Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[Cl:10][S:11](O)(=[O:13])=[O:12]>C(OCC)(=O)C>[Cl:8][C:5]1[CH:4]=[C:3]([OH:9])[C:2]([Cl:1])=[CH:7][C:6]=1[S:11]([Cl:10])(=[O:13])=[O:12]
Reactant: O=S(=O)(O)Cl
Reactant: Oc1cc(Cl)ccc1Cl
Solvent: CCOC(C)=O
Product: O=S(=O)(Cl)c1cc(Cl)c(O)cc1Cl
Temperature: 80 °C
Yield: 80.6 %

Procedure:
2,5-Dichlorophenol (1.00 g, 6.17 mmol) was gradually added to chorosulfonic acid (2 mL, 30.85 mmol) at 0° C. Then it was heated at 80° C. for 1 hour. Then it was cooled at room temperature and poured onto crushed ice. Then ethyl acetate was added. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo to give 1.30 g (81%) of the title compound as a white solid, which was used in the next reaction without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:35])[C@H:5]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:6][C:7](=[O:19])[C@H:8]([CH2:10][S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:9].[CH3:36][C:37]([CH3:52])([CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=1)[C:38](O)=[O:39]>>[CH3:2][O:3][C:4](=[O:35])[C@H:5]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:6][C:7](=[O:19])[C@H:8]([CH2:10][S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:9][C:38](=[O:39])[C:37]([CH3:36])([CH3:52])[CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=1
Reactant: COc1ccc(CSCC(C)(C)C(=O)O)cc1
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](N)CSCc1ccccc1
Agent: Cl
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CSCc1ccccc1)NC(=O)C(C)(C)CSCc1ccc(OC)cc1

Procedure:
Nα -(S-benzyl-L-cysteinyl)-Nε -benzyloxycarbonyl-L-lysine methyl ester hydrochloride and 2,2-dimethyl-3-(4-methoxybenzylthio)propionic acid were used as starting materials.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC(C)(C)[C:17]#[N:18].C([O-])([O-])=O.[K+].[K+]>C(O)C.C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([C:17]#[N:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: N#CC1(O)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
To a solution of 2 g (10.6 mmoles) of 1-benzyl-piperidin-4-one in 14 ml of ethanol are added 6.8 ml (74.5 mmoles) of 2-hydroxy-2-methyl-propionitrile and 0.41 g (3 mmoles) of K2CO3 at 0° C. The mixture is stirred at 0° C. for 5 hours and diluted with diethyl ether. The organic layer is washed with water, dried over Na2SO4 and concentrated. Chromatography on silica gel (CH2Cl2:MeOH=9:1) gives 1.94 g of desired 1-benzyl-4-hydroxy-piperidine-4-carbonitrile in 85% yield.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:20]=[CH:19][C:6]2[C:7](=[O:18])[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][O:10][C:5]=2[CH:4]=1.[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28](I)[CH:27]=1.[Cl-].[NH4+]>CN(C)C=O>[C:25]([C:26]1[CH:27]=[C:28]([C:3]2[CH:20]=[CH:19][C:6]3[C:7](=[O:18])[C:8]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:9][O:10][C:5]=3[CH:4]=2)[CH:29]=[CH:30][CH:31]=1)([O:24][CH3:23])=[O:33]
Reactant: COC(=O)c1cccc(I)c1
Reactant: C[Sn](C)(C)c1ccc2c(=O)c(Cc3ccccc3)coc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccc3c(=O)c(Cc4ccccc4)coc3c2)c1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
To a stirred solution of the compound of step F (7.0 g, 17.5 mmole) in dimethylformamide (DMF) (35 mL) was added Pd(PPh3)2C12 (490 mg, 0.7 mmole), 3 crystals of BHT and methyl-3-iodobenzoate (5.0 g, 19.1 mmole). The mixture was stirred at reflux for 1.5 hours, cooled to room temperature and poured into 150 mL of saturated aqueous ammonium chloride solution. The mixture was extracted with 3×150 mL of diethyl ether, and the combined extract was washed with 2×100 mL of water, and then brine. The solution was dried over sodium sulfate, filtered and evaporated in vacuo to afford a yellow oil. Chromatography over silica gel (4:1 hexane: ether elution) afforded 6.51 g of the title compound as a viscous oil.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](O)=[O:7])[C:3]([C:9]([OH:11])=O)=[CH:2]1.[CH2:12]([NH2:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:12]([N:24]1[C:9](=[O:11])[C:3]2=[CH:2][S:1][CH:5]=[C:4]2[C:6]1=[O:7])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)c1cscc1C(=O)O
Reactant: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCN1C(=O)c2cscc2C1=O
Yield: 55 %

