Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16]C)=[CH:13][CH:14]=3)[C:9](SC(C)(C)C)=[C:8]2[CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])=[CH:4][CH:3]=1.[CH2:32](S)C.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([O:27][CH3:32])=[O:26])=[CH:4][CH:3]=1
Reactant: CCS
Reactant: COc1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1cc2cc(O)ccc2n1Cc1ccc(Cl)cc1

Procedure:
A suspension of 1.0 g of 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-methoxyindol-2-yl]-2,2-dimethylpropanoic acid (from Example 1 Step B) in 50 mL of CH2Cl2 was treated with 1.3 mL of ethanethiol and 3.47 g of AlCl3 at 0° C. under argon. After 40 min the mixture was poured onto 50 mL 1N HCl, extracted with 3×50 mL of CH2Cl2 washed with 2×50 mL of H2O, dried with MgSO4 and the solvent removed. The residue was dissolved in 1.0 mL ether and ethereal diazomethane added until all the acid was consumed. The excess solvent was removed and the residue chromatographed on silica gel to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([Cl:11])[CH:7]=[CH:6]2.ClC1N(C2C=CC(Cl)=CC=2)N=C2C=1C=CC=C2.[CH2:36]([O:38][C:39]1[CH:40]=[C:41]([NH2:45])[CH:42]=[CH:43][CH:44]=1)[CH3:37]>CN1CCCC1=O>[Cl:11][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[C:2]([NH:45][C:41]3[CH:42]=[CH:43][CH:44]=[C:39]([O:38][CH2:36][CH3:37])[CH:40]=3)[N:3]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[N:4]=2)[CH:9]=1
Reactant: Clc1ccc(-n2nc3ccc(Cl)cc3c2Cl)cc1
Reactant: CCOc1cccc(N)c1
Agent: Clc1ccc(-n2nc3ccccc3c2Cl)cc1
Solvent: CN1CCCC1=O
Product: CCOc1cccc(Nc2c3cc(Cl)ccc3nn2-c2ccc(Cl)cc2)c1

Procedure:
In analogy to the procedure described in example 4.1, a mixture of 3,5-dichloro-2-(4-chloro-phenyl)-2H-indazole and 3-chloro-2-(4-chloro-phenyl)-2H-indazole was reacted with 3-ethoxy-phenylamine ([621-33-0]) in N-methyl 2-pyrrolidone for 4 d at 175° C. in a sealed tube to give the title compound after purification by column chromatography (silica gel, iPrOAc/heptane) as yellow foam. MS: m/e=398.1 [M+H+].
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:30])[NH:17][C:18]3[CH:23]=[C:22]([S:24](Cl)(=[O:26])=[O:25])[C:21]([CH3:28])=[CH:20][C:19]=3[CH3:29])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][NH2:38])[CH:32]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:30])[NH:17][C:18]3[CH:23]=[C:22]([S:24]([NH:38][CH2:37][C:33]4[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=4)(=[O:26])=[O:25])[C:21]([CH3:28])=[CH:20][C:19]=3[CH3:29])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NCc1cccnc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)cc1NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)NCc2cccnc2)cc1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 9H-fluoren-9-ylmethyl[5-(chlorosulfonyl)-2,4-dimethylphenyl]carbamate (1.0 g, 2.3 mmol) in CH2Cl2 (23 mL) was added 1-pyridin-3-ylmethanamine (0.46 mL, 4.5 mmol) and pyridine (0.55 mL, 6.8 mmol). The bright yellow solution was then stirred at room temperature overnight and then quenched by the addition of sat. aq. NaHCO3 solution. The reaction was extracted with EtOAc and the organic extracted were dried over Na2SO4 and concentrated in vacuo. Purification by silica gel column chromatography (0-5% MeOH/DCM) afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=O)[CH:15]=3)[N:10]([CH3:24])[C:9]=2[CH3:25])=[CH:4][CH:3]=1.[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]>>[CH2:26]([N:29]([CH2:30][CH2:31][CH3:32])[C:19](=[O:21])[C:18]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:24])[C:9]([CH3:25])=[C:8]2[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([CH3:22])[CH3:23])[CH2:27][CH3:28]
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)O)ccc2n1C
Reactant: CCCNCCC
Product: CCCN(CCC)C(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccc(Cl)cc1)c(C)n2C

