Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][C:11]([NH2:14])([CH3:13])[CH3:12].C(N(CC)CC)C>CC#N>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:14][C:11]([CH3:13])([CH3:12])[CH3:10])[CH:7]=1
Reactant: CC(C)(C)N
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1cc(Cl)nc(N)n1
Temperature: 170 °C
Yield: 89.9 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (400 mg, 2.44 mmol) in CH3CN (5 mL) were added (1,1-dimethylethyl)amine (0.34 mL, 3.17 mmol) and triethylamine (1.36 mL, 9.76 mmol), and the reaction mixture was heated in a microwave at 170° C. for a total of 2.25 hours, checking the progression of the reaction at regular intervals. The mixture was cooled down and evaporated. The resulting residue was partitioned between EtOAc and water, and extracted with EtOAc (2×) and CH2Cl2 (2×). The organics were washed with water and brine, dried (MgSO4), filtered and evaporated. The resulting solid was triturated with Et2O and dried in vacuo to afford the title compound (440 mg). LC-MS (ES) m/z=201, 203 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[C:9]2[O:10][C@@H:11]([CH2:14][O:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][C:5]=1[N+:26]([O-:28])=[O:27])[CH:2]=C.[O:29]=[O+][O-].O=O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([O:15][CH2:14][CH:11]2[O:10][C:9]3[C:4]([CH2:1][CH:2]=[O:29])=[C:5]([N+:26]([O-:28])=[O:27])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:17])=[O:18])=[CH:24][CH:23]=1
Reactant: C=CCc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: O=[O+][O-]
Agent: O=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])c(CC=O)c3O2)cc1
Reaction time: 24 h

Procedure:
A solution of 4.2 g (10 mmole) of toluene-4-sulfonic acid (2R)-8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-ylmethyl ester in 400 mL of methylene chloride was cooled in a dry ice/isopropanol bath and saturated with ozone. It was then purged with oxygen and 2.6 g (20 mmole) of diisopropylethylamine added. The mixture was allowed to come to room temperature and stirred under nitrogen for 24 hours. It was then washed with 300 mL portions of 2 N HCl (aq), water and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to give 3.8 g of the (R)-enantiomer of the title compound as a white solid one-quarter hydrate, m.p. 116-120° C.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[N:25](S(C3C=CC(C)=CC=3)(=O)=O)[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:7]1)C.[OH-].[K+]>CO>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]([OH:36])=[O:3])[CH:7]=[C:8]2[C:17]1[NH:25][C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1
Reactant: CCOC(=O)Cn1cc(-c2cc3cccnc3n2S(=O)(=O)c2ccc(C)cc2)c2cc(OC)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)c(-c1cc3cccnc3[nH]1)cn2CC(=O)O
Yield: 56.7 %

Procedure:
A mixture of {5-methoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-indol-1-yl}-acetic acid ethyl ester [4.67 g, Reference Example 13(a)], methanol (250 mL) and aqueous potassium hydroxide (S5M, 25 mL) were heated under reflux for 7 hours. The methanol was removed under reduced pressure and the residue was treated with water (20 mL) and the pH of this solution was adjusted to 7 by addition of concentrated hydrochloric acid. The resulting yellow solid was filtered and subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and methanol (7:3, v/v) to give the title compound (1.69 g) as a white solid. MS: 320 (M−H+). HPLC (METHOD A): RT=6.67 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:3]=1.[C:17]([O:21][C:22]([CH2:24][CH2:25][CH2:26][S:27]([C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39](F)(F)F)[CH:38]=1)[C:33](O)=[O:34])(=[O:29])=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18]>CCCCCCC.C(OCC)(=O)C>[C:17]([O:21][C:22](=[O:23])[CH2:24][CH2:25][CH2:26][S:27]([C:30]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:32]([C:33](=[O:34])[N:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH3:9])[CH:31]=1)(=[O:29])=[O:28])([CH3:18])([CH3:19])[CH3:20]
Reactant: CNc1nnc(Cl)cc1-c1ccccc1C
Reactant: CC(C)(C)OC(=O)CCCS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N(C)c2nnc(Cl)cc2-c2ccccc2C)cc(S(=O)(=O)CCCC(=O)OC(C)(C)C)c1
Yield: 14 %

