Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:19]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([O:30]C)[CH:24]=4)=[N:20][NH:21][CH:22]=3)[CH:15]=[CH:14][N:13]=2)[CH:6]=1)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:19]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([OH:30])[CH:24]=4)=[N:20][NH:21][CH:22]=3)[CH:15]=[CH:14][N:13]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Nc2nccc(-c3c[nH]nc3-c3ccc(Cl)c(OC)c3)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cccc(Nc2nccc(-c3c[nH]nc3-c3ccc(Cl)c(O)c3)n2)c1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
3-{4-[3-(4-Chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzoic acid ethyl ester (Example 41) (18 mg, 0.04 mmoles) is suspended in CH2Cl2 (2 mL) and cooled to −5° C. BBr3 (0.5 mL, 1M in CH2Cl2) is added dropwise at −5° C. After 10 min the suspension turns to a clear brown solution. After 2 h at −5° C. another 0.5 mL of BBr3 is added to the reaction mixture. Then the reaction mixture is warmed to rt and kept at that temperature for 30 min. The reaction is quenched with 5 mL water and stirred at rt overnight. The reaction mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, concentrated and chromatographed on SiO2 (80% EtOAc/Hexanes) affording the title compound: ES-MS 436.1178 [M+H]; single peak at tR=5.579 min (System 3).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1)=O>>[Cl:34][C:29]1[CH:28]=[C:27]([C:25]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:24]=2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 37 %

Procedure:
4-[4-(3,4-Dichloro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (109 mg, 37%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-3′,4′-dichloroacetophenone (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. The compound of Example 15 has the same formula as the compound of Example 16. 1H NMR (300 MHz, DMSO-d6) δ 13.18 (s, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 8.26-8.32 (m, 2H), 8.15 (d, J=8.2 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.41-7.81 (m, 5H).
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:37])=[C:23]([CH:36]=1)[C:24]([NH:26][C:27]1[N:32]=[CH:31][C:30]([C:33](Cl)=[O:34])=[CH:29][CH:28]=1)=[O:25]>ClCCl.O>[S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([C:33]([C:30]3[CH:29]=[CH:28][C:27]([NH:26][C:24](=[O:25])[C:23]4[CH:36]=[C:19]([F:18])[CH:20]=[CH:21][C:22]=4[CH3:37])=[N:32][CH:31]=3)=[O:34])[C:4]=2[CH:3]=[CH:2]1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1cc2c(s1)CCCCN2
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCCCc3sccc32)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
To a cooled (0° C.) mixture of 0.306 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 1.11 μl of triethylamine in 5 ml of dichloromethane is added 1.17 g of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride and the mixture is stirred overnight at room temperature under argon. The mixture is diluted with 50 ml of dichloromethane and 20 ml of water and the organic layer separated. The organic layer is washed with 20 ml each of 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate evaporated, concentrated to dryness under vacuum to give a glass. Crystallization from ethyl acetate-hexane gives 0.35 g of white crystals, m.p. 178°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=C(C#N)[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.S(=O)(=O)(O)O.[C:24]([OH:27])(=[O:26])[CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:25]([C:24]([OH:27])=[O:26])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: N#Cc1ccc2c(c1)Sc1ccc(Cl)cc1C=C2
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(c1)Sc1ccc(Cl)cc1C=C2

