Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.C1COCC1>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]([CH2:14][OH:15])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Temperature: 25 °C

Procedure:
To a solution of 61.2 (0.87 g, 3.40 mmol) in 3:2 MeOH/THF (25 mL) was added NaBH4 (0.13 g, 3.40 mmol) as a solid in one portion. The mixture was stirred for 2 Hours at room temperature and concentrated. The residue was suspended in 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to afford 61.3 as a white powder. The crude product was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, 2H), 7.62 (d, 2H), 7.26 (d, 1H), 7.01 (d, 1H), 4.86 (d, 2H), 1.84 (t, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][CH2:13][C:14]([N:16]([C:18]2[C:19]([Cl:39])=[C:20]([C:35]([Cl:38])=[CH:36][CH:37]=2)[CH2:21][O:22][C:23]2[C:31]3[N:30]=[C:29]([O:32][CH3:33])[N:28]([CH3:34])[C:27]=3[CH:26]=[CH:25][CH:24]=2)[CH3:17])=[O:15])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH3:48][C:49]1[C:54]([C:55](Cl)=[O:56])=[CH:53][CH:52]=[CH:51][N:50]=1>ClCCl>[Cl:39][C:19]1[C:18]([N:16]([CH3:17])[C:14](=[O:15])[CH2:13][NH:12][C:10](=[O:11])/[CH:9]=[CH:8]/[C:5]2[CH:6]=[N:7][C:2]([NH:1][C:55]([C:54]3[C:49]([CH3:48])=[N:50][CH:51]=[CH:52][CH:53]=3)=[O:56])=[CH:3][CH:4]=2)=[CH:37][CH:36]=[C:35]([Cl:38])[C:20]=1[CH2:21][O:22][C:23]1[C:31]2[N:30]=[C:29]([O:32][CH3:33])[N:28]([CH3:34])[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(N)nc4)c3Cl)cccc2n1C
Reactant: Cc1ncccc1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(NC(=O)c5cccnc5C)nc4)c3Cl)cccc2n1C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a solution of 4-[3-[N-[(E)-3-(6-aminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole (100 mg) and triethylamine (53.3 mg) in dichloromethane (2 ml) was added 2-methyl-3-pyridinecarbonyl chloride hydrochloride (74.2 mg) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and then for 3 hours at ambient temperature. The reaction mixture was concentrated, and the residue was dissolved in methanol (3 ml). To the solution was added 1N sodium hydroxide solution (0.5 ml), and the mixture was stirred for 1 hour. Chloroform was added to the reaction mixture, and the solution was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol, 10:1, v/v) to give 4-[2,6-dichloro-3-[N-methyl-N-[(E)-3-[6-(2-methylpyridin-3-carboxamido)pyridin-3-yl]acryloylglycyl]amino]benzyloxy]-2-methoxy-1-methyl-1H-benzimidazole (99 mg).
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[CH3:7][S:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)(=[NH:10])=[O:9]>N1C=CC=CC=1>[CH2:3]([O:2][C:1](=[O:5])[N:10]=[S:8]([CH3:7])([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)=[O:9])[CH3:4]
Reactant: CS(=N)(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)N=S(C)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 105.7 %

Procedure:
Ethyl chlorocarbonate (8.1 mL; 84.6 mmol) was added dropwise to a stirred solution of (rac)-1-[(S-methylsulfonimidoyl)methyl]-3-nitrobenzene (13.9 g; 65.1 mmol) in pyridine (615 mL) at 0° C. The batch was slowly warmed to room temperature. After 24 hours the batch was concentrated and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated to give the desired product (19.7 g) that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:11])[CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:4]1[CH:3]=[C:2]([Cl:1])[C:9]([Cl:10])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Cc1cc(Cl)c(Cl)cc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)c(Cl)cc1CBr
Yield: 44.5 %

