Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:22]=2)[CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)c1

Procedure:
N-tert-Butyl-3-{1-[6-(4-chloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(4-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.70) (0.68 g, 1.5 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.46 g, 1.8 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.34 g) which was subsequently deprotected.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([N:22]2[CH2:23][CH2:24][C:25]([F:29])([F:28])[CH2:26][CH2:27]2)[CH2:20][NH:21][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:2]=2[Cl:1])=[CH:17][CH:18]=1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccc(Cl)cc1)N1CCC(F)(F)CC1
Product: O=C(NCC(c1ccc(Cl)cc1)N1CCC(F)(F)CC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-chloro-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][C@H:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([CH3:24])[N:19]1[CH2:25][CH2:26][NH2:27]>>[CH3:17][C@H:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([CH3:24])[N:19]1[CH2:25][CH2:26][NH:27][C:14]([C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared by a similar method to Preparation 4 from (2S)-1-(tert butoxycarbonyl)-2-piperidinecarboxylic acid [see Preparation 13] and 2-[(cis)-2,6-dimethyl-1-piperidinyl]ethylamine [J. Med. Chem., 27; 5, (1984), 684-691]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 92:8, by volume, dichloromethane:methanol/0.88 aqueous ammonia solution (20/1), in 1% increments to afford tert-butyl(2S)-2-[(2-[(cis)-2,6-dimethyl-1-piperidinyl]ethylamino)carbonyl]-1-piperidinecarboxylate as an oil.
Reaction SMILES: [NH:1]([CH2:3][C:4]([O-:6])=[O:5])[CH3:2].[Na+].Cl.[N:9]#[C:10][NH2:11]>O>[OH2:5].[O:5]=[C:4]([CH2:3][N:1]([C:10](=[NH:9])[NH2:11])[CH3:2])[OH:6]
Reactant: CNCC(=O)[O-]
Reactant: N#CN
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN(CC(=O)O)C(=N)N
Temperature: 75 °C
Yield: 76.2 %

Procedure:
4625 g (16.7 mol) of a 40% by weight sodium sarcosinate solution prepared according to example 1 was added first. A pH of 9.6 (at 20° C.) was adjusted using concentrated hydrochloric acid while cooling externally with cold water and stirring vigorously. Subsequently it was heated to 75° C. 1403 g (16.7 mol) of a 50% by weight aqueous cyanamide solution (Degussa-Cyanamide L 500) was added uniformly over a period of 90 minutes while stirring vigorously at an internal temperature of 75 to 80° C. After the cyanamide addition was completed, the reaction mixture was stirred for a further 2 hours at an internal temperature of 75° C. After cooling to 5° C., the crystalline reaction product that can be readily filtered was suction filtered, washed three times chloride-free with 1250 ml water in each case and dried in a vacuum-drying cabinet at 40° C. and 20 mbar. The yield was 1897 g creatine monohydrate (corresponds to a yield of 76.2% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].Cl[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH:5][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1cc(F)cc(Br)c1
Reactant: ClCCN1CCCC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Fc1cc(Br)cc(NCCN2CCCC2)c1
Yield: 50.5 %

Procedure:
A solution of 3-bromo-5-fluoroaniline (CAS 134168-97-1) (380 mg, 2.0 mmol) and 1-(2-chloroethyl)pyrrolidine (CAS 505041-9) (380 mg, 2.2 mmol) in NMP (20 mL) was heated to 120° C. overnight. The solution was diluted with EtOAc (100 mL) and washed with saturated Na2CO3 aqueous solution (3×40 mL). The combined organic layer were dried over Na2SO4, concentrated and purified by prep-TLC (DCM:MeOH=10:1) to give the titled product (290 mg, 50%). LCMS (0-60 AB), RT=1.076 min, M+H, 289.0
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:26])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:26])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1c[nH]c2c(OC)cccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Yield: 58.5 %

