Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]1[C:6]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)([C:7]([F:10])([F:9])[F:8])[O:5][N:4]=[C:3]1[C:19]1[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH:26]2[CH2:29][S:28][CH2:27]2)=[O:24])=[C:21]([CH3:32])[CH:20]=1.C(=O)([O-])[OH:34].[Na+].ClC1C=C(C=CC=1)C(OO)=O>ClCCl.O>[Br:1][CH:2]1[C:6]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=[C:3]1[C:19]1[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH:26]2[CH2:29][S:28](=[O:34])[CH2:27]2)=[O:24])=[C:21]([CH3:32])[CH:20]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2Br)ccc1C(=O)NC1CSC1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2Br)ccc1C(=O)NC1CS(=O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[4-bromo-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-thietan-3-yl-benzamide (145 mg) (Example A22) in dichloromethane (8 ml) was added a solution of sodium hydrogen carbonate (128 mg) in water (4 ml). A solution of 3-chloroperoxybenzoic acid (“MCPBA”) (48 mg) in dichloromethane (1 ml) was added dropwise. The reaction mixture was stirred at ambient temperature for 4 hours. Dichloromethane was evaporated and the residue partitioned between aqueous sodium carbonate (1M) and ethyl acetate. The phases were separated and the aqueous phase extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC to give Compound No. A25 of Table A (101 mg) and Compound No. A26 of Table A (17 mg) as colorless solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[C:5]([NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1)=O.[C:23](=O)([O:25]CC)[NH2:24].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1>[C:12]([C:11]1[CH:17]=[C:18]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:5]([C:4]1[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=1[O:2][CH3:1])[NH:24][C:23]2=[O:25])([OH:14])=[O:13]
Reactant: CCOC(N)=O
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccccc2OC)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: COc1ccccc1-c1nc2ccc(C(=O)O)cc2c(=O)[nH]1
Reaction time: 2 h
Yield: 70.7 %

Procedure:
Ethyl 4-(2'-methoxy-benzoylamino)-benzoate (21 g), prepared according to Example 19 is reacted with ethyl carbamate (12 g) and P2O5 (70 g) in xylene (200 ml) for 6 hours at the reflux temperature. After cooling, the precipitate is filtered off, poured in ice-water and treated with NaOH to neutralization. The precipitate (23 g) is collected by filtering and is hydrolyzed by treatment with LiBr (10 moles/mole) in dimethylformamide (150 ml) at the reflux temperature for 2 hours. After cooling, acidify with acetic acid, filter and wash with hot ethanol to obtain 6-carboxy-2-(2'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline (14.7 g; m.p. 296°-297° C.).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([CH:30]=O)[CH:20]=1)[CH2:17][CH3:18]>>[CH2:16]([C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([CH2:30][NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH:20]=1)[CH2:17][CH3:18]
Reactant: NCCN1CCN(c2ccccc2)CC1
Reactant: CCCc1cc(C=O)nn1-c1ccccc1
Product: CCCc1cc(CNCCN2CCN(c3ccccc3)CC2)nn1-c1ccccc1
Yield: 55.6 %

Procedure:
Compound 4 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 5-propyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[Cl:9][C:10]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]>>[Cl:9][C:10]1[CH:17]=[C:16]([O:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:8])[CH:1]=2)[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]
Reactant: Cc1cccc(O)c1
Reactant: O=Cc1ccc(F)cc1Cl
Product: Cc1cccc(Oc2ccc(C=O)c(Cl)c2)c1

