Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[NH:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]=[N+:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.S(Cl)([Cl:20])(=O)=O>ClC(Cl)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[Cl:20][C:9]1[CH:8]=[C:7]([CH:11]=[N+:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[NH:6][CH:10]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: C(c1ccc[nH]1)=[N+]1CCCC1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(Cl)Cl
Product: Clc1c[nH]c(C=[N+]2CCCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of 215.4 g. (0.865 moles) of the product of Example IV in 4 liters of dichloroethane at 0° C. is added dropwise 116.8g. (0.865 moles) of freshly distilled sulfuryl chloride. After addition is complete (about 40 minutes), the reaction mixture is allowed to warm to ambient temperature and is stirred for about 4 hours, after which the solvent is evaporated to give a tan residue. Recrystallization of this residue from dichloroethane/ether gives 1-(4-chloropyrrol-2-ylmethylene) pyrrolidinium perchlorate; m.p. 122°-126° C.
Reaction SMILES: C([Li])CCC.[Br-].C1([C:13]([PH3+])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2C=CC=CC=2)C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[N:32]=[C:31]([NH:37][C:38]([NH:40][S:41](C2C=CC=CC=2C=O)(=[O:43])=[O:42])=[O:39])[N:30]=1>O1CCCC1>[CH3:27][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[N:32]=[C:31]([NH:37][C:38]([NH:40][S:41]([C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:13]=[CH2:14])(=[O:42])=[O:43])=[O:39])[N:30]=1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C=O)n1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=Cc1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 0.02 mol of n-butyllithium in 20 ml of anhydrous tetrahydrofuran is added 3.6 g of triphenylmethylphosphonium bromide. The above solution is stirred at room temperature for 4 hours. A slurry of 3.7 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-formylbenzenesulfonamide in 30 ml of dry tetrahydrofuran is then added dropwise. The resulting mixture is refluxed overnight and allowed to cool to room temperature. The precipitate is removed by suction filtration and washed with methylene chloride. The combined filtrates are washed with dilute hydrochloric acid, water, dried and evaporated to dryness to yield the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([C:12](Cl)=[O:13])[CH2:11][CH2:10]1.[NH2:15][C:16]1[N:21]([C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH2:20][N:19]=[C:18]2[O:29][CH:30]=[CH:31][C:17]=12>>[NH2:15][C:16]1[N:21]([C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:12]([C:9]3([C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH2:11][CH2:10]3)=[O:13])=[CH:26][CH:27]=2)[CH2:20][N:19]=[C:18]2[O:29][CH:30]=[CH:31][C:17]=12
Reactant: O=C(Cl)C1(c2cc(F)ccc2F)CC1
Reactant: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Product: NC1=c2ccoc2=NCN1c1ccc(NC(=O)C2(c3cc(F)ccc3F)CC2)cc1

Procedure:
The compound was prepared following the procedure described in Example 474, using 1-(2,5-Difluoro-phenyl)-cyclopropanecarbonyl chloride as the acid chloride of choice, and 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) as the diamine of choice. MS(ES) m/e 407 [M+H]+.
Reaction SMILES: Cl.[Br:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][NH2:12])[CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.C(O)(=O)C.[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH:27]=O.[BH3-]C#N.[Na+].C1COCC1>CO>[CH2:31]([O:30][C:26](=[O:29])[CH2:27][NH:12][CH2:11][CH2:10][CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([Br:2])[N:8]=1)[CH3:32]
Reactant: NCCCc1cccc(Br)n1
Reactant: CCOC(=O)C=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CNCCCc1cccc(Br)n1
Reaction time: 12 h

