Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:5]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
To a solution of 3.0 g (12.9 mmol) of Boc-Thz-OH and 2.15 ml (15.5 mmol) of triethylamine in 25 ml of DMF, 2.02 ml (15.5 mmol) of isobutyl chloroformate was added dropwise at -15° C. After stirring for 10 min at that temperature. 4.06 ml (38.7 mmol) of tert-butylamine was added. The reaction mixture was stirred for 10 min at that temperature and 100 min under ice cooling, concentrated under reduced pressure, diluted with 50 ml of ethyl acetate, washed with 5% NaHCO3 aqueous solution, 5% citric acid aqueous solution, and saturated NaCl aqueous solution successively, dried over Na2SO4, and evaporated under reduced pressure to give 3.13 g (Y. 84%) of Boc-Thz-NH-tBu which was convened to Qoa-Mta-AHPBA-Thz-NH-tBu by a similar method with processes 2-5 of Example 3.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[F:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[NH:32][C:31](=[O:34])[N:30]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37](B3OC(C)(C)C(C)(C)O3)[C:36]=1[CH3:50])[C:29]2=[O:51].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([N:30]2[C:29](=[O:51])[C:28]4[C:33](=[C:24]([F:23])[CH:25]=[CH:26][CH:27]=4)[NH:32][C:31]2=[O:34])[C:36]=1[CH3:50])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)[nH]c2c(F)cccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(-c2c(Cl)cc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1c(=O)[nH]c2c(F)cccc2c1=O
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (0.360 g, 0.943 mmol), 8-fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 17] (0.392 g, 0.990 mmol), PdCl2(dppf) DCM adduct (0.039 g, 0.047 mmol) and Cs2CO3 (0.615 g, 1.89 mmol) in dioxane (10 mL) and water (2.5 mL) was heated at 100° C. overnight. The cooled mixture was diluted with EtOAc and washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (gradient from 0-50%, then to 70% containing 1% MeOH), to provide 3-chloro-4-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a white solid (0.361 g, 67% yield). Mass spectrum m/z 354 (M+H—H2O)+, 394 (M+Na)+. 1H NMR (500 MHz, MeOH-d4) δ 8.09 (d, J=1.1 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.81-7.69 (m, 1H), 7.64-7.54 (m, 2H), 7.48 (dd, J=7.8, 1.1 Hz, 1H), 7.43-7.29 (m, 1H), 7.31-7.24 (m, 1H), 7.18 (dd, J=8.3, 1.7 Hz, 1H), 7.16-7.07 (m, 1H), 6.92 (dd, J=8.6, 5.3 Hz, 1H), 1.94-1.71 (m, 3H), 1.65-1.50 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[C:10]1([S:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][CH2:34][O:35][S:36]([C:39]4[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=4)(=[O:38])=[O:37])[CH:30]=3)[NH:25][N:24]=2)(=[O:22])=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:25]1[C:26]2[C:31](=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][S:36]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)(=[O:38])=[O:37])=[CH:28][CH:27]=2)[C:23]([S:20]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)(=[O:21])=[O:22])=[N:24]1
Reactant: Clc1cccc(CBr)c1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
3-Chlorobenzylbromide (0.90 mL, 6.8 mmol) was added to a stirring suspension of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (3.24 g, 6.20 mmol) and cesium carbonate (2.21 g, 6.78 mmol) in acetone (80 mL). The mixture was stirred at ambient temperature under nitrogen for 2 hours. It was then poured into excess water and extracted with chloroform. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 30-35% ethyl acetate in hexane. Drying at 65° C. in vacuo for 30 minutes gave toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol -5-yloxy]-ethyl ester as a dark yellow foam (2.55 g, 63.6%); Mass Spectrum (+EI, [M+H]+) m/z 647. 1HNMR (500 MHz, DMSO-d6): δ8.73-8.75 (m, 1H), 8.55-8.57 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.01-8.04 (m, 1H), 7.67-7.75 (m, 4H), 7.56-7.63 (m, 2H), 7.17-7.27 (m, 5H), 7.05-7.07 (m, 2H), 6.98 (dd, 1H, J=9.28 Hz and 2.32 Hz), 5.71 (s, 2H), 4.31-4.33 (m, 2H), 4.15-4.17 (m, 2H), 2.17 ppm (s, 3H). Elemental Analysis for C33H27ClN2O6S2: Calcd: C, 61.25; H, 4.21; N, 4.33; Found: C, 60.93; H, 4.22; N, 4.21.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[CH:13]2.[OH:19][C@@H:20]([CH3:38])[CH2:21][N:22]1[C:26]([CH3:27])=[C:25]([C:28](O)=[O:29])[C:24](=[O:31])[N:23]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:28]([C:25]2[C:24](=[O:31])[N:23]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:22]([CH2:21][C@@H:20]([OH:19])[CH3:38])[C:26]=2[CH3:27])=[O:29])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[CH:13]2
