Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[OH:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[N:3][C:2]([C:21]3[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=3)=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CCN(c2ccc(Cl)nn2)CC1
Reactant: OB(O)c1ccc(O)cc1
Product: CC(C)N1CCN(c2ccc(-c3ccc(O)cc3)nn2)CC1

Procedure:
4-[6-(4-Isopropyl-piperazin-1-yl)-pyridazin-3-yl]phenol was prepared by the general procedure I similar to that described in Example 71, starting from 3-chloro-6-(4-isopropyl-piperazin-1-yl)-pyridazine and (4-hydroxyphenyl)boronic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]([O:16]CC)=[O:15])[C:5]2[N:10]([CH:11]=1)[CH2:9][CH2:8][S:7](=[O:13])(=[O:12])[N:6]=2.[OH-].[Na+].Cl.O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[N:10]([CH:11]=1)[CH2:9][CH2:8][S:7](=[O:12])(=[O:13])[N:6]=2
Reactant: CCOC(=O)C1=CC(C)=CN2CCS(=O)(=O)N=C12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1=CN2CCS(=O)(=O)N=C2C(C(=O)O)=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of ethyl 7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine-9-carboxylate 2,2-dioxide (106 mg) in methanol (1 ml) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added 1N hydrochloric acid (1.05 mL) and water (1 mL), and the resulting precipitate was collected by filtration, washed successively with water and a small amount of THF, and dried to give the title compound (79 mg) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.CON(C)[C:16](=[O:30])[C@@H:17]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:18].[NH4+].[Cl-]>C(Cl)Cl.C([O-])([O-])=O.[K+].[K+].C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:16](=[O:30])[C@@H:17]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:18])[CH:3]=1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: Clc1ccncc1
Agent: CC(C)[Mg]Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(dimethylamino)ethanol (471 mg, 531 mL, 5.28 mmol) in dry hexanes (3.3 mL) was cooled to −5° C. and n-butyllithium (1.6 M in hexanes, 6.60 mL, 10.6 mmol) was added dropwise under N2. After 30 min at 0° C., the solution was cooled to −78° C. and a solution of 4-chloropyridine (obtained by washing a solution of the corresponding HCl salt (264 mg, 1.76 mmol) in CH2Cl2 (20 mL) with saturated K2CO3 (10 mL), then back extracting with CH2Cl2 (2×20 mL), combining the organic layers, drying (Na2SO4) and concentrating in vacuo) in hexanes (3.3 mL) was added dropwise by cannula. The solution became dark red in color and after 1 h at −78° C., a solution of the electrophile (prepared by adding isopropylmagnesium chloride (2M in THF, 1.29 mL, 2.59 mmol) to a solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (702 mg, 2.64 mmol) in dry THF (3.5 mL) at −15° C. under N2 and stirring for 15 min) was added by cannula. The reaction was allowed to warm slowly to room temperature overnight. Water (25 mL) and saturated NH4Cl (50 mL) were added and the mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-30% EtOAc in hexanes gradient) to afford benzyl [(1S)-2-(4-chloropyridin-2-yl)-1-methyl-2-oxoethyl]carbamate. Rf=0.46 (20% EtOAc in hexanes). LCMS calc.=319.1; found=319.3 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 8.58 (d, J=5.0 Hz, 1H), 8.04 (s, 1H), 7.47 (dd, J=5.2, 2.0 Hz, 1H), 7.35-7.30 (m, 5H), 5.78 (s, 1H), 5.72 (m, 1H), 5.11 (m, 2H), 1.47 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:21])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CO.O>[Cl:1][C:2]1[C:3](=[O:21])[NH:4][N:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=c1c(Cl)c(Oc2ccccc2)cnn1C1CCCCO1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=c1[nH]ncc(Oc2ccccc2)c1Cl
Temperature: 110 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
A solution of 4-chloro-5-phenoxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (2.84 g, 9.25 mmol) in methanol (6.17 mL, 1.5M) was treated with a 6N aqueous hydrochloric acid solution (7.71 mL, 1.2M). The reaction solution was heated to 110° C., where it stirred for 4 h and was then allowed to completely cool down to 25° C. The reaction was then diluted with water (200 mL). The resulting white precipitate was collected by filtration, washed with water (2×50 mL), and dried in vacuo to afford 4-chloro-5-phenoxy-2H-pyridazin-3-one (1.78 g, 86%) as a white solid; ES+-HRMS m/e calcd for C10H7N2O2Cl [M+H+] 223.0269, found 223.0269.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5](#N)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>[O-2].[Cd+2].C(O)(=O)C>[CH2:6]([C:5]1[O:2][CH2:1][CH2:3][N:4]=1)[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: NCCO
