Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.[CH3:25][C@@H:26]([CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:33][CH2:32]1)[C:27]([OH:29])=O.[N+:47]([C:50]1[CH:55]=[CH:54][C:53]([NH:56][CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)=[CH:52][C:51]=1[C:63]([F:66])([F:65])[F:64])([O-:49])=[O:48].C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CS(C)=O.ClCCl>[CH3:25][C@@H:26]([CH2:30][N:31]1[CH2:32][CH2:33][N:34]([C:37]2[CH:38]=[CH:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=2)[CH2:35][CH2:36]1)[C:27]([N:60]1[CH2:61][CH2:62][CH:57]([NH:56][C:53]2[CH:54]=[CH:55][C:50]([N+:47]([O-:49])=[O:48])=[C:51]([C:63]([F:64])([F:65])[F:66])[CH:52]=2)[CH2:58][CH2:59]1)=[O:29]
Reactant: C[C@@H](CN1CCN(c2ccc(C(F)(F)F)cc2)CC1)C(=O)O
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@@H](CN1CCN(c2ccc(C(F)(F)F)cc2)CC1)C(=O)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (8.74 g; 22.6 mmol) is added to a solution of (S)-2-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propionic acid (13.0 g; 41.1 mmol, prepared in accordance with Example 67) is a mixture of dichloromethane (540 mL) and dimethylsulfoxide (10 mL). After stiffing for 10 minutes, (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine (11.32 g; 39.1 mmol, free base of Example 8) and diisopropylethyl amine (15.15 g; 39.1 mmol) are added and the mixture is stirred at room temperature for 16 hours. The reaction mixture is then concentrated under reduced pressure and is dissolved in dichloromethane (250 mL). The organic phase is washed with water (2×500 mL), aq. sat. potassium carbonate (250 mL) and with brine (250 mL), is then dried over sodium sulfate and the solvent is removed under reduced pressure. The residue obtained is then diluted in ethyl acetate (250 mL), the organic phase is washed with water (2×1500 mL) is dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography on silica gel (ethyl acetate:acetone 1:0 and then 9:1). After concentration of the fractions of interest, the product is dissolved in hot methanol (800 mL), and the solution is concentrated under vacuum. The solid obtained is finally dried at 40° C. under 3 mbar to afford the desired product (15.56 g; 26.5 mmol). The structure was confirmed using Protocol I-B. Calculated mass=588; observed mass=588; HPLC retention time=5.03 min.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1.[Cl:23][C:24]1[C:25]([C:38](O)=[O:39])=[N:26][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][CH:29]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:25]([C:38]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[CH:9][N:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:39])=[N:26][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:28][CH:29]=1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)ncnc23)n1
Yield: 52.5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-8, 50 mg, 0.164 mmol), 3-chloro-6-(pivalamidomethyl)picolinic acid (Intermediate-3, 88 mg, 0.326 mmol), oxalyl chloride (59 mg, 0.47 mmol), DMF (1 drop) and DIPEA (63 mg, 0.49 mmol) in CH2Cl2 (2 mL) to afford 48 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 11.63 (s, 1H), 9.06 (d, J=7.8 Hz, 1H), 8.86 (s, 1H), 8.33 (br t, 1H), 8.12 (d, J=8.1 Hz, 2H), 7.88-7.82 (m, 2H), 7.76 (m, 3H), 7.48 (d, J=8.4 Hz, 1H), 4.48 (d, J=5.4 Hz, 2H), 1.16 (s, 9H); MS [M+H]+: 558.11.
Reaction SMILES: [C:1]([C:5]1([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)([O:3]C)=[O:2].[OH-].[K+]>C(O)C.O.O1CCCC1>[C:1]([C:5]1([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)([OH:3])=[O:2]
Reactant: COC(=O)C1(SCc2ccc(OC)cc2)CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CSC2(C(=O)O)CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
Dissolve 1-(carbomethoxy)-1-(4-methoxylbenzylthio)cyclopentane (3.3 mmol) in 95% ethanol (18 mL) , water (9 mL), and tetrahydrofuran (10 mL). Treat with potassium hydroxide (0.91 g, 16 mmol). Stir at room temperature for 2hours and evaporate the solvent in vacuo. Partition between water (50 mL) and ethyl ether (30 mL). Acidify the aqueous phase with cold concentrated hydrochloric acid and extract with methylene chloride (50 mL). Dry (MgSO4) and evaporate the solvent in vacuo to give 1-(carboxy)-1-(4-methoxybenzylthio)cyclopentane as a pale yellow oil (483 mg, 72%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]([O:35][N:36]=[CH:37][C:38]([OH:40])=O)[CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C.Cl.[CH3:49][NH:50][OH:51].N1C=CC=CC=1>C(Cl)Cl.C(Cl)(Cl)Cl.C(OCC)(=O)C.CN(C=O)C>[OH:51][N:50]([CH3:49])[C:38](=[O:40])[CH:37]=[N:36][O:35][CH:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH2:17][C:8]2[CH:9]=[CH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:7]=2)[CH:20]=1)[CH2:26][CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CNO
Reactant: O=C(O)C=NOC(CCCc1ccccc1)c1cccc(OCc2ccc3ccccc3c2)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(O)C(=O)C=NOC(CCCc1ccccc1)c1cccc(OCc2ccc3ccccc3c2)c1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 72.5 %

