Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[CH2:10]([C:12]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]2[C:18](=[O:26])[N:17]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH2:16][CH2:15][C:14]=2[N:13]=1)[CH3:11].[CH:33]1([C:36]2[C:41]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)=[C:40]([F:49])[C:39]([O:50][CH2:51][CH3:52])=[C:38]([CH:53]=O)[CH:37]=2)[CH2:35][CH2:34]1.[Na]>C1COCC1.CC(N(C)C)=O.C(O)(=O)C>[CH:33]1([C:36]2[C:41]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)=[C:40]([F:49])[C:39]([O:50][CH2:51][CH3:52])=[C:38]([CH2:53][N:30]3[CH2:29][CH2:28][CH:27]([N:17]4[CH2:16][CH2:15][C:14]5[N:13]=[C:12]([CH2:10][CH3:11])[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=5[C:18]4=[O:26])[CH2:32][CH2:31]3)[CH:37]=2)[CH2:35][CH2:34]1
Reactant: CCOc1c(C=O)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Reactant: CCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCNCC1)CC2
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCOc1c(CN2CCC(N3CCc4nc(CC)c(C(=O)OC)cc4C3=O)CC2)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
Triethylamine (3.84 g) was added to a suspension of methyl 2-ethyl-5-oxo-6-(piperidin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate dihydrochloride (7.41 g) in THF (90 mL) and DMA (30 mL) at room temperature. After being stirred at the same temperature for 30 minutes, 6-cyclopropyl-3-ethoxy-2,4′-difluorobiphenyl-4-carbaldehyde (6.89 g) was added to the reaction mixture. The mixture was stirred at room temperature under nitrogen atmosphere for 30 minutes. Sodium triacetoxyhydroborate (6.04 g) and acetic acid (1.141 g) were added to the reaction mixture at room temperature. The mixture was stirred at the same temperature under nitrogen atmosphere for 60 hours. The mixture was quenched with aqueous saturated sodium hydrogen carbonate solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (ethyl acetate/methanol) to give the title compound (7.17 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][CH:4]=1.Cl.[CH3:10][O:11][C:12](=N)[NH:13][N+:14]([O-:16])=[O:15].[Cl-].[Na+]>[OH-].[Na+]>[CH3:10][O:11][C:12](=[N:13][N+:14]([O-:16])=[O:15])[NH:1][CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][CH:4]=1
Reactant: COC(=N)N[N+](=O)[O-]
Reactant: NCc1cnc(Cl)s1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
5-(Aminomethyl)-2-chlorothiazole (1.49 g, 10.0 mmol), was dissolved in diluted hydrochloric acid (15 ml, 10.0 mmol), and O-methyl-N-nitroisourea (1.31 g, 11.0 mmol) and sodium chloride (4.68 g, 80.0 mmol) were added. The pH was 1.9 at this time. This reaction mixture was adjusted to pH 6.2 with aqueous sodium hydroxide solution (0.1 N, 5.0 ml, 0.50 mmol) using pH meter. After 16 hours of stirring at room temperature (pH was 6.7 at this time), the resulting white crystals were collected by filtration under reduced pressure, and washed with water. The washed crystals were dried under reduced pressure (80° C., 2 hours) to provide 1.74 g (69.4% yield) of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.[C-:25]#[N:26].[Na+].CCCCCC.CCOC(C)=O>C(#N)C.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.[Cu]I>[CH3:11][C:9]1[CH:10]=[C:2]([C:25]#[N:26])[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: [C-]#N
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 80 °C
Reaction time: 18 h
Yield: 94.5 %

