Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:6][CH:7]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[C:21]([C:20]1[CH:19]=[C:18]([CH:25]=[CH:24][CH:23]=1)[O:17][C:3]1[C:2]([NH:1][C:33]([NH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:34])=[CH:7][CH:6]=[C:5]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([C:12]#[N:13])[CH:10]=2)[N:4]=1)#[N:22]
Reactant: N#Cc1cccc(Oc2ccc(N)c(Oc3cccc(C#N)c3)n2)c1
Reactant: O=C=Nc1ccccc1
Solvent: CC#N
Product: N#Cc1cccc(Oc2ccc(NC(=O)Nc3ccccc3)c(Oc3cccc(C#N)c3)n2)c1

Procedure:
To 3,3′-[3-amino-2,6-pyridinediylbis(oxy)]bis(benzonitrile) (3.0 g, 8.7 mmol) dissolved in acetonitrile (100 mL) was added phenyl isocyanate (1.1 g, 9.5 mmol). After refluxing for 4 hours, the reaction was partitioned between ether and water. The organic layer was separated, washed with water, saturated aqueous sodium bicarbonate, and brine, dried (MgSO4), and the solvent was removed in vacuo. Chromatography on silica gel with ethyl acetate/hexane (1/4) as eluent gave material which was crystallized from ethyl acetate/hexane to give N-[2,6-bis(3-cyano-phenoxy)pyridin-3-yl]-N′-phenylurea; NMR (CDCl3) 8.65 (d,1), 7.4 (m,8), 7.1-7.3 (m,6), 6.8 (s,1), 6.7 (d,1) ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: COc1ccnc(Cl)c1
Product: COc1ccnc(-c2cc([N+](=O)[O-])ccc2F)c1

Procedure:
2-Chloro-4-methoxypyridine (2.0 g, 13.9 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (4.75 g, 17.8 mmol) using the method in Example 47. Purification by chromatography on silica gel eluting with dichloromethane containing 20% isohexane then recrystallisation from toluene/isohexane gave 2-(2-fluoro-5-nitrophenyl)-4-methoxypyridine as a white solid: δH (400 MHz, CDCl3) 3.93 (3H, s), 6.88 (1H, dd, J 6 and 2), 7.31 (1H, t, J 10), 7.35-7.37 (1H, m), 8.24-8.29 (1H, m), 8.59 (1H, d, J 6), 8.98 (1H, dd, J 7 and 3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH2:19]O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)[Cl:22]>>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH2:19][Cl:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1cc(OCc2ccccc2)c2ccccc2c1
Product: ClCc1cc(OCc2ccccc2)c2ccccc2c1

Procedure:
Chlorination of (4-benzyloxy-naphthalen-2-yl) [-methanol] using carbon tetrachloride analogously to Example 7(c) yielded 4-benzyloxy-2-chloromethyl-naphthalene as a colourless solid; MS: 282 (M)+.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:26])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:26][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[C:14]([CH3:15])=[C:13]2[CH:16]1[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:23])=[O:24])[CH2:18][CH2:17]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(C)(=O)=O)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.3 %

