Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:41]1[CH:67]=[CH:66][C:44]2[NH:45][C:46]([C@@H:48]3[CH2:52][C@H:51]([CH3:53])[CH2:50][N:49]3[C:54]([CH:56]([N:60]([CH3:65])[C:61](=[O:64])[O:62][CH3:63])[CH:57]([CH3:59])[CH3:58])=[O:55])=[N:47][C:43]=2[CH:42]=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH3:13])[CH2:10][CH:9]1[C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:41]4[CH:67]=[CH:66][C:44]5[NH:45][C:46]([C@@H:48]6[CH2:52][C@H:51]([CH3:53])[CH2:50][N:49]6[C:54](=[O:55])[C@@H:56]([N:60]([C:61]([O:62][CH3:63])=[O:64])[CH3:65])[CH:57]([CH3:59])[CH3:58])=[N:47][C:43]=5[CH:42]=4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(-c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N(C)C(C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(I)ccc2[nH]1)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N(C)[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(-c3ccc(-c4ccc(-c5c[nH]c(C6CC(C)CN6C(=O)OC(C)(C)C)n5)cc4)cc3)ccc2[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 37.3 %

Procedure:
To a suspension of (2S,4S)-4-methyl-2{-4-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (211 mg, 0.3985 mmol), methyl N-[1-[(2S,4S)-2-(5-iodo-1H-benzimidazol-2-yl)-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]-N-methyl-carbamate (198.6 mg, 0.3985 mmol), Pd(DPPF)(Cl)2.CH2Cl2 (32.54 mg, 0.03985 mmol) in 2-propnaol (2.1 mL) is added 1M aqueous NaHCO3 (2 mL, 2 mmol). The reaction mixture is stirred at 80° C. for 18 hours, cooled to RT, filtered on a bed of Celite and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (12 to 100% EtOAc in hexanes) to give 2S,4S)-2-{4-[4′-(2-{(2S,4S)-1-[(S)-2-(methoxycarbonyl-methyl-amino)-3-methyl-butyryl]-4-methyl-pyrrolidin-2-yl}-1H-benzoimidazol-5-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (115 mg, 37%).
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]([CH3:20])[C:10](=[O:19])[C:11]([O:17][CH3:18])=[C:12]([C:14]([OH:16])=O)[N:13]=1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:14]([C:12]2[N:13]=[C:8]([N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][S:2]3(=[O:1])=[O:21])[N:9]([CH3:20])[C:10](=[O:19])[C:11]=2[O:17][CH3:18])=[O:16])=[CH:25][CH:24]=1
Reactant: COc1c(C(=O)O)nc(N2CCCCS2(=O)=O)n(C)c1=O
Reactant: NCc1ccc(F)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1c(C(=O)NCc2ccc(F)cc2)nc(N2CCCCS2(=O)=O)n(C)c1=O
Reaction time: 3 h
Yield: 92.6 %

Procedure:
A mixture of 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-5-methoxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid (0.235 g, 0.74 mmol) and 4-fluorobenzylamine (0.14 g, 1.13 mmol) in acetonitrile (10 ml) was treated at 22° C. with triethylamine (0.32 ml, 2.3 mmol) followed by benzotriazole-1-yloxy-tris-pyrrolidino-phosphonium hexafluorophosphate (0.42 g, 0.81 mmol) and the resulting mixture was stirred for 3 h. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate 1:1 to ethyl acetate) gave 0.291 g (92% yield) of the title amide as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.6–1.7 and 2.3–2.5 (4H, m, 2×CH2), 3.2 and 3.5 (2×1H, m, CH2), 3.62 (3H, s, NCH3), 3.7 and 3.95 (2×1H, m, CH2), 4.04 (3H, s, OCH3), 4.59 (2H, d, J=5.8 Hz, NCH2), 7.04 (2H, m, aromatics), 7.31 (2H, m, aromatics), 7.75 (1H, broad, NH). HRMS (FAB POS) calculated for C18H22FN4O5S [M+H+]: 425.129495. found: 425.129040.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)C=C[C:6]=1[CH:15]([C:22]([CH:24]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)C1C=CC2C(=CC=CC=2)C=1)=[O:23])[C:16]1C=CN=CC=1.O>Cl>[OH:3][N:1]=[C:24]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)[C:22]([C:15]1[CH:6]=[CH:5][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:16]=1)=[O:23]
Reactant: O=C(C(c1ccncc1)c1ccc2ccccc2c1)C(c1ccncc1)c1ccc2ccccc2c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(C(=NO)c1ccncc1)c1ccc2ccccc2c1
Reaction time: 3 h