Procedure:
The title compound was synthesized as described hereinabove using thiophene-3,4-dicarboxylic acid (10.00 g, 58.08 mmol) and 1-dodecylamine (16.14 g, 87.12 mmol) to afford 10.27 g of the title product as a white solid (Y=55%). 1H NMR (400 MHz, CDCl3, ppm) δ: 7.80 (s, 2H); 3.60 (t, 2H, J=7.3 Hz); 1.65-1.62 (m, 2H); 1.30-1.24 (m, 18H); 0.87 (t, 3H, J=6.5 Hz); 13C NMR (100 MHz, CDCl3, ppm) δ: 162.92; 136.91; 125.71; 38.75; 32.15; 29.87; 29.85; 29.81; 29.75; 29.59; 29.45; 28.72; 27.12; 22.93; 14.39.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[CH:14][C:13]=1[F:23])=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[F:23][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([N:18]2[N:19]=[CH:20][CH:21]=[N:22]2)[C:12]=1[C:10]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1)=[O:11]
Reactant: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-n2nccn2)[C@@H]1CN
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-n2nccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 464 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.80-6.75 (m, 8H), 5.00-2.70 (m, 5H), 2.00-0.65 (m, 8H).
Reaction SMILES: C[O:2][C:3](=[O:9])[CH2:4][C:5]([CH2:7]Br)=O.[CH3:10][C:11]([NH:16][C:17]([NH2:19])=[O:18])([CH3:15])[CH2:12][CH2:13][CH3:14].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:10][C:11]([NH:16][C:17]([NH:19][C:5]1[CH2:7][O:2][C:3](=[O:9])[CH:4]=1)=[O:18])([CH3:15])[CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)CC(=O)CBr
Reactant: CCCC(C)(C)NC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCC(C)(C)NC(=O)NC1=CC(=O)OC1
Yield: 8 %

Procedure:
To a solution of 22 g of methyl-4-bromoacetoacetate in 200 ml benzene is added 14.4 g of 1,1-dimethylbutylurea and 100 mg of p-toluenesulfonic acid. The solution is heated at reflux under nitrogen for 4 hours with water removal. At the end of this period the solution is cooled and concentrated. The residual material is chromatographed on 400 g of silicic acid. Elution with a solution of benzene (60%), ethyl acetate (30%) and methanol (10%) gives crystalline material. Recrystallization of this material from ethyl acetate gives 1.8 g of 1-(1,1-dimethylbutyl)-3-(2,5-dihydro-5-oxo-3-furyl)urea, m.p. 130°-132°C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:25])=[C:12]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[C:22](O)=[O:23])[C:13]=1[Cl:14].C[N:27](C)C=O.[OH-].[NH4+]>C(Cl)Cl.O1CCCC1>[Cl:14][C:13]1[C:8]([CH3:7])=[CH:9][CH:10]=[C:11]([Cl:25])[C:12]=1[NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:22]([NH2:27])=[O:23]
Reactant: CN(C)C=O
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(Cl)c(Nc2ccccc2C(N)=O)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (1.90 g, 14.8 mmol) is added dropwise to a 0° C. suspension of meclofenamic acid (2.00 g, 6.7 mmol) and dimethylformamide (530 μl, 6.7 mmol) in 100 ml of methylene chloride. The clear yellow solution is stirred at 0° C. for one hour and then added by cannula to 3.6 ml of ammonium hydroxide (29% aqueous solution) in tetrahydrofuran at room temperature. After one hour the volatiles are removed and the residue partioned between ethyl acetate and water. The organic layer is washed with brine and dried over magnesium sulfate and concentrated. The white solid is recrystallized from ethyl acetate and isopropanol to give 1.30 g (69%), mp 185°-187° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:14]3=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([C:2]2[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[N:23]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:14]4=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=[C:13]4[CH:12]=3)=[O:10])=[CH:4][CH:3]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCNC1
Reactant: O=C(Nc1ccc(Cl)nc1)c1cc2ccc(C(F)(F)F)nc2n1Cc1cccc(F)c1
Product: O=C(Nc1ccc(N2CCCC2)nc1)c1cc2ccc(C(F)(F)F)nc2n1Cc1cccc(F)c1
Yield: 64.8 %