Procedure:
To a solution of DMF (0.5 mL) in methylene chloride (3 mL) at -30° to -20° C. was added oxalyl chloride (0.026 mL, 0.3 mmol) in methylene chloride (1 mL) dropwise. After 20 minutes, a solution of {[1-(3-[2-naphthylmethoxy]phenyl)-4-phenylbutyl]oximino}acetic acid (91 mg, 0.2 mmol) and triethylamine (0.03 mL, 0.2 mmol) in methylene chloride (5 mL) was added dropwise, and the mixture was stirred at -20° C. for 20 minutes. Then a solution of N-methylhydroxylamine hydrochloride (42 mg, 0.5 mmol), triethylamine (0.07 mL, 0.5 mmol) and pyridine (0.04 mL, 0.5 mmol) in chloroform (5 mL) was added. Upon completion of addition the mixture was allowed to warm to ambient temperature, stirred for 4 hours and then diluted with ethyl acetate (50 mL). The resulting mixture was washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1:1 methylene chloride-ethyl acetate to afford 70 mg of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 1.8 (m, 2H), 2.61 (t, J=7Hz, 2H), 2.77 (t, J=7Hz, 2H), 3.1 (s, 3H), 4.9 (s, 2H), 5.3 (s,2H), 7.2 (m, 9H), 7.53 (dd, J=6Hz, 4Hz, 2H), 7.6 (dd, J=8Hz, 2Hz, 1H), 7.96 (m, 4H), 9.9 (s,1H). IR (CDCl3): 3640, 3520, 3220, 1640,1600 cm-1. MS (DCI/NH3) m/e 483 (M+H)+, 500 (M+H+NH3)+. Analysis calcd for C30H30N2O4 ·0.5 H2O: C,73.30; H, 6.36; N, 5.70. Found: C, 73.24; H, 5.89; N. 5.39.
Reaction SMILES: [NH2:1][N:2]1[C:6]([C:7]#[N:8])=[C:5](Br)[CH:4]=[C:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[NH2:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:28]=2)[CH:4]=[C:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)c1cc(Br)c(C#N)n1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CCOC(=O)c1cc(-c2cccc(OCc3ccccc3)c2)c(C#N)n1N
Temperature: 80 °C
Yield: 49.9 %