Procedure:
NaNO2 (0.35 g, 5 mmol) was added to a suspension of the product of step (b) above, (0.98 g, 4 mmol), in 3N HCl (20 mL), and H2O (20 mL). The slurry was stirred for 3 hours, filtered, washed with water, air dried to give the title compound. MS(ES) m/e 277 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C@H:11]([C@@H:26]([OH:28])[CH3:27])[C:12]([NH:14][NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C@@H:11]([C:12]2[O:13][C:16]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[N:15][N:14]=2)[C@@H:26]([OH:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COc1ccc(C(=O)NNC(=O)[C@H](Nc2ccc(C#N)c(Cl)c2C)[C@H](C)O)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: COc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)O)o2)cc1
Temperature: 25 °C
Yield: 41.3 %

Procedure:
The crude material from the reaction immediately preceding (Intermediate 2a) N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-methoxy benzohydrazide (330 mg, 0.79 mmol) was added to THF (40 mL) and stirred at room temperature. PS-BEMP (1.08 g, 2.37 mmol base) was added to the solution followed by slow addition of p-TSCl (166 mg, 0.87 mmol). The reaction mixture was stirred for 3 h and the progress of the reaction was monitored by TLC. After the completion of the reaction the BEMP reagent was filtered off and the solution concentrated to get the crude material. The crude material was chromatographed on silica gel with Hex:EtOAc (6:4) to get the purified product (130 mg, 41%). 1H NMR(500 MHz, Acetone-d6, δ in ppm) 7.93 (d, J=9 Hz, 2H), 7.50 (d, J=9 Hz, 1H), 7.11 (d, J=9 Hz, 2H), 6.87 (d, J=9 Hz, 1H), 5.68 (d, J=9 Hz, 1H), 5.07 (m, 1H), 4.79 (m, 1H), 4.60 (m, 1H), 3.89 (s, 3H), 2.40 (s, 3H), 1.40 (d, J=6 Hz, 3H).
Reaction SMILES: ClC1C=CC=CC=1C.[S:9]1[C:13]([C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:25])=[C:22]([F:24])[F:23])=O)=[CH:12][C:11]2[CH:26]=[CH:27][CH:28]=[CH:29][C:10]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1.C(OC(C)C)(C)C>CCCCCC>[S:9]1[C:13]([C:14](=[S:39])[O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:25])=[C:22]([F:24])[F:23])=[CH:12][C:11]2[CH:26]=[CH:27][CH:28]=[CH:29][C:10]1=2
Reactant: CC(CCCCOC(=O)c1cc2ccccc2s1)=C(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCCCCC
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1Cl
Product: CC(CCCCOC(=S)c1cc2ccccc2s1)=C(F)F
Yield: 81.4 %

Procedure:
To 5 ml of 2-chlorotoluene was dissolved 0.20 g (0.64 mmol) of 6,6-difluoro-5-methyl-5-hexenyl benzo[b]thiophene-2-carboxylate, followed by the addition of 0.26 g (0.64 mmol) of Lawesson's reagent and stirring by heating under refluxing for 4 hours. To the reaction liquid were added 2 ml of isopropyl ether and 10 ml of hexane and precipitated solid was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:30) to obtain 0.17 g (yield: 81%) of O-(6,6-difluoro-5-methyl-5-hexenyl) benzo[b]thiophene-2-thiocarboxylate.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:12])[CH3:11]
Reactant: CCCCCCCCO
Reactant: CC(=O)OC(C)=O
Product: CCCCCCCCOC(C)=O
Temperature: 16 °C
Reaction time: 2 h