Reactant: Nc1ccc(-c2cccc3cnccc23)c(F)c1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C[C@H](C)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(-c3cccc4cnccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C[C@H](C)O
Reaction time: 120 h
Yield: 33435.8 %

Procedure:
3-fluoro-4-(isoquinolin-5-yl)benzenamine (309.9 mg, 1301 μmol) and (S)-1-(2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (359 mg, 1301 μmol) were suspended in DCM (6.5 ml) and DMF (0.65 ml) and hatu (579 mg, 1523 μmol) was added. The reaction was stirred under nitrogen for 5 days, and then filtered. The solid was washed with DCM, and the filtrate was concentrated and purified on silica gel (50:1->40:1->30:1->10:1 DCM/MeOH. The fractions with product were collected, concentrated, treated with MeOH and filtered. The solid was washed with MeOH, collected, and dried under high vacuum to afford the desired N-(3-fluoro-4-(isoquinolin-5-yl)phenyl)-1-((S)-2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (216.0 mg, 435.0 mmol, 33% yield). MS (ESI pos. ion) m/z: 497 (MH+). Calc'd exact mass for C29H25FN4O3: 496. 1H NMR (400 MHz, CDCl3) δ 10.93 (s, 1H), 9.30 (s, 1H), 8.49 (d, J=6.0 Hz, 1H), 8.01 (dd, J=7.0 Hz, 3.0 Hz, 1H), 7.87 (dd, J=12.0 Hz, 2.0 Hz, 1H), 7.71-7.64 (m, 2H), 7.59-7.52 (m, 3H), 7.48 (d, J=8.0 Hz, 1H), 7.42-7.34 (m, 3H), 7.31 (d, J=8.0 Hz, 1H), 4.00-3.83 (m, 2H), 3.72 (dd, J=15.0 Hz, 3.0 Hz, 1H), 2.89 (s, 3H), 1.29-1.24 (m, 1H), 1.11 (d, J=6.0 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-])=O>CO.C(Cl)Cl.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1cc(N2CCCCC2)ccc1N
Reaction time: 10 h
Yield: 57.1 %

Procedure:
To 2-Nitro-5-piperidin-1-yl-benzamide (948 mg, 4.07 mmol) in Methanol (100 mL) was added Pd/C (10%) followed by H2 (1 ATM). After 10 h, the solution was filtered and concentrated. Flash chromatography (0–5% methanol in methylene chloride) afforded the title compound as a white solid (510 mg, 51% yield). FIA m/z 220.1 (M+H) 218 (M−H)
Reaction SMILES: C(OC[O:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)C.Cl>CO.O>[F:22][C:19]([F:20])([F:21])[O:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]=[CH:7][C:6]([OH:5])=[CH:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: CCOCOc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1
Agent: Cl
Solvent: O
Solvent: CO
Product: Oc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.4 %

Procedure:
Ether 110 (379 mg, 1.21 mmol) was treated with 1.25M HCl in MeOH (11 mL) and the mixture was stirred at room temperature for 12 h, and then at 53° C. for 2 h. The resulting cooled solution was diluted with water (50 mL) and extracted with CH2Cl2 (5×50 mL). The combined extracts were evaporated to dryness and the residue was triturated in pentane to give 2-[4-(trifluoromethoxy)phenyl]-5-pyrimidinol (112) (305 mg, 99%) as a white solid: mp (pentane) 156-157° C.; 1H NMR (CDCl3) δ 8.45 (s, 2H), 8.38 (dt, J=8.9, 2.4 Hz, 2H), 7.29 (br dd, J=8.9, 0.7 Hz, 2H), 5.60 (br s, 1H); HRESIMS calcd for C11H8F3N2O2 m/z [M+H]+ 257.0532. found 257.0526.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[C:8](I)[C:7](=[O:22])[C:6]=2[CH:23]=1.CO[C:26]1[C:27](OC)=[C:28](B([O-])[O-])[C:29](OC)=[N:30][CH:31]=1.[Li+].[Li+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[C:8]([C:28]3[CH:29]=[N:30][CH:31]=[CH:26][CH:27]=3)[C:7](=[O:22])[C:6]=2[CH:23]=1
Reactant: CS(=O)(=O)c1ccc(-c2oc3ccc(F)cc3c(=O)c2I)cc1
Reactant: COc1cnc(OC)c(B([O-])[O-])c1OC
Agent: [Li+]
Product: CS(=O)(=O)c1ccc(-c2oc3ccc(F)cc3c(=O)c2-c2cccnc2)cc1