Procedure:
A mixture of 5-bromo-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.600 g, 1.5 mmol), Pd(PPh3)4 (0.175 g, 0.14 mmol), sodium cyanide (0.163 g, 3.4 mmol), and CuI (0.029 g, 0.15 mmol) in acetonitrile (6 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate (typically 2:1 hexane-EtOAc) afforded 7-methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carbonitrile (0.491 g, 95%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.78 (s, 3H), 4.26 (s, 2H), 4.79 (s, 2H), 7.18 (d, 2H), 7.35 (d, 2H), 7.52 (s, 2H).
Reaction SMILES: Cl.[O:2]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH2:16])=[CH:6][CH:5]=1)[CH3:3].[C:17]([O-])(=[O:19])[CH3:18].[Na+].C(OC(=O)C)(=O)C.O>C(O)C>[CH3:3][O:2][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:6][CH:5]=1
Reactant: COc1ccc2cccc(CCN)c2c1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc2cccc(CCNC(C)=O)c2c1
Yield: 92.5 %

Procedure:
173 kg of the compound obtained in Step C and 66 kg of sodium acetate in ethanol are introduced into a 1600 litre reactor. The mixture is stirred and then 79 kg of acetic anhydride are added; the reaction mixture is heated at reflux and 600 l of water are added. The reaction mixture is allowed to return to ambient temperature and the precipitate obtained is filtered off and washed with a 35/65 ethanol/water mixture to give the title product in a yield of 92.5% and with a chemical purity exceeding 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1=[N:11][C:12]([CH3:14])=[N:13][N:6]1[C:5]2([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)N.C(O)(=[O:24])C>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:7]2[N:11]=[C:12]([CH3:14])[NH:13][N:6]=2)=[C:4]([CH:3]=1)[C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24]
Reactant: CC(=O)O
Reactant: Cc1nc2n(n1)C(N)(c1ccccc1)c1cc(Cl)ccc1-2
Solvent: CO
Product: Cc1nc(-c2ccc(Cl)cc2C(=O)c2ccccc2)n[nH]1

Procedure:
Ten milligrams of 7-chloro-2-methyl-5-phenyl-5H-[1,2,4]triazolo-[5,1-a]-isoindol-5-amine (as prepared in Example 1) are refluxed for 10 minutes in 2 ml of 50% aqueous methanol containing a drop of acetic acid. The methanol is removed under vacuum and the aqueous residue made basic with 10% NaOH. The aqueous solution is washed with chloroform, neutralized with 10% HCl and extracted with chloroform. The chloroform solution is evaporated to dryness and the residue is recrystallized from a water-ethanol mixture, m.p. 148° to 150°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[C:19]([O:21][CH2:22][C:23]([NH2:25])=[O:24])[C:18]([C:26]#[N:27])=[C:17](S(C)=O)[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[C:19]([O:21][CH2:22][C:23]([NH2:25])=[O:24])[C:18]([C:26]#[N:27])=[C:17]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CS(=O)c1cc(-c2ccccc2OCc2ccccc2)nc(OCC(N)=O)c1C#N
Solvent: O
Product: N#Cc1c(N2CCOCC2)cc(-c2ccccc2OCc2ccccc2)nc1OCC(N)=O
Temperature: 130 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of 2-{[6-[2-(benzyloxy)phenyl]-3-cyano-4-(methylsulfinyl)-2-pyridinyl]oxy}acetamide (300 mg, 0.71 mmol) and morpholine (1.0 mL) was stirred at 130° C. for 1 hr, and then water was added. The resulting precipitates were collected by filtration and dried under reduced pressure to give 2-{[6-[2-(benzyl-oxy)phenyl]-3-cyano-4-(4-morpholinyl)-2-pyridinyl]oxy}acetamide as a yellow solid (304 mg, yield; 96%).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O.[N:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:13]=[N-:14]>C(O)C>[N:12]([C:15](=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[O:3][CH3:2])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:13]=[N-:14]
Reactant: COc1ccccc1C=O
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccccc1OC)N=[N+]=[N-]
Temperature: -18 °C
Reaction time: 3 h

