Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][OH:2].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]#[N:14])[C:8]([C:15]1[C:19]([CH3:20])=[CH:18][S:17][C:16]=1[CH3:21])=[C:7]2[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C(Cl)Cl.[Cl-].[Na+].O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13](=[N:1][OH:2])[NH2:14])[C:8]([C:15]1[C:19]([CH3:20])=[CH:18][S:17][C:16]=1[CH3:21])=[C:7]2[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1
Reactant: Cc1csc(C)c1-c1c(-c2ccc(O)cc2)c2cc(Cl)ccc2n1C#N
Reactant: NO
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1csc(C)c1-c1c(-c2ccc(O)cc2)c2cc(Cl)ccc2n1C(N)=NO
Temperature: 0 °C
Reaction time: 65 h
Yield: 15.4 %

Procedure:
Hydroxylamine (16.3 M solution in water, 0.69 mL, 11.0 mmol) was added to 5-chloro-2-(2,4-dimethylthiophen-3-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carbonitrile (42 mg, 0.11 mmol) in DCM (5 mL) at 0° C. and the reaction was stirred at 0° C. for 65 h. Brine was added and the aqueous mixture was extracted with DCM. The solvent was concentrated and the crude product was purified by preparative HPLC to give 5-chloro-2-(2,4-dimethylthiophen-3-yl)-N′-hydroxy-3-(4-hydroxyphenyl)-1H-indole-1-carboximidamide (7.0 mg, 35%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 414.5; 412.4 (M+H), 412.3; 409.9 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.65 (d, 1H, J=2.1 Hz), 7.58 (d, 1H, J=8.8 Hz), 7.25 (dd, 1H, J=8.8, 2.1 Hz), 7.10 (m, 2H), 6.83-6.80 (m, 3H), 2.18 (s, 3H) and 1.95 (d, 3H, J=1.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C([O-])(O)=O.[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O>[CH2:21]([O:20][C:18]([NH:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)CC[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 60 °C
Yield: 92 %

Procedure:
To a 1 L 3-necked flask equipped with a thermometer and a magnetic stirrer were added 4.90 g of L-glutamic acid γ-methyl ester (Sigma) and 200 mL of water. The solution was heated to 60° C., treated with 6.40 g of NaHCO3 followed by 5.20 mL of benzyl chloroformate (Aldrich) and allowed to cool to RT with vigorous stirring. After 4 h the reaction mixture was extracted with ethyl ether (4×100 mL) and the ether extracts were discarded. The aqueous solution was acidified to a congo red endpoint by addition of concentrated HCl. An oily emulsion resulted which was extracted with CH2Cl2 (4×60 mL). The combined organic extracts were washed with 0.05 N aqueous HCl (2×60 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to afford 8.23 g (92%) of N-((benzyloxy)carbonyl)-5-O-methyl-L-glutamic acid as a white crystalline solid, m.p. 61-63° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]([CH3:20])[CH3:19])[C:13]([C:21]([OH:23])=[O:22])=[CH:12]2)C1C=CC=CC=1>[Pd].C(OCC)(=O)C.C(O)C>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]([CH3:20])[CH3:19])[C:13]([C:21]([OH:23])=[O:22])=[CH:12]2
Reactant: CC(C)n1c(C(=O)O)cc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)n1c(C(=O)O)cc2cc(O)ccc21
Temperature: 25 °C

Procedure:
A mixture of 5-benzyloxy-1-isopropyl-1H-indole-2-carboxylic acid (41.6 g, 1.0 eq.) and palladium on activated charcoal (10% m:m, 4.3 g, 0.03 eq.) in ethyl acetate (330 mL) and ethanol (235 mL) was flushed with hydrogen, then vigorously stirred for 2 h30 at room temperature. The resulting back suspension was filtered through a dicalite pad. The pad was washed with a mixture of ethyl acetate and ethanol then the liquor was evaporated in vacuo to yield 26.3 g (quant.) of the desired product as off-white oil. MS (m/e): 218.2 (M−H, 100%).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH:9]=[CH:8][C:7]([C:11]([OH:13])=O)=[CH:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.COC(Cl)=O.[CH2:26]([NH2:29])[CH2:27][CH3:28]>ClCCl>[CH2:26]([NH:29][C:11]([C:7]1[CH:8]=[CH:9][CH2:10][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=1)=[O:13])[CH2:27][CH3:28]
Reactant: CC(=O)NC1C=C(C(=O)O)C=CC1
Reactant: CCCN
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)C1=CC(NC(C)=O)CC=C1

