Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]#[C:17][CH3:18])[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]#[C:17][CH3:18])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCC(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC#CCC(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the product from Step C (ca. 51.8 mmol) in THF (100 mL) and water (20 mL) was added at 0° C. a solution of lithium hydroxide monohydrate (6.5 g, 155 mmol). The solution was stirred for 1 hour at 0° C., then warmed to room temperature. After 48 hours, the solution was concentrated in vacuo. The aqueous mixture was extracted with EtOAc, acidified at 0° C. with 10% aq. HCl soln., then extracted with three portions of dichloromethane. The combined dichloromethane extracts were dried (Na2SO4), filtered, and concentrated in vacuo to provide the tilled product as an orange oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=4)[N:22]=3)=[CH:17][CH:16]=2)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+]>>[CH:1]1([CH2:4][NH:5][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:27]=[CH:28][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:30][CH:31]=4)[N:22]=3)=[CH:19][CH:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)CC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(CCNCC4CC4)cc3)n2)cc1

Procedure:
The title compound was prepared from tert-butyl (cyclopropylmethyl)(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)carbamate (CB66), neutralized with aqueous sodium bicarbonate, and isolated as a white solid (0.125 g, 100%): mp 162-166° C.; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.15-8.09 (m, 2H), 7.81-7.75 (m, 2H), 7.38 (dq, J=8.9, 0.9 Hz, 2H), 7.34-7.29 (m, 2H), 3.22 (dd, J=10.2, 6.0 Hz, 2H), 3.09 (dd, J=10.0, 6.1 Hz, 2H), 2.84 (d, J=7.3 Hz, 2H), 1.11 (ddd, J=12.7, 8.1, 4.8 Hz, 1H), 0.86 (dd, J=12.8, 5.8 Hz, 1H), 0.69-0.58 (m, 2H), 0.37-0.29 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 403 ([M+H]+).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C)C=O>[CH3:23][N:14]1[C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]2[CH:10]=[N:9][C:8]([C:5]3[N:4]=[C:3]([CH2:2][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[O:7][N:6]=3)=[C:12]2[CH2:13]1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CN4CCCCC4)n3)ncn2-c2ccccc2C1=O
Yield: 74 %

Procedure:
1.15 g (3.5 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature for 1 hour with 1 g (11.7 mmol) of piperidine and 10 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate/ethanol 9/1 there was obtained 0.98 g (74%) of 5-methyl-3-[5-(piperidin-1-yl)methyl-1,2,4-oxadiazol-3-yl]-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 167°-168°, which was converted into the hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[NH:11][CH2:10][C@H:9]1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>CC#N.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[N:11]([CH2:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:10][C@H:9]1[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN[C@@H](CN2CCCC2=O)CN1C(=O)OC(C)(C)C
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: C[C@@H]1CN(CC(=O)OCc2ccccc2)[C@@H](CN2CCCC2=O)CN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 97.7 %

Procedure:
To (2R,5S)-2-methyl-5-(2-oxo-pyrrolidin-1-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (2.73 g, 9.19 mmol) and potassium carbonate (1.4 g, 10.1 mmol) in MeCN (9.8 mL) was added benzyl bromoacetate (2.11 g, 9.2 mmol) at room temperature. The reaction was stirred at this temperature for 18 h then diluted with chloroform, filtered and the filtrate concentrated. Chromatography (silica gel, gradient elution, 0-60%, EtOAc in petrol 40-60) gave the title compound (4 g). MS: [M+H]+=446.
Reaction SMILES: Br[C:2]1[C:3](=[O:18])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1.[CH2:19](C([Sn])=C(CCCC)CCCC)[CH2:20]CC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:19]=[CH2:20])[C:3]1=[O:18]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1cccn(-c2ccc([N+](=O)[O-])cc2C)c1=O

