Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:27]([F:30])([F:29])[F:28])/[CH:11]=[CH:12]/[C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([O:22][C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[NH2:31][CH2:32][C:33]([NH:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[O:34].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:27]([F:30])([F:29])[F:28])/[CH:11]=[CH:12]/[C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:31][CH2:32][C:33](=[O:34])[NH:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[O:18])=[C:15]([O:22][C:23]([F:24])([F:25])[F:26])[CH:14]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: NCC(=O)NCC(F)(F)F
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)cc1OC(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(CNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)cc1OC(F)(F)F)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (E)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-(trifluoromethoxy)benzoic acid (0.25 g, 0.52 mmol), 2-amino-N-(2,2,2-trifluoroethyl)acetamide (0.158 g, 0.62 mmol), PyBOP (0.40 g, 0.78 mmol) and DIPEA (0.134 g, 1.04 mmol) in CH2Cl2 (10.0 mL) were stirred at ambient temperature for 16 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 20% ethyl acetate/pet ether) afforded the title compound as a pale yellow gummy material (0.15 g, 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]2[CH:23]=[CH:22][C:13]([CH2:14][NH:15]C(=O)C(F)(F)F)=[CH:12][CH:11]=2)[N:3]=1.CN>CO>[NH2:15][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][O:8][C:4]2[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccnc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Agent: CN
Solvent: CO
Product: NCc1ccc(COc2nccc(N)n2)cc1
Temperature: 25 °C

Procedure:
150 mg (0.46 mmol) of N-(4-((4-Aminopyrimidin-2-yloxy)methyl)benzyl)-2,2,2-trifluoroacetamide (1) is dissolved in 2 mL methanol and treated with 5 mL methylamine (33% in ethanol). The reaction mixture is stirred at room temperature over night and all volatiles are removed in vacuo. The product is used without further purification in the next step. ESI-MS m/z 231 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:26])/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25].[CH2:27]([C:32]12[CH2:39][CH2:38][C:35]([C:40]3[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=3)([CH2:36][CH2:37]1)[CH2:34][CH2:33]2)[CH2:28][CH2:29][CH2:30][CH3:31].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:20]([O:26][C:43]1[CH:44]=[CH:45][C:40]([C:35]23[CH2:38][CH2:39][C:32]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:37][CH2:36]2)[CH2:33][CH2:34]3)=[CH:41][CH:42]=1)/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25]
Reactant: CCCCCC12CCC(c3ccc(O)cc3)(CC1)CC2
Reactant: CCC/C=C/CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC/C=C/COc1ccc(C23CCC(CCCCC)(CC2)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (0.34 g, 0.0013 mol) was added in small portions to a solution of (E)-hex-2-en-1-ol (0.13 g, 0.0013 mol), 4-(4-pentylbicyclo[2.2.2]octyl)phenol (0.35 g, 0.0013 mol), diethylazodicarboxylate (0.22 g, 0.0013 mol) in dry tetrahydrofuran (20 cm3), cooled in an ice bath under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel using a 9:1 petroleum ether (40-60° C./ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield 0.18 g (39%), K 69° C., SA-N 59° C., N-I 134° C.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([O:37][CH2:38][CH3:39])(=[O:36])[C@H:33]([CH3:35])[OH:34].[C:40]1([C:46]2[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[C:40]1([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:45]=[CH:44][C:43]([O:34][C@H:33]([CH3:35])[C:32]([O:37][CH2:38][CH3:39])=[O:36])=[CH:42][CH:41]=1
Reactant: CCOC(=O)[C@H](C)O
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)Oc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diethylazodicarboxylate (8.66 ml) in dry tetrahydrofuran (25 ml) was added dropwise over 30 minutes to a stirred solution of triphenylphosphine (13.11 g), (S)-(−)-ethyl lactate (5.67 ml) and 4-phenylphenol (8.51 g) in dry tetrahydrofuran (100 ml). The resulting solution was stirred at room temperature for 18 hours then concentrated under reduced pressure. A mixture of isohexane: ether (9:1) (200 ml) was added to the residue and stirred at room temperature for 30 minutes. The solution was filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with isohexane : dichloromethane (2:3) to give the sub-title compound as an oil (11.79 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([C:22](OC)=[O:23])=[N:19][N:18]=4)=[C:13]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CO.[Li+].[BH4-]>C1COCC1.CCOC(C)=O>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH2:22][OH:23])=[N:19][N:18]=4)=[C:13]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1nnc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)o1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(CO)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-carboxylate (200 mg) in THF (10 mL): MeOH (10 mL) was cooled to 0° C. Added LiBH4 (3 equiv.) in portions to the reaction mixture, stirred for 30 min at 0° C. Gradually the reaction temperature was raised to room temperature and stirred for 30 min. The reaction was quenched using ice pieces. The reaction mass was concentrated under reduced pressure. The residue obtained was diluted with EtOAc. The organic layer was washed with water. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by prep HPLC to afford the desired compound, (5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methanol. 1H NMR: 400 MHz, DMSO-d6: δ 657.15 (d, J=524681.20 Hz, 6H), 3.71-3.79 (m, 1H), 4.71 (d, J=6.40 Hz, 2H), 5.93 (t, J=6.40 Hz, 1H), 6.21 (s, 1H), 7.36-7.38 (m, 1H), 7.52 (d, J=7.20 Hz, 1H), 7.61 (dd, J=2.00, 8.80 Hz, 1H), 7.97 (d, J=8.80 Hz, 1H), 8.49 (s, 1H), 8.65 (d, J=2.00 Hz, 1H), 9.17 (s, 1H), 9.44 (s, 1H). LC/MS: XBridge Phe 8, 4.6×30 mm, 3.5 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.454 min; LCMS (ES-API), m/z 383.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.528 min; Purity: 85.66%.
