Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:5])/[CH:2]=[CH:3]/[CH3:4].[C:6]([O:10][C:11](=[O:19])[NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7]>C(N(CC)CC)C.C(O)C>[C:6]([O:10][C:11](=[O:19])[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:3]([CH3:4])[CH2:2][C:1]#[N:5])[CH2:15][CH2:14]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: C/C=C/C#N
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(CC#N)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 60 °C

Procedure:
(E)-but-2-enenitrile (4.5 ml, 55.0 mmol) and triethylamine (2 drops) were added sequentially to a solution of piperidin-4-yl-carbamic acid tert-butyl ester (10 g, 50.0 mmol) in ethanol (120 ml) at 25° C. The reaction mixture was stirred at 60° C. for 1 week, then was cooled to 25° C. and concentrated under reduced pressure to afford crude [1-(2-cyano-1-methyl-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester as tan oil. 1H NMR (400 MHz, CDCl3) δ 4.48 (s, 1H), 3.42 (s, 1H), 3.09-2.95 (m, 1H), 2.81-2.61 (m, 3H), 2.49 (dd, J=16.7, 6.0 Hz, 2H), 2.39-2.23 (m, 3H), 1.94 (d, J=11.6 Hz, 2H), 1.44 (s, 9H), 1.18 (d, J=6.7 Hz, 3H). This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])=[CH:25][CH:24]=1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Reactant: CN(C)c1ccc(N=C=O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(NC(=O)C2C(=O)C3CC[C@](C)(C2=O)C3(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-(dimethylamino)phenyl isocyanate (0.32 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for seven hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a light gray solid (0.16 g, 23% yield), mp=93–95° C.; MS (−) ESI m/z=341 (M−H)−; [α]D25=−23.8° (c=1, EtOH).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8](=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21])[C:9](O)=[O:10].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26]>>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:9](=[O:10])[C:8]([C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])=[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:21])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1cc(C)c(C(C(=O)O)=C2C(=O)Nc3ccccc32)[nH]1
Product: Cc1cc(C)c(C(C(=O)Nc2ccc(F)c(Cl)c2)=C2C(=O)Nc3ccccc32)[nH]1

Procedure:
(3,5-Dimethyl-1H-pyrrol-2-yl)-(2-oxo-1,2-dihydroindol-3-ylidene)-acetic acid (90 mg) was reacted with 3-chloro-4-fluoroaniline (90 mg) using method B to give the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]([N:6]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:7](=[O:38])[CH2:8][N:9]1[C:15](=[O:16])[C:14]([CH3:26])([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[C:13](=[O:27])[N:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:11]2[CH:34]=[CH:35][CH:36]=[CH:37][C:10]1=2)([CH3:5])[CH3:4].I[CH3:46]>CN(C=O)C.Cl>[CH:3]([N:6]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:7](=[O:38])[CH2:8][N:9]1[C:15](=[O:16])[C:14]([CH3:26])([CH:17]([CH3:46])[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[C:13](=[O:27])[N:12]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:11]2[CH:34]=[CH:35][CH:36]=[CH:37][C:10]1=2)([CH3:5])[CH3:4]
Reactant: CI
Reactant: CC(C)N(C(=O)CN1C(=O)C(C)(CC(=O)c2ccccc2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CN1C(=O)C(C)(C(C)C(=O)c2ccccc2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.2 %

Procedure:
8.2 mg (0.21 mmol) of 60% sodium hydride is added to a solution of 0.075 g (0.14 mmol) of N-Isopropyl-2-[3-methyl-2,4-dioxo-3-(2-phenyl-2-oxoethyl)-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-phenyl acetamide, prepared as in Example 7, in 2 ml of DMF. After 5 min, 0.009 mL (0.15 mmol) of iodomethane is added and the solution stirred at RT for 25 min. The reaction mixture is diluted with 10 mL of 1N HCl and extracted with EtOAc (×3). The organic extracts are washed with H2O and brine, dried over MgSO4 and concentrated in vacuo to a bright yellow oil. Purification by reverse phase C-18 MPLC (70-75% methanol/H2O) gave 17 mg of the title compound as a white powder: 1H NMR (CDCl3 300 MHz) δ8.04 (d, 2H, J=7), 7.6-6.9 (m, 17H), 5.03 (m, 0.5H), 4.92 (m, 0.5H), 4.8-3.9 (m, 3H), 1.26 (dd, 3H, J=7,11), 1.12 (dd, 3H, J=2,7), 0.98 (t, 3H, J=7); low resolution MS (FAB) m/e 560 (MH+).
Reaction SMILES: [C:1]([NH:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Cl:30])[C:14]=2[N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22]C(=O)OC(C)(C)C)[CH2:17]2)[NH:9][CH:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]>C(O)(C(F)(F)F)=O>[NH2:22][C@@H:18]1[CH2:19][CH2:20][CH2:21][N:16]([C:14]2[C:13]([Cl:30])=[CH:12][N:11]=[C:10]3[NH:9][CH:8]=[C:7]([NH:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:15]=23)[CH2:17]1
Reactant: CCCC(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](N)C3)c12
Yield: 89.9 %

