Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][S-:11].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([S:11][CH3:10])[N:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CSc1cc(Cl)nc(C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.6 %

Procedure:
A mixture of 4,6-dichloro-2-methylpyrimidine (11.5 g, 70.6 mmol, Aldrich) and sodium methanethiolate (5.93 g, 85 mmol, Aldrich) in toluene (50 mL) was stirred at 25° C. for 24 h. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with brine, and dried over Na2SO4. The crude product was purified by recrystallization from hexane to give 4-chloro-2-methyl-6-(methylthio)pyrimidine (5.5 g, 31.5 mmol, 44.6% yield) as white crystals. 1H NMR (400 MHz, CDCl3) δ 7.01 (s, 1H); 2.64 (s, 3H); 2.56 (s, 3H). m/z (ESI, +ve ion) 175 (M+H)+.
Reaction SMILES: [Li+].[Cl-].[Li]OC(C)=O.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH:19]=[CH:20][C:21]3[CH:22]=[C:23]([CH:27]([OH:30])[CH:28]=[CH2:29])[CH:24]=[CH:25][CH:26]=3)=[N:16]2)=[CH:11][CH:10]=1.I[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]([CH2:48][CH3:49])[C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[O:40]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CN(C=O)C>[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH:19]=[CH:20][C:21]3[CH:22]=[C:23]([C:27](=[O:30])[CH2:28][CH2:29][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH:38]([CH2:48][CH3:49])[C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:47])[CH3:46])=[O:40])[CH:24]=[CH:25][CH:26]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: CCC(C(=O)OCC[Si](C)(C)C)c1ccccc1I
Reactant: C=CC(O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC(C(=O)OCC[Si](C)(C)C)c1ccccc1CCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a mixture of LiCl (3.26 g, 77 mmol), LiOAc (19.6 g, 192 mmol), n-Bu4NCl (42.7 g, 154 mmol), Pd (OAc)2 (0.52 g, 2.3 mmol) and the allyl alcohol of Example 80, Step 1 (24.7 g, 77 mmol) under N2 was added a solution of the aryl iodide of Step 2 (30.0 g, 77 mmol) in DMF (150 mL). The suspension was degassed and purged with N2, and was then stirred at 100° C. for 1 h. The dark red solution was then poured onto a mixture of ice (300 g) and saturated NaHCO3 (300 mL). The red syrup was extracted with EtOAc. Following filtration through celite, the organic phase was washed with H2O and saturated NaCl solution. After drying (MgSO4), the solvent was removed under vacuum and the residue was purified by flash chromatography. Elution was effected with 1:20 EtOAc:hexane, followed by 1:10 EtOAc:hexane to give 37.4 g of the title compound as a white solid, mp 109°-111° C.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]=[CH2:6].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]>C1COCC1.CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15]([OH:20])([CH2:6][CH2:5][CH:4]=[CH2:3])[C:16]([F:19])([F:17])[F:18]
Reactant: C=CCCBr
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a 300 mL oven dried 3 necked, round bottomed flask with a stirring bar, argon inlet, addition funnel and a reflux condenser was added magnesium (turnings, 3.03 g, 125 mmol) and dry THF (75 mL). To this well stirred mixture was added 4-bromo-1-butene (12.0 mL, 118.21 mmol) at such a rate as to maintain a gentle reflux. When the addition was complete, the mixture was aged 30 min then cooled to 0° C. in an ice bath. To this well stirred solution was added a solution of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (5.00 g, 22.36 mmol) in THF (35 mL), dropwise over 30 min. The cooling bath was allowed to expire and the mixture was stirred 20 h at ambient temperature. The reaction was diluted with EtOAc and 10% aqueous citric acid. This mixture was stirred for 4 h. The layers were separated and the organic phase was washed with aqueous NaHCO3 and brine. Drying (MgSO4), filtration, removal of the solvent in vacuo, and chromatography on 300 g of silica gel using 15% EtOAc in hexane as eluant gave 4.80 g of (+/-) 2-(2-amino-5-chlorophenyl)-1,1,1-trifluoro-5-hexen-2-ol as a yellow solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][OH:40])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH:32]5[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][OH:40])[CH2:34][CH2:33]5)=[CH:28][CH:27]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: Nc1ccc(C2CCN(CCO)CC2)cc1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCN(CCO)CC5)cc4)nn23)c1

