Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21](C(OCC)C)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1COCC1.[OH-].[Na+]>Cl>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(C)n1cc(-c2ncnc3c2ccn3COC(=O)C(C)(C)C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
To a solution of crude {4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (4) in THF (1 L, 12.3 mol), a 4 N aqueous HCl solution (500 mL) was added at room temperature. The resulting reaction mixture was subsequently stirred at room temperature for 5 h. When the reaction was deemed complete as confirmed by TLC and LCMS, the reaction mixture was cooled to 0-5° C. before pH was adjusted to 9-10 with a 1 M aqueous sodium hydroxide (NaOH) solution (2 L). The mixture was concentrated under reduced pressure to remove most of THF and the resulting suspension was stirred at room temperature for 2 h. The solids were collected by filtration, washed with water (3×500 mL), and dried in vacuum to afford crude [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (5, 157.5 g, 204.43 g theoretical, 77% yield for three steps) as white to off-white solids, which was found to be sufficiently pure (>98 area % by HPLC) to do the subsequent reaction without further purification. For 5: 1H NMR (DMSO-d6, 400 MHz) δ ppm 13.42 (br s, 1H), 8.76 (s, 1H), 8.67 (s, 1H), 8.33 (s, 1H), 7.68 (d, 1H, J=3.8 Hz), 7.11 (d, 1H, J=3.8 Hz), 6.21 (s, 2H), 1.06 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 177.74, 152.31, 152.09, 151.91, 139.52, 130.39, 120.51, 113.93, 101.91, 67.26, 38.98, 27.26; C15H17N5O2 (MW, 299.33), LCMS (EI) m/e 300 (M++H).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH2:11][CH2:10]1)(C)(C)C>O1CCOCC1.CO>[NH2:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH2:13][CH2:14]1.[ClH:1]
Reactant: CN(C)C(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)C(=O)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 mL of 4 N HCl in 1,4-dioxane was added to a solution of tert-butyl{4-[(dimethylamino)carbonyl]cyclohexyl}carbamate (0.20 g, 0.74 mmol) in methanol (1.0 mL). The reaction mixture was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure to afford the desired product as an HCl salt.
Reaction SMILES: [CH2:1]([C:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])[CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B.C1C[O:35]CC1>C1COCC1>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:7]2[CH2:6][CH2:5][C:4]([CH2:1][CH2:2][CH2:3][OH:35])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:9][C:8]2=[O:10])[CH:12]=1
Reactant: C1CCOC1
Reactant: C=CCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Agent: B
Product: O=C1OC(CCCO)(c2ccccc2)CCN1c1cccc(-c2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 6-allyl-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (18 mg, 0.045 mmol) in THF (1 mL) was added BH3.THF (60 μL, 1M THF solution) and the mixture was stirred overnight at rt. The reaction was cooled to 0° C. and NaBO3.H2O (19 mg, 0.20 mmol) was added and stirred for 2 h warming to rt. The solvent was removed in vacuo and the residue was redissolved in CH3CN (4 mL). The solution was filtered and purified by prep HPLC to afford 3-(2′,4′-difluorobiphenyl-3-yl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (4.44 mg). LC-MS Method 1, tR=1.97 min, m/z=424 (M+H). 1H NMR (CDCl3) 7.47-7.33 (m), 7.32-7.26 (m), 7.16-7.12 (m), 6.96-6.85 (m), 4.28 (t), 3.52-3.13 (m), 3.36-3.27 (m), 2.5-2.47 (m), 2.15-1.99 (m).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C@@H:11]([CH3:14])[CH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[OH:13][CH2:12][C@@H:11]([CH3:14])[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: C[C@H](Cl)CO
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](CO)Oc1ccc(C=O)cc1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
Under argon, 785 mg (6.43 mmol) of 4-hydroxybenzaldehyde and 759 mg (8.04 mmol) of (S)-(+)-2-chloro-1-propanol were initially charged in 15.7 ml of DMF. 2.04 g (19.3 mmol) of sodium carbonate were added, and the mixture was then stirred at 130° C. for 20 h. The reaction mixture was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16].C([BH3-])#N.[Na+].C(O)(=O)C>CN(C)C=O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CNc2cccc(C(=O)O)c2)cc1
Yield: 75.3 %

