Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:16])[C:5]2[CH2:6][CH:7]=[C:8](C)[CH:9]([CH3:14])[C:10]=2[C:11](=[O:13])[CH:12]=1.[K+].[Br-].[CH:19](Cl)(Cl)Cl>O=[Mn]=O>[CH3:1][O:2][C:3]1[C:4](=[O:16])[C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[C:9]([CH3:14])[CH:8]=[C:7]([CH3:19])[CH:6]=2
Reactant: COC1=CC(=O)C2=C(CC=C(C)C2C)C1=O
Reactant: ClC(Cl)Cl
Agent: O=[Mn]=O
Agent: [Br-]
Agent: [K+]
Product: COC1=CC(=O)c2c(C)cc(C)cc2C1=O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 5,8-dihydro-2-methoxy-5,6-dimethylnaphthalene-1,4-dione (4.00 g, 18.3 mmol) in CHCl3 (150 mL), there was added MnO2 (9.49 g, 110 mmol, Fluka). The stirred suspension was heated at reflux and monitored by 1H NMR (filtered aliquot through celite and removed solvent in vacuo). After 4.5 h, an additional portion of MnO2 (4.8 g, 55 mmol) was added and the reaction was allowed to reflux for an additional 3 h (7.5 h total). The reaction was allowed to stir overnight at rt and was filtered through Celite. The pad was washed with CHCl3 (3×30 mL). Solvent removal yielded a yellow powder (3.80 g, 95%, pure by TLC and 1H NMR); mp 146°-148° C.; 1H NMR (CDCl3) δ2.43 (s, 3H), 2.71 (s, 3H), 3.87 (s, 3H), 6.07 (s, 1H), 7.33 (s, 1H), 7.87 (s, 1H); IR (KBr) 3070 (w), 2982 (w), 2968 (w), 2946 (w), 2926 (w), 2850 (w), 1676 (s), 1646 (s), 1636 (s), 1619 (s), 1601 (s), 1247 (s), 1243 (s), 1236 (s), 1105 (s), 865 (m), 705 (m). Crystallization from EtOH yielded yellow needles (mp 147.5°-149° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11](=[O:31])[C@@H:10]([CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11](=[O:31])[C@@H:10]([CH2:32][C:33]([OH:35])=[O:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a round-bottomed flask with tert-butyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetate (0.057 g, 0.099 mmol; Example 21, Step D) in DCM (1 mL) was added TFA (1.129 g, 9.90 mmol) at 0° C. The ice-bath was removed and the mixture was stirred at rt for 3h. The solvent was removed. Purification by reversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 10 to 90% acetonitrile +0.1% TFA in water +0.1% TFA, gradient elution) provided the title compound as a white powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:21][C@@H:22]5[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]5)=[O:20])[CH:17]=4)[NH:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:21][C@@H:22]5[CH2:27][CH2:26][CH2:25][N:24]([CH2:34][C:29]6[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=6)[CH2:23]5)=[O:20])[CH:17]=4)[NH:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=Cc1ccccn1
Reactant: O=C(N[C@@H]1CCCNC1)c1ccc2[nH]nc(-c3ccc4c(c3)CCO4)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(N[C@@H]1CCCN(Cc2ccccn2)C1)c1ccc2[nH]nc(-c3ccc4c(c3)CCO4)c2c1
Reaction time: 0.25 h

Procedure:
In a flask, dichloromethane (1 mL) and acetic acid (2 drops) was added to (R)-3-(2,3-dihydrobenzofuran-5-yl)-N-(piperidin-3-yl)-1H-indazole-5-carboxamide (12 mg) and picolinaldehyde (7 mg). The reaction was stirred for 15 minutes. Sodium triacetoxyborohydride (28 mg) was added in one portion. The reaction was stirred overnight. The reaction was concentrated in vacuo and purified using prep LC/MS.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][N:67]=[CH:66][C:65]=1[O:70][CH3:71]>>[CH3:71][O:70][C:65]1[CH:66]=[N:67][CH:68]=[CH:69][C:64]=1[NH:63][C:30]([CH:20]1[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[CH:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:31]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cnccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cnccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 42.8 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.26 g, 0.45 mmol), was reacted with diisopropylethylamine (0.29 g, 2.2 mmol), diphenylphosphinic chloride (0.21 g, 0.9 mmol), then reacted with 4-amino-3-methoxypyridine (Tyger) (0.08 g, 0.67 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (3-methoxy-pyridin-4-yl)-amide as a light yellow solid (Yield 0.11 g, 41%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[CH3:5][C:6]1[CH:15]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)[C:13]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:12][C:7]=1[C:8](OC)=[O:9].O>CO>[NH2:3][C:2]([NH2:4])=[N:1][C:8](=[O:9])[C:7]1[CH:12]=[C:13]([S:21]([CH3:24])(=[O:23])=[O:22])[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[CH:15][C:6]=1[CH3:5]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(-n2cccc2)cc1C
Reactant: N=C(N)N
Solvent: O
Solvent: CO
Product: Cc1cc(-n2cccc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Yield: 66 %

