Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[C:14]=2[F:22])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]=2[F:22])[O:11][CH3:12])=[CH:24][CH:25]=1)#[N:2]
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)c1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)c1Oc1ccccc1
Reaction time: 24 h
Yield: 58.4 %

Procedure:
A mixture of (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-3-hydroxy-4-methoxy-phenyl)-2-methoxy-acetamide (150 mg), phenyl boronic acid (58 mg), copper (II) acetate (79 mg), pyridine (0.18 ml) and activated molecular sieves (4 A) at rt in CH2Cl2 under an argon atmosphere was stirred for 24 h. More copper (II) acetate (40 mg), phenyl boronic acid (29 mg) and pyridine (0.9 ml) were added to the mixture and stirring was continued for 16 h. The mixture was filtered and the cake washed with 15 ml CH2Cl2. The filtrate was washed with 1.0 N HCl (25 ml), 1.0 N NaOH (25 ml) and brine (25 ml), dried (MgSO4), filtered and concentrated (rotavapor) to leave the crude product as a brown gum. The crude product was purified by flash chromatography (cyclohexane=5 cyclohexane/EtOAc 2:3) to give (RS)-N-(4-Cyano-benzyl)-2-(2-fluoro-4-methoxy-3-phenoxy-phenyl)-2-methoxy-acetamide (107 mg) as an off-white foam. MS 421.2 ([M+H]+)
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1.[C:20](=O)([O:24]CC)[O:21][CH2:22][CH3:23]>C(O)C>[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:20]([O:21][CH2:22][CH3:23])=[O:24])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)Cc1ccc(-c2sccc2C)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1ccc(-c2sccc2C)cc1
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
To a solution of 1.4 g (0.06 mole) of metallic sodium in 50 ml of ethanol was added 10 g (0.038 mole) of ethyl 4-(3-methyl-2-thienyl)phenylacetate [I.R. (liquid film): νC=O 1735 cm-1 ], followed by adding 14.3 g (0.121 mole) of diethyl carbonate. The mixture was stirred at 50° to 60° C. for 30 minutes and freed from the ethanol by distillation under reduced pressure. To the residue were added 15 ml of 1 N hydrochloric acid and 50 ml of benzene and the mixture was shaken thoroughly. The organic layer was dried over anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: benzene/n-hexane=2/1) to obtain 7.8 g (58% yield) of oily diethyl [4-(3-methyl-2-thienyl)phenyl]malonate.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[CH:25]=3)=[CH:17][C:15]=2[N:16]=1)[CH2:2][CH3:3].[CH:30]1[C:35]([C:36]([OH:38])=[O:37])=[CH:34][C:33]2[C:39]([O:41][C:42](=O)[C:32]=2[CH:31]=1)=[O:40]>>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:39](=[O:40])[C:33]3[C:32](=[CH:31][CH:30]=[C:35]([C:36]([OH:38])=[O:37])[CH:34]=3)[C:42]2=[O:41])=[CH:7][C:6]=1[C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[CH:25]=3)=[CH:17][C:15]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(-c3cc4ccccc4o3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3cc4ccccc4o3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(2-propylamino-5-aminophenyl)-5-(2-benzofuranyl)benzoxazole (50 mg, 0.13 mmol) and 1,2,4-benzenetricarboxylic anhydride (30 mg, 0.13 mmol) the title compound was obtained (40 mg, 55%). 1H NMR (DMSO) δ 8.53(t, 1H), 8.46(dd, 1H), 8.37(d, 2H), 8.18(d, 1H), 8.12(d, 1H), 8.05(dd, 1H), 7.93(d, 1H), 7.72(m, 2H), 7.60(s, 1H), 7.54(dd, 1H), 7.36(m, 2H), 7.10(d, 1H), 3.44(m, 2H), 1.84(m, 2H), 1.15(t, 3H). MS 556 m/z (M−H)−.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[CH3:15][C:16]1[O:17][C:18]([C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[C:19]([C:21](O)=[O:22])[N:20]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:21]([C:19]2[N:20]=[C:16]([CH3:15])[O:17][C:18]=2[C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[O:22])[CH:9]=[N:8]1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(CCCCC(C)(F)F)c2)c1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.18 min; [M+H]+=403.28.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)=[O:4].[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.C(O)(=O)C>[CH:23]1([N:18]2[CH2:19][CH2:20][C:14]3[CH:13]=[C:12]([O:11][C:8]4[CH:9]=[CH:10][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:6][N:7]=4)[CH:22]=[CH:21][C:15]=3[CH2:16][CH2:17]2)[CH2:26][CH2:25][CH2:24]1
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)nc1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D40) (1.04 g, 3.5 mmol) in dichloromethane (12 ml) containing acetic acid (240 μL) at 0° C. was treated dropwise with cyclobutanone (400 μL, 5.3 mmol) and then stirred at room temperature for 1 hour. The mixture was then cooled to 0° C. and treated portionwise with sodium triacetoxyborohydride (1.11 g, 5.3 mmol) and stirred at room temperature for 16 hours. The solution was carefully basified with 2N sodium hydroxide, stirred for 30 minutes and then extracted with dichloromethane. The combined extracts were washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo. The crude material was purified by column chromatography eluting with dichloromethane then a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the title compound (E121); MS (ES+) m/e 352 [M+H]+.
Reaction SMILES: CC1(C)CO[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[N:3]1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])#[N:3]
Reactant: COC(=O)c1cccc(-c2ccccc2C2=NC(C)(C)CO2)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(-c2ccccc2C#N)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of methyl 3-[2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyl]benzoate (1.25 g) in pyridine (5 ml) at 7° C. was added dropwise phosphoryl chloride (0.75 ml) keeping the reaction temperature below 20° C. The reaction mixture was stirred at 100° C. for 4 hours. After being cooled to room temperature, the mixture was quenched by water, and the emulsion was extracted with ethyl acetate (50 ml). The organic layer was successively washed with 6N-hydrochloric acid and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (25 g) with dichloromethane as an eluent. The fractions containing the object compound were combined and evaporated in vacuo. The crystalline residue was recrystallized from methanol to afford methyl 3-(2-cyanophenyl)benzoate (0.7 g).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([C@@:7]1([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[CH2:9][CH2:8]1)[CH:5]=C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C@:7]2([CH2:4][CH:5]=[O:1])[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH3:15])[CH2:9][CH2:8]2)=[CH:24][CH:25]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(F)cc2)C(=O)O1
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](c1ccc(F)cc1)N1CC[C@](CC=O)(c2ccc(F)cc2)OC1=O
Reaction time: 8 h