Procedure:
The compound was prepared from 2-[3-(4-chlorophenyl)-1,2-dimethyl-1H-indole-5-yloxy]-2-methyl-propanoic acid and dipropylamine using a procedure analogous to that of Example 130.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][C:16]=3[CH3:17])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Cc1ccsc1-c1nn(N)c(=O)c2ccccc12
Product: Cc1ccsc1-c1nn(NC(=O)Cc2cc(F)cc(F)c2)c(=O)c2ccccc12

Procedure:
The product from Example 14B and 2-(3,5-difluorophenyl)acetic acid was processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.78 (s, 1H), 8.39-8.42 (m, 1H), 7.90-8.05 (m, 2H), 7.73 (d, J=5.1 Hz, 1H), 7.62-7.65 (m, 1H), 7.08-7.22 (m, 4H), 3.77 (s, 2H), 2.10 (s, 3H); MS (APCI) M/Z 412 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[SH:20]>>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[S:20][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Sc1ccncc1Cl
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccncc2Cl)s1
Yield: 16.9 %

Procedure:
Prepared by a similar procedure to that described for example 18 from the 1-(5-chloro-4-nitro-2-thienyl)ethanone (250 mg, 1.22 mmol) and 3-chloropyridine-4-thiol (178 mg, 1.22 mmol) to afford the title product as a solid (65 mg, 17% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (1H, s), 8.75 (1H, d), 8.57 (1H, s), 7.94 (1H, d), 2.54 (3H, s). MS m/z: 315.05 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)(=[O:19])=[O:18])[CH3:15])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([CH:14]([CH3:15])[N:16]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)(=[O:19])=[O:18])[C:4]=2[CH:3]=1)=[CH:10][CH:11]=[CH:12][CH:13]=3
Reactant: COc1cccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(Cl)cc2F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(S(=O)(=O)N2c3cc(Cl)ccc3-c3ccccc3C2C)c1

Procedure:
The title compound was prepared from N-[1-(4′-chloro-2′-fluoro-1,1′-biphenyl-2-yl)ethyl]-3-methoxybenzenesulfonamide (686 mg, 1.6 mmol), anhydrous N,N-dimethylformamide (2 mL), and potassium carbonate (442 mg, 3.2 mmol) according to the procedure and in the same manner as described in Example 105, step d resulting in the isolation of 547 mg (84%) of a white solid that was used without further purification;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N:3]=1.[O-:11][CH2:12][CH3:13].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:11][CH2:12][CH3:13])[CH:5]=[CH:4][N:3]=1
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 57.1 %

Procedure:
To a mixture of 2-chloro-4-nitropyridine (20 g, 126 mmol) in THF (200 mL) was added sodium ethoxide (25.8 g, 378 mmol) in portions. The mixture was stirred at 25° C. for 10 h. The mixture was filtered and the filtrate was concentrated. The crude material was purified by silica column chromatography (PE/EA=5:1). All fractions found to contain product by TLC (PE/EA=5:1, Rf=0.6) were combined and concentrated to yield a light yellow solid of 2-chloro-4-ethoxypyridine (13 g, 71.9 mmol, 57% yield): 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=5.2 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 6.73 (dd, J=2.0, 6.0 Hz, 1H), 4.09 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H); ES-LCMS m/z 158 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>>[C:25]([NH:1][C:2]1[C:3]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(NC(=O)c1ncccc1N)c1ccc(OCC(F)(F)F)nc1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)Nc1cccnc1C(=O)NC(C)c1ccc(OCC(F)(F)F)nc1
Yield: 52 %

