Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:62])([CH3:61])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([CH2:18][O:19][CH:20]2[CH:25]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][O:34]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)=[CH:28][CH:27]=3)[CH2:24][CH2:23][N:22]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:21]2)[CH:9]=1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>C(Cl)Cl.CO>[OH:34][CH2:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([CH:25]2[CH2:24][CH2:23][N:22]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:21][CH:20]2[O:19][CH2:18][C:10]2[CH:9]=[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:62])[CH3:61])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCO)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
Selective cleavage of the trityl group was effected analogously to the procedure published by E. Krainer et al. in Tetrahedron Letters 1993, 1713-1716 by treating a solution of 780 mg (0.92 mmol) of tert-butyl (3RS,4RS)-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-4-[4-(2-trityloxy-ethyl)-phenyl]-piperidine-1-carboxylate in 15 ml of methylene chloride with a solution of 436 mg (3.68 mmol) of trifluoroacetic acid and 803 mg (3.68 mmol) of trifluoroacetic anhydride in 2 ml of methylene chloride. After 30 seconds the reaction mixture was cooled to 0° C. and treated with 4 ml of triethylamine. After 5 minutes 10 ml of methanol were added and the mixture was stirred for 10 minutes. Subsequently, the mixture was washed with saturated sodium hydrogen carbonate solution and the aqueous phase was thereafter back-extracted with 10 ml of methylene chloride. The combined organic phases were dried over sodium sulphate and then evaporated under reduced pressure. The crude product was chromatographed on silica gel using a 4:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 553 mg of tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethyl)-phenyl]-3-[4-(2-trimethylsilanyl-ethoxy-methoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate as a colourless oil.
Reaction SMILES: BrC1C=C2C(=CC=1)C(=O)CC2.[CH:12]1([C:15]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=2)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH2:14]C1>>[OH:28][CH2:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[C:15]([C:16]([F:17])([F:18])[F:19])([OH:20])[CH2:12][CH2:14]2
Reactant: OCc1ccc(C(O)(C2CC2)C(F)(F)F)cc1
Agent: O=C1CCc2cc(Br)ccc21
Product: OCc1ccc2c(c1)CCC2(O)C(F)(F)F

Procedure:
5-Bromoindan-1-one was treated in a similar manner to Reference examples 41-(1), (2) and (3) to give 5-(hydroxymethyl)-1-(trifluoromethyl)indan-1-ol.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)CO)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f8) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.[F:24][C:25]([F:42])([F:41])[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=2)[CH2:29]1)=[O:27]>C(Cl)(Cl)Cl>[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][S:37]([C:33]2[CH:34]=[C:35]3[C:30](=[CH:31][CH:32]=2)[CH2:29][N:28]([C:26](=[O:27])[C:25]([F:42])([F:24])[F:41])[CH2:36]3)(=[O:38])=[O:39])=[CH:19][CH:18]=1
Reactant: O=C(N1Cc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Reactant: Nc1ccc(F)cc1
Agent: CN(C)c1ccccn1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(N1Cc2ccc(S(=O)(=O)Nc3ccc(F)cc3)cc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.7 %

Procedure:
Pyridine (2.57 mL, 31.9 mmol) and dimethylaminopyridine (195 mg, 1.59 mmol) were added to a solution of 4-fluoroaniline (1.86 g, 16.7 mmol) in chloroform (46 mL) at room temperature and the mixture was cooled in ice. 2-(Trifluoroacetyl)-2,3-dihydro-1 H-isoindole-5-sulfonyl chloride (5.00 g, 15.9 mmol) was added thereto and the mixture was warmed to room temperature and stirred for 15 hr. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate. The mixture was washed with 1 mol/L hydrochloric acid and brine, the organic layer was dried over anhydrous magnesium sulfate, and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was powdered with diethyl ether and collected by filtration to afford the title compound as a pale pink powder (5.85 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Li]CCCC.Cl[Si](C)(C)C.[C:17]1(=[O:21])[CH2:20][CH2:19][CH2:18]1>C1COCC1>[NH2:1][C:2]1[S:3][C:4]([C:17]2([OH:21])[CH2:20][CH2:19][CH2:18]2)=[CH:5][N:6]=1
Reactant: Nc1nccs1
Reactant: O=C1CCC1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ncc(C2(O)CCC2)s1
Temperature: -60 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
A solution of 2-aminothiazole (7.1 g, 71 mmol) in THF (360mL) cooled to −78° C. was treated dropwise with n-BuLi (56.18 mL, 142 mmol) while maintaining an internal temperature less than or about equal to −60° C. After addition was completed, the solution was treated dropwise with chlorotrimethylsilane (18 mL, 142 mmol). The reaction solution was warmed to −10° C., then was cooled back to −78° C. n-Butyllithium (28.4 mL, 71 mmol) was added dropwise and after 10 minutes, cyclobutanone (5.33 mL, 71 mmol) was added dropwise. The solution was stirred for 1 hour at −78° C., was quenched with saturated ammonium chloride solution, and was warmed to 23° C. The reaction mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with brine, was dried (MgSO4), was filtered, and solvent was removed in vacuo. The resulting residue was purified by silica gel chromatography (15:1→7:1 CHCl3—MeOH) to afford 7.24 g of 1-(2-amino-thiazol-5-yl)cyclobutanol. 1HNMR (400 MHz, DMSO-D6) δ 6.78 (s, 1H), 6.70 (s,2H), 5.58 (s,1H), 22 (m,4H), 1.69 (m, 1H), 1.50 (m,1H).
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5]C)=O.C1(C2NC=C([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH3:25])[CH:19]=3)N=2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][CH2:2][C:3]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH3:25])[CH:19]=1)=[O:5]
Reactant: Cc1cc(-c2c[nH]c(C3CCCCC3)n2)ccc1F
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)CBr)ccc1F
Temperature: 25 °C

