Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][OH:15])[C:6](=[O:16])[N:5]([CH3:17])[C:4]=2[N:3]=1.I[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:10]([CH2:19][CH3:20])[C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][OH:15])[C:6](=[O:16])[N:5]([CH3:17])[C:4]=2[N:3]=1
Reactant: CCI
Reactant: Cn1c(=O)n(CCCO)c(=O)c2[nH]c(Br)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(Br)nc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 50 °C
Yield: 91.5 %

Procedure:
To a solution of 8-bromo-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.4 g, 1.32 mmol, product of intermediate 16 step 2) in DMF (10 mL) was added iodoethane (0.25 g, 1.58 mmol) and potassium carbonate (0.27 g, 1.98 mmol). The reaction was heated at 50° C. for 2 h. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give 8-bromo-7-ethyl-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.4 g, 91.7% yield) as white solid. LCMS retention time 1.674 min; LCMS MH+ 331.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[Si:17]([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:8][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: Oc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)Oc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 21 h
Yield: 97 %

Procedure:
A dry 5 1, 3-neck flask with mechanical stirrer, connected to a mineral oil bubbler, was charged with m-bromophenol (A) (150 g, 870 mmol), dry tetrahydrofuran (THF, 2 l) and triethylamine (132.1 g, 1.3 mol). The contents of the flask were cooled to 0° C., and chlorotrimethylsilane was added dropwise. A voluminous white precipitate was formed. The reaction was allowed to equilibrate to room temperature over a period of 21 h. The mixture was then filtered to remove triethylamine hydrochloride. Removal of solvents precipitated some remaining hydrochloride salt. The mixture was further purified by repeatedly adding hexane followed by filtration to yield 3-bromo-O-trimethylsilylphenol (B) (207 g, 97% yield).
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:36]=[CH:35][C:16]([CH2:17][S:18][CH:19]([S:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[CH:15][CH:14]=1.CCOCC.Cl>C(Cl)(Cl)Cl>[ClH:1].[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][S:18]([CH:19]([S:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[O:9])=[CH:35][CH:36]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(CSC(Cn2ccnc2)SCc2ccc(C)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(CSC(Cn2ccnc2)S(=O)Cc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 85% m-chloroperbenzoic acid (1.66 g, 9.63 mmoles) in chloroform (80 ml) was added dropwise during 1 hour to a stirred, cooled (ice/water) solution of 1-[2,2-bis(4-methylbenzylthio)ethyl]-1H-imidazole (3.55 g, 9.63 mmoles) in chloroform (125 ml). The solution was stirred for 18 hours at ambient temperature and then washed successively with aqueous Na2CO3 (2×), H2O and brine. The solution was dried over Na2SO4 and concentrated to leave a mixture of the diastereoisomeric mono-sulfoxides as a cloudy oil. Trituration of the oil with ether afforded the free base of diastereomer A (1.45 g), mp 86°-92° which was converted into the hydrochloride salt, mp 167°-170° with ethereal hydrogen chloride. Hydrogen chloride was bubbled into the ethereal mother liquor from the trituration step to give a mixture of the hydrochloride salts which after recrystallization from acetonitrile provided additional diastereomer A, mp 164°-168° (0.42 g) and 0.57 g of diastereomer B, mp 141°-146°.
Reaction SMILES: C([N:8]1[CH2:15][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]2([CH2:13][CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:13]1[C:10]2([C@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:15][NH:8][CH2:9]2)[CH2:11][CH2:12]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)CC12CCC2
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CNCC12CCC2
Reaction time: 4 h

