Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:14][C:15]1([CH3:41])[CH:19]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[N:18]2[C:28](=[O:40])[CH:29]([NH:30][C:31](=[O:39])[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:17]2[S:16]1.O>C(N)=O>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:14][C:15]2([CH3:41])[CH:19]([C:20]([O:22][CH2:23][C:24]([Cl:25])([Cl:26])[Cl:27])=[O:21])[N:18]3[C:28](=[O:40])[CH:29]([NH:30][C:31](=[O:39])[CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C@H:17]3[S:16]2)=[N:4][N:3]=1
Reactant: Cc1nnc(S)s1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: NC=O
Solvent: O
Product: Cc1nnc(SCC2(C)S[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)OCC(Cl)(Cl)Cl)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.8 %

Procedure:
5-Methyl-1,3,4-thiadiazole-2-thiol (0.20 g) and sodium bicarbonate (0.85 g) were dissolved in formamide (7 ml). To this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.54 g), and the mixture was stirred for 5 hours at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography on silica gel using chloroform as developing solvent to give oily 2,2,2-trichloroethyl 2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.20 g) from the third fractions each of which was separated into about 30 ml.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)=[CH:23][C:11]=2[C:12]([O:14]CC2C=CC(F)=CC=2)=[O:13])=[CH:4][CH:3]=1.[Li+].[OH-]>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)=[CH:23][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)OCc3ccc(F)cc3)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)O)c2)cn1

Procedure:
(4-Fluorophenyl)methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-(1-methyl-1H-pyrazol-4-yl)benzoate (may be prepared as described in Description 120; 360 mg, 0.83 mmol) was dissolved in tetrahydrofuran (20 ml) and water (5 ml). Then LiOH (99 mg, 4.14 mmol) was added. The resultant mixture was stirred at room temperature for 16 hours. The solvent was removed. The residue was dissolved in water (20 ml). The solution was acidified by 1N HCl to pH<5. The precipitate was filtered, washed with ether, and dried in vacuo to yield the title compound as a white solid. 260 mg.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]N1C(=O)CCC1=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Br:29])=[CH:6][N:7]=1
Reactant: OCc1ccc(Br)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91.2 %

Procedure:
A solution of (6-bromo-3-pyridinyl)methanol (50) (2.503 g, 13.3 mmol) and triphenylphosphine (4.026 g, 15.4 mmol) in anhydrous CH2Cl2 (100 mL) was carefully treated with recrystallized N-bromosuccinimide (2.732 g, 15.4 mmol) (water bath cooling), and the mixture was stirred at room temperature for 3.5 h. The resulting solution was concentrated, and then added to excess petroleum ether at the top of a silica gel column (100 g in petroleum ether), rinsing on with minimal extra CH2Cl2. Elution with petroleum ether firstly gave foreruns, and then further elution with 15-25% Et2O/pentane gave pure 2-bromo-5-(bromomethyl)pyridine (51) (Schubert et al., 1999) (3.045 g, 91%) as a lachrymatory white solid that was used directly in the next step; 1H NMR (CDCl3) δ 8.38 (d, J=2.5 Hz, 1H), 7.59 (dd, J=8.2, 2.6 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 4.42 (s, 2H).
Reaction SMILES: [CH:1]1([C:4]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([CH2:17][CH3:18])[CH:5]=2)[CH2:3][CH2:2]1.Cl.[F:20][C:21]1([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:31]([C:30]1[CH:29]=[CH:28][C:27]([C:21]2([F:20])[CH2:26][CH2:25][N:24]([C:8]([C:7]3[C:6]([CH2:17][CH3:18])=[CH:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[C:12]([CH:11]=3)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH2:23][CH2:22]2)=[CH:34][CH:33]=1)#[N:32]
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Reactant: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of 4-cyclopropyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 226.6, 150 mg, 0.600 mmol, 1.00 equiv) in N,N-dimethylformamide (15 mL) were added 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2, 150 mg, 0.620 mmol, 1.00 equiv), DIPEA (450 mg, 3.49 mmol, 6.00 equiv), and HBTU (300 mg, 0.790 mmol, 1.30 equiv). The resulting solution was stirred for 4 h at 20° C., then quenched by the addition of 20 mL of brine. The resulting mixture was extracted with 4×30 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified via silica gel column with ethyl acetate/petroleum ether (1:3) as eluent. This resulted in 0.200 g (76%) of methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate as a light yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][N:15]=[C:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([F:28])[C:25]([Br:29])=[CH:24][C:23]=3[F:30])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][N:15]=[C:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([F:28])[C:25]([Br:29])=[CH:24][C:23]=3[F:30])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(Br)cc3F)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(N2CCC(=NOC3CCNCC3)CC2)c(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 77a (300 mg, 0.61 mmol) was dissolved in 20% TFA/DCM (2 mL) and stirred at r.t. for 2 h. The solvents were removed in vacuo and the residue re-dissolved in DCM. This solution was washed with 2M NaOH then water and dried over MgSO4 and concentrated to give 1-(4-bromo-2,5-difluoro-phenyl)-piperidin-4-one O-piperidin-4-yl-oxime 77b.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)=[N:21][CH:22]=1>>[C:13]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]3)=[N:21][CH:22]=1)=[N:10][C:9]([Cl:12])=[CH:8][CH:7]=2)(=[O:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccc(N)cn2)C1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 33.8 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (610 mg, 2.5 mmol) was reacted with tert-butyl 1-(5-aminopyridin-2-yl)piperidin-3-ylcarbamate (590 mg, 3.0 mmol) to afford the desired product (420 mg, 35%) as an orange-red solid: 1H NMR (500 MHz, CDCl3) δ 11.47 (s, 1H), 9.01 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 7.34-7.28 (m, 1H), 6.72 (d, J=9.1 Hz, 1H), 4.95-4.90 (m, 1H), 3.85-3.67 (m, 3H), 3.47-3.27 (m, 2H), 2.69 (s, 3H), 1.97-1.88 (m, 1H), 1.86-1.75 (m, 1H), 1.73-1.59 (m, 2H), 1.45 (s, 9H); ESI MS m/z 497 [M+H]+
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)O1.[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][C@H:30]([O:33][C:34]2[CH:35]=[N:36][CH:37]=[C:38](Br)[CH:39]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][C@H:30]([O:33][C:34]2[CH:35]=[N:36][CH:37]=[C:38]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]4)[CH:39]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cncc(Br)c2)C1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC(=O)N3)OC1(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cncc(-c3ccc4c(c3)CCC(=O)N4)c2)C1