Procedure:
To a solution of [6-fluoro-4-(1-methanesulfonyl-piperidin-4-yl)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (51 mg, 0.13 mmol) in THF (6.0 mL) was added a solution of lithium hydroxide monohydrate (62.1 mg, 2.6 mmol) in water (1.5 mL). The resulting solution was stirred for 15 hours at room temperature. The solvent was removed under vacuum. The residue was diluted with water (˜20 mL) and neutralized with 1.0 N aqueous HCl to form a suspension. The product was extracted into ethyl acetate (2×50 mL). The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give a crude solid which was triturated with dichloromethane and hexanes. The solids were collected by filtration and washed with hexanes. After air drying, [6-fluoro-4-(1-methanesulfonyl-piperidin-4-yl)-3-methyl-naphthalen-2-yl]-acetic acid (48 mg, 94%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.4 (br. s, 1H), 7.91 (dd, J=8.91, 6.65 Hz, 2H), 7.70 (s, 1H), 7.36 (t, J=8.41 Hz, 1H), 3.78 (br. s, 6H), 2.95 (s, 3H), 2.26-2.47 (m, 6H), 1.75 (d, J=12.05 Hz, 2H). MS cald. for C19H23FNO4S [(M+H)+] 380, obsd. 380.0.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:14]([O:10][C:9]1[C:2]([Cl:1])=[C:3]([C:6]([Cl:11])=[CH:7][CH:8]=1)[CH:4]=[O:5])[CH:13]=[CH2:12]
Reactant: O=Cc1c(Cl)ccc(O)c1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Cl)c(C=O)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2,6-dichloro-3-hydroxybenzaldehyde (960 mg, 5.03 mmol) (Synthesis, 2004, 12, 2062), allyl bromide (431 μL, 5.03 mmol) and potassium carbonate (563 mg, 10.06 mmol) were combined in DMF (5 mL) and stirred at room temperature for 18 hours. The DMF was removed in vacuo and the residue partitioned between diethyl ether (50 mL) and water (30 mL). The layers were separated and the aqueous extracted with diethyl ether (2×30 mL). The combined organic solution was dried over magnesium sulphate and concentrated in vacuo to afford the title compound as a yellow solid which was used without further purification in preparation 75.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26]Cl)[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[N-:50]=[N+:51]=[N-:52].[Na+].[I-].[Na+]>CCOC(C)=O>[N:50]([CH2:26][CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:16]2[S:15][C:14](=[C:11]3[S:10][C:9](=[N:28][C:29]4[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=4[NH:35][CH2:36][CH3:37])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]3=[O:13])[N:18]([CH3:19])[C:17]=2[CH:20]=1)=[N+:51]=[N-:52]
Reactant: [N-]=[N+]=[N-]
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCN=[N+]=[N-])cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 70 °C

Procedure:
To a 50 mL flask was added the product of Example 145 (225 mg, 345 μmol), anhydrous DMF (8 mL), sodium azide (112 mg, 1.73 mmol), and sodium iodide (15 mg, 103 μmol). The reaction slurry was heated at 70° C. for 6 h under N2. The reaction mixture was diluted with EtOAc (70 mL), washed with H2O (2×30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound. MS(ESI): 658 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[C:20]([CH3:35])=[N:21][N:22]4[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=3)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1)=[CH2:5])C.Cl.O1CCOCC1>C(Cl)Cl>[C:4]([C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[C:20]([CH3:35])=[N:21][N:22]4[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=3)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1)(=[O:3])[CH3:5]
Reactant: C=C(OCC)c1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)c1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
A solution of 7-(1-ethoxyvinyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (56.4 mg, 0.121 mmol) in DCM (1 mL) was treated at ambient temperature with a 4.0 M solution of HCl in dioxane (10 equivalents). The reaction mixture was stirred at ambient temperature for 0.5 hours, then quenched with saturated aqueous sodium bicarbonate. The resulting suspension was extracted with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative thin-layer chromatography (silica, 5% MeOH/DCM as eluent) to afford 24 mg of desired product as a solid. MS (ES+APCI) m/z=439 (M+H) detected.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[S:8])[O:5][C:6]=1[CH3:7].C(N1C(=O)C2=CC=CC=[C:13]2[C:12]1=[S:21])C>>[CH3:1][C:2]1[N:3]=[C:4]([S:8][S:21][CH2:12][CH3:13])[O:5][C:6]=1[CH3:7]
Reactant: Cc1[nH]c(=S)oc1C
Reactant: CCN1C(=O)c2ccccc2C1=S
Product: CCSSc1nc(C)c(C)o1

