Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23][C:24]1[CH:25]=[CH:26][C:27](I)=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O>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.O1CCCC1>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)=[N:28][CH:29]=1
Reactant: Brc1ccc(I)nc1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)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: C1CCOC1
Solvent: O
Product: Brc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)nc1
Temperature: 80 °C
Yield: 98.2 %

Procedure:
A mixture of 4-(diphenylamino)phenylboronic acid (7.00 g, 24.2 mmol), 5-bromo-2-iodopyridine (7.56 g, 26.6 mmol), tetrakis(triphenylphosphine)palladium(0) (1.40 g, 1.21 mmol), Na2CO3 (9.18 g, 86.6 mmol), H2O (84 mL) and tetrahydrofuran (THF) (140 mL) was degassed with argon for about 1.5 h. while stirring. The stirring reaction mixture was then maintained under argon at 80° C. for about 19 h. Upon confirming consumption of the starting material by thin layer chromatography (TLC) (SiO2, 19:1 hexanes-EtOAc), the reaction was cooled to RT and poured over EtOAc (500 mL). The organics were then washed with saturated sodium bicarbonate (NaHCO3, H2O) and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was then purified via flash chromatography (SiO2, 2:1 hexanes-dichloromethane) to afford Compound 23 (9.54 g, 98% yield) as a light yellow, crystalline solid.
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([Cl:15])[CH:6]=1.Cl>CN(C)C=O>[Cl:15][C:7]1[CH:6]=[C:5]([S:2][CH3:1])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: C[S-]
Reactant: COC(=O)c1ccc(Br)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC)cc1Cl
Reaction time: 2 h
Yield: 76.9 %

Procedure:
Sodium thiomethoxide (459 mg) was added to a solution of methyl 4-bromo-2-chlorobenzoate (1.25 g) in N,N-dimethylformamide (10 ml) under ice-cooling, and the mixture was stirred for 2 hr. 1N Hydrochloric acid was added to the reaction mixture and the resulting product was extracted three times with ether. The organic layers were combined, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=10/1) to give the objective compound (835 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[CH:16]=4)[C:4]=2[C:3]=1[CH3:27])[CH:12]=[CH:11][CH:10]=[CH:9]3.[H-].[Na+].[CH3:30][S:31][C:32]1[N:37]=[C:36]([C:38]2[S:42][C:41]([S:43](Cl)(=[O:45])=[O:44])=[CH:40][CH:39]=2)[CH:35]=[CH:34][N:33]=1>>[CH:22]1([C:17]2[CH:16]=[C:15]([C:14]3[C:4]4[C:3]([CH3:27])=[C:2]([CH3:1])[S:6][C:5]=4[CH:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)[CH:20]=[CH:19][C:18]=2[O:21][S:43]([C:41]2[S:42][C:38]([C:36]3[CH:35]=[CH:34][N:33]=[C:32]([S:31][CH3:30])[N:37]=3)=[CH:39][CH:40]=2)(=[O:44])=[O:45])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CSc1nccc(-c2ccc(S(=O)(=O)Cl)s2)n1
Reactant: Cc1sc2cc3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Agent: [H-]
Agent: [Na+]
Product: CSc1nccc(-c2ccc(S(=O)(=O)Oc3ccc(-c4c5ccccc5cc5sc(C)c(C)c45)cc3C3CCCC3)s2)n1
Yield: 57.8 %