Reaction SMILES: [CH2:1]([N:4]([C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=1[C:14]([OH:16])=O)[C:5](=[O:7])[CH3:6])[CH2:2][CH3:3]>CCO>[OH:16][C:14]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=2[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:7])[CH:6]=1
Reactant: CCCN(C(C)=O)C1=C(C(=O)O)CCCC1
Solvent: CCO
Product: CCCn1c2c(c(O)cc1=O)CCCC2

Procedure:
Cyclisation of a 60:40 mixture of the ethyl and methyl esters of 2-(N-n-propyl-acetamido) cyclohex-1-ene-1-carboxylic acid (34.82 g; 0.141 mole) as described in Example 8 afforded the title product as a white crystalline solid, m.p. (EtOH) 277° - 278° C
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:27])[C:9]([C:11]1[S:26][C:14]2[C:15]3[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].C([O-])([O-])=[O:29].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:27])[C:9]([C:11]1[S:26][C:14]2[C:15]3[CH:23]=[C:22]([C:24]([NH2:25])=[O:29])[CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C#N)ccc1OCC2)c1ccccc1Cl
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(N)=O)ccc1OCC2)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-(2-chlorophenyl)-9-cyano-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 120 (120 mg) and K2CO3 (49 mg) in dry DMSO (2 mL) was added 33% hydrogen peroxide (40 L). The resultant was stirred overnight at room temperature. Ice was added to the resulting solution and the solid formed was collected, washed with water and dried to give 119. NMR: (CDCl3): 3.04 (t, 2H, CH2, J=5.02 Hz), 3.42 (s, 3H, CH3), 4.28 (t, 2H, CH2, J=5.06 Hz), 5.75 (sbr, 2H, NH2), 6.71 (s, H, ArH), 7.03 (d, H, ArH, J=8.44 Hz), 7.39-7.45 (m, 3H, 3×ArH), 7.55-7.60 (m, 2H, 2×ArH), 7.99 (d, H, ArH, J=1.81 Hz). MS: (ESI+) MH+ 413.14
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([N:11]1[CH2:16][CH2:15][C:14]2[S:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)(=[O:10])[CH3:9].[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[C:8]([N:11]1[CH2:16][CH2:15][C:14]2[S:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=2[CH2:12]1)(=[O:10])[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CCc2sccc2C1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2sc([N+](=O)[O-])cc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
20 ml of an acetic anhydride solution containing 5.43 g (30 mmole) of 5-acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine [prepared as described in step (a) above] were added dropwise at 10° to 18° C. over a period of one hour to 30 ml of an acetic acid solution containing 4.2 g (60 mmole) of 90% fuming nitric acid, and the mixture was then stirred at a temperature not greater than 18° C. for 1 hour. The reaction mixture was then poured into ice-water and extracted with methylene chloride. The organic layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate and with water, in that order, and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was crystallized from a mixture of hexane and toluene, to give 4.46 g of the title compound as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[CH3:10][Mg]Br.O.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[N:3]=[CH:4][C:5]([CH:6]([OH:7])[CH3:10])=[CH:8][CH:9]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(F)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)c1ccc(F)nc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a stirred mixture of 6-fluoronicotinaldehyde (Frontier Science, 3.14 g, 25.1 mmol) in THF (40 mL) in 250 mL round-bottomed flask, methylmagnesium bromide (Aldrich, 3 M in diethyl ether, 9.21 mL, 27.6 mmol) was added dropwise at about 5 to 10° C. The mixture was stirred at about 5° C. for 30 min. A mixture of water (30 mL) and saturated aqueous ammonium chloride (30 mL) was added slowly and EtOAc (20 mL) was added. The layers were separated. The aqueous phase was extracted with EtOAc (2×60 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100 g, eluent: EtOAc in hexanes 20% to 70%) to afford (2.30 g, 65% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.19 (d, J=1.76 Hz, 1H) 7.85 (td, J=8.07, 2.45 Hz, 1H) 6.92 (dd, J=8.41, 2.93 Hz, 1H) 4.94-5.02 (m, 1H) 2.00 (d, J=3.72 Hz, 1H) 1.53 (d, J=6.46 Hz, 3H). m/z (ESI, positive ion): 142.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH:25]([O:27][CH2:28][CH3:29])[CH3:26].[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:26][CH2:25][O:27][CH2:28][CH3:29])=[C:18]([F:23])[N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)n2)cc1