Procedure:
(R)-tert-Butyl 1-(3-butyramido-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (221 mg, 0.507 mmol) was stirred in TFA (3 mL) at room temperature for 1.5 hours. The solvent was evaporated in vacuo, and the residue purified by reverse phase chromatography (Biotage SP4, C-18 12M+, 2-50% CH3CN/water, 16CV). The isolated product was taken up in a minimal volume of methanol and added to a stirred solution of 2N HCl-Et2O. The salt formed was collected by filtration, washed with acetonitrile and dried under vacuum to give (R)-N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)butyramide (153 mg, 74% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.83 (br s, 1H), 9.32 (s, 1H), 8.35 (br s, 2H), 8.13 (s, 1H), 7.57 (s, 1H), 3.54-3.46 (m, 1H), 3.45-3.30 (m, 2H), 3.27-3.04 (m, 2H), 2.41-2.34 (m, 2H), 2.18-2.09 (m, 1H), 1.91-1.79 (m, 1H), 1.72-1.59 (m, 3H), 1.59-1.39 (m, 1H), 0.96 (t, 3H). LCMS (APCI+) m/z 336.1, 338.1 (M+H)+, Retention time=2.38 minutes.
Reaction SMILES: [CH2:1]([S:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])[CH2:2][CH3:3].[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15](Cl)=[O:16])[CH2:12][CH3:13].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:4]([CH2:1][CH2:2][CH3:3])=[O:5])=[N:7]1)=[O:16])[CH2:12][CH3:13]
Reactant: CCCS(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)n1cnc(S(=O)CCC)n1

Procedure:
A mixture of 4.8 g. 3-propylsulphinyl-1,2,4-triazole, 6.0 ml. dipropylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The cooled reaction mixture was filtered and the filtrate distilled under reduced pressure to give an oily residue which crystallized on trituration with petroleum ether (b.p. 60° - 80° C.). The resulting solid product was recrystallized from petroleum ether (b.p. 60° - 80° C.) to give 1-dipropylcarbamoyl-3-propylsulphinyl-1,2,4-triazole, m.p. 50° - 52° C. Elemental analysis satisfactory.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=O)([CH3:3])[CH3:2].[N:15]1([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH2:27])[CH:21]=2)[CH:19]=[N:18][CH:17]=[N:16]1>[N+](C1C=CC=CC=1)([O-])=O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:8]2[NH:27][C:22]3[CH:21]=[C:20]([N:15]4[CH:19]=[N:18][CH:17]=[N:16]4)[CH:25]=[CH:24][C:23]=3[N:26]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])([CH3:3])[CH3:2]
Reactant: COc1ccc(C=O)cc1OC(C)C
Reactant: Nc1ccc(-n2cncn2)cc1N
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(-c2nc3ccc(-n4cncn4)cc3[nH]2)cc1OC(C)C
Temperature: 150 °C
Yield: 55 %

