Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([O:14][C@H:11]1[CH2:12][CH2:13][C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)=[O:19]
Reactant: O=C(O)c1ccccc1F
Reactant: O[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CC[C@@H](c2ccc(Br)cc2)CC1)c1ccccc1F
Reaction time: 12 h

Procedure:
(trans)-4-(4-Bromophenyl)cyclohexanol (100 mg), 2-fluorobenzoic acid (130 mg) and triphenylphosphine (225 mg) are dissolved in tetrahydrofurane (2 mL), treated dropwise with diisopropylazodicarboxylate (170 μL) and the mixture is stirred for 12 hours. Then the mixture is partitioned between ethylacetate and saturated aqueous NaHCO3 solution. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. LC (method 1): tR=1.29 min; Mass spectrum (ESI+): m/z=399 [M+Na]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH:9]1[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+].O.CCCCCC.C(OCC)(=O)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([N:19]=[N+:20]=[N-:21])[CH2:10][CH:9]1[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1CC(OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: CC1CC(N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
The 4-methanesulfonyloxy-2-methyl-pyrrolidine-1-carboxylic acid t-butyl ester (135.21 mg, 0.48 mmol) was taken up in dry DMF under argon and sodium azide (156.00 mg, 2.40 mmol) was added. The reaction was then heated to 60° C. for 48 h. The reaction was poured into water and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with sat NaHCO3 and brine then dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (5:1 hexane-ethyl acetate) Yield 93.41 mg.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.[Br:6][C:7]1[C:8](Cl)=[N:9][CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1>O>[Br:6][C:7]1[C:8]([O:2][CH3:1])=[N:9][CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ncc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium methoxide (28% methanol solution) (2 ml) was added to a methanol (2 ml) solution containing 3-bromo-2-chloro-5-nitropyridine (100 mg), followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and a yellow solid of 3-bromo-2-methoxy-5-nitropyridine (96 mg) was thus obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12](Cl)(=[O:14])=[O:13])=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:22]([C:29]([F:32])([F:31])[F:30])=[CH:21][C:19]=1[NH2:20]>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12]([NH:20][C:19]2[CH:21]=[C:22]([C:29]([F:30])([F:31])[F:32])[CH:23]=[C:24]([C:25]([F:26])([F:27])[F:28])[C:18]=2[CH3:17])(=[O:14])=[O:13])=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(N)cc(C(F)(F)F)cc1C(F)(F)F
Reactant: Cc1cc(C(C)(C)C)cc(C)c1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(C(C)(C)C)cc(C)c1S(=O)(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.5 %

