Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1.Cl>O1CCCC1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:8])=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
Benzaldehyde (8.5 g, 80 mmol) was dissolved in 100 mL of tetrahydrofuran and cooled in an ice bath. Then, a 1.0-M solution (88 mL, 88 mmol) of 4-fluorophenylmagnesium bromide in tetrahydrofuran was added dropwise thereto at 0° C. After the dropping was completed, the mixture was heated to a room temperature, and the completion of the reaction was confirmed by TLC. After the completion of the reaction, the reaction mixture was poured into 5% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform/ethanol (volume ratio)=10:1) to give the title compound (13 g, 81%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[N:27][CH:26]=[CH:25][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[N:27][CH:26]=[CH:25][C:10]=1[C:11]1[O:12][C:15]2[CH:16]=[CH:17][C:18]([C:20]([F:21])([F:23])[F:22])=[CH:19][C:14]=2[N:13]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1C(=O)Nc1cc(C(F)(F)F)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
To a mixture of 1.78 g of 3-tert-butoxycarbonylamino-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 20 ml of tetrahydrofuran and 1.29 g of triphenylphosphine, 2.15 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred at room temperature for one hour and then stirred while heating at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.69 g of 2-(3-tert-butoxycarbonylamino pyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 36”).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([OH:19])[C:14]([O:16]CC)=O)[CH:7]=[CH:6]2.[CH:20]([NH2:23])([CH3:22])[CH3:21]>>[CH:20]([NH:23][C:14](=[O:16])[CH:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)[OH:19])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C(O)c1ccc2cc(OC)ccc2c1
Reactant: CC(C)N
Product: COc1ccc2cc(C(O)C(=O)NC(C)C)ccc2c1

Procedure:
Ethyl 6-methoxy-2-naphthylglycolate (0.1 mole) is stirred with 20 ml. of isopropylamine at about 35°C with stirring overnight and the temperature is then raised to reflux for 28 hours. The reaction mixture is evaporated in vacuo and the residue distilled to obtain N-isopropyl-6-methoxy-2-naphthylglycolamide.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[NH:6][C:5](=[O:13])[C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[CH2:22]([NH2:24])[CH3:23]>C(O)C>[CH2:22]([NH:24][CH2:2][C:3]1[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[NH:6][C:5](=[O:13])[C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:23]
Reactant: COc1ccc(C2=C(CBr)C3(CCCCC3)NC2=O)cc1
Reactant: CCN
Solvent: CCO
Product: CCNCC1=C(c2ccc(OC)cc2)C(=O)NC12CCCCC2
Yield: 98 %

Procedure:
4-Bromomethyl-3-(4-methoxyphenyl)-1-azaspiro[4.5]dec-3-ene-2-one (250 mg, 0.71 mmol) was dissolved in ethanol (15 mL) and ethylamine (70% solution in water, 2 mL), the mixture was stirred overnight at room temperature and concentrated. The residue was dissolved in CH2Cl2, washed with water and extracted with 0.5 M HCl. After addition of NaOH and extraction with CH2Cl2 the organic layer was dried (Na2SO4) and evaporated to yield 0.22 g (98%)of 4-ethylaminomethyl-3-(4-methoxyphenyl)-1-azaspiro[4.5]dec-3-ene-2-one, shown below, as a solid. MS (IS): 315 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([OH:8])=[N:6][CH:7]=1.[C:10](=O)([O-])[O-].[Cs+].[Cs+].IC.Cl>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([I:9])[C:5](=[O:8])[N:6]([CH3:10])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ncc(F)cc1I
Agent: Cl
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1cc(F)cc(I)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-fluoro-3-iodo-pyridin-2-ol (31, 200 g, 838 mmol) in 3000 mL of acetone was cooled in an ice water bath. Cesium carbonate (354 g, 1088 mmol) was added, then iodomethane (58.1 mL, 929 mmol) was added dropwise over 30 minutes. The reaction was stirred overnight at room temperature. The reaction was concentrated under vacuum and the resulting material partitioned between ethyl acetate and water. The aqueous layer was isolated and adjusted to pH 3-4 with 3 N hydrochloric acid, then extracted with ethyl acetate. The combined organic layers were concentrated under vacuum to provide the desired compound as an off white solid. (32, 150 g, 593 mmol, 70.8%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[N+:13]([O-])([OH:15])=[O:14].C(O)(=O)C>C(OC(=O)C)(=O)C>[OH:1][C:2]1[C:11]([N+:13]([O-:15])=[O:14])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2
Reactant: O=C1CCc2c(O)cccc2N1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CCc2c(ccc([N+](=O)[O-])c2O)N1
Temperature: 5 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
In 110 ml of acetic anhydride was dissovled 25 g of 5-hydroxy-3,4-dihydrocarbostyril, and to the solution was added dropwise a mixture of 12 g of fuming nitric acid and 75 ml of acetic acid at 5° C. After stirring at 5° C. for 2 hours, 20 g of ice was added to the reaction mixture, and the precipitated crystals were collected. The crystals were suspended in a 3N sodium hydroxide aqueous solution, followed by filtration. The filtrate was neutralized with hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 22 g of the named compound.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Cl:10])=[C:6](Cl)[C:5]([Cl:12])=[N:4]1)[CH3:2].[CH2:13]([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH2:21])[CH2:14][CH3:15]>C(O)C>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Cl:10])=[C:6]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([O:16][CH2:13][CH2:14][CH3:15])[CH:18]=2)[C:5]([Cl:12])=[N:4]1)[CH3:2]
Reactant: CCCOc1cc(CN)ccc1OC
Reactant: CCn1nc(Cl)c(Cl)c(Cl)c1=O
Solvent: CCO
Product: CCCOc1cc(CNc2c(Cl)nn(CC)c(=O)c2Cl)ccc1OC
Reaction time: 3.5 h

