Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH:12]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[CH:8]=[N:9][N:10]([S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[C:11]=2[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(Br)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)cc2c1cnn2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
Sodium hydride (1.289 g, 32.2 mmol) was added portion wise to a solution of methyl 6-bromo-1H-indazole-4-carboxylate (4.11 g, 16.11 mmol) in N,N-dimethylformamide (50 ml) at 0° C. The dark orange mixture was stirred at 0° C. for 10 mins, then treated with 4-methylbenzenesulfonyl chloride (3.38 g, 17.72 mmol). The resultant pale cream mixture was stirred for 30 mins at 0° C. then poured into water (1000 ml). The cream precipitate was filtered off under vacuum and dried in the vacuum oven at 50° C. for 18 h to give the title compound as a yellow solid (5.51 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:22][C:23]([F:37])([F:36])[CH2:24][C:25]1[S:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][CH:26]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[S:29][C:25]([CH2:24][C:23]([F:37])([F:22])[F:36])=[CH:26][N:27]=3)[CH2:31][CH2:32]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: FC(F)(F)Cc1cnc(N2CCNCC2)s1
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(CC(F)(F)F)s2)CC1)C(F)(F)F
Yield: 32 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-[5-(2,2,2-trifluoro-ethyl)-thiazol-2-yl]-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white crystalline solid (yield 32%). MS (m/e): 546.3 (M+H+, 100%).
Reaction SMILES: CS[CH2:3][C:4]1[NH:18][C:17]2[C:19]3[C:5]=1[CH2:6][C@@H:7]1[C:12]([C:13]=3[CH:14]=[CH:15][CH:16]=2)=[CH:11][C@H:10]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:9][N:8]1[CH2:28][CH2:29][CH3:30].[C:31](C(C(C([O-])=O)O)O)(O)=O>N1C=CC=CC=1>[CH2:25]([N:22]([CH2:23][CH3:24])[C:21]([NH:20][C@H:10]1[CH2:11][C@H:12]2[C@@H:7]([CH2:6][C:5]3[C:19]4[C:17](=[CH:16][CH:15]=[CH:14][C:13]2=4)[NH:18][C:4]=3[CH2:3][CH3:31])[N:8]([CH2:28][CH2:29][CH3:30])[CH2:9]1)=[O:27])[CH3:26]
Reactant: O=C([O-])C(O)C(O)C(=O)O
Reactant: CCCN1C[C@@H](NC(=O)N(CC)CC)C=C2c3cccc4[nH]c(CSC)c(c34)C[C@H]21
Solvent: c1ccncc1
Product: CCCN1C[C@@H](NC(=O)N(CC)CC)C[C@@H]2c3cccc4[nH]c(CC)c(c34)C[C@H]21

Procedure:
3-(9,10-didehydro-2-methylthiomethyl-6-n-propyl-8α-ergolinyl)-1,1-diethylurea, yield 50% as hydrogen tartrate, [α]D +169° (c=0.5 in pyridine).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[CH:13]=[C:14]3[CH2:20][CH2:19][CH2:18][CH2:17][C:15]3=2)[CH:10]=[C:9]1[CH2:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)([O-])[O-].[Cs+].[Cs+].BrC[C:37]([O:39][CH3:40])=[O:38]>C(Cl)Cl.O>[CH3:40][O:39][C:37](=[O:38])[CH2:22][O:21][C:12]1[CH:13]=[C:14]2[CH2:20][CH2:19][CH2:18][CH2:17][C:15]2=[C:16]2[C:11]=1[CH:10]=[C:9]([CH2:23][CH3:24])[N:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc2c(OC)cc3c(c2n1Cc1ccccc1)CCCC3
Reactant: COC(=O)CBr
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Product: CCc1cc2c(OCC(=O)OC)cc3c(c2n1Cc1ccccc1)CCCC3
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.4 %

