Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.N[C:34]1[CH:39]=C(CC)C=CN=1>>[CH2:34]([C:9]1[CH:4]=[CH:5][N:6]=[C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:8]=1)[CH3:39]
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Reactant: CCc1ccnc(N)c1
Product: CCc1ccnc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)c1

Procedure:
The product from Example 1, Part C (0.3 g, 0.93 mmol) and 2-amino-4-ethylpyridine (0.171 g, 1.4 mmol) were converted to the title compound by the method described in Part B of Example 16 (121 mg, 30%). 1H NMR (300 MHz, CDCl3) δ 8.53 (broad s, 1H); 8.15 (d, J=5.16 Hz, 1H); 7.99 (s, 1H); 7.23 (d, J=8.4 Hz, 2H); 6.92 (m, 1H); 6.84 (d, J=8.5 Hz, 2H); 5.11 (d, J=15 Hz, 1H); 4.61 (s, 1H); 4.16 (d, 15 Hz, 1H); 3.77 (s, 3H); 2.90 (s, 2H); 2.67 (q, J=7.4 Hz, 2H); 1.95 (s, 3H); 1.84 (s, 3H); 1.27 (t, J=7.6 Hz, 3H). MS: m/z (MH+) 426.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8]C[C@H:6]1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)(=[O:3])[CH3:2].BrC1C=CC(O[C@@H]2CCC[C@H]2O)=CC=1[F:33]>>[C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:6]1[O:11][C:12]1[CH:13]=[CH:14][C:15]([Br:18])=[C:16]([F:33])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: O[C@@H]1CCC[C@H]1Oc1ccc(Br)c(F)c1
Reactant: CC(=O)O[C@@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Product: CC(=O)O[C@@H]1CCC[C@H]1Oc1ccc(Br)c(F)c1

Procedure:
The title compound in Step 2 was prepared according to the general procedure for the synthesis of (1R,2R)-2-(4-bromophenoxy)cyclohexyl acetate in Example 7, except that trans-2-(4-bromo-3-fluorophenoxy)cyclopentanol was used instead of trans-2-(4-bromophenoxy)cyclohexanol. The less polar material from the chromatographic purification on silica gel provided (1R,2R)-2-(4-bromo-3-fluorophenoxy)cyclopentyl acetate as an oil. Yield: 6.42 g, 20.2 mmol, 48% over 2 steps. 1H NMR (400 MHz, CDCl3) δ 1.67-1.75 (m, 1H), 1.79-1.92 (m, 3H), 2.05-2.20 (m, 2H), 2.08 (s, 3H), 4.60 (m, 1H), 5.14 (m, 1H), 6.66 (ddd, J=8.9, 2.8, 1.1 Hz, 1H), 6.78 (dd, J=10.5, 2.8 Hz, 1H), 7.40 (dd, J=8.8, 8.1 Hz, 1H).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][S:7][C@H:6]2[CH2:9][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:11](=[O:12])[N:5]12)(=[O:3])[NH2:2].C(OC(N[C@H]1C(=O)N2[C@H](SC[C@H]2C(OC)=O)C1)=O)(C)(C)C>>[C:1]([C@@H:4]1[CH2:8][S:7][C@@H:6]2[CH2:9][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[C:11](=[O:12])[N:5]12)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H]2SC[C@@H](C(N)=O)N2C1=O
Agent: COC(=O)[C@@H]1CS[C@@H]2C[C@@H](NC(=O)OC(C)(C)C)C(=O)N21
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2SC[C@@H](C(N)=O)N2C1=O

