Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[C:7](=[CH:16][N:17]([CH3:19])[N:18]=2)[N:8]=[CH:9][C:10]=1[C:11](OCC)=[O:12])[CH:2]=[CH2:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH2:1]([NH:4][C:5]1[C:6]2[C:7](=[CH:16][N:17]([CH3:19])[N:18]=2)[N:8]=[CH:9][C:10]=1[CH2:11][OH:12])[CH:2]=[CH2:3]
Reactant: C=CCNc1c(C(=O)OCC)cnc2cn(C)nc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCNc1c(CO)cnc2cn(C)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
A solution of ethyl 7-allylamino-2-methyl-2H-pyrazolo-[4,3-b]pyridine-6-carboxylate (100 mg, 0.38 mmol) in dry THF (2 ml) was added dropwise to an ice-cooled suspension of lithium aluminium hydride (15 mg, 0.39 mmol) in THF (1 ml). The mixture was stirred at room temperature, under nitrogen, for 16 h, then water (0.03 ml), 10% sodium hydroxide solution (0.4 ml) and water (0.09 ml) were added sequentially. The solids were filtered off and washed with ethyl acetate. The solution was evaporated in vacuo to give a solid, which was recrystallised from ethyl acetate to give the title compound as needles (40 mg, 48%), m.p. 151°-159° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][NH:14][CH2:13]1)[CH2:11][C:10]2=[O:21].[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH:33]=O)=[CH:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C([O-])([O-])=O.[Na+].[Na+]>[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][N:14]([CH2:33][C:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:24]([CH3:23])[CH:25]=3)[CH2:13]1)[CH2:11][C:10]2=[O:21]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNC1)O2
Reactant: Cn1cc(C=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3cn(C)c4ccccc34)C1)O2
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A suspension of (±)-(E)-3-[4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]acrylic acid methyl ester (284 mg, 0.88 mmol, Intermediate 1) in 1 M Na2CO3, was stirred for 10 min, then extracted with DCM and treated with N-methyl-indol-3-carbaldehyde (167 mg, 1.06 mmol) and NaBH(OAc)3 (297 mg, 1.32 mmol) following the procedure described in Example 2, step A, giving (±)-(E)-3-[1′(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (191 mg, 0.44 mmol, 42%) as a white solid. The resulting ester was hydrolyzed as described in Example 2, step B, giving (±)-(E)-3-[1′(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid (51 mg, 0.11 mmol, 25%) as an orange solid (hydrochloride salt). The product was suspended in DCM (3 ml), TEA (0.025 ml, 0.31 mmol) was added, and the clear solution was treated with NH2OTHP following the procedure described in Example 2, step C, giving (E)-3-[1′(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (53 mg, 0.10 mmol, 91%) as a light yellow solid. The compound was then dissolved in DCM (3 ml) and treated with 1 M HCl in diethyl ether (3 ml) as described in Example 2, step D, giving a light brown solid after aqueous workup and column chromatography (eluent: DCM/MeOH 9:1) (10 mg, 22%, free base)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[O-]CC.[Na+].Cl[CH2:21][C:22](=O)[CH3:23]>C(O)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[C:11]3[C:22]([CH3:23])=[CH:21][O:15][C:10]=3[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2)C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1coc2c1C(=O)CC(c1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(4-fluorophenyl)cyclohexane-1,3-dione (mp175-176° C.; 1.03 g) in ethanol (10 ml) was added sodium ethoxide (0.37 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added a solution of chloroacetone (0.45 ml) in DMF (10 ml), and the mixture was stirred at 100° C. overnight (13 hours). The reaction solution was cooled and concentrated under reduced pressure. To the residue was added ice-water, and the mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(4-fluorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.12 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:14]2[CH:19]=[C:18](Cl)[N:17]=[C:16]([NH2:21])[N:15]=2)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH2:22]1[C:26]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][C@@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:23]1[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38].C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH2:21][C:16]1[N:17]=[C:18]([N:29]2[CH2:28][CH2:27][C:26]3([CH2:22][N:23]([C:37]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[O:38])[C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25]3)[CH2:31][CH2:30]2)[CH:19]=[C:14]([O:13][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:9]([F:12])([F:11])[F:10])[N:15]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Reactant: Nc1nc(Cl)cc(O[C@H](c2ccc(Br)cc2)C(F)(F)F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
To a solution of (R)-4-(1-(4-bromophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine (19 mg, 0.50 mmol) in dioxane (25 ml) was added (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (175 mg, 0.50 mmol) and sodium bicarbonate (210 mg, 0.25 mmol), and the reaction mixture was heated to 100° C. for 48 h. Then the reaction mixture was cooled to RT, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)-pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as white solid.
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:48]([OH:49])[CH:41]6[CH:42]([O:43][CH2:44][C:45]([NH2:47])=[O:46])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:50]([CH3:52])[CH3:51])=[O:16])C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[NH2:47][C:45]([CH2:44][O:43][CH:42]1[CH:37]2[CH:38]3[O:39][C:35]([O:34][CH2:33][C:21]45[CH:20]6[CH2:29][C:28]([CH:30]=[O:31])([C:17]4([C:15]([OH:16])=[O:14])[C:18]([CH:50]([CH3:51])[CH3:52])=[CH:19]6)[CH:27]4[CH:23]([CH:24]([CH3:32])[CH2:25][CH2:26]4)[CH2:22]5)([CH:48]([OH:49])[CH:41]1[O:40]3)[O:36]2)=[O:46]
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(OCC(N)=O)C5O2)C4O)C13C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(OCC(N)=O)C5O2)C4O)C13C(=O)O
Yield: 80.1 %