Procedure:
A mixture comprising 455 mg of 2-ethyl-4,5,6-trichloro-3(2H)pyridazinone, 1.20 g of 3-n-propoxy-4-methoxybenzylamine and 20 ml of ethanol, was refluxed under stirring for 3.5 hours. Ethanol was distilled off under reduced pressure, and water was poured into the residue thereby obtained. The mixture was extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and water in this order and dried over sodium sulfate. Then, the solvent was distilled off to obtain a light brown viscous oily substance. The product was purified by silica gel column chromatography by using a solvent mixture of benzene-ethyl acetate (15:1 v/v) as the eluent, to obtain 277 mg of the above identified compound. The physical properties and the spectrum data of NMR and MS of the compound completely agreed to those of the compound prepared by the method (1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[O:15]1[C@H:17]2[CH2:18][C@H:19]([C:22]([CH3:24])=[CH2:23])[CH2:20][CH2:21][C@@:16]12[CH3:25]>C1(C)C=CC=CC=1.CN(C)C=O>[C:7]1([S:13][C@H:17]2[CH2:18][C@H:19]([C:22]([CH3:24])=[CH2:23])[CH2:20][CH2:21][C@@:16]2([OH:15])[CH3:25])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=C(C)[C@@H]1CC[C@@]2(C)O[C@H]2C1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=C(C)[C@@H]1CC[C@](C)(O)[C@@H](Sc2ccccc2)C1
Temperature: 25 °C
Yield: 100 %

