Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH:12]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13]1)[CH2:6][C:5]2=O.[CH3:19][C:20]([S:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>CC1CCCO1.CCOC(C)=O.O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH:12]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13]1)[CH2:6][C:5]2=[N:25][S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24]
Reactant: O=C1CC(C2CCCOC2)Oc2ccc(Br)cc21
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Solvent: O
Product: CC(C)(C)S(=O)N=C1CC(C2CCCOC2)Oc2ccc(Br)cc21
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
6-Bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-one (Intermediate 27, 1.5 g, 4.82 mmol) and 2-methylpropane-2-sulfinamide (1.052 g, 8.68 mmol) were dissolved in dry 2-methyl-tetrahydrofuran (12 mL). Neat titanium ethoxide (1.788 mL, 8.68 mmol) was added. The resulting mixture was heated by MW at 130° C. for 60 min. The mixture was diluted with EtOAc (150 mL) and water (40 mL) was added dropwise during vigorous stirring of the reaction mixture. The stirring was continued for 15 min. The solid was decanted and the mixture filtered through a pad of diatomaceous earth. The organic layer was separated, dried over MgSO4 and vacuum filtered directly through a pad of silica (approx. 10 g) and concentrated in vacuo to give the title compound (1.8 g, 90% yield). MS (ES+) m/z 414 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([OH:16])=O)[CH:7]=[CH:6]2.C(N(CC)CC)C.Cl.[F:26][C:27]([F:41])([F:40])[C:28]1[CH:29]=[C:30]([C:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=2)[CH:31]=[CH:32][CH:33]=1.C(OCC)(=O)C>C(Cl)Cl>[F:41][C:27]([F:26])([F:40])[C:28]1[CH:29]=[C:30]([C:34]2[CH2:39][CH2:38][N:37]([C:14](=[O:16])[CH:13]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=3)[CH3:17])[CH2:36][CH:35]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc2cc(C(C)C(=O)N3CC=C(c4cccc(C(F)(F)F)c4)CC3)ccc2c1
Yield: 60.7 %

Procedure:
A solution of 6-methoxy-α-methyl-2-naphthylacetic acid (3.5 g, 0.015 mol), triethylamine (4.3 ml, 0.03 mol), 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (3.9 g, 0.015 mol), and benzotriazolyl-N-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (6 g, 0.015 mol) in methylene chloride (40 ml) is stirred at room temperature for 4 hours. Ethyl acetate (150 ml) is then added thereto and the mixture is washed in sequence with water, 10% NaHCO3, water, 1N HCl, and water. The reaction mixture is then filtered over silica and concentrated to dryness affording 1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-1-oxo-2-(6-methoxy-naphth-2-yl)propane (4 g) as a thick oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Reactant: BrC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2c1cnn2C1CCOCC1

Procedure:
Ethyl 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 equiv.) was suspended in acetonitrile and K2CO3 (1.5 equiv.) and 4-bromotetrahydro-2H-pyran (2 equiv.) was added to it. The reaction mixture was refluxed for 8 h. On completion, acetonitrile was removed under reduced pressure and water was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([Cl:23])=[O:19])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc2c1cnn2-c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (0.400 g, 1.56 mmol) in CH2Cl2 (5 mL) at room temperature was added oxalyl chloride (0.86 mL, 1.7 mmol) followed by DMF (20 μL). Gas evolution was observed. After 30 minutes, the solution was concentrated in vacuo to afford 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid chloride which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[O:18][CH3:19].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([Li])CCC.CCCCCC.Br[CH2:46][CH2:47][CH2:48][Cl:49]>O1CCCC1.C(OCC)(=O)C>[Cl:49][CH2:48][CH2:47][CH2:46][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:18][CH3:19])[CH:5]=1)[S:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1
Reactant: ClCCCBr
Reactant: COc1ccc(CSc2ccc(C)cc2)cc1OC
Agent: [Li]CCCC
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(CCCCl)Sc2ccc(C)cc2)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 13.72 g of 1,2-dimethoxy-4-[[(4-methylphenyl)thio]methyl]benzene and a crystal of phenanthroline in 250 mL of tetrahydrofuran (dried over 3A sieves), under nitrogen at -78° C. is added 21.0 mL of 2.5M n-butyl lithium/hexane via a syringe. After 10 minutes, the brown solution is warmed to 0° C. for 1 hour, then it is recooled to -78° C. and 8.02 mL of 1-bromo-3-chloropropane is added via syringe. The reaction is permitted to warm to room temperature overnight. To the now light yellow reaction mixture is added 10 mL of ethyl acetate and the resulting solution concentrated in yacuo. The residue is partitioned between ethyl acetate and water, the organic phase dried (sodium sulfate) and concentrated in vacuo to a yellow oil. Purification by chromatography on silica gel with gradient elution progressing from hexane to chloroform to methyl alcohol, repeated three times, affords 16.47 g of the desired product as a yellow oil. MS(CI): m/z 227 and 229(MH+ (-TolSH)). Calcd for C19H23ClO2S 1/8H2O: C=63.80, H=6.59, Cl=11.15, S=8.95 Found C=63.68, H=6.44, Cl=10.89, S=8.98
Reaction SMILES: [Li][C:2]1([CH3:13])[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[Si]([N:21]=[C:22]=S)(C(C)(C)C)(C)C.[Si](Cl)(C(C)(C)C)(C)C>C1COCC1>[C:22]([C:2]1([CH3:13])[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1)#[N:21]
Reactant: [Li]C1(C)CCCc2cc(C)cnc21
Reactant: CC(C)(C)[Si](C)(C)N=C=S
Agent: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCOC1
Product: Cc1cnc2c(c1)CCCC2(C)C#N
Reaction time: 16 h