Procedure:
was obtained in analogy to the synthesis of 2e) starting from 540 mg of methyl (3R,6R,8R)-6-tert-butoxycarbonylamino-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carboxylate (2d).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12]([O-:14])=O)[N:4]=1.[CH3:17][NH2:18]>>[CH3:17][NH:18][C:12]([C:5]1[N:4]=[C:3]([C:2]([F:1])([F:16])[F:15])[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]=12)=[O:14]
Reactant: O=C([O-])c1nc(C(F)(F)F)n2c1CNCC2
Reactant: CN
Product: CNC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (500 mg, 2 mmol) was dissolved in 8 mL of methylamine solution (20% to 30%) was added in a 20 mL sealed tube. After stirring at 60° C. for 6 hours, the reaction mixture was concentrated under reduced pressure to obtain the crude N-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydro imidazo[1,5-a]pyrazine-1-carboxamide 13a (498 mg) as a white solid. The product was used directly in the next reaction without purification.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([NH:14][C:15](=[O:17])[CH3:16])([CH3:13])[CH2:9]1)C1C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[H][H]>[Pd].C(O)C>[CH3:13][C:10]1([NH:14][C:15](=[O:17])[CH3:16])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC(=O)NC1(C)CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Product: CC(=O)NC1(C)CCNC1
Yield: 54.1 %

Procedure:
A mixture of N-(1-benzyl-3-methylpyrrolidin-3-yl)-acetamide (600 mg, 2.6 mmol), palladium on carbon (400 mg, 10%) and ethanol (20 mL) was stirred at 40° C. under 50 Psi of hydrogen for 16 hours. The resulting mixture was filtrated. The filtrate was concentrated in vacuo to give 200 mg of the desired product (yield was 54%), which was used for next step without any purification.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[C:18]1([C:24]2(Cl)[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:31][C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO>N1C=CC=CC=1>[I:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][O:13][C:24]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:31][C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@@H:9]([OH:10])[CH2:8]1
Reactant: ClC1(c2ccccc2)c2ccccc2Oc2ccccc21
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Solvent: c1ccncc1
Solvent: CO
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC3(c4ccccc4)c4ccccc4Oc4ccccc43)O2)cc1I
Reaction time: 0.5 h
Yield: 70 %

Procedure:
5-Iodo-2'-deoxyuridine (IDU) (3.54 g, 10 mmol) was coevaporated with dry pyridine (3×20 mL). The IDU was redissolved in dry pyridine (15mL) and 9-phenyl-9-chloroxanthen (3.82 g, 13 mmol) was added to the stirring solution in two equal portions over 0.5 h. After 1h, MeOH (5 mL) was added and the solution stirred for a further 0.5 h. The solvent was then removed under vacuum, and the residue recrystallized from a 1% Et2N/ethyl acetate solution giving 7 as colourless crystals (4.27 g, 70%), mp 200-2° C. 1H NMR (d6 -DMSO): δ2.20 (m, 2H, H2'), 2.99 (dd, 1H, H5', J-10.5, 4.2 Hz), 3.10 (dd, 1H, H5", J=10.5, 2.7 Hz), 3.85 (m, 1H, H4'), 4.15 (m, 1H, H3'), 5.29 (d, 1H, 3'OH, J=4.2 Hz), 6.08 (t, 1H, H1', J=7.0 Hz), 7.10-7.42 (m, 13H, Px CH), 8.08 (s, 1H, H6). 13C NMR (d6 -DMSO): δ40.4 (C2'), 63.8 (C5'), 69.9 (C5), 71.0 (C3'), 75.6 (Px C9), 85.2 (Cl'), 85.9 (C4'), 116.3, 116.4 (Px CH), 122.3, 122.4 (Px C8a and C9a), 123.8, 124.0, 125.8, 126.8, 128.2, 129.3, 129.69, 129.7, 129.73 (Px CH), 143.9 (C6), 148.4(Px Cl'), 150.0 (C2), 150.51, 150.58 (Px C4a and C10a), 160.6 (C4). FABMS m/z 633 (M+Na'). Anal. calcd for C28H23N2P6I: C, 55.1; H,3.81, N, 4.59. Found: C, 55.0; H, 3.81, N, 4.54.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:5]2=[N:6][CH:7]=1.BrC1[N:19]=[C:18]2NC(C)=C(C)C2=CC=1.C([Cu])#N.Cl>O.N1C=CC=CC=1>[C:18]([C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:5]2=[N:6][CH:7]=1)#[N:19]
Reactant: Cc1[nH]c2ncc(Br)cc2c1C
Reactant: Cc1[nH]c2nc(Br)ccc2c1C
Agent: N#C[Cu]
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1[nH]c2ncc(C#N)cc2c1C
Temperature: 220 °C
Yield: 40 %