Procedure:
A solution of 694 g of guanidine and 310 g of methyl 2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoate in 3 l of methanol is stirred for 3 h at 50°. Then, water is added to the reaction mixture, and the crude product which forms as a result is filtered off and recrystallized from methanol. This gives N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide in a yield of 66%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1O.P(Cl)(Cl)[Cl:13].C(N(CC)C1C=CC=CC=1)C>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[Cl:13]
Reactant: ClP(Cl)Cl
Reactant: O=[N+]([O-])c1cncc(Br)c1O
Solvent: CCN(CC)c1ccccc1
Product: O=[N+]([O-])c1cncc(Br)c1Cl
Reaction time: 2 h

Procedure:
3-bromo-5-nitropyridin-4-ol (49.8 g, 0.227 mol) prepared in Step 1 was slowly added at 0° C. to 200 ml of phosphorus trichloride. N,N-diethylaniline (34.65 ml, 0.227 mol) was slowly added thereto at the same temperature. The reaction mixture was refluxed under stirring for 2 hours and then concentrated under reduced pressure. The resulting residue was added to ice water and then extracted with 300 ml of ether. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give 32.4 g of the titled compound as a pale yellow solid. The product was used in the subsequent step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.C(O)C.[Cl:13][C:14]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:15]=1[CH2:16][N:17]=[C:18]=[O:19].O>C(=O)([O-])O.[Na+]>[CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:18]([NH:17][CH2:16][C:15]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:14]=3[Cl:13])=[O:19])[NH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Reactant: Nc1cc(C2CC2)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(NCc1ccc(Cl)cc1Cl)Nc1cc(C2CC2)n[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.7 %

Procedure:
1 g (8.13 mmol) of 3-cyclopropyl-5-amino-1H-pyrazole are dissolved in 10 ml of ethanol containing 1.37 g (16.26 mmol) of sodium hydrogen carbonate and 3.27 g (16.26 mmol) of 2,4-dichlorobenzyl isocyanate. After 3 hours at room temperature 50 ml of water were added and the solid was filtered. The filtrate was evaporated to dryness and then redissolved with 10 ml of methanol. 8.2 ml of 1M sodium hydrate were added and the mixture stirred 4 h at room temperature. Methanol is evaporated and the residue is dissolved with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1.5 g (60% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].CN(C)C=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:55][CH2:56][CH2:57][N:58]1[CH2:62][CH2:61][CH2:60][CH2:59]1>C(N(CC)CC)C>[N:58]1([CH2:57][CH2:56][NH:55][C:19]([C:15]2[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]3\[C:6](=[O:11])[NH:7][C:8]4[C:4]\3=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[NH:17][C:16]=2[CH3:18])=[O:21])[CH2:62][CH2:61][CH2:60][CH2:59]1
Reactant: NCCN1CCCC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 g) and dimethylformamide (500 mL) were stirred and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (221 g), 1-(2-aminoethyl)pyrrolidine (45.6 g) and triethylamine (93 mL) were added. The mixture was stirred for 2 hours at ambient temperature. The solid product was collected by vacuum filtration and washed with ethanol. The solids were slurry-washed by stirring in ethanol (500 mL) for one hour at 64° C. and cooled to room temperature. The solids were collected by vacuum filtration, washed with ethanol, and dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (101.5 g, 77% yield). 1H-NMR (dimethylsulfoxide-d6) δ 1.60 (m, 4H, 2×CH2), 2.40, 2-44 (2×s, 6H, 2×CH3), 2.50 (m, 4H, 2×CH2), 2.57, 3.35 (2×m, 4H, 2XCH2), 7.53, 7.70, 7.73, 7.76 (4×m, 4H, aromatic and vinyl), 10.88 (s, 1H, CONH), 13.67 (s, 1H, pyrrole NH). MS m/z 396 [M+].
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH3:16])[C:14](=[O:17])[CH:13]3[CH2:18][CH2:19][CH2:20][N:12]3[CH2:11][C:10]=2[CH:21]=1.Cl.[C:23](=O)([O-])[O-:24].[Na+].[Na+]>O.CO>[CH3:23][O:24][C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH3:16])[C:14](=[O:17])[CH:13]3[CH2:18][CH2:19][CH2:20][N:12]3[CH2:11][C:10]=2[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: CN1C(=O)C2CCCN2Cc2cc(N)ccc21
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CN1CCCC1C(=O)N2C
Reaction time: 1 h