Procedure:
Pieces of sodium (3.678 g, 160 mmol) were added portionwise to ethanol (200 ml) over a period of 30 minutes. The resulting solution was cooled to −18° C. and a mixture of 2-methoxybenzaldehyde (4.832 g, 40 mmol) and ethyl azidoacetate (160 mmol) were then added over a period of one hour at a rate which allowed the temperature to be maintained below −15° C. After 3 hours, the solution was stored at 5° C. for 2 days in order to give a crystalline product which was collected by filtration and washed with cold hexane.
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C@H:18]([C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:19][C:20]([O:22]CC)=[O:21])=[O:16].CCO.[Li+].[OH-].Cl.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>O=[Pt]=O>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[N:27]1[C:28]2[CH2:29][CH2:30][CH2:31][CH2:32][C:33]=2[CH:34]=[C:25]([C@@H:18]([NH:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][NH:9][C:10]=3[N:1]=2)[CH2:19][C:20]([OH:22])=[O:21])[CH:26]=1
Reactant: CCOC(=O)C[C@H](NC(=O)CCCCc1ccc2c(n1)NCCC2)c1cnc2ccccc2c1
Agent: O=[Pt]=O
Agent: Cl
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: O=C(O)C[C@H](NC(=O)CCCCc1ccc2c(n1)NCCC2)c1cnc2c(c1)CCCC2
Reaction time: 3 h

Procedure:
A mixture of 5-8 (0.1 g, 0.3 mmol) and PtO2 (0.04 g) in 10 mL TFA was purged with argon 3 times under vacuum, and treated under balloon hydrogenation condition for 18 hr. It was then filtered through a celite pad. The solution was concentrated. EtOH (3 mL) and LiOH (1 mL, 1 M, 1 mmol) were added. After stirring for 3 hr, the reaction mixture was treated with 2N HCl (2 mL), concentrated and purified by reverse phase HPLC (C18 column; gradient: H2O/CH3CN/TFA from 95:5:0.1 to 5:95:0.1 over 45 min) to give the desired product 5-10 as the TFA salt.
Reaction SMILES: O[CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.S(Cl)([Cl:12])=O.N1C=CC=CC=1>ClCCCl>[Cl:12][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1
Reactant: CC1(CO)COC(=O)N1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC1(CCl)COC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(hydroxymethyl)-4-methyloxazolidin-2-one (1.89 g, 14.4 mmol) in 1,2-dichloroethane (10 ml) was added thionyl chloride (5.0 ml, 69 mmol). The solution was stirred for 30 min at RT, and then pyridine (5.0 ml, 62 mmol) was added. The solution was heated to 90° C. for 16 h and then 110° C. for an additional 2 h, then cooled to RT and evaporated. The residue was purified by flash chromatography (30% to 100% ethyl acetate in hexanes, Rf=0.25 in 1:1 ethyl acetate:hexanes) to give the title compound as a clear oil which solidified to a white solid upon standing (1.52 g, 10.2 mmol, 71%). 1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 3H), 3.55 (m, 2H), 4.12 (d, 1H, J=9.2 Hz), 4.31 (d, 1H, J=8.8 Hz), 5.4 (br s, 1H). LRMS (ESI/APCI): 150 [M+H]+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@H:19]1[CH2:31][OH:32])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@H:19]1[CH:31]=[O:32])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reaction time: 0.5 h

Procedure:
A solution of dimethyl sulfoxide (3.6 ml, 50.7 mmol) in methylene chloride (15 ml) was dropwise added to a solution of oxalyl chloride (2.89 ml, 33.9 mmol) in methylene chloride (100 ml) in a nitrogen stream at -78° C. The reaction solution was stirred at the same temperature for 30 minutes. To this mixture, a solution of (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-hydroxymethylpyrrolidine (8.0 g, 24.2 mmol) in methylene chloride (50 ml) was dropwise added at -78° C. This mixture was stirred at the same temperature for 30 minutes, and then triethylamine (11.1 ml, 79.8 mmol) was added thereto. The mixture was stirred further for 30 minutes. The reaction mixture was poured into methylene chloride (200 ml), and the organic layer was washed sequentially with dilute hyrochloric acid, water and a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain an oily residue of (2S,4 R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-formylpyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])(O)[CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[C:4]([CH3:25])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])=[CH:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[C:4]([CH3:25])[CH:3]=1
Reactant: Cc1cc(F)ccc1C(O)(Cc1nnnn1C)c1ccc(F)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1C(=Cc1nnnn1C)c1ccc(F)cc1C