Procedure:
50 g (162 mmol) of the compound from Example 12A are dissolved in 700 ml of anhydrous dioxane, 62 g (194 mmol) of tributylvinyltin and 4.7 g (4 mmol) of tetrakis(triphenylphosphine)palladium are added and the mixture is heated at reflux for 15 h. The mixture is allowed to cool and filtered through kieselguhr. The filter cake is washed with ethyl acetate and the combined filtrates are evaporated to dryness under reduced pressure. The residue is applied to silica gel and chromatographed on 800 g of silica gel using a gradient of cyclohexane and ethyl acetate. This gives 27 g (62% of theory) of the desired product.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][N:5]=1.[CH2:14]([NH:21][CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.O>[CH2:14]([N:21]([CH2:10][C:9]1[C:4]([CH:3]([O:12][CH3:13])[O:2][CH3:1])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNCc1ccccc1
Reactant: COC(OC)c1ncccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: O
Product: COC(OC)c1ncccc1CN(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.3 %

Procedure:
To a mixture of 2.0 g (11 mmol) of 2-dimethoxymethyl-pyridin-3-carbaldehyde and 1.6 mL (12 mmol) of N-benzyl methyl amine in 30 mL of dichloroethane is added 4.7 g (22 mmol) of sodium triacetoxyborohydride. The reaction is stirred for 18 hours at room temperature. To this mixture is added 20 mL of water. After 1 hour of stirring the pH of the reaction mixture is adjusted to 8.0 with 1N NaOH. The organic layer is separated from the water layer, dried and evaporated to yield 1.9 grams of benzyl-(2-dimethoxymethyl-pyridin-3-ylmethyl)-methyl-amine. 1H NMR (CDCl3) δ8.5 (d, 1H), 7.9 (d, 1H), 7.3 (m, 6H), 5.6 (s, 1H), 3.7 (s, 2H), 3.5 (s, 2H), 3.3 (s, 6H) 2.1 (s, 3H). Mass spectrum: m/e=287.8 (p+1). TLC (1/1 ethyl acetate/hexanes) Rf=0.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[F:20].[I-:21]>S([O-])([O-])(=O)=O.[Ag+2].CO>[F:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[C:16]([I:21])[C:15]([O:18][CH3:19])=[CH:14][C:13]=1[F:20]
Reactant: [I-]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2F)c(F)c1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(I)c(OC)cc2F)c(F)c1

Procedure:
methyl 2,2′-difluoro-4′-methoxybiphenyl-4-carboxylate (585 mg, 2.10 mmol), methanol (10 mL), iodide (534 mg, 2.10 mmol), silver sulfate (655 mg, 2.10 mmol) were stirred at room temperature. LCMS indicated formation of the desired compound. Reaction crude was worked up w/Na2HSO3 (aq., sat.). All volatiles were removed from the resulting mixture. The pot residue was worked up w/Na2SO4/EtOAc/filtration/concentration to afford a light brown solid. The crude solid was purified by flash chromatography (SiO2, Biotage 40+M cartridge). The column was eluted by a 0% to 20% EtOAc/hexanes mixture. 5 major fractions were spilled by accident. The remaining related fractions were pooled and concentrated in vacuo to afford the title compound. LCMS (ESI) calc.=403.97; found=404.92 (M+1)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([CH:9]2[CH2:12][C:11](=C)[CH2:10]2)=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:5]1)([CH3:3])[CH3:2].[OH2:19]>CC#N.[O-]S([O-])(=S)=O.[Na+].[Na+].C(Cl)Cl>[CH:1]([N:4]1[C:8]([CH:9]2[CH2:12][C:11](=[O:19])[CH2:10]2)=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:5]1)([CH3:3])[CH3:2]
Reactant: C=C1CC(c2cc(C(=O)OCC)nn2C(C)C)C1
Reactant: O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1cc(C2CC(=O)C2)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Compound 8c (6.45 g, 26.0 mmol) was dissolved in a mixture of MeCN (77 mL) and water (13 mL) and cooled in an ice-bath. To this solution RuCl3×H2O (0.19 g, 0.86 mmol) was added, followed by portion-wise addition of NaIO4 (19.35 g, 90.9 mmol). An exotherm was observed during this addition. The obtained thick slurry was stirred at rt for 45 min. The reaction mixture was diluted with Na2S2O3 aq. sol. (10%, 260 mL), water (50 mL) and DCM (100 mL). The phases were separated and the aq. phase was extracted with DCM (2×70 mL). The combined organic phases were washed with Na2S2O3 aq. sol. (10%, 50 mL), water (100 mL), brine (100 mL) and dried over anh. Na2SO4. The crude product (6.5 g) was purified on silica, eluting with hexanes/MTBE to give pure product as an oil that solidified upon storage at −20° C. Yield: 5.8 g (78% over two steps). 1H-NMR (DMSO-d6), δ (ppm): 6.78 (s, 1H), 4.57 (h, J=8.0 Hz, 1H), 4.26 (q, J=8.0 Hz, 2H), 3.85-3.75 (m, 1H), 3.58-3.45 (m, 2H), 3.35-3.25 (m, 2H), 1.39 (d, J=8.0 Hz, 6H), 1.28 (t, J=8.0 Hz, 3H).
Reaction SMILES: CO.C([O:10][C:11]1[CH:38]=[C:37]([N:39]([CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])[CH3:40])[CH:36]=[CH:35][C:12]=1[C:13]([NH:15][C:16]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:14])C1C=CC=CC=1>[C].[Pd].C(Cl)(Cl)Cl>[CH3:45][N:43]([CH3:44])[CH2:42][CH2:41][N:39]([CH3:40])[C:37]1[CH:36]=[CH:35][C:12]([C:13]([NH:15][C:16]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:25][C:17]=2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:14])=[C:11]([OH:10])[CH:38]=1
Reactant: CN(C)CCN(C)c1ccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C)CCN(C)c1ccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c(O)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 75 %

