Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[F:12].Cl.[CH3:14][NH:15][CH3:16].C(N(CC)CC)C>C(Cl)Cl>[F:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:15]([CH3:16])[CH3:14]
Reactant: O=[N+]([O-])c1cccc(CBr)c1F
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1cccc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
To a stirred mixture of 1-(bromomethyl)-2-fluoro-3-nitrobenzene (0.70 g, 2.99 mmol) and dimethylamine hydrochloride (0.48 g, 5.98 mmol) in CH2Cl2 (10 mL) was added triethylamine (0.91 g, 8.97 mmol) dropwise. The mixture was stirred at room temperature for 3 h and evaporated to dryness under reduced pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (2×25 mL). The EtOAc solution was washed with water (20 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 1-(2-fluoro-3-nitrophenyl)-N,N-dimethylmethanamine (0.45 g, 76%) as a yellow viscous liquid. 1H NMR (400 MHz, CD3OD): δ 8.04-7.99 (m, 1H), 7.78-7.73 (m, 1H), 7.37 (td, 1H, J=8.0, 1.0 Hz), 3.64 (d, 2H, J=2.0 Hz), 2.29 (d, 6H, J=0.8 Hz).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:14][C:15]1([CH3:31])[CH2:24][CH2:23][C:22]2[N:21]=[CH:20][C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18](O)[C:17]=2[CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[CH2:7]([O:14][C:15]1([CH3:31])[CH2:24][CH2:23][C:22]2[N:21]=[CH:20][C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18]([Cl:4])[C:17]=2[CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cnc2c(c1O)CC(C)(OCc1ccccc1)CC2
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(c1Cl)CC(C)(OCc1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (5.2 g) is added to 200 mL of DMF dropwise under stirring and cooling keeping the temperature below -20°. Stirring is continued for 0.5 hour at the same temperature. To the mixture 7.0 g of ethyl 6-benzyloxy-4-hydroxy-6-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate is added in small portions and stirring is continued for 2 hours at -30° to -20°, then at room temperature overnight. The mixture is evaporated to dryness and the residue is taken up in CH2Cl2, washed with sat. NAHCO3, dried (MgSO4) and evaporated to dryness to an oil which is chromatographed on silica gel to yield ethyl 6-benzyloxy-4-chloro-6-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]3[C:24]4[CH2:32][CH2:31][C:30]5[C:26](=[CH:27][N:28]([CH2:33][C:34](O)=[O:35])[N:29]=5)[C:25]=4[S:37][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:38][N:39]([CH3:48])[CH2:40][CH2:41][CH2:42][N:43]=[C:44]=NCC.CN1CCOCC1.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:19]=[CH:20][N:21]=[C:22]3[S:37][C:25]4[C:26]5[C:30]([CH2:31][CH2:32][C:24]=4[C:23]=23)=[N:29][N:28]([CH2:33][C:34]([N:43]2[CH2:42][CH2:41][C@H:40]([N:39]([CH3:48])[CH3:38])[CH2:44]2)=[O:35])[CH:27]=5)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)[C@H]1CCN(C(=O)Cn2cc3c(n2)CCc2c-3sc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 36.9 %

Procedure:
To DMF (3 mL) were sequentially added [6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl]acetic acid (80 mg, 0.15 mmol), 3(R)-(−)-3(Dimethylamino)pyrrolidine (23 mg, 0.20 mmol), (3-Dimethylamino-propyl)-ethyl-carbodiimide (50 mg, 0.26 mmol), 4-methylmorpholine (0.03 ml, 0.29 mmol), and 1-Hydroxybenzotriazole (39 mg, 0.29 mmol). The mixture was stirred at rt for 14 h after which time the reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The combined organic layers were concentrated in vacuo and purified by prep HPLC. The combined fractions were treated with saturated Na2CO3 and dried to afford free base product (35 mg, 42%) as a white solid. 1H-NMR (CD2Cl2) δ 8.38 (s, 1H), 7.81 (d, 1H), 7.53 (s, 1H), 7.45 (dd, 1H), 7.38 (dd, 1H), 7.28-7.22 (m, 2H), 6.97-7.08 (m, 3H), 5.15 (s, 2H), 4.84 (s, 2H), 3.64-3.80 (m, 2H), 3.15-3.53 (m, 3H), 3.07 (t, 2H), 2.61-2.81 (m, 1), 2.25 (s, 3H), 2.23 (s, 3H), 1.69-2.20 (m, 3H); LCMS RT=3.80 min, [M+H]+=632.2
