Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>ClC1C=CC=CC=1>[CH:5]1([N:11]=[C:1]=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C=NC1CCCCC1
Temperature: 78.5 °C
Yield: 123.6 %

Procedure:
500 g of chlorobenzene and 8.7 g of Cyanex® 923 (commercial product from Cytec Industries, a mixture of different tri-C6-C8-alkylphosphine oxides having an average molecular weight of 348 g/mol) (0.025 mol) were placed in the glass vessel and 53 g of gaseous phosgene was introduced at room temperature. The reaction mixture was subsequently heated to 80° C., with vigorous phosgene reflux being established. While stirring vigorously at 77-80° C., a total of 99.2 g of cyclohexylamine (1 mol) dissolved in 200 g of chlorobenzene and at the same time a further 113 g of phosgene were introduced over a period of 3 hours. After addition was complete, the system was maintained at 77-80° C. for a further one hour without introduction of phosgene to allow further reaction to occur and the residual unreacted phosgene was subsequently stripped out at 40° C. by means of nitrogen. The reaction mixture obtained was a fluid suspension from which the solid obtained was separated by filtration. A few milligrams of solid were able to be isolated in this way. The filtered crude product was worked up by distillation. Removal of the solvent and fractional distillation gave 82.8 g of cyclohexyl isocyanate (0.662 mol). This corresponds to 66.2% of the theoretical yield.
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11].[Cl:12][C:13]1[CH:14]=[N:15][C:16](=[O:19])[NH:17][CH:18]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:5]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[O:3][CH2:2][N:17]1[CH:18]=[C:13]([Cl:12])[CH:14]=[N:15][C:16]1=[O:19]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: ClCOc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ncc(Cl)cn1COc1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 7 h

Procedure:
The title compound was prepared in a manner similar to that described in Example 6 by the addition of a solution of 1-chloromethoxy-2,4-dichlorobenzene (see preparation 6) (5 mmol) in dichloromethane (25 ml) to a solution of 5-chloropyrimidin-2-one (5 mmol) and triethylamine (5 mmol) in dichloromethane (75 ml). The mixture was stirred at room temperature for 2 h and at 40° C. for 7 h before being worked up as above; yield 1.30 g (80%), isomer ratio 3:1. The title compound crystallized from DMSO: m.p. 170° C. 1H NMR (TFA): δ 6.10 (CH2),, 6.9-7.4 (Ph), 9.0-9.2 (H-4, H-6). IR (KBr): 1680 cm-1 (CO). MS (70 eV, m/z (% rel. int.)): 304 (l,M), 162 (3), 145 (35), 143 (100), 116 (28 ).
Reaction SMILES: CS[C:3]1[N:8]=[CH:7][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]=1.[CH2:14]([NH2:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:14]([NH:30][C:3]1[N:8]=[CH:7][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: CCOC(=O)c1cnc(SC)nc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ncc(C(=O)OCC)cn1

Procedure:
A mixture of 2.0 g of ethyl 2-methylthio-5-pyrimidinecarboxylate, 3.0 g. of hexadecylamine, and 20 ml. of hexamethylphosphoramide is heated at 110° C. for 10 hours, allowed to cool, and diluted with water. Filtration affords a solid which is crystallized from hexane to yield ethyl 2-hexadecylamino-5-pyrimidinecarboxylate as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[C:3]=1[NH2:11].O.O.[C:14](O)(=[O:18])[C:15](O)=[O:16]>Cl>[OH:16][C:15]1[C:14]([OH:18])=[N:11][C:3]2[C:2](=[CH:10][CH:9]=[C:5]3[N:6]=[CH:7][S:8][C:4]3=2)[N:1]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1ccc2ncsc2c1N
Agent: Cl
Solvent: O
Product: Oc1nc2ccc3ncsc3c2nc1O
Yield: 87.8 %

