Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8](=[O:39])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:16]2[C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][C:19]=3[CH2:18][CH2:17]2)[N:26]=[C:25]([CH3:29])[N:24]([CH2:30][O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:23]4=[O:38])=[CH:11][CH:10]=1)#[N:2].[CH2:43](Br)[C:44]#[CH:45]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8](=[O:39])[C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH:16]2[C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][C:19]=3[CH2:18][CH2:17]2)[N:26]=[C:25]([CH3:29])[N:24]([CH2:30][O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:23]4=[O:38])[CH2:45][C:44]#[CH:43])=[CH:13][CH:14]=1)#[N:2]
Reactant: C#CCBr
Reactant: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Nc1ccc(C(=O)NCc2cccc(C#N)c2)cc1)CC3
Product: C#CCN(c1ccc(C(=O)NCc2cccc(C#N)c2)cc1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 1, N-(3-cyanobenzyl)-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzamide (0.36 g) was reacted with propargyl bromide to give N-(3-cyanobenzyl)-p-[N-(2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzamide (0.154 g).
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][CH:16]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[Cl:29][C:30]([Cl:34])([Cl:33])[CH2:31]O.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:1]([C:12]([O:14][CH2:15][CH:16]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[C@H:2]([C:9]([O:11][CH2:31][C:30]([Cl:34])([Cl:33])[Cl:29])=[O:10])[CH2:3][O:4][C:5]([CH3:7])([CH3:6])[CH3:8]
Reactant: OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
Fmoc-Ser(tBu)-OH (1 g, 2.6 mmol) was dissolved in CH2Cl2 (7 mL). DMAP (0.15 g, 1.3 mmol, 0.5 equiv) and 2,2,2-trichloroethanol (Tce) (0.3 mL, 3.1 mmol, 1.2 equiv) were first added, and then DCC (0.63 g, 3.1 mmol, 1.2 equiv) in CH2Cl2 (2.5 mL) was added under N2 atmosphere at 0° C. The reaction mixture was allowed to stir for 18 h at room temperature. The organic reaction was cooled to 0° C., filtered and the filtrate was concentrate in vacuo. The resulting crude was dissolved in EtOAc (7 mL) and washed with 10% aqueous citric acid (2×10 mL), saturated aqueous NaHCO3 (2×10 mL) and brine (2×10 mL), dried (MgSO4), and concentrated in vacuo to give Fmoc-Ser(OtBu)-OTce (1.34 g), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1.Br[C:18]1[N:22]2[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:26][C:21]2=[N:20][CH:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[N:22]3[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:26][C:21]3=[N:20][CH:19]=2)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1
Reactant: OB(O)c1ccc(F)c(-c2ccncn2)c1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4ccncn4)c3)cnc2n1

Procedure:
4-Fluoro-3-(pyrimidin-4-yl)phenylboronic acid (50 mg, 0.23 mmol) was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol (56 mg, 0.22 mmol) using the method of Example 20. Purification by chromatography (silica gel, 3% MeOH/CH2Cl2) then recrystallisation from hot toluene gave the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 1.57 (6H, s), 5.77 (1H, s), 7.62 (1H, dd, J 11, 9 Hz), 7.98-8.01 (1H, m), 8.28-8.33 (1H, m), 8.49 (1H, s), 8.80 (1H, dd, J 7, 2 Hz), 8.97 (1H, d, J 5 Hz), 9.05 (1H, s), 9.38 (1H, d, J 1 Hz); MS (ES+) m/z 351 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].C(N(CC)CC)C.[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][N:14]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH2:13][CH2:12]1)[C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])=[O:4]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C(=O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-methylcyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester (100 mg, 0.23 mmol) in dichloromethane (3 mL) was added triethylamine (3 mL) and isobutyryl chloride (28 μL, 0.27 mmol). The reaction mixture was stirred at room temperature for 12 h and then quenched with a saturated solution of NaHCO3. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:1) as eluent to obtain 5-cyclohex-1-enyl-3-[(1-isobutyryl-piperidin-4-yl)-(trans-4-methyl cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (55 mg, 47%) as a white solid.
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=1[CH3:15])[C:3]#[CH:4]>ClCCCl>[CH3:15][C:8]1[CH2:9][CH2:10][CH2:11][C:12]([CH3:13])([CH3:14])[C:7]=1[CH2:6]/[CH:5]=[C:2](/[CH3:1])\[C:3]#[CH:4]
Reactant: C#CC(C)(O)CCC1=C(C)CCCC1(C)C
Solvent: ClCCCl
Product: C#C/C(C)=C\CC1=C(C)CCCC1(C)C
Temperature: 60 °C

