Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]12[NH:20][C:19](=S)[C:18]([CH3:22])=[N:17]1.[NH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]12[N:20]=[C:19]([NH2:23])[C:18]([CH3:22])=[N:17]1
Reactant: CC1=NC2(CC3(CCCOC3)Oc3ccc(Br)cc32)NC1=S
Reactant: N
Product: CC1=NC2(CC3(CCCOC3)Oc3ccc(Br)cc32)N=C1N
Temperature: 120 °C
Yield: 42.5 %

Procedure:
6′-Bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4(3H)-thione (Example 45 Step 3, 319 mg, 0.84 mmol) was taken up in ammonia (7M in MeOH, 10 mL, 70.00 mmol) and the resulting mixture was heated in the microwave reactor at 120° C. for 2 h. The solvent was evaporated and ammonia (7M in MeOH, 10 mL, 70.00 mmol) was added and the reaction was heated using MW for 1 h at 120° C. The solvent was evaporated and the resulting residue was taken up in DCM and saturated NaHCO3 and poured into a phase separator. The organic phase was dried and concentrated. The crude product was purified by flash chromatography using a gradient of 0-100% EtOAc in heptane followed by a gradient of 0-40% MeOH with 1% NH3 in DCM. The desired fractions were evaporated to give the title compound (130 mg, 43% yield) as a mixture of diastereomers in a 1:1 ratio as determined by NMR: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.41-1.49 (m), 1.76-1.89 (m), 1.89-1.95 (m), 1.95-2.06 (m), 2.21 (s), 2.23 (s), 3.16 (m), 3.41 (d), 3.51 (dd), 3.69 (dd), 3.92 (t), 4.07-4.12 (m), 6.45 (d), 6.47 (d), 6.57 (br. s.), 6.61 (br. s.), 6.82 (d), 7.25 (d), 7.26 (d); MS (ES+) m/z 366.0 [M+H]+.
Reaction SMILES: CO[CH:3](CSC(=O)NCCCCCCCCCCCCCCCCCC)[CH2:4]N.[CH2:29]([S:45][CH2:46][CH:47]([O:50][CH3:51])[CH2:48][NH2:49])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>>[NH2:49][CH2:48][C:47]1([CH2:46][S:45][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:4][CH2:3][CH2:51][O:50]1
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CN)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC
Product: CCCCCCCCCCCCCCCCSCC1(CN)CCCO1

Procedure:
2-Hexadecylthiomethyl-2-hydroxymethyltetrahydrofuran IV b1 is allowed to react and worked by the same procedure as described in (3), the summary of the experimental condition and the physical data of the product are listed in the Tables 5 and 6.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1.[CH2:12]([N:16]=[C:17]=[O:18])[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>C(C(C)=O)C>[CH2:12]([NH:16][C:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1)=[O:18])[CH2:13][CH2:14][CH3:15]
Reactant: O=c1oc2ccc(O)cc2s1
Reactant: CCCCN=C=O
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CCCCNC(=O)Oc1ccc2oc(=O)sc2c1

Procedure:
5-hydroxy-1,3-benzoxathiol-2-one (14.3 grams) was mixed with n-butyl isocyanate (8.85 grams) in 175 milliliters of methyl ethyl ketone in the presence of 1.3 milliliters of triethylamine. The reaction mixture was then heated at reflux temperature for 2.5 hours. The solvent was then removed from the reaction mixture by evaporation in vacuo. The off-white solid residue was recrystallized from toluene and the purified product, 5-(n-butylcarbamoyloxy)-1,3-benzoxathiol-2-one was obtained, as a white, fluffy, crystalline solid with a melting point of 99°-100° C. Elemental analysis calculated for C12H13NO4S (percent): carbon--53.92; hydrogen--4.90; nitrogen--5.24. Found: carbon--54.1; hydrogen--4.89; nitrogen--5.27.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.[CH2:34]([S:36]([CH2:39][CH2:40]O)(=[O:38])=[O:37])[CH3:35]>C(#N)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:35][CH2:34][S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: CCS(=O)(=O)CCO
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)CCOc1cc(C(=O)O)c(O)c2ccccc12
Temperature: 95 °C
Yield: 53 %