Procedure:
4-cyanobenzaldehyde (0.65 g; 5 mmoles), 3-aminobenzoic acid (0.68 g; 5 mmoles) and sodiumcyanoborohydride (0.35 g; 5 mmols) were stirred in N,N-dimethylformamide (25 ml) containing 1% acetic acid at room temperature for 2 hrs. The product was precipitated out by addition of water. The solid was filtered and dried in vacuo to give 0.95 g white solid. FAB-MS: MH+ =253.
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.S(=O)(=O)(O)O.[OH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([Br:31])[CH:25]=[CH:24]2>CCCCCCC>[C:5]12([C:30]3[CH:29]=[C:28]4[C:23]([CH:24]=[CH:25][C:26]([Br:31])=[CH:27]4)=[CH:22][C:21]=3[OH:20])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Product: Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2

Procedure:
In a 100 ml flask, under a nitrogen atmosphere, are placed 2 g of 1-acetoxyadamantane and 20 ml of n-heptane, and 0.5 g of concentrated sulfuric acid is introduced drop by drop. At a temperature of about 22.C, 2.3 of 6-hydroxy-2-bromonaphthalene are added slowly and the mixture is left in vigorous agitation. The solvent is eliminated by filtration and the solid residue in suspension in the water is collected. The residue is filtered and then washed until neutrality is obtained. The resulting reddish solid is washed again with hexane until a colorless filtrate is obtained. After drying in a vacuum oven for 24 hours at 30 C one obtains a raw product which is chromatographed with a silica column using an ethyl acetate and hexane mixture of 1:9 as the eluent. After evaporation of the solvents, 1.3 g of desired raw product were obtained (Melting point: 218°-224° C.).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:23][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: OCc1ccc(F)cc1
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3ccc(F)cc3)c21
Yield: 59.3 %

Procedure:
The title compound (cis/trans=98/2) was prepared as pale brown crystals in 59.3% yield in a similar procedure to that described in. Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=94/6) and 4-fluorobenzyl alcohol.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH2:11][CH:12]([OH:15])[CH2:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]1[CH2:11][CH:12]([O:15][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])[CH2:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CC=C(COCc2ccccc2)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CC=C(COCc2ccccc2)C1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 81.6 %

Procedure:
To a solution of 3-(benzyloxymethyl)cyclopent-3-enol (CAS 153186-83-5; Nucleosides, Nucleotides, and Nucleic Acids 26: 935-37, 2007) (5.75 g, 28.1 mmol) and imidazole (2.87 g, 42.2 mmol) in dry N,N-dimethylformamide (20 ml) at 0° C. was added tert-butyldimethylchlorosilane (5.09 g, 33.8 mmol). Stiffing was continued at 0° C. for 5 minutes, the cooling bath was removed and the mixture was stirred at 23° C. for 2 h. For the workup, the reaction mixture was poured into water, followed by extraction with TBME. The organic layer was washed with brine and dried over Na2SO4. Removal of the solvent at reduced pressure left a yellow oil, which was purified by flash chromatography (silica gel, 50 g, 0% to 15% EtOAc in heptane) to give the (3-(benzyloxymethyl)cyclopent-3-enyloxy)(tert-butyl)dimethylsilane (7.3 g, 81.4% yield) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([CH3:23])=[C:19]([CH3:22])[CH:20]=2)[N:15]=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([CH3:23])=[C:19]([CH3:22])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: Cc1cc2ncnc(Cl)c2cc1C
Product: Cc1cc2ncnc(N3CCc4ccc(Cl)cc43)c2cc1C
Yield: 16 %