Procedure:
According to a method similar to that described in Stage 6.2, by reacting 0.3 g (0.67 mmol) of N-[6-chloropyridin-3-yl]-6-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, described in the preceding stage, with 0.56 mL (6.68 mmol) of pyrrolidine, we obtain 0.21 g of the expected compound.
Reaction SMILES: [NH2:1][C:2]([NH2:7])=[CH:3][N+:4]([O-:6])=[O:5].[C:8]([CH2:11][C:12](=O)[CH3:13])(=O)[CH3:9]>>[NH2:1][C:2]1[C:3]([N+:4]([O-:6])=[O:5])=[C:12]([CH3:13])[CH:11]=[C:8]([CH3:9])[N:7]=1
Reactant: NC(N)=C[N+](=O)[O-]
Reactant: CC(=O)CC(C)=O
Product: Cc1cc(C)c([N+](=O)[O-])c(N)n1
Yield: 52 %

Procedure:
For the example of the reaction of 1,1-diamino-2-nitroethene with acetylacetone to give 2-amino-3-nitro-4,6-dimethylpyridine, this reaction is described by Troschutz et al., in Arch. Pharm., 325 (1992), 785-789. A yield of 52 percent is described.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17](O)[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:22])=[O:21])=[CH:4][CH:3]=1.[C:23](=[O:26])([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([O:26][CH2:23][CH:2]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]4)[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:22])=[O:21])=[CH:4][CH:3]=1
Reactant: CN1C(=O)N(c2ccc(Cl)cc2)S(=O)(=O)c2ccc(O)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ccc(Cl)cc2)S(=O)(=O)c2ccc(OCC3CCCCC3)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 143.3 %

Procedure:
A suspension of 2-(4-chlorophenyl)-6-hydroxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (250 mg), potassium carbonate (122 mg) and bromomethylyclohexane (159 mg) in N,N-dimethyl formamide (1 ml) was stirred for 2 hours at 60° C. The mixture was poured into ice water. The separator solid was collected by filtration, dried, and recrystallized from ethanol to yield 2-(4-chlorophenyl)-4-methyl-6-cyclohexylmethoxy-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (230 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]([C:27]([OH:29])=O)=[CH:17][C:16]=2[CH2:15][CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:70]([NH2:74])([CH3:73])([CH3:72])[CH3:71]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:18]([C:27]([NH:74][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:29])=[CH:17][C:16]=2[CH2:15][CH2:14]1)=[O:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2cc(C(=O)O)c(C(F)(F)F)nc2C1)Cc1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)c1cc2c(nc1C(F)(F)F)CN(C(=O)C[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the product (33 mg, 0.061 mmol) from Example 3, Step B, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC; 12 mg, 0.063 mmol), 1-hydroxybenzotriazole (HOBt; 9 mg, 0.067 mmol) and N,N-diisopropylethyl amine (0.026 mL, 0.15 mmol) in 1.0 mL of dichloromethane was added tert-butylamine (0.011 mL, 0.100 mmol). The solution was stirred at room temperature for 18 h. The reaction mixture was subjected directly to flash chromatography (silica gel; 35 to 75% ethyl acetate/hexanes step-gradient elution) to afford the title compound as a white foam.
Reaction SMILES: C[N:2](C)/[CH:3]=[C:4](\[CH2:24][CH3:25])/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[C:27]1([NH:33]N)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.C(O)(=O)C>[CH2:24]([C:4]1[CH:3]=[N:2][N:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]=1[C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)[CH3:25]
Reactant: CC/C(=C\N(C)C)C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCc1cnn(-c2ccccc2)c1-c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O

