Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:19](=[O:20])[NH:18][N:17]=[C:7]3[CH2:8][C:9]([CH3:16])([CH3:15])[CH2:10][C:11]4[NH:12][C:13]([CH:14]=1)=[C:5]2[C:6]=43.C(=O)([OH:23])N>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:19](=[O:20])[NH:18][N:17]=[C:7]3[CH2:8][C:9]([CH3:16])([CH3:15])[C:10](=[O:23])[C:11]4[NH:12][C:13]([CH:14]=1)=[C:5]2[C:6]=43
Reactant: NC(=O)O
Reactant: CC1(C)CC2=NNC(=O)c3cc(F)cc4[nH]c(c2c34)C1
Solvent: C1COCCO1
Product: CC1(C)CC2=NNC(=O)c3cc(F)cc4[nH]c(c2c34)C1=O
Yield: 38.9 %

Procedure:
To a solution of carbamate 8-fluoro-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one (0.5 g, 1.8 mmol) in anhydrous dioxane (25 mL) was added SeO2 (0.32 g, 2.7 mmol). The mixture was refluxed for 40 h and filtered through Celite. The solid material was thoroughly washed with Et2O. The filtrate was concentrated, and the residue was chromatographed to give product (200 mg, 38%) as a solid. 1H NMR (DMSO-d6) δ 12.70 (s, 1H), 10.90 (s, 1H), 7.41 (dd, 1H, J=10.2, 1.8 Hz), 7.09 (dd, 1H, J=9.6, 1.8 Hz), 2.87 (s, 2H), 1.23 (s, 6H). MS (ESI) m/e [M+1]+ 286.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[C:18]1[N:23]=[CH:22][C:21]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:20][CH:19]=1>>[C:34]([O:33][C:31]([N:28]1[CH2:27][CH2:26][CH:25]([O:24][C:21]2[CH:22]=[N:23][C:18]([N:1]3[C:9]4[C:4](=[CH:5][C:6]([CH2:10][NH:11][C:12](=[O:16])[CH:13]([CH3:14])[CH3:15])=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)=[CH:19][CH:20]=2)[CH2:30][CH2:29]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)C(=O)NCc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)C(=O)NCc1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using N-((1H-indol-5-yl)methyl) isobutyramide (intermediate 3) and tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate 6) (0.103 g, 21.77%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](N)([CH3:23])([CH3:22])[CH3:21].Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16]([CH:15]=[CH:14][C:13]([OH:19])=[C:12]2[C:14]2[C:23]3[C:20](=[CH:22][CH:18]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH:21]=[CH:12][C:13]=2[OH:19])=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2ccc(OCc3ccccc3)cc2c1
Reactant: CC(C)(C)N
Agent: Cl
Solvent: CO
Product: Oc1ccc2ccc(OCc3ccccc3)cc2c1-c1c(O)ccc2ccc(OCc3ccccc3)cc12
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
To 23.6 g (0.094 mol) of 2-benzyloxy-7-hydroxynaphthalene and 25.6 g (0.19 mol) of cupric chloride was added 600 ml of methanol, and 56.32 g (0.77 mol) of t-butylamine and 200 ml of methanol were added thereto dropwise over a period of 1.5 hours, followed by stirring for 20 hours. The reaction mixture was cooled with an ice bath, and 200 ml of a 6N hydrochloric acid aqueous solution was added thereto dropwise. The reaction mixture was concentrated with an evaporator. Ethyl acetate was added to the residue, followed by liquid-liquid separation. The organic layer was washed with a saturated sodium chloride aqueous solution, and the solvent was removed by evaporation. The residue was recrystallized from toluene-cyclohexane to yield 20 g (85%) of the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:13]2[C:5](=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9]C(=O)[C:7]3=[O:15])[CH2:4][CH2:3]1.[OH-:17].[Na+].OO.Cl>O>[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[S:2](=[O:1])(=[O:16])[CH2:3][CH2:4][C:5]=2[C:6]=1[C:7]([OH:15])=[O:17]
Reactant: [OH-]
Reactant: O=C1Nc2ccc3c(c2C1=O)CCS3(=O)=O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1ccc2c(c1C(=O)O)CCS2(=O)=O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 60.6 %

