Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28]#[N:29]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][C:28]#[N:29])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCCl
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.8 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (150 mg, 0.55 mmol) was suspended in dimethylformamide (10 ml). To the suspension were added potassium carbonate (81 mg, 0.59 mmol) and chloroacetonitrile (44 mg, 0.59 mmol) in order. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and to the residue was added water. The mixture was extracted with chloroform and the organic layer was dried on sodium sulfate. After removal of the solvent in vacuo, the residue was purified by silica gel chromatography (1% ammonia, 5% methanol/chloroform) to give the subject compound (58 mg, yield 25%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2([CH2:33][C:34](O)=[O:35])[S:13](=[O:15])(=[O:14])[CH2:12][CH2:11][N:10]([C:16]([O:18][CH2:19][CH:20]3[C:32]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:26]4[C:21]3=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[O:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[O:43][NH2:44].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[O:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[O:43][NH:44][C:34](=[O:35])[CH2:33][C:7]1([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)[S:13](=[O:14])(=[O:15])[CH2:12][CH2:11][N:10]([C:16]([O:18][CH2:19][CH:20]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:17])[CH2:9][CH2:8]1
Reactant: O=C(O)CC1(c2ccc(Br)s2)CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CCS1(=O)=O
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CC1(c2ccc(Br)s2)CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CCS1(=O)=O)NOC1CCCCO1
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 2-[7-(5-bromo-2-thienyl)-4-(9-fluorenylmethoxycarbonyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetic acid (400 mg), O-(2-tetrahydropyranyl)-hydroxylamine (95.2 mg) and 1-hydroxybenzotriazole (110 mg) in N,N-dimethylformamide (10 ml) was added WSCD-HCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) (156 mg) at room temperature. After being stirred at the same temperature overnight, the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (30 ml) and the solution was washed successively with 5% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent; 1% MeOH in chloroform (CHCl3)) to afford N-(2-tetrahydropyranyloxy)-2-[7-(5-bromo-2-thienyl)-4-(9-fluorenylmethoxycarbonyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (313 mg) as an amorphous powder.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]1>N1C=CC=CC=1>[C:1]([NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: COC(=O)[C@@H]1CC[C@H](N)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1CC[C@H](NC(C)=O)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.9 %

Procedure:
Acetic anhydride (0.07 ml, 7.00 mmol) was added to a stirred solution of (1R,3S)-methyl 3-aminocyclopentanecarboxylate (200 mg, 1.39 mmol) in pyridine (5 ml) and stirred for 15 h at ambient temperature. The reaction mixture was concentrated under reduced pressure, water and CHCl3 were added. The organic layer was separated and washed with saturated sodium bicarbonate solution, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 180 mg (69%) of (1R,3S)-methyl 3-acetamidocyclopentanecarboxylate as brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:15][N:14]=[C:13]([N+:16]([O-])=O)[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1>C(OCC)(=O)C.C(O)C.[Pt](=O)=O>[NH2:16][C:13]1[CH:12]=[C:11]([C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[O:10])[NH:15][N:14]=1
Reactant: O=C(Nc1cccc(F)c1)c1cc([N+](=O)[O-])n[nH]1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(C(=O)Nc2cccc(F)c2)[nH]n1
Yield: 73.8 %

Procedure:
N-(3-fluorophenyl)-3-nitro-1H-pyrazole-5-carboxamide (100 mg, 0.4 mmol) in ethyl acetate:ethanol (10:4) was stirred with platinum dioxide (10 mg) under an atmosphere of hydrogen (70 psi) for 3 hours. The catalyst was filtered off and the solvent was evaporated in vacuo to yield 3-amino-N-(3-fluorophenyl)-1H-pyrazole-5-carboxamide (65 mg, 73% yield):
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:56][O:57][C:58]([C:60]1[O:61][C:62]2[CH:68]=[CH:67][C:66]([NH2:69])=[CH:65][C:63]=2[N:64]=1)=[O:59]>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:69][C:66]2[CH:67]=[CH:68][C:62]3[O:61][C:60]([C:58]([O:57][CH3:56])=[O:59])=[N:64][C:63]=3[CH:65]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc2cc(N)ccc2o1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1nc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2o1
Reaction time: 0.33 h

