Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:4]=2[S:5][CH:6]=1.Cl.[CH3:15]O>>[CH3:15][O:12][C:11]([C:8]1[CH:9]=[CH:10][C:3]2[C:2]([CH3:1])=[CH:6][S:5][C:4]=2[CH:7]=1)=[O:13]
Reactant: CO
Reactant: Cc1csc2cc(C(=O)O)ccc12
Agent: Cl
Product: COC(=O)c1ccc2c(C)csc2c1

Procedure:
A solution of 3-methylbenzo[b]thiophene-6-carboxylic acid (3.65 g) in methanol (100 ml) was saturated with hydrogen chloride gas and the solution was heated under reflux for 4 hours, and then evaporated. The residue was dissolved in ether and the solution was washed with water, sodium bicarbonate solution and dried (Na2SO4). Evaporation of the solvent gave 3-methylbenzo[b]thiophene-6-carboxylic acid methyl ester (3.70 g) pure enough for further reaction. A sample crystallized from petrol (b.p. 40°-60°) had m.p. 46°-47° C.
Reaction SMILES: Cl.[Na].CC1(C)[O:9][CH2:8][CH:7]([N:10]2[C:14]([SH:15])=[N:13][N:12]=[N:11]2)[CH2:6][O:5]1.[OH-].[Na+]>O>[OH:5][CH2:6][CH:7]([N:10]1[C:14]([SH:15])=[N:13][N:12]=[N:11]1)[CH2:8][OH:9]
Reactant: CC1(C)OCC(n2nnnc2S)CO1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: OCC(CO)n1nnnc1S
Temperature: 80 °C
Yield: 61.4 %

Procedure:
4 N hydrochloric acid (50 cc) is added to the sodium salt of 1-(2,2-dimethyl-1,3-dioxan-5-yl)-5-mercaptotetrazole (as obtained in accordance with Example 7) (22 g) in water (100 cc) and the mixture is heated for 30 minutes at 80° C. 4 N sodium hydroxide solution (25 cc) is added and the mixture is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). The residue is taken up in boiling acetonitrile (2×100 cc), an insoluble material is filtered off, the acetonitrile is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) and the residue is taken up in ethyl ether (100 cc). 1-(1,3-Dihydroxyprop-2-yl)-5-mercaptotetrazole (11 g), melting at 138° C., is isolated by filtration.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(N(C(C)C)C(C)C)C.[C:19]([C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=3[Cl:44])=[CH:30][CH:29]=2)[C:25]([CH3:45])=[N:24][C:23]=1[CH3:46])(=[O:21])[NH2:20].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C>[C:19]([C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][C:41]([NH:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])=[O:42])=[CH:36][C:35]=3[Cl:44])=[CH:30][CH:29]=2)[C:25]([CH3:45])=[N:24][C:23]=1[CH3:46])(=[O:21])[NH2:20]
Reactant: COC(=O)C(C)(C)N
Reactant: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)nc1C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 124.3 %

Procedure:
A mixture of methyl 2-amino-2-methylpropanoate hydrochloride (88 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (342 μL) were treated with a solution of 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid (Example 1; 205 mg, 0.52 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (70.0 mg, 0.52 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (2049 μL) at RT. The resulting solution was stirred at RT for 20 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (5 mL), and washed with water (5 mL). The organic layer was evaporated to afford methyl 2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)-2-methylpropanoate (320 mg, 125%) which was used without further purification.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:16][CH3:17])(=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH:1](=[C:10]([C:9]([O:16][CH3:17])=[O:15])[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CC(=O)OC
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1ccccc1)C(=O)OC

Procedure:
Into a one-liter three-necked conical flask are introduced in succession 60 g (565.39 mmol) of benzaldehyde, 77 g of dimethyl malonate (565.32 mmol), 3.85 g of piperidine (45.21 mmol), 130 ml of toluene and 2.71 g (45.16 mmol) of acetic acid.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[CH:4]=[N:3][CH:2]=1.C([O-])(=O)C.[Na+].[Br:15]Br>C(O)(=O)C>[Br:15][C:7]1[C:6]2[N:1]=[CH:2][N:3]=[CH:4][C:5]=2[S:9][CH:8]=1
Reactant: BrBr
Reactant: c1ncc2sccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1csc2cncnc12
Temperature: 90 °C
Yield: 58.9 %

