Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1.C1(C)C=CC=CC=1>CN(C)C=O.[I-].[K+]>[CH:18]1([O:6][C:5]2[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=2[O:8][CH3:9])[CH:2]=[O:1])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(C=O)cc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 80.5 %

Procedure:
A solution of 100 g (0.66 mol) of isovanillin, 136.2 g (0.99 mol) of anhydrous potassium carbonate, and 3 g of potassium iodide in 650 ml of anhydrous dimethylformamide was stirred at 65° C. 127.3 g (0.85 mol) of cyclopentyl bromide was slowly added dropwise for 1 hour to the solution. This solution was stirred at 65° C. for 1 day and, then, its temperature was lowered to a room temperature. It was diluted by 2.0 L of toluene and was washed with 1M sodium hydroxide (2×1.5 L). The aqueous layer was extracted with 0.5 L of toluene, and the organic layer was washed with distilled water (2×1.5 L). The organic layer was dried and concentrated to obtain 117 g of light brown oily title compound. 1H NMR(CDCl3,d): 9.84(s, 1H) 7.42(m, 2H) 6.95(d, 1H, J=9 Hz) 4.87(m, 1H) 3.93(s, 3H) 2.1-6(m, 8H)
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH3:16])[NH2:12]>C(O)(=O)C>[CH3:16][C:15]1[CH:14]=[CH:13][C:11]([NH:12][C:5]([CH3:6])=[O:7])=[CH:10][C:9]=1[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(N)cc1C
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C)c(C)c1

Procedure:
95 ml of acetic anhydride was added to a stirred solution of 3,4-dimethylaniline in 300 ml of glacial acetic acid at such a rate the temperature of the mixture slowly rose to 60° C. The resulting mixture was stirred while the temperature dropped to room temperature, then evaporated to dryness. A mixture of water and ice was added to the residue, followed by methylene chloride. The resulting mixture was stirred and treated with solid sodium bicarbonate until neutral. The organic phase was separated, and dried (MgSO4), and the solvent was evaporated to give 3,4-dimethylacetanilide (4A).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)#[N:18]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:23]([C:22]2[CH:26]=[CH:27][C:19]([C:17]#[N:18])=[CH:20][CH:21]=2)[OH:24])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc(C#N)cc1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 4-cyanobenzoic acid
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C:15]1=[O:20])(=[O:13])=[O:12])([O-:4])=[O:3].[CH:21]([O:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][N:41]([CH2:44][C:45](O)=[O:46])[C:40](=[O:48])[N:39]=1)=[O:36])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:21]([O:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][N:41]([CH2:44][C:45]([N:17]2[CH2:18][CH2:19][N:14]([S:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N+:2]([O-:4])=[O:3])(=[O:12])=[O:13])[C:15](=[O:20])[CH2:16]2)=[O:46])[C:40](=[O:48])[N:39]=1)=[O:36])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1CNCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C(O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Agent: Cl
Product: O=C(Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C(=O)C2)c(=O)n1)OC(c1ccccc1)c1ccccc1
Yield: 195.6 %

Procedure:
The title compound (2.53 g, 78%) was synthesized by reaction of 1-(2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (679 mg, 2.0 mmol) with [4-N-(benzhydryloxycarbonyl)-cytosin-1-yl]-acetic acid (1.90 g, 5.0 mmol) as per the procedure of example 77.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH2:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:12]1([CH2:18][C:19]([N:9]2[CH2:10][CH2:11][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: c1ccc(C2CCNC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.6 %