Procedure:
A solution of 1-benzyl-2-ethyl-4-methoxy-6,7,8,9-tetrahydro-1H-benz[g]indole (660 mg, 2.07 mmol) in methylene chloride (10 mL) was cooled to 0° C. and treated with boron tribromide (0.38 mL, 4.0 mmol). The mixture was stirred for 10 min, poured into ice water, and extracted twice with methylene chloride. The combined methylene chloride layers were washed once with saturated sodium bicarbonate solution, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide (10 mL) and treated with cesium carbonate (652 mg, 2.00 mmol) and methyl bromoacetate (0.28 mL, 2.0 mmol) at room temperature for 3 h. The mixture was diluted with water and extracted three times with ether. The combined ether extracts were washed once with water, dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, methylene chloride) provided 479 mg (62%) of the title compound as an off-white solid. 1H NMR (CDCl3) δ 7.25 (m, 3H), 6.85 (d, J=7.6 Hz, 2H), 6.52 (s, 1H), 6.16 (s, 1H), 5.57 (s, 2H), 4.79 (s, 2H), 3.86 (s, 3H), 2.97 (m, 2H), 2.84 (m, 2H), 2.59 (q, J=7.3 Hz, 2H), 1.72 (m, 4H), 1.32 (t, J=7.3 Hz, 3H); MS ES+ m/e 378 (p+1); IR (CHCl3, cm1) 2830, 1756, 1732.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][N:16]=1)[C:12]#[N:13].[Br:17]N1C(=O)CCC1=O>C(#N)C>[NH2:8][C:9]1[CH:10]=[C:11]([C:14]([Br:17])=[CH:15][N:16]=1)[C:12]#[N:13]
Reactant: N#Cc1ccnc(N)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: N#Cc1cc(N)ncc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
In an aluminum foil-covered flask in a darkened hood, 2-amino-isonicotinonitrile TFA salt (125 mg, 0.54 mmol) was dissolved in acetonitrile (3.5 mL). Solid N-bromosuccinimide (89.2 mg, 0.501 mmol) was added to the stirred solution in one portion at RT. The reaction solution was stirred at room temperature in darkness for 90 minutes. After evaporation of the solvent, the crude material was further purified by silica gel chromatography to give 2-amino-5-bromo-isonicotinonitrile (53 mg, 49%). LC/MS (m/z): 197.9 (MH+), Rt 2.92 minutes.
Reaction SMILES: C(O[CH:4]=[CH:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[NH:8][CH:9]=[N:10]2)C.C(=O)(O)[O-:16].[Na+]>Cl>[N:14]1[C:6]([C:5](=[O:16])[CH3:4])=[C:7]2[C:11]([N:10]=[CH:9][NH:8]2)=[N:12][CH:13]=1
Reactant: O=C([O-])O
Reactant: CCOC=Cc1ncnc2nc[nH]c12
Agent: Cl
Agent: [Na+]
Product: CC(=O)c1ncnc2nc[nH]c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.04 g of 6-(ethoxyvinyl)purine was dissolved in 80 ml of 1 N hydrochloric acid and stirred at room temperature for 15 hours. After neutralizing with a saturated aqueous solution of sodium bicarbonate, it was extracted with dichloromethane and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, 0.70 g of crude title compound was obtained as a colorless oily substance.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH:6]([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:4].C([O-])([O-])=O.[Ca+2].[I:24]Cl>CO>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][CH:6]([CH3:16])[CH2:7][C:8]1[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][C:13]=1[I:24])=[O:4]
Reactant: COc1cccc(CC(C)NC(=O)C(F)(F)F)c1
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: COc1ccc(I)c(CC(C)NC(=O)C(F)(F)F)c1
Reaction time: 8 h
Yield: 110.6 %

Procedure:
A solution of N-trifluoroacetyl-1-(3-methoxyphenyl)-2-propylamine (4.29 g, 15.7 mmol) in methanol (100 mL) was cooled to −78 C and treated with CaCO3 (3.17 g, 31.4 mmol), followed by a solution of ICl (6.37 g, 39.3 mmol) in methanol (50 mL). The reaction was allowed to warm to 20 C while stirring overnight. The product mixture was filtered, concentrated, dissolved in EtOAc (200 mL), washed twice with 5% aqueous sodium bisulfite (100 mL), once with brine (100 mL), dried with Na2SO4 and concentrated to give 6.72 g of a white solid powder. MS calculated for C12H13F3INO2+H: 388, observed: 388.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[C:3]=1[CH3:21]
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(N3CCCC3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 22.6 h
Yield: 38.5 %

