Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=O)[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]3[CH2:16][CH2:17][C:18]([CH:19]=1)=[C:5]23.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]3[CH2:16][CH2:17][C:18]([CH:19]=1)=[C:5]23
Reactant: Cc1cc2c3c(c1)NC(=O)c1ccccc1N3CC2
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc2c3c(c1)N=C(N1CCN(C)CC1)c1ccccc1N3CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methyl-1,2-dihydrobenzo[c]pyrrolo[1,2,3-ef][1,5]benzodiazepin-7-one (3.6 g, 14.3 mmoles), N-methylpiperazine (16 ml) and toluene (350 ml) was heated to 110° C. Titanium tetrachloride (4.3 ml) was added in three portions in two minute intervals. The mixture was heated under reflux for two hours and cooled to room temperature. Toluene (500 ml) and ice-water (500 ml) were added. The mixture was stirred for 30 minutes and the insoluble material was removed by filtration. The organic phase was separated. The aqueous phase was extracted with toluene (200 ml). The combined toluene solutions were washed with water (300 ml), brine (2 times, 300 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was triturated with ethanol:hexane to a solid. Recrystallization of the solid from chloroform:hexane yielded 2.4 g of product. The mother liquor was concentrated and the residue was purified on a silica gel column (60 g, 230-400 mesh) to give a second crop of 1.3 g of product (77% overall yield). Recrystallization from 2-propanol gave the analytical sample, mp 173°-174° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C@@H:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S(=O)(=O)(O)O>C1C=CC=CC=1>[CH3:11][CH:12]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCC[C@@H](C)O
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCCCCCC(C)OC(=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 43 %

Procedure:
27.6 g of p-hydroxybenzoic acid and 39.0 g of (R)-2-octanol were refluxed for 10 hours in 300 ml of benzene in the presence of 0.5 ml of conc. sulfuric acid. Then, the reaction solution was cooled to the room temperature, and then concentrated and purified by column chromatography, to obtain 21.5 g of p-hydroxybenzoic acid 1-methylheptyl ester. (yield: 43%)
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[C@H:12]3[CH2:31][C@H:13]3[C:14]2=[C:15]([O:18][C:19](=[O:21])[CH3:20])[CH:16]=[O:17])[CH2:6]1)(=[O:3])[CH3:2].[Li].S(=O)(=O)(O)O>O1CCCC1>[OH:17][CH2:16][C:15]([O:18][C:19](=[O:21])[CH3:20])=[C:14]1[C@:22]2([CH3:30])[C@H:11]([C@H:10]3[C@H:25]([CH2:24][CH2:23]2)[C@:26]2([CH3:29])[C:7]([CH2:6][C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:28][CH2:27]2)=[CH:8][CH2:9]3)[C@H:12]2[CH2:31][C@@H:13]12
Reactant: CC(=O)OC(C=O)=C1[C@@H]2C[C@@H]2[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=S(=O)(O)O
Agent: [Li]
Solvent: C1CCOC1
Product: CC(=O)OC(CO)=C1[C@@H]2C[C@@H]2[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C

Procedure:
6.5 g. of 3β,20-diacetoxy-15α,16α-methylene-5,17(20)-pregnadien-21-al is mixed in 65 ml. of tetrahydrofuran with 6.5 g. of lithium tri-tert.-butoxyalanate and agitated for 30 minutes at room temperature. The mixture is then stirred into ice water, acidified with dilute sulfuric acid, and extracted with methylene chloride. After drying and evaporation, 6.5 g. of crude 21-hydroxy-3β,20-diacetoxy-15α,16α-methylene-5,17(20)-pregnadiene is obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(Cl)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-chloro-2-oxindole to give 0.3 g of 5-chloro-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](O)=[O:7].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([Cl:16])=[O:7]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1OC

