Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:45]=[CH:44][C:12]([O:13][C:14]2[C:22]3[NH:21][C:20](=[O:23])[N:19]([CH3:24])[C:18]=3[CH:17]=[CH:16][C:15]=2[C:25]2[C:26]3[CH:35]=[CH:34][N:33](COCC[Si](C)(C)C)[C:27]=3[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=2)=[CH:11][CH:10]=1.C(N)CN>C(Cl)Cl.CO>[Cl:8][C:9]1[CH:45]=[CH:44][C:12]([O:13][C:14]2[C:22]3[NH:21][C:20](=[O:23])[N:19]([CH3:24])[C:18]=3[CH:17]=[CH:16][C:15]=2[C:25]2[C:26]3[CH:35]=[CH:34][NH:33][C:27]=3[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=2)=[CH:11][CH:10]=1
Reactant: Cn1cc(-c2ccc3c([nH]c(=O)n3C)c2Oc2ccc(Cl)cc2)c2ccn(COCC[Si](C)(C)C)c2c1=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2ccc3c([nH]c(=O)n3C)c2Oc2ccc(Cl)cc2)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
Trifluoroacetic acid (1.50 mL) was added dropwise to a solution of 4-(4-chlorophenoxy)-1-methyl-5-(6-methyl-7-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one (0.057 g, 0.103 mmol) in methylene chloride (0.50 mL), and the resultant reaction mixture was stirred at RT for 3 h, after which time the reaction mixture was concentrated in vacuo to give a residue. This residue was dissolved in methanol (0.50 mL), treated with ethylenediamine (0.131 mL, 1.95 mmol) dropwise, and the resultant solution was stirred at RT for 16 h. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (24.6 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ 11.96 (br s, 1H), 11.20 (br s, 1H), 7.23 (dd, J=2.7, 2.7 Hz, 1H), 7.21-6.99 (m, 5H), 6.70-6.48 (m, 2H), 6.25-6.06 (m, 1H), 3.43 (s, 3H), 3.33 (s, 3H); LCMS calculated for C22H18ClN4O3 (M+H)+: m/z=421.1. found: 421.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:26]\[OH:27])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(Br)cc2)C2CCCC2)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(Br)cc2)C2CCCC2)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-cyclopentyl-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=403.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19]CC)=[O:18])=[CH:5]2.[OH-].[Li+].Cl.C(OCC)C>CO.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]([C:13]([F:16])([F:14])[F:15])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C)c2NC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Cc1cc(Cl)cc2c1NC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Yield: 2627.5 %