Procedure:
A solution of 3-(6-bromo-pyridin-2-yl)propylamine 20-4 (25.6 g, 89.1 mmol), diisopropylethylamine (46.5 mL, 267 mmol), acetic acid (28 mL, 490 mmol), and ethyl glyoxylate (10.9 g, 107 mmol) in 200 ml of methanol was stirred at room temperature for one hour. A 1M solution of NaCNBH3 in THF (98.0 mL, 98.0 mmol) was added slowly with a syringe pump over 4 hours. The resulting solution was stirred for 12 hours, after which the solvent was removed in vacuo and the residue taken up in chloroform and filtered. The solution was then washed with 10% Na2CO3, dried over Na2SO4, and the solvent removed in vacuo to give the crude amine. The crude product was purified by silica gel chromatography (7% MeOH/CHCl3) to give 20-5 in a 3:2 mixture of ethyl and methyl esters.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[NH:9][C:8]=1[C:18]([OH:20])=O)(=[O:3])[CH3:2].[CH:21]([N:24](C(C)C)CC)(C)C.Cl.CN.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[NH:9][C:8]=1[C:18]([NH:24][CH3:21])=[O:20])(=[O:3])[CH3:2]
Reactant: COc1ccc2[nH]c(C(=O)O)c(CCNC(C)=O)c2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1[nH]c2ccc(OC)cc2c1CCNC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-acetamidoethyl)-5-methoxy-1H-indole-2-carboxylic acid (100 mg), diisopropylethylamine (0.310 mL), methylamine hydrochloride (73.3 mg), and N,N-dimethyl formamide (1.75 mL) was added 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (206 mg), followed by stirring at room temperature overnight. To the mixture was added ice water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration, the filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 20:1) to obtain 3-(2-acetamidoethyl)-5-methoxy-N-methyl-1H-indole-2-carboxamide (80.0 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22]I.[C-:24]#[N:25].[K+].O>CN(C=O)C.[Cl-].[Na+].O>[C:24]([CH2:22][CH2:21][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)/[C:7](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:6]=1[CH3:20])#[N:25]
Reactant: CSc1ccc(/C=C2/C(C)=C(CCI)c3cc(F)ccc32)cc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(/C=C2/C(C)=C(CCC#N)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of the iodide from Step 1 (3.7 g, 8.5 mmol) and potassium cyanide (5.5 g, 85 mmol) in DMF (40 mL) was stirred at room temperature for 45 minutes. There was added water (50 mL) and brine (100 mL) and the mixture was extracted with 1:1 ethyl acetate-hexane (4×100 mL); the combined extracts were washed with water (2×50 mL) and brine (1×50 mL), dried and evaporated. The crude residue was chromatographed on silica gel eluting with a 1:2 mixture of ether-ethyl acetate to afford the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]=[O:25].C([O-])([O-])=O.[K+].[K+].[Cl:32][C:33]1[CH:34]=[C:35]([OH:39])[CH:36]=[CH:37][CH:38]=1>CN(C=O)C.CC(=O)OCC.O>[Cl:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=1)[O:39][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]=[O:25]
Reactant: Oc1cccc(Cl)c1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Br)sc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Oc3cccc(Cl)c3)sc21
Temperature: 65 °C
Yield: 59 %