Procedure:
20.4 g (0.1 mol) of 1,4-dihydroxy-2-naphthoic acid and 19 g (0.1 mol) of p-toluenesulfonic acid were added to 200 ml of dehydrated toluene. To the mixture, 27.6 g (0.2 mol) of β-ethylsulfonylethanol was added dropwise for 30 minutes under heating at 95° C. with stirring. After heating with stirring for 7 hours, the mixture was cooled to 20° to 30° C. 100 ml of acetonitrile was added to the mixture, the solid deposited was separated by filtration to obtain 17.2 g (53%) of 1-hydroxy-4-(β-ethylsulfonylethoxy)-2-naphthoic acid.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:7][C:8]=2[C:11]([OH:13])=O)[N:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O=[C:27]1NC2C(=NC(C3C=NC=CC=3)=NC=2C(N)=O)[N:28]1C1C=CC=CC=1>CS(C)=O.Cl>[CH3:27][NH:28][C:11]([C:8]1[N:7]=[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:5]=[C:4]2[C:9]=1[NH:10][C:2](=[O:1])[N:3]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:13]
Reactant: NC(=O)c1nc(-c2cccnc2)nc2c1[nH]c(=O)n2-c1ccccc1
Reactant: O=C(O)c1nc(-c2cccnc2)nc2c1[nH]c(=O)n2-c1ccccc1
Agent: Cl
Solvent: CS(C)=O
Product: CNC(=O)c1nc(-c2cccnc2)nc2c1[nH]c(=O)n2-c1ccccc1
Temperature: 90 °C
Yield: 54 %

Procedure:
8-Oxo-9-phenyl-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxylic acid. 8-Oxo-9-phenyl-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide (0.2 g, 0.55 mmol) was dissolved in a mixture of DMSO (3 mL) and aqueous 6N hydrochloric acid solution (1.2 mL). The mixture was heated to 90° C. for 24 h and then poured into an ice/water slurry. The pH was adjusted to 5 and the resulting precipitate was filtered and dried to afford the title compound as a solid (0.108 g, 0.323 mmol, 54% yield), which was used directly in the next step. MS (ESI) m/z 334.1 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C@H:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:9])=[CH:6][C:5]=1[F:26])([O-])=O.CO>C(O)C.[Pd]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C@H:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:9])=[CH:6][C:5]=1[F:26]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc([N+](=O)[O-])c(F)c1)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)c(F)c1)C(=O)OCC
Reaction time: 1.5 h

Procedure:
A solution of diethyl N-(4-nitro-3-fluorobenzoyl)-(L)-glutamate (5.3 g, 14 mmoles) in 95% ethanol (150 mL) was mixed with 10% palladium on carbon (0.4 g) and placed on a Parr apparatus. The mixture was shaken under hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered, spin evaporated, and dried to give a cream solid; yield, 4.7 g (98%); mp 92°-97° C.; 1H-NMR (CDCl3) δ 1.22 and 1.29 (2t overlapped, 6H), 1.6 (br s, 2H), 2.1-2.5 (m, 4H), 4.10 and 4.22 (2q overlapped, 4H), 4.74 (m, 1H), 6.75 (t, 1H), 6.84 (d, 1H), 7.4-7.5 (m, 2H); uv (MeOH) 281 nm max (12000), 236 min (1480), 210 sh (10600); mass spec (CI) m/e 341 (100%), 138 (64).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([CH2:24][CH2:25]OS(C)(=O)=O)[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[C:16]=2[CH2:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)(=O)=O.[CH2:31]([NH2:34])[CH:32]=[CH2:33]>C(O)CC>[CH2:31]([N:34]1[CH2:25][CH2:24][C:8]2([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[C:16]=3[CH2:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:7][CH2:6]1)[CH:32]=[CH2:33]
Reactant: C=CCN
Reactant: COc1cccc2c1Cc1ccccc1C2(CCOS(C)(=O)=O)CCOS(C)(=O)=O
Solvent: CCCO
Product: C=CCN1CCC2(CC1)c1ccccc1Cc1c(OC)cccc12