Procedure:
20 g (0.1 mole) of 3,4-dimethoxybenzoic acid are suspended in 170 ml of thionyl chloride and refluxed for 2 hours. The solution is concentrated under reduced pressure. The residual oil crystallizes immediately after the addition of petroleum ether. The crystals are spun and washed with petroleum ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=[O:34])[NH:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:39].[NH4+].[Cl-]>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24](=[O:34])[N:23]([CH3:39])[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)NCC4)cc2)CCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN1CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of tert-butyl(1-(4-(5-oxo-3-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (30 mg, 0.06 mmol) in dry DMF (1 mL) was added sodium hydride (3 mg, 0.07 mmol) at 0° C. under nitrogen. After 1 h at 0° C., iodomethane (17 μL, 0.19 mmol) was added and the resulting mixture was stirred for an additional 10 min at 0° C. A saturated solution of NH4Cl was added and the mixture was extracted with dichloromethane (3×) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient 0 to 50% EtOAc in hexane) to give the title compound (22 mg, 71%). 1H NMR (500 MHz, CDCl3): 8.35 (1H, s), 7.34 (2H, d), 7.29 (2H,d), 7.24-7.22 (3H, m), 7.19-7.17 (2H, m), 5.06 (1H, br s), 3.70 (2H, t), 3.29 (2H, t), 3.19 (3H, s), 2.54-2.30 (4H, m), 2.08-2.00 (1H, m), 1.83-1.74 (1H, m), 1.44-1.18 (9H, br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH2:12][C:13]4[C:19]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=5)=[N:18][N:17](COCC[Si](C)(C)C)[C:14]=4[C:15]=3[CH:16]=2)=[CH:5][CH:4]=1.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]3[CH2:12][C:13]4[C:19]([C:20]5[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=5)=[N:18][NH:17][C:14]=4[C:15]=3[CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc3c(s2)Cc2c(-c4ccc(OC)cc4)nn(COCC[Si](C)(C)C)c2-3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2cc3c(s2)Cc2c(-c4ccc(OC)cc4)n[nH]c2-3)cc1
Temperature: 100 °C
Yield: 95 %

