Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:20][CH2:21][CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCCNCC2)cc1
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1ccc(CN2CCCN(CCC(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
The resulting benzyihomopiperazine was dissolved in 3 mL of ethanol, to which were added 296 mg of 3,3-diphenylpropyl methanesulfonate and 136 mg of potassium carbonate. The mixture was stirred at 70° C. for 15 hours and it was cooled to room temperature and the solvent was removed under reduced pressure. 20 mL of aqueous 2N sodium hydroxide was added and the solution was extracted with 20 mL×2 of ethyl acetate. The organic layers were combined and washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate) to obtain 135 mg of the titled compound. This was treated with a hydrogen chloride solution in ether followed by removing the solvent under reduced pressure and drying to give the hydrochloride salt of the titled compound.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][S:30](=[O:33])[CH2:29][CH2:28]1>O1CCOCC1>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([N:27]3[CH2:32][CH2:31][S:30](=[O:33])[CH2:29][CH2:28]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1CCNCC1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CC1
Solvent: C1COCCO1
Product: O=S1CCN(c2nc(N3CCS(=O)CC3)c3ncnc(SCc4ccccc4)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-(1-oxido-thiomorpholino)pyrimido[5,4-d]pyrimidine (melting point: 188°-190° C.) and thiomorpholine-1-oxide by refluxing for three hours in dioxane.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.C([O-])(=O)C.[Na+].[I:26]Cl>C(O)(=O)C>[I:26][C:18]1[N:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:10][CH:9]=3)[CH:7]=[C:2]([CH3:1])[C:3]2=[N:20][CH:19]=1
Reactant: ClI
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2ccnc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Temperature: 23 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
To a solution of 8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.20 step 2) (5.0 g, 18 mmol) in 50 mL of acetic acid was added sodium acetate (1.68 g, 20 mmol) and a solution of iodine monochloride (2 M, 10.3 mL, 20.6 mmol)—slightly exothermic. The reaction mixture was stirred at 23° C. for 16 h, then partitioned between 300 mL of water and 300 mL of EtOAc. The organic layer was washed with sat. NaHCO3, water, aq. sodium sulfite, water, then dried over Na2SO4, filtered and concentrated to give the title compound as an off-white solid (6.47 g, 89%). MS (ISP) 403.3 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[S:13][C:12]([CH2:14]O)=[N:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:30]1([CH2:33][NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[O:45])=[CH:40][CH:39]=2)=[O:36])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH:30]1([CH2:33][NH:34][C:35]([NH:37][C:38]2[CH:39]=[CH:40][C:41]([C:44]([N:46]3[CH2:51][CH2:50][N:49]([CH2:14][C:12]4[S:13][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:17])([F:16])[F:1])=[CH:10][N:11]=4)[CH2:48][CH2:47]3)=[O:45])=[CH:42][CH:43]=2)=[O:36])[CH2:31][CH2:32]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCNCC2)cc1
Reactant: OCc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCN(Cc3ncc(C(O)(C(F)(F)F)C(F)(F)F)s3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 0.5 %

Procedure:
To a stirring solution of 1,1,1,3,3,3-hexafluoro-2-(2-(hydroxymethyl)thiazol-5-yl)propan-2-ol (0.533 mmol, 150 mg) and triethylamine (1.600 mmol, 162 mg) in dichloromethane (4 mL) at 0° C. was added methanesulfonyl chloride (0.533 mmol, 61.1 mg). The mixture was stirred at 0° C. for 1 hour before warming to room temperature and stirring for 1 hour. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (2×20 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (4 mL) and 1-(cyclopropylmethyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea (0.635 mmol, 192 mg) was added followed by potassium carbonate (1.905 mmol, 263 mg). The mixture was heated to reflux for 6 hours then was cooled, diluted with dichloromethane (75 mL) and washed with water (2×20 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC, strong cation exchange column chromatography and silica gel column chromatography (10% methanol/90% dichloromethane) to afford the title compound (1.5 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH2:13][CH:14](O)[CH2:15][C:11]=2[C:10]([C:17]#[N:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:25])CC>ClCCl.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]2[CH2:13][CH:14]([F:25])[CH2:15][C:11]=2[C:10]([C:17]#[N:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: N#Cc1nn(Cc2ccccc2)c2c1CC(O)C2
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nn(Cc2ccccc2)c2c1CC(F)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.1 %