Procedure:
Ozone was passed into a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-fluorophenyl)ethyl)-1,3-oxazinan-2-one (500 mg, 1.40 mmol) in anhydrous CH2Cl2 (20 mL) at −78° C. until a blue color appeared. Then Ph3P (920 mg, 3.5 mmol) was added at −78° C. The formed mixture was stirred overnight. The mixture was concentrated to give crude 2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-fluorophenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)acetaldehyde, which was used for the next step without purification.
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[C:10]([O:14][C:15]([C@H:17]([CH2:21][S:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[C:41]4[O:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=5[C:40]=4[CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[C:18]([OH:20])=[O:19])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(O)(=O)C.C(OCC)(=O)C>[C:10]([O:14][C:15]([C@H:17]([CH2:21][S:22]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[C:41]4[O:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=5[C:40]=4[CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:28][CH:29]=1)(=[O:6])=[O:5])[C:18]([OH:20])=[O:19])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)[C@H](CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@H](CS(=O)(=O)Cc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
Sodium perborate tetrahydrate (105 mg, 0.68 mmol) was added as a solid to a stirred solution of (2R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethyl-sulfanyl)-propionic acid (150 mg, 0.27 mmol), in acetic acid (10 mL) at 50° C. This solution was stirred at 40° C. for 2 hours (HPLC control) and then diluted with ethyl acetate (50 mL), washed with water, brine (2×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by trituration of the product with diethyl ether afforded the title compound as a white solid (138 mg, 87%): Rf 0.5 (20% methanol in dichloromethane). 1H NMR (MeOH-d4, 300 MHz): δ 7.90 (4H, m, Ar—H), 7.70 (4H, m, Ar—H), 7.53 (2H, m, Ar—H), 7.29-7.49 (5H, m, Ar—H), 4.62 (1H, m, CHN) 4.41 (2H, s, PhCH2S), 3.42 (2H, m, CH2CHN), 1.46 (9H, s, CMe3); ESI-LCMS e/z calcd for C33H31NO7S 585.674, found 586 (M+H)+, 608 (M+Na)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH3:19])[C:12]2=[N:11][C:10]=1[C:20](O)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:30][CH2:31][C:32]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:33]=1[C:34]([NH:36][CH3:37])=[O:35]>>[F:42][C:39]1[CH:40]=[CH:41][C:32]([CH2:31][NH:30][C:20]([C:10]2[N:11]=[C:12]3[N:18]([CH3:19])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:21])=[C:33]([C:34](=[O:35])[NH:36][CH3:37])[CH:38]=1
Reactant: CNC(=O)c1cc(F)ccc1CN
Reactant: CN1CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCN2C
Yield: 54.4 %

