Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2([C:18]3=[C:19]4[C:24](=[N:25][C:17]3=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH2:15]3)[NH:10]2)[CH:23]=[CH:22][CH:21]=[CH:20]4)[CH2:6][CH2:5]1)(=O)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>C1COCC1.CO.C(Cl)Cl>[CH2:1]([N:4]1[CH2:5][CH2:6][C:7]2([C:18]3=[C:19]4[C:24](=[N:25][C:17]3=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH2:15]3)[NH:10]2)[CH:23]=[CH:22][CH:21]=[CH:20]4)[CH2:8][CH2:9]1)[CH3:2]
Reactant: CC(=O)N1CCC2(CC1)NC1=CC=CCC1=C1N=c3ccccc3=C12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CCN1CCC2(CC1)NC1=CC=CCC1=C1N=c3ccccc3=C12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
A solution of 7.5 g of 1'-acetyl-5,6-dihydrospiro-[1H-indolo-[3,2-c]quinoline-6,4'-piperidine] in 60 ml of THF was added dropwise to 45 ml of 1M LiAlH4 /THF. The solution was stirred at room temperature for 30 minutes and thereafter quenched with NH4Cl, filtered through celite and concentrated to give 9.2 g of crude product. Flash chromatography using 7% CH3OH/CH2Cl2 as an eluent gave 3.5 g of solid, m.p. 238°-240° dec.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[H-].[Na+].[CH3:24]I>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:24]
Reactant: CI
Reactant: CC(=O)c1cc(Cl)c2cn[nH]c2c1-c1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Cl)c2cnn(C)c2c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
To a mixture of 1-[4-chloro-7-(3,5-difluorophenyl)-1H-indazol-6-yl]ethanone (1.0 g, 3.3 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (200 mg, 4.9 mmol). After being stirred at room temperature for 30 minutes, to the resulting mixture was added methyl iodide (0.30 mL, 4.9 mmol). The reaction was stirred at room temperature for another 30 minutes, then quenched with sat. ammonium chloride and extracted with Ethyl acetate. The combined organic layers were washed with water, brine and dried over sodium sulfate, then concentrated to dryness under reduced pressure. The residue was purified on silica gel, eluting with 0 to 30% ethyl acetate in hexane, to give the desired product (0.438 g, 42%). LCMS calculated for C16H12ClF2N2O (M+H)+: m/x=321.1; Found: 321.0. The other isomer, 1-[4-chloro-7-(3,5-difluorophenyl)-2-methyl-2H-indazol-6-yl]ethanone, was also isolated in a yield of 47%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH2:31][O:32][CH2:33][CH2:34][OH:35])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:36]1[CH:40]=[CH:39][C:38]([C:41](O)=[O:42])=[CH:37]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:16]=[CH:17][N:18]=[C:19]([CH2:31][O:32][CH2:33][CH2:34][O:35][C:41]([C:38]3[CH:39]=[CH:40][O:36][CH:37]=3)=[O:42])[C:20]=2[O:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[Cl:30])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)c(Oc2c(COCCO)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: O=C(O)c1ccoc1
Product: COc1ccc(Cl)c(Oc2c(COCCOC(=O)c3ccoc3)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
By reacting 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy-methyl)-pyrimidin-4-yl]-benzenesulphonamide with 3-furancarboxylic acid there was obtained furan-3-carboxylic acid 2-[6-(4-tert-butyl-phenylsulfonylamino)-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-ylmethoxy]-ethylester. MS: (M+H)+=618.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([CH3:13])[C:9]=1[O:10][CH2:11][CH3:12])[NH2:6])[CH3:2].[C:14](Cl)(Cl)=[O:15].[CH:18]([OH:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:6][C:14](=[O:15])[O:21][CH:18]([CH3:20])[CH3:19])[CH:7]=[C:8]([CH3:13])[C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CC(C)O
Reactant: O=C(Cl)Cl
Reactant: CCOc1c(C)cc(N)cc1CC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOc1c(C)cc(NC(=O)OC(C)C)cc1CC
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
A mixture of 3-ethyl-4-ethoxy-5-methylaniline (1.8 g) in toluene (20 ml) was dropwise added to a toluene solution containing 10 g of phosgene at 10° to 20° C. The resulting mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation under reduced pressure to gove 3-ethyl-4-ethoxy-5-methylphenyl isocyanate (2.1 g). The thus obtained crude substance was added to an isopropanol solution (20 ml) containing triethylamine (1 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with toluene. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene as the eluent to give isopropyl N-(3-ethyl-4-ethoxy-5-methylphenyl)carbamate (Compound No. 93) (2.4 g) in a yield of 91% (calculated from the starting 3-ethyl-4-ethoxy-5-methylaniline). M.P., 68°- 69.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13](I)[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2].[F:21][C:22]([F:33])([F:32])[C:23]([F:31])([F:30])[C:24]([F:29])([F:28])C([O-])=O.[K+].C1(C)C=CC=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13]([C:24]([F:29])([F:28])[C:23]([F:31])([F:30])[C:22]([F:33])([F:32])[F:21])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)C(F)(F)F)cc21