Procedure:
0.38 mL methyl bromoacetate was added to 940 mg 2-cyclohexyl-4-(4-fluoro-3-methyl-phenyl)-1H-imidazole and 1.52 g potassium carbonate in 10 mL DMF. The reaction was stirred over night at RT and evaporated. Methanol and 1 mol/L sodiumhydroxide solution was added and the mixture was stirred 2 h at RT. The solvent was removed. The residue was dissolved in water and acidified with 1 mol/L HCL solution. The precipitate was filtered and dried to give 700 mg desired product. Rt: 0.92 min (method A), (M+H)+: 317
Reaction SMILES: O[CH2:2][N:3]1[CH2:7][CH2:6][N:5]([CH2:8]O)[C:4]1=[O:10].[C:11]([C:15]1[CH:16]=[C:17]([SH:26])[CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])([CH3:14])([CH3:13])[CH3:12].Cl>CO>[C:11]([C:15]1[CH:16]=[C:17]([S:26][CH2:2][N:3]2[CH2:7][CH2:6][N:5]([CH2:8][S:26][C:17]3[CH:16]=[C:15]([C:11]([CH3:12])([CH3:13])[CH3:14])[C:20]([OH:21])=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=3)[C:4]2=[O:10])[CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C1N(CO)CCN1CO
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(SCN2CCN(CSc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C2=O)cc(C(C)(C)C)c1O
Yield: 78 %

Procedure:
A solution of 3.65 grams of 1,3-bis(hydroxymethyl)-2-imidazolidone and 11.92 grams of 3,5-di-t-butyl-4-hydroxybenzenethiol in 100 ml of methyl alcohol was treated with anhydrous hydrogen chloride. The reaction mixture was cooled and the product recrystallized from methyl alcohol to give 11.43 grams of white solid, m.p. 173°-176° C.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C@H:9]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C@@H:8]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[O:7][CH:5]1[OH:6])=[N+]=[N-].SC[C@H]([C@@H](CS)O)O.C(N(CC)CC)C.C(OCC)C>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C@@H:4]1[C@@H:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C@H:9]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C@@H:8]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[O:7][CH:5]1[OH:6]
Reactant: COc1ccc(COC[C@H]2OC(O)[C@H](N=[N+]=[N-])[C@@H](OCc3ccc(OC)cc3)[C@@H]2OCc2ccc(OC)cc2)cc1
Agent: O[C@H](CS)[C@H](O)CS
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(COC[C@H]2OC(O)[C@H](N)[C@@H](OCc3ccc(OC)cc3)[C@@H]2OCc2ccc(OC)cc2)cc1
Reaction time: 24 h
Yield: 69 %

