Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[Cl:6]C1C2C(=CC=CC=2)C(CNC(O)C(C)CO)=C2C=1C=CC=C2.[N:29]1([C:34]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]([CH:48]=O)=[C:40]3[C:35]=2[CH:36]=[CH:37][CH:38]=[CH:39]3)[CH:33]=[CH:32][N:31]=[CH:30]1.[NH2:50][C:51]([CH3:56])([CH2:54][OH:55])[CH2:52][OH:53]>>[ClH:6].[N:29]1([C:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:41]([CH2:48][NH:50][C:51]([CH3:56])([CH2:54][OH:55])[CH2:52][OH:53])=[C:42]3[C:47]=2[CH:46]=[CH:45][CH:44]=[CH:43]3)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: CC(N)(CO)CO
Reactant: O=Cc1c2ccccc2c(-n2ccnc2)c2ccccc12
Reactant: CC(CO)C(O)NCc1c2ccccc2c(Cl)c2ccccc12
Agent: CS(=O)(=O)O
Product: CC(CO)(CO)NCc1c2ccccc2c(-n2ccnc2)c2ccccc12
Product: Cl

Procedure:
Using the reductive amination procedure outlined in 2B, 10(1H-imidazol-1-yl)-9-anthracenecarbaldehyde (29A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-(((10-(1H-imidazol-1-yl)-9-anthracenyl)methyl)amino)-2-methyl-1,3-propanediol hydrochloride.11/10 H2O mp 212°-215° (dec), (EtOH/Et2O), (C, H, Cl, N).
Reaction SMILES: C([O:3][P:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=1)=[O:13]>>[CH2:24]([O:23][C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][C:12]([P:4](=[O:3])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])=[O:13])=[CH:16][CH:17]=1)=[O:22])[CH3:25]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)c1ccc(OC(=O)Cl)cc1
Product: CCOC(=O)c1ccc(OC(=O)P(=O)(OCC)OCC)cc1

Procedure:
From 21.6 g (0.13 mole) of triethylphosphite and 22.8 g (0.10 mole) of 4-ethoxycarbonylphenyl chloroformate. (120° C., 2 hours). Yield 26.1 g (88%). Bp0.01 190°-2° C. nD25 1.4890.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:31])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=3[NH:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:32].[CH:33]1([CH:36]=O)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[Cl:54]CCCl>C(O)(=O)C>[ClH:54].[CH:33]1([CH2:36][N:28]2[CH2:29][CH2:30][CH:25]([NH:24][C:15]3[CH:16]=[C:17]([C:20]([F:22])([F:23])[F:21])[CH:18]=[CH:19][C:14]=3[C:13]([NH:12][C:9]3[CH:10]=[C:11]4[C:6]([CH2:5][CH2:4][C:3](=[O:32])[N:2]4[CH3:1])=[CH:7][CH:8]=3)=[O:31])[CH2:26][CH2:27]2)[CH2:35][CH2:34]1
Reactant: ClCCCl
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3NC3CCNCC3)cc21
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3NC3CCN(CC4CC4)CC3)cc21
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
After dissolving N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-(piperidin-4-ylamino)-4-(trifluoromethyl)benzamide (200 mg), cyclopropanecarbaldehyde (0.10 mL) and acetic acid (0.026 ml) in 1,2-dichloroethane (4 ml), sodium triacetoxyborohydride (285 mg) was added thereto. After stirring at room temperature for 2 hours, 1 M sodium hydroxide aqueous solution was added thereto, followed by extraction with chloroform. After drying the organic layer with sodium sulfate, the solution was concentrated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia, 1:0:0 to 90:9:1). By treating the resulting free base with 4 M hydrogen chloride/ethyl acetate, 2-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethyl)benzamide hydrochloride (199 mg) was obtained as an amorphous.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(=O)([O-])O.[Na+].[CH2:15]([O:22][C:23]([NH:25][CH2:26][C:27](C1CC(=O)N(O)C1=O)=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O.C(COC)OC.C(OCC)(=O)C>[CH2:15]([O:22][C:23]([NH:25][CH2:26][C:27]([N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(NCC(=O)C1CC(=O)N(O)C1=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCC(=O)N1C[C@H](O)C[C@H]1C(=O)O)OCc1ccccc1
Yield: 68.9 %