Procedure:
The title compound was prepared according to the procedure in Example 10, step 1, using 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenol (0.300 g, 0.805 mmol), 60% sodium hydride/mineral oil (0.032 g, 0.805 mmol) and commercial 5-[2-(methylthio)pyrimidin-4-yl]thiophene-2-sulphonyl chloride (0.272 g, 0.886 mmol). Purification on Biotage KP-Sil eluting with 25% EtOAc/pet. ether gave 0.299 g (58%) of the title compound as a yellow solid, mp 100-110° C. 1H NMR (DMSO-d6) δ 1.32-1.37 (m, 2 H), 1.45-1.65 (m, 8 H), 1.84-1.90 (m, 1 H), 2.37 (s, 3 H), 2.55 (s, 3 H), 3.15 (quintet, 1 H), 7.25-7.38 (m, 5 H), 7.44 (ddd, 1 H), 7.90 (d, 1 H), 7.96 (d, 1 H), 8.08 (d, 1 H), 8.27 (d, 1 H), 8.48 (s, 1 H), 8.77 (d, 1 H). mass spectrum (+APCI) m/z 643 (M+H). C34H30N2O3S4 : C, 63.52; H, 4.70; N, 4.36. Found: C, 63.18; H, 4.46; N, 4.19.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[C:18]([F:39])=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26](=[O:37])[NH:27][C:28]2[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[O:30][N:29]=2)[C:21]([CH3:38])=[CH:20]3)[N:13]=[CH:12][N:11]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:33]([C:31]1[O:30][N:29]=[C:28]([NH:27][C:26]([N:22]2[C:23]3[C:19](=[C:18]([F:39])[C:17]([O:16][C:14]4[CH:15]=[C:10]([CH2:9][NH:7][CH3:6])[N:11]=[CH:12][N:13]=4)=[CH:25][CH:24]=3)[CH:20]=[C:21]2[CH3:38])=[O:37])[CH:32]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1cc2c(F)c(Oc3cc(CN(C)C(=O)OC(C)(C)C)ncn3)ccc2n1C(=O)Nc1cc(C(C)(C)C)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(Oc2ccc3c(cc(C)n3C(=O)Nc3cc(C(C)(C)C)on3)c2F)ncn1

Procedure:
To a solution of {6-[1-(5-tert-Butyl-isoxazol-3-ylcarbamoyl)-4-fluoro-2-methyl-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-methyl-carbamic acid tert-butyl ester (0.25 g, 0.452 mmol) in DCM (10 mL) is added TFA (1.5 mL). After 3 h the solvent is removed by rotary evaporation and the residue is diluted with DCM and water. Concentrated NH4OH is added to neutralize and the aqueous phase is extracted twice with DCM. The organic layers are washed with brine, dried over Na2SO4, and concentrated to give the title compound. MS (ESI) m/z 453.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (d, J=1.01 Hz, 1H) 7.52 (d, J=8.59 Hz, 1H) 7.19 (s, 1H) 7.15 (dd, J=8.72, 7.71 Hz, 1H) 6.65 (s, 1H) 6.58 (s, 1H) 3.76 (s, 2H) 2.56 (s, 3H) 2.33 (s, 3H) 1.34 (s, 9H).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]=[C:18]3[NH2:26])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CC1C=CC=CC=1>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[N:26][C:33](=[O:35])[CH3:34])[CH2:10][CH2:9]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1nc2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)N=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 10.7 parts of 1-{3-[4-(diphenylmethyl)piperazinyl]propyl}-1H-benzimidazol-2-amine, 5.1 parts of acetic acid anhydride and 90 parts of methylbenzene is stirred and refluxed for 5 hours. The reaction mixture is evaporated and the residue is stirred in water. The whole is alkalized with ammonium hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from ethanol. The product is filtered off and dried, yielding N-[1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-ylidene]acetamide; mp. 143.3° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O-:16])=[O:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>C(O)C>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])Cc1ccc(-c2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(-c2ccccc2)cc1
Yield: 462.5 %

Procedure:
A suspension of (4′-biphenyl)acetate acid (6.4 g) in 60 ml of ethanol is added with 1.1 g of para-toluensulfonic acid, then the reaction mixture is refluxed for 4 hours 30 minutes. The solvent is evaporated off, the residue is dissolved in diethyl ether and the resulting organic phase is washed three times with a saturated aqueous solution of sodium hydrogencarbonate and once with brine. The organic phase is then dried over sodium sulfate and the solvent is evaporated off to give 7.1 g of the product as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].F[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc(C(F)(F)F)n1
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(C)(C)C)cc1Oc1cccc(C(F)(F)F)n1
Temperature: 70 °C
Yield: 40.8 %