Procedure:
A mixture of 1-octanol (40 mL, 252 mmol), acetic anhydride (26 mL, 278 mmol) and compound from Example 1 (0.6 g, 1 wt %) was stirred at 16° C. for 2 h. The solution was filtered and excess acetic anhydride removed by distillation to give 1-octyl acetate as the only product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3o2)CC1
Temperature: 170 °C

Procedure:
A mixture of 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (390 mg), 4-(methanesulfonyl)phenyl boronic acid (350 mg), aqueous Na2CO3 solution (2 M; 1.50 mL), and dioxane (10 mL) is sparged with argon for 10 min and Pd(PPh3)4 (100 mg) is added. The resulting mixture is heated to 170° C. in a microwave oven until the conversion is complete. The reaction mixture is concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic phase is washed with brine, dried over MgSO4, and the solvent is evaporated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 60:40→40:60) to give the title compound. LC (method 5): tR=1.32 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[CH:29]2.[CH2:35](Cl)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCOCC.O>[CH2:35]([N:31]1[C:32]2[C:28](=[CH:27][C:26]([F:25])=[CH:34][CH:33]=2)[CH:29]=[CH:30]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: ClCc1ccccc1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: Fc1ccc2c(ccn2Cc2ccccc2)c1
Reaction time: 0.5 h
Yield: 14.1 %

Procedure:
To a solution of 0.8 g (3.03 mmoles) of 18-crown-6 in 100 ml of dry ether was added 3.27 g (29.14 mmoles) of potassium tert-butoxide. The mixture was stirred while a solution of 3.75 g (27.75 mmoles) of 5-fluoroindole in 80 ml of ether was added. The stirring was continued for 0.5 hour. Solid was present. Then 3.69 g (29.15 mmoles) of benzyl chloride in 80 ml of ether was added. The mixture was stirred for 28 hours. Water (100 ml) was added. The layers were separated. The aqueous layer was extracted with 100 ml of ether. The combined ether layers were washed with 50 ml of brine and dried over MgSO4. Evaporation of the solvent left 6.95 g of orange oil. The oil was chromatographed on a 600 g column of silica gel. The column was eluted with 30% CH2Cl2 -Skellysolve B and 200 ml fractions were collected. The fractions were assayed by silica gel tlc (1×4") (30% CH2Cl1 -Skellysolve B). Fractions 11-15 were combined giving 0.88 g (14%) of 1-benzyl-5-fluoroindole as a pale yellow oil which contained a small amount of 1,3-dibenzyl-5-fluorindole.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=1.[H-].[Na+].[CH3:24][NH:25][C:26](=O)[O:27]C1C=CC=CC=1.O>CN(C)C=O.C(OCC)(=O)C>[NH2:20][C:16]1[CH:15]=[C:14]([O:13][C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][C:4]=2[O:3][CH:2]([F:1])[F:21])[N:10]([C:26]([NH:25][CH3:24])=[O:27])[CH:9]=[CH:8]3)[CH:19]=[CH:18][N:17]=1
Reactant: CNC(=O)Oc1ccccc1
Reactant: Nc1cc(Oc2cc3cc[nH]c3cc2OC(F)F)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)c(OC(F)F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
4-((6-(Difluoromethoxy)-1H-indol-5-yl)oxy)pyridin-2-amine described in Production Example 19-6 (4.4 mg, 0.015 mmol) was dissolved in N,N-dimethylformamide (500 μL), then 50-72% oily sodium hydride (4.1 mg) was added under nitrogen atmosphere at 0° C., and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 0° C. again and phenyl methylcarbamate described in Production Example 1-7 (16.4 mg, 0.108 mmol) was added, and the mixture was stirred at room temperature for 50 minutes. Water and ethyl acetate were added to the reaction mixture for partition. The organic layer was washed with a saturated saline solution, then dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane and the resultant was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1-ethyl acetate:methanol=99:1-9:1), and then the target fraction was concentrated under vacuum to obtain the title compound (4.3 mg, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:20])[C:6]=1[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:63]([O:67][C:68]([NH:70][C:71]1[S:75][C:74]([C:76]2[C:81]([F:82])=[CH:80][CH:79]=[CH:78][C:77]=2[F:83])=[N:73][C:72]=1[C:84](O)=[O:85])=[O:69])([CH3:66])([CH3:65])[CH3:64]>C(Cl)Cl>[F:83][C:77]1[CH:78]=[CH:79][CH:80]=[C:81]([F:82])[C:76]=1[C:74]1[S:75][C:71]([NH:70][C:68](=[O:69])[O:67][C:63]([CH3:65])([CH3:64])[CH3:66])=[C:72]([C:84](=[O:85])[NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:20])[C:6]=2[C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:9][CH:8]=2)[N:73]=1
Reactant: Cn1ncc(N)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.2 %

