Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[C:13]3[NH:20][CH:19]=[C:18]([C:21](O)=[O:22])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:3][CH2:2]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([NH:37][C:21]([C:18]2[C:14]3[N:15]=[CH:16][N:17]=[C:12]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:13]=3[NH:20][CH:19]=2)=[O:22])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C(O)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A78) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[C:26](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH:4]([OH:7])[CH2:5][O:6][C:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCCCCCCCCCCCCCCCCCN(C)CC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(C)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
50 mmol of 1a was treated for 12 hours with 60 mmol of trityl chloride and 120 mmol of triethylamine in 150 ml of boiling toluene. After conventional working up, the remaining oil was chromatographed (Flash chromatography, eluent chloroform) and gave 2a (yield 85%) m.p. 45° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15].FC(F)(F)S(O[CH2:22][CH2:23][O:24][C:25]([F:28])([F:27])[F:26])(=O)=O>CN(C=O)C>[CH3:15][O:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[O:3][CH2:22][CH2:23][O:24][C:25]([F:28])([F:27])[F:26])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCOC(F)(F)F)c(OC)c1
Reaction time: 0.17 h

Procedure:
To sodium hydride (200 mg, 5.0 mmol) in DMF (6 mL) under N2 was added methyl 4-hydroxy-3-methoxy-benzoate (920 mg, 5.0 mmol) and the mixture was stirred for 10 min. 2-(trifluoromethoxy)ethyl trifluoromethanesulfonate (1.2 g, 4.6 mmol) was then added dropwise and the solution was stirred at room temperature for 2 h, then at 50° C. for 2 h. The mixture was concentrated to a solid, and the residue was taken up in 50 mL of CH2Cl2 before it was washed with brine (20 mL), dried over MgSO4 and purified by column chromatography (0-25% EtOAc/hexane) to give methyl 3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoate as a white solid. ESI-MS m/z calc. 294.1, found 295.3 (M+1)+; Retention time: 1.63 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N+:5]([O-])=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.P(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12
Reactant: CC(C)Oc1cc(Cl)c2c([n+]1[O-])CCC2
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: CC(C)Oc1cc(Cl)c2c(n1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a solution of 4-chloro-2-isopropoxy-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (0.079 g, 0.35 mmol) in methylene chloride (5 mL) was added phosphorous trichloride (0.096 g, 0.70 mmol). The mixture stirred at rt for 30 min. After this time, the mixture was quenched with a saturated solution of NaHCO3 and extracted with methylene chloride. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.057 g, 77%) as a clear oil. MW=211.69. 1H NMR (CDCl3, 300 MHz) δ 6.47 (s, 1H), 5.27-5.18 (m, 1H), 3.01-2.84 (m, 4H), 2.11 (quin, J=7.5 Hz, 2H), 1.31 (d, J=6.0 Hz, 6H); APCI MS m/z 212 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(NCCO)c1cccc(Br)c1
Product: O=S(=O)(NCCO)c1cccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 3-bromo-N-(2-hydroxy-ethyl)-benzenesulfonamide (example B.34) (252 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (300 mg, 55%). MS (ISP) 537.3 [(M+H)+]; mp 113–115° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](NCC(OC(C)(C)C)=O)[CH:23]=2)=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37]([O:41]C(N[C@@H](CC1C=CC(OS(C(F)(F)F)(=O)=O)=CC=1)C(OCC)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH:37]=[O:41])[CH:23]=2)=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2cccc(NCC(=O)OC(C)(C)C)c2)cc1)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Product: CCOC(=O)[C@H](Cc1ccc(-c2cccc(C=O)c2)cc1)NC(=O)OC(C)(C)C
Yield: 61 %

