Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:31]1[CH:36]=[C:35]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH:34]=[C:33]([CH2:43][S:44][C:45]2[S:46][C:47]([CH2:50][CH3:51])=[N:48][N:49]=2)[N:32]=1)[CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][O:17]C2CCCCO2)[CH:13]=[C:12]([NH:24][C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH:11]=1)=O)(C)(C)C>Cl.CO.C(OCC)(=O)C>[CH2:50]([C:47]1[S:46][C:45]([S:44][CH2:43][C:33]2[N:32]=[C:31]([NH:8][CH2:9][C:10]3[CH:11]=[C:12]([NH:24][C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH:13]=[C:14]([CH2:16][OH:17])[CH:15]=3)[CH:36]=[C:35]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:34]=2)=[N:49][N:48]=1)[CH3:51]
Reactant: C=CCOC(=O)Nc1cc(COC2CCCCO2)cc(CN(C(=O)OC(C)(C)C)c2cc(N3CCOCC3)cc(CSc3nnc(CC)s3)n2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCOC(=O)Nc1cc(CO)cc(CNc2cc(N3CCOCC3)cc(CSc3nnc(CC)s3)n2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-{N-tert-butoxycarbonyl-N-[3-(2-propenyloxycarbonylamino)-5-(2-tetrahydropyranyl)oxymethylbenzyl]amino}-6-(5-ethyl-1,3,4-thiadiazol-2-ylthiomethyl)-4-morpholinopyridine (51 mg) was dissolved in 10% hydrogen chloride-methanol (2 ml), followed by stirring at 60° C. for two hours. After cooling naturally, the reaction solution was diluted with ethyl acetate, washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution and then, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by thin layer chromatography for separation (chloroform/methanol=10/1) to obtain the above identified compound (55 mg) as a pale yellow amorphous solid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1COCC1.CCOC(C)=O.[Cl:23][C:24]1[CH:25]=[C:26]([C:31]2[N:35]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[N:34]=[C:33]([CH2:44][O:45]C3CCCCO3)[CH:32]=2)[CH:27]=[CH:28][C:29]=1[Cl:30]>CO>[Cl:23][C:24]1[CH:25]=[C:26]([C:31]2[N:35]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=3)[N:34]=[C:33]([CH2:44][OH:45])[CH:32]=2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: COc1ccc(-n2nc(COC3CCCCO3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(CO)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reaction time: 18 h
Yield: 63.7 %

Procedure:
A solution of p-toluenesulfonic acid (1.22 kg, 6.28 mol) in methanol (20.0 L) was added to the THF/EtOAc solution of 5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-1H-pyrazole (Example 515) at rt and the resulting mixture was stirred overnight (18 h). When HPLC analysis indicated the disappearance of the starting material, the reaction mixture was concentrated to remove methanol. The resulting mixture was washed with 10% aq. NaHCO3 (40.0 L) followed by brine (40.0 L). The organic layer was added to n-heptane and the resultant suspension was filtered, washed, and vacuum dried to afford [5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-methanol (4.65 kg, 63.7% over 3 chemical steps) as a solid. Data compared favorably with that obtained for Example 1, Step C.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([NH:11][C:12](OC(C)(C)C)=O)[C:6]([O:8]CC)=[O:7])C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].Cl[CH2:35]Cl>>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH2:28]([N:11]([C:5]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:4]([OH:3])=[O:26])[C:6]([OH:8])=[O:7])[CH2:12][CH3:35])[CH3:29]
Reactant: ClCCl
Reactant: CCOC(=O)C(Cc1ccccc1)(NC(=O)OC(C)(C)C)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(Cc1ccccc1)(C(=O)O)C(=O)O
Reaction time: 1 h

Procedure:
To the product of Step A (7.5 g, 20.52 mmol) in dichloromethane (24 mL) was added trifluoroacetic acid (12 mL, 156 mmol) and the mixture stirred for 1 h. The solvent was removed in vacuo and the oil azeotroped with toluene (2×20 mL) to afford the title compound as a tan amorphous solid. LC/MS 266.1 (M+1).