Procedure:
Utilizing a procedure analogous to that described in Example 24, this product was prepared in 16% yield from 6-chloro-indoline and 4-chloro-6,7-dimethyl-quinazoline. (M.P. 199° C.; LC-MS: 310 (MH+)).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][C:20]1[CH:29]=[C:28]([C:30]#[C:31][Si](C)(C)C)[CH:27]=[CH:26][C:21]=1[O:22][CH2:23][CH2:24][OH:25].CCOC(C)=O>C1COCC1>[C:30]([C:28]1[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24][OH:25])=[C:20]([CH3:19])[CH:29]=1)#[CH:31]
Reactant: Cc1cc(C#C[Si](C)(C)C)ccc1OCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1ccc(OCCO)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20.8 g (74.4 mmol) of TBAF was added at RT to a solution of 16.8 g (67.6 mmol) of 2-(2-methyl-4-trimethylsilanylethynylphenoxy)ethanol in 500 mL of THF and the mixture was stirred for 3 hours at RT. The reaction mixture was evaporated down in vacuo and the residue dissolved in EtOAc. The organic phase was washed with water and saturated aqueous NaCl solution, dried over sodium sulfate, and evaporated down in vacuo. The crude product was used in the next reaction step without further purification. Yield: 12.0 g (quant. yield); C11H12O2 (M=176.212); calc.: molpeak (M)+: 176; found: molpeak (M)+: 176; Rf value: 0.24 (silica gel, cyc/EtOAc 2:1).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([C@:11]12[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][C@H:12]1[CH2:13][CH2:14][O:15][C:16]1[C:17]2=[CH:18][C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=3)[C:23]=2[CH:24]=1)[CH3:10]>CS(C)=O.C1COCC1>[CH2:9]([C:11]12[CH2:35][CH2:34][C:33]3([CH2:4][O:36]3)[CH2:32][CH:12]1[CH2:13][CH2:14][O:15][C:16]1[C:17]2=[CH:18][C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=3)[C:23]=2[CH:24]=1)[CH3:10]
Reactant: C[S+](C)(C)=O
Reactant: CC[C@]12CCC(=O)C[C@H]1CCOc1cc3c(cnn3-c3ccnc(C)c3)cc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCC12CCC3(CO3)CC1CCOc1cc3c(cnn3-c3ccnc(C)c3)cc12
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
A 100 mL round-bottom flask equipped with rubber septum and nitrogen inlet needle was charged with sodium hydride (60 wt % in oil, 0.212 g, 5.29 mmol) in DMSO (13 mL) and then the mixture was heated at about 60° C. in a heating block for about 30 min. The mixture was allowed to cool to rt, at which point trimethylsulfoxonium iodide (1.16 g, 5.29 mmol) was added in one portion and the reaction mixture was stirred for about 15 min. A solution of rac-(4aR,12bS)-12b-ethyl-9-(2-methylpyridin-4-yl)-4,4a,5,6,9,12b-hexahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3 (2H)-one (92, R1=2-methylpyridin-4-yl, R2=Ethyl) (0.993 g, 2.64 mmol) in THF (13 mL) was added in one portion. After about 30 min the reaction was concentrated under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on silica gel (40 g, EtOAc). Collection and concentration of the appropriate fractions gave rac-(2′R,4aS,12bR)-12b-ethyl-9-(2-methylpyridin-4-yl)-1,2,4,4a,5,6,9,12b-octahydrospiro[benzo[4,5]oxepino[3,2-f]indazole-3,2′-oxirane] (93, R1=2-methylpyridin-4-yl, R2=Ethyl) (0.844 g, 82%). LC/MS, method 3, Rt=2.40 min, MS m/z 390 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.61-8.55 (m, 1H), 8.23 (s, 1H), 7.91-7.76 (m, 2H), 7.69 (s, 1H), 7.56 (s, 1H), 4.43-4.31 (m, 1H), 3.84-3.71 (m, 1H), 2.98-2.70 (m, 3H), 2.71-2.56 (m 2H), 2.56-2.16 (m, 4H), 2.07-1.93 (m, 1H), 1.93-1.77 (m, 1H), 1.73-1.33 (m, 4H), 0.97-0.83 (m, 1H), 0.74-0.56 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([S:32]([C:35]2[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH2:28][CH2:27]1>>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([S:32]([C:35]2[CH:36]=[C:37]([NH:41][C:22]([C:21]3[CH:20]=[N:19][N:12]4[C:13]([C:15]([F:17])([F:18])[F:16])=[CH:14][C:9]([C:4]5[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)=[N:10][C:11]=34)=[O:24])[CH:38]=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH2:28][CH2:27]1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: CN1CCN(S(=O)(=O)c2cccc(N)c2)CC1
Product: CN1CCN(S(=O)(=O)c2cccc(NC(=O)c3cnn4c(C(F)(F)F)cc(-c5ccc(Cl)c(Cl)c5)nc34)c2)CC1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.9) and 3-(4-methyl-piperazine-1-sulfonyl)-phenylamine [CAS 436095-35-1] according to general procedure II. Yellow solid. MS (ISP) 613.3 [(M+H)+]; mp 181° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]3([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH:13]3[CH2:12][O:11]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]2[C:14]3([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH2:15][NH:16][CH2:17][CH:13]3[CH2:12][O:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CN2OCC3CN(C(=O)OC(C)(C)C)CC32c2cccnc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN2OCC3CNCC32c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To a stirred solution of tert-butyl 1-[(4-methoxyphenyl)methyl]-6a-(3-pyridyl)-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (2.9 g, 7.05 mmol) in dichloromethane (80 mL) is added trifluoroacetic acid (16 mL). The reaction mixture is stirred for 1 hour 30 minutes at room temperature. The solvent is concentrated and the residue is partitioned between saturated aqueous sodium bicarbonate (30 mL) and dichloromethane (100 mL). The resulting solution is stirred for 30 minutes then the phases are separated. The aqueous phase is re-extracted with dichloromethane. The combined dichloromethane extracts are dried over magnesium sulfate, filtered, and concentrated under vacuum to give a residue. The residue is purified by silica gel chromatography using a 0-10% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (1.33 g, 43%). ES/MS (m/e): 312 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[C:3](=[O:9])[CH2:4][C:5](OC)=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:22]([OH:25])([CH3:24])[CH3:23]>>[CH3:1][CH:2]([CH3:10])[C:3](=[O:9])[CH2:4][C:5]([O:25][CH:22]([CH3:24])[CH3:23])=[O:6]
Reactant: CC(C)O
Reactant: COC(=O)CC(=O)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)OC(=O)CC(=O)C(C)C
Temperature: 90 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
Methyl 4-methyl-3-oxo-pentanoate (304 g), isopropyl alcohol (500 ml) and p-toluenesulfonic acid (3.8 g) were stirred together and heated to reflux at 90° C. After 3 hours, 400 ml of solvent was collected by distillation at atmospheric pressure. Fresh isopropyl alcohol was added and the mixture refluxed for a further 3 hours. The cycle of distillation, addition of fresh solvent and refluxing was continued until the conversion had reached 95%, determined by a peak area ratio of product:starting material of 95:5 measured by LC. The remaining volatile solvents were removed by distillation and the resultant liquid washed with 10% sodium carbonate solution and dried over anhydrous sodium sulfate and filtered to give isopropyl 4-methyl-3-oxo-pentanoate as a clear liquid (301 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[S:30]([CH3:29])(=[O:32])=[O:31])=[CH:4][CH:3]=1
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1C1CCN(C(=O)c2cn(S(C)(=O)=O)c3cc(Cl)ccc23)CC1
Yield: 17.4 %