Procedure:
To a mixture of 6-bromo-1-methyl-2,4-dioxo-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (100 mg, 0.23 mmol), K2CO3 (159 mg, 1.15 mmol) in DMF (3 mL) was added 3-chlorophenol (90 mg, 0.70 mmol). The reaction was heated at 65° C. for 1 h, cooled to RT then diluted with EA (30 mL) and water (30 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography and eluted with PE/EA (5:1) to give 6-(3-chlorophenoxy)-1-methyl-2,4-dioxo-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (65 mg, 58.6% yield) as a yellow oil. LCMS: MH+ 479 and TR=1.836 min.
Reaction SMILES: B.C1CCCCC=1.C1(BC2CCCCC2)CCCCC1.[CH3:21][O:22][C:23](=[O:43])[CH2:24][C:25]1([CH3:42])[CH2:30][CH2:29][C:28]2[C:31]([CH3:41])=[C:32]([O:37][CH2:38][CH:39]=[CH2:40])[C:33]([CH3:36])=[C:34]([CH3:35])[C:27]=2[O:26]1.C([O-])(=O)C.[Na+].[I:49]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.CCOCC.O>[CH3:21][O:22][C:23](=[O:43])[CH2:24][C:25]1([CH3:42])[CH2:30][CH2:29][C:28]2[C:31]([CH3:41])=[C:32]([O:37][CH2:38][CH2:39][CH2:40][I:49])[C:33]([CH3:36])=[C:34]([CH3:35])[C:27]=2[O:26]1
Reactant: C=CCOc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)OC)O2
Reactant: II
Agent: B
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CC1(C)CCc2c(C)c(OCCCI)c(C)c(C)c2O1
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
To a stirred, ice-cold solution of 1M borane in tetrahydrofuran (10 ml) was added, dropwise, a solution of 2 ml (1.64 g) of cyclohexene in 6 ml of dry tetrahydrofuran. The mixture was allowed to stir at 0°-5° C. for 1.5 hours. To the resulting slurry of dicyclohexylborane was added, dropwise a solution of 1.59 g of the allyl ether from Example 18 in 4 ml of tetrahydrofuan. The mixture was stirred at 0°-5° C. for 1 hour and at room temperature for 18 hours at which point 20 ml of 1M methanolic sodium acetate was added dropwise followed by 23.8 ml of 0.4M methanolic iodine. The resulting mixture was stirred at room temperature for 4 hours whereupon 3.1 ml of aqueous sodium thiosulfate was added. The reaction mixture was poured into water and worked-up with ether in he usual manner. Chromatography of the crude product (4.4 g) on 100 g of silica gel afforded 1.71 g (76.7%) of racemic-3,4-dihydro-6-(3-iodopropoxy)-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetic acid methyl ester as an oil, eluted with 19:1 and 9:1 hexane-ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:22][OH:23])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccc(-c2ccc(F)cc2)cc1
Yield: 92.6 %

Procedure:
A stirred mixture of 4-(4′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid (2.72 g, 0.0100 mol), hydroxylamine hydrochloride (0.848 g, 0.0122 mol) and sodium carbonate (1.304 g, 0.0123 mol) in absolute ethanol (60 mL) was refluxed for 22 hours and allowed to cool. The solids were filtered, washed with additional ethanol, and allowed to air dry overnight. The solids were dissolved in methanol-water, and the solution acidified with 1.0 M hydrochloric acid (10 mL, 0.010 mol HCl). The mixture was concentrated to approximately 30 mL on a rotary evaporator, and the resulting precipitate filtered and dried in vacuo to give 2.66 g of 4-(4′-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid as a pale yellow solid; mp 152-153° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.[H-].[Na+].Br[CH:22]([CH3:28])[C:23]([CH:25]1[CH2:27][CH2:26]1)=[O:24].O>CN(C=O)C>[CH:25]1([C:23](=[O:24])[CH:22]([N:6]2[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]2=[N:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH3:28])[CH2:27][CH2:26]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(I)cn2)cc1
Reactant: CC(Br)C(=O)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(I)cn2C(C)C(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of N-(5-iodopyridin-2-yl)-4-methylbenzenesulfonamide (33.1 g) in DMF (400 ml) was added NaH (40% oil dispersion, 3.89 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Then 2-bromo-1-cyclopropylpropan-1-one (23.5 g) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and concentrated. The resulting solid was suspended in IPE, stirred for 1 h, and collected by filtration. The crude product was dissolved in EtOAc (1100 ml) at 70° C., and hexane (400 ml) was added while the temperature was maintained at 60° C. Seed crystal was added, and the mixture was stirred at the same temperature for 1 h. Additional hexane (400 ml) was added at 60° C., and the mixture was allowed to cool to room temperature overnight. The precipitate was collected by filtration, washed with hexane/EtOAc (1/1) 3 times, and dried to give the title compound (30.5 g) as a white solid.
Reaction SMILES: Cl.C(O[C:10]([N:12]([CH2:14][C:15]1[NH:16][CH2:17][CH2:18][N:19]=1)C)=O)C1C=CC=CC=1.[BrH:20]>C(O)(=O)C.CCOCC>[BrH:20].[BrH:20].[CH3:10][NH:12][CH2:14][C:15]1[NH:19][CH2:18][CH2:17][N:16]=1
Reactant: CN(CC1=NCCN1)C(=O)OCc1ccccc1
Agent: Br
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: CNCC1=NCCN1
Reaction time: 0.5 h