Reaction SMILES: [I-].[K+].[Cl-].[CH3:4][S+](C)(C)=O.[H-].[Na+].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[C:18](=[O:24])[CH:17]=[CH:16]2>CS(C)=O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20]([N:19]([CH3:23])[C:18](=[O:24])[CH:17]3[CH2:4][CH:16]32)=[CH:21][CH:22]=1
Reactant: C[S+](C)(C)=O
Reactant: COc1ccc2c(ccc(=O)n2C)c1
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)C1CC1C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A suspension of 7.0 gm (42.0 mmol) potassium iodide and 4.89 gm (38.0 mmol) trimethylsulfoxonium chloride in 30 ml of DMSO under nitrogen was treated portionwise with 1.69 gm (42.0 mmol) of 60% sodium hydride in mineral oil. The mixture was stirred for one hour and then treated with 2.0 gm (11.0 mmol) 6-Methoxy-1-methyl-1H-quinolin-2-one followed by stirring for 0.5 hours at ambient temperature and 4 days at 90° C. The reaction mixture was allowed to cool to ambient temperature before quenching into ice followed by extraction into ether. The ether layer was washed with brine, dried over sodium sulfate and evaporated. The residue was partitioned between acetonitrile and pentane. The acetonitrile layer was concentrated. The residue was partitioned between 1:1 hexane/ethyl acetate and 50% saturated (sat'd) brine solution. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated in vacuo to afford 1.6 gm of a mixture of desired product and starting material. The residue was purified by silica gel chromatography eluting with 7/3 hexane/ethyl acetate to afford 972 mg (44%). Mass spectrum APCI m/e 204 (p+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:36])=[CH:33][C:34]=1[OH:35].C(N(CC)CC)C>CO.C(Cl)(Cl)Cl.CN(C)C=O.C(OCC)(=O)C>[OH:35][C:34]1[CH:33]=[C:32]([CH3:36])[CH:31]=[CH:30][C:29]=1[NH:28][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1ccc(N)c(O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(NC(=O)CNC(=O)OC(C)(C)C)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
To 50 ml of ethyl acetate, there were added 4.27 g (24.4 mmol) of N-(tert-butoxycarbonyl)glycine and 5.03 g (24.4 mmol) of N,N'-dicyclohexyl carbodiimide and stirred at room temperature for 30 minutes. The obtained solution was cooled in an ice bath and 3.00 g (24.4 mmol) of 6-amino-m-cresol and 2.51 g (24.4 mmol) of triethylamine were added thereto. After putting back to room temperature, the mixture was stirred for 12 hours. After the completion of the reaction, 50 ml of N,N-dimethylformamide was added thereto and the crystals thus precipitated were filtered and washed with 20 ml of N,N-dimethylformamide. The filtrate was combined with the washing liquor and the solvent was distilled off therefrom under reduced pressure to thereby give a brown solid. This product was subjected to silica gel column chromatography (Si60 manufactured by Merck; 230-400 mesh; 300 g; eluent: 3% methanol-chloroform). From the 900-1,300 ml fraction, the solvent was distilled off under reduced pressure and 20 ml of chloroform was added thereto to cause thereby crystallization. After filtering and drying, 2.00 g (7.1 mmol) of N-(2-hydroxy-4-methylphenyl)-tert-butoxycarbonylaminoacetamide was obtained as yellow crystals. The yield was 29%.