Procedure:
The title compound was prepared from 6-fluoro-3-iodo-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one and lithium trimethoxy-3-pyridinylboronate by the same method as described in Step 5 of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.CN1CCCC1=O.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:19]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NNC(=O)c1ccc(Br)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(NNC(=O)c1ccc(Br)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
In a 200 mL three-necked flask were placed 15 g (71 mmol) of 4-bromobenzoylhydrazine and 20 mL of N-methyl-2-pyrrolidone (abbreviation: NMP). To this mixture was dripped a solution of 9.4 mL (81 mmol) of benzoyl chloride in 5 mL solution of N-methyl-2-pyrrolidone through a 50 mL dropping funnel. This solution was stirred at 80° C. for 3 hours under a stream of nitrogen. After a predetermined time, this solution was added to about 100 mL of water, and the precipitated solid was collected by suction filtration. The collected solid was washed with methanol, and 19 g of a white powder, which was a target substance, was obtained at a yield of 84%.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:35][N:36]1[CH:40]=[C:39]([S:41](Cl)(=[O:43])=[O:42])[N:38]=[C:37]1[CH3:45]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:35][N:36]1[CH:40]=[C:39]([S:41]([N:23]2[CH2:24][CH2:25][CH:20]([C:11]3[C:10]4[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH:9]=4)[NH:13][N:12]=3)[CH2:21][CH2:22]2)(=[O:43])=[O:42])[N:38]=[C:37]1[CH3:45]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(S(=O)(=O)N2CCC(c3n[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)cn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a solution of 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (Example 2) (50 mg, 0.14 mmol) in DMF (3 mL) was added diisopropylethylamine (100 uL, 0.56 mmol), DMAP (20 mg, 0.014 mmol) and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (33 mg, 0.168 mmol). The reaction mixture was stirred at room temperature overnight. The solution was filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (25 mg, 37%)
Reaction SMILES: N[C:2]1[C:13]([C:14]([O:16]N2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1.[Cl:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([F:39])[C:32]=1[C:33]1[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=1.O1CC(=O)C1.CO>C1COCC1>[Cl:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([F:39])[C:32]=1[C:33]1[CH2:34][CH2:35][N:36]([CH:13]2[CH2:14][O:16][CH2:2]2)[CH2:37][CH:38]=1
Reactant: Fc1cncc(Cl)c1C1=CCNCC1
Reactant: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Agent: O=C1COC1
Solvent: CO
Solvent: C1CCOC1
Product: Fc1cncc(Cl)c1C1=CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
Sodium triacetoxyborohydride (Sodium Ion (1)) (1.026 g, 4.842 mmol) was added in portions to a stirred solution of 3-chloro-5-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)pyridine (468 mg, 2.201 mmol) and 3-oxetanone (269.7 mg, 239.9 μL, 3.742 mmol) in THF (10 mL) at 0° C. under an atmosphere of nitrogen. The reaction was allowed to warm to ambient temperature over 16 hours. MeOH (2 mL) was added dropwise and the mixture stirred at ambient temperature for 30 minutes. The mixture was concentrated in vacuo and partitioned between water and EtAOc. The pH of the aqueous layer was adjusted to pH 7-8 by the addition of NH4OH and the layers separated. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts washed with brine (×1), dried (MgSO4), filtered and concentrated in vacuo to give 3′-chloro-5′-fluoro-1-(oxetan-3-yl)-1,2,3,6-tetrahydro-4,4′-bipyridine as a white solid (573 mg, 97% Yield). MS (ES+) 269.1.