Procedure:
The title compound was prepared in analogy to example 1, from (6-chloro-4-o-tolyl-pyridazin-3-yl)-methyl-amine (example 4, intermediate a) and 3-(3-tert-butoxycarbonyl-propane-1-sulfonyl)-5-trifluoromethyl-benzoic acid after a reaction time of 18 hours and using a gradient of n-heptane:ethyl acetate (100:0 to 30:70) for the chromatographic purification. Another purification step using preparative HPLC (Gemini NX column) with a gradient of methanol:water with 0.05% formic acid (80:20 to 98:2) yielded the desired compound as a colorless solid (14%). MS (ESI+): m/z=541.090 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Reactant: Oc1ccc(-c2ncc(Cl)cn2)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ncc(Cl)cn3)cc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-chloro-pyrimidin-2-yl)-phenol (Preparation 19) and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (160 mg, 65.7%)
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:19][C:15]1[CH:14]=[C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:18]=[CH:17][CH:16]=1
Reactant: C1CNCCN1
Reactant: O=Cc1c(Cl)n(-c2cccc(Cl)c2)c2ccccc12
Product: O=Cc1c(N2CCNCC2)n(-c2cccc(Cl)c2)c2ccccc12
Yield: 64 %

Procedure:
2-Chloro-1-(3-chlorophenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(3-chlorophenyl-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde (64% yield) as a cream solid. ESI/MS 340 (M+H); RT 2.66 min.
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[CH2:10]([N:12]([CH2:24][CH3:25])[C:13](=[O:23])[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1)[CH3:11]>>[CH3:3][CH:2]([O:20][C:19]1[CH:21]=[CH:22][C:14]([C:13]([N:12]([CH2:24][CH3:25])[CH2:10][CH3:11])=[O:23])=[CH:15][C:16]=1[O:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CCN(CC)C(=O)c1ccc(O)c(OC)c1
Reactant: CC(C)CCCC(C)Br
Product: CCN(CC)C(=O)c1ccc(OC(C)CCCC(C)C)c(OC)c1

Procedure:
2-bromo-6-methyl-heptane was reacted with vanillic acid N,N-diethyl amide to obtain p-[(1,5-dimethyl-hexyl)-oxy]-m-methoxy-N,N-diethyl-benzamide (boiling point = 180°-182° C/0.1 mmHg);
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[S:10]1[CH:14]=C[CH:12]=[C:11]1CC(OCCl)=O.CN(C)C=[O:24]>C(OCC)(=O)C>[C:11]([S:10][CH2:14][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)(=[O:24])[CH3:12]
Reactant: Sc1ccccn1
Reactant: CN(C)C=O
Reactant: O=C(Cc1cccs1)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)SCSc1ccccn1
Temperature: 25 °C
Reaction time: 0.04 h
Yield: 72 %

Procedure:
To a solution of 2-mercaptopyridine (1.11 g : 9.98 mMol.) in dimethylformamide (10 ml) is added sodium hydride (400 mg : 60% dispersion in oil), and the mixture is stirred at room temperature for 2 to 3 minutes. To this reaction mixture at -30° C. is added a solution of chloromethyl thiolacetate (1.12 g : 9.00 mMol.) in dimethylformamide (2 ml), and the mixture is stirred at -20 to -30° C. for 1 hour. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene : ethyl acetate=20: 1) to give 2-acetylthiomethylthiopyridine (1.43 g) as yellow oil. Yield: 72%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29](I)[CH3:30]>CN(C=O)C.C(OCC)(=O)C>[CH2:29]([N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=1)[S:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH3:30]
Reactant: CCI
Reactant: COc1ccc(CNS(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 165 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
4-(N-(4-methoxybenzyl)sulfamoyl)benzoic acid (Example 5-1b) (160 mg, 0.5 mmol) and Cesium Carbonate (325 mg, 1 mmol) were placed in a microwave vial and dissolved in 2 mL DMF. Ethyl iodide (155 mg, 1 mmol) was added into the reaction mixture. The reaction was placed in a microwave reactor and heated at 165° C. for 5 minutes. The reaction mixture was dissolved in Ethyl Acetate and washed with water. The organic layer was dried over sodium sulfate and evaporated under vacuum. The crude product was dissolved in 4/1 solution of 6N NaOH (aq)/tetrahydrofuran (3 mL) and stirred at ambient temperature for 6 hours. The solution was acidified with 3N HCl (aq) to a pH of ˜3 and the product was extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The residue was taken up in methanol (3 mL) and purified by reverse phased HPLC (5-95% acetonitrile in H2O gradient:25 minutes). The compound was known to inhibit the hT2R14 with IC50 of 20 μM. Yield 35%. MS M+H calculated 350.11, found 350.0.
Reaction SMILES: [NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:19][NH:20][C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Li+].[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][CH2:42]Br)=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C)C=O.O1CCCC1>[NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]([CH2:42][CH2:41][CH2:40][NH:39][C:37]([O:36][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:38])[N:20]=[C:11]3[C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CCOC(=O)c1n[nH]c2c1CCc1cnc(Nc3ccccc3)nc1-2
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2c(nn1CCCNC(=O)OC(C)(C)C)-c1nc(Nc3ccccc3)ncc1CC2

