Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.CS[CH:8]1[N:11]([C:12](=[C:17]2[S:21][C:20]([C:23]([F:26])([F:25])[F:24])([OH:22])[CH2:19][S:18]2)[C:13]([O:15][CH3:16])=[O:14])[C:10](=[O:27])[CH2:9]1>C(Cl)Cl>[Cl:4][CH:8]1[N:11]([C:12](=[C:17]2[S:21][C:20]([C:23]([F:26])([F:25])[F:24])([OH:22])[CH2:19][S:18]2)[C:13]([O:15][CH3:16])=[O:14])[C:10](=[O:27])[CH2:9]1
Reactant: COC(=O)C(=C1SCC(O)(C(F)(F)F)S1)N1C(=O)CC1SC
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(=C1SCC(O)(C(F)(F)F)S1)N1C(=O)CC1Cl

Procedure:
Sulphuryl chloride (59.7 mg, 35.8 μl, 0.442 mmole) was added to a solution of methyl 2-(4-methylthio-2-azetidinon-1-yl)-2-(4-trifluoromethyl-4-hydroxy-1,3-dithiolan-2-ylidene)acetate (166 mg, 0.442 mmole) in methylene chloride (3 ml) at room temperature, with stirring. After this addition, the solution was stirred for 3 minutes and then the solvent was distilled off to give the crude methyl 2-(4-chloro-2-azetidinon-1-yl)-2-(4-trifluoromethyl-4-hydroxy-1,3-dithiolan-2-ylidene)acetate. This 4-chloroazetidinone compound was dissolved in methylene chloride (3 ml) without purification, and triethylamine (185 μl) was added thereto, after which the mixture was stirred at room temperature for 2 hours. The solvent was distilled off from the reaction mixture under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulphate. The solvent was distilled off under reduced pressure and the residue was purified by preparative thin layer chromatography (eluent: a 3:2 by volume mixture of benzene and ethyl acetate), to give 63 mg of the desired product as crystals.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[C:8]=2[N:9]=1)[CH3:2].F[C:29](C1C=CC=CC=1)(F)F.F[B-](F)(F)F.C[O+](C)C>C(OCC)(=O)C>[CH2:1]([S:3][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:29])[C:8]=2[N:9]=1)[CH3:2]
Reactant: FC(F)(F)c1ccccc1
Reactant: CCSc1nc2c(=O)[nH]ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: CCSc1nc2c(OC)nccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a mixture of 2-(ethylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (40 mg) and (trifluoromethyl)benzene (10 ml) was added trimethyloxonium tetrafluoroborate (22 mg) at room temperature, and the reaction mixture was heated under reflux for 3 hr, allowed to be cooled to room temperature, and diluted with ethyl acetate. The reaction mixture was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from a mixed solvent of ethyl acetate/hexane to give the title compound (16 mg).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18](=[O:20])[CH3:19].[C:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>O.C1(C)C=CC=CC=1.C(O)C.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>[C:18]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:15]=[CH:16][CH:17]=[C:8]2[C:27]1[CH:28]=[CH:29][C:24]([C:21](=[O:23])[CH3:22])=[CH:25][CH:26]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1cccc2c(Br)cccc12
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2cccc3c(C(C)=O)cccc23)cc1
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
A solution of sodium carbonate (2.55 g, 24.09 mmol) in water (20 mL) was added to a solution of 1-(5-bromonaphthalen-1-yl)ethanone (1.2 g, 4.8 mmol) and 4-acetylphenylboronic acid (1.03 g, 6.26 mmol) in toluene (20 mL) and ethanol (20 mL) and then heterogeneous solution was vigorously stirred with bubbling nitrogen for 15 min. Then Pd(PPh3)4 (0.111 g, 0.096 mmol) was added and the reaction vessel was sealed and heated at reflux for 6 h. The reaction was cooled and concentrated to dryness. The crude residue was taken into EtOAc (˜150 mL) and water (˜100 mL). The layers were separated and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated to an orange solid. The orange solid was purified on a BIOTAGE® Horizon (40 g SiO2, DCM) to yield 1-(4-(5-acetylnaphthalen-1-yl)phenyl)ethanone (1.31 g) as an off-white solid. LC-MS retention time 3.736 min; m/z 289.19 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 8.75 (d, J=8.8 Hz, 1H), 8.11 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.5 Hz, 1H), 7.94 (dd, J=7.2, 1.1 Hz, 1H), 7.67 (dd, J=8.5, 7.0 Hz, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.45-7.51 (m, 2H), 2.79 (s, 3H), 2.70 (s, 3H).