Procedure:
To a solution of tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (85 mg, 0.31 mmol) in DCM (20 mL) was added DIPEA (0.5 mL, 2.87 mmol), PyBOP (0.238 g, 0.46 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (0.114 g, 0.32 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM and washed with water. The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-75% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-(tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a white solid (54 mg, 29%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[F:12][C:13]([F:16])([F:15])I.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([S:9][C:13]([F:16])([F:15])[F:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: FC(F)(F)I
Reactant: Fc1ccc(S)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(SC(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Bromo-4-fluorobenzenethiol (2.071 g, 10 mmol) in dimethylformamide (10 mL) was treated with 60% sodium hydride (0.480 g, 12.00 mmol). The solution was stirred for 10 minutes at room temperature. Trifluoroiodomethane (2.74 g, 14.00 mmol) was released into a balloon with a three-way stopcock. The balloon was then put onto the flask and trifluoroiodomethane was released into the reaction. After 1 hour, all the content in the balloon was gone. And the balloon was filled with 2.74 g of trifluoroiodomethane again. The reaction mixture was stirred for 16 hours. The reaction mixture was poured into water, and extracted with ethyl acetate several times. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting oil was used directly in the next reaction.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.F[C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30].C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[N+:29]([C:20]1[CH:21]=[C:22]([S:25](=[O:27])(=[O:26])[NH2:28])[CH:23]=[CH:24][C:19]=1[NH:2][CH2:3][C@H:4]1[CH2:5][CH2:6][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:8][CH2:9]1)([O-:31])=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN)CC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CNc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of tert-butyl trans-4-(aminomethyl)cyclohexylcarbamate HCl (1.0 g) and 4-fluoro-3-nitrobenzenesulfonamide (0.83 g) in tetrahydrofuran (5 mL) was added diisopropylethylamine (1.98 mL) and the reaction stirred at room temperature for 1 hour. The reaction was diluted with ethyl acetate (75 mL) and washed with saturated ammonium chloride (50 mL), brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting solid was triturated with dichloromethane (50 mL), filtered and dried to give the title compound.
Reaction SMILES: [C:1]([N:5]1[C:12]2[C@@H:11]3[CH2:13][C@@H:10]3[CH2:9][C:8]=2[C:7]([C:14](O)=[O:15])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[C:48]1([C:54]([NH2:57])([CH3:56])[CH3:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[CH3:55][C:54]([NH:57][C:14]([C:7]1[C:8]2[CH2:9][C@H:10]3[CH2:13][C@H:11]3[C:12]=2[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:6]=1)=[O:15])([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH3:56]
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(C)(C)n1nc(C(=O)O)c2c1[C@@H]1C[C@@H]1C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1nn(C(C)(C)C)c2c1C[C@H]1C[C@@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
To a solution of (1aR,5aR)-2-tert-butyl-1a,2,5,5a-tetrahydro-1H-2,3-diazacyclopropa[a]pentalene-4-carboxylic acid (30 mg, 0.136 mmol), HATU (55 mg, 0.143 mmol) in DMF (1 mL) was added Et3N (16 mg, 0.15 mmol). After stirring for 5 min at room temperature, 2-phenylpropan-2-amine (20 mg, 0.143 mmol) was added into the reaction. The reaction was stirred for 1 h at room temperature, and purified by preparative HPLC to give the title compound (25 mg). LCMS m/z=338.5 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.34 (td, J=4.5 and 3.4 Hz, 1H), 1.11 (td, J=7.8 and 4.5 Hz, 1H), 1.63 (s, 9H), 1.78 (s, 6H), 2.11-2.18 (m, 2H), 2.75 (d, J=16.7 Hz, 1H), 2.86 (dd, J=16.6 and 5.8 Hz, 1H), 7.21 (t, J=7.3 Hz, 1H), 7.32 (t, J=8.0 Hz, 2H), 7.36 (bs, 1H), 7.42-7.46 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([F:14])[CH2:10][CH2:9]2)[CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)Cl>[F:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:7]=[C:2]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[CH:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1N1CCC(F)CC1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N3CCC(F)CC3)c2)CC1
Temperature: 80 °C
Yield: 93 %

