Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[C:8]1(=[O:18])[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>C(Cl)(Cl)Cl>[S:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[CH2:2][NH:1][C:8](=[O:18])[C:9]1[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:11]([OH:13])=[O:12]
Reactant: NCc1cccs1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccccc1C(=O)NCc1cccs1
Yield: 82.5 %

Procedure:
A solution of 2-aminomethyl-thiophene (2.1 ml, 20.5 mmol) in CHCl3 (25 ml) is treated with phthalic anhydride (3.0 g, 20.5 mmol) at r.t. for 5 min, then at reflux for 20 min, whereupon a white powder precipitated out. This powder is collected by filtration and dried in vacuo to give N-thiophen-2-ylmethyl-phthalamic acid (4.42 g, 83%) as white crystals. An aliquot of this phthalamic acid (2.13 g, 8.12 mmol) is dissolved in MeOH (12 ml), treated with H2SO4 (440 μl, 8.25 mmol) and heated to reflux for 1.5 h, whereupon a white powder precipitated out. This powder is collected by filtration and dried in vacuo to give 1.38 g (70%) of the title phthalimide as white crystals: 1H NMR (DMSO-d6) δ7.92-7.82 (m., 4H), 7.42 (dd, J=5.1, 1.2 Hz, 1H), 7.08 (dd, J=4.0, 0.8 Hz, 1H), 6.95 (dd, J=5.1, 3.5 Hz, 1H), 4.92 (s, 2H).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([Br:26])[C:24]=1O)[CH:20]=[O:21].O>N1C=CC=CC=1>[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([Br:26])[C:24]=1[O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])[CH:20]=[O:21]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Solvent: c1ccncc1
Solvent: O
Product: O=Cc1cc(Br)c(OS(=O)(=O)C(F)(F)F)c(Br)c1
Reaction time: 1 h

Procedure:
14.73 ml of triflic anhydride is added, under inert gas and at 0° C., to 19.0 g of 3,5-dibromo-4-hydroxy-benzaldehyde in 100 ml of pyridine. Agitation is carried out for 1 hour while allowing the temperature to return to ambient, the reraction medium is poured into water and the aqueous phase is extracted with 3 times 150 ml of dichloromethane. The organic phases are dried and evaporated to dryness under reduced pressure. 23.83 g of crude product is obtained which is purified by filtration chromatography using a cyclohexane/ethyl acetate mixture 1/1 as eluant. In this way 23.83 g of expected product is obtained. Rf: 0.71, cyclohexane/ethyl acetate 1/1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([C:14]2[C@H:23]3[C@H:18]([CH2:19][CH:20]=[CH:21][CH2:22]3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=1.Cl>CN(C)C=O.O>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([C:14]2[C@H:23]3[C@H:18]([CH2:19][CH:20]=[CH:21][CH2:22]3)[C:17](=[O:24])[N:16]([CH2:28][C:29]3[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=3)[N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)c2c1OC(C)(C)C2
Reactant: O=C(O)c1ccc(CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2=NN(Cc3ccc(C(=O)O)cc3)C(=O)[C@H]3CC=CC[C@@H]23)c2c1OC(C)(C)C2
Reaction time: 18 h

Procedure:
To a solution of 0.05 mole of (cis)-4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one (starting compound A12) and 0.15 mole of sodium hydride in 100 ml of dimethylformamide is stirred at RT for 30 min, after which 0.05 mole of 4-chloromethylbenzoic acid is added. This mixture is left stirring for 18 h, after which it is poured into water. This solution is acidified with hydrochloric acid and subsequently extracted with dichloromethane. The organic solution is dried over magnesium sulfate and evaporated. The compound is crystallized from diethyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([S:10][CH3:11])[CH:4]=1.C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[CH2:20]([O:19][C:17]([C:16]1[C:15](=[O:14])[C:8]2[C:6](=[C:5]([S:10][CH3:11])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=2)[NH:7][CH:22]=1)=[O:18])[CH3:21]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)c(SC)c1
Product: CCOC(=O)c1c[nH]c2c(SC)cc(OC)cc2c1=O
Yield: 81.5 %