Procedure:
trans-4-Hydroxy-L-proline 1 (0.28 g, 2.13 mmol) and sodium hydrogen carbonate (0.18 g, 2.13 mmol) were dissolved in water (3 cm3) at room temperature. N-benzyloxycarbonyl-glycyl-N-hydroxysuccinimide 2 (0.44 g, 1.44 mmol) in dimethoxyethane (3 cm3) was added dropwise over a period of 5 min. The solution was stirred for 2.5 then acidified with conc. hydrochloric acid (38%) to pH 1. The solution was placed in a refrigerator overnight. Ethyl acetate (2×20 cmr3) was added and the resulting organic layers dried (MgSO4), filtered and evaporated under reduced pressure to yield a light pinky foam, which was purified by flash column chromatography (10% methanol/methylene chloride) to produce acid 3 (0.32 g, 70%) as a clear foam. Acid 3 was shown to be an 77:23 trans:cis mixture of conformers by 1H NMR analysis (the ratio was estimated from the integration of the signals at (δ 4.33-4.38 and 4.52-4.54, assigned to the Proα-H of the major and minor conformers respectively): [α]D −75.5 (c 0.08 in MeOH); OH (300 MHz; CD3OD) 1.89-1.94 (0.77H, m, Proβ-HAHB), 2.08-2.14 (1H, m, Proβ-HAHB), 2.14-2.16* (0.23H, m, Proβ-HAHB), 3.17-3.20 (1H, m, Proδ-HAHB), 3.53-3.57 (1H, m, Proδ-HAHB), 3.73-3.78 (1H, d, J 17.1, Glyα-HAHB), 3.87-3.93 (1H, d, J 17.1, Glyα-HAHB), 4.20-4.30* (0.23H, m, Proγ-H), 4.33-4.38 (1.54H, m, Proγ-H and Proα-H), 4.52-4.54* (0.23H, t, J 7.0, Proα-H) 4.94 (2H, s, OCH2Ph) and 7.11-7.23 (5H, m, Ph); δC (75 MHz, CD3OD) 39.0 (CH2, Proβ-C), 41.3* (CH2, Pro-C), 44.2* (CH2, Proδ-C), 44.8 (CH2, Proδ-C), 55.9 (CH2, Glyα-C), 56.2* (CH2, Glyα-C), 59.5* (CH, Proα-C), 60.1 (CH, Proα-C), 68.5 (CH2, OCH2Ph), 68.7* (CH2, OCH2Ph), 69.7* (CH, Proγ-C), 71.7 (CH, Proγ-C), 129.6 (CH, Ph), 129.7 (CH, Ph), 130.2 (CH, Ph), 138.9 (quat., Ph), 159.6 (quat., NCO2), 170.1 (quat., Gly-CO), 171.6* (quat., Gly-CO), 175.9* (quat., CO2H) and 176.3 (quat., CO2H),; m/z (FAB+) 323.1240 (M+.C16H20N2O5 requires 320.1243).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH2:12]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1)=[O:17])[CH:13]=[CH2:14].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH2:12]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C:20]([OH:23])([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:19]1)=[O:17])[CH:13]=[CH2:14]
Reactant: C#C[Si](C)(C)C
Reactant: C=CCOC(=O)N1CCC(=O)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CCC(O)(C#C[Si](C)(C)C)C1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a solution of trimethylsilylacetylene (16.3 ml) in tetrahydrofuran (100 ml) were added successively a solution of n-butyllithium in n-hexane (1.50M, 70 ml) and a solution of 1-allyloxycarbonyl-3-oxopyrrolidine (15 g) in tetrahydrofuran (15 ml) at -50° C. After stirring at -50° C. for 1 hour, to the mixture was added a mixture of aqueous ammonium chloride and ethyl acetate at 0° C. The organic layer was separated and the aqueous layer was extracted with ethyl acetate twice. The organic layers were combined washed with 1N hydrochloric acid, water and brine successively and dried over magnesium sulfate. Evaporation of the solvent in vacuo gave 1-allyloxycarbonyl-3-hydroxy-3-trimethylsilylethynylpyrrolidine (19.5 g).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([S:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=3)[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[C:35](Cl)[N:34]=[CH:33][N:32]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[C:35]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([S:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=4)[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:34]=[CH:33][N:32]=1
Reactant: COc1ccc(Sc2ccn3nc([C@H](C)N)n(-c4ccccc4)c(=O)c23)cc1F
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1ccc(Sc2ccn3nc([C@H](C)Nc4ncnc(N)c4C#N)n(-c4ccccc4)c(=O)c23)cc1F
Yield: 69.5 %

