Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[CH:4]=1)=O.[NH:32]1[CH2:39][CH2:38][CH2:37][C@@H:33]1[C:34]([NH2:36])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[NH2:36][C:34]([C@H:33]1[CH2:37][CH2:38][CH2:39][N:32]1[CH2:1][C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:21][CH2:22][N:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH2:24][CH2:25]2)[CH:4]=1)=[O:35]
Reactant: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Reactant: NC(=O)[C@H]1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC[C@@H]5C(N)=O)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.7 %

Procedure:
To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide (25 mg, 0.054 mmol) in DMSO (2 mL) was added D-prolinamide (114 mg, 1 mmol) and 2 drops of acetic acid. The resulting mixture was stirred at room temperature for 4 h followed by an addition of sodium triacetoxyborohydride (212 mg, 1.0 mmol). The mixture was reacted overnight. It was then purified by Gilson Preparatory HPLC to give 20.4 mg of the title compound.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1(C(C2C=CC=CC=2)=[N:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])C=CC=CC=1.[N+:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br)([O-:31])=[O:30]>C1COCC1>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([CH2:35][C:34]1[CH:37]=[CH:38][CH:39]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=1)[NH2:16])[CH3:22]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(N)Cc1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 90.7 %

Procedure:
LDA (2M in heptane/THF/ethyl benzene, 25.45 ml, 50.9 mmol) was added dropwise to a solution of ethyl N-(diphenylmethylene)glycinate (13 g, 48.5 mmol) in THF (200 ml) at −78°. After 40 min a solution of 3-nitrobenzyl bromide (10 g, 46.3 mmol) in THF (40 ml) was added dropwise. The mixture was stirred for 2 h and then partitioned between EtOAc (100 ml) and water (100 ml). The aqueous layer was separated and extracted with EtOAc (2×50 ml) and the combined organics dried (Na2SO4) and evaporated in vacuo. The residue was then dissolved in ethanol (200 ml) and hydrochloric acid (1M, 50 ml) was added and the mixture stirred for 0.25 h. The volatiles were then removed in vacuo and the residue purified by chromatography (SiO2, Et2O) to give the title compound as an orange oil (10.0 g, 96%). δH (CDCl3) 8.09-8.06 (2H, m, Ar), 7.56-7.53 (1H, m, ArH), 7.48-7.43 (1H, m, ArH), 4.15 (2H, q, J 7.2, OCH2CH3), 3.71 (1H, dd, J 7.8, 5.5 Hz, CHCH2), 3.14 (1H, dd, J 13.7, 5.5 Hz, CHCHAHB)2.95 (1H, dd, J 13.7, 7.8 Hz, CHCHAHB), 1.51 (2H, br s, NH2) and 1.23 (3H, t, J 7.2, OCH2CH3); m/z (ESI, 60V) 239 (M++1).
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]1[CH:21]=[N:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O.[NH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:24]=1[OH:36]>N1C=CC=CC=1>[Cl:12][C:13]1[CH:21]=[N:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])[CH:26]=[CH:25][C:24]=1[OH:36])=[O:17]
Reactant: Nc1cc(C(F)(F)C(F)(F)F)ccc1O
Reactant: O=C(O)c1ccncc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)C(F)(F)F)ccc1O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.4 %

Procedure:
To a mixture of 0.44 g of WSC and 4 ml of pyridine, 0.36 g of 3-chloroisonicotinic acid was added. The reaction mixture was stirred at room temperature for 15 minutes. To the reaction mixture, 0.45 g of 2-amino-4-(pentafluoroethyl)phenol was added and stirred while heating at 60° C. for two hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 3-chloro-N-[2-hydroxy-5-(pentafluoroethyl)phenyl]isonicotinamide.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH2:12])[CH:4]=1)[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([C:20]2[N:25]=[C:24]([CH3:26])[C:23]([C:27](O)=[O:28])=[CH:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][C:27]([C:23]2[C:24]([CH3:26])=[N:25][C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=3)=[N:21][CH:22]=2)=[O:28])[CH:4]=1)[CH3:2]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: CCc1cn(N)c2ncccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cn(NC(=O)c2cnc(-c3cccc(F)c3)nc2C)c2ncccc12
Temperature: 150 °C
Yield: 43.7 %