Procedure:
1.5 g (6.32 mmol) of 3,3-dioxo-1,2,3,6-tetrahydro-3λ6-thieno[3,2-e]indole-7,8-dione were introduced into a 10 ml three-neck round-bottom flask and dissolved in 6.5 ml of 1M (207.2 mmol) sodium hydroxide solution. 1.5 ml (1.32 mmol) of a 30% strength hydrogen peroxide solution were slowly added dropwise over the course of 30 minutes. The internal temperature during the addition was kept between 30-40° C. despite the exothermic reaction. After the addition was complete, the mixture was stirred at 40° C. for 1.5 h. The mixture was then cooled to RT and, after addition to a little water (about 7 ml), acidified with a 10% strength HCl to pH 1, and the precipitated solid was filtered off with suction. The latter was washed successively with water and diethyl ether and dried in vacuo overnight. 870 mg of the desired compound were obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([C:22]([F:25])([F:24])[F:23])[CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.N1(S(N)(=O)=O)CCC1.[CH:34]1([S:37]([NH2:40])(=[O:39])=[O:38])[CH2:36][CH2:35]1>>[CH:1]1([C:4]2[C:5]([O:14][CH2:15][C@H:16]3[CH2:17][CH2:18][C@H:19]([C:22]([F:25])([F:23])[F:24])[CH2:20][CH2:21]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([NH:40][S:37]([CH:34]2[CH2:36][CH2:35]2)(=[O:39])=[O:38])=[O:11])[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(C2CC2)c(OC[C@H]2CC[C@H](C(F)(F)F)CC2)cc1F
Agent: NS(=O)(=O)N1CCC1
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OC[C@H]2CC[C@H](C(F)(F)F)CC2)cc1F

Procedure:
Following the procedure as described in Example 226 step 4, and making variations as required to replace 5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluorobenzoic with trans-5-cyclopropyl-2-fluoro-4-((4-(trifluoromethyl)cyclohexyl)-methoxy)benzoic acid and to replace azetidine-1-sulfonamide with cyclopropanesulfonamide, the title compound was obtained (0.15 g, 81%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.96 (d, J=13.0 Hz, 1H), 3.92 (d, J=6.0 Hz, 2H), 3.12-3.03 (m, 1H), 2.08-1.78 (m, 6H), 1.38-1.10 (m, 9H), 0.93-0.87 (m, 2H), 0.70-0.65 (m, 2H); MS (ES+) m/z 464.1 (M+1); MS (ES−) m/z 462.2 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[C:43](Cl)=[O:44].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[C:43]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1)=[O:44]
Reactant: Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.7 %

Procedure:
To a mixture of 4-(3-aminophenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (480 mg) and triethylamine (0.23 ml) in dichloromethane (7 ml) was added 2-naphthoyl chloride (291 mg). The mixture was stirred at room temperature for 20 minutes, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from ethanol to give 4-[3-(2-naphthoylamino)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (280 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].[CH:28](Br)([CH3:30])[CH3:29].O>CN(C)C=O>[CH:28]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20])([CH3:30])[CH3:29]
Reactant: CC(C)Br
Reactant: CCOC(=O)c1sc(-c2ccc(O)c([N+](=O)[O-])c2)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(OC(C)C)c([N+](=O)[O-])c2)nc1C
Temperature: 70 °C
Yield: 75.7 %

Procedure:
200 mg of Ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate prepared in (1) was dissolved in 3 ml of N,N-dimethylformamide, 540 mg of anhydrous potassium carbonate and 440 mg of isopropyl bromide were added thereto, and the mixture was heated at 70° C. for 18 hours. After the reaction mixture was cooled, 20 ml of water was added thereto. The mixture was extracted twice with 30 ml of ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and the solvent was removed by distillation. The resulting crystal was recrystallized from ethanol to give 172 mg of ethyl 2-(4-isopropoxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate. This product was hydrolyzed by a conventional process, and the resulting crystal was recrystallized from a 80% aqueous ethanol solution to give 135 mg of 2-(4-isopropoxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylic acid (yield:
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]([CH3:18])[CH2:8][CH:9]1[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH2:10]1)(=O)C.[OH-].[Na+]>O>[CH3:18][CH:7]([CH2:8][CH:9]1[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:16])([CH3:17])[CH2:10]1)[CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCC(C)CC1CC(C)CC(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CCO)CC1CC(C)CC(C)(C)C1
Temperature: 92.5 °C
Reaction time: 11 h
Yield: 92 %