Procedure:
(S)-2-(1-Aminoethyl)-5-((3-fluoro-4-methoxyphenyl)thio)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (203 mg, 0.43 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (102 mg, 0.66 mmol) and DIEA (230 μl, 1.32 mmol) in 10 ml of tert-BuOH were heated at 80° C. for 72 h. After evaporation of the solvent under reduced pressure, the residue (158 mg, 35% yield) was used in the next synthetic step without further purification. Purity 50%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.[O-:10][Mn](=O)(=O)=O.[K+].[C:16]([O-])([O-])=[O:17].[K+].[K+].CI>O.CN(C=O)C>[CH3:16][O:17][C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=1)=[O:10]
Reactant: COc1ccc(C)nc1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(OC)cn1
Temperature: 80 °C
Reaction time: 5 h
Yield: 22.1 %

Procedure:
5-Methoxy-2-methyl-pyridine (700 mg, 5.69 mmol) was dissolved in H2O (20 ml) and heated to 80° C. KMnO4 (4 g, 25.3 mmol) was added in portion to the solution over 1 h. After stirring at 80° C. for 5 h the mixture was filtrated and the filtrate was washed with H2O (60° C.). The combined water phase was concentrated. DMF (20 ml), K2CO3 (785 mg, 5.7 mmol) followed by MeI (540 ml, 8.6 mmol) was added to the remaining residue and the mixture was heated to 80° C. on. The reaction was cooled to ambient temperature and H2O was added and the mixture was extracted three times with toluene. The combined organic phases were dried and concentrated. Flashchromatography (SiO2, Heptane/EtOAc 1:1) afforded 210 mg (22%) of the title compound. 1H NMR (CDCl3): d ppm 3.93 (s, 3 H) 4.00 (s, 3 H) 7.23 (m, 1 H) 8.13 (d, 1 H) 8.40 (d, 1 H). Step 2: 4-Ethyl-5-(5-methoxy-pyridin-2-yl)-2,4-dihydro-[1,2,4]triazole-3-thione: NaOMe (4 ml, 4.0 mmol, 1M) was added to a solution of 5-Methoxy-pyridine-2-carboxylic acid methyl ester (200 mg, 1.2 mmol), 4-ethyl-3-thiosemicarbazide (145 mg, 1.2 mmol) in MeOH (10 ml) and the mixture was heated to 70° C. on. The reaction was cooled to ambient temperature and evaporated to dryness. H2O (10 ml) was added to the residue and the mixture was acidified with concentrated hydrochloric acid and the title compound 50 mg (18%) was collected by filtration. LC-MS (M++1): 237.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Li+].[Cl-].Br[CH2:12][C:13](=[CH2:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C([Cu])#N>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:19][C:13](=[CH2:12])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: C=C(CBr)C(=O)OCC
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Cc1ncc(Cl)nc1Cl)C(=O)OCC
Temperature: -50 °C
Yield: 71.6 %