Procedure:
An autoclave was charged with 5-bromo-2,3-dimethyl-pyrrolo[2,3-b]pyridine (prepared in a similar manner as 6-bromo-2,3-dimethyl-pyrrolo[2,3-b]pyridine (247 mg, 1.1 mmol) and CuCN (135 mg. 1.5 mmol). The mixture was covered with pyridine and heated to 220° C. for 12 h. After cooling the raction mixture was poured into a mixture of FeCl3 hexahydrate (0.9 g), conc HCl (0.5 ml), and water (10 ml). The mixture was heated to 80° C. for 1 h and extracted with CH2Cl2. The organic layer was washed four times with 2M HCl, dried over MgSO4 and evaporated leaving 77 mg (40%) 5-cyano-2,3-dimethyl-pyrrolo[2,3-b]pyridine.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:22][CH2:23][CH2:24][C@@H:25]([NH:29][C:30]1[C:35]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][O:47][Si](C(C)(C)C)(C)C)=[CH:39][C:38]=2[O:55][CH3:56])=[C:34]([CH3:57])[N:33]=[C:32]([NH2:58])[N:31]=1)[CH2:26][CH2:27][CH3:28])(=[O:21])[CH3:20]>C1COCC1.O.C(=O)([O-])O.[Na+]>[C:19]([O:22][CH2:23][CH2:24][C@@H:25]([NH:29][C:30]1[C:35]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][OH:47])=[CH:39][C:38]=2[O:55][CH3:56])=[C:34]([CH3:57])[N:33]=[C:32]([NH2:58])[N:31]=1)[CH2:26][CH2:27][CH3:28])(=[O:21])[CH3:20]
Reactant: CCC[C@@H](CCOC(C)=O)Nc1nc(N)nc(C)c1Cc1ccc(OCCCO[Si](C)(C)C(C)(C)C)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@@H](CCOC(C)=O)Nc1nc(N)nc(C)c1Cc1ccc(OCCCO)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Tetra-n-butylammonium fluoride (561 mg) was added to the mixture of the product from step (iii) in THF (14 mL). After the mixture was stirred at RT for 1.5 h, the reaction mixture was diluted with water and sat. sodium hydrogen carbonate and extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (660 mg) as a colourless oil; 1H NMR (CDCl3); 6.82 (1H, d), 6.45 (1H, d), 6.39 (1H, dd), 4.71 (2H, br s), 4.23-4.13 (1H, m), 4.07 (2H, t), 3.85 (3H, s), 3.85-3.74 (4H, m), 3.58 (2H, s), 2.33 (3H, s), 2.15 (1H, br s), 2.04-1.97 (2H, m), 1.97 (3H, s), 1.88-1.75 (1H, m), 1.60-1.47 (1H, m), 1.45-1.32 (1H, m), 1.31-1.19 (1H, m), 1.17-1.03 (2H, m), 0.79 (3H, t); LC-MS: m/z 461.
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](=[O:14])[CH3:13])=[C:5]2[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:17][CH2:16]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:19][CH2:20]2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N1CCC(CN2CCCC2)CC1
Yield: 55.9 %