Procedure:
A mixture of 9,9-di(2-methanesulphonyloxyethyl)-4-methoxy-9,10-dihydroanthracene (1.5 g.) and allylamine (7.0 g.) in n-propanol (30 ml.) is heated under reflux for 18 hours. The solvent is evaporated and 2N sodium hydroxide (20 ml.) is added; the suspension is extracted with ether and the ether layer washed with water, and extracted with 2N hydrochloric acid. The acid extract is washed with ether, basified with 15N ammonia solution, and the precipitated product is extracted into ether, the ether is washed with water and with brine, dried (MgSO4) and evaporated to give 1'-allyl-4-methoxy-9,10-dihydroanthracene-9-spiro-4'-piperidine as an oil.
Reaction SMILES: C(S([C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[C:14]([C:25]([O:27][CH3:28])=[O:26])=[C:13]([CH3:29])[N:12]=1)(=O)=O)C1C=CC=CC=1.[NH:30]1[CH2:35][CH2:34][S:33][CH2:32][CH2:31]1>O1CCOCC1>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[C:15]1[C:14]([C:25]([O:27][CH3:28])=[O:26])=[C:13]([CH3:29])[N:12]=[C:11]([N:30]2[CH2:35][CH2:34][S:33][CH2:32][CH2:31]2)[N:16]=1
Reactant: COC(=O)c1c(C)nc(S(=O)(=O)Cc2ccccc2)nc1-c1ccc(Cl)cc1Cl
Reactant: C1CSCCN1
Solvent: C1COCCO1
Product: COC(=O)c1c(C)nc(N2CCSCC2)nc1-c1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a stirred solution of methyl 2-(benzylsulfonyl)-4-(2,4-dichlorophenyl)-6-methylpyrimidine-5-carboxylate (17 mg, 0.037 mmol) in dioxane (2 mL) was added thiomorpholine (4.5 mL, 0.045 mmol). After at 40° C. for 1 hr, the reaction was concentrated under reduced pressure and diluted with EtOAc (10 mL). The organic layer was extracted with saturated NaHCO3 solution (2×6 mL), brine (5 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give methyl 4-(2,4-dichlorophenyl)-6-methyl-2-thiomorpholinopyrimidine-5-carboxylate (15 mg, 100%). The crude reaction product (>98% purity) was moved onto next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:15](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)[C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: Fc1ccc(CS)cc1
Agent: [Na]
Product: Fc1ccc(C(/C=C\c2ccc(Cl)cc2)SC(/C=C\c2ccc(Cl)cc2)c2ccc(F)cc2)cc1

Procedure:
A solution of 4-chlorophenylacetylene (0.02 mol) and 4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-chlorostyryl 4-fluorobenzylsulfide. The title compound was obtained in 82% yield following oxidation. 1HNMR (CDC13) δ 4.60 (2H, s), 6.70 (1H, d, JH,H=11.78), 7.18-7.60 (8H aromatic+1H ethylenic).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[C:6](Cl)(Cl)=[S:7].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][C:12]=1[Cl:22].Cl>C(Cl)Cl.O.C(Cl)Cl>[Cl:22][C:12]1[CH:13]=[C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:16][C:11]=1[N:10]=[C:6]=[S:7]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: S=C(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1ccc(N=C=S)c(Cl)c1
Temperature: 0 °C
Yield: 107.9 %