Procedure:
2,6-Dichloropyrazine (9) (149 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 30 min according to TP 2. After cooling down to −50° C., ethyl 2-(bromomethyl)acrylate (230 mg, 1.2 mmol) and CuCN.2LiCl (1.0 M solution in THF, 5 drops) were added and the resulting mixture was allowed to warm up slowly to −20° C. The reaction mixture was quenched with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:3) furnished compound 11c (187 mg, 72%) as a colourless oil.
Reaction SMILES: [C:1]([C:5]1[CH:52]=[CH:51][C:8]2[N:9](COCC[Si](C)(C)C)[C:10]([CH2:12][CH:13]3[CH2:16][CH:15]([CH2:17][N:18]([CH2:22][C@@H:23]4[C@H:27]5[O:28]C(C)(C)[O:30][C@H:26]5[C@H:25]([N:33]5[C:37]6[N:38]=[CH:39][N:40]=[C:41]([NH2:42])[C:36]=6[CH:35]=[CH:34]5)[CH2:24]4)[CH:19]([CH3:21])[CH3:20])[CH2:14]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO>Cl>[NH2:42][C:41]1[C:36]2[CH:35]=[CH:34][N:33]([C@@H:25]3[CH2:24][C@H:23]([CH2:22][N:18]([CH2:17][CH:15]4[CH2:14][CH:13]([CH2:12][C:10]5[NH:9][C:8]6[CH:51]=[CH:52][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=6[N:11]=5)[CH2:16]4)[CH:19]([CH3:20])[CH3:21])[C@@H:27]([OH:28])[C@H:26]3[OH:30])[C:37]=2[N:38]=[CH:39][N:40]=1
Reactant: CC(C)N(CC1CC(Cc2nc3cc(C(C)(C)C)ccc3n2COCC[Si](C)(C)C)C1)C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Agent: Cl
Solvent: CO
Product: CC(C)N(CC1CC(Cc2nc3cc(C(C)(C)C)ccc3[nH]2)C1)C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O
Yield: 55.2 %

Procedure:
7-[(3aS,4R,6R,6aR)-6-{[({3-[(5-tert-butyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)methyl]cyclobutyl}methyl)(propan-2-yl)amino]methyl}-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (58.7 mg, 0.08 mmol) was dissolved in conc. HCl solution (5 ml) and methanol (5 ml) and heated to 40° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue partitioned between sat. NaHCO3(aq) (10 ml) and EtOAc (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2×10 ml), the combined organics were then dried (MgSO4) and concentrated. The crude material was purified by prep TLC, eluting with 10% 2M NH3 in MeOH in DCM to afford the title compound (24.7 mg, 55%) as a colourless gum: MS (ESI+) for C32H45N7O2 m/z 560.4 [M+H]+; LC purity 100% (UV), (ret. time, 5.10 min); 1H NMR (500 MHz, Acetone) δH 8.12 (s, 1H), 7.30-7.60 (m, 2H), 7.13-7.28 (m, 2H), 6.54 (d, J=3.5 Hz, 1H), 6.33 (br. s., 1H), 4.85-5.07 (m, 1H), 4.36 (t, J=6.2 Hz, 1H), 4.08 (t, J=5.2 Hz, 1H), 3.01 (d, J=7.7 Hz, 1H), 2.93 (d, J=7.4 Hz, 2H), 2.78 (br. s., 2H), 2.59-2.73 (m, 2H), 2.15-2.56 (m, 7H), 1.68 (dt, J=12.4, 9.7 Hz, 1H), 1.44-1.62 (m, 2H), 1.35 (s, 9H), 0.90-1.07 (m, 6 II).
Reaction SMILES: [O:1]=[V:2].Cl.Cl.Cl.BrC1C=CC([Si:13]([C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)(C2C=CC(Br)=CC=2)[OH:14])=CC=1>>[O-2:14].[Br:28][C:25]1[CH:26]=[CH:27][C:22]([SiH2:13][O:1][V+2:2]([O:14][SiH2:13][C:22]2[CH:23]=[CH:24][C:25]([Br:28])=[CH:26][CH:27]=2)[O:14][SiH2:13][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)=[CH:23][CH:24]=1
Reactant: O[Si](c1ccc(Br)cc1)(c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: O=[V]
Agent: Cl
Product: Brc1ccc([SiH2]O[V+2](O[SiH2]c2ccc(Br)cc2)O[SiH2]c2ccc(Br)cc2)cc1
Product: [O-2]

