Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH:18]1[CH2:23][CH2:22][CH:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:20][CH2:19]1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[OH:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][CH:18]2[CH2:19][CH2:20][CH:21]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH2:22][CH2:23]2)[CH:33]=[CH:34][C:35]=1[OH:36]
Reactant: OB(O)c1ccc(O)c(Cl)c1
Reactant: CCN(CC)C1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CCN(CC)C1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(-c4ccc(O)c(Cl)c4)cc23)CC1
Yield: 33.4 %

Procedure:
Following general procedure F, {6-bromo-4-[4-(diethylamino)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (65 mg, 0.146 mmol) was reacted with 3-chloro-4-hydroxyphenyl boronic acid (38 mg, 0.219 mmol) to afford the desired product (24 mg, 33%) as a light yellow-brown solid: 1H NMR (500 MHz, CD3OD) δ 9.29 (s, 0.5H), 9.20 (s, 0.5H), 8.38 (s, 1H), 8.12-8.04 (m, 1H), 7.98-7.91 (m, 1H), 7.74 (d, J=2.3 Hz, 0.5H), 7.68 (d, J=2.3 Hz, 0.5H), 7.58-7.48 (m, 1H), 7.06 (dd, J=9.5, 8.5 Hz, 1H), 3.59-3.49 (m, 1H), 3.45-3.15 (m, 4H), 2.98-2.83 (m, 1H), 2.45 (d, J=11.9 Hz, 1H), 2.30-2.19 (m, 2H), 2.11-1.88 (m, 4H), 1.86-1.70 (m, 2H), 1.38 (q, J=7.4 Hz, 6H), 1.27-1.20 (m, 2H), 1.19-1.10 (m, 2H); ESI MS m/z 492 [C29H34ClN3O2+H]+; HPLC 97.5% (AUC), tR=4.53 min.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][CH3:18])(=[O:16])[CH2:14][SH:15].[CH2:19]([SH:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>ClCCl>[CH3:18][O:17][C:13]([CH2:14][S:15][S:27][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:16]
Reactant: COC(=O)CS
Reactant: CCCCCCCCS
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: ClCCl
Product: CCCCCCCCSSCC(=O)OC
Reaction time: 1.5 h

Procedure:
In a N2 purged flask there was dissolved Diethyl azodicarboxylate (5.0 g, 28.71 mmol) in dichloromethane (150 mL). A solution of Methyl thioglycolate (2.89 g, 27.27 mmol) in dichloromethane (50 mL) was then added dropwise at room temperature over 20 minutes. After 1.5 hours stirring, a solution of octanethiol (4.8 mL, 27.27 mmol) in dichloromethane (50 mL) was added dropwise over 20 minutes, and the resulting solution was stirred for an additional 12 hours at room temperature. The solvent was then removed under reduced pressure, and the resulting oil was then purified over flash silica with 5% ethyl acetate in hexanes to yield MeOC(O)CH2SSC8H17 as a clear, colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br)[CH3:2].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:18]1[C:14](=[O:24])[C:15]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17]1=[O:19])[CH3:2]
Reactant: CCOC(=O)CCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCN1C(=O)c2ccccc2C1=O
Yield: 79.4 %

Procedure:
A mixture of 26.4 g (0.1 mole) of ethyl-8-bromooctanoate (95%, Pfaltz and Bauer) and 19.6 g (0.1 mole) of potassium phthalimide (98%, Aldrich) in 250 mL of dimethylformamide was stirred and heated at reflux for 4 hr. The solvent was evaporated under reduced pressure and the viscous residue was partitioned between ethyl ether and water (400 mL each). The aqueous layer was further extracted with two 200 mL of ethyl ether. The combined ether extracts were washed with 200 mL of water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the viscous, oily