Procedure:
A solution of 6,7-diaminobenzothiazole (1.3 g, 7.9 mmol) and oxalic acid dihydrate (1.3 g, 10.3 mmol) in 40 ml of 4M hydrochloric acid was refluxed on an oil bath for 11/2 h, and cooled. The resulting precipitate was collected by filtration and washed successively with water and ethanol to give 1.52 g (88%) of the title compound; m.p. >360° C.; IR (KBr): 1700 cm-1 ; 1H-NMR (DMSO-d6): ca. 6.3 (very broad s, lH, OH), 7.40 (d, J=9 Hz, lH, ArH), 7.87 (d, J=9 Hz, lH, ArH), 9.33 (s, lH, H-2), 12.07 (broad s, lH, OH).
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][C:5]2=[N:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[CH2:17]([N:21]1[C:25]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH2:33])[CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([N:21]1[C:25]2[CH:26]=[C:27]([C:2]3[N:6]4[CH2:7][CH2:8][CH2:9][C:5]4=[N:4][C:3]=3[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH2:33])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)Cn1c(N)nc2ccc(B(O)O)cc21
Reactant: Fc1ccc(-c2nc3n(c2Br)CCC3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)Cn1c(N)nc2ccc(-c3c(-c4ccc(F)cc4)nc4n3CCC4)cc21
Temperature: 90 °C
Reaction time: 0.13 h
Yield: 31.3 %

Procedure:
Bubble nitrogen through a solution of 3-bromo-2-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (750 mg, 2.67 mmol) in dimethoxyethane (20 ml). Add bis(triphenylphosphine)palladium(II) chloride (175 mg, 0.095 mmol) and stir at room temperature for 3 minutes. Add (1-isobutyl-2-amino-1H-benzimidazol-6-yl)boronic acid (750 mg, 3.211 mmol) by 2M aqueous sodium carbonate (2.7 mL, 5.40 mmol). Heat at 90° C. for 16 hours. Cool to room temperature, dilute with water (50 ml), and extract with ethyl acetate (150 ml). Dry over magnesium sulfate and concentrate under reduced pressure. Subject the residue to HPLC (Xterra MS C18 5 μm, 19×100 mm; Solvent A: 10 mM ammonium carbonate at pH 9; Solvent B: acetonitrile; Gradient: from 35 to 50% B in 8 minutes and then 50 95% B in 1 minute; Flow rate: 20 mL/min) to provide 1-isobutyl-2-amino-6-(2-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-1H-benzimidazole (325 mg, 31%). MS (ES): m/z=390 (M++H) The free base is treated with two equivalents of methanesulfonic acid essentially as previously described to provide the title compound (50%).
Reaction SMILES: C1[O:6][C:5]([CH2:11][C:12]([OH:14])=[O:13])([CH2:7][C:8]([OH:10])=[O:9])[C:3](=[O:4])[O:2]1.C(N(CC)CC)C.[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(O)C>[CH2:22]([CH:7]([C:5]([CH2:11][C:12]([OH:14])=[O:13])([C:3]([OH:2])=[O:4])[OH:6])[C:8]([OH:10])=[O:9])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=C(O)CC1(CC(=O)O)OCOC1=O
Reactant: CCCCCCCCO
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCCCCC(C(=O)O)C(O)(CC(=O)O)C(=O)O
Yield: 82.7 %