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([N:16]([C@H:19]2[CH2:24][CH2:23][C@H:22]([N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:26])[CH2:21][CH2:20]2)[CH2:17][CH3:18])[C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C>[C:30]([O:29][C:27]([N:25]([CH3:26])[C@H:22]1[CH2:21][CH2:20][C@H:19]([N:16]([CH2:17][CH3:18])[C:7]2[C:8]([CH3:15])=[C:9]([CH:14]=[C:5]([C:4]#[C:3][CH2:2][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:6]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:24][CH2:23]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCN(c1cc(C#CCBr)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: CCN(c1cc(C#CCN2CCOCC2)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of methyl 5-(3-bromoprop-1-yn-1-yl)-3-(((trans)-4-((tert-butoxy carbonyl)-(methyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate (1 equiv.) in DMF, morpholine (5 equiv.) was added and reaction was stirred for 12 h at room temperature. On completion, the reaction was quenched with ice water and extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure to afford desired crude title compound that was used in the next step without further purification (98.7% yield)
Reaction SMILES: [C:1]1([C:7]2[S:13][CH2:12][CH2:11][NH:10][C:9](=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[C:1]1([C:7]2[S:13][CH2:12][CH2:11][NH:10][CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=C(c2ccccc2)SCCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C1=C(c2ccccc2)SCCNC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
3,4-Dihydro-7-phenyl-1,4-thiazepin-5(2H)-one (3.30 g, 16.2 mm cl) is added to 50 mL of absolute diethyl ether. The reaction mixture is then cooled to 0° C. and lithium aluminum hydride (16.7 mL of a 1M ethereal solution) is added. The reaction mixture is then stirred overnight at room temperature and is quenched by the addition of 2.5 mL of water followed by 5 mL of 10% aqueous sodium hydroxide solution. The solids are filtered and washed with absolute ethanol. The filtrates are combined and concentrated under reduced pressure and the resulting residue is chromatographed on silica eluting with 10:1 dichloromethane:methanol to obtain 1.63 g of the product as a clear oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:29])[C:12]([N:14]3[CH2:19][CH2:18][C:17](=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:21]#[N:22])[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:10][C:3]=12.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[N:39][CH:38]=[CH:37][N:36]=1)CCC.O1CCOCC1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:29]=[C:11]([C:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([C:35]3[CH:40]=[N:39][CH:38]=[CH:37][N:36]=3)=[C:3]2[NH:10][CH:9]=1)[C:12]([N:14]1[CH2:19][CH2:18][C:17](=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]#[N:22])[CH2:16][CH2:15]1)=[O:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(Cl)ccnc23)CC1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(-c4cnccn4)ccnc23)CC1)c1ccccc1
Temperature: 140 °C
Yield: 7.8 %

Procedure:
A mixture of compound of Example 101 (30 mg, 0.074 mmol), 2-tributylstannanyl pyrazine (82 mg, 0.22 mmol), Pd(PPh3)4 (88 mg, 0.076 mmol) and dioxane (1 mL) in a sealed tube was heated at 140° C. for 15 h. The reaction mixture was diluted with MeOH, filtered through Celite and concentrated. The residue was purified by preparative HPLC to yield title compound (2.6 mg, 0.0058 mmol, 9%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]([O:18]C)=[O:17])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]([OH:18])=[O:17])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 72.5 %

Procedure:
A mixture of 4-(1-methoxycarbonylethyl)-piperidine-1-carboxylic acid tert-butyl ester (40 g crude from last step, about 0.15 mol), LiOH (12.6 g, 0.3 mol) in water (200 mL) and THF (400 mL) was heated to reflux for 4 hours. The cooled mixture was diluted with water (200 mL) and washed with Et2O (200 mL×2). The aqueous layer was acidified with HCl (10%) at 0° C. to pH3-4. The mixture was extracted with Et2O (200 mL×3) and the combined extracts were washed with brine, dried and concentrated to give the product as a white solid (28 g, 73% from N-benzyl-4-piperidone). 1HNMR (CDCl3) δ 4.11 (m, 2H), 2.69-2.63 (m, 2H), 2.30 (p, 1H, J=7.2 Hz), 1.72-1.62 (m, 3H), 1.44 (s, 9H), 1.27-1.18 (m, 2H), 1.16 (d, 3H, J=7.2 Hz).