Procedure:
The procedure of Preparation Example 1 (6) was repeated using 2,2-bisfluoromethyl-6-iodo-2H-1-benzopyran-4-carboxylic acid ethyl ester, potassium heptafluorobutyrate, cuprous iodide, toluene and N,N-dimethylformamide to give 2,2-bisfluoromethyl-6-heptafluoropropyl-2H-1-benzopyran-4-carboxylic acid ethyl ester as an oil;
Reaction SMILES: [CH2:1]([CH:21](CCC(CCCC(CCCC(CCCC(C)C)C)C)C)[OH:22])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].Cl.CN(C)CCCC(O)=O.C(Cl)CCl.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([CH2:21][OH:22])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCC(O)CCC(C)CCCC(C)CCCC(C)CCCC(C)C
Agent: CN(C)CCCC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCO
Yield: 87.3 %

Procedure:
To a solution of diphytanyl methanol (6.4 g, 10.3 mmol) and 4-(dimethylamino) butyric acid hydrochloride (2.25 g, 13.4 mmol) in anhydrous dichloromethane (60 mL) under nitrogen at room temperature was added EDC (2.77 g, 18.0 mmol), diisopropylethylamine (5.4 mL, 31.0 mmol), and 4-dimethylaminopyridine (45 mg, 0.37 mmol). After 16 hours the reaction mixture was diluted with dichloromethane (75 mL). The organic layer was washed with saturated NaHCO3, water, and brine, and then dried on MgSO4, filtered, and concentrated. The resulting yellow oil was purified by column chromatography (column 10″L×2″W; eluted with a gradient of 100% hexanes→10%→50% ethyl acetate in hexanes) to afford the product as a pale yellow oil (3.53 g, 49%) with recovery of some phytanyl methanol (2.81 g, 44%).
Reaction SMILES: [Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:7]([CH2:9][CH2:10][CH2:11][CH:12]=O)=[N:8][C:4]=2[CH:3]=1.[CH3:25][C:26]1([CH3:52])[O:30][C@@H:29]2[C@@H:31]([CH2:47][NH:48][CH:49]([CH3:51])[CH3:50])[CH2:32][C@@H:33]([N:34]3[C:38]4[N:39]=[CH:40][N:41]=[C:42]([NH:43][CH:44]5[CH2:46][CH2:45]5)[C:37]=4[CH:36]=[CH:35]3)[C@@H:28]2[O:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:21])[CH3:20])[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:48]([CH2:47][C@@H:31]3[C@H:29]4[O:30][C:26]([CH3:52])([CH3:25])[O:27][C@H:28]4[C@H:33]([N:34]4[C:38]5[N:39]=[CH:40][N:41]=[C:42]([NH:43][CH:44]6[CH2:46][CH2:45]6)[C:37]=5[CH:36]=[CH:35]4)[CH2:32]3)[CH:49]([CH3:50])[CH3:51])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)NC[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reactant: C[Si](C)(C)CCOCn1c(CCCC=O)nc2cc(Cl)c(Cl)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)N(CCCCc1nc2cc(Cl)c(Cl)cc2n1COCC[Si](C)(C)C)C[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reaction time: 0.25 h
Yield: 74 %