Procedure:
4-Methoxy-2-methylsulfenylaniline (1.5 g) and diethyl ethoxymethylenemalonate (1.9 g) were reacted in the same manner as in Experimental Example 1 to obtain 3-ethoxycarbonyl-6-methoxy-8-methylsulfenyl-4(1H)-quinolone (2.1 g). The compound (1.3 g) was subjected to hydrolysis and decarboxylation in the same manner as in Experimental Example 2 to obtain 6-methoxy-8-methylsulfenyl-4(1H)-quinolone (compound 30, 0.95 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>CCO>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:23]=1[CH2:24][NH:25][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2ccc([N+](=O)[O-])c(C#N)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
To an ice-cooled solution of 6-chloro-2-cyano-3-nitropyridine (52.0 g, 283 mmol) and triethylamine (43.0 mL, 425 mmol) in EtOH (950 mL) was added dropwise 2,4-dimethoxybenzylamine (53.2 mL, 312 mmol). The reaction was stirred at ambient temperature for 1.5 hours. The precipitate was filtered and washed with petrol to afford 75 g of 6-(2,4-dimethoxy-benzylamino)-3-nitro-pyridine-2-carbonitrile as a yellow solid. NMR 1H NMR (400 MHz, Me-d3-OD): 8.19 (1H, d), 7.24 (1H, d), 6.77 (1H, d), 6.57 (1H, d), 6.49 (1H, dd), 4.56 (2H, s), 3.86 (3H, s), 3.80 (3H, s). MS: [M+H]+=315.
Reaction SMILES: C(COC)OC.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[N:27]=[CH:26][C:25](Br)=[CH:24][N:23]=2)=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[N:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.[F-].[Cs+]>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.CO>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[N:27]=[CH:26][C:25]([C:32]3[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=3)=[CH:24][N:23]=2)=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ncc(Br)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ncc(-c3ccncc3)cn2)CC1

Procedure:
To a mixed solvent of dimethoxyethane (60 ml) and methanol (120 ml) were added 1-(tert-butoxycarbonyl)-4-[(5-bromopyrimidin-2-yl)carbonyl]piperazine (2.97 g), (pyridin-4-yl)boronic acid (1.48 g), cesium fluoride (4.25 g) and tetrakis(triphenylphosphine)palladium (924 mg). After purging with argon, the reaction mixture was refluxed for 19 hours. The solvent was then distilled off under reduced pressure. The residue was purified by moderate-pressure chromatography on a silica gel column (size D, methanol methylene chloride=1:9), whereby the title compound (1.31 g) was obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[CH2:7][CH2:6][CH2:5][C:4]([Cl:9])([F:8])[CH:3]1[OH:10].CC(C)=[O:14]>>[Cl:1][C:2]1([Cl:11])[CH2:7][CH2:6][CH2:5][C:4]([Cl:9])([F:8])[CH:3]1[OH:10].[Cl:1][C:2]1([Cl:11])[CH2:7][CH2:6][CH2:5][C:4]([Cl:9])([F:8])[C:3]1([OH:14])[OH:10]
Reactant: CC(C)=O
Agent: OC1C(F)(Cl)CCCC1(Cl)Cl
Product: OC1(O)C(F)(Cl)CCCC1(Cl)Cl

