Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]([F:28])([F:27])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=2)[CH:10]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:8].CO>C(Cl)Cl>[F:28][C:6]([F:5])([F:27])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[CH:10]1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:8]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccccc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(N1CCc2cc(O)ccc2C1c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 146.8 %

Procedure:
A 1M solution of BBr3 in CH2Cl2 (0.77 ml, 0.77 mmol) was added slowly to a solution of 2,2,2-trifluoro-1-(6-methoxy-1-phenyl-3,4-dihydro-1H-isoquinoline-2-yl)ethanone (0.172 g, 0.513 mmol) in anhydrous CH2Cl2 (10 ml) at 0° C. under N2. The resulting yellow solution was stirred at 0° C. for 30 min, then warmed to rt and stirred at rt for 22 hr. MeOH (5 ml) was slowly added to the reaction mixture with stirring and the resulting solution was concentrated in vacuo to give 0.242 g of yellow oil. Purification by flash chromatography, eluting with hexane:EtOAc (8:2) gave 0.143 g (87% yield) of white solid.
Reaction SMILES: [CH2:1]([NH:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:29][C:30]([NH:22][S:19]([C:17]2[CH:16]=[CH:15][C:12]3[CH2:13][CH2:14][N:8]([C:6](=[O:7])[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:9][CH2:10][C:11]=3[CH:18]=2)(=[O:21])=[O:20])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCCCNC(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Reactant: O=C=NC1CCCCC1
Product: CCCCNC(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2CC1

Procedure:
By the reaction of 3-butylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with cyclohexylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-cyclohexyl-3-[(3-butylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea. The starting material can be prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with butylisocyanate in a manner analogous to that described in Example 8.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[Br-].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Zn+])=[CH:23][C:22]=1[F:28]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[O:6][C:5]([C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=3)=[N:4][C:3]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:23][C:22]=1[F:28]
Reactant: Fc1cc([Zn+])ccc1Cl
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2)oc1Br
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccc(F)cc2)oc1-c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 5-bromo-2-(4-fluorophenyl)oxazol-4-carboxylate (600 mg), 0.05M (4-chloro-3-fluorophenyl) zinc bromide (6 ml, tetrahydrofuran solution), and tetrakis-(triphenylphosphine) palladium (231 mg) in tetrahydrofuran (5 ml) was stirred under argon atmosphere at room temperature for 2 hours, followed by refluxing for 40 minutes. The reaction mixture was cooled and concentrated under reduced pressure, and water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was successively washed with 10% hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent: ethyl acetate:n-hexane=1:8) to obtain ethyl 5-(4-chloro-3-fluoro-phenyl)-2-(4-fluorophenyl)oxazol-4-carboxylate (580 mg) as pale reddish solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[N:37]=[C:36]([CH3:38])[O:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][C:36]1[O:35][N:34]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[N:37]=1
Reactant: Cc1nc(CCl)no1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)no1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (200 mg; compound B50) is reacted with 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole (62 mg; compound D2) in the presence of potassium carbonate (65 mg) in DMF (5 ml). Using WU1 the title compound is obtained as a solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@@:21]([F:26])([CH3:25])[C:22](O)=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:42])([F:41])[CH2:38][CH2:39][NH2:40]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@@:21]([F:26])([CH3:25])[C:22]([NH:40][CH2:39][CH2:38][C:37]([F:42])([F:41])[F:36])=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCCC(F)(F)F
Product: C[C@@](F)(C(=O)NCCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)—N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-fluoro-2-methyl-malonamic acid and 3,3,3-trifluoropropylamine, the title compound was prepared in the same manner as described for example 1c. Colorless, viscous oil (72%). MS: m/e=572(M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH3:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([N:25]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)(=[O:17])=[O:18])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:7][CH:8]=2)[CH3:24])=[CH:27][CH:28]=1
Reactant: CNc1ccc(Cl)cc1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1cccs1
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2cccs2)cc1)c1ccc(Cl)cc1
Yield: 69 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}thiophene-2-sulfonamide, and N-methyl-4-chloro aniline, the title compound was isolated as a yellow solid in 69% yield (94% purity by HPLC).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([C:10]([CH3:14])([CH3:13])[CH2:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=1[N+:26]([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:26][C:17]1[CH:18]=[C:19]([C:22]([F:23])([F:24])[F:25])[CH:20]=[CH:21][C:16]=1[O:15][C:5]1[CH:6]=[CH:7][C:8]([C:10]([CH3:13])([CH3:14])[CH2:11][CH3:12])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:29]
Reactant: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c(C(=O)OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2N)c(C(=O)OC)c1
Reaction time: 3 h