Procedure:
4-Tert-butyl-2,6-dimethyl-benzenesulfonyl chloride (0.100 g, 0.383 mmol) was added to a solution of 2-methyl-3,5-bis(trifluoromethyl)aniline (0.094 g, 0.387 mmol) in dry pyridine (1 mL). The reaction was capped and stirred at room temperature for 1 day then stirred at 30° C. for 1 day. The reaction was then concentrated under vacuum. To this was added diethyl ether (60 mL) and the mixture was washed with 0.1 N HCl (3×20 mL) followed by 0.1 N NaOH (2×20 mL) then saturated NaCl (2×20 mL). After drying the organic layer over MgSO4, the solution was filtered and concentrated under vacuum. The crude compound was triturated with hexanes (3×10 mL) to afford the title compound (0.051 g, 28% yield). LCMS (M+Na) 490.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:39]1[NH:40][C:41]2[CH:42]=[CH:43][CH:44]=[C:45]3[C:51](=[O:52])[NH:50][CH2:49][CH2:48][C:47]=1[C:46]=23.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO.C(Cl)(Cl)Cl.O>[CH2:11]([N:10]([CH2:13][CH3:14])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:39]2[NH:40][C:41]3[CH:42]=[CH:43][CH:44]=[C:45]4[C:51](=[O:52])[NH:50][CH2:49][CH2:48][C:47]=2[C:46]=34)=[CH:3][CH:4]=1)[CH3:12]
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Reactant: CCN(CC)CCc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)CCc1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
(As described in Tet. Lett. 1997 p. 3841) [2-(4-Bromo-phenyl)-ethyl]-diethylamine (256 mg, 1.00 mmol), diboron pinacol ester (279 mg, 1.10 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (24 mg, 0.03 mmol), and potassium acetate (294 mg, 3.00 mmol) were combined in a schlenk tube. The vessel was evacuated then refilled with argon thrice. Degassed DMF (6 mL) was added and the mixture stirred at 80° C. under an argon atmosphere for 2 h. 2-Bromo-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one (239 mg, 0.90 mmol), a second portion of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (24 mg, 0.03 mmol), and sodium carbonate (2.5 mL of a 2.0 M aqueous solution, 5.00 mmol) were then added and the reaction stirred under an argon atmosphere at 80° C. for another 17 h. The reaction mixture was then poured into 25 mL water then extracted with 25% IPA/CHCl3 (3×20 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacou leaving a brown oil. The crude product was passed through a short silica plug with 25% MeOH/CHCl3 then purified by radial chromatography eluting with 20% MeOH/CHCl3. Crystallization from MeOH/CHCl3/hexanes yielded 2-[4-(2-diethylamino-ethyl)-phenyl]-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one, 69 mg (19%) as a white solid: m.p. 224-224.5° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ0.98 (t, J=6.9 Hz, 6H), 2.53 (q, J=7.2 Hz, 4H), 2.69 (m, 4H), 3.04 (m, 2H), 3.37 (m, 2H), 7.19 (t, J=7.8 Hz, 1H), 7.36 (d, J=8.1 Hz, 2H), 7.55 (m, 3H), 7.88 (dd, J=7.5, 0.9 Hz, 1H), 8.06 (br t, 1H), 11.51 (br s, 1H). MS (FAB, MH+): 362. Anal. (C23H27N3O) C, H, N.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])=[O:24])=[C:18]([Cl:34])[CH:17]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].[CH3:43][NH:44][CH2:45][CH2:46][OH:47].O>CN(C)C=O>[Cl:34][C:18]1[CH:17]=[C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:44]([CH2:45][CH2:46][OH:47])[CH3:43])=[C:6]([O:35][CH3:36])[CH:7]=3)[N:12]=[CH:11][CH:10]=2)[CH:21]=[CH:20][C:19]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])=[O:24]
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCCBr
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCCN(C)CCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
A starting compound (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-(2,4-difluorophenyl)urea, 50 mg), potassium carbonate (138 mg), and 2-(methylamino)ethanol (0.040 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 48 mg (yield 97%) of the title compound.
Reaction SMILES: C(OC([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[C:13]=2[CH2:12]1)=O)C1C=CC=CC=1.[ClH:35]>CO.O1CCOCC1.[Pd]>[ClH:35].[F:34][C:31]([F:32])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH2:22][CH2:23][NH:11][CH2:12][C:13]2=3)=[CH:26][CH:27]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c(n(Cc3ccc(C(F)(F)F)cc3)c3ccccc23)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Cn2c3c(c4ccccc42)CCNC3)cc1
Reaction time: 6 h
Yield: 92 %

Procedure:
To a solution of 2-benzyloxycarbonyl-9-{[4-(trifluoromethyl)phenyl]methyl}-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (8.73 g, 18.81 mmole) in methanol (50 mL), dioxane (50 mL) and HCl (19 mL, 1M in dioxane) at RT in a Parr hydrogenation flask was added 10% Pd/C (0.5 g). The reaction mixture was shaken under 45 psi of H2 for 6 hr. The suspension was filtered through celite®, and the filter pad was washed with methanol. The filtrate was concentrated on the rotavap, and the residue was dried under high vacuum to afford the titled compound (6.33 g, 92%) as a white solid: MS (ES) m/e 331 (M+H−HCl)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1.Cl.[N:32]1([CH:37]2[CH2:41][CH2:40][NH:39][CH2:38]2)[CH:36]=[CH:35][N:34]=[N:33]1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:39]4[CH2:40][CH2:41][CH:37]([N:32]5[CH:36]=[CH:35][N:34]=[N:33]5)[CH2:38]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: c1cn(C2CCNC2)nn1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCC(n4ccnn4)C3)c(F)cc2c1=O
Temperature: 80 °C