Procedure:
To a stirred solution of ethyl 1-amino-4-bromo-5-cyano-1H-pyrrole-2-carboxylate (1.43 g, 5.55 mmol), 4-benzyloxybenzeneboronic acid (3.80 g, 16.7 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II) complex with dichloromethane (453 mg, 0.56 mmol) in degassed DME (41 mL) was added aqueous Na2CO3 solution (2 M, 8.3 mL). The reaction was heated (80° C.) for 17 h and then cooled to rt. The reaction was filtered through a pad of Celite® and the filter cake was rinsed well with ethyl acetate. The filtrate was partitioned between ethyl acetate (100 mL) and water (100 mL) and the layers were separated. The organic phase was further washed with water (75 mL), brine, was dried (Na2SO4), and concentrated. The crude material was purified by flash chromatography on silica gel using a gradient of 10 to 20% ethyl acetate in hexanes to afford 1.0 g (50%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.47-7.43 (m, 2 H), 7.41-7.25 (m, 6 H), 7.18 (s, 1 H), 7.02-6.97 (m, 1 H), 6.55 (s, 2 H), 5.15 (s, 2 H), 4.31 (q, 2 H), 1.33 (t, 3 H); ES-MS m/z 362.02 [M+H]+, HPLC RT (min) 3.38.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH:12]1([C:18]([O:20][CH:21]([O:25][C:26](ON2C(=O)CCC2=O)=[O:27])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CC(OC)(C)C.CC(C)=O.O>[CH:12]1([C:18]([O:20][CH:21]([O:25][C:26]([NH:11][CH2:10][C@H:2]2[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]2)=[O:27])[CH:22]([CH3:23])[CH3:24])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CC(C)C(OC(=O)ON1C(=O)CCC1=O)OC(=O)C1CCCCC1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(C)=O
Product: CC(C)C(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)C1CCCCC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (1.4 g, 8.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]-2-methylpropyl cyclohexanecarboxylate (1.0 g, 2.9 mmol) were reacted in the MTBE/acetone/water mixture (16 L) to yield the title compound 48 (300 mg, 27% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.83-0.92 (br. m, 8H), 1.15-1.35 (br. m, 8H), 1.54-1.95 (br. m, 10H), 2.08 (tt, J=12.0, 3.6 Hz, 1H), 2.27-2.32 (br. m, 1H), 2.74-2.83 (br. m, 2H), 6.41 (d, J=5.2 Hz, 1H), 7.39 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 406.14 (M+Na)+; 382.17 (M−H)31.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[CH3:4][S:5]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([S:3][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([S:5]([CH3:4])(=[O:7])=[O:6])=[CH:15][CH:14]=1)[CH3:2]
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSCc1ccc(S(C)(=O)=O)cc1
Reaction time: 18 h

Procedure:
To a solution of ethanethiol (0.3 mL, 4.9 mmol) and 4-methanesulfonylbenzyl chloride (1 g, 4,9 mmol) in DMF (10 mL) at 21° C. was added cesium carbonate (0.8 g, 2.5 mmol). After 18 h, the reaction mixture was poured into water and then filtered off to provide the 1-ethylsulfanylmethyl-4-methanesulfonyl-benzene compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[C:47]([CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)=[O:48]>CC(C)=O.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:53][CH2:54][CH:49]([C:47]([C:39]3[N:38]([CH2:37][C:33]4[O:32][CH:36]=[CH:35][CH:34]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)=[O:48])[CH2:50][CH2:51]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Reactant: O=C(c1nc2ccccc2n1Cc1ccco1)C1CCNCC1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccco4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-phenyl-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-(1-(fur-2-ylmethyl)-1 H-benzoimidazole-2-carbonyl)-piperidine obtain, after chromatography on silica gel eluting with 80% acetone/hexane, the title compound: Mass Spectra (CI/NH3) M++H=677.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][CH2:52][O:53][CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][O:55]3)[CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][CH2:52][O:53][CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][O:55]3)[CH:45]=2)[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Reactant: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
A mixture of Intermediate 139c (125 mg, 0.33 mmol), Intermediate 39b (177 mg, 0.33 mmol) and DIPEA (115 μL, 0.66 mmol) in dioxane (3 mL) was stirred at 80° C. overnight. After cooling, the reaction mixture was partitioned between water and DCM. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% MeOH in DCM, to afford the title compound (214 mg, 85%). LCMS (Method 4): Rt 3.65 min, m/z 765 [MH+].
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Li]CCCC.C[C:14]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].CN(P(N(C)C)(N(C)C)=O)C.C[Li].[Li]C([O-])=O.[Li+].CC([N-]C(C)C)C.C(=O)C>C1COCC1>[Br:23][C:21]1[CH:20]=[C:19]2[C:15](=[CH:14][CH:22]=1)[C:16](=[O:17])[O:18][CH:5]([CH3:6])[CH2:7]2
Reactant: CC(C)NC(C)C
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: CC=O
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC1Cc2cc(Br)ccc2C(=O)O1
Reaction time: 0.17 h

