Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9]>C1(C)C=CC=CC=1.CO.[Pd]>[OH:1][C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(O)c2c(-c3ccc(C#CCCCO)cc3)csc2[nH]c1=O
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Product: N#Cc1c(O)c2c(-c3ccc(CCCCCO)cc3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of Pd (BaSO4) (15 mg) in toluene (2 mL) and methanol (1 mL), was added 4-hydroxy-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (50 mg) in a single portion. The reaction was purged with hydrogen, and stirred under atmosphere hydrogen at rt for 24 h. The mixture was filtered through celite, and rinsed with methanol. The filtrate was concentrated and purified via reverse phase HPLC to afford the titled compound. MS (ESI) m/e 353 (M−H)+; 1H NMR (500 MHz, DMSO-d6): δ 1.31–1.47 (m, 4H), 1.55–1.61 (m, 2H), 1.94 (t, J=7.64 Hz, 2H), 2.58 (t, J=7.64 Hz, 2H), 6.91 (s, 1H), 7.15 (d, J=8.11 Hz, 2H), 7.31 (d, J=8.11 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20]CC4C=CC=CC=4)[CH:18]=3)[C:13]([C:28]#[N:29])=[CH:12]2)=[CH:7][C:6]=1[O:30][CH2:31][O:32][CH3:33])[CH3:2].C(OCC)(=O)C>[C].[Pd].CO>[CH2:1]([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=3)[C:13]([C:28]#[N:29])=[CH:12]2)=[CH:7][C:6]=1[O:30][CH2:31][O:32][CH3:33])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(OCc4ccccc4)cc32)cc1OCOC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(O)cc32)cc1OCOC
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(6-benzyloxy-3-cyanoindol-1-yl)-2-methoxymethoxybenzoic acid ethyl ester in a mixed solvent of ethyl acetate (60 mL) and methanol (60 mL) was added palladium-carbon powder (0.61 g) under argon atmosphere at 0° C. and this mixture was stirred at 40° C. under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (2.5 g)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH:15]([CH3:17])[CH3:16])([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[N:19]1([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(O)(=O)C>C(O)CCC>[CH:15]([C:10]1([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:31][CH:30]=3)[N:7]=2)[C:9]1=[O:18])([CH3:17])[CH3:16]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CC(C)C1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Solvent: CCCCO
Solvent: CC(=O)O
Product: CC(C)C1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Yield: 35.2 %

Procedure:
A solution of 1-(2-chloropyrimidin-4-yl)-3-isopropyl-2-oxopyrrolidine-3-carbonitrile (100 mg) obtained in Step C, 4-(morpholin-4-yl)aniline (77 mg) and acetic acid (25 jL) in 1-butanol (2 mL) was stirred in a microwave reactor at 160° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/ethyl acetate) to give the title compound (54 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:16]1[CH:17]=[CH:18][CH:19]=[N:20][C:15]=1[C:5]1([CH2:3][OH:2])[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1
Reactant: COC(=O)C1(c2ncccn2)CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(c2ncccn2)CCC2(CC1)OCCO2
Temperature: -45 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a solution of 8-pyrimidin-2-yl-1,4-dioxa-spiro[4,5]decane-8-carboxylic acid methyl ester (1.02 g, 3.67 mmol) in THF (15 mL) was added LAH (1.0 M in Et2O, 3.67 ml, 3.67 mmol) dropwisely at −45° C. for 10 min. After being stirred at −45° C. for 3 h, the reaction was quenched by adding H2O (150 μL), 15% aqueous NaOH (150 μL), and H2O (450 μL) successively and stirred at 25° C. for 1 h. The resulting inorganic gel was removed by filtration and the filter cake was rinsed with EtOAc. The combined filtrates were then concentrated under reduced pressure and purification of the residue by flash chromatography (SiO2, 90-100% EtOAc/Hexanes, gradient elution) gave (8-pyrimidin-2-yl-1,4-dioxa-spiro[4,5]dec-8-yl)-methanol (518 mg, 2.07 mmol, 56%) as a colorless liquid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)=[CH:16][C:15]([O:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:14][CH:13]=2)(C)(C)C.[ClH:37]>C(OCC)(=O)C>[ClH:37].[NH2:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1)=[CH:16][C:15]([O:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:14][CH:13]=2
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c3ccc(OCC(N)=O)cc23)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(CN)n(CC(C)C)c(=O)c3ccc(OCC(N)=O)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
Tert-butyl[6-(2-amino-2-oxoethoxy)-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.15 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml) and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-[[3-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamide hydrochloride (0.11 g, 91.7%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([NH:18][C:19](=[O:25])[C:20]([O:22]CC)=[O:21])=[CH:13][C:12]=2[CH3:26])=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([NH:18][C:19](=[O:25])[C:20]([OH:22])=[O:21])=[CH:13][C:12]=2[CH3:26])=[CH:32][CH:33]=1
Reactant: CCOC(=O)C(=O)Nc1cc(C)c(Cc2ccc(OC)c(Cc3ccc(F)cc3)c2)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1ccc(Cc2c(C)cc(NC(=O)C(=O)O)cc2C)cc1Cc1ccc(F)cc1
Reaction time: 2.5 h