Procedure:
A mixture of 1,1-bis-(4-fluoro-2-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol (0.5 g, 1.5 mmoles) and p-toluenesulfonic acid (0.2 g) was heated at reflux in toluene (30 mL) for 16 hours. The mixture was cooled, diluted with diethyl ether (50 mL) and extracted with saturated sodium bicarbonate solution and water. The organic layer was dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:12]=2)[NH:8][N:9]=1)=[O:4].[OH-].[Na+].Cl>>[C:3]([C:5]1[CH:6]=[C:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:12]=2)[NH:8][N:9]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cc(Nc2nc(-c3ccccc3)nc3ccccc23)[nH]n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(Nc2nc(-c3ccccc3)nc3ccccc23)[nH]n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 94.2 %

Procedure:
(5-Methoxycarbonyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine (III-73) (345 mg, 1 mmole in THF, 6 mL) was treated with NaOH (1M, 4.0 mL), stirred at 50° C. for 5 hours, cooled to room temperature, and neutralised with 1M HCl. The mixture was concentrated in vacuo to remove THF then diluted with water and the resulting precipitate filtered. The residual solid was dried at 80° C. under vacuum to afford III-72 as an off-white solid (312 mg, 94%): mp 289-291° C. (dec.); 1H NMR (DMSO) δ7.45 (1H, br s), 7.50-7.60 (5H, m), 7.80-7.88 (2H, ), 7.40-7.50 (2H, m), 8.60-8.70 (1H, d), 10.70 (1H, s), 13.00-13.80 (2H, br s); IR (solid) 1699, 1624, 1607, 1570,1539, 1506, 1486, 1398, 1333, 1256, 1177, 1004, 827, 764, 705; MS 332.3(M+H)+.
Reaction SMILES: N1C=CC=CC=1.[C:7]([OH:16])(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([O:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[C:7]([OH:16])=[O:15])(=[O:19])[CH3:18]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
Pyridine (64 μl, 0.80 mmol) was added to an ice cooled mixture of salicylic acid (10 mg, 0.72 mmol) and methylene chloride (10 mL). After 5 minutes, acetic anhydride (10 μl, 1.09 mmoles) was added. The resulting mixture was stirred at room temperature for 4 hrs. The product was extracted with methylene chloride and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 2-acetoxybenzoic acid in 76% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([F:16])[C@:13]([CH3:24])([C:17]([O:19]C(C)(C)C)=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([F:16])[C@:13]([CH3:24])([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@]1(C)CN(C(=O)OCc2ccccc2)CC1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(C(=O)O)CN(C(=O)OCc2ccccc2)CC1F
Reaction time: 2 h

Procedure:
To a solution of tert-butyl(3S)-1-benzyloxycarbonyl-4-fluoro-3-methylpyrrolidine-3-carboxylate isomer B (1.35 g, 4.00 mmol) in dichloromethane (7 mL), trifluoroacetic acid (7 mL) was added dropwise in an ice bath, and the mixture was stirred for 2 hours. After concentrating the reaction mixture under reduced pressure, saturated aqueous solution of sodium hydrogencarbonate (30 mL) was added to the concentrate in an ice bath, and the aqueous solution was washed with diethylether (50 mL). To the aqueous layer was added 1 mol/l hydrochloric acid to pH 2 to 3, and the solution was extracted with chloroform (150 mL×2). The organic layer was dried with anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure. The concentrate was azeotropically distilled by adding toluene (20 mL), and dried under reduced pressure to obtain 1.25 g (quantitative) of the title compound (isomer B) as a colorless oily substance.
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.Cl.[F:16][C:17]1([F:21])[CH2:20][NH:19][CH2:18]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:12]1([CH2:11][O:10][C:3]2[C:2]([N:19]3[CH2:20][C:17]([F:21])([F:16])[CH2:18]3)=[CH:7][N:6]=[C:5]([C:8]#[N:9])[CH:4]=2)[CH2:14][CH2:13]1
Reactant: FC1(F)CNC1
Reactant: N#Cc1cc(OCC2CC2)c(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: N#Cc1cc(OCC2CC2)c(N2CC(F)(F)C2)cn1
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 99.8 %