Procedure:
In a manner similar to the preparation of ethyl (S)-2-tert-butoxycarbonylamino-3-[3′-(tert-butoxycarbonylmethylamino)biphenyl-4-yl]propionate (Example 1e), using 173 g (391 mmol) of ethyl (S)-2-tert-butoxycarbonylamino-3-(4-trifluoromethanesulfonyloxyphenyl)propionate and 82 g (547 mmol) of 3-boronic acid-benzaldehyde, 95.7 g of coupled product are isolated with a 61% yield.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[N:9][N:8]=1.C1COCC1.[NH3:30].C1COCC1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[C:7]([CH2:6][CH2:5][CH2:4][C:3]([NH2:30])=[O:2])=[N:8][N:9]=[C:10]2[C:19]1[S:20][CH:21]=[CH:22][N:23]=1
Reactant: N
Reactant: COC(=O)CCCc1nnc(-c2nccs2)c2cc(OC)ccc12
Solvent: C1CCOC1
Product: COc1ccc2c(CCCC(N)=O)nnc(-c3nccs3)c2c1
Temperature: 85 °C
Yield: 73.1 %

Procedure:
A suspension of 4-(6-methoxy-4-thiazol-2-yl-phthalazin-1-yl)-butyric acid methyl ester (1.2 g, 3.5 mmoles), prepared as described in example 115, in NH3/THF (10 ml) was added with THF (15 ml), then placed in autoclave at 85° C. After 1 night the mixture was dried, taken up in CH3OH (30 ml) and saturated with NH3 at 0° C., then heated at 85° C. for 44 hours. The mixture was cooled and dried to give a residue which was chromatographed (eluent: CH2Cl2/CH3OH 95:5 to 90:10). The solid was triturated in CH2Cl2 to give 840 mg of the title compound (yield: 73.1%)
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=C[CH:2]=1.[NH2:12][C:13]1[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][C:14]=1[C:22]([F:25])([F:24])[F:23].S([O-])([O-])(=O)=O.[Mg+2].[OH-].[Na+]>C1C=CC=CC=1.C(O)C>[CH2:1]([O:20][C:19]([C:17]1[CH:16]=[CH:15][C:14]([C:22]([F:23])([F:24])[F:25])=[C:13]([NH2:12])[CH:18]=1)=[O:21])[CH3:2]
Reactant: Nc1cc(C(=O)O)ccc1C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(C(F)(F)F)c(N)c1

Procedure:
To a solution containing 5.62 g. of anhydrous p-toluenesulfonic acid pre-dissolved in 100 ml. of anhydrous ethanol and 500 ml. of benzene is added 6.1 g. of 2-amino-α,α,α-trifluoro-p-toluic acid. The solution is refluxed under an extractor containing a thimble of anhydrous magnesium sulfate for 11 days with periodic replacement of the drying agent. The resultant solution is then cooled, neutralized with 2 N sodium hydroxide and the organic layer is separated, washed with 2 N sodium hydroxide, and then with brine. After drying the organic solution over anhydrous magnesium sulfate, the solvents are removed on a rotary evaporator and the resulting crystals are dried to yield 2-amino-α,α,α-trifluoro-p-toluic acid ethyl ester (4-trifluoromethylanthranilic acid ethyl ester), m.p. 38°-39° C.
Reaction SMILES: [C:1]1([C:17]([N:19]2[CH2:33][CH2:32][CH2:31][N:30](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH2:29][C:28]3[N:46]=[C:24]([CH:25]=[CH:26][CH:27]=3)[CH2:23][N:22](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH2:21][CH2:20]2)=[O:18])[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>>[C:1]1([C:17]([N:19]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][C:28]3[N:46]=[C:24]([CH:25]=[CH:26][CH:27]=3)[CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2C(=O)N1CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2cccc(n2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Product: O=C1c2ccccc2C(=O)c2c1cccc2C(=O)N1CCCNCc2cccc(n2)CNCC1
Yield: 79.8 %