Procedure:
The titled compound was prepared in analogous fashion as Example 522 using N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide, 2-[4-(4-amino-phenyl)-piperidin-1-yl]-ethanol and N-phenylbis(trifluoromethanesulphonimide) to give N-tert-butyl-3-(2-{4-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide as a orange lyophilate (150.9 mg, 82% yield). LCMS (E/I+) 549 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.27 (s, 1H), 9.04 (s, 1H), 8.58 (s, 1H), 8.33 (d, 1H, J=7.8 Hz), 7.87 (d, 1H, J=7.8 Hz), 7.72 (d, 2H, J=7.6 Hz), 7.60 (s, 1H), 7.21 (m, 3H), 7.0 (d, 1H, J=4.5 Hz), 3.78 (t, 2H, J=5 Hz), 3.61 (d, 2H, J=11 Hz), 3.38 (m, 1H), 3.18 (m, 2H), 3.12 (m, 2H), 2.76 (m, 1H), 1.97 (m, 4H), 1.11 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:31][C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[C:5]=1[N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:13])=[O:14])[CH2:31][C:27]1[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=1
Reactant: ClCc1cccnc1
Reactant: COC(=O)c1cccc(O)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(OCc2cccnc2)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.1 %

Procedure:
To a solution of 0.40 g (1.187 mmol) of the product of Example 31 dissolved in 5.0 mL of DMF was added 0.409 g (2.492 mmol) of 3-picolyl chloride hydrochloride and 1.03 g (7.477 mmol) of potassium carbonate. The reaction mixture was then stirred at room temperature for 18 h, diluted with water and extracted with ether. The organics were then extracted with 6N HCl solution and the aqueous acid layer was then basified with 6N NaOH solution and then extrrcted with ether. The resulting ether layer was dried over sodium sulfate, filtered and concentrated in vacuo to provide 0.34 g (55%) of the desired product as a brown oil. Electrospray Mass Spec: 520.2 (M+H)+
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH:14]=[C:15]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH2:19][O:18][C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]2=3)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].[ClH:33]>C(O)C.ClCCl>[ClH:33].[CH:30]1[C:16]2[C:15](=[CH:14][CH2:13][CH2:12][N:9]3[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH2:19][O:18][C:17]=2[CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1CCN(CCC=C2c3ccccc3OCOc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)C1CCN(CCC=C2c3ccccc3OCOc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 73 %

Procedure:
The above ester (2.30 g, 5.6 mmol) was dissolved in ethanol (30 ml), a 20% solution of sodium hydroxide (3.5 ml) was added and the mixture was stirred at room temperature for 7 h. The solution was diluted with dichloromethane (240 ml) and acidified with concentrated hydrochloric acid (3 ml). The mixture was washed with water (10 ml), the organic phase was dried over MgSO4 and evaporated in vacuo. The solid residue was washed with acetone, filtered off and dried in vacuo, affording the title compound (1.8 g, 73%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([Cl:19])=[CH:6][C:7]2[S:12](=[O:14])(=[O:13])[N:11]=[CH:10][N:9]([CH:15]3[CH2:17][CH2:16]3)[C:8]=2[CH:18]=1>C(O)(C)C>[Cl:3][C:4]1[C:5]([Cl:19])=[CH:6][C:7]2[S:12](=[O:14])(=[O:13])[NH:11][CH2:10][N:9]([CH:15]3[CH2:16][CH2:17]3)[C:8]=2[CH:18]=1
Reactant: O=S1(=O)N=CN(C2CC2)c2cc(Cl)c(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=S1(=O)NCN(C2CC2)c2cc(Cl)c(Cl)cc21
Temperature: 52.5 °C

Procedure:
Finely ground NaBH4 (1 g) is added to a solution of 6,7-dichloro-4-cyclopropyl-4H-1,2,4-benzothiadiazine 1,1-dioxide from the Step above (1.9 g) in isopropanol (50 mL) and then heated at 50-55° C. for 5-10 minutes. The solvent is removed by evaporation under reduced pressure. The residue is taken up in water (50 mL) and brought to acid pH by adding 6N HCl. The title product is extracted with dichloromethane (3×30 mL). The organic phase is dried over MgSO4 and filtered. The filtrate is evaporated to dryness and the residue obtained is recrystallised from methanol/water 1/1 (60 mL).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@H:6]([C:10]([NH:12][CH:13]([CH:21]([OH:44])[CH:22]([OH:43])[CH:23]([NH:31][C:32](=[O:42])[C@H:33]([CH:39]([CH3:41])[CH3:40])[NH:34][C:35](=[O:38])[CH2:36]Br)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[SH:45][C:46]1[NH:47][CH:48]=[CH:49][N:50]=1>>[NH:47]1[CH:48]=[CH:49][N:50]=[C:46]1[S:45][CH2:2][C:3]([NH:5][C@H:6]([C:10]([NH:12][CH:13]([CH:21]([OH:44])[CH:22]([OH:43])[CH:23]([NH:31][C:32](=[O:42])[C@H:33]([CH:39]([CH3:41])[CH3:40])[NH:34][C:35]([CH2:36][S:45][C:46]1[NH:47][CH:48]=[CH:49][N:50]=1)=[O:38])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: CC(C)[C@H](NC(=O)CBr)C(=O)NC(Cc1ccccc1)C(O)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)CBr)C(C)C
Reactant: Sc1ncc[nH]1
Product: CC(C)[C@H](NC(=O)CSc1ncc[nH]1)C(=O)NC(Cc1ccccc1)C(O)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)CSc1ncc[nH]1)C(C)C
Yield: 47.5 %