Procedure:
A mixture of methyl 4-tert-butyl-2-hydroxybenzoate (0.70 g, 3.4 mmol), 2-fluoro-6-(trifluoromethyl)pyridine (0.55 g, 3.4 mmol), and Cs2CO3 (1.1 g, 3.4 mmol) in DMF (15 mL) was heated at 70° C. for 19 hours. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine and water, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel with 0-15% ethyl acetate in hexanes to give methyl 4-tert-butyl-2-(6-(trifluoromethyl)pyridin-2-yloxy)benzoate (0.49 g, 41% yield). LC/MS: m/z 354.3 (M+H)+ at 2.13 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1>>[CH3:25][O:24][C:21]1[N:22]=[CH:23][C:18]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:30]4[CH:31]=[N:26][CH:27]=[N:28][CH:29]=4)[CH:3]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)=[CH:19][N:20]=1
Reactant: COc1ncc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)cn1
Reactant: OB(O)c1cncnc1
Product: COc1ncc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3ccccc32)cn1
Yield: 54 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-methoxypyrimidin-5-yl)-1H-isoindol-3-amine (Example 106) as described in Example 67 Scheme #10, D in 54% yield using pyrimidine-5-boronic acid. 1H NMR (DMSO-d6) δ 9.18 (s, 1 H), 9.05 (s, 2H), 8.55 (s, 2 H), 7.98-8.11 (m, 1 H), 7.79-7.88 (m, 1 H), 7.70-7.77 (m, 1 H), 7.67 (d, J=7.58 Hz, 1 H), 7.41-7.57 (m, 4 H), 6.96 (br s, 2 H), 3.87 (s, 3 H); MS (ESI) m/z 395 [M+1]+.
Reaction SMILES: [C:1]([C:6]1[C:10]([OH:11])=[CH:9][N:8]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[N:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[H-].[Na+].[Cl:26][C:27]([F:31])=[C:28]([F:30])[F:29]>O1CCOCC1>[C:1]([C:6]1[C:10]([O:11][C:28]([F:30])([F:29])[CH:27]([Cl:26])[F:31])=[CH:9][N:8]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:20])([F:22])[F:21])=[CH:14][C:13]=2[Cl:23])[N:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1O
Reactant: FC(F)=C(F)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1OC(F)(F)C(F)Cl
Reaction time: 6 h

Procedure:
3-Carboethoxy-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-hydroxypyrazole (2.0 g) was added to a stirred suspension of sodium hydride (80% dispersion in oil; 0.2 g) in dry dioxan (20 ml). When the resultant effervescence had subsided, the solution was heated to 80°-900 °C. and stirred while 2-chloro-1,1,2-trifluoroethylene was passed through. After 6 hours, the reaction was complete and the solvent was evaporated to dryness. The residue was dissolved in dilute hydrochloric acid (2M; 10 ml) and dichloromethane (20 ml) and the layers were separated. The aqueous layer was extracted with dichloromethane (30 ml) and the combined organic layers were washed with water (20 ml), dried over magnesium sulfate, filtered and evaporated. The residue was purified by dry-column chromatography (eluant ether:hexane 1:3) to give (RS)-3-carboethoxy-4-(2-chloro-1,1,2-trifluoroethoxy)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (1.0 g). This was recrystallised from hexane to yield colorless needles, m.p. 105°-106.5° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[N:16][N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=34)[N:9]=2)[CH2:2]1.Br[C:24]1[N:28]=[CH:27][NH:26][N:25]=1>>[N:25]1[N:26]=[C:27]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]3[CH:13]=[CH:12][N:11]=[C:10]([C:14]4[CH:15]=[N:16][N:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=45)[N:9]=3)[CH2:2]2)[NH:28][CH:24]=1
Reactant: Brc1nc[nH]n1
Reactant: c1ccn2ncc(-c3nccc(N[C@@H]4CCCNC4)n3)c2c1
Product: c1ccn2ncc(-c3nccc(N[C@@H]4CCCN(c5nnc[nH]5)C4)n3)c2c1
Temperature: 150 °C
Yield: 52.1 %