Procedure:
Coupling of 6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 1.0 mmol) and 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetate salt (0.295 g, 1.0 mmol) as described for the synthesis of intermediate 3 gave 0.253 g (54% yield) of the title amide as white crystals; mp 184° C. (ethyl acetate-hexane). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.78 (3H, d, J=4.5 Hz, NCH3), 2.91 (3H, s, NCH3), 3.66 (2H, t, J=8.9 Hz, CH2), 4.02 (2H, t, J=8.9 Hz, CH2), 4.46 (2H, d, J=6.2 Hz, NCH2), 4.90 (2H, s, OCH2), 7.04 (1H, m, aromatic), 7.25 (1H, dd, J=2.6 Hz and J=9.1 Hz, aromatic), 7.29-7.46 (6H, m, aromatics), 8.49 (1H, broad q, NH), 8.78 (l H, broad t, NH). HRMS (ESI+) calculated for C24H25FN5O4 [M+H+]: 466.1891. found: 466.1899.
Reaction SMILES: CO.[OH-].[K+].[Br:5][C:6]([Br:26])=[C:7]([C:17]1[CH:22]=[CH:21][C:20]([O:23]C#N)=[CH:19][CH:18]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14]C#N)=[CH:10][CH:9]=1.Cl>O>[Br:5][C:6]([Br:26])=[C:7]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1
Reactant: N#COc1ccc(C(=C(Br)Br)c2ccc(OC#N)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Oc1ccc(C(=C(Br)Br)c2ccc(O)cc2)cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A 4-necked 5-liter flask, equipped with a mechanical stirrer, a thermometer, and a condenser, is charged with methanol (800 g). Potassium hydroxide (440 g) is added in portions to the methanol solution. After the addition, the solution is cooled to 20° C. To this stirring solution, 1,1,1-tribromo-2,2-(4-hydroxyphenyl)ethane (420 g) is added in portions. The reaction temperature is kept below 40° C. After the addition, the temperature is raised to 50° C. and kept for 2 hours. The reaction mixture is cooled to room temperature and neutralized with 25% HCl solution. After the neutralization, the mixture is heated to reflux and water is added. The mixture is allowed to cool to the room temperature. The precipitates formed are filtered and dried to afford 1,1-dibromo-2,2-bis(4-hydroxyphenyl)ethene.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][NH2:19])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:20]([O-])(O)=[O:21].[Na+].C(Cl)(Cl)=O>C(Cl)Cl.O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]3[O:17][C:20](=[O:21])[NH:19][N:18]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C([O-])O
Reactant: NNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]nc(OCC2c3ccccc3-c3ccccc32)o1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
A suspension of N-[(9H-fluoren-9-ylmethoxy)carbonyl]hydrazine (141) (1.49 g, 5.78 mmol), CH2Cl2 (60 ml) and saturated NaHCO3 solution (60 ml) was stirred vigorously at 0° C. for 5 minutes, and the solution was then left for 5 minutes without stirring. Phosgene (1.89 M in toluene, 7.95 ml, 15.0 mmol) was then carefully added to the lower, organic phase using a syringe, and stirring of the reaction mixture was begun again immediately after the addition. After 10 minutes, water (20 ml) and CH2Cl2 (20 ml) were added to the reaction mixture. The phases were then separated rapidly, the aqueous phase was extracted with CH2Cl2 (50 ml), and the combined organic phases were dried over Na2SO4. Removal of the solvent under reduced pressure and drying gave a colourless solid (1.35 g, 4.82 mmol, 83%).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[CH2:3][OH:4].ClCCl.[C:17]([N:21]=[C:22]=[S:23])([CH3:20])([CH3:19])[CH3:18]>C(O)C>[C:17]([NH:21][C:22]([NH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[CH2:3][OH:4])=[S:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: NC(CO)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)N=C=S
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)NC(=S)NC(CO)c1cccc([N+](=O)[O-])c1
Reaction time: 7 h