Procedure:
3-Butyryl-8-methoxy-4(1H)-quinolone (9.0 g, 0.037 mol) and phosphorus oxychloride (100 ml) were heated under reflux for 30 minutes. When cool, the mixture was poured onto ice, adjusted to pH 4 with sodium bicarbonate and extracted with dichloromethane. Evaporation and crystallisation from ethyl acetate-petroleum ether gave 3-butyryl-4-chloro-8-methoxyquinoline (5.5 g, 58.5%), m.p. 114°-116°.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]([C:5]1[O:9][C:8]([CH2:10][Br:15])=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C(C)(C)C)oc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(C(C)(C)C)oc1CBr
Temperature: 25 °C
Yield: 98.1 %

Procedure:
A mixture of methyl 5-tert-butyl-2-methylfuran-3-carboxylate (10.4 g, 53 mmol), N-bromosuccinimide(9.9 g, 55 mmol), and azobisisobutyronitrile (0.1 g, 0.6 mmol) in carbon tetrachloride (100 mL) was heated to reflux for 1.5 h. The suspension was cooled to room temperature, and succinimide was removed by filtration and rinsed with carbon tetrachloride. The combined filtrates were evaporated to dryness. The residue was subjected to Kugelrohr distillation (<1 mbar, 110-120° C.) to yield methyl 5-tert-butyl-2-(bromomethyl)furan-3-carboxylate (14.3 g, 98% yield) as a light-yellow oil. 1H-NMR (300 MHz, CDCl3): δ 6.28 (s, 1H), 4.80 (s, 2H), 3.85 (s, 3H), 1.28 (s, 9H) ppm.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[NH:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=1>O.Cl>[F:13][C:12]([F:15])([F:14])[C:10]1[CH:9]=[CH:8][C:7]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:29][CH:30]=3)[N:1]=[N:5][C:6]=2[CH:11]=1
Reactant: O=N[O-]
Reactant: CCOC(=O)C(C)Oc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc(-n2nnc3cc(C(F)(F)F)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2.1 g of sodium nitrite in 25 ml of water was added drop-by-drop over a 5-minute period to a stirred solution of 7.4 g of 1C in 150 ml of 12% hydrochloric acid, at 0° C. The mixture then was allowed to warm to room temperature and was stirred for 24 hours. It then was diluted with 200 ml of water and extracted with ether. The ether extract was dried (MgSO4), filtered and concentrated to dryness. The residue was absorbed on silica gel and chromatographed, using as eluent a 2:15:33 v/v/v mixture of tetrahydrofuran, ethyl acetate and hexane (hereinafter, Solvent A), to give 1, as an amber syrup.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[N:13])=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:19].[OH-].[Ca+2].[OH-]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[N+:9]([O-:19])[C:8]([C:12]#[N:13])=[CH:7][CH:6]=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2ccc(C#N)nc2c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc2ccc(C#N)[n+]([O-])c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-methylquinoline-2-carbonitrile (14.2 g, 84 mmol) in dichloromethane (400 mL) was added 3-chloroperoxybenzoic acid (50%, 36.4 g, 106 mmol) and stirred at room temperature overnight. Solid calcium hydroxide (7.8 g, 106 mmol) was added and 15 min later the mixture was filtered through celite, rinsed with dichloromethane and the liquors evaporated to dryness to give the crude compound. The compound was purified by flash chromatography on silica gel (eluting with 5% acetone in dichloromethane) to afford the title compound. 1H NMR (400 MHz, acetone-d6): δ 8.40 (s, 1H), 8.05 (d, 1H), 7.97 (d, 1H), 7.75 (m, 2H), 2.65 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[N:24]=1>>[CH3:1][N:2]([CH2:3][C:4]1([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1)[C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([C:25]2[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=2)[CH:29]=1
Reactant: CNCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CN(CC1(c2nc(-c3ccccc3)cs2)CCOCC1)C(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 14 %

