCC.[NH2:8][C:9]1[CH:14]=[CH:13][N:12]([CH:15]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](=[O:27])[C:10]=1[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]2[NH:46][N:45]=[N:44][N:43]=2)=[CH:32][CH:31]=1.NC1C(=O)N(C(C(=O)N(C)C)C2C=CC=CC=2)C=CC=1N[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.BrCC1C=CC(C2C=CC=CC=2C#N)=CC=1.C(NC1C=CN(C(C(=O)N(C)C)C2C=CC=CC=2)C(=O)C=1NCC1C=CC(C2C=CC=CC=2C#N)=CC=1)C1C=CC=CC=1.C[Sn](N=[N+]=[N-])(C)C>>[CH2:55]([NH:8][C:9]1[CH:14]=[CH:13][N:12]([CH:15]([C:22](=[O:26])[N:23]([CH3:24])[CH3:25])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](=[O:27])[C:10]=1[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]2[NH:46][N:45]=[N:44][N:43]=2)=[CH:32][CH:31]=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: CN(C)C(=O)C(c1ccccc1)n1ccc(N)c(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Reactant: CN(C)C(=O)C(c1ccccc1)n1ccc(NCc2ccccc2)c(N)c1=O
Agent: CN(C)C(=O)C(c1ccccc1)n1ccc(NCc2ccccc2)c(NCc2ccc(-c3ccccc3C#N)cc2)c1=O
Agent: C[Sn](C)(C)N=[N+]=[N-]
Agent: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: CCCCC(=O)O
Product: CN(C)C(=O)C(c1ccccc1)n1ccc(NCc2ccccc2)c(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O

Procedure:
A mixture of 1.02 g of valeric acid, 5.2 g of 4-amino-1,2-dihydro-2-oxo-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethylamino]-1-(α-N,N-dimethylcarbamoylbenzyl)pyridine [obtainable by reaction of 3-amino-4-benzylamino-1,2-dihydro-2-oxo-1-(α-N,N-dimethylcarbamoylbenzyl)pyridine with 4-bromomethyl-2'-cyanobiphenyl to give 4-benzylamino-3-(2'-cyanobiphenyl-4-ylmethylamino)-1,2-dihydro-2-oxo-1-(α-N,N-dimethylcarbamoylbenzyl)pyridine, reaction with trimethyltin azide to give 4-benzylamino-1,2-dihydro-2-oxo-3-(2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethylamino)-1-(α-N,N-dimethylcarbamoylbenzyl)pyridine, and hydrogenolytic cleavage of the benzyl group] and 50 g of polyphosphoric acid is heated for 5 hours at 140°. 4-Amino-1,2-dihydro-2-oxo-2-(N-(2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl)-N-valerylamino)-1-(α-N,N-dimethylcarbamoylbenzyl)pyridine and 1,2-dihydro-2-oxo-3-(2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethylamino)-1-(α-N,N-dimethylcarbamoylbenzyl)-4-valerylaminopyridine are formed in situ as intermediates. The mixture is cooled, poured onto ice, rendered alkaline with sodium hydroxide solution and worked up in a conventional manner to give 2-butyl-3-(2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl)-4,5-dihydro-4-oxo-5-(α-N,N-dimethylcarbamoylbenzyl)-3H-IP.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH3:11])=[CH:4][N:3]=1.C1C[O:15][CH2:14]C1.C([Li])(C)(C)C.CN(C)C=O>O.C(OCC)(=O)C>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:14]=[O:15])=[N:3][CH:4]=1)[CH2:10][CH3:11]
Reactant: CCCOc1ccc(I)nc1
Reactant: C1CCOC1
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(C=O)nc1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A mixture comprising 2-iodo-5-propoxypyridine (0.27 g, 1 mmol) and THF (10 mL) was cooled to -78° C. and then tert-butyl lithium (1.3 mL, 1.7 M in pentane, 2.1 mmol) was added dropwise to give an orange slurry. The slurry was cooled to -78° C. and stirred for 5 minutes and then anhydrous N,N-dimethylformamide (0.4 mL, 5 mmol) was added dropwise. The mixture was allowed to warm to ambient temperature, stirred 20 minutes and then poured into a mixture comprising ethyl acetate and water. The mixture was washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to provide 5-propoxypyridine-2-carboxaldehyde (0.2 g, 1.3 mmol) as a dark oil. 1H-NMR (300 Mhz, CD3OD): 1.1 (t, 3H), 1.9 (m, 2H), 4.1 (t, 2H), 7.5 (m, 2H), 8.4 (m, 1H), 10.5 (s, 2H); MS (CI); Calculated for C9H11NO2, 165.2, Found (MH+): 166.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][CH:17]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:18]([O:20][CH3:21])=[O:19])[CH2:12][CH2:11]2)=[CH:2]1.[F:28][C:29]1[CH:30]=[C:31]([CH:37]=[C:38]([F:40])[CH:39]=1)/[CH:32]=[CH:33]/[C:34](O)=[O:35]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([NH:16][CH:17]([CH:22]3[CH2:23][CH2:24][N:25]([C:34](=[O:35])/[CH:33]=[CH:32]/[C:31]4[CH:30]=[C:29]([F:28])[CH:39]=[C:38]([F:40])[CH:37]=4)[CH2:26][CH2:27]3)[C:18]([O:20][CH3:21])=[O:19])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: O=C(O)/C=C/c1cc(F)cc(F)c1
Reactant: COC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Product: COC(=O)C(N[C@H]1CC[C@H](c2c[nH]c3ccccc32)CC1)C1CCN(C(=O)/C=C/c2cc(F)cc(F)c2)CC1