Procedure:
In analogy to the procedure described for the preparation of example 45, 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (intermediate A-34) has been coupled to (S)-3-(5-bromo-pyridin-3-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate A-29) to give the title compound as a dark grey amorphous solid. MS: 410.6 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:18][S:19]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30]CS([O-])(=O)=O)(=[O:21])=[O:20]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:30][CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][S:19]([CH3:18])(=[O:20])=[O:21])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CS(=O)(=O)Oc1ccccc1CCCS(=O)(=O)[O-]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Product: CCOC(=O)C(Cc1ccc(OCCc2ccccc2OS(C)(=O)=O)cc1)OCC

Procedure:
2-Ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester was alkylated with 2-(2-methanesulfonyloxyphenyl)ethylmethanesulfonate using the same method as in Example 1 (b) to give 2-ethoxy-3-{4-[2-(2-methanesulfonyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][SH:17])=[CH:14][CH:13]=1.[Na]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:16]([S:17][CH:16](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])[C:15]1[CH:18]=[CH:19][C:12]([Br:11])=[CH:13][CH:14]=1)[C:15]1[CH:18]=[CH:19][C:12]([Br:11])=[CH:13][CH:14]=1
Reactant: SCc1ccc(Br)cc1
Reactant: C#Cc1cccc(Cl)c1Cl
Agent: [Na]
Product: Clc1cccc(/C=C\C(SC(/C=C\c2cccc(Cl)c2Cl)c2ccc(Br)cc2)c2ccc(Br)cc2)c1Cl

Procedure:
A solution of 2,3-dichlorophenylacetylene (0.02 mol), 4-bromobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,3-dichlorostyryl-4-bromobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][NH:6][C:7]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]4[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=4[F:38])=[O:29])=[C:23]([F:39])[CH:22]=3)[CH:17]=[CH:16][N:15]=2)[NH:11][CH:10]=1)=[O:8])C.Cl.O.C([O-])(O)=O.[Na+]>C1COCC1>[F:39][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[NH:27][C:28]([NH:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[F:38])=[O:29])[O:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]2[NH:11][CH:10]=[C:9]([C:7]([NH:6][CH2:5][CH:4]=[O:3])=[O:8])[CH:13]=2)[CH:19]=1
Reactant: CCOC(CNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCC=O)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-(2,2-diethoxyethyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (550 mg, 0.95 mmol) in 10 ml of THF was added 2 ml of 2M HCl. The mixture was stirred at room temperature under nitrogen for overnight, and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8. The precipitates were filtered, washed with water, and dried to give 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2-oxoethyl)-1H-pyrrole-3-carboxamide as off-white solid. Yield: 475 mg, 99%.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C(O)(C)C>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([NH:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]5)[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CN1CCN(CCCN)CC1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N1CCc2cc(Oc3cc(Cl)ncn3)ccc21
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: CC(C)O
Product: CN1CCN(CCCNc2cc(Oc3ccc4c(c3)CCN4C(=O)Nc3cccc(C(F)(F)F)c3)ncn2)CC1