Procedure:
A solution of 3-phenylpyrrolidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and phenyl-acetyl chloride (386.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:5). The fractions containing the 2-phenyl-1-(3-phenylpyrrolidin-1-yl)ethan-1-one are collected and the solvent is removed in vacuo to give 465 mg of colorless oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[NH2:42][CH:43]1[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:42][CH:43]5[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.16 mL (0.90 mmole) of ethyldiisopropyl amine and 0.028 g (0.25 mmole) of 4-amino-1-methyl-piperidine in 3.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.057 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-59) as a white solid.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[C:9]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[CH2:17][CH2:16]2)(=[O:11])[CH3:10]>>[CH3:3][N:4](/[CH:6]=[C:17]1/[C:18](=[O:22])[C:19]2[C:15]([CH2:16]/1)=[CH:14][C:13]([NH:12][C:9](=[O:11])[CH3:10])=[CH:21][CH:20]=2)[CH3:5]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Nc1ccc2c(c1)CCC2=O
Product: CC(=O)Nc1ccc2c(c1)C/C(=C\N(C)C)C2=O
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
Dimethylformamide dimethylacetal was added to 5-acetamido-1-indanone (2.5 g, 13.2 mmol), which was stirred at 100° C. for 3.5 hours, and cooled to room temperature. The precipitated crude products were collected, which was washed with ethyl acetate to give the titled compound (2.73 g).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([C:32]1[N:33]=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.CNC1CCNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH:24]([NH:33][CH3:32])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CNC1CCNC1
Product: CNC1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and N-methylpyrrolidin-3-amine. MS(m/e): 400.3 (MH+).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([O:16]CC)=[O:15])=[C:7]2[NH:19][C@@H:20]1[CH2:24][CH2:23][O:22][CH2:21]1>C1COCC1.O>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([OH:16])=[O:15])=[C:7]2[NH:19][C@@H:20]1[CH2:24][CH2:23][O:22][CH2:21]1
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1N[C@@H]1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc2ccc(Br)cc2c1N[C@@H]1CCOC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Sodium hydroxide (0.657 g, 16.43 mmol) was added to ethyl 6-bromo-4-[[(3R)-tetrahydrofuran-3-yl]amino]quinoline-3-carboxylate (3 g, 8.21 mmol) in THF (60 mL) and water (30 mL) and the resulting mixture stirred at 60° C. overnight. The aqueous component was removed under reduced pressure and the remaining solution was adjusted to pH 6 with 2 M HCl. The solids were collected by filtration and dried in an oven to afford the desired material as a white solid (2.1 g, 76%). NMR Spectrum: 1H NMR (300 MHz, MeOH-d4) δ 2.05-2.08 (1H, m), 2.38-2.48 (1H, m), 3.72-3.93 (4H, m), 4.83-5.01 (1H, m) 7.09 (1H, d), 8.04 (1H, d), 8.55 (1H, s), 8.95 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=339.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:15]2[CH:11]([N:12](C(OCC3C=CC=CC=3)=O)[CH2:13][CH:14]2[C:16](=[O:28])[NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]2[NH:12][CH2:13][CH:14]([C:16](=[O:28])[NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[CH:15]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2NCC(C(=O)Nc3cccc4ccccc34)C21
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
A solution of 53 (490 mg, 0.95 mmol) in 1:1 MeOH/EtOAc (4 mL) was treated with Pd/C (5% wet, ca. 100 mg) and placed under H2 (50 psi) using a Parr apparatus. After 1.5 h, the reaction mixture was filtered through syringe filter disc (Acrodisc-PSF-0.45 μM) and rinsed with MeOH. The filtrate was concentrated to afford crude 54 (360 mg) which was used without further purification. Mass spectrum, m/z [382.2] (M+H)+.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[OH:12])(=[O:4])=[O:3].C(N(CC)CC)C.[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C(#N)C>[C:20]([O:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[NH:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)Cl
Reactant: CS(=O)(=O)NC1CCCCC1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(C)C(=O)OC1CCCCC1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 63 %