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.2 g, 0.65 mmol) in DMF (1.3 mL) was added pyrrolidine (0.046 g, 0.65 mmol) followed by potassium carbonate (0.180 g, 1.3 mmol). The reaction was stirred at 100° C. for 22.6 h. After which, the reaction mixture is cooled to rt and water was added. The crude reaction was extracted with EtOAc, dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-3-methyl-2-(6-(pyrrolidin-1-yl)pyridin-3-yl)quinoline (0.09 g, 0.250 mmol, 38.6% yield). Mass Spectrum (ESI) m/e=360.0 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[CH3:9][O:10][C:11]1[CH:32]=[CH:31][C:14]([C:15](Cl)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([O:6][CH2:5][CH:4]([OH:7])[CH2:3][N:2]([CH3:8])[CH3:1])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:14]2[CH:31]=[CH:32][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CN(C)CC(O)CO
Solvent: c1ccncc1
Product: COc1ccc(C(OCC(O)CN(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
3-Dimethylamino-1,2-propanediol (6.0 g, 50 mmol) was weighed into a 1 L round bottomed flask with a stir bar. The flask was sealed, flushed with argon, charged with pyridine and cooled to 0° C. 4,4′-Dimethoxytrityl chloride (17.9 g, 1.05 equiv.) was weighed into a 100 mL round bottomed flask, sealed and then dissolved in pyridine (80 mL). The 4,4′-dimethoxytrityl chloride solution was transferred to the stirring reaction mixture slowly, using additional fresh pyridine (20 mL) to effect the transfer of residual 4,4′-dimethoxytrityl chloride. The reaction was allowed to come to room temperature while stirring overnight. The reaction was concentrated in vacuo and re-dissolved in dichloromethane (300 mL). The organic phase was washed with saturated bicarbonate (2×200 mL) and brine (1×200 mL), dried over MgSO4, filtered, concentrated and dried under high vacuum to afford 22.19 g of a yellow gum that was used without further purification.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH:19]1([C:22]2[C:23]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[C:23]([N:29]3[CH2:34][CH2:33][N:32]([C:11]([C:10]4[CH:9]=[N:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:17][CH:16]=4)=[O:13])[CH2:31][CH2:30]3)=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=2)[CH2:20][CH2:21]1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3)CC2)c(C2CC2)c1
Yield: 45.9 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (300 mg) described in Preparation Example 25 and 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine (241 mg) described in Preparation Example 86 and by the reaction and treatment in the same manner as in Example 109, the title compound (225 mg) was obtained.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C:28]1([CH2:44][O:45][Si](C(C)(C)C)(C)C)[O:33][C:32]2[CH:34]=[CH:35][C:36]([N+:38]([O-:40])=[O:39])=[CH:37][C:31]=2[N:30]2[N:41]=[N:42][N:43]=[C:29]12)(C(C)(C)C)(C)C.CC(O)=O>C1COCC1>[N+:38]([C:36]1[CH:35]=[CH:34][C:32]2[O:33][C:28]([CH2:27][OH:26])([CH2:44][OH:45])[C:29]3[N:30]([N:41]=[N:42][N:43]=3)[C:31]=2[CH:37]=1)([O-:40])=[O:39]
Reactant: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)Oc2ccc([N+](=O)[O-])cc2-n2nnnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)-n1nnnc1C(CO)(CO)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
Tetra-butylammonium fluoride (1M solution in THF; 37.2 mL, 37.2 mmol) was added to a stirred solution of 4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)-8-nitro-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazine (6.3 g, 12.4 mmol) and AcOH (2.1 mL, 37.2 mmol) in THF (200 mL). The mixture was stirred at room temperature for 2 hr then concentrated under vacuum. The residue was partitioned between EtOAc (200 mL) and H2O (150 mL) and the organic layer was washed with brine (1×100 mL), dried (Na2SO4), filtered and the solvent removed under vacuum to leave a crude residue. The residue was dry-loaded on to silica gel then purified by column chromatography on silica gel using DCM/MeOH (1:0 to 92:8) as eluent to provide the desired compound (1.6 g). The desired compound was dissolved in EtOAc (150 mL) and washed with H2O (12×100 mL). The organic layer was dried (Na2SO4), filtered and the solvent removed under vacuum to leave the product (0.9 g) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14](/[N:18]=N/C4C=CC=CC=4)=[C:13]([NH2:26])[N:12]=3)=[N:9][N:8]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[C:5]2=[N:6][CH:7]=1.[H][H]>CN(C=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:26])[N:12]=3)=[N:9][N:8]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[C:5]2=[N:6][CH:7]=1
Reactant: [H][H]
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc(N)c1/N=N/c1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc(N)c1N
Reaction time: 8 h