Procedure:
550 Mg. 8-chloro-3-cyanodibenzo[b,f]-thiepin is refluxed for 16 hours in a mixture of 15 cc. acetic acid and 15 cc. 50% aqueous sulfuric acid. The reaction mixture is cooled down and the product filtered, washed with water and dried to yield 485 mg. (82% of the pure acid, m.p. 302°-304° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:18][S:19][C@@H:20]([C:45](=[O:58])N4[C@@H](C5C=CC=CC=5)COC4=O)[C@@H:21]([C:30]4[CH:44]=[CH:43][C:33]([O:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:32][CH:31]=4)[NH:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:18][S:19][C@H:20]4[C:45](=[O:58])[N:22]([C:23]5[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=5)[C@@H:21]4[C:30]4[CH:44]=[CH:43][C:33]([O:34][CH2:35][C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])=[CH:32][CH:31]=4)[O:11][CH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][O:15]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC1(C)COC(CS[C@@H](C(=O)N2C(=O)OC[C@@H]2c2ccccc2)[C@H](Nc2ccc(F)cc2)c2ccc(OCC(=O)OC(C)(C)C)cc2)(c2ccc3c(c2)OCO3)OC1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)COC(CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)OC(C)(C)C)cc2)(c2ccc3c(c2)OCO3)OC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
tert-Butyl (4-{(1R,2R)-2-({[2-(1,3-benzodioxol-5-yl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)-1-[(4-fluorophenyl)amino]-3-oxo-3-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]propyl}phenoxy)acetate (Method 15) (22.30 g, 27.4 mmol) was dissolved in dry toluene (800 mL) and heated to 90° C. under inert atmosphere. N,O-Bis(trimethylsilyl)acetamide (BSA, 20.1 mL, 82.1 mmol) was added and the mixture was stirred at 90° C. for one hour. The mixture was then given 45° C. and tetrabutylammonium fluoride trihydrate (TBAF, cat., 1 g) was added and the mixture was stirred at 45° C. for 1 hour. The mixture was then concentrated under reduced pressure and purified by flash-chromatography (heptane:EtOAc 5:1). This afforded 10.0 g (56%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:20](CC)CC)C.ClC(OCC)=O.N>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15](=[O:17])[NH2:20])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution cooled at 0° C. of cis-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (68.0 g, 280 mmol) and triethylamine (31.1 g, 307 mmol) in THF (300 mL) was added ethyl chloroformate (29.3 mL, 308 mmol) dropwise. After stirring at 0° C. for 30 min, 25% aqueous ammonia (168 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hr and concentrated. The residue was extracted with EtOAc (three times). The combined organic layer was washed with saturated aqueous NaHCO3, 1 M HCl, brine, and water, dried over Na2SO4, filtered, and concentrated to give cis-(4-carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (62.0 g, 88%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([OH:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:7]=1)=[O:5])C.CO>O>[OH:11][C:9]1[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(O)n(-c2ccccn2)n1
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(O)n(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
To a suspension of 5-hydroxy-1-pyridin-2-yl-1h-pyrazole-3-carboxylic acid ethyl ester (351.6 mg, 1.5 mmol) in MeOH (5.0 mL, 120 mmol) at room temperature was added LiOH monohydrate (126.5 mg, 3.0 mmol), forming a clear solution. The solution was stirred at room temperature overnight. The solution was then concentrated. To the resulting residue was added 1N aqueous HCl to achieve pH˜2, forming a precipitate. Water (4.0 mL) was added and the resulting mixture was stirred at room temperature for 1 hour, then filtered. The solids were rinsed with water and dried under vacuum to yield the title compounds as a white solid (128 mg).
Reaction SMILES: C([S@]([NH:7][C@:8]([C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)=[N:24][CH:25]=1)([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:9]([F:12])([F:11])[F:10])=O)(C)(C)C.CO>Cl.O1CCOCC1>[F:12][C:9]([F:10])([F:11])[C@:8]([C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)([C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:24][CH:25]=1)[NH2:7]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc([C@@](N[S@](=O)C(C)(C)C)(c3ccc(F)cc3)C(F)(F)F)cn2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@](c1ccc(F)cc1)(c1cnc(N2CCNCC2)nc1)C(F)(F)F
Yield: 99.1 %

