Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[C:12]([C:16](=O)[CH2:17][C:18](=[O:20])[CH3:19])[CH:13]=[CH:14][CH:15]=1.[C:22](=[S:24])=[S:23].O>C1COCC1>[Br:9][C:10]1[CH:11]=[C:12]([C:16]2[S:23][C:22]([SH:24])=[CH:19][C:18](=[O:20])[CH:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)CC(=O)c1cccc(Br)c1
Reactant: S=C=S
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1cc(S)sc(-c2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of LDA (20 mL, 40 mmol) in 40 mL anhydrous THF under an atmosphere of nitrogen was added slowly a solution of 1-(3-Bromophenyl)-butane-1,3-dione (4.84 g, 20 mmol) dissolved in THF (30 mL). After addition was complete the mixture was allowed to warm slowly to ambient temperature and stir for 10 minutes. The solution was re-cooled to −78° C. for the addition of a solution of carbon disulfide (1.2 mL, 20 mmol) in THF (20 mL). This temperature was maintained for 2 hours, before warm warmed slowly to ambient temperature and stirred for 18 hours. Cold water (150 mL) was added and mixture was heated to 60° C. with good stirring for 3 hours. The volatiles were removed in vacuo and the aqueous solution was washed with diethyl ether (2×100 mL). The aqueous solution was acidified to pH 1 with 2N HCl, and the orange precipitate was filtered from the acid, washed with water, and dried by vacuum desiccation. Orange solid (4.28 g, 72%); m.p. 188° C. (decomp); LCMS m/z 299, 301 ([M+1]+) 298, 300 ([M−1]−), 1H-NMR (D6-DMSO): 7.07 (d, 1H, J=1.4 Hz, H-3), 7.36 (d, 1H, J=1.4 Hz, H-5), 7.47–7.52 (dd, 1H, J1=J2=7.9 Hz, Ar-5), 7.69–7.72 (d, 1H, J=7.9 Hz, Ar-4/6), 7.76–7.78 (d, 1H, J=7.9 Hz, Ar-4/6), 7.92 (s, 1H, Ar-2); infrared spectrum (cm−1): 815, 950, 1008, 1072, 1202, 1451, 1364, 1451, 1487, 1508, 1584.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]([NH:18][C@H:19]([B:32]2OC3C(C)(C4CC(C3)C4(C)C)[O:33]2)[CH2:20][C:21]2[C:22]([O:30]C)=[C:23]([CH:27]=[CH:28][CH:29]=2)[C:24]([OH:26])=[O:25])=[O:17])[CH2:11][CH2:10]1)=O)(C)(C)C.B(Cl)(Cl)Cl>>[NH2:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][C:16]([NH:18][C@H:19]2[CH2:20][C:21]3[CH:29]=[CH:28][CH:27]=[C:23]([C:24]([OH:26])=[O:25])[C:22]=3[O:30][B:32]2[OH:33])=[O:17])[CH2:13][CH2:14]1
Reactant: COc1c(C[C@H](NC(=O)C[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Agent: ClB(Cl)Cl
Product: N[C@H]1CC[C@@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
Prepared from 3-((2R)-2-(2-(cis-4-(tert-butoxycarbonylamino)cyclohexyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoic acid and BCl3 following the procedure described in Step 2 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 347 (MH)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:10][C:11]2[CH:15]=[C:14]([C:16]3[S:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[O:13][N:12]=2)[CH:7]=[N:8][CH:9]=1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:21][C:18]1[S:17][C:16]([C:14]2[O:13][N:12]=[C:11]([CH2:10][N:6]3[C:5]([C:3]([OH:4])=[O:2])=[CH:9][N:8]=[CH:7]3)[CH:15]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cncn1Cc1cc(-c2ccc(Cl)s2)on1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cncn1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 720 mg 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazole-4-carboxylic acid methyl ester in 10 ml THF and 3 ml water, 57.0 mg lithium hydroxide monohydrate were added. After stirring for 2 h at 60° C. the reaction was cooled to RT. The mixture was acidified with half concentrated hydrochloric acid and the precipitate collected by filtration and washed with 3 ml water. The product was obtained as a white solid which was dried under reduced pressure. Yield: 650 mg
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[ClH:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[C:11]([OH:13])=[O:12]>C(O)(C(F)(F)F)=O>[ClH:5].[CH3:6][O:7][C:8]1[C:16]([O:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:15][C:14]([N+:1]([O-:4])=[O:2])=[C:10]([CH:9]=1)[C:11]([OH:13])=[O:12]
Reactant: COc1cc(C(=O)O)ccc1OCCCN1CCCC1
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Fuming nitric acid (2.4 ml, 57.9 mmol) was added slowly at 0° C. to a solution of 3-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid hydrochloride (12.15 g, 38.17 mmol) in TFA (40 ml). The cooling bath was removed and the reaction mixture stirred at ambient temperature for 1 hour. The TFA was removed by evaporation and ice/water was added to the residue and the solvent removed by evaporation. The solid residue was dissolved in dilute hydrochloric acid (pH2.2), poured onto a Diaion (trade mark of Mitsubishi) HP20SS resin column and eluted with methanol (gradient 0 to 50%) in water. Concentration of the fractions by evaporation gave a precipitate which was collected by filtration and dried under vacuum over phosphorus pentoxide to give 5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid hydrochloride (12.1 g, 90%).
Reaction SMILES: [NH2:1][C@H:2]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH2:3][OH:4].Cl.CCN(C(C)C)C(C)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:5]1([C@@H:2]2[CH2:3][O:4][C:22](=[O:24])[NH:1]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: N[C@@H](CO)C1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1N[C@H](C2CCCCC2)CO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (R)-2-Amino-2-cyclohexyl-ethanol.HCl salt (1.0 g, 5.57 mmol, 1.0 equiv) in CH2Cl2 (30.0 mL) at 0° C. was added DIPEA (1.94 mL, 11.1 mmol, 2.0 equiv) followed by triphosgene (4.95 g, 16.7 mmol, 3.0 equiv) and the resulting solution was stirred at room temperature for 12 hours. The solution was then concentrated and the residue was diluted with EtOAc. The solution was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, (EtOAc 100%) to give product 520 mg.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1.CN(C)C=O>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:4]=1[O:3][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])#[N:7]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(OCc2ccccc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)COc1cc(OCc2ccccc2)ccc1C#N