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[CH:18]=[CH:19][C:20]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:21]([CH:31]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][N:28]=[N:27][CH:26]=1)=[O:23]>COCCOC.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>[F:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][O:32][C:20]2[CH:19]=[CH:18][C:17]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[CH:31][C:21]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][N:28]=[N:27][CH:26]=2)=[O:23])=[CH:39][CH:38]=1
Reactant: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Reactant: OB(O)c1ccncc1
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: COCCOC
Product: O=C(Nc1ccnnc1)c1cc(-c2ccncc2)ccc1OCc1ccc(F)cc1
Temperature: 120 °C

Procedure:
4-Pyridinylboronic acid (81 mg, 0.66 mmol), sodium carbonate (1.09 ml, 1.09 mmol) and tetrakis(triphenylphosphine)palladium(0) (37.9 mg, 0.03 mmol) were added to a solution of 5-bromo-2-{([(4-fluorophenyl)methyl]oxy}-N-4-pyridazinylbenzamide (may be prepared as described in Example 77; 220 mg, 0.55 mmol) in 1,2-dimethoxyethane (5 ml). The reaction was heated at 120° C. for one hour. The solvent was removed in vacuo, redissolved in 1:1 dimethylsulfoxide/methanol and purified by MDAP to yield the title compound as a white solid. 58 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])[C:5]=2[CH:4]=1
Reactant: C=C(C)C(=O)Cl
Reactant: COc1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)N1c2ccccc2Sc2ccc(OC)cc21
Yield: 99.2 %

Procedure:
A mixture of 23 g of 2methoxy-phenothiazine, 21 g of methacryloyl chloride and 120 ml of toluene was refluxed for 3 hours and was then cooled and washed with 250 ml of N sodium hydroxide. The organic phase was decanted and the aqueous phase was washed twice with 50 ml of toluene. The combined organic phases were washed with water, dried over magnesium sulfate, treated with carbon black and evaporated to dryness to obtain 29.6 g of 2-methoxy-10-(α-methyl acryloyl)-phenothiazine melting at 91°-92° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:38])([F:37])[C:8]1[CH:9]=[C:10]([C@H:18]([O:20][C@@H:21]2[C@@H:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[C@H:25]([CH2:35][OH:36])[CH2:24][CH2:23][O:22]2)[CH3:19])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.C(N(CC)CC)C>ClCCl>[F:38][C:7]([F:6])([F:37])[C:8]1[CH:9]=[C:10]([C@H:18]([O:20][C@@H:21]2[C@@H:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[C@H:25]([CH2:35][O:36][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:24][CH2:23][O:22]2)[CH3:19])[CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O[C@H]1OCC[C@@H](CO)[C@@H]1c1ccc(F)c(F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O[C@H]1OCC[C@@H](COS(C)(=O)=O)[C@@H]1c1ccc(F)c(F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (50 μl, 0.63 mmol) was added to a mixture of [(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-yl]methanol (Description 15; 235 mg, 0.49 mmol), triethylamine (133 ml, 0.97 mmol), 4-N,N-dimethylaminopyridine (3 mg, 0.02 mmol) and dichloromethane (5 ml) at 0° C. The mixture was stirred for 30 minutes, then quenched with saturated aqueous NaHCO3 and extracted into dichloromethane. The combined organic extracts were dried and concentrated. The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7](C(OC(C)(C)C)=O)[NH:8]C(OC(C)(C)C)=O)[CH:4]=[N:3]1.[CH:23]1([C:26](=O)[CH2:27][C:28]#[N:29])[CH2:25][CH2:24]1>>[CH:23]1([C:26]2[CH:27]=[C:28]([NH2:29])[N:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[N:8]=2)[CH2:25][CH2:24]1
Reactant: N#CCC(=O)C1CC1
Reactant: Cn1cc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cn1
Product: Cn1cc(-n2nc(C3CC3)cc2N)cn1

Procedure:
The title compound was prepared according to the method described for Preparation 296: using di-tert-butyl 1-(1-methyl-1H-pyrazol-4-yl)hydrazine-1,2-dicarboxylate (Preparation 295) and 3-cyclopropyl-3-oxopropanenitrile to afford the title compound in 48% yield, 1.7 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])=[O:11])[CH3:25]