Procedure:
Thieno[3,2-d]pyrimidine (0.163 g, 1.20 mmol) was dissolved in acetic acid (3 mL). Sodium acetate (0.196 g, 2.39 mmol) was added while stirring, followed by bromine (0.38 g, 2.4 mmol). The reaction mixture was heated in a microwave reactor at 90° C. for 90 min. Solvent was removed by rotary evaporation, then under high vacuum. Purification by ISCO chromatography (0 to 10% methanol:DCM) afforded 0.152 g (59%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.36 (s, 1 H), 9.30 (s, 1 H), 8.05 (s, 1 H); MS (ESI): 214.97, 216.99 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:10]#[N:11].Cl.Cl[CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1.[OH-].[Na+]>CS(C)=O>[C:10]([C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([CH2:12][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)#[N:11]
Reactant: N#CC(CCCN1CCCCC1)c1ccc(Cl)cc1Cl
Reactant: ClCn1cncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#CC(CCCN1CCCCC1)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
This compound (5.0 g.) was prepared using the procedure described in Example 9b except using 5.0 g. (0.016 mole) of 2-(2,4-dichlorophenyl)-5-(1-piperidinyl)valeronitrile, 2.7 g. (0.0176 mole) of 1-(chloromethyl)-1,2,4-triazole hydrochloride, 3.2 g. (0.040 mole) of aqueous 50% sodium hydroxide, and 50 ml. of DMSO and was isolated as an oil.
Reaction SMILES: CS(O[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:7]1)(=O)=O.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Br:21][C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([N:8]3[CH2:9][CH2:10][CH2:11][C@H:6]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH2:7]3)[S:13][C:14]=2[CH:20]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)O[C@@H]1CCCN(c2nc3ccc(Br)cc3s2)C1
Product: Brc1ccc2nc(N3CCC[C@H](N4CCOCC4)C3)sc2c1

Procedure:
The title compound was prepared by the method of Example 34, substituting (R)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-yl methanesulfonate (Reference Example 12) in place of (S)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-yl methanesulfonate (Reference Example 10) and substituting morpholine in place of azetidine to give (S)-4-(1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-yl)morpholine. 1H NMR (300 MHz, CD3OD) δ ppm 1.75-2.01 (m, 2H), 2.02-2.14 (m, 1H), 2.32-2.43 (m, 1H), 3.29-3.48 (m, 3H), 3.50-3.73 (m, 4H), 3.80-3.96 (m, 3H), 4.03-4.19 (m, 2H), 4.56-4.65 (m, 1H), 7.33 (d, J=9 Hz, 1H), 7.39 (dd, J=2, 9 Hz, 1H), 7.79 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 382 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH2:7]/[C:6](=[CH:9]\[CH2:10][OH:11])/[CH2:5][O:4][C:3]1([CH2:13][CH2:14][CH2:15][CH:16]([CH3:25])[CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[CH3:12]>[O-2].[O-2].[Mn+4].C(Cl)Cl>[CH3:12][C:3]1([CH2:13][CH2:14][CH2:15][CH:16]([CH3:25])[CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:2]2[O:1][C:6]([CH2:9][CH:10]=[O:11])([CH2:7][CH2:8]2)[CH2:5][O:4]1
Reactant: CC(CCCC1(C)OC/C(=C/CO)CCC1O)COC1CCCCO1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(CCCC1(C)OCC2(CC=O)CCC1O2)COC1CCCCO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.8 %

Procedure:
A mixture of 5-[(2RS,3SR)-3-hydroxy-6-[(E)-2-hydroxyethylidene]-2-methyl-2-oxepanyl]-2-methyl-1-(tetrahydropyran-2-yloxy)pentane (953 mg, 2.67 mM), manganese dioxide (4 g) and methylene chloride (20 ml) is stirred for three days at room temperature under nitrogen. The mixture is filtered through a pad of Celite and washed with methylene chloride (2×30 ml). The solvent is removed in vacuo and the residue purified by column chromatography on silica gel (15 g) with 30% ether in petroleum ether to give (1RS,4SR,5RS)-4-methyl-4-[4-methyl-5-(tetrahydropyran-2-yloxy)pentyl]-3,8-dioxabicyclo [3.2.1] octane-1-acetaldehyde (0.813 g, 73%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH:10]=[O:11])=[CH:8][N:7]=[C:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>CO.O>[CH2:1]([N:5]1[C:9]([CH2:10][OH:11])=[CH:8][N:7]=[C:6]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(C=O)cnc1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCn1c(CO)cnc1-c1ccccc1

