Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:18])=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]([CH3:16])[CH:12]=[C:11]([CH3:17])[CH:10]=2)=O)C.C1(C)C=CC=CC=1.CO.[K].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:18][C:7]1[C:6]([CH2:4][OH:3])=[CH:15][C:14]2[C:9](=[CH:10][C:11]([CH3:17])=[CH:12][C:13]=2[CH3:16])[N:8]=1
Reactant: CCOC(=O)c1cc2c(C)cc(C)cc2nc1C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(C)c2cc(CO)c(C)nc2c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2,5,7-trimethylquinoline-3-carboxylic acid ethyl ester (50 mg, 0.206 mmol) in DCM (1.7 ml) at −78° C. was added DIBAI-H 1M in Toluene (29.2 mg, 0.206 mmol). Reaction mixture was stirred 1 h at −78° C. Methanol (1 ml) was added to quench the reaction at −78° C. Mixture was then warmed up to 23° C. Sat. potassium/sodium tartrate solution (Rochelle's salt, 2 ml) was added and mixture was stirred 30 min at RT. Solid was filtered off and filtrate was extracted twice with DCM. Combined organic layer was washed with sat. NaHCO3 solution, brine, dried over sodium sulfate, filtered and evaporated to afford the title compound. HPLC (Method G) Rt=1.113 min, MS (Method V) [M+H]+=202.1
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8](N)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].[Cl-].[Cl:14][C:15]1[CH:31]=[CH:30][C:18]([C:19]([NH:21]C2C=CC(I)=C(C)C=2)=[O:20])=[CH:17][N:16]=1>>[Cl:14][C:15]1[CH:31]=[CH:30][C:18]([C:19]([NH:21][C:9]2[CH:10]=[C:11]3[C:6]([CH:5]=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:7][CH:8]=2)=[O:20])=[CH:17][N:16]=1
Reactant: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Reactant: CCn1ccc2cc(N)ccc21
Agent: [Cl-]
Product: CCn1ccc2ccc(NC(=O)c3ccc(Cl)nc3)cc21

Procedure:
6-Chloro-N-(1-ethyl-1H-indol-6-yl)-nicotinamide was prepared from 1-ethyl-1H-indol-5-ylamine (prepared as described in J. Med. Chem. 2007, 5509), and 6-chloronicotincyl chloride in a procedure similar to the one described in the synthesis of 6-chloro-N-(4-Iodo-3-methyl-phenyl)-nicotinamide, above. LCMS calcd for C16H14ClN3O (m/e) 299, obsd 300 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2].[NH2:22][NH2:23]>CCO>[C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:22][NH2:23])=[O:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2ccc(C#N)cc2)CC1
Solvent: CCO
Product: N#Cc1ccc(CN2CCN(CC(=O)NN)CC2)cc1
Yield: 67.1 %

Procedure:
Synthesized according to General Procedure C: 51d (2.71 g, 9.43 mmol, 1.0 equiv.), anhydrous hydrazine (1.18 mL, 37.7 mmol, 4.0 equiv.), EtOH (19 mL, 0.5 M). 46d (1.73 g, 67.1%) was obtained as an off-white solid after extraction without further purification. 1H-NMR (500 MHz, CDCl3) δ 8.10 (br s, 1H), 7.60 (d, 2H, J=8.0 Hz), 7.43 (d, 2H, J=8.5 Hz), 3.84 (br d, 2H, J=5.0 Hz), 3.55 (s, 2H), 3.08 (s, 2H), 2.55 (br s, 4H), 2.46 (br s, 4H). 13C-NMR (125 MHz, CDCl3) δ 170.6, 144.1, 132.4, 129.6, 119.1, 111.2, 62.5, 60.8, 53.8, 53.3. HRMS (ESI): 274.1673 (M+1); calcd. for C14H20N5O: 274.1668.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[C@@H:6]([OH:9])[CH:5]([O:10][CH3:11])[O:4]1.O.[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1>CC(C)=O.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:11][O:10][CH:5]1[O:4][C@H:3]2[C@H:7]([O:8][C:13]([CH3:18])([CH3:14])[O:1][CH2:2]2)[C@H:6]1[OH:9]
Reactant: COC1O[C@H](CO)[C@H](O)[C@H]1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: COC1O[C@@H]2COC(C)(C)O[C@@H]2[C@H]1O
Reaction time: 60 h
Yield: 5030.4 %