Procedure:
Following general procedure D, 1-{6-bromo-4-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]quinolin-3-yl}ethanone (30 mg, 0.072 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.150 mmol) to afford the desired product (19.4 mg, 56%) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD) δ 8.81 (s, 1H), 8.26 (d, J=1.8 Hz, 1H), 8.07-7.96 (m, 2H), 7.56-7.48 (m, 1H), 7.44 (dd, J=11.6, 2.2 Hz, 1H), 3.48 (d, J=12.6 Hz, 2H), 3.38-3.33 (m, 4H), 3.23-3.13 (m, 4H), 2.71 (s, 3H), 2.16-2.06 (m, 5H), 2.00 (d, J=11.1 Hz, 2H), 1.78-1.65 (m, 2H); ESI MS m/z 482 [C27H29ClN3O2+H]+; HPLC 98.9% (AUC), tR=10.36 min.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=O.N1CCCCC1>C(O)C>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:11][C:10]1=[O:16]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 70 °C
Yield: 56.7 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (41.9 mg, 0.20 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (49.9 mg, 0.20 mmol) in ethanol (1 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at 70° C. for over-night. The solvent was evaporated and the residue was crystallized from EtOAc-hexanes to provide 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one as a yellow solid (50 mg, 57%).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)=[O:4].[OH-].[NH4+:17]>C(OCC)C>[CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:17])=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: [NH4+]
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)Cl)cc1
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(C)C(=O)c1ccc(C(N)=O)cc1

Procedure:
3.1 grams (14 mmoles) of 4-(2,2-dimethyl-1-oxopropyl) benzoyl chloride is dissolved in 15 milliliters of diethylether, and the resulting solution is added dropwise to concentrated ammonium hydroxide with vigorous stirring at 0°-10° C. The white crystalline precipitate which forms is filtered off and washed with water and with ether. The product is dried in vacuo to yield 4-(2,2-dimethyl-1-oxopropyl)-benzamide (m.p. 138°-140° C.) .
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C>CO.[OH-].[OH-].[Pd+2]>[CH3:11][C:8]1[C:4]2[N:5]=[CH:6][N:7]=[CH:2][C:3]=2[S:10][CH:9]=1
Reactant: Cc1csc2c(Cl)ncnc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1csc2cncnc12
Reaction time: 5 h
Yield: 85.1 %

Procedure:
4-chloro-7-methyl-thieno[3,2-d]pyrimidine (6.5 g, 35.2 mmol) was dissolved in methanol (200 mL), added with Pd(OH)2 (1.3 g) and triethylamine (4.9 mL, 35.2 mmoL), and stirred for 5 hours under hydrogen pressure conditions. The reaction mixture was filtered through a Celite pad under reduced pressure, and concentrated. The concentrated compound was purified using silica gel chromatography (ethyl acetate:hexane=1:1 (v/v=1/1)) to obtain the title compound (4.5 g, 85%).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:17][C:18]1[C:23](O)=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28].C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[C:4]([O:3][C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][C:23]1[C:22]([F:25])=[C:21]([F:26])[C:20]([F:27])=[C:19]([F:28])[C:18]=1[F:17])=[O:15])=[O:2])([CH3:6])([CH3:7])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reaction time: 16 h
Yield: 93.9 %