Reactant: CCCCCC#N
Agent: [Cd+2]
Agent: [O-2]
Solvent: CC(=O)O
Product: CCCCCC1=NCCO1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A mixture of about 3.24 grams cadmium oxide, about 3.00 grams acetic acid, about 64.8 grams ethanolamine, and about 98.2 grams hexanenitrile is heated and stirred under nitrogen at about 120 degrees C. to 125 degrees C. for about two days. The liquid is decanted from the catalyst and distilled under vacuum. The fraction boiling at about 86 degrees C. to about 93 degrees C. at about 28 mmHg to about 30 mm Hg is collected.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:32]=[CH:31][C:7]([O:8][C:9]2[CH:30]=[CH:29][C:12]([CH2:13][NH:14][C:15]([C:17]3([NH:20][C:21]([C:23]4[CH:24]=[N:25][CH:26]=[N:27][CH:28]=4)=[O:22])[CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)=[C:6]([C:33]([F:36])([F:35])[F:34])[CH:5]=1)[CH3:3]>ClCCl.[O-2].[O-2].[Mn+4]>[C:2]([C:4]1[CH:32]=[CH:31][C:7]([O:8][C:9]2[CH:30]=[CH:29][C:12]([CH2:13][NH:14][C:15]([C:17]3([NH:20][C:21]([C:23]4[CH:28]=[N:27][CH:26]=[N:25][CH:24]=4)=[O:22])[CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)=[C:6]([C:33]([F:34])([F:35])[F:36])[CH:5]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cncnc4)CC3)cc2)c(C(F)(F)F)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)c1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cncnc4)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21 %

Procedure:
A solution of 70 mg (0.14 mmol) of pyrimidine-5-carboxylic acid(1-{4-[4-(1-hydroxyethyl)-2-trifluoromethyl-phenoxy]-benzylcarbamoyl}-cyclopropyl)amide (product from Example 153) in 10 mL dichloromethane was combined with 300 mg (3.5 mmol) of manganese dioxide and stirred for three days at ambient temperature. The mixture was then filtered and evaporated down. The crude product thus obtained was purified by chromatography (reversed phase HPLC).
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH:11]1[C:10]1[C:9]([OH:13])=[CH:8][CH:7]=[CH:6][C:5]=1[O:4][CH2:3]2.C([O-])([O-])=O.[K+].[K+].Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1>CN(C)C=O>[CH3:1][C:2]12[CH2:12][CH:11]1[C:10]1[C:9]([O:13][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=3)=[CH:8][CH:7]=[CH:6][C:5]=1[O:4][CH2:3]2
Reactant: CC12COc3cccc(O)c3C1C2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC12COc3cccc(Oc4ccc([N+](=O)[O-])cn4)c3C1C2
Temperature: 110 °C
Yield: 77.7 %

Procedure:
To a solution of 1a-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-7-ol (Intermediate 125, 190 mg) in dry N,N-dimethylformamide (10 ml) were added K2CO3 (447 mg, 3.23 mmol) and 2-chloro-5-nitropyridine (171 mg, 1.078 mmol) to give a light brown solution. The reaction was heated at 110° C. for 1 hour and then quenched with water, extracted with ethyl acetate, washed with brine, dried over sodium sulphate, filtered and concentrated under vacuum. The residue obtained was purified by silica gel chromatography (Companion system, with a gradient from pure Cyclohexane to cyclohexane/ethyl acetate 5/1) to give the title compound as a light brown solid (250 mg).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:6]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([C:14]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[O:15])=[CH:10][CH:9]=3)[N:5]=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: O=C(c1ccc(Cn2nccc2Br)cc1)N1CCCC1
Reactant: OB(O)c1ccc(O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(Cn2nccc2-c2ccc(O)cc2)cc1)N1CCCC1
Temperature: 140 °C
Yield: 71.1 %

Procedure:
To a solution of (4-((5-bromo-1H-pyrazol-1-yl)methyl)phenyl)(pyrrolidin-1-yl)methanone (231 mg, 0.7 mmol) in dioxane:water (5:1, 25 ml) was added (4-hydroxyphenyl)boronic acid (207 mg, 1.5 mmol), Cs2CO3 (487 mg, 1.5 mmol) and Pd(dppf)Cl2 (86 mg) and the mixture purged with nitrogen. The mixture was then stirred at 140° C. under microwave mediated heating irradiation for 40 min. The mixture was diluted with water, extracted with ethyl acetate three times and the organic layer dried over Na2SO4 before concentration. The crude product was then purified by column chromatography to yield the desired product (173 mg, yield 70%). LCMS (m/z): 348.2 [M+H]+
Reaction SMILES: C1(C)C=CC=CC=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].[CH2:22]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][C@H:33]2[CH2:38][CH2:37][C@H:36]([C:39](OCC)=[O:40])[CH2:35][CH2:34]2)[CH2:27][CH2:26]1)[CH2:23][CH3:24].Cl>C1(C)C=CC=CC=1>[CH2:22]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][C@H:33]2[CH2:34][CH2:35][C@H:36]([CH2:39][OH:40])[CH2:37][CH2:38]2)[CH2:27][CH2:26]1)[CH2:23][CH3:24]
Reactant: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C(=O)OCC)CC2)CC1
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](CO)CC2)CC1
Temperature: 25 °C

Procedure:
A 70% sodium bis(2-methoxyethoxy)aluminum hydride toluene solution (60.0 g) was added by titration to a toluene solution (100 mL) of ethyl trans-4-(2-(trans-4-propylcyclohexyl)ethyl)cyclohexanecarboxylate (55.1 g), and thereafter, the resultant was continuously stirred until it cooled down to room temperature due to subdued heating. After the reaction was halted by adding ice water to a reaction solution, toluene was added, and concentrated hydrochloric acid was added until the dissolution of the deposited solid. An organic layer was separated and extracted with toluene from a water layer. Thus collected organic layer was washed by using water, a saturated sodium bicarbonate aqueous solution and brine in that order, and dried with anhydrous magnesium sulphate. Solvents were removed by distillation to obtain a slightly yellow solid of 47.3 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([CH3:13])=[C:6]([I:14])[CH:5]=1>C1COCC1.CO>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[C:6]([I:14])[C:7]([CH3:13])=[C:8]([NH2:10])[CH:9]=1
Reactant: COC(=O)c1cc(I)c(C)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(N)c(C)c(I)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 67.3 %

Procedure:
To a solution of 3-iodo-4-methyl-5-nitro-benzoic acid methyl ester (2.0 g, 6.23 mmol) in a mixture of THF (40 mL) and methanol (1 mL) was added SnCl2 dihydrate (4.22 g, 18.69 mmol). The reaction mixture was stirred at 60° C. for six hours, then cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford 1.22 g (67%) of 3-amino-5-iodo-4-methyl-benzoic acid methyl ester.
Reaction SMILES: O.[O:2]1CCCC1.[CH3:7][C:8](/[CH:15]=[CH:16]/[CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[BH4-].[Na+]>[OH-].[Na+]>[OH:2][C:22]([CH3:23])([CH3:24])[CH2:21][CH2:20][CH2:19][CH:18]([CH3:25])[CH2:17][CH:16]=[CH:15][C:8]([CH3:7])=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: C1CCOC1
Reactant: CCOC(=O)C=C(C)/C=C/CC(C)CCC=C(C)C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C=C(C)C=CCC(C)CCCC(C)(C)O
Reaction time: 0.33 h

Procedure:
To a mixture of 1.9 g. of mercuric acetate, 6 ml. of water and 20 ml. of tetrahydrofuran is added 1.49 g. of trans ethyl 3,7,11-trimethyldodeca-2,4,10-trienoate slowly. After addition is complete, the reaction mixture is stirred for about 20 minutes. The mixture is cooled to about 0° and 6 ml. of aqueous sodium hydroxide (3 molar) is added followed by 0.49 g. of sodium borohydride in aqueous sodium hydroxide (about 3 molar). The mixture is stirred for about 30 minutes. The mixture is then decanted, concentrated, diluted with water and then extracted with ether. The ethereal extract is washed with water, dried over magnesium sulfate and the product chromatographed on silica gives ethyl 11-hydroxy-3,7,11-trimethyldodeca-2,4-dienoate (trans).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[C:9]([CH:13]1[CH2:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:16]2=[C:24]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:25]3[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:30]=3[N:15]2[CH2:14]1)([O:11][CH3:12])=[O:10].IC>C1COCC1>[CH:35]1([C:24]2[C:25]3[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:30]=3[N:15]3[CH2:14][C:13]([C:9]([O:11][CH3:12])=[O:10])([CH3:2])[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=23)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)Cc1ccccc1-3
