Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C@:14]23[CH:17]=[C:18]([CH3:21])[C@H:19]([OH:20])[C@@:13]2([OH:22])[C@H:12]([OH:23])[C:11]([CH2:24][OH:25])=[CH:10][C@H:9]([C:15]3=[O:16])[C@@H:5]2[C:6]([CH3:8])([CH3:7])[C@@H:4]2[CH2:3]1.C([O-])(O)=O.[Na+].O.[C:32]1(C)[CH:37]=CC(S(O)(=O)=O)=C[CH:33]=1>CC(C)=O>[CH3:1][C@H:2]1[C:14]23[CH:17]=[C:18]([CH3:21])[C@H:19]([OH:20])[C@@:13]2([OH:22])[C@H:12]2[C:11]([CH2:24][O:25][C:32]([CH3:37])([CH3:33])[O:23]2)=[CH:10][CH:9]([C:15]3=[O:16])[CH:5]2[C:6]([CH3:8])([CH3:7])[CH:4]2[CH2:3]1
Reactant: CC1=C[C@]23C(=O)[C@@H](C=C(CO)[C@@H](O)[C@]2(O)[C@H]1O)[C@H]1[C@@H](C[C@H]3C)C1(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1=CC23C(=O)C(C=C4COC(C)(C)O[C@H]4[C@]2(O)[C@H]1O)C1C(C[C@H]3C)C1(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 69 %

Procedure:
Ingenol (1.00 g, 2.30 mmol) was dissolved in a solution of p-toluenesulphonic acid monohydrate in acetone (0.47 mg/mL, 22.5 mL). The solution was stirred at room temperature for 25 min. To this solution was added a saturated aqueous solution of NaHCO3 (0.2 mL). The obtained mixture was concentrated in vacuo. The residue was taken up in brine and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (heptane/ethyl acetate 19:1 heptane/ethyl acetate 0:1), giving the title compound as a white solid (616 mg, 69%). (See also: Opferkuch, H. J. et. al., Z. Naturforsch., (1981), 86b, 878-887.)
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[NH2:9][C:10]1[S:11][C:12]2[CH:18]=[C:17]([O:19][C:20]([F:23])([F:22])[F:21])[CH:16]=[C:15]([Si](C)(C)C)[C:13]=2[N:14]=1>C(#N)C.O>[NH2:9][C:10]1[S:11][C:12]2[CH:18]=[C:17]([O:19][C:20]([F:23])([F:21])[F:22])[CH:16]=[C:15]([N+:7]([O-:8])=[O:6])[C:13]=2[N:14]=1
Reactant: C[Si](C)(C)c1cc(OC(F)(F)F)cc2sc(N)nc12
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: Nc1nc2c([N+](=O)[O-])cc(OC(F)(F)F)cc2s1
Temperature: 0 °C
Reaction time: 12 h
Yield: 43.3 %

Procedure:
0.68 g of nitronium tetrafluoroborate are added in small portions to a solution of 0.76 g of 2-amino-4-trimethylsilyl-6-trifluoromethoxybenzothiazole in 20 cm3 of acetonitrile cooled to 0° C. Stirring is continued for 12 hours at a temperature close to 20° C. The solution is then diluted with 50 cm3 of water and extracted with 2 times 50 cm3 of ethyl acetate. The organic phases are combined, dried over sodium sulphate and concentrated in vacuum. The residue is purified by flash chromatography on silica gel with a cyclohexane-ethyl acetate mixture (7-3 by volume) as eluent. After recrystallization from a cyclohexane-ethyl acetate mixture (3-2 by volume), 0.3 g of 2-amino-4-nitro-6-trifluoromethoxybenzothiazole melting at 260° C. is obtained.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][NH:9][CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]>>[CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][N:9]([C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6]
Reactant: CON=C(C#N)C1=CCCNC1
Reactant: O=C(Cl)Oc1ccccc1
Product: CON=C(C#N)C1=CCCN(C(=O)Oc2ccccc2)C1
Yield: 81.8 %

