Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH2:23][CH3:24])[C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH2:23][CH3:24])[C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N(CC)CCCc2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CCCc1ccc(Cl)cc1)c1ccc(C(=O)O)cc1

Procedure:
A 2.0 g. portion of 4-[[3-(p-chlorophenyl)propyl]ethylamino]benzoic acid, ethyl ester is dissolved in 50 ml. of 95% ethanol. A 4.0 g. portion of potassium hydroxide is added, and the solution is refluxed overnight. The solution is filtered, then diluted with 100 ml. of water, and adjusted to pH 6.5 with 37% hydrochloric acid. This mixture is extracted with two 50 ml. portions of dichloromethane, which are combined, washed with 50 ml. of water, and evaporated to an oil. This oil is chromatographed on a silica gel column, eluting with chloroform, followed by 10% ethyl acetate in chloroform. The ethyl acetate-chloroform eluate is crystallized from ethanol, giving 700 mg. of the desired product as a tan solid.
Reaction SMILES: [CH3:1][CH:2]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=O.Cl.[NH2:25][OH:26].C([O-])(O)=O.[Na+]>>[CH3:1][CH:2]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)/[C:3](/[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[N:25]\[OH:26]
Reactant: NO
Reactant: CC(C(=O)c1ccncc1)C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(/C(=N\O)c1ccncc1)C(c1ccccc1)c1ccccc1

Procedure:
In analogy to example 151, step 3, 2-methyl-3,3-diphenyl-1-pyridin-4-yl-propan-1-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as an off-white solid, MS (ESI+): m/z=317.16 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[OH-].[K+].C(COC)OC>O.CN(C)P(N(C)C)(N(C)C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[N:3]=1
Reactant: COc1ccc(O)cc1
Reactant: Clc1cccc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COc1ccc(Oc2cccc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution comprising 14.8 grams (0.1 mole) of 2,6-dichloropyridine, 12.4 grams (0.1 mole) of 4-methoxyphenol and 8.4 grams (0.15 mole) of flake potassium hydroxide in 100 milliliters of a 1:1 mixture of monoglyme and hexamethylphosphoramide was stirred for 24 hours at room temperature. The resulting mixture was diluted with water and thoroughly extracted with hexane. The extract was washed with water, dried and concentrated under reduced pressure. The residue was recrystallized from pentane giving 14.5 grams (64 percent of theoretical) of 2-chloro-6-(4-methoxyphenoxy)pyridine which melted at 63°-65° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(=O)(O)[O-].[Na+]>CN(C)C(=O)C.C(=O)([O-])[O-].[K+].[K+]>[OH:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([C:22]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=Cc1cccc(OCCO)c1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(OCCO)c3)nc2c1
Temperature: 130 °C
Reaction time: 14 h

Procedure:
A mixture of 2-amino-4,6-dimethoxy-benzamide (195 mg, 1.00 mmol), 3-(2-hydroxy-ethoxy)-benzaldehyde (166 mg, 1.00 mmol), p-toluenesulfonic acid monohydrate (38 mg, 0.20 mmol), and sodium bisulfite (264 mg, 1.50 mmol) in N,N-dimethylacetamide (10 mL) was stirred at 130° C. under nitrogen for 14 hours, cooled to room temperature, and diluted with 0.2 N potassium carbonate aqueous solution (50 mL). It was extracted with ethyl acetate (250 mL), dried over sodium sulfate, and concentrated. The solid residue was re-dissolved in dichloromethane (5 mL), and precipitated with ethyl acetate (15 mL) and hexanes (50 mL). It was filtered and washed with hexanes to afford the title compound as a yellow solid. Yield: 70 mg (20%). MP 244.8-246.0° C. 1H NMR (400 MHz, CDCl3): δ 7.64 (d, 1H), 7.60 (d, 1H), 7.45 (t, 1H), 7.12 (dd, 1H), 6.84 (d, 1H), 6.48 (d, 1H), 4.21 (t, 2H), 4.03 (t, 2H), 3.99 (s, 3H), 3.94 (s, 3H). MS (ES+) m/z: 343.55 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1.[H][H]>[Ni].O1CCCC1>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1
Reactant: CN(C)c1ccc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CN(C)c1ccc(N)cn1
Yield: 99.5 %