Procedure:
Under nitrogen atmosphere, 16.1 mg (0.03 mmol, 5 mol-%) of [(C5(CH3)5)RuCl(μ2-SMe)2Ru(C5(CH3)5)Cl] were dissolved in 7.5 ml of anhydrous 1,2-dichloroethane. To the dark red solution was added drop wise at room temperature a solution of 129 mg (0.5 mmol) of 3-methyl-5-(2,6,6-trimethylcyclohex-1-enyl)pent-1-yn-3-ol (compound of formula (II)) in 5.0 ml of anhydrous 1,2-dichloroethane. After complete addition of the starting material, the solution was heated to 60° C. After 24 hours at 60° C. the brown solution was cooled to room temperature.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].[C:20]([O-])([O-])=O.[K+].[K+].IC.O>CS(C)=O.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:20])[CH:8]=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]cc(C#N)c1-c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(Br)cc2)c(C#N)cn1C
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A solution of 3-(4-bromo-phenyl)-4-cyano-1H-pyrrole-2-carboxylic acid ethyl ester (41.59 g, 0.130 mol) in DMSO (400 mL) is treated with K2CO3 (19.76 g, 0.143 mol). The resulting solution is allowed to stir at room temperature for several minutes, and then treated with iodomethane (9.75 mL, 0.156 mol). The resulting reaction mixture is allowed to stir under nitrogen at room temperature overnight, then poured into water (2,000 mL) and extracted with EtOAc (4×500 mL each). The combined organics are washed with water (2×1,000 mL each), brine (700 mL), dried over anhydrous MgSO4, filtered, then concentrated in vacuo to afford an off-white solid. The solid is dissolved in a minimum amount of EtOAc, then treated with excess hexanes, causing a solid to crash out. The solid is recovered by vacuum filtration, washed with hexanes, and dried under vacuum filtration to afford the final title compound, 3-(4-bromo-phenyl)-4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester, (33.45 g, 77% yield) as a off-white solid: 1H NMR (500 MHz; CDCl3) δ 1.07 (t, 3H), 3.97 (s, 3H), 4.13 (q, 2H), 7.23 (s, 1H), 7.26 (d, 2H), 7.52 (d, 2H); MS(ES): m/z 333.1 (M+H+). Anal. Calcd. for C15H13BrN2O2: C 54.07; H 3.93; N 8.40; Br 23.98. Found C 53.91; H 3.93; N 8.35; Br 24.06.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11]CC1C=CC=CC=1>CCOC(C)=O.CCO.[Pd]>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11]
Reactant: BrCCCCCCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCOCCCCCCBr
Yield: 98 %

Procedure:
A solution of [(2-[(6-bromohexyl)oxy]ethoxy)methyl]benzene (1.5 g) in EtOAc (20 ml) and EtOH (20 ml) was hydrogenated over 10% palladium on carbon (200 mg). After 2 h the mixture was filtered through celite and the filtrate evaporated in vacuo to give the title compound (1.05 g). TSP+ve 242 (MNH4)+, 244 (MNH4)+.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1>[Pd]>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc(C2=CCOCC2)n1
Agent: [Pd]
Product: O=C(O)c1cccc(C2CCOCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 7 b, using 6-(3,6-dihydro-2H-pyran-4-yl)-pyridine-2-carboxylic acid and 10% Pd/C as starting materials, MS (EI): m/e 208.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][O:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:39]5[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][O:33][CH3:32])[CH2:37][CH2:38]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-(2-methoxy-ethyl)-piperazine following General Procedure C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:31][CH2:32][CH3:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([OH:29])=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:30])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[Br:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51]O)=[CH:49][CH:48]=1>CS(C)=O.CN(C)C1C=CN=CC=1>[Br:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][O:28][C:27]([CH2:26][C:8]2([NH:15][C:16]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[O:17])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:31][CH2:32][CH3:33])[C:7]2=[O:30])=[O:29])=[CH:49][CH:48]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CCOC(CN1C(=O)C(CC(=O)O)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CS(C)=O
Product: CCOC(CN1C(=O)C(CC(=O)OCc2ccc(Br)cc2)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Reaction time: 18 h
Yield: 47.5 %

Procedure:
In 10 ml of dimethyl sulfoxide was dissolved 0.336 g of (+)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N′-(4-methylphenyl)ureido)indolin-2-one. To the solution were added successively 0.108 g of 4-dimethylaminopyridine, 0.170 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.166 g of 4-bromobenzyl alcohol. The resulting mixture was stirred for 18 hours, followed by concentration. The concentrate was diluted with ethyl ether, washed successively with dilute hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give 0.219 g (48%) of the title compound as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]2[O:7][C:8]([CH3:30])([CH3:29])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)=[CH:13][C:12]3=[O:28])[C:5]=2[CH:4]=1)#[N:2].Cl>CO.O1CCOCC1>[C:1]([C:3]1[CH:32]=[CH:31][C:6]2[O:7][C:8]([CH3:30])([CH3:29])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:13][C:12]3=[O:28])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(C)C=C(n2ccc(CCCO[Si](C)(C)C(C)(C)C)cc2=O)c2cc(C#N)ccc2O1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC1(C)C=C(n2ccc(CCCO)cc2=O)c2cc(C#N)ccc2O1
Yield: 94.4 %