Procedure:
The title compound was prepared following the procedures illustrated above in Example 78 using 6-(1-anthraquinonecarbonyl)-3,10-bis(2-nitrobenzenesulfonyl)-3,6,10,16-tetraazabicyclo[10.3.1]hexadeca-1(16),12,14-triene (1.02 g, 1.24 mmol), thiophenol (0.41 g, 3.72 mmol) and K2CO3 (1.7 g, 12.5 mmol). The crude material was purified by flash chromatography on a silica gel column using CH2Cl2 and then MeOH, 15:1 MeOH—NH4OH (30%) as eluents to give 0.45 g (80%) of the title compound as a pale yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH2:14])[CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH:14][C:15](=[O:17])[CH3:16])[CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH:3]=1
Reactant: COCCCC(N)c1cc(Br)ccn1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCCCC(NC(C)=O)c1cc(Br)ccn1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 32.0 g of 1-(4-bromopyridin-2-yl)-4-methoxybutylamine in 150 ml of glacial acetic acid is mixed with 37 ml of acetic anhydride. The reaction solution is stirred at 50° C. for 30 minutes and then diluted with ethyl acetate. It is basified with 2M sodium hydroxide solution, and the phases are separated. The aqueous phase is extracted with ethyl acetate (2×). The combined organic phases are evaporated. The title compound is obtained as a yellowish solid from the residue by flash chromatography (SiO2 60 F). Rf=0.38 (EtOAc-methanol 9:1); Rt=2.33 (Gradient I).
Reaction SMILES: [H-].[Li+].[F:3][C:4]([F:17])([F:16])[C:5]([C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[C:9]([Cl:15])[CH:8]=1)=[O:6].[CH3:18][O:19][C:20]([C:22]1[O:23][C:24]([C:28](=[O:30])[CH3:29])=[CH:25][C:26]=1[CH3:27])=[O:21].C(OC)(C)(C)C>C1COCC1.O>[CH3:18][O:19][C:20]([C:22]1[O:23][C:24]([C:28](=[O:30])[CH2:29][C:5]([OH:6])([C:7]2[CH:8]=[C:9]([Cl:15])[C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=2)[C:4]([F:3])([F:16])[F:17])=[CH:25][C:26]=1[CH3:27])=[O:21]
Reactant: O=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1oc(C(C)=O)cc1C
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1oc(C(=O)CC(O)(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C
Yield: 106.3 %

Procedure:
LiH (0.41 g) is added to a solution of 2,2,2-trifluoro-1-(3,4,5-trichloro-phenyl)-ethanone (6.76 g) and 5-acetyl-3-methyl-furan-2-carboxylic acid methyl ester (4.46 g) in THF (50 ml). After 3 hours at 60° C. methyl tert-butyl ether (MTBE, 20 ml) is added and the reaction mixture is poured into water (20 ml) at 0° C. The organic phase is extracted once with water and a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo to yield 11.9 g of 3-methyl-5-[4,4,4-trifluoro-3-hydroxy-3-(3,4,5-trichloro-phenyl)-butyryl]-furan-2-carboxylic acid methyl ester. The crude product is used without further purification. MS (HPLC/MS): 459 (MH+). Retention time: 2.01 min.
Reaction SMILES: C[O-].[Na+].CO.C([O:9][C@@H:10]1[C@@H:16]([CH2:17][O:18]C(=O)C)[O:15][C@H:13]([CH3:14])[CH:12]=[CH:11]1)(=O)C>CO>[CH3:14][C@H:13]1[O:15][C@H:16]([CH2:17][OH:18])[C@@H:10]([OH:9])[CH:11]=[CH:12]1
Reactant: CC(=O)OC[C@H]1O[C@H](C)C=C[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1C=C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium methoxide/methanol solution (28% w/w, 0.40 ml, 2.1 mmol) was added to a methanol (15 ml) solution of 5,7-di-O-acetyl-2,6-anhydro-1,3,4-trideoxy-D-arabino-hept-3-enitol (Synlett, 1996, 185; and Tetrahedron: Asymm., 2003, 14, 757) (1.56 g, 6.83 mmol) and the resulting mixture was stirred at room temperature for 3 hours. DOWEX 50WX8-200 was added to the reaction mixture to adjust its pH to 4 and then insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]2[C:10]([C:11](=[O:30])[C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[Cl-:33].OCC1N=C[NH2+]N=1>N1C=CC=CC=1.[Cu]>[Cl:33][C:2]1[N:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]2[C:10]([C:11](=[O:30])[C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Reactant: [Cl-]
Agent: [Cu]
Agent: OCC1=N[NH2+]C=N1
Solvent: c1ccncc1
Product: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Temperature: 145 °C
Yield: 19.8 %