Procedure:
A solution of 180 mg (1 m mole) of 3-acetamido-1,5-cyclohexadiene carboxylic acid in 5 ml of dichloromethane is treated with 202 mg (2 m mole) of triethylamine and 94 mg (1 m mole) of methylchloroformate. After 30 minutes at 25° C. the solution is treated with 60 mg (1 m mole) of n-propylamine for 1 hour at 25° C. after which the solution is diluted with dichloromethane and, washed with water, dried and evaporated to give N-propyl-3-acetamido-1,5-cyclohexadienecarboxamide.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH:12]([N:15](C(C)C)CC)(C)C.Cl.CN>O1CCCC1>[CH3:12][NH:15][C:1](=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccccc1C(=O)Cl
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1OC
Reaction time: 1 h

Procedure:
Combine o-anisoyl chloride (2-methoxybenzoyl chloride) (2.9 g, 17.0 mmol) and tetrahydrofuran (170 mL) and cool to 0° C. Add diisopropylethylamine (5.92 mL, 34 mmol). Add methylamine hydrochloride (1.26 g, 18.7 mmol). Allow to stir for 1 hour and concentrate in vacuo. Chromatograph on silica gel eluting sequentially with 50% ethyl acetate/hexane to give N-methyl-2-methoxybenzamide: TLC Rf =0.45 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [CH3:1][Li].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:6][CH:5]=1>O1CCCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:10]([NH:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH3:1])=[CH:18][CH:19]=1
Reactant: Fc1ccc(C(=Nn2cncn2)c2ccc(F)cc2)cc1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(Nn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 10 mL (1.5M, 150 mmol) of methyllithium in 30 mL of tetrahydrofuran was cooled to -78° C. A solution of 2.0 g (7.0 mmol) of N-[bis(4-fluorophenyl)methylene]-1H-1,2,4-triazol-1-amine in 10 mL tetrahydrofuran was added dropwise. The solution was stirred 10 min. quenched with saturated ammonium chloride and warmed to room temperature. Dilution with ethyl acetate, washing with water and brine, drying (MgSO4) and removal of solvent gave product as a viscous oil. Chromatography on silica gel (10:1 methylene chloride-acetate) gave of desired product as a white solid; yield 1.1 g, mp 114°-119° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[C:8]([CH3:14])[CH:7]=1.CN(C)C=O>CC1C=CC=CC=1>[Cl:3][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][C:8]=1[CH3:14]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(F)ccc1CO
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To 14.3 parts of thionyl chloride is added dropwise a solution of 14 parts of 4-fluoro-2-methylbenzenemethanol and 0.9 parts of N,N-dimethylformamide in 45 parts of methylbenzene while cooling in ice-water. Then there are added 135 parts of methylbenzene and stirring is continued for 1 hour at room temperature. The reaction mixture is evaporated, yielding 17 parts (100%) of 1-(chloromethyl)-4-fluoro-2-methylbenzene as a residue.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][CH:6]=[C:7]=[CH:8][CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O.[OH-].[Li+].Cl>C(O)C>[C:3]([OH:22])(=[O:2])[CH2:4][CH2:5][CH:6]=[C:7]=[CH:8][CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCSCC=C=CCCC(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCSCC=C=CCCC(=O)O
Yield: 59.7 %

Procedure:
Methyl-8-thianonadeca-4,5-dienoate (210 mg) was treated in 10 ml of ethanol and 1 ml of water with 160 mg of lithium hydroxide at room temperature for 18 hours. The solution was acidified to pH 4 with dilute HCl and extracted with diethyl ether twice. The ethereal extracts were washed with brine and dried over potassium carbonate to give 120 mg of 8-thianonadeca-4,5-dienoic acid. This procedure can be used to convert the compounds of Example VI to their corresponding acid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([NH:13][C:14]2([CH2:20][NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:29][C:30](Cl)=[O:31].O>CN(C)C=O>[O:31]=[C:30]1[N:21]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:29]1
Reactant: CCOC(=O)CNCC1(Nc2ccccc2)CCCCC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CC2(CCCCC2)N(c2ccccc2)CC1=O
Yield: 96.5 %