Procedure:
To a methanol (3.0 mL) solution of the obtained tert-butyl 2-(2-(benzyloxy)-4-((2-(dimethylamino)ethyl)(methyl)amino)benzamido)-4-phenylbenzoate (0.071 g), 10% palladium-carbon (0.035 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour and 45 minutes. Methanol (2.0 mL) and chloroform (1.0 mL) were added to the reaction mixture, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.045 g of tert-butyl 2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-hydroxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClCCl.[OH-].[Na+].[F:14][C:15]1[C:22]([F:23])=[CH:21][CH:20]=[C:19]([F:24])[C:16]=1[CH2:17]Br>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[NH2:1][C:2]1[C:7]([O:8][CH2:17][C:16]2[C:19]([F:24])=[CH:20][CH:21]=[C:22]([F:23])[C:15]=2[F:14])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1O
Reactant: Fc1ccc(F)c(CBr)c1F
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Nc1ncccc1OCc1c(F)ccc(F)c1F
Reaction time: 0.08 h

Procedure:
A mixture of 2-amino-3-hydroxy pyridine (2.44 g, 0.022 mol), dichloromethane (20 ml) and 40% aqueous sodium hydroxide solution (20 ml) was stirred for five minutes, then 2,3,6-trifluorobenzyl bromide (5.00 g, 0.022 mol) and Adogen 464 (3 ml) were added and stirring continued for 16 hours. The mixture was diluted with water and extracted with dichloromethane. Drying and evaporation of the organic extracts, and trituration with ether gave the desired product. Yield 2.94 g (53%), m.p. 108°-110 ° C.
Reaction SMILES: CCCCC.[H-].[Na+].[NH2:8][C:9]1[C:24]([Cl:25])=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:14])=[C:11]([OH:26])[CH:10]=1.Cl[CH2:28][CH2:29][CH2:30][C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32]>CN(C=O)C.[Cl-].[Na+].O>[NH2:8][C:9]1[C:24]([Cl:25])=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH2:17][N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[O:14])=[C:11]([O:26][CH2:28][CH2:29][CH2:30][C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32])[CH:10]=1
Reactant: CCN(CC)C(=O)CCCCl
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Solvent: O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCCC(=O)N(CC)CC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.8 %