Procedure:
To a solution of 1-benzyl-5-hydroxy-1,4,5,6-tetrahydrocyclo-penta[c]pyrazole-3-carbonitrile (see Example 9.7, 30 mg, 0.125 mmol) in anhydrous dichloromethane (0.9 mL) was added DAST (33 μL, 0.25 mmol) under a nitrogen atmosphere. After stirring at room temperature for 15 minutes, the reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3 solution and brine. The organic layer was dried over anhydrous Na2SO4 filtered and concentrated in vacuo. The residue was purified by PTLC (SiO2) using 30% ethyl acetate-hexanes to give the desired compound (16 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.C(O)C.[H][H]>[Pd].C1COCC1>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(Oc2ccc([N+](=O)[O-])cc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1nccc(Oc2ccc(N)cc2)n1
Yield: 96.4 %

Procedure:
A mixture of 120.0 g (456 mmol) 2-methylsulfanyl-4-(4-nitrophenoxy)-pyrimidine, 1200 ml ethanol, 1200 ml THF, and 24.0 g 10% palladium/C is hydrogenated at 46 mbar hydrogen pressure at r.t. for 8 h. The catalyst was removed by filtration, washed with 600 ml ethanol, then 300 ml THF and the combined filtrates evaporated. The residue was dissolved in a mixture of 700 ml ethyl acetate and 300 ml THF. The solution was dried over sodium sulphate and evaporated. The residue was stirred with 250 ml isohexane, the precipitate isolated and washed with 400 ml isohexane. Drying in vacuum at r.t. gave 102.5 g (96%) 4-(2-Methylsulfanyl-pyrimidin-4-yloxy)-phenylamine.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:26]2[N:30]([CH3:31])[C:29]([C:32]3[C:33]([C:38]([F:41])([F:40])[F:39])=[N:34][CH:35]=[CH:36][CH:37]=3)=[C:28]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:27]=2)[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[OH:8][C:9]1[CH:10]=[C:11]([C:26]2[N:30]([CH3:31])[C:29]([C:32]3[C:33]([C:38]([F:41])([F:40])[F:39])=[N:34][CH:35]=[CH:36][CH:37]=3)=[C:28]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:27]=2)[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]=1[OH:15]
Reactant: CCOC(=O)c1cc(-c2cc(OCc3ccccc3)c(OCc3ccccc3)c([N+](=O)[O-])c2)n(C)c1-c1cccnc1C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2cc(O)c(O)c([N+](=O)[O-])c2)n(C)c1-c1cccnc1C(F)(F)F
Temperature: -78 °C

Procedure:
A solution of ethyl 5-(3,4-bis(benzyloxy)-5-nitrophenyl)-1-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrrole-3-carboxylate (0.189 g, 0.30 mmol) in dichloromethane (10 mL) was cooled to −78° C. with stirring and treated under argon with boron tribromide (0.30 g, 1.21 mmol). The resulting deep purple suspension was then allowed to stir at room temperature for one hour before cooling again to −78° C. The mixture was quenched by the careful addition of methanol. After stirring at room temperature for thirty minutes, the volatiles were evaporated and the residue stirred with 2 N hydrochloric acid (5 mL) for thirty minutes. The resulting solid was filtered off, washed with water (25 mL) and then cold isopropanol (5 mL) to give ethyl 5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrrole-3-carboxylate as a yellow solid, 0.126 g (93%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:10][C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[S:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[S:40][C:41]1[CH:42]=[C:43]([NH:44][C:13]([NH:12][C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]([C:22]([F:23])([F:24])[F:25])[CH:10]=2)=[O:21])[CH:45]=[CH:46][CH:47]=1
Reactant: O=C(Nc1cc(C(F)(F)F)nn1-c1ccccc1)Oc1ccccc1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccccc4)c3)c2cc1OC
Yield: 44 %