Procedure:
To a solution 4,5-Dichloro-2-methyl-benzonitrile 7 (6.3 g, 33.9 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (9.0 g, 50.8 mmol) and 2,2′-azobisisobutyronitrile (cat.). The reaction mixture was refluxed 6 hrs, filtered, concentrated, and partitioned between ether and water. The ether layer was dried, concentrated, and purified by silica gel chromatography (10% ether/hexanes) to yield the tittle compound 4.0 g. (45%). 1H NMR (400 MHz, CDCl3) δ7.75 (s, 1 H, Ar), 7.66 (s, 1 H, Ar), 2.55 (s, 2 H, CH3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][CH:3]=1.[CH3:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][NH:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:12]2[CH2:11][C@H:10]([CH3:9])[O:15][C@H:14]([CH3:16])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H]1CN(c2ccc(Br)cc2)C[C@H](C)O1
Temperature: 150 °C
Reaction time: 25 h

Procedure:
A mixture of 1-bromo-4-fluorobenzene (10 g), cis-2,6-dimethylmorpholine (7.74 ml) and potassium carbonate (15.8 g) in dimethylsulfoxide (50 ml) was stirred for 25 hours at 150° C. The reaction mixture was cooled and poured into water (500 ml), and stirred for 10 minutes. The reaction mixture was extracted with ethyl acetate (100 ml×2), washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give a crude yellow oil (680 mg). The crude oil was purified by silica gel chromatography (1:0-10:1 hexane-ethyl acetate) to give 4-(4-bromophenyl)-cis-2,6-dimethylmorpholine (360 mg).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[CH:39]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[O:37][N:36]=1>>[C:40]([C:38]1[O:37][N:36]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[CH:39]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)no1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)on4)c4ccccc43)cn12