Procedure:
500 mg of ethyl 8-anilino-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (1.5 mmol) were dissolved in 10 mL of dry dimethylformamide and 1.63 mL of 1M lithium tert-butoxide in tetrahydrofuran were added to the cooled solution. After 30 minutes under stirring at 0° C. a solution of 432 mg of tert-butoxycarbonylaminopropyl bromide in 8 mL of dry tetrahydrofuran were added dropwise. After a night at room temperature the mixture was poured into a solution of NaH2PO4 and extracted with dichloromethane. The organic layer was then dried over Na2SO4 and the solvent evaporated, giving an oil that was treated according to the following step 7, without any further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:15][C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:19]=[CH:18][N:17]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CO.CCOC(C)=O>C1COCC1>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:19]=[CH:18][N:17]=[C:16]([NH:15][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:8]=3[NH:7][C:6]([CH2:4][OH:3])=[CH:14]4)[CH:21]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1cc2cccc(Nc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cc2cccc(Nc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-1H-indole-2-carboxylic acid ethyl ester (285 mg, 0.67 mmol) in THF (2 mL) at 0° C. was added 1 M solution of LiAlH4 in THF (1.0 mL, Aldrich). The mixture was stirred at room temperature and the progress of the reaction was monitored by thin-layer chromatography. After completion of the reaction, to the mixture was added Na2SO4.10H2O (2 g), followed by the addition of MeOH (1 mL) and EtOAc (20 mL) with stirring at 0° C. The stirring was continued for 5 min and the mixture was filtered through a pad of Celite®. The filtrate was concentrated under vacuo and the residue was purified by silica gel column chromatography with gradient from 2% to 10% solution of (2 M NH3 in MeOH) in CH2Cl2 to afford the title compound as a yellow solid. MS (ESI, pos. ion.) m/z: 385 (M+1). MP: 221-223° C.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:19]([OH:21])=O)=[C:10]([C:12]3C=CC(Cl)=CC=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3]C=1.CC[N:24](C(C)C)C(C)C.[CH3:31][CH:32]([NH2:46])[CH2:33][N:34]1[CH2:39][CH2:38][N:37]([C:40]2[N:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH2:36][CH2:35]1>>[CH3:31][CH:32]([NH:46][C:19]([C:9]1[S:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][N:24]=2)=[N:11][C:10]=1[CH3:12])=[O:21])[CH2:33][N:34]1[CH2:35][CH2:36][N:37]([C:40]2[N:41]=[CH:42][CH:43]=[CH:44][N:45]=2)[CH2:38][CH2:39]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(N)CN1CCN(c2ncccn2)CC1
Reactant: O=C(O)c1sc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Product: Cc1nc(-c2ccccn2)sc1C(=O)NC(C)CN1CCN(c2ncccn2)CC1

Procedure:
Proceeding as set forth in part (A) above, but substituting 4-methyl-2-pyridin-2-yl-thiazole-5-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole-5-carboxylic acid and substituting intermediate XIIId and DIEA (0.03 mL) for 1-methyl-2-(4-pyrimidin-2-yl-piperazin-1-yl)ethyl amine, the compound 2-(pyrid-2-yl)-4-methyl-thiazole-5-carboxylic acid [1-methyl-2-(4-pyrimidin-2-yl-piperazin-1-yl)-ethyl]-amide (compound 31) was prepared. M+H=424
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC([CH2:17][C:18]([OH:20])=[O:19])=O.[C:21]([O:24]C(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[CH:8]1([CH2:7][C:1]2[C@@H:2]([O:20][C:18](=[O:19])[CH3:17])[C@@H:3]([O:24][C:21](=[O:23])[CH3:22])[CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: c1ccc(CC2CCCCC2)cc1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)CC(=O)O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C=CC=C(CC2CCCCC2)[C@H]1OC(C)=O

