Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[OH:15][C:16]([CH3:21])([CH3:20])[C:17](O)=[O:18]>>[NH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:17](=[O:18])[C:16]([OH:15])([CH3:21])[CH3:20])=[CH:10][CH:9]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: CC(C)(O)C(=O)O
Product: CC(C)(O)C(=O)Nc1ccc(Nc2ccccc2)cc1
Temperature: 250 °C
Yield: 88.8 %

Procedure:
A 100 milliliter flask was charged with 18.4 grams (0.10 mole) p-aminodiphenylamine and 10.6 grams (0.102 mole) α-hydroxy isobutyric acid from Example 1. The mixture was heated to 190° C. where dehydration of the amine-acid salt begins. Water was distilled from the mixture as the temperature slowly increased to 250° C. 2.35 milliliters of distillate was collected and the color of the mixture turned from blue-black to clear amber. After cooling the mixture to 190° C., the amber liquid was poured into a crystallizing dish whereupon it immediately crystallized to give 24.0 gram of N-(4-anilinophenyl)-2-hydroxy-isobutyramide (89% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](I)[CH:21]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C(OC(C1CCN(C2C=CC(C(=O)NC3C=CC(C4C=CC=CC=4)=C(C)C=3)=CN=2)CC1)=O)C>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:21]=[C:22]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[F:29])[C:23]([CH3:26])=[CH:24][CH:25]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1F
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Agent: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(-c4ccccc4)c(C)c3)cn2)CC1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(-c4ccccc4F)c3)cn2)CC1

Procedure:
5′-(2′-Fluoro-6-methyl-biphenyl-3-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from 5′-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester and 2-fluorophenyl boronic acid following a method similar to the one described in the synthesis of 5′-(2-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester, above. The product was isolated after silica gel column purification with 20-40% EtOAc in hexanes gradient. HRMS m/z calcd for C27H28N3O3F [M+H]+: 462.2188. Found: 462.2187.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11]I)[C:6]=2[CH:13]=1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11][N:28]3[CH2:29][CH2:30][N:25]([C:23]4[CH:24]=[C:15]([Cl:14])[CH:16]=[C:17]5[C:22]=4[N:21]=[CH:20][CH:19]=[CH:18]5)[CH2:26][CH2:27]3)[C:6]=2[CH:13]=1
Reactant: Clc1ccc2occ(CCI)c2c1
Reactant: Clc1cc(N2CCNCC2)c2ncccc2c1
Product: Clc1cc(N2CCN(CCc3coc4ccc(Cl)cc34)CC2)c2ncccc2c1

Procedure:
8-{4-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline was prepared by generally following the procedure outlined in example 12, step 6, starting from the 2-(5-chloro-1-benzofuran-3-yl)ethyl iodide (306 mg, 1 mmol) and 6-chloro-8-piperazino quinoline (247 mg, 1 mmol). The product was purified by silica-gel column chromatography by initially eluting it with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown oil. Yield: 110 mg (25%); (M+H): 427; 1HNMR (400 MHz, CDCl3):δ 8.86˜8.85 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.03˜8.01 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.57˜7.10 (m, 7H); 3.51˜2.50 (m, 12H).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[CH2:15][CH2:14][C:13]3[C:17]4[C:23]([NH:24][C:25]5[CH:26]=[C:27]6[C:31](=[CH:32][CH:33]=5)[N:30]([CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=5)[N:29]=[CH:28]6)=[N:22][CH:21]=[N:20][C:18]=4[S:19][C:12]=3[C:11]=2[CH:10]=[N:9]1)(=O)=O.[NH:42]1[CH:46]=[CH:45][N:44]=[CH:43]1.C(N(C(C)C)CC)(C)C>>[F:41][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=1)[CH2:34][N:30]1[C:31]2[C:27](=[CH:26][C:25]([NH:24][C:23]3[N:22]=[CH:21][N:20]=[C:18]4[S:19][C:12]5[C:11]6[CH:10]=[N:9][N:8]([CH2:7][CH2:6][N:42]7[CH:46]=[CH:45][N:44]=[CH:43]7)[C:16]=6[CH2:15][CH2:14][C:13]=5[C:17]=34)=[CH:33][CH:32]=2)[CH:28]=[N:29]1
Reactant: CS(=O)(=O)OCCn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Reactant: c1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc(Cn2ncc3cc(Nc4ncnc5sc6c(c45)CCc4c-6cnn4CCn4ccnc4)ccc32)c1