Procedure:
The title compound was prepared starting from Intermediate 81d and (5-tert-butyl-isoxazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (for reference procedure see WO 2006/091671, which is incorporated herein by reference in its entirety) using analogous procedures to those described in Example 110 step c. LCMS (Method 5): Rt 4.67 min, m/z 544 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.28 (9H, s), 1.44-1.57 (2H, m), 1.60-1.73 (2H, m), 1.74-1.86 (2H, m), 1.88-2.22 (4H, m), 2.86-2.94 (1H, m), 3.12-3.20 (2H, m), 4.86-4.95 (1H, m), 5.54 (1H, t, J=4.2 Hz), 6.40 (1H, s), 7.00 (1H, d, J=8.6 Hz), 7.21-7.26 (1H, m), 7.27-7.33 (1H, m), 7.34-7.42 (3H, m), 7.64 (1H, dd, J=9.8, 0.8 Hz), 7.71 (1H, d, J=2.10 Hz), 9.31 (1H, s).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[N:12]([CH2:13][C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[N:11]=[C:10]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)[N:9]=1.Br[CH2:38][CH2:39][O:40][CH3:41]>CN(C=O)C.O>[CH3:41][O:40][CH2:39][CH2:38][O:20][C:16]1[CH:15]=[C:14]([CH2:13][N:12]2[C:8]([CH3:7])=[N:9][C:10]([C:21]3[O:25][N:24]=[C:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=4)[N:22]=3)=[N:11]2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(O)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)no3)nc2C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of K2CO3 (19.9 mg, 0.144 mmol), 3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)phenol (Example 59; 30.0 mg, 0.072 mmol) and 1-bromo-2-methoxyethane (19.9 mg, 0.144 mmol) in DMF (0.36 mL) was stirred at RT for 16 h. The mixture was diluted with H2O and extracted with 4:1 CHCl3:i-PrOH. The organic layer was separated, dried with MgSO4 and concentrated under reduced pressure. The residue was dissolved in DMSO and purified using Prep-HPLC to furnish the title compound. MS (ES+) C22H20F3N5O4 requires: 475. found 476 [M+H]+; 1H-NMR (600 MHz, CD3OD) δ ppm 8.29 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.28 (m, 1H), 6.91 (m, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.81 (m, 1H), 5.42 (s, 2H), 4.09 (m, 2H), 3.73 (m, 2H), 3.43 (s, 3H), 2.52 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)[C:5]([CH3:24])=[CH:4][N:3]=1.Cl.[CH3:26][N:27]1[C:35]([CH3:36])=[C:34]2[C:29]([CH:30]=[C:31]([NH2:37])[CH:32]=[CH:33]2)=[N:28]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:26][N:27]1[C:35]([CH3:36])=[C:34]2[C:29]([CH:30]=[C:31]([NH:37][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:10][CH:11]5[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:13][CH:12]5[CH2:23]4)[C:5]([CH3:24])=[CH:4][N:3]=3)[CH:32]=[CH:33]2)=[N:28]1
Reactant: Cc1c2ccc(N)cc2nn1C
Reactant: Cc1cnc(Cl)nc1NC1CC2CN(C(=O)OC(C)(C)C)CC2C1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 150 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a suspension of tert-butyl 5-((2-chloro-5-methylpyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (421.5 mg, 1.19 mmol) and 2,3-dimethylindazol-6-amine hydrochloride (734.5 mg, 3.72 mmol) in n-BuOH (10 mL) was added DIPEA (795.2 mg, 6.09 mmol). The reaction mixture was stirred at 150° C. under microwave for 2 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as brown oil (570.5 mg, 100%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3](O)=[O:4].[NH2:28][CH2:29][CH2:30][OH:31].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH3:24])=[CH:20][CH:21]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3]([NH:28][CH2:29][CH2:30][OH:31])=[O:4]
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C(=O)O)ccc2-3)cc1
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C(=O)NCCO)ccc2-3)cc1
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of 2-hydroxy-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetic acid (Example 127, 18 mg, 0.050 mmol) in DMF (1 mL) was added 2-aminoethanol (5.45 mg, 0.089 mmol), 4-methylmorpholine (0.033 mL, 0.29 mmol) and BOP (39.4 mg, 0.089 mmol). The reaction mixture was stirred overnight and was then purified by preparative HPLC (Phenomenex Luna 5 u C18 21.2×100 mm, Solvent A: 90% water with 10% MeOH and 0.1% TFA, Solvent B: 90% MeOH with 10% water and 0.1% TFA, Gradient: 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=11.9 min) to give 2-hydroxy-N-(2-hydroxyethyl)-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetamide (14.5 mg, 0.033 mmol, 67.4% yield): product HPLC ret. time=8.79 min. (condition G); LC/MS M+1=407.1; 1H NMR (400 MHz, CD3OD) δ ppm 7.87 (1H, d, J=7.92 Hz), 7.72 (2H, d, J=8.36 Hz), 7.44-7.55 (2H, m), 7.37 (2H, d, J=8.36 Hz), 5.07 (1H, s), 3.58-3.69 (2H, m), 3.34-3.43 (2H, m), 3.05 (4H, s), 2.59-2.74 (2H, m), 1.61-1.80 (2H, m), 0.97 (3H, t, J=7.37 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][C:7]=3[N:8]([CH2:11][CH3:12])[C:9]=2[CH:10]=1.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][N:35]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][C:7]=4[N:8]([CH2:11][CH3:12])[C:9]=3[CH:10]=2)[C:34](=[O:38])[CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: CCn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: CCn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 48.1 %

Procedure:
Prepared from tert-butyl 7-bromo-5-ethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (500 mg, 1.32 mmol) and 4-benzyloxypyridone (265 mg, 1.32 mmol), according to the procedure of Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) gave the title compound (317 mg, 48%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=8.2 Hz, 1H), 7.44-7.37 (m, 5H), 7.32-7.29 (m, 2H), 7.04 (d, J=8.0 Hz, 1H), 6.10-6.03 (m, 2H), 5.08 (s, 2H), 4.66 (br s, 2H), 4.10 (q, J=7.1 Hz, 2H), 3.86 (br m, 2H), 2.84 (br m, 2H), 1.53 (s, 9H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CC(O)C.C([O-])(O)=O.[Na+]>[CH3:9][N:8]([CH:10]1[CH2:14][CH2:13][N:12]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:11]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccncc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccncc2)C1
Yield: 61 %