Procedure:
A solution of 5,6,7,8-tetrahydro-8-lithio-3,8-dimethylquinoline (20 mM) was generated as described in Example 2 and allowed to react with t-butyldimethylsilyl isothiocyanate (20 mM) as described in Example 2. After 0.5 hours a solution of t-butyldimethylsilyl chloride (3.1 g, 20 mM) in THF (10 ml) was added and the mixture allowed to stand for 16 hours at ambient temperature. The reaction was quenched with 2N hydrochloric acid (50 ml). After 1 hour the aqueous layer was separated, basified (to pH9) and extracted with dichloromethane (2×50 ml) and the organic extracts were dried and evaporated. Kugelrohr distillation of the residue gave the nitrile title compound. (2.8 g, 75%) bp. 90°/0.01 mm (bath temp.)
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([C:14](O)=[O:15])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[N+:19]([N:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[C-:20]>C1COCC1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[O:15][CH:20]=[N:19][N:21]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: [C-]#[N+]N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)OCCc1sc(-c3nnco3)nc1-2

Procedure:
To a solution of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (22.2 g, 68.1 mmol) in THF (360 mL) was added (isocyanoimino)triphenylphosphorane (20.6 g, 68.1 mmol) portionwise over 1 hour. The resultant mixture was stirred at RT for 18 hours before being concentrated in vacuo and triturated with 1:1 DCM/cyclohexane (200 mL). The title compound was collected by filtration as a yellow solid (14.5 g, 61%). LCMS: RT=4.03 min, M+H+=350/352.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:13][C:12]1[S:11][C:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1sc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2nc(-c3ccccc3)sc2CBr)cc1
Yield: 68.8 %

Procedure:
A mixture of 4-(4-chlorophenyl)-5-methyl-2-phenylthiazole (35.1 g), N-bromosuccinimide (24.0 g), azobisisobutyronitrile (4.11 g) and carbon tetrachloride (400 mL) was stirred with heating under reflux for 3 hrs. The precipitated solid was removed by filtration and the organic layer was concentrated. The residue was purified by silica gel column chromatography. 5-(Bromomethyl)-4-(4-chlorophenyl)-2-phenylthiazole (30.8 g, 69%) was obtained as crystals from a fraction eluted with hexane-ethyl acetate (19:1, volume ratio). Recrystallization from ethyl acetate gave colorless prism crystals. melting point: 108–109° C.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=[O:2].C([O-])([O-])=[O:19].[K+].[K+].OO>CS(C)=O>[CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[O:19])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reaction time: 3 h
Yield: 171.3 %