Procedure:
To a solution of 5-Bromo-4-cyclopropylmethoxy-pyridine-2-carbonitrile (Example 53c, 150 mg, 593 μmol) in dry toluene (3.95 ml) under an argon atmosphere in a microwave vial were added 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7, 84.4 mg, 652 μmol), palladium(II) acetate (13.3 mg, 59.3 μmol), BINAP (36.9 mg, 59.3 μmol) and cesium carbonate (386 mg, 1.19 mmol). The reaction mixture was stirred at 120° C. for 45 minutes under microwave radiation. The reaction mixture was filtered over a pad of celite and the filtrate was concentrated in vacuo. The residue was dissolved in ethylacetate and extracted with an aqueous solution of 1.0M sodium bicarbonate. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (157 mg, 79%) as a white solid. MS (ESI, m/z): 266.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](I)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[C:14](=[NH:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CO>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]1([C:14](=[N:27][C:10]2[CH:9]=[C:4]([CH:3]=[C:2]([F:1])[C:11]=2[CH3:12])[C:5]([O:7][CH3:8])=[O:6])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc(F)c(C)c(I)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(F)c(C)c(N=C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 3-fluoro-5-iodo-4-methylbenzoate (115.5 g, 392.8 mmol) in toluene (˜1600 mL) at ambient temperature was charged benzophenone imine (67.6 g, 373.0 mmol), 1,1′-bis(diphenylphosphino)ferrocene (9.80 g, 17.68 mmol) and cesium carbonate (179.2 g, 550.0 mmol). The reaction vessel was vacuum purged with nitrogen three times. Tris(dibenzylideneacetone)dipalladium(0) (5.34 g, 6.05 mmol) was added before the vessel was again vacuum purged with nitrogen three times. The reaction mixture was then stirred and heated to reflux for 4 d before being cooled to ambient temperature and filtered through GF/F filter paper under a nitrogen atmosphere. The filter cake was washed with toluene (230 mL) and the filtrates combined and washed with aq. sodium sulfite (5% w/w, 580 mL). The phases were separated and the aq. phase re-extracted with toluene (580 mL). The organic fractions were combined and washed with water (580 mL), dried over sodium sulfate and filtered through GF/F filter paper. The filter cake was washed with toluene (230 mL) and the combined filtrates concentrated to ˜1000 mL in vacuo. After cooling the solution to ambient temperature, TBME (1040 mL) was charged followed by decolourising charcoal (60 g). The slurry was heated to 45-50° C. and then cooled to ambient temperature over 1 h and filtered through GF/F filter paper. The filter cake was washed with TBME/toluene (1:1 v/v, 2×230 mL). The filtrates were combined to afford a solution of methyl 3-[(diphenylmethylene)amino]-5-fluoro-4-methylbenzoate to which methanol (127 mL, 3135.4 mmol) was added. Sulfuric acid (21 mL, 394.0 mmol) was then charged over at least 1 h ensuring that the temperature was maintained in the range 18-23° C. The resulting slurry was filtered through 100 μm cloth. The filter cake was washed with TBME (580 mL) and dried on the filter under a flow of nitrogen for at least 2 h. The isolated solid was then slurried in acetonitrile (500 mL) at ambient temperature for 4-5 h before being filtered through 100 μm cloth. The filter cake was washed with acetonitrile (1×300 mL, 1×115 mL) and dried on the filter at up to 45° C. to afford methyl 3-amino-5-fluoro-4-methylbenzoate sulfuric acid salt (92.2 g, 94.5% w/w).