Reaction SMILES: CO[C:3](=O)[C@@H:4]1[CH2:8][C@@H:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:6][N:5]1[C:17](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-])=O.[H-].C([Al+]CC(C)C)C(C)C.CO.[Cl-].[NH4+]>ClCCl>[Si:10]([O:9][C@H:7]1[CH2:6][N:5]2[C@H:4]([CH2:3][NH:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]2=[O:27])[CH2:8]1)([C:13]([CH3:14])([CH3:16])[CH3:15])([CH3:11])[CH3:12]
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)c1ccccc1[N+](=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CNc3ccccc3C(=O)N2C1
Temperature: -70 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a solution of 9.0 g of (2S, 4R)-4-(tert-butyldimethylsilyloxy)-1-(2-nitrobenzoyl) proline methyl ester in 90 ml of dichloromethane, there was dropwise added 44 ml of a 1M solution of diisobutyl aluminum hydride in dichloromethane at −70° C. over 30 minutes in a nitrogen gas atmosphere and then the mixture was stirred at −70° C. for one hour. A mixture containing 1 ml of methanol and 1 ml of dichloromethane was added to the reaction solution at −60° C., then 10 ml of a saturated aqueous ammonium chloride solution was added thereto and the mixture was stirred at room temperature for one hour. The precipitates separated out were filtered off, the filtrate was washed with water, dried and concentrated under reduced pressure. The resulting oily substance was dissolved in 50 ml of methanol, followed by addition of 4.5 g of a 10% palladium-carbon catalyst to the solution and stirring at room temperature for 15 hours in a hydrogen gas atmosphere. The catalyst present in the reaction solution was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, followed by elution with methanol/chloroform. (1/100) to thus give 3.7 g (yield 51.2%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].CO.S(=O)(=O)(O)O.[C:23](=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:23])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: NCCCCCCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCCCCCCCCCCN
Temperature: 60 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
To a 3-l flask equipped with a stirrer, 200.0 g (0.93 mol) of 12-aminododecanoic acid, 600 g of methanol and 100 g (1.0 mol) of sulfuric acid were charged, followed by stirring at 60° C. for 5 hours. After the reaction mixture was allowed to cool down, it was diluted with methylene chloride, followed by neutralization with an aqueous solution of sodium carbonate. The solvent was distilled off under reduced pressure, followed by purification by chromatography on an alumina short column, whereby 201.7 g of the title compound (7-a) were obtained (yield: 95%).
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[C:29]([C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:52])[O:39][CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45](Br)=[CH:44][C:43]=2[O:49][CH2:50][CH3:51])[CH:34]=[CH:35][CH:36]=1)#[N:30]>>[C:29]([C:31]1[CH:32]=[C:33]([NH:37][C:38]([O:39][CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([B:25]([OH:27])[OH:26])=[CH:44][C:43]=2[O:49][CH2:50][CH3:51])=[O:52])[CH:34]=[CH:35][CH:36]=1)#[N:30]
Reactant: CCOc1cc(Br)ccc1CCOC(=O)Nc1cccc(C#N)c1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Product: CCOc1cc(B(O)O)ccc1CCOC(=O)Nc1cccc(C#N)c1
Yield: 54 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 62F (811 mg, 2.1 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 62G (400 mg, 54%) as a white solid. MS (ESI) m/z 355.2 (M+H)+.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:16]([O:18][CH:19]([O:24][CH2:25][CH3:26])[CH2:20][CH2:21][CH2:22]Cl)[CH3:17]>>[CH2:16]([O:18][CH:19]([O:24][CH2:25][CH3:26])[CH2:20][CH2:21][CH2:22][O:3][CH2:2][CH2:1][OH:4])[CH3:17]
Reactant: OCCO
Reactant: CCOC(CCCCl)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(CCCOCCO)OCC
Temperature: 25 °C