residue was triturated with ethyl ether-petroleum ether (30°-60° C.) and the resulting solid was collected by filtration. The filtrate was evaporated under reduced pressure to give 25.2 g (79%) of crude title compound as a viscous oil. A 2.0 g sample of this oil was purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500A; PrepPak® 500 silica; ethyl acetate-hexanes, 1:20; flow rate: 200 mL/min.). Fractions containing title compound were combined and the solvents were evaporated under reduced pressure to give 1.9 g (95% recovery) of clear liquid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f15) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[C:11]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:10][CH:9]=1.Cl[CH2:29][C:30]1[CH:49]=[CH:48][C:33]([O:34][CH2:35][C:36]2[N:37]=[C:38]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:39][C:40]=2[CH3:41])=[C:32]([O:50][CH3:51])[CH:31]=1>O>[CH3:51][O:50][C:32]1[CH:31]=[C:30]([CH:49]=[CH:48][C:33]=1[O:34][CH2:35][C:36]1[N:37]=[C:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:39][C:40]=1[CH3:41])[CH2:29][N:19]1[C:20]2[CH:8]=[CH:9][CH:10]=[C:11]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:12]=2[C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)COc1cccc2[nH]c3ccccc3c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1c1ccccc1n2Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
18 mg of sodium hydride (60%) was added to N,N-dimethylformamide (5 mL) solution of 107 mg of ethyl 2-(9H-carbazole-4-yloxy)acetate, and stirred at room temperature for 20 minutes. Thereafter, 144 mg of 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-5-methyl-2-phenyloxazole was added thereto, and stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The combined extract was washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, the residue was crystallized from methanol, isolated by filtration, and washed with methanol. The residue was dried under reduced pressure, and 107 mg of the subject compound was prepared as white crystal.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:25])OCC(Cl)(Cl)Cl)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[C:28]([CH3:45])=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:35][CH2:34]2)=[N:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:26][C:27]2[CH:32]=[N:31][C:30]([N:33]3[CH2:34][CH2:35][N:36]([C:39](=[O:44])[C:40]([CH3:42])([CH3:41])[CH3:43])[CH2:37][CH2:38]3)=[CH:29][C:28]=2[CH3:45])=[O:25])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Cc1cc(N2CCN(C(=O)C(C)(C)C)CC2)ncc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cnc(N3CCN(C(=O)C(C)(C)C)CC3)cc2C)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Add (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid, 2,2,2-trichloro-ethyl ester (Preparation 38, 0.32 mmol, 0.1 r) over a solution of 1-[4-(5-amino-4-methyl-pyridin-2-yl)-piperazin-1-yl]-2,2-dimethyl-propan-1-one (0.3 mmol, 0.08 g) and potassium carbonate (0.3 mmol, 0.05 g) in acetonitrile (3 mL), and stir the solution for 4 hours at 80° C. Add water and extract with CH2Cl2. Combine the organic layers and wash with saturated aq. sodium chloride. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Subject residue to silica gel chromatography eluting with hexanes/ethyl acetate in gradient (from 20% to 80%). MS(ES+): m/z=532 [M+H].