Reactant: CCOC(C)Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccc(OCCOCC)c(F)n2)cc1

Procedure:
A mixture of 0.1 mol of 2C, 0.1 mol of 1-bromoethoxyethane, 0.1 mol of sodium hydroxide, 20 ml of ethanol and 50 ml of water is heated at the boil for 2 hours. The mixture is cooled, dilute hydrochloric acid is added, and the aqueous phase is extracted with dichloromethane. The solvent is removed under reduced pressure, and the residue is purified by column chromatography, giving the product 2-(4-octyloxyphenyl)-5-(2-ethoxyethoxy)-6-fluoropyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][C:36]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)([OH:39])[CH2:35][CH2:34]1.O>CN(C=O)C.C(Cl)Cl>[OH:39][C:36]1([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][O:14][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH2:34][CH2:35]1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(CC2(O)CCN(CCO)CC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(CC2(O)CCN(CCOC(=O)c3ccc(OCc4ccccc4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.1 %

Procedure:
4-Benzyloxybenzoic acid (0.685 g, 3 mmol) was dissolved in DMF (6 ml), and 1,1,-carbonyldiimidazole (0.58 g, 3.6 mmol) was added portionwise. The reaction mixture was heated to 55°-60° C. for 20 min. and then cooled to room temperature. A solution of 1-(2-hydroxy-ethyl)-4-(4-methyl-benzyl)-piperidin-4-ol (0.78 g, 3.3 mmol) in DMF (2 ml) was added. The reaction mixture was stirred 23 hours at room temperature and 4 hours at 60° C. H2O (50 ml) was added followed by CH2Cl2. Organic phase was washed with sat. NaHCO3, dried over Na2SO4, and concentrated. The residue was chromatographed over silica gel (CH2Cl2 --MeOH, 19:1) to provide 4-benzyloxy-benzoic acid 2-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-yl]-ethyl ester (0.65 g, 47%) as a colorless solid, m.p. 102° C. and MS: m/e=460.3 (M+H+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:10]=[C:9]([F:11])[C:7]([NH2:8])=[C:6]([F:12])[CH:5]=1.[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[N:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([NH:8][C:7]3[C:9]([F:11])=[CH:10][C:4]([Br:3])=[CH:5][C:6]=3[F:12])=[N:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Nc1c(F)cc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(F)cc(Br)cc3F)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
Sodium hydride (60%, 612 mg, 15.3 mmol) was added to a solution of 4-bromo-2,6-difluoroaniline (2.77 g, 6.65 mmol) in DMF (80 ml). After stirring for 30 minutes at ambient temperature, 7-benzyloxy-4-chloro-6-methoxyquinazoline (2 g, 6.65 mmol), (prepared, for example, as described in WO 97/22596, Example 1, but the free base was generated prior to use), was added and stirring was maintained for 4 hours. The mixture was partitioned between ethyl acetate and water (200 ml). The organic layer was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with isopropanol, collected by filtration, washed with ether and dried under vacuum to give 7-benzyloxy-4-(4-bromo-2,6-difluoroanilino)-6-methoxyquinazoline (1.95 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:14]([O:18][C:19](=[O:28])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27])([CH3:17])([CH3:16])[CH3:15].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[C:14]([O:18][C:19](=[O:28])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH2:1])[S:3][C:4]=2[CH:10]=1)=[O:13])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: Nc1nc2ccc(C(=O)O)cc2s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