Procedure:
The title compound was prepared from methyl 2-(4-(1H-indol-3-yl)cyclohexyl)amino)-2-(piperidin-4-yl)acetate (from Example 24, step A) and trans-3,5-difluorocinnamic acid, by the method of Example 1, step K, giving a solid that was mostly the more polar cyclohexyl diastereomer by LCMS. Mass spectrum (LCMS, APCI pos.) calcd. for C31H35F2N3O3: 536 (M+H). Found: 536.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCC#CCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)CCCC#CCNS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 24 h
Yield: 19 %

Procedure:
4-Chlorobenzenesulphonyl chloride (0.31 g) in chloroform (2 ml) was added to a rapidly stirred solution of 7-aminohept-5-ynoic acid (0.2 g) and sodium hydroxide (0.21 g) in water (3 ml) and stirring was continued for 24 hours. The solution was extracted with chloroform (4×10 ml). The remaining aqueous layer was cooled, treated with hydrochloric acid and the resulting precipitate was collected by filtration and recrystallised from isopropanol-water to give the title compound (0.085 g). m.p. 91°-93° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][N:20]=[N+]=[N-])[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2].[H][H]>C(O)C.C(=O)([O-])[O-].[Ba+2].[Pd+2].C(=O)([O-])[O-]>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][NH2:20])[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: [H][H]
Reactant: COC(=O)c1cc(CN=[N+]=[N-])cc(-c2cccc(C#N)c2)c1
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Product: COC(=O)c1cc(CN)cc(-c2cccc(C#N)c2)c1
Reaction time: 6 h

Procedure:
The Methyl 3-(3-cyanophenyl)-5-(azidomethyl)benzoate obtained as above was put in a flask, dissolved in 66 mL of ethanol, and after 1.1 g of palladium-barium carbonate was added, the air in flask was displaced with hydrogen. Stirring was continued at room temperature for 6 hours, the catalyst was subjected to celite-filteration, and the filtrate was concentrated and purified with silica gel chromatography to produce 794 mg of the title compound (Yield of the two steps: 90%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH2:23]([N:26]=[C:27]=[S:28])[CH2:24][CH3:25]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:27]([NH:26][CH2:23][CH2:24][CH3:25])=[S:28])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCN=C=S
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Product: CCCNC(=S)NCCCn1c(CCOC)nc2c(N)nc3ccccc3c21
Yield: 46.4 %

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with propyl isothiocyanate (570 mg, 5.62 mmol) to provide 950 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-propylthiourea as a tan powder, m.p. 172–173° C. Analysis: Calculated for C20H28N6OS: % C, 59.97; % H, 7.05; % N, 20.98; Found: % C, 59.83; % H, 7.01; % N, 20.95.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15].[NH2:34][CH2:35][CH2:36][OH:37].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>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:10])[CH3:11])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([NH:34][CH2:35][CH2:36][OH:37])=[O:31])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15]
Reactant: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Reactant: NCCO
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: C1CCOC1
Product: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)NCCO)cc2OCC3)c(Cl)c1