Procedure:
The process is performed as in Example 2, starting with 5.1 g of 2-amino-2-(3-nitrophenyl)-1-ethanol in 170 cm3 of ethanol containing 85 cm3 of dichloromethane and 4.6 cm3 of tert-butyl isothiocyanate, at a temperature in the region of 20° C. for 3 days and then at a temperature in the region of 60° C. for 7 hours. After addition of a further 0.35 cm3 of tert-butyl isothiocyanate and 16 hours at a temperature in the region of 60° C., an identical work-up gives 5.7 g of N-(tert-butyl)-N′-[2-hydroxy-1-(3-nitrophenyl)ethyl]thiourea in the form of an ocher-colored solid melting at 162° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[CH:12][CH:11]=2)=[N:4][S:5][C:6]=1[C:7]([NH2:9])=[O:8].[N:27]([O-])=O.[Na+]>Cl.CN1CCCC1=O.O>[CH2:20]([O:19][C:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([C:3]2[C:2]3[N:1]=[N:27][NH:9][C:7](=[O:8])[C:6]=3[S:5][N:4]=2)=[CH:15][CH:14]=1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1snc(-c2ccc(NC(=O)OCc3ccccc3)cc2)c1N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(-c2nsc3c(=O)[nH]nnc23)cc1)OCc1ccccc1
Yield: 71.6 %

Procedure:
22.5 g of 4-amino-3-(4-benzyloxyformamidophenyl)-5-isothiazolecarboxamide in 25 ml of concentrated hydrochloric acid and 150 ml of N-methylpyrrolidone were cooled in an ice-bath and stirred during the addition of 4.89 g of sodium nitrite dissolved in 20 ml of water. After 0.5 hour 150 ml of water were added and the resulting precipitate was filtered off, washed with water, dried in vacuo and recrystallized from ethyl acetate to yield 16.6 g of 7-(4-benzyloxyformamidophenyl)isothiazolo[4,5-d]-1,2,3-triazin-4(3H)-one of melting point 190°-191° C. (dec.).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4](OC)=[O:5].[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13]>>[CH2:10]([NH:14][C:4](=[O:5])[C:3]([CH3:9])([CH3:8])[CH2:2][OH:1])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCN
Reactant: COC(=O)C(C)(C)CO
Product: CCCCNC(=O)C(C)(C)CO
Yield: 100 %

Procedure:
Prepared as in Example 197d (Method A) from methyl 3-hydroxy-2,2-dimethylpropanoate and n-butyl amine in 100% yield. MS 174 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=12.[F:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[OH:25].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[F:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[O:25][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: COC(=O)c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 180 °C
Yield: 58.7 %