Procedure:
3-{2-[1-Dimethylamino-meth-(E)-ylidene]-butyryl}-1-(3-methanesulfonyl-phenyl)-1H-pyridazin-4-one and phenyl hydrazine (1.5 eq) were dissolved in a sealed tube in DMF with 2 drops acetic acid and irradiated in MW at 120° C. for 15 min. The solvent of the reaction mixture was removed and the crude product was purified by preparative HPLC yielding the desired product. MS: M=421.2 (M+H)+
Reaction SMILES: [F:1][CH2:2][C:3]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:7][C:8](=[CH2:18])[CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]([OH:6])=[O:5].[N+](=[CH2:29])=[N-]>CCOCC>[F:1][CH2:2][C:3]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:7][C:8](=[CH2:18])[CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]([O:6][CH3:29])=[O:5]
Reactant: C=C(CNC(=O)OC(C)(C)C)CC(CF)(NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: C=C(CNC(=O)OC(C)(C)C)CC(CF)(NC(=O)OC(C)(C)C)C(=O)OC

Procedure:
2-Fluoromethyl-2,5-di(tert-butoxycarbonylamino) 4-methylene-pentanoic acid (0.7 g) obtained in Step B above is dissolved in ether, and etheral diazomethane is added until a yellow colour persists Evaporation gives an oil (0.76 g) which is chromatographed on silica (AcOEt/petroleum ether 1:4). Yield of pure product 0.72 g.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[Cl:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[S:39]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=2)[CH2:18][CH2:19]1)(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1cnccc1Cl
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cnccc1Cl)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 20 mL resealable vial was added 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.26 g, 0.64 mmol, Example 91, Step 1), DCM (6 mL), triethylamine (0.44 mL, 3.2 mmol) and 4-chloro-3-pyridinesulfonyl chloride (0.16 g, 0.76 mmol). The mixture was stirred at room temperature for 15 min. To the reaction mixture was added saturated aqueous NaHCO3. The mixture was stirred for 5 min and then the solution was transferred onto a phase separation cartridge (Radleys Discovery Technologies) with the organic phase being collected and passed through a plug of Na2SO4. The collected solution was concentrated and purified by silica gel chromatography (0 to 70% EtOAc/hexane) to afford 2-(4-(4-((4-chloro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol as a white solid.
Reaction SMILES: [K+].[CH3:2][O:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([S-:13])[S:12][C:8]=2[C:7]=1[F:16])=[O:5].[K].S[C:19]1SC2C(N=1)=NC=C(C(OCC)=O)C=2>>[F:16][C:7]1[C:8]2[S:12][C:11]([S:13][CH3:19])=[N:10][C:9]=2[CH:14]=[CH:15][C:6]=1[C:4]([O:3][CH3:2])=[O:5]
Reactant: CCOC(=O)c1cnc2nc(S)sc2c1
Reactant: COC(=O)c1ccc2nc([S-])sc2c1F
Agent: [K+]
Agent: [K]
Product: COC(=O)c1ccc2nc(SC)sc2c1F

Procedure:
Methyl 7-fluoro-2-(methylthio)benzo[d]thiazole-6-carboxylate was synthesized as a clear oil (400 mg, 29%) using a procedure analogous to that described in Step 2 of Example 114, substituting 6-(methoxycarbonyl)-7-fluorobenzo[d]thiazole-2-thiolate potassium salt from the previous step for ethyl 2-mercaptothiazolo[4,5-b]pyridine-6-carboxylate potassium salt used in Example 114. 1H NMR (500 MHz, DMSO-d6) δ 7.96 (m, 1H), 7.77 (d, J=8.6 Hz, 1H), 3.89 (s, 3H), 2.85 (s, 3H); LCMS (ESI) m/z 258 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][CH3:5])[C:2]#[CH:3].I[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1/[C:9](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[C:10](=[O:16])[NH:11]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:5][O:4][CH2:1][C:2]#[C:3][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1/[C:9](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[C:10](=[O:16])[NH:11]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, methyl propargyl ether (34 mg, 0.49 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-methoxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 69 mg, 55%).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:26][O:27][C:28](=[O:39])[CH2:29][C:30]1[CH:35]=[CH:34][C:33](O)=[C:32]([O:37][CH3:38])[CH:31]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:26][O:27][C:28](=[O:39])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:32]([O:37][CH3:38])[CH:31]=1
Reactant: OC1CCCC1
Reactant: COC(=O)Cc1ccc(O)c(OC)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC2CCCC2)c(OC)c1
Temperature: 25 °C
Reaction time: 44 h
Yield: 66.1 %