Procedure:
A 5.98 g portion of a known compound 3-isopropoxy-4-methoxybenzaldehyde was added to 4.49 g of 4-(1,2,4-triazol-1-yl)-o-phenylenediamine obtained in Reference Example 2, and the mixture was stirred for 18 hours in 37 ml of nitrobenzene while heating at 150° C. After cooling, nitrobenzene was evaporated under a reduced pressure. By crystallizing the resulting residue with ethyl acetate/hexane, 4.90 g (55%) of the title compound was obtained. Its physical property values are shown as the Compound No. 1 in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[CH3:25][O:26][CH2:27][CH2:28][NH2:29]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([NH:29][CH2:28][CH2:27][O:26][CH3:25])=[O:20])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: COCCN
Product: COCCNC(=O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (120.0 mg, 0.29 mmol) from example 210 and 2-methoxyethylamine (26.4 mg, 0.35 mmol). The title compound was obtained as a solid (70.0 mg, 52% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.17 (1H, m), 8.99 (2H, m), 8.47 (1H, s), 8.04 (1H, m), 3.79 (2H, m), 3.33 (2H, m), 3.22 (3H, s), 3.20 (2H, m). MS m/z: 463.09, 465.12 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([O:17][C@H:18]3[CH2:22][N:21](C(OC(C)(C)C)=O)[C@H:20]([C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])[CH2:19]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:39]=[CH2:40])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1.[CH2:48]([O:51][C:52]([NH:54][C@H:55]([C:60](O)=[O:61])[CH2:56][CH2:57][CH2:58][CH3:59])=[O:53])[CH:49]=[CH2:50].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:48]([O:51][C:52]([NH:54][C@H:55]([C:60]([N:21]1[CH2:22][C@H:18]([O:17][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:39]=[CH2:40])[CH:13]=3)[N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:16]=2)[CH2:19][C@H:20]1[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])=[O:61])[CH2:56][CH2:57][CH2:58][CH3:59])=[O:53])[CH:49]=[CH2:50]
Reactant: C=Cc1ccc2nc(-c3ccccc3)cc(O[C@@H]3C[C@@H](C(=O)OCC[Si](C)(C)C)N(C(=O)OC(C)(C)C)C3)c2c1
Reactant: C=CCOC(=O)N[C@@H](CCCC)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N[C@@H](CCCC)C(=O)N1C[C@H](Oc2cc(-c3ccccc3)nc3ccc(C=C)cc23)C[C@H]1C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a flask containing 1-tert-butyl 2-[2-(trimethylsilyl)ethyl] (2S,4R)-4-[(2-phenyl-6-vinylquinolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate 5 (45 mg, 0.08 mmol) was added a 4 M solution of HCl in dioxane (1.4 mL, 5.6 mmol). After 1 h, LC-MS analysis indicated complete consumption of the starting material (5) and formation of the desired -Boc product. The volatile components were then removed in vacuo, and the crude material was taken up in DMF (1 mL). To this mixture was added alloc-Nle-OH (4) (26 mg, 0.12 mmol), DIPEA (0.144 mL, 0.8 mmol), and TBTU (39 mg, 0.12 mmol). After stirring at RT for 30 min, complete consumption of the amine was evidenced via LC-MS. The reaction mixture was then worked-up with 1N HCl and EtOAc. The organic layer was washed with brine and dried over MgSO4. The solvent was then removed in vacuo and the crude product was purified on silica (10-50% EtOAc/hexanes) to yield 50 mg (95% yield) of 2-(trimethylsilyl)ethyl N-[(allyloxy)carbonyl]-L-norleucyl-(4R)-4-[(2-phenyl-6-vinylquinolin-4-yl)oxy]-L-prolinate 6. 1H NMR (500 MHz, CDCl3) ppm: mixture of amide rotamers: 8.07 (m, 3H), 7.97 (br s, 1H), 7.88 (m, 1H), 7.54-7.47 (m, 3H), 7.07 (s, 1H), 6.92 (dd, J=17.5 Hz, 10.5 Hz, 1H), 5.90 (d, J=17.5 Hz, 1H), 5.83 (m, 1H), 5.43-5.63 (m, 3H), 5.25-5.13 (m, 2H), 4.79 (app t, J=8 Hz, 1H), 4.65-4.37 (m, 4H), 4.26 (m, 2H), 4.10 and 4.08 (2 d, J=4.0 Hz and 4.5 Hz, 1H), 2.78 (m, 1H), 2.42 (m, 1H), 1.83 (m, 1H), 1.63 (m, 1H), 1.44-1.33 (m, 4H), 1.05-0.98 (m, 2H), 0.92 (m, 3H), 0.05 (s, 9H). LRMS (CI, [M+H]) Calc'd=658.4. Found=658.4. HRMS (APCI, [M+H]+) Calc'd for C37H48N3O6Si: 658.3307. found: 658.3348.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Li]CCCC>CN(C=O)C.CO>[C:13]1([S:19]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([CH3:3])=[CH:5]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reaction time: 0.25 h
Yield: 85 %