Procedure:
304 ring (0.70 mMol) of 5-(6-Chloro-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (WO 03/099771; Stage 163), 477 μl (2.8 mMol) 1-(3-aminopropyl)-4-methyl-piperazine and a trace of Nal are heated in 10 ml isopropanol for 22 h at 50° C. Then the mixture is concentrated partially in vacuo. The residue is dissolved in EtOAc and NaHCO3 and the aqueous layer extracted twice with EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2/MeOH/NH3conc. 9:1:0→90:10:1) gives the title compound: m.p.: 163° C.; MS: [M+1]+=556; TLC(CH2Cl2/MeOH/NH3conc. 90:10:2): Rf=0.29.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][N:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][N:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CCOC(=O)c1ccnc(-c2ccc(Cl)cc2)c1

Procedure:
4-Chlorophenylboronic acid (185 mg) and ethyl 2-chloroisonicotinate (200 mg) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][C:36]([CH2:39][CH3:40])=[CH:37][CH:38]=2)[CH:28]=1)=[O:26])(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][C:36]([CH2:39][CH3:40])=[CH:37][CH:38]=2)[CH:28]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CCc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (193 mg, 0.75 mmol) and 3-[3-(6-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K23) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (307 mg, 81%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][NH:7][N:6]=1)=[O:4].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu-]=O>[CH3:1][N:2]([CH3:13])[C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: Brc1ccccn1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1nn(-c2ccccn2)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A solution of 4-nitro-1H-pyrazole-3-carboxylic acid dimethylamide (250 mg, 1.36 mmol) in DMF (5 ml) was flushed with argon. 2-Bromopyridine (0.17 ml, 1.76 mmol), ferric acetylacetone (144 mg, 0.4 mmol), copper(I)oxide (20 mg, 0.14 mmol) and cesium carbonate (885 mg, 2.7 mmol) were added consecutively and the reaction mixture was stirred at 110° C. overnight. After cooling down, the reaction mixture was partitioned between ethyl acetate (30 ml) and water (15 ml) and extracted. The organic layer was washed with brine, dried and the solvent was evaporated. The product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light yellow solid (102 mg, 29%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[CH:12]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[CH:12]1([NH:18][C:19](=[O:20])[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: O=C=NC1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)OCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 mL toluene, 3.1 g 2-nitrobenzyl alcohol, and 2.5 g cyclohexylisocyanate were introduced into a 100-mL three-neck flask and heated under reflux for 1 hour under nitrogen. After cooling, an additional 0.5 g cyclohexylisocyanate was added and the reaction was stirred for 1 hour at ambient temperature. The reaction solution was then washed several times with water and the resulting toluene solution was dried over sodium sulfate. The sodium sulfate was thereafter filtered off and the solvent was eliminated from the filtrate on a rotary evaporator. The resulting solid was recrystallized from toluene to yield ortho-nitrobenzyl cyclohexylcarbamate as light-yellow, needle-like crystals. mp=101°-102° C. Identification by the proton NMR spectrum.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[Cu][C:18]#[N:19].CN1C(=O)CCC1.O>C(OCC)C>[CH3:15][C:11]1([CH3:16])[CH2:12][CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:4]=[CH:3][C:2]([C:18]#[N:19])=[N:7][CH:6]=2)[CH2:10]1
Reactant: CC1(C)CCCC(Oc2ccc(Cl)nc2)C1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCCC(Oc2ccc(C#N)nc2)C1
Temperature: 190 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
Add 6-chloro-3-(3,3-dimethylcyclohexyloxy)-pyridine (1.1 g, 4.59 mmol) and copper(I) cyanide (1.23 g, 13.8 mmol) to NMP (20 mL). Heat the mixture to 190° C. and stir overnight. Cool the mixture to room temperature, add water (30 mL) and diethyl ether (30 mL). Extract the aqueous phase with diethyl ether (3×20 mL). Wash the combined organic extracts with brine (20 mL), dry over Na2SO4, filter, and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 60 min, 80 mL/min) to obtain the desired intermediate as a colorless oil (412 mg, 39%). MS (APCI+) m/z: 231 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.[N:7]1([CH2:12]/[CH:13]=[C:14](/[C:22]2[N:27]=[C:26](/[CH:28]=[CH:29]/[CH2:30][OH:31])[CH:25]=[CH:24][CH:23]=2)\[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([O:31][CH2:30]/[CH:29]=[CH:28]/[C:26]1[CH:25]=[CH:24][CH:23]=[C:22](/[C:14](/[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:13]/[CH2:12][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[N:27]=1)(=[O:34])[CH3:33]
Reactant: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/CO)n2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC/C=C/c1cccc(/C(=C/CN2CCCC2)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
Pyridine (110 μl, 1.36 mmol) was added to a solution of 3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-en-1-ol (227 mg, 0.68 mmol) in DCM (3 ml) under an inert atmosphere. Acetyl chloride (72 μl, 1.02 mmol) was added and the reaction stirred for 18 hours at room temperature. The reaction mixture was partitioned between DCM and brine. The organic layer was separated, dried over sodium sulphate, filtered and concentrated under vacuum to leave a brown oil. The product was purified by column chromatography on silica gel eluting with 5% methanol/DCM. Product containing fractions were combined and solvent removed to yield 3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-en-1-yl acetate as a brown gum (184 mg, 73%). 1H-NMR; δ (CDCl3), 7.49 (1H, t, J=7.8 Hz), 7.24 (2H, d, J=7.9 Hz), 7.18-7.11 (2H, m), 7.06 (2H, d, J=7.9 Hz), 6.91-6.66 (3H, m), 4.79 (2H, dd, J=5.4, 0.7 Hz), 3.72 (2H, m), 3.20 (4H, bm), 2.40 (3H, s), 2.12 (3H, s) and 2.11-2.02 (4H, m).
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25].CCN(C(C)C)C(C)C.[F:36][C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][C@H:37]([F:36])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25]
Reactant: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)CCC1(F)F
Reactant: F[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](F)C4)ccc23)CCC1(F)F

