Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH3:34])[CH:26]=3)[C:22]([CH3:35])=[CH:21][N:20]=2)=[C:11]([O:36][CH3:37])[CH:10]=1>FC(F)(F)CO.C(O)C>[CH3:37][O:36][C:11]1[CH:10]=[C:9]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]=1[NH:18][C:19]1[N:24]=[C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH3:34])[CH:26]=2)[C:22]([CH3:35])=[CH:21][N:20]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Solvent: OCC(F)(F)F
Solvent: CCO
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Temperature: 120 °C
Yield: 62.3 %

Procedure:
1-Methylpiperazine (0.453 mL, 4.08 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 79, 554 mg, 1.36 mmol) in 2,2,2-trifluoroethanol (10 mL). The mixture was heated in a microwave at 120° C. for 1 h. The mixture was then concentrated in vacuo and the residue was dissolved in CH2Cl2 (50 mL). This solution was washed water (2×50 mL) and sat. brine (50 mL), then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-10% CH3OH in CH2Cl2 gave an orange gum. This gum was dissolved in ethanol (25 mL) and a solid precipitated. This solid was collected by filtration and washed with ethanol to give the title compound (413 mg, 62%) as a yellow/orange solid; 1H NMR: 2.25 (3H, s), 2.39 (3H, s), 2.45-2.54 (4H, m), 3.03-3.10 (4H, m), 3.91 (3H, s), 3.98 (3H, s), 6.86 (1H, s), 7.06 (1H, dd), 7.22-7.28 (1H, m), 7.51 (1H, d), 8.02 (1H, s), 8.07 (1H, s), 8.26-8.30 (1H, m), 8.38 (1H, d), 8.69 (1H, s); m/z: ES+ MH+ 488.29.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:35]I>C1COCC1>[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:34])[C@H:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[CH3:35])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CI
Reactant: COc1ccccc1CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1[C@H](C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
As shown in step 5-ii of Scheme 5, to a solution of sodium hexamethyldisilazide (NaHMDS, 5.06 g, 26.2 mmol) in THF (100 mL) under an atmosphere of nitrogen at −78° C. was added (4S)-4-benzyl-3-[2-(2-methoxyphenyl)acetyl]oxazolidin-2-one (7.11 g, 21.9 mmol) and the reaction was stirred for 1.5 hours. Methyl iodide (3.08 g, 1.35 mL, 21.7 mmol) was then added dropwise and stirring continued at −78° C. for 4 hours, then the reaction was warmed to room temperature over 18 hours. The reaction was cooled to −20° C. and quenched with NH4Cl (sat). The organics were removed under reduced pressure and the aqueous layer was extracted with DCM (3×). The organic extracts were combined and washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by medium pressure silica gel chromatography (5 to 25% EtOAc in hexanes) to give (4S)-4-benzyl-3-[(2S)-2-(2-methoxyphenyl)propanoyl]oxazolidin-2-one as a white solid with a de of 9:1 (S/R). The solid was then purified via supercritical fluid chromatography (SFC) on an IC column (10% MeOH/CO2 isocratic gradient) to give (4S)-4-benzyl-3-[(2S)-2-(2-methoxyphenyl)propanoyl]oxazolidin-2-one (Compound 2015, 3.14 g, 41.8% yield) with an enantiomeric excess of 99.9% by analytical SFC: 1H NMR (300 MHz, CDCl3) δ 7.41-7.20 (m, 7H), 6.96 (dd, J=13.8, 6.6 Hz, 1H), 6.93-6.84 (m, 1H), 5.30 (q, J=7.1 Hz, 1H), 4.68 (qd, J=6.7, 3.5 Hz, 1H), 4.22-4.11 (m, 2H), 3.84 (s, 3H), 3.35 (dd, J=13.3, 3.2 Hz, 1H), 2.82 (dd, J=13.3, 9.7 Hz, 1H), 1.64-1.46 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O>C(O)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccccn1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CC(C)O
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccccn1

Procedure:
In a manner similar to the method described in example 1, 6-chlorooxindole (4.12 g, 24.7 mmol) (Avocado) and pyridine-2-carbaldehyde (2.96 g, 24.7 mmol) (Aldrich) in isopropanol to give a mixture of E/Z-6-chloro-3-pyridi-2-ylmethene-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 6.0 g, 94.6%) and used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:13][C:14]([OH:16])=[O:15])C(O)=O)[CH:6]=[CH:7][CH:8]=1.[CH2:17](O)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(CC(=O)O)C(=O)O)c1
Reactant: CCO
Product: CCOC(=O)CCc1cccc(OC)c1
Yield: 93 %