Procedure:
Following the procedures in Examples 47 and 235, 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with 2-aminoethanol, HATU and DIPEA in THF to give 338 as a colorless solid after reverse phase HPLC. MS: (ESI+) 528.0
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[C:10]1[C:11](=[O:16])[CH2:12][CH:13](O)[CH:14]=1)([OH:3])=[O:2].[SH:17][CH2:18][CH2:19][OH:20].C[O-].[Na+].C(O)(=O)C>CO>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[C:10]1[C:11](=[O:16])[CH2:12][CH:13]([S:17][CH2:18][CH2:19][OH:20])[CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)CCCC/C=C\C1=CC(O)CC1=O
Reactant: OCCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)CCCC/C=C\C1=CC(SCCO)CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2.24 g. (10 mmols) of 2-(6-carboxy-2-cis-hexenyl)-4-hydroxycyclopent-2-en-1-one (U.S. Pat. No. 3,952,033) and 0.82 g (10.5 mmols) of β-mercaptoethanol in 50 ml of methanol is added 10.5 ml of N/1 sodium methoxide in methanol solution during 30 minutes at room temperature. After the addition the solution is stirred at room temperature for 1 hour and treated with 4.8 g of glacial acetic acid (80 mmols). The solution is concentrated to volume of 10 ml, treated with 30 ml of brine, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:18][C:12]2[C:11]3[C:16](=[CH:17][C:8]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)[N:15]=[CH:14][N:13]=2)=[CH:25][CH:24]=1
Reactant: C1COCCN1
Reactant: COc1ccc(COc2ncnc3cc(Br)ccc23)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(COc2ncnc3cc(N4CCOCC4)ccc23)cc1
Yield: 81.7 %

Procedure:
Under a nitrogen atmosphere, 2.82 g (12.5 mmol) of tris(dibenzylideneacetone)dipalladium-(0) and 5.41 g (15.1 mmol) of 2-(dicyclohexylphosphino)biphenyl were dissolved in 1.5 l of toluene, and 269.0 ml (3.1 mol) of morpholine and 213.0 g (0.62 mol) of 7-bromo-4-(4-methoxybenzyloxy)quinazoline [dissolved in 2 l of toluene] were added successively. 73.0 g (0.8 mol) of sodium tert-butoxide were subsequently added in portions, and the mixture was stirred. Conventional work-up gave 178 g of 4-(4-methoxybenzyloxy)-7-morpholin-4-ylquinazoline; HPLC/MS (M+H)+=350 as oil [crude product; was reacted further directly].
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1>ClCCl>[F:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([Br:1])[CH:14]=3)[S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: Nc1ccc(-c2nc3c(F)cccc3s2)cc1
Solvent: ClCCl
Product: Nc1ccc(-c2nc3c(F)cccc3s2)cc1Br
Reaction time: 0.17 h

Procedure:
Bromine (0.8 mmol) was added to a solution of the 4-fluoro-2-(4′-aminophenyl) benzothiazole prepared as described in Example 3 (0.8 mmol) in dichloromethane (20 ml) at 10° C. The resulting solution was stirred for 10 min, then poured into water/ice (10 ml). The organic layer was removed and washed with 10% sodium thiosulfate (10 ml), water (10 ml) and evaporated. The product was purified by column chromatography (dichloromethane) to leave a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.[H-].[Na+].[CH3:18]I.O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:18])=[C:4]([C:9]2([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1
Reactant: CI
Reactant: CC1(c2cc(Br)ccc2O)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1C1(C)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
The 4-bromo-2-(1-methylcyclohexyl) phenol (9.26 g, 34.4 mmoles) is dissolved in 50 ml of THF. The solution is cooled to 0° C. and there is added in small fractions sodium hydride (80% in oil, 1.14 g, 37.8 mmoles). The reaction mixture is stirred for 30 minutes at ambient temperature and 5.37 g (37.8 mmoles) of methyl iodide are slowly added. Stirring is continued for 16 hours at which point water (300 ml) is added and the reaction mixture is extracted with ether (3×300 ml). The organic phase is washed with a saturated sodium bicarbonate solution and then with a saturated sodium chloride solution. The reaction mixture is dried on MgSO4, filtered and the solvents are evaporated. The residue is purified by chromatography on a silica column, eluted by a 20/80 mixture of dichloromethane and hexane, yielding 9 g (92% yield) of 4-bromo-2-(1-methylcyclohexyl) anisole in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]([O:8][CH2:9][CH2:10][CH3:11])=[C:3]([C:6]#[N:7])[C:4]#[N:5].C(N(CC)CC)C.[SH2:19]>N1C=CC=CC=1.O>[NH2:1][C:2]([O:8][CH2:9][CH2:10][CH3:11])=[C:3]([C:4]#[N:5])[C:6](=[S:19])[NH2:7]
Reactant: CCCOC(N)=C(C#N)C#N
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: O
Product: CCCOC(N)=C(C#N)C(N)=S