Procedure:
A stirred solution of (S)-tert-butyl (6-benzyl-6-azaspiro[3.4]octan-8-yl)carbamate (enantiopure Intermediate 13, 0.364 g, 1.149 mmol) in Ethanol (21.3 mL) with Pd/C (10% b/w) (0.291 g, 2.73 mmol), was charged with hydrogen gas @ 50 psi in a pressure bottle and agitated for 4 hrs. +/−MS analysis after 3 hrs 15 min indicated that essentially no starting material remained (m/e 227.2, M+H for desired product). The catalyst was removed by filtration, and the filtrate was concentrated under vacuum to yield 0.247 g of the desired product as a tan oil. +/−MS: m/e 227.2 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.66 (br. s., 1H), 3.96 (br. s., 1H), 3.24 (dd, J=11.3, 6.1 Hz, 1H), 3.05 (d, J=11.0 Hz, 1H), 2.89 (d, J=11.2 Hz, 1H), 2.72 (dd, J=11.6, 3.4 Hz, 1H), 2.13 (dd, J=9.6, 3.4 Hz, 3H), 2.04-1.71 (m, 5H), 1.46 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([CH2:16][OH:17])[CH:15]=[C:5]2[C:4]1=[O:18])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([CH:16]=[O:17])[CH:15]=[C:5]2[C:4]1=[O:18])[CH3:2]
Reactant: CCn1c(=O)c2cc(CO)cn2c2ccccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCn1c(=O)c2cc(C=O)cn2c2ccccc21
Yield: 78.8 %

Procedure:
A mixture of 40 g of activated manganese dioxide and a solution of 5.0 g (20.6 mmole) of the product of Example 24 in 500 ml of chloroform was vigorously stirred for 3 hours and was then filtered through celite. The filtrate was evaporated to dryness and the residue was triturated with ether to obtain 3.9 g (80% yield) of 4,5-dihydro-5-ethyl-4-oxopyrrolo-[1,2-a]-quinoxaline-2-carboxaldehyde in the form of colorless needles melting at 252°-255° C.
Reaction SMILES: [F:1][C@H]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)OC1.N[C:27]1[S:31][C:30]([C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2F)=[N:29][C:28]=1[C:40]([NH:42][C:43]1[CH:44]=[N:45][N:46]([CH3:57])[C:47]=1[CH:48]1[CH2:54][CH2:53][C@@H:52]([NH2:55])[C@@H:51]([F:56])[CH2:50][O:49]1)=[O:41]>>[NH2:55][C@H:52]1[C@H:51]([F:56])[CH2:50][O:49][C@H:48]([C:47]2[N:46]([CH3:57])[N:45]=[CH:44][C:43]=2[NH:42][C:40]([C:28]2[N:29]=[C:30]([C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([F:1])[C:37]=3[F:38])[S:31][CH:27]=2)=[O:41])[CH2:54][CH2:53]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CC[C@@H](N)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3cccc(F)c3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(2,3-difluorophenyl)thiazole-4-carboxylic acid (Intermediate 119) gave 306. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.59 (s, 1H), 8.28-8.21 (m, 1H), 7.87 (s, 1H), 7.68-7.58 (m, 1H), 7.44-7.36 (m, 1H), 4.88 (dd, J=10.5, 3.5 Hz, 1H), 4.67-4.49 (m, 1H), 4.41-4.29 (m, 1H), 4.20-4.03 (m, 2H), 3.79 (s, 3H), 3.45-3.35 (m, 1H), 2.15-2.05 (m, 1H), 1.91-1.73 (m, 3H). LCMS (ES+) m/z 452 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[C:3]=1[N+:12]([O-:14])=[O:13].CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:23])=[O:7])=[C:4]([F:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1F
Reaction time: 2 h

