Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][CH2:22][NH:23][CH2:24][C:25](OCC)=[O:26])=[C:9]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[NH3:35]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]([NH2:35])=[O:26])=[C:9]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: N
Reactant: CCOC(=O)CNCCOCC1=C(C(=O)OCC)C(c2ccccc2Cl)C(C(=O)OC)=C(C)N1
Solvent: CCO
Product: CCOC(=O)C1=C(COCCNCC(N)=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Ethyl N-(2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}ethyl)aminoacetate (2.50 g) in a mixture of ethanol (40 ml) and 0.880 aqueous ammonia (30 ml) was stirred at room temperature for four days and then evaporated. The residue was partitioned between ethyl acetate and water and the organic layer washed with water, dried (MgSO4), and evaporated. The residue was chromatographed on silica (t.l.c. grade Merck Kieselgel 60H, [Trade Mark] 30 g) eluting with dichloromethane plus 0-5% methanol. Appropriate fractions were combined and evaporated. The residue was triturated with ethyl acetate and the resulting solid collected, washed with ethyl acetate, and dried to give the title compound (1.23 g), m.p. 126°-129°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12](O)=[O:13])[C:8]=1[C:15]([F:18])([F:17])[F:16].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:27]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12]([F:27])=[O:13])[C:8]=1[C:15]([F:18])([F:17])[F:16]
Reactant: Fc1nc(F)nc(F)n1
Reactant: O=C(O)c1noc(-c2ccccn2)c1C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(F)c1noc(-c2ccccn2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a solution of 5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-3-carboxylic acid (54.3 mg, 0.210 mmol) and pyridine (0.037 mL, 0.463 mmol) in dichloromethane (2 mL) was added cyanuric fluoride (0.021 mL, 0.252 mmol). The reaction mixture was stirred at room temperature for 2 hrs., diluted with dichloromethane (2 mL), and washed with ice water (1 mL). The aqueous layer was extracted with dichloromethane (2×1 mL), and the combined organic layers were washed with brine (1 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride (0.048 g, 0.185 mmol, 88% yield). The product had an HPLC retention. time=2.50 min. (The product reacted readily with methanol and a small portion was characterized as the methyl ester)—Column: YMC S5 COMBISCREEN® 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][CH2:11][CH2:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[CH:24]=1.CC1ON=C(CCC(OC)=O)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][CH2:11][CH2:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[CH:24]=1
Reactant: Oc1ccc(C2=NCCO2)cc1Cl
Reactant: Cc1cc(CCCCCCCCBr)on1
Agent: COC(=O)CCc1cc(C)on1
Product: Cc1cc(CCCCCCCCOc2ccc(C3=NCCO3)cc2Cl)on1

Procedure:
5-{8-[2-Chloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]octyl}-3-methylisoxazole [IX; R=CH3, R2, R3, R4, R5 and R6 =H, R1 =2-Cl, Y=(CH2)8, oxazole at 4-position] was prepared from 4,5-dihydro-2-(3-chloro-4-hydroxyphenyl)oxazole (Example 13b) and 5-(8-bromooctyl)-3-methylisoxazole (Example 18a) according to the procedure of Example 9, part (d), and was obtained in the form of a colorless solid, m.p. 63°-64° C. when recrystallized from ether.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[N:27]1([CH2:26][CH2:25][CH2:24][NH:23][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[O:14][CH3:13])[CH:11]=[CH:10]3)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: COc1ccccc1CN
Reactant: NCCCn1ccnc1
Product: COc1ccccc1CNc1ccc2cc(NCCCn3ccnc3)ccc2n1

Procedure:
The title compound, MS: m/e=388.4 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and 1-(3-aminopropyl)imidazole.
Reaction SMILES: C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(OC(C)(C)C)=O.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][O:39][C@H:38]([CH2:42][C:43]2[CH:48]=[CH:47][C:46](OS(C(F)(F)F)(=O)=O)=[C:45]([Cl:57])[CH:44]=2)[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].[F:58][C:59]1[CH:60]=[C:61](B(O)O)[CH:62]=[CH:63][C:64]=1[CH3:65]>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][O:39][C@H:38]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:61]3[CH:62]=[CH:63][C:64]([CH3:65])=[C:59]([F:58])[CH:60]=3)=[C:45]([Cl:57])[CH:44]=2)[CH2:37]1)=[O:35])([CH3:31])([CH3:32])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c2)C1
Reactant: Cc1ccc(B(O)O)cc1F
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Product: Cc1ccc(-c2ccc(C[C@@H]3CN(C(=O)OC(C)(C)C)CCO3)cc2Cl)cc1F