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (120 mg, 0.486 mmol), DBU (190 mg, 1.25 mmol), 3-(1,2,3-triazol-1-yl)pyrrolidine hydrochloride (216 mg, 1.25 mmol) in pyridine (8 ml) was heated at 80° C. for 18 h. The reaction mixture was concentrated and treated with water. The separated solid was collected by filtration, washed with water and acetonitrile to give light brown solid. Yield: 71 mg (38%), m.p. 284° C. (dec). 1H NMR (TFA) δ: 1.5 (m, 4H), 3.0 (m, 2H), 4.0 (m, 4H), 4.65 (bs, 1H), 5.9 (bs, 1H), 7.5 (d, 1H),8.20 (d, 1H), 8.6 (s, 1H), 8.7 (s, 1H), 9.2 (S, 1H).
Reaction SMILES: [N+]12([O-])CCC(CC1)CC2.CN(CCN(C)C)C.C([Li])CCC.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](C=O)=[CH:25][CH:24]=1>C(Cl)(Cl)Cl.CCCCCCC.C(O)(C)C>[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccnc2ccccc12
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Agent: [O-][N+]12CCC(CC1)CC2
Solvent: CC(C)O
Solvent: CCCCCCC
Solvent: ClC(Cl)Cl
Product: c1ccc2ncccc2c1

Procedure:
The synthesis is carried out in a similar manner to Example A5 using 3.58 g (28.2 mmol) of azabicyclo[2.2.2]octane N-oxide, 4.70 ml (31.1 mmol) of TMEDA, 20.00 ml (32.0 mmol) of n-butyllithium (1.6 M in n-hexane) and 5.00 g (31.7 mmol) of quinoline-4-carbaldehyde. The 1H NMR spectrum of the crude product shows that the two diastereomers are formed in a 1:1 ratio. Chromatographic purification on a silica gel column (ethyl acetate/triethylamine, 9:1) provides 2.95 g (39%) of rubanol as a colourless solid. Semipreparative HPLC (Chiracel OD-H®, n-heptane/isopropanol 98:2, 0.5 ml/min, tr[(−)-rubanol]=52.1 min, tr[(+)-rubanol]=63.8 min) separates the erythro-enantiomers from each other to 99% ee in each case. 1H NMR (CDCl3, 400 MHz): 8.90 (d, 1H, 3J=4.6 Hz), 8.12 (dd, 1H, 3J=8.6 Hz, 4J=0.8 Hz), 7.97 (d, 1H, 3J=8.4 Hz), 7.69-7.64 (m, 2H), 7.43 (dt, 1H, 3J=7.0 Hz, 4J=1.2 Hz), 5.78 (d, 1H, 3J=3.5 Hz), 4.70 (br, 1H), 3.57-3.52 (m, 1H), 3.14-2.49 (m, 4H), 1.89-1.27 (m, 7H). 13C NMR (CDCl3, 101 MHz): 150.6 (q), 148.7 (t), 148.4 (q), 130.8 (t), 129.4 (t), 126.9 (t), 126.1 (t), 125.5 (q), 123.4 (t), 118.7 (t), 72.0 (t), 60.4 (t), 51.1 (s), 44.3 (s), 26.7 (s), 26.3 (s), 25.9 (s), 22.3 (t). Melting point: 222-224° C. [α]D20: +99° (c=0.51, CHCl3).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>CO>[C:1]([C:5]1[CH:10]=[C:9]([S:11][C:9]2([S:11][C:20]3[CH:21]=[C:22]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:17]([OH:23])=[C:18]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:19]=3)[CH2:10][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C1CCCCC1
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(SC2(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CCCCC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,6-di-t-butyl-4-mercaptophenol (3.00 g, 12.60 mmol) in methanol (10 mL) was added cyclohexanone (1.40 mL, 13.80 mmol) and a catalytic amount of concentrated hydrochloric acid. The mixture was stirred at a room temperature for 2 hours and then heated under reflux for one hour. The mixture was allowed to cool. Thereafter, the generated precipitate was separated by a filtration and dried to synthesize objective bis(3,5-di-t-butyl-4-hydroxyphenylthio)cyclohexane (yield 2.50 g and 71%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl.[NH2:14][OH:15].[OH-].[K+].Cl>C(O)C.O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[N:14][OH:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(=O)CCCCC
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCC(CCCCC)=NO
Temperature: 0 °C
Yield: 100.2 %