Procedure:
0.5 g (2.26 mmol) of alcohol 1b in solution in 3 cm3 of acetone were introduced into a 10-cm3 round bottom flask fitted with a condenser and with magnetic stirring. 5 cm3 of the Jones reactant were introduced gently; the reaction was highly exothermic; the reaction mixture was then heated to 45°-50° C. for 16 h (1 cm3 of Jones reactant having been added after 4 h and 2 cm3 after 9 h of reaction). At the end of reaction the Jones reactant was destroyed with 10 cm3 of isopropanol, the mixture was diluted with 10 cm3 of water, extracted with dichloromethane and dried over magnesium sulfate, and the solvents were evaporated off. The material was incorporated onto silica and purified by flash chromatography. 0.16 g of starting alcohol 1b (32%) and 0.30 g of pure diol 3a were isolated, that was a 56% yield of compound 3a (Yld based on the unrecovered alcohol 1b =85%). m.p.=42°-43° C. 1H NMR (CDCl3): 3.75 (s, 1H mobile); 3.60 (s, 1H mobile); 2.70-1.40 (m, 6H). IR in cm-1 (CDCl3): νOH =3540 (very broad). Microanalysis: C6 H8Cl3FO; Th.: % C 30.34 % H 3.39; F.: 30.26 3.15
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:6]2[CH2:12][CH2:13][OH:14].[CH2:22]1[NH:27][CH2:26][CH2:25][N:24]2[C:28](=[O:31])[CH2:29][CH2:30][CH:23]12.C(N(CC)CC)C>C(O)C>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:5]1[N:6]([CH2:12][CH2:13][OH:14])[C:7]2[C:3]([N:4]=1)=[C:2]([N:27]1[CH2:26][CH2:25][N:24]3[C:28](=[O:31])[CH2:29][CH2:30][CH:23]3[CH2:22]1)[N:10]=[C:9]([CH3:11])[N:8]=2
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(CCO)c2n1
Reactant: O=C1CCC2CNCCN12
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(N2CCN3C(=O)CCC3C2)c2nc(-c3ccccc3Cl)n(CCO)c2n1
Temperature: 82.5 °C
Yield: 75618.7 %

Procedure:
Charge a 500 mL three necked round bottomed flask with 2-[6-chloro-8-(2-chlorophenyl)-2-methyl-purin-9-yl]ethanol (13.3 g, 0.0412 mmol) and ethanol (200 mL), followed by 2,3,4,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-6-one (6.365 g, 0.0453 mol) and triethylamine (14.8 mL, 3.5 eq). Heat the mixture to 80-85° C. for 24 h. Cool the reaction to room temperature and concentrate under vacuum to give a yellow solid as the crude product. Purify the crude material by column chromatography, using 400 g of silica gel and eluting with dichloromethane/methanol (50:1), to give the product as a yellow solid (13.3 g). 1H NMR (dmso-d6): δ 7.55-7.41 (m, 4H); 5.72 (bs, 2H); 4.16-3.92 (m, 3H); 3.71 (s, 2H); 3.71-3.68 (m, 1H); 3.02-2.93 (m, 2H); 2.74 (m, 1H); 2.70 (s, 3H); 2.44 (m, 2H); 2.32-2.29 (m, 1H); 1.76-1.69 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[CH2:23][C:22](=[O:24])[N:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH:19]3[C:33]([O:35]C)=[O:34])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]3[CH2:23][C:22](=[O:24])[N:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH:19]3[C:33]([OH:35])=[O:34])(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[O:7])=[CH:37][CH:38]=1
Reactant: CCCCCCCCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc(NC(=O)c3ccc(Cl)cc3)cc2)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCN1CC(C(=O)O)N(S(=O)(=O)c2ccc(NC(=O)c3ccc(Cl)cc3)cc2)CC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
The compound of Example 59 (0.56 g, 0.99 mmol) was dissolved in 8 mL of THF, and 2 mL of 2N NaOH were added dropwise while maintaining the temperature at 0° C. After stirring at room temperature for 2 hours, 20 mL of distilled water were added and a 2N HCl solution was further added to control the pH to 1-2, and then the reactant was extracted with ethyl acetate. The supernatant was collected, and dried and concentrated under reduced pressure, and then recrystallized with ethyl acetate/hexane to obtain a light yellow solid compound (0.15 g, yield 27%).
Reaction SMILES: [BH4-].[Na+].O1CCCC1.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:13]([C:15](O)=[O:16])[CH:14]=1.II>CO>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[C:13]([CH:14]=1)[CH2:15][OH:16]
Reactant: Nc1ccc(N2CCOCC2)c(C(=O)O)c1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(N2CCOCC2)c(CO)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A 50 mL two necked round bottom flask was fitted with a magnetic stirrer bar and a dropping funnel. A suspension of NaBH4 in tetrahydrofuran (100 mg, 2 4 mmol/10 mL) was added, followed by 5-amino-2-morpholinobenzenecarboxylic acid (222 mg, 1.0 mmol) in one portion. A reflux condenser was fitted and the reaction mixture was cooled to 0° C. under nitrogen atmosphere. A solution of iodine in tetrahydrofuran (250 mg, 1.0 mmol/15 mL) was added dropwise to the reaction mixture. After iodine addition was completed and gas evolution had ceased, the reaction mixture was heated at reflux for 6 hours and left stirring at room temperature overnight. Methanol was added slowly until the mixture became clear. The resulting solution stirred at room temperature for 30 minutes then solvent was removed under reduced pressure. The residue was dissolved in 20% KOH (30 mL), stirred for 4 hours and extracted with dichloromethane (3×30 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated to give 5-amino-2-morpholinobenzyl alcohol as an off-white solid (150 mg, 72% yield). 1H NMR (300 MHz, CDCl3) δ 7.05 (d, J=8.7 Hz, 1H), 6.59 (dd, J=8.4, 2.7 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H), 5.51 (br s, 1H), 4.71 (s, 2H), 3.84 (t, J=5.1 Hz, 4H), 3.60 (br s, 2H), 2.91 (t, J=5.1 Hz, 4H). LC-ESI-MS (method B): rt 2.31 min.; m/z 209.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:1]([N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:9][CH2:10][CH2:11][C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=2)=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(Oc2ccc(CCCNCc3ccccc3)cc2)nc1
Reactant: CCCCCBr
Product: CCCCCN(CCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1)Cc1ccccc1