Procedure:
The title compound was prepared following the procedure described for example 277, utilizing 2-(6-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}-4,5-dihydro-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl)ethyl methanesulfonate (1.53 g, 3.0 mmol), imidazole (17 mg, 0.25 mmol), and diisopropylethylamine (0.06 mL, 0.34 mmol). The desired product was collected as a white solid (37 mg, 39%). 1H-NMR (CD2Cl2-d2) δ 8.26 (s, 1H), 8.04 (s, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.50 (d, 1H), 7.40 (d, 1H), 7.21-7.38 (m, 2H), 6.90-7.00 (m, 3H), 6.82 (dd, 1H), 6.72 (s, 1H), 5.60 (s, 2H), 4.42 (t, 2H), 4.35 (t, 2H), 3.17 (t, 2H), 2.40 (t, 2H); LCMS RT=2.58 min; [M+H]+=562.4
Reaction SMILES: CO[C:3](=[O:20])[CH2:4][CH2:5][C@H:6]1[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Mg]([CH2:23][CH2:24][CH2:25][CH2:26][Mg]Br)Br>C1COCC1>[OH:20][C:3]1([CH2:4][CH2:5][C@H:6]2[CH2:10][O:9][C:8]([CH3:11])([CH3:12])[N:7]2[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Br[Mg]CCCC[Mg]Br
Reactant: COC(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CCC2(O)CCCC2)COC1(C)C
Temperature: -10 °C
Reaction time: 2 h

Procedure:
The (S)-tert-butyl 4-(3-methoxy-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate (1.02 g, 3.55 mmol, 1.0 equiv) was dissolved in 50 mL of THF and cooled to −10° C. A 1.0 M solution of BrMg(CH2)4MgBr (7.1 mL, 2.0 equiv) was added and the mixture stirred for 2 h. After this time a second portion of BrMg(CH2)4MgBr was added and the mixture stirred for 1 h. The mixture was quenched by addition of saturated NH4Cl and the mixture transferred to a separatory funnel, and the organic layer was washed with brine, then dried over Na2SO4, filtered, and evaporated to provide crude (S)-tert-butyl 4-(2-(1-hydroxycyclopentyl)ethyl)-2,2-dimethyloxazolidine-3-carboxylate.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[C:15]=3[F:23])[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:31][O:32][C:33]1[N:38]=[C:37]([O:39][CH3:40])[C:36](B(O)O)=[CH:35][N:34]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:20][C:18]1[C:17](=[O:21])[N:16]([CH3:22])[C:15]([F:23])=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:36]4[C:37]([O:39][CH3:40])=[N:38][C:33]([O:32][CH3:31])=[N:34][CH:35]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH:19]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1F)C2=O
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cc2)N(c2cc(Cl)c(=O)n(C)c2F)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 2-bromo-5-(5-chloro-2-fluoro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate AT) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. The title compound was obtained as a light pink foam. ESI-MS: tR=1.08 min, [M+H]+ 572/574/576 (LC-MS 1); TLC: Rf=0.14 (4:1 EtOAc/heptanes).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.ClC1C=CC(C[CH:14]2[C:19](=[O:20])[O:18][C:17]([CH3:22])([CH3:21])[O:16][C:15]2=[O:23])=CC=1.BrC1C=C2C(=CC=1)N=C(Cl)C(CC1C=CC(Cl)=CC=1)=C2Cl>>[CH3:21][C:17]1([CH3:22])[O:18][C:19](=[O:20])[CH:14]([CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:15](=[O:23])[O:16]1
Reactant: CC1(C)OC(=O)C(Cc2ccc(Cl)cc2)C(=O)O1
Reactant: O=Cc1cccs1
Agent: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Product: CC1(C)OC(=O)C(Cc2cccs2)C(=O)O1