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ncccc1C
Reactant: CCNCc1ccccn1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[C:20]([Cl:21])=[CH:19][C:18]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:17][C:16]=3[Cl:30])[CH:11]=[CH:10][C:9]=2[O:31]C)(=[O:7])=[O:6])[CH2:3][CH2:2]1.B(Br)(Br)Br>ClCCl>[CH:1]1([NH:4][S:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[C:16]([Cl:30])=[CH:17][C:18]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:19][C:20]=3[Cl:21])[CH:11]=[CH:10][C:9]=2[OH:31])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1S(=O)(=O)NC1CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1NC(=O)C(Cc2cc(Cl)c(Oc3ccc(O)c(S(=O)(=O)NC4CC4)c3)c(Cl)c2)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of the title compound of Step F (16 mg, 0.032 mmol) in dichloromethane (0.5 ml) at 0° C. was added boron tribromide (1M in dichloromethane, 0.06 ml, 0.06 mmol). The reaction mixture was stirred at room temperature for one hour, then quenched by addition of 1N HCl (5 ml). The resulting solution was extracted with dichloromethane (3×5 ml). The combined extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (7% methanol in dichloromethane) to afford the title compound (11 mg, 68% yield) as a white solid. MS (APCI−) Calc: 502.0, Found: 501.2 (M−1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[C:16]1[O:15][C:14]([C:20]3[O:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:21]=3[C:31]([F:34])([F:33])[F:32])=[N:13][C:12]=1[CH2:11][CH2:10]2)(=O)=O.[CH2:37]([Sn](CCCC)(CCCC)C=C)[CH2:38]CC.[Cl-].[Li+]>O1CCOCC1.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>[C:25]1([C:22]2[C:21]([C:31]([F:33])([F:32])[F:34])=[C:20]([C:14]3[O:15][C:16]4[C:17]5[C:9](=[CH:8][C:7]([CH:37]=[CH2:38])=[CH:19][CH:18]=5)[CH2:10][CH2:11][C:12]=4[N:13]=3)[O:24][N:23]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(Oc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2
Temperature: 100 °C
Reaction time: 20 h
Yield: 45.8 %

Procedure:
To a solution of 2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]oxazol-7-yl trifluoromethanesulfonate (Preparation 48A, 140 mg, 0.264 mmol) in dioxane (1 mL) in a 150 mL sealed tube were sequentially added tributyl(vinyl)tin (0.085 mL, 0.290 mmol), lithium chloride (33.6 mg, 0.792 mmol), and tetrakis(triphenylphosphine)palladium(0) (30.5 mg, 0.026 mmol). The solution was purged with argon for 5 mins. It was stirred for 20 hrs in a 100° C. oil bath. After cooling, the solution was diluted with ˜20 mL of ether and filtered thru CELITE® and evaporated to give an oily residue. The residue was purified by Combiflash (24 g silica gel) eluting with 1:9 followed by 2:8 EtOAc-hexane to give 2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydronaphtho[2,1-d]oxazole (49.4 mg, 46% yield). LC/MS M+1=409.25.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10].Br[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1.O>CN(C=O)C>[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1
Reactant: Cc1ccccc1N
Reactant: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1NCc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Temperature: 80 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
A mixture of 8.75 g (63.4 mmol) of K2CO3, 9.25 g (86.4 mmol) of 2-methylaniline and 20.0 g (57.6 mmol) of 2-[2-(bromomethyl)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 450 ml of DMF was stirred at 80° C. for 12 h. The resulting mixture was poured into 100 cm3 of water, and the product was extracted with 3×250 ml of ethyl acetate. The combined organic extract was dried over MgSO4 and then evaporated to dryness. Crystallization of this crude product from 250 ml of hexanes gave 14.4 g (67%) of brown crystals of the title compound. Anal. Calc. for C24H2813NO2: C, 77.22; H, 7.56; N, 3.75. Found: C, 77.39; H, 7.70; N, 3.64. 1H NMR (CDCl3): 8.20 (m, 1H, 8-H in naphthyl), 7.84 (d, J=8.5 Hz, 1H, 4-H in naphthyl), 7.82 (m, 1H, 5-H in naphthyl), 7.43-7.52 (m, 3H, 3,6,7-H in naphthyl), 7.14 (m, 1H, 5-H in Ph), 7.06 (m, 1H, 3-H in Ph), 6.79 (m, 1H, 6-H in Ph), 6.68 (m, 1H, 4-H in Ph),