Procedure:
To a solution of 0.035 g (0.09 mmol) (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone in 2 ml N,N-dimethylformamide were added 0.005 g (0.10 mmol) sodium hydride (50% in oil). After 45′, 0.008 ml (0.10 mmol) methanesulfonyl chloride were added. The reaction mixture was quenched with water after 3 h and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (2×30 ml) and brine (1×30), dried over sodium sulfate and concentrated to dryness. The residue was chromatographed (loaded as a solution in toluene; Flashpac 5 g; n-heptane/ethyl acetate 100:0→75:25) to give the title compound (0.007 g; 17%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[SH-:10].[Na+]>CO>[NH2:8][C:7]1[C:6]([SH:10])=[N:5][CH:4]=[N:3][C:2]=1[Cl:1]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: [SH-]
Agent: [Na+]
Solvent: CO
Product: Nc1c(S)ncnc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4,6-dichloropyrimidine-5-amine (E-2) (16.0 g, 98.2 mmol) and sodium hydrosulphide (7.15 g, 128 mmol) in MeOH (320 mL) is stirred at reflux for 3 h. The resulting mixture is allowed to cool to RT and then concentrated in vacuo. The residue is poured into aqueous NaOH solution (200 mL, 1 M) and then neutralized with acetic acid to adjust the pH value to 5-6. The resulting mixture is stirred at RT for 30 min. The solid is collected by filtration, rinsed with water (2×50 mL) and dried in vacuo to afford the product, 5-amino-6-chloropyrimidine-4-thiol (E-3).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[H-].[Na+].[C:9]([O:13][C:14](=[O:30])[NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[C:25]([C:26](F)=[O:27])=[CH:24][N:23]=[C:22]([Cl:29])[N:21]=1)([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14](=[O:30])[NH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:20]2[N:21]=[C:22]([Cl:29])[N:23]=[CH:24][C:25]=2[C:26](=[O:27])[C:3]([C:4](=[O:5])[NH2:6])=[C:1]1[NH2:2])([CH3:12])([CH3:11])[CH3:10]
Reactant: N#CCC(N)=O
Reactant: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1C(=O)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCn1c(N)c(C(N)=O)c(=O)c2cnc(Cl)nc21
Temperature: 3.5 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
To a solution, cooled to 2-5°C. on an ice bath, of 1.21 g (14.39 mmol) of cyanoacetamide in 20 mL of anhydrous DMF are added portionwise 1.73 g (43.17 mmol) of 60% sodium hydride. The mixture is stirred for 15 minutes at 2-5°C., and this suspension is then added rapidly to the solution of 4.56 g (13.70 mmol) of the acid fluoride prepared in step 11.2 in 30 mL of anhydrous DMF, precooled to 2-5°C. on an ice bath. The mixture is stirred overnight at room temperature and then cooled to 2-5°C., and a further 0.22 g of 60% sodium hydride is added. The medium is stirred overnight at room temperature, and ice is then added slowly to destroy the excess hydride, and the reaction mixture is poured into an ice-water mixture. The resulting mixture is acidified by adding aqueous 1 N HCl solution. The precipitate formed is isolated by filtration, rinsed with water and then dried. The expected product is obtained in the form of an orange solid, which is used as obtained in the following step. Yield=64%.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]=[C:10]([CH2:14][C:15](O)=[O:16])[C:11]([OH:13])=[O:12]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:15](=[O:16])[CH2:14][CH:10]([C:11]([OH:13])=[O:12])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc(F)cc1
Product: O=C(O)C1CC(=O)N(c2ccc(F)cc2)C1