Procedure:
m-Cresol and 2-chloro-4-fluorobenzaldehyde were reacted according to the same experiment procedures as in Reference Example 1 of the pamphlet of WO 03029184 to obtain the target product as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.C(OO)(=[O:17])C.C(O)(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][C:6]1[CH:7]=[N+:8]([O-:17])[CH:9]=[CH:10][CH:11]=1
Reactant: Clc1cccc(Oc2cccnc2)c1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Solvent: CC(C)O
Product: [O-][n+]1cccc(Oc2cccc(Cl)c2)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A solution of 110 g of 3-(m-chlorophenoxy)pyridine [Agr. Biol. Chem., 34, 68 (1970)] at 35° C. in 125 ml of glacial acetic acid is treated with 112 g of 40% peracetic acid in acetic acid in four equal portions. The mixture is held at 27° C. for 16 hours and heated at reflux for 1 hour. The mixture is cooled to 70° C., 100 ml of isopropanol is added and the mixture is heated at 95° C. for 1 hour. The warm mixture is concentrated at reduced pressure, dissolved in 500 ml of dichloromethane and extracted with excess 25% sodium hydroxide solution. The dichloromethane is removed at reduced pressure and the 3-(m-chlorophenoxy)pyridine N-oxide is isolated by distillation; 150°-152° C. at 0.15 mm, mp 72°-75° C.
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH2:9][C:10](=O)[C:11]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].O.[NH2:21][NH2:22]>C(O)C>[C:1]([C:3]1[C:8]2[CH2:9][C:10](=[N:21][NH2:22])[C:11]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: N#Cc1cccc2c1CC(=O)c1ccc(F)cc1S2
Solvent: CCO
Solvent: O
Product: N#Cc1cccc2c1CC(=NN)c1ccc(F)cc1S2

Procedure:
The mixture of 1.0g of 9-cyano-3-fluoro-10,11-dihydrodibenzo-[b,f]thiepin-11-one, 1.1g of 100% hydrazine hydrate and 16ml of ethanol was heated under reflux for 4.5 hours. The reaction mixture was concentrated to about one-fifth. After cooling, crystals was collected by filtration, there was obtained 9-cyano-3-fluoro-10,11-dihydrodibenzo[b,f]thiepin-11-one hydrazone having a melting point of 178°-179° C in quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[Br:10]Br>C(O)(=O)C>[Br:10][C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:9])[CH:6]=1
Reactant: Nc1c(F)cccc1F
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1c(F)cc(Br)cc1F
Temperature: 10 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
507.5 g of 2,6-difluoroaniline are added to 2500 ml of acetic acid, the mixture is cooled to 10° C., and a solution of 195 ml of bromine in 250 ml of acetic acid is added dropwise at 10-15° C. over the course of 3 hours. The mixture is subsequently stirred at room temperature for a further 1 hour and poured into 5000 ml of ice-water, the precipitated crystals are filtered off with suction and washed a number of times with a total of 3000 ml of ice-water, and the crystals are dried over Al2O3 under reduced pressure, giving 4-bromo-2,6-difluoroaniline, yield 91.7%, GC 99.6%.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH2:12][CH2:11][CH2:10][NH:9][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCNc1nc(Cl)ncc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccccc1OCCCNc1nc(Cl)ncc1Br
Reaction time: 21 h

Procedure:
A solution of 500 mg (1.29 mmol) of (5-bromo-2-chloro-pyrimidin-4-yl)-[3-(2-nitro-phenoxy)-propyl]-amine in 20 ml of THF is mixed at room temperature with 6.0 ml of an approximately 10% solution of Ti(III)Cl in 20-30% hydrochloric acid. After 21 hours, another 2.0 ml of the Ti(III)Cl solution is added. Renewed additions of the Ti(III)Cl solution are carried out after 4 hours (3.0 ml) or 16 hours (4.0 ml). After another 6 hours, the batch is diluted with ethyl acetate and made basic with 1N NaOH solution. It is filtered on Celite, and the filter cake is washed with ethyl acetate. The organic phase is separated, dried (Na2SO4), filtered and concentrated by evaporation. The residue that is obtained is purified by chromatography (hexane/ethyl acetate 7:3). 290 mg (0.81 mmol, corresponding to 62% of theory) of the product is obtained.
Reaction SMILES: Br[C:2]1[C:3](C2C=CC=CC=2)=[N:4][NH:5][CH:6]=1.C1C=C[C:16](/[CH:19]=[CH:20]/[C:21](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:17][CH:18]=1.C1C=C[C:34](/[CH:37]=[CH:38]/[C:39](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd:67].[Pd].Cl>>[CH2:2]([C:3]1[N:4]([C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:42]2[CH:34]=[CH:37][CH:38]=[C:39]([OH:40])[CH:41]=2)[N:5]=[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:23]=1[C:21]1[CH:18]=[CH:17][CH:16]=[CH:19][CH:20]=1)[CH3:6].[Pd:67]
Reactant: Brc1c[nH]nc1-c1ccccc1
Reactant: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Pd]
Agent: Cl
Product: CCc1c(-c2ccccc2)c(-c2ccccc2)nn1-c1ccccc1-c1cccc(O)c1
Reaction time: 1 h