Procedure:
A solution of 4,5-dihydro-2-(N-benzyloxycarbonyl-N-methylaminomethyl)imidazole hydrochloride (2.0 g) in 2 ml glacial acetic acid was added dropwise to 10 ml of a 30% solution of HBr in acetic acid. After stirring 0.5 hour the reaction was diluted gradually with 15 ml of ether. The mixture was then stirred 24 hours at ambient temperature. The product separated as a white solid which was collected on a filter, washed with ether, and dried. The yield was 1.97 g, m.p. 181°-183° C.
Reaction SMILES: O[CH:2]([CH3:24])[CH:3]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:44](C(OCC)=O)=NC(OCC)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[NH2:44][CH:2]([CH3:24])[CH:3]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:6]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)O)o1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)N)o1
Temperature: 25 °C

Procedure:
3.66 g of ethyl 5-{(2RS,3SR)-3-hydroxy-2-(4-nitrophenyl)butyl}-2-furancarboxylate in 40 ml of tetrahydrofuran was mixed with 4.32 g of triphenylphosphine, 2.60 ml of diethyl azodicarboxylate and 4.53 g of diphenylphosphoryl azide under cooling with ice under stirring and stirred at room temperature for 18 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography [hexane/ethyl acetate=50/1→30/1]. The resulting azide was refluxed together with 2.37 g of triphenylphosphine in 55 ml of 10% hydrous tetrahydrofuran under heating for 6 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [ethylene chloride/methanol=100/1→20/1] to give 2.89 g of the title compound as a yellow oily substance.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[N:16]([CH3:17])[CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[N:11]=1)([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH3:4][C:3]1([CH3:5])[CH2:2][O:1][C:28](=[O:30])[N:6]1[C:7]1[S:8][CH:9]=[C:10]([C:12]2[N:16]([CH3:17])[CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[N:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cn1cc(C#N)cc1-c1csc(NC(C)(C)CO)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1cc(C#N)cc1-c1csc(N2C(=O)OCC2(C)C)n1
Reaction time: 2 h
Yield: 66.5 %

Procedure:
To a solution of 5-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}-1-methyl-1H-pyrrole-3-carbonitrile (1.10 g, 3.98 mmol), prepared in the previous step, in dry tetrahydrofuran (10 mL) under nitrogen was added triethylamine (0.56 mL, 4 mmol), followed by triphosgene (1.18 g, 4 mmol). After 2 h, the mixture was partitioned between water and ethyl acetate. The organic layers were washed with water, dried (anhydrous sodium sulfate) and evaporated. The residue was then purified by silica gel column chromatography (ethyl acetate:hexanes, gradient elution) to afford the title compound (0.80 g, 66%) as an off white powder. HRMS: calcd for C14H14N4O2S [M+H]+, 303.09102; found (ESI, [M+H]+), 303.093, ANLC 99.4% at 210-370 nm, 8.6 min; 99.7% at 246 nm, 8.6 min, the Xterra® RP18 column, 3.5%, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]1[N:15]=[C:16]([C:20](OCC)=[O:21])[NH:17][C:18](=[O:19])[C:7]1=[CH:6]2.Cl.[NH2:26][OH:27].C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]1[N:15]=[C:16]([C:20]([NH:26][OH:27])=[O:21])[NH:17][C:18](=[O:19])[C:7]1=[CH:6]2
Reactant: NO
Reactant: CCOC(=O)c1nc2nc3cc(OC)c(OC)cc3cc2c(=O)[nH]1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2cc3c(=O)[nH]c(C(=O)NO)nc3nc2cc1OC
Temperature: 95 °C
Yield: 74 %

