Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.O[CH2:44][CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]>>[C:49]([O:48][C:46]([CH2:45][CH2:44][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)CCO
Product: COc1cc(C(=O)OCCC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with tert-butyl 3-hydroxypropanoate to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-tert-butoxycarbonyl-ethyl ester. MS (ES+) m/z calcd. for C38H42Cl2F2N3O6: [(M+H)+]: 744. found: 744.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5](C)=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][C:11]=1F.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][N:4]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:26][CH:27]=2)[C:3](=[O:19])[C:2]=1[Br:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccc(Cn2ccc(OCc3ccccc3)c(Br)c2=O)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 3.3 %

Procedure:
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(0.5 g, 1.78 mmol) was dissolved in N,N-dimethylformamide (5 mL). 4-(Bromomethyl)phenylacetic acid (0.5 g, 2.14 mmol) was added followed by K2CO3 (0.3 g, 2.14 mmol). The reaction was heated to 80° C. and shaken for 16 hours, then heated to 100° C. and shaken for 16 hours more. The reaction mixture was partitioned between water and ethyl acetate and extracted with ethyl acetate (2×50 mL). The aqueous layer was acidified (pH 2) with 1N HCl and extracted with ethyl acetate (3×50 ml). The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated to an oil, and purified by chromatography (silica gel, hexane/ethyl acetate) followed by reversed phase chromatography (C18, 0.1% aqueous trifluoroacetic acid /acetonitrile) to yield a white solid (25 mg, 3%). 1H NMR (400 MHz, CDCl3) δ 7.40-7.38 (m, 3H), 7.25-7.20 (m, 7H), 6.05 (d, J=8.0 Hz, 1H), 5.21 (s, 2H); 5.13, (s, 2H); 3.62, (s, 2H). ES HRMS m/z 428.0510 (M+H C21H18BrNO4 requires 428.0492).
Reaction SMILES: [F:1][C:2]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:3]=1[O:4][C:5]1[C:14]([C:15]2[C:16]3[CH:25]=[CH:24][N:23](S(C4C=CC(C)=CC=4)(=O)=O)[C:17]=3[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[CH:13][C:8]2[NH:9][C:10](=[O:12])[NH:11][C:7]=2[CH:6]=1.C(O)C.[OH-].[Na+].O>>[F:1][C:2]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:3]=1[O:4][C:5]1[C:14]([C:15]2[C:16]3[CH:25]=[CH:24][NH:23][C:17]=3[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[CH:13][C:8]2[NH:9][C:10](=[O:12])[NH:11][C:7]=2[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc5[nH]c(=O)[nH]c5cc4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cc(-c2cc3[nH]c(=O)[nH]c3cc2Oc2ccc(F)cc2F)c2cc[nH]c2c1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
A solution of 5-(2,4-difluorophenoxy)-6-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (0.024 g, 0.035 mmol) in ethanol (0.4 mL, 7 mmol) was treated with 1.0 M sodium hydroxide in water (0.18 mL, 0.18 mmol) and stirred at 80° C. for 30 min. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 30 mL/min) gave the desired product (3 mg, 20%). 1H NMR (500 MHz, DMSO-d6) δ 11.93 (br s, 1H), 10.62 (br s, 2H), 7.34-7.26 (m, 1H), 7.22 (d, J=2.8 Hz, 1H), 7.17 (s, 1H), 7.02-6.87 (m, 3H), 6.52 (s, 1H), 6.17 (d, J=2.7 Hz, 1H), 3.50 (s, 3H); LCMS calculated for C21H15F2N4O3 (M+H)+: m/z=409.1. found: 409.1.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[C:37]3[CH:36]=[N:35][CH:34]=[N:33][C:32]=3[N:31](S(C3C=CC(C)=CC=3)(=O)=O)[CH:30]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Li+]>COCCOC.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH:13]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:29]3[C:37]4[CH:36]=[N:35][CH:34]=[N:33][C:32]=4[NH:31][CH:30]=3)[N:7]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cncnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(Br)n2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(-c3c[nH]c4ncncc34)n2)CC1
Temperature: 90 °C
Yield: 43.2 %

Procedure:
As shown in FIG. 7—step iii, a mixture of compound 1032 (0.18 g), 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (compound 1005, 0.20 g), tetrakis(triphenylphosphine) palladium (50 mg), and 2N sodium carbonate (0.8 mL) in DME (5 mL) was heated at 90° C. overnight. Saturated aqueous lithium hydroxide (2 mL) was added and the reaction was heated at 60° C. for 1 hour. The reaction mixture was diluted with EtOAc and washed with brine. The organics were dried over sodium sulfate, concentrated, and purified by chromatography (SiO2, 50% ethyl acetate/hexane) to afford 6-(7H-Pyrrolo[2,3-d]pyrimidin-5-yl)-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (compound 1033, 81.6 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=O)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].Cl.[NH2:17][OH:18].C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5](=[N:17][OH:18])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCc1ccccc1)=NO
Yield: 47.8 %

