Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>>[CH2:7]([NH:14][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: C[Si](C)(C)CCl
Agent: [Na+]
Agent: [OH-]
Product: C[Si](C)(C)CNCc1ccccc1
Temperature: 200 °C

Procedure:
Into a round bottom 3-neck flask equipped with a nitrogen flow, a magnetic stirrer, and a friedrichs condenser was added (chloromethyl)trimethylsilane (0.100 mol). To the flask was added benzylamine (0.300 mol), with stirring, and the resulting solution heated at 200° C. for 2.5 hours. Sodium hydroxide aqueous solution (0.1N) was added in order to hydrolyze the white organic salt that had formed. The mixture was extracted with ether and the ether layer was dried over magnesium sulfate and concentrated under reduced pressure through a Vigreux column to give the product at b.p. 68-72° C./0.7-0.8 mm.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=[C:11]([CH3:12])[C:4]=2[N:3]=1.[Cl:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:22]([NH2:23])=[C:21]([O:27][CH3:28])[CH:20]=1.CN1CCCC1=O>O>[Cl:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:22]([NH:23][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=[C:11]([CH3:12])[C:4]=3[N:3]=2)=[C:21]([O:27][CH3:28])[CH:20]=1
Reactant: COc1cc(Cl)cc(C)c1N
Reactant: CCC(CC)c1ccc(C)c2nc(Cl)n(C)c12
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(C)c2nc(Nc3c(C)cc(Cl)cc3OC)n(C)c12
Temperature: 120 °C
Reaction time: 48 h
Yield: 34.4 %

Procedure:
A mixture of 2-chloro-7-(1-ethylpropyl)-1,4-dimethyl-1H-benzimidazole (100 mg, 0.399 mmol), 4-chloro-2-methoxy-6-methylaniline (205 mg, 1.20 mmol) and 1-methyl-2-pyrrolidone (0.2 mL) was stirred at 120° C. for 2 days under nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate, washed with brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1-1:1) and crystallized from iso-propanol to afford the title compound as colorless crystals (53 mg, 34%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH2:13]([OH:16])[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:15]1[CH2:14][CH2:13][O:16][CH:1]1[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: OCCO
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(C2OCCO2)cc1
Yield: 99.2 %

Procedure:
To stirred solution of methyl 4-formylbenzoate (5.0 g, 30.46 mmol) in toluene (196 mL) was added ethylene glycol (8.49 mL, 152.3 mmol) and para-toluenesulfonic acid monohydrate (0.58 g, 3.05 mmol). The reaction mixture was heated at reflux under Dean and Stark conditions for 1.5 hours. The solvent was evaporated at reduced pressure and the residue partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic phase was removed and washed with further saturated aqueous sodium hydrogen carbonate, brine and dried (magnesium sulfate). The mixture was filtered and the solvent evaporated at reduced pressure to afford the title compound (6.29 g, 99%).
Reaction SMILES: CC(C)[C@H](N1CC2C(=CC(C3C=CC([N+]([O-])=O)=CC=3)=CC=2)C1=O)C(OC)=O.Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2)=[CH:32][C:31]=1[C:45]([O:47]C)=O.Cl.[NH2:50][C@@H:51]1[CH2:55][CH2:54][CH2:53][C@@H:52]1[C:56]([O:58][CH3:59])=[O:57]>>[N+:42]([C:39]1[CH:38]=[CH:37][C:36]([C:33]2[CH:32]=[C:31]3[C:30]([CH2:29][N:50]([C@@H:51]4[CH2:55][CH2:54][CH2:53][C@@H:52]4[C:56]([O:58][CH3:59])=[O:57])[C:45]3=[O:47])=[CH:35][CH:34]=2)=[CH:41][CH:40]=1)([O-:44])=[O:43]
Reactant: COC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1CBr
Reactant: COC(=O)[C@H]1CCC[C@H]1N
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Agent: Cl
Product: COC(=O)[C@H]1CCC[C@H]1N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Yield: 75 %