Procedure:
In a nitrogen atmosphere, a mixture of 108 g of 1,2-epoxycyclohexane, 95.1 g of methanesulfonamide, 11.2 g of t-butoxypotassium, and 1,000 g of tetrahydrofuran was heated under reflux for 100 hours. The reaction solution was neutralized with hydrochloric acid and then subjected to conventional aqueous work-up. Purification by column chromatography yielded an alcohol compound, 2-[(methylsulfonyl)amino]cyclohexanol. In a nitrogen atmosphere, the alcohol compound was combined with 111 g of triethylamine and 2,000 g of acetonitrile, to which 105 g of methacryloyl chloride was added dropwise at −20° C. The mixture was gradually warmed to room temperature and then stirred for 10 hours. The reaction mixture was subjected to conventional aqueous work-up and purified by column chromatography, obtaining 165 g of 2-[(methylsulfonyl)amino]-cyclohexyl methacrylate. The yield was 63% based on the methanesulfonamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][CH:15]([CH2:23][CH3:24])[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17]>>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([NH:14][C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH2:23][CH3:24])[CH:20]([CH3:21])[CH3:22]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 4-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH2:29])=[CH:13][CH:14]=2)[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:47]=[C:48]([O:50][CH3:51])[CH:49]=1)[C:44](Cl)=[O:45]>ClCCl>[CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH:29][C:44](=[O:45])[C:43]3[CH:47]=[C:48]([O:50][CH3:51])[CH:49]=[C:41]([O:40][CH3:39])[CH:42]=3)=[CH:13][CH:14]=2)[CH:9]=1)(=[O:6])=[O:7])([CH3:3])[CH3:2]
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(N)ccc3c2O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(NC(=O)c4cc(OC)cc(OC)c4)ccc3c2O)cc1
Reaction time: 16 h
Yield: 39.6 %

Procedure:
7-Amino-4-hydroxy-3-(4-methoxy-phenylazo)-napthalene-2-sulfonic acid isopropyl ester (Example 6, 200 mg, 0.48 mmol ) was dissolved in dichloromethane (3 mL) and diisopropylethylamine (160 μL, 114 mg, 0.96 mmol ) was added. 3,5-Dimethoxybenzoyl chloride (111 mg, 0.6 mmol ) was added under nitrogen. The reaction mixture was allowed to stir for 16 h. The suspension was filtered to provide the title compound (110 mg, 0.19 mmol, 40% ) as a red solid: NMR (DMSO-d6): δ 10.72 (s, 1H). 8.46 (s, 1H), 8.32 (d, 9 Hz, 1H), 8.05 ( d, 9 Hz, 1H), 7.80 (d, 9 Hz, 3H), 7.12 (m, 4H), 6.79 (s, 1H), 4.86 (m, 1H), 3.86 (m, 9H), 1.22 (d, 6 Hz, 6H). Analytical HPLC: 87% pure. MS (ES-NEG): [M−H] 578; Anal. Calc. for C29H29N3O8S: C, 60.09, H, 5.04, N, 7.25. Found: C, 57.60, H, 5.17, N, 6.88.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]O)=[CH:16][CH:15]=1)(=[O:13])=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1>ClCCl>[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1)(=[O:12])=[O:13]
Reactant: CS(=O)(=O)c1ccc(CCO)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(CCOc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
1.83 g (15 mmole) 4-hydroxybenzaldehyde was dissolved in 35 ml dichloromethane under argon atmosphere. 1.5 g (7.5 mmole) 2-[4-(methylsulfonyl)phenyl]-1-ethanol was added followed by 3.93 g (15 mmole) triphenylphosphine and 3.78 g (15 mmole) 1,1-(azodicarbonyl)dipiperidine. The reaction mixture was stirred at room temperature and after 2 hours a precipitate is observed. The reaction was disrupted after 5 hours and the reaction mixture was filtered. The filtrate was purified by chromatography on silica gel using dichloromethane:methanol (98:2) as eluent giving 1.66 g (yield 54.5%) of 4-[2-(4-formylphenoxy)ethyl]phenyl methyl sulfone.
Reaction SMILES: [OH:1][CH2:2][CH2:3]OC1C2C(=O)C3C(=CC=CC=3)SC=2C=CC=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:37])[CH:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28]2)=[CH:23][CH:22]=1.C1(=O)OCCO1>C(N(CC)CC)C>[OH:1][CH2:2][CH2:3][O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:37])[CH:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28]2)=[CH:23][CH:22]=1
Reactant: O=c1c2ccccc2sc2cccc(OCCO)c12
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Solvent: O=C1OCCO1
Solvent: CCN(CC)CC
Product: O=c1cc(-c2ccccc2)oc2cc(OCCO)ccc12
Yield: 83 %