Procedure:
A mixture of (R)—N-(piperidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-amine (Preparation 34, 298 mg, 1.01 mmol) and 3-bromo-1H-1,2,4-triazole (75 mg, 0.51 mmol, prepared as described in Journal of Medicinal Chemistry, 2004, 47 (19), 4645-4648) was heated at 150° C. overnight. The crude mixture was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (96 mg, 52%) as a white solid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:37][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:29])[F:28])[N:25]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[Cl:36]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)c2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(3,4-dichloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.39 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (4 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield the title compound as an off-white solid (0.24 g, 51%). MS (ISN) 527.9 [(M−H)−]; mp 203° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[N:27]=[C:26]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[C:35]([NH2:37])=[O:36])[CH:25]=[CH:24][CH:23]=1>>[NH2:9][C:7]([C:6]1[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:12][C:11]=2[F:20])[S:3][C:2]=1[NH:1][C:22]1[N:27]=[C:26]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[C:35]([NH2:37])=[O:36])[CH:25]=[CH:24][CH:23]=1)=[O:8]
Reactant: NC(=O)C1COCCN1Cc1cccc(Br)n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCOCC4C(N)=O)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (80 mg, 0.27 mmol) and 4-[(6-bromopyridin-2-yl)methyl]morpholine-3-carboxamide (82 mg, 0.27 mmol) as starting materials.
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[CH:13]=2)[N:8]=[C:7]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])[CH:6]=1)C=C.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][NH2:34])[CH:28]=1>>[F:24][C:22]1[CH:21]=[CH:20][C:19]([O:25][CH3:26])=[C:18]([CH:23]=1)[CH2:17][NH:16][C:7]1[CH:6]=[C:5]([NH2:4])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:34][CH2:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)[CH:13]=2)[N:8]=1
Reactant: NCc1cccnc1
Reactant: C=CCNc1cc(NCc2cc(F)ccc2OC)nc2ccc(Cl)cc12
Product: COc1ccc(F)cc1CNc1cc(N)c2cc(NCc3cccnc3)ccc2n1

Procedure:
The title compound, MS: m/e=404.5 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(5-fluoro-2-methoxy-benzyl)-quinoline-2,4-diamine and 3-picolylamine
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:32])[N:11]([CH2:15][C:16](=[O:31])[N:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[OH:8][C:9]1[C:10](=[O:32])[N:11]([CH2:15][C:16](=[O:31])[N:17]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C(Cn1cccc(OCc2ccccc2)c1=O)N(Cc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(Cn1cccc(O)c1=O)N(Cc1ccccc1)c1ccccc1
Yield: 22 %