Procedure:
To 4-chloro-2-fluoro-3-nitro-benzoic acid (5.0 g, 22.8 mmol) suspended in dry DCM (60 mL), was added DMF (0.5 mL) followed by the slow addition of oxalyl chloride (2.4 mL, 27.3 mmol, 2M in DCM). The mixture was stirred for 2 hrs, then concentrated to yield 4-chloro-2-fluoro-3-nitro-benzoyl chloride as a yellow solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:21]=[CH:20][C:8]([O:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Na].[CH3:23][O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][S:36]([C:38]2[NH:42][C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[N:39]=2)=[O:37])[C:30]=1[CH3:47]>ClCCl.C(N(CC)CC)C>[CH3:23][O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][S:36]([C:38]2[N:39]([S:2]([C:5]3[CH:21]=[CH:20][C:8]([O:9][CH2:10][C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)=[O:12])=[CH:7][CH:6]=3)(=[O:4])=[O:3])[C:40]3[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=3[N:42]=2)=[O:37])[C:30]=1[CH3:47]
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Reactant: O=C(COc1ccc(S(=O)(=O)Cl)cc1)Nc1ccccn1
Agent: [Na]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2ccc(OCC(=O)Nc3ccccn3)cc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
170 mg of 2-[p-(chlorosulfonyl)phenoxy]-N-(2-pyridyl)acetamide was added to 191 mg of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole sodium salt in dichloromethane (15 ml) and triethylamine (0.1 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water. Organic layer was dried over anhydrous magnesium sulfate, and evaporated. Residual material was lyophilized in vacuo to give 244 mg of the titled product.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5])[CH3:2].[Cl:21][S:22](O)(=[O:24])=[O:23]>ClCCl>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[S:8][C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[C:17]([S:22]([Cl:21])(=[O:24])=[O:23])[CH:18]=2)=[C:10]([CH3:12])[N:11]=1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCNC(=O)Nc1nc(C)c(-c2ccc(OC)cc2)s1
Solvent: ClCCl
Product: CCNC(=O)Nc1nc(C)c(-c2ccc(OC)c(S(=O)(=O)Cl)c2)s1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
A suspension of 1-ethyl-3-[5-(4-methoxy-phenyl)-4-methyl-thiazol-2-yl]urea (Example 28c) (1.0 g, 3.44 mmol) in dichloromethane (15 ml) is added portionwise to chlorosulfonic acid (25 ml, excess) cooled at −10° C. The temperature is kept below 0° C. throughout the addition. The reaction mixture is left to warm up to room temperature. After 3 hours, the reaction mixture is poured carefully onto ice (2 litres). Once ice is melted, the aqueous layer is extracted with dichloromethane (DCM) (3×200 ml). The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated to afford 5-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy benzenesulfonylchloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[C:28](O)=[O:29])[CH:21]=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:28]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:27]=2[N:18]=[CH:19][CH:20]=[CH:21]3)=[O:29])[CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc2cccnc12
Reactant: CCCC[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC[C@H]1CN(C(=O)c2cccc3cccnc23)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step A, except using 1-tert-butoxycarbonyl-2(S)-n-butyl-piperazine (0.261 g, 1.078 mmol), 8-quinoline carboxylic acid (0.187 g, 1.078 mmol), EDC.HCl (0.217 g, 1.13 mmol), HOBT (0.157g, 1.02 mmol) in DMF at pH 7 (adjusted with triethylamine). The crude product was chromatographed on silica gel with 5% methanol in chloroform. The title compound was obtained as an oil (0.253 g).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[Cl:36][C:37]1[N:42]=[C:41](B(O)O)[CH:40]=[CH:39][CH:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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>[Cl:36][C:37]1[N:42]=[C:41]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][C:14]([NH:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=5)=[N:13][N:12]=4)[CH:9]=3)[N:4]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH:3]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Reactant: OB(O)c1cccc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Temperature: 85 °C
Yield: 53.5 %

Procedure:
To the solution of 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (1.0 g, 1.66 mmol) and 6-chloropyridin-2-ylboronic acid (0.392 g, 2.49 mmol) in DMF (10 mL) was added K3PO4 (0.704 g, 3.32 mmol) and this solution was purged under N2 for 15 min. Then Pd(PPh3)4 (0.176 g, 0.152 mmol) was added and the reaction was heated at 85° C. for 5 h. The solution was poured in ice cold water (50 mL) and extracted with EtOAc. The combined organic layers were washed with H2O, dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 15% EtOAc in Hex) to give 5-(3-(6-chloropyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (0.52 g, 53.3%) as a brown solid. MS (ESI, pos. ion) m/z: 586 (M+1); 1H NMR (DMSO-d6, 300 MHz): δ ppm 8.94 (s, 1H), 8.79 (s, 1H), 8.16-8.14 (m, 2H), 8.03-7.97 (m, 4H), 7.67-7.55 (m, 1H), 7.49-7.42 (m, 3H), 7.34 (d, J=8.4 Hz, 2H), 6.9 (d, J=8.1 Hz, 2H), 4.38 (s, 2H), 3.72 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]O.S(Cl)([Cl:15])=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][Cl:15]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CO)cc1OC
Solvent: ClCCl
Product: COc1ccc(CCl)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
In a nitrogen atmosphere, 5 g (29.73 mmol.) of 3,4-dimethoxybenzyl alcohol was dissolved in 25 ml of dichloromethane. The obtained solution was placed in an ice-bath, and to this was dropwise added a solution of 2.16 ml (29.74 mmol.) of thionyl chloride in 5 ml of methylene chloride. The mixture was then stirred at room temperature for 1 hour. The mixture was placed under reduced pressure at room temperature to distill off the solvent to give 5.624 g of the desired compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[O:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[N:7]2.C(N(CC)CC)C.[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH:31]=[CH2:32].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:27][O:28][C:29](=[O:33])[CH2:30]/[CH:31]=[CH:32]/[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[O:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[N:7]2
Reactant: Cc1ccc(CNc2ccc3c(Br)cccc3n2)o1
Reactant: C=CCC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C/C=C/c1cccc2nc(NCc3ccc(C)o3)ccc12
Temperature: 120 °C

