Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C>[N:15]1([CH2:14][CH2:13][O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: N#Cc1ccc(O)cc1
Reactant: ClCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a solution of 4-cyanophenol (5.95 g, 0.05 mol) in DMF (35 mL) at 0° C. was added 60% NaH (2.2 g, 0.055 mol). The reaction mixture was stirred at 0° C. for 15 minutes, then at room temperature for 15 minutes and then N-(2-chloroethyl)morpholine (prepared from 11.16 g, 0.06 mol of the hydrochloride salt) was added and the reaction mixture was stirred at room temperature for about 2 days. There was still a small amount of starting material present so the reaction mixture was heated on a steam bath for 4 hours. The reaction mixture was cooled to room temperature and then the solvent was removed. Ice-water was added to the residue and the solid which precipitated was collected by filtration and dried to afford 11.3 g (97%) of 4-[2-(4-morpholinyl)ethoxy]benzonitrile.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH:9]([OH:12])[CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14]CCOC.C(=O)(OCC)OCC.C[O-].[Na+]>O>[OH:11][CH2:10][CH:9]1[O:12][C:13](=[O:14])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8]1
Reactant: OCC(O)CNc1ccccc1
Reactant: COCCOC
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(=O)OCC
Solvent: O
Product: O=C1OC(CO)CN1c1ccccc1

Procedure:
A mixture of 83.6 g (0.5 mole) of 3-phenylamino-1,2-propanediol, 250 ml of 1,2-dimethoxyethane and 61 ml of diethyl carbonate was refluxed in a nitrogen atmosphere. Solid sodium methoxide (about 0.15 g) was added and refluxing continued for approximately 21/2 hours. The mixture was cooled, stirred with water and filtered to yield 41.1 g of 5-(hydroxymethyl)-3-phenyl-2-oxazolidinone, m.p. 122°-124° C. The 41.1 g was recrystallized from 100 ml of absolute ethanol to give 38.0 g, m.p. 125.5°-126° C. A further crop of 25.3 g (m.p. 124.5°-125° C.) was obtained from the water filtrate by concentrating and recrystallizing from ethanol.
Reaction SMILES: [NH:1]([CH:8]([CH3:23])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=1[Cl:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]=O>C(O)C>[CH3:23][CH:8]1[N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:24][N:11]([C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=2[Cl:22])[C:9]1=[O:10]
Reactant: C=O
Reactant: CC(Nc1ccccc1)C(=O)Nc1ccc(S(N)(=O)=O)cc1Cl
Solvent: CCO
Product: CC1C(=O)N(c2ccc(S(N)(=O)=O)cc2Cl)CN1c1ccccc1

Procedure:
2-Anilino-N-(2-chloro-4-sulfamoylphenyl)-propionamide (3.5 g) was dissolved in ethanol (100 ml) and reacted with paraformaldehyde (0,7 g) as before to yield 1.8 g, m.p. 202°C
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:32][O:33]CC1C=CC=CC=1)[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:21](=[O:25])[NH:20][C:19]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[N:18][C:17]1=2)C1C=CC=CC=1>CO.[Pd]>[OH:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:32][OH:33])[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:21](=[O:25])[NH:20][C:19]([NH:26][C:27](=[O:31])[CH:28]([CH3:29])[CH3:30])=[N:18][C:17]1=2
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@@]3(COCc4ccccc4)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)[nH]1
Reaction time: 24 h