Procedure:
Compound 35.2 (120.45 g, 734 mmol) was dissolved in 1.5 L acetone, treated with p-toluene sulfonic acid monohydrate (0.6 g, 3.15 mmol) and CuSO4 (225 g, 1.41 mol). The mixture was stirred for 60 h. The solid was removed by filtration and washed with (3×200 mL) acetone. The filtrate and the washings were combined and neutralized with 2.5 mL concentrated ammonium hydroxide. The solvent was removed by reduced pressure and the residue was dissolved in 750 mL CH2Cl2 and washed with 3'100 mL water. The water extracts were combined and extracted with 3×100 mL CH2Cl2. The CH2Cl2 extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 0-3% MeOH in CH2Cl2 to give compound 35.3 (32.36 g, 21.6% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([Cl:34])[C:13]([N:20]3[CH2:24][CH2:23][C@H:22]([N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:26])[CH2:21]3)=[C:14]([F:19])[CH:15]=2)[N:10]([CH:35]2[CH2:37][CH2:36]2)[C:9]1=[O:38])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:43]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:39])[N:7]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([Cl:34])[C:13]([N:20]3[CH2:24][CH2:23][C@H:22]([N:25]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH3:26])[CH2:21]3)=[C:14]([F:19])[CH:15]=2)[N:10]([CH:35]2[CH2:36][CH2:37]2)[C:9]1=[O:38])[CH3:43])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(c2c(F)cc3c(=O)n(NC(=O)OC(C)(C)C)c(=O)n(C4CC4)c3c2Cl)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCN(c2c(F)cc3c(=O)n(N(C)C(=O)OC(C)(C)C)c(=O)n(C4CC4)c3c2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of {7-[(S)-3-(tert-butoxycarbonyl-N-methylamino)-pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid tert-butyl ester from Example 8 (0.238 g, 0.421 mmol) in N,N-dimethylformamide (5 mL) at −78° C. under nitrogen atmosphere is added sodium hydride (60% dispersion in mineral oil, 0.025 g, 0.631 mmol). After 30 minutes, iodomethane (0.052 mL, 0.842 mmol) is added, and the reaction mixture is warmed to room temperature. After 1 hour, the reaction mixture is diluted with ethyl acetate and washed with saturated ammonium chloride solution, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate concentrated. The resulting residue is purified by flash column chromatography (1:1 ethyl acetate/hexanes) to afford the title compound (0.118 g). 1H NMR (CDCl3): δ 7.63 (dd, 1H), 4.78 (bs, 1H), 3.87-3.45 (m, 6H), 2.62-2.44 (m, 6H), 2.31-2.12 (m, 2H), 1.49-1.47 (m, 18H), 1.23-1.07 (m, 2H), 0.75-0.53 (m, 2H). MS CI: m/z 582 (MH+).
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>ClCCl.O1CCCC1.C(OCC)(=O)C>[Si:14]([O:7][CH:3]1[CH2:4][CH2:5][CH2:6][CH:1]([OH:8])[CH2:2]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCCC(O)C1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCCC(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a solution of 1,3-cyclohexanediol (cis and trans mixture, 25 g) and imidazole (8.8 g) in a mixture of dichloromethane (150 ml) and tetrahydrofuran (150 ml) was added dropwise a solution of tert-butyldimethylsilyl chloride (16.2 g) in a mixture of dichloromethane (40 ml) and tetrahydrofuran (40 ml) at 0° C. A reaction mixture was allowed to warm to ambient temperature and stirred overnight. Insoluble material was removed by filtration and mother liquor was concentrated under reduced pressure to give residue, which was dissolved in ethyl acetate (300 ml) and washed in turn with 1N-aqueous hydrochloric acid (100 ml), brine (100 ml), saturated sodium hydrogen carbonate in water (100 ml), and saturated sodium chloride in water, and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (500 ml) eluting in turn with 10% and 20% ethyl acetate in n-hexane to give 3-(tert-butyldimethylsilyl)oxy-1-cyclohexanol (cis and trans mixture) (12.52 g).
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)[N:9]=[N:8][N:7]=1)(=O)C.[Li+].[OH-]>CCO.O>[OH:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)[N:9]=[N:8][N:7]=1
Reactant: CC(=O)OCc1nnnn1-c1ccc(C#N)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(-n2nnnc2CO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[4-cyano-3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl acetate (Intermediate 22, 45 g) in EtOH and water (2:1) was added LiOH (8.21 g, 0.342 mol) at 0° C. The reaction was stirred for 3 hours at room temperature. The solvent was removed under vacuum and the residue diluted with DCM, washed with ice-water, saturated aqueous NaHCO3 and brine. The solution was dried over anhydrous Na2SO4 and the solvent removed under vacuum. The crude product was purified by triturating with ether (500 mL) to yield 4-[5-(hydroxymethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile as a viscous oil (30 g).
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10]Cl)[N:6]=1)[C:2]([CH3:4])=[O:3].[CH3:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(Cl)(Cl)Cl.CO>CN(C=O)C>[CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:12])[N:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CNCc1ccccc1
Reactant: CC(=O)Cc1nc(CCl)no1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Cc1nc(CN(C)Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
A mixture of 800 mg of 5-acetonyl-3-chloromethyl-1,2,4-oxadiazole, 720 mg of N-methylbenzylamine and 1.0 g of triethylamine in 5 ml of DMF was stirred at room temperature for 8 hours. The reaction mixture was then poured into ice-water and the resultant mixture was extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo to yield a brown oil. Chromatography on silica gel using chloroform-methanol (20:1, v/v) as eluent afforded 780 mg of 5-acetonyl-3-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazole as a colorless oil, IR νmaxneat cm-1 : 1730, 1635, 1580, 1545, 1450, 1360.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13]2.CO.[BH4-].[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C(OCC)(=O)C.O>[NH:15]1[C:16]2[C:12](=[CH:11][C:10]([NH:9][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:18][CH:17]=2)[CH:13]=[N:14]1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.4 %