Procedure:
The title compound is prepared in 52% yield (15 mg) from 3-amino-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)picolinamide (24 mg, 0.071 mmol, Step-1, single enantiomer) and isobutyryl chloride (23 mg, 0.21 mmol) by the similar manner in Step-2 of Example-8.
Reaction SMILES: C(C1C2OC(C)(C)CC=2C(C)=C(NC(=O)CC(C)(C)C)C=1C)=O.CC1C=CC=CC=1[Mg]Br.O[CH:34]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[CH3:62])[C:35]1[C:43]2[O:42][C:41]([CH3:45])([CH3:44])[CH2:40][C:39]=2[C:38]([CH3:46])=[C:37]([NH:47][C:48](=[O:54])[CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C:36]=1[CH3:55]>C(OCC)(=O)C.CCCCCC>[CH3:51][C:50]([CH3:53])([CH3:52])[CH2:49][C:48]([NH:47][C:37]1[C:36]([CH3:55])=[C:35]([CH2:34][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[CH3:62])[C:43]2[O:42][C:41]([CH3:44])([CH3:45])[CH2:40][C:39]=2[C:38]=1[CH3:46])=[O:54]
Reactant: Cc1ccccc1C(O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OC(C)(C)C2
Agent: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Agent: Cc1ccccc1[Mg]Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1Cc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OC(C)(C)C2
Yield: 24 %

Procedure:
Using N-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethyl-butanamide obtained in Example 340 and 2-methylphenylmagnesium bromide, N-(7-(hydroxy(2-methylphenyl)methyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide was synthesized in the same manner as in Example 239. Using the compound, the title compound was synthesized in the same manner as in Example 271. Yield: 24%. Melting point: 175-176° C. (ethyl acetate-hexane).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[CH:13][N:14]([CH3:16])C)[C:11]#[N:12].C([N:19](CC)CC)C.S(O)(O)(=O)=O.CNN>CCO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[N:12][N:14]([CH3:16])[C:13]=1[NH2:19]
Reactant: CCN(CC)CC
Reactant: CN(C)C=C(C#N)c1nc2ccccc2s1
Agent: CNN
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cn1ncc(-c2nc3ccccc3s2)c1N
Yield: 49 %

Procedure:
A mixture of the 2-benzothiazol-2-yl-3-dimethylaminoacrylonitrile prepared above (96 mg, 0.42 mmol) and triethylamine (0.3 mL) in EtOH (10 mL) was treated with methylhydrazine sulfate (180 mg, 1.25 mmol) and the mixture was heated to reflux for 2 days. The solution was concentrated in vacuo and the residue was purified by flash chromatography (hexanes:EtOAc=1:1) to yield 47 mg (49%) of the title compound as a yellow powder. MS (m/z, ES+): 231 (M+1, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37](=[O:68])[NH:38][CH:39]([C:43]([N:45]1[CH:51]([C:52]2[NH:53][C:54]([C:57]3[CH:66]=[CH:65][C:64]4[C:59](=[CH:60][CH:61]=[C:62](Br)[CH:63]=4)[CH:58]=3)=[CH:55][N:56]=2)[CH2:50][C:47]2([CH2:49][CH2:48]2)[CH2:46]1)=[O:44])[CH:40]([CH3:42])[CH3:41].C([O-])([O-])=O.[K+].[K+]>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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:62]3[CH:61]=[CH:60][C:59]4[C:64](=[CH:65][CH:66]=[C:57]([C:54]5[NH:53][C:52]([CH:51]6[CH2:50][C:47]7([CH2:48][CH2:49]7)[CH2:46][N:45]6[C:43](=[O:44])[CH:39]([NH:38][C:37]([O:36][CH3:35])=[O:68])[CH:40]([CH3:42])[CH3:41])=[N:56][CH:55]=5)[CH:58]=4)[CH:63]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)CC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(C#N)CN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Yield: 68.4 %

Procedure:
4-Cyano-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.990 g, 2.13 mmol), (1-{6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1.007 g, 1.92 mmol), Pd(PPh3)4 (222 mg, 0.192 mmol) and K2CO3 (2.0 M in H2O, 2.1 mL, 4.2 mmol) were combined in 1,2-dimethoxymethane. The mixture was degassed for 10 min with bubbling N2 then heated to reflux for 4 h then cooled. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine before being dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (EtOAc, then 2% MeOH/DCM, then 4% MeOH/DCM) to provide the title compound (1.028 g, 68%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.Br[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[CH3:23].C([O-])(=O)C.[K+].O>CN(C=O)C.[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>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([C:5]2[O:1][C:2]([C:6]3[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=3)=[CH:3][CH:4]=2)=[C:16]([CH3:23])[CH:17]=1)#[N:20]
Reactant: N#Cc1ccc(-c2ccco2)nc1
Reactant: Cc1cc(C#N)ccc1Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C#N)ccc1-c1ccc(-c2ccc(C#N)cn2)o1
Temperature: 120 °C
Yield: 40 %