Procedure:
The title compound was synthesized in analogy to example 80, intermediate (a), from (R)-2-(3-chloro-4-trifluoromethanesulfonyloxy-benzyl)-morpholine-4-carboxylic acid tert-butyl ester and 3-fluoro-4-methylbenzeneboronic acid to give the compound as a colorless oil (97%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:6]=1[C:7]#[N:8].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]O)=[CH:16][CH:15]=1.C(C=C1CCP(C)C1(C)C)#N>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:3]2[C:4]([C:9]([F:10])([F:12])[F:11])=[CH:5][C:6]([C:7]#[N:8])=[C:2]2[CH3:1])=[CH:16][CH:15]=1
Reactant: Cc1[nH]c(C(F)(F)F)cc1C#N
Reactant: OCCc1ccc(F)cc1
Agent: CP1CCC(=CC#N)C1(C)C
Solvent: Cc1ccccc1
Product: Cc1c(C#N)cc(C(F)(F)F)n1CCc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A 266 mg portion of 2-methyl-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile was dissolved in 10 ml of toluene, and 0.382 ml of 2-(4-fluorophenyl)ethanol and 352 mg of cyanomethylenetrimethylphospholan were added, followed by stirring at 100° C. for 1.5 hours. The reaction liquid was concentrated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9-1:4) to obtain 451 mg of 1-[2-(4-fluorophenyl)ethyl]-2-methyl-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile as a white solid.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([CH3:52])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[C@@H:16]([CH2:47][C:48]([NH:50][NH2:51])=O)[CH2:15]2)=[CH:10][CH:9]=1)[CH3:2].CO[CH:55](OC)[N:56](C)[CH3:57]>C(Cl)Cl>[CH2:1]([O:3][C@H:4]([CH3:52])[CH2:5][O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]2[CH2:15][C@H:16]([CH2:47][C:48]3[N:56]([CH3:57])[CH:55]=[N:51][N:50]=3)[NH:17][CH2:18][C@@H:19]2[O:20][CH2:21][C:22]2[CH:36]=[CH:26][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:24]=3[CH:23]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CC(=O)NN)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](Cc3nncn3C)NC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 25 °C

Procedure:
A solution of 1.0 mmol of [(2R,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl) -piperidin-2-yl]-acetic acid hydrazide in 5 ml of CH2Cl2 is treated at RT with1.1 mmol of N,N-dimethylformamide dimethylacetal and refluxed for 1 h. The mixture is cooled to RT, and concentrated under reduced pressure to afford the title compound, which is identified based on its Rf value.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:21]=[CH:22][C:23]4[C:27]([C:28]([OH:30])=O)=[C:26]([CH3:31])[S:25][C:24]=4[CH:32]=3)[CH:11]=2)=[O:9])[CH2:4]1.[NH2:33][CH2:34][CH:35]1[CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:35]1([CH2:34][NH:33][C:28]([C:27]2[C:23]3[CH:22]=[CH:21][C:20]([O:19][C:16]4[CH:15]=[CH:14][N:13]=[C:12]5[CH:11]=[C:10]([C:8]([N:5]6[CH2:6][CH2:7][C@@H:3]([O:2][CH3:1])[CH2:4]6)=[O:9])[S:18][C:17]=45)=[CH:32][C:24]=3[S:25][C:26]=2[CH3:31])=[O:30])[CH2:37][CH2:36]1
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)sc5c4)c3s2)C1
Reactant: NCC1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NCC6CC6)c(C)sc5c4)c3s2)C1
Yield: 29 %

Procedure:
This material was prepared by the reaction of 6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 123b (130 mg, 0.278 mmole) with (aminomethyl)cyclopropane (120 μL, 1.39 mmole), diisopropylethylamine (0.15 mL, 0.83 mmole), and HBTU (263 mg, 0.694 mmole) in a manner similar to that previously described for example 117 to afford a pale yellow solid (42 mg, 24%). 1H NMR (DMSO-d6, 300 MHz) δ 8.61 (1H, d, J=5.56 Hz), 8.49 (1H, t, J=5.56 Hz), 8.06 (1H, s), 7.97 (1H, s), 7.84 (1H, d, J=8.59 Hz), 7.34 (1H, dd, J=2.27, 8.84 Hz), 6.79 (1H, d, J=5.56 Hz), 4.11–3.80 (3H, m), 3.70–3.46 (2H, m), 3.27, 3.24 (3H, s), 3.20 (2H, t, J=6.19 Hz), 2.62 (3H, s)2.18–1.91 (2H, m), 1.08 (1H, m), 0.47 (2H, m), 0.26 (2H, m).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:14]1[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=1[Cl:12])=[O:22]
Reactant: Cc1cccc(Cl)c1N=C=O
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: Cc1cccc(Cl)c1NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Yield: 29 %

