Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[OH:20]O.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH2:19])=[O:20])[CH:16]=3)[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: OO
Reactant: COc1ccc(-c2n[nH]c3ccc(C#N)cc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2n[nH]c3ccc(C(N)=O)cc23)cc1
Temperature: 50 °C
Yield: 41.6 %

Procedure:
A mixture of 20 mg (0.080 mmol) of 3-(4-methoxyphenyl)-1H-indazole-5-carbonitrile, 0.428 mL of 95% denatured ethanol, 0.021 mL of H2O, 0.32 mL of 30% aqueous hydrogen peroxide (aq. H2O2) and 0.032 mL of 6.0 N aq. NaOH (0.192 mmol, 2.4 equiv.) was heated at 50° C. for 3 h, and then acidified to pH=6.0 with 0.052 mL of 6.0 N 10 aq. HCl. The mixture was extracted with 2× EtOAc. The combined organics were washed with 2× sat. aq. NaHCO3, dried (Na2SO4), filtered, and concentrated affording the title compound (8.9 mg, 41.6% yield): 1H NMR (CDCl3/DMSO-d6) δ 12.5 (br s, 1H), 8.60 (s, 1H), 7.95 (d, 2H), 7.85 (d, 2H), 7.55 (d, 1H), 7.05 (d, 2H), 3.89 (s, 3H); ES-MS (m/z) 268 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([S:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.C(O[C:19](=[O:30])[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]1)(C)(C)C.[O:31]=[C:32]1[NH:37][C:36]2[CH:38]=[C:39](C(O)=O)[CH:40]=[CH:41][C:35]=2[S:34][CH2:33]1>>[CH3:13][S:12][C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[CH:11][C:2]([O:29][CH2:28][CH2:27][N:24]3[CH2:23][CH2:22][CH:21]([NH:20][C:19]([C:39]4[CH:40]=[CH:41][C:35]5[S:34][CH2:33][C:32](=[O:31])[NH:37][C:36]=5[CH:38]=4)=[O:30])[CH2:26][CH2:25]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: CSc1ccc2ncc(Cl)nc2c1
Product: CSc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1

Procedure:
The title compound is prepared as a light yellow lyophilizated powder following Scheme 1 and in analogy to Example 1 using 2-chloro-7-methylsulfanyl-quinoxaline, [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[CH:11]1([Mg]Br)[CH2:13][CH2:12]1>O1CCCC1>[CH:11]1([CH:5]([C:4]2[CH:3]=[C:2]([F:1])[CH:9]=[C:8]([F:10])[CH:7]=2)[OH:6])[CH2:13][CH2:12]1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: OC(c1cc(F)cc(F)c1)C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3,5-difluorobenzaldehyde (1.0 g, 7.0 mmol) was dissolved in tetrahydrofuran (10 mL) was cooled in an ice bath. cyclopropylmagnesium bromide (0.5 M in THF, 1.2 equiv., 8.4 mmol) was added slowly and the mixture was stirred at 0° C. for 60 min. The reaction was quenched with sat. ammonium chloride and extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated to give the title compound of sufficient purity to be used directly.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.O=[C:16]([CH3:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH2:24][C:25]([CH3:36])=[CH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:28].C(O)(=O)C>CC(O)C>[CH3:23][C:16]1[NH:24][C:25]([CH3:36])=[C:26]([C:27](=[O:28])[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CC(N)=CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)c2ccc(F)cc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
210 mg (1.11 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 145 mg (1.11 mmol) of ethyl 3-oxobutanoate, 200 mg (1.11 mmol) of 3-amino-1-(4-fluorophenyl)but-2-en-1-one and 6 μl (0.11 mmol) of acetic acid in 10 ml of 2-propanol and heated under reflux under argon for 30 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 172 mg (33% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[C:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[ClH:35]>O1CCCC1>[ClH:35].[N:16]1([CH2:15][CH2:14][NH:13][C:1]([N:32]2[CH2:33][CH2:34][N:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30][CH2:31]2)=[O:2])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCN1CCCCCC1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NCCN1CCCCCC1)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53 %

Procedure:
To a solution of 5.0 g (0.03 mole) of 1,1'-carbonyldiimidazole in 75 ml of tetrahydrofuran (THF) was added a solution of 4.0 g (0.028 mole) of N-(2-aminoethyl)homopiperidine in 75 ml of THF, and the reaction mixture was stirred at ambient temperature for 1.5 hr. A solution of 5.0 g (0.03 mole) of 1-phenylpiperazine in 50 ml of THF was added, and the reaction mixture was heated at reflux for 20 hr. The solution was concentrated under reduced pressure, and the residue was dissolved in 150 ml of benzene. The solution was washed thrice with 50 ml portions of water and once with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil, which was converted to the hydrochloride with ethereal hydrogen chloride. The collected solid was recrystallized from 2-propanol to yield 6.7 g (53%) of title compound as a white solid, m.p. 190°-193° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]1([C@@H:50]([NH2:52])[CH3:51])[CH2:49][CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:52][C@H:50]([CH:47]4[CH2:49][CH2:48]4)[CH3:51])=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: C[C@H](N)C1CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@@H](C)C2CC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with N-((S)-1-cyclopropyl-ethyl)-amine (Alfa) to give the title compound. LC-MS (ES+) 732 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:23][C:24]1[CH:28]=[CH:27][N:26]([CH2:29][C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:39])[CH3:38])[CH:33]=[CH:34][CH:35]=2)[N:25]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:37]([NH:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][N:26]1[CH:27]=[CH:28][C:24]([NH:23][C:13](=[O:15])/[C:12](/[C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)=[N:16]/[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:25]1)(=[O:39])[CH3:38]
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Reactant: CC(=O)Nc1cccc(Cn2ccc(N)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cccc(Cn2ccc(NC(=O)/C(=N/OC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Yield: 41.4 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 100 mg, 0.29 mmol), N-[3-(3-amino-pyrazol-1-ylmethyl)-phenyl]-acetamide (67 mg, 0.29 mmol) and N,N-diisopropylethylamine (151 μL, 0.87 mmol) were combined in methylene chloride (1.5 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol) was added and the ice bath was removed. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/chloroform to 80% ethyl acetate/hexanes) to afford (E)-N-[1-(3-acetylamino-benzyl)-1H-pyrazol-3-yl]-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-acetamide (67 mg, 42%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C26H28ClN5O5S [M+] 557.15, found 558 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.63 (m, 4 H, 2×CH2), 1.84 (m, 4 H, 2×CH2), 2.16 (s, 3 H, CO2CH3), 3.29 (s, 3 H, SO2CH3), 4.86 (m, 1 H, OCH), 5.20 (s, 2H, NCH2), 6.75 (d, J=2.3 Hz, 1 H, Ar), 6.92 (brd, J=7.7 Hz, 1 H, Ar), 7.29 (brt, J=8.0 Hz, 1 H, Ar), 7.37 (m, 3 H, 2 Ar and NH), 7.43 (brd, J=7.9 Hz, 1 H, Ar), 7.54 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.64 (d, Jm=1.5 Hz, 1 H, Ar), 8.17 (d, Jo=8.2 Hz, 1 H, Ar), 9.20 (s, 1 H, NH).
Reaction SMILES: C([C@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[S:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)[CH2:5]1)(=O)C.[O-:19]CC.[Na+].Cl>C(O)C.O1CCOCC1>[CH2:17]([O:16][C:14]([C:12]1[N:13]=[C:9]([N:6]2[CH2:7][CH2:8][C@H:4]([OH:19])[CH2:5]2)[S:10][CH:11]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)c1csc(N2CC[C@H](C(C)=O)C2)n1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1csc(N2CC[C@H](O)C2)n1
Reaction time: 8 h
Yield: 1953.3 %

Procedure:
To a solution of (3S)-3-acetyl-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)pyrrolidine (5.0 g, 17.6 mmol) (obtained as described in Reference Example 20(2)) in ethanol (150 ml) was added sodium ethoxide (60 mg, 0.879 mmol) at room temperature, and the mixture was stirred overnight under the same conditions. After checking the completion of the reaction, a solution of 4N hydrogen chloride in 1,4-dioxane (0.22 ml) was added thereto to neutralize the reaction mixture. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using toluene:acetonitrile (1:1→1:2) as the eluant to afford (3S)-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-3-hydroxypyrrolidine (4.16 g, yield 98%) as a white solid.
Reaction SMILES: [CH2:1]([N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:24]([Br:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(O)(C)C>[Br-:32].[CH2:1]([N:17]1[CH:21]=[CH:20][N:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:18]1[CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCn1ccnc1CC
Reactant: CCCCCCCCBr
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCN1C=CN(CCCCCCCC)C1CC
Product: [Br-]

Procedure:
0.5 mole of 1-n-hexadecyl-2-ethylimidazole and 0.6 mole of n-octyl bromide are dissolved in 250 ml of i-propanol and boiled with reflux for 5 hours. The solvent then is separated and the residue washed with ether.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:24])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:8]=1[CH3:23]>C1COCC1.CO>[CH3:23][C:8]1[N:9]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]=1[CH2:6][C:5]([OH:24])=[O:4]
Reactant: COC(=O)Cc1c(C)n(Cc2cccnc2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1cccnc1
Reaction time: 2 h

Procedure:
1M Aqueous NaOH (0.5 mL) is added to a stirring solution of (2-methyl-1-pyridin-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (35 mg, 0.12 mmol) in 1:1 THF/MeOH (2 mL). After 2 hours, the reaction is evaporated and the residue dissolved in water. The aqueous solution is acidified to pH 3-4, and the resulting precipitate collected by filtration to furnish (2-methyl-1-pyridin-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid; MH+=282.
Reaction SMILES: O1CCCC1.[CH:6]1([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][C:18](Cl)=[N:19][OH:20])[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7]1.[C:22]([C:24]1[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=1)#[CH:23].C(N(CC)CC)C>O>[CH:6]1([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=3)[O:20][N:19]=2)[CH2:8][CH2:7]1
Reactant: ON=C(Cl)Cc1cccc(OCC2CC2)c1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ncccc1-c1cc(Cc2cccc(OCC3CC3)c2)no1
Temperature: 50 °C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-cyclopropylmethoxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.624 mmol) described in Manufacturing Example 66-1-4 and 3-ethynyl-pyridin-2-ylamine (47 mg, 0.398 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (220 μL, 1.56 mmol) at room temperature, which was stirred for 2 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (26 mg, 13%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:24][CH2:25]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:32]1([C:38]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:24][CH2:25][N:41]3[CH2:40][CH2:39][C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]3)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1ccc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc1

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(4-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.63 mmol) and 4-phenylpiperidine-4-carboxylic acid amide hydrochloride (0.3 g). Purify by chromatographed on silica gel eluting sequentially with 50% ethyl acetate/hexane, 4% methanol/dichloromethane, and then 6% methanol/dichloromethane to give the title compound: Rf =0.58 (silica gel, 10% methanol in dichloromethane).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:30][CH3:31])=[C:8]([C:19]([CH2:22][S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:21]=2)[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:2]1.[N:32]#[C:33][NH2:34].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(#N)C>[C:33]([N:34]=[S:23]([CH2:22][C:19]1[C:8]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[C:7]([O:30][CH3:31])[C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[CH:21][CH:20]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[N:32]
Reactant: N#CN
Reactant: COc1c(-c2ccoc2)ccc(CSc2ccccc2)c1C(=O)OCc1ccccc1
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1c(-c2ccoc2)ccc(CS(=NC#N)c2ccccc2)c1C(=O)OCc1ccccc1
Yield: 16.2 %

Procedure:
A solution of benzyl 3-(furan-3-yl)-2-methoxy-6-(phenylthiomethyl)benzoate (Intermediate 226, 0.96 g), cyanamide (0.19 g) and iodobenzene diacetate (0.79 g) in acetonitrile (20 ml) was stirred for 16 hours. The mixture was evaporated to dryness and the residue was purified by chromatography on silica eluting with ethyl acetate and DCM with a gradient of 0-5% to give benzyl 6-[(N-cyano-S-phenylsulphinimidoyl)methyl]-3-(furan-3-yl)-2-methoxybenzoate (0.17 g) as a colourless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(N(CC)C(C)C)(C)C.Br[CH2:37][CH:38]1[CH2:40][CH2:39]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:38]1([CH2:37][CH2:19][C:18]2[O:17][N:16]=[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]=2[C:11]2[O:10][C:9]([C:8]3[CH:7]=[CH:6][C:5]([NH2:26])=[CH:4][C:3]=3[O:2][CH3:1])=[N:13][N:12]=2)[CH2:40][CH2:39]1
Reactant: BrCC1CC1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2CCC2CC2)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 12.2 %

Procedure:
To a suspension of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in THF were added N,N-diisopropyl ethyl amine (128 μL, 0.75 mmol) and bromomethyl-cyclopropane (61 μL, 0.63 mmol) and the reaction mixture was stirred for 24 h at ambient temperature. After addition of potassium bis(trimethylsilyl)amide (0.91 M in THF, 0.82 mL, 0.75 mmol) was added stirring was continued for 15 min and further bromomethyl-cyclopropane (78 μL, 0.80 mmol) was added. After stirring for 18 h at ambient temperature further bromomethyl-cyclopropane (0.12 mL, 1.2 mmol) was added and stirring continued for 24 h at this temperature. The reaction mixture was extracted with aqueous sodium carbonate (saturated, 20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers dried over sodium sulfate. Concentration and then purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=40:40:20 to 0:80:20) afforded the title compound (28 mg, 12%) as a light brown solid. MS: m/e=403.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[N:5]=[C:4]([NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:3]=1[C:23]1[C:28]([F:29])=[CH:27][C:26]([F:30])=[CH:25][C:24]=1[F:31]>CO.C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]([NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:3]([C:23]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[CH:25][C:24]=3[F:31])=[C:2]([Cl:1])[N:7]=2)=[N:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)c(-c3c(F)cc(F)cc3F)c(NCC(F)(F)F)n2)nc1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nc(Cl)c(-c3c(F)cc(F)cc3F)c(NCC(F)(F)F)n2)nc1
Temperature: 100 °C
Yield: 104.8 %

Procedure:
A mixture of 6-chloro-2-(5-nitropyridin-2-yl)-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine (101 mg, 0.22 mmol) and Iron powder (256 mg, 4.58 mmol) in 2 mL of methyl alcohol and 1 mL of acetic acid is heated at 100° C. for 1 h. The reaction mixture is cooled to room temperature and diluted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate and then with saturated sodium chloride, dried over magnesium sulfate, filtered, concentrated and dried under reduced pressure to yield 2-(5-aminopyridin-2-yl)-6-chloro-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine as a light yellow oil (100 mg). MS: m/z 434.2 (M+H). This product is used in the next step with out further purification.
Reaction SMILES: [C:1]([C:3](=[C:7]([S:10][CH3:11])SC)[C:4]([NH2:6])=O)#[N:2].[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1>CCO>[CH3:11][S:10][C:7]([NH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[C:3]([C:1]#[N:2])[C:4]#[N:6]
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: Nc1cccnc1
Solvent: CCO
Product: CSC(Nc1cccnc1)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dissolved 2-cyano-3,3-bis(methylthio)acrylamide I-2 (1.0 g) in EtOH (15 mL), and heated to 75° C. until solids dissolved. 3-Aminopyridine (1.0 eq., 0.608 g) was then added and solution continued stirring for 2 days. Precipitate formed which was found to be product. Reaction was cooled to room temperature and filtered to obtain 2-((methylthio)(pyridin-3-ylamino)methylene)malononitrile as a yellow powder.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH2:20]([N:22]([CH2:29][CH:30]1[CH2:32][O:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:21]>O1CCCC1.O>[CH2:20]([N:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:29][CH:30]([OH:31])[CH2:32][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:21]
Reactant: Cc1cccnc1
Reactant: CCN(CC1CO1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CCN(CC(O)CCc1cccnc1)c1ccccc1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
Under argon gas, a solution of diisopropylamine (1.67 g, 16.5 mmol) in tetrahydrofuran (5 mL) was added dropwise to n-butyllithium (1.53 M in hexane, 9.8 mL, 15 mmol) at 5° C. and the mixture was stirred for 30 minutes. To this was further added a solution of 3-methylpyridine (2.794 g, 30 mmol) in tetrahydrofuran (5 mL) dropwise at 5° C. and the mixture was stirred for 30 minutes. Then, a solution of 2-([ethyl(phenyl)amino]methyl)oxirane (1.77 g, 10 mmol) in tetrahydrofuran (5 mL) was added at 5° C., and the reaction was carried out for 2 hours. This reaction mixture was diluted with 20 mL of water for hydrolysis, and extracted with 20 mL of ethyl acetate. The organic layer was washed with 20 mL of water twice and the solvent was distilled off under reduced pressure to give a yellow oil. This oil was purified by silica gel column chromatography (Merck's Kieselgel 60, hexane/ethyl acetate=1/1) to give 2.322 g (isolation yield: 86%) of 1-[ethyl(phenyl)amino]-4-pyridin-3-ylbutan-2-ol (yellow oil).
Reaction SMILES: [OH:1][C@H:2]([CH2:27][CH2:28][OH:29])[C:3](=[O:26])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6].[C:30]12(CS(O)(=O)=O)C(C)(C)C(C[CH2:36]1)C[C:31]2=O>CN(C=O)C>[CH3:31][C:30]1([CH3:36])[O:1][C@@H:2]([C:3](=[O:26])[CH2:4][S:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)(=[O:6])=[O:7])[CH2:27][CH2:28][O:29]1
Reactant: O=C(CS(=O)(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1)[C@H](O)CCO
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CN(C)C=O
Product: CC1(C)OCC[C@H](C(=O)CS(=O)(=O)c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)O1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of Example 270A (1.1 g, 2.4 mmol) and dimethyl acetal (350 mL) in DMF (10 mL) was treated with a catalytic amount of camphorsulfonic acid, stirred at rt for 15 h than partitioned between water ant ethyl acetate. The organics were washed with brine, dried (MgSO4), filtered, concentrated and purified via silca gel column chromatography eluting with 25% hexanes-ethyl acetate to give 693 mg of the title compound as a viscous oil.