Procedure:
Methyl-2-(nitro-4-trifluoromethylphenoxy)-5-(1,1-dimethylpropyl)benzoate (2.5 g, 0.006 mol) was mixed in ethyl acetate (50 mL) and a palladium on carbon catalyst (600 mg) was added under argon. This mixture was hydrogenated at 50 psi for 3 h. The mixture was filtered through Celite® and washed with methanol and ethyl acetate. The solvents were evaporated to yield the title compound. 1H NMR (250 MHz, CDCl3) δ7.84 (d, 1H), 7.44 (dd, 1H), 7.03 (d, 1H), 684-6.97 (m, 2H), 6.72 (d, 1H), 4.22 (s, 2H), 3.81 (s, 3H), 1.55-1.72 (m, 2H), 1.29 (s, 6H), 0.60-0.77 (t, 3H),
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([O:11][CH3:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14](Br)[C:15]#[CH:16]>>[CH2:16]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[C:3]([OH:13])=[C:4]([O:11][CH3:12])[CH:5]=1)[C:15]#[CH:14]
Reactant: C#CCBr
Reactant: COc1cc(C(=O)O)cc(Br)c1O
Product: C#CCOC(=O)c1cc(Br)c(O)c(OC)c1

Procedure:
By utilizing the procedure of Example 5, by reacting 5-bromovanillic acid with propargyl bromide, there is obtained 5-bromovanillic acid propargyl ester; M.P. 121-122°C.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:94][CH2:93][CH2:92][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([N:59]([CH2:61][C:62]([NH:64][C@H:65]([C:72]([NH:74][C@H:75]([C:88]([O:90][CH3:91])=[O:89])[CH2:76][CH2:77][CH2:78][CH2:79][NH:80][C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])=[O:73])[CH2:66][C:67]1[N:71]=[CH:70][NH:69][CH:68]=1)=[O:63])[CH3:60])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[H][H]>CO>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:94][CH2:93][CH2:92][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([N:59]([CH2:61][C:62]([NH:64][C@H:65]([C:72]([NH:74][C@H:75]([C:88]([O:90][CH3:91])=[O:89])[CH2:76][CH2:77][CH2:78][CH2:79][NH:80][C:81]([O:83][C:84]([CH3:86])([CH3:87])[CH3:85])=[O:82])=[O:73])[CH2:66][C:67]1[N:71]=[CH:70][NH:69][CH:68]=1)=[O:63])[CH3:60])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:52])[CH3:53])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: [H][H]
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CN(C)C(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Solvent: CO
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CN(C)C(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N

Procedure:
100 mg of Z-Arg-Arg-Pro-Phe-His-Sta-Sar-His-Lys(Boc)-OMe (see Example 16) are dissolved in 2 ml of 95% strength MeOH and, after the addition of 10 mg of Pd-on-carbon (10% Pd), hydrogenated by passing hydrogen through until the starting material has disappeared completely (monitoring by thin layer ohromatography). The catalyst is filtered off, the filtrate is concentrated to dryness and the residue is dissolved in 2 ml of H2O and lyophilised, yielding H-Arg-Arg-Pro-Phe-His-Sta-Sar-His-Lys(Boc)-OMe; Rf (D)=0.15; Rf (M)=0.25; Rf (O)=0.22.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[NH:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[O:16].C([O-])(=O)C.[Na+]>C(O)(=O)C>[OH:8][C:7]1[C:9]([O:10][CH3:11])=[CH:12][C:2](/[CH:1]=[C:20]2/[C:18](=[O:19])[NH:17][C:15](=[O:16])[NH:14]/2)=[CH:3][C:4]=1[O:5][CH3:6]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: O=C1CNC(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(/C=C2\NC(=O)NC2=O)cc(OC)c1O

