Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:33])[C:20]([OH:32])([C:25]3[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=3)[C:21]([F:24])([F:23])[F:22])=[C:15]([Cl:34])[CH:14]=2)=[CH:7][CH:6]=1)C.[Li+].[OH-].Cl>O1CCCC1.CO>[Cl:34][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[CH:19]([CH3:33])[C:20]([OH:32])([C:25]1[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=1)[C:21]([F:24])([F:22])[F:23])[O:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:35])=[O:3])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(COc2ccc(C(C)C(O)(c3cnc(C)cn3)C(F)(F)F)c(Cl)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cnc(C(O)(C(C)c2ccc(OCc3ccc(C(=O)O)cc3)cc2Cl)C(F)(F)F)cn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To a solution of 4-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenoxymethyl}-benzoic acid ethyl ester (Example 1, 130 mg, 0.26 mmol) in tetrahydrofuran (2.5 ml) and methanol (0.5 ml) was added a 1 M aqueous LiOH solution (0.31 ml). The mixture was stirred for 4 h at 60° C. (bath temperature). The cooled mixture was acidified with 1 M aqueous HCl. Tetrahydrofuran and methanol were evaporated in vacuo. To the suspension water was added. The precipitation was filtered, washed with water and dried to give the title compound as a white solid (105 mg). MS (m/e, ISP neg. ion)=479.4 [M−H+].
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][NH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:12]2[CH:13]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11]2)=[CH:32][CH:33]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)c1c[nH]cc1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2ccc(OCc3ccccc3)cc2)cc1-c1ccccc1
Reaction time: 1 h
Yield: 96.6 %

Procedure:
Sodium hydride (60%, oily, 2.55 g) was added to a mixture of methyl 4-phenylpyrrole-3-carboxylate (11.61 g), 4-benzyloxybenzyl chloride (15.23 g) and N,N-dimethylformamide (100 ml) at 0° C., and the mixture was stirred for one hour. The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and methyl 1-(4-benzyloxybenzyl)-4-phenylpyrrole-3-carboxylate (22.16 g, yield: 97%) was obtained from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 97–98° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[F:12][C:13]([F:16])([F:15])I.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([S:9][C:13]([F:16])([F:15])[F:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: FC(F)(F)I
Reactant: Fc1ccc(S)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(SC(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Bromo-4-fluorobenzenethiol (2.071 g, 10 mmol) in dimethylformamide (10 mL) was treated with 60% sodium hydride (0.480 g, 12.00 mmol). The solution was stirred for 10 minutes at room temperature. Trifluoroiodomethane (2.74 g, 14.00 mmol) was released into a balloon with a three-way stopcock. The balloon was then put onto the flask and trifluoroiodomethane was released into the reaction. After 1 hour, all the content in the balloon was gone. And the balloon was filled with 2.74 g of trifluoroiodomethane again. The reaction mixture was stirred for 16 hours. The reaction mixture was poured into water, and extracted with ethyl acetate several times. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting oil was used directly in the next reaction.
Reaction SMILES: C1(S(C2(SC)[CH2:15][C@@H:14]3[C@@:12]([C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:18][CH:17]=4)([CH2:13]3)[CH2:11]2)(=O)=O)C=CC=CC=1.[CH3:28][OH:29].Cl>C(OCC)(=O)C.CCCCCC>[C:16]1([C@@:12]23[CH2:13][C@@H:14]2[CH2:15][C:28](=[O:29])[CH2:11]3)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CSC1(S(=O)(=O)c2ccccc2)C[C@H]2C[C@@]2(c2cccc3ccccc23)C1
Reactant: CO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1C[C@H]2C[C@@]2(c2cccc3ccccc23)C1
Yield: 99 %

Procedure:
(1R,5R)-3-Benzenesulfonyl-1-(1-naphthyl)-3-methylsulfanyl-bicyclo[3.1.0]hexane (620 mg, 1.6 mmol), methanol (4 mL) and concentrated hydrochloric acid (0.7 mL) were heated to reflux for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane (20:80)) The reaction mixture was concentrated under reduced pressure to remove methanol. The pH of the reaction mass was adjusted to 8-9 with saturated sodium bicarbonate solution. The aqueous layer was extracted with diethyl ether (50 mL). The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 458 mg of crude oil, which was purified by preparative HPLC to yield 135 mg (39%) of 99% pure product. 1H NMR δ(300 MHz,CDCl3) 0.76-0.79 (1H,t, J=4 Hz), 1.38 (1H,m), 2.01 (1H,m), 2.49-2.56 (1H,d, J=10Hz), 2.75 (2H,d,J=6 Hz), 3.05-3.15 (2H,dd,J=10 Hz), 7.40-7.45 (1H,m), 7.50-7.56 (3H,m), 7.76-7.79 (1H,d,J=9 Hz), 7.88-7.90 (1H,m), 8.13-8.15 (2H,d ,J=6 Hz). 13CNMR(CDCl3)δ: 218.25, 139.12, 134.01, 128.96, 127.80, 126.77, 126.17, 125.78, 125.33, 124.0, 48.18, 42.46, 27.80, 20.62, 20.05.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[C:18]([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: CC(C)(C)CI
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)cc(Cl)n(CC(C)(C)C)c1=O
Reaction time: 48 h

Procedure:
6-Chloro-3-methyl uracil (10.0 g) and potassium carbonate (10.34 g) in DMF (70 ml) under nitrogen were treated with neopentyl iodide (9.9 ml) and stirred for 48 h. Neopentyl iodide (7.4 ml) was added and the reaction was stirred under reflux for a further 37 h. The reaction was poured into water (700 ml) and extracted with ethyl acetate. The combined organics were dried and concentrated in vacuo to afford the subtitle compound an orange oil, 8.1 g.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1F.[SH:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:16][CH2:17][CH2:18][OH:19]
Reactant: N#Cc1ccc(C2OCCCO2)c(F)c1
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2OCCCO2)c(SCCO)c1

Procedure:
The reaction was carried out under argon. 4-(1,3-Dioxan-2-yl)-3-fluorobenzonitrile (2.07 g, 10 mmol; 1.1 eq.) and 2-mercaptoethanol (0.71 g, 9.1 mmol; 1 eq.) were initially charged in DMF (50 ml). Potassium carbonate (3.14 g, 22.7 mmol; 2.5 eq.) was added at RT, and the mixture was stirred at boiling point for 1 h. TLC control then showed complete conversion. The mixture was concentrated and the residue was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 1:2). The title compound was obtained as a solid (2.33 g, 88% of theory).
Reaction SMILES: [F:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[CH:10][CH:9]=[C:8]([F:19])[C:3]=1[C:4]([O:6]C)=[O:5].CO.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[CH:10][CH:9]=[C:8]([F:19])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(F)ccc(-c2cccc(F)c2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c(F)ccc(-c2cccc(F)c2)c1F
Yield: 86.7 %

Procedure:
To a solution of methyl 2,6-difluoro-3-(3-fluorophenyl)benzoate (1.7 g, 6.4 mmol, 1.0 eq) in mixture of MeOH (20 mL) and THF (20 mL) was added a solution of aqueous NaOH (1M aqueous solution, 20 mL, 20 mmol, 3.1 eq) at room temperature. The reaction mixture was heated to reflux for 30 mins, then cooled and the resulting mixture concentrated in vacuo to remove the organic solvent. The residue was diluted with water and adjusted to pH 5-6, by addition of 1M HCl. The precipitate that formed was collected by filtration, washed with water and dried in vacuo to give the title compound as a white solid (1.4 g, 87%).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[C@@H:37]([OH:39])[CH3:38])[N:16]=3)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[C@@H:37]([OH:39])[CH3:38])[N:16]=3)[CH2:9]1
Reactant: C[C@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-{2-[2-((S)-1-hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl}azetidine-1-carboxylic acid tert-butyl ester (109 mg, 0.20 mmol) in DCM (5 mL) was added TFA (2 mL) and the resulting mixture stirred at r.t. for 45 min. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound (70 mg, 80%). LCMS (method A): RT 1.87 min [M+H]+ 449.4
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[F:13][C:14]1[CH:15]=[C:16]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]3)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: COc1ccc(B(O)O)cc1F
Product: COc1ccc(-c2ccc3cc(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 6-bromo-2-naphthol (3.2 g, 18.8 mmol) with 3-fluoro-4-methoxyphenylboronic acid (3.5 g, 15.7 mmol) according to method A to yield 3.3 g (78%) of white solid: mp 174-176° C.; 1H NMR (DMDO-d6): δ 3.89 (3H, s), 7.11 (1H, dd, J=8.79 Hz, J=1.95 Hz), 7.13 (1H, s), 7.26 (1H, J=8.79 Hz), 7.57 (1H, d, J=8.79 Hz), 7.66 (1H, dd, J=13.18 Hz, J=1.95 Hz), 7.71 (1H, dd, J=8.79 Hz, J=1.46 Hz), 7.75 (1H, d, J=8.79 Hz), 7.82 (1H, d, J=8.79 Hz), 8.07 (1H, s), 9.81 (1H, s); MS (ESI) m/z267 (M−H)−.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11](NN)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[Br:20]Br>CCCCCC>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([Br:20])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: BrBr
Reactant: NNS(=O)(=O)c1cccc2cccnc12
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: O=S(=O)(Br)c1cccc2cccnc12
Yield: 749.2 %

Procedure:
A 500 ml, single-neck flask equipped with a magnetic stirrer is charged with 6.59 g (0.0295 mol) of 8-quinolinesulfonyl hydrazine and 200 ml of chloroform. Crushed ice is added, and the slurry is vigorously stirred. 9.50 g of bromine is added dropwise to the slurry with stirring. After the addition of bromine is complete and all of the bromine color has disappeared, the layers are separated. The chloroform layer is dried over anhydrous magnesium sulfate, and the chloroform is removed in vacuo leaving a pale yellow solid. The solid is slurried with hexane, filtered, and vacuum dried to give 6.00 g (0.221 mol) of 8-quinolinesulfonyl bromide m.p. 142°-144° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].C(N(C(C)C)CC)(C)C.[CH3:26][O:27][CH2:28]Cl>C(Cl)Cl>[CH3:26][O:27][CH2:28][O:16][C:3]1[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])=[CH:7][C:2]=1[Br:1]
Reactant: COCCl
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 45 °C
Yield: 95.4 %

Procedure:
To a solution of 2-bromo-4,6-di-t-butylphenol (Compound D 2.54 g, 8.88 mmol) and catalytic amount of BU4NI in 20 ml of dry CH2Cl2 at 0° C. was added diisopropylethylamine (9.51 ml, 53 mmol), followed by methoxymethyl chloride (2.02 ml, 26.6 mmol). The reaction mixture was heated to 45° C. for 12 hours. The reaction mixture was then washed with 10% citric acid, then NaHCO3 (sat.), brine, and dried over MgSO4. After filtration and removal of the solvent under reduced pressure, the residue was purified by column chromatography (pure hexane) to yield the title compound (2.79 g) as a colorless oil. 1H NMR δ 7.40 (d, J=2.44 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 5.22 (s, 2H), 3.70 (s, 3H), 1.43 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].[NH3:14]>CO.O>[CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([NH2:14])=[O:6]
Reactant: N
Reactant: COC(=O)c1ccccc1N(C)C
Solvent: O
Solvent: CO
Product: CN(C)c1ccccc1C(N)=O
Temperature: 25 °C
Yield: 5 %