Procedure:
14 mg of compound (70) was dissolved in 3 ml of ethyl acetate and stirred together with a catalytic amount of 10% palladium-carbon under a hydrogen atmosphere at room temperature for 1.5 hours. The reaction solution was filtered and concentrated in vacuo. The reaction product was dissolved in 10 ml of methanol and washed with 10 ml of n-hexane four times, and the lower layer was concentrated in vacuo to give 8.6 mg of compound (71) as a colorless solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Cl[C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=2)[N:13]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=2)[N:11]=1>>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=2)[N:13]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=2)[N:11]=1
Reactant: Cc1ccc(-c2nc(Cl)nc(-c3ccc(C)c(C)c3)n2)cc1C
Reactant: Oc1cccc(O)c1
Product: Cc1ccc(-c2nc(-c3ccc(C)c(C)c3)nc(-c3ccc(O)cc3O)n2)cc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To the above reaction mixture was added 1.1 eq of resorcinol and the mixture was heated to 80° C. Within 2 h, an HPLC analysis indicated 2-chloro-4,6-bis(3,4-dimethylphenyl)-1,3,5-triazine and its isomer had completely reacted to form 83% of 2-(2,4-dihydroxyphenyl)-4,6-bis(3,4-dimethylphenyl)-1,3,5-triazine and 6% of its isomer.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6]>C1(CN)CC1>[CH:25]1([CH2:24][NH:23][C:2]2[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=2)[C:5]([NH:7][C:8]2[CH:9]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]4[CH2:27][CH2:26]4)=[O:22])=[CH:17][CH:16]=3)[C:11]([CH3:14])=[CH:12][CH:13]=2)=[O:6])[CH2:27][CH2:26]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Agent: NCC1CC1
Product: Cc1ccc(NC(=O)c2ccnc(NCC3CC3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reaction time: 48 h
Yield: 62.7 %