Procedure:
A mixture of Example 175A (5.27 g, 31.5 mmol) and Raney Nickel (5.27 g, 90 mmol) in tetrahydrofuran (60 mL) was subjected to an atmosphere (30 psi) of hydrogen gas for 2 hours at ambient temperature. Mixture was filtered and concentrated to afford 4.3 g (100%) of the title compound. MS (ESI) m/z 138 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH2:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>FC1C=CC=CC=1>[CH3:16][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: C=C(C)CCOc1cccc(NC(C)=O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Fc1ccccc1
Product: CC(=O)Nc1ccc2c(c1)OCCC2(C)C
Yield: 54 %

Procedure:
A mixture of N-[3-(3-methyl-but-3-enyloxy)-phenyl]-acetamide (2.5 g, 11.4 mmol) and AlCl3 (4.52 g, 34.3 mmol) in fluoro-benzene (50 mL) was heated at reflux overnight. After cooling, the reaction mixture was poured into water. The organic layer was separated and the aqueous phase was extracted with EtOAc (40×3 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to give N-(4,4-dimethyl-chroman-7-yl)-acetamide (1.35 g, 54%).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)([OH:12])[CH2:10][CH2:9][CH2:8][C:3]21OCC[O:4]2.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[OH:12][C:11]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:10][CH2:9][CH2:8][C:3](=[O:4])[C:2]1([CH3:36])[CH3:1]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCCC4(OCCO4)C3(C)C)s2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCCC(=O)C3(C)C)s2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To a stirred solution of the product of Step 1 (600 mg, 1.15 mmol) in THF (4 mL) was added HCl (6 M, 3.84 mL, 23.1 mmol). The reaction mixture was allowed to stir at room temperature for 30 min, neutralized with aqueous saturated sodium bicarbonate, and extracted with dichloromethane (3×). The combined organics were dried (sodium sulfate), filtered, concentrated, and purified by flash chromatography on silica to afford 3-hydroxy-2,2-dimethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanone (534 mg, 1.12 mmol) as a yellow foam. MS ESI: [M+H]+ m/z 477.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12](I)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.C(OC([N:28]1[C:32](B(O)O)=[CH:31][C:30]([CH3:36])=[N:29]1)=O)(C)(C)C>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:32]4[NH:28][N:29]=[C:30]([CH3:36])[CH:31]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: Cc1cc(B(O)O)n(C(=O)OC(C)(C)C)n1
Reactant: NC(=O)c1nc2n(c1I)CCOc1cc(F)c(Br)cc1-2
Product: Cc1cc(-c2c(C(N)=O)nc3n2CCOc2cc(F)c(Br)cc2-3)[nH]n1

Procedure:
10-bromo-9-fluoro-3-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2-tert-butoxycarbonyl-5-methyl-pyrazol-3-yl)boronic acid similarly to as described in Example 4 to produce crude 10-bromo-9-fluoro-3-(3-methyl-1H-pyrazol-5-yl)-5,6dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide. 10-bromo-9-fluoro-3-(3-methyl-1H-pyrazol-5-yl)-5,6dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol via General Procedure E to afford 5.8 mg (6.6%) 9-fluoro-10-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]-3-(3-methyl-1H-pyrazol-5-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase purification. M+1=478.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[B:9]([OH:11])[OH:10].O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[B:9]1[O:10][C:16]([CH3:18])([CH3:17])[C:13]([CH3:15])([CH3:14])[O:11]1
Reactant: Cc1ccc(B(O)O)c(F)c1
Reactant: CC(C)(O)C(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a solution of (2-fluoro-4-methylphenyl)boronic acid (500 mg, 3.24 mmol) in diethyl ether (20 mL) was added pinacol (360 mg, 3.24 mmol) and 4-toluenesulfonic acid monohydrate (30 mg, 162 μmol) and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid, 740 mg, in a 97% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (s, 12H), 2.34 (s, 3H), 6.82 (d, 1H), 6.93 (d, 1H), 7.60 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=O)=[N:9]2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][NH:19][CH2:18][C:17]3[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=3[O:15][CH3:14])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2ccc(Br)cc2n1
Reactant: COc1ccc(CN)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CNCc2ccc3ccc(Br)cc3n2)c(OC)c1
Reaction time: 3.5 h
Yield: 98.3 %