Procedure:
2,6-Bis-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.11 g, 0.2 mmol) was dissolved in MeOH and treated with concentrated HCl (0.06 mL, 2.0 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 2,6-Bis-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.08 g, 0.19 mmol) as white solid in 95% yield.
Reaction SMILES: [CH2:1]([N:8]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[C:24](=[O:25])[NH:23][N:22]=[N:21]3)[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44](=O)([O-])[O-].[K+].[K+].IC>C(Cl)Cl>[CH2:1]([N:8]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[C:24](=[O:25])[N:23]([CH3:44])[N:22]=[N:21]3)[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:27]=[C:28]([CH3:33])[CH:29]=[C:30]([CH3:32])[CH:31]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(-n4nn[nH]c4=O)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Product: Cc1cc(C)cc(-c2[nH]c3ccc(-n4nnn(C)c4=O)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a solution of 1-[3-{2-[benzyl-(4-pyridin-3-yl-butyl)-amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1,4-dihydrotetrazol-5-one (25 mg in 1.5 mL dry N,N-dimethylformamide) at 0° C. was added 13 mg potassium carbonate followed by 0.033 mL of a 10% solution of iodomethane in methylene cloride, and the mixture stirred at low temperature. After 2 hours, the reaction was quenched by the addition of saturated aqueous ammonium chloride and the mixture extracted with ethyl acetate. The organic portion was washed successively with water and brine, dried over sodium sulfate and concentrated in vacuo. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 95:5) gave the title compound (20 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:34]=[N:33][N:32]([CH:35]([CH3:37])[CH3:36])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:24][CH:25]=2)[CH:19]=1)=[O:13].CCN(CC)CC.[S:45](Cl)([CH3:48])(=[O:47])=[O:46]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:34]=[N:33][N:32]([CH:35]([CH3:37])[CH3:36])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([CH:26]3[CH2:27][CH2:28][N:29]([S:45]([CH3:48])(=[O:47])=[O:46])[CH2:30][CH2:31]3)[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCNCC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCN(S(C)(=O)=O)CC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(piperidin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.2 g, 0.397 mmol) in DCM (5 mL), Et3N (0.06 g, 0.596 mmol) and mesyl chloride (0.046 g, 0.403 mmol) were added at 0° C. and stirred it at room temperature for 2 h. After completion, reaction was quenched with ice-water. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford crude material which was purified by prep. HPLC to give the desired compound. LCMS: 582.30 (M+1)+; HPLC: 92.74% (@ 254 nm) (Rt;5.006); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 9.86 (bs, 1H), 8.87 (t, 1H, J=4.8 Hz), 8.34 (s, 1H), 7.90 (s, 1H), 6.93 (s, 1H), 5.90 (s, 1H), 5.23-5.20 (m, 1H), 4.39 (d, 2H, J=4.4 Hz), 4.08 (bs, 2H), 3.80 (bs, 2H), 3.72 (d, 2H, J=11.60 Hz), 3.30 (bs, 2H), 3.15 (d, 2H, J=15.60 Hz), 2.93 (s, 3H), 2.84-2.76 (m, 2H), 2.27 (m, 1H), 2.21 (s, 3H), 2.12 (s, 3H), 1.81-1.73 (m, 2H), 1.51 (d, 6H, J=6.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH:12]([CH3:14])[CH3:13])[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH:12]([CH3:14])[CH3:13])[C:9]([Cl:18])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)[C@@H](C(=O)O)c1ccc(F)cc1
Solvent: ClCCl
Product: CC(C)[C@@H](C(=O)Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 32.3 g (0.165 mol) of [R]-(-)-2-(p-fluorophenyl)-3-methylbutyric acid in 250 ml of abs. methylene chloride was treated with 27.3 ml of oxalyl chloride. After stirring at room temperature for 4 hours and evaporation of the solvent under reduced pressure, [R]-(-)-2-(p-fluorophenyl)-3-methylbutyryl chloride was obtained as an oil, b.p. 100°/65 Pa; [α]D20 =-53.2° (c=1, chloroform).
Reaction SMILES: C(NC1SC=C(/C(=N/OC2CCNC2=O)/C(O)=O)N=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.N[C@@H:64]1[C:82](=[O:83])[N:66]2[C:67]([C:79]([OH:81])=[O:80])=[C:68]([CH2:71][S:72][C:73]3[N:77]([NH2:78])[N:76]=[N:75][N:74]=3)[CH2:69][S:70][C@H:65]12>O1CCCC1.CN(C)C(=O)C.O.C(OCC)(=O)C.C(N(CC)CC)C>[NH2:78][N:77]1[C:73]([S:72][CH2:71][C:68]2[CH2:69][S:70][C@@H:65]3[CH2:64][C:82](=[O:83])[N:66]3[C:67]=2[C:79]([OH:81])=[O:80])=[N:74][N:75]=[N:76]1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)/C(=N\OC1CCNC1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Temperature: 0 °C