Procedure:
A solution of 3.5 g. of sodium nitrite in 30 ml. of water is added over 1 hour at 48°-50°C. to a solution of 11.5 g. of 7-amino-1,2,3,5,10,11a-hexahydro-10-methyl-11H- pyrrolo[2,1-c] [1,4]benzodiazepin-11-one in 20 ml. of concentrated hydrochloric acid and 500 ml. of methanol. The reaction mixture is held at this temperature for 1 hour longer, diluted with an equal volume of water, neutralized with sodium carbonate and concentrated under reduced pressure to remove the methanol. The aqueous residue is extracted with benzene and the benzene layer is concentrated to remove the crude 1,2,3,5,10,11a-hexahydro-7-methoxy-10-methyl-11H- pyrrolo[2,1-c] [1,4]benzodiazepin-11-one. Further purification is by partition chromatography on a diatomaceous earth column using a heptane/methyl cellosolve solvent system.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[O:28][CH2:29][CH2:30]O>CN(C)C=O.O>[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[O:28][CH2:29][CH2:30][S:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: OCCOc1ccc2ccccc2c1
Reactant: CC(=O)c1ccc(S)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(SCCOc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
A stirred mixture of 1-(4-mercaptophenyl)ethanone (1.2 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.350 g), stirred for 15 minutes and treated with the mesylate of 2-(2-naphthyloxy)ethanol (2.2 g). The mixture was heated at 60° C. for 2 hours and diluted with water and filtered. The solids were dissolve in dichloromethane, washed once with water, dried (Na2SO4), filtered and evaporated. Crystallization from dichloromethane-hexane provided 2.0 g of 1-[4-[[2-(2naphthalenyloxy)ethyl]thio]phenyl]ethanone, mp 151°-152° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:49][O:50][CH:51]([O:54][CH3:55])[CH2:52][NH2:53]>CN(C=O)C>[CH3:49][O:50][CH:51]([O:54][CH3:55])[CH2:52][NH:53][C:13](=[O:15])[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])[CH3:16]
Reactant: COC(CN)OC
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(CNC(=O)C(C)(C)NC(=O)OCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-(benzyloxycarbonylamino)-2-methylpropanoic acid (20 g, 0.084 mol), HATU (CAN 148893-10-1, 41.56 g, 0.11 mol) and N-methylmorpholine (CAN 109-02-4, 25.54 g, 0.253 mol) in DMF (400 mL) was stirred at room temperature for 10 min. 2,2-Dimethoxyethanamine (CAN 22483-09-6, 9.75 g, 0.093 mol) was added and the mixture was stirred overnight. After evaporation of solvents, the residue was diluted with methylene chloride (500 mL) and saturated sodium bicarbonate solution (500 mL). After being separated, the organic layer was washed with 5 N citric acid solution (500 mL), brine (500 mL) and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure left a yellow oil (27 g, 99%) which was used in the next reaction step without further purification. 1H NMR (300 MHz, CDCl3): δ 7.36-7.33 (m, 5H), 6.44-6.38 (b, 1H), 5.31 (s, 1H), 5.09 (s, 2H), 4.34-4.33 (m, 1H), 3.40-3.37 (m, 8H), 2.06-2.03 (m, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li:10]CCCC.ClB(Cl)C1CCCC1.O>CCOCC>[S:1]1[C:5]([Li:10])=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: [Li]CCCC
Reactant: c1ccc2sccc2c1
Agent: ClB(Cl)C1CCCC1
Solvent: O
Solvent: CCOCC
Product: [Li]c1cc2ccccc2s1
Temperature: -90 °C