Procedure:
A mixture of nucleoside 50 (717 mg, 1.31 mmol) and 10% palladium over carbon (500 mg) was suspended in methanol (8 cm3) at room temperature. The mixture was degassed several times under reduced pressure and placed under a hydrogen atmosphere. After stirring for 24 h the mixture was purified by silica gel column chromatography using methanol/dichloromethane (8-20%, v/v) as eluent to give nucleoside 51 as a glass-like solid (440 mg, 92%). δH (CD3OD) 8.12 (1H, br s, 8-H), 5.86 (1H, s, 1′-H), 4.50 (1H, s, 2′-H), 4.30 (1H, s, 3′-H), 4.05 (1H, d, J 8.0, 1″-Ha), 3.95 (2H, s, 5′-H), 3.87 (1H, d, J 7.9, 1″-Hb), 2.74 (1H, m, CHCO), 1.23 (6H, d, J 6.9, CH3CH). δC (CD3OD, signals from the carbohydrate part) 90.2, 87.6 (C-1′, C-4′), 81.1 (C-3′), 72.9, 71.3 (C-2′, C-5′), 58.2 (C-1″), 37.1 (COCH), 19.5 (CH3CH). FAB-MS m/z 366 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH:19]=2)=[O:17])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(C1C=CC(C(CCC)CCCCCCC(C2C3C(=CC=CC=3)N(CCCC(OCC)=O)C=2)=O)=CC=1)C(C)C>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:19]=2)=[O:17])=[CH:7][CH:6]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CCCCC(CCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Agent: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Product: CCCCC(CCCCC(=O)c1cn(CCCC(=O)O)c2ccccc12)c1ccc(CC(C)C)cc1

Procedure:
The procedure of Ex. 16 was repeated except that ethyl 4-[3-[6-(4-isobutylphenyl)decanoyl]-1-indolyl]butyrate obtained in Ex. 17 was used in place of ethyl 4-[3-[8-(4-isobutylphenyl)undecanoyl]-1-indolyl]butyrate to give 4-[3-[6-(4-isobutylphenyl)decanoyl]-1-indolyl]butyric acid.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21].O>CS(C)=O>[CH3:13][O:12][C:11]1[C:2]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:18]=2[O:17][CH3:16])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([O:14][CH3:15])=[CH:6][CH:5]=2
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COc1ccc2nc(Cl)c(OC)nc2c1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CNc2nc3ccc(OC)cc3nc2OC)c(OC)c1
Temperature: 60 °C
Reaction time: 118 h
Yield: 76.7 %

Procedure:
To 2-chloro-3,6-dimethoxyquinoxaline (3.87 g, 17.2 mmol) dissolved in dimethyl-sulfoxide (70 ml), 2,4-dimethoxybenzylamine (6.07 g, 36.3 mmol) was added at room temperature. The mixture was stirred at 60° C. for 118 hours and then water was added thereto. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (6:1) mixture and concentration gave 4.69 g of the titled compound (yield, 77%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.Cl[CH2:12][C:13](=[O:15])[CH3:14]>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:12][C:13](=[O:15])[CH3:14])=[C:4]([CH3:10])[CH:3]=1
Reactant: CC(=O)CCl
Reactant: Cc1cc(Br)cc(C)c1O
Product: CC(=O)COc1c(C)cc(Br)cc1C

Procedure:
The title compound was prepared according to procedures analogous to those as described in Reference Example 25 by using 4-bromo-2,6-dimethylphenol and chloroacetone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[S:10]([N:13]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:12])=[O:11]
Reactant: NS(=O)(=O)c1cc(C=O)ccc1Cl
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: CN(C)C=NS(=O)(=O)c1cc(C=O)ccc1Cl
Temperature: 25 °C
Yield: 82.4 %

Procedure:
5.0 g (22.8 mmol) of 2-Chloro-5-formyl-benzenesulfonamide were dissolved in 50 ml of dichloromethane. 4.08 g (34.3 mmol) of dimethylformamide dimethylacetal were added and the mixture was refluxed for 2 h. After cooling to room temperature, the solution was washed twice with H2O, dried over magnesium sulfate and evaporated. 5.16 g of the crude product were obtained and used in the next step without further purification. Rt=1.14 min (Method #1). Detected mass: 275.1/277.1 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5](=[C:12]1[CH:17]2[CH2:18][CH:14]3[CH:15]([CH2:16]2)[CH:13]13)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:19]([NH2:21])[CH3:20]>C1C=CC=CC=1>[CH2:19]([NH:21][CH2:2][CH2:3][O:4][C:5](=[C:12]1[CH:17]2[CH2:18][CH:14]3[CH:15]([CH2:16]2)[CH:13]13)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:20]
Reactant: ClCCOC(=C1C2CC3C(C2)C13)c1ccccc1
Reactant: CCN
Solvent: c1ccccc1
Product: CCNCCOC(=C1C2CC3C(C2)C13)c1ccccc1