Procedure:
A solution of 3-methoxyphenylsuccinic acid (1.500 g, 8.32 mmol) in dry ethanol (15 mL) with a small quantity of DOWEX™ strong acid ion exchange resin was refluxed for 22 h. The reacion mixture was filtered and the solvent evaporated in vacuo to give 1.618 g of ester 25. Yield 93%. 1H NMR (300 MHz, CDCl3) δ ppm: 7.15 (q, J=8.6 Hz, 1H), 6.72 (d, J=7.8 Hz, 1H), 6.65-6.70 (m, 2H), 4.06 (q, J=7.1 Hz, 2H), 3.72 (s, 3H), 2.86 (t, J=7.9 Hz, 2H), 2.54 (t, J=7.9 Hz, 2H), 1.17 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ ppm: 172.9, 159.7, 142.2, 129.4, 120.6, 114.0, 111.6, 60.4, 55.1, 35.8, 31.0, 14.2; HRMS (EI) m/z: calcd for C12H16O3: 208.1099. found: 208.1104.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]([CH3:25])=[CH:19][C:20](OCC)=[O:21])=[S:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([N:14]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:25])[NH:17][C:15]2=[S:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(C)NC(=S)Nc1ccc(Cl)c(C(=O)OC(C)C)c1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: Cc1cc(=O)n(-c2ccc(Cl)c(C(=O)OC(C)C)c2)c(=S)[nH]1

Procedure:
using isopropyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-methylvinyl]thioureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-5-[3,6-dihydro-4-methyl-6-oxo-2-thioxo-1(2H)-pyrimidinyl]-benzoate,
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.Cl.[Cl:18][C:19]1[CH:25]=[C:24]([F:26])[C:22]([NH2:23])=[C:21]([F:27])[CH:20]=1.CCCCCC>C(O)(C)C>[ClH:2].[Cl:18][C:19]1[CH:25]=[C:24]([F:26])[C:22]([NH:23][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:21]([F:27])[CH:20]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1c(F)cc(Cl)cc1F
Agent: Cl
Solvent: CC(C)O
Solvent: CCCCCC
Product: COc1cc2ncnc(Nc3c(F)cc(Cl)cc3F)c2cc1OC
Yield: 14.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline hydrochloride (210 mg, 0.8 mmol), (prepared as described for the starting material in Example 1 but without the aqueous work up), and 4-chloro-2,6-difluoroaniline hydrochloride (177 mg, 0.89 mmol) in isopropanol (8 ml) were heated at reflux for 2 hours. The reaction mixture was then allowed to cool, hexane added and the precipitated product collected by filtration, washed with isopropanol and dried to give 4-(4-chloro-2,6-difluoroanilino)-6,7-dimethoxyquinazoline hydrochloride (45 mg, 16%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:7]=[C:8]([C:10](=S)[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH:9]=1)=[O:4].[NH2:25][NH2:26]>C(Cl)Cl.CCO>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:7]=[C:8]([C:10](=[N:25][NH2:26])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH:9]=1)=[O:4]
Reactant: NN
Reactant: COC(=O)c1cc(C(=S)Nc2cccc(F)c2F)cn1S(C)(=O)=O
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)c1cc(C(=NN)Nc2cccc(F)c2F)cn1S(C)(=O)=O
Reaction time: 3 h