Procedure:
A dry 100 mL round-bottomed flask equipped with a mechanical stirrer, a reflux condenser, a low temperature thermometer and a silicone rubber septum was flushed with argon. 2-benzo[B]thienyllithium was prepared in situ from 1.1 g of benzo[B]thiophene (8.21 mmol) and 3.3 mL of 2.5 m solution of n-BuLi (in hexanes) in 20 mL of ether. The mixture was cooled to -90° C. and the solution of dichlorocyclopentylborane obtained in step 1 was added over 10 min while stirring was maintained. The mixture was brought to 20° C. and stirred for 2 h at this temperature. Distilled water (20 mL) was added with vigorous stirring. The top layer formed was separated and discarded. The aqueous layer was poured into 30 mL of saturated solution of NME4CL and shaken. The precipitate formed was filtered, washed with 60 ml of distilled water, and recrystallized from acetone/methanol=3/2 yielding 1.2 g (79%) of white crystalline solid. m.p. 234-236° C. 1H NMR (D6 -DMSO, 200 MHz) δ 7.69 (d, J=7.6 Hz, 3H), 7.57 (d, J=7.6 Hz, 3H), 7.14 (t, J=7.4 Hz, 3H), 7.07 (s, 3H), 7.04 (t, J=7.4 Hz, 3H), 3.04 (s, 12H), 1.85 (m, 2H), 1.65 (m, 1H), 1.37 (br s, 6H). 13C NMR (D6 -DMSO, 50 MHz) δ 141.9, 124.1, 122.5, 121.4, 120.9, 54.51 (t, J=4 HZ), 31.38, 27.34. 11B NMR (DMSO, 128 MHz) δ -30.36. Anal. Calcd. for C33H36BNS3 : C, 71.59; H, 6.55; N, 2.53; S, 17.37. Found: C, 71.50; H, 6.63; N, 2.53; S, 17.30.
Reaction SMILES: [CH3:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=1[I:23]>>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[C:2]=2[CH3:1])=[O:19])=[CH:16][C:15]=1[I:23]
Reactant: O=C(Cl)c1ccc(Cl)c(I)c1
Reactant: Cc1c(N)cccc1C(F)(F)F
Product: Cc1c(NC(=O)c2ccc(Cl)c(I)c2)cccc1C(F)(F)F

Procedure:
4-Chloro-3-iodo-N-(2-methyl-3-(trifluoromethyl)phenyl)benzamide was synthesized from 2-methyl-3-(trifluromethyl)aniline and 4-chloro-3-iodobenzoyl chloride according to the procedure dscribed in Example 183. 4-Chloro-3-iodo-N-(2-methyl-3-(trifluoromethyl)phenyl)benzamide was obtained as a white solid. MS (M−H+) 437.8; Calculated for C15H10ClF3INO: 439.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:12](OC)(OC)OC>CO.C1(C)C=CC=CC=1>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: COC(OC)OC
Reactant: O=C(O)Cc1cccc(Br)c1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cccc(Br)c1
Reaction time: 0.25 h
Yield: 100.8 %

Procedure:
A solution of (3-bromo-phenyl)-acetic acid (10.4 g, 48.5 mmol), in methanol (80 mL), was treated with trimethyl orthoformate (6.5 mL, 59.4 mmol). HCl gas was bubbled through the stirred solution for 10 minutes. The HCl addition was exothermic. After stirring for 15 minutes HPLC analysis of the solution showed complete conversion to product. After stirring for 16 hrs at ambient temperature the solution was diluted with toluene (100 mL) and concentrated under reduced pressure to afford a biphasic mixture. This liquid was diluted with toluene and concentrated under reduced pressure to afford (3-bromo-phenyl)-acetic acid methyl ester (11.2 g, quantitative yield) as a pale yellow liquid. 1H-NMR (400 MHz, CDCl3): δ 7.46-7.38 (2H, m), 7.23-7.18 (2H, m), 3.71 (3H, m), 3.60 (2H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([CH2:36][CH3:37])=[N:29][N:30]3[CH:33]([CH3:35])[CH3:34])=[CH:26][CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([CH2:36][CH3:37])=[N:29][N:30]3[CH:33]([CH3:34])[CH3:35])=[CH:26][CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:2]1[N:1]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCc1nn(C(C)C)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Reactant: O=C(O)Cc1ncccn1
Product: CCc1nn(C(C)C)c2cc(N3CCN(C(=O)Cc4ncccn4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 64 %