Procedure:
Using the procedure described in Example 159B, using phenyl 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 161C (0.139 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50° C. for 6 hours, to afford 1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.100 g, 44%). 1H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.80 (s, 1H), 8.70 (s, 1H), 7.78 (s, 1H), 7.53 (m, 5H), 7.25-7.48 (m, 5H), 6.81 (s, 1H), 3.99 (s, 6H); LC-MS (ESI) m/z 567 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C(OC([N:42]1[CH2:47][CH2:46][N:45]([C:48]2SC(=CC3C=C4C(=CC=3)N(CC3C=CC(C(O)(C)C)=CC=3C(F)(F)F)N=C4)C(=O)N=2)[CH2:44][CH:43]1[CH2:79][OH:80])=O)(C)(C)C>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][C@@H:43]4[CH2:79][OH:80])=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4C(F)(F)F)c3)S2)CC1CO
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)[C@@H](CO)C1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(2R)-2-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2R) (4-Methyl-piperazin-2-yl)-methanol following General Procedure C.
Reaction SMILES: F[C:2]1C=C(B(O)O)C=CC=1.NC1C=CC(Br)=CC=1C#N.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)=[CH:24][C:23]=1[C:35]#[N:36].C[Mg]Br.Cl.[C:41](=[O:44])([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)=[CH:24][C:23]=1[C:35]#[N:36].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)=[CH:26][C:27]=1[C:41](=[O:44])[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C([O-])[O-]
Agent: C[Mg]Br
Agent: Cl
Agent: N#Cc1cc(-c2cccc(F)c2)ccc1N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(-c2cccc(F)c2)ccc1N
Temperature: 25 °C
Yield: 43 %

Procedure:
4-Amino-3′-fluoro[1,1′-biphenyl]-3-carbonitrile was prepared from 3-fluorophenyl boronic acid and 2-amino-5-bromobenzonitrile according to procedure A. A solution of 4-amino-3′-fluoro[1,1′-biphenyl]-3-carbonitrile (6.65 g, 31.3 mmol) in anhydrous THF (100 mL) was treated drop wise at rt under nitrogen with methylmagnesium bromide (3.0 M in ether, 21 mL, 63 mmol). After addition, the reaction mixture was heated at gentle reflux for 1.5 hours, cooled to rt, and treated with 3N aqueous hydrogen chloride solution (30 mL). The mixture was heated at reflux for 3 hours, cooled to ambient temperature, and adjusted to pH 5-6 by addition of a saturated aqueous sodium carbonate solution. Ethyl acetate (100 mL) was added, organic layer was separated and aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate/3:1) to afford 1-(4-amino-3′-fluoro[1,1 ′-biphenyl]-3-yl)ethanone (3.1 g, 43%): mp 156-157° C.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1>CO>[Br:1][CH:6]1[CH2:5][C:4]([CH3:11])([CH3:3])[CH2:9][CH2:8][C:7]1=[O:10]
Reactant: CC1(C)CCC(=O)CC1
Reactant: BrBr
Solvent: CO
Product: CC1(C)CCC(=O)C(Br)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
1.71 g (10.7 mmol) of bromine were added in one portion to a solution of 1.35 g (10.7 mmol) of 4,4-dimethyl-cyclohexanone in methanol (10 ml) at −10° C. The reaction mixture was then stirred for 10 min at −10° C., for 30 min at 0° C. and finally for 8 h at RT. The reaction was then quenched by addition of water (5 ml) and stirred overnight at RT. Additional water was added (20 ml) leading to the formation of a precipitate that was collected by filtration. The crude 2-bromo-4,4-dimethyl-cyclohexanone (1.72 g, 78%) that was obtained as an orange solid was used in the next reaction step without further purification. 1HNMR (CDCl3, 300 MHz): δ 1.09 (s, 3H), 1.23 (s, 3H), 1.75 (m, 2H), 2.09 (t, J=13.1 Hz, 1H), 2.34 (ddd, J=13.3 and 6.1 and 2.8 Hz, 1H), 2.59 (m, 2H), 4.77 (dd, J=12.9 and 5.9 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[N:13]([CH3:24])[N:14]=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=2)=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2N(C)N=NC=2C2C=CC=CN=2)=NC=1>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[N:15]=[N:14][N:13]([CH3:24])[C:12]=2[CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][N:6]=2)=[N:18][CH:19]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cn3)nnn2C)nc1
Agent: COC(=O)c1ccc(OCc2c(-c3ccccn3)nnn2C)nc1
Product: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)cn1
Yield: 102.5 %

Procedure:
As described for example 26a, 6-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid methyl ester (396 mg, 0.8 mmol), instead of 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid methyl ester, was converted to the title compound (270 mg, 81%) which was obtained as a white solid. MS: m/e=328.3 [M−H]−.
Reaction SMILES: [CH3:1][CH:2](/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([O:20][CH3:21])[CH:19]=1)=[O:11])[CH3:3].C([O-])([O-])=O.[K+].[K+].[I-].[Na+].Cl[CH:32]([CH3:37])[C:33]([O:35][CH3:36])=[O:34]>CC(C)=O>[CH3:36][O:35][C:33](=[O:34])[CH:32]([O:22][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH:2]([CH3:1])[CH3:3])=[CH:19][C:18]=1[O:20][CH3:21])[CH3:37]
Reactant: COc1cc(CNC(=O)CCCC/C=C/C(C)C)ccc1O
Reactant: COC(=O)C(C)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(C)Oc1ccc(CNC(=O)CCCCC=CC(C)C)cc1OC
Yield: 31.1 %