Procedure:
A mixture of 3-ethyl-pyrrolo[2,3-b]pyridin-1-ylamine (126 mg, 0.78 mmol), 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (180 mg, 0.78 mmol), HATU (356 mg, 0.036 mmol) and DIPEA (302 mg, 2.34 mmol) in DMF (4 mL) is heated at 150° C. for 1 h. The reaction is quenched with water and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is chromatographed through silica gel eluting with 0-100% ethyl acetate in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-ethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide (128 mg). MS: 376 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.10 (s, 1H), 8.25-8.33 (m, 2H), 8.16 (d, 1H), 8.05 (d, 1H), 7.62 (q, 1H), 7.39-7.48 (m, 2H), 7.16 (dd, 1H), 2.78 (s, 3H), 2.75 (q, 2H), 1.29(t, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:37])([CH3:36])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([O:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)[CH:9]=1.C1C(=O)N([I:45])C(=O)C1>C(#N)C>[CH3:33][Si:32]([CH3:35])([CH3:34])[CH2:31][CH2:30][O:29][CH2:28][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:36])([CH3:1])[CH3:37])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:45])=[C:12]2[N:11]=[C:10]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=2)[CH:9]=1
Reactant: COC(=O)c1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Methyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yloxy)benzoate (450 mg, 0.81 mmol) was dissolved in ACN (15 mL) and NIS (200 mg, 0.88 mmol) was added. The resulting mixture was stirred at room temperature for 2 h and then the solvent was removed under reduced pressure. The residue was purified with column (silica gel, 10% EtOAc/Hexane) gave the product, methyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yloxy)benzoate (541 mg) as yellowish oil. HPLC-MS tR=3.10 min (UV254 nm); mass calculated for formula C26H39IN4O5Si2 670.2, observed LCMS m/z 671.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[CH2:15]([Mg]Br)[CH2:16][CH2:17][CH2:18][CH3:19]>>[CH3:14][O:13][C:9]1[CH:8]=[C:5]([C:6](=[O:7])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12]
Reactant: CCCCC[Mg]Br
Reactant: COc1cc(C=O)cc(OC)c1OC
Product: CCCCCC(=O)c1cc(OC)c(OC)c(OC)c1

Procedure:
Substantially the same procedure as in Process 1 of Example 48 was repeated using 3,4,5-trimethoxybenzaldehyde (3.92 g) and pentylmagnesium bromide (2.0 M diethyl ether solution, 12 ml) to give 1-(3,4,5-trimethoxyphenyl)-1-hexanone (3.27 g).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=1F.CO>C1COCC1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=1[O:4][CH3:2]
Reactant: Fc1cc(Br)ccc1Br
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Br)ccc1Br
Temperature: 70 °C
Yield: 84 %