Procedure:
Using a method similar to example 2, using 6-[4-(3-benzylamino-propyl)-phenoxy]-nicotinamide (Step 3, Example 131) and 1-bromopentane gives the title compound: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 8.40 minutes, Purity: 99.8%; mass spectrum (ion spray): m/z=432.3 (M+1).
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[N:6]([CH:16]1[CH2:20][CH:19]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]#[N:36])[CH2:25][CH2:24]2)=[O:22])[N:18]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=2[F:45])[CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15].C(O)(=O)C>CO.[Zn]>[F:45][C:39]1[C:40]([F:44])=[CH:41][CH:42]=[CH:43][C:38]=1[CH2:37][N:18]1[CH2:17][CH:16]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])[CH2:20][CH:19]1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]#[N:36])[CH2:25][CH2:24]1)=[O:22]
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(N(Cc3ccc(F)cc3F)C(=O)OCC(Cl)(Cl)Cl)CN2Cc2cccc(F)c2F)CC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccccc1N1CCN(C(=O)C2CC(NCc3ccc(F)cc3F)CN2Cc2cccc(F)c2F)CC1
Reaction time: 0.5 h
Yield: 7.7 %

Procedure:
{1-(2,3-Difluoro-benzyl)-5-[4-(2-cyano-phenyl)-piperazine-1-carbonyl]-pyrrolidin-3-yl}-(2,4-difluoro-benzyl)-carbamic acid 2,2,2-trichloro-ethyl ester (0.13 mmol) and Zn (0.068 g, 1.04 mmol) was dissolved in MeOH (5 ml), and PH was adjust to 5-6 using acetic acid. The mixture was heated to reflux and stirred for 30 min. After removal of methanol, the residue was purified by HPLC to afford final product (5.5 mg, 0.01 mmol) as yellow oil in 8% yield. MS m/e=552.4 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:33])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].C(N(CC)CC)C>C(Cl)Cl>[C:34]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9](=[O:33])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:16][CH:17]=1)(=[O:36])[CH3:35]
Reactant: CCCCCCCCCCCCCCOc1ccc(COC(=O)NCc2ccccn2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(COC(=O)N(Cc2ccccn2)C(C)=O)cc1
Temperature: 100 °C
Yield: 43.3 %