Procedure:
To a well-stirred suspension of pentane-washed sodium hydride (0.52 g of 60%, 3 mmole) in 3 ml dry DMF was added 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (3.43 g, 12 mmoles) (prepared as in Example 53). To this was added 10 ml of DMF and the mixture was stirred at ambient temperature for 45 minutes then warmed to about 50° C. for 15 minutes whereupon 4-chloro-N,N-diethylbutyramide (1.92 g, 11 mmoles) was added. The mixture Was then stirred at 60°-70° C. for 6 hours, at room temperature for 2 days and then at 60°-70° C. for a further 4 hours. After cooling, the mixture was poured into 400 ml of brine and extracted with methylene chloride (4×100 ml). After combining, the organic phase was washed two times with 100 ml of 10% aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil (3.75 g). This was purified by flash chromatography on silica gel to give 1.64 g of the title compound as an oil.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:47]1[CH:52]=[C:51]([O:53][C@@H:54]([C@@H:56]2[CH2:60][O:59][C:58]([CH3:62])([CH3:61])[O:57]2)[CH3:55])[N:50]=[C:49]([S:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[C:66]=2[F:72])[N:48]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:72][C:66]1[C:67]([F:71])=[CH:68][CH:69]=[CH:70][C:65]=1[CH2:64][S:63][C:49]1[N:48]=[C:47]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:52]=[C:51]([O:53][C@@H:54]([C@@H:56]2[CH2:60][O:59][C:58]([CH3:61])([CH3:62])[O:57]2)[CH3:55])[N:50]=1
Reactant: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Reactant: CS(N)(=O)=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(NS(C)(=O)=O)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of methane sulfonamide (0.25 g), tris(dibenzylideneacetone)dipalladium (0) (55 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (29 mg), cesium carbonate (0.30 g) and 4-chloro-2-[(2,3-difluorobenzyl)thio]-6-{(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy}pyrimidine (the product of Example 47, step i) (0.25 g) in dioxane (5 ml). The crude material was purified by column chromatography using EtOAc/isohexane (2:8) as eluent to give the subtitle compound as a yellow oil. Yield: 0.25 g.
Reaction SMILES: [Na].[F:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([OH:20])=O)[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1.Cl.CN(C)CCCN=C=NCC.[CH3:33][C@H:34]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35]1>N1C=CC=CC=1.CN(C)C=O.O>[F:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([N:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:42][C@@H:34]3[CH3:33])=[O:20])[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1
Reactant: O=C(O)Cc1nc(N2CCOC(CF)C2)cc(=O)[nH]1
Reactant: C[C@H]1Cc2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOC(CF)C2)cc(=O)[nH]1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
In a three-necked flask under argon, 0.5 g of the sodium salt of [4-(2-fluoromethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid previously obtained (example 30b, step 3b) is placed in 7 ml of pyridine and 7 ml of dimethylformamide, and then N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride is added at ambient temperature, followed by 0.25 g of (S)-2-methylindoline (CAS 22160-09-4). The reaction medium is stirred at ambient temperature (20° C.) for 72 hours. 25 ml of water are added, extraction is carried out with 3 times approximately 25 ml of dichloromethane, washing is carried out with 25 ml of water, washing is carried out with twice approximately 15 ml of 1M hydrochloric acid solution, washing is carried out with 25 ml of water, washing is carried out with 25 ml of saturated NaCl solution, drying is carried out over MgSO4, filtration is carried out through a VF filter, and the resulting product is concentrated under vacuum. The compound obtained is chromatographed on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and ethanol (95/5, v/v). The fractions containing the expected compound are combined and evaporated. The compound obtained is triturated from 1 ml of dichloromethane and 10 ml of diisopropyl ether, filtered, and dried at ambient temperature (20° C.). (+)-6-(2-Fluoromethylmorpholin-4-yl)-2-[2-((S)-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-3H-pyrimidin-4-one is isolated (0.315 g).