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
9.7 g (0.20 mol) of 50% sodium hydride are slowly added portionwise to a solution of 46 g (0.20 mol) of 2-hydroxy-4-(phenylmethoxy)benzonitrile in a mixture of 450 ml of tetrahydrofuran and 450 ml of dimethylformamide. The mixture is stirred for 30 minutes and then 22.4 ml (0.20 mol) of ethyl bromoacetate are added dropwise. Reaction is allowed to take place for 30 minutes, the reaction mixture is then poured into ice-cold water and the product is extracted with ethyl acetate. The organic phase is then washed with water, dried over sodium sulphate and concentrated under reduced pressure. After trituration of the residue in diisopropyl ether, 50 g of product are obtained.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH:8]2[CH2:9][CH2:10][CH:4]1[CH2:5][N:6]([CH2:11][CH2:12][CH2:13][NH:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[CH2:7]2.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][CH2:13][CH2:12][CH2:11][N:6]2[CH2:7][CH:8]3[CH:3]([N:2]([CH3:1])[C:24](=[O:25])[O:26][CH2:27][CH3:28])[CH:4]([CH2:10][CH2:9]3)[CH2:5]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: CCOC(=O)Cl
Reactant: CNC1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N(C)C1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
A mixture of 4-({3-[8-(methylamino)-3-azabicyclo[3.2.1]oct-3-yl]propyl}amino)benzonitrile (Preparation G; 74.6 mg, 0.25 mmol) and ethyl chloroformate (29.8 mg, 0.27 mmol) in DMF (2.5 mL) was stirred at rt for 24 h. Mass spectroscopic analysis showed that the amine starting material had not been totally consumed, and so additional ethyl chloroformate (50 μL) was added. The mixture was stirred overnight, after which time it was concentrated in vacuo. The resulting residue was dissolved in a mixture of DCM (0.5 mL) and MeCN (2 mL). K2CO3 (100 mg, 0.7 mmol) was added and the mixture stirred for 4 h. Filtration of the mixture and evaporation of the filtrate gave a residue that was dissolved in CHCl3 (1 mL). The solution was filtered through an ion-exchange solid-phase extraction plug (CBA, 2 g). The source flask was washed with additional CHCl3 (0.75 mL), which was then added to the extraction plug, and eluted as fraction 1. The plug was then eluted with CHCl3:MeOH:TEA (8:1:1; 4×2 mL) to give further fractions that were found not to contain any product. Fraction 1 was then added to a silica plug, which was eluted with CHCl3:MeCN (4:1; 3×2.5 mL). Evaporation of the fractions collected gave 79.6 mg (85.9%) of the title compound.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][O:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH2:34])[CH2:23][CH3:24])[CH3:21]>C(#N)C>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][O:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH:34][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH2:23][CH3:24])[CH3:21]
Reactant: CCN(CC)CC1COCCN1CCN
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC#N
Product: CCN(CC)CC1COCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 67 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[(diethylamino)methyl]-morpholin-4-yl]ethanamine in a yield of 67% of theory. Colourless crystals, m.p. 150°-151° C. (acetonitrile).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10]([Cl:13])(=[O:12])=[O:11])[CH:9]=1)(=O)[NH2:2].S(Cl)(Cl)=O.CN(C)C=O>C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10]([Cl:13])(=[O:12])=[O:11])[CH:9]=1)#[N:2]
Reactant: COc1ccc(C(N)=O)cc1S(=O)(=O)Cl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1S(=O)(=O)Cl
Temperature: 55 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
5-Carbamoyl-2-methoxybenzenesulfonyl chloride (150 g) was suspended in 1800 mL of ethyl acetate. After 219 mL of thionyl chloride was dropped to the stirred suspension under ice-cooling, 2.3 mL of N,N-dimethylformamide was added to the mixture. After being stirred at 55° C. for 3 hours, the reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and water, and the separated organic layer was washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained crude product was recrystallized from ethyl acetate-hexane to give 86.8 g of 5-cyano-2-methoxybenzenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH2:12][O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH2:12][O:13][CH3:14]
Reactant: COCCBr
Reactant: Oc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(F)cc1Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To 2-chloro-4-fluorophenol (52, 2.40 mL, 0.0213 mol) in N,N-dimethylformamide (30.0 mL), 1-bromo-2-methoxy-ethane (2.00 mL, 0.0213 mol) and potassium carbonate (3.00 g, 0.0217 mol) were added under an atmosphere of nitrogen. The reaction was stirred at 80° C. for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (122, 1.50 g, 34.4%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=O)=[CH:6][C:5]=1[C:14]([OH:16])=[O:15])([O-:3])=[O:2].Cl.[CH2:18]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([NH:34]N)[C:29]=2[F:36])=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH3:21]>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[CH2:18]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]3[C:9]4[CH2:8][C:7]5[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:14]([OH:16])=[O:15])[CH:6]=5)[C:10]=4[NH:34][C:30]=3[C:29]=2[F:36])=[CH:26][CH:27]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1ccc(-c2cccc(NN)c2F)cc1
Reactant: O=C1CCc2cc(C(=O)O)c([N+](=O)[O-])cc21
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2F)-c2cc([N+](=O)[O-])c(C(=O)O)cc2C4)cc1
Temperature: 105 °C
Yield: 41.2 %