Procedure:
This compound was synthesized from N-methyl-1-(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (30 mg, yield 14%). 1H NMR (400 MHz, CDCl3) δ 8.13-8.09 (m, 2H), 7.96-7.94 (m, 2H), 7.57-7.55 (m, 2H), 7.48-7.41 (m, 3H), 7.36-7.32 (m, 1H), 3.99-3.96 (m, 2H), 3.92 (s, 2H), 3.66-3.60 (m, 2H), 2.53 (s, 3H), 2.48-2.44 (m, 2H), 2.23-2.16 (m, 2H). MS (ESI) m/z: Calculated for C26H23F3N4O3S: 528.14. found: 529.2 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[C:9](Cl)(=[O:13])[O:10][CH2:11][CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:10][C:9]([O:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1)=[O:13])[CH3:12]
Reactant: CCOC(=O)Cl
Reactant: O=C1C=CC(O)OC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1C=CC(=O)CO1
Temperature: 0 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
12 g of 6-hydroxy-2H-pyran-3(6H)-one was dissolved in 100 ml of methylene chloride, and the solution was cooled to 0° C. Then, 11.4 g of ethyl chlorocarbonate was added, and a solution comprising 10.6 g of triethylamine and 20 ml of methylene chloride was dropwise added thereto. The mixture was stirred for 3 hours, and the reaction mixture was poured into ice water and extracted with methylene chloride. The solvent was distilled off under reduced pressure, and the residue was subjected to distillation under reduced pressure to obtain 12.3 g (yield: 63%) of the above-identified compound.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:5]([C:15]([O:17]CC)=[O:16])=[CH:4][N:3]=1.[OH-].[Na+].Cl>CCO.O>[OH:1][C:2]1[N:7]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:10])([F:11])[F:12])[C:5]([C:15]([OH:17])=[O:16])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(O)nc1C(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc(O)nc1C(F)(F)C(F)(F)F
Yield: 98.4 %

Procedure:
A solution of ethyl 2-hydroxy-4-pentafluoroethylpyrimidine-5-carboxylate (4.0 g, 13 mmol) and NaOH (1.60 g, 39 mmol) in EtOH (20 mL) and H2O (45 mL) was heated at reflux for 1 h. The solution was cooled and acidified (conc. HCl). The resulting solid was filtered and dried to provide 2-hydroxy-4-pentafluoroethylpyrimidine-5-carboxylic acid (3.3 g, 98% yield); 1H NMR (DMSO-d6) δ 9.90 (bs, 1H), 8.43 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:33])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]3[CH:20]=[N+:21]([O-:33])[CH:22]=[CH:23][CH:24]=3)[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2cccnc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2ccc[n+]([O-])c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of 3-nitro-2-[3-[(E)-2-(3-pyridyl)vinyl]phenylamino]pyridine (2.22 g) in dichloromethane (70 ml) was added m-chloroperbenzoic acid (1.81 g). The mixture was stirred at room temperature for 1 hour, then poured into aqueous sodium bicarbonate and extracted with chloroform. The organic solution was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (8% methanol in chloroform) to give 3-nitro-2-[3-[(E)-2-(1-oxido-3-pyridyl)vinyl]phenylamino]pyridine (1.51 g).
Reaction SMILES: [Cl:1][C:2]1[C:13]([N:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4]OS(C)(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C>[N:17]([CH2:4][C:3]1[C:2]([Cl:1])=[C:13]([N:14]([CH3:16])[CH3:15])[CH:12]=[CH:11][CH:10]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)c1cccc(COS(C)(=O)=O)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1cccc(CN=[N+]=[N-])c1Cl
Temperature: 60 °C