Procedure:
95 mg (0.69 mmol) of potassium carbonate are added to a solution of 200 mg (0.69 mmol) of ethyl [(1-phenylaminocyclohexylmethyl)amino]-acetate and 55 μl (0.69 mmol) of chloroacetyl chloride in 15 ml of dimethylformamide. The reaction medium is stirred at reflux for 6 h and poured into water and extracted with ethyl acetate. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. 220 mg of ethyl (3-oxo-1-phenyl-1,4-diazaspiro[5.5]undec-4-yl)acetate are obtained in the form of an orange oil. Yield=97%.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.F[C:15]1[C:16]([CH3:35])=[N:17][C:18]2[C:23]([N:24]=1)=[C:22]([C:25]1[NH:33][C:32]3[CH2:31][CH2:30][NH:29][C:28](=[O:34])[C:27]=3[CH:26]=1)[CH:21]=[CH:20][CH:19]=2>CS(C)=O>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:15]2[C:16]([CH3:35])=[N:17][C:18]3[C:23](=[C:22]([C:25]4[NH:33][C:32]5[CH2:31][CH2:30][NH:29][C:28](=[O:34])[C:27]=5[CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[N:24]=2)[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 85 °C
Yield: 32.7 %

Procedure:
Prepared according to Example 131 using (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (189 mg, 1.012 mmol) and 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 100 mg, 0.337 mmol) in DMSO (1.5 mL) and heating to 85° C. for 2 h. Purification by column chromatography (silica gel: 0 to 10% MeOH/DCM) provided (S)-tert-butyl-3-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)amino)pyrrolidine-1-carboxylate (51 mg, 32.8%). 1H NMR (400 MHz, MeOH-d4) δ ppm 7.90-7.96 (1H, m) 7.63-7.69 (1H, m) 7.42 (1H, t, J=1.00 Hz) 7.11 (1H, s) 4.65-4.80 (1H, m) 3.87-4.03 (1H, m) 3.57-3.68 (3H, m) 3.49-3.55 (1H, m) 3.40-3.49 (1H, m) 2.94-3.03 (1H, m) 2.61 (3H, s) 2.35-2.49 (2H, m) 2.19-2.34 (1H, m) 1.45-1.54 (9H, m). m/z (ESI, +ve) 463.2 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:35])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:24][N:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:22]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1.[H-].[Na+].I[CH3:39].O>CN(C=O)C>[F:35][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH3:39])[CH:21]3[CH2:22][N:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CN(S(C)(=O)=O)C2)nc(N2CCOCC2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(C)C2CN(S(C)(=O)=O)C2)n1
Temperature: 20 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine (Example 28) (170 mg, 0.33 mmol) in DMF (4 mL) at 0° C. was added NaH (24 mg, 1.0 mmol). The mixture was stirred for 30 min at this temperature and iodomethane (0.3 mL, excess) was added. The resulting mixture was allowed to warm to 20° C. and stirred for 2 hrs. Water was added and the resulting precipitate was filtered, washed with water, and dried. Recrystallization from CH2Cl2/MeOH gave 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine (156 mg, 89% yield): mp (CH2Cl2/MeOH) 242-244° C.; 1H NMR (DMSO-d6) δ7.97-7.60 (m, 2H), 7.42 (t, J=8.1 Hz, 1H), 6.96 (d, J=7.9 Hz, 1H), 5.50 and 5.26 (2m, 1H), 4.17-4.12 (m, 4H), 3.98 (s, 3H), 3.81 (m, 4H), 3.71-3.69 (m, 4H), 3.24 (s, 3H), 3.09 (s, 3H); Anal. Calcd. for C21H26F2N8O4S: C, 48.1; H, 5.0; N, 21.3. Found: C, 48.0; H, 5.0; N, 21.3%.
Reaction SMILES: [OH:1][C:2]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:5]([C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10](=[O:18])(=[O:17])[CH2:9]2)=[O:7])=[CH:4][C:3]=1[C:25]([N:27]1[CH2:31][CH2:30][S:29][CH2:28]1)=[O:26].[OH:32]OS([O-])=O.[K+].Cl>O1CCCC1.O>[OH:1][C:2]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:5]([C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10](=[O:18])(=[O:17])[CH2:9]2)=[O:7])=[CH:4][C:3]=1[C:25]([N:27]1[CH2:31][CH2:30][S:29](=[O:32])[CH2:28]1)=[O:26]
Reactant: O=S([O-])OO
Reactant: O=C(c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C(F)(F)F)c1O)N1CCSC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C(F)(F)F)c1O)N1CCS(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
3-[4-hydroxy-3-(1,3-thiazolidine-3-carbonyl)-5-trifluoromethylbenzoyl]-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (67 mg) was dissolved in tetrahydrofuran (0.5 mL) and water (0.5 mL), and oxone (45 mg) was added to the solution, and then the mixture was stirred at room temperature for 1 hour. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-chloroform to obtain the title compound (46 mg) as a colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[F:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH2:28][N:29]1[C:37]([NH2:38])=[C:36]2[C:31]([CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=[CH:35]2)=[N:30]1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]2=[C:8]([C:33]3[CH:34]=[CH:35][C:36]4[C:31]([CH:32]=3)=[N:30][N:29]([CH2:28][C:27]3[CH:48]=[CH:49][CH:50]=[CH:51][C:26]=3[F:25])[C:37]=4[NH2:38])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2ccc3c(N)n(Cc4ccccc4F)nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc4c(N)n(Cc5ccccc5F)nc4c3)c3c(N)ncnn23)CC1
Temperature: 110 °C