Reaction SMILES: N([C:8]1[C:9](=[O:21])[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([CH3:19])=[C:12]([CH3:20])[CH:11]=2)C1C=CC=CC=1.S(=O)(=O)(O)[OH:23]>O>[CH3:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[CH3:20])[C:9](=[O:21])[C:8]([OH:23])=[CH:17][C:16]2=[O:18]
Reactant: O=S(=O)(O)O
Reactant: Cc1cc2c(cc1C)C(=O)C(Nc1ccccc1)=CC2=O
Solvent: O
Product: Cc1cc2c(cc1C)C(=O)C(O)=CC2=O

Procedure:
A solution of 2-anilino-6,7-dimethyl-1,4naphthoquinone (3.1; 0.014 mole) in concentrated sulphuric acid (70ml) was diluted with an equal volume of water and refluxed for 1 minute. After pouring into cold water the precipitated hydroxy derivative was filtered off and extracted into petrol ether (b.p. 100°-102° C). After treatment of the extract with charcoal the title compound separated as a yellow solid, 1.29g (55%), m.p. 175°-177° C (d). (Found; C, 71.29; H, 5.07 C12H10O3 requires; C, 71.28; H, 4.98%)
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[O:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][C:26]2=[O:31])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:28]3[CH2:29][CH2:30][N:25]([CH:22]4[CH2:21][CH2:20][O:19][CH2:24][CH2:23]4)[C:26](=[O:31])[CH2:27]3)=[CH:4][C:5]=2[N:6]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: O=C1CNCCN1C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN1C1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.3 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (200 mg, 0.57 mmol), in DMF (4 mL), was added 1-(tetrahydro-pyran-4-yl)-piperazin-2-one (116 mg, 0.63 mmol) and potassium carbonate (238 mg, 1.72 mmol). The mixture was stirred at RT for 4 h, then the reaction mixture was diluted with water and extracted with DCM. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to give the title compound as a yellow solid (212 mg, 82%).
Reaction SMILES: [CH2:1]([N:5]([CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]2[S:20][C:19]([CH:21]=O)=[CH:18][CH:17]=2)=[C:8]([O:23][CH3:24])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:29]([C:31]1[C:32](=[C:39]([C:42]#[N:43])[C:40]#[N:41])[O:33][C:34]([CH3:38])([CH3:37])[C:35]=1[CH3:36])#[N:30].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:25]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]2[S:20][C:19]([CH:21]=[CH:36][C:35]3[C:34]([CH3:37])([CH3:38])[O:33][C:32](=[C:39]([C:40]#[N:41])[C:42]#[N:43])[C:31]=3[C:29]#[N:30])=[CH:18][CH:17]=2)=[C:8]([O:23][CH3:24])[CH:7]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN(CCCC)c1ccc(C=CC=Cc2ccc(C=O)s2)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)s2)c(OC)c1
Temperature: 50 °C
Yield: 68.3 %

Procedure:
In 7 ml of ethanol and 2 ml of tetrahydrofuran were dissolved 248 mg (0.62 mmol) of 5-[4-(4-dibutylamino-2-methoxyphenyl)-1,3-butadienyl]thiophene-2-carboaldehyde and 137 mg (0.61 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene) propanedinitrile. To this mixture was added 50 mg of ammonium acetate, and the mixture was stirred with heating at 50° C. for 4 hours. The product was separated by filtration, washed with ethanol, and purified by silica gel column chromatography to give 241 mg of a dark brown crystal (yield: 66.8%; mp: 185-187° C.)