Procedure:
A suspension of 164 g (1 M) of the above diastereomeric mixture, 83 g of potassium carbonate and 60.5 g (0.556 M) of thiophenol in a mixture of 380 ml of toluene and 20 ml of dimethylformamide was heated under reflux for 10 hours. After cooling to room temperature and addition of water, the separated organic layer was successively washed with water and with brine, dried over sodium sulfate and evaporated. After distillation in a bulb apparatus, the desired thioether (131 g; ca. 100% yield) was separated from unreacted (+)-(1R,2S,4R)-1,2-epoxy-8-p-menthene. The title compound thus prepared was characterized as follows:
Reaction SMILES: C(OC(=O)C[C@@H](N1C=CC(C2C=CC=CC=2)=C1)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.[CH2:36]([O:43][C:44](=[O:77])[CH2:45][C@@H:46]([NH:69][C:70](OC(C)(C)C)=O)[C:47]([NH:49][C@@H:50]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH2:51][O:52][C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])=[O:48])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CO[CH:80]1[CH:84]([C:85]2[CH:90]=[CH:89][C:88]([C:91]3[CH:96]=[CH:95][N:94]=[CH:93][CH:92]=3)=[CH:87][CH:86]=2)[CH2:83]C(OC)O1.CO.C(Cl)Cl>ClCCCl>[CH2:36]([O:43][C:44](=[O:77])[CH2:45][C@@H:46]([N:69]1[CH:70]=[CH:83][C:84]([C:85]2[CH:90]=[CH:89][C:88]([C:91]3[CH:96]=[CH:95][N:94]=[CH:93][CH:92]=3)=[CH:87][CH:86]=2)=[CH:80]1)[C:47]([NH:49][C@@H:50]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH2:51][O:52][C:53]([O:55][CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)=[O:54])=[O:48])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](COC(=O)OCc1ccccc1)c1ccccc1
Reactant: COC1CC(c2ccc(-c3ccncc3)cc2)C(OC)O1
Agent: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccccc2)c1)C(C)(C)C
Solvent: ClCCl
Solvent: CO
Solvent: ClCCCl
Product: O=C(C[C@H](C(=O)N[C@H](COC(=O)OCc1ccccc1)c1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)OCc1ccccc1
Yield: 56 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, N-(2-benzyloxycarbonyloxy-1(S)-phenyl-ethyl)-3(R)-(t-butoxycarbonylamino)succinamic acid benzyl ester and 2,5-dimethoxy-3-(4-pyridin-4-yl-phenyl)-tetrahydrofuran (prepared as described in Example 5(a)) were condensed in wet 1,2-dichloroethane at 80-90° C. after 18 hours. Flash column chromatagraphy with 4% MeOH/CH2Cl2 as eluant gave 140 mg(56%) of N-(2-benzyloxycarbonyloxy-1(S)-phenylethyl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester as a yellow solid, mp 138-40° C. 1H NMR (CDCl3): δ 8.66 (bs, 2H), 7.60 (s, 5H), 7.50 (d, 3H, J=5.3 Hz), 7.34-7.22 (m, 10H), 7.19 (d, 1H, J=2.2 Hz), 7.17 (d, 1H, J=1.9 Hz), 7.09 (t, 1H, J=1.9 Hz), 6.77 (dd, 1H, J=2.5, 2.8 Hz), 6.57 (bt, 1H, J=1.9, 2.5 Hz), 6.24 (d, 1H, J=7.8 Hz), 5.26 (m, 1H), 4.25 (dd, 1H, J=7.2, 11.5 Hz), 3.44 (dd, 1H, J=7.2, 16.8 Hz), 3.00 (dd, 1H, 8.7, 16.8 Hz). IR (KBr): 2985, 1738, 1657, 1598, 1560, 1495, 1202, 815, 697 cm−1. HRFABMS: Calculated for C42H37N3O6Cs (M+Cs+): 812.1737. Found: 812.1712. Anal. Calculated for C42H37N3O6.0.25CHCl3: C, 71.51; H, 5.29. Found: C, 71.72; H, 5.60.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)=[CH:9][C:8]=2[C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:6][CH2:5]1)[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=3)=[CH:9][C:8]=2[C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC)CC3)c(C(C)(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-benzoate (Compound 103, 70.0 mg, 0.18 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (240.0 mg, 6.0 mmols, 3.0 mL of a 2N aqueous solution) and stirred overnight at room temperature. Work-up afforded 40 mg (62%) the title compound as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1>CO.C(OCC)(=O)C.[OH-].[Pd+2].[OH-].[C]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(-c3cccc(F)c3)n[nH]c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2c(-c3cccc(F)c3)n[nH]c2c1
Reaction time: 7.5 h
Yield: 53.6 %