Procedure:
A mixture of 37 (4.0 g, 17.6 mmol), 2-fluoro-4-nitrophenol (5.5 g, 35.0 mmol) and K2CO3 (12.1 g, 87.5 mmol) in Ph2O was heated at 180° C. for 5 hours. The mixture was cooled to room temperature, diluted with EtOAc and washed with water. The organic phase was collected, dried over anhydrous sodium sulfate and the solvents were removed under reduced pressure. The residue was purified by flash chromatography using hexane—AcOEt (70:30) as an eluent. The product from the column was re-crystallized from a mixture of ethyl acetate-hexanes to afford 38 (3.6 g, 59% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.69 (d, J=5.2 Hz, 1H), 8.47 (dd, J=2.4 and 10.0 Hz, 1H), 8.27 (s, 1H), 7.77 (dd, J=8.0 and 9.2 Hz, 1H), 7.06 (dd, J=0.8 and 5.2 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[OH:34])[N:17]=2)[CH2:12]1.Cl[C:36]([O:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:37].ClC([O-])=O>C1COCC1>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:34])[C:27]=1[C:18]1[N:17]=[C:16]([N:13]2[CH2:14][CH2:15][C@@H:11]([NH:10][C:36](=[O:37])[O:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:12]2)[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[N:19]=1
Reactant: CC(C)(C)COC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Agent: O=C([O-])Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCC(C)(C)C)C3)nc(-c3c(O)cccc3F)nc2c1
Temperature: -60 °C
Yield: 95.1 %

Procedure:
At RT, diisopropyl ethylamine (273 μL, 1.57 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (266 mg, 0.79 mmol) in THF (15 mL), and the reaction was cooled to −60° C. Neopentyl chloroformate (116 μL in 2.0 μL THF, 0.79 mmol) was added dropwise over a period of 10 minutes. After addition of the chloroformate was complete, the reaction mixture was warmed to RT, quenched with H2O, and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified via silica gel chromatography using 0-10% EtOAc in a 1:1 mixture of hexanes and CH2Cl2 to give (R)-neopentyl 1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 11) (340 mg, 94%). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.64-7.58 (m, 3H), 7.47 (q, J=7.8 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 6.87 (t, J=9.2 Hz, 1H), 4.28-3.99 (m, 5H), 3.71-3.64 (m, 2H), 2.56 (s, 3H), 2.23-2.14 (m, 1H), 2.07-1.92 (m, 1H), 0.89 (s, 9H) ppm. LC/MS: m/z 453.5 (M+H)+ at 2.66 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([O:38][CH3:39])[CH:32]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([O:38][CH3:39])[CH:32]=4)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(CCN)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)CC1
Product: COc1cc(CCNc2nccc(-c3cccc(NC4CCN(C(=O)OC(C)(C)C)CC4)c3)n2)ccc1O

Procedure:
Intermediate 7 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 520. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.30 (d, 1H) 7.25-7.4 (m, 3H) 6.8-7.0 (m, 2H) 6.65-6.78 (m, 3H) 5.45 (m, 1H) 4.0 (m, 2H) 3.82 (s, 3H) 3.7 (m, 4H) 3.49 (m, 1H) 2.85 (m, 4H) 2.0 (m, 2H) 1.5 (s, 9H).
Reaction SMILES: [Na].CO.[OH:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1.Br[CH:17]([CH2:23][CH2:24][CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CS(C)=O>[CH2:21]([O:20][C:18]([CH:17]([O:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1)[CH2:23][CH2:24][CH3:25])=[O:19])[CH3:22]
Reactant: CCCC(Br)C(=O)OCC
Reactant: Oc1ncn(-c2ccccc2)n1
Agent: [Na]
Solvent: CO
Solvent: CS(C)=O
Product: CCCC(Oc1ncn(-c2ccccc2)n1)C(=O)OCC

Procedure:
The synthesis was carried out substantially as shown above in Example 7, except that it was necessary to chromatograph the product as described in Example 8. The reactants were 0.7 g of sodium, 20 ml of methanol, 5 g of 3-hydroxy-1-phenyl-1,2,4-lH-triazole and 6.5 g of ethyl 2-bromopentanoate. The solvent was 80 ml of dimethylsulfoxide. Five g of the desired product, an oil, was obtained.