Procedure:
The compound of example 591 was prepared analogous to compound of example 5 by reaction of compound of example 4 with (1S,2R)-methyl 2-aminocyclopentanecarboxylate hydrochloride.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[C:14]1([C:13]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:10][NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: NNC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NN=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A four neck flask (1 liter) equipped with a thermometer, a reflux condenser and a stirrer was charged with 68.0 g (0.5 mol) of benzohydrazide, 700 ml of methanol and 3.5 ml of acetic acid. Added thereto was 109.2 g (0.6 mol) of benzophenone while stirring at room temperature, and heating under reflux was continued for 12 hours. The reaction liquid was cooled down to 5° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby white crystal was obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[CH2:9]([Li])CCC.IC>O1CCCC1>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)([CH3:9])[CH3:2]
Reactant: CCc1ccccn1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)c1ccccn1
Temperature: -45 °C
Reaction time: 1.5 h

Procedure:
2-Isopropylpyridine was prepared by the method of P. Rocca, et. al. (Tetrahedron Vol. 54, pp. 8771-8782 (1998). A solution of 2-ethylpyridine (1000 g, 9.332 moles) in anhydrous Tetrahydrofuran (6000 mL) was cooled to −35° C. by a dry ice/acetone bath. n-Butyllithium (3970 mL of 2.5 Molar, 9.925 moles) was added at a fast drop wise rate over a period of 1.5 hours, while maintaining the internal temperature at −20° C. to −25° C. Stirring was continued for an additional 1.5 hours at −20° C., then the reaction was cooled to −45° C. Iodomethane (642 mL, 1458 g, 10.272 moles) was added at a moderate drop wise rate over a period of 1.5 hours, while maintaining the reaction temperature between −40° C. and −45° C. After the addition was complete, the mixture was allowed to stir for an additional 2 hours at −40° C., then was quenched by the fast drop wise addition of water (4000 mL) added over a period of 30 minutes. The reaction mixture was cooled to 0° C. and treated with concentrated Hydrochloric acid (1150 mL) added over a period of 15 minutes. The mixture was allowed to stir for an additional hour while warming to 15° C., then was transferred to a separatory funnel with diethyl ether (2000 mL), and the layers separated. The aqueous phase was further washed with diethyl ether (3×1000 mL), then made basic (pH=9) by treatment with solid potassium carbonate. The aqueous mixture was extracted with diethyl ether (4×1000 mL). The combined extracts were washed with saturated brine (1000 mL) then dried (anhydrous magnesium sulfate). Filtration, followed by removal of the solvent under reduced pressure at room temperature, gave the crude product as a reddish-orange liquid (˜2000 mL). This crude product was distilled (twice) at atmospheric pressure through a three inch, glass vigreaux column, collecting the desired 2-isopropylpyridine (b.p. 158-163° C.) as a light yellow liquid (926 g, 82% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.53 (d, J=4.22 Hz, 1H) 7.59 (td, J=7.59, 1.69 Hz, 1H) 7.16 (d, J=8.01 Hz, 1H) 7.08 (ddd, J=7.38, 4.85, 0.84 Hz, 1H) 2.94-3.25 (m, J=6.91, 6.91, 6.91, 6.91, 6.91, 6.74 Hz, 1H) 1.31 (d, J=6.74 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.CCCCCC>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)nc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: COC(=O)c1ccc(CBr)nc1
Temperature: 25 °C
Yield: 35.5 %

Procedure:
To a solution of methyl 6-methylnicotinate (6.3 g) in carbon tetrachloride (100 mL) is added successively N-bromosuccinimide (8.9 g) and 2,2′-azobisisobutyronitrile (342 mg), and the mixture is refluxed under heating for 6 hours. After cooling to room temperature, to the reaction mixture is added n-hexane (300 mL) and the insoluble materials are removed by filtration. The filtrate is concentrated in vacuo and the resultant crude product is purified by column chromatography on silica gel (Solvent; n-hexane:ethyl acetate=10:1) and stirred in n-hexane to give methyl 6-(bromomethyl)nicotinate (3.4 g, yield; 35%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54]([C:56]2[CH:61]=[CH:60][C:59](Br)=[CH:58][N:57]=2)=[O:55])[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42].COC(=O)C1C=CC(Br)=CC=1>>[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54]([C:56]2[CH:61]=[CH:60][C:59]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=6)[CH2:30][C:31]6[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)=[CH:58][N:57]=2)=[O:55])[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)cn2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: COC(=O)c1ccc(Br)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cn2)cc1