Procedure:
To a solution of tert-butyl 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (0.5 g, 1.26 mmol) in DMF (15 mL) was added 2-(2-fluorobenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-3-amine (0.695 g, 1.89 mmol), solid Na2CO3 (0.4 g, 3.79 mmol) and water (1.9 mL). The solution was degassed for 10 min and tetrakis(triphenylphosphine)palladium(0) (0.146 g, 0.126 mmol) was added and the mixture was degassed for another 10 min. The mixture was heated at 110° C. for 1 h 15 min and then cooled to rt. The mixture was filtered through a plug of Celite® and the filtrate was concentrated. The crude purified using an ISCO® instrument using 40-100% ethyl acetate in hexanes. LC-MS [M+H]+=557.2, RT=2.65 min.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Cl:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1>CCOCC>[Cl:13][C:14]1[N:19]=[C:18]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Ic1ccccc1
Reactant: Clc1ncccn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Clc1nccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of iodobenzene (3.53 ml) in ether (10 ml) was added n-butyllithium (1.6M in hexane, 20 ml), and the mixture was stirred at room temperature for 20 minutes. The above solution was added to a solution of 2-chloropyrimidine (3.52 g) in ether (90 ml) at −30° C. The mixture was stirred at −30° C. for 30 minutes and then at 0° C. for 30 minutes, quenched with a solution of acetic acid (1.83 ml) and water (0.31 ml) in tetrahydrofuran (6 ml), and treated with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (7.26 g) in tetrahydrofuran (30 ml). The mixture was stirred at 0° C. for 5 minutes, cooled to 0° C., treated with a cold aqueous solution of sodium hydroxide (3M, 9.2 ml), and stirred at 0° C. for 5 minutes. The organic phase was separated, washed with water and brine, dried over magnesium sulfate, concentrated and subjected to silica gel column chromatography (hexane-ethyl acetate, 7:3) to afford 2-chloro-4-phenylpyrimidine (3.39 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.Br[CH2:27][C:28](=[O:38])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.O>CC#N>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][C:28](=[O:38])[CH2:27][N:3]2[C:2]([CH3:1])=[CH:6][N:5]=[CH:4]2)=[CH:32][CH:33]=1
Reactant: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C(CBr)CCc1ccc(Cl)cc1
Solvent: CC#N
Solvent: O
Product: Cc1cncn1CC(=O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A mixture of 4-methyl-1-tritylimidazole (12.9 g, 39.8 mmol) and 1-bromo-4-(4-chlorophenyl)butan-2-one (12.5 g, 47.8 mmol, 1.2 equivalents) in CH3CN (~200 mL) was heated at reflux for 16 hours. The reaction mixture was then cooled to room temperature and 2N HCL (30 mL) was added. The reaction mixture was then heated at reflux for 30 minutes, cooled to room temperature and treated with water (~500 mL). The resulting mixture was then washed with ether (~1×100 mL) and the pH adjusted to between 9 and 10 with 2N NaOH. The aqueous layer was extracted with ethyl acetate (3×100 mL), and the combined extracts were then washed with brine and dried over Na2SO4. After filtration and concentration, the resulting crude product (8.5 g) was purified by silica gel chromotography, eluting with 1-8% methanol in methylene chloride to give 8.2 g of 4-(4-chlorophenyl)-1-(5-methylimidazol-1-yl)butan-2-one (70% yield). The hydrochloride salt was recrystallized from methanol/ethyl acetate with m.p. 227°-228° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: O=S(=O)(O)c1cccnc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccnc1