Procedure:
Ethyl 6-chloro-8-methyl-2-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylate (4.5, 0.51 mmol) was suspended in methanol-tetrahydrofuran-water (50 mL, 7:2:1). Lithium hydroxide (1.70 g, 42.3 mmol) was added, and the mixture was gently heated to reflux for two hours. The reaction was cooled to room temperature and 1 N aqueous hydrochloric acid added until pH=1. The organic solvent was removed in vauco to afford a suspension of a crude yellow solid. Diethyl ether (200 mL) was added, and the solution was washed with water (2×200 mL), saturated ammonium sulfate (2×200 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 6-chloro-8-methyl-2-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid (3.8 g, 13.4 mmol) as a yellow solid (95% yield). (CDCl3, 300 MHz) 7.56 (s, 1H), 6.93 (s, 1H), 6.90 (s, 1H), 5.11 (q, 1H, J=7.2 Hz), 4.78 (bs, 1H), 2.08 (s, 3H). HRMS m/z 291.0286(M+, C12H9ClF3NO2, calcd 291.0274).
Reaction SMILES: [Li][CH2:2]CCC.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.[NH4+].[Cl-]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[CH2:2])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1
Reactant: [Li]CCCC
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=Cc1ccc(N2CCN(C)CC2)cc1
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
Dropwise, 39 ml of n-BuLi (1.7 M, 66 mmol) was added to a stirred, cold (0° C.) solution of methyltriphenylphosphonium bromide (23.2 g, 65 mmol) in 100 ml of THF (dried) under N2. After 15 min, a solution of 4-(4-methylpiperazinyl)benzaldehyde (11.9 g, 58 mmol) in 30 ml of THF was added dropwise via needle. The yellow suspension was stirred for 4 hours and treated with NH4Cl. The solution was filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography elution with hexane, EtOAc, and Et3N in a 70:20:10 ratio to yield 10.6 g (90%) of white solid product. Without being bound by theory, it is believed that the following reaction took place.
Reaction SMILES: [S:1]([C:5]1[S:13][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br)#[N:15].C(N(CC)CC)C>C(#N)C.O>[S:1]([C:5]1[S:13][C:8]2[CH2:9][N:10]([CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:16]([C:14]#[N:15])[CH:17]=3)[CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: NS(=O)(=O)c1cc2c(s1)CNCC2
Reactant: N#Cc1cccc(CBr)c1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(CN2CCc3cc(S(N)(=O)=O)sc3C2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a partial suspension of 2-sulfamoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2.20 g, 10.1 mmol) in acetonitrile (50 ml) containing 3-cyanobenzylbromide (2.36 g, 12 mmol) was added triethylamine (1.70 ml, 12.2 mmol). After stirring at room temperature for three hours, the clear solution was diluted with water and the product was extracted into ethyl acetate/methanol, dried over anhydrous sodium sulfate, filtered and evaporated to give a residue which was triturated with methylene chloride/diethyl ether to give purified product (3.2 g, 96% yield). Recrystallization from hot ethanol gave product (2.4 g), m.p. 137°-139° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:24])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH2:19][CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH2:31]([O:33][C:34](Cl)=[O:35])[CH3:32]>ClCCl>[C:1]1([C:7]2[NH:8][C:9](=[O:24])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:34]([O:33][CH2:31][CH3:32])=[O:35])[CH2:19][CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c(-c2ccccc2)cn1S(=O)(=O)c1ccc2c(c1)CCN2
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1CCc2cc(S(=O)(=O)n3cc(-c4ccccc4)[nH]c3=O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
4-Phenyl-1-(indoline-5-sulfonyl)-2-imidazolone (150 mg, 0.44 mmol) prepared in Preparation 3 was dissolved in 10 ml of dichloromethane and then pyridine (39 μl, 0.484 mmol) and ethylchloroformate (46 μl, 0.484 mmol) were added thereto one after another. After the reaction mixture was stirred for one hour at room temperature, it was diluted with dichloromethane and washed twice with brine. The organic layer thus obtained was dried over anhydrous magnesium sulfate, concentrated to an oily state under reduced pressure, and then purified by silica gel column chromatography (eluent:dichloromethane/methanol=15/1, v/v) to afford 173 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][S:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:23]C=2C=1.CCN=C=NCCCN(C)C.Cl.N>CN(C=O)C.CCOC(C)=O>[C:14]([CH:10]1[S:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)(=[O:16])[NH2:23]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCSC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCSC(C(N)=O)C1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
4-(tert-butoxycarbonyl)thiomorpholine-2-carboxylic acid (2.47 g, 10 mmol) and HOBt (1.62 g, 12 mmol) were dissolved in DMF (20 mL), and EDCl (2.11 g, 11 mmol) was added. The reaction mixture was stirred for 1 hour, and 25% aqueous ammonia (5 mL) was added, and the reaction was stirred for another 2 hours. The reaction was then diluted with EtOAc (200 mL) and partitioned with water (100 mL). The organic layer was washed with saturated aq. NaHCO3 (2×100 mL), and then dried with Na2SO4. The solvent was removed in vacuo to afford title compound as white solid 2.46 g. MS (m/z): 147 (M+H-Boc)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C:10](=[CH:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=O)([O-])[O-].[Na+].[Na+].CB1OB(C)OB(C)O1.[OH-].[Na+]>COCCOC.C1COCC1.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:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C:10](=[CH:11][C:12]3[C:17]2=[N:16][C:15]([CH3:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)Cc2cc3ccc(Br)nc3n21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: Cc1ccc2cc3n(c2n1)[C@H](C)CN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of 0.20 g (0.55 mmol) (R)-6-bromo-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate a) in 10 ml 1,2-dimethoxyethane was added 63 mg (55 μmol) tetrakis(triphenylphosphine)palladium. After 30 min, 5 ml saturated aqueous sodium carbonate solution and 0.09 ml (0.65 mmol) of a 1M trimethylboroxine solution in THF were added and the resulting suspension was heated to reflux for 5 h. The reaction mixture was cooled to room temperature, poured into 20 ml 1M aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:1) as eluant to yield the desired product as a yellow solid (71.1%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][CH:15]=[CH:14][C:13]=3[CH:17]=2)O1.I[C:20]1[C:28]2[C:23](=[N:24][CH:25]=[N:26][C:27]=2[NH2:29])[N:22]([CH:30]([CH3:32])[CH3:31])[N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[O:16]1[C:12]2[CH:11]=[CH:10][C:9]([C:20]3[C:28]4[C:23](=[N:24][CH:25]=[N:26][C:27]=4[NH2:29])[N:22]([CH:30]([CH3:32])[CH3:31])[N:21]=3)=[CH:17][C:13]=2[CH:14]=[CH:15]1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc3occc3c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 64.8 %