Procedure:
Add dropwise potassium tert-butoxide (118.2 ml, 118.2 mmol, 1 M in hexane) to a solution of 1,4-dibromo-2-fluorobenzene (25.0 g, 98.5 mmol) in THF (492 mL) and MeOH (40 mL, 984.7 mmol) at RT. Heat the mixture at 70° C. overnight. Quench the mixture with water (50 mL), dilute with Et2O (400 mL), wash once with saturated NH4Cl (300 mL) and back extract the aqueous with Et2O (200 mL). Dry the combined organic phase over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatograph, eluting with 5-10% ethylacetate/hexane to give 22.0 g (84%) of the title compound. GC m/z (79Br81Br) 266 [M]+.
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.C[O:8][C:9]([CH:11]1[CH2:16][CH2:15][CH:14]([CH3:17])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O>C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]([N:13]1[C@H:14]([CH3:17])[CH2:15][CH2:16][C@@H:11]([C:9](=[O:8])[NH2:2])[C@@H:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [NH4+]
Reactant: COC(=O)C1CCC(C)N(C(=O)OCc2ccccc2)C1c1ccccc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@H]1CC[C@@H](C(N)=O)[C@H](c2ccccc2)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
(A mixture of two diastereomers and their enantiomers.). To ammonium chloride (1.18 g, 22.1 mmol) in 20 mL of benzene at 0° C. was added trimethylaluminum (22.1 mmol, 11.0 mL of a 2.0 M solution in toluene) The resultant mixture was stirred for 30 minutes at 0° C., and warmed to room temperature for an additional 30 minutes. To the mixture was then added 6-Methyl-2-phenyl-piperidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester as a solution in 20 mL of benzene, and the resultant mixture was heated to reflux for 6 hours. The reaction was then cooled to 0° C. and quenched carefully with 10 mL of 1 M HCl. The mixture was stirred for 30 minutes, filtered through celite, and the filter pad was rinsed with CH2Cl2. The filtrate was concentrated and the residue was dissolved in EtOAc, washed with saturated NaHCO3, dried over MgSO4 and concentrated. Silica gel chromatography (CHCl3 to eluted nonpolar material followed by 95:5 CHCl3/MeOH to elute the product) gave 560 mg (36%) of a mixture of the title compounds as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.10–7.42 (comp, 20H, both diastereomers), 5.99 (d, J=5.1 Hz, 1H), 5.68–5.90 (br, 2H, both diastereomers), 5.67 (d, J=4.3 Hz, 1H), 5.00–5.26 (comp, 4H, both diastereomers), 4.53 (m, 1H), 4.17 (br, 1H), 3.15 (m, 1H), 2.75 (m, 1H), 2.28 (app dq, J=4.1, 13.2 Hz, 1H), 1.9–2.08 (m, 2H), 1.50–1.90 (comp, 5H), 1.34 (d, J=6.6 Hz, 3H), 0.68 (d, J=7.1 Hz, 3H); 13C NMR (100 MHz) δ 174.2, 128.6, 128.4, 128.3, 128.2, 128.1, 127.8, 127.6, 127.2, 127.1, 126.7, 67.6, 67.1, 56.9, 52.8, 47.4, 46.6, 30.2, 25.5, 22.3, 19.8, 16.3; Mass spectrum m/e calcd. for M+H=353.2. Found 353.0, 309.1, 219.0 (base).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39](Br)[N:38]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:28][O:27][C:23](=[O:26])[CH:24]=[CH:25][C:39]1[CH:40]=[CH:41][CH:42]=[C:37]([NH2:36])[N:38]=1
Reactant: C=CC(=O)OC
Reactant: Nc1cccc(Br)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1cccc(N)n1

Procedure:
Tri(o-toly)phosphine (26 mg, 0.086 mmol), palladium(II) acetate (214 mg, 0.96 mmol), methyl acrylate (90 mg, 1.04 mmol), triethylamine (351 mg, 3.47 mmol) and 2-amino-6-bromopyridine (37) (150 mg, 0.87 mmol) in acetonitrile (3 mL) were heated in a CEM Discover microwave for 1 hour at 90° C. The solvent was removed under a stream of nitrogen gas; 4N HCl was added and the aqueous extracted with TBME (×2). The aqueous layer was then basified to pH 9/10 using K2CO3(aq) and extracted with EtOAc (×5). The organic layer was washed with brine, dried (Na2SO4) and the solvent concentrated in vacuo. The crude product was partially purified by column chromatography eluting with 50% EtOAc in heptane to give the title compound. Yield: 95 mg, 61%; LC-MS tr 0.76 min; HPLC Purity: 42%; MS (ES+) m/z 179 (M+H)
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH2:13][CH:14]1[N:19]([S:20]([CH3:23])(=[O:22])=[O:21])[C:18]2[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=2[O:16][CH2:15]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CN1CCCC1=O>[N:28]1([CH2:13][CH:14]2[N:19]([S:20]([CH3:23])(=[O:22])=[O:21])[C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[O:16][CH2:15]2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: CS(=O)(=O)N1c2ccccc2OCC1CO
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)N1c2ccccc2OCC1CN1CCOCC1