Procedure:
1-Methyl-4-piperidone (300 mg) was dissolved in titanium tetraisopropoxide (1.5 g). 5-Aminoindazole (282 mg) was added to the solution, and the mixture was stirred at room temperature for 18 hr. Methanol and sodium borohydride (50 mg) were added to the reaction solution, and the mixture was stirred for 18 hr. The reaction solution was diluted with ethyl acetate, and a minor amount of water was added thereto, and the mixture was then filtered under the reduced pressure. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel [chloroform/methanol] to give the title compound (202 mg, yield 41.4%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11]O)[N:10]=[C:4]2[CH:3]=1.S(Cl)([Cl:15])=O.O.C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11][Cl:15])[N:10]=[C:4]2[CH:3]=1
Reactant: OCc1cn2ccc(Br)cc2n1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: ClCc1cn2ccc(Br)cc2n1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a solution of 110 mg (0.48 mmol) of (7-bromoimidazo[1,2-a]pyrid-2yl)methanol, prepared according to the protocol described in step 8.2, in 8 mL of anhydrous dichloromethane, stirred at room temperature under an inert atmosphere, is added 0.03 mL (0.53 mmol) of thionyl chloride. The reaction mixture is stirred at room temperature for 4 hours, hydrolysed at 0° C. by successive addition of 3 mL of cold water and 5 mL of saturated aqueous NaHCO3 solution and then extracted with three times 10 mL of dichloromethane. The combined organic phases are dried over sodium sulfate and then concentrated under reduced pressure. 80 mg of the expected product are obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[C:9](F)=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:13]=1.CN(C)C(=O)C.[CH3:32][C:33]1[N:34]=[CH:35][C:36]([NH:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[C:47]([OH:50])[CH:48]=3)[N:43]=[CH:42][N:41]=2)=[N:37][CH:38]=1>O>[Cl:7][C:8]1[C:9]([O:50][C:47]2[CH:48]=[C:49]3[C:44](=[CH:45][CH:46]=2)[N:43]=[CH:42][N:41]=[C:40]3[NH:39][C:36]2[CH:35]=[N:34][C:33]([CH3:32])=[CH:38][N:37]=2)=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:13]=1
Reactant: Fc1ncc(OCCCOC2CCCCO2)cc1Cl
Reactant: Cc1cnc(Nc2ncnc3ccc(O)cc23)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cnc(Nc2ncnc3ccc(Oc4ncc(OCCCOC5CCCCO5)cc4Cl)cc23)cn1
Temperature: 180 °C
Reaction time: 14 h
Yield: 70.7 %