Procedure:
Referring now to Scheme 6, a mixture of 1 (680 mg, 4 mmol), 4-bromo-3-methylbenzonitrile (784 mg, 4 mmol), tetrakis(triphenylphosphine)-palladium(0) (228 mg) and potassium acetate (981.5 mg, 10 mmol) in dry DMF (15 mL) was heated under nitrogen at 120° C. for 16 h. The reaction mixture then poured onto cold-water. The precipitate that formed was collected, dissolved in methylene chloride, and the solution was passed through celite to remove Pd. The solution was evaporated, the solid was filtered and purified to afford 28 (SiO2, hexanes/EtOAc, 1:1), yield 40%, mp 233–234° C. 1H nmr (DMSO-d6); δ 2.61 (s, 3H), 7.25 (d, J=3.6 Hz, 1H), 7.51 (d, J=3.6 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.82 (s, 1H). 8.03–8.07 (m, 2H), 8.36 (dd, J=8.1, 2.1 Hz, 1H), 9.02 (d, J=2.1 Hz, 1H). 13C nmr; δ 153.2, 152.7, 151.9, 150.2, 140.8, 135.6, 134.8, 132.5, 129.8, 127.3, 118.3, 117.0, 114.4, 110.2, 106.8, 21.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:14][CH:15]([CH3:22])[CH2:16][O:17][CH2:18]B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:16]([O:17][CH2:18][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)[CH:15]([CH3:22])[CH3:14]
Reactant: CC(C)COCB(O)O
Reactant: Clc1ccc(-c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)COCc1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 28.5 %

Procedure:
To a solution of 4-chlorobiphenyl (25 mg, 0.13 mmol) in 1,4-dioxane (1 ml) and water (100 μl) were added (2-methylpropoxy)methyl boronic acid (35 mg, 0.27 mmol), palladium (II) acetate (3.0 mg, 0.013 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (11 mg, 0.027 mmol), and cesium carbonate (130 mg, 0.40 mmol) at room temperature. The reaction mixture was stirred at 100° C. for 7 hours and 50 minutes under the nitrogen atmosphere. After the reaction mixture was cooled at room temperature, water was added to the mixture, followed by filtration using Celite. After the filtrate was extracted with ethyl acetate, the organic layer was washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was distilled off from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethylacetate=30:1) to obtain the title compound (9.0 mg, 0.037 mmol, 28%) as a colorless oil.
Reaction SMILES: [BrH:1].[CH2:2]([N:5]([CH2:20][CH2:21][CH3:22])[CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:19])[C:12]=2[N+:16]([O-])=O)[CH2:7]1)[CH2:3][CH3:4]>C(O)C.[Pd]>[BrH:1].[CH2:20]([N:5]([CH2:2][CH2:3][CH3:4])[CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:19])[C:12]=2[NH2:16])[CH2:7]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1CCc2c(ccc(O)c2[N+](=O)[O-])C1
Agent: [Pd]
Agent: Br
Solvent: CCO
Product: CCCN(CCC)C1CCc2c(ccc(O)c2N)C1

Procedure:
7 g of 2-dipropylamino-6-hydroxy-5-nitro-1,2,3,4-tetrahydronaphthalene hydrobromide are suspended in 250 ml of ethanol and hydrogenation is carried out at ambient temperature, in the presence of 1 g of 5% palladium-on-charcoal, under a pressure of about 0.3 MPa. The solvent is then evaporated off and the residue is triturated in diethyl ether. The product obtained melts at 215°-218° C. (with decomposition).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[CH:19]1([NH:25][C:26]2[C:31]([NH2:32])=[CH:30][N:29]=[C:28]3[CH:33]=[CH:34][S:35][C:27]=23)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1.C(O)C>[CH:19]1([N:25]2[C:26]3=[C:27]4[S:35][CH:34]=[CH:33][C:28]4=[N:29][CH:30]=[C:31]3[N:32]=[C:3]2[C@H:2]([OH:1])[CH3:6])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: C[C@@H](O)C(N)=O
Reactant: Nc1cnc2ccsc2c1NC1CCCCC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2 %