Procedure:
290 mg (0.64 mmol) of ethyl ({4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylphenyl-}amino)(oxo)acetate (Example 3) in 8 ml of dichloromethane at −78° C. under argon are treated slowly with 356 mg (1.41 mmol) of BBr3. The mixture is allowed to fall to room temperature and is stirred for 2.5 h. The reaction mixture is poured into buffer of pH 7, the organic phase is separated off, and the pH of the aqueous phase is adjusted to pH 7 and it is then extracted. The combined organic phases are washed with saturated NaCl solution, dried and concentrated in a rotary evaporator. The residue is stirred with diethyl ether, filtered off with suction and dried.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.Br[C:20]1[S:21][CH:22]=[C:23](Br)[N:24]=1>>[CH3:18][C:4]1[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:12][CH:13]=2)[CH:7]=[C:2]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[N:3]=1
Reactant: Brc1csc(Br)n1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(I)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nccs2)n1

Procedure:
The title compound was prepared from 2-iodo-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example A.31) (4.0 g, 9.36 mmol) and commercially available 2,4-dibromothiazole (2.53 g, 10.4 mmol) according to the general procedure IVc protocol b. Obtained as a side product as a light yellow solid (0.065 g, 2%). MS (ISP) 321.2 [(M+H)+]; mp 103° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C@@H:21]([C:41]3[O:45][N:44]=[C:43]([C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)[N:42]=3)[CH2:22][C:23]3[CH:31]=[C:30]([CH3:32])[C:29]4[C:25](=[CH:26][N:27](COCC[Si](C)(C)C)[N:28]=4)[CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.FC(F)(F)C(O)=O.C(Cl)Cl>>[O:1]=[C:2]1[C:11]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C@@H:21]([C:41]3[O:45][N:44]=[C:43]([C:46]4[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=4)[N:42]=3)[CH2:22][C:23]3[CH:24]=[C:25]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[NH:28][N:27]=[CH:26]4)=[O:19])[CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)c2nc(-c3ccc(F)cc3)no2)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)c2nc(-c3ccc(F)cc3)no2)cc2cn[nH]c12
Yield: 64.8 %