Procedure:
A sealable reaction vial was charged with 6-nitro-1-oxo-indan-5-carboxylic acid (26 mg, 0.12 mmol), (4′-Butyl-2-fluoro-biphenyl-3-yl)-hydrazine hydrochloride (example 78, step 1) (25 mg, 0.12 mmol), zinc (II) chloride (24 mg, 0.18 mmol), and acetic acid (1.5 mL), sealed, and heated to 105° C. overnight. Reaction was then cooled to RT, concentrated in vacuo, and purified by UV-triggered HPLC to afford 22 mg (41%) of 7-(4-Butyl-phenyl)-6-fluoro-3-nitro-5,10-dihydro-indeno[1,2-b]indole-2-carboxylic acid; LC/MS calculated for [M+H]+ C26H21FN2O4: 445.1, found: 445.1.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1>>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)=[O:9]
Reactant: Cc1ccc(CCN)cc1
Reactant: Cc1ccoc1C(=O)O
Product: Cc1ccc(CCNC(=O)c2occc2C)cc1

Procedure:
Prepared in a similar manner as described in example 4 from 3-methylfuran-2-carboxylic acid and 2-p-tolylethanamine. MS (M+H, 244).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:17][C:16](=O)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([N:1]2[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: O[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CC[C@H](O)C2)C1
Yield: 53.6 %