Procedure:
Ethyl 7,8-dimethoxypyrimido-[4,5-b]quinolin-4(3H)-one-2-carboxylate (200 mg., 6.08 millimoles) is added to a solution of hydroxylamine hydrochloride (69 mg., 100 millimoles) and triethylamine (100 mg., 100 millimiles) in absolute ethanol (50 ml.). The mixture is heated at 95° C. overnight in a bomb and then cooled. The insoluble yellow solid is filtered off, washed with hot ethanol and dried to provide 143 mg. (74%) of the title product. M.P. 337° C. (dec.).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:26])[CH:4]1[CH2:25][CH2:24][N:7]2[C:8]3[CH:21]=[C:20](OC)[CH:19]=[CH:18][C:9]=3[N:10]([CH3:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:6]2[CH2:5]1>>[CH3:2][N:3]([CH3:26])[CH:4]1[CH2:25][CH2:24][N:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[N:10]([CH3:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:6]2[CH2:5]1
Reactant: COc1ccc2c(c1)N1CCC(N(C)C)CC1c1ccccc1N2C
Agent: Cl
Product: CN1c2ccccc2C2CC(N(C)C)CCN2c2ccccc21

Procedure:
melting point: 210°-212° C as HCl salt. 2-dimethylamino-10-methyl-7-methoxy-1,2,3,4,10,14b-hexahydro-pyridino[ 1,2-d]-dibenzo[b,f](1,4)-diazepine.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1>CCOCC>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2([OH:1])[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]2)=[CH:14][CH:13]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)C1CC(=O)C1
Solvent: CCOCC
Product: CCOC(=O)C1CC(O)(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a stirred solution of ethyl 3-oxocyclobutanecarboxylate (2 g, 14.07 mmol) in dry Et2O (30 mL), cooled to −80° C., was added 4-fluorophenyl magnesium bromide (16.88 mL, 16.88 mmol, 1 M in THF) dropwise. The reaction mixture was then allowed to warm to RT and stir for an additional 2 h. The reaction mixture was quenched with a saturated aq. solution of NH4Cl (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude reaction mixture was purified by silica gel chromatography (24 g REDISEP® column, eluting with 15% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 276A as a colorless liquid (1.7 g, 51%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.54 (dd, J=5.5, 9.0 Hz, 2H), 7.15 (t, J=8.8 Hz, 2H), 4.09 (q, J=7.4 Hz, 2H), 2.83-2.71 (m, 1H), 2.61 (s, 2H), 2.55-2.51 (m, 2H), 1.24-1.12 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.[O:29]1[CH2:34][CH2:33][N:32]([CH2:35]/[CH:36]=[CH:37]/[C:38](O)=[O:39])[CH2:31][CH2:30]1>>[NH2:12][C:8]1[N:9]=[CH:10][N:11]=[C:6]([O:5][C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:39])/[CH:37]=[CH:36]/[CH2:35][N:32]3[CH2:31][CH2:30][O:29][CH2:34][CH2:33]3)[CH:28]=[CH:27][CH:26]=2)[C:7]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1
Reactant: Nc1cccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)c1
Reactant: O=C(O)/C=C/CN1CCOCC1
Product: Nc1ncnc(Oc2cccc(NC(=O)/C=C/CN3CCOCC3)c2)c1-c1ccc(Oc2ccccc2)cc1
Yield: 19 %

Procedure:
(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-morpholinobut-2-enamide was prepared from 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and (E)-4-morpholinobut-2-enoic acid using Method E (19% yield). HPLC: 100%, RT=3.605 min. MS: m/z=524 [M+H]+, RT=3.59 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:14]=3)=[CH:11][C:10]([NH2:27])=[N:9]2)=[CH:4][CH:3]=1.[O:28]=[C:29]1[NH:33][CH2:32][C@@H:31]([C:34](O)=[O:35])[CH2:30]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:24])([F:23])[F:25])[CH:14]=3)=[CH:11][C:10]([NH:27][C:34]([C@H:31]3[CH2:30][C:29](=[O:28])[NH:33][CH2:32]3)=[O:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1cccc(-c2cc(N)nn2-c2ccc(Cl)cc2)c1)C(F)(F)F
Reactant: O=C1C[C@H](C(=O)O)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OCc1cccc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccc(Cl)cc2)c1)C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of 1-(4-chlorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (about 0.125 mmol) prepared in the previous step in N,N-dimethylformamide (1 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid prepared according to the same procedures as preparation 14 (18 mg) and WSC.HCl (29 mg) at room temperature, and the mixture was stirred for 3 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. The resulting organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (33 mg).