Procedure:
A stirred solution of (R)-1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethyl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (16.2 mg, 0.0224 mmol) in 1:1 trifluoroacetic acid/methylene chloride 91 mL) was stirred at room temperature for 2 h. Removal of the solvents in vacuo followed by purification using preparative HPLC afforded a tan gum (8.6 mg, 65%). 1H-NMR (CDCl3, 400 MHz) δ 8.22 (s, 1H), 8.12-8.01 (m,2H), 7.80 (s, 1H), 7.76-7.45 (m, 5H), 7.35-7.45 (m, 2H), 7.30 (s,1H), 7.20-7.07 (m,2H), 6.28-6.15 (m,1H), 4.42-4.25 (m,2H), 3.57-3.45 (m,2H) 3.31-2.85 (m, 4H), 2.60 (s,3H), 2.09-1.88 (m,2H), 1.70-1.53 (m,2H). Mass spec. 593.28 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:17]=[CH:16][C:9]2[NH:10][C:11](=[O:15])[CH2:12][S:13](=[O:14])[C:8]=2[CH:7]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:17]=[CH:16][C:9]3[NH:10][C:11](=[O:15])[CH2:12][S:13](=[O:14])[C:8]=3[CH:7]=2)[CH2:31][CH2:30]1
Reactant: c1ccc2nc(CN3CCNCC3)ccc2c1
Reactant: O=C1CS(=O)c2cc(OCCCCl)ccc2N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CS(=O)c2cc(OCCCN3CCN(Cc4ccc5ccccc5n4)CC3)ccc2N1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture consisting of 7-(3-chloropropoxy)-3,4-dihydro-2H-1,4-benzothiazin-3-one-1-oxide (2.02 g, 7.38 mmol), N-(2-quinolylmethyl)piperazine (2.52 g, 11.07 mmol), potassium carbonate (2.04 g, 14.76 mmol), potassium iodide (2.45 g, 14.76 mmol) and DMF (50 ml) was stirred at 80° C. for 4 hours. The solvent was distilled off from the reaction mixture under reduced pressure, followed by the addition of water. The resulting mixture was extracted with chloroform-methanol (10:1). The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column while using chloroform-ammonia-saturated methanol (10:1) as an eluent. Fractions containing the target compound were collected and then concentrated under reduced pressure, whereby 1.23 g of the title compound was obtained as a yellow oil (4.49 mmol, 60.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[CH:17]=O.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[CH2:17][NH:22][CH:19]1[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: O=Cc1cc(CNC(=O)CC(F)(F)F)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(CC(F)(F)F)NCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A mixture of N-(4-chloro-3-formyl-benzyl)-3,3,3-trifluoro-propionamide (840 mg, 3.00 mmol) and cyclopropylamine (0.320 mL, 4.51 mmol) in MeOH (30 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt. NaBH4 (170 mg, 4.51 mmol) was added in portions. The mixture was stirred for 1 h, and the solvents were removed under reduced pressure. The residue was diluted with EtOAc, and the resulting mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 90:10) yielded the title compound (929 mg, 96%). LC-MS: tR=0.64 min; ES+: 321.05.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH3:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:30]=[O:31]>>[CH2:1]([O:8][C:9]1[C:13]([CH:30]=[O:31])=[C:12]([CH3:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)nn1-c1ccccc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)c(OCc2ccccc2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-5-methyl-1-phenyl-1H-pyrazole (5.1 g) in N,N-dimethylformamide (30 mL) was added phosphorus oxychloride (2.2 mL) at 80° C., and the mixture was stirred for 1 hour. After cooling to room temperature, the reaction mixture was poured into 1 mol/L aqueous sodium hydroxide solution. The mixture was extracted with diethyl ether, and the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane) to give the title compound (4.6 g).
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1)(C)(C)C>Cl.O1CCOCC1.C(Cl)Cl>[CH3:17][NH:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:22])=[O:5])=[O:21])=[CH:11][C:12]=1[N+:18]([O-:20])=[O:19]
Reactant: CNc1ccc(C(=O)NCC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1ccc(C(=O)NCC(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
(4-Methylamino-3-nitro-benzoylamino)-acetic acid (800 mg) was prepared starting from (4-methylamino-3-nitro-benzoylamino)-acetic acid tert-butyl ester (1.2 g) in 4 M HCl-dioxane (2 mL) and DCM (2 mL). The reaction was stirred at room temperature for 8 h. The solvent was evaporated to isolate pure compound without any further purification.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[CH:6]([N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:7]>>[CH:6]([N:8]1[C:9]2[CH:10]=[C:11]([S:2]([OH:5])(=[O:4])=[O:3])[CH:12]=[CH:13][C:14]=2[S:15][C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:7]
Reactant: O=S(=O)(O)Cl
Reactant: O=CN1c2ccccc2Sc2ccccc21
Product: O=CN1c2ccccc2Sc2ccc(S(=O)(=O)O)cc21
Temperature: 20 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
Into a reactor, equipped with mechanical stirrer and thermometer, chlorosulfonic acid (17.49 g) and, slowly under stirring, N-formyl-phenothiazine (7.5 g) were charged, under nitrogen at 20° C. The reaction mixture was left under stirring at 20° C. for 3 hours. The HPLC analysis showed the formation of N-formyl-phenothiazine-2-sulfonic acid (75% yield).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:13]([NH2:14])=[CH:12][CH:11]=[N:10]1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]2[C:25]([O:27][C:28](=O)[C:16]=12)=[O:26]>C1(C)C=CC=CC=1>[CH3:8][N:9]1[C:13]([N:14]2[C:28](=[O:27])[C:16]3[CH:15]=[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]4=[CH:18][C:17]=3[C:25]2=[O:26])=[CH:12][CH:11]=[N:10]1
Reactant: O=C1OC(=O)c2cc3ccccc3cc21
Reactant: Cn1nccc1N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1nccc1N1C(=O)c2cc3ccccc3cc2C1=O
Temperature: 25 °C
Yield: 87.6 %