Procedure:
From bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 4-(5-bromo-pyridine-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (prepared in the same manner as Step A in Example 1-D-79, 76 mg), instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, a crude product of 4-[5-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridine-2-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester was obtained, and then the PMB groups and BOC group were removed according to the above Deprotection method 1, to obtain the desired compound (D-128) as a yellow solid (47 mg, 39%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][C:15]([NH:19]CC4C=CC(OC)=CC=4)=[N:14][C:13]=3[N:12]([C:29]34[CH2:33][CH:31]([CH2:32]3)[CH2:30]4)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][C:42]([OH:44])=O)=[N:39][CH:40]=1.CCCP(O)(O)=O>C1COCC1>[NH2:19][C:15]1[N:16]=[CH:17][C:18]2[C:10]([C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:42](=[O:44])[CH2:41][C:38]4[CH:37]=[CH:36][C:35]([F:34])=[CH:40][N:39]=4)[CH:7]=[N:6][CH:5]=3)=[O:9])=[CH:11][N:12]([C:29]34[CH2:32][CH:31]([CH2:33]3)[CH2:30]4)[C:13]=2[N:14]=1
Reactant: COc1ccc(CNc2ncc3c(C(=O)c4cncc(N)c4)cn(C45CC(C4)C5)c3n2)cc1
Reactant: O=C(O)Cc1ccc(F)cn1
Agent: CCCP(=O)(O)O
Solvent: C1CCOC1
Product: Nc1ncc2c(C(=O)c3cncc(NC(=O)Cc4ccc(F)cn4)c3)cn(C34CC(C3)C4)c2n1
Reaction time: 18 h
Yield: 31 %