Procedure:
In 7.50 ml of methanol, is dissolved 819 mg of 6-cyano-2,2-dimethyl-4-{2-oxo-4-(3-t-butyldimethylsilyloxypropyl)-1-pyridinyl}-2H-benzo[b]pyran obtained in Example 40. Then, 1.90 ml of 4N hydrochloric acid in dioxane is added thereto at 0° C., and reacted at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure, the residue is mixed with ethyl acetate and water, and the product is extracted into ethyl acetate. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/10 mixture of methanol/methylene chloride as a developing solvent. Thus, 577 mg of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(3-hydroxypropyl)-1-pyridinyl}-2H-benzo[b]pyran is obtained.
Reaction SMILES: [CH3:1][C@@:2]([NH2:15])([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.[CH3:16][C:17]([O:20][C:21](OC1C(Cl)=CC(Cl)=C(Cl)C=1)=[O:22])([CH3:19])[CH3:18]>CN(C)C=O>[C:17]([O:20][C:21]([NH:15][C@:2]([CH3:1])([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1)=[O:22])([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)OC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: C[C@](N)(Cc1ccc(O)c(O)c1)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@](C)(Cc1ccc(O)c(O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 127 %

Procedure:
A mixture of 1.19 g (5.00 m moles) L-3-(3,4-dihydroxyphenyl)-2-methylalanine, 1.49 g (5.00 m moles) t-butyl 2,4,5-trichlorophenylcarbonate and 6 ml dimethylformamide is flushed with nitrogen and 1.39 ml (10.0 m moles) triethylamine is added. After stirring at room temperature for 24 hours, 60 ml H2O and 4 ml 2.5 N HCl is added. The solution is extracted 3 times with 50 ml of ethyl acetate and the extract is washed 3 times with 50 ml of water and 1 time with 50 ml of saturated sodium chloride solution and is dried (MgSO4). The solvent is removed in vacuum to give 1.98 g of a blue oil.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[Li]CCCC.CCCCCC.[CH2:20]([CH:32]1[CH2:34][O:33]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl>O.CN(P(N(C)C)(N(C)C)=O)C>[OH:33][CH:32]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:34][C:6]#[C:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7]
Reactant: CCCCCCCCCCCCC1CO1
Reactant: C#CCCCC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: CCCCCCCCCCCCC(O)CC#CCCCC(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a dry flask under argon was placed 10.2 g of 5-hexynoic acid, the product of lb, and 100 ml of HMPA (distilled over NaH). The solution was cooled to 0° C. and a solution of n-BuLi in hexane (115 ml, 0.185 mol) was added dropwise. After stirring for 1 hr., 21.7 g (0.118 mole) of dodecyl oxirane, the product of 1 c, was added dropwise. The reaction mixture was allowed to stir at room temperature for 3 days and then poured into 150 ml of ice and water. The aqueous solution was acidified with 5% HCl and then extracted with ether. The ether solution was washed with H2O, saturated with NaCl solution and then dried over MgSO4. Removal of solvent yielded crude product which was recrystallized in cyclohexane to give the title compound, mp 80.5°-81°.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]\[CH3:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:19])[CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:8][CH:7]=1>>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C@@:12]2([CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[CH:3]([CH3:4])[C@@H:2]([CH3:1])[O:19]2)=[CH:8][CH:7]=1
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1
Reactant: C/C=C\C
Product: CC1[C@@H](C)O[C@@]1(Cn1cncn1)c1ccc(F)cc1
Yield: 5.3 %

Procedure:
Following a procedure similar to that described in Example 39, but using cis-2-butene and 950 mg (5.68 mmole) of 4'-fluoro-2-(1H-1,2,4-triazol-1-yl)-acetophenone, 80 mg (yield 5.3%) of a 1:1 mixture of stereoisomers at the 3-position of the title compound were obtained, in the form of oil.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[N:11]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[CH:17][C:16]([C:25]([OH:27])=[O:26])=[CH:15][CH:14]=2)=O)(C)(C)C.[ClH:33]>C(OCC)(=O)C>[ClH:33].[NH2:8][CH2:9][C:10]1[N:11]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[CH:17][C:16]([C:25]([OH:27])=[O:26])=[CH:15][CH:14]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(C(=O)O)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2cccs2)c2cc(C(=O)O)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
3-{[(Tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylic acid (0.14 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate-diisopropyl ether to give 3-(aminomethyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylic acid hydrochloride (0.10 g, 90.9%) as crystals.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)=[N+]=[N-].O.NN>[Ni].CO>[NH2:1][C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](O)[C@@H](N=[N+]=[N-])C[C@@H]12
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](O)[C@@H](N)C[C@@H]12