Procedure:
The title compound was prepared using thiophene-2-carbaldehyde in place of 4-chlorobenzaldehyde using the procedure described for the preparation of 5-(4-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 3: step a).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@@H:5]2[CH3:27].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)(=[O:18])=[O:17])[C@@H:5]2[CH3:27]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3[C@H]2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: C[C@@H]1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
The title compound was prepared from (R)-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.74 g, 1.93 mmol), cyclohexene (7.0 mL, 70.0 mmol), and 1 M boron tribromide in dichloromethane (23 mL, 23 mmol) according to the procedure and in the same manner as described in Example 32, Method B, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:9 to 1:4 gradient), followed by trituration from hot hexane to yield 4-{[(R)-8-fluoro-6-methylphenanthridin-5(6H)-yl]sulfonyl}phenol* as a solid (0.52 g, 73%), m.p. 193° C.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:23][C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:26]4)=[CH:21][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:35]1CCOC[CH2:36]1>>[O:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:8]3[S:23][C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH2:26]4)=[CH:21][C:9]=3[N:10]=[C:11]([N:13]3[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:20][C:36]3=[O:35])[N:12]=2)[CH2:2][CH2:3]1
Reactant: Nc1ccccc1Nc1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Reactant: C1COCCO1
Product: O=c1[nH]c2ccccc2n1-c1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Temperature: 110 °C
Yield: 32 %

Procedure:
A mixture of N-[4-morpholin-4-yl-6-(3-morpholin-4-yl-azetidin-1-ylmethyl)-thieno[3,2-d]pyrimidin-2-yl]benzene-1,2-diamine (50 mg, 0.10 mmol) and N,N′-carbonyldiimidazole (50 mg, 0.31 mmol) in 1,4-dioxane (0.5 mL) was heated at 110° C. for 4 h. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: 2 M NH3 in MeOH 100:0 to 98:2 to 96:4) to afford 173 as a tan solid (17 mg, 32%). LCMS (method E): RT=6.42 min, [M+H]+=508.1. 1H NMR (CDCl3, 400 MHz) δ 8.50 (bs, 1 H), 7.76-7.72 (m, 1 H), 7.32 (s, 1 H), 7.13-7.04 (m, 3 H), 4.05 (t, J=4.7 Hz, 4 H), 3.97 (s, 2 H), 3.86 (t, J=4.7 Hz, 4 H), 3.73 (m, 4 H), 3.62 (m, 2 H), 3.06 (s, 3 H), 2.33 (m, 4 H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20][Si](C(C)C)(C(C)C)C(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=1.CC(C)([O-])C.[K+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[Si](Sc1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1)(C(C)C)C(C)C
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2Sc2ccc(C(F)(F)F)cc2)CC1
Temperature: 110 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A mixture of 4-(2-tri-iso-propylsilanylsulfanyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (38 mg, 0.085 mmol) and 1-iodo-4-trifluoromethyl-benzene (23 mg, 0.085 mmol) was dissolved in dry degassed toluene (0.3 mL). Pd2dba3 (1 mg) and DPEphos (1 mg) dissolved in dry toluene (0.2 mL) were added. To this solution were added potassium tert-butoxide (10 mg) and tetra-n-butyl ammonium fluoride (TBAF, 1M in TBF, 0.1 mL, 0.1 mmol) and the reaction mixture was stirred at 110° C. for 1 h under argon. The solution was filtered and the solvent was evaporated off. The crude product was purified by chromatography on silica gel (eluent: An increasing amount (0-100%) of ethyl acetate in heptane) to produce 4-[2-(4-trifluoromethyl-phenylsulfanyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (3a1) as a clear oil (22 mg, 59% yield). This material was dissolved in methanol (1 mL) and hydrogen chloride in diethyl ether (2M, 1 mL) was added and the solution was stirred overnight at rt. The solvent was evaporated of and the crude product was purified by BPLC (containing 0.1% TFA in the standard eluent) to produce 4-[2-(4-trifluoromethyl-phenylsulfanyl)-phenyl]-piperidine 3a1 as the trifluoro-acetic acid salt. Yield: 3.2 mg (8% overall). LC/TOF (m/z) 338.0 (MH+); RT=2.29 min; purity (UV, ELSD): 98.3%, 97.1%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)[CH3:10])[C:5]([C:27]#[N:28])=[CH:4][N:3]=1.[OH-].[NH4+:30]>O1CCOCC1>[NH2:30][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)[CH3:10])[C:5]([C:27]#[N:28])=[CH:4][N:3]=1
Reactant: C[C@H](Nc1nc(Cl)ncc1C#N)c1nc2ccn(C)c2cc1-c1ccnn1C
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(N)ncc1C#N)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 100 °C
Yield: 24.9 %