Procedure:
7-Bromo-quinoline-2-carbaldehyde (354 mg, 1.50 mmol, prepared as described in EP 239746) was dissolved in 1,2-dichloroethane (15 mL) and 2,4-dimethoxybenzylamine (251 mg, 225 μL, 1.50 mmol) was added and the reaction mixture stirred for 5 minutes before sodium triacetoxyborohydride (477 mg, 2.25 mmol) was added. After 3.5 h stirring the reaction mixture was quenched with saturated sodium hydrogen carbonate solution and ethyl acetate was added. The organic layer was separated and washed with sodium hydrogen carbonate and the combined aqueous layers were extracted with ethyl acetate. The organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to give the crude, title compound as a yellow gum (571 mg) which was used without further purification. LCMS (m/z) 387.0, 389.0 [M+H], Tr=1.57 min.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([O:16][P:17]([O-:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1>[P:17]([Cl:1])([O:16][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:26]
Reactant: O=C1CCC(=O)N1Cl
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Solvent: c1ccccc1
Product: O=P(Cl)(OCc1ccccc1)OCc1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Dibenzyl chlorophosphate was prepared by adding N-chlorosuccinimide (1.28 g) to a stirred solution of dibenzylphosphite (2.5 g) in benzene (100 ml) at room temperate. After 2 hrs at room temperature the solid (succinimide) was filtered off and the filtrate concentrated to about 5 ml, which was added dropwise to a solution of phenyl 2,3,4-tri-O-acetyl-D-mannoside (3.3 g) in dry pyridine (15 ml) at 0° C. with sting over 1 hour and the mixture allowed to stand at room temperature over night. The mixture was then heated at 40° C. for 2 hours. The solvent was evaporated off under reduced pressure and the residue chromatographed on a silica gel column (silica gel 60; 2.5×50 cm). Initial fractions eluted with methylene chloride were discarded and subsequent elution with ehloroform gave phenyl 2,3,4-tri-O-acetyl-D-mannoside 6-dibenzylphosphate (2.6 g). Calculated for C32H35O12P.2H2O; C, 56.6%; H, 5.8%. Found: C, 56.7%; H, 5.8%.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:9][C:10]1([F:31])[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[O:12][C@H:11]1[N:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:20][C:19]1=[O:30]>N1C=CC=CC=1.O>[Si:1]([O:17][CH2:16][C@H:13]1[O:12][C@@H:11]([N:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:20][C:19]2=[O:30])[C:10]([F:31])([F:9])[C@@H:14]1[OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccn([C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)C2(F)F)c(=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
tert-Butyldimethylsilyl chloride (737 mg, 4.89 mmol) was added to a solution of 8 (1.367 g, 4.08 mmol) in 8 mL of pyridine at 0° C. under N2. The reaction mixture was stirred overnight at RT, diluted with H2O, then extracted with EtOAc. The organic extract was washed with saturated aqueous CuSO4 solution, and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (1:1→3:1 EtOAc/Hexane) to give 1.4 g of 57 (white solid, 76% yield): 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.14-8.16 (d, 1H), 7.14-7.16 (d, 1H), 6.42-6.43 (d, 1H), 6.20-6.23 (t, 1H), 4.17-4.23 (m, 3H), 3.98-4.08 (m, 2H), 3.87-3.90 (m, 1H), 1.25-1.28 (t, 3H), 0.94 (s, 9H), 0.14 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([OH:16])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]I.[H-].[Na+].O>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([O:16][CH3:17])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
2-tert-Butoxycarbonylamino-3-hydroxy-3-methyl-butyric acid (1.0 g, 4.29 mmol) was dissolved in THF (14 mL) and cooled to 0° C. in an external ice/brine bath. MeI (2.13 mL, 34.3 mmol) was added at 0° C. Solid NaH (60% dispersion in mineral oil, 0.514 g, 12.87 mmol) was added slowly at 0° C. Upon completion of the addition, the solution was removed from the ice bath and allowed to warm to room temperature, and stirred. After 18 hours, the crude reaction mixture was diluted in ethyl acetate and water was added slowly with stirring. The quenched mixture was concentrated in vacuo and partitioned between diethyl ether and water. The ether layer was extracted with sodium bicarbonate twice. The combined bicarbonate layers were acidified with aqueous citric acid to pH 3 and extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water, sodium thiosulfate, water, dried with sodium sulfate and concentrated to yield 2-tert-Butoxycarbonylamino-3-methoxy-3-methyl-butyric acid (0.99 g, 94%) as an oil.
Reaction SMILES: [BH4-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:12]=[C:11]([CH:13]=[O:14])[NH:10][N:9]=1.O.[Br:16]N1C(=O)CCC1=O>CO.[O-2].[O-2].[Mn+4]>[Br:16][C:12]1[C:8]([C:4]2[S:3][CH:7]=[CH:6][CH:5]=2)=[N:9][NH:10][C:11]=1[CH:13]=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cc(-c2cccs2)n[nH]1
Agent: [Mn+4]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=Cc1[nH]nc(-c2cccs2)c1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.8 %