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:31]=[C:32]([C:34](=[O:43])[NH:35][C:36]4[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=4)[CH:33]=3)[O:17][CH:18]([CH2:24][CH2:25]OS(C)(=O)=O)[C:19](OCC)=[O:20])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[Na+].[I-].[CH:46]1([NH2:49])[CH2:48][CH2:47]1>C(#N)C>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:33]=[C:32]([CH:31]=[C:16]([O:17][C@H:18]4[CH2:24][CH2:25][N:49]([CH:46]5[CH2:48][CH2:47]5)[C:19]4=[O:20])[CH:15]=3)[C:34]([NH:35][C:36]3[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=3)=[O:43])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(CCOS(C)(=O)=O)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2cnc(C)cn2)c1
Reactant: NC1CC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@H]3CCN(C4CC4)C3=O)c2)cn1
Temperature: 120 °C
Yield: 42 %

Procedure:
To a solution of ethyl 2-[3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(5-methylpyrazin-2-yl)carbamoyl]phenoxy]-4-methylsulfonyloxy-butanoate (Intermediate 27) (250 mg, 0.41 mmol) in acetonitrile (5 mL), was added NaI (62 mg, 0.41 mmol) and cyclopropylamine (56 μL, 0.81 mmol). The resulting mixture was heated in a microwave at 120° C. for 60 minutes. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography eluting with 0-40% methanol in DCM to afford the racemic product (91 mg, 42%). 3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3S)-1-cyclopropyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide was separated from its enantiomer by chiral HPLC using a Merck 50 mm 20 μm Chiralcel OJ column eluting with methanol at a flow rate of 60 mL/min. 91 mg of racemic material was separated in 1 injection of 5 mL at 18 mg/ml in methanol to afford the product which eluted after its enantiomer (29 mg, 13%). 1H NMR δ (300 MHz, CDCl3) 0.66-0.91 (m, 4H), 2.14 (sextet, 1H), 2.35 (quintet, 2H), 2.48-2.62 (m, 4H), 2.66-2.78 (m, 1H), 3.27-3.49 (m, 2H), 4.25 (t, 2H), 4.70 (t, 2H), 4.92 (t, 1H), 6.96 (s, 1H), 7.22 (s, 1H), 7.38 (d, 1H), 7.45 (s, 1H), 8.11 (d, 1H), 8.13 (s, 1H), 8.33 (s, 1H), 8.57 (s, 1H), 9.51 (s, 1H); m/z 529 (M+H)+.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[C:14]([O:18][C:19]([C@H:21]1[CH2:26][CH2:25][C@@H:24]([O:27][CH2:28][CH2:29][CH2:30]O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)(O)[O-].[Na+]>ClCCl>[C:14]([O:18][C:19]([C@H:21]1[CH2:26][CH2:25][C@@H:24]([O:27][CH2:28][CH2:29][CH2:30][F:11])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@@H](OCCCO)CC1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H]1CC[C@@H](OCCCF)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Deoxo-Fluor (5 mg, 0.02 mmol) was added to a solution of cis-4-(3-hydroxy-propoxy)-cyclohexanecarboxylic acid tert-butyl ester (3.9 mg, 0.015 mmol) in dichloromethane (0.1 ml), and the mixture was stirred at room temperature for two hours. An aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give cis-4-(3-fluoro-propoxy)-cyclohexanecarboxylic acid tert-butyl ester (3.1 mg, 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([CH3:23])[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>C1COCC1>[CH3:23][C:4]1[CH:3]=[C:2]([NH:1][C:34](=[O:35])[O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:22]=[CH:21][C:5]=1[O:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=2)=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2C)n1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)Oc3ccccc3)cc2C)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To 4-(2-(4-amino-2-methylphenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (200 mg, 0.65 mmol) in THF (4 mL) was added diisopropylethylamine (0.097 mL, 0.72 mmol) and phenyl chloroformate (102 mg, 0.65 mmol). The mixture was stirred for 3.5 hours at RT and used without purification.