Procedure:
Potassium tert-butoxide (0.89 g, 7.90 mmol) and 3-chloro-2-fluoro-5-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]pyridine (2.52 g, 8.69 mmol) were added to an N,N-dimethylacetamide solution (2.5 ml) of 4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-ol (1.0 g, 3.95 mmol), and stirred at 180° C. for 14 hours under a nitrogen atmosphere in a sealed tube. The reaction solution was cooled with ice, water was added, and extracted with chloroform/methanol (10:1). The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Moritex NH, hexane:ethyl acetate=3:1 to 3:2) to obtain 6-({3-chloro-5-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]pyridin-2-yl}oxy)-N-(5-methylpyrazin-2-yl)quinazoline-4-amine (1.46 g, yield: 71%) as an orange oil.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[CH:7][C:8]=1[C:9]([OH:11])=[O:10])=[O:2].S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O.[N+:26]([O-])([OH:28])=[O:27]>>[CH:1]([NH:3][C:4]1[S:5][C:6]([N+:26]([O-:28])=[O:27])=[CH:7][C:8]=1[C:9]([OH:11])=[O:10])=[O:2]
Reactant: O=CNc1sccc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=CNc1sc([N+](=O)[O-])cc1C(=O)O
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
51.3 parts of 2-formylaminothiophene-3-carboxylic acid are added to 500 parts of sulphuric acid (sp.gr. 1.84) at a temperature below 10°C, and 56.7 parts of a nitrating mixture (obtained by mixing together 633 parts of 20% oleum and 348 parts of nitric acid of sp.gr. 1.50) are then slowly added, the temperature of the mixture being maintained at -10° to -5°C by external cooling. The mixture is stirred for 5 minutes at -5°C, poured into an ice/water mixture and the precipitated 2-formylamino-5-nitrothiophene-3-carboxylic acid (90% yield) is filtered off, washed with water and dried.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]2[CH2:12][N:13]([CH:16]([C:18]3[CH:19]=[N:20][C:21]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[C:22]([CH3:24])[CH:23]=3)[CH3:17])[C:14](=[O:15])[C:10]=2[CH:9]=[CH:8][N:7]=1)=[O:4].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CN(C=O)C>[CH3:24][C:22]1[CH:23]=[C:18]([CH:16]([N:13]2[C:14](=[O:15])[C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[C:11]=3[CH2:12]2)[CH3:17])[CH:19]=[N:20][C:21]=1[O:25][CH2:26][C:27]([F:28])([F:30])[F:29]
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3NC(=O)CCl)C2=O)cnc1OCC(F)(F)F
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Cc1cc(C(C)N2Cc3c(ccnc3NC(=O)CN3CCOCC3)C2=O)cnc1OCC(F)(F)F
Temperature: 60 °C
Yield: 38.4 %

Procedure:
A mixture of 2-chloro-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (25 mg, 0.056 mmol, Step-1, single enantiomer), and morpholine (15 mg, 0.17 mmol) in DMF (1.0 mL) is heated at 60° C. for 3 hours. The reaction mixture is concentrated. The residue is purified by preparative LC-MS to give 10.6 mg (38% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([C:12]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:19]([F:30])[C:15]2[N:16]=[CH:17][NH:18][C:14]=2[CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>>[CH2:1]([O:8][CH2:9][C:10]([C:12]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:19]([F:30])[C:15]2[N:16]=[CH:17][NH:18][C:14]=2[CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(COCc1ccccc1)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: O=C(COCc1ccccc1)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl

Procedure:
The title compound is prepared from 2-benzyloxy-1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-ethanol 10r by the procedure described in Example 42, Step B except that the reaction mixture is not treated with saturated aqueous NaHCO3 containing sodium thiosulfate pentahydrate: MS APCI (+) m/z 488, 490 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.02 (s, 1H), 7.51 (d, 1H), 7.26 (m, 5H), 7.19 (dd, 1H), 6.46 (dd, 1H), 4.77 (s, 2H), 4.58 (s, 2H); 19F NMR (376 MHz, CD3OD) −134.52 (s).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12](I)[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:41]1[C:42](=[O:58])[N:43]([CH3:57])[C:44](=[O:56])[C:45]=1[C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[N:48]([CH3:55])[CH:47]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:55][N:48]1[C:49]2[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46]([C:45]2[C:44](=[O:56])[N:43]([CH3:57])[C:42](=[O:58])[C:41]=2[C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:11]=2)=[CH:47]1
Reactant: Ic1cccc(OCCN2CCOCC2)c1
Reactant: CN1C(=O)C(Br)=C(c2cn(C)c3ccccc23)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Product: CN1C(=O)C(c2cccc(OCCN3CCOCC3)c2)=C(c2cn(C)c3ccccc23)C1=O
Temperature: 80 °C
Yield: 70 %