Procedure:
Under a nitrogen atmosphere, sodium borohydride (0.51 g, 13.60 mmol) was added portionwise to a solution of 3-(thiophen-2-yl)-1H-pyrazole-5-carbaldehyde (34b) (2.02 g, 11.33 mmol) in anhydrous methanol (80 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added (50 mL) and the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (40 mL) and successively washed with water (40 mL) and brine (40 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in acetonitrile (100 mL) and N-bromosuccinimide (1.35 g, 7.59 mmol) was added. The mixture was stirred for 60 minutes at room temperature, then concentrated in vacuo. The residue was dissolved in ethyl acetate (40 mL) and washed with brine (40 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in a mixture of chloroform (14 mL) and N,N-dimethylformamide (28 mL). Manganese dioxide (3.74 g, 43.02 mmol) was added and the mixture was stirred at 50° C. for 1 hour. The mixture was filtered through a pad of Celite®, rinced with N,N-dimethylformamide, the filtrate was concentrated in vacuo, and co-evaporated with toluene. The residue was triturated with diethyl ether and filtered to provide 4-bromo-3-(thiophen-2-yl)-1H-pyrazole-5-carbaldehyde (34c) (1.07 g, 4.16 mmol, 37%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.CN(C)[C:20](=[O:22])[CH3:21]>O>[N:15]1[CH:16]=[CH:17][C:12]([C:4]2[N:3]=[C:2]([NH:3][C@H:2]3[C:11]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:21][C@H:20]3[OH:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: Clc1nc(-c2ccncc2)nc2ccccc12
Reactant: CC(=O)N(C)C
Solvent: O
Product: O[C@@H]1Cc2ccccc2[C@@H]1Nc1nc(-c2ccncc2)nc2ccccc12
Temperature: 85 °C
Reaction time: 2 h