Procedure:
A mixture of 3.0 g of product from Example 95, 13.5 g of acetic anhydride, 0.081 g of 4-N,N-dimethylaminopyridine, 3.34 g of triethylamine and 25 ml of methylene chloride is heated, in a sealed tube, at 100° C. for 54 hours. The reaction is concentrated in vacuo, dissolved in methylene chloride, washed with saturated sodium bicarbonate, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 20% ethyl acetate/hexane) to give 1.42 g of the desired product as colorless crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.ClC1C=CC=CC=1N1C(=O)C2C(=CC=C(F)C=2)N=C1C.C[C:34]1[C:35]([F:42])=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=[O:38]>O1CCCC1>[F:42][C:35]1[CH:34]=[CH:41][CH:40]=[CH:39][C:36]=1[CH:37]=[O:38]
Reactant: Cc1cccc(C=O)c1F
Agent: Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1ccccc1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of diisopropylamine (0.60 mL, 4.57 mmol) in tetrahydrofuran (27 mL) was chilled to -78° C. and butyllithium (1.30 mL, 3.25 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 minutes and then a solution 3-(2-chloro-phenyl)-6-fluoro-2-methyl-3H-quinazolin-4-one (1.04 g, 3.60 mmol) in tetrahydrofuran (7 mL) was added dropwise. The solution became intense red and was stirred 30 minutes. In a separate vessel a solution of 2-fluorobenzaldehyde (0.575 mL, 6.33 mmol) in tetrahydrofuran (20 mL) was prepared and chilled to -78 ° C. The cold red anion solution was added to the cold methyl 2-fluorobenzaldehyde solution via canula over 30 seconds. The resulting mixture was stirred 1 hour at -78° C. and then quenched with saturated aqueous bicarbonate and warmed to ambient temperature. The mixture was concentrated and the residue was diluted with water (50 mL), ethyl acetate (10 mL) and saturated aqueous sodium bisulfite (50 mL). This mixture was stirred 1 h and then repeatedly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residues from the two side by side reactions were combined and flash chromatographed on silica gel (45×150 mm) with elution proceeding as follows: 20% ethyl acetate/hexane (500 mL), nil; 30% ethyl acetate/hexane (500 mL) and 40% ethyl acetate/hexane (500 mL), two diastereomers of 3-(2-chloro-phenyl)-6-fluoro-2-[2-(2-fluoro-phenyl)-2-hydroxy-ethyl]-3H-quinazolin-4-one, both as viscous oils. The faster eluting diastereomer weighed 0.231 g (17%) and had: 1H NMR δ7.92 (dd, J=3, 8.5 Hz, 1 H), 7.77 (dd, J=5, 9 Hz, 1 H), 7.60 (dd, J=1.5, 7.5 Hz, 1 H), 7.57-7.55 (m, 1 H), 7.53 (dd, J=3,8 Hz, 1 H), 7.48-7.42 (sym m, 2 H), 7.36-7.31 (m, 1 H), 7.24-7.18 (m,1 H), 7.12 (t, J=7.5 Hz, 1 H), 6.96-6.90 (m, 1 H), 5.65 (br s, 1 H), 5.55 (dd, J=2.5, 9 Hz, 1 H), 2.70 (dd, J=2.5, 17 Hz, 1 H), 2.61 (dd, J=9, 17 Hz, 1 H). The slower eluting diastereomer weighed 0.283 g (21%) and had: 1H NMR δ7.91 (dd, J=3, 9 Hz, 1 H), 7.76 (dd, J=5, 9 Hz, 1 H), 7.58 (dd, J=1.5, 8 Hz, 1 H), 7.54 (dd, J=3, 9 Hz, 1 H), 7.51 (dd, J=1.5, 8 Hz, 1 H), 7.44 (dt, J=2, 8 Hz, 1 H), 7.39 (dt, J=1.5, 8 Hz, 1 H), 7.23-7.17 (m, 1 H), 7.13-7.07 (m, 2 H), 6.98-6.91 (m, 1 H), 5.61 (br s, 1 H), 5.57 (dd, J=4, 8 Hz, 1 H), 2.72-2.60 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.Cl.[F:29][C:30]1([F:34])[CH2:33][NH:32][CH2:31]1>CCN(CC)CC>[F:29][C:30]1([F:34])[CH2:33][N:32]([C:24](=[O:26])[CH2:25][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[N:7]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[C:6]=2[C:22]([OH:23])=[O:27])[CH2:31]1