Procedure:
(5-Bromo-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine (400 mg, 1.3 mmol) was dissolved in 4 mL N,N-dimethylformamide. Triethylamine (167 mg, 1.7 mmol), methyl-3-butenoate (173 mg, 1.7 mmol), tri-ortho-tolylphosphin (31 mg, 0.1 mmol) and palladium acetate (11 mg, 0.05 mmol) were added. The reaction mixture was heated at 120° C. for 1 hour and quenched by addition of 50 mL water. The mixture was extracted three times with ethyl acetate (100 mL each). The organic phases were pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->75:25 gradient). (E)-4-{2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinolin-5-yl}-but-3-enoic acid methyl ester was obtained as a yellow oil (294 mg, 69%), MS: m/e=337.4 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7](O)(=[O:10])[CH2:8][CH3:9].[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH3:35])[C:19]2[O:25][C:24]3[C:26]([Cl:31])=[CH:27][C:28]([NH2:30])=[CH:29][C:23]=3[CH2:22][S:21](=[O:33])(=[O:32])[C:20]=2[CH:34]=1)=[O:15]>ClCCl.CN(C=O)C>[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH3:35])[C:19]2[O:25][C:24]3[C:26]([Cl:31])=[CH:27][C:28]([NH:30][C:7](=[O:10])[CH2:8][CH3:9])=[CH:29][C:23]=3[CH2:22][S:21](=[O:33])(=[O:32])[C:20]=2[CH:34]=1)=[O:15]
Reactant: CCC(=O)O
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1O2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(=O)Nc1cc(Cl)c2c(c1)CS(=O)(=O)c1cc(C(=O)OC)cc(C)c1O2
Reaction time: 18 h