Procedure:
Starting from 4,5-dimethyl-2-thiono-4-oxazoline and N-ethylthiophthalimide there is obtained (4,5-dimethyl-2-oxazolyl)ethyl-disulphide. nD20 =1.5467. IR (liq.): bands inter alia at 3020, 2970, 1640, 1450, 1175, 1105, 950, 745 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:21]=1[C:22](Cl)=O>C1(C)C=CC=CC=1>[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:21]=1[C:22]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3c(Cl)cccc3Cl)oc(=O)c2c1
Temperature: 25 °C

Procedure:
2-Amino-5-methylbenzoic acid (0.5 g) and triethyl amine (10 ml) were mixed in dry toluene (20 ml). 2,6-Dichlorobenzoyl chloride (1.52 g) was added dropwise under cooling and stirring. The mixture was subsequently heated to RT for 24 h, then heated to 80° C. for 1 h. After cooling on ice the precipitate was filtered off and the filtrate evaporated to dryness. The residue was partitioned between methylene chloride and potassium carbonate (2N), the organic layers separated, dried over magnesium sulfate and evaporated to dryness. The raw product was purified by column chromatography on silicagel using heptane/ethyl acetate as eluent.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[C:35]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](Cl)=[O:41])#[N:36]>C1COCC1>[C:35]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=2)[CH:15]=[C:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:41])#[N:36]
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1cccc(C(=O)n2c(-c3cccnc3)cc3cc(C#N)ccc32)c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 210 mg, 0.96 mmol) in THF (20 mL) at room temperature is added 0.5 M KHMDS in toluene (4.10 mL, 2.05 mmol). After 30 min, 3-cyanobenzoyl chloride (510 mg, 3.08 mmol) is added. The mixture is stirred under N2 overnight. The reaction is quenched with aqueous ammonium chloride and the volatiles are removed in vacuo. The residue is redissolved in dichloromethane and poured into saturated aqueous sodium bicarbonate (100 mL). Extraction with dichloromethane, drying over sodium sulfate followed by concentration affords a residue which is purified on an XBridge RP18 using a 0.1% ammonium hydroxide in acetonitrile gradient. Further purification by silica gel flash chromatography (heptane-ethyl acetate, 3:2 to 2:3) affords 1-(3-cyano-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.20 (d, J=0.5 Hz, 1H), 7.22-7.26 (m, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.73-7.79 (m, 2H), 7.84 (d, 1H), 7.92-7.98 (m, 2H), 8.11 (t, J=1.5 Hz, 1H), 8.29-8.33 (m, 1H), 8.39 (dd, J=4.8, 1.5 Hz, 1H), 8.60 (dd, J=2.3, 0.8 Hz, 1H). HRMS (ESI) m/z 349.1106 [(M+H)+ Calcd for C22H13N4O: 349.1089].
Reaction SMILES: Cl.O1CCOCC1.[F:8][CH:9]([F:56])[C:10]([C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=2)=[CH:45][CH:44]=1)([OH:42])[CH2:11][C:12]1[N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])[N:16]=1>CO>[F:56][CH:9]([F:8])[C:10]([C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=2)=[CH:45][CH:44]=1)([OH:42])[CH2:11][C:12]1[NH:13][CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])[N:16]=1
Reactant: CC(C)(CO)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)F)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(CO)Cc1c[nH]c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)F)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
4M Hydrogen chloride in dioxane (1 mL, 0.25 mmol) was added to a solution of 3-(2-{3,3-difluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]-2-hydroxypropyl}-1-trityl-1H-imidazol-4-yl)-2,2-dimethylpropan-1-ol (from previous step) in methanol (1 mL). After stirring at 70° C. for 1 h, volatiles were removed. The residue was basified with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. Combined extracts were dried (magnesium sulfate) and concentrated Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded the title compound. LCMS: 420 (M+H) found.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[OH:26])[CH3:2].[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[O:26][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][Br:28])[CH3:2]
Reactant: CCOC(=O)CCc1cc(C(=O)c2ccc(C(=O)OCC)cc2)ccc1O
Reactant: BrCCCCCBr
Product: CCOC(=O)CCc1cc(C(=O)c2ccc(C(=O)OCC)cc2)ccc1OCCCCCBr
Yield: 72.6 %