Procedure:
vanadium oxytrichloride was reacted with tri (p-bromophenyl) silanol, (m.p. = 120-121° C.) to produce tris[(p-bromophenyl)-siloxy]-vanadium oxide (m.p. = 175° C.); and
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[O:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][CH2:50][C:51](O)=[O:52])[CH2:44][CH2:43]1.C(Cl)[Cl:55]>CO.C(Cl)(Cl)Cl>[ClH:55].[CH3:25][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:24][C:51](=[O:52])[CH2:50][CH2:49][CH2:48][N:45]3[CH2:44][CH2:43][O:42][CH2:47][CH2:46]3)=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Reactant: ClCCl
Reactant: O=C(O)CCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
6.4 g. (18.7 mmole) of 4,4-Dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta[ c][1] benzopyran, 4.33 g. (21.0 mmoles) of dicyclohexylcarbodiimide and 4.26 g. (20.3 mmoles) of γ-morpholinobutyric acid hydrochloride were combined with 325 ml. of methylene chloride and stirred at room temperature for a total of 24 hours. The insoluble by-product of dicyclohexylurea was separated by filtration and the methylene chloride was removed using a rotary evaporator. The brown viscous residue was dissolved in about 100 ml. of benzene and the benzene solution was filtered to remove a small amount of insoluble material. The benzene was removed using a rotary evaporator and the remaining residue was triturated with approximately 250 ml. of ether. The solid which formed was filtered, washed with ether and dried to give 8.6 g. of beige solid. The material was crystallized from benzene/ether to give 3.5 g. of product as a colorless solid, m.p. 151°-153°C. The material was pure by thin layer chromatography (10% MeOH/CHCl3); the infrared and nuclear magnetic resonance spectra were in agreement with the proposed structure. An additional 3.3 g. of somewhat impure material was recovered from the mother liquor.
Reaction SMILES: C[O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:22]([C:23]=2[CH2:24][CH:25]=1)[CH2:21][CH2:20][C@@:18]1([CH3:19])[C@H:9]3[CH2:10][CH2:11][C:12]21[CH2:16][CH:15]([OH:17])[CH2:14][O:13]2.C(O)(=O)C>O>[OH:17][CH:15]1[CH2:14][O:13][C:12]2([CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:22]([CH2:21][CH2:20][C@:18]23[CH3:19])[C:23]2[CH2:24][CH2:25][C:3](=[O:2])[CH2:4][C:5]=2[CH2:6][CH2:7]4)[CH2:16]1
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC23CC(O)CO3)C1
Solvent: CC(=O)O
Solvent: O
Product: C[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC21CC(O)CO1)CC(=O)CC4
Reaction time: 4 h

Procedure:
A suspension of 1 part of 4',5'-dihydro-3-methoxyspiro[estra-2,5(10)-diene-17,2'(3'H)-furan]-4'-ol in 20 parts of aqueous 90% acetic acid is stirred for 13/4 hours, during which solution occurs. Approximately 100 parts of cold water is thereupon introduced, whereupon the precipitate which forms is filtered off, washed with water, dried in air, and recrystallized from ethyl acetate to give 4',5'-dihydro-4'-hydroxyspiro[estr-5(10)-ene-17,2'(3'H)-furan] -3-one melting at 118°- 123°.
Reaction SMILES: [ClH:1].Cl.C1(NC(C2C3C=C(C4C([Cl:24])=CN=C(NCCC5CCNCC5)N=4)SC=3C=CC=2)=O)CC1.[CH:34]1([NH:37][C:38]([C:40]2[C:48]3[CH:47]=[C:46]([C:49]4[C:54]([Br:55])=[CH:53][N:52]=[C:51]([Cl:56])[N:50]=4)[S:45][C:44]=3[CH:43]=[CH:42][CH:41]=2)=[O:39])[CH2:36][CH2:35]1.C(OC([N:64]1[CH2:69][CH2:68][N:67]([CH2:70][CH2:71][CH2:72][NH2:73])[CH2:66][CH2:65]1)=O)(C)(C)C>>[ClH:24].[ClH:56].[ClH:1].[CH:34]1([NH:37][C:38]([C:40]2[C:48]3[CH:47]=[C:46]([C:49]4[C:54]([Br:55])=[CH:53][N:52]=[C:51]([NH:73][CH2:72][CH2:71][CH2:70][N:67]5[CH2:68][CH2:69][NH:64][CH2:65][CH2:66]5)[N:50]=4)[S:45][C:44]=3[CH:43]=[CH:42][CH:41]=2)=[O:39])[CH2:36][CH2:35]1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCC4CCNCC4)ncc3Cl)cc12
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)CC1
Agent: Cl
Product: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCN4CCNCC4)ncc3Br)cc12