Procedure:
A mixture of (S)-pyrrolidin-3-ol (261 mg, 3.0 mmol), 3-oxoazetidine-1-carboxylic acid tert-butyl ester (513 mg, 3.0 mmol) and 4 Å powdered molecular sieves (1.0 g) in DCE (10 mL) was stirred at room temperature for 6 h before the addition of sodium triacetoxyborohydride (1.27 g, 6.0 mmol). The reaction mixture was filtered through celite, washing with DCM. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, Acetone:DCM, 0-40%) affording 3-((S)-3-Hydroxypyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a brown oil (390 mg, 54%). LCMS (Method A): RT 0.28 min [M+H]+ 243.0
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH2:30][CH2:31][CH3:32])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:33][CH3:34])=O)C1C=CC=CC=1>[Pd].CO>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH2:30][CH2:31][CH3:32])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:33][CH3:34]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)oc1CCC
Agent: [Pd]
Solvent: CO
Product: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)oc1CCC
Yield: 96.8 %

Procedure:
The same operation as in Example (95b) was performed using butyl cis(±)-2-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-propyl-1,3-oxazole-4-carboxylate obtained in Example (116b) (1.0 g, 2.1 mmol), 10% Pd/C (0.25 g) and methanol (10 mL), to obtain 0.69 g of the title compound as a yellow oily substance (96%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][CH:19]3[CH2:23][CH2:22][NH:21][CH2:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][CH:19]3[CH2:23][CH2:22][N:21]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OCC1CCNC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OCC1CCN(S(C)(=O)=O)C1
Yield: 67 %

Procedure:
Using a similar procedure to that described in Example 29, 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(pyrrolidin-3-ylmethoxy)quinazoline hydrochloride (300 mg) was reacted with methane sulfonyl chloride to give the title product (200 mg, 67%); 1H-NMR Spectrum: (DMSO d6+CD3COOD) 1.75-1.89 (m, 1H); 2.08-2.18 (m, 1H); 2.77-2.86 (m, 1H); 2.91 (s, 3H); 3.12-3.18 (m, 1H); 3.25-3.43 (m, 2H); 3.47-3.52 (m, 1H); 3.94 (s, 3H; 4.06-4.09 (m, 2H); 7.15-7.30 (m, 2H); 7.43-7.53 (m, 2H): 7.81 (s, 1H); 8.38 (s, 1H); Mass Spectrum: (M+H)+ 481.
Reaction SMILES: C1(C(N)=O)CC1.[F:7][C:8]([F:12])([F:11])[CH2:9][NH2:10].[CH:13]1([C:16]2N(C)[C:19]([CH:22]=[O:23])=[CH:18][N:17]=2)[CH2:15][CH2:14]1>>[CH:13]1([C:16]2[N:10]([CH2:9][C:8]([F:12])([F:11])[F:7])[C:19]([CH:22]=[O:23])=[CH:18][N:17]=2)[CH2:15][CH2:14]1
Reactant: Cn1c(C=O)cnc1C1CC1
Reactant: NCC(F)(F)F
Agent: NC(=O)C1CC1
Product: O=Cc1cnc(C2CC2)n1CC(F)(F)F