Procedure:
A solution of methyl 2-dimethylamino-benzoate (1.79 g, 10 mmol) in 2 M ammonia in methanol (20 mL) was heated at 80° C. in a sealed reaction vessel for 3 d. Upon cooling to room temperature, it was diluted with water. The product was extracted with diethyl ether. The ethereal extracts were washed with brine and dried over anhydrous magnesium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 20% ethyl acetate in hexanes yielded 2-dimethylamino-benzamide (85 m g, 5%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:35])[CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OC(=O)C)C>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:35])[CH2:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=3)[CH2:23][CH2:24]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)CCCN2CCN(c3ccc(C(F)(F)F)cc3)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)NC1CCNCC1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
Trifluororoacetic acid (1 mL) is added to a solution of 4-{4-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-butyrylamino}-piperidine-1-carboxylic acid tert-butyl ester (660 mg; 1.32 mmol, prepared in accordance with Example 74) in dichloromethane (4 mL) and the resulting mixture is stirred at room temperature. After 3 hours reaction time, the excess acid is neutralized by the addition of potassium carbonate, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue obtained is diluted in ethylacetate (20 mL) and the organic phase is extracted with water (2×10 mL). The combined aqueous phases are extracted with dichloromethane (10 mL) and diethylether (10 mL). The combined organic layers are dried over magnesium sulfate and the solvents removed under reduced pressure to afford the desired product (417 mg; 1.05 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].C(N(CC)CC)C.[CH2:18]([O:20][C:21]([C:23]1[S:24][C:25]([C:28](Cl)=[O:29])=[CH:26][CH:27]=1)=[O:22])[CH3:19]>C(#N)C>[CH2:18]([O:20][C:21]([C:23]1[S:24][C:25]([C:28](=[O:29])[NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)=[CH:26][CH:27]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1ccc(C(=O)Cl)s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 22 h
Yield: 90 %

Procedure:
Starting material (12(e)) was prepared as follows. To a stirring solution of 3,4-dichlorobenzylamine (0.53 mL; 4.0 mmole) in acetonitrile (10 mL) was added triethylamine (1.67 mL; 12.0 mmole) and a solution of (11(a)) (0.87 g; 4.0 mmole, see Example 11) in acetonitrile (20 mL). The solution was stirred at ambient temperature. under argon, for 22 hours. The solvent and excess triethylamine were removed in vacuo and the residue partitioned between chloroform and water. The organic phase was washed with water and brine, dried over magnesium sulphate and vacuumed to dryness to give 5-(3,4-dichlorobenzyl-carbamoyl)-thiophene-2-carboxylic acid ethyl ester (12(a)) as a cream solid ( 90%).
Reaction SMILES: CO/[CH:3]=[C:4]1/[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]2[C:13]/1=[CH:12][CH:11]=[CH:10][CH:9]=2.[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29]/[CH:3]=[C:4]3\[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:25][CH:24]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccccc21
Product: O=C1NC(=O)c2ccccc2/C1=C/Nc1ccc(CN2CCOCC2)cc1
Yield: 18.7 %

Procedure:
Using the procedure described for the preparation of example 14, 100 mg (15% yield) of a yellow solid from 300 mg (1.47 mmol) of (4E)-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione and 4-morpholin-4-ylmethyl-phenylamine 283.5 mg (1.47 mmol); mp 221-2MS (ESI) m/z 463.1 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[Cl:19][C:20]1[C:29]2[C:24](=[C:25]([O:34][CH3:35])[C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1>C(O)(C)C>[ClH:19].[C:10]([NH:9][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[F:1])[NH:8][C:20]1[C:29]2[C:24](=[C:25]([O:34][CH3:35])[C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(F)c(NC(=O)c2ccccc2)c1
Reactant: COc1cc2c(Cl)ncnc2c(OC)c1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(F)c(NC(=O)c4ccccc4)c3)ncnc2c(OC)c1OC
Temperature: 80 °C
Yield: 52.7 %

Procedure:
N-(2-Fluoro-5-aminophenyl)benzamide (276 mg) was added to a suspension of 4-chloro-6,7,8-trimethoxyquinazoline hydrochloride (293 mg) in isopropanol (8 ml) and the resultant mixture stirred and heated to 80° C. for 18 hours. The mixture was cooled to ambient temperature and the precipitated solid was isolated, washed with isopropanol then diethyl ether to yield the title compound as a solid (257 mg, 53%); NMR: 4.0 (s, 3H), 4.01 (s, 3H), 4.07 (s, 3H), 7.42 (t, 1H), 7.52 (m, 2H), 7.62 (m, 2H), 8.0 (m, 3H), 8.35 (s, 1H), 8.72 (s, 1H), 10.28 (s, 1H), 11.84 (broad s, 1H); m/s: M+H+ 449.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[Cl:7][C:8]1[C:9](S(C)(=O)=O)=[N:10][CH:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:9]2[C:8]([Cl:7])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=1
Reactant: CS(=O)(=O)c1ncccc1Cl
Reactant: Brc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cccnc1-n1cnc(Br)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 96.9 %