Procedure:
The title compound is prepared by the microbial oxidation of cyclohexylmethylbenzene (W. Korte et al. J. Org. Chem. 39, 1168-70 (1974)) by Pseudomonas putida 39D using the method of T. Hudlicky et al. J. Am. Chem. Soc. 110, 4735-41 (1988) and D. Gibson et al. Biochemistry, 9, 1626-30 (1970) followed by protection as the diacetate using acetic anhydride in pyridine.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[NH:9]1[C:17](=O)[C:15](=O)[C:13](=[O:14])[NH:12][C:10]1=[O:11]>O>[CH:4]1[CH:5]=[CH:6][C:1]2[C:2](=[N:7][C:15]3[C:13](=[O:14])[NH:12][C:10](=[O:11])[NH:9][C:17]=3[N:8]=2)[CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Solvent: O
Product: O=c1[nH]c(=O)c2nc3ccccc3nc2[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
There was charged 800 ml of water into an Erlenmeyer flask, then 3.5 g (30 mmoles) of o-phenylenediamine and 5.0 g (30 mmoles) of alloxan were added thereto, and the mixture was stirred at room temperature in a nitrogen atmosphere for about 5 hours. The obtained reaction mixture was cooled with ice for 3 hours, then the formed yellow precipitate was filtered off, and washed in ethanol and ether (50 ml, twice). This precipitate was recrystallized from an aqueous dimethylformamide solution to give pale yellow powdery crystals. Yield: 7.5 g (90%). M.p. 300° C. or higher. IR spectrum: Found values (cm-1): 1730, 1705 (C=O stretching), 1572 (Broad peak) --C=N (amide II band). Literature values (cm-1): 1727, 1700, 1574.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][C:5](=O)[CH2:6]2.[NH2:12]O.Cl.CCO>O>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][CH:5]([NH2:12])[CH2:6]2
Reactant: NO
Reactant: CN1C2CCCC1CC(=O)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1C2CCCC1CC(N)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a 250 mL RB flask were added 9-methyl-9-azabicyclo[3.3.1]nonan-3-one (10 g), NH2OH.HCl (5.26 g), NaOAc.3H2O (10.26 g), EtOH (56 mL), and H2O (26 mL). The mixture was refluxed for 1.5 h and cooled to RT. Solvents were removed and the residue was partitioned between aqueous K2CO3 (3M) and CHCl3. The organic phase was separated and the aqueous phase extracted twice with CHCl3. The combined CHCl3 solution was washed once with brine, dried over Na2SO4, filtered, and evaporated to a brownish oil, which solidified upon standing. The solid was transferred to a 500 mL Parr flask. To this were added Raney-Ni (6.2 g, wet) and NH3 solution in MeOH (150 mL), made by bubbling NH3 into MeOH for 20 min. This mixture was hydrogenated under a pressure of 40-45 psi of H2 at RT for 18 h. The mixture was filtered through a pad of Celite. All volatiles were removed on a rotary evaporator. EtOH (50 mL) was added to the residue and then evaporated to give an I-1 as an oil (9.5 g, 94%). This crude product contained two isomers, and was used without further purification.
Reaction SMILES: C([Li])CCC.[CH:6]1[CH2:10][CH:9]=[CH:8][CH:7]=1.[CH3:11][Si:12]([CH3:35])([C:14]1[C:26]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=3)[C:18]=2[CH:17]=[CH:16][C:15]=1[C:31]([CH3:34])([CH3:33])[CH3:32])Cl>CCCCCC.O=O.O>[CH3:11][Si:12]([CH3:35])([C:14]1[C:26]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:27]([CH3:28])([CH3:29])[CH3:30])[CH:23]=3)[C:18]=2[CH:17]=[CH:16][C:15]=1[C:31]([CH3:34])([CH3:33])[CH3:32])[CH:7]1[CH:6]=[CH:10][CH:9]=[CH:8]1
Reactant: CC(C)(C)c1ccc2c(c1)Cc1c-2ccc(C(C)(C)C)c1[Si](C)(C)Cl
Reactant: C1=CCC=C1
Agent: O=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)c1ccc2c(c1)Cc1c-2ccc(C(C)(C)C)c1[Si](C)(C)C1C=CC=C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
8.5 ml (21 mmol) of a 2.5M solution of butyllithium in hexane were added dropwise to 1.4 g (21 mmol) of cyclopentadiene in 45 ml of O2 -free and H2O-free THF at 0° C. under argon and the mixture was stirred for a further 2 hours at room temperature. This solution was subsequently added at room temperature to a solution of 7.9 g (21 mmol) of 2 in 100 ml of O2 -free and H2O-free THF over a period of 2 hours and the mixture was stirred for a further 1 hour at room temperature. 50 ml of H2O were added, the phases were separated and the aqueous phase was further extracted twice with 30 ml of Et2O each time. The combined organic phases were dried (MgSO4) and the solvent was removed in vacuo. After chromatography on 200 g of silica gel (hexane/methylene chloride 20:1), 4.4 g (51%) of 3 were obtained as a colorless oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=3)=[CH:11][CH:10]=2)O1.Br[C:38]1[S:39][CH:40]=[CH:41][N:42]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CCO>[S:39]1[CH:40]=[CH:41][N:42]=[C:38]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:31][C:32]([F:33])([F:34])[F:35])[C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:28])[F:29])[CH:20]=2)=[CH:11][CH:10]=1
Reactant: Brc1nccs1
Reactant: CC1(C)OB(c2ccc(OCCN(CC(F)(F)F)c3ccc(C#N)c(C(F)(F)F)c3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(N(CCOc2ccc(-c3nccs3)cc2)CC(F)(F)F)cc1C(F)(F)F
Temperature: 80 °C
Yield: 6.6 %