Procedure:
3-(N-Tert-butoxycarbonyl-N-methylamino)pyrrolidine (4.993 mmol, 1 eq) and 4-chloropyridine hydrochloride (14.979 mmol, 3 eq) were dissolved in 2-propanol (15 ml) and DIPEA (19.972 mmol, 4 eq) and refluxed for 16 h. After monitoring by thin-layer chromatography, the reaction solution was diluted with sat. NaHCO3 solution and extracted with ethyl acetate (3×20 ml). The combined org. phases were washed with sat. NaCl solution, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, ethyl acetate:ethanol 10:1+ammonia (25% aq)). Yield: 61%.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[N:7][NH:6][N:5]=1)([O-:3])=[O:2].Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:14][CH:10]([F:15])[N:6]1[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(C(F)F)n1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A 100-mL single-neck round-bottomed flask containing 4-nitro-2H-1,2,3-triazole (500 mg, 4.38 mmol, 1.0 eq.), sodium 2-chloro-2,2-difluoroacetate (1310 mg, 8.76 mmol, 2.0 eq.), K2CO3 (1140 mg, 8.76 mmol, 2.0 eq.), and acetonitrile (20 mL) was stirred at reflux for 5 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 4:1 petroleum ether/ethyl acetate to afford 159a (350 mg, 48%) as a brown liquid. 1H NMR (500 MHz, CDCl3) δ 8.38 (s, 1H), 7.39 (t, J=57.5 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]1[O:20][C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:13][CH2:12]1>C1COCC1>[CH2:11]1[O:20][C:14]2([CH2:19][CH2:18][N:17]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])[CH2:16][CH2:15]2)[O:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C1CC2(CCN1)OCCO2
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1N1CCC2(CC1)OCCO2

Procedure:
A solution of 1-fluoro-2-nitrobenzene (5.80 g, 41.1 mmol) and 4-piperidone ethylene ketal (6.68 g, 46.6 mmol) in THF (100 mL) was stirred at room temperature (2 h). The resulting mixture was washed with water and sodium bicarbonate solution. The aqueous layer was extracted with two portions of ethyl acetate and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (10% ethyl acetate/hexane) afforded the title compound (7).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.O>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4ccc(C(C)(C)C)cc4)c3)c2cc1OC
Temperature: 50 °C
Reaction time: 4 h
Yield: 36.7 %

Procedure:
To 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) in DMF (3 mL) was added 4-tert-butylphenyl isocyanate (54 μL, 0.3 mmol) and the solution stirred at 50° C. for 4 h. The reaction was allowed to cool to room temperature, diluted with H2O, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by column chromatography (25-100% EtOAc/hexanes) to give 1-(4-tert-butylphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (54 mg, 0.11 mmol, 38%). 1H NMR (300 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 7.60 (s, 1H), 7.56 (s, 1H), 7.40-7.21 (m, 7H), 6.91 (d, 1H), 3.99 (s, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 473 (M+14)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH:10](Cl)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:6][CH:5]=1.[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1>CC#N.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:23]2[C:22]([CH3:21])=[CH:26][C:25]([CH3:27])=[N:24]2)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:6][CH:5]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: COC(=O)c1ccc(C(Cl)c2cccc(OC)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Product: COC(=O)c1ccc(C(c2cccc(OC)c2)n2nc(C)cc2C)cc1
Temperature: 25 °C
Yield: 29.7 %