Procedure:
To a solution of N-Boc-6-aminohexanoic acid (4.78 g, 20.8 mmol) and pentafluorophenol (3.68 g, 20 mmol) in 50 mL of EtOAc was added DCC (4.12 g, 20 mmol). This was allowed to stir for 16 h, and was then filtered and the filtrate evaporated in vacuo to a syrup. On standing, this crystallized to give 7.46 g (94%) of the ester. Rerystallization from isopropanol/1% acetic acid gave 6.26 g of white needles, mp 81°-83° C. 1H NMR (CDCl3) δ 1.4-1.6 (m, 15H, Boc CH3 and internal CH2), 1.8 (m, 2H, C2CH2CO2), 2.67 (5, J=7.3 Hz, 2H, CH2CO2), 3.1 (m, 2H, NHCH2), 4.5 (b, 1H, NH). 13C NMR (CDCl3) δ 24.38 (C4), 26.00 (C3), 28.39 (Boc CH3), 29.70 (C5), 33.20 (C2), 40.28 (C6), 79 (Boc C), 156 (Boc C=0), 169 (C1). Anal. Calcd for C17H20NO4F5 : C, 51.4; H, 5.1; N, 3.5. Found: C, 51.5; H, 5.0; N, 3.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Li]CCCC.CCCCCC.[I:22]I>C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([I:22])=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: II
Reactant: Clc1nccn2cncc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Clc1nccn2c(I)ncc12
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 8-chloro-imidazo[1,5-a]pyrazine (200.00 mg, 1.30 mmol) in THF (10.0 mL) was slowly added n-BuLi in hexane (2.5 M, 0.62 mL, 1.55 mmol) at −78° C. under nitrogen. The resulting mixture was stirred at the same temperature for 15 min. Then to this mixture a solution of iodine (429.7 mg, 1.693 mol) in 3 mL of THF was slowly added. The mixture was allowed to warm up to 30° C. in 1 hour. Reaction was quenched by 2 mL saturated aq. solution of NH4Cl. The reaction mixture was extracted with DCM. The solvent was removed under reduced pressure and the residue was used in next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=5.05 Hz, 1H), 7.71 (dd, J=5.05, 1.01 Hz, 1H), 7.94 (d, J=1.01 Hz, 1H). MS (ES+): m/z 279.86/281.90 [MH+]; HPLC: tR=2.70 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:12])=O.[OH-].[Na+]>ClP(=O)(Cl)C1C=CC=CC=1>[C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)#[N:12]
Reactant: NC(=O)c1cc2ccccc2[nH]1
Agent: O=P(Cl)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cc2ccccc2[nH]1
Temperature: 0 °C
Yield: 90.2 %

Procedure:
A solution of indole-2-carboxamide (3.02 g, 18.8 mmol) in dichlorophenylphosphine oxide (20 mL) was heated at 80° C. overnight. The cooled reaction mixture was then poured over 100 mL ice and the pH was adjusted to 11 with 50% aqueous sodium hydroxide. Extraction with ethyl acetate followed by concentration in vacuo gave an off-white solid which was purified by silica gel chromatography (1% MeOH/CH2Cl2) to yield the title compound (2.41 g, 90%): 1H NMR (400 MHz, DMSO-d6) δ 7.68 (d, 1H), 7.46 (d, 1H), 7.36 (s, 1H), 7.34 (t, 1H), 7.14 (t, 1H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:8]([CH3:26])[NH:7][C:6]1=[O:27])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]Cl.[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44]>C(OCC)(=O)C.O.CC(C)=O>[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44].[C:1]([O:4][C@H:5]1[C@@H:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[S:10][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:8]([CH3:26])[N:7]([CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[C:6]1=[O:27])(=[O:3])[CH3:2]
Reactant: COc1ccc([C@H]2SC(c3ccccc3)=C(C)NC(=O)[C@H]2OC(C)=O)cc1
Reactant: CN(C)CCCl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc([C@H]2SC(c3ccccc3)=C(C)N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Yield: 43.8 %