Procedure:
A solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (56 mg, 0.23 mmol) in EtOH (1.65 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.1 mmol) in DME (6 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (0.95 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA96 (19 mg, 72% yield). ESI-MS (M+H)+ m/z calcd 296.1, found 296.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([NH2:14])[CH:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.C(#N)C.[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>CN(C=O)C>[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH:14][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:13][N:12]=1)=[O:33]
Reactant: COc1ccc(-c2cc(N)n[nH]2)cc1
Reactant: O=C(Cl)CCCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(NC(=O)CCCCBr)n[nH]2)cc1
Yield: 70 %

Procedure:
A solution of 5-(4-methoxyphenyl)-1H-pyrazol-3-amine and diisopropylethylamine in 10 volumes of a 9:1 mixture of acetonitrile:DMF was cooled to −10° C. 5-Bromovaleryl chloride was added dropwise over a minimum of 3 hr at −10° C. The resulting solution was held at −10° C. until reaction completion, generally 2 hr. The reaction mixture was quenched with water. The product was isolated by filtration, washed with water, TBME and suction dried. The product-wet cake was purified by re-slurrying in TBME at 35° C. for a minimum of 2 hr. The yield was 70-80%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.[OH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:16])[CH2:27]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Oc1cccc2c1CNC2
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(O)c4C3)c(F)cc2c1=O
Yield: 19.3 %

Procedure:
136 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 130 mg of 4-hydroxyisoindoline hydrobromide, 114 mg of 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 1 to produce 37 mg of the target compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1(/[CH:13]=[CH:14]/[C:15]2[O:16][CH:17]=[C:18]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][C:31](OCC)=[O:32])=[CH:24][CH:23]=3)[N:19]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O1CCCC1.Cl>C(OCC)C.O>[C:7]1(/[CH:13]=[CH:14]/[C:15]2[O:16][CH:17]=[C:18]([CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][OH:32])=[CH:26][CH:27]=3)[N:19]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a suspension of lithium aluminum hydride (350 mg) in diethyl ether (10 ml) was added dropwise, at 0° C., a solution of ethyl 4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyrate (3.00 g) in diethyl ether (10 ml)—tetrahydrofuran (10 ml). The mixture was stirred at 0° C. for one hour and at room temperature for further one hour, followed by addition of water. The mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:1,v/v), 4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butanol (2.00 g, 74%) was obtained. Recrystallization from ethyl acetate-hexane afforded colorless needles, mp 90-91° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[C:18]([O:20][CH3:21])=[O:19].Br[CH2:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC.O.C(OCC)(=O)C>[C:32]([O:31][C:30]([NH:29][CH2:28][C:27]1[CH:37]=[CH:38][C:24]([CH2:23][C:14]2([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:16][CH2:17][O:13]2)=[CH:25][CH:26]=1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CBr)cc1
Reactant: COC(=O)C1CCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: COC(=O)C1(Cc2ccc(CNC(=O)OC(C)(C)C)cc2)CCCO1
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a solution of diisopropylamine in 10 ml of tetrahydrofuran was added 5.5 ml of 1.6 M solution of n-butyllithium in hexane at −78° C. under an atmosphere of nitrogen gas. After stirring for 30 minutes, a solution of 1.17 g of methyl tetrahydro-2-furancarboxylate in 10 ml of tetrahydrofuran was added dropwise. After stirring for further 30 minutes, a solution of 1.20 g of t-butyl N-[4-(bromomethyl)benzyl]carbamate in 20 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at −78° C. for 3 hours. 50 ml of saturated aqueous ammonium chloride, 200 ml of ethyl acetate and 100 ml of water were added, and the organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography, to give 0.961 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:33])[NH:12][C:11]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Yield: 69.8 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(1H-1,2,4-triazol-1-yl)-1,4-dihydropyrimidine-5-carboxylate (1.23 g, 3 mmol) was reacted with NBS (0.54 g, 3 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (1.02 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:34])=[C:24]([C:27]4[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH3:44][S:45]([CH2:48][CH2:49][NH2:50])(=[O:47])=[O:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:34])=[C:24]([C:27]4[O:31][C:30]([CH2:32][NH:50][CH2:49][CH2:48][S:45]([CH3:44])(=[O:47])=[O:46])=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)CCN
Reactant: O=Cc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cc2F)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CS(=O)(=O)CCNCc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cc2F)o1
Reaction time: 18 h
Yield: 61 %