Procedure:
In the same manner, the isomeric 3-hydroxymethyl-4-methanesulfonyl-3,4-dihydro-2H-1,4-benzoxazine p-toluenesulfonate obtained above (40.8 g, 0.10 mole) was reacted with 60 ml of morpholine in 100 ml of N-methylpyrrolidone to give 22.5 g of 3-(4-morpholinylmethyl)-4-methanesulfonyl-3,4-dihydro-2H-1,4-benzoxazine.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH2:11][CH3:12])[CH3:10])=[N:5][N:4]=[C:3]1[S:13][CH3:14].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH:15](=[N:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH2:11][CH3:12])[CH3:10])=[N:5][N:4]=[C:3]1[S:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCC(C)c1nnc(SC)n(N)c1=O
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCC(C)c1nnc(SC)n(N=Cc2ccccc2)c1=O
Temperature: 0 °C

Procedure:
21.4 g of 4-amino-6-sec.-butyl-3-methylthio-1,2,4-triazin-5(4H)-one and 11.0 ml of benzaldehyde, dissolved in 50 ml of isopropanol, were briefly heated to the reflux temperature after adding 0.1 g of p-toluenesulfonic acid. On cooling to 0° C, 23.2 g of crude product crystallized out and were purified further by dissolving in 200 ml of boiling toluene. A small amount of a high-melting by-product crystallized out at 0° C and was filtered off and discarded. On concentration on a rotary evaporator, the mother liquor left 21.1 g (70%) of a pale oil which crystallized after trituration with a little methanol. The pure 4-benzylideneamino-6-sec.-butyl-3-methylthio-1,2,4-triazine-5 (4H)-one melted at 73° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:19].[OH-:20].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:17]1[CH:16]=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH2:11][C:10]([OH:19])=[O:20]
Reactant: O=C1Cc2cc(O)ccc2N1c1c(Cl)cccc1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1cc(O)ccc1Nc1c(Cl)cccc1Cl
Yield: 95 %

Procedure:
A solution of 1-(2,6-dichlorophenyl)-5-hydroxy-2-indolinone (2.0 g, 6.8 mmol) in 25 mL of 2.5N NaOH is heated at reflux for 2 hours. The cool reaction mixture is diluted with 20 mL of water and washed with ethyl ether. The basic layer is acidified with concentrated HCl and extracted with ethyl acetate (2×25 mL). The organic phase is washed with brine and dried (Na2SO4). Removal of solvent affords the product (2.0 g, 95%) as a brown foam (of suitable purity for use in the next step).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=3)=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
A solution of the 2-(4-((3-chloro-5-(trifluoromethyl)-2-pyridinyl)oxy)phenoxy)propionyl chloride (prepared in Step A) in 50 ml of acetonitrile was added to a mixture of 3.82 g (19.4 mmol) of 4-aminobenzotrifluoride, hydrochloride and 4.90 g (48.4 mmol) of triethylamine in 25 ml of acetonitrile. The reaction mixture was warmed at reflux for 4.0 hours and then poured over crushed ice. The resulting precipitate was collected by filtration and dried. The residual solid was recrystallized from methylcyclohexane to give 9.1 g (93 percent of theoretical) of the above-named product as a tan solid which melted at 140°-143° C. The structure of the product was confirmed by its IR and NMR spectrum. (Compound 1)
Reaction SMILES: C([O:8][NH:9][C:10](=[O:38])[C@H:11]([N:14]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]2[O:35][CH2:36][O:37][C:31]=2[CH:30]=1)[S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[CH:20][C:19]=1[CH3:27])(=[O:17])=[O:16])[CH2:12][OH:13])C1C=CC=CC=1>[Pd].C(O)C.O1CCCC1>[OH:8][NH:9][C:10](=[O:38])[C@H:11]([N:14]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]2[O:35][CH2:36][O:37][C:31]=2[CH:30]=1)[S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[CH:20][C:19]=1[CH3:27])(=[O:17])=[O:16])[CH2:12][OH:13]
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CO)C(=O)NOCc2ccccc2)c(C)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CO)C(=O)NO)c(C)c1
Reaction time: 0.75 h
Yield: 97.6 %