Procedure:
To a suspension of 2 (50.0 g, 0.245 mole), in ethanol-free chloroform (500 ml), was added triethylamine (75 ml, 0.538 mole) followed by octanol (80 ml. 0.508 mole). The resulting solution was refluxed for 45 hours, cooled and the chloroform removed by evaporation at 40° C. The residue was dissolved in ethyl acetate (400 ml) and this solution washed 3 times with cold saturated sodium bicarbonate solution (200 ml). The combined bicarbonate extract was washed twice with ethyl acetate (200 ml). The bicarbonate extract was then adjusted to pH 2 by the drop wise addition of concentrated HCl (≈78 ml). The cloudy solution was extracted with three portions of ethyl acetate (200 ml), the combined ethyl acetate extract dried (magnesium sulfate), filtered and evaporated, finally in high vacuum at 50° C. to give 3a (61.7 g, 90%) as an oil. The oil was dissolved in 200 ml of hot toluene on the steam bath and filtered from some insoluble material. The filtrate was kept at room temperature overnight, then, the crystals were collected, washed with toluene and dried to give 3a (43.09 g, 58%), mp 65.8°-66.7° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(Cl)Cl.[F:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:13]3[CH2:25][N:26]([CH2:28][CH2:29][CH2:30][CH:31]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)[OH:32])[CH2:27][C:12]=3[C:11]=2[CH:10]=1>N1C=CC=CC=1>[F:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:13]3[CH2:25][N:26]([CH2:28][CH2:29][CH2:30][CH:31]([C:33]4[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=4)[O:32][C:1](=[O:3])[CH3:2])[CH2:27][C:12]=3[C:11]=2[CH:10]=1
Reactant: CC(=O)Cl
Reactant: OC(CCCN1Cc2c(n(-c3ccc(F)cc3)c3ccc(F)cc23)C1)c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(CCCN1Cc2c(n(-c3ccc(F)cc3)c3ccc(F)cc23)C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (260 mg., 3.3 m moles) in 10 ml. of methylene chloride is added dropwise to a cold solution of 959 mg. (2.2m moles) of 7-fluoro-4-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydropyrrolo[3,4-b]indole in 30 ml. of methylene chloride containing 350 mg. (4.4 m mols) of pyridine. Following the addition, the reaction mixture is allowed to warm to room temperature and stir overnight. The mixture is decanted into a cold saturated aqueous sodium bicarbonate solution, and the crude product is extracted (3 × 50 ml.) with methylene chloride. The combined organic extracts are dried over magnesium sulfate and concentrated to an oil, which on chromatographing on a silica gel column, using 1:1 benzene-ethyl acetate as an eluate, provides the purified product.
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][C@H:14]([N:18]2[C:24](=[O:25])[CH2:23][CH2:22][NH:21][C@H:20]([CH3:26])[CH2:19]2)[CH2:15][O:16][CH3:17])[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:27][C:28]1[CH:29]=[C:30]([N:35]=[C:36]=[O:37])[CH:31]=[CH:32][C:33]=1[Cl:34]>>[Cl:27][C:28]1[CH:29]=[C:30]([NH:35][C:36]([N:21]2[CH2:22][CH2:23][C:24](=[O:25])[N:18]([C@H:14]([CH2:15][O:16][CH3:17])[CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:7][CH2:6]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:19][C@H:20]2[CH3:26])=[O:37])[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)NCCC1=O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)N(C(=O)Nc2ccc(Cl)c(Cl)c2)CCC1=O
Yield: 74 %

Procedure:
In analogy to the procedure described for intermediate 58F, (R)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-methoxymethyl-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride (example 65H) and 3,4-dichlorophenyl isocyanate gave the title compound in 74% yield as white solid. MS: 527.2 (MH+, 2Cl).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])[CH:5]=[C:4](Cl)[N:3]=1.[Si:19]([O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Si:19]([O:26][CH:27]1[CH2:28][CH2:29][N:30]([C:4]2[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=3)[CH3:10])[CH:5]=2)[CH2:31][CH2:32]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: C[C@H](Nc1cc(Cl)nc(Cl)n1)c1ccc(F)cn1
Reactant: CC(C)(C)[Si](C)(C)OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](Nc1cc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)nc(Cl)n1)c1ccc(F)cn1
Temperature: 130 °C
Yield: 49.2 %

Procedure:
A mixture of 2,6-dichloro-N-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]pyrimidin-4-amine (Preparation 10a, 0.66 g, 2.31 mmol), 4-(tert-butyl-dimethylsilanyloxy)piperidine (prepared as described in WO2004/006926, 0.60 g, 2.77 mmol) and cesium carbonate (1.13 g, 3.46 mmol) in N,N′-dimethylformamide (15 mL) was stirred and heated to 130° C. in a sealed tube for 2 hours. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate (×3). The combined organic extract was washed with water and brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexanes to 6:4 hexanes/ethyl acetate) to give the title compound (0.53 g, 50%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:68][O:69][C:70]1[CH:75]=[CH:74][CH:73]=[C:72]([NH2:76])[CH:71]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:76][C:72]2[CH:73]=[CH:74][CH:75]=[C:70]([O:69][CH3:68])[CH:71]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Reactant: COc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2cccc(OC)c2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47 %