Procedure:
A mixture of anhydrous ethylene glycol (120 g, 1.93 moles), a 11.0M solution of potassium tert-butoxide in tert-butanol (70 ml, 0.07 moles), and 4-chlorobutyraldehyde diethyl acetal (11 g, 0.061 moles) is stirred overnight at 100° C. under an argon atmosphere. After cooling to room temperature, the reaction mixture is added to 600 ml distilled water. The product is extracted with dichloromethane (150, 125, and 125 ml). The combined extracts are then dried with anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. Next the product is subjected to vacuum distillation (kugelrohr, t=90-110° C., 0.10 mm Hg). Yield 5.5 g.
Reaction SMILES: [OH:1][CH:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5][N:4]([CH3:16])[C:3]1=[O:17].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[OH:1][CH:2]1[C:7]2[N:8]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][CH:23]=3)[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5][N:4]([CH3:16])[C:3]1=[O:17]
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)C(=O)C3O
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)C(O)C(=O)N(C)C1

Procedure:
The title compound is prepared from a mixture of 1,2-dihydro-4-hydroxy-2,8-dimethyl-4H-pyrido[4,3-b]indol-3(5H)-one, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([CH3:25])=[CH2:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[C:4]([CH3:27])[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]3([CH3:25])[CH2:24][O:33]3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:12][C:11]2=[O:26])[CH3:9])=[C:4]([CH3:27])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2C)C(=O)O1
Solvent: ClCCl
Product: Cc1cc(Br)ccc1[C@H](C)N1CC[C@](CC2(C)CO2)(c2ccccc2)OC1=O
Temperature: 5 °C
Reaction time: 8 h

Procedure:
3-[(S)-1-(4-Bromo-2-methyl-phenyl)-ethyl]-(R)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazin-an-2-one (1.34 g) dissolved in dichloromethane (15 mL) was added to a solution of 3-chloroperoxybenzoic acid (77%, 0.81 g) in dichloromethane (15 mL) cooled to 5° C. The cooling bath was removed and the solution was stirred at room temperature overnight. Aqueous 10% Na2S2O3 solution (10 mL) and aqueous saturated NaHCO3 solution (25 mL) were added and the resulting mixture was stirred for further 30 min. The organic phase was separated and washed with aqueous Na2S2O3 solution combined with aqueous saturated NaHCO3 solution, water, and brine. The organic phase was dried (MgSO4) and concentrated to furnish the title compound. Yield: 1.55 g (ca. 85-90% pure); LC-MS (Method 4): tR=4.28 min; Mass spectrum (ESI+): m/z=444/446 (Br) [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([O:28][CH3:29])=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[N:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)[CH2:32][CH2:31]2)[N:25]=[C:24]([CH3:46])[N:23]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pt]=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([O:28][CH3:29])=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:32][CH2:31]2)[N:25]=[C:24]([CH3:46])[N:23]=1)[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(NCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)nc(C)nc1N1CCC(c2ccc3cccnc3n2)CC1
Agent: O=[Pt]
Solvent: CCO
Product: COc1c(NCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)nc(C)nc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Reaction time: 2 h
Yield: 69.4 %