Reaction SMILES: [C:1]([C:3]1[N:4](C(OC(C)(C)C)=O)[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([F:17])[CH:16]=2)[NH:13][C:12](=[O:18])[C:11]3([CH3:20])[CH3:19])=[CH:6][CH:7]=1)#[N:2]>CC(N(C)C)=O.C(OCC)(=O)C>[F:17][C:15]1[CH:16]=[C:8]([C:5]2[NH:4][C:3]([C:1]#[N:2])=[CH:7][CH:6]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12](=[O:18])[C:11]2([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1cc(F)c2c(c1)C(C)(C)C(=O)N2
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)Nc2c(F)cc(-c3ccc(C#N)[nH]3)cc21
Temperature: 180 °C
Yield: 89.9 %

Procedure:
tert-butyl 2-cyano-5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrrole-1-carboxylate (0.18 g, 0.50 mmol) was dissolved in 10 mL of dimethylacetamide and the solution was heated to 180° C. for 1 h. The mixture was cooled, diluted with ethyl acetate and washed with water, saturated aqueous NaCl, dried over MgSO4, and concentrated. Flash chromatography (25% acetone/hexane) afforded 0.121 g (91%) of the title compound as a white solid.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([O:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:16]1[C:17]2[NH:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[C:14]([C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][O:29][C:28]3=[O:32])[CH:21]=[N:20][CH:19]=2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(OCCN4CCOC4=O)c3)cnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OCCN1CCOc1cncc(-c2cnc3c(c2)CCCN3)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-{5-[2-(2-Oxo-oxazolidin-3-yl)-ethoxy]-pyridin-3-yl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (0.305 mmol) is dissolved in 2 mL of a 20% TFA solution in CH2Cl2 and the solution is shaken overnight at room temperature. The reaction is evaporated to dryness to give crude 3-{2-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yloxy]-ethyl}-oxazolidin-2-one and used as is in the next step.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]([O:15][C:16](OC1CC(=O)NC1=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[C:16]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17]
Reactant: O=C1CC(OC(=O)OCc2ccccc2)C(=O)N1
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N(CCO)CCO
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a 0° C. solution of diethanolamine (1.9 ml, 20 mmol) in 50 ml of THF was added benzyloxycarbonyloxysuccinimide (5.0 g, 20 mmol) followed by the slow addition of a solution of sodium carbonate (3.2 g, 30 mmol) in 50 ml of water. The reaction was stirred at 0° C. for 2 hours, diluted with 50 ml of water, and the majority of the THF was removed under vacuum. The reaction mixture was extracted with ethyl acetate (2×75 ml), washed with brine and dried over sodium sulfate. The solvent was concentrated and the residue was purified by SiO2 chromatography (250 g SiO2, 8% MeOH/methylene chloride) to give N-Cbz-diethanolamine (4.25 g) as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12)[NH2:5].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:32](=[O:33])[C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=[N:28]2)=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]([C:31]2[C:32](=[O:33])[N:27]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[N:28]=[CH:29][CH:30]=2)=[O:35])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A, 1.00 g, 2.59 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (0.728 g, 3.11 mmol, example 104, step C), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.596 g, 3.11 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.420 g, 3.11 mmol), N-ethyl-N-isopropylpropan-2-amine (0.669 g, 5.178 mmol) and DMF (50 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (200 mL) and H2O (200 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×200 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (1.34 g, 85.8%). LRMS (APCI pos): >99% purity, 254 nm, m/e 603 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.85 (s, 1H), 8.43 (m, 2H), 8.24 (d, 1H), 7.96 (dd, 1H), 7.77 (s, 1H), 7.60 (m, 2H), 7.40 (m, 1H), 7.21-7.28 (m, 3H), 6.48 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:19])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1.I[CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:19])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: COc1nc(N)ccc1C(=O)CCC1CCNCC1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN1CCC(CCC(=O)c2ccc(N)nc2OC)CC1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A mixture of 1-(6-amino-2-methoxy-3-pyridinyl)-3-(4-piperidinyl)-1-propanone (step 1, 175 mg, 0.665 mmol), 1-iodobutane (0.083 ml, 0.732 mmol) and potassium carbonate (184 mg, 1.33 mmol) in tetrahydrofuran (5 ml) was refluxed for 6 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 ml), washed with water (5 ml) and brine (10 ml) and dried over potassium carbonate. Removal of solvent gave the pale yellow oil, which was chromatographed on a column of silica gel eluting with 25% ammonium hydroxide/methanol/dichloromethane (0.2:1:10) to give pale yellow solid, which was washed with acetonitrile to afford 107.0 mg (50%) of the title compound as pale yellow solids.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.Br[C:28]1[CH:29]=[N:30][C:31]([Cl:34])=[N:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([C:28]3[CH:29]=[N:30][C:31]([Cl:34])=[N:32][CH:33]=3)=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)CC1CCC(c2ccc(-c3cnc(Cl)nc3)cc2)CC1
Temperature: 120 °C

Procedure:
PdCl2dppf (120 mg, 0.140 mmol) is added to a degassed mixture of {4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (1.00 g, 2.79 mmol), 5-bromo-2-chloro-pyrimidine (540 mg, 2.79 mmol), 2 M Na2CO3 (2.8 mL), and DME (7.5 mL). The mixture is sealed in a glass tube and heated to 120° C. for 20 min by microwave irradiation. The reaction is diluted with EtOAc (150 mL), and the resulting suspension filtered. The filtrate is extracted with 1 N HCl (25 mL) and the organic layer dried over Na2SO4. Concentration followed by silica gel chromatography (20% EtOAc/Hexanes) affords {4-[4-(2-chloro-pyrimidin-5-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δppm 1.14-1.27 (m, 2H) 1.49-1.61 (m, 2H) 1.86-1.98 (m, 5H) 2.28 (d, J=6.82 Hz, 2H) 2.56 (tt, J=12.22, 3.19 Hz, 1H) 3.70 (s, 3H) 7.37 (d, J=8.08 Hz, 2H) 7.49 (d, J=8.34 Hz, 2H) 8.81 (s, 2H); (M+H)+345.1.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.[Cl:43][C:44]1[C:45]([NH:73][C:74](=[O:95])[C:75]2[CH:80]=[CH:79][C:78]([N:81]3[CH2:86][CH2:85][N:84]([C:87](=[O:93])[C:88]([CH3:92])([CH3:91])[CH2:89][OH:90])[CH2:83][C@H:82]3[CH3:94])=[N:77][CH:76]=2)=[CH:46][C:47]([O:68][C:69]([F:72])([F:71])[F:70])=[C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[N:57]=[C:58]([C@@H:61]4[CH2:65][C@H:64]([O:66][CH3:67])[CH2:63][NH:62]4)[NH:59][CH:60]=3)=[CH:52][CH:51]=2)[CH:49]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([N:62]1[CH2:63][C@@H:64]([O:66][CH3:67])[CH2:65][C@H:61]1[C:58]1[NH:59][CH:60]=[C:56]([C:53]2[CH:52]=[CH:51][C:50]([C:48]3[CH:49]=[C:44]([Cl:43])[C:45]([NH:73][C:74]([C:75]4[CH:76]=[N:77][C:78]([N:81]5[CH2:86][CH2:85][N:84]([C:87](=[O:93])[C:88]([CH3:91])([CH3:92])[CH2:89][OH:90])[CH2:83][C@H:82]5[CH3:94])=[CH:79][CH:80]=4)=[O:95])=[CH:46][C:47]=3[O:68][C:69]([F:71])([F:72])[F:70])=[CH:55][CH:54]=2)[N:57]=1)=[O:9]
Reactant: CO[C@@H]1CN[C@H](c2nc(-c3ccc(-c4cc(Cl)c(NC(=O)c5ccc(N6CCN(C(=O)C(C)(C)CO)C[C@H]6C)nc5)cc4OC(F)(F)F)cc3)c[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)C(C)(C)CO)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C1CCOCC1
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
To a solution of (S)-methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (37.6 mg, 0.17 mmol) in DMA (1 mL) was added HATU (65.9 mg, 0.17 mmol). The reaction mixture was stirred for 15 min and N-{5-chloro-4′-[2-((2S,4S)-4-methoxy-pyrrolidin-2-yl)-1H-imidazol-4-yl]-2-trifluoromethoxy-biphenyl-4-yl}-6-[(R)-4-(3-hydroxy-2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-nicotinamide 3HCl (100 mg, 0.12 mmol; Preparation 34) was added followed by DIPEA (0.10 mL, 0.58 mmol) and the reaction mixture was stirred at RT overnight, concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water (4 mL) and purified by reverse phase HPLC. Fractions containing the desired compound were combined and lyophilized to provide the di-TFA salt of the title compound (65.2 mg) as a white powder. Impure fractions were lyophilized, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide additional di-TFA salt of the title compound (75 mg total, 55% yield). (m/z): [M+H]+ calcd for C46H54ClF3N8O9 955.37. found 955.