Procedure:
A solution of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (59.8 mg, 0.128 mmol) in dichloromethane (3 ml) was treated with DIPEA (66.8 mg, 0.517 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (80.7 mg, 0.341 mmol) and stirred for 20 min under argon. 5-AMINO-BENZOOXAZOLE-2-CARBOXYLIC ACID METHYL ESTER (25.8 mg, 134 μmol, JW PharmLab) was added and stirred 2 hrs. The reaction mixture was diluted with dichloromethane and washed with water, sat'd NaHCO3, water and brine. After drying over Na2SO4 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes giving chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzo[d]oxazole-2-carboxylate (73.7 mg., 89.8%) as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 641.15. found: 641.2.
Reaction SMILES: [Na].[CH3:2][C:3]1[C:8]([Cl:9])=[CH:7][NH:6][C:5](=[O:10])[N:4]=1.[CH3:11]I.[OH-].[K+]>C(O)C>[CH3:11][N:6]1[CH:7]=[C:8]([Cl:9])[C:3]([CH3:2])=[N:4][C:5]1=[O:10]
Reactant: CI
Reactant: Cc1nc(=O)[nH]cc1Cl
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(=O)n(C)cc1Cl
Yield: 35 %

Procedure:
A solution of the sodium salt of 4-methyl-5-chloropyrimid-2-one (0.005 mol) and methyl iodide (0.0055 mol) in abs. ethanol (70 ml) was heated under reflux until ca. neutral pH. Another 0.005 mol of potassium hydroxide and methyl iodide were added and the heating continued to ca. neutral pH. The reaction mixture was then filtered and the filtrate evaporated to dryness. The residual material was repeatedly extracted with chloroform and the chloroform extracts evaporated and the solid extract recrystallised from isopropanol; yield 35%, m.p. 132°-134° C. (Found: C, 45.51; H, 4.51. Calc. for C6H7ClN2O: C, 45.44; H, 4.43).
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.C[O-].[Na+].CO>C(OCC)(=O)C>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=Cc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 178.2 %

Procedure:
10.0 g of p-acetoxystyrene was dissolved in 40.0 g of ethyl acetate, and the resulting solution was cooled to 0° C. Subsequently, 4.76 g of sodium methoxide (a 28 mass % methanol solution) was added dropwise over 30 minutes, and the resulting solution was stirred at room temperature for 5 hours. The organic layer was washed with distilled water three times and dried over anhydrous sodium sulfate, and the solvent was removed by distillation to obtain 13.2 g of p-hydroxystyrene (the compound represented by the following formula (1), a 54 mass % ethyl acetate solution). Thereafter, 11.0 g of a 54 mass % ethyl acetate solution of the obtained p-hydroxystyrene (1) (containing 5.9 g of p-hydroxystyrene (1)), 9.4 g of the compound represented by the following formula (2) (produced by KNC Laboratories Co., Ltd.), 2.2 g of the compound represented by the following formula (3) (produced by Daicel Corporation) and 2.3 g of polymerization initiator V-601 (produced by Wako Pure Chemical Industries, Ltd.) were dissolved in 14.2 g of propylene glycol monomethyl ether (PGME). After charging 3.6 g of PGME into a reaction vessel, the solution prepared above was added dropwise at 85° C. over 4 hours in a nitrogen gas atmosphere, and the reaction solution was heated with stirring for 2 hours and then allowed to cool to room temperature. The obtained reaction solution was added dropwise and reprecipitated in 889 g of a mixed solution of hexane/ethyl acetate (8/2 (by mass)), and the precipitate was filtered to obtain 15.5 g of (P-2).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]([CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([NH:21][CH2:22][CH:23]([OH:32])[C:24]2[N:25]=[C:26]([CH:29]([CH3:31])[CH3:30])[S:27][CH:28]=2)[CH3:20])=[CH:14][CH:13]=1)=[O:9].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:8]([CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH:19]([N:21]2[C:3](=[O:4])[CH2:2][O:32][CH:23]([C:24]3[N:25]=[C:26]([CH:29]([CH3:31])[CH3:30])[S:27][CH:28]=3)[CH2:22]2)[CH3:20])=[CH:16][CH:17]=1)([O:7][CH3:6])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(C)C)n2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)COc1ccc(CC(C)N2CC(c3csc(C(C)C)n3)OCC2=O)cc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
0.60 ml (7.89 mmol) of chloroacetyl chloride is added dropwise to a stirred solution of 3.10 g (7.89 mmol) of N-[2-(4-methoxycarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-isopropyl-thiazol-4-yl)-ethanamine and 1.10 ml (7.89 mmol) of triethylamine in 20 ml of chloroform at 25° C. internal temperature. After the mixture has stood overnight at 20° C., it is concentrated in vacuo, and the resudue is dissolved in 30 ml of anhydrous dimethyl formamide. To this is added 0.888 g (15.78 mmol) of a 55% dispersion of sodium hydride in oil, during which brief foaming is observed. The mixture is stirred at 20° C. for 3 hours, concentrated in vacuo, and the residue is partitioned between water and ether. The ether solution is dried, filtered and concentrated in vacuo, and the oily residue is purified on silica gel (toluene/acetone =4:1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([O:41][CH3:42])[C:27]=1[OH:43]>>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][N:22]([CH3:23])[CH3:24])[CH2:17][CH2:16]2)[CH:29]=[C:28]([O:41][CH3:42])[C:27]=1[OH:43]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N1CCC(CN(C)C)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(C)=O)c(N4CCC(CN(C)C)CC4)c3c2)cc(Cl)c1O
Yield: 49.4 %