Procedure:
The reaction of Example 1 (reaction scale: 10 mmol of bromophenyl pyrazole) was conducted with 0.15 mole % of Pd2(dba)3. After the reaction was judged to be essentially complete, the reaction mixture was neutralized with 1N aq. HCl to a pH of 7.0 to 7.5. After filtration, the crude solid was dissolved in acetone (25 mL/g of bromophenyl pyrazole starting material) at 55° C. TMT (0.05 equiv.) was added, and the mixture was stirred for 1 h while the temperature was allowed to decrease to 30° C. The resulting solution was filtered twice through a Darco zeta pad. The filtrate was concentrated by partial removal of the organic solvents. Recrystallization from acetone/water afforded 2′-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)-[1,1′]-biphenyl-3-ol containing 33 ppm of palladium.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:24]1([C:34](Cl)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:35])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added 1-naphthoyl chloride (97 mg, 0.64 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1), and recrystallized from ethyl acetate-hexane to give the title compound (145 mg, 72%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([CH3:7])(=[O:6])=[O:5].Cl[C:9]1[N:14]=[C:13]([C:15]2[S:19][C:18]([CH:20]([CH3:22])[CH3:21])=[N:17][C:16]=2[C:23]2[CH:24]=[C:25]([NH:29][S:30]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:12]=[CH:11][N:10]=1>>[CH3:22][CH:20]([C:18]1[S:19][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:1][CH2:2][CH2:3][S:4]([CH3:7])(=[O:6])=[O:5])[N:14]=2)=[C:16]([C:23]2[CH:24]=[C:25]([NH:29][S:30]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[N:17]=1)[CH3:21]
Reactant: CS(=O)(=O)CCN
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using 2-aminoethyl-methyl-sulfone (391 mg, 3.18 mmol) and N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-pyridinesulfonamide (150 mg, 0.318 mmol) the title compound was obtained as a white foam (72 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (s, 1H) 8.84 (d, J=1.8 Hz, 1H) 8.76 (dd, J=4.8, 1.3 Hz, 1H) 8.02-8.13 (m, 2H) 7.58 (dd, J=7.9, 4.8 Hz, 1H) 7.46 (t, J=5.3 Hz, 1H) 7.32 (t, J=8.2 Hz, 1H) 7.12-7.27 (m, 3H) 5.98-6.16 (m, 1H) 3.64 (dd, J=2.4, 1.3 Hz, 2H) 3.31-3.37 (m, 2H) 3.16-3.29 (m, 1H) 2.99 (s, 3H) 1.33 (d, J=6.9 Hz, 6H). MS (ESI): 559.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:21]=1[CH:22]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:21]=1/[CH:22]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(C(F)(F)F)ccc1Cl)C2=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a solution of 6-methoxy-5-morpholino-2, 3-dihydro-1H-inden-1-one 13 (0.120 mg, 0.485 mmol) in toluene (10 mL) was added 2-chloro-5-(trifluoromethyl)benzaldehyde 75 (0.101 mg, 0.485 mmol). PTSA (0.184 mg, 0.971 mmol) was added to the reaction mass, reaction stirred at 100° C. for 6 h, diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 157 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 15% ethyl acetate in hexane to afford yellow coloured solid (E)-2-(2-chloro-5-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2, 3-dihydro-1H-inden-1-one 157.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[NH:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:24]=2[N:23]=[CH:22]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:30]([C:28]3[CH:27]=[CH:26][C:25]4[N:21]=[CH:22][NH:23][C:24]=4[CH:29]=3)=[O:31])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc2nc[nH]c2c1