Procedure:
A mixture of (S)-2-chloro-4-((1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile (60 mg, 0.153 mmol) in dioxane (1 mL) and ammonium hydroxide (1 mL, 7.19 mmol) was heated at 100° C. in a microwave reactor for 1 hour. The reaction mixture was subsequently concentrated and purified by preparative HPLC (basic mode, 25% to 50% ACN/water gradient) to give the title compound as an off-white solid (14.2 mg, 24.9%). 1H NMR (500 MHz, CD3OD) δ ppm 1.41 (br s, 3 H), 3.59-3.74 (m, 3 H), 3.86-3.92 (m, 3 H), 5.16-5.36 (m, 1 H), 6.39-6.50 (m, 1 H), 6.63-6.73 (m, 1 H), 7.57-7.67 (m, 2 H), 7.77-7.88 (m, 1H), 8.04-8.13 (m, 1H); ESI-MS m/z [M+H]+ calc'd for C19H19N9, 374.18; found 374.3.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[N:6][NH:7][C:8]=1[CH:9]([O:12][CH3:13])[O:10][CH3:11].I[CH3:20].O>CN(C)C=O>[Br:3][C:4]1[C:5]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[N:6][N:7]([CH3:20])[C:8]=1[CH:9]([O:12][CH3:13])[O:10][CH3:11]
Reactant: COC(OC)c1[nH]nc(-c2nccs2)c1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1c(Br)c(-c2nccs2)nn1C
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
Under a nitrogen atmosphere, sodium hydride 60% in oil (0.236 g, 5.92 mmol) was added portionwise to a solution of 2-[4-bromo-5-(dimethoxymethyl)-1H-pyrazol-3-yl]-1,3-thiazole (8c) (900 mg, 2.96 mmol) in dry dimethylformamide (5 mL). After 10 minutes stirring, iodomethane (0.28 mL, 4.44 mmol) was added and the reaction mixture was stirred at room temperature for 40 minutes. Water (15 mL) was added and the mixture was extracted with ethyl acetate (2×15 mL). The organic layer was washed with brine (2×10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 100/0 to 95/5) to provide 2-[4-bromo-5-(dimethoxymethyl)-1-methyl-1H-pyrazol-3-yl]-1,3-thiazole (8d) (586 mg, 1.84 mmol, 62%) and the regioisomer 2-[4-bromo-3-(dimethoxymethyl)-1-methyl-1H-pyrazol-5-yl]-1,3-thiazole (199 mg, 0.62 mmol, 21%).
Reaction SMILES: [CH2:1]([C:3]12[CH2:24][CH2:23][C:18]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:17][CH:4]1[CH2:5][CH2:6][O:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][NH:14][C:15]=2[CH:16]=1)[CH3:2].I[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>O1CCOCC1.[Cu]I>[CH2:1]([C:3]12[CH2:24][CH2:23][C:18]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:17][CH:4]1[CH2:5][CH2:6][O:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=3)[C:15]=2[CH:16]=1)[CH3:2]
Reactant: Cc1cc(I)ccn1
Reactant: CCC12CCC3(CC1CCOc1cc4[nH]ncc4cc12)OCCO3
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCC12CCC3(CC1CCOc1cc4c(cnn4-c4ccnc(C)c4)cc12)OCCO3
Yield: 86.8 %