Procedure:
A mixture of 820 mg (1.3 mmoles) of tert-butyl 2-benzyloxycarbonylamino-3-[5-methoxy-2-methyl-6-(4-[1,8]naphthyridin-2-yl-piperidin-1-yl)-pyrimidin-4-ylamino]-propionate and 30 mg of platinum oxide in 50 ml of ethanol is stirred for 2 hours under hydrogen at atmospheric pressure. The reaction mixture is filtered on Clarcel then evaporated to dryness under reduced pressure (2 kPa). The residue is crystallized from diisopropyl ether. 570 mg of expected product is obtained in the form of an amorphous white solid.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:54])[NH:29][C@H:30]([CH2:35][O:36][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:31][CH:32]([CH3:34])[CH3:33])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:54])[NH:29][C@H:30]([CH2:35][OH:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[N:27]=2)[CH2:20]1
Reactant: CC(C)C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](CO)NC(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 74.1 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[(1S)-1-(t-butyldiphenylsilyloxymethyl)-3-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidine (2.14 g, 3.72 mmol) (obtained as described in Reference Example 37(2)) in anhydrous tetrahydrofuran (107 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (8.94 ml, 8.94 mmol) in an ice bath. The mixture was stirred in the ice bath for 4 hours. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate ethyl acetate:methanol (9:1) as the eluant to afford 3-hydroxy-1-{4-[(1S)-1-(hydroxymethyl)-3-methyl-butylcarbamoyl]-1,3-thiazol-2-yl}azetidine (825 mg, yield 74%) as a pale yellow oil.
Reaction SMILES: [CH:1]1([N:4]([C@@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[F:18])C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=1>>[Cl:26][C:23]1[CH:22]=[N:21][C:20]([N:15]2[CH2:16][CH2:17][C@@H:12]([NH:4][CH:1]3[CH2:2][CH2:3]3)[C@@H:13]([F:18])[CH2:14]2)=[N:25][CH:24]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N(C1CC1)[C@@H]1CCNC[C@@H]1F
Product: F[C@H]1CN(c2ncc(Cl)cn2)CC[C@H]1NC1CC1

Procedure:
The title compound is prepared from tert-butyl N-cyclopropyl-N-[(3S,4R)-3-fluoropiperidin-4-yl]carbamate and 2,5-dichloropyrimidine following a procedure analogous to that described for Intermediate 87. LC (method 20): tR=1.86 min; Mass spectrum (APCI): m/z=271 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:6][C:5]=1[CH3:17].[OH-].[Na+]>>[CH3:17][C:5]1[CH:6]=[C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:18])=[O:2]
Reactant: COC(=O)c1ccc(N2CCN(C)CC2)cc1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(N2CCN(C)CC2)ccc1C(=O)O
Temperature: 40 °C

Procedure:
To a solution of 2-methyl-4-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester (660 mg, 2.66 mmol) in MeOh (4 ml), 2M NaOH (4 ml, 8 mmol) was added. The reaction was heated for 3 hours at 40° C. until HPLC revealed the disappearance of the starting-material. The solvent was removed under reduced pressure and the solution was diluted with water and neutralized to pH 7 with aqueous 25% HCl. The precipitate was filtrated and washed with Et2O to afford the desired final compound as with solid (400 mg, 64%).
Reaction SMILES: [CH:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([NH:26]C(=O)OC(C)(C)C)=[CH:22][CH:21]=2)[N:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)[N:9]=1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)S(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
Tert-butyl (4-{4-[(isopropylsulfonyl)methyl]-6-morpholin-4-ylpyrimidin-2-yl}phenyl)carbamate (2.7 g, 5.67 mmol) was dissolved in DCM (20 mL) and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at room temperature for 2 hours then diluted with DCM (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). Organic phase collected, dried over magnesium sulphate, filtered and concentrated in vacuo to give the desired material as a cream solid (2.1 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:34][C:35]1[CH:44]=[C:43]2[C:38]([C:39]([O:45][C:46]3[CH:47]=[C:48]4[C:52](=[CH:53][CH:54]=3)[NH:51][C:50]([CH3:55])=[CH:49]4)=[N:40][CH:41]=[N:42]2)=[CH:37][C:36]=1[O:56][CH3:57].[CH3:58][N:59]([CH3:63])[CH2:60][CH2:61]O>C(Cl)Cl>[CH3:58][N:59]([CH2:60][CH2:61][O:34][C:35]1[CH:44]=[C:43]2[C:38]([C:39]([O:45][C:46]3[CH:47]=[C:48]4[C:52](=[CH:53][CH:54]=3)[NH:51][C:50]([CH3:55])=[CH:49]4)=[N:40][CH:41]=[N:42]2)=[CH:37][C:36]=1[O:56][CH3:57])[CH3:63]
Reactant: CN(C)CCO
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
0.5M Triphenylphosphine in methylene chloride and diisopropyl azodicarboxylate (150 μl, 0.75 mmol) were added in portions to a suspension of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (112 mg, 0.35 mmol), (prepared as described in Example 49), and N,N-dimethylethanolamine (62 mg, 0.7 mmol) in methylene chloride (2 ml). After stirring for 2 hours at ambient temperature, the reaction mixture was poured onto an Isolute® column (10 g of silica) and eluted with ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene chloride (10/40/50), methanol/methylene chloride (10/90), and 3M ammonia in methanol/methanol/methylene chloride (5/15/80). After removal of the volatiles by evaporation, the residue was dissolved in the minimum amount of methylene chloride (about 3 ml) and ether and petroleum ether (about 10 ml) was added. The resulting precipitate was collected by filtration and dried under vacuum to give 7-(2-(N,N-dimethylamino)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (52 mg, 38%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21].O>CCOCC>[F:18][C:19]([F:26])([F:25])[C:20]([C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([F:8])[CH:7]=1)=[O:21]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: O=C(c1cc(F)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 75.9 %