Procedure:
A mixture of 4-[(2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxy}ethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.100 g, 0.19 mmol; step A above), 2-bromothiazole (0.020 mL, 0.21 mmol), Pd(PPh3)4 (0.011 g, 0.010 mmol), Na2CO3 (0.106 g, 1.00 mmol), toluene (1 mL), EtOH (0.50 mL) and H2O (0.5 mL) was sparged with N2 for 10 min and then heated at 80° C. in a sealed vial for 72 h. The mixture was cooled, poured into water, and extracted with EtOAc (×3). Combined organics were washed (H2O, brine), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.0059 g of the title compound as a yellow film: MS (ESI) m/z 472 (M+1).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[NH:3][C:2]1=[O:11].[Br:12]Br>CC(O)=O>[Br:12][C:7]1[C:6]2[NH:1][C:2](=[O:11])[NH:3][C:4](=[O:10])[C:5]=2[S:9][CH:8]=1
Reactant: O=c1[nH]c(=O)c2sccc2[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2scc(Br)c2[nH]1
Temperature: 90 °C
Reaction time: 24 h
Yield: 93.7 %

Procedure:
To 100 mL glass tube containing thieno[3,2-d]pyrimidin-2,4-dione 4 (5.88 g, 34.86 mmol), AcOH (60 mL) and bromine (3.6 mL, 69.72 mmol) were added and the tube capped. The sealed tube was stirred in a preheated oil bath at 90° C. for 24 h. An additional portion of bromine (3.6 mL, 69.72 mmol) was added to the sealed tube and mixture stirred for another 24 h at 90° C. The AcOH was evaporated to obtain a solid residue to which water was added (200 mL) and the suspension filtered and residue washed repeatedly with water and dried under vacuum to obtain 8 as an off-white solid (8.07 g, 32.67 mmol, 94%). Mp 251.0-252.9° C. 1H NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1H), 11.40 (br s, 1H, NH), 11.58 (br s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δ 99.6, 112.1, 133.4, 145.1, 152.1, 159.0. FAB-MS m/z for C6H3BrN2O2S calculated [M+H]+ 246.9171. found 246.9175 (79Br), 248.9161 (81Br).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:1][CH2:2][C@@H:3]([NH:11][C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCO1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCCO1
Reaction time: 1 h
Yield: 49 %

Procedure:
At 0° C., tert-butyl (2S)-1-hydroxy-3-(tetrahydro-2H-pyran-2-yl)propan-2-ylcarbamate (1.41 g, 5.44 mmol) in CH2Cl2 (50 mL) was treated with Et3N (2.3 mL, 16.3 mmol) followed by methanesulfonyl chloride (1.1 mL, 13.6 mmol). The reaction was allowed to stir for 1 h and quenched with water. The organic layer was washed with satd aq NaHCO3 and brine, dried over Na2SO4, and filtered. After removal of solvent, the crude material was purified using chromatography on silica gel (EtOAc/Hex) to afford (2S)-2-(tert-butoxycarbonylamino)-3-(tetrahydro-2H-pyran-2-yl)propyl methanesulfonate (0.90 g) as a solid. MS m/z 360 (M+Na).