Procedure:
A 25 mL round-bottom flask equipped with air cooled reflux condenser was charged with rac-(4aR,12bS)-12b-ethyl-1,2,4,4a,5,6,9,12b-octahydro spiro[benzo[4,5]oxepino[3,2-f]indazole-3,2′-[1,3]dioxolane] (90, R2=Ethyl) (1.00 g, 3.05 mmol), 4-iodo-2-methylpyridine (prepared as described in US 20070287708; 1.19 g, 4.57 mmol), CuI (0.058 g, 0.30 mmol), K3PO4 (1.29 g, 6.09 mmol) and (+/−)-trans-cyclohexane-1,2-diamine (0.070 g, 0.61 mmol) in dioxane (7.5 mL). The reaction mixture was heated at reflux in a heating block for about 18 h. The reaction mixture was filtered through a pad of Celite® using washes of EtOAc (2×20 mL). The filtrate was concentrated under reduced pressure and the residue was purified on silica gel (40 g, eluted with 0% to 100% EtOAc in DCM). Collection and concentration of the appropriate fractions gave rac-(4aR,12bS)-12b-ethyl-9-(2-methylpyridin-4-yl)-1,2,4,4a,5,6,9,12b-octahydrospiro[benzo[4,5]oxepino[3,2-f]indazole-3,2′-[1,3]dioxolane] (91, R1=2-methylpyridin-4-yl, R2=Ethyl) (1.11 g, 87%). LC/MS, method 3, Rt=2.47 min, MS m/z 420 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J=5.9 Hz, 1H), 8.19 (s, 1H), 7.86-7.70 (m, 2H), 7.65 (s, 1H), 7.53 (s, 1H), 4.39-4.30 (m, 1H), 4.01-3.85 (m, 4H), 3.82-3.70 (m, 1H), 2.87-2.68 (m, 4H), 2.50-2.40 (m, 1H), 2.32-2.21 (m, 2H), 2.03-1.32 (m, 7H), (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].O.[C:8]([NH:15][C@H:16]([C:21]([OH:23])=O)[CH2:17][CH:18]([CH3:20])[CH3:19])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:8]([NH:15][C@H:16]([C:21]([CH2:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6])=[O:23])[CH2:17][CH:18]([CH3:19])[CH3:20])([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: COCCCN
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)COCCCN

Procedure:
In substantially the same manner as Working Example 2, 3-methoxypropylamine (6.1 ml, Wako Pure Chemical Industries, Ltd.) was condensed with Boc-L-leucine monohydrate (5.00 g, manufactured by Peptide Institute, Inc.) to afford N-(Boc-L-leucyl)methoxypropylamine (17.5 g) as a colorless waxy product (yield 89%). The Boc group was deprotected by using TFA, and 1.21 g of the resultant compound was condensed, in substantially the same manner as Working Example 2, with (2S,3S)-ethyl hydrogen N-Z-aziridine-2,3-dicarboxylate (Compound 1, 1.93 g) to afford the above-titled compound (Compound 20; 2.55 g) as a white crystalline product (yield 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH:13](N)[N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[CH:5][CH:4]=1.C(N(CC)C1C=CC=CC=1)C.Cl>CN1CCCC1=O>[C:18]1(=[O:19])[N:14]([CH2:13][CH2:12][CH2:11][C:10]2[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:27]=[CH:26][C:6]=3[O:7][CH2:8][CH:9]=2)[C:15](=[O:24])[C:16]2=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]12
Reactant: COc1ccc(OCC#CCCC(N)N2C(=O)c3ccccc3C2=O)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)c1ccccc1
Product: COc1ccc2c(c1)C(CCCN1C(=O)c3ccccc3C1=O)=CCO2