Procedure:
tert-Butyl 4-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (302 mg, 0.540 mmol) was stirred in 4 M HCl in 1,4-dioxane (3 mL)/MeOH (3 mL) at room temperature for 1 hour. The solvent was removed in vacuo and the residue was partitioned between saturated NaHCO3 and EtOAc. The organic phase was extracted a second time with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give (S)-2,2,2-trifluoro-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanamine (190 mg, 0.535 mmol, 99% yield) with ˜88% e.e. Further purification by chiral SFC gave (S)-2,2,2-trifluoro-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanamine (123.7 mg, 0.348 mmol, 71.2% yield) with ˜99% e.e.
Reaction SMILES: [CH2:1]([C:3]([C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[C:27]([CH3:40])[CH:26]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH3:24])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:41][O:42][C:43](=[O:52])[CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[C:49](Br)[CH:50]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[CH3:41][O:42][C:43](=[O:52])[CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[C:49]([C:28]2[CH:29]=[CH:30][C:25]([C:3]([CH2:4][CH3:5])([C:6]3[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]4([O:19][Si:20]([CH3:22])([CH3:23])[CH3:21])[CH2:18][CH2:17][CH2:16][CH2:15]4)=[C:8]([CH3:24])[CH:7]=3)[CH2:1][CH3:2])=[CH:26][C:27]=2[CH3:40])[CH:50]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 140 °C
Yield: 67.8 %

Procedure:
A solution of 2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 32-(4); 54.1 mg, 0.0968 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 33.4 mg, 0.14 mmol), tetrakistriphenylphosphine palladium (15.6 mg, 0.0135 mmol) and potassium phosphate (30.8 mg, 0.14 mmol) in N,N-dimethylformamide (0.27 mL) was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was filtered through cotton plug, and the mixture was purified by silica gel chromatography (45% ethyl acetate/hexane) to give the title compound (38.2 mg, 67%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[C:31]5[C:26](=[CH:27][C:28](F)=[CH:29][CH:30]=5)[N:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[CH2:39][CH2:40][OH:41]>>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[C:31]5[C:26](=[CH:27][C:28]([O:41][CH2:40][CH2:39][CH:34]6[CH2:35][CH2:36][CH2:37][CH2:38][NH:33]6)=[CH:29][CH:30]=5)[N:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: OCCC1CCCCN1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)N1CCC(c2ncnc3cc(F)ccc23)CC1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)N1CCC(c2ncnc3cc(OCCC4CCCCN4)ccc23)CC1

Procedure:
Prepared from 4-(7-Fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-morpholin-4-yl-phenyl)-amide, synthesized as described in the previous step, and 2-piperidin-2-yl-ethanol using the protocol described in Example 67a. 1H NMR (CD3OD) δ 9.03 (s, 1H), 8.34 (d, J=9.31 Hz, 1H), 7.37 (dd, J=9.19 and 2.54 Hz, 1H), 7.33 (d, J=2.47 Hz, 1H), 7.26 (d, J=9.06 Hz, 2H), 6.93 (d, J=9.10 Hz, 2H), 4.34 (m, 2H), 4.28 (m, 2H), 3.94 (m, 1H), 3.82 (t, J=4.69 Hz, 4H), 3.16 (m, 2H), 3.08 (t, J=4.78 Hz, 4H), 3.04 (m, 1H), 2.82 (m, 1H), 2.66 (m, 1H), 1.40-2.10 (12H). Calcd for C31H41N6O3 (MH+) 545.3, found 545.1.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[C:5](Br)[C:3]=1[NH2:4].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.CCOCC.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>[C:2]1([C:11]2[C:10]([C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:3]=3)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]([NH2:4])=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1c(Br)cccc1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Nc1ccccc1-c1ccccc1-c1ccccc1
Yield: 90 %