Procedure:
103.14 g (0.5 mole) 2-oxo-4-phenyl butyric acid ethyl ester, 34.75 g (0.5 mole) hydroxylamine hydrochloride, 104 ml (0.75 mole) triethylamine and 500 ml ethanol were agitated overnight at room temperature. The batch was then evaporated to dryness and the residue taken up in 700 ml methyl-tert-butyl ether. After washing with 200 ml water, 200 ml 0.2N hydrochloric acid and 100 ml water, the organic phase was evaporated to dryness and the residue recrystallized after filtration from 170 ml toluene. 52.9 g (48%) 2-hydroxyimino-4-phenyl butyric acid ethyl ester were isolated in the form of colorless crystals. A 1H-NMR spectrum corroborated the suggested structure.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[CH:6][NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][S:2][C:3]1[C:4]2[C:5]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)=[C:6]([Br:27])[NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CSc1cccc2[nH]cc(Cc3ccc(Cl)cc3)c12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1cccc2[nH]c(Br)c(Cc3ccc(Cl)cc3)c12
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of the indole of Step 6 (700 mg, 2.4 mmol) in CCl4 (15 mL) was added NBS (475 mg, 2.7 mmol). The reaction mixture was heated to 50° C. and stirred for 20 minutes. The resulting suspension was filtered on SiO2 pad eluted with 50% EtOAc in hexanes and concentrated. The title compound was obtained in quantitative yield as a brownish solid foam and used as such.
Reaction SMILES: CC1(C)[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([C:14]([CH2:17][CH3:18])=[CH:15][CH3:16])[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CO>[CH2:17]([C:14](=[CH:15][CH3:16])[C@H:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:12])([CH3:11])[CH3:13])[CH2:4][OH:3])[CH3:18]
Reactant: CC=C(CC)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CC=C(CC)[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
A solution of (S)-tert-butyl 2,2-dimethyl-4-(pent-2-en-3-yl)oxazolidine-3-carboxylate (Intermediate 201, 15.815 g, 58.71 mmol) and p-toluenesulfonic acid monohydrate (3.35 g, 17.61 mmol) in methanol (100 mL) was heated to 85° C. for 3 h. The reaction mixture was cooled to room temperature and triethylamine (8.18 mL, 58.71 mmol) and di-tert-butyl dicarbonate (6.82 mL, 29.35 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give a yellow oil. Purification by flash column chromatography (0-100% ethyl acetate/hexanes) afforded the title compound (10.12 g, 75%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:27]=2[NH2:28])[CH2:22][CH2:21]1.Cl.O1CCOCC1>CO>[N:23]1([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:27]=2[NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:3]=2[CH3:19])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-2-(2-fluorophenyl)-3-methylquinoline (103 mg, 0.38 mmol), 2,5-dimorpholinoaniline (100 mg, 0.38 mmol) and a 4.0M solution of HCl in dioxane (0.095 mL, 0.38 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinylphenyl)-2-(2-fluorophenyl)-3-methyl-4-quinolinamine was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.29 (1H, d, J=8.6 Hz), 7.93 (1H, d, J=8.2 Hz), 7.68-7.76 (1H, m), 7.65 (1H, td, J=7.4, 1.6 Hz), 7.40-7.55 (3H, m), 7.34 (1H, t, J=7.4 Hz), 7.19 (1H, t, J=9.0 Hz), 7.11 (1H, d, J=8.6 Hz), 6.47 (1H, dd, J=8.8, 2.9 Hz), 6.06-6.20 (1H, m), 3.85-4.00 (4H, m), 3.67-3.80 (4H, m), 3.01-3.17 (4H, m), 2.88-3.00 (4H, m), 2.21 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=499.2 (M+1).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][NH2:26])[C:5]1=[O:29])[CH:2]=[CH2:3].[C:30](OC(=O)C)(=[O:32])[CH3:31]>CN(C=O)C>[CH2:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][NH:26][C:30](=[O:32])[CH3:31])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCC1CC(c2cccc(Cl)c2)C(c2ccc(Cl)cc2)N(C(CC)CN)C1=O
Solvent: CN(C)C=O
Product: C=CCC1CC(c2cccc(Cl)c2)C(c2ccc(Cl)cc2)N(C(CC)CNC(C)=O)C1=O