Procedure:
To a solution of the azide 63 (110.2 mmol) in dry DMF (275 mL) was added dithiothreitol (220.4 mmol). The reaction mixture was then degassed with a stream of nitrogen, cooled to 0 C, and triethylamine (220.4 mmol) added. The solution was then allowed to return to room temperature and subsequently stirred for 24 h. The solution was then diluted with ethyl acetate and washed with water, brine, dried (MgSO4), the solvents removed in vacuo, and resulting residue treated with diethyl ether (˜250 mL) to give the desired product 64 as a white solid (69%), LCMS [M+H]+=540.25.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])[S:3]([CH3:6])(=[O:5])=[O:4].[Cl-].[NH4+].C1COCC1>CO.[Zn]>[NH2:13][C:11]1[CH:10]=[CH:9][C:8]([C:16]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[O:17])=[C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])[CH:12]=1
Reactant: CN(c1cc([N+](=O)[O-])ccc1C(=O)N1CCOCC1)S(C)(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cc(N)ccc1C(=O)N1CCOCC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
A suspension of N-methyl-N-(2-(morpholine-4-carbonyl)-5-nitrophenyl)methanesulfonamide (101.3 mg, 0.295 mmol), zinc (193 mg, 2.95 mmol), ammonium chloride (158 mg, 2.95 mmol) in MeOH (0.5 mL), and THF (0.5 mL) was stirred at room temperature for 16 h. The crude material was loaded onto a silica gel cartridge and dried in vacuo. The dry cartridge was then connected to an ISCO cartridge, eluting with 2-10% MeOH in CH2Cl2 to give the desired product as white solid (68.2 mg, 74% yield). LCMS: (M+H)+=314.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.94 (1H, d, J=8.28 Hz), 6.61 (1H, br. s.), 6.53 (1H, dd, J=8.28, 2.01 Hz), 5.52 (2H, s), 3.51 (4H, br. s.), 3.19-3.26 (1H, m), 3.15-3.18 (3H, m), 3.08 (3H, br. s.), 3.03 (3H, br. s.).
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[O:12]=[C:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH2:18][C:19]([NH2:21])=O.N1C=CC=CC=1>C(#N)C>[O:12]=[C:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH2:18][C:19]#[N:21]
Reactant: NC(=O)CN1CCCC1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: N#CCN1CCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dimethylformamide (4.65 mL, 60 mmol) was taken up in acetonitrile (100 mL) and the solution cooled to 0° C. with an ice bath. Oxalyl chloride (4.8 mL, 55 mmol), diluted with acetonitrile (20 mL) was added to the reaction dropwise. The mixture was stirred for 30 min, then 2-(2-oxopyrrolidin-1-yl)acetamide (7.11 g, 50 mmol) in 30 mL of acetonitrile was added slowly to the reaction. The mixture was allowed to stir for 30 min and pyridine (6.1 mL, 100 mmol) was added to the reaction in one portion. The reaction was stirred for an additional 30 min and the volatiles were removed in vacuo. Water was added to the residue which was extracted with ethyl acetate. The aqueous layer was acidified to pH 2 with 1 N HCl and further extracted with ethyl acetate. All the organic layers were combined, washed with brine, dried with sodium sulfate, concentrated and placed on a high vacuum line to afford a clear oil. Yield=4.4 g
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:25])[NH:11][N:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1F.[F:26][C:27]1[CH:28]=[C:29](Br)[CH:30]=[CH:31][C:32]=1[F:33].N>>[F:26][C:27]1[CH:28]=[C:29]([N:11]2[C:10](=[O:25])[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:13]=[N:12]2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: Fc1ccc(Br)cc1F
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(F)c(F)c2)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2-c2cccc(F)c2)cc1

Procedure:
The title compound was prepared as described in Example 62, starting with 4-(3,4-difluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 3,4-difluorobromobenzene in place of 1-bromo-4-fluorobenzene (yield: 185 mg, 46.5%). mp 182–185° C. 1H NMR (300 MHz, DMSO-d6) δ 3.23 (s, 3 H), 6.98 (d, J=9 Hz, 1H), 7.18 (m, 2H), 7.32 (m, 1H), 7.52 (d, J=9 Hz, 2 H), 7.6 (m, 2H), 7.85 (m, 1 H), 7.9 (d, J=9 Hz, 2H), 8.3 (s, 1 H). MS (DCI/NH3) m/z 457 (M+H)+, 474 (M+NH4)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:26]4[CH2:27][CH2:28][CH:24]([CH2:23][NH:22][CH3:21])[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CNCC1CCNC1
Solvent: CC#N
Product: CNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To 0.80 g (2.8 mmol) of the 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile and 0.43 g (2.8 mmol) of 1,8-diazobicyclo [5.4.0] undec-7-ene, was added 0.35 g (3.1 mmol) of N-methyl-3-pyrrolidinemethanamine. The mixture was refluxed for one hour and stirred overnight. The solids were filtered and washed with acetonitrile:ether (1:6) to give 0.81 g of the title compound, mp 265°-267° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([NH:18][C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20])[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26]I.[H-].[Na+]>CN(C=O)C.[NH4+].[Cl-]>[C:1]([O:5][C:6]([C:8]1([N:18]([C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20])[CH3:26])[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)COC(=O)NC1(C(=O)OC(C)(C)C)CCc2ccccc2C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)COC(=O)N(C)C1(C(=O)OC(C)(C)C)CCc2ccccc2C1
Reaction time: 6 h
Yield: 83.6 %

Procedure:
The carbamate from Example 33D (1.5 g, 4.3 mmol) was dissolved in DMF (4.0 mL) followed by addition of MeI (1.1 g, 8.0 mmol) and NaH (50%, 384 mg, 8.0 mmol) at 0° C. The mixture was stirred for 6 hours, diluted with aqueous NH4Cl and extracted with ethyl acetate(3×75 mL). The combined organic layers were dried with MgSO4, filtered, concentrated under reduced pressure to provide the titled compound (1.3 g, 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[CH:16]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:17]O)[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:23]1([S:20]([N:19]2[CH2:17][CH:16]2[C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:14][CH2:13]2)=[O:29])(=[O:22])=[O:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C(CO)NS(=O)(=O)c3ccccc3)CC2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68.9 %