Procedure:
Combine 6-(4-Formyl-phenoxy)-nicotinonitrile (3.02 g, 13.5 mmol), powdered K2CO3 (0.93 g, 6.7 mmol), and DMSO (100 mL) in a RB flask and add H2O2, 30% wt. Aq (4.05 mL, 13.5 mmol) by dropwise addition at 0° C. Stir the reaction mixture for 3 hours allowing it to come to room temperature then quench the reaction slowly at 0° C. with water. Extract the product out of the water layer with ethyl acetate several times and then wash with brine. Dry over Na2SO4 and concentrate under reduced pressure to give 2.78 g (95% yield) of the title compound: 1H NMR (500 MHz, DMSO); 7.2 (1H, d), 7.3-7.4 (2H, m), 7.5 (1H, br s), 7.9-8.0 (2H, m), 8.1 (1H, br s), 8.3 (1H, d), 8.7 (1H, s), 10.0 (1H, s); MS m/z 243 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.9 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-propionic acid (49 mg, 0.21 mmol) in tetrahydrofuran (5 mL) was treated with N,N-diisopropylethylamine (0.04 mL, 0.25 mmol) and benzoyl chloride (0.02 mL, 0.21 mmol). The reaction mixture was stirred at 25° C. for 24 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 2-(4-benzoylamino-phenyl)-3-cyclopentyl-propionic acid (41 mg, 57.9%) as a white solid: mp 192.5-194° C.; EI-HRMS m/e calcd for C21H23NO3 (M+) 337.1677, found 337.1670.
Reaction SMILES: [OH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([NH2:5])=[O:4].C(N(CC)CC)C.[C:35]([O:38][CH2:39]C)(=[O:37])C>ClCCl.O1CCCC1>[CH3:39][O:38][C:35]([O:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([NH2:5])=[O:4])=[O:37]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(O)C(N)=O)cc1
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)OC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(N)=O
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of 2-hydroxy-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionamide (550 mg, 1.50 mmol) obtained in Example 36 in dichloromethane-tetrahydrofuran (1:1, 50 ml) was added equivalent of methyl chlorofornate and triethylamine under ice-cooling until the reaction completed. The mixture was stirred for 1 hr, and the reaction mixture was diluted with ethyl acetate (100 ml) and washed successively with saturated brine, 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine. The mixture was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; dichloromethane:methanol=98:2) to give the title compound (110 mg, yield 17%) as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].O1CCCC1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[F:20].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24](C(N)=O)[CH:23]=1>CS(C)=O.O>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:15][C:14]=1[F:20]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccncc2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
Potassium tert-butoxide (214 g) was dissolved in dimethyl sulfoxide (750 ml) and tetrahydrofuran (250 ml) under a nitrogen stream, and a solution of 4-amino-3-fluorophenol ½ naphthalene-2,6-disulfonate (242 g) and 4-chloropyridine-2-carboxamide (100 g) in dimethyl sulfoxide (1000 ml) was added dropwise to the solution with stirring and cooling on ice. The reaction mixture was stirred at room temperature for 30 minutes, then in an oil bath at 90° C. (external temperature) for 2 hours. The reaction mixture was allowed to cool down to room temperature, and water (3000 ml) was added, and the reaction mixture was stirred for 2 hours. The precipitated solid was collected by filtration, and washed with water (500 ml, twice). The residue was suspended in water (2000 ml), stirred for 30 minutes, collected by filtration again, and washed with water (500 ml, twice). Drying by hot air at 60° C. gave the title compound (119 g, 75.3%).
Reaction SMILES: C1(O[C:8](=[O:25])[NH:9][CH:10]2[CH2:15][CH2:14][C:13]([N:22]([CH3:24])[CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>O1CCOCC1>[CH3:24][N:22]([CH3:23])[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11][CH:10]([NH:9][C:8]([N:40]2[CH2:41][CH2:42][CH:37]([C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([O:27][CH3:26])[CH:29]=4)[NH:33][CH:32]=3)[CH2:38][CH2:39]2)=[O:25])[CH2:15][CH2:14]1
Reactant: COc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(NC(=O)Oc2ccccc2)CC1
Solvent: C1COCCO1
Product: COc1ccc2[nH]cc(C3CCN(C(=O)NC4CCC(c5ccccc5)(N(C)C)CC4)CC3)c2c1