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C)(C(=O)OC)Cc1ccccc1-3
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A solution of LDA in THF (1.2 mL of 0.5 N, 0.60 mmol) was added to a solution of methyl (±)-6-carbomethoxy-13-cyclohexyl-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (160 mg, 0.37 mmol) in THF (5 mL) at −78° C. Stirring was continued at −78° C. for 15 min when the mixture was slowly warmed to −50° C. Iodomethane (35 μL, 0.56 mmol) was added and the mixture was slowly warmed to −10° C. Stirring was continued for 30 min. The solution was quenched with MeOH. The solution was extracted with ethyl acetate and the extract washed with dilute HCl (2×), brine (3×), and then dried (Na2SO4). The extract was concentrated and the crude product purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (140 mg, 85%). ESI-MS m/z 446 (MH+) 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.19-1.33 (m, 3 H) 1.31-1.52 (m, 3 H) 1.63-1.84 (m, 3 H) 1.87-2.15 (m, 4 H) 2.34 (d, J=13.73 Hz, 0.4 H) 2.70 (d, J=13.73 Hz, 0.6 H) 2.88-3.12 (m, 2 H) 3.21 (d, J=13.73 Hz, 0.4 H) 3.33 (d, J=14.65 Hz, 0.6 H) 3.75 (d, J=10.68 Hz, 3 H) 3.95 (s, 3 H) 4.34 (d, J=14.65 Hz, 0.4 H) 4.87 (d, J=14.65 Hz, 0.6 H) 7.30-7.48 (m, 4 H) 7.69-7.79 (m, 1 H) 7.82-7.92 (m, 1 H) 8.11 (s, 0.4 H) 8.22 (s, 0.6 H).
Reaction SMILES: O=[CH:2][C:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[BH4-].[Na+]>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:19]1([C:3]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([CH2:2][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)NCC(C=O)(c1ccccc1)c1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(CN1CCCCC1)(c1ccccc1)c1ccccc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
A mixture of tert-butyl 3-oxo-2,2-diphenylpropylcarbamate (0.60 g, 1.844 mmol) and piperidine (0.314 g, 3.688 mmol) in ethanol (10 mL) was treated with titanium isopropoxide (1.62 mL, 5.53 mmol) and this was stirred at 65° C. overnight. The reaction was then cooled down to 23° C. and sodium borohydride (0.279 g, 7.38 mmol) was added. The reaction was stirred for 2 more hours, then quenched with 10% ammonium hydroxide (10 mL), diluted with ethyl acetate and stirred for 30 minutes. The solid was removed by filtration and the filtrate was acidified with 1N HCl and washed with ethyl acetate. The filtrate was then basified with sat. aq. sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude title material (0.28 g) as a colorless film. This was purified by silica gel chromatography (Biotage, ethyl acetate/hexane 20% to 50%) to give tert-butyl 2,2-diphenyl-3-(piperidin-1-yl)propylcarbamate (0.13 g, 18%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm: 1.28-1.46 (6H, m), 1.41 (9H, s), 2.04-2.11 (4H, m), 3.06 (2H, br s), 3.98 (2H, d, J=5.56 Hz), 7.19-7.30 (10H, m). HPLC ret. time (Condition B): 2.633 min. LC/MS (M+H)+: 395.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[S:19][N:20]=[C:21]3[C:26]=2[CH:25]=[CH:24][CH:23]=[N:22]3)[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.[OH-].[Na+].OO.CC(O)=[O:33]>CCO.CS(C)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[S:19][N:20]=[C:21]3[C:26]=2[CH:25]=[CH:24][CH:23]=[N:22]3)[C:12]([C:15]([NH2:16])=[O:33])=[N:13][CH:14]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1snc2ncccc12
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1snc2ncccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-((1R,2S)-2-aminocyclohexylamino)-3-(isothiazolo[3,4-b]pyridin-3-ylamino)pyrazine-2-carbonitrile (36 mg) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (1 mL) and aq. H2O2 (30%, 1 mL) were added. The mixture was stirred at room temperature for 20 h. After being neutralized with HOAc (0.3 mL), the mixture was purified by HPLC to give the titled compound (7 mg). MS found for C17H20N8OS as (M+H)+ MS 385.3. UV: λ=UV 207.4, 245.8, 298.6, 343.2 nm. 1H NMR: (CD3OD) δ 8.50 (dd, 1H), 8.22 (dd, 1H), 7.73 (s, 1H), 7.05 (dd, 1H), 4.70-4.62 (m, 1H), 4.12-4.05 (m, 1H), 2.14-1.60 (m, 8H).