Procedure:
50% sodium hydride (1.1 g) was added to a solution of 3-methylindole (4 g) dissolved in anhydrous DMF (50 ml), keeping the temperature under 30° C. Stir for 15 minutes, then drip carefully the phenylsulphonyl chloride (4.7 ml) dissolved in anhydrous DMF (20 ml) and leave under stirring for 2 hours at 25° C. Then add methanol (5 ml) to decompose the possible present traces of BuLi; remove the solvent under reduced pressure, add water (20 ml) and extract exhaustively with methylenchloride. The organic phase is made anhydrous on sodium sulfate and the solvent is removed under reduced pressure. The residue (9.5 g) is ground in methylenchloride/hexane 1:1 to obtain N-(phenylsulphonyl)-3-methylindole (2 g) (m.p. 116-120° C.). The mother liquors are chromatographied to recover more product, eluting with methylenchloride/hexane 1:1. N-(phenylsulphonyl)-3-methylindole (7 g) is recovered from the intermediate fractions, removing the solvent under reduced pressure.
Reaction SMILES: [N:1]1([CH:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[Br:24]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:24][C:9]1[CH:10]=[CH:11][C:2]2[N:1]([CH:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCCc3ccccc32)C1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCCc3cc(Br)ccc32)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
A solution of compound 2 (3.15 g, 9.97 mmol) in DMF (15 mL) was cooled to 0° C. and treated drop wise with a solution of N-bromosuccinimide (1.77 g, 9.97 mmol) in DMF (15 mL). The reaction mixture was stirred at 0° C. for 3 hours then diluted with H2O (100 mL) and extracted into EtOAc (2×100 mL). The combined organic fractions were washed with brine (100 mL), dried (Na2SO4) and concentrated. The crude product was purified by column chromatography (EtOAc:hexanes, 1:9) to obtain compound 3 (3.26 g, 83%) as a foam. 1H NMR (DMSO-d6) δ 1.38 (s, 9H), 1.41-1.52 (m, 5H), 1.80-1.87 (m, 1H), 2.12-2.17 (m, 1H), 2.65-2.69 (m, 2H), 2.79-2.92 (m, 2H), 3.00-3.08 (m, 1H), 3.15-3.25 (m, 1H), 3.53-3.59 (m, 1H), 3.96-4.04 (m, 1H), 6.93-6.96 (d, 1H, J=8.4 Hz), 7.23 (dd, 1H, J=2.4, 8.4 Hz), 7.29 (d, 1H, J=2.4 Hz); ESI-MS (m/z, %): 395 (MH+, 7), 341 (92), 339 (100).
Reaction SMILES: [Br:1]C1C=CC(CC(OCC)=O)=CC=1.Br[C:15]1[CH:24]=[C:23]2[C:18]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][C:22]2=[O:25])=[CH:17][CH:16]=1>>[Br:1][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:15]=1)[C:22](=[O:25])[CH2:21][CH2:20][C:19]2([CH3:27])[CH3:26]
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Product: CC1(C)CCC(=O)c2ccc(Br)cc21

Procedure:
Important starting materials for the synthesis of the preferred compounds of the invention are 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F), 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G), and the isomeric bromo compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H). Compound G can be obtained as described in J. Mez Chem. 1995, 38, 4764-4767, and as shown in Reaction Scheme 1. Thus, referring now specifically to Reaction Scheme 1, ethyl 3-bromophenylacetate (Compound B, made by esterification of 3-bromophenylacetic acid) is reduced with diisobutylaluminum hydride (DIBAL H) to yield (3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with (carbethoxymethylene)triphenylphosphorane to provide a mixture of E and Z ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds are hydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with the Grignard reagent derived from methylbromide to give the tertiary alcohol 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should be apparent to those skilled in the art, that the choice of the Grignard reagent used in this reaction step determines the nature of the R1 substituent in the resulting compounds of the invention.) Compound E is then treated with acid to cyclize it and to form 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F). Compound F is oxidized with chromium trioxide to yield 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). The isomeric compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can be obtained, starting with ethyl (4-bromophenyl)acetate, in accordance with the sequence of reactions illustrated in Reaction Scheme 1 for Compound G. 6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can also be obtained in accordance with the published literature procedure: Mathur et al. Tetrahedron, 41, 1509-1516 (1985).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][C:5]2([CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13](/[CH:19]=[CH:20]/[C:21](O)=[O:22])[CH:14]=3)[O:9]2)[CH2:4][CH2:3]1.[NH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1>>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][C:5]2([CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13](/[CH:19]=[CH:20]/[C:21]([NH:24][O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[O:22])[CH:14]=3)[O:9]2)[CH2:4][CH2:3]1
Reactant: CN1CCCC2(CC1)CC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Reactant: NOC1CCCCO1
Product: CN1CCCC2(CC1)CC(=O)c1cc(/C=C/C(=O)NOC3CCCCO3)ccc1O2

