Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]([NH:10][C:11]1[C:16]([C:17](OCC)=[O:18])=[CH:15][N:14]=[C:13]([N:22]([O:24][CH3:25])[CH3:23])[CH:12]=1)([CH3:9])[CH3:8]>C1COCC1>[CH:7]([NH:10][C:11]1[CH:12]=[C:13]([N:22]([O:24][CH3:25])[CH3:23])[N:14]=[CH:15][C:16]=1[CH2:17][OH:18])([CH3:9])[CH3:8]
Reactant: CCOC(=O)c1cnc(N(C)OC)cc1NC(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CON(C)c1cc(NC(C)C)c(CO)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.3 %

Procedure:
LiAlH4 (0.9 g, 24.0 mmol) was added in portions to a solution of ethyl 4-(isopropylamino)-6-(methoxy(methyl)amino)nicotinate (3.2 g, 12.0 mmol) in THF (60 mL) at 0° C. and the resultant reaction mixture was stirred at RT for 30 min. The reaction was quenched by the addition of water (1 mL) and aqueous 2N NaOH (1 mL). The resulting precipitates were removed by filtration and the filtrate was concentrated to afford (4-(isopropylamino)-6-(methoxy(methyl)amino)pyridine-3-yl)methanol (2.9 g, >100% yield), which was used without further purification. 1HNMR (400 MHz, DMSO-d6): δ 7.62 (s, 1 H), 6.16 (s, 1 H), 5.44 (d, J=7.2 Hz, 1 H), 5.02 (bs, 1 H), 4.33 (s, 2 H), 3.69-3.61 (m, 4 H), 3.06 (s, 3 H), 1.18 (d, J=6.4 Hz, 6 H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:7]2=1.[H-].[Na+].I[CH3:36]>CN(C=O)C>[CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([N:25]([CH3:36])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:7]2=1
Reactant: CI
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N(C)C(=O)OC(C)(C)C)ccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 36.7 %

Procedure:
(S)-tert-Butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.150 g, 0.341 mmol), prepared as described in Example 16, Part H, was taken up in DMF (1 mL) and cooled to 0° C. NaH (0.027 g, 0.683 mmol) was added and the reaction mixture was stirred for 45 min at 0° C. Iodomethane (0.107 mL, 1.706 mmol) was then added and reaction mixture was warmed to room temperature and stirred for 15 min. The mixture was quenched with ice and partitioned between ethyl acetate (4 mL) and water (2 mL). The organic layer was separated, washed with brine (2 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude which was purified by preparative HPLC to afford (S)-tert-butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)(methyl)carbamate (60 mg, 0.125 mmol, 37% yield) as a light yellow solid. LC/MS (ESI) m/e 454.4 [(M+H)+, calcd for C26H36N3O2 454.3]; LC/MS retention time (method E): tR=1.21 min.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[O:16][N:15]=[C:14]([C:17]([F:20])([F:19])[F:18])[C:13]=1[CH3:21]>>[CH3:21][C:13]1[C:14]([C:17]([F:20])([F:18])[F:19])=[N:15][O:16][C:12]=1[NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: Cc1c(C(F)(F)F)noc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Product: Cc1c(C(F)(F)F)noc1NS(=O)(=O)c1ccccc1
Yield: 72 %

Procedure:
This compound was prepared according to the method in Example 96 from benzenesulfonyl chloride and 5-amino-4-methyl-3-trifluoromethylisoxazole (see, U.S. Pat. No. 4,910,326 or corresponding EP A 0220947) in 72% yield as an off white solid after recrystallization from ethyl acetate/hexanes, m.p. 99.5°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]1.C(N(CC)CC)C.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:13][CH2:14]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccccc1N1CCN(CCCO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCOC(=O)C(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of 3-[4-(2-methoxyphenyl)-1-piperazinyl]propanol (4.76 g, 0.019 mol) and triethylamine (6 g, 0.06 mol) in 100 mL of methylene chloride was added pivaloyl chloride (2.28 g, 0.019 mol) and stirring was continued overnight at room temperature. The organic layer was washed with water, dried (anhydrous Na2SO4) and evaporated. The title compound was isolated by preparative HPLC and converted to the dihydrochloride salt; mp.=202°-204° C.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]1[CH2:11][C:10]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([CH2:13][CH:14]=[CH2:15])[CH:6]1[CH2:7][CH2:8][CH:9]2[OH:22])#[N:4].[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28]Br.C1OCCOCCOCCOCCOCCOC1>C1COCC1>[F:23][C:24]([F:37])([F:38])[C:25]1[CH:26]=[C:27]([CH2:28][O:22][C@@H:9]2[CH2:8][CH2:7][C@@H:6]3[N:12]([CH2:13][CH:14]=[CH2:15])[C@@:10]2([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C@H:5]3[C:3]#[N:4])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: C=CCN1C2CCC(O)C1(c1ccccc1)CC2C#N
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)C[C@H]2C#N
Reaction time: 22 h
Yield: 71.9 %

Procedure:
Sodium hydride (60% in oil, 100 mg, 2.5 mmol) was added to a stirred mixture of 1R*,2R*,5S*,6R*)-6-cyano-1-phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1]octan-2-ol (Description 24; 400 mg, 1.49 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (1 ml, 5.45 mmol) and 18-crown-6 (87 mg, 0.33 mmol) in THF (5 ml) at room temperature. The reaction mixture was stirred for 22 hours, quenched with water and extracted into dichloromethane. The combined organic extracts were washed with water, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (530 mg, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:21])=[C:11]([CH2:13][CH2:14][CH:15]3SCCCS3)[N:12]=2)=[CH:4][CH:3]=1.C1C[O:25]CC1.C(Cl)Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:21])=[C:11]([CH2:13][CH2:14][CH:15]=[O:25])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCC1SCCCS1
Reactant: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCC=O
Reaction time: 6 h
Yield: 86 %

Procedure:
Add HgClO4.4H2O (1.49 g, 4.00 mmol) to a solution of 2-(4-bromo-phenyl)-4-(2-[1,3]dithian-2-yl-ethyl)-5-methyl-oxazole (0.672 g, 1.75 mmol) in 1:1 THF:CH2Cl2 (16 mL) and water (1.6 mL). After 6 hours, filter and wash the solids with dichloromethane. Concentrate to give 3-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-propionaldehyde (0.445 g, 86%). MS (m/e): 294 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH3:24][O:25][CH2:26][CH:27]([NH2:29])[CH3:28]>O1CCOCC1>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:29][CH:27]([CH3:28])[CH2:26][O:25][CH3:24])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COCC(C)N
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Solvent: C1COCCO1
Product: COCC(C)Nc1c([N+](=O)[O-])cnc2cc(-c3c(C)noc3C)c(OC)cc12
Temperature: 70 °C
Yield: 111.5 %

Procedure:
To a solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethylisoxazole (Manchester Organics) (20 g, 59.9 mmol) in 1,4-dioxane (200 ml) was added 1-methoxypropan-2-amine (31.6 ml, 300 mmol) and the reaction mixture heated at 70° C. for 1.5 h. The solvent was removed under reduced pressure and the resulting solid partitioned between ethyl acetate (3×750 ml) and water (750 ml). The organic layers were combined, dried (hydrophobic frit) and evaporated under reduced pressure to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N-(1-methoxypropan-2-yl)-3-nitroq uinolin-4-amine (25.8 g), which was used without further purification in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:34])[CH3:33])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>CN(C)C=O>[CH3:43][O:42][C:40](=[O:41])[CH2:39][O:32][C:30]1[CH:29]=[CH:28][C:19]2[O:20][CH2:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:35])[C:9]([CH3:33])([CH3:34])[CH2:10]3)[C:18]=2[CH:31]=1
Reactant: CC1(C)CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Temperature: 25 °C
Yield: 48.4 %

Procedure:
5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (0.4 g, 0.814 mmol) was dissolved in dimethyl formamide (10 mL). Sodium hydride (0.029 g, 1.22 mmol, 1.5 equiv, 48 mg of a 60% suspension in mineral oil) was added at room temperature and gas evolution was visible. Methyl bromoacetate (0.187 g, 1.22 mmol, 116 uL) was added and the mixture was stirred at room temperature. After stirring overnight at room temperature, the reaction was quenched with water (10 mL). The resulting suspension was extracted with ethyl acetate (3×10 mL). The combined ethyl acetate extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give an oil. The crude oil was purified by silica gel chromatography (methylene chloride to 10% methanol in methylene chloride gradient) to afford the title compound as a white solid (222 mg, 48%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.O[CH2:28][C:29]1[CH:44]=[CH:43][C:32]([CH2:33][NH:34][C:35]([C:37]2[N:38]=[CH:39][N:40]([CH3:42])[CH:41]=2)=[O:36])=[CH:31][CH:30]=1>ClCCl>[I:25][CH2:28][C:29]1[CH:44]=[CH:43][C:32]([CH2:33][NH:34][C:35]([C:37]2[N:38]=[CH:39][N:40]([CH3:42])[CH:41]=2)=[O:36])=[CH:31][CH:30]=1
Reactant: Cn1cnc(C(=O)NCc2ccc(CO)cc2)c1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cn1cnc(C(=O)NCc2ccc(CI)cc2)c1
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
Gently stir for 30 min a mixture of polymer supported triphenylphosphine (1.0 g, 3 mmol/g, 3.0 mmol), 1H-imidazole (208 mg, 3.06 mmol), and iodine (776 mg; 3.06 mmol) in anhydrous dichloromethane (12 mL). To the reaction mixture, add a mixture of N-(4-(hydroxymethyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (500 mg, 2.04 mmol) in anhydrous dichloromethane (5.0 mL). Gently stir the reaction mixture for 5 hrs at room temperature. Filter the reaction mixture and wash the filtrate with an aqueous 10% sodium thiosulfate solution. Separate the aqueous layer. Wash the organic layer with water, dry over magnesium sulfate, and concentrate to the title compound (532 mg, 1.50 mmol). MS (m/z): 356 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:6]([CH2:8][C:9]#[N:10])[CH:7]=1.Cl.[NH:18]1CCN=[C:19]1[CH2:23]OC1C=C(NS(C)(=O)=O)C=CC=1.NC1C=C(C=CC=1)OCC#N>>[ClH:1].[Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH:5]=[C:6]([CH2:8][C:9]2[NH:18][CH2:19][CH2:23][N:10]=2)[CH:7]=1
Reactant: CS(=O)(=O)Nc1cccc(OCC2=NCCN2)c1
Reactant: Cc1c(Cl)cc(CC#N)cc1NS(C)(=O)=O
Agent: Cl
Agent: N#CCOc1cccc(N)c1
Product: Cc1c(Cl)cc(CC2=NCCN2)cc1NS(C)(=O)=O

Procedure:
N-(3-chloro-5-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-methylphenyl]methane-sulfonamide hydrochloride (mp 256.2-256.7° C.) was prepared from N-(3-chloro-5-cyanomethyl-2-methylphenyl) methanesulfonamide in a manner similar to that described in Example 1 for the preparation of N-[3-(4,5-dihydro-1H-imidazol-2-ylmethoxy)phenyl] methanesulfonamide hydrochloride from (3-aminophenoxy)acetonitrile.
Reaction SMILES: [CH2:1]([C:5]1[C:6]2[N:20]=[C:19]([C:21]3[CH:35]=[C:34]([CH3:36])[C:24]([O:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[C:23]([CH3:37])[CH:22]=3)[O:18][C:7]=2[N:8]=[C:9]([O:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:10]=1)[CH:2]([CH3:4])[CH3:3].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[C:6]2[N:20]=[C:19]([C:21]3[CH:22]=[C:23]([CH3:37])[C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[C:34]([CH3:36])[CH:35]=3)[O:18][C:7]=2[N:8]=[C:9]([O:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(-c2nc3c(CC(C)C)nc(OCCC(F)(F)F)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nc3c(CC(C)C)nc(OCCC(F)(F)F)nc3o2)cc(C)c1OCC(=O)O
Yield: 56 %

Procedure:
Analogously to example 1 (j), the reaction of 8 mg of tert-butyl {4-[7-isobutyl-5-(3,3,3-trifluoropropoxy)oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}acetate with trifluoroacetic acid gave 4 mg (56%) of the title compound.
Reaction SMILES: [OH-].[Na+].FC(F)(F)C([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([S:19]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=2[O:32][CH3:33])[CH2:9][CH2:8]1)=O.O>CO>[CH3:33][O:32][C:14]1[CH:15]=[CH:16][C:17]([S:19]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:18][C:13]=1[N:10]1[CH2:11][CH2:12][NH:7][CH2:8][CH2:9]1
Reactant: COc1ccc(S(=O)(=O)c2cccc3ccccc23)cc1N1CCN(C(=O)C(F)(F)F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(S(=O)(=O)c2cccc3ccccc23)cc1N1CCNCC1
Yield: 68.2 %

Procedure:
A solution of 6N NaOH (0.5 mL) was added to a suspension of 2,2,2-trifluoro-1-{4-[2-methoxy-5-(naphthalene-1-sulfonyl)-phenyl]-piperazin-1-yl}-ethanone (1) (0.110 g; 0.23 mmol ) in methanol. After stirring at 80° C. for 10 min water was added (10 ml) and the mixture was extracted into ethyl acetate (20 ml). The organic phase was dried (Na2SO4) and concentrated in vacuo to give 1-[2-methoxy-5-(naphthalene-1-sulfonyl)-phenyl]-piperazine (101) as a white solid (0.060 g , 68%), MS, MH+ 383. The hydrochloride salt was prepared from ethanol-hydrogen chloride, m. p. 154-158° C.
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][C:6]1([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:43])[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[O:32])=[C:26]([O:41][CH3:42])[CH:25]=3)=[CH:17][CH:16]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)C.[OH-].[Na+]>C(O)C>[CH3:42][O:41][C:26]1[CH:25]=[C:24]([CH2:23][C:22]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([C:6]3([CH2:5][C:4]([OH:44])=[O:3])[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7]3)=[CH:20][CH:19]=2)=[O:43])[CH:29]=[CH:28][C:27]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32]
Reactant: CCOC(=O)CC1(c2ccc(NC(=O)Cc3ccc(NC(=O)Nc4ccccc4C)c(OC)c3)cc2)Cc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(CC(=O)Nc2ccc(C3(CC(=O)O)Cc4ccccc4C3)cc2)ccc1NC(=O)Nc1ccccc1C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
A solution of [2-(4-(2-(3-methoxy-4-(3-o-tolyl-ureido)-phenyl)-acetylamino)-phenyl)-indan-2-yl]-acetic acid ethyl ester (0.06 g, Reference Example 16) in ethanol (10 mL) was treated with aqueous sodium hydroxide (300 μL, 1N) and the mixture was heated at reflux temperature for 8 hours and then left at room temperature overnight and then evaporated. The residue was treated with water (20 mL) and the mixture was warmed to aid dissolution. This solution was acidified to pH 1 by addition of hydrochloric acid (1N) when a precipitate was formed. The mixture was kept at 0° C. for 30 minutes then extracted with ethyl acetate. The ethyl acetate extract was dried over magnesium sulfate and then evaporated. The residual white solid was subjected to chromatography [gradient HPLC using 50% acetonitrile and water, 1 mL/minute] to give the title compound (0.03 g) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8](\[NH:12][C:13]([CH:15]1[CH2:17][C:16]1([CH3:19])[CH3:18])=[O:14])/[C:9]([OH:11])=[O:10].[CH3:20][NH:21][CH2:22][C:23]([OH:25])=[O:24].O>N#N>[C:23]([CH2:22][N:21]([CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8](\[NH:12][C:13]([CH:15]1[CH2:17][C:16]1([CH3:19])[CH3:18])=[O:14])/[C:9]([OH:11])=[O:10])([OH:25])=[O:24]
Reactant: CC1(C)CC1C(=O)N/C(=C\CCCCCBr)C(=O)O
Reactant: CNCC(=O)O
Agent: N#N
Solvent: O
Product: CN(CCCCC/C=C(\NC(=O)C1CC1(C)C)C(=O)O)CC(=O)O

Procedure:
3.32 g. of Z-8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid, 1.0 g. of CH3NHCH2CO2H, 3.5 g. of Na2Co3 and 30 ml of water were heated at 80° C. in N2 for 1.5 hours. After purification, 1.0 g. of product was obtained, calc. for C17H28N2O5.2H2O:C, 54,24; H, 8.57; N, 7.44; found: C, 54.40; H,8.34; N, 7.16.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[C:25](Cl)(=[O:29])[O:26][CH2:27][CH3:28]>>[CH2:27]([O:26][C:25](=[O:29])[NH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:4]=1)[CH3:28]
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Reactant: CCOC(=O)Cl
Product: CCOC(=O)NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product from Example 42 and ethyl carbonochloridate were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.45 (d, J=7.8 Hz, 1H), 8.14-8.16 (bs, 1H), 7.73-7.97 (m, 3H), 7.30-7.50 (m, 4H), 5.38-5.49 (bs, 1H), 4.69 (d, J=5.4 Hz, 2H), 4.18 (q, J=7.1 Hz, 2H), 3.80-3.82 (m, 2H), 1.27 (t, J=6.2 Hz, 3H); MS (ESI−) M/Z 413 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[C:26]([NH:28][C:29]4[CH:34]=[CH:33][N:32]=[CH:31][N:30]=4)[C:25](=[O:35])[N:24]([CH3:36])[CH:23]=3)[C:17]=2[CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])=[C:8]([C:10]([O:12]C)=[O:11])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C(O)(C)C.O>[C:1]([C:5]1[S:6][C:7]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[C:26]([NH:28][C:29]4[CH:34]=[CH:33][N:32]=[CH:31][N:30]=4)[C:25](=[O:35])[N:24]([CH3:36])[CH:23]=3)[C:17]=2[CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])=[C:8]([C:10]([OH:12])=[O:11])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nc(C(C)(C)C)sc1CNc1cccc(-c2cc(Nc3ccncn3)c(=O)n(C)c2)c1CO[Si](C)(C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cn1cc(-c2cccc(NCc3sc(C(C)(C)C)nc3C(=O)O)c2CO[Si](C)(C)C(C)(C)C)cc(Nc2ccncn2)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of methyl 2-tert-butyl-5-((2-((tert-butyldimethylsilyloxy)methyl)-3-(1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl)phenylamino)-methyl)thiazole-4-carboxylate (125d) (590 mg, 0.9 mmol) and lithium hydroxide (1090 mg, 45 mmol) in isopropyl alcohol (20 mL) and water (20 mL) was stirred at 25° C. for 5 h. The reaction mixture was concentrated to about 50% of the original volume and acidified to pH˜4 with 1M HCl (aq.). It was then extracted with CH2Cl2:MeOH(−7:1). The organic layers were combined, dried with anhydrous MgSO4, and concentrated to afford 125e, which was used in the next step without further purification. LCMS: (M+H)+ 635.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH:14]1([NH:20][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH:11]=[CH:12][S:13][C:3]=23)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: NC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2ccsc2c1NC1CCCCC1
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.055 g, 0.26 mmol) (Example 1, Step 2), cyclohexanamine (59 μL, 0.51 mmol) and N,N-diisopropylethylamine (0.13 mL, 0.77 mmol) in isopropyl alcohol (0.87 mL) was heated at 90° C. for 2 h. The resulting mixture was concentrated to give the desired product, which was used directly in the next step. LCMS calculated for C13H16N3O2S (M+H)+: m/z=278.1. Found: 278.0.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][NH2:12])=[CH:4][C:3]=2[O:2]1.[CH:13](=O)[CH3:14]>CCOCC>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][N:12]=[CH:13][CH3:14])=[CH:4][C:3]=2[O:2]1
Reactant: CC=O
Reactant: NNc1ccc2c(c1)OCCO2
Solvent: CCOCC
Product: CC=NNc1ccc2c(c1)OCCO2
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To a solution of 17 g of 3,4-ethylenedioxyphenylhydrazine in 100 ml of ether was added dropwise 11 g of 80 % acetaldehyde at 5° - 10°C over a period of 30 minutes. After stirring for an additional 2 hours at 5° - 10°C, the ethereal solution was separated, and dried over anhydrous sodium sulfate. The ether was evaporated, and the resultant residue was distilled to give 15.4 g of acetaldehyde-3,4-ethylenedioxyphenylhydrazone having a boiling point of 139° - 142°C (0.15 mmHg).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[N:29]=[C:28]([C:30](O)=[O:31])[O:27][N:26]=2)[CH:20]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:28]3[O:27][N:26]=[C:25]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[N:29]=3)=[O:31])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1nc(-c2cccnc2)no1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1nc(-c2cccnc2)no1
Yield: 11.9 %

Procedure:
Following the method of Example 34(d), the title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.27 g, 1.05 mmol), 3-(pyridin-3-yl)-1,2,4-oxadiazole-5-carboxylic acid (0.2 g, 1.05 mmol), HOBt (0.21 g, 1.57 mmol), DIPEA (0.55 mL, 3.14 mmol) and EDCI (0.3 g, 1.57 mmol) using DMF as solvent to afford 54 mg of the title product. 1H NMR (400 MHz; d6-DMSO): δ 1.23 (d, 3H), 4.37 (m, 2H), 4.50 (m, 1H), 6.96 (d, 1H), 7.65 (m, 1H), 7.88 (d, 1H), 7.92 (m, 2H), 8.04 (m, 1H), 8.38 (m, 1H), 8.83 (dd, 1H), 9.19 (dd, 1H), 9.50 (m, 1H).