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[F:16][C:17]([F:37])([F:36])[C:18]1[C:27]([C:28](Cl)=[O:29])=[C:26]([OH:31])[C:25]2[C:20](=[C:21]([C:32]([F:35])([F:34])[F:33])[CH:22]=[CH:23][CH:24]=2)[N:19]=1>C(OCC)(=O)C.[OH-].[Na+]>[F:36][C:17]([F:16])([F:37])[C:18]1[C:27]([C:28]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)=[O:29])=[C:26]([OH:31])[C:25]2[C:20](=[C:21]([C:32]([F:35])([F:33])[F:34])[CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Reactant: Nc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Cl)c1)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Temperature: 25 °C
Yield: 54.6 %

Procedure:
A solution of 4.083 g of m-chloroaniline, 9.71 g of triethylamine and 65 ml of ethyl acetate was poured over 15 minutes at 8° C.-10° C. into a solution of 11.96 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-3-quinoline-carboxylic acid chloride in 130 ml of ethyl acetate with violent stirring and the temperature was allowed to return to room temperature. The mixture was refluxed for one hour and was cooled and vacuum filtered. The filtrate was washed with water, was dried and evaporated to dryness at 40° C. under reduced pressure to obtain 17.14 g of a triethylamine salt. The residue was dissolved in 2 N sodium hydroxide solution which was then heated to reflux and cooled to room temperature. The mixture was vacuum filtered and the recovered product was dissolved in water. The solution was adjusted to a pH of 1 by addition of 20% hydrochloric acid and the mixture was vacuum filtered. The recovered product was crystallized from benzene to obtain 7.599 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-N-(3-chlorophenyl)-3-quinolinecarboxamide melting at 152° C.
Reaction SMILES: C([Mg]Cl)CCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1.CN(C)[CH:22]=[O:23]>O1CCCC1.CCCCCC.C(O)(=O)C.C1(C)C=CC=CC=1>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([CH:22]=[O:23])=[CH:14][CH:15]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.5 %

Procedure:
n-Butylmagnesium chloride (4.00 mmol) in 2.00M tetrahydrofuran solution (2.00 mL) was added to ice-cooled n-butyllithium (8.06 mmol) in 1.55M hexane (5.20 mL). The mixture was stirred at 0° C. for 15 minutes to give a suspension. To the suspension was added dropwise a toluene solution (25 mL) containing 1,4-dibromobenzene (2.36 g, 10 mmol) over a period of 15 minutes, while keeping the temperature below 5° C., to give a white suspension. After the suspension was stirred at 0° C. for 5 hours, N,N-dimethylformamide (1.0 mL, 13 mmol) was added thereto. The resultant mixture was stirred at 0° C. for 30 minutes, and 10% acetic acid solution (20 mL) was added. The organic phase was separated and the aqueous phase was extracted with toluene (20 mL). The organic layers were combined, washed with water (20 mL), and dried over magnesium sulfate. Toluene was added to the solution to a volume of 100 mL. The solution (98 ml) was purified by flash column chromatography on silica gel in a developing solvent system of hexane-ethyl acetate (30:1, v/v) to give the title compound (1.507 g, 81% yield) as a colorless crystalline solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:9][CH3:10])[CH:3]=1.CC1(C)C(C)(C)CB([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)C1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)=[CH:3][C:4]=1[O:9][CH3:10]
Reactant: COc1cc(Br)ccc1N
Reactant: CC(C)(C)OC(=O)N1CC=C(B2CC(C)(C)C(C)(C)C2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Temperature: 90 °C

Procedure:
A mixture of 4-bromo-2-methoxybenzenamine (1.21 g, 6.0 mmol), tert-butyl 4-(3,3,4,4-tetramethylborolan-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.95 g, 6.3 mmol), sodium carbonate (1.91 g, 18 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.22 g, 0.3 mmol) in dioxane (25 mL) and water (5 mL) was degassed with nitrogen and heated to 90° C. for 15 hours. After cooling to ambient temperature, the mixture was filtered, concentrated and purified by flash chromatography eluting with 200:1 dichloromethane:methanol to give the title compound. MS: 305 (M+H+).