Procedure:
α-(Methoxyimino)-α-(1,2,5,6-tetrahydropyridin-3-yl)acetonitrile (D8) (0.5 g, 0.003 moles) was treated with phenyl chloroformate (0.42 ml, 0.0033 moles) according to the method of Example 1. The crude product was crystallised from diethyl ether/pentane to give the title compound (E3) as a white crystalline solid (0.7 g, 81%) m.p. 111°-112° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][CH:21]=[C:22]1[CH:26]=[CH:25][O:24][CH2:23]1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([N:20]=[CH:21][C:22]4[CH:26]=[CH:25][O:24][CH:23]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: NC=C1C=COC1
Product: Fc1cnc(N=Cc2ccoc2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-aminomethylenefurane were reacted to give N4-(3,4-ethylenedioxyphenyl)-N2-(3-furanylmethylene)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 19.99 min.; purity: 88.4%; MS (m/c): 343.07 (MH+).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH3:13]>CC(C)=O.CO>[NH2:13][C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: N
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)cnc1N
Temperature: 25 °C
Reaction time: 216 h
Yield: 148.1 %

Procedure:
Performed in duplicate on identical scales in two pressure vessels, methyl 2,5-dichloronicotinate (4.5 g, 22 mmol) was dissolved in ammonia solution (250 mL, 0.5 M in 1,4-dioxane; 0.125 mol). The pressure vessels were sealed and heated at (85±5)° C. for 9 days. The two reaction mixtures were allowed to cool to room temperature, then combined and concentrated under reduced pressure to yield a white solid. Dissolution of the solid in 1:1 acetone-methanol (˜500 mL), followed by adsorption onto silica gel (25 g) and then purification by flash column chromatography (25:10:1 hexanes-dichloromethane-ether), gave methyl 2-amino-5-chloronicotinate (6.08 g, 75% yield).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([NH2:12])[CH3:11]>O>[CH2:10]([NH:12][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:11]
Reactant: CCN
Reactant: N#Cc1cccnc1Cl
Solvent: O
Product: CCNc1ncccc1C#N

Procedure:
A stirred mixture of 4 g. of 2-chloronicotinonitrile in 200 ml. of a saturated ethanolic ethylamine solution was heated under reflux for 5 hours. The solution was cooled and was diluted with 400 ml. of water. The precipitate of 2-ethylaminonicotinonitrile which formed was collected, air dried and was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:6]=1[C:7](=[O:16])[NH:8][S:9]2(=[O:11])=[O:10])([CH3:4])[CH3:3].[C:17]1([S:23][CH2:24]Cl)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:17]1([S:23][CH2:24][N:8]2[C:7](=[O:16])[C:6]3[C:12](=[CH:13][CH:14]=[CH:15][C:5]=3[C:2]([CH3:1])([CH3:3])[CH3:4])[S:9]2(=[O:11])=[O:10])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCSc1ccccc1
Reactant: CC(C)(C)c1cccc2c1C(=O)NS2(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cccc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Temperature: 25 °C
Yield: 96.8 %

Procedure:
The 4-(1,1-dimethylethyl) saccharin (0.025 g 1.0 mmol) was mixed with chloromethyl phenyl sulfide (0.25 g, 1.5 mmol) and tetrabutyl ammonium bromide (0.2 g, 0.6 mmol) in toluene (25 mL) and refluxed under nitrogen for 16 hr. The resulting mixture was cooled to room temperature, evaporated to dryness and purified by chromatography on silica gel (80%) MDC in hexanes) to give 0.35 g (98%) of 2-phenylthiomethyl-4-(1,1-dimethylethyl]saccharin, which was treated with sulfuryl chloride (0.25 g, 1.8 mmol) in MDC to give 0.21g (75%) of 2-chloromethyl-4-(1,1-dimethylethyl]saccharin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[CH:9]([CH2:10]I)[CH2:8][C:7]1=[O:12].[CH3:19][N:20](C)C=O.[C-]#N.[Na+]>O>[C:19]([CH2:10][CH:9]1[N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7](=[O:12])[CH2:8]1)#[N:20]
Reactant: CN(C)C=O
Reactant: COc1ccc(CN2C(=O)CC2CI)c(OC)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: COc1ccc(CN2C(=O)CC2CC#N)c(OC)c1
Yield: 70 %