Procedure:
To a stirring solution of 4-[Chloro-(3-methoxy-phenyl)-methyl]-benzoic acid methyl ester (5.0 g, 17.3 mmol) in 87 mL CH3CN was added 3,5-dimethyl pyrazole (5.0 g, 51.8 mmol) and tetra-n-butyl ammonium iodide (3.2 g, 8.6 mmol). The mixture was heated to reflux for 24 h, cooled to room temperature and concentrated under reduce pressure. The crude oil was purified by flash chromatography with 30% ethyl acetate/hexanes, collecting 8 mL fractions. The product containing fractions were collected and concentrated under reduce pressure to give the desired product (1.8 g, 30%) as a clear yellow oil. 400 MHz 1H NMR (CDCl3) δ 7.97 (d, J=8.5 Hz, 2H), 7.19-7.25 (m, 3H), 6.81-6.83 (m, 1H), 6.68-6.73 (m, 2H), 6.52 (s, 1H), 5.85 (s, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 2.20 (s, 3H), 2.16 (s, 3H); MS (M+1) 351.2.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[C:9]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1.[Cl:23][C:24]1[N:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>CN1C(=O)CCC1>[Cl:23][C:24]1[N:29]=[CH:28][C:27]([O:30][C:8]2[C:9]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:26][CH:25]=1
Reactant: CC(=O)N1CCC(c2nccnc2Cl)CC1
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(Cl)nc2)CC1
Temperature: 130 °C

Procedure:
To a mixture of cesium carbonate (0.505 g, 1.55 mmol), 1-(4-(3-chloropyrazin-2-yl)piperidin-1-yl)ethanone (0.129 g, 0.538 mmol), and 6-chloropyridin-3-ol (0.140 g, 1.08 mmol) was added NMP (2 mL). The reaction mixture was degassed and heated to 130° C. for 2 h. The reaction mixture was diluted with EtOAc. The organic phase was washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (50% to 100% EtOAc (10% MeOH) in hexanes) gave 1-(4-(3-(6-chloropyridin-3-yloxy)pyrazin-2-yl)piperidin-1-yl)ethanone as a colorless oil that was used in the next step without further purification. MS (ESI, pos. ion) m/z: 333.2 (M+1).
Reaction SMILES: C(O)(=O)C.Br.[CH2:6]([C:8]1[CH:13]=[C:12](CC#N)[CH:11]=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=1)[CH3:7].[C:25]([O:28][CH2:29]C)(=[O:27])[CH3:26]>>[CH2:6]([C:8]1[CH:13]=[C:12]([CH2:26][C:25]([O:28][CH3:29])=[O:27])[CH:11]=[CH:10][C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1)[CH3:7]
Reactant: CCOC(C)=O
Reactant: CCc1cc(CC#N)ccc1-c1ccc(OC)cc1
Agent: Br
Solvent: CC(=O)O
Product: CCc1cc(CC(=O)OC)ccc1-c1ccc(O)cc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 85 %

Procedure:
Acetic acid (55 ml) and hydrobromic acid (55 ml) were added to (2-ethyl-4′-methoxy-1,1′-biphenyl-4-yl)acetonitrile (5.5 g, 22 mmol) obtained in Example (26-3), and the mixture was stirred at 100° C. for 10 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added thereto and the mixture was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. After methanol (150 ml) was added to the residue obtained by removing the solvent under reduced pressure, sulfuric acid (3 ml) was added to the mixture under ice-cooling. After the mixture was stirred at room temperature for 1 hour, the solvent was removed under reduced pressure. After ethyl acetate was added to the obtained residue, the mixture was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=5/1-2/1) to give methyl (2-ethyl-4′-hydroxy-1,1′-biphenyl-4-yl)acetate as a colorless solid (5.0 g, yield: 85%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.[Cl:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[CH2:31][CH:32]=O>>[Cl:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[CH2:31][CH2:32][N:6]1[CH2:5][CH2:4][N:3]([CH:8]2[CH2:17][CH2:16][C:15]3[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=3[CH2:9]2)[C:2](=[O:1])[CH2:7]1
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Reactant: O=CCc1ccc2c(c1Cl)COC2=O
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc4c(c3Cl)COC4=O)CC1=O)C2

Procedure:
The title compound was prepared from 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and (4-Chloro-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 450 [M+1]+.