Procedure:
4-(5,6-Dichloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)butanal (0.285 g, 0.735 mmol) and 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-[(propan-2-ylamino)methyl]-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.270 g, 0.700 mmol) were dissolved in DCE (17 ml) at r.t. under N2 and left for 15 mins. Sodium triacetoxyborohydride (0.208 g, 0.981 mmol) was added and the reaction left overnight. The reaction was quenched by the addition of sat. Na2CO3 solution (20 ml) and DCM (20 ml). The organic layer was separated and the aqueous layer was extracted with DCM (3×20 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the crude product. The product was purified by flash column chromatography using between 100% DCM to 15% MeOH:85% DCM as eluent to give the product as a white foam (0.392 g, 74%): MS (ESI+) for C38H55Cl2N7O3Si m/z 379.2 [M+H]2+, 756.4 [M+H]+; LC purity 100% (ret. time, 1.76 min); 1H NMR (500 MHz, CDCl3) δ 8.29 (s, 1H), 7.78 (s, 1H), 7.50 (s, 1H), 6.98 (d, J=3.63 Hz, 1H), 6.63 (br. s., 1H), 5.47 (br. s., 1H), 5.40 (s, 2H), 4.86-5.04 (m, 2H), 4.47 (br. s., 1H), 3.45-3.56 (m, 2H), 2.94-3.04 (m, 2H), 2.91 (t, J=7.72 Hz, 2H), 2.67 (br. s., 1H), 2.24-2.59 (m, 5H), 2.03 (br. s., 1H), 1.82-1.95 (m, 2H), 1.59 (br. s., 2H), 1.55 (s, 3H), 1.28 (s, 3H), 0.99 (br. s., 5H), 0.84-0.96 (m, 5H), 0.65-0.74 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([C:8]2[S:19][C:11]3[N:12]=[C:13]([CH3:18])[N:14]=[C:15]([CH2:16][OH:17])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:21][S:22]([O:17][CH2:16][C:15]1[C:10]2[CH:9]=[C:8]([CH:5]3[CH2:6][CH2:7][C:2]([CH3:20])([CH3:1])[CH2:3][CH2:4]3)[S:19][C:11]=2[N:12]=[C:13]([CH3:18])[N:14]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(CO)c2cc(C3CCC(C)(C)CC3)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(COS(C)(=O)=O)c2cc(C3CCC(C)(C)CC3)sc2n1
Reaction time: 1 h

Procedure:
To a mixture of [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (16.0 g), TEA (10 mL) and DCM (200 mL) was added dropwise MsCl (5.0 mL) at 0° C. for 15 minutes, followed by stirring at the same temperature for 1 hour. To the reaction mixture was added saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate and brine. To the organic layer were added MgSO4, activated carbon (5 g), and basic silica gel (20 mL), followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure to obtain [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl methanesulfonate (18.9 g).
Reaction SMILES: S=[C:2]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][NH:3]1.[F:13][C:14]([F:20])([F:19])[C:15]([NH:17][NH2:18])=O>C1COCC1.[Hg](OC(C)=O)OC(C)=O>[F:13][C:14]([F:20])([F:19])[C:15]1[N:3]2[CH2:4][CH2:5][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][C:2]2=[N:18][N:17]=1
Reactant: NNC(=O)C(F)(F)F
Reactant: CCOC(=O)C1CCNC(=S)C1
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCn2c(nnc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of ethyl 2-thioxopiperidine-4-carboxylate (5.7 g, 14.95 mmol) in THF (203 mL) was added 2,2,2-trifluoroacetohydrazide (7.8 g, 60.88 mmol) and Hg(OAc)2 (10.71 g, 33.48 mmol) at ice-water. The mixture was stirred at room temperature for 2 hours and heated at 60° C. for overnight, then filtered. Removed the solvent under reduced pressure and the filtrate was concentrated and purified by silica gel column chromatography (PE/EA=3/1) to afford ethyl 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylate (3.5 g, yield 43.8%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.10-1.32 (m, 3H) 2.16 (br. s., 1H) 2.36 (br. s., 1H) 2.93 (br. s., 1H) 3.02-3.39 (m, 2H) 3.90-4.30 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([S:47][CH2:48][CH3:49])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:46])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[C:40]([O:41][CH3:42])=[CH:39][C:29]3[C:30](=[O:38])[N:31]4[CH2:37][CH2:36][CH2:35][C@H:32]4[CH2:33][NH:34][C:28]=3[CH:27]=2)=[CH:13][C:12]=1[N+:43]([O-])=O)[CH3:2].CO.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([O:3][CH:4]([S:47][CH2:48][CH3:49])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:46])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[C:40]([O:41][CH3:42])=[CH:39][C:29]3[C:30](=[O:38])[N:31]4[CH2:37][CH2:36][CH2:35][C@H:32]4[CH2:33][NH:34][C:28]=3[CH:27]=2)=[CH:13][C:12]=1[NH2:43])[CH3:2]
Reactant: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1N