Procedure:
In an acetic acid (1.6 mL) solvent, a suspension including syringaldehyde (300 mg, 1.65 mmol), hydantoin (198 mg, 1.98 mmol), and sodium acetate (405 mg, 4.94 mmol) was refluxed for 24 hours, and after cooling, the produced precipitate was filtered. The filtered solid was washed with methylene chloride and a small amount of water. After drying under reduced pressure, a target compound was obtained (192.9 mg, 44.3%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Cl.Cl[CH2:16][CH:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:18]>>[N:19]1([CH:17]([CH3:18])[CH2:16][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: CC(CCl)N1CCCC1
Agent: Cl
Product: CC(Cn1cnc(-c2cc(C#N)ccn2)c1)N1CCCC1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 1-(2-chloro-1-methylethyl)pyrrolidine hydrogen chloride according to the procedure for the preparation of Example 43, part A (heating to 120°). [M+H] Calc'd for C16H19N5, 282. Found, 282.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH:24]1([CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CN(C)CCCN=C=NCC>CN(C)C=O>[CH:24]1([CH2:30][CH2:31][CH2:32][C:33]([C:1]2[C:6](=[O:7])[O:5][CH2:4][C:2]=2[OH:3])=[O:34])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1COC(=O)C1
Reactant: O=C(O)CCCC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCCC1CCCCC1)C1=C(O)COC1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1.0 g (10.0 mmol) of tetronic acid in 30 mL of dry N,N-dimethylformamide at 0° C. is added 1.5 mL (11 mmol) of triethylamine followed by 0.37 g (30 mmol) of 4 dimethylaminopyridine. After stirring at 0° C. for 5 minutes, 2.0 g (11.7 mmol) of 4-cyclohexyl butyric acid is added, followed by 2.25 g (11.7 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide. After 10 minutes, the ice bath is removed and the reaction mixture is allowed to stir overnight. The reaction mixture is quenched with 1N HCl and the solution is washed three times with hexanes. The combined organic layers are washed with water, dried over magnesium sulfate and evaporated. The residue is flash chromatographed on silica gel using 5% methanol/ethyl acetate with 2 mL of acetic acid/liter to give an orange solid: m.p. 38°-42° C.; IR (film) 2920, 2840, 1770, 1690, 1660, 1600 cm-1; NMR (CDCl3) δ5 0.9 (m, H), 1.2 (m, 6H), 1.7 (m, 6H), 2.9 (q, J=7 Hz, 2H), 4.6 and 4.7 (s, 2H), 12.1 (bs, H); MS (EI): M+252. Anal. Calc'd. for C14H20O4 : C, 66.64; H, 7.99 Found: C, 66.38; H, 7.90
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](O)=[O:27]>>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:26](=[O:27])[CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH3:17]
Reactant: COc1ccccc1CC(=O)O
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Product: COc1ccccc1CC(=O)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 53 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and 2-methoxyphenylacetic acid in 53% yield following procedure 1. The product was crystallized from acetonitrile. 100% Purity by LC/MS (230 DAD), Mass-spec [M+H+]=357, 1H NMR (MeOH-d4): 3.45 s (3H, OMe), 3.67 s (2H), 6.17 s (1H), 6.75 d, 8 Hz (1H), 6.83 t, 8 Hz (1H), 7.06 t, 8 Hz (1H), 7.14 t, 8 Hz (1H), 7.17–7.21 m (3H), 7.23–7.36 m (2H), 7.49 t, 8 Hz (2H), 8.13 d, 8 Hz (1H).
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.Cl[CH:14](Cl)[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:31][CH3:32])=[C:22]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:23]=2)[CH2:18][CH2:17][N:16]=1>CCO.C(Cl)Cl>[CH3:32][O:31][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][C:22]=1[O:25][CH2:26][C:27]([F:30])([F:28])[F:29])[C:15]([CH2:14][S:3][C:4]1[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=1)=[N:16][CH:17]=[CH:18]2
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COc1cc2c(cc1OCC(F)(F)F)C(C(Cl)Cl)=NCC2
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: COc1cc2ccnc(CSc3nc4ccccc4[nH]3)c2cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a solution of 514.8 mg of 86% KOH (7.87 mmol) in 20 ml of 99% EtOH were added 434.1 mg of 2-mercaptobenzimidazole (II-1) (2.89 mmol) and 900.1 mg of 1-dichloromethyl-6-methoxy-7-(2,2,2-trifluoroethoxy)-3,4-dihydroisoquinoline (IV-1) (2.63 mmol) in order. After stirring for 30 min. at room temperature, the mixture was refluxed for 3 hr. and concentrated under reduced pressure. The residue was mixed with water and extracted with CHCl3. The objective compound existing as an insoluble material was filtered and combined with CHCl3 extract to give 722.5 mg of the crude product. It was dispersed in 15 ml of CH2Cl2, filtered and washed with CH2Cl2 to give 666.5 mg of the titled compound 2-{[6-methoxy-7-(2,2,2-trifluoroethoxy)isoquinolin-1-yl]methylthio}-benzimidazole (Ia-7) (Yield: 60.4%).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:41])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4Br)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:30])[C:12]=2[C@H:31]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:32]([O:34][CH3:35])=[O:33])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].CCN(CC)CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:37]([O:36][C@@H:31]([C:12]1[C:13]([CH3:30])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:41])([O:4][CH2:1][CH:2]=[CH:3][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][O:21][CH2:20]3)[CH2:6][CH2:7]1)[C:32]([O:34][CH3:35])=[O:33])([CH3:40])([CH3:39])[CH3:38]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(COCc4ccccc4Br)nn23)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=Cc1ccccc1COC3
Temperature: 120 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-bromobenzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.025 g, 0.040 mmol) in acetonitrile (1 ml) in a pressure tube were added Et3N (0.055 ml, 0.397 mmol), triphenylphosphine (3.12 mg, 0.012 mmol) and tris(dibenzylideneacetone)dipalladium (0) (3.64 mg, 3.97 μmol). The tube was sealed and the mixture was stirred at 120° C. After 18 h, the dark mixture was cooled and concentrated. The brown residue was purified by flash chromatography (Biotage; 0%-60% EtOAc/hexane; 20 CV) to afford the title compound as mixture of cis- and trans-isomers (16.9 mg, 0.031 mmol, 78% yield) as a pale yellow oil. LCMS (M+H) calcd for C31H41N4O5: 549.30. found: 549.4.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:18])[CH:24]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1cccc(Cl)c1
Product: Cc1c2n(c3c(-c4cccc(Cl)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (66 mg, 77%), MS (ISP) m/z=345.4 [(M+H)+], mp 218.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 3-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH2:15]O)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].CN(C)C=O.S(Cl)([Cl:33])=O>ClCCl>[Cl:33][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH:8]=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:6]2[CH2:5][C:4]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:2]([Cl:1])[CH:3]=1
Reactant: CCOC(=O)c1cc2c(CO)cccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(CCl)cccc2n1Cc1ccc(Cl)c(Cl)c1
Yield: 67 %