Procedure:
To a solution of (5-amino-pyridin-3-yl)-[7-bicyclo[1.1.1]pent-1-yl-2-(4-methoxy-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-methanone (Preparation 287) (50 mg, 0.11 mmol) in THF (5 mL) at room temperature was added 5-fluoro pyridine-2-yl acetic acid (27 mg, 0.17 mmol), TEA (0.08 mL, 0.56 mmol) and 1-propylphosphonic acid cyclic anhydride (50% solution in EtOAc, 0.20 mL, 0.34 mmol). The resulting mixture was before stirred for 18 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between saturated sodium bicarbonate solution (10 mL) and ethyl acetate (25 mL). The organic phase was dried over sodium sulphate and concentrated under reduced pressure. TFA (1.5 mL) was added and the resulting mixture stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue partitioned between saturated sodium bicarbonate (10 mL) and ethyl acetate (30 mL). The organic phase was dried over sodium sulphate, concentrated under reduced pressure purified by Preparative TLC (MeOH:DCM 5:95) to afford the title compound as off white solid in 31% yield, 16 mg. 1H NMR (400 MHz, DMSO-d6) δ: 2.32 (s, 6H), 2.66 (s, 1H), 3.94 (s, 2H), 6.57 (s, 2H), 7.49 (m, 1H), 7.69-7.73 (m, 2H), 8.38 (s, 1H), 8.50 (d, 1H), 8.65 (d, 1H), 8.92 (s, 1H), 8.96 (d, 1H), 10.67 (s, 1H); LCMS (System 10): Rt=2.85 min; m/z 458 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([NH2:14])=[C:9]([NH2:15])[CH:8]=1)=[O:4].[N:27]([O-])=O.[Na+].[OH-].[NH4+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]([C@H:5]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:14][N:27]=[N:15][C:9]=2[CH:8]=1)=[O:4]
Reactant: O=N[O-]
Reactant: COC(=O)[C@@H](Cc1cc(C)c(N)c(N)c1)NC(=O)OCc1ccccc1
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@@H](Cc1cc(C)c2[nH]nnc2c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
To a solution of benzyl (R)-1-(methoxycarbonyl)-2-(3,4-diamino-5-methylphenyl)ethylcarbamate (250 mg, 0.58 mmol) in acetic acid (6 mL) and water (10 mL) was added a solution of sodium nitrite (40 mg, 0.58 mmol) in water (1 mL), dropwise over several minutes at room temperature. The resulting mixture was stirred at room temperature for 30 min, then cooled to 0° C. A mixture of ammonium hydroxide and water (1:1, 15 mL) was added to adjust pH to 11. The mixture was extracted with ethyl acetate twice. The organic layers washed with brine and dried over sodium sulfate. After filtration, solvents were removed in vacuo and the residue was purified by flash column chromatography (1:1 ethyl acetate/hexanes) on silica gel to afford the title compound as a tan solid (155 mg, 72% yield). 1H-NMR (CDCl3, 300 MHz) δ 7.34 (s, 1H), 7.32-7.28 (m, 6H), 6.93 (s, 1H), 5.40 (d, J=8.1 Hz, 1H), 5.13-5.02 (m, 2H), 4.76-4.69 (m, 1H), 3.73 (s, 3H), 3.28 (dd, J=13.9, 5.5 Hz, 1H), 3.16 (dd, J=13.9, 6.2 Hz, 1H), 2.64 (s, 3H). LC/MS: tR=2.30 min, 369 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10](C1C=CC=CC=1C)[C:11]([OH:13])=[O:12].[NH:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24]>O(CC)CC>[NH:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([NH:21][C:25]1[CH:26]=[CH:4][CH:3]=[CH:2][C:7]=1[CH3:6])[C:11]([OH:13])=[O:12]
Reactant: Cc1ccccc1C(C(=O)O)c1c(Cl)ccc(Cl)c1Cl
Solvent: CCOCC
Solvent: OCCNCCO
Product: Cc1ccccc1NC(C(=O)O)c1c(Cl)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 8.62 parts of 2,3,6-trichloro-α-(2-methylphenyl)benzeneacetic acid in 175 parts of 1,1'-oxy-bisethane are added 2.62 parts of 2,2'-iminobis[ethanol] and the whole is stirred for 1 hour at room temperature. The precipitated product is filtered off and stirred in 70 parts of 1,1'-oxybisethane. It is filtered off again and dried, yielding 10 parts of 2,3,6-trichloro-α-[(2-methylphenyl)amino]benzeneacetic acid compound with 2,2'-iminobis[ethanol] (1:1); mp. 145.2° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[CH2:11][O:12][CH3:13].[OH:14][CH:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)Cl>[CH3:13][O:12][CH2:11][O:14][CH:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(C)(C)C(O)c1ccccc1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)C(OCOC)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Diisopropylethylamine (15.9 ml) and chloro(methoxy)methane (5.48 ml) were added dropwise to a methylene chloride (270 ml) solution of ethyl 3-hydroxy-2,2-dimethyl-3-phenylpropanoate (13.5 g) under ice cooling, followed by stirring at room temperature for 3 days. After the reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate and water and the organic layer washed with an aqueous hydrochloric acid solution (1M), a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic layer was subjected to evaporation under reduced pressure and then the residue was purified by silica gel column chromatography to obtain ethyl 3-(methoxymethoxy)-2,2-dimethyl-3-phenylpropanoate (13.1 g).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20](OCC)=[O:21])[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].CCN(C(C)C)C(C)C>O1CCOCC1>[CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]([NH:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:21])[C:10]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN
Reactant: CCOC(=O)c1c(O)c2ccccc2n(OCc2ccccc2)c1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)CNC(=O)c1c(O)c2ccccc2n(OCc2ccccc2)c1=O
Temperature: 100 °C
Yield: 37 %