Procedure:
The non-polar diastereoisomer of (4-dimethylamino-4-phenylcyclohexyl)-carbamic acid phenyl ester (338 mg, 1.0 mmole) was added to a solution of 5-methoxy-3-piperidine-4-yl-1H-indole (230 mg, 1.0 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 32 hours. The reaction mixture was worked up by distilling off dioxane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The non-polar diastereoisomer of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl)-amide was recrystallised from methanol (5 ml). It was obtained in a yield of 170 mg (36%) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]1(O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: Oc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1ccccc1)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 70 °C
Reaction time: 24 h
Yield: 52.2 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (500 mg, 1.72 mmol) (compound of Example 9) and 1,1′-carbonyldiimidazole (418 mg, 2.58 mmol) in N,N-dimethylformamide (7 mL) was stirred for 16.75 hours. In one portion, phenol (486 mg, 5.16 mmol) was added and the solution was stirred for 24 hours at 70° C. To the resulting solution was added water (30 mL), giving a precipitate which was separated by filtration. This crude product was purified by chromatography eluting with chloroform: 2-propanol (98:2-90:10) to give the title compound (330 mg, 53% yield, m.p. 265° C.).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.CN1C(=O)N(C)CCC1.C(N(CC)CC)C.[CH2:31]([N:33]([CH2:37][CH3:38])[C:34](Cl)=[S:35])[CH3:32]>O>[CH2:11]([N:10]([CH2:13][CH3:14])[C:8](=[O:9])[C:3]1[C:2]([O:1][C:34](=[S:35])[N:33]([CH2:37][CH3:38])[CH2:31][CH3:32])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:12]
Reactant: CCN(CC)C(=S)Cl
Reactant: CCN(CC)C(=O)c1ncccc1O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCN(C)C1=O
Product: CCN(CC)C(=O)c1ncccc1OC(=S)N(CC)CC
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
258.3 g (1.33 mol) of 3-hydroxy-N,N-diethylpicolinamide are introduced into 1 l of dimethylpropyleneurea and 213.2 ml (1.53 mol) of triethylamine at 0° C., and 222 g (1.464 mol) of diethylthiocarbamoyl chloride are introduced in the form of a solid. After the reaction mixture has been stirred for 2 hours at 0° C., it is poured into 2 l of water and extracted three times using ethyl acetate, the ethyl acetate phases are washed five times using 500 ml of water in each case, and the combined organic phases are dried over Na2SO4 and concentrated in vacuo at 60° C. Recrystallization from Et2O/hexane gives 341 g (83%) of brown crystals, m.p. 70°-72° C.
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:22]=1)[CH2:16][N:17]=[N+]=[N-])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].ClCCl.[N-]=[N+]=[N-]>[Pd].CCOCC.CO>[CH2:24]([O:23][C:21]1[CH:20]=[C:15]([CH:14]=[C:13]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:22]=1)[CH2:16][NH2:17])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCOc1cc(CN=[N+]=[N-])cc(OCCCCCCCCCCC)c1
Agent: [Pd]
Agent: [N-]=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCCOc1cc(CN)cc(OCCCCCCCCCCC)c1
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Catalytic (5% by mass) palladium on carbon (0.58 g) was placed into a hydrogenation bottle. The bottle was then placed under N2. To the bottle, 50/50 ether methanol (10 mL) was added. 3,5-diundecoxybenzyl azide (5.0 g, 11.2 mmol) was dissolved in 50/50 ether/methanol (60 mL) and transferred to the bottle. The bottle was attached to a hydrogenator with H2 pressure set at 40 psi and left for 1 hour. Thin layer chromatography (dichloromethane/10% hexanes) indicated that the azide was still present. As a result, the bottle was left on a hydrogenator with H2 pressure at 40 psi for an additional 30 minutes. Thin layer chromatography then showed that the starting material was completely consumed. The contents of the bottle were then vacuum filtered over celite. The filtrate was concentrated using rotary evaporation and then placed under high vacuum for 4 or more hours. This produced a 4.4 g yield or a 93.1% yield of the derivative. The NMR characterization data for the derivative is as follows. 1NMR (300 MHz, CDCl3): 0.86 (t, J=6.3, 6H, CH2CH3), 1.25-1.45 (m, 32H, CH2(CH2)8), 1.74 (p, J=6.6, 4H, OCH2CH2), 3.76 (s, 4H, OCH2), 3.90 (t, J=6.6, 2H, ArCH2Cl), 6.32 (t, J=2.2, 1H, ArH), 6.43 (d, J=2.2, 2H, ArH). 13C NMR (75 MHZ, CDCl3): 14.20, 22.78, 26.14, 29.36, 29.42, 29.49, 29.67, 31.99, 46.35, 68.07, 99.86, 105.56, 144.47, 160.59.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C@H:10]([NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:11][CH2:12][S:13][CH3:14])=[CH:4][CH:3]=1.[CH3:27][I:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C@H:10]([NH:15][C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:11][CH2:12][SH:13]([CH3:27])[CH3:14])=[CH:6][CH:7]=1.[I-:28]
Reactant: CSCC[C@@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc(Cl)cc1
Reactant: CI
Product: C[SH](C)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc(Cl)cc1
Product: [I-]
Reaction time: 48 h

Procedure:
To neat (2R)-N-(4-chlorophenyl)-4-methylthio-2-[(phenylmethoxy)carbonylamino]butanamide (2.0 g, 5.09 mmol) was added methyl iodide (10 ml, 161 mmol). The solution was allowed to stir for 48 hours. Methyl iodide was then removed under vacuum to yield (2R)-N-(4-chlorophenyl)-5-methyl-2-[(phenylmethoxy)carbonylamino]-5-thiahexanamide, iodide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[CH:26]([NH:28][CH2:29][CH:30]1[O:35][CH2:34][CH2:33][NH:32][CH2:31]1)=[O:27]>>[F:19][C:17]1[CH:16]=[C:15]([F:21])[CH:14]=[CH:13][C:18]=1[N:9]1[C:3]2[C:4](=[CH:5][C:6]([F:8])=[C:7]([N:32]3[CH2:33][CH2:34][O:35][CH:30]([CH2:29][NH:28][CH:26]=[O:27])[CH2:31]3)[C:2]=2[F:1])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1
Reactant: O=CNCC1CNCCO1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Product: O=CNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c2F)CCO1

Procedure:
By the use of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(formylaminomethyl)morpholine, the reaction is similarly carried out as Example 26 to give 1-(2,4-difluorophenyl)-6,8-difluoro-7-[2-(formylaminomethyl)morpholino]-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid, melting at 230°-233° C. with decomposition.