Procedure:
The urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-chloro 6-methyl phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.31 g, 29%). EI-MS m/z 322(M+H)+
Reaction SMILES: O.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])([CH3:5])([CH3:4])[CH3:3].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]1[CH2:30][CH2:29][N:28]([C:15]([C@@H:10]([NH:9][C:7](=[O:8])[O:6][C:2]([CH3:3])([CH3:4])[CH3:5])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:17])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(Cc2ccccc2)CC1
Yield: 57.9 %

Procedure:
Tert-butoxycarbonyl-L-leucine monohydrate (8.92 g) and 1-benzylpiperazine (6.30 g) were condensed in the same manner as in the preparation of tert-butyl (s)-1-(4-diphenylmethylpiperazine-1-yl carbonyl)-3-methyl butylcarbamate to yield 8.06 g of tert-butyl (s)-1-(4-benzylpiperazine-1-yl carbonyl)-3-methylbutylcarbamate as a colorless amorphous substance (yield: 58%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([N:14]=[CH:15][C:16]([NH2:20])=[N:17]2)=[CH:12][CH:11]=1.C(N(CC)CC)C.[C:28](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:29]>C(Cl)Cl>[N:20]([C:16]1[CH:15]=[N:14][C:13]2[C:18](=[CH:19][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)[N:17]=1)=[C:28]=[S:29]
Reactant: COc1ccc2ncc(N)nc2c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ncc(N=C=S)nc2c1
Yield: 19.3 %

Procedure:
A mixture of 7-methoxyquinoxalin-2-amine 2,2,2-trifluoroacetate (578 mg, 2 mmol), triethylamine (335 μL, 2.400 mmol), and 1,1′-thiocarbonyldipyridin-2(1 H)-one (557 mg, 2.400 mmol) was stirred in 5 mL DCM for 24 h. The reaction was directly eluted on a 120 g silica gel cartridge with 0 to 25% EtOAc in hexane, 25 min, at 35 mL/min to afford 2-isothiocyanato-7-methoxyquinoxaline (84 mg, 0.387 mmol, 19% yield).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10](O)=[O:11])=[CH:8][N:7]=[C:6]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]5[O:23][C:24]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:25][N:26]=5)[CH:20]=4)[N:15]([S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[CH:14]=3)[N:5]=2)[CH2:3][CH2:2]1.C1C[N:44]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O1CCOCC1.N>CN(C=O)C>[CH:1]1([C:4]2[C:9]([C:10]([NH2:44])=[O:11])=[CH:8][N:7]=[C:6]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]5[O:23][C:24]([NH:27][CH:28]([CH3:29])[CH3:30])=[N:25][N:26]=5)[CH:20]=4)[N:15]([S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[CH:14]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(C(=O)O)c(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(C(N)=O)c(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 243.8 %