Procedure:
To a solution of 4-(2,3-difluoro-phenylthiocarbamoyl)-1-methanesulfonyl-1H-pyrrole-2-carboxylic acid methyl ester (420 mg, 1.12 mmol) in CH2Cl2 (5 mL) and EtOH (5 mL) was added NH2NH2 (50 mg, 1.56 mmol) at room temperature. The mixture was stirred for 3 hours and the solvents were removed by evaporation under reduced pressure. The crude yellow solid product (410 mg, 98%) was dried on the pump for direct use. MS (ES+): m/e=373.1 (M+H); LC/Method A/2.70 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:19]([CH3:22])([CH3:21])[OH:20])[CH:5]=[C:6]([O:17][CH3:18])[C:7]=1[O:8][C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([CH3:16])[N:10]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:19]([CH3:22])([CH3:21])[OH:20])[CH:5]=[C:6]([O:17][CH3:18])[C:7]=1[O:8][C:9]1[N:14]=[C:13]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:12]=[C:11]([CH3:16])[N:10]=1
Reactant: COc1cc(C(C)(C)O)cc(Br)c1Oc1nc(C)nc(Cl)n1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: COc1cc(C(C)(C)O)cc(Br)c1Oc1nc(C)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-4-[[4-chloro-6-methyl-1,3,5-triazin-2-yl]oxy]-5-methoxy-a,a-dimethylbenzenemethanol (3.0 g) in anhydrous 1,4-dioxane (80 mL), morpholine (1.39 mL) was added and the solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was taken up in water and extracted with methylene chloride. The extracts were combined and dried over MgSO4. The solvent was stripped under reduced pressure and the residue was purified on silica gel using a 2:1 mixture of ethyl acetate and hexane to yield 3-bromo-4-[[6-methyl-4-(4-morpholinyl)-1,3,5-triazin-2-yl]oxy]-5-methoxy-a,a-dimethylbenzenemethanol as a colorless powder, mp 199-201° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([CH3:22])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O.Cl[Pd]Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:7])=[C:15]([CH3:22])[CH:14]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Cc1cc(Cl)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cccc(C(=O)c2ccc(Cl)cc2C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a chilled stirred solution of 3-methoxybenzoyl chloride (5.0 g, 29.3 mmole) in acetone/water (3:1) was added 4-chloro-2-methylphenylboronic acid (5.0 g, 29.3 mmole) followed by PdCl2 (0.259 g, 5 mole %) and sodium carbonate (23.87 mL, 47 mmole). The solution was allowed to stir at room temperature overnight. The reaction workup and purification was conducted according to Example 9a, Step 1 producing the title compound (5.8 g, 76%). This ester was of suitable purity to use without further purification: ESLRMS m/z 261.1 (M+H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=O)[CH2:20][CH:21]=O)=[CH:15][CH:14]=2)[CH2:3]1.O.[NH2:25][NH2:26]>CO.O>[CH3:1][C@H:2]1[CH2:7][C@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][NH:26][N:25]=3)=[CH:15][CH:14]=2)[CH2:3]1
Reactant: C[C@H]1C[C@H](C)CN(CCCOc2ccc(C(=O)CC=O)cc2)C1
Reactant: NN
Solvent: CO
Solvent: O
Product: C[C@H]1C[C@H](C)CN(CCCOc2ccc(-c3cc[nH]n3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of trans-3,5-dimethyl-1-{3-[4-(3-oxopropanoyl)phenoxy]propyl}-piperidine (200 mg) in a mixture of hydrazine hydrate (50 μL) and methanol (4 mL) is stirred for one hour at room temperature. The mixture is diluted with water and extracted twice with ethyl acetate, dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel. Fractions containing the expected product are pooled, concentrated under reduced pressure and salted with oxalic acid to afford 142 mg of trans-3,5-dimethyl-1-{3-[4-(pyrazol-3-yl)phenoxy]propyl}piperidine, oxalate as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][C:43]1[O:47][C:46]([C:48]([F:51])([F:50])[F:49])=[C:45]([S:52](Cl)(=[O:54])=[O:53])[CH:44]=1>C(#N)C>[F:51][C:48]([F:49])([F:50])[C:46]1[O:47][C:43]([CH3:42])=[CH:44][C:45]=1[S:52]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:54])=[O:53]
Reactant: Cc1cc(S(=O)(=O)Cl)c(C(F)(F)F)o1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)c(C(F)(F)F)o1
Yield: 22.8 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0277 g, 0.0600 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 5-methyl-2-trifluoromethyl-3-furansulfonyl chloride (0.0486 g, 0.195 mmol) to obtain 4-(2-trifluoromethyl-5-methyl-3-furansulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0092 g, yield 23%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]([CH2:29][CH3:30])[C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)C1C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>>[Cl:27][C:25]1[CH:26]=[C:21]([S:20][C:14]2[N:13]([CH2:29][CH3:30])[C:12]([CH2:11][CH2:10][CH2:9][OH:8])=[N:16][C:15]=2[CH:17]([CH3:18])[CH3:19])[CH:22]=[C:23]([Cl:28])[CH:24]=1
Reactant: CCn1c(CCCOCc2ccccc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCn1c(CCCO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 110 °C
Yield: 75.2 %