Procedure:
39.23 g (85.75 mmol) of the compound from example 29A were initially charged in DMF (800 ml) and then 4 g of palladium (10% on charcoal) were added. Hydrogenation was effected at standard hydrogen pressure while stirring overnight. The mixture was filtered through kieselguhr, washed through with a little DMF and a little methanol and concentrated to dryness. The residue was admixed with ethyl acetate and stirred vigorously, and the precipitate was filtered off with suction, washed with ethyl acetate and diisopropyl ether and dried under a high vacuum over Sicapent.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([OH:15])=O)[CH2:8][CH2:7]1.[NH2:21][C@@H:22]([CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)=[O:24]>>[CH2:42]([O:41][CH2:40][C@H:22]([NH:21][C:13](=[O:15])[CH2:12][N:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]2[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:3]=2[Cl:2])[CH2:11][CH2:10]1)[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)=[O:24])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(O)CN1CCN(Cc2c(F)cccc2Cl)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCN(Cc2c(F)cccc2Cl)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 40.1 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(2-chloro-6-fluorobenzyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 239, (S)-3-(benzyloxy)-2-(2-(4-(2-chloro-6-fluorobenzyl)piperazin-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (20.8 mg, 40.1%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.93 (d, 1H), 7.60 (d, 2H), 7.37 (m, 2H), 7.29 (m, 5H), 7.21 (t, 3H), 7.04-6.98 (m, 4H), 4.68 (m, 1H), 4.51 (s, 2H), 3.77 (m, 1H), 3.70 (m, 1H), 3.60 (s, 2H), 2.96 (m, 2H), 2.51 (m, 8H). MS (EI) for C35H35ClF2N4O4. found 650.1 (MH+).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[N:8]=[CH:7][N:6]=1>C(O)C>[CH:17]1([N:14]2[CH2:15][CH2:16][N:11]([C:9]3[CH:10]=[C:5]([NH:2][NH2:3])[N:6]=[CH:7][N:8]=3)[CH2:12][CH2:13]2)[CH2:20][CH2:19][CH2:18]1
Reactant: NN
Reactant: Clc1cc(N2CCN(C3CCC3)CC2)ncn1
Solvent: CCO
Solvent: O
Product: NNc1cc(N2CCN(C3CCC3)CC2)ncn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
At RT, 4.4 ml (4.5 g, 89.7 mmol) of hydrazine hydrate are added dropwise with stirring to a solution of 1.9 g (7.5 mmol) of 4-chloro-6-(4-cyclobutylpiperazin-1-yl)pyrimidine in 28 ml of ethanol. The reaction solution is stirred at 80° C. for 16 h. For work-up, the mixture is concentrated under reduced pressure, the residue is triturated repeatedly with diethyl ether, and the precipitated solid is filtered off and dried under reduced pressure. The residue is then purified by column chromatography on silica gel (mobile phase dichloromethane/methanol 10/2). Yield: 1.5 g (80% of theory)
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:15][C:16]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:18]([C:17]3[CH:21]=[CH:22][C:23]([I:25])=[CH:24][C:16]=3[F:15])=[O:19])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(I)cc1F
Product: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3F)CC2)c(C)c1
Yield: 80.8 %

Procedure:
Using 1-(3,5-dimethylpyridin-2-yl)piperazine (1.44 g) described in Preparation Example 79 and 2-fluoro-4-iodobenzoic acid (2 g) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (2.67 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]=3[NH:8][C:9]=2[CH:10]=1.O[C@H:25]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]1>>[C:15]1([C:13]2[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]3[NH:8][C:9]4[CH:10]=[C:2]([O:1][C@@H:25]5[CH2:29][CH2:28][NH:27][CH2:26]5)[CH:3]=[CH:4][C:5]=4[C:6]=3[N:14]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(O)ccc12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Product: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(O[C@@H]3CCNC3)ccc12

Procedure:
This was similarly prepared from 7-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxamide and (5)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate. MS (ESI) m/z 373.1 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.28 (1H, d, J=8.85 Hz), 8.16 (1H, s), 8.11 (2H, d, J=7.02 Hz), 7.54 (2H, t, J=7.63 Hz), 7.44 (1H, t, J=7.32 Hz), 7.17 (1H, d, J=2.14 Hz), 6.92 (1H, dd, J=8.85, 2.14 Hz), 5.05-5.13 (1H, m), 3.14-3.23 (3H, m), 3.00 (1H, ddd, J=11.22, 8.32, 4.88 Hz), 2.16-2.27 (1H, m), 2.05-2.15 (1H, m).
Reaction SMILES: [CH3:1]NN.[CH:4]1([C:7]2[N:8](C)[N:9]=[C:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:11]=23)[CH2:6][CH2:5]1>CO>[CH:4]1([C:7]2[C:11]3[CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:10]=3[N:9]([CH3:1])[N:8]=2)[CH2:6][CH2:5]1
Reactant: CNN
Reactant: Cn1nc2c(c1C1CC1)CN(C(=O)OC(C)(C)C)CC2
Solvent: CO
Product: Cn1nc(C2CC2)c2c1CCN(C(=O)OC(C)(C)C)C2