Procedure:
To a mixture of Capsaicin (2 g, 6.56 mmol), anhydrous K2CO3 (3 g, 22 mmol), and sodium iodide (2 g, 14.2 mmol) in anhydrous acetone (50 ml) was added methyl 2-chloropropionate (1.2 g, 10 mmol) and refluxed for 16 hours. Acetone was distilled off and water (15 ml) was added. Crude 11 was filtered, dried and recrystallised from a mixture of chloroform:hexane (1:5) to give pure 11 (0.8 g, 31.2%) as a white powder. The melting point was found to be 62.3-64° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:38]1[CH2:47][C@H:46]([OH:48])[CH2:45][C@H:39]1[C:40]([N:42]([CH3:44])[CH3:43])=[O:41])[C:28]1[CH:33]=[C:32]([CH:34]=O)[CH:31]=[CH:30][C:29]=1[O:36][CH3:37].[CH2:49]([NH:51][CH2:52][CH3:53])[CH3:50]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:25])([F:26])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:38]1[CH2:47][C@H:46]([OH:48])[CH2:45][C@H:39]1[C:40]([N:42]([CH3:44])[CH3:43])=[O:41])[C:28]1[CH:33]=[C:32]([CH2:34][N:51]([CH2:52][CH3:53])[CH2:49][CH3:50])[CH:31]=[CH:30][C:29]=1[O:36][CH3:37]
Reactant: CCNCC
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Product: CCN(CC)Cc1ccc(OC)c(C2(N3C[C@H](O)C[C@H]3C(=O)N(C)C)C(=O)N(S(=O)(=O)c3ccc(OC)cc3OC(F)(F)F)c3ccc(Cl)cc32)c1

Procedure:
With 101 mg of the compound obtained in Step 204-7 and diethyl amine (18 μl) as starting material, 31.0 mg of the title compound (colorless amorphous) was obtained by a similar method to Step 195-1.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>O1CCCC1.[OH-].[Na+].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCC1CC(n2c3ccccc3c3ccccc32)c2ccccc2N1C(=O)c1ccc(OC)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.2 %

Procedure:
Ethyl 5-[4-(9H-9-carbazolyl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-2-quinolinyl]pentanoate (0.20 g, 0.34 mmol) prepared in Example 127 was dissolved in tetrahydrofuran (10 ml), to which 1N NaOH (5 ml) and tetrabutylammonium bromide (0.11 g, 0.34 mmol) were then added and stirred at room temperature for 4 hours and then at 60° C. for 4 hours. After the reaction mixture was partitioned between ethyl acetate and 1N HCl, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was applied to silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/5) to give the titled compound (0.14 g, yield: 74%) as a white crystal (cis:trans=4:1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:19](=O)[CH3:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:22][O:23][C:24]([NH2:26])=[NH:25].OS(O)(=O)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:22][O:23][C:24]1[NH:26][C:19]([CH3:20])=[C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:25]=1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(C)(C)C
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1=NC(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)(C)C)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 122.7 %

Procedure:
A mixture of 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, t-butyl ester (6.80 g, 23.3 mmol), o-methylisourea hydrogen sulfate (5.22 g, 30.3 mmol), and sodium bicarbonate (5.87 g, 69.9 mmol) in dimethylformamide (35 ml) was stirred at room temperature overnight under argon. After 23 hours at room temperature, the reaction was heated at 60° C. (oil bath) for 5.5 hours. It was then partitioned between ethyl acetate and 5% sodium bicarbonate. The organic phase was washed several times with water, washed with saturated sodium chloride, and dried over potassium carbonate. Evaporation gave crude title compound as a light brown oil (9.93 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:9]([OH:20])[CH2:10][NH:11][CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][C:16]#[N:17])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>C(Cl)Cl>[CH2:42]([O:41][C:39](=[O:40])[N:11]([CH2:10][C@@H:9]([OH:20])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][C:16]#[N:17])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 4.7 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethyl-butylamino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (1.300 g, 3.34 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (1.740 ml, 10.01 mmol) and benzyl chloroformate (0.683 g, 4.00 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by column chromatography (10% Et2O in CH2Cl2) gave 0.083 g of a white solid. MS (ES): 524 (M+1).