Procedure:
11.5 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-[((3RS)-2-pyrrolidon-3-yl)oxyimino]acetic acid are suspended in 150 ml of tetrahydrofuran, and 3.2 g of 1-hydroxybenzotriazole and 4.7 g of dicyclohexylcarbodiimide are added thereto under ice-cooling and stirring. The mixture is stirred at room temperature for 2 hours. The mixture is cooled with ice, and 4.9 g of 7β-amino-3-(1-amino-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid dissolved in a mixture of 50 ml of N,N-dimethylacetamide, 2 ml of water and 3 g of triethylamine are added thereto. The mixture is stirred at 5° to 10° C. for one hour and further at room temperature for 15 hours. The reaction mixture is poured into 750 ml of ice-water, and 250 ml of ethyl acetate are added thereto. The mixture is stirred for 10 minutes and insoluble materials are filtered off. The aqueous layer is collected from the filtrate and is adjusted to pH 3 with 10% hydrochloric acid. The oily material thus obtained is extracted with a mixture of ethyl acetate and tetrahydrofuran (10:3). The extract is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is triturated with ethyl acetate and thus-precipitated powder is collected by filtration. The powder is dissolved in 100 ml of tetrahydrofuran with heating, and 250 ml of ethyl acetate are added thereto. After cooling, crystalline precipitates are collected by filtration. 4.8 g of 7β-{(Z)-2-tritylaminothiazol-4-yl)- 2-[((3RS)-2-pyrrolidon-3-yl)oxyimino]acetamido}-3-(1-amino-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid are obtained as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:12])[CH:9]([F:11])[F:10])=[N:6][CH:7]=1.[CH3:13][Mg+].[Br-].[NH4+].[Cl-]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:12])([CH3:13])[CH:9]([F:10])[F:11])=[N:6][CH:7]=1
Reactant: O=C(c1ccc(Br)cn1)C(F)F
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Br)cn1)C(F)F
Reaction time: 0.17 h

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)-2,2-difluoroethanone (1.5 g, 6.4 mmol) in tetrahydrofuran (15 mL) under nitrogen was added 3 N solution of MeMgBr in THF (3.2 mL, 9.6 mmol) dropwise at −15° C. The resulting solution was stirred at ambient temperature for 2 hours before the addition of saturated aqueous NH4Cl solution (10 mL) at 0° C. The resulting mixture was vigorously stirred for 10 minutes, and then extracted with ethyl acetate (3×20 mL). All the organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography with 1-3% ethyl acetate in hexane to afford the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J=2.0 Hz, 1H), 7.92 (dd, J=8.4, 2.0 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 5.76 (t, J=56.4 Hz, 1H), 5.22 (br, 1H), 1.60 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[N:5][N:4]([CH3:11])[C:3]=1[C:12]1[CH:13]=[C:14]([NH2:20])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[Cl:1][C:2]1[C:6]([C:7]([F:10])([F:8])[F:9])=[N:5][N:4]([CH3:11])[C:3]=1[C:12]1[CH:13]=[C:14]([NH:20][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[O:30])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(N)cc1-c1c(Cl)c(C(F)(F)F)nn1C
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(Cl)c(C(F)(F)F)nn1C
Yield: 63.6 %

Procedure:
3-(4-Chloro-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.03 g, 0.11 mmol) was treated with 4-fluorophenyl isocyanate (0.02 g, 14.6 μL, 0.13 mmol, 1.2 equiv.) in CH2Cl2 (4.0 mL), in a similar manner as described in Example 1.102. The product was further purified via reverse phase C-18 HPLC to afford Compound 40 (0.03 g, 0.07 mmol, 63% yield) as a white solid: LCMS m/z (%)=443 (M+H37Cl, 100), 445 (M+H35Cl, 36). 1H NMR (400 MHz, MeOH-d4) δ: 7.58 (dd, J=10.0, 2.0 Hz, 1H), 7.42 (dd, J=4.0 Hz, 2H), 7.40 (dd, J=8.0, 4.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.03 (dd, J=10.0, 6.0 Hz, 2H), 3.84 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]([O:29]CCCC)=[CH2:28].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)C.CN(C=O)C>[C:27]([C:3]1[C:4]2[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=2[CH:17]=[CH:18][C:2]=1[Cl:1])(=[O:29])[CH3:28]
Reactant: C=COCCCC
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
Combine 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.6 g, 1.41 mmol), butyl vinyl ether (0.9 mL, 7.06 mmol), palladium(II) acetate (32 mg, 0.14 mmol), DPPP (58 mg, 0.14 mmol), triethylamine (90.4 mL, 2.82 mmol), anhydrous DMF (10 mL) and stir at 90° C. for 2 h. Cool the reaction mixture to room temperature, add diethyl ether (25 mL) and wash with brine (15 mL). Separate the organic layer, dry over anhydrous Na2SO4, filter and concentrate in vacuo. Dissolve the residue in methanol (20 mL), add 1N aqueous HCl (18 mL) and stir at 70° C. for 2 h. Cool the reaction mixture to room temperature and remove methanol by evaporation. Dissolve the residue in diethyl ether (20 mL), wash with brine, collect the organic layer and dry over Na2SO4. Concentrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 3:2 gradient) to obtain the desired intermediate as a colorless oil (0.4 g, 90%). MS (ES+) m/z: 320 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)(=[O:22])[CH3:21]
Reactant: Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Yield: 50 %