Procedure:
Cyclopentanol (7.7 ml, 85 mmol) and triphenylphosphine (28 g, 107 mmol) were added to a solution of (4-hydroxy-3-methyoxy-phenyl)-acetic acid methyl ester (14 g, 71 mmol) in tetrahydrofuran (280 ml) under nitrogen at 0° C. Diethylazodicarboxylate (15.7 ml, 100 mmol) was then added dropwise and the reaction was allowed to warm to room temperature and stirred for 44 hours. The solvent was removed under reduced pressure, pentane (200 ml) was added and the suspension was filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography on silica gel eluting with a solvent gradient of cyclohexane:ethyl acetate (90:10 changing to 85:15, by volume) to give (4-cyclopentyloxy-3-methoxy-phenyl)-acetic acid methyl ester (12.4 g) as a colourless oil. 1H NMR (400 MHz, CD3OD): δ=6.79-6.85 (2H, m), 6.73-6.79 (1H, d), 4.73-4.79 (1H, brs), 3.79 (3H, s), 3.64 (3H, s), 3.53 (2H, s), 1.74-1.89 (6H, m), 1.56-1.67 (2H, m) ppm. LRMS (electrospray): m/z [M+Na]+ 287. Anal. Found C, 68.01; H, 7.74. C15H20O4 requires C, 68.16; H, 7.63%.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][CH:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=5)[N:24]=[CH:23][CH:22]=4)[O:13][C:12]3=[O:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].[Na+].[I-]>C1COCC1>[CH2:50]([O:49][C:47](=[O:48])[CH2:46][CH2:45][CH2:44][N:18]([CH2:17][CH2:16][CH:14]1[O:13][C:12](=[O:33])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:15]1)[CH2:19][CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=2)[N:24]=[CH:23][CH:22]=1)[CH3:51]
Reactant: CCOC(=O)CCCBr
Reactant: COc1ccc2nccc(CCNCCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)c2n1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(CCc1ccnc2ccc(OC)nc12)CCC1CN(c2ccc3c(c2)OCCO3)C(=O)O1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
A solution of the compound of Example 72 (0.2 g, 0.44 mmol) in THF (3 mL) was treated with DIPEA (0.147 mL, 2 eq.), ethyl 4-bromobutyrate (0.087 g, 1 eq.) and NaI (0.067 g, 1 eq.). The mixture was heated at 80° C. for 2 h, then partitioned between EA and water. The org. phase was dried over MgSO4 and concentrated. The residue was purified by FC (EA) to give the title compound as a yellowish oil (0.17 g, 68% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=3[CH:17]=2)[C:4](=[O:18])[CH2:3]1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([N:25]=[CH:26][C:27](=[O:36])[N:28]2[CH2:31][CH2:32][CH2:33][CH:34]=O)=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([N:25]=[CH:26][C:27](=[O:36])[N:28]2[CH2:31][CH2:32][CH2:33][CH2:34][NH:1][CH:2]2[CH2:6][N:5]([C:7]3[CH:8]=[CH:9][C:10]4[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=4[CH:17]=3)[C:4](=[O:18])[CH2:3]2)=[CH:23][CH:22]=1
Reactant: COc1ccc2ncc(=O)n(CCCC=O)c2c1
Reactant: NC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCCCNC3CC(=O)N(c4ccc5c(c4)NC(=O)CO5)C3)c2c1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 84.3 %

Procedure:
6-(4-Amino-2-oxopyrrolidin-1-yl)-2H-1,4-benzoxazin-3(4H)-one (56.9 mg, 0.230 mmol) and 4-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)butanal (Reference Example 3; 56.6 mg, 0.230 mmol) were dissolved in chloroform/methanol (10:1, v/v, 3 ml), molecular sieve 3 A (powder 700 mg) was further added, and the mixture was stirred at 60° C. for 4.5 hours. After cooling, sodium triacetoxyborohydride (154 mg, 0.69 mmol) was added to the reaction solution and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the molecular sieve was removed by filtration and a saturated sodium hydrogen carbonate aqueous solution was added to the filtrate and stirred. After separating the organic layer, the aqueous layer was extracted twice with chloroform/methanol (10:1, v/v) and combined with the organic layer. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 92.6 mg (84%) of the title compound in the form of a colorless solid.