Procedure:
Following general procedure D, 1-(6-bromo-4-{4-[(dimethylamino)methyl]piperidin-1-yl}quinolin-3-yl)ethanone (17.7 mg, 0.045 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (28 mg, 0.100 mmol) to afford the desired product (10.4 mg, 49%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.76 (s, 1H), 8.32 (d, J=1.3 Hz, 1H), 8.07-7.97 (m, 2H), 7.31 (d, J=2.1 Hz, 1H), 7.25 (d, J=2.1 Hz, 1H), 4.00 (s, 3H), 3.48 (d, J=12.5 Hz, 2H), 3.16 (t, J=11.5 Hz, 2H), 2.68 (s, 3H), 2.43 (d, J=6.6 Hz, 2H), 2.36 (s, 6H), 2.01-1.85 (m, 3H), 1.67-1.54 (m, 2H); ESI MS m/z 468 [C26H30ClN3O3+H]+; HPLC>99% (AUC), tR=10.12 min.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16])=[O:4].[CH:19]1[C:31]2[CH:30]([CH2:32][O:33][C:34]([N:36]3[C:47]4[C:39](=[C:40]5[C:44](=[CH:45][CH:46]=4)[NH:43]C(C(O)=O)[CH2:41]5)[CH:38]=[CH:37]3)=[O:35])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C=O)C>[CH:28]1[C:29]2[CH:30]([CH2:32][O:33][C:34]([N:36]3[C:47]4[C:39](=[C:40]5[C:44](=[CH:45][CH:46]=4)[NH:43][CH:2]([C:3]([O:5][C:6]4[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=4[F:16])=[O:4])[CH2:41]5)[CH:38]=[CH:37]3)=[O:35])[C:31]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]=2[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: O=C(O)C1Cc2c(ccc3c2ccn3C(=O)OCC2c3ccccc3-c3ccccc32)N1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C1Cc2c(ccc3c2ccn3C(=O)OCC2c3ccccc3-c3ccccc32)N1

Procedure:
Pentafluorophenyl trifluoroacetate (0.3 mL, 1.75 mmol) was added to a solution of acid 9 (0.3 g, 0.7 mmol) and triethylamine (0.3 mL, 2.1 mmol) in 4 mL of anhydrous DMF. After 1 h DMF was evaporated and the residue chromatographed on silica eluting with 2% acetone in methylene chloride. Concentration of the pure product fraction and drying afforded 0.29 g (70%) of PFP ester 10 as a yellow solid.
Reaction SMILES: CO[CH:3]([O:18]C)[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1O.OS(O)(=O)=O>C(Cl)(Cl)Cl>[CH2:4]1[CH:3]2[N:8]([C:9](=[O:17])[C:10]3[C:11]([O:18]2)=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:7][CH2:6][NH:5]1
Reactant: COC(CNCCNC(=O)c1ccccc1O)OC
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2OC2CNCCN12
Temperature: 25 °C