Procedure:
Starting with 0.484 g (1.31 mmol) of 5-[[4-(ethoxycarbonyl)phenyl]carbonyl]-2-hydroxybenzenepropanoic acid ethyl ester, and 2.4 g (10.44 mmol) of 1,5-dibromopentane, the title compound was obtained in 72.6% yield as a white solid, mp 76.5°-78° C., using the procedure of example 21.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][C:7](=[O:20])[C:8]3[CH:14]=[C:13]([CH:15]([CH3:19])[C:16](N)=[O:17])[CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.C(O)(=[O:25])C.Cl>O>[F:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][C:7](=[O:20])[C:8]3[CH:14]=[C:13]([CH:15]([CH3:19])[C:16]([OH:25])=[O:17])[CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: CC(=O)O
Reactant: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1ccc(F)cc1S2
Agent: Cl
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1ccc(F)cc1S2
Temperature: 100 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a mixture of 300 mg of 2-(10,11-dihydro-7-fluoro-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide and 3 ml of acetic acid was added 3 ml of hydrochloric acid, and the resulting mixture was stirred at 100° C. for 2 hours. After cooling, to this was added water, and the mixture was extracted with ethyl acetate. The extract was re-extracted with a dilute sodium hydroxide solution. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain yellow crystals, which were recrystallized from benzene, thereby obtaining 200 mg (yield: 67%) of 2-(10,11-dihydro-7-fluoro-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as colorless crystals having a melting point of 147.5°-148° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][S:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: COc1cccc(-c2scnc2C(=O)O)c1
Product: COc1cccc(-c2scnc2C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-methoxy-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][C:6]=1[CH:7]=O.[CH:27]1([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:3][C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=3)([C:14]([F:16])([F:15])[F:17])[O:11][N:10]=2)=[CH:5][C:6]=1[CH2:7][NH:32][C:30]([CH:27]1[CH2:29][CH2:28]1)=[O:31]
Reactant: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C=O
Reactant: NC(=O)C1CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1CNC(=O)C1CC1
Yield: 86.4 %

Procedure:
A mixture of 2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-carbaldehyde (250 mg, Example 3, step I), cyclopropanecarboxylic acid amide (160 mg), trifluoroacetic acid (0.142 ml) and triethylsilane (0.301 ml) in toluene (4 ml) is refluxed overnight. After 23 hours the reaction mixture is concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield cyclopropanecarboxylic acid {2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-ylmethyl}-amide (251 mg, compound 2.2 in Table 2) as a yellowish foam. MS (HPLC/MS): 495 (MH+). Retention time: 2.02 min.
Reaction SMILES: [Na].[N+:2]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([O-:4])=[O:3].Br[C:12]([N+:15]([O-:17])=[O:16])([CH3:14])[CH3:13]>>[CH3:13][C:12]([C:5]1([N+:2]([O-:4])=[O:3])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([N+:15]([O-:17])=[O:16])[CH3:14]
Reactant: O=[N+]([O-])C1CCCCC1
Reactant: CC(C)(Br)[N+](=O)[O-]
Agent: [Na]
Product: CC(C)([N+](=O)[O-])C1([N+](=O)[O-])CCCCC1