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:9]=[CH:8]2)([CH2:3]C)[CH3:2].C(C1C=CC(NCC(OCC)OCC)=CC=1)(CC)C>>[CH:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14](=[O:19])[C:15]([F:16])([F:17])[F:18])[CH:9]=[CH:8]2)([CH3:3])[CH3:2]
Reactant: CCC(C)c1ccc2c(ccn2C(=O)C(F)(F)F)c1
Agent: CCOC(CNc1ccc(C(C)CC)cc1)OCC
Product: CC(C)c1ccc2c(ccn2C(=O)C(F)(F)F)c1

Procedure:
5-Sec-butyl-1-trifluoroacetylindole; from 4-sec-butyl-N-(2,2-diethoxyethyl) aniline (Example 1c) (18%).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1.C[Si](C)(C)[Cl:34]>CC(CC)=O>[ClH:34].[CH3:31][N:2]([CH3:1])[C:3]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][CH2:5][CH:6]([NH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:7][CH2:8]1.[CH3:31][N:2]([CH3:1])[C:3]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][CH2:5][CH:6]([NH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(NC(=O)NCCc2c[nH]c3ccc(F)cc23)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
In order to produce the hydrochloride (compound 20), the more polar diastereoisomer of 1-(4-dimethylamino-4-phenylcyclohexyl)-3-[2-(5-fluoro-1H-indol-3-yl)ethyl]urea (267 mg, 0.63 mmole) was dissolved in ethyl methyl ketone (5 ml) and combined with trimethylchlorosilane (120 μl, 0.95 mmole). The resulting solid was filtered out and dried. The hydrochloride of the more polar diastereoisomer of 1-(4-dimethylamino-4-phenylcyclohexyl)-3-[2-(5-fluoro-1H-indol-3-yl)ethyl]urea was obtained in this manner as a colorless solid with a melting point of 219-221° C. in a yield of 290 mg (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(N(CC)CC)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[N:10]([C:27](=[O:29])[CH3:28])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC1Cc2cc3c(cc2C(c2ccc(N)cc2)=NN1)OCO3
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1C)OCO3
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of 3.58 g (12.1 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine in 100 ml of chloroform first 1.68 ml (12.1 mmol) of triethylamine, then under constant ice-cooling and stirring 1.15 ml (12.1 mmol) of acetic anhydride were added. Stirring was continued for additional 2 hours, then the solution was extracted with 3×100 ml of water, the organic layer was dried and evaporated under reduced pressure. The crystalline residue was recrystallized from 40 ml of isopropanol to obtain 3.50 g (85.7%) of the aimed product, m.p. 220°-222° C. After repeated recrystallization the m.p. increased to 223°-225° C.
Reaction SMILES: O[CH2:2][C:3]#[C:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:12][CH2:2][C:3]#[C:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)C#CC#CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)C#CC#CCBr
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A solution of 5.0 g (37.3 mmole) of 1-hydroxy-6,6-dimethyl-2,4-heptadiyne and 14.8 g (44.7 mmole) of carbon tetrabromide in 250 mL of H2CCl2 was cooled to 0°-5° C. and 12.7 g (48.4 mmole) of triphenylphosphine was added thereto. The so formed mixture was stirred for 2 hours at 0°-5° C. The reaction mixture was concentrated to about 50 ml and poured into 1 liter of petroleum ether. The mixture was stirred 15 min. and the petroleum ether was removed by decantation. The oily residue was stirred for 15 min. with another 1 liter of petroleum ether which was decanted off. The combined petroleum ether extracts were concentrated to an oil which was chromatographed on silica gel, eluting with petroleum ether to give 6.87 g of the title compound, M/e, M+ 200.