Procedure:
To a solution of 5.11 g of 6-undecanone in 20 ml of ethanol were successively added a solution of 3.47 g of hydroxylamine hydrochloride in 6 ml of water and a solution of 4.77 g of potassium hydroxide in 6 ml of water. The resulting mixture was heated under reflux for 3 hours. The reaction mixture was then poured into 150 ml of ice-containing water. The resulting aqueous mixture was made acidic by addition of 2 N hydrochloric acid, and extracted with benzene. The organic layer was washed with saturated aqueous sodium chloride and evaporated under reduced pressure to remove the solvent. There was obtained 5.57 g (corresponding to theoretical amount) of 6-undecanone oxime as a pale yellow solid,
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][CH:25]([CH2:30][CH:31]3[O:33][CH2:32]3)[C:26]([O:28]C)=[O:27])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([S:21]([NH:24][CH:25]([CH2:30][CH:31]([OH:33])[CH2:32][S:1][C:2]3[NH:3][CH:4]=[CH:5][N:6]=3)[C:26]([OH:28])=[O:27])(=[O:22])=[O:23])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: Sc1ncc[nH]1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3ncc[nH]3)C(=O)O)cc2)cc1

Procedure:
Example 22 is prepared from 2-mercaptoimidazole and 1d using the procedure described for compound 20.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=[O:5].[OH-:14].[Na+]>>[OH:14][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=[O:5]
Reactant: [OH-]
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Agent: [Na+]
Product: O=Cc1c(O)cccc1C(F)(F)F
Temperature: 80 °C

Procedure:
A mixture of 2-fluoro-6-trifluoromethylbenzaldehyde (25 g) and aqueous sodium hydroxide solution (0.5 M; 866 ml) was stirred and heated at 80° C. under nitrogen for 43 hours. The cooled solution was washed with ether (2×350 ml), acidified with concentrated hydrochloric acid, then extracted with ether (2×500 ml). The combined extracts were dried over magnesium sulphate and the solvent removed in vacuo. The residue was purified by flash chromatography over silica eluting with a 95:5 mixture of dichloromethane and methanol. Appropriate fractions were combined and the solvent removed in vacuo to give 2-hydroxy-6-trifluoromethylbenzaldehyde (6.2 g) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:18]([C:20]2[C:28]3[C:27]([Cl:29])=[N:26][CH:25]=[N:24][C:23]=3[N:22]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:21]=2)[OH:19])[C:12]=1[F:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[CH2:1]([O:8][C:9](=[O:41])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([C:20]2[C:28]3[C:27]([Cl:29])=[N:26][CH:25]=[N:24][C:23]=3[N:22]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=3)(=[O:32])=[O:31])[CH:21]=2)=[O:19])[C:12]=1[F:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(O)c3c(F)ccc(NC(=O)OCc4ccccc4)c3F)c3c(Cl)ncnc32)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)c3c(F)ccc(NC(=O)OCc4ccccc4)c3F)c3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
In a round bottom flask, (3-{[4-chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-hydroxy-methyl}-2,4-difluoro-phenyl)-carbamic acid benzyl ester (34, 311 mg, 0.519 mmol) is dissolved in 35 mL of tetrahydrofuran and Dess-Martin periodinane (242 mg, 0.571 mmol) is added. The resulting mixture is stirred at room temperature, and additional Dess-Martin periodinane is added. After 60 minutes, the reaction is quenched with water and extracted with ethyl acetate. The organic layer is washed with aqueous sodium bicarbonate, then brine, and dried with magnesium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified by silica gel chromatography eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (35, 152 mg). MS (ESI) [M+H+]+=596.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16][CH2:17][NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)(=[O:21])=[O:20])([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:28]=1.CCCCCC>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C@@:7]([CH2:16][CH2:17][NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)(=[O:21])=[O:20])([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:28]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(CCNS(=O)(=O)c2ccccn2)(C(F)(F)F)O1
Solvent: CC(C)O
Solvent: CCCCCC
Product: O=C1Nc2ccc(Cl)cc2[C@](CCNS(=O)(=O)c2ccccn2)(C(F)(F)F)O1