Procedure:
To a solution of 53 mg (0.123 mmol) of (3SR,5RS,6SR)-3-allyl-1-((RS)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Step B) in DMF (307 μL) was added acetic anhydride (116 μL, 1.229 mmol) at 25° C. After being stirred at 25° C. for 14h the reaction was quenched (H2O) and extracted (2×EtOAc). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Separation by reversed phase HPLC (50 to 80% AcCN/H2O in 25 min, 2 injections, tR=15.683 min) provided the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][NH2:13]>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:13][CH3:12])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CN
Product: CNC(=O)c1ccc(C#N)cc1

Procedure:
By the reaction in the same manner as in Example 26-i) using 4-cyanobenzoyl chloride (5.17 g) and 40% aqueous methylamine solution (20 ml), the title compound (4.13 g) was obtained as colorless powder crystals.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13]I>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:13])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccc(Br)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
To a solution of 6-bromo-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.55 mmol) in DMF (10 mL) was added NaH (306 mg, 7.65 mmol, m %/60%). The mixture was stirred at room temperature for 1 h and then MeI (398 mg, 2.8 mmol) was added. The reaction mixture was then stirred at room temperature for 4 h after which, TLC showed the completion of the reaction. The reaction mixture was quenched by addition of water and then extracted with EtOAc. Combined organic layers were concentrated and the residue was purified by Prep-TLC (PE:EA=5:1) to give the desired product (200 mg) which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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]>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)cc(N2CCOCC2)n1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2cncnc2)cc(N2CCOCC2)n1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
Similarly to Example 55, a mixture of 1-[4-chloro-6-(4-morpholinyl)-2-pyrimidinyl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (106 mg, 0.268 mmol), pyrimidine-5-boronic acid (188 mg, 1.52 mmol), PdCl2(dppf) (40 mg, 0.05 mmol) and aq. K2CO3 (2M, 4 mL) in 1,4-dioxane (20 mL) was refluxed under nitrogen for 24 hrs. After cooling to room temperature, the mixture was diluted with H2O, and extracted with CH2Cl2 (4×). The combined organic extracts were dried (Na2SO4), and the solvents removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 97:3), followed by recrystallization from CH2Cl2/MeOH/hexanes gave 2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4,5′-bipyrimidine (89 mg, 75%): mp 222-224° C.; 1H NMR (CDCl3) δ 9.38 (s, 2H), 9.36 (s, 1H), 7.92 (dd, J=8.4, 0.6 Hz, 1H), 7.49 (t, J=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.86 (s, 1H), 6.84 (d, J=7.7 Hz, 1H), 4.07 (s, 3H), 3.89 (m, 4H), 3.85 (m, 4H); Anal. Calcd. for C21H19F2N7O20.25 MeOH: C, 57.0; H, 4.5; N, 21.9. Found: C, 56.95; H, 4.45; N, 22.0%.
Reaction SMILES: CC(O[C:6](=[O:20])[NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([NH:17][CH3:18])=[O:16])[C:9]1=[O:19])(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+].[Cl:34][C:35]1[CH:44]=[C:43]2[C:38]([C:39]([N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[CH:40][C:41]([NH2:45])=[N:42]2)=[CH:37][CH:36]=1>>[NH2:45][C:41]1[CH:40]=[C:39]([N:46]2[CH2:47][CH2:48][N:49]([C:6]([NH:7][C@@H:8]3[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([NH:17][CH3:18])=[O:16])[C:9]3=[O:19])=[O:20])[CH2:50][CH2:51]2)[C:38]2[C:43](=[CH:44][C:35]([Cl:34])=[CH:36][CH:37]=2)[N:42]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CNC(=O)N1CCCC[C@@H](NC(=O)OC(C)(C)C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)N1CCCC[C@@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O

Procedure:
As described for example 213, [(3R)-hexahydro-1-[(methylamino)carbonyl]-2-oxo-1H-azepin-3-yl]-carbamic acid-1,1-dimethylethyl ester, TFA, K2CO3 (sat.) 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product. 1H NMR (DMSO-d6): δ 1.2 (m, 1H), 1.6 (m, 1H), 1.71 (m, 2H), 1.84 (m, 2H), 2.73 (s, 3H), 2.98 (m, 4H), 3.31 (m, 2H), 3.58 (m, 4H), 4.57 (m, 1H), 4.64 (t, 1H), 6.22 (s, 1H), 6.45 (br. s, 1H), 6.78 (d, 1H), 7.11 (d, 1H), 7.37 (s, 1H), 7.76 (d, 1H), 8.84 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([CH:18]=1)[CH2:7][N:8]1[C:12]([CH:13]([F:15])[F:14])=[N:11][N:10]([CH3:16])[C:9]1=[O:17].[CH3:20][C:21]([OH:25])([C:23]#[CH:24])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.COC(C)(C)C.C(#N)C>[F:14][CH:13]([F:15])[C:12]1[N:8]([CH2:7][C:6]2[CH:18]=[C:2]([C:24]#[C:23][C:21]([OH:25])([CH3:22])[CH3:20])[CH:3]=[CH:4][C:5]=2[CH3:19])[C:9](=[O:17])[N:10]([CH3:16])[N:11]=1
Reactant: Cc1ccc(Br)cc1Cn1c(C(F)F)nn(C)c1=O
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: Cc1ccc(C#CC(C)(C)O)cc1Cn1c(C(F)F)nn(C)c1=O
Temperature: 25 °C
Yield: 59.6 %