Procedure:
To a solution of (RS)—N-{2-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-1-hydroxymethyl-2-oxo-ethyl}-benzenesulfonamide (1.417 g) and triphenylphosphine (0.979 g) in tetrahydrofuran (12 ml) was added diethylazodicarboxylate (DEAD, 0.65 g) at 0° C. After 15 min the ice bath was removed and the mixture was stirred at room temperature for 45 min. The solvent was evaporated and the product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 4:1=>1:1) to give (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (0.934 g) as a colorless solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH3:30])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:17]([CH3:18])[C:11]=2[N:10]([CH3:31])[C:9]1=[O:32])(=O)C.O[Li].O>C1COCC1.O.C(Cl)Cl>[OH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH3:30])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:17]([CH3:18])[C:11]=2[N:10]([CH3:31])[C:9]1=[O:32]
Reactant: CC(=O)OCCCn1c(=O)c2c(c(C)c(-c3cccc(OC(F)(F)F)c3)n2C)n(C)c1=O
Agent: [Li]O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2cccc(OC(F)(F)F)c2)n(C)c2c(=O)n(CCCO)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a solution of 3-(1,5,7-trimethyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (20 mg, 0.044 mmol) in THF (5 mL) and water (5 mL) was added LiOH.H2O (3.70 mg, 0.088 mmol). The reaction was stirred at RT for 30 min then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to give a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-1,5,7-trimethyl-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (5 mg, 27.6% yield) as a white solid. 1H NMR (CDCl3) δ: 7.56 (t, J=8.0 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 7.16 (s, 1H), 4.33-4.14 (m, 2H), 3.80 (s, 3H), 3.73 (s, 3H), 3.52 (dd, J=12.8, 7.5 Hz, 2H), 2.21 (s, 3H), 2.03-1.83 (m, 2H). LCMS: MH+ 412 and TR=2.613 min.
Reaction SMILES: [CH:1]([O:6][CH3:7])([O:4][CH3:5])OC.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH:22]2[CH2:27]C[CH2:25][C:24](=O)[CH2:23]2)[CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH:22]2[CH2:23][CH2:24][CH2:25][C:1]([O:4][CH3:5])([O:6][CH3:7])[CH2:27]2)[CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CCCC(c2cccc(OCc3ccccc3)c2)C1
Reactant: COC(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COC1(OC)CCCC(c2cccc(OCc3ccccc3)c2)C1
Reaction time: 0.08 h

Procedure:
Trimethyl orthoformate (2 ml) was added to montmorillonite clay (1.3 g) and the mixture was shaken for 5 minutes and then filtered. The solid so obtained was added to a solution of 3-(3-benzyloxyphenyl)cyclohexanone (0.28 g) in carbon tetrachloride (4 ml) and the resultant mixture was stirred at ambient temperature for 20 hours. The mixture was basified by the addition of sodium bicarbonate (0.05 g) and filtered. The filtrate was evaporated to give 3-(3-benzyloxyphenyl)-1,1-dimethoxycyclohexane as an oil (0.326 g) which was used without further purification.
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:15]([C:18]1[S:22][C:21]([NH2:23])=[N:20][N:19]=1)([CH3:17])[CH3:16]>N1C=CC=CC=1>[CH:15]([C:18]1[S:22][C:21]([NH:23][S:2]([C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[N:20][N:19]=1)([CH3:17])[CH3:16]
Reactant: CC(C)c1nnc(N)s1
Reactant: CC(=O)Oc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(S(=O)(=O)Nc2nnc(C(C)C)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
4.1 g acetic acid 4-chlorosulfonyl-phenyl ester were added to a stirred solution of 2.5 g 5-isopropyl-[1,3,4]thiadiazol-2-ylamine in 35 ml pyridine. The reaction mixture was stirred at room temperature overnight. The pyridine was removed in vacuo and the residue dissolved in 200 ml dichloromethane and washed with 60 ml water. The organic layer was dried over MgSO4. Then the solvent was removed in vacuo and the resulting residue purified by flash chromatography on silica gel with the eluents n-heptane:ethyl acetate=1:1=>1:3 to obtain 4.47 g Acetic acid 4-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenyl ester impurified with 40% of the byproduct N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-acetamide. The material was used without further purification.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:25]1([NH:31][NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([N:31]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NNc1ccccc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(C(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(C(F)(F)F)cc2)nc1-c1ccnn1-c1ccccc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-22) and phenylhydrazine according to the method described for example 1. MS: M=383.2 (M+H)+