Procedure:
The (2S)-N-{4-[4-(7-methoxy-(2R)-hydroxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy)butoxy]-5-methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal (718 mg, 1.0 mmol) of the formula III was dissolved in dichloromethane (5 mL), methanol (10 mL) and added SnCl2.2H2O (1.124 g, 5.0 mmol) was refluxed for 1.5 h. The reaction mixture was then carefully adjusted to pH 8 with saturated NaHCO3 solution and then extracted with ethyl acetate (3×20 mL). The combined organic phase was dried over Na2SO4 and evaporated under vacuum to afford the crude (2S)-N-{4-[4-(7-Methoxy-(2R)-hydroxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-5-one-8-yloxy)butoxy]-5-methoxy-2-aminobenzoyl}-pyrrolidine-2-carboxaldehyde diethyl thioacetal IV.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([F:19])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.C(O)C.[H][H]>[Pd].C1COCC1>[F:19][C:12]1[CH:11]=[C:10]([O:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)[CH:15]=[CH:14][C:13]=1[NH2:16]
Reactant: CSc1nccc(Oc2ccc([N+](=O)[O-])c(F)c2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1nccc(Oc2ccc(N)c(F)c2)n1
Yield: 39.2 %

Procedure:
A mixture of 570 mg (2.03 mmol) 2-methylsulfanyl-4-(3-fluoro-4-nitrophenoxy)-pyrimidine, 10 ml ethanol, 10 ml THF, and 200 mg 10% palladium/C is hydrogenated at 50 mbar hydrogen pressure at r.t. for 8 h. The catalyst was removed by filtration, washed with 10 ml ethanol and evaporated. The residue was purified by chromatography on silica (ethyl acetate/n-heptane 1:2) to give 200 mg (39%) 2-fluoro-4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenylamine.
Reaction SMILES: C(O)(=O)C.[C:5]([C:8]1[CH:32]=[CH:31][C:11]([O:12][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)(=[NH:7])[NH2:6].C([O-])(O)=O.[Na+].Cl[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>C(Cl)Cl>[CH2:42]([O:41][C:39]([NH:7][C:5]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:31][CH:32]=1)=[NH:6])=[O:40])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CCOc1cc(C(Oc2ccc(C(=N)N)cc2)C(=O)OC)ccc1OC(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOc1cc(C(Oc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)OC)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a suspension of 9C (570 mg, 1.12 mmol) in CH2Cl2 (12 mL) was added 1.0 M NaHCO3 (11.2 mL, 11.2 mmol), followed by benzyl chloroformate (0.22 mL, 1.5 mmol) in CH2Cl2 (3.0 mL). The mixture was stirred at rt for 30 min. TLC indicated some 9C still present. Another portion of benzyl chloroformate (0.1 mL, 0.84 mmol) in CH2Cl2 (3.0 mL) was added. After stirring at rt for 1.0 h, the reaction was quenched with ammonium hydroxide (0.65 mL), and extracted with CH2Cl2. The organic extract was washed with brine and dried over Na2SO4. After removal of the solvent, the crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (1:1) to give 9D (570 mg, 73% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (d, J=6.16 Hz, 6H) 1.38 (t, J=7.03 Hz, 3H) 3.71 (s, 3H) 4.04 (q, J=7.03 Hz, 2H) 4.46 (m, 1H) 5.18 (s, 2H) 5.58 (s, 1H) 6.85 (d, J=8.8 Hz, 1H) 6.90 (d, J=8.35 Hz, 2H) 7.09 (m, 2H) 7.20-7.40 (m, 6H), 7.82 (d, J=9.20 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20](O)=[O:21])=[CH:14]3)=[O:10])[CH2:4]1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.Cl.C(N=C=NCCCN(C)C)C>>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:21])=[CH:14]3)=[O:10])[CH2:4]1
Reactant: C1COCCN1
Reactant: CN(C)C1CCCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CN(C)C1CCCN(C(=O)c2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)C1

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(3-dimethylamino-piperidine-1-carbonyl)-1H-indole-2-carboxylic acid, morpholine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as an off-white solid (37%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]2[CH:11]=[CH:12][CH:13]=[C:6]12)=[O:4].[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([C:19](=[O:20])[C:18]3[CH:22]=[CH:23][C:15]([F:14])=[CH:16][CH:17]=3)=[CH:12][CH:13]=[C:6]12)=[O:4]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=O)C1CCCn2cccc21
Solvent: Cc1ccccc1C
Product: COC(=O)C1CCCn2c(C(=O)c3ccc(F)cc3)ccc21