Procedure:
4-Cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyrimidine-5-carboxylic acid (107 mg, 0.192 mmol) was treated with PyBOP (169 mg, 0.326 mmol) and 1,4-dioxane (5 mL) and DMF (1.0 mL) and stirred at RT for 10 min. The reaction was then cooled in an ice bath and treated with NH3, 0.5 M solution in 1,4-dioxane (1.9 mL, 0.96 mmol) and stirred at 0° C. for 1.5 h. The reaction was quenched with water, extracted with EtOAc (25 mL), washed with brine (2×25 mL), dried over MgSO4, filtered and concentrated affording 261 mg of the crude amide. MS (ESI, pos. ion) m/z: 558.2 (M+H)+. The crude material was used without further purification.
Reaction SMILES: CN(C)C(N(C)C)=N.[C:9]1([C@:15]23[CH2:23][NH:22][CH2:21][C@H:20]2[CH2:19][S:18][C:17]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:16]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:33][C:34]1[CH:35]=[N:36][C:37](Cl)=[N:38][CH:39]=1.O>CS(C)=O>[F:33][C:34]1[CH:35]=[N:36][C:37]([N:22]2[CH2:21][C@@H:20]3[C@@:15]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)([N:16]=[C:17]([NH:24][C:25](=[O:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[S:18][CH2:19]3)[CH2:23]2)=[N:38][CH:39]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3)CNC[C@H]2CS1)c1ccccc1
Agent: CN(C)C(=N)N(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(NC1=N[C@@]2(c3ccccc3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
N,N,N′,N′-tetramethylguanidine (3.4 mL, 27 mmol) is added to a solution of N-[(4aR,7aS)-7a-phenyl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (7.5 g, 22 mmol) and 5-fluoro-2-chloropyrimidine (3.5 g, 27 mmol) in dimethylsulfoxide (75 mL). The reaction is stirred at 100° C. for 2 hours, cooled to room temperature and water is added (225 mL). The precipitated product is isolated by filtration and is dried in a vacuum oven at 45° C. to give the title compound (9.5 g, 99%). ES/MS (m/e): 434 (M+H).
Reaction SMILES: ClC1C=CC=C2C=1NC([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=C2.[Br:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]2[C:29]=1[NH:28][CH:27]=[CH:26]2>>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]2[C:29]=1[NH:28][C:27]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:26]2
Reactant: COc1ccc(Br)c2[nH]ccc12
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: COc1ccc(Br)c2[nH]c(B3OC(C)(C)C(C)(C)O3)cc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-bromo-4-methoxy-1H-indole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[N:13]([O-])=O.[Na+].[Cl:17][Sn]Cl>Cl.O>[ClH:17].[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)[NH2:13]
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Reactant: COC(=O)Cc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)Cc1ccc(NN)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of methyl 4-aminophenylacetate (5.5 g, 33.3 mmol) in concentrated HCl (35 mL) at 0° C. is added a solution of NaNO2 (2.3 g, 33.3 mmol) in water (10 mL). The temperature of the reaction is maintained at 0-5° C. After stirring for 30 minutes, a solution of SnCl2 (19 g, 99.9 mmol) in concentrated HCl (10 mL) is added and the mixture is vigorously stirred with a stirring rod. The mixture is then diluted with water (50 mL), and the resulting precipitate is collected by suction filtration and washed with water. The solid is dried under vacuum to give 5 g of 18, which is used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH2:17]([O:19][C:20](=[O:32])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH3:18]>C(Cl)Cl>[CH2:17]([O:19][C:20](=[O:32])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:29])=[O:30])=[CH:24][CH:23]=1)[CH3:18]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of N-methylpiperazine (9.23 g, 10.21 ml, 0.092 mol), DIEA (13 g, 17.4 mL, 0.10 mol) and DCM 80 mL is cooled to 0° C., and to this is added a solution of the title B compound, (4-chlorosulfonyl-phenyl)-acetic acid ethyl ester (22 g, 0.083 mol) in 50 mL of DCM within 30 min. Reaction mixture stirred at 0° C. for 2 h, and the reaction mixture is washed with water (100 mL), followed by 0.1 N aqueous hydrochloric acid solution (1×200 mL). The organic layer dried over sodium sulfate, filtered and concentrated under vacuo to give crude [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester. Column chromatography over silicagel (60-120 mesh), using ethyl acetate afforded pure [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester as white crystalline solid: 1H NMR (400 MHz, CDCl3) δ 1.3 (t, J=7.4, 3H), 2.3 (s, 3H), 2.5 (m, 4H), 3.0 (br s, 4H), 3.7 (s, 2H), 4.2 (q, J=7.4, 2H), 7.4 (d, J=8.3, 2H), 7.7 (d, J=7.3, 2H); MS 327 [M+1]+.
Reaction SMILES: [Cl-].[C:2]([O:7][C@H:8]1[C@H:16]([CH3:17])[O:15][C:14](=[O:18])[C@@H:13]([NH3+:19])[CH2:12][O:11][CH2:10][C@@H:9]1[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:6])[CH:3]([CH3:5])[CH3:4].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[OH:64][C:65]1[C:66]([C:73](O)=[O:74])=[N:67][CH:68]=[CH:69][C:70]=1[O:71][CH3:72].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:2]([O:7][C@@H:8]1[C@@H:9]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:10][O:11][CH2:12][C@H:13]([NH:19][C:73](=[O:74])[C:66]2[C:65]([OH:64])=[C:70]([O:71][CH3:72])[CH:69]=[CH:68][N:67]=2)[C:14](=[O:18])[O:15][C@H:16]1[CH3:17])(=[O:6])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(=O)O[C@@H]1[C@@H](Cc2cccc3ccccc23)COC[C@H]([NH3+])C(=O)O[C@H]1C
Reactant: COc1ccnc(C(=O)O)c1O
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3cccc4ccccc34)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1O
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a suspension of (3S,7S,8R,9S)-8-(isobutyryloxy)-9-methyl-7-(naphthalen-1-ylmethyl)-2-oxo-1,5-dioxonan-3-aminium chloride in CH2Cl2 (2 mL) were added PyBOP (248 mg, 0.477 mmol) and 3-hydroxy-4-methoxypicolinic acid (81 mg, 0.477 mmol) followed by the dropwise addition of N-ethyl-N-isopropylpropan-2-amine (249 μl, 1.43 mmol). After 10 min everything solubilized and stirring was continued for 2 h. The reaction was treated with Celite®, the solvent removed under reduced pressure, and the resulting adsorbed crude material was purified by flash chromatography (SiO2, 0→100% EtOAc/hexanes) to provide (3S,6S,7R,8S)-3-(3-hydroxy-4-methoxypicolin-amido)-6-methyl-8-(naphthalen-1-ylmethyl)-4-oxo-1,5-dioxonan-7-yl isobutyrate as a white powder (210 mg, 88%): mp 139-142° C.; 1H NMR (400 MHz, CDCl3) δ 11.91 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 8.01-7.92 (m, 2H), 7.89-7.82 (m, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.49 (dddd, J=14.7, 8.1, 6.9, 1.5 Hz, 2H), 7.40 (dd, J=8.2, 7.0 Hz, 1H), 7.30 (dd, J=6.9, 1.2 Hz, 1H), 6.84 (d, J=5.2 Hz, 1H), 5.20-5.02 (m, 3H), 4.04 (dd, J=11.7, 7.3 Hz, 1H), 3.92 (s, 3H), 3.60 (d, J=4.1 Hz, 2H), 3.43 (dd, J=11.7, 7.1 Hz, 1H), 3.23 (dd, J=14.2, 3.2 Hz, 1H), 2.79-2.64 (m, 2H), 2.36-2.23 (m, 1H), 1.43-1.37 (m, 3H), 1.29 (dd, J=7.0, 3.6 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 176.37, 171.12, 168.88, 155.32, 148.71, 140.60, 134.68, 133.97, 131.94, 130.09, 128.97, 127.76, 127.35, 126.02, 125.57, 125.37, 123.45, 109.55, 76.95, 74.38, 72.09, 56.07, 51.42, 44.93, 34.37, 32.19, 19.14, 19.07, 18.26; HRMS-ESI (m/z) [M+H]+ calcd for C30H35N2O8 expected, 551.2388. found 551.2388.
Reaction SMILES: [F:1][C:2]1C=CC=C[C:3]=1[NH2:4].C(OC(=O)C)(=[O:11])C.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[F:1][CH2:2][C:3]([NH:4][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11]
Reactant: c1ccccc1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1F
Product: O=C(CF)Nc1ccccc1