Procedure:
2-Cyclopropyl-3-(2,2,2-trifluoro-ethyl)-3H-imidazole-4-carbaldehyde was prepared from cyclopropyl carboxamide and 2,2,2-trifluoroethylamine in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].[N-]=C=S>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[S:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Reactant: CC(C)(C)N
Agent: [N-]=C=S
Solvent: CCCCC
Product: CC(C)(C)N=NC1(NC(=S)NC(C)(C)C)CCCCC1
Reaction time: 3 h

Procedure:
To 9.1 grams (0.0394 moles) of 1-t-butylazo-1isothiocyanatocyclohexane stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 2.88 grams (0.0394 moles) of t-butylamine at room temperature. A solid slowly started to form and pentane was added to keep the reaction mixture from solidifying and the reaction mixture was stirred for 3 hours and the pentane stripped off to leave a yellow solid weighing 10.9 grams (91% crude yield). The product melted at 95°-98° C. and the infrared spectrum of the product had strong bands at 1520 and 1550 cm-1 and a sharp NH band at 3300 cm-1. There was a small amount of unreacted starting material presence, indicated by the presence of a weak isothiocyanate band at 2040 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C:20](=[O:22])[CH:17]4[CH2:18][CH2:19][CH:14]3[CH2:15][CH2:16]4)[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCC(Nc2nc(-c3ccc(Br)cc3)cs2)CC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1COCCO1
Product: O=C1C2CCC(CC2)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 100 °C
Yield: 67.8 %

Procedure:
A portion of 4-[4-(4-Bromo-phenyl)-thiazol-2-ylamino]-cyclohexanecarboxylic acid (50 mg, 0.13 mmol) was dissolved in dioxane (10 mL). Carbonyl diimidazole (26 mg, 0.16 mmol) was added and the mixture was heated to 100° C. for 16 h. The mixture was concentrated and chromatographed with 10% acetone in hexane to give 32 mg of 2-[4-(4-bromophenyl)-1,3-thiazol-2-yl]-2-azabicyclo[2.2.2]octan-3-one.
Reaction SMILES: [C:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[CH3:28]I>C1COCC1>[CH3:28][CH:2]([CH2:3][CH2:4][CH2:5][CH3:6])[C:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)=[O:7]
Reactant: CCCCCC(=O)c1cccc(OCc2ccc3ccccc3n2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(C)C(=O)c1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C

Procedure:
A solution of the ketone, 2-(3-hexanoylphenoxymethyl)quinoline (prepared from 3-hexanoylphenol and 2-chloromethyl quinoline)(6 g, 0.018 mol) in dry THF (25 ml) was added slowly to a mildly refluxing suspension of sodium hydride (1.3 g, 0.054 mol) in dry THF (75 ml) containing excess methyl iodide (10.3 g, 0.073 mol) After the addition of the ketone was complete (30 min.), the reaction mixture was refluxed for 4 hours. After cooling the mixture to room temperature, excess NaH was destroyed by adding methanol. All volatiles were removed at the rotary evaporator and the residue was taken up in ethyl acetate. The organic extract was washed with water and brine, and dried over anhydrous magnesium sulfate. Upon removal of all solvent, the mono-methylated eetone (2-[3-(2-methylhexanoyl) phenoxymethyl]quinoline, was obtained as a yellow oil weighing 8 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:16]1[C@@H:25]([CH2:26][CH3:27])[CH2:24][CH2:23][C@H:17]1[C:18]([O:20]CC)=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C(O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:16]1[C@@H:25]([CH2:26][CH3:27])[CH2:24][CH2:23][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H]1CC[C@H](CC)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC[C@H]1CC[C@@H](C(=O)O)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
Ethyl N-(tert-butoxycarbonyl)-L-leucyl-(5S)-5-ethyl-L-prolinate (0.965 g, 2.5 mmol) was dissolved in 3 mL of ethanol. The resultant solution was treated with 1.2 M LiOH solution (3.8 mL, 4.52 mmol) at room temperature. After 4 hours, the volatiles were removed under reduced pressure, and 1 N HCl was added. The mixture was extracted with ethyl acetate (3×), and the combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide the titled compound. MS (ESI) m/z 357 (M+H)+.