The acid 114 (1.80 g, 9.27 mmol) was combined with (2-amino-phenyl)-carbamic acid tert-butyl ester (2.31 g, 11.1 mmol) and BOP (4.91 g, 11.1 mmol) in DMF. To this solution Et3N (5.16 ml, 37.1 mmol) was added and the mixture was stirred overnight at room temperature under nitrogen, concentrated in vacuo and purified by flash column chromatography (30% hexane/EtOAc). To further purify the product, the mixture was partitioned between EtOAc and water, organic layer was separated, dried over MgSO4 and evaporated give the title compound 115 (1.84 g, 52%). 1H-NMR (DMSO) δ: 9.72 (s, 1H), 8.66 (m, 1H); 8.22 (d, J=1.8 Hz, 1H); 7.80 (m, 3H); 7.50 (m, 2H); 7.37 (m, 1H); 7.14 (m, 2H); 1.44 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7](CC3C=CC(OC)=CC=3)[C:6]=2[N:25]=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][NH:7][C:6]=2[N:25]=1
Reactant: COc1ccc(CN2CC(F)(F)C(=O)N(C)c3cnc(Cl)nc32)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C(F)(F)CNc2nc(Cl)ncc21
Yield: 12.8 %

Procedure:
A solution of 0.3 g (0.0082 mole) of 2-chloro-7,7-difluoro-9-(4-methoxy-benzyl)-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-291) and 0.3 mL of anisole in 10 mL of trifluoroacetic acid was heated at 85 degrees in a pressure tube for 24 hours. The mixture was concentrated under reduced pressure, a small amount of methanol was added followed by ether. The resulting solid was collected by filtration and washed with ether to give 0.26 g of 2-chloro-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-292). as a lightly yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][NH:17][C:16]1=[O:20])[CH:6]=[N:7][OH:8].[O-]Cl.[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][NH:17][C:16]1=[O:20])[C:6]#[N+:7][O-:8]
Reactant: COc1cc(C=NO)ccc1OCCN1CCNC1=O
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc(C#[N+][O-])ccc1OCCN1CCNC1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 3-methoxy-4-[2-(2-oxoimidazolidin-1-yl)ethoxy]benzaldehyde oxime (21.7 g, 0.078 mol) in CH2Cl2 (950 mL) at −3° C., is added dropwise an aqueous NaOCl solution in water (Aldrich, >4% of active chlorine) (161 mL) over 10 minutes. The reaction medium is then stirred for 20 minutes at 0° C. The organic phase is separated and the aqueous phase is extracted with CH2Cl2 (4 times 100 mL). The combined organic phases are washed with water (3 times 100 mL), dried over Na2SO4 and then concentrated under reduced pressure (Tbath 22° C.) to 200-220 mL. The precipitate obtained is filtered, washed with CH2Cl2 (twice 10 mL) and dried under atmospheric pressure at room temperature.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:16][C:17]([OH:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[C:1]1([CH:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][CH:8]2[CH2:16][C:17]([OH:19])=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1oc2cccc-2cc1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CC1OC2=CC=CC2=CC1c1ccccc1

Procedure:
3-Phenyl-7-benzofuranacetic acid (2.5 g., 0.01 mole) is reduced with hydrogen gas using palladium on charcoal as catalyst and ethanol as solvent in a Brown hydrogenator. After the absorption of hydrogen stops, the reaction mixture is filtered, then the filtrate is evaporated in vacuo to a white solid. Recrystallization from a benzene-hexane mixture gives white crystals of 2,3-dihydro-3-phenyl-7-benzofuranacetic acid, m.p. 110.5°-111.5° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH:14]([O-])=[O:15].[Na+].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH:14]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)=[O:15]
Reactant: O=C[O-]
Reactant: COC(=O)c1ccc(Br)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=O)cc1OC
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A slow stream of CO was passed into a suspension of methyl 4-bromo-2-methoxybenzoate (2.4 g, 0.010 mol), bis(triphenylphosphine)palladium(II) chloride (140 mg, 0.00020 mol), sodium formate (1.02 g, 0.0150 mol), and dry DMF (10 mL). The mixture was vigorously stirred at 110° C. for 2 h. After cooling, the mixture was treated with aqueous Na2CO3 solution and extracted with EtOAc. The extract was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography on silica gel with AcOEt-hexane as eluent (0 to 50%) to give a colorless oil.