Procedure:
(±)-(E)-3-[1′-Methyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid (330 mg, 0.94 mmol) was treated with NH2OTHP according to the procedure described in Example 23, Step C, giving (±)-(E)-3-[1′-methyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a yellow solid (220 mg).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][O:11]1)=[O:10]>CCOCC>[OH:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[C:9]([NH:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10]
Reactant: O=C1OCc2ccccc21
Reactant: NNc1ccccc1
Solvent: CCOCC
Product: O=C(NNc1ccccc1)c1ccccc1CO
Temperature: 20 °C

Procedure:
The method adopted is disclosed in Wislicenus (Berichte 20 401). Phenyl hydrazine (27 ml) and phthalide (33 g) were heated together at 70° to 80° C. for 3 hours. After cooling to 20° C. the solid product was stirred with ether (100 ml) and the product collected by filtration, washed with ether and recrystallised from 2-propanol. Yield 9.6 g (16%) melting point 170°-172° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][CH:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[C:4](=[O:15])[O:3]1.C=O.[OH-].C[N+](C)(C)C.[C:25](O)(=[O:27])C>N1C=CC=CC=1.CO>[CH3:1][C:2]1([CH3:16])[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])([CH2:25][OH:27])[C:4](=[O:15])[O:3]1
Reactant: CC(=O)O
Reactant: CC1(C)OC(=O)C(c2ccc(Cl)cc2Cl)O1
Agent: C=O
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CO
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(CO)(c2ccc(Cl)cc2Cl)O1
Temperature: -5 °C
Reaction time: 12 h

Procedure:
104.4 g (0.4 mole) of 2,2-dimethyl-4-(2,4-dichlorophenyl)-1,3-dioxolan-5-one are dissolved in 700 ml of pyridine and to the solution are added 48 g of paraformaldehyde. Then 40 ml of a 40% solution of tetramethylammonium hydroxide in methanol are slowly added dropwise. The mixture is stirred for 12 hours, cooled to -5° C., and a solution of 100 ml of glacial acetic acid and 400 ml of pyridine is added dropwise until the pH value is 6.5 to 7. The reaction solution is poured into ice-water and extracted with methylene chloride. The extract is dried over sodium sulfate and the product is crystallised by addition of diethyl ether. The crystalline precipitate is washed with a small amount of diethyl ether and petroleum ether. It has a melting point of 182°-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: NCc1cccs1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cccs1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A solution of 4-chlorobenzoyl chloride (0.114 mol) in 50 ml dry CH2Cl2 is added over 30 min to a stirred solution of 2-aminomethylthiophene (0.137 mol) and iPr2NEt (0.25 mol) in CH2Cl2 (200 ml) at 0° C. A white solid is formed and the reaction is allowed to warm to room temperature over 1 h. The mixture is diluted with 200 ml of CH2Cl2, washed twice with HCl aq. (0.1N) and dried over MgSO4. Evaporation of the solvents afforded 28 g (98%) of the title benzamide as a white solid: mp 153-54° C., 1H NMR (CDCl3) δ7.9 (d, J=8.67 Hz, 2H), 7.58 (d, J=8.67 Hz, 2H), 7.44 (dd, J=3.77, 1.13 Hz, 1H), 7.22 (d, J=5.27 Hz, 1H), 7.16 (dd, J=3.39, 5.27 Hz, 1H), 6.62 (br d, 1H), 4.98 (d, J=5.65 Hz, 2H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[NH:13]([C:20]([C:23]1[N:24]([CH3:35])[C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[N:26][N:27]=1)([CH3:22])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH2:8]([NH:10][C:11](=[O:12])[O:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[N:24]([CH3:35])[C:23]([C:20]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([CH3:22])[CH3:21])=[N:27][N:26]=2)=[CH:29][CH:30]=1)[CH3:9]
Reactant: CCN=C=O
Reactant: Cn1c(-c2ccc(O)cc2)nnc1C(C)(C)Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCNC(=O)Oc1ccc(-c2nnc(C(C)(C)Nc3ccccc3)n2C)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Triethylamine and ethyl isocyanate were added to a chloroform solution (3 ml) of 4-[5-(1-anilino-1-methylethyl)-4-methyl-4H-1,2,4-triazol-3-yl}phenol (20 mg), followed by stirring at 60° C. for 3 hours. After concentration, a small amount of ethyl acetate was added to the residue and the resulting crystalline powder was filtered to obtain 4-[5-(1-anilino-1-methylethyl)-4-methyl-4H-1,2,4-triazol-3-yl}phenyl ethylcarbamate.