Procedure:
To a solution of 300 mg of 3-(3-fluorophenyl)-6-nitro-1H-indazole in 5 ml methanol and 2.5 ml ethyl acetate was added 60 mg of 20% palladium hydroxide-carbon (water content: 50%), and the mixture was subjected to hydrogenation at room temperature at normal pressure for 7.5 hours. After adding 2.5 ml of ethyl acetate to the reaction mixture, the catalyst was filtered off through Celite. The solvent was evaporated, and the crude product was suspended in ethyl acetate-diisopropyl ether, to give 142 mg of the title compound as white crystals.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1)=[O:7]>O.O1CCCC1>[N:15]1[C:16]2[C:11](=[CH:10][CH:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc2cccnc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2cccnc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Lithium hydroxide monohydrate (5.42 g, 141 mmol, 3 equiv.) in water (50 ml) was added to a solution of quinoline-7-carboxylic acid methyl ester (8.8 g, 47 mmol) in tetrahydrofuran (200 ml) and the solution was stirred at room temperature for 16 hours. The tetrahydrofuran was evaporated under reduced pressure and the solution adjusted to pH 7 with 1N HCl (aq) (141 ml), forming a white precipitate. The precipitate was filtered and washed with water and heptane. The solid was dried in a vacuum oven at 50° C. to give quinoline-7-carboxylic acid, 8.4 g (100% yield) as a white solid. LC @215 nm; Rt 0.66: 100%, m/z (ES+): 174 (M+H+.); δH (400 MHz; d6-DMSO) 9.02 (1H, dd), 8.58 (1H, s), 8.48 (1H, d), 8.09 (2H, m), 7.66 (1H, dd).
Reaction SMILES: [C:1]([C:3]1[C:7]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:6]([N:16]=CN(C)C)[N:5]([C:21]2[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][C:22]=2[Cl:32])[N:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:42][CH:43]1[CH2:45][CH2:44]1.Cl>CC(C)=O.CO>[NH2:16][C:6]1[N:5]([C:21]2[C:22]([Cl:32])=[CH:23][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:25][C:26]=2[Cl:27])[N:4]=[C:3]([C:1]#[N:2])[C:7]=1[N:8]([CH2:42][CH:43]1[CH2:45][CH2:44]1)[S:9]([C:12]([F:13])([F:15])[F:14])(=[O:11])=[O:10]
Reactant: CN(C)C=Nc1c(NS(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Solvent: CO
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1N(CC1CC1)S(=O)(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of N-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)-1,1,1-trifluoromethanesulfonamide (250 mg, 0.48 mmol) in acetone (6 ml) was added potassium carbonate (100 mg, 0.72 mmol), a catalytic amount of sodium iodide and (bromomethyl)cyclopropane (69.5 μl, 0.72 mmol). The reaction mixture was then stirred at 60° C. overnight. The reaction mixture was concentrated under a stream of nitrogen and the residue was partitioned between dichloromethane (20 ml) and water (20 ml). The two layers were separated and the organic phase was washed with water, dried (Na2SO4) and concentrated in vacuo to give the protected compound. To a solution of the protected compound in methanol (5 ml) was added hydrochloric acid (4M, 3 ml) and the reaction mixture was heated at reflux. The reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (20 ml). The organic phase was washed with water (2×20 ml), dried (Na2SO4) and concentrated in vacuo. The crude product was dissolved in a mixture of acetonitrile (1 ml), dimethyl sulphoxide (2.4 ml) and water (0.6 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm×30 mm Phenomonex LUNA C18(2) 10 μm column) using an acetonitrile:water gradient [60:40 to 95:5]. The appropriate fractions were concentrated in vacuo to give the titled compound (120 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[CH:23]1([C:26]2[O:27][CH:28]=[C:29]([CH2:31][NH2:32])[N:30]=2)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:12][N:11]=[C:10]([C:20]([NH:32][CH2:31][C:29]3[N:30]=[C:26]([CH:23]4[CH2:25][CH2:24]4)[O:27][CH:28]=3)=[O:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NCc1coc(C2CC2)n1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Product: O=C(NCc1coc(C2CC2)n1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1

Procedure:
The title compound was synthesized in analogy to Example 1 using 4-(4-chlorophenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 2-cyclopropyl-oxazol-4-methanamine (example BH) as starting materials; LC-MS (UV peak area/ESI) 96.5%, 452.0987 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:19]=[C:18]2[C:14]([C:15]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1.Cl.O1CCOC[CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:27])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:19]=[C:18]2[C:14]([C:15]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1
Reactant: C1COCCO1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(-c2ccc3c(c2)NC(=O)C32CCCC2)c1
Yield: 91.4 %