Procedure:
Using an analogous procedure to that described in Example 11, 6-amino-4-(3'-chloroanilino)quinazoline was reacted with acetic anhydride to give 6-acetamido-4-(3'-chloroanilino)quinazoline in 50% yield, m.p. 260°-262° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[SH:17]>>[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[S:17][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1]
Reactant: Sc1nccs1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Product: O=[N+]([O-])c1ccc(Sc2nccs2)c(Cl)c1
Yield: 26 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 8 which is concerned with the preparation of starting materials, 3-chloro-4-fluoronitrobenzene was reacted with 2-thiazolethiol to give a precipitated solid which was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated to give 2-chloro-4-nitrophenyl 2-thiazolyl sulphide in 26% yield.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[NH:5][N:4]=1.[I:14](O)(=O)=O.II>C(O)C>[I:14][C:7]1[C:3]([C:2]([F:1])([F:12])[F:13])=[N:4][NH:5][C:6]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Nc1cc(C(F)(F)F)n[nH]1
Reactant: [O-][I+2]([O-])O
Agent: II
Solvent: CCO
Product: CC(=O)Nc1[nH]nc(C(F)(F)F)c1I
Temperature: 65 °C
Reaction time: 3.25 h
Yield: 296.8 %

Procedure:
To a solution of N-[3-(trifluoromethyl)-1H-pyrazol-5-yl]acetamide (7.3 g, 38 mmol) in ethanol (120 mL) were added iodic acid (1.65 g, 9.4 mmol) and iodine (4.8 g, 18.9 mmol). The reaction was stirred for 3.25 h at 65° C. The reaction mixture was concentrated in vacuo and the residue was suspended in hot CH2Cl2 (150 ml) with stirring, the solid was filtered and resuspended in hot CH2Cl2 (100 ml) filtered and dried in vacuo to provide the title compound as a white solid (8.9 g) which was used in the subsequent step.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([O:25]CC)=[O:24])[CH:18]=2)=[CH:14][C:13]=1[F:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>C(O)C.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=[O:24])[CH:18]=2)=[CH:14][C:13]=1[F:30])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(Oc2ccc(NC(=O)OCc3ccccc3)c(F)c2)ccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc(Oc2ccnc(C(=O)O)c2)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
After suspending ethyl 4-(4-benzyloxycarbonylamino-3-fluorophenoxy)pyridine-2-carboxylate (7.51 g) in ethanol (100 ml) and water (20 ml), lithium hydroxide (657 mg) was added at room temperature. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was stirred while cooling in an ice bath and then 1N hydrochloric acid (60 ml) was added thereto. After stirring for 5 minutes, the reaction mixture was concentrated. After concentration, the crystals precipitated in the reaction mixture were filtrated, and the crystals were washed with water. The crystals were then dissolved in ethyl acetate-tetrahydrofuran, the solution was dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure. The obtained precipitate was suspended in hexane and the precipitate was filtered. The solid was dried to provide the title compound (5.04 g, 72.0%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24]O)[CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([O:12][CH2:24][CH2:23][CH2:22][N:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Reactant: CN1CCN(CCCO)CC1
Product: COc1cc2ncnc(Cl)c2cc1OCCCN1CCN(C)CC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-6-hydroxy-7-methoxy-quinazoline and 3-(4-methylpiperazin-1-yl)-propan-1-ol. LC/ESI-MS: m/z=351 [M+H].