Reaction SMILES: [CH:1]1([C:6]([O:8][CH2:9][O:10][C:11]2[N:16]=[C:15](/[N:17]=[CH:18]/N(C)C)[C:14]([F:22])=[CH:13][N:12]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C([O-])(O)=[O:25].[Na+]>O1CCOCC1>[CH:1]1([C:6]([O:8][CH2:9][O:10][C:11]2[N:16]=[C:15]([NH:17][CH:18]=[O:25])[C:14]([F:22])=[CH:13][N:12]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])O
Reactant: CN(C)/C=N/c1nc(OCOC(=O)C2CCCC2)ncc1F
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=CNc1nc(OCOC(=O)C2CCCC2)ncc1F
Reaction time: 5 h
Yield: 95.4 %

Procedure:
A 25 mL vial was charged with (E)-(4-((dimethylamino)methyleneamino)-5-fluoropyrimidin-2-yloxy)methyl cyclopentanecarboxylate (50.0 mg, 0.161 mmol), 1,4-dioxane (4 mL), and 1.0 M aqueous HCl (78 μL, 0.078 mmol) and was agitated on an orbital shaker for 5 h. The reaction was monitored by ultra performance liquid chromatography (UPLC) and determined to be incomplete, therefore an additional portion of 1.0 M aqueous HCl (78 μL, 0.078 mmol) was added. After 1 h, the reaction was quenched by the addition of 1.0 M aqueous NaHCO3 (260 μL, 0.260 mmol) and concentrated under reduced pressure at 45° C. The dried residue was then extracted with EtOAc (5 mL×4), and concentrated to dryness under reduced pressure to obtain (5-fluoro-4-formamidopyrimidin-2-yloxy)methyl cyclopentanecarboxylate (43.5 mg, 95%) as a white solid: mp 76-79° C.; 1H NMR (300 MHz, DMSO-d6) δ 11.38 (bs, 1H), 9.31 (d, J=5.7 Hz, 1H), 8.52 (d, J=2.6 Hz, 1H), 5.97 (s, 2H), 2.71-2.85 (m, 1H), 1.40-1.89 (m, 8H); MS (ESI) m/z 306 (M+Na)+, 282 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[CH:10]=[C:9]([CH:11]=O)[CH:8]=[CH:7][C:6]=1[NH:13][C:14]([C:16]1[C:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:15])=[O:4].Cl.[CH3:34][O:35][C:36](=[O:40])[CH2:37][NH:38][CH3:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C>[CH3:34][O:35][C:36](=[O:40])[CH2:37][NH:38][CH2:39][CH2:11][C:9]1[CH:8]=[CH:7][C:6]([NH:13][C:14]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=3)=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:15])=[C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:32])[CH:10]=1
Reactant: CNCC(=O)OC
Reactant: CN(C)C(=O)c1cc(C=O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)CNCCc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
To a solution of 4′-trifluoromethylbiphenyl-2-carboxylic acid (2-dimethylcarbamoyl-4-formylphenyl)amide (137 mg) and N-methylglycine methyl ester hydrochloride (45 mg) in dichloromethane (2 mL) was added sodium triacetoxyborohydride (97 mg). The mixture was stirred at room temperature for 4 hours, diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=100:1, v/v) to give the title compound (120 mg).
Reaction SMILES: O[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.CN(C)C=O.S(Cl)([Cl:19])=O>C(OCC)C>[Cl:19][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2ccccc2o1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: ClCc1cc2ccccc2o1
Reaction time: 1 h

Procedure:
Compound 4 (155.25 g) was dissolved in anhydrous ethyl ether (250 ml) containing dimethylformamide (1 ml). The reaction flask was placed into an ice bath, and when the solution temperature was between 0° C. and 4° C., thionyl chloride (124.3 g, 76.2 ml) was added dropwise, while stirring, over the period of 1 hour. The mixture was then stirred for another hour, washed with water (250 ml), 3% sodium bicarbonate solution (250 ml), and with water again (250 ml). The material was dried over magnesium sulfate, filtered, and the solvent evaporated. The product was distilled in vacuo, and the yield was approximately 117 g. The boiling point is about 78° C. at 1.5 mm Hg.