Procedure:
Aldehyde 102 is dissolved in methanol (150 mL). Sodium borohydride (3g) is added in portions. After the addition is complete, the reaction is diluted with water and concentrated. The residue is dissolved in ethyl acetate, washed with brine, dried (Na2SO4) and concentrated. The product is purified by flash chromatography on silica gel (5% MeOH/CHCl3) to give 103 as a cream colored solid. 1HNMR (400 MHz, CDCl3) δ 0.79 (3H, t, J=7.4 Hz), 1.18 (2H, m, J=7.4 Hz), 1.60 (2H, m, J=7.6 Hz), 4.03 (2H, dd, J=7.6 Hz), 4.56 (2H, s), 6.84 (1H, s), 7.39-7.50 (3H, m), 7.50-7.53 (2H, m).
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[CH3:26][O:27][CH2:28][CH2:29][O:30][C:31]1[N:36]=[C:35]([C:37]([OH:39])=O)[CH:34]=[N:33][C:32]=1[N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.[CH3:46][O:47][C:48](=[O:55])[C:49]([NH2:54])([CH2:52][CH3:53])[CH2:50][CH3:51]>>[CH3:46][O:47][C:48](=[O:55])[C:49]([CH2:52][CH3:53])([NH:54][C:37]([C:35]1[CH:34]=[N:33][C:32]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[C:31]([O:30][CH2:29][CH2:28][O:27][CH3:26])[N:36]=1)=[O:39])[CH2:50][CH3:51]
Reactant: CCC(N)(CC)C(=O)OC
Reactant: COCCOc1nc(C(=O)O)cnc1N1CCOCC1
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: CCC(CC)(NC(=O)c1cnc(N2CCOCC2)c(OCCOC)n1)C(=O)OC

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 6-(2-methoxy-ethoxy)-5-morpholin-4-yl-pyrazine-2-carboxylic acid and 2-amino-2-ethyl-butyric acid methyl ester (European Journal of Medicinal Chemistry 1984, 19, 261). m/z (ES+): 411.5 (M+H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][CH2:19][CH2:20][CH2:21][OH:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][CH2:19][CH2:20][CH:21]=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCOCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCCOCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
Into a 100-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed DMSO (5.1 mL, 71.79 mmol) in dichloromethane (40 mL). This was followed by the addition of oxalyl chloride (3.1 mL, 54.16 mmol) dropwise at −78° C. and stirred for 30 min at −78° C. To this was added a solution of 3-(benzyloxy)propan-1-ol (4.8 mL, 30.08 mmol) in dichloromethane (10 mL) dropwise at −78° C. The resulting solution was stirred for 1 h at −78° C., then triethylamine (16.5 mL, 118.59 mmol) was added to the reaction. The resulting solution was stirred for 1 h at −78 to −20° C., then quenched with 50 mL of NH4Cl (sat.). The aqueous phase was extracted with 2×50 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc:PE (1:5) as eluent to furnish 2.0 g (40%) of the title compound as light yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([Cl:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=2[Cl:14])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[C:25](=[CH:30]\[O:31][CH3:32])/[C:26]([O:28][CH3:29])=[O:27]>CN(C)C=O.O>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([Cl:14])=[CH:8][C:9]([O:13][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3/[C:25](=[CH:30]\[O:31][CH3:32])/[C:26]([O:28][CH3:29])=[O:27])=[CH:10][C:11]=2[Cl:12])[CH2:2][CH2:3]1
Reactant: Oc1cc(Cl)c(OCC2CC2)c(Cl)c1
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(Cl)c(OCC2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
A solution of 4-cyclopropylmethoxy-3,5-dichlorophenol (1.54 g; 6.6 mmoles) in DMF (5 ml) is added dropwise, at 0° C., to a suspension of sodium hydride (0.16 g; 6.6 mmoles) in N,N-dimethyl formamide (DMF; 5 ml). The mixture is kept under stirring at room temperature for 30 minutes and a solution of methyl (E)-2-(2bromomethylphenyl)-3-methoxyacrylate (1.9 g; 6.6 mmoles) in DMF (5 ml) is then added. The mixture is kept under stirring for 4 hours; the mixture is diluted with water (40 ml) and an extraction is effected with ethyl acetate (3×25 ml). The organic phases are joined, washed with water (2×20 ml), dried with sodium sulfate, filtered and concentrated at reduced pressure. The raw product obtained is purified by means of silica gel chromatography, eluting with hexane/ethyl acetate 9:1. 1.9 g of the desired product (thick oil) are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:25][O:26][CH2:27][CH3:28])[N:14]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.O.[OH-].[Na+]>C(O)(C(F)(F)F)=O.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:25][O:26][CH2:27][CH3:28])[N:14]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(=O)C(C)C
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOCc1nc2c(N)nc3c(c2n1NCCCNC(=O)C(C)C)CCCC3
Temperature: 25 °C
Reaction time: 17 h
Yield: 52.1 %