Procedure:
The resultant compound of Example 251 (150 mg, 0.2 mmol) was reacted with 2-mercaptoimidazole (40.6 mg) by the procedure described in Example 252 and similarly purified to afford the title compound (74 mg, 47%). 1H NMR (DMSO-d6, 300 MHz) δ 0.63 (m, 12H), 1.84 (m, 2H), 2.25-2.80 (m, 4H), 3.05-3.82 (m, 12H), 4.44 (m, 2H), 7.14 (m, 14H), 7.48 (bd, 2H), 8.07 (bd, 2H). MS (FAB) m/e 779 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:6]=[N:7][CH:8]=1.Cl>O1CCOCC1>[F:22][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1cncc(N2CCNCC2)c1

Procedure:
tert-Butyl 4-[5-(trifluoromethyl)pyridin-3-yl]piperazine-1-carboxylate (0.24 g, 0.25 mmol) was treated with a 4.0 M solution of HCl in 1,4-dioxane (7 mL) at room temperature for 1 h and concentrated. The residue was used for next step without further purification. MS calculated for C10H12F3N3: (M+H) 232; found 232.1.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]3([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:14]2)=[O:12])[CH:5]=1.O.[OH-].[Li+]>O1CCCC1>[Cl:28][C:24]1[CH:23]=[C:22]2[C:27]([C:19]([CH:15]3[CH2:16][CH2:17][CH2:18][N:13]([C:11]([NH:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:38])=[O:2])=[O:12])[CH2:14]3)([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)[C:20](=[O:29])[NH:21]2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1cccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of rac-3-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid methyl ester (50 mg, 0.090 mmol) (from Example 68 supra) in tetrahydro furan (2 mL) was added the suspension of lithium hydroxide monohydrate (38 mg, 0.9 mmol) (Aldrich). The mixture was stirred at room temperature for 2 days. The solvent was removed and the residue was partitioned between ethyl acetate and water. The aqueous layer was acidified to pH<5 with dilute HCl, then extracted with ethyl acetate several times. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The rsidue was triturated with Dichloromethane-Hexane to give rac-3-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid as a white solid. (Yield 40 mg, 81.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:17])[CH:13](Br)[CH2:14]Br)=[O:10])=[CH:4][CH:3]=1>C(O)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[CH2:14])[C:12](=[O:17])[NH:11][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(NC(=O)C(Br)CBr)Nc1ccc(Cl)cc1
Solvent: CC(C)(C)O
Product: C=C1C(=O)NC(=O)N1c1ccc(Cl)cc1

Procedure:
25.0 g of the N-(4-chlorophenyl)-N'-(2,3-dibromopropionyl)-urea obtained in accordance with Example 4(b) are heated under reflux for 1 hour with 26.0 g of potassium tert.-butylate (90%) in 250 ml of tert.-butanol. The solvent is then distilled off under normal pressure and the residue is heated in vacuo for 20 minutes to 120° C. The reaction product is taken up with 500 ml of water at 60° C, precipitated with dilute acetic acid, filtered and dried. Yield: 12.0 g, m.p: 185° - 187° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH2:28]([C@@H:30]1[CH2:34][O:33][C:32](=[O:35])[NH:31]1)[CH3:29].C(=O)([O-])[O-].[K+].[K+].CNCCNC.[Cl-].[NH4+]>[Cu]I.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:31]5[C@H:30]([CH2:28][CH3:29])[CH2:34][O:33][C:32]5=[O:35])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC[C@@H]1COC(=O)N1
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1
Yield: 81.9 %