Procedure:
Ethyl N-(3,4-dichlorobenzyl)-4-hydroxymethylindole-2-carboxylate (0.89 g), dimethylformamide (0.5 ml) and thionyl chloride (189 μl) in dichloromethane (40 ml) were stirred at ambient temperature overnight and the resulting precipitate as filtered and dried in vacuo to give the product as a white solid (0.62 g, 67%); NMR δ(CD3SOCD3) 1.30 (t, 3H), 4.30 (q, 2H), 5.10 (s, 2H), 5.85 (s, 2H), 6.90 (m, 1H), 7.30 (m, 3H) 7.55 (m, 3H), M/z (+) 396.2 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:14][CH:13]=[CH:12][CH2:11][N:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:23])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]1[CH2:14][CH:13]=[CH:12][CH2:11][N:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC=CCN(OCc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CC=CCN(OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4.14 g (12.45 mmoles) of (1-benzyloxy-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-(R)-yl)-carbamic acid tert-butyl ester from Step C in 30 mL of dichloromethane was added 20 mL of trifluoroacetic acid. The reaction mixture was stirred for two hours at room temperature, and the solvent was removed under vacuum. Next, the reaction mixture was diluted in dichloromethane, and neutralized with NaHCO3(s). The reaction mixture was then extracted with NaHCO3(aq.) and NaCl (aq.) solutions. The aqueous layers were re-extracted with dichloromethane twice, and the organic layers combined and dried over Na2SO4(s). Filtration and solvent removal gave 3.685 g of a purple, viscous oil. MS: 465 (2M+H), 233 (M+H).
Reaction SMILES: [Br-].[O:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]1[CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:35][C:36]1[CH:37]=[C:38](/[CH:39]=[CH:15]\[CH2:14][CH2:13][N:4]2[C:5](=[O:12])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]2=[O:2])[CH:41]=[CH:42][CH:43]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=C1c2ccccc2C(=O)N1CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC/C=C\c1cccc(Cl)c1
Temperature: -75 °C
Reaction time: 0.33 h
Yield: 81.7 %

Procedure:
To a stirred suspension of (3-(1,3-dioxoisoindolin-2-yl)propyl)triphenylphosphonium bromide (17.6 g, 33.2 mmol) in tetrahydrofuran (170 mL) at ambient temperature was added 3-chlorobenzaldehyde (3.76 mL, 33.2 mmol), and the resulting mixture was cooled with a dry-ice acetone bath to −75° C. Solid potassium t-butoxide (3.72 g, 33.2 mmol) was added, and stirring was continued in the bath for an additional 20 minutes; the temperature was −80° C. The cooling bath was removed, and when the internal temperature reached −30° C., the flask was placed in a water-ice bath. The temperature eventually settled at 10° C. and was maintained for 2 hours. The reaction mixture was poured into a separatory funnel containing water (250 mL), and this was extracted with ethyl acetate (250 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 90/10 hexanes/ethyl acetate, to afford (Z)-2-(4-(3-chlorophenyl)but-3-enyl)isoindoline-1,3-dione as a white solid (8.46 g, 82% yield).