Procedure:
A solution of N-(3-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)-2-methylpropanamide (0.450 g, 1.17 mmol) in 25 mL of TFA was treated with platinum (IV) oxide (0.266 g, 1.17 mmol). The reaction mixture was shaken under an atmosphere of hydrogen (3.8×105 Pa) at ambient temperature. After 17 h, the reaction mixture was filtered through a pad of CELITE filter agent and rinsed with portions of 4:1 CHCl3:MeOH (1% TFA). The filtrate was concentrated under reduced pressure to yield a white oil. The oil was suspended in a minimum amount of H2O and treated with 50% NaOH solution until the pH was 13. A white solid precipitated and was triturated in the basic H2O for 1 h and then filtered to yield a sticky white solid. The solid was then triturated with Et2O for 2 h, filtered and dried to yield N-(3-{[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)-2-methylpropanamide (0.237 g) as a white solid. mp 163–165° C.; 1H NMR (500 MHz, DMSO-d6) δ 7.69 (t, J=5.5 Hz, 1H), 6.31 (t, J=5.9 Hz, 1H), 5.80 (s, 2H), 4.61 (s, 2H), 3.55 (q, J=7.0 Hz, 2H), 3.15–3.11 (m, 2H), 3.04–3.00 (m, 4H), 2.66 (t, J=5.7 Hz, 2H), 2.31 (h, J=6.8 Hz, 1H), 1.81–1.69 (m, 4H), 1.62 (p, J=7.1 Hz, 2H), 1.14 (t, J=7.0 Hz, 3H), 0.98 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 176.3, 149.9, 149.3, 147.0, 137.6, 122.7, 105.4, 65.7, 63.3, 51.7, 36.6, 34.4, 32.5, 28.0, 23.3, 23.0, 22.4, 19.9, 15.3; MS (ESI) m/z 389 (M+H)+; Anal. Calcd for C20H32N6O2: C, 61.83; H, 8.30; N, 21.63; Found: C, 61.63; H, 8.23; N, 21.55.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:14])([CH3:13])[C:5]1=[O:15])(=O)C>Cl>[CH3:13][C:6]1([CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:5]1=[O:15]
Reactant: CC(=O)N1C(=O)C(C)(C)c2ccccc21
Agent: Cl
Product: CC1(C)C(=O)Nc2ccccc21
Yield: 97 %

Procedure:
To a stirred solution of 2a (3.2 g, 18.29 mmol) in dry THF (100 mL) was added MeI (2.6 mL, 41.75 mmol, 2.3 eq), followed by the addition of 18-crown-6 (0.51 g, 4.57 mmol, 0.25 eq) at −78° C. under nitrogen. Potassium tert-butoxide (5.12 g, 45.73 mmol, 2.5 eq) was added portionwise. The resulting slurry was stirred at −78° C for 1 h. The mixture was stirred at −78° C. to rt for 3. h. Cooled in an ice bath, sat'd NH4Cl was added. It was extracted with EtOAc, washed with H2O, brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give pure 1-acetyl-3,3-dimethylindolin-2-one (1.3 g) (LC-MS ESI 204 (M+H)) and pure 3,3-dimethylindolin-2-one (1.0 g) (LC-MS ESI 162 (M+H)) respectively. 1-Acetyl-3,3-dimethylindolin-2-one (1.3 g) was heated in 6N HCl at reflux for 1 h. After cooling, it was poured into crushed ice. It was extracted with Et2O, washed with sat'd NaHCO3, H2O, brine, dried over Na2SO4, filtered, and concentrated to dryness to give almost pure 2b (1.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:12]1([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:23])=[CH:20][N:19]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ccccc2)nc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (100 mg, 0.69 mmol) and 6-phenylnicotinic acid (D48) (198 mg, 1 mmol) as a solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.23 (d, 1H), 8.92 (dd, 1H), 8.33 (dd, 1H), 8.23 (s, 1H), 8.15, (d, 1H), 8.14 (s, 1H), 8.08 (m, 3H), 7.90 (d, 1H), 7.87 (d, 1H), 7.50 (m, 3H), 7.38 (dd, 1H).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:18](OC)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O.C1(C)C=CC=CC=1>[C:19]1([C:18](=[O:25])[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:10])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)C(C(=O)c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 15 h
Yield: 60.3 %