Procedure:
In an analogous fashion to 2-hydroxyethoxythioxanthone in Example 29, 7-hydroxyflavone (Aldrich) was reacted with ethylene carbonate and triethylamine to obtain 7-hydroxyethoxyflavone (83% yield). This product was dissolved in THF. One equivalent of VDM and several drops of DBU were added. The reaction mixture was stirred overnight.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cc(F)cc(F)c1F
Agent: N
Product: Fc1cc(F)c(F)c(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,3,5-trifluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.55-7.68 (m, 2H), 7.83-7.90 (m, 1H), 8.57 (dt, J=8.1, 1.9 Hz, 1H), 8.75 (dd, J=5.1, 1.7 Hz, 1H), 9.30 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 278 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:36]([NH2:40])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([NH:40][CH2:24][C:21]1[N:20]=[C:19]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[O:23][N:22]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: CC(C)(C)N
Product: CC(C)(C)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and tert-butylamine (216 mg, 2.96 mmol) as starting materials.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([CH3:19])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[C:1]([C:5]1[CH:10]=[C:9]([C:15]2[CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]([CH3:12])[CH:14]=2)[N:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Cl)ncn1
Reactant: Cc1cc(C)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)cc(-c2cc(C(C)(C)C)ncn2)c1
Yield: 96 %

Procedure:
Next, 2.01 g of 4-tert-butyl-6-chloropyrimidine obtained in Step 2, 3.63 g of 3,5-dimethylphenylboronic acid, 2.48 g of sodium carbonate, 0.10 g of bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of DMF were put into a recovery flask equipped with a reflux pipe, and the mixture was bubbled with argon for 15 minutes. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes to be heated. Here, into the flask were further put 0.90 g of 3,5-dimethylphenylboronic acid, 0.64 g of sodium carbonate, and 0.025 g of Pd(PPh3)2Cl2, and the mixture was bubbled with argon for 15 minutes. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) again for 60 minutes to be heated. Then, water was added to this solution and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and saturated brine, and was dried with magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, and the obtained residue was purified by silica gel column chromatography using dichloromethane and ethyl acetate as a developing solvent in a ratio of 10:1, so that HtBudmppm (abbreviation), which was the pyrimidine derivative to be produced, was obtained as a pale yellow oil in a yield of 96%. Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme of Step 3 is shown in (k-3).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]3[C:15]4=[C:16]([NH:20][C:21]5[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=6)=[C:23]([Cl:35])[CH:22]=5)[N:17]=[CH:18][N:19]=[C:14]4[S:13][C:10]=32)=[N:5]1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:35][C:23]1[CH:22]=[C:21]([NH:20][C:16]2[N:17]=[CH:18][N:19]=[C:14]3[S:13][C:10]4[C:11]5[C:6]([CH2:7][CH2:8][C:9]=4[C:15]=23)=[N:5][N:4]([CH2:3][CH2:2][N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)[CH:12]=5)[CH:26]=[CH:25][C:24]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: Clc1cc(Nc2ncnc3sc4c(c23)CCc2nn(CCBr)cc2-4)ccc1OCc1ccccn1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(CCn2cc3c(n2)CCc2c-3sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 34.1 %

Procedure:
To a stirring solution of 2-(2-bromoethyl)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine (100 mg, 0.16 mmol) in DMF (4 mL) were sequentially added 1-methyl-piperazine (0.023 mL, 0.24 mmol), sodium iodide (23.8 mg, 0.16 mmol), and sodium carbonate (33.6 mg, 0.32 mmol). The mixture was stirred at 60° C. for 4 h, after which time the contents were allowed to cool to rt and the solvent removed under reduced pressure. The crude product was purified via reverse phase HPLC to afford the desired product (32 mg, 34%) as a white solid. 1H-NMR (DMSO-d6) δ 8.58 (d, 1H), 8.40 (s, 1H), 8.36 (s, 1H), 7.93 (s, 1H), 7.83 (dd, 1H), 7.78 (s, 1H), 7.47-7.59 (m, 2H), 7.31 (dd, 1H), 7.19 (d, 1H), 5.25 (s, 2H), 4.12 (t, 2H), 3.35 (t, 2H), 2.85 (t, 2H), 2.63 (t, 2H), 2.35-2.45 (br s, 4H), 2.22-2.32 (br s, 4H), 2.12 (s, 3H); LCMS RT=2.18 min; [M+H]+=587.4.