Procedure:
To 5.3 g (11.4 mmol) of the above oil (136b) was added 24 ml of concentrated hydrochloric acid and the mixture was heated at 110° C. for 2 hours. After cooling, the mixture was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, arid concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% methanol-ethyl acetate) and recrystallized from n-hexane to provide 3.2 g (yield 75%) of 3-(5-(3,5-dichlorophenylthio)-1-ethyl-4-isopropyl-1H-imidazol-2-yl)-propan-1-ol (137b) as crystals. mp 73° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH:23]([CH3:25])[N:11]2[C:12]3[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][C:17]=3[CH2:18][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:24][C@@H:23]([CH3:25])[N:11]2[C:12]3[CH:13]=[C:14]([C:19]([F:20])([F:21])[F:22])[C:15]([Br:26])=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(C(=O)OC(C)(C)C)CC2Cc3ccc(C(F)(F)F)cc3N12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(C(F)(F)F)cc3N21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Methyl-7-trifluoromethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester (0.83 g; 2.4 mmol) was dissolved in dimethylformamide (7 mL) and N-bromosuccinimide (0.43 g, 2.5 mmol) was added in portions. The mixture was stirred for 1 h, added to ice water (500 mL) and extracted with diethylether (2×150 mL). Organic phases were pooled, washed with water, dried with MgSO4 and the solvent was removed in vacuo. Chromatography on silica gel (n-hexane/diethylether 4:1) yielded the title product as a colorless wax (0.99 g, 98%). ISP-MS: m/e=435.3, 437.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C@@H:5]([CH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([NH2:20])=[C:15]([CH3:21])[C:14]=1[CH2:22][O:23]C(=O)C)[CH2:6][C:7]([O:9][CH2:10]C)=[O:8])C.COC(=O)[C@@H](CC1C(CO)=C2C(=CC=1)N[N:42]=C2)CC(OC)=O>>[Cl:19][C:17]1[CH:18]=[C:13]([CH2:12][C@@H:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:4]([O:3][CH3:1])=[O:27])[C:14]([CH2:22][OH:23])=[C:15]2[C:16]=1[NH:20][N:42]=[CH:21]2
Reactant: COC(=O)C[C@H](Cc1ccc2[nH]ncc2c1CO)C(=O)OC
Reactant: CCOC(=O)C[C@H](Cc1cc(Cl)c(N)c(C)c1COC(C)=O)C(=O)OCC
Product: COC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1CO)C(=O)OC
Yield: 99 %

Procedure:
2-(S)-(2-Acetoxymethyl-4-amino-5-chloro-3-methyl-benzyl)-succinic acid diethyl ester (2.21 g, 5.4 mmol) was converted to the title compound in a manner analogous to the preparation of 2-(S)-(4-Hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethyl ester. Material was obtained as amber solid in 99% yield. MS m/e (M+H)+=241.2.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH:20]1[CH2:23][CH:22]([N:24]2[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]2)[CH2:21]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:20]3[CH2:23][CH:22]([N:24]4[CH2:29][CH2:28][C:27]([F:30])([F:31])[CH2:26][CH2:25]4)[CH2:21]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Reactant: FC1(F)CCN(C2CNC2)CC1
Product: FC1(F)CCN(C2CN(Cc3ccc4nc(Cl)nc(N5CCOCC5)c4n3)C2)CC1

Procedure:
4-(6-(Bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.1 g) was reacted with 1-(azetidin-3-yl)-4,4-difluoropiperidine via General Procedure B to give 80 mg 4-(2-chloro-6-((3-(4,4-difluoropiperidin-1-yl)azetidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine.
Reaction SMILES: CS(O)(=O)=O.[C:6]([C:10]1[C:15]2[CH:16]=[CH:17][O:18][C:14]=2[CH:13]=[CH:12][C:11]=1[OH:19])([CH3:9])([CH3:8])[CH3:7].[C:20](O)([CH3:23])([CH3:22])[CH3:21].[OH-].[Na+]>C(Cl)(Cl)Cl>[C:20]([C:17]1[O:18][C:14]2[CH:13]=[C:12]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:11]([OH:19])=[C:10]([C:6]([CH3:9])([CH3:7])[CH3:8])[C:15]=2[CH:16]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)c1c(O)ccc2occc12
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc2c(C(C)(C)C)c(O)c(C(C)(C)C)cc2o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 39.9 %