Procedure:
2,6-Dibromoaniline (6.02 g, 24 mmol) and Pd(PPh3)4 (3.88 g, 3.00 mmol) were dissolved in toluene (240 ml). Phenyl boronic acid (8.80 g, 72 mmol) in EtOH (50 ml) was added. Na2CO3 (13 g, 144 mmol) in H2O (70 ml) was added. The reaction mixture was reflux for 24 hrs. The organic layer was thin separated and the amine precipitated as hydrochloride salt by addition of 20 ml of HCl. The precipitate was isolated. The salt was suspended in ether, and 2 M Na2CO3 was added. The organic layer was dried over Na2SO4 and the solvent was evaporated. The yield was 90%. 1H NMR (CDCl3): δ 7.44 (t, 4H, Harom), 7.39 (t, 4H, Harom), 7.29 (d, 2H, Harom), 7.07 (d, 2H, Harom), 6.82 (t, 1H, Harom), 3.77 (s, 2H, NH2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.CS(C)=O.O.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][CH:9]1[CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1CCNC(=O)OCc1ccccc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(=O)CC1CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 92 %

Procedure:
A solution containing 5 (10.2 g, 28.0 mmol) in DCM (100 mL) and DMSO (20 mL) was cooled to 0° C. TEA (14.1 g, 140 mmol) and SO3.pyridine complex (17.9 g, 112 mmol) were then added and the mixture stirred until homogeneous (approx. 45 min) then warmed to ambient temperature. After 3 h, the reaction mixture was diluted with water (200 mL) and diethyl ether (500 mL). The layers were separated and the organic phase was washed successively with 1N HCl, water, aqueous NaHCO3, water, and brine then dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (2:1 to 1:1 hexanes/EtOAc) to afford 9.34 g (92%) of 6 as a pale yellow-colored oil. 1H NMR (CDCl3, 300 MHz): δ7.32 (m, 5H), 5.90 (br s, 1H), 5.09 (app dd, J=19.4, 12.2 Hz, 2H), 4.52 (m, 1H), 3.95 (br d, 1H), 3.52 (m, 2H), 2.93 (m, 1H), 2.80 (dd, J=18.3, 9.3 Hz, 1H), 2.22 (br d, 1H), 1.69 (m, 1H), 1.55 (m, 1H), 1.57 (s, 9H) ppm. Mass spectrum, m/z [363.2] (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([N+:21]([O-])=O)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>O1CCCC1.C(O)C.O>[NH2:21][C:20]1[C:14]2[O:13][CH2:12][CH2:11][N:10]3[C:16](=[C:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:8]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][C:9]=43)[C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c-3cccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(N)cccc1-3
Temperature: 100 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
To a solution of methyl 12-cyclohexyl-4-nitro-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (9.94 g, 23.6 mmol) in tetrahydrofuran (85 ml), ethanol (170 ml) and water (42.5 ml) were added ammonium chloride (6.31 g, 118 mmol) and reduced iron (6.60 g, 118 mmol), and the mixture was stirred at 100° C. for 2 hr. After filtration of the reaction solution, saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was concentrated under reduced pressure to give a solid. The obtained solid was washed with a mixed solvent (hexane:ethyl acetate-20:1). The solid was collected by filtration to give methyl 4-amino-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (8.62 g, yield 93%).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH3:11])[NH:5]1>C(O)(=O)C>[F:3][C:4]1([CH:12]([Br:1])[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH3:11])[NH:5]1
Reactant: CSC1=NC=CC(F)(CC(=O)c2ccccc2)N1
Reactant: BrBr
Solvent: CC(=O)O
Product: CSC1=NC=CC(F)(C(Br)C(=O)c2ccccc2)N1
Yield: 99.7 %

Procedure:
Bromine (1.22 g, 7.6 mmol) in acetic acid (5.6 ml) is added to a solution of 4-Fluoro-2-(2-methylthio-4-pyrimidyl)acetophenone (2 g; 7.6 mmol) in acetic acid (40 ml. The initially thick precipitate is almost dissolved after 20 min, filtered and the filtrate evaporated to dryness. The residue is taken up in a saturated solution of NaHCO3 and extracted three times with tert.butyl methyl ether. The combined organic phases are dried over Na2SO4 and evaporated to dryness to yield 2.6 g (100%) of a brown oil, which is used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][O:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[O:4][C@H:3]1[CH2:16][OH:17].C(N(CC)CC)C.CS(C)=O>ClCCl>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:5]2[O:4][C@@H:3]([CH:16]=[O:17])[C:2]([CH3:18])([CH3:1])[CH2:7][O:6]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C2OCC(C)(C)[C@H](CO)O2)cc1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(C2OCC(C)(C)[C@H](C=O)O2)cc1
Yield: 93.8 %