Procedure:
Methanesulfonic acid 2-chloro-3-dimethylamino-benzyl ester was placed in a round bottomed flask with DMF (8 mL). Sodium azide (0.35 g, 5.38 mmol) was added and the reaction was heated to 60° C. for 3 h. The reaction was cooled to rt, and the solvent was removed in vacuo. The residual crude material was purified by column chromatography using hexanes/ethyl acetate (1:1) as eluent to afford (3-azidomethyl-2-chloro-phenyl)-dimethyl-amine
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=1.[C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH3:18].[Li]>>[C:21]([O:20][C:17](=[O:19])[CH2:18][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-c2cccnc2)c1
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from 3-pyridin-3-yl-benzoic acid methyl ester [CAS-No. 79601-27-7] (1.00 g, 4.69 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Obtained as an orange oil (673 mg).
Reaction SMILES: [C:1](NC1NC(=O)C2N=CN(C=2N=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1OC)(=O)C(C)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.CO>N1C=CC=CC=1>[S:33]([CH3:1])([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)(=[O:35])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Solvent: c1ccncc1
Solvent: CO
Product: Cc1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
(see FIG. 8B) N2-Isobutyryl-2′-O-methylguanosine (6) (Inoue et al., Nucleic Acids Res. 1987, 15, 6131-6148, and is incorporated by reference herin in its entirety) (1.6 g, 4.36 mmol) was dissolved in dry pyridine (25 mL) and the solution was cooled to 0° C. while protected from moisture. p-Toluenesulfonyl chloride (1.0 g, 5.23 mmol) was added and the reaction mixture was left at 0-3° C. for 48 h. MeOH (10 mL) was added and the mixture evaporated to a syrup. After standard work up and column chromatography using 1-2% MeOH in CH2Cl2, 7 was obtained as a colorless foam, 1.06 g (47%), 1H NMR δ12.25 (br s, 1H, NH), 9.55 (br s, 1H, NH), 7.83 (d, JH,H=8.3, 2H, Ts), 7.78 (s, 1H, H8), 7.42 (d, JH,H=8.3, 2H, Ts), 5.83 (d, J1′,2′=6.2, 1H, H1′), 4.82 (app t, J2′,3′=5.7, 1H, H2′), 4.64 (m, 1H, H3′), 4.37 (dd, J5′,4′=2.2, J5′,5″=10.3, 1H, H5′), 5.23 (dd, J4′,5″=2.9, J4′,3′=5.2, 1H, H4′), 4.29 (dd, J5″,4′=2.9, J5″,5′=10.3, 1H, H5″), 3.47 (s, 3H), OMe), 2.76 (m, 1H, CH(CH3)2), 2.51 (s, 3H, Ts-Me),1.29 (m, 6H, 2×Me).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][N:13]1[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]1=[O:24].S(OC)(O[CH3:29])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][N:13]1[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:29])[C:14]1=[O:24]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1Cc1cc([N+](=O)[O-])cc(Cl)c1Cl
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(Cc2cc([N+](=O)[O-])cc(Cl)c2Cl)c1=O
Yield: 20.8 %

Procedure:
By the method of Example 1, Step H, 24.5 grams (0.064 mole) of 3-(2,3-dichloro-5-nitrophenylmethyl)-6-trifluoromethyluracil, 12.07 grams (0.096 mole) of dimethyl sulfate, and 17.64 grams (0.127 mole) of potassium carbonate were reacted in 300 mL of acetone, yielding 5.30 grams of 3-(2,3-dichloro-5-nitrophenylmethyl)-1-methyl-6-trifluoromethyluracil as a bright yellow solid. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:11][C:12]([F:15])([F:14])[F:13].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][C:12]([F:13])([F:14])[F:15])=[C:4]([CH2:3][OH:2])[CH:9]=1
Reactant: COC(=O)c1cc(N)ccc1OC(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc(OC(F)(F)F)c(CO)c1
Reaction time: 1 h
Yield: 93.2 %

Procedure:
5-Amino-2-trifluoromethoxybenzoic acid methyl ester (3.0 g, 12.8 mmol) was dissolved in THF (20 mL) in a three-necked flask equipped with a thermometer and an addition funnel under nitrogen. Under stirring and ice-cooling lithium aluminum hydride (1M in THF, 15 mL) was added dropwise within 10 minutes. Stirring was continued at room temperature for 1 hr, and the reaction was concentrated in vacuo. The residue was suspended in dichloromethane (150 mL) and water (50 mL), then filtered through celite, washed with dichloromethane and water. The filtrate was separated, and the water phase was extracted once more with dichloromethane (30 mL). The combined organic phases were washed with water (2×20 mL), dried (MgSO4) and concentrated in vacuo to give 2.47 g of (5-amino-2-trifluoromethoxyphenyl)methanol.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([F:19])[F:18])=[C:13]([F:20])[CH:12]=2)[O:4][C:3]1=[O:26].[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]2[N:35]=[C:36]([SH:38])[N:37]=[C:30]2[N:29]=1.C(N(CC)CC)C>CN(C=O)C>[CH:21]1([C:5]2([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]([F:19])[F:18])=[C:13]([F:20])[CH:12]=3)[O:4][C:3](=[O:26])[C:2]([S:38][C:36]3[N:37]=[C:30]4[N:29]=[C:28]([CH3:27])[CH:33]=[C:32]([CH3:34])[N:31]4[N:35]=3)=[C:7]([OH:8])[CH2:6]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1CC(CCc2ccc(C(F)F)c(F)c2)(C2CCCC2)OC(=O)C1Cl
Reactant: Cc1cc(C)n2nc(S)nc2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)n2nc(SC3=C(O)CC(CCc4ccc(C(F)F)c(F)c4)(C4CCCC4)OC3=O)nc2n1
Temperature: 55 °C
Yield: 67.9 %