Procedure:
A solution of 90 g. (0.345 mol) of β-chloroethyl-{α[tricyclo-(2.2.1.02.6)hept-3-ylidene]-benzyl}-ether and 69 g. (1.53 mol) of ethylamine in 250 ml. of anhydrous benzene was heated for 5 hours to 140° C. in a 1 litre capacity autoclave. After cooling, the ethylamine hydrochloride was filtered off under suction, the mother liquor concentrated in vacuo and the residue subjected to acid-alkaline working up. The basic fraction was fractionated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:18][C:11]3[N:12]=[C:13]([CH3:17])[NH:14][C:15](=O)[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.[Cl:57][C:58]1[CH:73]=[CH:72][C:61]([O:62][CH2:63][C:64]([N:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)=[O:65])=[CH:60][CH:59]=1>CC#N>[Cl:57][C:58]1[CH:59]=[CH:60][C:61]([O:62][CH2:63][C:64]([N:66]2[CH2:71][CH2:70][N:69]([C:15]3[C:10]4[CH:9]=[C:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)[S:18][C:11]=4[N:12]=[C:13]([CH3:17])[N:14]=3)[CH2:68][CH2:67]2)=[O:65])=[CH:72][CH:73]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCNCC1
Reactant: Cc1nc2sc(-c3ccc(F)cc3)cc2c(=O)[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2cc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
To a solution of 6-(4-fluorophenyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (40 mg, 0.15 mmol) and BOP (88 mg, 0.20 mmol) in CH3CN (1 ml) was added DBU (34 μl, 0.23 mmol). After stirring for 10 minutes at room temperature, 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone (59 mg, 0.23 mmol) was added. The reaction was stirred at room temperature overnight and then heated at 60° C. for 4 hours. The solvents were removed under reduced pressure, and the crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (66 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[CH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22]I.O>CN(C)C=O.CCCCCC>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[C:17][CH3:22])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.72 g (10 mmol) of 7-chloro-3-ethynyl-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was dissolved in 20 ml of N,N-dimethylformamide. 1.31 g (30 mmol) of sodium hydride dispersion (55% in oil) was washed with n-hexane and then introduced at room temperature into the above solution. After 10 minutes 0.95 ml (15 mmol) of methyl iodide was added thereto and the mixture was stirred at room temperature for a further 3 hours. The reaction mixture was poured into 300 ml of water and extracted four times with methylene chloride. The organic extracts were washed four times with water and dried over magnesium sulphate. After chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from ethyl acetate, there was obtained 7-chloro-4,5-dihydro-5-methyl-3-(1-propynyl)-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 243°-244°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>ClCCl.CCN(C(C)C)C(C)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH:17]3[CH2:18][CH2:19][N:20]([C:29]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:30])[CH2:21][CH2:22]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCN(C1CCNCC1)C1CCc2ccc(OC)cc2C1
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(C1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine (200 μL of 0.025 M in dichloromethane, 50 μmole) was added 200 μL of 0.25 M solution of morpholine 4-carbonyl chloride in dichloromethane and 30 μL of DIEA. The solution was allowed to stir for 24 h at 25° C. under N2. Concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford {4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone 1 (11.9 mg), [M+H]+=461.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][C:50]([N:52]2[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]2)=[O:51])=[CH:44][CH:43]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[CH:44][C:45]([CH2:48][CH2:49][C:50]([N:52]6[CH2:53][CH2:54][N:55]([CH3:58])[CH2:56][CH2:57]6)=[O:51])=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: CN1CCN(C(=O)CCc2ccc(Br)cc2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CCC(=O)N4CCN(C)CC4)cc3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 3-(4-bromo-phenyl)-1-(4-methyl-piperazin-1-yl)-propan-1-one (174 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 3-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-(4-methyl-piperazin-1-yl)-propan-1-one was obtained, and further PMB group was removed according to the above Deprotection method 2, to obtain the desired compound (D-188) as a pale yellow powder (70 mg, 36%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH:38]([CH3:40])[CH3:39])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH2:41].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH:38]([CH3:39])[CH3:40])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH:41][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: CC(C)OCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCOC(C)C)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Yield: 66.1 %