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.N([O-])=O.[Na+].[BrH:18]>O.[Cu]Br>[Br:18][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the cooled and vigorously stirred suspension of 4-amino-2-(trifluoromethyl)benzonitrile (5.00 g, 26.8 mmol) in 25 ml of concentrated hydrogen bromide a solution of sodium nitrite (1.85 g, 26.8 mmol) in 10 ml of water was added dropwise while keeping the temperature below 5° C. during the addition. This mixture was then poured into a solution of copper(I)bromide (3.85 g, 26.8 mmol) in 30 ml of concentrated hydrogen bromide and stirred at RT for two hours. The reaction mixture was then poured into an ice-water (300 ml) mixture and extracted four times with ethyl acetate. The combined extracts were washed with saturated sodium bicarbonate and water, dried and evaporated to dryness. Combiflash purification using heptane/ethyl acetate as eluent system afforded 5.1 g of the title product. 1H-NMR (400 MHz; d6-DMSO): δ 8.13 (d, 1H), 8.18 (d, 1H), 8.27 (s, 1H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.[Li]CCCC.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17]>C1COCC1>[F:9][C:4]1[CH:3]=[C:2]([Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:7]=[CH:6][C:5]=1[NH2:8]
Reactant: C[Si](C)(C)Cl
Reactant: Nc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(N)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
To a solution of 4-bromo-2-fluoro-phenylamine (114 g, 0.6 mol) in anhydrous THF (750 mL) at −78° C. was added a 1.6M solution of nBuLi in hexanes (1500 mL, 2.4 mol) dropwise keeping the internal temperature below −60° C., under an inert atmosphere. The reaction mixture was treated dropwise with TMSCl (256 mL, 2.0 mol), keeping the internal temperature below −60° C. The reaction mixture was allowed to warm to 0° C. over a 1 hour period and poured into ice-cold 2M HCl (ca. 1 L). The mixture was vigorously stirred for 10 min, then the organic layer was separated, and washed with water and a saturated solution of potassium carbonate, dried (Na2SO4), filtered and concentrated to give the title compound as a light brown oil (89 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH:7]=[CH:6]2.[BH4-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:7][CH2:6]2
Reactant: COc1cccc(-c2ccc3cc(OC)ccc3n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(C2CCc3cc(OC)ccc3N2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 6-methoxy-2-(3-methoxy-phenyl)-quinoline (96 mg, 0.36 mmol) in EtOH (3 mL) at 0° C. is added NiCl2·6H2O (86 mg, 0.36 mmol). The reaction mixture is stirred for 30 min before the addition of NaBH4 (55mg, 1.45 mmol). The mixture is stirred for 16 h while warming to room temperature. An additional portion of NaBH4 (50 mg) is then added and stirring is continued for 3 h. The solvent is removed in vacuo and the resulting residue is partitioned between water and CH2Cl2. The organic phase is washed with water and brine, dried over MgSO4, filtered and concentrated. Flash chromotography (0–50% EtOAc/hexanes) yields 6-methoxy-2-(3-methoxy-phenyl)-1,2,3,4-tetrahydro-quinoline.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14]2[CH:15]=[CH:16][C:17]([CH2:23][CH2:24]C(OC)=O)=[C:18]([C:19]([O:21]C)=O)[C:13]=2[N:12]=[C:11]1[CH3:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[OH-].[Na+]>O1CCCC1.CO>[CH2:3]([N:10]1[C:14]2[CH:15]=[CH:16][C:17]3[CH2:23][CH2:24][C:19](=[O:21])[C:18]=3[C:13]=2[N:12]=[C:11]1[CH3:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CCc1ccc2c(nc(C)n2Cc2ccccc2)c1C(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c3c(ccc2n1Cc1ccccc1)CCC3=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a suspension of 60% sodium hydride (33 mg, 0.81 mmol) in tetrahydrofuran (5 mL) were added a solution of methyl 1-benzyl-5-(3-methoxy-3-oxopropyl)-2-methyl-1H-benzimidazole-4-carboxylate (148 mg, 0.40 mmol) in tetrahydrofuran (3 mL) and methanol (1 drop), and the mixture was heated under reflux for 2.5 hr. The reaction solution was concentrated to dryness to give yellow-brown crystals. The obtained crystals were gradually added to 12M hydrochloric acid (3 mL) heated to 100° C., and the mixture was stirred for 2 hr. The reaction solution was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (62 mg, yield 56%).