Procedure:
Using the synthetic method of 2-[5-chloro-2-(2-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-(5-bromo-2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 4-(3-aminopropyl)-piperazine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid (59% yield). ES+(m/z) 515 (79Br) and 517 (81Br) [M(free base)+H].
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[CH:6][O:5][N:4]=1.ClCC[O:11][CH2:12][C:13]1C=CO[N:14]=1.[CH3:18][N:19]=[C:20]=[S:21]>>[CH3:18][NH:19][C:20]([NH:14][CH2:13][CH2:12][O:11][CH2:2][C:3]1[CH:7]=[CH:6][O:5][N:4]=1)=[S:21]
Reactant: ClCc1ccon1
Reactant: ClCCOCc1ccon1
Reactant: CN=C=S
Product: CNC(=S)NCCOCc1ccon1

Procedure:
By the procedure of Example 38, 3-chloromethylisoxazole is converted to 3-(2-chloroethoxymethyl)isoxazole which is then reacted with methyl isothiocyanate to give N-methyl-N'-[2-(3-isoxazolylmethoxy)ethyl]thiourea.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[C:8]([CH2:11][CH2:12][NH2:13])=[CH:9][NH:10][C:3]=2[CH:2]=1.Cl.[OH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[C:17]=1[C:18](O)=[O:19].C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[OH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[C:17]=1[C:18]([NH:13][CH2:12][CH2:11][C:8]1[C:4]2[C:3](=[CH:2][CH:1]=[C:6]([OH:7])[CH:5]=2)[NH:10][CH:9]=1)=[O:19]
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: O=C(O)c1c(O)cccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(O)cc12)c1c(O)cccc1O
Temperature: 0 °C
Reaction time: 16 h
Yield: 14.9 %

Procedure:
Serotonin hydrochloride (430 mg, 2 mmol) and 2,6-dihydroxybenzoic acid (312 mg, 2 mmol) were dissolved in N,N-dimethylformamide (25 ml), and the solution temperature was maintained at 0° C. To this solution were added triethylamine (310 μl, 2.1 mmol), 1-hydroxybenzotriazole hydrate (HOBt H2O, 346 mg, 2.1 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI HCl, 429 mg, 2.1 mmol), the solution temperature was gradually warmed from 0° C. to room temperature, and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, water (20 ml) was added to the residue, and the mixture was extracted twice with ethyl acetate (20 ml). The ethyl acetate layer was washed twice with 5% aqueous citric acid solution (5 ml), once with saturated brine (5 ml), twice with 5% aqueous sodium hydrogen carbonate solution (5 ml), and once with saturated brine (5 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure, purified by preparative thin-layer chromatography (PTLC, eluent: ethyl acetate:hexane=3:1) to give 2,6-dihydroxy-N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-benzamide (93 mg, yield 14.9%) as a powder.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:20]=1[N+:21]([O-])=O)[C:8]([NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:9])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:21][C:20]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)=[O:9])=[CH:6][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C(=O)NC2CCN(C)CC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)Oc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Yield: 95.3 %

Procedure:
To a solution of 1.2 g (3.6 mmole) of 3-isopropoxy-N-(1-methyl-piperidin-4-yl)-4-nitro-benzamide in 25 mL of methanol was added 0.12 g of 10% palladium on carbon. The hydrogenation reaction was carried out under 50 psi of hydrogen for 2 hours. The mixture was filtered, concentrated under reduced pressure and triturated with ether. The solid was collected by filtration, washed with ether and dried under vacuum to give 1.0 g of 4-amino-3-isopropoxy-N-(1-methyl-piperidin-4-yl)-benzamide as a white solid.