Procedure:
3H-Benzoimidazole-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1H-benzimidazole-5-carboxylic acid. MS calcd. for C24H18ClN4O2 [(M+H)+] 429.1, obsd. 429.0.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([OH:15])=[O:14])=[O:7])=[CH:4][CH:3]=1.[CH3:18]OC(OC)(C)C.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([O:15][CH3:18])=[O:14])=[O:7])=[CH:16][CH:17]=1
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of trans-2-(4-bromobenzoyl)cyclopentanecarboxylic acid (2.0 g, 6.26 mmol) in MeOH (70 mL) was added 2,2-dimethoxypropane (1.63 g, 15.65 mmol) and HCl (4.0 M in dioxane) (1.0 mL). The resulting solution was stirred at 40° C. overnight and then evaporated to dryness. The resulting residue was purified by flash chromatography (Biotage Flash 40M) using 7 to 11% ethyl acetate in hexanes to afford methyl trans-2-(4-bromobenzoyl)cyclopentanecarboxylate (1.62 g, 83%). 1H NMR (400 MHz, CD2Cl2) δ 1.70–1.95 (m, 4H), 2.08–2.21 (m, 2H), 3.40 (m, 1H), 3.64 (s, 3H), 4.04 (m, 1H), 7.64 (m, 2H), 7.86 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)[C:49]([CH3:51])([CH3:50])[CH:48]2[OH:52])=[O:21])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2cc(F)cc(F)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(F)cc(F)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.8 %

Procedure:
To a mixture of 4-{[1-(3,5-difluoro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (4.27 g, 14.8 mmol) and ytterbium(III) triflate hydrate (0.92 g, 1.48 mmol) in dry tetrahydrofuran (50 mL) at 25° C. was added isobutyraldehyde (1.34 mL, 14.8 mmol) and water (0.27 mL, 14.8 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3,5-difluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (5.34 g, 100%) as a light yellow oil: LC/MS m/e calcd for C20H21F2NO3 M+: 361.4, observed: 344.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.[S:13]1CC(O)S[CH2:15][CH:14]1O.C(NCC)C>C(O)C>[NH2:11][C:10]1[S:13][CH:14]=[CH:15][C:9]=1[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:12]
Reactant: N#CCC(=O)c1ccc(F)cc1
Reactant: OC1CSC(O)CS1
Solvent: CCO
Solvent: CCNCC
Product: Nc1sccc1C(=O)c1ccc(F)cc1
Temperature: 50 °C
Yield: 86.2 %

Procedure:
Following a procedure described in J. Med. Chem. 2002, 45, 382-389; 0.44 g (2.7 mmol) 3-(4-fluoro-phenyl)-3-oxo-propionitrile (the preparation of which is described in example 17), 0.33 g (2.15 mmol) [1,4]dithiane-2,5-diol, 0.16 ml (2.15 mmol) diethyl-amine and 5 ml ethanol were charged in a sealed tube. The reaction mixture was heated at 50° C. for 6 h. The tube was then placed in a fridge (about 4° C.) for the night, and the product was collected by filtration and dried under vacuum to afford 0.41 g (69%) (2-amino-thiophen-3-yl)-(4-fluoro-phenyl)-methanone as a light brown crystals.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32](OC(F)(F)F)=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:40][S:41](C1C=CC(B(O)O)=CC=1)(=[O:43])=[O:42]>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32]([S:41]([CH3:40])(=[O:43])=[O:42])=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(S(C)(=O)=O)cc2)CC1