Procedure:
This was prepared using the method described in example 4 using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (200 mg, 0.59 mmol), 5-chloro-7-(3-isopropoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine (174 mg, 0.65 mmol) and a solution of sodium bis(trimethylsilyl)amide (1.0M in THF, 1.24 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (222 mg, 66%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 1.15 (d, 6H), 1.97 (quintet, 2H), 2.39 (m, 4H), 2.47 (t, 2H), 3.59 (m, 4H), 3.80 (m, 1H), 3.93 (s, 3H), 4.20 (t, 2H), 4.40 (s, 2H), 6.16 (s, 2H), 7.14 (s, 1H), 7.19 (s, 1H), 7.82 (s, 1H), 8.32 (s, 1H), 9.50 (s, 1H); Mass Spectrum: M+H+ 569/571
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11](I)[NH:12][C:13]=1[CH2:14][CH2:15][CH3:16])=[O:8]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]([C:11]2[NH:12][C:13]([CH2:14][CH2:15][CH3:16])=[C:9]([C:7]([NH:6][CH2:5][C:4]3[CH:18]=[C:19]([F:21])[CH:20]=[C:2]([F:1])[CH:3]=3)=[O:8])[N:10]=2)[NH:12][C:13]=1[CH2:14][CH2:15][CH3:16])=[O:8]
Reactant: CCCc1[nH]c(I)nc1C(=O)NCc1cc(F)cc(F)c1
Solvent: CO
Product: CCCc1[nH]c(-c2nc(C(=O)NCc3cc(F)cc(F)c3)c(CCC)[nH]2)nc1C(=O)NCc1cc(F)cc(F)c1
Temperature: 25 °C
Yield: 39.2 %

Procedure:
Iodide 6b (0.44 g; 1.1 mmol) was used as starting material. After cooling to rt, the reaction mixture was diluted with CH3OH and filtered. The filtrate was evaporated under vacuum, and the residue was dissolved in CHCl3. Slow addition of CH3CN caused a brown solid to precipitate. This material was collected by filtration and washed with CH3CN to afford 0.12 g (40%) of 1b as an off-white solid. mp 173–174 C; TLC (CH2Cl2-EtOAc, 1:1): Rf=0.51; 1H NMR (DMSO-d6): δ 0.85 (t, 6H), 1.60 (m, 4H), 2.90 (t, 4H), 4.42 (d, 4H), 6.99 (d, 411), 7.05 (t, 2H), 8.20 (br t, 2H); 13C NMR (DMSO-d6): δ 14.1, 23.1, 30.2, 41.8, 110.9, 131.0, 141.7, 145.5, 161.3, 163.8, 164.7; UV/vis (CH3OH): max (M−1cm−1)=287 (21800), 294 (20700), 309 (10700); LRMS (CI+): m/z (%): 557 (100) [M+H]+; HRMS (CI+): calcd for C28H29F4 N6O2 557.2288; found 557.2292.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12](O)=[O:13])[C:8]=1[C:15]([F:18])([F:17])[F:16].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:27]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12]([F:27])=[O:13])[C:8]=1[C:15]([F:18])([F:17])[F:16]
Reactant: Fc1nc(F)nc(F)n1
Reactant: O=C(O)c1noc(-c2ccccn2)c1C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(F)c1noc(-c2ccccn2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a solution of 5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-3-carboxylic acid (54.3 mg, 0.210 mmol) and pyridine (0.037 mL, 0.463 mmol) in dichloromethane (2 mL) was added cyanuric fluoride (0.021 mL, 0.252 mmol). The reaction mixture was stirred at room temperature for 2 hrs., diluted with dichloromethane (2 mL), and washed with ice water (1 mL). The aqueous layer was extracted with dichloromethane (2×1 mL), and the combined organic layers were washed with brine (1 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride (0.048 g, 0.185 mmol, 88% yield). The product had an HPLC retention. time=2.50 min. (The product reacted readily with methanol and a small portion was characterized as the methyl ester)—Column: YMC S5 COMBISCREEN® 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA.
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])[C:9]([CH3:20])([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[O:8][CH2:7][CH2:6]2.C(O)(=[O:23])C>O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:20])([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[O:8][CH2:7][C:6]2=[O:23]
Reactant: COc1cc2c(cc1OC)C(C)(CCC(=O)O)OCC2
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: COc1cc2c(cc1OC)C(C)(CCC(=O)O)OCC2=O
Reaction time: 1.5 h