Procedure:
To a stirring solution of N-[2-(2,2-dimethoxy-ethylamino)-ethyl]-2-hydroxy benzamide (300 mg, 1.11 mmol) in CHCl3 (100 mL) was added conc H2SO4 (2 mL). The reaction was refluxed overnight, then cooled to room temperature then poured into a mixture of ice-saturated NaHCO3 solution. The mixture was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine, dried on MgSO4, and conc in vacuo to yield a yellowish oil. The oil was then purified by chiral HPLC using an OD column with 10% iPrOH in heptane to yield 50 mg of the R enantiomer as white solid, MS (ESI) 205 (M+H), and 56 mg of the S enantiomer as white solid, MS (ESI) 205 (M+H).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[S:12].[OH-].[K+].I[CH3:16]>CC(C)=O>[CH3:16][S:12][C:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:1]=1
Reactant: S=C1CCCc2ccccc2N1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CSC1=Nc2ccccc2CCC1
Reaction time: 0.08 h

Procedure:
A solution of Example 182B (2.3 g, 12.97 mmol) in acetone (51.9 mL) was heated to 60° C. in and oil bath. Then potassium hydroxide (36.4 g, 649 mmol) was added followed by the dropwise addition of iodomethane (0.811 mL, 12.97 mmol). The resulting yellow slurry was stirred for 5 minutes and then the solids were collected by filtration. The solids were washed with acetone and the filtrate was concentrated to obtain the crude title compound which was used was used without purification for the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].Cl.[NH2:12][OH:13].CCN(CC)CC>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:12][OH:13])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C=O)ccc1Br
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(C=NO)ccc1Br
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a mixture of 4-bromo-3-methyl-benzaldehyde (372 mg, 1.87 mmol) and hydroxylamine hydrochloride (306.5 mg, 4.41 mmol) in ethanol (5 mL) at rt was added Et3N (0.15 mL). The reaction mixture was heated under reflux for 2 h, cooled to rt and concentrated under reduced pressure. The residue was dissolved in EA (10 mL), washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to give 4-bromo-3-methylbenzaldehyde oxime (384 mg; yield 96%) as a white solid.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O:19]([NH2:21])[CH3:20]>N1C=CC=CC=1.CCO>[CH3:20][O:19][N:21]=[C:1]([C:9]1[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(B(O)O)cc1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(c1ccccc1)c1ccc(B(O)O)cc1

Procedure:
A solution of 4-benzoyl phenyl boronic acid (226.00 mg, 1.00 mmol) and methoxyl amine hydrochloride (101.00 mg, 1.20 mmol) in pyridine (5 mL) and EtOH (5 mL) was refluxed at 125° C. for 24 h. Reaction was then concentrated in vacuo to give a crude product which was used for next step without further purification. MS (ES+): m/z 256.00 (100)[MH+]. HPLC: tR=3.17 min (Open Lynx polar—5 min).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH2:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])[CH3:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:29][N:28]([CH2:30][C:31]1[CH:32]=[C:33]([NH:34]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:35]=[CH:36][CH:37]=1)[CH3:27]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN(C)Cc1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)Cc1cccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: O.O.[Na+:3].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([O-:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1.[OH-].[Na+].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>O.[Cl-].[Na+].O>[Na+:3].[CH3:17][S:18]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([O-:14])(=[O:12])=[O:13])=[CH:7][CH:6]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)Oc1ccc(S(=O)(=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
4-Hydroxybenzenesulfonic acid sodium salt dihydrate (11.6 g, 50.0 mmol) and sodium hydroxide (2.00 g, 50.0 mmol) were dissolved in distilled water (50 mL) and the solution cooled to 0° C. Methane sulfonyl chloride (4.25 mL, 55.0 mmol) was added dropwise with stirring and the mixture then allowed to warm to room temp. and left for 2 h. Brine (20 mL) was added and the solution left to stand for 1 h with the formation of white crystalline solid. The solids were filtered, recrystallised (brine), and dried under vacuum to give the title compound as a white crystalline solid (7.81 g, 57%),
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1([C@@H]([NH:20][C@H:21]2[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][C@H:22]2[C:31]([O:33][CH2:34][CH3:35])=[O:32])C)C=CC=CC=1.[H][H]>[Pd].C(O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[NH2:20][C@H:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][C@H:22]1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H]1CC2(CC[C@@H]1N[C@@H](C)c1ccccc1)OCCO2
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC2(CC[C@@H]1N)OCCO2
Temperature: 40 °C
Reaction time: 10 h
Yield: 83 %