Procedure:
A stirred mixture of 141 g of 3-amino-2-cyano-3-propoxypropenenitrile and 94.4 g of triethylamine in 250 ml of pyridine was heated at 80° for 4 hours while hydrogen sulfide gas was continually passed through the mixture. Thin-layer chromatography indicated reaction to be complete. The reaction mixture was diluted to 2 liters with water and the pale yellow precipitate was collected by filtration. The precipitate was recrystallized from ethanol to give 114 g of 3-amino-2-cyano-3-propoxypropenethioamide, m.p. 174°.
Reaction SMILES: C(O[C:6]([N:8](C)[C@@H:9]([CH2:13][C:14](C)(C)[CH3:15])[C:10](O)=[O:11])=O)(C)(C)C.[F:19][C:20]([F:38])([F:37])[O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:32][C@@H:31]3[C@@H:33]([NH2:36])[CH2:34][CH2:35][C@@H:30]3[CH2:29]2)=[CH:24][CH:23]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH3:6][NH:8][C@H:9]([C:10]([NH:36][C@@H:33]1[C@@H:31]2[C@@H:30]([CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:37])[F:38])=[CH:27][CH:26]=3)[CH2:32]2)[CH2:35][CH2:34]1)=[O:11])[CH2:13][CH2:14][CH3:15]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(OC(F)(F)F)cc3)C[C@@H]21
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CCC[C@H](NC)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(OC(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-norvaline for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-(4-(trifluoromethoxy)phenyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 716 Step 1 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (400 MHz, pyridine-d5, temperature 90° C.) δ ppm 7.60-7.71 (m, 1H), 7.10-7.15 (m, 2H), 6.56-6.59 (m, 2H), 4.24-4.32 (m, 1H), 3.47 (dd, J=9.9, 3.6 Hz, 1H), 3.31 (dd, J=9.8, 7.9 Hz, 1H), 3.19 (dd, J=9.5, 7.9 Hz, 1H), 3.10 (dd, J=6.9, 5.8 Hz, 1H), 3.01 (dd, J=9.6, 4.0 Hz, 1H), 2.71-2.83 (m, 1H), 2.56-2.70 (m, 1H), 2.40 (s, 3H), 2.09 (dq, J=12.6, 6.3 Hz, 1H), 1.92-2.01 (m, 1H), 1.74-1.83 (m, 1H), 1.58-1.70 (m, 2H), 1.38-1.53 (m, 3H), 0.88 (t, J=7.3 Hz, 3H); MS (ESI+) m/z 400 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([C:7]1[CH:23]=[CH:22][C:10]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3[O:19][CH:20]=[CH:21][C:15]=3[CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:6].[CH3:27][NH:28][CH3:29].[CH2:30]=O>C(O)(=O)C>[CH3:27][N:28]([CH2:30][C:20]1[O:19][C:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:10]3[CH:22]=[CH:23][C:7]([C:5](=[O:6])[C:4]4[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[CH:3]=4)=[CH:8][CH:9]=3)[CH2:14][C:15]=2[CH:21]=1)[CH3:29]
Reactant: C=O
Reactant: CNC
Reactant: O=C(c1ccc(C(=O)N2CCc3occc3C2)cc1)c1cccc(Cl)c1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)c1ccc(C(=O)c3cccc(Cl)c3)cc1)C2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.190 g (0.519 mmol) of 5-[4-(3-chlorobenzoyl)benzoyl]-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 10 ml of acetic acid, 0.070 ml (0.78 mmol) of 50% aqueous dimethylamine and 0.063 ml (0.78 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 60 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform/methanol=50/1) to yield the desired product.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.O>ClCCl>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([O:25][C:24]([F:23])([F:35])[F:36])=[CH:27][CH:28]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(NC1CCN(C(=O)c2ccc(OC(F)(F)F)cc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-fluorobenzoylamino)piperidine (0.15 g) in dichloromethane (5 ml) were added in turn pyridine (82 μl) and 4-trifluoromethoxybenzoyl chloride (106 μ) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 4 hours, which was taken up into a mixture of water and dichloromethane. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate, and brine, and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave 4-(4-fluorobenzoylamino)-1-(4-trifluoromethoxybenzoyl)piperidine (205 mg).
Reaction SMILES: [OH:1][CH:2]1[CH:6]=[CH:5][S:4][CH:3]1[C:7]#[N:8].[CH:9](Cl)(Cl)Cl>[N+](=C)=[N-].CCOCC>[CH3:9][O:1][CH:2]1[CH:6]=[CH:5][S:4][CH:3]1[C:7]#[N:8]
Reactant: N#CC1SC=CC1O
Reactant: ClC(Cl)Cl
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: COC1C=CSC1C#N
Temperature: 0 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
12.7 Parts of 3-hydroxy-2-cyanodihydrothiophene are dissolved in 100 parts by volume of chloroform and 200 parts by volume of a 4 percent strength by weight solution of diazomethane in ether are added at 0° C. The solution is stirred for 12 hours at 0° C. and is concentrated under reduced pressure. The residue is distilled. 10.1 parts (72% of theory) of 3-methoxy-2-cyanodihydrothiophene of boiling point 82°-83° C./0.35 mbar are obtained.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH2:11]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=1[CH3:24])[CH:12]=[CH2:13]>C(O)(=O)C>[CH2:11]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=1[CH2:24][C:2](=[O:4])[C:1]([O:8][CH2:9][CH3:10])=[O:7])[CH:12]=[CH2:13]
Reactant: CCOC(=O)C(=O)OCC
Reactant: C=CCOc1cccc([N+](=O)[O-])c1C
Solvent: CC(=O)O
Product: C=CCOc1cccc([N+](=O)[O-])c1CC(=O)C(=O)OCC