Procedure:
4-Fluoroaniline (0.7 ml, 7.6 mmol) was added to 2-methylenebutanedioic acid (1.0 g, 7.6 mmol) in a sealed tube. The mixture was heated to 110 degrees for 3 hours after which a precipitate formed. The reaction was filtered and the solid was dissolved in ethyl acetate and concetrated to yield 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (M+1=223.8). The product was taken to next step without determining mass.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][C:3]=1[O:15][CH3:16].[CH3:17][Mg+].[Br-]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:15][CH3:16])[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[CH3:17]
Reactant: COc1cc2c(cc1Br)C(=O)CCC2(C)C
Reactant: C[Mg+]
Agent: [Br-]
Product: COc1cc2c(cc1Br)C(C)=CCC2(C)C
Yield: 94 %

Procedure:
Following General Procedure A 7-bromo-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 92, 1.0 g, 3.5 mmol) was reacted with MeMgBr to give 0.93 g (94%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:15][CH:16]([CH3:39])[CH:17]([NH:22][C:23]([C:25]1[S:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=2)[N:29]=1)=[O:24])[C:18]([O:20][CH3:21])=[O:19]>>[CH3:15][CH:16]([CH3:39])[CH:17]([NH:22][C:23]([C:25]1[S:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:10](=[O:11])[C:9]3[CH:13]=[CH:14][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=3)=[CH:32][CH:31]=2)[N:29]=1)=[O:24])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3csc(C(=O)NC(C(=O)OC)C(C)C)n3)cc2)cc1
Yield: 56 %

Procedure:
The title compound was synthesized analogous to Example 27, using 4-pentylbenzoyl chloride and intermediate 3. Yield: 56%; 1H NMR (DMSO-d6, 300 MHz): δ 10.32 (s, 1H), 8.84 (d, 1H), 8.37 (s, 1H), 8.12 (d, 2H), 7.91 (bs, 4H), 7.37 (d, 2H), 4.37 (t, 1H), 3.70 (s, 3H), 2.66 (s, 2H), 2.32 (m, 1H), 1.61 (s, 2H), 1.29 (s, 4H), 0.98 (t, 6H), 0.87 (s, 3H).