Procedure:
To a hydrogenator were charged ethyl (7R,8S)-8-((S)-1-phenyl-ethylamino)-1,4-dioxa-spiro[4.5]decane-7-carboxylate 4-toluenesulfonate salt 1A (1417 g, 2.8 moles, c.f: WO2004098516, prepared analogous to U.S. Pat. No. 6,835,841), ethanol (200 proof, 11.4 L), and 10% Pd/C catalyst (50% wet, 284 g). The mixture was inerted with nitrogen, then pressurized with hydrogen gas (45 psig) and agitated vigorously at approx. 40° C. until starting material was consumed (HPLC). The suspension was cooled, purged with nitrogen gas and the catalyst was removed by filtration while inerted. The spent catalyst was washed with ethanol (4.3 L). The filtrate and washings were combined and concentrated under vacuum to a volume of 2-3 L while maintaining the batch between 40°-60° C. Isopropyl acetate (5 L) was charged and the mixture was concentrated to a volume of ˜2 L until most ethanol was removed (<0.5%) and residual moisture content was <1,000 ppm. Batch volume was adjusted to ˜7.5 L by the addition of isopropyl acetate. The mixture was heated to 80° C. until clear, then cooled 65°-70° C. Seed crystals of 1 (5 g) were added and the batch was cooled to 50° C. over 2 hours, then further cooled to 20° C. over 4 hours and held for ˜10 hours. The resulting slurry was filtered and the cake was washed with isopropyl acetate (2 L). The product was dried under vaccum at ˜35° C. until volatiles were reduced below ˜1% (LOD). Ethyl (7R,8S)-8-amino-1,4-dioxa-spiro[4.5]decane-7-carboxylate 4-toluenesulfonate salt 1 was obtained as a white, crystalline solid (936 g, 83% yield; HPLC purity: 99.8%). 1H-NMR: (300 MHz, CDCl3) 8.14-7.89 (brs, 3H), 7.75 (d, J 9.0 Hz, 2H), 7.15 (d, J 8.0 Hz, 2H), 4.22-4.04 (m, 2H), 4.01-3.77 (m, 4H), 3.55-3.43 (m, 1H,), 3.20-3.13 (m, 1H), 2.40-2.27 (m, 4H), 2.21-1.94 (m, 2H), 1.81-1.51 (m, 3H), 1.23 (t, J 7.0 Hz, 3H); HPLC: Waters Xterra MS C18 4.6 mm×150 mm i.d., 3.5 μm particle size, 0.05% NH4OH (5% ACN, 95% H2O, solvent A), to 0.05% NH4OH (95% ACN, 5% H2O, solvent B), 5% B to 20% B in 10 minutes, changed to 95% B in 25 minutes, and then changed to 5% B in 1 minute; 11.1 minutes (aminoester 1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][C:15]1[C:19](B2OC(C)(C)C(C)(C)O2)=[C:18]([CH3:29])[O:17][N:16]=1.O.C([O-])([O-])=O.[Cs+].[Cs+]>CCOC(C)=O>[NH2:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([C:19]2[C:15]([CH3:14])=[N:16][O:17][C:18]=2[CH3:29])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(F)cc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2c(C)noc2C)c(F)cc1N
Temperature: 120 °C

Procedure:
To methyl 2-amino-5-bromo-4-fluorobenzoate (20 g, 80.6 mol.) and 3,5-Dimethylisoxazole-4-boronic acid pinacol ester (24.2 g, 108.9 mol., 1.35 mmol) was added to a solvent mixture of 1,2-dimethoxymethane (120 ml) and water (60 ml). To the above mixture were added PEPPSI-Ipr (3120 mg, 4.2 mmol, 0.05 equiv.) and Cs2CO3 (78.8 g, 241 mol., 3 equiv.). The reaction mixture was heated at 120° C. for 2 h in a pressure tube. The reaction mixture was then diluted with EtOAc (100 ml), washed with bring (50 ml×2). The organic solvent was evaporated and the residue was dissolved in DCM and purified with combi-flash column chromatography (product came out at 50% EtOAc/Hexane) to afford methyl 2-amino-5-(3,5-dimethylisoxazol-4-yl)-4-fluorobenzoate.