Procedure:
A solution of 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) in cyclopropylmethylamine (1 ml) was heated at 85° C. for 48 h and then at 110° C. for 48 h in a sealed tube. The reaction was concentrated under vacuum, the residue triturated with water and purified by preparative HPLC. The solvent was evaporated under vacuum to give 2-(cyclopropylmethylamino)-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (17.1 mg, 32%). NMR; εH [2H6]—DMSO 10.27,(1H, s), 8.62,(1H, t), 8.08,(1H, d), 7.93,(2H, d), 7.70-7.66,(2H, m), 7.44,(2H, d), 7.28,(1H, d), 6.89-6.87,(3H, m), 3.16,(4H, m), 2.20,(3H, s), 1.04,(2H, m), 0.43,(4H, m), 0.25-0.19,(4H, m). LCMS: retention time 2.96 min, MH+455.
Reaction SMILES: [Br:1]/[CH:2]=[C:3]1\[CH2:4][CH2:5][CH2:6][C@@:7]2([CH3:26])[C@H:11]\1[CH2:10][C:9](=O)/[C:8]/2=[CH:13]\N(CCC1C=CC=CC=1)C(=O)C.[BH4-].[Na+].S(=O)(=O)(O)[OH:30]>CO.O1CCCC1.C(OCC)C.O>[Br:1]/[CH:2]=[C:3]1/[C@H:11]2[C@:7]([CH3:26])([CH2:6][CH2:5][CH2:4]/1)[C:8]([CH:13]=[O:30])=[CH:9][CH2:10]2
Reactant: O=S(=O)(O)O
Reactant: CC(=O)N(/C=C1\C(=O)C[C@H]2/C(=C/Br)CCC[C@]12C)CCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@]12CCC/C(=C\Br)[C@@H]1CC=C2C=O
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
The crude product of N-[(1Z)-{(E,3aS,7aR)-7-(bromomethylene)-octahydro-3a-methyl-2-oxoindene-3-ylidene}methyl]-N-phenethylacetamide (Compound 28) (178 mg, 0.428 mmol) was dissolved in methanol (2 ml), and sodium borohydride (20 mg, 0.529 mmol) was added thereto at 0° C. After stirring the resulting mixture for 10 minutes, the solvent was removed by evaporator. The residue was dissolved in ethyl acetate, and the resulting mixture was passed through a small amount of silica gel to obtain a crude product (154 mg). The obtained crude product (146 mg, 0.349 mmol) was dissolved in tetrahydrofuran (2 ml), and 2 N sulfuric acid (0.5 ml) was added thereto. The resulting mixture was heated to 70° C. and stirred for 4.5 hours. After cooling, the reaction solution was diluted with diethyl ether, and water was added thereto. The resulting mixture was extracted with diethyl ether. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate and with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure to obtain a crude product (140 mg). The crude product was purified by flash column chromatography to obtain (3aR,4E,7aS)-4-(bromomethylene)-3a,4,5,6,7,7a-hexahydro-7a-methyl-3H-indene-1-carbaldehyde (84 mg, 94%).
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13]([CH2:15][NH2:16])[OH:14]>C(O)C>[OH:14][CH2:13][CH2:15][NH:16][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccc([N+](=O)[O-])c1Cl
Reactant: NCCO
Solvent: CCO
Product: N#Cc1cccc([N+](=O)[O-])c1NCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
2-chloro-3-nitrobenzonitrile (74 g, 0.408 mol) is mixed with ethanol (370 ml) and ethanolamine (57 ml). The mixture is stirred for 16 hrs at room temperature. To complete the reaction, the mixture is refluxed for 2 hours. After cooling, the mixture is concentrated under vacuum; the product precipitates as a red solid. To eliminate the ethanolamine hydrochloride salt, the suspension is triturated with 500 ml of water and filtrated under vacuum. The solid is washed with ethanol and ether then dried to give the desired product (75 g, 89%).
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:35]1[CH:39]=[CH:38][N:37]([S:40]([C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)(=[O:42])=[O:41])[CH:36]=1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]1([C:39]2[CH:35]=[CH:36][N:37]([S:40]([C:43]3[CH:44]=[CH:45][C:46]([C:49]([F:51])([F:52])[F:50])=[CH:47][CH:48]=3)(=[O:41])=[O:42])[CH:38]=2)[CH2:3][CH2:2]1
Reactant: OB(O)C1CC1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)n1ccc(Br)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)n1ccc(C2CC2)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 70.1 %