Procedure:
Following the general procedure for the oxidation reaction of Description 7, 23.0 g (91.2 mmol) of [(4R)-5,5-dimethyl-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]methan-1-ol (8a) in 650 mL of dichloromethane (DCM) in the presence of 63.5 mL (46.1 g, 456 mmol) of triethylamine and 52.0 mL (57.3 g, 733 mmol) of dimethylsulfoxide (DMSO) was reacted with 43.5 g (274 mmol) of sulfur trioxide pyridine complex to afford 21.4 g (94% yield) of the crude title compound (8b) as a yellow oil. The crude material was of sufficient purity to be used in the next step without further isolation and purification. Rf=0.53 (MTBE/Hxn=1:2). 1H NMR (400 MHz, CHCl3): δ=1.03 (s, 3H), 1.26 (s, 3H), 3.67 (d, J=11.6 Hz, 1H), 3.72 (d, J=11.6 Hz, 1H), 3.83 (s, 3H), 3.95 (d, J=1.2 Hz, 1H), 5.51 (s, 1H), 6.90-6.96 (m, 2H), 7.46-7.51 (m, 2H), 9.65 (d, J=1.6 Hz, 1H) ppm. MS (ESI) m/z: 251.1 (M+H)+, 272.9 (M+Na)+. The analytical data for the compound was consistent with the proposed structure and with the data given in the literature (Blakemore, et al., J. Org. Chem. 2005, 70, 5449-5460; and Shiina, et al., Bull. Chem. Soc. Jpn. 2001, 74, 113-122). Similar yields were obtained using classical Swern-oxidation conditions.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:30])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[O:24][CH2:25][C:26]([NH:28][NH2:29])=[O:27])(=[O:11])=[O:10])[CH:8]=1)#[N:2].Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.O>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:30])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[O:24][CH2:25][C:26]2[O:27][C:32](=[O:34])[NH:29][N:28]=2)(=[O:10])=[O:11])[CH:8]=1)#[N:2]
Reactant: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)NN)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCc2n[nH]c(=O)o2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
5-Cyano-N-[2-(2-hydrazinocarbonylmethoxy-4-isopropylphenyl)ethyl]-2-hydroxybenzenesulfonamide (0.258 g) was dissolved in 10 mL of tetrahydrofuran. To the stirred solution was added 0.177 g of triphosgene under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 0.26 g of 5-cyano-2-hydroxy-N-[2-[4-isopropyl-2-(5-oxo-4,5-dihydro[1,3,4]-oxadiazol-2-ylmethoxy)phenyl]ethyl]benzenesulfonamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:30][CH:31]([OH:33])[CH3:32]>C1COCC1.C(OCC)(=O)C>[CH:31]([O:33][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1)[NH2:1])([CH3:32])[CH3:30]
Reactant: COc1cc(N)cc(O)c1
Reactant: CC(C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(N)cc(OC(C)C)c1
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To a solution of 3-amino-5-methoxyphenol (Example 20, step i, 140 mg, 1.0 mmol), triphenylphosphine (390 mg, 1.5 mmol) and propan-2-ol (90 ul, 1.2 mmol) in THF (3 ml) was added portion wise di-tert-butyl diazocarboxylate (345 mg, 1.5 mmol) at room temperature. After stirring for 3 hours the reaction mixture was diluted with ethyl acetate and extracted with a 1N aqueous solution of HCl. The combined aqueous phases were brought to pH=10 with a aqueous solution of 1N NaOH and then extracted with ethyl acetate. The combined organics were filtered through a hydrophobic frit and the solvents were removed under reduced pressure to give 3-isopropoxy-5-methoxyaniline as a light brown oil (169 mg).