Procedure:
A solution of chromium trioxide (25.7 g) in a mixture of acetic acid (120 ml) and water (35 ml) is added dropwise to a solution of 6,7-dimethoxy-1-methylisochroman propionic acid (27.0 g), described in Example 16, in acetic acid (140 ml) keeping the temperature of the mixture below 20° C. The mixture is kept at room temperature for 1.5 hr. and then poured into water and extracted with chloroform. The extracts are thoroughly washed with water, dried and evaporated. The residue is crystallized from benzene to give the title compound, m.p. 172°-173° C.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:13]=[C:14]([O:33][CH2:34][CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]([CH2:26][N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH2:28]3)[CH2:24][N:25]=1)=[CH:17]2)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:5])=[O:4].C([OH:43])C.OOS([O-])=O.[K+].S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.O>[CH3:1][N:2]([C:12]1[CH:13]=[C:14]([O:33][CH2:34][CH2:35][CH2:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]([CH2:26][N:27]3[CH2:32][CH2:31][S:30](=[O:43])[CH2:29][CH2:28]3)[CH2:24][N:25]=1)=[CH:17]2)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:5])=[O:4]
Reactant: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reactant: CCO
Agent: O=S([O-])OO
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C3=NCC(CN4CCS(=O)CC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a mixture of N-methyl-N-{5-[3-(methylsulfonyl)propoxy]-2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}pyridine-2-sulfonamide (0.35 g), ethanol (60 mL), water (30 mL) and tetrahydrofuran (30 mL) was added OXONE (registered trade mark, 0.19 g), and the mixture was stirred at room temperature for 3 hr. Aqueous sodium sulfite solution was added to the reaction mixture, the mixture was stirred for 30 min, and the organic solvent was evaporated under reduced pressure. The residue was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained colorless crystals were recrystallized from ethyl acetate-hexane to give the title compound (193 mg, yield: 54%) as colorless crystals. MS: 641 (MH+). melting point 107-110° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18]([O:22][CH3:23])(=[O:21])[C:19]#[CH:20]>C1COCC1>[CH3:23][O:22][C:18](=[O:21])[C:19]#[C:20][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C#CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(I)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C#Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
1-Iodo-4-nitrobenzene (2.5 g, 10 mmol) was added to a solution of triethylamine (2.0 g, 20 mmol) in THF (40 mL). PdCl2 (PPh3)2 (0.14 g, 0.20 mmol), cuprous iodide (0.076 g, 0.40 mmol) and methyl propiolate (3.4 g, 40 mmol) were added and the resulting mixture was heated to reflux overnight. The reaction mixture was cooled to r.t., the solvent evaporated, and the crude compound dissolved in dichloromethane. The organics were filtered to remove insoluble material and the filtrate was washed with water, brine solution and dried over sodium sulfate. The filtrate was concentrated and the residue purified over silica gel using 15% ethyl acetate in petroleum ether as eluent to afford (4-nitrophenyl)-propynoic acid methyl ester (1.20 g, 59%) as a white solid.