Procedure:
3-Methyl-4(3,3,5-trimethylcyclohex-1-yl)butyl acetate (2.54 kg, 10.0 mols, purity: 97%) sodium hydroxide (420 g, 10.5 mols) and water (8400 ml) were mixed together and heated at 90-95° C. under stirring for 10-12 h. The reaction mixture was cooled to 35° C. The aqueous phase was separated from the organic phase. The organic phase was washed once with 5% w/w aqueous NaCl and twice with water. The crude product was fractionated under reduced pressure to provide 3-Methyl-4(3,3,5-trimethylcyclohex-1-yl) butan-1-ol (1.95 kg, yield: 92%; GC purity: 98% sum of the isomers).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([C:18]([OH:20])=O)[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].C(Cl)(=O)C(Cl)=O.[CH2:27]([NH2:30])[CH2:28][CH3:29]>C(Cl)(Cl)Cl>[CH3:17][C:16]1[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)=[CH:12][C:13]([C:18]([NH:30][CH2:27][CH2:28][CH3:29])=[O:20])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(-c2cc(C(=O)O)ccc2C)cc1
Reactant: CCCN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)c1ccc(C)c(-c2ccc(C(=O)OC)cc2)c1
Reaction time: 0.75 h

Procedure:
4′-(Methoxycarbonyl)-6-methyl-1,1′-biphenyl-3-carboxylic acid (190 mg, 0.7 mmol) and oxalyl chloride (70 μl, 0.77 mol) in chloroform (4 ml) were stirred at room temperature for 15 min. Propylamine (200 μl) was added and stirring continued for 45 min. The reaction was quenched with water (4 ml), the phases separated and the organic phase passed through an aminopropyl SPE eluting with chloroform. After evaporation of the solvent this gave methyl 6′-methyl-3′-[(propylamino)carbonyl]-1,1′-biphenyl-4-carboxylate (216 mg). LCMS: retention time 3.26 min, MH+312.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:28][C:29](O)=[O:30].O.ON1C2C=CC=CC=2N=N1.Cl.[OH:44][CH:45]1[CH2:48][NH:47][CH2:46]1.Cl.C(/N=N/CCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][N:25]=3)[CH2:18][CH2:19]2)[CH:5]=[CH:4][C:3]=1[CH2:28][C:29]([N:47]1[CH2:48][CH:45]([OH:44])[CH2:46]1)=[O:30]
Reactant: OC1CNC1
Reactant: COc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)nc1
Agent: CC/N=N/CCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CC(O)C4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
[2-Fluoro-4-(2-{(1S,2R)-2-[1-(5-methoxypyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)phenyl]acetic acid (80 mg, 0.186 mmol), 1-hydroxybenzotriazole hydrate (42.8 mg, 0.279 mmol), 3-hydroxyazetidine hydrochloride (30.6 mg, 0.279 mmol) and (E)-3-(ethyldiazenyl)-N,N-dimethylpropan-1-amine hydrochloride (50.2 mg, 0.279 mmol) were dissolved in CH2Cl2 (4 ml). The mixture was stirred at RT for 5 min. and triethylamine (0.078 ml, 0.556 mmol) was added. The mixture was stirred at RT overnight and loaded directly on Preparative TLC that was developed with pure EtOAc. The desired product (Rf=0.35 @ pure EtOAc) was collected to give the title compound. 1H NMR (500 MHz, CDCl3) δ 8.1 (s, 2H), 7.21 (m, 1H), 6.65 (m, 2H), 4.60 (m, 3H), 4.30 (m, 2H), 4.05 (m, 3H), 3.90 (m, 1H), 3.80 (s, 3H), 3.72 (s, broad, 1H), 3.41 (s, 2H), 2.83 (m, 2H), 2.15 (m, 1H), 2.05 (s, broad, 1H), 1.92 (m, 2H), 1.55 (m, 1H), 1.40 (m, 2H), 0.95 (m, 2H), 0.68 (m, 2H), −0.40 (m, 1H). LC/MS (m/z): 485 (M+H)+. GPR119 Human EC50: 2.1 nM.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:21]=[CH:22][C:23]([OH:30])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26])#[CH:19]>C(N(CC)CC)C.O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:30][C:23]1[CH:22]=[CH:21][C:20]([C:18]#[C:19][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: C#Cc1ccc(O)c(C(=O)OC)c1
Reactant: O=S(=O)(Nc1ccccn1)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Temperature: 60 °C