Procedure:
Calcium carbonate (626 mg, 6.25 mmol) and thiophosgene (191 μl, 2.51 mmol) were suspended in methylene chloride-water (10 ml, 1:1, v/v). To the resulting suspension was added a solution of methyl 4-amino-3-chlorophenylacetate (500 mg, 2.50 mmol) in methylene chloride (5 ml) under stirring at 0° C. The temperature of the reaction mixture was raised from 0° C. to room temperature over 1.5 hours. The reaction mixture was acidified with 1N HCl, followed by extraction with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent to give methyl 3-chloro-4-isothiocyanatophenylacetate (652 mg, 100%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:17])([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27]I>CN(C)C=O.CCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:15][N:16]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:17])([O:14][CH3:27])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CN(Cc1ccccc1)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: COC1(CN(C)Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Alcohol (35)-(69.3 g, 200 mmol) was dissolved in dimethyl formamide (500 ml). NaH (9.2 g 230 mmol), washed with pentane, was added in 5 portions over 30 min. After complete addition the mixture was stirred at ambient temperature for 45 min. Methyl iodide (14.8 ml, 240 mmol) was added over 1.5 min. The mixture was stirred for 1.5 h at ambient temperature. TLC analysis revealed ca. 80-90% conversion. Extra NaH, 0.8 g, 20 mmol) and methyl iodide (1.2 ml, 20 mmol) was added and the mixture was stirred for another 2 h at ambient temperature. The excess of NaH was destroyed with water (100 ml) and the mixture was further diluted with water (3.5 l). The mixture was extracted with ethyl acetate (2×1 l, 500 ml). The organic layer was washed with brine (1 l), dried over Na2SO4 and concentrated to dryness. The traces of dimethyl formamide were removed by evaporation in vacuo (0.4 mbar, 80° C.). The remaining mixture was purified over silica (eluent: heptane/ethyl acetate, 4/1 to 3/1 v/v). Yield: 55.2 g of amine (36) (80%) as light yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].C1(C)C=CC(S(O[CH2:30][CH:31]2[CH2:34][CH2:33][CH2:32]2)(=O)=O)=CC=1>>[CH:31]1([CH2:30][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])[CH2:34][CH2:33][CH2:32]1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Product: CCc1c(Oc2cc(C)cc(C)c2)n(CC2CCC2)c(=O)[nH]c1=O
Yield: 58.5 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (cyclobutyl)methyl para-toluenesulfonate were reacted by the same way with the example 1 to obtain the titled compound (192 mg, yield: 58.5%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([NH:10][CH3:11])=[O:9])=[O:4].[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:2][C:3]([NH:5][C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[C:8]([NH:10][CH3:11])=[O:9])=[O:4])=[CH:18][CH:19]=1)(=[O:25])[CH3:24]
Reactant: CNC(=O)c1ccccc1NC(=O)CCl
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)c1ccccc1NC(=O)COc1ccc(C(C)=O)cc1
Yield: 84.3 %

Procedure:
To a solution of 2-(2-chloroacetamido)-N-methylbenzamide 22.65 g (0.1 mol) and p-hydroxyacetophenone 16.32 g (0.12 mol) in 200 mL of butanone was added 27.60 g (0.2 mol) potassium carbonate. The mixture was stirred and heated to reflux for 4-5 hours, and monitored by TLC until the reaction was over, the reaction mixture was concentrated under reduced pressure and extracted with 300 mL of ethyl acetate to separate the organic phase, the organic phase was washed with 50 ml of 5% sodium hydroxide aqueous solution and 50 ml of brine successively, dried via anhydrous magnesium sulfate and evaporated, and the residual was purified via silica gel column chromatography to obtain 27.50 g 2-(2-(4-acetylphenoxy)acetamido)-N-methylbenzamide as white solid with yield of 84.4%, m.p. 252-253° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[CH:9]=2)[CH:4]=1.C(O)(=O)C>O>[CH2:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]3)[CH2:14][CH2:15]1)[CH2:20][CH3:21]
Reactant: CCC[C@H]1CC[C@H](c2ccc3cc(OC)ccc3c2)CC1
Solvent: CC(=O)O
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc3cc(O)ccc3c2)CC1
Temperature: 25 °C

Procedure:
To 28.0 g of 2-methoxy-6-(trans-4-propylcyclohexyl)naphthalene were added 280 ml of acetic acid and 280 ml of 48% hydxobromic acid. The reaction mixture was then heated under reflux for 12 hours. The reaction solution was then allowed to cool to room temperature. To the reaction solution was then added 500 ml of water to cause crystallization. The crystal thus precipitated was then filtered off. The crystal was washed with water, and then dried under reduced pressure to obtain 26.8 g of 6-(trans-4-propylcyclohexyl)-2-naphthol.
Reaction SMILES: C(N(CC)CC)C.[CH2:8](Cl)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:18]([NH2:21])[CH:19]=[CH2:20]>O1CCCC1>[CH2:8]([NH:21][CH2:18][CH:19]=[CH2:20])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CCN
Reactant: ClCC=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCNCC=Cc1ccccc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 33.1 %