Reaction SMILES: [CH:1]([CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2([CH3:31])[CH2:15][C:14]3[C:16]([CH3:30])=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]([CH3:21])=[C:19]([CH3:20])[C:13]=3[O:12]2)[CH2:6][CH2:5]1)=O.[C:32]1([CH:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:39][CH2:40][NH2:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:42]1([CH:38]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:39][CH2:40][NH:41][CH2:1][CH2:3][CH:4]2[CH2:9][CH2:8][N:7]([CH2:10][C:11]3([CH3:31])[CH2:15][C:14]4[C:16]([CH3:30])=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]([CH3:21])=[C:19]([CH3:20])[C:13]=4[O:12]3)[CH2:6][CH2:5]2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CN1CCC(CC=O)CC1)O2
Reactant: NCCC(c1ccccc1)c1ccccc1
Product: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CN1CCC(CCNCCC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 97 %

Procedure:
Using tert-butyl [2-[[4-(formylmethyl)-1-piperidinyl]methyl]-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5yl]carbamate and (3,3-diphenylpropyl)amine, the procedure of Reference Example 44 was otherwise repeated to provide the title compound. Yield 97%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([NH:11][C:12](=[O:14])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].Br[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>CC(CC(C)=O)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]([NH:11][C:12](=[O:14])[CH3:13])([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH3:10]
Reactant: CC(C)=CCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C(CCC=C(C)C)(NC(C)=O)C(=O)OCC

Procedure:
27.1 g of acetamidomalonic acid diethyl ester are heated for 14 hours with 19.6 g of 5-bromo-2-methyl-2-pentene and 16.6 g of potassium carbonate in 100 ml of MIBK in a water separator. The reaction solution was extracted with 100 ml of water, and the organic phase was concentrated in vacuo. LC-MS analysis of the residue shows that it is a mixture of N-acetyl-D,L-2-amino-6-methyl-5-heptenoic acid ethyl ester (M+H+=228) and acetamido-(4-methyl-3-pentenyl)-malonic acid diethyl ester (M+H+=300) in a ratio of 3:2.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].BrC1C=CC([F:26])=CC=1C(O)=O>>[F:26][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1Br
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Product: O=C(O)c1cc(F)ccc1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 2-bromo-5-fluorobenzoic acid. MS (ESI) 208 (M+H).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH:17]2[CH:13]([C:14](=[O:18])[NH:15][CH2:16]2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C2C(NC(=O)C2)CC1)(=O)C1C=CC=CC=1.[H-].[Na+].Br[CH2:40][C:41]1[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[C:43]([Cl:49])[C:42]=1[CH3:50]>C1COCC1.CN(C=O)C>[C:1]([O:9][CH:10]1[CH:17]2[CH:16]([N:15]([CH2:40][C:41]3[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[C:43]([Cl:49])[C:42]=3[CH3:50])[C:14](=[O:18])[CH2:13]2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(CBr)ccc(C#N)c1Cl
Reactant: O=C(OC1CCC2C(=O)NCC12)c1ccccc1
Agent: O=C1CC2C(CCC2OC(=O)c2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(CN2C(=O)CC3C(OC(=O)c4ccccc4)CCC32)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution containing mixtures of compound 1I and 1J (170 mg, 0.69 mmol, different batch than previous lot in example 1) in anhydrous THF (4 mL) and anhydrous DMF (4 mL) was added sodium hydride (27.7 mg, 0.69 mmol) at 0° C., and stirred at 0° C. for 45 min. Compound 7C (169 mg, 0.69 mmol) was added at 0° C., the ice-water bath was removed, and the stirring was continued between 0° C. to RT for 2 hr before it was quenched with saturated NH4Cl solution. The mixture was diluted with EtOAc, organic layer was separated, washed with water, dried over MgSO4, and concentrated. Purification by silica gel chromatography (30-100% EtOAc in hexanes) provide the title compound 7D (90 mg) and 7E (151 mg). Compound 7D: (ES) m/z 409 [M+H]+. Compound 7E: (ES) m/z 409 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[N:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[C:6]1=[O:26].C([O-])([O-])=O.[Cs+].[Cs+].F[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[O:1][CH2:2][CH2:3][CH2:4][N:5]1[N:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=3)=[CH:10][CH:11]=2)[C:6]1=[O:26]
Reactant: O=c1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2cnn1CCCO
Reactant: Fc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=c1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2cnn1CCCOc1ccccn1
Temperature: 155 °C

Procedure:
A mixture of 2-(3-hydroxypropyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one (25 mg, 0.069 mmol), Cs2CO3 (67 mg, 0.21 mmol) and 2-fluoropyridine (100 μL) was heated to 155° C. overnight. The reaction was concentrated and purified by reverse phase HPLC to afford 2-(3-(pyridin-2-yloxy)propyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one as a white solid. C23H18F3N3O3. 441.9 (M+1).