Procedure:
To a solution of N-benzyloxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-hydroxypropionamide (3.0 g, 5.39 mmol) in argon deoxygenated 80% ethanol-tetrahydrofuran (160 mL) was added 10% Pd-C (1.3 g), and the resulting mixture was hydrogenated at atmospheric pressure for 45 min. The reaction mixture was degassed under argon and the slurry was filtered over Celite. The Celite cake was washed with ample 80% ethanol-methylene chloride and the filtrate was concentrated to almost dryness forcing the mixture to crystallize. The slurry was filtered, washing with 50% diethyl ether-hexanes to afford N-hydroxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-hydroxypropionamide (2.38 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[C:4]([C:3]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=1[N:1]=[CH:15][N:16]([CH3:18])[CH3:17])#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1ccc([N+](=O)[O-])cc1C#N
Temperature: 100 °C
Yield: 87.2 %

Procedure:
A mixture of 2-amino-5-nitrobenzonitrile (30.0 g, 184 mmol) and dimethoxy-N,N-dimethylmethanamine (29.6 mL, 223 mmol) was heated to 100° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and dissolved in dichloromethane. The solution was run through a silica plug washing the plug with ethyl acetate. The filtrate was concentrated under reduced pressure, stirred with ether and filtered to provide the product (35.0 g, 87%) as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[N:3]=1.Cl.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH:12]1[C:17]([NH2:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH2:8][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH:12]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1cccc(Br)n1
Reactant: NC(=O)C1COCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)C1COCCN1Cc1cccc(Br)n1
Temperature: 25 °C

Procedure:
2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (150 mg, 0.60 mmol), morpholine-3-carboxamide hydrochloride (100 mg, 0.560 mmol) and potassium carbonate (207 mg, 1.50 mmol) were taken up in DMF (3 mL) and the reaction was maintained at room temperature overnight. Water was then added and the mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as an orange oil.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:14][N:13]=[C:4]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1Nc2ccccc2C1=NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a suspension of 73.6 g of isatin in 1.2 l of ethanol was added a solution of 64.1 g of hydroxylamine hydrochloride and 64.1 g of sodium acetate in 500 ml of water. The mixture was stirred at room temperature for 30 minutes and concentrated. The residue was washed with water and recrystallized from ethanol to give 51.8 g (64%) of 3-(hydroxyimino)indolin-2-one as yellow crystals.
Reaction SMILES: [O:1]1[CH:3]2[C:4]3[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=3[O:6][C:7]([CH3:9])([CH3:8])[CH:2]12.[N-:14]=[N+:15]=[N-:16].[Na+].O>O1CCOCC1>[N:14]([C@H:3]1[C@H:2]([OH:1])[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]1=2)=[N+:15]=[N-:16]
Reactant: CC1(C)Oc2ccccc2C2OC21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)Oc2ccccc2[C@@H](N=[N+]=[N-])[C@@H]1O
Yield: 82 %

Procedure:
3,4-Epoxy-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran (3.00g.) and sodium azide (1.23g.; and excess) were refluxed in dioxane (25 ml.) and water (5 ml.) mixture for 24 hours. Dilution with water and extraction via diethyl ether gave trans-4-azido-3,4-dihydro-2,2-dimethyl-2H-benzo[b]-pyran-3-ol (3.06g.) as needles from 60°-80° petroleum ether m.p. 70°-71°. To a solution of the hydroxy azide (2.90g.) in acetone (50 ml.) containing concentrated hydrochloric acid (10 ml.) was added with stirring and in portions, zinc dust (10 g.). Stirring was continued until gas evolution ceased. The zinc was filtered and washed with acetone. The combined washings and filtrate with water and extracted with diethyl ether. Basification of the aqueous layer and isolation via diethyl ether gave trans-4-amino-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol (2.70 g.), re-crystallised from ethanol m.p. 138°. Treatment with anhydrous hydrochloric acid as in Example 1 yielded trans-4-amino-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol hydrochloride, m.p. 223°-225°.