Procedure:
175 ml (1.27 mol) of triethylamine were added to 173 ml (1.16 mol) of cinnamyl chloride in 1,350 ml of tetrahydrofuran, the mixture was heated to 60° C., and then 105 ml (1.40 mol) of allylamine were added dropwise. The mixture was refluxed for 6 h and then stirred at room temperature for 10 h. After concentration under water pump vacuum, the contents of the flask were partitioned between methyl t-butyl ether and water (pH=10). The aqueous phase was extracted twice more with methyl t-butyl ether and subsequently the combined organic phases were extracted with a mixture of 250 ml of concentrated hydrochloric acid and 2 l of water. The aqueous phase was then extracted with 1.2 l of methylene chloride, and the methylene chloride phase washed five times with 500 ml of 10% strength hydrochloric acid each time. The combined aqueous phases were made alkaline with concentrated sodium hydroxide solution and extracted twice with methylene chloride. Drying and concentration of the organic phase resulted in 66.5 g of crude product which was distilled at 86°-88° C. under oil pump vacuum (0.25 mbar). Yield: 64 g (32%).
Reaction SMILES: [NH2:1][C:2]1([C:9]#[N:10])[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][CH2:5]2.[CH2:11]([O:13]CC)[CH3:12]>C(OC(=O)C)(=O)C>[C:11]([NH:1][C:2]1([C:9]#[N:10])[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][CH2:5]2)(=[O:13])[CH3:12]
Reactant: N#CC1(N)CC2CCC1C2
Reactant: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC1(C#N)CC2CCC1C2

Procedure:
The procedure is as in Example 3, but starting from 2-amino-2-cyano-bicyclo[2.2.1]heptane (6.33 g), in the form of the mixture of the exo and endo racemates in a ratio of (8/1), in diethyl ether (100 cc) and acetic anhydride (4.7 cc); after recrystallization from a mixture of ethanol and water (15/85 by volume) (300 cc), 2-acetylamino-2-cyano-bicyclo[2.2.1]heptane (7.14 g) is obtained in the form of fine white crystals which melt at 164° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].CN([CH:21]=[O:22])C1C=CC=CC=1.S(=O)(=O)(O)O>CCOCC>[F:10][C:9]([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:21]=[O:22]
Reactant: CN(C=O)c1ccccc1
Reactant: FC(F)(F)c1ccccc1Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: O=Cc1ccccc1C(F)(F)F
Reaction time: 3 h
Yield: 68.3 %

Procedure:
2.8 Grams of metallic magnesium, 25 g of 2-bromo-α,α,α-trifluorotoluene and 120 ml of ether were reacted to prepare a Grignard ragent by a conventional method, then 15 g of N-methylformanilide were added dropwise thereto, and the reaction mixture was allowed to stand for 3 hours. Under an ice-cooled condition, a dilute sulfuric acid was added to the reaction mixture. The ethereal layer was separated and was washed with a saturated sodium chloride aqueous solution and with a saturated sodium hydrogencarbonate aqueous solution, then was dried with anhydrous sodium sulfate, and was concentrated. The residue was purified by distillation under reduced pressure to yield 13.2 g of 2-trifluoromethylbenzaldehyde. Boiling point: 62°-65° C. (at 17 mm-Hg).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:30][CH2:29][C@:21]3([NH:25][C@:24]([CH2:27][OH:28])([CH3:26])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Si:42](Cl)([CH3:45])([CH3:44])[CH3:43].O>ClCCl>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:30][CH2:29][C@:21]3([NH:25][C@@:24]([CH3:26])([CH2:27][O:28][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@](C)(CO)N2
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@](C)(CO[Si](C)(C)C)N2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.3 %

Procedure:
To a solution of (2R,5S,7R)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-7-(4-fluoro-2-methylphenyl)-2-(hydroxymethyl)-N,2-dimethyl-1,8-diazaspiro[4.5]decane-8-carboxamide (Example 18, 80 mg, 0.136 mmol) in Dichloromethane (DCM) (2 ml), TEA (0.021 ml, 0.149 mmol) was added and the reaction mixture was stirred at 0° C. for 5 min. TMS-Cl (0.026 ml, 0.204 mmol) was added dropwise and mixture was stirred at the same temperature overnight. Water (2 ml) was added and two phases were separated. The organic layer was dried and evaporated in vacuo affording the title compound (84 mg) that was used in the next step without further purifications. LC/MS (Basic gradient conditions): Rt=4.205 min, m/z 662 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:24][NH:25][C:26](=[O:32])[CH:27]([CH3:31])[C:28](O)=[O:29]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:24][NH:25][C:26](=[O:32])[CH:27]([CH3:31])[C:28]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:29]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: COc1ccc(CNC(=O)C(C)C(=O)O)cc1OC
Product: COc1ccc(CNC(=O)C(C)C(=O)NC2C(=O)N(C)c3ccccc3-c3ccccc32)cc1OC

Procedure:
The title compound, MS: m/e=488.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,4-dimethoxy-benzyl)-2-methyl-malonamic acid.