Procedure:
A mixture of 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione (30 mg, 0.061 mmol), 3-(hydroxymethyl)-1H-1,2,4-triazol-1-ium chloride (18.15 mg, 0.183 mmol) and copper (11.64 mg, 0.183 mmol) in pyridine (1 mL) was heated at 145° C. for 2 hours, LCMS indicated no starting material remained. The reaction mixture was filtered and the clear solution purified by prep. HPLC to give 1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione as a colorless oil (5.4 mg, 19%). LCMS: m/e 447.02 (M+H)+, 1.52 min (method 9). 1H NMR (500 MHz, MeOD) δ ppm 2.80-3.06 (m, 2H) 3.67-3.99 (m, 5H) 4.75-5.08 (m, 2H) 7.32-7.67 (m, 3H) 7.72-7.83 (m, 1H) 7.94-8.18 (m, 2H) 8.32-8.42 (m, 1H) 8.51-8.67 (m, 1H) 8.84-8.95 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=1.O1CCOCC1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=4)[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COc1cccc(Br)n1
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cccc(Nc2cc3ccc(-c4cc(F)ccc4C)cc3cn2)n1
Reaction time: 0.17 h
Yield: 105.4 %

Procedure:
To 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (151.4 mg, 0.6001 mmol) and 2-bromo-6-methoxypyridine (110.0 uL, 0.8951 mmol) was added 1,4-dioxane (4.0 mL, 51 mmol). Nitrogen gas was bubbled through this mixture while stirring for 10 minutes, and then palladium (II) acetate (14.5 mg, 0.0646 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (57.1 mg, 0.0987 mmol), and cesium carbonate (397.6 mg, 1.220 mmol) were added. The reaction mixture was stirred in a sealed vial at 100° C. for 90 minutes. The reaction mixture was diluted with dichloromethane, filtered through celite, and evaporated in vacuo. The crude residue was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-80% ethyl acetate in dichloromethane) to yield 227.4 mg of the title compound as 80% pure material. 52.4 mg of this material was purified via reverse phase HPLC and lyophilized to yield 17.9 mg of 7-(5-fluoro-2-methylphenyl)-N-(6-methoxypyridin-2-yl)isoquinolin-3-amine. LCMS (ESI): RT (min)=5.057, M+H=360.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.11 (s, 1H), 8.58 (s, 1H), 7.97 (s, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.38 (q, J=6.3 Hz, 1H), 7.15 (t, J=8.5 Hz, 2H), 6.82 (d, J=7.8 Hz, 1H), 6.28 (d, J=7.8 Hz, 1H), 4.01 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.CO>O1CCCC1>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Br)cc1F
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc(F)c(Br)cc1F
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 2 g (8.44 mmol) of 4-bromo-2,5-difluorobenzoic acid (prepared according to the procedure of Ishikawa et al., Kogyo Kagaku Zasshi, pg 972-979, 1970) in 20 mL of tetrahydrofuran was added 40 mL of a 1M solution of borane-tetrahydrofuran complex. The solution was heated under reflux for 64 h, cooled to ambient temperature and 100 mL of methanol was added. The reaction was then heated for a further 2 h, cooled and concentrated in vacuo. Purification by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) afforded 1.6 g of 4-bromo-2,5-difluorobenzyl alcohol. To a solution of 1.3 g (5 6 mmol) of 4-bromo-2,5-difluorobenzyl alcohol in 20 mL of dichloromethane at 0° C. was added 2.27 g (6.7 mmol) of carbon tetrabromide and 1.8 g (6.7 mmol) of triphenylphosphine. The reaction was stirred for 2 h at this temperature, the solvent was removed in vacuo and the residue stirred with 100 mL of diethyl ether. The solution was filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) to afford 1.5 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=1[CH:18]=[O:19].[BH4-].[Na+]>CO.O.CCOC(C)=O>[OH:19][CH2:18][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[F:1])[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:7]=[CH:6]2
Reactant: CC(C)(C)OC(=O)n1ncc2cc(C=O)c(F)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)n1ncc2cc(CO)c(F)cc21
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A solution of tert-butyl 6-fluoro-5-formyl-1H-indazole-1-carboxylate (29E, 3.55 g, 13.4 mmol) in methanol (50.00 mL) was treated with NaBH4 (1.02 g, 26.9 mmol) at 0° C. and stirred for 1 h. The reaction mixture was diluted with water and EtOAc (500 mL). The organic layer was separated and washed with aq. HCl (1M, 200 mL), aq. NaOH (1M, 200 mL) brine (200 mL) dried (MgSO4), filtered, concentrated in vacuo and residue was purified using chromatography (SiO2, EtOAc/hexanes) to yield tert-butyl 5-(hydroxymethyl)-6-fluoro-1H-indazole-1-carboxylate (29F, 3.00 g; Yield=83.9%) as a colorless solid.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][C:26]#[N:27])[CH2:22][C:23]#[N:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(#N)C.F[B-](F)(F)F.[Li+].[OH-].[NH4+]>O>[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[CH:17]=[N:18][N:19]([CH:21]([CH2:22][C:23]#[N:24])[CH2:25][C:26]#[N:27])[CH:20]=2)=[N:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CC#N)c3)ncnc21
Agent: F[B-](F)(F)F
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: N#CCC(CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentanedinitrile (10.0 g, 0.0245 mol) was dissolved in ACN (200 mL, 3.83 mol) and water (20 g, 1.1 mol) at rt. To this lithium tetrafluoroborate (23.0 g, 0.245 mol) was added giving a cloudy solution. The reaction was heated to reflux and monitored by HPLC. After heating for 24 h the reaction was allowed to cool to rt and then cooled in an ice bath. To this, ammonium hydroxide (23 mL, 0.59 mol) was added slowly. The reaction was allowed to warm to rt. After stirring for 18 h the reaction was diluted with water and concentrated in vacuo to remove the ACN, giving a precipitate. The solids were collected, washed with water and dried to give the title compound as an off-white solid (6.2 gm, 91%), LC/MS (M+H)+: 278, 1H NMR (DMSO-d6) δ 8.9(s, 1H), 8.72(s, 1H), 8.43(s, 1H), 7.59(d, 1H), 6.92(d, 1H), 5.21(m, 1H), 3.25(m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][S:18][CH2:17][CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:27](Cl)(Cl)=[S:28]>C(Cl)(Cl)Cl>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:27]=[S:28])[C:14]([N:15]3[CH2:16][CH2:17][S:18][CH2:19][CH2:20]3)=[CH:13][C:5]=2[N:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1nc2cc(N3CCSCC3)c(N)cc2s1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1nc2cc(N3CCSCC3)c(N=C=S)cc2s1