Procedure:
4-Chloro-2-pyridin-4-ylquinazoline (1 mmol) was dissolved into N,N-dimethylacetamide (0.5 M), followed by addition of diispropylethylamine (2 mmol) and 1S, 2R-(−)-cis-1-amino-2-indanol (1.2 mmol) and was stirred at 85° C. for 2 h. The reaction was poured into water and back-extracted with ethyl acetate (3×). The combined organic layers were washed with 1N HCl, followed by a brine wash, and dried over magnesium sulfate. The final product was purified by MPLC and lyophilized to a yellow powder. (78%) 1H NMR (400 MHz, d6-DMSO): δ 8.75 (d, 2H), 8.55 (d, 1H), 8.35 (m, 2H), 7.85 (d, 2H), 7.55 (m, 1H), 7.35 (d, 2H), 7.25 (m, 2H), 6.15 (m, 1H), 4.85 (m, 1H), 3.25 (dd, 1H), 3.00 (d, 1H). MS (EI) for C22H18N4O: 355 (MH+).
Reaction SMILES: [Na].[CH3:2][N:3]1[C:7]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[N:6][CH:5]=[N:4]1.[CH2:13]([OH:15])[CH3:14]>>[CH3:2][N:3]1[C:7]([C:8]2([C:11](=[NH:12])[O:15][CH2:13][CH3:14])[CH2:10][CH2:9]2)=[N:6][CH:5]=[N:4]1
Reactant: CCO
Reactant: Cn1ncnc1C1(C#N)CC1
Agent: [Na]
Product: CCOC(=N)C1(c2ncnn2C)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Sodium metal (37 mg, 1.61 mmol) was added to anhydrous ethanol (5 mL) at room temperature. The mixture was stirred for 30 min. A solution of 1-(1-methyl-1H-1,2,4-triazol-5-yl)cyclopropanecarbonitrile (0.3 g, 2.0 mmol) in ethanol (5 mL) was added and the reaction mixture was heated to 60° C. for 1 h. The resulting mixture was used without further purification. MS (ES+APCI) (M+H) 195.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25]S(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[F:33][C:34]([F:39])([F:38])[CH:35](O)[CH3:36]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][CH:35]([CH3:36])[C:34]([F:39])([F:38])[F:33])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CC(O)C(F)(F)F
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Product: CCOC(=O)c1c(OC(C)C(F)(F)F)nc2ccc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
This compound was prepared in analogy to example 29 step D from 6-chloro-4-(2-chloro-benzyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 29 step C, 75 mg, 0.15 mmol) and 1,1,1-trifluoro-propan-2-ol (0.026 ml, 0.2 mmol). Off white solid (10 mg, 14%). LC-MS (ESI): 472 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:18](OS(OCC)(=O)=O)[CH3:19].N>CC(=O)CC>[CH2:18]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)[CH3:19]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CCOS(=O)(=O)OCC
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1ccc([N+](=O)[O-])c(C)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 106.7 %

Procedure:
3-Methyl-4-nitrophenol 403 (500 mg, 3.0 mmol) was dissolved in 2-butanone (10 mL). Potassium carbonate (903 mg, 6.5 mmol) was added to the solution followed by diethylsulfate (0.45 mL, 3.2 mmol). The reaction mixture was heated at 70° C. for 2 h. Upon completion, the mixture was cooled to rt and aqueous ammonia (30%, 1 mL) was added and stirred for 18 h at rt. The reaction mixture was filtered and washed with 2-butanone (30 mL). The filtrate was collected and evaporated in vacuo to yield a white solid (580 mg, 97%). mp 50-52° C. (lit.53 mp 51° C.). TLC Rf 0.65 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 8.11-8.09 (d, 1H, J=8.88 Hz), 6.82-6.78 (m, 2H), 4.14-4.10 (q, 2H, J=6.96 Hz), 2.65 (s, 3H), 1.48-1.46 (t, 3H, J=6.95 Hz). 13C NMR (150 MHz, CDCl3) δ 162.5, 142.0, 137.1, 127.6, 117.9, 112.2, 64.2, 21.8, 14.6.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:16]([CH3:19])=[N:17][N:18]=3)[C:10]=2[CH:9]=[C:8]1[CH3:20].B(Br)(Br)Br>C(Cl)Cl>[CH3:19][C:16]1[N:15]2[C:10]3[CH:9]=[C:8]([CH3:20])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([OH:2])[CH:23]=[CH:22][CH:21]=4)[C:11]=3[CH:12]=[CH:13][C:14]2=[N:18][N:17]=1
Reactant: COc1cccc(Cn2c(C)cc3c2ccc2nnc(C)n23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc(O)c1
Temperature: 25 °C

Procedure:
To 6-(3-methoxybenzyl)-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (0.030 g, 0.098 mmol, from Example 22) in DCM (4 mL) at −78° C. was added 1.0 M BBr3 in DCM (0.57 mL, 0.57 mmol, Aldrich) and the mixture was allowed to warm to ambient temperature. The reaction was quenched by the addition of water, and saturated NaHCO3 solution was added. DCM was removed by rotary evaporation and the aqueous mixture was diluted with MeOH, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (0.02 g, 70%).