Procedure:
A solution of 1.2 g (3.3 millimoles) of 1-(2,4-dimethoxy-benzyl)-4-iodomethyl-2-azetidinone and 5 ml of dimethyl formamide is stirred with 0.35 g (7 millimoles) of sodium cyanide at room temperature for 48 hours. The solution is poured onto 30 ml of water and extracted five times with 20 ml of ether each. The etheral solution is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo. Thus 0.6 g of 4-cyanomethyl-1-(2,4-dimethoxy-benzyl)-2-azetidinone are obtained. Yield: 70%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc2c(-c3ccc(OC)c(OC)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3,4-dimethoxy-phenylboronic acid to give [1-(3,4-dimethoxy-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 391(MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([OH:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]2[CH3:19])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[CH3:27][O:26][C:24](=[O:25])[CH2:23][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[C:10]([CH3:19])[N:9]2[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: Cc1cc2c(O)cccc2n1Cc1ccc(F)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1ccc(F)cc1
Yield: 80.9 %

Procedure:
Using the procedure described in Example 1, Part E, 1-[(4-fluorophenyl)methyl]-4-hydroxy-2-methyl-1H-indole (881 mg, 3.45 mmol) was treated with 138 mg (3.45 mmol) of 60% NaH/mineral oil and then 0.33 mL (3.45 mmol) of methyl bromoacetate. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 914 mg (81% yield) of [[1-[(4-fluorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester, mp, 92°-98° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([F:27])[CH:18]=1>CN(C=O)C>[F:27][C:19]1[CH:18]=[C:17]([CH2:16][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[F:1])[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: Nc1ccccc1F
Reactant: COC(=O)c1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNc2ccccc2F)cc1F
Temperature: 60 °C

Procedure:
To a mixture of 2-fluoroaniline (0.12 mL, 1.2 mmol) and potassium carbonate (207 mg, 1.5 mL) in DMF (5 mL) was added methyl 4-(bromomethyl)-2-fluoro-benzoate (247 mg, 1 mmol). The mixture was heated to 60° C. for 18 hours. The solvent was removed in vacuo. The mixture was partitioned between DCM (15 mL) and water (15 mL), the layers were separated and the organic phase was passed through a hydrophobic fit. The solvent was removed in vacuo and the residue was used directly in the next step without any further purification. LCMS (Method 2): [MH+]=278 at 3.60 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[F:9].O[CH2:11][CH:12]([CH2:14]O)O.[OH-].[NH4+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[F:9])[N:8]=[CH:14][CH:12]=[CH:11]2
Reactant: Nc1ccc(Br)c(F)c1
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Fc1cc2ncccc2cc1Br
Temperature: 130 °C
Yield: 37.8 %

Procedure:
To a suspension of 4-bromo-3-fluoro-phenylamine (100 g, 526 mmol) in concentrated sulfuric acid (290 mL) was added glycerol (220 g, 2.39 mol, 4.5 eq.) followed by ferrous sulfate (30 g, 0.2 eq.). The reaction mixture was heated at 130° C. for 14 h, cooled to rt and poured into ice-water. The solution was neutralized with saturated aqueous ammonium hydroxide to pH 8 and extracted with DCM (2 L×3). The combined organic layers were washed with brine (1 L×3), dried over sodium sulfate and concentrated under reduced pressure to afford the crude product as a brown solid, which was purified by column chromatography (Petroleum:Ethyl acetate=10:1) to give 6-bromo-7-fluoro quinoline as a white solid (45 g, 39%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.86 (s, 1H), 8.56 (m, 1H), 8.45 (m, 1H), 7.90 (d, 1H), 7.71 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[O-]CC.[Na+].Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>C(O)C>[C:15]([O:14][C:12](=[O:13])[CH2:11][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: c1nc[nH]n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)Cn1cncn1
Temperature: 0 °C
Reaction time: 60 h
Yield: 88.2 %