Procedure:
To a solution of C28 (100 g, 0.374 mol) in methanol (1.2 L) was added methylhydrazine (40% solution in water, 47.4 g, 0.411 mol). The reaction mixture was heated at reflux for 2 hours, then concentrated to dryness. Purification via silica gel chromatography (Gradient: 5% to 9% ethyl acetate in petroleum ether) provided a mixture of product C49 and tert-butyl 3-cyclopropyl-2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (C50). LCMS m/z 278.0 [M+H]+. Separation via supercritical fluid chromatography (Column: Chiral Technologies, Chiralcel OJ-H, 5 um; Eluent: 97:3 carbon dioxide/methanol) afforded the product C49 as the second-eluting isomer, isolated as a solid. NOE studies supported the indicated regiochemical assignment. Yield: 33 g, 120 mmol, 32%. 1H NMR (400 MHz, CDCl3) δ 4.40 (br s, 2H), 3.65-3.73 (br m, 2H), 3.65 (s, 3H), 2.57-2.64 (m, 2H), 1.68-1.76 (m, 1H), 1.49 (s, 9H), 0.77-0.89 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].F[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1>>[CH3:17][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH:16]=1
Reactant: N#Cc1cccc(O)c1
Reactant: Cc1ccnc(F)c1
Product: Cc1ccnc(Oc2cccc(C#N)c2)c1

Procedure:
3-Hydroxy-benzonitrile was reacted with 2-fluoro-4-methylpyridine according to the method of Example 78A to provide the title compound. MS (DCI/NH3) m/z 211 (M+1)+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][CH:6]([CH2:10][CH3:11])[C:7](Cl)=[O:8].[C:12]1([S:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C(Cl)(Cl)Cl>[CH3:19][S:18][C:12]1[CH:17]=[CH:16][C:15]([C:7](=[O:8])[CH:6]([CH3:5])[CH2:10][CH3:11])=[CH:14][CH:13]=1
Reactant: CSc1ccccc1
Reactant: CCC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC(C)C(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of AlCl3 (35.4 g) in CHCl3 (500 mL) at -10° C. was added dropwise 2-methylbutyryl chloride (31.3 g) followed by thioanisole (31.2 mL). The mixture was then stirred at r.t. for 20 min. and was then cooled back to 0° C. Water (200 mL) was then added over 30 min. The CHCl3 layer was separated and dried over MgSO4. After filtration and removal of the solvent, the residue was dried under vacuum at 80° C. for 2 h to give 35 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16](B(O)O)[S:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:16]2[S:17][CH:18]=[C:14]([CH3:13])[CH:15]=2)=[N:3][N:4]=1
Reactant: Cc1csc(B(O)O)c1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1csc(-c2nnc(Cl)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1,4-Dichlorophthalazine (1.40 g, 7.03 mmol), 4-methylthiophen-2-ylboronic acid (999 mg, 7.03 mmol), and PdCI2(DPPF)(721 mg, 985 μmol) were added into a sealed tube. The tube was purged with Argon. Then sodium carbonate (2.0 M in water)(7.74 ml, 15.5 mmol) and 1,4-dioxane (35.2 ml, 7.03 mmol) were added. The tube was sealed, stirred at rt for 5 min, and placed in a preheated oil bath at 110° C. After 1 h, LC-MS showed product and byproduct (double coupling), and SM dichlorophthalazine. The reaction was cooled to rt, filtered through a pad of celite with an aid of EtOAc, concentrated, and loaded onto column. The product was purified by column chromatography using Hex to remove the top spot, then 80:20 Hex:EtOAc to collect the product. The product, 1-chloro-4-(4-methylthiophen-2-yl)phthalazine was obtained as yellow solid. LC-MS showed that the product was contaminated with a small amount of SM dichlorophthalazine and biscoupling byproduct. MS m/z=261 [M+1]+. Calcd for C13H9ClN2S: 260.12.