Procedure:
To a mixture of 2 g of 6-amino-2-tert-butyl-5-[thiomorpholin-4-yl]benzothiazole and 2 g of anhydrous potassium carbonate in 150 ml of chloroform at 0° is added 0.6 ml of thiophosgene in 5 ml chloroform, under stirring. After 4 hours of stirring at ambient temperature the mixture is filtered. The filtrate is evaporated to a solid which is purified by silica gel column chromatography. The column is eluted with hexane/methylenechloride (1:1) to give 2-tert-butyl-6-isothiocyanato-5-[thiomorpholin-4-yl]benzothiazole, melting at 155°-159°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:13]=1[N+:26]([O-:28])=[O:27].Cl.[CH:30]1([CH:33]([NH2:36])[CH2:34][CH3:35])[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:36][CH:33]([CH:30]2[CH2:32][CH2:31]2)[CH2:34][CH3:35])[C:13]=1[N+:26]([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1c(-c2ccc(C(F)(F)F)cc2Cl)ccnc1OS(=O)(=O)C(F)(F)F
Reactant: CCC(N)C1CC1
Agent: Cl
Product: CCC(Nc1nccc(-c2ccc(C(F)(F)F)cc2Cl)c1[N+](=O)[O-])C1CC1
Yield: 99.7 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl-ester (0.62 g, 1.38 mmol), prepared substantially as described in Part C of Example 19a, and 1-cyclopropyl-propylamine HCl (0.37 g, 2.75 mmol) were treated substantially as described in Part C of Example 19a to produce 0.55 g (100%) of [4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine: MS (AP) m/z 399.8 [(M+H)+, 25].