Procedure:
Triethylamine (1.10 mL) was added to a toluene (14 mL) suspension that contained 1-methyl-1H-pyrazol-5-amine (400 mg) and 2,3-naphthalenedicarboxylic anhydride (816 mg), and the obtained solution was then heated to reflux for 2 hours. Thereafter, the reaction solution was cooled to a room temperature, and the precipitated solid was then collected by filtration. The collected solid was washed with ethyl acetate, so as to obtain the title compound (1.00 g) in the form of a colorless solid.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>>[C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([O:14][CH2:23][CH3:24])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc(C(=O)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 0.05 h

Procedure:
A 100-mL round bottom flask was charged with of 3-benzoylbenzoic acid (2.20 g, 9.7 mmol), ethanol (40 mL), and sulfuric acid (3 mL). The reaction mixture was heated at 100° C. for 15 h, poured into ice water and extracted twice with Et2O. The combined organic phase was washed with satd aq NaHCO3 and dried over K2CO3. The crude ethyl 3-benzoylbenzoate was used in the next step without further purification. LC-MS (3 min) tR=1.87 min in 3 min chromatography, m/z 255 (MH+). 1H NMR (400 MHz, CDCl3) δ 8.45-8.44 (m, 1H), 8.28-8.25 (m, 1H), 8.00-7.97 (m, 1H), 7.82-7.79 (m, 2H), 7.64-7.48 (m, 4H), 4.40 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:11])[C:6](=[O:16])[NH:5]1)[CH:2]=[CH2:3].C1C[O:27]CC1>>[CH3:13][C:12]([CH3:14])([CH3:15])[C@@H:10]([N:7]1[CH2:8][CH2:9][C@@:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH2:1][CH2:2][CH2:3][OH:27])[NH:5][C:6]1=[O:16])[CH3:11]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)N1
Reactant: C1CCOC1
Product: C[C@H](N1CC[C@](CCCO)(c2ccc(F)cc2)NC1=O)C(C)(C)C
Reaction time: 2 h
Yield: 12 %