Procedure:
18 (280 mg, 0.7 mmol) was suspended in 150 mL of EtOH. 10% (w/w, 38 mg) of 10% Pd/C catalyst was added to the hydrogenation flask (500 mL Pyrex® Parr reaction bottle tested to 120 psi, max. working pressure of 60 psi). The hydrogen pressure was set to 35 psi with agitation, and the process went on for 19 h. The catalyst was removed by vacuum filtration and separated from the product by dissolving the white precipitate in 100 mL hot CH2Cl2. An additional batch of product was isolated by cooling the EtOH filtrate to 0° C. for 2 h. The clear solution was concentrated by rotary evaporation to yield a white solid. The solid was washed with MeOH to remove residual DCU. Yield: 22%. 1H NMR (d6-DMSO, 400 MHz, 25° C.): δ 4.34 (d, J=6.0 Hz, 2H, —CH2—), 4.63 (s, 2H, —CH2—), 6.08 (t, J=7.2 Hz, 1H, Ar—H), 6.69 (d, J=7.2 Hz, 1H, Ar—H), 7.10 (d, J=6.4 Hz, 1H, Ar—H), 7.44 (m, 5H, Bz—H), 7.64 (m, 4H, Phenyl-H), 8.70 (t, J=5.6 Hz, 1H, —NH—), 9.02 (s, 1H, —OH). APCI-MS: m/z 334.9 [M+H]+. Anal. Calcd for C20H18N2O3: C, 71.84; H, 5.43; N, 8.38. Found: C, 71.49; H, 5.78; N, 8.52.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)([OH:15])[CH2:6][CH2:5]2.[CH3:29][NH2:30]>CCO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17][NH:30][CH3:29])([OH:15])[CH2:6][CH2:5]2
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@]2(O)CCc3cc(F)ccc3[C@@H]2C(C)C)cc1
Solvent: ClCCl
Solvent: CCO
Product: CNCC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
8 g of toluene-4-sulfonic acid 2-((1S,2S)-6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl ester were dissolved in a 8 M solution of MeNH2 in EtOH (100 mL). The mixture was stirred overnight in at 40° C., diluted with DCM and washed with sat.-NaHCO3. The organic phase was dried over anh. Na2SO4 and concentrated to give 5.29 g of (1S,2S)-6-fluoro-1-isopropyl-2-(2-methylamino-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol as beige solid.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:6]=[C:7]([NH:17][C:18]2[N:35]=[C:21]3[CH:22]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:23][C:24](=[O:27])[CH2:25][CH2:26][N:20]3[N:19]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:16])=[N:12]1>C1COCC1.[Cu]I>[F:4][C:5]1[CH:6]=[C:7]([NH:17][C:18]2[N:35]=[C:21]3[C@@H:22]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:23][C@:24]([CH3:1])([OH:27])[CH2:25][CH2:26][N:20]3[N:19]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:16])=[N:12]1
Reactant: Cc1ncn(-c2ccc(Nc3nc4n(n3)CCC(=O)CC4c3ccc(F)cc3)cc2F)n1
Reactant: C[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: Cc1ncn(-c2ccc(Nc3nc4n(n3)CC[C@@](C)(O)C[C@@H]4c3ccc(F)cc3)cc2F)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 7 %

Procedure:
A 25 mL round bottom flask was charged with copper (I) iodide (26.2 mg, 0.138 mmol) in THF (4 mL), and cooled to 0° C. A solution of methyl magnesium bromide (4.92 mL, 6.89 mmol) was added dropwise. The mixture was stirred for 20 min. To the solution of methyl cuprate was added 2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (300 mg, 0.689 mmol) in THF (1 mL). The mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched with saturated ammonium chloride and diluted with EtOAc. The organic layer was sequentially washed with H2O (100 mL), aq sat. NaHCO3 solution (100 mL), and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford (7S,9R)-2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-9-(4-fluorophenyl)-7-methyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-7-ol (21 mg, 7% yield, Example 155, first to elute) and (7R,9R)-2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-9-(4-fluorophenyl)-7-methyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-7-ol (43.7 mg, 11% yield, Example 154). Data for Example 153: LC-MS (M+H)+ 452.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.71 (1 H, br. s.), 8.55 (1 H, br. s.), 7.59-7.68 (2 H, m), 7.21-7.28 (2 H, m), 7.06-7.18 (3 H, m), 4.58-4.67 (2 H, m), 4.39 (1 H, ddd, J=14.8, 5.0, 2.4 Hz), 2.50 (3 H, s), 2.17-2.26 (1 H, m), 2.10-2.16 (1 H, m), 1.99-2.07 (1 H, m), 1.89-1.98 (1 H, m), 1.44 (3 H, s). Data for Example 153: LC-MS (M+H)+ 452.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.40 (1 H, d, J=2.4 Hz), 7.58-7.69 (2 H, m), 7.21 (2 H, dd, J=8.5, 5.2 Hz), 7.16 (1 H, s), 7.07-7.13 (2 H, m), 7.03 (1 H, dd, J=8.9, 2.1 Hz), 4.54 (1 H, ddd, J=14.8, 8.4, 2.1 Hz), 4.22 (1 H, ddd, J=14.9, 8.8, 1.7 Hz), 4.03-4.11 (1 H, m), 2.51 (3 H, s), 2.42 (1 H, dd, J=14.0, 10.7 Hz), 2.02-2.17 (4 H, m), 1.51 (3 H, s).