Procedure:
Cyclopropyl boronic acid (1.6 g, 18.7 mmol), palladium (II) acetate (323 mg, 1.44 mmol), tricyclohexylphosphine (808 mg, 2.88 mmol) and potassium phosphate (10.7 g, 50.5 mmol) were added to a solution of 3-bromo-1-(4-(trifluoromethyl)phenylsulfonyl)-1H-pyrrole (5.11 g, 14.4 mmol) in toluene/H2O (75 mL, 19/1). The resulting suspension was evacuated and purged with nitrogen three times and then placed in an oil bath pre-heated to 100° C. The reaction was stirred for 6 h and was subsequently concentrated under vacuum. The residue was purified on a silica gel column (eluant hexane/EtOAc, 9/1, v/v) to give compound 113 (3.21 g, 10.1 mmol, 71%). MS (ESI) 316.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][CH:8]2[CH2:10][CH2:9]2)=[C:4]([CH3:13])[CH:3]=1.[CH2:14](I)[CH3:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][N:7]([CH:8]2[CH2:9][CH2:10]2)[CH2:14][CH3:15])=[C:4]([CH3:13])[CH:3]=1
Reactant: CCI
Reactant: Cc1cc(Br)ccc1CNC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(Cc1ccc(Br)cc1C)C1CC1
Temperature: 60 °C

Procedure:
A mixture of (4-bromo-2-methyl-benzyl)-cyclopropyl-amine (Intermediate 158, 600.0 mg, 2.49 mmols), ethyl iodide (1.56 g, 10.0 mmols), and K2CO3 (690.0 mg, 5.00 mmols) in 10 mL acetone was heated at 60° C. for 18 hours. The mixture was cooled to room temperature, diluted with H2), and extracted with EtOAc. The combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound was isolated by column chromatography (2.5% EtOAc-hexanes).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:9][OH:10])[C:5]([F:8])=[CH:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][C@H:23]([CH3:25])[N:22]([C:26](Cl)=[O:27])[C@H:21]([CH3:29])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[Br:1][C:2]1[C:3]([F:11])=[C:4]([C:5]([F:8])=[CH:6][CH:7]=1)[CH2:9][O:10][C:26]([N:22]1[C@H:23]([CH3:25])[CH2:24][N:19]([C:17]([O:16][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:18])[CH2:20][C@@H:21]1[CH3:29])=[O:27]
Reactant: OCc1c(F)ccc(Br)c1F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)OCc1c(F)ccc(Br)c1F

Procedure:
The compound was prepared from (3-bromo-2,6-difluoro-phenyl)-methanol and 4-chlorocarbonyl-cis-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedures described in Example 121 and 54 to give the product as a colorless oil (9.75 g); MS (ISP): 482.3 (M+NH4)+.
Reaction SMILES: [Br-].[F:2][C:3]([F:13])([F:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][Zn+].Cl[C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=1)[C:18]([O:20][CH3:21])=[O:19]>O1CCCC1>[F:2][C:3]([F:13])([F:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: FC(F)(F)c1ccccc1C[Zn+]
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2ccccc2C(F)(F)F)c1
Temperature: 60 °C
Yield: 80 %

Procedure:
Freshly made (2-(trifluoromethyl)benzyl)zinc(II) bromide (8.91 g, 29.28 mmol) in tetrahydrofuran (50 mL) was added to a solution of methyl 2-chloroisonicotinate (3.35 g, 19.52 mmol) and bis(tri-tert-butylphosphine)Pd(0) (0.399 g, 0.78 mmol) in tetrahydrofuran (50 mL) under nitrogen in a dried flask. The resulting red mixture was heated to 60° C. overnight (16 h). After cooling to room temperature, the reaction was quenched by the addition of 10% aq NH4Cl and diluted with ethyl acetate. After phase separation, the organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was dissolved in 100 mL MTBE. Insolubles were filtered off and the filtrate was evaporated. Purification via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 1 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 6 CV to yield methyl 2-(2-(trifluoromethyl)benzyl)isonicotinate (4.61 g, 80%) as a yellow oil. 1H NMR (400 MHz, cdcl3) δ 3.91 (s, 3H), 4.43 (s, 2H), 7.28-7.40 (m, 2H), 7.47 (t, 1H), 7.54-7.65 (m, 1H), 7.65-7.72 (m, 2H), 8.71 (d, 1H). MS m/z 296 (M+H)+
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl[CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39]>CC#N>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:33][CH2:32][N:31]([CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39])[CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNC4)cn3)cc2)no1
Agent: Cl
Solvent: CC#N
Product: CN(C)C(=O)CN1CCC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)C1
Temperature: 85 °C
Yield: 66.7 %