Procedure:
0.625 mol Potassium tert.-butylate, 542 ml. diethyl oxalate and 95.7 g. 2-allyloxy-6-nitrotoluene are stirred for 3 hours at 60° C., then mixed with 1 N acetic acid and extracted with diethyl ether. The oxalic acid ester remaining behind in the ether residue is removed at an elevated temperature at water-pump pressure, 171 g. ethyl 2-allyloxy-6-nitrophenylpyruvate being obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:11][S:12][C:13]([CH2:16]O)=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:32]([CH2:16][C:13]1[S:12][S:11][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:15][CH:14]=1)=[N+:33]=[N-:34]
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(CO)SS1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCC1=CC=C(CN=[N+]=[N-])SS1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a stirred solution of 3.4 g (11.7 mmol) of 3-[(tert-butyldimethylsilyloxy)methyl]-6-hydroxymethyl-1,2-dithiin (10) in 12 mL of toluene was added diphenylphosphoryl azide (3.02 mL; 3.86 g, 14.0 mmol) in 8 mL of toluene and the solution was cooled to 0° C. To the cold solution was added dropwise 2.09 mL (2.13 g; 14.0 mmol) of DBU. The reaction mixture became dark. In 2 hours at 0° C., the reaction mixture was allowed to warm up to room temperature. After 14 hours the reaction mixture was purified on a silica gel column using 5% ethyl acetate in hexane to give 2.75 g (74.5%) of azide 15. 1H NMR (CDCl3) δ6.38 (m, 2H, C=CH), 4.30 (s, 2H, CH2O), 3.98 (s, 2H, CH2O), 0.92 (s, 9H, CCH3), 0.10 (s, 6H, SiCH3). 13C NMR (CDCl3) δ136.898 128.007, 123.471, 64.726, 55,145, 25.780, 25.735, 18.278, -5.443; MS (EI) m/z=315.1 (100%; M+).