Procedure:
A mixture of (2R)-2-hydroxypropanamide (49 mg, 0.55 mmol) and triethyloxonium tetrafluoroborate (98 mg, 0.51 mmol) in tetrahydrofuran (0.75 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (0.32 mL) and added to a suspension of N7-cyclohexylthieno[3,2-b]pyridine-6,7-diamine (42 mg, 0.17 mmol) in ethanol (1.1 mL). The reaction mixture was stirred at 80° C. for 1 h. The solvent was removed, and the residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1 mg, 2%). LCMS calculated for C16H20N3OS (M+H)+: m/z=302.1. Found: 302.1.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([F:17])[CH:9]=2)=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:49]1[CH2:53][CH2:52][CH2:51][C@H:50]1[CH2:54][N:55]1[CH2:59][CH2:58][CH2:57][CH2:56]1>CN(C=O)C>[F:17][C:10]1[CH:9]=[C:8]([C:6]2[S:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:16]=[CH:15][C:11]=1[C:12]([N:49]1[CH2:53][CH2:52][CH2:51][CH:50]1[CH2:54][N:55]1[CH2:59][CH2:58][CH2:57][CH2:56]1)=[O:14]
Reactant: N#Cc1ccc(-c2ccc(C(=O)O)c(F)c2)s1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2ccc(C(=O)N3CCCC3CN3CCCC3)c(F)c2)s1
Yield: 9.2 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 6 mL DMF using 4-(5-Cyano-thiophen-2-yl)-2-fluoro-benzoic acid (248 mg, 1.0 mmol), EDC-HCl (287 mg, 1.5 mmol), HOBt (203 mg, 1.5 mmol), DIEA (0.43 mL, 2.5 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (131 mg, 0.85 mmol) to give the title compound (30 mg, 10% yield). MS (ES+) 384.2 (M+H)+
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].[CH2:15](I)[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([N:6]1[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]12)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CI
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Product: CC(C)Cn1c(=O)oc(=O)c2ccccc21

Procedure:
Reagents: Isatoic anhydride (6.13 mmols, 1 g); Sodium hydride (9.2 mmols, 0.22 g); isobutyl iodide (18 mmols, 3.4 g). Yield: 0.6 g (46%), white solid, m.p.=85° C.-86° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:9]([C@H:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:30])=[CH:7][C:5]=2[N:6]=1.[NH4+].[Cl-].[CH3:33][CH2:34][O:35][C:36](C)=[O:37]>CN(C=O)C.[Cu](I)I.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>[C:26]([O:25][C@@H:19]([C:9]1[C:8]([CH3:30])=[CH:7][C:5]2[N:6]=[C:2]([C:36]([O:35][CH2:34][CH3:33])=[O:37])[S:3][C:4]=2[C:10]=1[O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2cc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(OS(=O)(=O)C(F)(F)F)c2s1
Temperature: 45 °C
Reaction time: 2.5 h

Procedure:
To a a solution of (S)-ethyl 2-(2-bromo-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-tert-butoxyacetate (32) (1.07 g, 2.00 mmol) in DMF (10 mL) was added tributyl(1-ethoxyvinyl)starmane (867 mg, 2.40 mmol), copper iodide (38 mg, 0.20 mmol), and Pd(PPh3)4 (116 mg, 0.10 mmol). The reaction mixture was stirred at 45° C. for 2.5 h. A saturated solution of NH4Cl was added and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. Methanol and CH2Cl2 (1:1, 20 mL) added. The mixture was cooled to −78° C. and ozone (O3) was bubbled through the solution for about 15 min until the reaction mixture was blue-green. Dimethysulfide (1 mL) was added and the reaction was stirred at rt for 20 min. The mixture was concentrated in vacuo and purified by column chromatography (EtOAc/hexanes) to give 811 mg of 37.