Procedure:
A solution of methyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate (2.0 g., 0.01 moles) in dry xylene (30 ml.) containing 4-fluorobenzoyl chloride (4.5 g., 0.028 moles) is heated at reflux temperature in a nitrogen atmosphere for 20 hours. The solvent is removed in vacuo and the residue is purified by t.l.c. on silica gel using hexane-ethyl acetate (3:1) as the developing solvent. Removal of the solvent gives methyl-3-p-fluorobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate which, when crystallized from acetone-hexane exhibits a m.p. of 78°-79° C.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][CH2:9]Br)[C:3]([O:5][CH3:6])=[O:4].[OH:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[K+].[K+].[C:28]([O-:31])(=[S:30])[CH3:29].[K+]>CN(C=O)C.CCOC(C)=O>[C:28]([S:30][CH2:9][CH2:8][CH2:7][CH:2]([C:3]([O:5][CH3:6])=[O:4])[O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])(=[O:31])[CH3:29]
Reactant: COC(=O)c1cccc(O)c1
Reactant: COC(=O)C(Br)CCCBr
Reactant: CC([O-])=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OC(CCCSC(C)=O)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.9 %

Procedure:
To a solution of methyl 2,5-dibromopentanoate XIII (22.00 g, 80.3 mmol) and methyl 3-hydroxybenzoate XIV (10.18 g, 66.9 mmol) in DMF (80 mL) was added K2CO3 (12.94 g, 93.7 mmol) at room temperature. The mixture was stirred at room temperature under N2 for 12 hours, then heated at 70° C. for 1 h. Potassium thioacetate (22.93 g, 200.8 mmol) was added to the mixture, which was heated at 70° C. for 2 hours. The mixture was allowed to cool to room temperature and was diluted with EtOAc (1000 mL). The mixture was washed with H2O (3×300 mL) and brine (2×300 mL). The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (gradient elution: 10% to 20% EtOAc/hexanes) to afford methyl 3-(4-acetylthio-1-methoxycarbonyl-butoxy)-benzoate XV (8.40 g, 24.7 mmol, 37%) as a yellow oil: Rf 0.26 (hexanes/EtOAc, 4:1): 1H NMR (CDCl3) δ 1.73-1.88 (m, 2H), 2.01-2.08 (m, 2H), 2.32 (s, 3H), 2.93 (t, J=7.2 Hz, 2H), 3.75 (s, 3H), 3.89 (s, 3H), 4.69 (t, J=6.2 Hz, 1H), 7.07 (dm, J=8.0 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.50 (m, 1H), 7.65 (dm, J=7.7 Hz, 1H); 13C NMR (CDCl3) δ 25.3, 28.3, 30.5, 31.4, 52.1, 52.2, 75.8, 115.4, 120.0, 122.8, 129.5, 131.4, 157.5, 166.4, 171.3, 195.4.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([CH3:4])=[O:3].[CH2:7]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[CH3:8].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH2:7]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:1](=[O:6])[C:2]([CH3:4])=[O:3])[CH3:8]
Reactant: CC(=O)C(=O)O
Reactant: CCOC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1CCCN1C(=O)C(C)=O
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A solution of 60 mmoles of pyruvic acid plus 60 mmoles of L-proline ethyl ester in redistilled chloroform is cooled to -50° C. in an acetone-dry ice bath. To this solution is added 60 mmoles of a precooled solution of dicyclohexylcarbodiimide (DCC) in cloroform and the mixture is stirred at -5° C. for 1 hour. The reaction mixture is slowly warmed to room temperature and stirred for an additional 2 hours and then stirred at 4° C. overnight. The mixture is filtered to remove dicyclohexylurea, then cooled in an ice bath. The organic phase is washed with cold water, cold 1N NaHCO3 and finally with cold saturated NaCl. The organic phase is dried over anhydrous MgSO4 and filtered. The solvent is removed with a rotary evaporator yielding N-pyruvoyl-L-proline ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[O:21]1[C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=[N:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:26]([C:25]3[O:21][N:22]=[CH:23][CH:24]=3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccno1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccno1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-isoxazolecarboxylic acid as starting materials, MS (LC/MS): 398.0 (M+H).