Procedure:
A mixture of 1.7 g (0.0044 mol) of cis-rac.-6-(acetyloxy)-6,7-dihydro-7-(4-methoxyphenyl)-3-methyl-2-phenyl-1,4-thiazepin-5(4H)-one, 0.7 g (0.005 mol) of powdered potassium carbonate and 0.6 g (0.0049 mol) of 2-dimethylaminoethyl chloride in 30 ml of ethyl acetate was stirred at reflux for 2 hours, then twice an additional 0.2 g of dimethylaminoethyl chloride was added at 2 hour intervals. The mixture was heated at reflux for a total of 12 hours, then cooled to room temperature and diluted with water. The organic solution was separated, washed with brine then dried (MgSO4) and the solvent was removed under reduced pressure. The residue was dissolved in acetone and passed through a 10 g silica gel pad which was washed with acetone (12×30 ml). The solvent was evaporated to give 1.8 g (0.039 mol) of crude base which was dissolved in acetone and 0.5 g (0.04 mol) of fumaric acid was added. The resulting crystals were collected to give 1.1 g (44%) cis-rac.-6-(acetyloxy)-6,7-dihydro-7-(4-methoxyphenyl)-3-methyl-4-[2-(dimethylamino)ethyl]-2-phenyl-1,4-thiazepin-5(4H)-one (E)-2-butenedioate, mp 176°-177°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:26]=[N:25][C:24]2[NH:23][CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=C[C:29]=1[S:34]([NH2:37])(=[O:36])=[O:35]>>[O:20]1[CH2:21][CH2:22][NH:23][C:24]2[N:25]=[CH:26][C:17]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[C:29]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:28][CH:33]=[CH:32][CH:31]=4)=[CH:7][C:2]=3[F:1])=[CH:18][C:19]1=2
Reactant: NS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OC(c2ccc(-c3cnc4c(c3)OCCN4)c(F)c2)OC1(C)C
Product: NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3c(c2)OCCN3)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using 7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine and 2-bromobenzenesulfonamide. MS (ESI): mass calcd. for C19H16FN3O3S, 385.09; m/z found, 386.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.14-8.11 (m, 1H), 7.80 (d, J=1.0, 1H), 7.73-7.71 (m, 1H), 7.68-7.62 (m, 1H), 7.61-7.52 (m, 2H), 7.39-7.31 (m, 3H), 4.40-4.34 (m, 2H), 3.75-3.69 (m, 2H).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][C:14]#[CH:15])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>C1COCC1>[CH2:22]([N:24]([CH2:25][CH3:26])[CH2:12][CH2:13][C:14]#[CH:15])[CH3:23].[CH2:14]1[CH2:15][O:11][CH2:12][CH2:13]1
Reactant: CCNCC
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C#CCCN(CC)CC
Temperature: 25 °C

Procedure:
A mixture of 3-butynyl 4-methylbenzenesulfonate (10 mL, 57 mmol), K2CO3 (7.9 g, 57 mmol), and diethylamine (23.5 mL, 228 mmol) in 100 mL of THF was heated to reflux for 31 hours, cooled to room temperature, and filtered. The filtrate was concentrated under vacuum at a distillation temperature of 60° C. to provide 11.2 g of a 53 wt % solution of the desired product in THF (5.9 g assay, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ 0.93 (t, J=7.07 Hz, 6H) 2.21 (m, 2H) 2.44 (q, J=7.04 Hz, 4H) 2.55 (m, 2H) 2.72 (t, J=2.68 Hz, 1H).
Reaction SMILES: [N:1]1[N:2]=[C:3]([SH:10])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl[C:12]1[N:17]=[N:16][C:15]([NH2:18])=[CH:14][CH:13]=1>C(O)(=O)C>[N:1]1[N:2]=[C:3]([S:10][C:12]2[N:17]=[N:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Nc1ccc(Cl)nn1
Reactant: Sc1nnc2ccccn12
Solvent: CC(=O)O
Product: Nc1ccc(Sc2nnc3ccccn23)nn1
Temperature: 80 °C

Procedure:
A reaction mixture of [1,2,4]triazolo[4,3-a]pyridine-3-thiol (8.49 g, 55.0 mmol) and 6-chloropyridazin-3-amine (6.82 g, 50 mmol) in acetic acid (100 mL) was heated at 80° C. for 20 hrs. The reaction was stripped to dryness via rotary evaporation and the resulting material was suspended in H2O (100 mL). To this suspension, solid Na2CO3 was added in portions until pH 10 was achieved and then the mixture was sonicated. The resulting solid was collected by filtration and rinsed thoroughly with water followed by ethyl ether. The solid was dried in vacuum over P2O5 to provide the title compound, 6-([1,2,4]Triazolo[4,3-a]pyridin-3-ylsulfanyl)-pyridazin-3-ylamine, as a white power (11.0 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.15-7.25 (m, 1 H) 7.53-7.58 (m, 1 H) 7.61 (ddd, J=9.22, 6.69, 1.26 Hz, 1 H) 7.84-7.90 (m, 1 H) 7.99 (dt, J=9.09, 1.01 Hz, 1 H) 8.51 (dt, J=7.01, 1.04 Hz, 1 H) 8.79 (br. s., 2 H). ESI-MS:m/z 553.2 (M+H)+.