Procedure:
A flask charged with 3-(2-morpholin-4-ylethyloxy)iodobenzene (0.33 g, 1 mmol), bis(pinacolato)diboron (0.279 g, 1.1 mmol), potassium acetate (0.294 g, 3 mmol) and PdCl2(dppf) (48 mg, 0.06 mmol) was flushed with nitrogen. N,N-Dimethylformamide (6 mL) was added and the reaction mixture was stirred at 80° C. for 3h and then cooled to room temperature. 3-Bromo-4-(1-methylindol-3-yl)-1-methylpyrrole-2,5-dione (0.255 g, 0.8 mmol) ((synthesized according to the procedures described in Brenner, M. et al., Tet. Lett. 44, 2887, (1988)) was added to the reaction mixture, followed by the addition of PdCl2(dppf) (48 mg, 0.06 mmol)) and 2M aq. Na2CO3 (2.5 mL). The resulting mixture was stirred at 80° C. for 2.5 h, then cooled to room temperature, and quenched with H2O. The product was extracted with EtOAc. The EtOAc layer was washed with H2O, NaCl (sat.), dried over Na2SO4, and concentrated. Purification of the crude product on a silica gel column with 2/3/5 of acetone/CH2Cl2/hexane gave 3-(1-methylindol-3-yl)-4-[3-(2-morpholin-4-ylethyloxy)-phenyl]-1-methylpyrrole-2,5-dione as an orange-red oil. (0.25 g, 70% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:46][Si:47]([C:50]#[CH:51])([CH3:49])[CH3:48]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C.CN(C)C=O>[C:14]1([S:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:51]#[C:50][Si:47]([CH3:49])([CH3:48])[CH3:46])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Br)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C

Procedure:
In tetrahydrofuran (7.00 ml), 5-bromo-1-phenylsulfonylindole (1.50 g) and triphenylphosphine (351 mg) were dissolved. Triethylamine (20 ml), N,N-dimethylformamide (7.00 ml), trimethylsilylacetylene (945 up) and palladium acetate (100 mg) were added to the resulting solution at room temperature, followed by heating under reflux for 5 hours. After the reaction mixture was allowed to cool down to room temperature, ethyl acetate and water were added to the reaction mixture to separate the organic layer. The resulting organic layer was dried over anhydrous sodium sulfate and then distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=20:1 to 10:1), whereby the title compound (935 mg, 59%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](=O)[NH:7][CH:8]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13]>P(Cl)(Cl)(Cl)=O>[Cl:13][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:10])[F:1])=[CH:8][N:7]=1
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(Cl)nc1

Procedure:
25 g of this 5-trifluoromethyl-2-pyridone was then added to 100 cc of phosphorous oxychloride and 40 g of phosphorous pentachloride and heated to 100° C. to 8 hours, the excess phosphorous oxychloride removed by distillation at reduced pressure and the residue remaining taken up in 200 cc of water. The pH was adjusted to 7 with sodium hydroxide. Extraction of the solution three times with 100 cc of with chloroform gave 2-chloro-5-trifluoromethylpyridine on removal of the solvent.
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[C:11]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:16]#[N:17])=[C:10]([F:22])[C:9]([CH2:23]O)=[CH:8][CH:7]=1>C(Cl)Cl>[Br:5][C:6]1[C:11]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:16]#[N:17])=[C:10]([F:22])[C:9]([CH2:23][Br:2])=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CO)c2F)c1
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CBr)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of PBr3 (0.74 mL of a 1 M solution in DCM, 1.1 equiv) was added to a solution of 107 (0.24 g, 0.67 mmol) in DCM (5 mL). The mixture was stirred at RT for 1 h and then concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3, and dried (MgSO4). Evaporation of the volatile materials afforded 0.17 g (60%) of 96.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([OH:17])[CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([O:17][C:20](=[O:22])[CH3:21])[CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@H](O)C[C@@H]2CCCN2C)c1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc([C@@H](C[C@@H]2CCCN2C)OC(C)=O)c1

Procedure:
3,5 g of (R*,S*)-1-(3-methoxyphenyl)-2-(1-methyl-2-pyrrolidinyl)-ethanol and 40 ml of acetic acid anhydride are stirred for 15 minutes at room temperature. 6 N sodium hydroxide solution is added with cooling up to a pH of 8-9. The mixture is extracted with diethyl ether, and the organic layer is concentrated to the oily title compound. The hydrochloride (from methanol/diethyl ether) melts at 155°-157°.