Procedure:
To a stirred suspension of N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(pyrrolidin-3-yloxy)picolinamide hydrochloride (150 mg, 0.30 mmol) in CH3CN (3 mL) was added TEA (126 μL, 0.90 mmol), KI (10 mg, 0.060 mmol), and 2-chloro-N,N-dimethylacetamide (21 μL, 0.30 mmol). The resulting mixture was heated at 85° C. for 1 h. LC-MS indicated that the reaction was complete. The reaction mixture was evaporated under reduced pressure and the residue was purified by reverse phase HPLC to give N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(1-(2-(dimethylamino)-2-oxoethyl)pyrrolidin-3-yloxy)picolinamide (110 mg, 67%). LC-MS (ESI) m/z 550 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:13])[C@H:10]([CH3:12])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:39][O:40][C:41]([CH2:43][CH:44]([CH3:48])[C:45](O)=[O:46])=[O:42].COC(CC(=C)C(O)=O)=O>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:13])[C@H:10]([CH3:12])[NH:11][C:45](=[O:46])[CH:44]([CH3:48])[CH2:43][C:41]([O:40][CH3:39])=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC(C)C(=O)O
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C=C(CC(=O)OC)C(=O)O
Agent: Oc1cccc2[nH]nnc12
Solvent: C1COCCO1
Product: COC(=O)CC(C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1

Procedure:
L-alanine benzyl ester (44.7 g.) and hydroxybenzotriazole (34 g.) are dissolved in dioxane (750 ml.) and the solution is chilled with stirring in an ice-water bath. Dicyclohexylcarbodiimide (51.5 g.) and 3-methoxycarbonyl-2-methylpropanoic acid (36 g.), prepared by hydrogenation of 3-methoxycarbonyl-2-methylene propanoic acid, are added in that order and the mixture is stirred at room temperature for 18 hours. The precipitate is filtered off, and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed neutral. The ethyl acetate is dried over magnesium sulfate and concentrated to dryness in vacuo to yield N-(3-methoxycarbonyl-2-methylpropanoyl)-L-alanine benzyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[C:9]([CH:26]=C)[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1.I([O-])(=O)(=O)=[O:30].[Na+]>O.O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[C:9]([CH:26]=[O:30])[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: C=Cc1cc(-c2c(C)noc2C)c2c3c1[nH]c(=O)n3[C@@H](c1ccccn1)CO2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1cc(C=O)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 60 °C
Yield: 47 %

Procedure:
A mixture of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-9-vinyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (1690 mg, 4.51 mmol) in water (7.8 mL) and tetrahydrofuran (104 mL) was treated with sodium metaperiodate (2.90 g, 13.5 mmol) and heated at 60° C. for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (50% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) gave the desired product (0.797 g, 47%) as a single enantiomer. LCMS calculated for C20H17N4O4 (M+H)+: m/z=377.1. found: 376.9.
Reaction SMILES: [Br-].[CH:2]1([Zn+])[CH2:5][CH2:4][CH2:3]1.Br[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=1>>[CH:2]1([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: [Zn+]C1CCC1
Agent: [Br-]
Product: COC(=O)c1ccc(C2CCC2)cc1C
Temperature: 65 °C

Procedure:
Cyclobutylzinc(II) bromide (50 ml, 0.5 M in THF, 25.0 mmol) was added to a mixture of methyl 4-bromo-2-methylbenzoate (compound 152.1, 5.2 g, 22.7 mmol) and PdCl2(dppf)CH2Cl2 (1.85 g, 2.27 mmol). The mixture was degassed and the flask was filled with argon through a balloon. The mixture was heated at 65° C. under argon for 24 hours. The mixture was cooled to 0° C. and quenched with water (10 ml). The mixture was diluted with EtOAc (200 ml), washed with water then with brine. The EtOAc layer was dried (Na2SO4), concentrated under reduced pressure, and purified using column (silica gel) chromatography (hexanes:EtOAc 30:1 to 20:1). Yield: 4.1 g, clear oil, 89.1%. 1H NMR (400 MHz, Chloroform-d) δ 7.86 (d, 1H), 7.12-7.02 (m, 2H), 3.88 (s, 3H), 3.59-3.48 (m, 1H), 2.59 (s, 3H), 2.35 (m, 2H), 2.22-1.96 (m, 3H), 1.86-1.84 (m, 1H).