Procedure:
To a stirring suspension of ethyl 1-(benzyloxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (700 mg, 2.063 mmol), ethyl 2-aminoacetate hydrochloride (387 mg, 2.77 mmol) in dioxane (5 mL) was added DIPEA (0.660 ml, 3.78 mmol). Reaction mixture was heated at 100° C. for 12 h. Solvent from reaction mixture was distilled out to get crude product which was then column purified using 15% EtOAC in hexane to get titled product in 37% yield.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[CH3:17][N:18](C)C=O>[C-]#N.[C-]#N.[Zn+2]>[F:16][C:12]1[C:13]([F:15])=[CH:14][C:2]([C:17]#[N:18])=[C:3]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[CH:11]=1
Reactant: Fc1cc(Br)c(Oc2ccccn2)cc1F
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(F)c(F)cc1Oc1ccccn1
Temperature: 120 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of product of Example 136A (0.8 g, 2.76 mmol) in N,N-dimethylformamide (10 ml) were added Zn(CN)2 (0.18 g, 1.52 mmol) and Pd(Ph3)4 (0.32 g, 0.28 mmol) and stirred at 120° C. for overnight. The crude product was purified by flash column chromatography using 0%, 5% and 10% of ethylacetate in hexanes to yield 0.28 g (44%) of product. MS (ESI+) m/z 233 (M+H)+;
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.Br[C:15]1[CH:23]=[CH:22][C:18]2[CH2:19][CH2:20][O:21][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(C1CCCCC1=O)(=O)C.CN(C=O)C>[O:21]1[C:17]2[CH:16]=[C:15]([NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[N:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][CH:5]=3)[CH:23]=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: NCCc1ccc(C(F)(F)F)nc1
Reactant: Brc1ccc2c(c1)OCC2
Agent: CC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(CCNc2ccc3c(c2)OCC3)cn1
Temperature: 120 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine (955 mg, 5.0 mmol) were added 6-bromo-2,3-dihydro-benzofuran (1.00 g, 5.0 mmol), cuprous iodide (48 mg, 0.25 mmol) and cesium carbonate (3.27 g, 10.0 mmol) under an Ar-atmosphere. Then DMF (2.0 ml) and 2-acetylcyclohexanone (133 μl, 0.10 mmol) were added and the reaction mixture was stirred for 2 h at 120° C. It was cooled to ambient temperature and separated between TBME (40 ml) and water (15 ml). The organic layer was washed with brine (15 ml) and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 67:33) afforded the title compound (803 mg, 52%) as a yellow oil. MS m/e: 309.3 [M+H]+.
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([CH2:8]C(O)=O)[CH2:6][CH2:5][N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[O:13])[CH2:3]1.C([N:25](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1>[NH2:25][CH2:8][C@H:7]1[CH2:6][CH2:5][N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[O:13])[CH2:3][C@H:2]1[F:1]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(COC(=O)N2CC[C@H](CC(=O)O)[C@H](F)C2)cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1ccc(COC(=O)N2CC[C@H](CN)[C@H](F)C2)cc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
To a suspension of crude acid (±)-((cis)-3-fluoro-1-{[(4-methylbenzyl)oxy]carbonyl}piperidin-4-yl)acetic acid (9.1 g, 29.4 mmol) in toluene (80 mL) was added triethylamine (10.2 mL, 73.5 mmol) and diphenylphosphoryl azide (9.52 mL, 44.1 mmol). The reaction mixture was heated to 70° C. and stirred for 20 min. A mixture of dioxane (80 mL) and 1 M NaOH (80 mL) was added and the reaction mixture was cooled to RT. The reaction mixture was concentrated to remove the dioxane and extracted with EtOAc three times, dried over Na2SO4, filtered and concentrated. The residue was suspended in CH2Cl2, stirred for 30 min, and the white preciptate filtered off. The filtrate was concentrated to give crude product (7.5 g) as a yellow oil, used directly in the next step. An analytical sample was purified by silica gel chromatography (gradient elution: CH2Cl2 to 80:20:2 CH2Cl2:MeOH:NH4OH) for characterization:
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:10](=[O:11])[C@H:9]([CH3:12])[C@@H:8]([C:13]([OH:15])=[O:14])[CH2:7]1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:12][C@H:9]1[C:10](=[O:11])[NH:6][CH2:7][C@@H:8]1[C:13]([OH:15])=[O:14]
Reactant: COc1ccc(CN2C[C@H](C(=O)O)[C@@H](C)C2=O)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1C(=O)NC[C@@H]1C(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
To a crude product of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (8.11 g) were added anisole (3.76 ml) and trifluoroacetic acid (40 ml), and the mixture was stirred at 80° C. for 5 hours. This reaction solution was cooled to room temperature, and concentrated under reduced pressure. To the resulting residue was added diisopropyl ether, and the mixture was stirred. The insoluble substance was collected by filtration, and dried under reduced pressure to give a crude product of the titled compound (2.23 g). To the resulting solid was added ethanol (8 ml), and the mixture was heated at reflux to dissolve, and then the solution was stirred at room temperature. A solid precipitated from the mixed solution was collected by filtration, washed with a small amount of cooled ethanol, and dried under reduced pressure to give the titled compound (1.36 g).