Procedure:
4-Iodo-N-(2-pyridinyl)benzenesulfonamide (35 g, 97 mmol) was dissolved in a mixture of triethylamine and tetrahydrofuran (750+750 ml). The mixture was deaerated with nitrogen and dichlorobis(triphenylphosphine)palladium (1.2 g, 1.7 mmol) and copper(I) iodide (0.6 g, 3.4 mmol) were added. Finally methyl 5-ethynyl-2-hydroxybenzoate (23 g, 130 mmol) was added. The mixture was heated to 60° C. for 4 h, evaporated to dryness. The residue was dissolved in chloroform (1000 ml) and washed with water (3 x 200 ml) and dried with MgSO4. The solvent was evaporated in vacuo. Yield 31 g (77% ). The product can be purified by flash-chromatography on silica with chloroform as the eluent.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]1.[NH4+].[Cl-]>C1COCC1>[CH2:1]([CH:12]1[CH2:13][CH2:14][CH2:15][C:10](=[O:16])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C1C=CCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1CCCC(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.1 h

Procedure:
To a solution of benzylmagnesiumchloride in THF (1.31 M, 393 mmol, 300 mL) CuCl (1.9 g) was added and the mixture was cooled to 0° C. The mixture was stirred for 6 min., and a solution of cyclohex-2-enone (193 mmol, 18.9 g) in THF (75 mL) was added dropwise at 0° C. over a period of 1 h. The reaction mixture was warmed to RT overnight. After cooling again to 0° C., saturated aqueous NH4Cl (450 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×500 mL). The combined org. layers were washed with saturated aqueous NH4Cl (500 mL) and dried over Na2SO4. After evaporation, the crude product was subjected to column chromatography (SiO2, EtOAc/Hept=1/19→1/9) to give two fractions of product 01-1. Fraction 1 (23.5 g, 125 mmol, 65%, yellow oil) was used in the next step.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:9]CCC(OC)=O)=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+]>O1CCCC1>[S:9]=[C:4]1[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][NH:5]1
Reactant: COC(=O)CCSc1ncccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc[nH]c1=S
Yield: 69.1 %

Procedure:
A mixture of methyl 3-(3-cyanopyridin-2-ylthio)propanoate (1.5 g, 6.8 mmol), sodium hydride (0.36 g, 15 mmol) and tetrahydrofuran (30 ml) was heated at reflux for 5 h. The reaction was quenched by the addition of ethanol (5 ml). The solvents removed under reduced pressure and the residue was treated with water (50 ml). The ph was adjusted to 6 and the mixture was filtered to yield 2-thioxo-1,2-dihydropyridine-3-carbonitrile (0.64 g). An analytically pure sample was prepared by recrystallisation from ethanol, yellow needles, mp 243-246° C. (lit. mp 248-250° C.). 1H NMR (DMSO-d6): 14.30 (br s, exchangeable, 1H), 8.12 (dd, 1H), 7.94 (dd, 1H), 6.86 ppm (dd, 1H). MW=136 confirmed by LC-MS, tr=5.27 min (Method C) MH+=137.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=1[O:36][CH3:37].C(#N)C>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][O:26][C:27]4[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=4[O:36][CH3:37])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCN1CCN(c2n[nH]c3cc(Cl)ccc23)CC1
Yield: 23 %