Procedure:
N-{2-[6-chloro-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]ethyl}pyridine-2-sulfonamide was subjected to optical resolution by HPLC (Chiralpack AD-H, hexane:2-propanol=3:1), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](CO)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27]>O1CCCC1>[CH3:25][S:26]([C:29]1[CH:34]=[C:33]([CH:32]=[CH:31][CH:30]=1)[CH2:20][Cl:24])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1cccc(CO)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
Triphenylphosphine (7.5 g, 29 mmol), carbon tetrachloride (11.0 mL, 114 mmol) and tetrahydrofuran (18 mL) were combined and stirred at room temperature for 10 minutes. A suspension of (3-methanesulfonyl-phenyl)-methanol (2.68 g, 14.3 mmol) in 18 mL tetrahydrofuran was added, then the reaction mixture was heated at 75° C. for 3 hours. The reaction mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic phase was dried over MgSO4, filtered, and concentrated to give the crude product as an oily solid. A solution of this crude product and dichloromethane was evaporated over silica gel, and the resulting silica gel supported crude product was loaded onto an Analogix SuperFlash™ column. Flash chromatography (15%-35% ethyl acetate in hexanes) afforded 2.26 g (77%) of 3-(methanesulfonyl)benzyl chloride as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.01 (s, 1 H), 7.91 (d, J=7.8 Hz, 1 H), 7.81 (d, J=7.8 Hz, 1 H), 7.68 (t, J=7.8 Hz, 1 H), 4.90 (s, 2 H), 3.24 (s, 3 H). HRMS (EI+) cald. for C8H9ClO2S [M+] 204.0012, obsd. 204.0012.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH2:18][CH3:19])=[C:15]([CH:17]=3)[NH2:16])[N:10]=2)[N:7]=1.C(#N)C.N1C=CC=CC=1.[CH3:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH2:18][CH3:19])=[C:15]([NH:16][C:31](=[O:32])[C:30]([CH3:35])([CH3:34])[CH3:29])[CH:17]=3)[N:10]=2)[N:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCc1ccc(-c2cn3nc(Cl)ccc3n2)cc1N
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: CCc1ccc(-c2cn3nc(Cl)ccc3n2)cc1NC(=O)C(C)(C)C
Yield: 92.1 %

Procedure:
A flask is charged with 5-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-ethylaniline (4.00 g, 0.0146 mol), acetonitrile (120 mL) and pyridine (3.54 mL, 0.0438 mol). The mixture is stirred and trimethylacetyl chloride (1.98 mL, 0.0161 mol) is added and the mixture stirred for 16 hr at room temp. When the reaction is complete the mixture is diluted with water (500 mL) and stirred for 1 hour, and solid collected, washed with water (3×50 mL). Crude product is purified by silica gel chromatography (0-50% EtOAc in CH2Cl2) to give the title compound (4.8 g, 92%). LCMS m/z=357.5, 359.4 [M+H]+, tR=2.57 min.