Procedure:
A mixture of pyridine-3-sulphonic acid (3.0 g) and PCl5 (7.9 g) was stirred in an oil bath maintained at 150° for 3 hours, in a flask fitted with a reflux condenser. After cooling, the liquid formed set solid. The solid was triturated with xylene (10 cm3) and evaporated at the water pump in an oil-bath maintained at a maximum temperature of 110°, and with a splash-head to reduce frothing. The evaporation was repeated twice more, and the residue was pumped on a rotary evaporator to remove the last traces of xylene. The yellow, semi-crystalline mass (6.87 g) occluded unreacted PCl5.
Reaction SMILES: [C:1]1(/[C:7](/[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:25][CH:26](Br)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:1]1([C:7]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:27][CH2:26][Br:25])=[CH:22][CH:23]=2)=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC/C(=C(\c1ccccc1)c1ccc(O)cc1)c1ccccc1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCC(=C(c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1

Procedure:
A mixture containing 31,6 g of (Z)-1,2-diphenyl-1-(4-hydroxyphenyl)-1-buten-4-ol, 93,9 g of dibromoethane, 20,7 g of anhydrous potassium carbonate and 250 ml of methyl ethyl ketone is refluxed for 24 h. The inorganic salts are removed by filtration followed by evaporating the solvent and recrystallizing frommethanol. The yield is 17,3 g (41%) and m.p. 133°-7° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:5]([C:6]([OH:8])=O)=[C:4]([F:13])[C:3]=1[F:14].[O:15]=[C:16]1[O:20][CH:19]([O:21][CH2:22][CH2:23][C:24]2C=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]([NH:30][C:31]([CH:33]2[CH2:37][CH2:36][CH2:35][N:34]2[C:38](=[O:52])[CH:39]([NH:41]C(=O)C2C=CC(N)=C(Cl)C=2)[CH3:40])=[O:32])[CH2:17]1>>[CH2:22]([O:21][CH:19]1[CH:18]([NH:30][C:31]([CH:33]2[CH2:37][CH2:36][CH2:35][N:34]2[C:38](=[O:52])[CH:39]([NH:41][C:6](=[O:8])[C:5]2[C:4]([F:13])=[C:3]([F:14])[C:2]([NH2:1])=[C:10]([F:11])[C:9]=2[F:12])[CH3:40])=[O:32])[CH2:17][C:16](=[O:15])[O:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: Nc1c(F)c(F)c(C(=O)O)c(F)c1F
Product: CC(NC(=O)c1c(F)c(F)c(N)c(F)c1F)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 73 %

Procedure:
Prepared from {2-[2-(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbmoyl)-pyrrolidin-1-yl]-1-methyl-2-oxo-ethyl}-carbamic acid tert-butyl ester and 4-amino-2,3,5,6-tetrafluoro-benzoic acid according to the procedure used to prepare 98a to afford 58 mg of title compound (73% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.30-1.50 (m, 3H), 1.62-2.35 (m, 4H), 2.45-3.12 (m, 2H), 3.50-3.90 (m, 2H), 4.20-4.95 (m, 5H), 5.42 (s, 0.4H), 5.52 (s, 0.1H), 5.64 (d, 0.4H), 5.82 (d, 0.1H), 7.25-7.65 (m, 5H). Analytical HPLC: 16.56, 16.90 min. LC-MS (ES+): m/e=567.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@@H:17]([NH:16][C:11]([C:8]1[O:9][C:10]3[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:18]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2cccc(Br)c2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1

Procedure:
5.20 g (21.57 mmol) of 7-bromobenzofuran-2-carboxylic acid (Example 29A), 4.3 g (21.57 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 9.84 g (25.89 mmol) of HATU, 13.53 ml (74.68 mmol) of N,N-diisopropylethylamine and 21 ml of DMF are reacted by general method C. The solvent is removed under reduced pressure, and the crude product is taken up in 100 ml of ethyl acetate and washed 15 times with a total of 1.5 1 of 1N sodium hydroxide solution. The organic phase is dried over magnesium sulphate and freed of solvent. 5.2 g (69% of theory) of the title compound are isolated.