Procedure:
To a mixture of [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (473 mg) described in Preparation Example 95, (R)-4-ethyloxazolidin-2-one (138 mg) described in Preparation Example 26, potassium carbonate (415 mg) and copper (I) iodide (38 mg) were added toluene (2 mL) and N,N′-dimethylethylenediamine (43 μL), and the mixture was heated under reflux for 3 hr. The reaction mixture was cooled, ethyl acetate and aqueous ammonium chloride solution were added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a 1:1 mixture of saturated aqueous ammonium chloride solution and ammonium water, washed once with saturated aqueous ammonium chloride solution, once with saturated aqueous sodium chloride solution, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (377 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f27) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.CN(C)C=O.S(Cl)([Cl:18])=O.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Cl:18])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: ClCCc1ccc(Cl)cc1
Temperature: 62.5 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
To a 4-L, jacketed glass reactor containing a solution of 2-(4-chlorophenyl)ethanol (Compound II) (591 g, 3774 mmol) dissolved in toluene (1250 mL) and N,N-dimethylformamide (41.4 g, 566 mmol) at 60° C. was charged thionyl chloride (302 mL, 4151 mmol) over 30 min. The addition was exothermic with significant gas evolution. The reaction mixture was stirred for 1.5 h at 60 to 65° C. Reaction conversion was monitored by HPLC and 1H NMR. When the amount of 2-(4-chlorophenyl)ethanol remaining was <1 area % by HPLC, the reaction mixture was cooled to 20 to 25° C. Water (1000 mL) was charged to the reactor and the mixture was stirred for 15 min. The aqueous layer was removed and the organic phase was washed twice with saturated sodium bicarbonate solution (1000 mL). Evaporation of the organic phase afforded the title compound as a colorless to yellow oil (641 g, 97% yield, 100 area % by HPLC). 1H NMR (400 Hz, CDCl3) δ 3.06 (t, J=7.2 Hz, 2H), 3.72 (t, J=7.2 Hz, 2H), 7.19 (d, J=10 Hz, 2H), 7.32 (d, J=10 Hz, 2H).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13](Br)[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[NH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:23]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([N:22]4[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24][CH2:23]4)[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Fc1cc(Br)c2nc(-c3nnc4ccccn34)ccc2c1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC1CCN(c2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 95 °C
Yield: 97 %

Procedure:
2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-bromo-6-fluoroquinoline (70 mg, 0.20 mmol), tert-butyl piperidin-4-ylmethylcarbamate (56.8 mg, 0.27 mmol), and Cs2CO3 (66 mg, 0.20 mmol) were weighed into a 5.0 mL reaction vial and suspended in 2.0 mL of anhydrous toluene. The solution was purged with Argon followed by addition of Pd2 dba3 (93.4 mg, 0.10 mmol), Binap-rac (12.7 mg, 0.020 mmol), then heated to 95° C. for 48 hours. The reaction was cooled to ambient temperature, followed by filtration through a celite plug to remove catalyst. The crude reaction was concentrated in vacuo and used without further purification (97 mg, 97% yield). MS APCI (+) m/z 477 (M+1) detected.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][O:26][C:27](=[O:30])[CH2:28]Br>CN(C)C=O>[CH3:25][O:26][C:27]([CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[CH:6][CH:7]=1)=[O:30]
Reactant: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(CC(=O)OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a suspension of 8.4 g (0.035 Mol) of benzyl 4-hydroxyphenylacetate and 4.8 g (0.035 Mol) of dried potassium carbonate in 100 ml of dimethylformamide are added slowly, after 45 minutes stirring at ambient temperature, 5.3 g (0.038 Mol) of methylbromoacetate and the mixture is then heated to 80° C. for 5 minutes whilst stirring continues. It is then stirred overnight at ambient temperature. The solid matter is filtered off and the mother liquor is evaporated to dryness under reduced pressure. The residue is purified over a silica gel column, using methylene chloride as eluant. Yield: 7.9 g amorphous solid (72.9% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]2[C:10]=1[C:9](=[O:11])[CH2:8][CH2:7]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]2[C:10]=1[C@@H:9]([OH:11])[CH2:8][CH2:7]2
Reactant: O=C1CCc2c(C3CCOCC3)ccc(F)c21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: O[C@H]1CCc2c(C3CCOCC3)ccc(F)c21

Procedure:
The title compound is prepared from 7-fluoro-4-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-inden-1-one following a procedure analogous to that described in Step 2 of Intermediate 1. Mass spectrum (ESI+): m/z=363 [M+Na]+.