Procedure:
1.0 g 16β-azido-3-methoxy-estra-1,3,5(10)-triene-17α-ol, 10 ml methanol, 2 ml 80% hydrazine hydrate and a spatula tip of Raney nickel are heated on a water bath for 15 min. After filtration, the Raney nickel is washed with methanol, subsequently wash fluid and filtrate are combined and methanol is removed by distillation under vacuum. The residue is recrystallized from methanol/ether. Yield: 0.8 g (87%), F=158-160° C.; [α]D+68° (pyridine).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[CH3:15][CH:16]([CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[NH2:17].C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH:17][CH:16]([CH3:15])[CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[N:7]=1
Reactant: CC(N)Cc1c[nH]c2ccccc12
Reactant: Clc1cc(N2CCCCC2)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: CC(Cc1c[nH]c2ccccc12)Nc1nc(Cl)cc(N2CCCCC2)n1
Temperature: 150 °C

Procedure:
A mixture of 2,4-dichloro-6-(1-piperidinyl)pyrimidine (80 mg, 0.34 mmol), α-methyltryptamine (59 mg, 0.34 mmol), and potassium carbonate (47 mg, 0.34 mmol) in chlorobenzene (1 mL) was heated at 150° C. in a sealed tube for 16 hours. The solvent was removed and the crude material was purified by preparative TLC, eluting with cyclohexane/ethyl acetate (4:1). 4-Chloro-N-[2-(1H-indol-3-yl)-1-methylethyl]-6-(1-piperidinyl)-2-pyrimidinamine (Rf=0.19) was obtained as a solid (64.5 mg, 51%). 1H NMR (300 MHz, CDCl3) δ 8.29 (br s, 1H), 7.68 (br d, 1H, J=7.5), 7.32 (d, 1H, J=7.8), 7.16 (t, 1H, J=7.8), 7.12 (t, 1H, J=7.8), 6.95 (d, 1H, J=2.1), 5.87 (s, 1H), 4.89 (br d, 1H, J=8.1), 4.36 (sextet, 1H, J=6.6), 3.58-3.50 (m, 4H), 3.07 (dd, 1H, J=14.4, 5.1), 2.83 (dd, 1H, J=14.1, 7.2), 1.70-1.55 (m, 6H), 1.16 (d, 3H, J=6.6).
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20].CCOCC>COCCOC>[CH2:17]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8])[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: OCCCCCCO
Reactant: CC(C)CCOCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CC(C)CCOCCCCOCCCCCCO
Reaction time: 3 h

Procedure:
17.8 g (0.163 mol) of 1,6-hexandiol in 30 cc of absolute 1,2-dimethoxy ethane are added dropwise over the course of 15 minutes, under nitrogen and while stirring, to 4.85 g (0.117 mol) of 55% sodium hydride dispersion in oil, suspended in 140 cc of absolute 1,2-dimethoxy ethane. The mixture is stirred at 60° for 3 hours, 22.5 g (0.101 mol) of 1-bromo-4-isopentyloxy-butane are then added and then it is stirred at 60° for 40 hours. After cooling to 20°, 400 cc of ether are added to the reaction mixture. The ether solution is washed three times with water, subsequently with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The residue is chromatographed with hexane/ethyl acetate (95:5) to (75:25) on silica gel. The almost pure fractions are fractionally distilled and 6-(4-isopentyloxy-butyloxy)-hexanol, having a B.P. of 134°-142°/0.5 mm Hg, is obtained as a colourless liquid.
Reaction SMILES: N[C:2]1N(CC)[N:5]=[CH:4][CH:3]=1.Cl[C:10]1[CH:18]=CC(S(C(F)(F)F)(=O)=O)=C[C:11]=1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(O)(=O)C.O>[C:12]([OH:14])(=[O:13])[C:11]1[C:4](=[CH:3][CH:2]=[CH:18][CH:10]=1)[NH2:5]
Reactant: O=C(O)c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: CCn1nccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5-amino-1-ethylpyrazole (0.56 g, 5 mmol), 2-chloro-5-(trifluoromethylsulfonyl)benzoic acid (1.4 g, 4.9 mmol), K2CO3 (0.69 g, 5 mmol), Cu(OAc)<2>(0.1 g) and DMF (10 ml) is refluxed for 4 hours and then is cooled to room temperature and is allowed to stand for about 3 days. Water is added to the reaction mixture, and then the solution is acidified with acetic acid to a pH of about 5. The mixture is extracted with CH2Cl2 and then the CH2Cl2 layer is evaporated to afford N-(1-ethylpyrazol-5-yl)-5-trifluoromethylsulfonyl)anthranilic acid.