Procedure:
A −78° C. solution of diisopropylamine (13.26 ml, 93 mmol)) in THF (155 ml) was treated with nBuLi (1.6M in Hexanes; 58.1 ml, 93 mmol) over a period of 15 minutes using a syringe pump. In a separate flask, a solution of 2-methyl-4-bromo benzoic acid (10 g, 46.5 mmol) and HMPA (8.33 ml, 46.5 mmol) in THF (155 ml) was cooled to −78° C. Methyl Lithium (29.1 ml, 46.5 mmol) was added slowly via syringe to the cooled solution in order to make the lithio carboxylate. The resulting solution was stirred for 10 minutes and then transferred via cannula to the LDA solution at −78° C. The resulting bright red solution was stirred at −78° C. for an additional 1 hour before being quenched with anhydrous acetaldehyde (7.88 ml, 140 mmol) (color changed from red to orange to clear yellow) and the reaction was then taken out of the dry ice acetone bath and allowed to stir for an additional 1 hour. The flask containing the reaction mixture was then resubmerged in the dry ice acetone bath before it was quenched with 4M HCl in Dioxane (50 mL) followed by 25 mL of MeOH. The reaction was stirred at room temp for an additional 1 hour. The crude reaction was partitioned b/w 200 mL EtOAc and 200 mL water. The organic layer was washed with waster, brine, dried with mag. sulfate, filtered and concentrated. Purification via MPLC (30-70% DCM/Hexanes) afforded 6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14](Cl)=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[IH:20]>>[CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14]([I:20])=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(Cl)nc2sc(SCc3ccccc3)nn12
Reactant: I
Product: O=c1cc(I)nc2sc(SCc3ccccc3)nn12
Reaction time: 4 h
Yield: 55 %

Procedure:
A mixture of 12.2 g of the thus obtained 2-benzylthio-7-chloro-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one and 124 g of 57% hydroiodic acid was heated to 100°-105° C. and stirred for 4 hours. After cooling, the mixture was filtered and the solid was washed with water and dissolved in chloroform. The organic layer was washed with a sodium hydrogen carbonate aqueous solution, a sodium thiosulfate aqueous solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off and thus 13.9 g of 55% pure 2-benzylthio-7-iodo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 48%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:29])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15](O)=[O:16])=[CH:11]2.O[N:31]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[OH-].[NH4+]>O.CN(C)C=O>[CH3:1][O:2][CH2:3][CH:4]([CH3:29])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([NH2:31])=[O:16])=[CH:11]2
Reactant: On1nnc2ccccc21
Reactant: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
A mixture of 7-(2-methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (1.40 g), 1-hydroxybenzotriazole (670 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.95 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 30 min. An aqueous solution of ammonium hydroxide (25%, 5 mL) was added to the mixture. The whole was stirred at room temperature for 15 h. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was washed with ethyl acetate-hexane to give the title compound (1.35 g, 98%) as colorless crystals. MS 420 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:15])[N:7]2[CH2:12][CH:13]=O.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][N:38]([CH2:13][CH2:12][N:7]4[C:8]5[C:3](=[C:2]([Br:1])[CH:11]=[CH:10][CH:9]=5)[CH:4]=[CH:5][C:6]4=[O:15])[CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: O=CCn1c(=O)ccc2c(Br)cccc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(Br)cccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To 25 mL of a chloroform solution containing 520 mg of (5-bromo-2-oxoquinolin-1(2H)-yl)acetaldehyde and 705 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 112 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 629 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform], to give 890 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-bromo-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow foam.
Reaction SMILES: [N:1]1([CH2:7][C:8]#[CH:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:10][C:11]1[C:12]([C:9]#[C:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]
Reactant: C#CCN1CCOCC1
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN3CCOCC3)c21

Procedure:
Using Method C above, 3-(4-morpholinyl)-1-propyne (63.6 mg, 0.51 mmol) (prepared according to H. Kano et al., J. Med. Chem. 10:411-418 (1967)) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (75 mg, 0.203 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (23.5 mg) and CuI (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-4-[3-(4-morpholinyl)-1-propynyl]-2H-indol-2-one. (Yield 40 mg, 54%).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH2:8]([O:10]/[CH:11]=[CH:12]/[CH3:13])[CH3:9].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3](=[O:4])/[C:12](/[CH3:13])=[CH:11]/[O:10][CH2:8][CH3:9]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C/C=C/OCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCO/C=C(\C)C(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 119.7 %

Procedure:
To a solution of 2,2,2-trichloroacetyl chloride (10.6 g, 6.52 mL, 58.1 mmol) in dichloromethane (15 mL) cooled to −10° C. was added a mixture of (E)-1-ethoxyprop-1-ene (5 g, 6.43 mL, 58.1 mmol) and pyridine (4.59 g, 4.7 mL, 58.1 mmol) over a period of 15 min. After the addition was complete, the mixture was stirred at RT for 16 h. The resulting precipitate was filtered and washed with dichloromethane. The filtrate was concentrated in vacuo and dried at 40° C. in high vacuum to give the product as brown semisolid (16.1 g with 80% purity, 95.8%). The crude material was used directly in the next step without any further purification.