Procedure:
Prepared by the method outlined for Example 189 using 2-(pyrimidin-2-yl)acetic acid and 6-((S)-3-benzyl-piperazin-1-yl)-1-isopropyl-3-ethyl-1H-indazole as starting materials. Product was obtained as a colorless solid (64%). LC/MS (Method B) 3.7 min, [M+1]+ 483.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24](=[O:27])[CH2:25]Br)=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:34]([NH2:38])(=S)[CH2:35][CH3:36].C1COCC1>C(O)C>[NH2:38]/[C:34](/[CH2:35][CH3:36])=[CH:25]\[C:24]([C:6]1[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=2)[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)=[O:27]
Reactant: CCC(N)=S
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)CBr)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CC/C(N)=C/C(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 34.7 %

Procedure:
A mixture of 6-bromo-3-(2-bromoacetyl)-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one (300 mg), thiopropionamide (70 mg), THF (3 ml) and ethanol (3 ml) was stirred at 80° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-hexane:ethyl acetate=1:2) and recrystallized (ethyl acetate-hexane) to give the title compound (100 mg).
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[C:6]1([CH2:12][CH2:13][CH:14]([NH2:16])[CH3:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(C)C>[C:6]1([CH2:12][CH2:13][CH:14]([NH:16][CH2:1][CH:2]([OH:3])[CH2:4][OH:5])[CH3:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(N)CCc1ccccc1
Reactant: OCC1CO1
Solvent: CC(C)O
Product: CC(CCc1ccccc1)NCC(O)CO
Temperature: 70 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of glycidol (11.5 g, 0.155 mol) in isopropanol (25 ml) was added dropwise under N2 at 40° C. to a solution of 1-phenyl-3-butylamine in isopropanol (50 ml). After 1 hour, the solution was heated to 70° C. for 1.5 hours and then at room temperature overnight. The isopropanol was removed under reduced pressure and the residue distilled to yield 24 g (70%) of 94; b.p.0.2 140°-5° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(O[C:39]1(O[Si](C)(C)C)[CH2:41][CH2:40]1)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([CH:39]5[CH2:41][CH2:40]5)[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ncnn2c(C3CCN(C4CC4)C3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 29.2 %

Procedure:
(5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.244 mmol) was dissolved in methanol (3.5 mL). Acetic acid (140 uL, 2.44 mmol) was added followed by a small scoop of activated molecular sieves. [(1-ethoxycyclopropyl)oxy](trimethyl)silane (255 mg, 1.47 mmol) was added to the flask via syringe. Solid sodium cyanoborohydride was added (61 mg, 0.977 mmol) to the reaction which was then heated under nitrogen overnight. The mixture was partitioned between ethyl acetate (100 mL) and sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layer was washed with brine and then dried with sodium sulfate. The product was purified using column chromatography, eluent 2-3% (7N NH3 in Methanol)/dichloromethane to afford 32 mg (29%) of desired product. 1H NMR (300 MHz, dichloromethane-d2) δ 8.04 (s, 1 H), 7.89 (s, 1 H), 7.78-7.73 (m, 3 H), 7.60-7.40 (m, 4 H), 7.25 (d, 1 H), 6.63 (s, 1H), 5.62 (s, 2 H), 5.52 (bs, 2 H), 3.90 (m, 1H), 3.40 (m, 1H), 2.80 (m, 3 H), 2.40 (m, 1 H), 1.95 (m, 1 H), 1.75 (m, 1 H), 1.40-0.90 (m, 3 H); ES-MS m/z 450.2 [M+H]+, HPLC RT (min) 2.17.