Procedure:
A mixture of 3-iodo-phthalic acid dimethyl ester (1.0 g, 3.1 mmol), cesium carbonate (1.4 g, 4.3 mmol), Pd2(dba) (0.13 g, 0.14 mmol) and rac-BINAP (0.058 g, 0.093 mmol) in toluene (6 mL) was stirred at room temperature for 5 minutes. m-Anisidine (0.38 g, 3.1 mmol) was then added, and the reaction mixture was refluxed for 48 hours. The reaction mixture was diluted with methylene chloride (20 mL) and filtered through celite. The filter was washed with additional methylene chloride (25 mL). The combined filtrates were evaporated, and the residue was purified by ISCO silica gel flash chromatography using a hexanes-ethyl acetate gradient, eluting the product at 7:3 hexanes-ethyl acetate. It was then purified by preparative HPLC using an acetonitrile-water gradient, eluting the product at 6:4 acetonitrile:water to give the title product, 0.46 g in 47% yield; 1H NMR (CDCl3) δ 3.79 (s, 3H), 3.87 (s, 3H), 3.89 (s, 3H), 6.59-6.75 (m, 3H), 7.09-7.46 (m, 4H), 8.00 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:28]1([NH2:32])[CH2:31][CH2:30][CH2:29]1>>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([NH:32][CH:28]2[CH2:31][CH2:30][CH2:29]2)=[C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:16]#[N:17])[CH:4]=[C:3]([C:2]([F:26])([F:1])[F:27])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)C(C)C
Reactant: NC1CCC1
Product: CC(C)S(=O)(=O)C(C#N)=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CCC1
Yield: 89 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-methylsulfanyl-2-propenenitrile (0.500 g, 1.16 mmol) was stirred in cyclobutylamine (2 ml) for 24 h at 80° C. under nitrogen in a sealed flask. Work up as described in Example 40, 2) gave 470 mg (89%) of the title compound as white crystals. Mp 148-150° C. 1H NMR (200 MHz, CDCl3): δ=1.38 (d, 6H), 1.49-1.85 (m, 2H), 2.02 (q, 4H), 3.26 (heptet, 1H), 3.53-3.77 (m, 1H), 7.46 (s, 2H), 7.64 (s, 1H), 7.96-8.14 (m, 1H), 9.17 (brs, 1H)
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:13]O>>[ClH:1].[ClH:1].[NH2:3][C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: CO
Reactant: NC1(C(=O)O)CCNCC1
Agent: Cl
Product: COC(=O)C1(N)CCNCC1

Procedure:
Into a heterogeneous mixture of 4-amino-4-carboxypiperidine dihydrochloride (61.0 g, 0.34 mmol) in methanol (600 mL) is bubbled hydrogen chloride gas at room temperature. The reaction mixture is concentrated to dryness in vacuo, dissolved in 1,4-dioxane (200 mL), and concentrated in vacuo. The residue is redissolved in methanol (1600 mL) into which hydrogen chloride gas is bubbled for 45 minutes. The reaction mixture is refluxed for 18 hours. Most of the solvent is then evaporated, the product is collected by filtration, and washed with ethyl acetate to give 4-amino-4-carbomethoxypiperidine dihydrochloride.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:26]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1Br
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1Br
Yield: 61.3 %

Procedure:
1.79 g (0.0093 mol) of 1-benzyl-4-hydroxypiperidine and 2.3 ml (0.0164 mol) of triethylamine were dissolved in 70 ml of toluene and treated with 1.63 g (0.00745 mol) of 2-bromo-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 1.71 g (61%) of 1-benzyl-piperidin-4-yl 2-bromo-benzoate were obtained as yellowish crystals; m.p. 69°-70°.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][C:13]1([CH3:33])[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C:16]2[C:25]([CH3:32])=[C:26]([NH2:31])[C:27]([CH3:30])=[C:28]([CH3:29])[C:15]=2[O:14]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.[OH-].[Na+]>O1CCCC1>[CH3:12][C:13]1([CH3:33])[CH:17]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[C:16]2[C:25]([CH3:32])=[C:26]([N:31]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])[C:27]([CH3:30])=[C:28]([CH3:29])[C:15]=2[O:14]1
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C2c3c(C)c(N4C(=O)c5ccccc5C4=O)c(C)c(C)c3OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a solution of phthalic anhydride (566.4 mg, 3.82 mmol) in tetrahydrofuran (5 ml) was added a solution of 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine (987.3 mg, 3.38 mmol) in tetrahydrofuran(10 ml) and the resulting mixture was refluxed with heating for 11 hours. The reaction mixture was cooled down to room temperature and then concentrated under reduced pressure. Sodium acetate (314.6 mg, 3.84 mmol) and acetic anhydride (20 ml) were added into the residue and the resulting mixture was stirred at 90° C. for 2 hours. The reaction mixture was cooled down to room temperature and then an 8 N aqueous solution of sodium hydroxide was added into the mixture until it became basic. The product was extracted twice with ethyl acetate. The combined extracts were washed with an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate to obtain 1.16 g (81% yield) of the title compound. Melting point: 222-224° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].I[CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:13][CH:12]([O:10][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=1)[CH3:14]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 85.7 %