Procedure:
Prepared according to Procedure D from a mixture of 5-(4-(4-benzyloxy-phenylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride (0.13 grams) in 1,2-dichloroethane (3 ml), diisopropylethylamine (65 mg), acetic acid (45 mg), 2-methanesulphonylethylamine (0.125 grams), and sodium triacetoxyborohydride (0.27 grams). The mixture was stirred for 18 hours. The reaction mixture was quenched with methanol (3 ml) and poured into a separatory funnel containing aqueous saturated sodium hydrogen carbonate (100 ml) and ethyl acetate (100 ml). The mixture was extracted. The organic layer was washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was treated with ethyl acetate/hexanes and collected by filtration (0.083 g, 61% yield). δ 1H NMR (400 MHz, DMSO-d6) 9.98 (s, 1H), 8.83 (d, 1H), 8.44 (s, 1H), 7.58 (m, 3H), 7.44 (m, 2H), 7.37 (m, 2H), 7.31 (m, 1H), 7.03 (d, 1H), 6.91 (m, 1H), 6.5 (d, 1H), 5.1 (s, 2H), 3.84 (s, 1H), 3.25 (m, 2H), 2.99 (s, 3H), 2.96 (m, 2H). ESI-MS m/z 545 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([OH:18])=[O:17])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(O[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O.C1(O)C=CC=CC=1>C1(C)C=CC=CC=1.CCCCCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([O:18][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: Cc1cc(=O)c(C(=O)Oc2ccccc2)nn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.1 %

Procedure:
To an ice cooled suspension of 5.29 g (0.02 mol) 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methyl pyridazine-3-carboxylic Acid (see Example 12) and 2.02 g (0.02 mol) of triethylamine in 125 mol of toluene there is added dropwise 3.13 g (0.02 mol) of phenyl chloroformate. The suspension formed is stirred at room temperature for 15 minutes and to it there is added 1.88 g (0.02 mol) of phenol in 25 ml of toluene. The mixture is stirred at room temperature for 18 hrs. and to it there is added 100 ml of water. The suspension is stirred at room temperature for 2 hrs. and is poured into 800 ml of hexane. The suspension formed is stirred at room temperature for 3 hrs. and is vacuum filtered. The filter cake is slurried in 25 ml of toluene and is filtered. The filtrate is added to 150 ml of hexane and the suspension formed is stirred at room temperature for 2 hrs. The suspension is vacuum filtered and the filter cake air dried to afford 1.3 g (19% yield) of product, mp 140°-146° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:5][C@@H:4]1[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:13][N:12]=1)[CH3:10])=[O:7].[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1.O>[O:1]([CH2:2][C@H:3]1[CH2:5][C@@H:4]1[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])=[CH:13][N:12]=1)[CH3:10])=[O:7])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccccc1
Reactant: C[C@@H](NC(=O)[C@H]1C[C@@H]1CO)c1ccc(OCC(F)(F)F)cn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)[C@H]1C[C@@H]1COc1ccccc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.6 %

Procedure:
To a mixture of (1S*,2S*)-2-(hydroxymethyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cy clopropanecarboxamide (30 mg, 0.094 mmol) and phenol (16.0 mg, 0.17 mmol) in tetrahydrofuran (1 mL), triphenylphosphine (45 mg, 0.17 mmol) and di-tert-butyl azodicarboxylate (28.2 mg, 0.12 mmol) were added successively. After stirring at room temperature for 1 day, the mixture was poured into water, and the aqueous layer was extracted with dichloromethane three times. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 12.1 mg (33% yield) of the title compound.