Procedure:
A mixture of 3-chloro-6-cyclopentyl-6-{-[4-(difluoromethyl)-3-fluorophenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione (200 mg, 0.514 mmol), from Step 1, below, and 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol (93 mg, 0.514 mmol) in DMF (4 mL) was treated with triethylamine (52 mg, 0.514 mmol, 1 equiv). The mixture stirred and heated at 55° C. for 4 h. The reaction was cooled to room temperature, and the DMF removed in vacuo. Water and ethyl acetate were added to the resinous material, resulting in the precipitation of a solid. This was filtered, washed with ether, and allowed to air dry, affording 186 mg (68%) of the title product. 1H NMR (DMF-d7) δ 1.81-2.00 (m, 8H) 2.56-2.62 (m, 2H) 2.71 (s, 3H) 2.76 (s, 3H) 2.80 (m, 1H) 3.07(m, 2H) 3.14 (d, J=6 Hz, 1H) 3.32 (d, J=18 Hz, 1H) 7.40 (t, J=57 Hz, 1H), 7.24 (s, 1H) 7.66 (m, 2H) 7.84 (m, 1H,). MS (APCI) calcd for C26H27F3O3S: 532.58; MS found; (M+H+) 533.1. Anal. Calc'd for C26H27F3O3S: C, 58.64; H, 5.11; N, 10.52; S, 6.02. Found: C, 58.26, 58.33; H, 5.25, 5.14; N, 10.69, 10.61; S, 5.78, 5.79.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:6]=2[N:7]=1.[CH2:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)[CH3:22]>>[CH2:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29]2[N:34]=[CH:33][C:32]([NH:35][C:2]3[N:3]=[CH:4][C:5]4[S:10][CH:9]=[C:8]([C:11]5[CH:12]=[N:13][C:14]6[C:19]([CH:20]=5)=[CH:18][CH:17]=[CH:16][CH:15]=6)[C:6]=4[N:7]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)[CH3:22]
Reactant: CCN1CCN(c2ccc(N)cn2)CC1
Reactant: Clc1ncc2scc(-c3cnc4ccccc4c3)c2n1
Product: CCN1CCN(c2ccc(Nc3ncc4scc(-c5cnc6ccccc6c5)c4n3)cn2)CC1
Yield: 68.4 %

Procedure:
N-(6-(4-Ethylpiperazin-1-yl)pyridin-3-yl)-7-(quinolin-3-yl)thieno[3,2-d]pyrimidin-2-amine (32 mg, 67% yield) was prepared in the same manner as Step 10 of Example 1 using 2-chloro-7-(quinolin-3-yl)thieno[3,2-d]pyrimidine (30 mg, 0.10 mmol) and 6-(4-ethylpiperazin-1-yl)pyridin-3-amine (31 mg, 0.15 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:14][CH:13]=3)=[O:11])=[C:8]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[S:7][C:6]=2[CH:33]=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>N1C=CC=CC=1>[C:34]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)=[CH:16][CH:17]=3)=[O:11])=[C:8]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[S:7][C:6]=2[CH:33]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(C2CCCCC2)sc2cc(O)ccc12
Solvent: c1ccncc1
Product: O=C(Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(C3CCCCC3)sc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
27 mg of (6-hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone was dissolved in 1 ml of pyridine, 0.1 ml of benzoyl chloride was added, and the mixture was stirred at room temperature for 1 hour. After addition of ice, the reaction mixture was stirred for 1 hour and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resultant crude product was purified by TLC (developing solvent, chloroform:methanol=9:1) to obtain 37 mg of (6-benzoyloxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone.