Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>CC(C)=O>[OH:18][C:8]1([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]1
Reactant: OC1(c2ccc(I)cc2)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C1CCC(O)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.8 %

Procedure:
To a solution of 8-(4-iodo-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (2 g) in acetone (10 mL) was added 5% HCl (20 mL) and the mixture was stirred at rt for 14 hours. The mixture was neutralized with 1N NaOH to pH 7, concentrated on rotovap, and then extracted with ethyl acetate (2×50 mL). The organic extracts were combined, washed with saline solution (2×50 mL), dried over sodium sulfate, concentrated in vacuo to provide 4-hydroxy-4-(4-iodophenyl)cyclohexanone (1.7 g, 98%). LCMS: 317.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:23]([O:25]CC)=[O:24])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)CO>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:23]([OH:25])=[O:24])[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(Nc2ccc(C)cc2)CCN(CCc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: OCCO
Product: Cc1ccc(NC2(C(=O)O)CCN(CCc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A mixture of 60.1 parts of ethyl 4-[(4-methylphenyl)amino]-1-(2-phenylethyl)-4-piperidinecarboxylate, 27.6 parts of potassium hydroxide and 150 parts of 1,2-ethanediol is stirred and refluxed for 3 hours. The reaction mixture is cooled to room temperature and poured onto water. The whole is neutralized with acetic acid. The precipitated product is filtered off and crystallized from N,N-dimethylformamide. The product is filtered off and dried in vacuo, yielding 43.9 parts (79.2%) of 4-[(4-methylphenyl)amino]-1-(2-phenylethyl)-4-piperidinecarboxylic acid; mp. 264.6° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([Cl:48])[C:34]=1[OH:49]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:22][CH2:23]2)=[CH:3][C:2]([C:37]2[CH:38]=[C:33]([Cl:32])[C:34]([OH:49])=[C:35]([Cl:48])[CH:36]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexylcarbamate (43 mg, 0.088 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (38 mg, 0.132 mmol) to afford the desired product (25 mg, 51%) as an off-white solid: ESI MS m/z 570 [C30H33C12N3O4+H]+.
Reaction SMILES: C(C1C=C(C=C(C(C)(C)C)C=1O)C(O)=O)(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.O[C@@H:32]1[C@H:38](C2C=CC(OC)=CC=2)[S:37][C:36]2[C:47]3[C:52]([CH:53]=[CH:54][C:35]=2[N:34](CCN(C)C)[C:33]1=[O:60])=[CH:51][CH:50]=[CH:49][CH:48]=3>O1CCCC1>[S:37]1[CH:38]=[CH:32][C:33](=[O:60])[NH:34][C:35]2[CH:54]=[CH:53][C:52]3[C:47]([C:36]1=2)=[CH:48][CH:49]=[CH:50][CH:51]=3
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1C=CSc2c(ccc3ccccc23)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.35 g (0.00054 mol) of 3,5-di-tert.-butyl-4-hydroxybenzoic acid and 0.9 g (0.0054 mol) of 1,1'-carbonyldiimidazole in 20 ml of dry tetrahydrofuran was stirred at room temperature for 30 minutes. To the above mixture 1.3 g (0.00031 mol) of (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b][1,4]thiazepin-4(5H)-one was added and stirred at room temperature for 17 hours then at reflux for 7 hours. After cooling the solids were filtered and the filtrate was concentrated to dryness. The residue was partitioned between ethyl acetate and dilute ammonium hydroxide. The ethyl acetate solutions were washed with brine, dried (MgSO4) and the solvent was removed under reduced pressure. The residue was dissolved in acetonitrile and chromatographed on 45 g of silica gel. The column was eluted wtih 50 ml portions of acetonitrile. Fractions 10-20 were combined and the solvent was removed to give 0.9 g of crude product, which was crystallized from ether to give 0.8 g (40%) of (±)-cis-2,3-dihydro-3-[[4-hydroxy-3,5-bis(1,1-dimethylethyl)benzoyl]oxy]-2-(4-methoxyphenyl)-5-[2-dimethylamino)ethyl]naphtho[1,2-b][1,4]thiazepin-4(5H)-one, mp 181°-182°.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CS(C)=O.C[O-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([O:11][C:1]1[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1cccc2c1CC=CC2
Reactant: BrCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C1=CCc2c(cccc2OCc2ccccc2)C1

Procedure:
A solution of 73 g. (0.5 m) of 5,8-dihydro-1-naphthol in 100 ml. DMSO is treated with 0.5 m sodium methoxide. The mixture is cooled in an ice bath and treated dropwise with 0.5 mole benzyl bromide with shaking periodically. The mixture is gradually allowed to warm up to about 45° toward the end of addition. The mixture is stirred 3 hrs. longer, then poured into 1 liter H2O and extracted into ether. Extracts are washed twice with 10% NaOH, dried, taken to dryness leaving almost a quantitative yield of crystalline 5,8-dihydro-1-naphthyl benzyl ether.
Reaction SMILES: [C:1]([Si:5]([CH2:8]Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[I-:10].[Na+]>CC(C)=O>[C:1]([Si:5]([CH2:8][I:10])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)CCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)[Si](C)(C)CI
Reaction time: 24 h
Yield: 81576.9 %

Procedure:
t-Butyl(chloromethyl)dimethylsilane [Makoto Kumada, Mitsuo Ishikawa, Sajiro Meada and Katsuyata Ikura, J. Organometal. Chem. 2, 146, (1964)] (16.4 g, 0.1 mmol) and sodium iodide (60 g, 0.4 mmol) in acetone (500 ml) are refluxed with stirring during 24 hours. The reaction mixture is cooled, filtered and the solvent is evaporated under reduced pressure. The residue is dissolved in ether and washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to afford t-butyl(iodomethyl)dimethylsilane (20.9 g, 80%) as a slightly yellow oil.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[CH:15]2[N:12]([C:13](=[O:17])[C:14]2=O)[CH:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].[CH:23]1[CH:28]=CC=[CH:25][CH:24]=1>>[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])[C:14]2=[C:23]([CH3:28])[C:24](=[O:6])[CH3:25])[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21]
Reactant: c1ccccc1
Reactant: C=S1C2C(=O)C(=O)N2C(C(=O)O)C1(C)C
Agent: CC(C)(C)C(=O)O
Product: C=S1[C@@H]2C(=C(C)C(C)=O)C(=O)N2[C@@H](C(=O)O)C1(C)C
Reaction time: 0.17 h

Procedure:
A solution of 7.8 g of methylene-6,7-dioxo-3,3-dimethyl-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate in 200 ml of benzene is treated at room temperature with 10 g of triphenylphosphinemethylacetylmethylene. After 10 minutes, the reaction mixture is evaporated. The residue is chromatographed on silica gel while eluting with cyclohexane/ethyl acetate (6:4). There is obtained methylene-(2S,5R)-3,3-dimethyl-6-(1-methyl-2-oxopropylidene)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate as white crystals of melting point 59°-60° [Rf: 0.30; cyclohexane/ethyl acetate (6:4)].
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:19]C(OC(C)(C)C)=O)[CH2:7][O:8][C:9]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[O:11][N:10]=1)(=[O:3])[NH2:2].Cl.O1CCOCC1>C(Cl)(Cl)Cl.CO.C(O)C>[ClH:18].[NH2:19][CH:6]([CH2:5][O:4][C:1](=[O:3])[NH2:2])[CH2:7][O:8][C:9]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[O:11][N:10]=1
Reactant: CC(C)(C)OC(=O)NC(COC(N)=O)COc1noc2ccc(Cl)cc12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)OCC(N)COc1noc2ccc(Cl)cc12

Procedure:
To a suspension of 3.28 g of 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-chloro-1,2-benzoisoxazole in 33 ml of chloroform and 33 ml of methanol is added 7.1 ml of conc hydrochloric acid at 20°-25° C., and they are subjected to reaction at the same temperature overnight. The solvent is removed from the reaction mixture by distillation under reduced pressure, and ethyl acetate and water are added to the residue obtained. After shaking, the aqueous layer is separated. To the separated aqueous layer is again added ethyl acetate, and the pH is adjusted to 10 with a 10% (w/w) aqueous sodium hydroxide solution, after which the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The crystals obtained are dissolved in 66 ml of ethanol, and to this solution is added 4.5 ml of a dioxane solution (2.2N) of hydrogen chloride at 20°-25° C., after which the crystals precipitated are collected by filtration, to obtain 2.16 g of colorless, crystalline 3-(2-amino-3-carbamoyloxypropoxy)-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 215°-216° C.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([NH2:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:16]([NH:22][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: CCCCCCN
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCNc1ccc(C(=O)c2ccccc2)cc1
Yield: 95.2 %

Procedure:
According to the general procedure B, 4-Bromobenzophenone (131 mg, 0.50 mmol) reacted with n-hexylamine (52 mg, 0.52 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (58 mg, 0.60 mmol) in toluene at 50° C. for 13 h to give the title compound (134 mg, 93%) as a solid: 1H-NMR (300 MHz, CDCl3): δ 7.74, (t, 4H, J=8.4 Hz), 7.53-7.43 (m, 3H), 6.58 (d, 2H, J=8.7 Hz), 4.46 (bs, 1H), 3.17 (t, 2H, J=6.6 Hz), 1.61 (m, 2H), 1.42-1.32 (m, 6H), 0.91 (t, 3H, J=6.6 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 195.00, 152.27, 139.11, 132.93, 131.00, 129.30, 127.89, 125.42, 111.02, 43.17, 31.44, 29.09. GC/MS(EI): m/z 281 (M+).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:22]=[C:21]([C:32]([F:35])([F:34])[F:33])[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[CH:22]=[C:21]([C:32]([F:33])([F:35])[F:34])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[N:15]=[CH:16]3)[N:24]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)cn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.5 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.37 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as an off-white solid (0.18 g, 67%). MS (ISN) 468.0 [(M−H)−]; mp 244.5° C.
Reaction SMILES: N1(CCC[O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)CCCC1.Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][OH:36])[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:36][CH2:35][CH2:34][CH:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:29][CH2:30]1
Reactant: OCCC1CCN(CCCCl)CC1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(OCCCN3CCC(CCO)CC3)cc2)CCOCC1
Yield: 64.9 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (185 mg, 0.91 mmol), 2-[1-(3-chloro-propyl)-piperidin-4-yl]-ethanol (300 mg, 1.46 mmol), DMF (4 ml) and K2CO3 (497 mg, 3.60 mmol) were reacted together according to general procedure E. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (92:6:2) provided the title compound (220 mg, 65%) as a pale pink solid. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, 2H), 6.93 (d, 2H), 4.11-4.04 (m, 2H), 4.01 (t, 2H), 3.89 (td, 2H), 3.70 (t, 2H), 2.97-2.87 (m, 2H), 2.48 (t, 2H), 2.15-1.88 (m, 8H), 1.77-1.57 (m, 3H), 1.57-1.38 (m, 3H), 1.35-1.21 (m, 2H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[S:15][C:16]([S:19][CH2:20][C:21]2[O:22][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][N:25]=2)=[CH:17][N:18]=1.[CH:30]1([N:33]2[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH2:34]2)[CH2:32][CH2:31]1.CN(C)C=O>CN(C)C1C=CN=CC=1.O.C(Cl)Cl>[CH:30]1([N:33]2[CH2:34][CH2:35][CH:36]([C:39]([NH:13][C:14]3[S:15][C:16]([S:19][CH2:20][C:21]4[O:22][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][N:25]=4)=[CH:17][N:18]=3)=[O:40])[CH2:37][CH2:38]2)[CH2:32][CH2:31]1
Reactant: O=C(O)C1CCN(C2CC2)CC1
Reactant: CC(C)(C)c1cnc(CSc2cnc(N)s2)o1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cnc(CSc2cnc(NC(=O)C3CCN(C4CC4)CC3)s2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g, 5.2 mmol, 2 eq) was added to a mixture of 2-amino-5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]thiazole (0.7 g, 2.6 mmol, 1 eq), 1-cyclopropyl-4-piperidine carboxylic acid (0.77 g, 3.9 mmol, 1.5 eq), 4-(dimethylamino)pyridine (0.16 g, 1.3 mmol, 0.5 eq), N,N-dimethylformamide (2.6 mL) and CH2Cl2 (7.8 mL). The reaction mixture was stirred at rt for 1 h, diluted with water (30 mL), and extracted with ethyl acetate (2×70 mL). The combined organic extracts were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography on silica gel eluting with a gradient of 0-10% triethylamine in ethyl acetate. The material was crystallized from ethyl acetate and hexanes to provide 0.7 g (65%) of 1-cyclopropyl-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide as white crystals. MS: 421 [M+H]+; HPLC: 100% at 3.13 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: N[CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[CH2:22](N)C#C>>[CH2:3]([NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6])[C:2]#[CH:22]
Reactant: C#CCN
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Product: C#CCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using propargylamine instead of tert-butyl-2-amino ethyl carbamate to afford N-(prop-2-yn-1-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-ylamino)thiophene-2-carboxamide.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16](=[O:41])[NH:17][C@H:18]([C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]2)=[O:29])[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[C:24]([O:23][C:21]([CH2:20][CH2:19][C@H:18]([NH:17][C:16]([C:8]1[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:41])[C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:34][CH2:35]1)=[O:29])=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: CCOC(=O)c1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)O)c3ccccc3n2)CC1

Procedure:
To a solution of 1.1 g of 2-[(S)-3-tert-Butoxycarbonyl-1-(4-ethoxycarbonyl-piperazine-1-carbonyl)-propylcarbamoyl]-quinoline-4-carboxylic acid ethyl ester in 10 ml of THF, 2 ml of a 1 M aqueous NaOH solution was added. After stirring for 5 h at RT additional 1 ml of a 1 M aqueous NaOH solution was added and allowed to stir upon completion of the reaction. Then, the reaction was acidified to pH 1 with diluted aqueous hydrochloric acid and extracted with DCM (3×100 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was used in the next reaction step without further purification. Yield: 1.0 g.
Reaction SMILES: [CH2:1]([C:4]1([CH2:12][CH:13]=[CH2:14])[CH2:8][C@H:7]([CH2:9][OH:10])[NH:6][C:5]1=O)[CH:2]=[CH2:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[CH2:12]([C:4]1([CH2:1][CH:2]=[CH2:3])[CH2:5][NH:6][C@@H:7]([CH2:9][OH:10])[CH2:8]1)[CH:13]=[CH2:14]
Reactant: C=CCC1(CC=C)C[C@H](CO)NC1=O
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C=CCC1(CC=C)CN[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a solution of (R)-3,3-diallyl-5-(hydroxymethyl)pyrrolidin-2-one (0.43 g, 2.202 mmol) in THF (5.51 ml) cooled to 0° C., lithium aluminum hydride, 1.0 M solution in THF (2.86 ml, 2.86 mmol) was added. The mixture was stirred at room temperature overnight. Extra lithium aluminum hydride, 1.0 M solution in THF (2.86 ml, 2.86 mmol) was added and it was refluxed for 6 h. More lithium aluminum hydride, 1.0 M solution in THF (2.86 ml, 2.86 mmol) was added and the mixture was refluxed overnight. The reaction mixture was cooled to 0° C. prior to addition of aq. Rochelle's salt into the mixture slowly. The resulting slurry solution was extracted with EtOAc (10 mL). The combined extracts were washed with brine, dried and concentrated to afford (R)-(4,4-diallylpyrrolidin-2-yl)methanol (0.34 g, 1.876 mmol, 85% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.72-5.88 (m, 2H), 5.00-5.17 (m, 4H), 3.49-3.59 (m, 1H), 3.30-3.46 (m, 2H), 2.79 (d, J=11.30 Hz, 1H), 2.67 (d, J=11.35 Hz, 1H), 2.08-2.19 (m, 4H), 1.72 (dd, J=6.97, 13.04 Hz, 1H), 1.22-1.39 (m, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9]2[CH:11]=[CH:12][S:13][C:8]=2[CH:7]=1)=O)C.[NH3:14].[OH-].[Li+]>CO>[S:13]1[C:8]2[CH:7]=[C:6]([C:4]([NH2:14])=[O:3])[NH:10][C:9]=2[CH:11]=[CH:12]1
Reactant: N
Reactant: CCOC(=O)c1cc2sccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cc2sccc2[nH]1
Temperature: 100 °C
Yield: 38 %

Procedure:
Add to 4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (1.74 gm, 8.9 mmol) and 7M ammonia in methanol (100 ml) in a steel bomb a chip of lithium hydroxide (0.1 gm). Seal the bomb and heat to 100° C. for 16 hrs. Cool to room temperature, and concentrate to remove the volatiles. Purify the crude product via flash chromatography (ISCO, silica cartridge, 40 gm, elute with methanol 0-5% in methylene chloride) to provide the title compound (560 mg, 38%) as an off-white solid.
Reaction SMILES: [CH2:1]([N:8]([C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]2[N:20]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:26]=3[Cl:33])[N:21]=[C:22]([S:23][CH3:24])[C:14]=12)[CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:36][N:37]=[C:38]=[O:39]>C1COCC1>[CH3:36][NH:37][C:38]([O:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]2[N:20]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:26]=3[Cl:33])[N:21]=[C:22]([S:23][CH3:24])[C:14]=12)=[O:39]
Reactant: CN=C=O
Reactant: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2nc(C)nc(N(CCCO)Cc3ccccc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)OCCCN(Cc1ccccc1)c1nc(C)nc2c1c(SC)nn2-c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 71.3 %

Procedure:
A solution of 3-{benzyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-propan-1-ol (100 mg, 0.191 mmol) in 2 ml of dry THF was treated with 6 mg of 60% sodium hydride in oil and methyl isocyanate (39 mg, 6.78 mmol) at room temperature and stirred at room temperature for 10 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 110 mg of white form. The form was purified through silica gel column chromatography to give 79 mg of the title compound as a white glass form. 1H NMR (CDCl3): 2.03(m,2H), 2.51(s,3H), 2.59(s,3H), 2.77(d,3H), 3.79(t,2H), 4.12(t,2H), 4.50(brs,1H), 5.17(s,2H), 7.2-7.45(m,5H), 7.51(s,2H)ppm.
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24]C1C=CC=CC=1)[C:6]([CH:8]1[CH2:10][N:9]1[CH:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:7])[CH2:2][CH:3]=[CH2:4]>ClC1C=CC=CC=1Cl>[C:13]1([CH:11]([N:9]2[CH:8]3[C:6](=[O:7])[N:5]([CH2:23][CH2:24][C:13]4[CH:22]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:1][CH2:2][CH:3]3[CH2:4][CH2:10]2)[CH3:12])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: C=CCCN(CCc1ccccc1)C(=O)C1CN1C(C)c1cccc2ccccc12
Solvent: Clc1ccccc1Cl
Product: CC(c1cccc2ccccc12)N1CCC2CCN(CCc3ccccc3)C(=O)C21
Yield: 42.7 %

Procedure:
A solution of 3 (15 g, 58.7 mmol) in o-dichlorobenzene (100 mL) is heated at 250° C. for 1200 s in a microwave reactor. The mixture is purified by flash chromatography (silica gel; Hexane/EtOAc 1:1; second spot) to provide 5 g (33%) of the title compound as an enantiomerically pure compound. M+H+=399.32.