Procedure:
In benzene, 2-fluoroaniline was acetylated with acetic anhydride to obtain 2-fluoroacetanilide. This 2-fluoroacetanilide was held in glacial acetic acid at 43°-52° C. and an equivalent of chlorine gas was introduced, whereby 2-fluoro-4-chloroacetanilide was obtained. This product was deacetylated with hydrochloric acid and neutralized with sodium hydroxide to recover 2-fluoro-4-chloroaniline as an oil boiling at 64°-65° C./0.25 mmHg.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.C(N(CC)CC)C.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C[C:43](C)=[O:44]>C(#N)C>[ClH:1].[CH3:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:43]([N:39]2[CH2:40][CH2:41][CH:36]([C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=4)[NH:32][CH:31]=3)[CH2:37][CH2:38]2)=[O:44])=[CH:7][C:6]=1[N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1
Reactant: CC(C)=O
Reactant: Fc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)N2CCC(c3c[nH]c4ccc(F)cc34)CC2)cc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-methoxy-3-(4-methylpiperazin-1-yl)aniline dihydrochloride (2.65 g; 9 mmol), triethylamine (4.5 ml; 31.5 mmol) and N,N′-carbonyldiimidazole (1.6 g; 10 mmol) in 125 ml of acetonitrile is stirred at room temperature for 3 hours. A suspension of 2.0 g (9 mmol) of 5-fluoro-3-piperidin-4-yl-1H-indole and 1.3 ml (9 mmol) of triethylamine in 125 ml of acetonitrile is added to the mixture and it is stirred at room temperature for a further 12 hours. After customary working up, the residue is dissolved in acetone and the hydrochloride is precipitated using 1N HCl. By recrystallization from ethanol/diethyl ether, 4-(5-fluoro-1H-indole-3-yl)piperidine-1-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide hydrochloride is obtained