Reactant: FC1(F)CNC1
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(O)c1c(CC(=O)N2CC(F)(F)C2)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from Example 68.1.) was ring opened with 3,3-difluoro-azetidine hydrochloride and NEt3 at 22° C. to give the title compound as a white solid. MS: 450.9 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:12])[CH:3]=1.C[O-].[Na+].CO.S(OC)(O[CH3:22])(=O)=O>CO.O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([O:8][CH3:22])=[O:7])=[C:4]([OH:12])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: Nc1cc(O)c(C(=O)O)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)cc1O
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
A solution of 4-amino-5-chloro-2-hydroxybenzoic acid (1.88 g, 0.010 mole) in absolute methanol (20 ml) was treated with 25% sodium methoxide/methanol (2.16 g, 0.010 mole), stirred for 30 minutes, and concentrated in vacuo. The solid residue was taken up in anhydrous acetone (30 ml), treated with dimethyl sulfate (1.64 g, 0.013 mole) and refluxed for 2 hours. The resultant solution was diluted with water (100 ml), and the precipitate was filtered, washed with water, and dried exhaustively in vacuo to afford 1.75 g (87%) of the title compound as fine colorless needles. The material was recrystallized from ethyl acetate/hexane; mp 138°-139° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[C:23](N(OC)C)=[O:24]>>[CH3:33][O:32][C:30]1[CH:29]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[CH:31]=1)[C:23]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:24]
Reactant: COc1cc(OC)cc(C(=O)N(C)OC)c1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(=O)c2ccc(OC)cc2C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 3,5-dimethoxy-N-methoxy-N-methylbenzamide. It is crystallized from diisopropyl ether.
Reaction SMILES: [C:1]([CH2:3][S:4]([NH:7][CH3:8])(=[O:6])=[O:5])#[N:2].[H-].[Na+].[CH2:11]([O:18][CH2:19]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[CH2:11]([O:18][CH2:19][N:7]([CH3:8])[S:4]([CH2:3][C:1]#[N:2])(=[O:6])=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNS(=O)(=O)CC#N
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(COCc1ccccc1)S(=O)(=O)CC#N
Temperature: 25 °C
Yield: 61.3 %

Procedure:
To a stirred solution of 1-cyano-N-methylmethanesulfonamide (from step (b), 250 mg, 1.9 mmol) in tetrahydrofaran (5 ml) at 0-5° C. under an atmosphere of nitrogen was added sodium hydride (60% dispersion in mineral oil, 75 mg, 1.9 mmol) in one portion. The resulting slurry was stirred at 0-5° C. for 45 min, before benzyloxymethyl chloride (80% purity, 0.368 g, 1.9 mmol) in tetrahydrofuran (5 ml) was added dropwise over a 15 min period. The mixture was then allowed to warm to ambient temperature over a 3 hr period. The solvents were then evaporated in vacuo and the resulting oil was purified by flash column chromatography (diethyl ether:hexanes 3:1 as eluant) to yield the subtitle compound (296 mg, 61.6%) as a colourless oil.