Procedure:
Seigle and Hass, J. Org. Chem., 5, 100(1940), reported the reaction of the sodium salt of nitrocyclohexane with 2-bromo-2-nitropropane to give 1-(1-methyl-1-nitroethyl)-1-nitrocyclohexane. From the sodium salt of 2-nitropropane and 2-bromo-2-nitropropane they obtained 2,3-dimethyl-2,3-dinitrobutane. Other compounds prepared in like manner were 2,3-dimethyl-2,3-dinitropentane and 3,4-dimethyl-3,4-dinitrohexane. The method is limited to the preparation of α,β-dinitro compounds, and only low yields were reported.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[CH:12]1[C:17]([CH:18]=O)=[CH:16][C:15]2[O:20][CH2:21][O:22][C:14]=2[CH:13]=1.[OH-].[Na+].C(O)C>O>[O:22]1[C:14]2[CH:13]=[CH:12][C:17]([CH:18]=[CH:1][C:2]([C:4]3[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=3[OH:11])=[O:3])=[CH:16][C:15]=2[O:20][CH2:21]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccc2c(c1)OCO2)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
1 g (5.86 mmol) of 5-chloro-2-hydroxyacetophenone, 3 molar equivalents of piperonal, and 3 molar equivalents of sodium hydroxide was mixed in 15 ml of aqueous 80% ethanol solution, and then the mixture was stirred at room temperature for 15 hours. After the reaction was completed, 50 ml of water was added thereto, and the mixture was stirred for about 10 minutes. The obtained pale yellow solid was filtered, washed with water and diethylether, and dried to give 1.42 g (Yield 80%) of the title compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]1)=O)[CH2:8]2>C1COCC1>[CH:3]12[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]([CH2:10]3)[CH:2]1[NH:11][CH2:12][C:14]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:9]2
Reactant: NC1(C(=O)NC2C3CC4CC(C3)CC2C4)CCCC1
Solvent: C1CCOC1
Product: NC1(CNC2C3CC4CC(C3)CC2C4)CCCC1
Yield: 74.4 %

Procedure:
To a solution of 1-amino-cyclopentanecarboxylic acid adamantan-2-ylamide (220 mg) in THF (10 mL) was added borane-THF complex (4.65 mL) under argon. The mixture was then heated to reflux for 12 hours. It was then cooled and quenched with methanol (1 mL) to give a clear solution that was concentrated in vacuo. The residue was taken up in water, basified with 1 M NaOH and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated. The crude material was purified by flash chromatography using 0.5% NH4OH in ethyl acetate as an eluent to give adamantan-2-yl-(1-amino-cyclopentylmethyl)-amine as a colorless semisolid (155 mg). MS (ESI): 249.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH3:20]>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:20])=[O:5]
Reactant: N
Reactant: Cc1cc(OC(F)(F)F)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(OC(F)(F)F)ccc1C(N)=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
795 mg (3.61 mmol) of 2-methyl-4-(trifluoromethoxy)benzoic acid are heated under reflux with 4 ml (54.8 mmol) of thionyl chloride and one drop of DMF for 30 minutes. After cooling, the reaction solution is introduced slowly dropwise into an ice-cooled concentrated aqueous ammonia solution. The resulting precipitate is collected by suction filtration, taken up in 30 ml of water and stirred at 60° C. for 1 h. The mixture is allowed to cool and the solid is collected by filtration and dried under vacuum. Yield 562 mg (71% of theory).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]>[Pd]>[C:1]([C:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccnc1
Agent: [Pd]
Product: CC(=O)C1=CNCCC1

Procedure:
3-acetyl-1,4,5,6-tetrahydropyridine was prepared by hydrogenation of 3-acetyl pyridine in the presence of palladium on carbon according to the method of Freifelder, J.Org.Chem. 29, 2895 (1964).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:13]=[C:14]([CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH:15]=[CH:16][CH:17]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:13]=[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:16][CH:17]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)c1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1cccc(-c2nc(=O)c3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.6 %

Procedure:
After tert-butyl 3-[3-(4-oxo-4H-1,3-benzothiazin-2-yl)phenyl]propionate (0.19 g, 0.52 mmol) was dissolved in trifluoroacetic acid (1.0 ml), the mixture was stirred at room temperature for 2 hours. Isopropyl ether was added to the reaction solution and the precipitated crystals were taken by filtration. The precipitates were recrystallized from ethanol-isopropyl ether to give the title compound (0.056 g, 35%) as crystals.