Procedure:
In a 500-ml four-necked flask were placed 16.0 g (0.40 mole) of 60% sodium hydride (an oil-added grade), 39.6 g (0.20 mole) of deoxybenzoin, 200.0 g of toluene, and 198.8 g (1.46 moles) of methyl benzoate. The mixture was then heated under reflux with stirring for 15 hours while distilling off methanol. After the reaction was over, the reaction mixture was cooled to 40° C. and 60.8 g (0.60 mole) of concentrated hydrochloric acid and 180.0 g of water were added in drops. The reaction mixture was transferred to a separatory funnel and an organic layer was separated. The organic layer was concentrated under reduced pressure to dryness. The residue was purified by reslurrying with methanol and a solid was recovered by filtration and dried under reduced pressure to give 36.2 g of 1,2,3-triphenylpropane-1,3-dione.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].[C@@H]1(N)CCCC[C@H]1N.CCCCCCCCCCCC.I[C:41]1[CH:42]=[C:43]([CH3:48])[CH:44]=[C:45]([CH3:47])[CH:46]=1>[Cu]I.O1CCOCC1>[CH3:47][C:45]1[CH:46]=[C:41]([N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:42]=[C:43]([CH3:48])[CH:44]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: N[C@@H]1CCCC[C@H]1N
Solvent: C1COCCO1
Solvent: CCCCCCCCCCCC
Product: Cc1cc(C)cc(N(c2ccccc2)c2ccccc2)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 74.2 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (2.0 mg, 0.0105 mmol, 1.0 mol %), diphenylamine (210 mg, 1.24 mmol), sodium tert-butoxide (145 mg, 1.51 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (13 μL, 0.108 mmol, 11 mol %), dodecane (235 μL), 5-iodo-m-xylene (150 μL, 1.04 mmol) and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 24 h. The resulting pale brown suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of hexane-ethyl acetate 5:1. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×25 cm; hexane-ethyl acetate 40:1; 15 mL fractions). Fractions 9-13 provided 211 mg (74% yield) of the product as white crystals. The 1H NMR spectrum was in accord with that reported by Goodbrand et al. Goodbrand, H. B.; Hu, N. X. J. Org. Chem. 1999, 64, 670.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[C:11]([Cl:20])[CH:10]=2)[C:5]([F:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]2[O:30][CH:29]([C:31]([O:33][CH3:34])=[O:32])[CH2:28][C:27]=2[CH:35]=1>>[Cl:20][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:21])=[CH:4][N:3]=[C:2]([NH:22][C:23]3[CH:24]=[CH:25][C:26]4[O:30][CH:29]([C:31]([O:33][CH3:34])=[O:32])[CH2:28][C:27]=4[CH:35]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][C:16]([F:19])([F:18])[F:17]
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Reactant: Fc1cnc(Cl)nc1Nc1ccc(OC(F)(F)F)c(Cl)c1
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(OC(F)(F)F)c(Cl)c4)n3)ccc2O1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamine and 5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted to produce N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.99 (bs, 1H), 9.49 (bs, 1H), 8.18 (d, 1H, J=4.5 Hz), 8.08 (t, 1H, J=2.4 Hz), 7.81–7.74 (m, 1H), 7.49 (d, 1H, J=8.1 Hz), 7.42 (s, 1H), 7.20 (d, 1H, J=8.1 Hz), 6.78 (d, 1H, J=8.7 Hz), 5.36 (m, 1H), 3.80–3.47 (m, 4H), 3.20 (dd, 1H, J=6.0 and 16.5 Hz); LCMS: purity: 100%; MS (m/e): 500(MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9]Cl)[CH:4]=1.[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13]>>[C:11]([O:15][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:15][C:11](=[O:14])[CH:12]=[CH2:13])[CH:4]=1)(=[O:14])[CH:12]=[CH2:13]
Reactant: ClCc1cccc(CCl)c1
Reactant: C=CC(=O)O
Product: C=CC(=O)OCc1cccc(COC(=O)C=C)c1

Procedure:
The above compound was synthesized from α,α′-dichloro-m-xylene and acrylic acid.