Procedure:
A mixture of 1.0 g of 4-bromoimidazole, 1.3 g of 3-chloro-2-(methanesulfonyl)pyridine, 2.7 g of cesium carbonate and 10 ml of N,N-dimethylformamide was stirred at 100° C. for 6 hours. The reaction mixture was allowed to cool to room temperature, and water was poured into the mixture. A deposited precipitate was collected by filtration to obtain 1.7 g of 2-(4-bromo-1H-imidazol-1-yl)-3-chloropyridine of the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][CH:22]=[CH2:23]>>[CH2:23]([N:15]1[CH2:16][CH2:17][O:18][CH:13]([CH2:12][NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH2:14]1)[CH2:22][CH:21]=[CH2:20]
Reactant: C=CCCBr
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Product: C=CCCN1CCOC(CNC(=O)Nc2ccc(Cl)cc2)C1

Procedure:
Example 27 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and 4-bromobut-1-ene (4.1 μl) to give the title compound (0.0027 g).
Reaction SMILES: CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[OH:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=1I.[CH3:28][N:29](C)C.O1CCOCC1>O>[C:28]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:17]=1[OH:16])[C:21]([O:23][CH3:24])=[O:22])#[N:29]
Reactant: CN(C)C
Reactant: COC(=O)c1ccc(O)c(I)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 154.5 %

Procedure:
(Boc)2O (44.7 g, 0.21 mol) was added portion-wise over 10 min to a 0° C. solution of compound 2 (42 g, 0.19 mol), trimethyl amine (51.9 mL, 0.37 mol), dioxane (140 L) and water (56 mL). After another 10 min, the ice bath was removed and the reaction mixture was stirred while warming to room temperature for another 2 hours. The reaction mixture was diluted in ethyl acetate (150 mL) and washed with 0.5 N HCl (200 mL×3). The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo giving compound 3 (52 g, yield 97%) which was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[CH2:15]([C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26](=O)[C:27](OC)=[O:28])=[CH:22][NH:23]2)=[CH:19][CH:18]=1)[CH3:16].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH2:15]([C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]3[C:27](=[O:28])[NH:14][C:12](=[O:13])[C:11]=3[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:22][NH:23]2)=[CH:19][CH:18]=1)[CH3:16]
Reactant: CCc1ccc2c(C(=O)C(=O)OC)c[nH]c2c1
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c[nH]c2c1
Temperature: 50 °C
Reaction time: 7 h
Yield: 30 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (370 mg, 1.97 mmol) and methyl 2-(6-ethyl-1H-indol-3-yl)oxoacetate (446 mg, 1.93 mmol) in DMF (8.0 mL) at 4° C. under N2, was added a 1.0 M solution of potassium tert-butoxide in THF (6.0 mL, 6.0 mmol) dropwise over 20 min. The reaction was heated to 50° C. and stirred for 7 h at this temperature. The reaction mixture was then cooled to room temp and quenched with 1.0 N hydrochloric acid (5.0 mL), extracted with EtOAc (2×15 mL), washed with saturated NaHCO3 (30 mL), saturated NaCl (30 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 50% EtOAc/hexanes containing 1% TEA) gave the title compound (214 mg, 30%) as a red solid, mp 98–100° C. 1H NMR (DMSO-d6) δ 11.69 (s, 1H), 11.06 (s, 1H), 7.78 (m, 1H), 7.60 (m, 1H), 7.28 (m, 1H), 7.16 (s, 1H), 6.95 (m, 1H), 6.86 (m, 1H), 6.50 (m, 1H), 6.32 (m, 1H), 6.20 (m, 1H), 3.69 (s, 3H), 3.32 (m, 2H), 1.11 (m, 3H). MS (ESI, negative mode): m/z=368 [C23H19N3O2−H]−