Procedure:
(R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(methylsulfonyl)phenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one was synthesized as per (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (Example 220) in 86% yield using 4-methanesulfonyl phenylboronic acid as the reagent (0.0997 g, 0.000498 mol).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:12])[CH:3]=1.O=S(Cl)Cl.[CH3:17]O>>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Br)cc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(F)c(Br)cc1Cl
Temperature: 0 °C
Reaction time: 72 h
Yield: 95 %

Procedure:
4-bromo-2-chloro-5-fluorobenzoic acid (Apollo PC9723, 5 g; 19.73 mmol; 1 eq.) was dissolved in MeOH (100 mL). The solution was cooled down to 0° C. SOCl2 (4.29 mL; 59.18 mmol; 3 eq.) was added dropwise (addition took 15 min and IT increased to 9° C.). The reaction mixture was stirred at RT for 3 days. The reaction mixture was concentrated and the crude mixture was dissolved in EtOAc (200 mL) and washed with a saturated aqueous solution of NaHCO3(50 mL), brine (50 mL), dried over MgSO4 and concentrated affording the title compound as a white solid (5.04 g, 95%). 1H NMR (DMSO-d6, 300 MHz) δ 8.10-8.08 (d, J=6.30 Hz), 1H), 7.86-7.83 (d, J=8.82 Hz, 1H), 3.87 (s, 3H). HPLC (Method A) Rt 4.32 min (Purity: 99.7%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[C:8](=O)[N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5].CO>C1COCC1>[CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8][N:7]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[O:5]
Reactant: CCOC(=O)[C@@H]1CCC(C)C(=O)N1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)[C@@H]1CCC(C)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
To a solution of (S)-5-methyl-6-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (10 g, 35 mmol) in THF (150 mL) was added borane dimethylsulfide complex (49 mL, 49 mmol). The reaction mixture was stirred at 0° C. for 1 h, and then stirred at 40° C. for 3 h. Methanol was added and the reaction mixture was concentrated, washed with 1 M HCl, and extracted with EtOAc/water to give the oil layer, which was dried, and concentrated. The crude product was purified by silica gel chromatography (20:1 petroleum ether:EtOAc) to provide the title intermediate (2 g, 21% yield). (m/z): [M-100+H]+ calcd for C14H25NO4 172.18 found 172.2.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][O:30][C:31]2[CH:32]=[C:33](CN)[CH:34]=[CH:35][CH:36]=2)[CH2:25][CH2:24]1>CO>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([CH2:14][C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([O:30][CH2:29][CH:26]5[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]5)[CH:36]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:20][CH:19]=1
Reactant: CN1CCC(COc2cccc(CN)c2)CC1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Solvent: CO
Product: CN1CCC(COc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)CC1

Procedure:
5-(4-Chloro-phenyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester (0.165 g, 0.51 mmol) and 1-{3-[(1-methylpiperidin-4-yl)methoxy]phenyl}-methanamine (0.100 g, 0.43 mmol) in MeOH (2 mL) was heated by microwave at 120° C. in 20 minutes, cooled, the formed precipitate filtered off and washed with MeOH to give the title compound as a white solid. Yield: 0.075 g (31%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.58-7.63 (m, 2H), 7.45 (s, 1H), 7.38-7.43 (m, 2H), 7.22 (m, 1H), 6.79-6.91 (m, 3H), 5.17 (s, 2H), 3.76 (d, 2H, J=6.4 Hz), 2.82-2.89 (m, 2H), 2.25 (s, 3H), 1.87-1.96 (m, 2H), 1.76-1.83 (m, 2H), 1.68-1.76 (m, 1H), 1.32-1.44 (m, 2H).