Procedure:
To a solution of (R)-4-allyl-1-((S)-3,3-dimethylbutan-2-yl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (100 mg, 0.31 mmol) in THF (3 mL) was added BH3 THF (1 mL, 1 mol/L) at 0° C. under nitrogen atmosphere. The formed mixture was stirred for 2 h. The reaction was quenched with water. Aqueous NaOH solution (3 mol/L, 0.2 mL) and H2O2 (30%, 0.2 mL) were added and the resulting mixture was stirred for 1.5 h. The mixture was extracted with ethyl acetate and the combined organic phase was concentrated to give the crude product, which was purified by preparative TLC to give (R)-1-((S)-3,3-dimethylbutan-2-yl)-4-(4-fluorophenyl)-4-(3-hydroxypropyl)tetrahydropyrimidin-2(1H)-one (12 mg, 12%). 1H NMR (CDCl3): 0.73 (s, 3H), 1.04 (d, 3H), 1.29 (m, 1H), 1.48 (m, 1H), 1.81-2.07 (m, 4H), 2.46 (s, 1H), 2.57 (m, 1H), 3.07 (m, 1H), 3.58 (m, 1H), 4.46 (m, 1H), 5.93 (s, 1H), 6.98-7.03 (m, 2H), 7.29 (m, 2H).
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[Cl:9][C:10]1[C:11]([F:22])=[C:12]([CH:19]=[CH:20][CH:21]=1)[CH2:13][C:14]1[NH:18][CH:17]=[N:16][CH:15]=1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:36])=CC=1>C1COCC1.O>[Cl:9][C:10]1[C:11]([F:22])=[C:12]([CH:19]=[CH:20][CH:21]=1)[CH2:13][C:14]1[NH:18][C:17](=[S:36])[NH:16][CH:15]=1
Reactant: Fc1c(Cl)cccc1Cc1cnc[nH]1
Reactant: S=C(Cl)Oc1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1c(Cl)cccc1Cc1c[nH]c(=S)[nH]1
Reaction time: 3 h

Procedure:
A solution of 5-(3-chloro-2-fluoro-benzyl)-1H-imidazole fumaric acid salt (Intermediate B3) (0.24 mmol) in THF (3 mL) and water (3 mL) was treated with NaHCO3 (0.12 g) at rt for 10 m. Phenyl chlorothionoformate (0.11 mL, 0.6 mmol) was added and stirring was continued for 3 h. The mixture was diluted with water (10 mL) and extracted with ether (3×15 mL). The organic portions were combined, dried over MgSO4, filtered and freed of solvent. The residue was dissolved in MeOH (5 mL) and treated with NEt3 (0.3 mL) for 16 h. The solvent was removed under vacuum and the product was washed on a glass frit with CH2Cl2 to give a white solid, 4-(3-chloro-2-fluoro-benzyl)-1,3-dihydro-imidazole-2-thione (Compound 2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1O>>[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1
Reactant: Oc1ccc(F)cc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(F)cc3F)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2,4-difluorophenol: ESMS m/e: 511.1 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:18]([CH3:34])=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[C:25]([F:33])[CH:24]=3)=[CH:21][CH:22]=2)=[CH:11][C:10]=1[CH3:35])([CH3:7])[CH3:6])C.[OH-].[Na+]>C1COCC1.CCO>[F:33][C:25]1[CH:24]=[C:23]([C:20]2[N:19]=[C:18]([CH3:34])[C:17]([CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:36])=[O:3])=[C:10]([CH3:35])[CH:11]=3)=[CH:22][CH:21]=2)[CH:28]=[CH:27][C:26]=1[C:29]([F:31])([F:32])[F:30]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)c(F)c3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)c(F)c3)nc2C)ccc1OC(C)(C)C(=O)O
Reaction time: 2 h

Procedure:
0.214 g (0.423 mmol) of the above prepared 2-{4-[6-(3-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyridin-3-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester was dissolved in 0.85 ml of THF/EtOH=1/1, treated with 1.27 ml (3 eq.) of 1N NaOH and kept at ambient temperature for 2 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase extracted again with AcOEt; the combined organic layers were washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Recrystallisation from AcOEt/hexane yielded finally 0.191 g of the title compound as white crystals of mp. 175–76°C.
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][CH:9]=1>[Pd].C(O)C>[CH3:15][O:14][C:12](=[O:13])[CH2:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][C:2](=[O:1])[CH3:16])[CH:5]=1
Reactant: COC(=O)/C=C/c1cccc(CC(C)=O)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1cccc(CC(C)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of methyl (2E)-3-[3-(2-oxopropyl)phenyl]acrylate (5.00 g, Preparation 138) and 10% palladium on carbon (500 mg) in ethanol (50 ml) was stirred under an atmosphere of hydrogen (60 psi) at room temperature for 16 hours. The catalyst was filtered off through arbocel and the filtrate concentrated in vacuo to give the title compound as a pale yellow oil which was used without further purification.