Procedure:
A suspension of 4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzoic acid (preparation 38, 0.47 g, 1.5 mmol) and a 4M solution of hydrochloric acid in dioxane (2.00 mL, 8.0 mmol) in methanol (2 mL) was heated in a sealed tube at 80° C. with stirring. After stirring overnight the mixture was cooled and ethyl acetate and saturated aqueous potassium carbonate solution were added. The organic layer was washed with brine, dried (MgSO4) and evaporated in vacuo. The resultant oil was taken up in a small amount of ethyl acetate and the suspension was filtered. The filtrate was evaporated to give the title compound (0.46 g, 86%) as a foam.
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([N:20]3[C:28]4[CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][C:24](=[O:31])[C:23]=4[C:22]([CH3:32])=[CH:21]3)=[CH:16][C:17]=2F)[N:12]=[CH:11][N:10]=1>CN(C=O)C>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([N:20]3[C:28]4[CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][C:24](=[O:31])[C:23]=4[C:22]([CH3:32])=[CH:21]3)=[CH:16][C:17]=2[S:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:12]=[CH:11][N:10]=1
Reactant: CCCCS
Reactant: Cc1cn(-c2cc(F)c3c(N)ncnc3c2)c2c1C(=O)CC(C)(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCSc1cc(-n2cc(C)c3c2CC(C)(C)CC3=O)cc2ncnc(N)c12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a small microwave vial with a stir bar, butanethiol (0.494 mmol, 44.56 mg) is dissolved in 3 mL DMF. To this solution is added NaH (60% suspension in mineral oil) (0.494 mmol, 20 mg) and the mixture is stirred at rt for 5 minutes and then 1-(4-Amino-5-fluoro-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.0988 mmol, 33.4 mg) is added. The reaction is sealed and placed in the microwave reactor where it is heated to 120° C. for 30 min. The reaction is cooled and quenched by pouring into 30 ml sat. NH4Cl aq. and extracted 3 times with 10 mL EtOAc. The combined organics are dried with Na2SO4, concentrated, and purified by silica gel chromatography on Biotage using a gradient of 0-20% MeOH in DCM. 1-(4-Amino-5-butylsulfanyl-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one is isolated (22.1 mg, LC/MS m/z=409 [M+H]+) as a yellow powder.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH:7]1[C:13]([NH2:14])=[N:12][C:10](=[O:11])[N:9]([C@@H:15]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:17]([OH:22])[C:16]2([F:24])[F:23])[CH:8]=1.Cl>>[F:24][C:16]1([F:23])[C@H:17]([OH:22])[C@@H:18]([CH2:20][OH:21])[O:19][C@H:15]1[N:9]1[CH:8]=[CH:7][C:13]([NH:14][C:2]([O:4][CH2:5][CH3:6])=[O:3])=[N:12][C:10]1=[O:11]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Yield: 64 %

Procedure:
Using Method A and ethyl chloroformate, gemcitabine hydrochloride was converted to 8 (white solid, 64% yield): 1H NMR (400 MHz, DMSO-d6)δ10.88 (s, 1H), 8.24-8.27 (d, 1H), 7.13-7.16 (d, 1H), 6.34-6.37 (d, 1H), 6.18-6.22 (t, 1H), 5.32-5.36 (t, 1H), 4.17-4.23 (m, 3H), 3.90-3.94 (m, 1H), 3.82-3.86 (m, 1H), 3.65-3.72 (m, 1H), 1.25-1.29 (t, 3H); MS (HR-ESI): m/z 334.0853 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10]C)[C:5]([Cl:12])=[C:4]([Cl:13])[N:3]=1.N[C:15]1N=C(NCCCC)C(Cl)=C(Cl)N=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH3:10])[CH3:15])[C:5]([Cl:12])=[C:4]([Cl:13])[N:3]=1
Reactant: CCCCNc1nc(N)nc(Cl)c1Cl
Reactant: CCCNc1nc(N)nc(Cl)c1Cl
Product: CC(C)Nc1nc(N)nc(Cl)c1Cl

Procedure:
In analogous manner to that described in Example 3, 2-amino-4-n-propylamino-5,6-dichloro-pyrimidine and 2-amino-4-n-butylamino-5,6-dichloro-pyrimidine may be produced. Isolation and purification may be effected in conventional manner.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:16]1[C:21]([CH:22]=O)=[CH:20][C:19]2[O:24][CH2:25][O:26][C:18]=2[CH:17]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH:13][CH2:22][C:21]3[CH:16]=[CH:17][C:18]4[O:26][CH2:25][O:24][C:19]=4[CH:20]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCCOc1ccc(-n2ccnc2)cc1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1cn(-c2ccc(OCCNCc3ccc4c(c3)OCO4)cc2)cn1
Reaction time: 1 h
Yield: 51.9 %

Procedure:
To 2-[4-(imidazol-1-yl)phenoxy]ethylamine (4.0 g, 20 mmol) dissolved in MeOH (150 mL) was added piperonal (3.0 g, 20 mmol) and acetic acid (1.5 mL). After stirring for 1 h, NaBH3CN (2.6 g, 40 mmol) was added. After stirring for 18 hour, the solvent was removed in vacuo and the residue was chromatographed on silical gel with 2% methanol in methylene chloride to give 3.5 g of N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine, 1H NMR (DMSO-d6) 8.12 (s, 1), 7.62 (s, 1), 7.54 (d, 2), 7.08–7.02 (m, 3), 6.90 (s, 1), 6.82–6.75 (m, 2), 5.94 (s, 2), 4.03 (t, 2), 3.62 (s, 2), 3.32 (s, 1), 2.80 (t, 2) ppm.