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:10].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>O.C1(C)C=CC=CC=1>[C:4]1([CH3:10])[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH2:11][CH:13]2[O:15][CH2:14]2)[CH:3]=1
Reactant: ClCC1CO1
Reactant: Cc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(OCC2CO2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of 50 g (1.25 mol) of NaOH in 1200 ml H2O was added 108 g (1 mol) of m-cresol freshly distilled and at 15° C. in one lot 117ml (1.5 mol) of epichlorohydrin. The emulsion was stirred at room temperature for 16 hours in a creased flask. The product was taken up in 1000 ml of toluene and washed with 500 ml water. Distillation yielded 135.7 g=82% of product, bp 61° C. (0.05 mm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[N:24]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:15]2=[N:16][CH:17]=[C:18]3[CH:22]=[N:21][N:20]([CH3:23])[C:19]3=[C:14]2[CH:13]=1.[H-].[Na+].Cl[CH2:38][CH:39]1[CH2:41][O:40]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:38][CH:39]1[CH2:41][O:40]1)[CH:7]=[C:6]2[C:12]1[N:24]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:15]2=[N:16][CH:17]=[C:18]3[CH:22]=[N:21][N:20]([CH3:23])[C:19]3=[C:14]2[CH:13]=1
Reactant: COc1ccc2[nH]cc(-c3cc4c5c(cnc4n3S(=O)(=O)c3ccc(C)cc3)cnn5C)c2c1
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2CC1CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a reaction flask was added 7-(5-methoxy-1H-indol-3-yl)-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.100 g, 0.212 mmol; Preparation #P.1.1), DMF (3 mL) and 60 wt % NaH (0.010 g, 0.254 mmol) and 2-(chloromethyl)oxirane (0.026 g, 0.276 mmol). The mixture was stirred for about 2 h at rt. The mixture was concentrated in vacuo to provide 7-(5-methoxy-1-(oxiran-2-ylmethyl)-1H-indol-3-yl)-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (100% yield assumed and carried forward to Step B): LC/MS (Table 2, Method c) Rt=1.49 min; MS m/z 528 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:12]=[C:13]=[S:14])([CH3:11])([CH3:10])[CH3:9].Cl.Cl.[NH2:17][C@H:18]([CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:19][OH:20]>C(O)C.C(OCC)(=O)C.O.ClCCl>[C:8]([NH:12][C:13]([NH:17][C@H:18]([CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:19][OH:20])=[S:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: N[C@@H](CO)Cc1cccnc1
Reactant: CC(C)(C)N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CC(C)(C)NC(=S)N[C@@H](CO)Cc1cccnc1
Temperature: 60 °C

Procedure:
22.7 cm3 of triethylamine and then 14 cm3 of tert-butyl isothiocyanate are added dropwise to a suspension, under an inert atmosphere, of 16.51 g of (2R)-2-amino-3-(3-pyridyl)-1-propanol dihydrochloride in 200 cm3 of ethanol. The mixture is then heated at a temperature in the region of 60° C. for 1 hour 30 min. After cooling to a temperature in the region of 20° C., the insoluble material is filtered off on a sinter funnel and the filtrate is then evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. A yellow paste is obtained, and is taken up in 200 cm3 of ethyl acetate and 100 cm3 of water. The aqueous phase is extracted and then washed with twice 200 cm3 of ethyl acetate. The organic phases are combined, washed with 3 times 50 cm3 of saturated sodium chloride solution and dried over magnesium sulfate. After filtration and then evaporation under reduced pressure (2 kPa) at a temperature in the region of 40° C., a yellow oil is obtained, which is taken up in dichloromethane and re-evaporated to give 3.25 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-pyridylmethyl)-ethyl]thiourea in the form of a pale yellow foam: [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.41 (s: 9H); 2.84 (mt: 2H); 3.37 (mt: 2H); 4.43 (unres. mult.: 1H); 4.96 (t, J=5 Hz: 1H); 7.24 (d, J=8 Hz: 1H); 7.27 (broad s: 1H); 7.33 (dd, J=8 and 5 Hz: 1H); 7.67 (dt, J=8 and 2 Hz: 1H); 8.42 (dd, J=5 and 2 Hz: 1H); 8.46 (d, J=2 Hz: 1H)].