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-fluoro-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.66 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.56 (m, 1H), 1.27-1.32 (m, 1H), 1.00 (d, 3H). m/z: 456 [M+H]
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH:16]=[CH:17][C:18](=[N:20][OH:21])[CH3:19])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].II.C([O-])(O)=O.[Na+]>O.C1COCC1.OS([O-])=O.[Na+]>[CH3:19][C:18]1[CH:17]=[C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[O:21][N:20]=1
Reactant: CC(C=C[C@@H]1CCCN1C(=O)OCc1ccccc1)=NO
Agent: II
Agent: O=C([O-])O
Agent: O=S([O-])O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc([C@@H]2CCCN2C(=O)OCc2ccccc2)on1
Temperature: 25 °C

Procedure:
A 169 mg sample (0.59 mmol.) of the product from step 23d above, 344 mg (2.07 mmol) of KI, 156 mg ((0.61 mmol) of I2, and 198 mg (2.36 mmol) of NaHCO3 were dissolved in 3 mL of water and 3 mL of THF. The mixture was heated at reflux for 6 hr, then cooled to room temperature. The mixture was diluted With 20 mL of 1.7M NaHSO3 solution, then extracted with ether. The combined extracts were washed with brine and dried over MgSO4, then concentrated to give 143 mg of crude product. Chromatography on silica gel, eluting with 20% ethyl acetate in hexane afforded 102 mg of the title compound after removal of the solvent.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2]>O>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:4]=1[NH:5][CH:11]=[CH:10]2)[CH3:2]
Reactant: CCc1cccc(CC)c1N
Solvent: O
Product: CCc1cccc2cc[nH]c12
Temperature: 610 °C
Yield: 41 %

Procedure:
The reactor filed with Cu-chromite/BaO catalyst was heated to 610° C. Into the reactor was fed 68.4 g of 2.6-diethylaniline and 41.4 g of water per hour. The organic reaction product after 5 hours of such reaction conditions was collected and subjected to partial hydrogenation as described in Example 1. After filtering of the hydrogenation catalyst, 332.4 g of organic liquid containing 45.8 g percent of 2.6-diethylaniline and 41.0 percent of 7-ethyl indole was obtained.