Procedure:
664 mg (2.0 mmol) of 4-(5-bromo-2-methylbenzyl)-5-difluoromethyl-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Compound 40), 1.00 g (11.9 mmol) of 2-methyl-3-butyn-2-ol, 70.2 mg (0.10 mmol) of PdCl2(PPh3)2, 57.1 mg (0.30 mmol) of copper iodide, 78.7 mg (0.30 mmol) of triphenylphosphine, 1.0 ml of triethylamine and 10 ml of acetonitrile were mixed, and the mixture was heated under reflux for 5 hours in nitrogen atmosphere. After cooling to room temperature, t-butyl methyl ether was added to the reaction solution, and the mixture was filtrated through celite, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluant: hexane/ethyl acetate=2/1 (v/v)) to obtain 400 mg of 5-difluoromethyl-4-{5-(3-hydroxyl-3-methyl-1-butynyl)-2-methylbenzyl}-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Compound 290).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:31]1([CH2:37][S:38](Cl)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>CN(C)C=O>[C:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:20]=[CH:21][C:2]([NH:1][S:38]([CH2:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:40])=[O:39])=[CH:3][CH:4]=1)#[N:19]
Reactant: N#Cc1cccc(OCCNC(=O)c2ccc(N)cc2)c1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(OCCNC(=O)c2ccc(NS(=O)(=O)Cc3ccccc3)cc2)c1
Reaction time: 13 h

Procedure:
670 mg (2.38 mmol) of 4-amino-N-[2-(3-cyanophenoxy)ethyl]benzamide was dissolved in 10 ml of dimethylformamide. 0.42 ml (2.38 mmol) of diisopropylethylamine and 454 mg (2.38 mmol) of α-toluenesulfonyl chloride were added to the solution at 0° C., and they were stirred for 13 hours. After the treatment with ethyl acetate as the extractant in an ordinary manner, the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C@H:19]([NH2:23])[CH2:18][CH2:17][CH2:16]3)[O:4][N:3]=1.[O:24]=[C:25]1[NH:30][CH2:29][CH2:28][N:27]([S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:26]1[CH2:41][C:42](O)=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C@H:19]([NH:23][C:42](=[O:43])[CH2:41][CH:26]2[C:25](=[O:24])[NH:30][CH2:29][CH2:28][N:27]2[S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH2:18][CH2:17][CH2:16]3)[O:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCNC(=O)C2CC(=O)O)cc1
Reactant: Cc1noc(-c2ccccc2-c2ccc3c(c2)CCC[C@H]3N)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N2CCNC(=O)C2CC(=O)N[C@@H]2CCCc3cc(-c4ccccc4-c4nc(C)no4)ccc32)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a 100 mL round bottom flask was added (1R)-6-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-1,2,3,4-tetrahydronaphthalen-1-amine (25.0 mg, 0.06 mmol), followed by 2-(3-oxo-1-tosylpiperazin-2-yl)acetic acid (50 mg, 0.016 mmol), dry CH2Cl2 (10 mL), HATU (12 mg, 0.03 mmol), EDCI (13 mg, 0.068 mmol) and hunig base (0.022 mL, 0.123 mmol). The resulting mixture was stirred at rt for 20 h. Removed solvent to dryness. Solvent was removed. The residue was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH mixture (97:3) gave final compound. MS m/z: 600.3 (M+H). Calc'd. for C32H33N5O5S -599.71.s
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29].[H-].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7](=[O:10])[N:8]([CH:27]([C:28]([O:30][CH3:31])=[O:29])[CH3:32])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C(C)Br
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCc1nn(C(C)C(=O)OC)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 84 %

Procedure:
The alkylation of 5-n-butyl-4-[(2'-cyanobiphenyl-4-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 9, Step C) with methyl 2-bromopropionate was carried out as described in Example 3, Step A, except that no excess sodium hydride was used. After work-up, the residue was flash chromatographed over silica gel (eluted with 0.5% MeOH/CH2Cl2) to give the desired material in 84% yield as a colorless oil, homogeneous by TLC in 2% MeOH/CH2Cl2, mass spectrum (FAB) 419 (M+1)+.