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]([N:24]1[C@H:29]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C@@H:28]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH2:27][C@@:26]([CH2:45][C:46]([O:48][CH3:49])=[O:47])([CH3:44])[C:25]1=[O:50])[CH:21]1[CH2:23][CH2:22]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:43][C:39]1[CH:38]=[C:37]([C@@H:28]2[C@@H:29]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[N:24]([C@@H:20]([CH:21]3[CH2:22][CH2:23]3)[CH2:19][OH:18])[C:25](=[O:50])[C@:26]([CH2:45][C:46]([O:48][CH3:49])=[O:47])([CH3:44])[CH2:27]2)[CH:42]=[CH:41][CH:40]=1
Reactant: COC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2CC2)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of methyl 2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate (578 mg, 0.793 mmol; Example 263, Step B) in THF (3.2 mL) was added 1 M TBAF in THF (2.38 mL, 2.38 mmol) at 0° C. and the reaction mixture was allowed to warm to rt. After being stirred at rt for 6 h, the reaction was quenched (sat. NH4Cl), extracted (2×EtOAc) and washed (brine). The combined organic layers were dried (Na2SO4) and concentrated under the reduced pressure. Purification of the residue by chromatography on silica gel (40 g SiO2, 10% and 50% EtOAc/Hex) provided the title compound as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([O:12][C:11]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cnc(Cl)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(Cl)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 6-chloro-5-hydroxynicotinate (3.71 g) in DMF (30 mL) were added potassium carbonate (5.47 g) and benzyl bromide (2.59 mL), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture at 0° C., and the resulting precipitate was collected by filtration. The obtained crude crystals were washed with water and hexane, and dried at 50° C. for 15 min under reduced pressure to give a crude product of the title compound (4.57 g) as a pale-yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:18])=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][Mg]I>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:17]([OH:18])[CH3:22])[CH:19]=[CH:20][CH:21]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[Mg]I
Reactant: O=Cc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C

Procedure:
3-[2(E)-(7-Chloroquinolin-2-yl)ethenyl}benzaldehyde (Example 6a part i) (2.44 g, 8.3 mmol) in dry THF (75 ml) was cooled in an ice bath under nitrogen and stirred as 1M methyl magnesium iodide in diethyl ether (9.9 ml) was added over 5 minutes. The reaction was stirred at 0° C. for half an hour, warmed to room temperature and quenched with water. The mixture was extracted into ethyl acetate, the combined organic extracts dried, filtered and evaporated in vacuo.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([CH2:14][C:13]2[CH:12]=[C:11]([C:10]#[C:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:18]=[CH:17][CH:16]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=Cc1cccc(C#CCCN2CCOCC2)c1
Reactant: C1COCCN1
Product: C(#Cc1cccc(CN2CCOCC2)c1)CCN1CCOCC1

Procedure:
May be prepared analogously to Example 15 using the product of Example 10 and morpholine.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][CH2:32][OH:33])[CH3:29]>>[CH2:28]([N:30]([CH2:31][CH2:32][OH:33])[C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:16][CH2:15]2)=[O:18])=[CH:27][CH:26]=1)=[O:25])[CH3:29]
Reactant: CCNCCO
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Product: CCN(CCO)C(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Yield: 86 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using 2-(ethylamino)ethanol. Then, the product was recrystallized using ethyl acetate and petroleum ether, filtered and dried to give the desired compound as white crystal.
Reaction SMILES: CN(C)CCN(C)C.C([Li])CCC.[C:14]([O:18][C:19](=[O:28])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[N:22]=1)([CH3:17])([CH3:16])C.[N+:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)CC(=O)C2)([O-:31])=[O:30]>C1COCC1>[Cl:27][C:23]1[CH:24]=[CH:25][C:26]2[C:14]3([CH2:16][C:34]4[C:38](=[CH:39][CH:40]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=4)[CH2:17]3)[O:18][C:19](=[O:28])[NH:20][C:21]=2[N:22]=1
Reactant: O=C1Cc2ccc([N+](=O)[O-])cc2C1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)n1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2nc(Cl)ccc2C2(Cc3ccc([N+](=O)[O-])cc3C2)O1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of N,N,N′,N′-tetramethylethylenediamine (3.3 mL, 22 mmol) in THF (8 mL) is cooled to −20° C. and treated with n-butyllithium (2.5 Min hexanes, 8.8 mL, 22 mmol) over 10 min. After stirring for 30 min, the mixture is cooled to −78° C. and treated with a solution of tert-butyl(6-chloropyridin-2-yl)carbamate (2.29 g, 10 mmol) [Williams US2006/028835] in THF (6 mL) over 15 min. After 1 h, the mixture is warmed to −50° C. and treated with a solution of 5-nitro-1,3-dihydro-2H-inden-2-one (2.66 g, 15 mmol) in THF (8 mL) over 10 min. The mixture is then allowed to warm to rt and stirred for 24 h. The reaction is quenched by addition of saturated aqueous NaHCO3 and the mixture is then extracted with EtOAc (×3). The combined organic extracts are washed successively with water and brine, dried (anhydrous MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient elution with hexanes-EtOAc) to afford the title compound.