Procedure:
A mixture of 40 g of 6-(4-methoxyphenoxy)-1-phthalimido-4-hexynylamine and 8.5 g of N,N-diethylaniline in 400 ml of N-methylpyrrolidinone is heated at 210° for 30 hours. After pouring onto water containing 57 ml of 1N hydrochloric acid the product is extracted with ether, dried, and the solvent is removed in vacuo. The residue is crystallized from isopropyl alcohol to afford 4-(3-phthalimidopropyl)-6-methoxy-2H-[1]-benzopyran, melting point 78°-80°.
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.[CH2:12]([NH:14][C:15]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[Cl:22])=[O:16])[CH3:13].CN(CCN(C)C)C.[CH3:31][Si:32](Cl)([CH3:34])[CH3:33]>C1COCC1.CCOCC>[Cl:22][C:18]1[S:19][CH:20]=[C:21]([Si:32]([CH3:34])([CH3:33])[CH3:31])[C:17]=1[C:15]([NH:14][CH2:12][CH3:13])=[O:16]
Reactant: CCNC(=O)c1ccsc1Cl
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CCNC(=O)c1c([Si](C)(C)C)csc1Cl
Temperature: -100 °C
Reaction time: 0.5 h
Yield: 11.5 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (16.15 mL, 21 mmol) was added dropwise to an ether/liquid N2 cooled (-100° C.) solution of N-ethyl-2-chloro-3-thiophenecarboxamide (1.90 g, 10 mmol) and TMEDA (3.17 mL, 21 mmol) in THF (100 mL). After stirring for 30 min at -100° C., TMSCl (2.28 g, 21 mmol) was added in a single portion. The resulting reaction mixture was warmed to -25° C. over 1 h, quenched with dilute aq citric acid, and extracted with EtOAc (3×). The combined organic extracts were dried (MgSO4), concentrated, and purified by HPLC with 3:17 EtOAc/hexanes to afford 0.3 g of the title compound as a white solid, an 11% yield. m.p. 46°-48° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[NH2:27])=[CH:22][C:21]=2[CH3:29])=[CH:16][C:15]=1[Cl:30])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[ClH:32]>C(OCC)(=O)C.O1CCOCC1.CO>[ClH:30].[Cl:32][C:22]1[C:21]([CH3:29])=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][NH:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:15][CH:16]=2)[CH:25]=[CH:24][C:23]=1[C:26]([NH2:27])=[O:28]
Reactant: Cc1cc(C(N)=O)ccc1-c1ccc(CN(CCC(C)C)C(=O)OC(C)(C)C)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(CNCCC(C)C)cc2)ccc(C(N)=O)c1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(4′-Carbamoyl-3-chloro-2′-methyl-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-3e: 12.6 g, 28.3 mmol) was dissolved in ethyl acetate and treated with 30 ml of 4.0M hydrogen chloride in dioxane. After stirring for 24 hours at room temperature, the volatiles were removed under reduced pressure and the product was isolated by dissolving the crude material in methanol and slowly adding ethyl acetate to precipitate the product, which was isolated via filtration. The solid was crystallized by dissolving in 10 parts of hot ethanol before cooling to room temperature. After stirring for 48 hours, the resulting slurry was collected via filtration, rinsing with chilled ethanol, to provide the title compound (E3-01) as a colorless solid.