Procedure:
Methanesulfonic acid (140 ml) was added dropwise, under ice cooling, to a solution consisting of 4-tert-butyl-5-hydroxybenzofuran [J. Org. Chem., 53, 4135 (1988); 35 g, 0.18 mol], tert-butyl alcohol (70 g, 0.84 mol) and chloroform (50 ml). After stirring at 0° C. for 20 min, the mixture was poured into ice water. Subsequently, the mixture was neutralized with an aqueous solution of 1N sodium hydroxide and subjected to extraction with ethyl acetate. The extracted layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel chromatography (n-hexane) to afford 2,4,6-tri-tert-butyl-5-hydroxybenzofuran [10.87 g (yield, 20%)]. Also obtained, though in low yield, was 4,6-di-tert-butyl-5-hydroxybenzofuran.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:20][C:21]([CH:23]2[CH2:32][C:31]3[CH:30]=[C:29]([O:33][C:34]4[CH:39]=[CH:38][N:37]=[C:36]([C:40](OC)=[O:41])[CH:35]=4)[CH:28]=[CH:27][C:26]=3[CH2:25][CH2:24]2)=[O:22])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[OH:41][CH2:40][C:36]1[CH:35]=[C:34]([O:33][C:29]2[CH:30]=[C:31]3[C:26]([CH2:25][CH2:24][CH:23]([C:21]([NH:20][C:12]4[CH:11]=[C:10]([CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=4)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])[CH2:32]3)=[CH:27][CH:28]=2)[CH:39]=[CH:38][N:37]=1
Reactant: COC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(CNC(=O)OC(C)(C)C)cc(C(F)(F)F)c2)CC3)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(CO)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a solution of methyl 4-{[7-({[3-{[(tert-butoxycarbonyl)amino]methyl}-5-(trifluoromethyl)phenyl]amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}pyridine-2-carboxylate (1.03 g, 1.72 mmol) in MeOH (17 mL) at 0° C., was added sodium borohydride (0.39 g, 13.3 mmol) in small portions. The reaction mixture was allowed to warm slowly to rt and then allowed to stir for 18 h. Water was added and the precipitate which formed was filtered, washed with water and hexane and dried under vacuum to give tert-butyl [3-{[(7-{[2-(hydroxymethyl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalen-2-yl)carbonyl]amino}-5-(trifluoromethyl)benzyl]carbamate (913 mg, 93.0%) as a white solid. LCMS: (FA) ES+ 572.3, ES− 570.4.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4](I)[N:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccc(I)nc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(-c2ccccc2)nc1Br
Temperature: 70 °C

Procedure:
To a degassed solution of 2-bromo-3-chloro-6-iodopyridine (350 mg, 1.099 mmol) and phenylboronic acid (134 mg, 1.099 mmol), saturated potassium carbonate solution (5.50 mL, 5.50 mmol) in acetonitrile (5 mL) was added tetrakistriphenylphosphine palladium (63.5 mg, 0.055 mmol) and the mixture heated at 70° C. for 2 hours. The mixture was cooled and filtered through diatomaceous earth. The filtrate was concentrated and the residue washed with diethyl ether to afford the crude title compound. LCMS: 267 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][C:11]([OH:13])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N+]=[N-].C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[C:17]([N:9]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:10][C:11]([OH:13])=[O:12])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: O=C(O)CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
N-Benzylglycine hydrochloride (7.38 g, 36.6 mmol), tert-butyl azidoformate (10.7 mL, 73.2 mmol) and sodium bicarbonate (12.3 g) were reacted in 150 mL dioxane/H2O-1:1 (v/v) at 45° (24 hr) and then at room temperature (24 h). The reaction suspension was evaporated to dryness and the resulting white residue was dissolved in 200 mL glacial acetic acid/H2O--1:1(v/v) with cooling to 4°. Water (800 ml) was slowly added with rapid stirring and cooling. The resulting turbid solution was seeded with Boc-N-benzyl-glycine obtained from Method A and allowed to stand in an ice bath for 30 min. The resulting material was gathered by filtration, washed with water followed by petroleum ether (bp 30°-75°) and dried to give 8.34 g (86%) of crude product as a white solid. Recrystallization from dichloromethane petroleum ether (bp 30°-75°) gave 7.34 g (76%) of white, crystalline product identical to Boc-N-benzylglycine (Method A) by NMR and melting point (106°).