Procedure:
5.00 g (20.57 mmol) of 3-bromo-5-fluorobenzotrifluoride were stirred in 60 ml of dry ether and admixed dropwise at −78° C. under a protective gas atmosphere (argon) with 1.33 ml (20.75 mmol) of ten-butyllithium solution [cf. also trifluoroacylation: H. K. Nair. D. M. Quinn Bioorganic & Medicinal Chemistry Letters 3(12), 2619-22 (1993): G. J. Pork et al. J. Org. Chem. 22, 993 (1957)]. Subsequently, the reaction mixture was stirred at −78° C., for 45 minutes and then added dropwise, with the aid of a syringe, in portions at −78° C., to a solution of 3.71 g (26.17 mmol) of ethyl trifluoroacetate in 40 ml of dry ether. Thereafter, the entire reaction mixture was stirred first at −78° C. for 10 minutes and then at room temperature for one hour. For workup, the entire reaction mixture was added to water and extracted with ether. The organic phase was removed and dried at 40° C. under reduced pressure (not less than 10 mbar owing to the high volatility of the compound). This gave 4.06 g (75.9% of theory) of 2,2,2-trifluoro-[3-fluoro-5-(trifluoromethyl)phenyl]-ethanone, which was isolated as the hydrate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16](Br)[CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2].[CH3:30][O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCO.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([O:31][CH3:30])[CH:37]=4)[CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1cc(Br)ccc21
Reactant: COc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1cc(-c3cccc(OC)c3)ccc21
Temperature: 80 °C
Yield: 93.6 %

Procedure:
To a stirred solution of 8-bromo-3-(4-fluorobenzoyl)-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (compound in Example 37A, 70 mg, 0.15 mmol), 3-methoxyphenylboronic acid (58 mg, 0.38 mmol), and (o-tolyl)3P (24 mg, 0.077 mmol) in toluene/EtOH (2:1, 3 mL) was added 0.55 mL of 1M NaHCO3 solution and Pd(OAc)2 (7 mg) at ambient temperature. The reaction mixture was heated at 80° C. under N2 for 1.5 hours and samples monitored by LC-MS. The solution was diluted with DCM (10 mL) and washed with brine. The aqueous phase was extracted with DCM (10 mL) twice. The combined organic phase was dried over Na2SO4 and concentrated. The crude product was purified by flash chromatograph on silica gel, eluting with EtOAc-hexane (0-30%) to yield the title compound (68 mg) as a light yellow solid; 1H-NMR (CDCl3): δ 10.76 (1H, s), 8.20 (1H, s), 7.78 (4H, m), 7.52 (2H, m), 7.42 (1H, d), 7.36 (3H, m), 7.04 (1H, m), 4.43 (4H, m), 4.05 (3H, s), 3.45 (2H, m), 1.39 (3H, t). MS (ESI): 485 (MH+).