Procedure:
A solution of oxalyl chloride (0.17 mL, 2.03 mmol) and propionic acid (0.15 mL, 2.03 mmol) in dichloromethane (20 mL) was stirred for 1 h. Compound of Example 1 (0.5 g, 1.35 mmol) in DMF (5 mL) was added to the reaction mixture at 25° C. and stirred for 18 h. The solvent was removed under vacuum, water (25 mL) was added and the solid precipitated was filtered. The crude product was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 0.28 g, (60%); mp: 226-228° C.; 1H NMR (DMSO-d6, 300 MHz): δ 1.06 (t, 3H, CH3), 2.33 (q, 2H, CH2), 2.64 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 5.30 (s, 2H, CH2), 7.66 (d, 1H, Ar), 7.88 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.15 (s, 1H, Ar), 10.26 (s, 1H, NH); MS: m/e (EI) 423 (M+); analysis: C19H18ClNO6S requires C, 53.66; H, 4.28; N, 3.30; Cl, 8.32; S, 7.56. found: C, 53.38; H, 4.27; N, 3.48; Cl, 8.64; S, 7.75%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[CH3:13][O:14][C:15](=[O:55])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=3)[N:27]([CH:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:26]=2[CH2:48][CH2:49][OH:50])=[CH:18][C:17]=1[O:51][CH:52]([CH3:54])[CH3:53]>ClCCl>[CH3:13][O:14][C:15](=[O:55])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=3)[N:27]([CH:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:26]=2[CH2:48][CH2:49][O:50][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:18][C:17]=1[O:51][CH:52]([CH3:53])[CH3:54]
Reactant: COC(=O)c1ccc(OCCc2c(CCO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCCc2c(CCOS(C)(=O)=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Methane sulfonyl chloride (0.03 mL, 0.39 mmol) and Et3N (0.06 mL, 0.43 mmol) were added to a solution of the alcohol from Step 4 (0.10 g, 0.17 mmol) in dichloromethane (8 mL) at 0° C. Reaction was stirred at 0° C. for one hour and then warmed to room temperature and stirred an additional hour. Reaction solution was concentrated by rotary evaporation. Obtained 0.115 g of 4-{2-[1-Benzhydryl-5-chloro-2-(2-methanesulfonyloxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-isopropoxy-benzoic acid methyl ester in quantitative yield.
Reaction SMILES: [CH3:1][Si:2]([CH3:50])([CH3:49])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH2:29][CH:30]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]2)[CH:9]=1.[Br:51]N1C(=O)CCC1=O>C(#N)C>[CH3:46][Si:45]([CH3:48])([CH3:47])[CH2:44][CH2:43][O:42][CH2:41][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:49])[CH3:50])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH2:29][CH:30]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]2)[C:9]=1[Br:51]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Solvent: CC#N
Product: CCOC(=O)C1CCC(Cc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 20 mL scintillation vial was charged ethyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarboxylate (Int-4l, 265 mg, 0.37 mmol) and N-bromosuccinimide (80 mg, 0.45 mmol). To this was added acetonitrile (5 mL). The resulting solution was stirred at room temperature for 18 hours. At 18 hours, the reaction was reduced in vacuo and the residue was purified via silica gel chromatography to yield the title compound as yellow oil. Yield=255 mg.
Reaction SMILES: Br[C:2]1([CH3:19])[O:6][C:5]([CH3:17])([C:7]23[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]4)[CH2:8]2)[CH2:14]3)[O:4][C:3]1=[O:18].C1CCN2C(=NCCC2)CC1>C(OC(C)C)(C)C>[CH2:19]=[C:2]1[O:6][C:5]([C:7]23[CH2:14][CH:13]4[CH2:15][CH:9]([CH2:10][CH:11]([CH2:12]4)[CH2:16]2)[CH2:8]3)([CH3:17])[O:4][C:3]1=[O:18]
Reactant: CC1(Br)OC(C)(C23CC4CC(CC(C4)C2)C3)OC1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)OC(C)C
Product: C=C1OC(C)(C23CC4CC(CC(C4)C2)C3)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.7 %

Procedure:
16.5 g (0.05 mol) of 5-bromo-2,5-dimethyl-2-(1-adamantyl)-1,3-dioxolan-4-one was placed in a 500 ml egg-plant type flask, and 200 g of isopropyl ether was added thereto and dissolved therein. While cooling with a refrigerant of −10° C., 9.1 g (0.06 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene diluted with 20 g of isopropyl ether was added by drops into the solution over 1 hour, followed by stirring at room temperature for 2 hours. After completion of the stirring, the reaction solution was analyzed. As a result, it was found that the reaction solution contained only 1.7 g of 5-methylene-2-(1-adamantyl)-2-methyl-1,3-dioxolan-4-one (yield: 14%) and that 80% of the raw materials was decomposed into adamantyl methyl ketone.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:18])=[CH:15]/[CH:16]=[O:17])[CH:5]=[CH:4][C:3]1=2.[Br:20]Br.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[Br:20]/[C:15](=[C:14](/[C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:19])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)\[CH3:18])/[CH:16]=[O:17]
Reactant: BrBr
Reactant: C/C(=C\C=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C/C(=C(\Br)C=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -75 °C
Reaction time: 0.17 h

Procedure:
2.86 g of (E)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-but-2-enal were dissolved in 16 ml of CH2Cl2 and cooled to -75° C. 1.1 eq. of Br2 (0.63 ml), dissolved in 3 ml of CH2Cl2, was added drop by drop and the mixture kept for 10 minutes at this temperature. TLC indicated the formation of the dibromide. 4.98 ml of DBU was then added all at once and the temperature raised to 0° C. After 1/2 hour the reaction mixture was poured onto crushed ice/HCl, extracted with EtOEt, washed twice with brine, dried over Na2 SO4 and the solvents removed i.V. Flash chromatography (silica gel, hexane/AcOEt=96:4) yielded 0.95 g of the labile (E)-2-bromo-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-but-2-enal as yellow crystals of m.p. 115°-117° C. Double bond geometry was proven by NOE.