Procedure:
34.53 gms of 1,2,4-triazole were added to 250 mls of ethanol along with 34.0 gms of sodium ethoxide. The system was placed under an argon atmosphere and cooled to about 0° C. After cooling, 107.28 gms of t-butyl bromoacetate were dropwise added to the system. The system was then allowed to come to room temperature and stirred there for 60 hours. The reaction was stopped and the system filtered. The solvent was removed by stripping and the residue was dissolved in hot ether and then filtered. The ether was removed by stripping and the resulting solid triturated with hexane and dried to yield 80.81 gms of the title compound as a beige solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Cl:30])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:3][C:2]([O:1][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Cl:30])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCl)cc1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCCCCOc1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of 4-hydroxybiphenyl (34 g), 1-(p-toluenesulfonyloxy)-6-chlorohexane (60 g), anhydrous potassium carbonate (60 g) and dimethylformamide (400 ml) was stirred at 60° C. for 6 hours. Excess potassium carbonate was removed by filtration. Water and ethyl acetate were then added and the resultant solution washed with water, dried with magnesium sulfate and evaporated. The resulting crude residue was then dissolved in ethyl acetate/hexane and recrystallized to yield 1-(4-biphenyloxy)-6-chlorohexane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH3:15].[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21](Cl)=[O:22]>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH3:15])[C:21](=[O:22])[C:20]1[CH:19]=[C:18]([C:17]([F:32])([F:31])[F:16])[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccncc1F
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccncc1F

Procedure:
The title compound was prepared in analogy to example 55, from (3′-fluoro-[4,4′]bipyridinyl-3-yl)-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using preparative HPLC for the chromatographic purification. Off-white solid (5%). MS (ESI): m/z=444.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].[H-].[Na+].[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19]
Reactant: BrC1CCCC1
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)c(C)c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C3CCCC3)c3c(Cl)cccc23)c(C)c1
Yield: 50.8 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.150 g, 0.52 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and cyclopentyl bromide (0.075 mL, 0.7 mmol) to give the title compound (0.090 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.O1CCC[CH2:18]1>CN>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH3:18])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: C1CCOC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: CN
Product: CNc1nc(Cl)nc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-4-amino-6,7-dimethoxyquinazoline (2.0 g) in tetrahydrofuran (100 ml), methylamine was introduced over a period of 15 min. The reaction mixture was stirred for 2 hr at room temperature and evaporated. The residue was triturated with cold aqueous sodium carbonate solution and the solid was washed and dried to give 1.769 g of 2-chloro-4-methylamino-6,7-dimethoxyquinazoline. A portion of this compound was crystallized from methylene chloride-hexane to mp 216°-217° C.; ir (nujol mull) 3470 cm-1 ; nmr (DMSO-d6) δ 3.0 (d, 3H), 3.9 (s, 6H), 7.05 (s, 1H), 7.55 (s, 1H) and 8.3 (broad s, 1H); and Anal. Calcd for C11H12ClN3O2 : C, 52.07% H, 4.77% N, 16.56% and Found: C, 51.95% H, 4.70% N, 16.45%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N+:9]([O-])[C:10]3[C:15]([C:16]=2[N+:17]([O-:19])=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.N1C=CC=CC=1.C(OC(=O)C)(=[O:29])C>>[OH:29][C:8]1[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[C:16]([N+:17]([O-:19])=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: O=[N+]([O-])c1c(N2CCOCC2)c[n+]([O-])c2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1c(N2CCOCC2)c(O)nc2ccccc12