Procedure:
A mixture of 3-nitrophenol (20 g; 144 mmol), 2-iodopropane (21.45 m 36.6 g; 216 mmol) and potassium carbonate (23.8 g; 172 mmol) in dimethylformamide (100 ml) was stirred at 50° for 2 h and then the temperature was increased to 70° for a further 2 h. More 2-iodopropane (7.15 ml; 72 mmol) was added and stirring at 70° continued for a further 1.5 h whereupon the mixture was poured into water (400 ml) and extracted with ethyl acetate (2×400 ml). The combined organic extracts were washed with sodium hydroxide (300 ml), then saturated brine (300 ml), dried and evaporated. The residue was chromatographed on silica (675 g) using petroleum ether (40°-60°)-ethyl acetate (10:1) as eluant to give the title compound (Intermediate 43; 22.37 g; 86%) as a yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C@:6]([CH3:11])([C:8]([OH:10])=[O:9])[NH2:7].S(Cl)(Cl)=O.[CH3:19]O>>[I:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C@:6]([CH3:11])([C:8]([O:10][CH3:19])=[O:9])[NH2:7]
Reactant: C[C@@](N)(Cc1cccc(I)c1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@](C)(N)Cc1cccc(I)c1

Procedure:
A solution of 3-iodo-α-methyl-D-phenylalanine (0.9 g) in MeOH (50 ml) was treated with thionyl chloride (3.5 ml) and the mixture was heated to reflux for 3 days. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and washed with aqueous sodium bicarbonate, brine, dried (MgSO4) and evaporated to dryness to give the title compound (0.73 g) LCMS RT=2.12 min.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1)=[O:3].[OH:11][C@:12]1([CH3:35])[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:26]2[CH2:25][CH2:24][C@@:22]2([CH3:23])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[O:31][CH2:32][C:33]#[CH:34])[CH2:13]1>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:34]#[C:33][CH2:32][O:31][C@H:21]2[CH2:20][CH2:19][C@H:18]3[C@H:17]4[C@H:26]([CH2:25][CH2:24][C@:22]23[CH3:23])[C@:27]2([CH3:30])[C@H:14]([CH2:13][C@@:12]([OH:11])([CH3:35])[CH2:29][CH2:28]2)[CH2:15][CH2:16]4)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(I)cc1
Reactant: C#CCO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(=O)c1ccc(C#CCO[C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@](C)(O)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 68.4 %

Procedure:
A solution of 4-iodoacetophenone (16 mg, 0.06 mmol), 3α-hydroxy-3β-methyl-17β-(2-propynyloxy)-5α-androstane (22 mg, 0.06 mmol) in dry degassed triethylamine (1 mL) was stirred under argon at 23° C. Bis(triphenylphosphine)palladium chloride (2 mg) and CuI (2 mg) were added and the mixture was stirred at this temp. for 45 min. CH2Cl2 (4 mL) was added and the mixture was stirred at 23° C. for 1 hr. The TLC showed 100% conversion of the starting material, hence, the solvent was removed and the residue was purified by chromatography on silica gel. Elution with hexane:acetone (85:15) gave 17β-[3-(4-acetylphenyl)-2-propynyloxy]-3α-hydroxy-3β-methyl-5α-androstane (19 mg) as a colorless solid; mp 52-55° C.; TLC Rf (hexane:acetone 85:15)=0.15.
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:8]=[CH:7][C:6]=1[C:17]([O:19]CC)=[O:18])#[N:4].O.Cl>C(O)C>[C:3]([C:5]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[N:8]=[CH:7][C:6]=1[C:17]([OH:19])=[O:18])#[N:4]
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2)c1C#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Yield: 83.4 %

Procedure:
A hot solution of 5.61 g of potassium hydroxide dissolved in 110 ml of 3A ethanol was added to a hot solution of 11.3 g of 5-cyano-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester dissolved in 225 ml of 3A ethanol. The precipitated salt that was formed was dissolved into 1 liter of water and the solution was acidified with concentrated hydrochloric acid. The precipitated solid was collected by filtraton and recrystallized from toluene to provide 8.47 g of 5-cyano-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylic acid. MP=192°-195° C.