Procedure:
A mixture of 6-chloro-[3-(1-piperazinyl)]-1H-indazole (2.1 g, 8.9 mmol, K2CO3 (1.5 g, 10.7 mmol), KI (100 mg), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (2.2 g, 9.8 mml) and acetonitrile (70 ml) was stirred at reflux for 48 hours under N2. The cooled reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The organic extract was washed with water, dried with MgSO4 and concentrated to yield 6.0 of a light yellow oil. The oil was purified by preparative HPLC (Waters Associates prep LC/System 500, employing 2 silica gel columns and 5.5% methanol/methylene chloride as eluent). Concentration of later fractions provided 1.6 g, of an off-white solid. This was combined with an additional sample (3.4 g total) and two consecutive recrystallizations from ethanol yielded 2.1 g (23%) of 1-[4-[2-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxy-phenyl]ethanone as an off-white solid, m.p.=154-156° C.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:30][N:31]([CH3:34])[CH:32]=[O:33]>>[CH:30]([N:31]1[CH2:34][CH2:5][N:4]([CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]2=[O:21])[CH2:3][C:32]1=[O:33])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: O=C1N(CCBr)CCC1(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: O=C1CN(CCN2CCC(c3ccccc3)(c3ccccc3)C2=O)CCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from the Example 28A (0.182 g, 0.6 mmol) in N,N-dimethylformamide (5 mL) was added 1-(2-bromoethyl)-3,3-diphenylpyrrolidin-2-one (Example 64B, 0.2 g, 0.6 mmol), potassium carbonate (0.25 g, 1.8 mmol), and a catalytic amount of potassium iodide. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and partitioned in H2O/dichloromethane. The organic layer was separated, dried over MgSO4, and concentrated. The obtained residue was chromatographed eluting with 5% methanol/dichloromethane to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.31 (m, 10H), 7.20 (m, 11H), 3.50 (t, J=6.10 Hz, 2H), 3.38 (t, J=6.44 Hz, 2H), 3.33 (m, 2H), 3.00 (m, 2H), 2.71 (m, 4H), 2.58 (t, J=6.27 Hz, 2H), MS (ESI+) m/z 530 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([OH:27])=O)[C:20]=2[CH3:28])/[C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:29]1([CH2:34][C@@H:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)[CH2:33][CH2:32][CH2:31][CH2:30]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1.C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([N:37]4[CH2:38][CH2:39][CH2:40][C@@H:35]([CH2:34][N:29]5[CH2:30][CH2:31][CH2:32][CH2:33]5)[CH2:36]4)=[O:27])[C:20]=2[CH3:28])/[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: C1CNC[C@H](CN2CCCC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c(C)c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CC#N
Solvent: ClCCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c(C)c1C(=O)N1CCC[C@@H](CN2CCCC2)C1
Yield: 54.9 %

Procedure:
5-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (112 mg, 0.3 mmol) was coupled with (R)-3-pyrrolidin-1-ylmethyl-piperidine (99 mg, 2 eq.), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (1 mL) and acetonitrile (1 mL) at rt for overnight to give 89.5 mg (55%) of the titled compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](/[CH:12]=[CH:13]/[C:14](=[O:45])[N:15]([CH3:44])[C@@H:16]([C:28](=[O:43])[N:29]([CH3:42])[C@@H:30]([C:38](=[O:41])[NH:39][CH3:40])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([CH:12]=[CH:13][C:14](=[O:45])[N:15]([CH3:44])[C@@H:16]([C:28](=[O:43])[N:29]([CH3:42])[C@@H:30]([C:38](=[O:41])[NH:39][CH3:40])[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)C=CC1CN(C(=O)OC(C)(C)C)C1
Reaction time: 0.12 h
Yield: 64.8 %

Procedure:
3-((E)-2-(Methyl((1R)-1-(methyl-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)vinyl)azetidine-1-carboxylic acid tert-butyl ester (0.45 g; 0.73 mmol) was dissolved in methylene chloride (2 mL). Trifluoroacetic acid (2 mL) was added and the reaction mixture was stirred for 7 min. Methylene chloride (50 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (50 mL; pH 9) and sodium carbonate were added to the reaction mixture until pH 8. The organic phase was dried (magnesium sulfate) and evaporated in vacuo to afford 0.29 g of the title compound.