Procedure:
The 3-morpholino-4-nitroquinoline-N-oxide obtained in Example 5-(a) was dissolved in acetic anhydride (16 ml) and pyridine (16 ml) and the solution was heated on an oil bath at 80° C. for 1 hour. Excess acetic anhydride and pyridine were distilled off under vacuum from the whole reaction mixture and the residue was dissolved in chloroform, followed by washing with 10% NaHCO3. The insoluble matter was recovered by filtration under vacuum, dissolved in acetone and treated with charcoal. The chloroform layer was dried with anhydrous Na2SO4 and CHCl3 was distilled off under vacuum. The residue was combined with the charcoal treated (insoluble) matter and washed with ethanol to obtain 2-hydroxy-3-morpholino-4-nitroquinoline in an amount of 3.5 g (yield, 44%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C=O)C.[Br:16][CH2:17][C:18](Br)=[O:19]>O1CCOCC1>[Br:16][CH2:17][C:18]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:19]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A solution of 4-nitroaniline (10.0 g, 72.4 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (14.60 g, 6.35 mL, 72.4 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 16.92 g (90%) of the title compound as a greenish yellow solid, mp 175°-178° C.: 1H NMR (DMSO-d6) δ10.98 (s, 1H), 8.24 (d, J=9.2, 2H), 7.83 (d, J=9.2, 2H), 4.10 (s, 2H); 13C NMR (DMSO-d6) δ165.77, 144.67, 142.62, 125.05, 119.01, 30.15; MS (EI, m/z) 285 (M+).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]([O:13][C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:33]([C:35]#[N:36])=[CH2:34])=[C:21]([CH:32]=1)[CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:15])([CH3:12])([CH3:11])[CH3:10]>CS(C)=O>[C:9]([O:13][C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:33]2([C:35]#[N:36])[CH2:4][CH2:34]2)=[C:21]([CH:32]=1)[CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: C[S+](C)(C)=O
Reactant: C=C(C#N)c1ccc(NC(=O)OC(C)(C)C)cc1CN(C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(Cc1cc(NC(=O)OC(C)(C)C)ccc1C1(C#N)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a suspension of sodium hydride (0.019 g, 0.795 mmol) in DMSO (2 mL), was added trimethylsulfoxonium iodide (0.191 g, 0.867 mmol). The mixture was stirred at rt for 2 h. To the resultant clear solution was added to a solution of 36F (0.280 g, 0.723 mmol) in DMSO (2 mL) to give a yellow solution. The mixture was stirred at rt for 1 h, then at 60° C. for 5 h. Reaction mixture was quenched with sat. NH4Cl (10 mL), extracted with EtOAc (4×25 mL). Combined organic phase was washed with water (2×25 mL), brine (1×25 mL) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography (0-40% EtOAc/hexanes) to give 36G (0.144 g, 0.359 mmol, 49.6% yield) as a colorless syrup. MS (ESI) m/z: 402.2 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 7.33-7.58 (1H, m), 7.23 (1H, d, J=8.28 Hz), 6.91-7.11 (1H, m), 6.60-6.79 (1H, m), 4.71 (2H, br. s.), 2.82-2.98 (3H, m), 1.66 (2H, br. s.), 1.37-1.58 (18H, m), 1.19-1.32 (2H, m).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:5][CH:4]=1.N1C=CC=CC=1.[OH-].[Na+].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>O>[O:20]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:21])[N:11]1[CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:22]=[CH:23][C:3]([NH:2][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:4][CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 7.0 g sample of 2-[3-(4-aminophenoxy)-propyl]-1H-isoindole-1,3(2H)-dione monohydrochloride (Example 95) is added to 100 ml of pyridine, 2.2 ml of 10N NaOH and 2.5 g methanesulfonyl chloride. The mixture is stirred at room temperature for 6 hours and 1 hour on a steam bath. The reaction mixture is poured into 900 ml of cold water and stored at 0° C. for 18 hours. The precipitate is collected, washed with 200 ml of water and dried to give 6.5 g of solid. A 1.0 g sample is crystallized from 100 ml of boiling ethanol after treatment with activated carbon to give 0.6 g of solid, m.p. 176°-178° C.