Procedure:
A solution of 1-(5-chloro-2-nitro-phenyl)-4-fluoro-piperidine (as prepared in the previous step, 0.44 g, 1.7 mmol) in 4-methylpiperazine (2 mL) was heated to 80° C. for 18.5 h. The solution was cooled to room temperature, diluted with CH2Cl2, and washed with water. The aqueous layer was further extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (0.51 g, 93%) as a bright yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 8.04 (d, 1H, J=9.2 Hz), 6.45 (dd, 1H, J=9.2 Hz, J=2.4 Hz), 6.34 (d, 1H, J=2.4 Hz), 4.97-4.79 (m, 1H), 3.38 (app t, 4H, J=5.2 Hz), 3.26-3.15 (m, 4H), 3.07-2.98 (m, 4H), 2.54 (app t, 4H, J=5.2 Hz), 2.35 (s, 3H). LC-MS (ESI, m/z): Calcd. for C16H23FN4O2, 323.2 (M+H), found 323.2.
Reaction SMILES: F[C:2]12[O:13][CH2:12][O:11][CH:3]1[CH:4]=[C:5]([CH:9]=[CH:10]2)[CH2:6][CH2:7][NH2:8].Cl[C:15]1[C:16]2[C:29]([CH3:30])=[CH:28][S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:2]4[O:13][CH2:12][O:11][C:3]=4[CH:4]=3)[C:16]3[C:29]([CH3:30])=[CH:28][S:27][C:17]=3[N:18]=2)[CH:22]=1
Reactant: NCCC1=CC2OCOC2(F)C=C1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Product: Cc1csc2nc(-c3cccnc3)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluoro-3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-methylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:25])[C:12]([C:20]([O:22]CC)=[O:21])=[CH:13][N:14]3[CH:17]3[CH2:19][CH2:18]3)=[C:9]([CH3:26])[C:8]=2[F:27])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[Na+].C(O)C>O>[N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:25])[C:12]([C:20]([OH:22])=[O:21])=[CH:13][N:14]3[CH:17]3[CH2:18][CH2:19]3)=[C:9]([CH3:26])[C:8]=2[F:27])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)c(C)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(F)c(N2CCNCC2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 56.4 %

Procedure:
To ethyl 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (23 mg) are added 10% aqueous solution of sodium hydroxide (3 ml) and ethanol (3 ml), and the mixture is refluxed for 1 hour. After cooling, the reaction mixture is diluted with water and washed with dichloromethane. The aqueous layer is made acidic with acetic acid and then made weakly alkaline with an aqueous sodium hydrogen carbonate. The resultant product is extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure and to the residue is added ethanol. The precipitated crystals are filtered and recrystallized from dimethylformamide to give 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (12 mg), as white powder, m.p. 231°-233° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)cc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, white solid (66 mg, 79%), MS (ISP) m/z=334.5 [(M+H)+], mp 278° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).