Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[C:33]([S:35][CH3:36])[N:32]=[C:31]([C:37]([NH:39][O:40][CH3:41])=[O:38])[CH:30]=2)[CH2:25][CH2:24]1)=[O:21]>C(Cl)Cl>[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[C:33]([S:35]([CH3:36])=[O:9])[N:32]=[C:31]([C:37]([NH:39][O:40][CH3:41])=[O:38])[CH:30]=2)[CH2:25][CH2:24]1)=[O:21]
Reactant: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(SC)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(S(C)=O)n1
Yield: 26.3 %

Procedure:
mCPBA (70%, 86 mg, 0.35 mmol) was added to a suspension of 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-N-methoxy-2-(methylthio)pyrimidine-4-carboxamide (Example 8, 166 mg, 0.35 mmol) in DCM (12 ml) at 0° C. and the resultant mixture was stirred for 2 h. The reaction mixture was diluted with DCM (50 ml), washed with Na2SO3 solution (5%, 10 ml), dried over Na2SO4, filtered and concentrated under vacuum. Purification by reversed-phase HPLC (water/acetonitrile gradient, 10-95%) gave 45 mg of the title product.
Reaction SMILES: [O:1]=[C:2]([O-:11])[C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[K+].O=C([O-])[C@H]([C@@H]([C@@H](CO)O)O)O>O>[O:1]=[C:2]([OH:11])[C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C([O-])[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [K+]
Solvent: O
Product: O=C(O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Potassium arabinonate (15 mmoles) was dissolved in 20 mL of water. The arabinonate was acidified to approximately 50% neutralization by adding cation exchange resin (Amberlite IRC747 H+ form) and lowering the pH from 8.4 to 3.5. The arabinonate was filtered to remove the resin, diluted to 30 mL, and transferred to a glass cell for electrolysis. The initial arabinonate was quantified by HPLC-RI against an arabinonate standard and was found to contain 9.2 mmoles (0.37 M). There was a loss of 3.3 mmoles of arabinonate from the cation exchange resin.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[O:6][CH:7]=[C:8](N)[C:9]2[C:10]=1[N:11]=[C:12]1[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]1.[CH2:20]=[O:21]>CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[O:6][CH:7]=[C:8]([O:21][CH3:20])[C:9]2[C:10]=1[N:11]=[C:12]1[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]1
Reactant: C=O
Reactant: COC(=O)Cc1occ(N)c2c3ccccc3nc1-2
Solvent: CO
Product: COC(=O)Cc1occ(OC)c2c3ccccc3nc1-2
Yield: 80 %

Procedure:
When the 4-aminopyrano[3,4-b]indole acetic acid methyl ester 12 was treated with aqueous formaldehyde in methanol, an 80% yield of 4-methoxypyrano[3,4-b]indole acetic acid methyl ester 16 was obtained as an 8.5:1 diastereomeric mixture.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9](O)[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].N1C=CC=CC=1.CS(Cl)(=O)=O.C(OCC)(=O)C.CCCCCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][CH:9]=[C:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:18][CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][O:22]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.2 %

Procedure:
To a mixture of 49.0 mg (0.1 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-hydroxypregna-5-en-3β-yl acetate, 0.24 ml (3 mmoles) of pyridine, 0.5 mg (0.004 mmole) of 4-(dimethylamino)pyridine and 10 ml of methylene chloride was added 0.10 ml (1.3 mmoles) of methanesulfonyl chloride dropwise at a temperature of 0° C. and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with 20 ml of methylene chloride, then washed successively with cold 1N-hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. Finally the residue was purified by silica gel chromatography (eluent:ethyl acetate-hexane=1:10, v/v) to give 25.5 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate (yield: 54%). The 1H-NMR spectrum of this product was in agreement with that of the 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate obtained in Example 17.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4]([OH:6])=[O:5].[H-].[Na+].Br[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>[C:11]([O:10][C:8]([NH:7][C@@H:3]([CH2:2][O:1][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:4]([OH:6])=[O:5])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: BrCC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COCC1CCCCC1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-3-hydroxy-2-t-butoxycarbonylaminopropanoic acid (10.11 g) in dimethylformamide (200 ml, abbreviated as DMF), sodium hydride (60%, 3.95 g) was added under cooling with ice. The mixture was stirred for 30 minutes at 0° C. To the reaction mixture, (bromomethyl)cyclohexane (9.0 ml) was added at a dropwise under cooling with ice. Tetra-n-butylammonium iodide (910 mg) was added thereto. The mixture was stirred for 23 hours at room temperature. In addition, to the reaction mixture, (bromomethyl)cyclohexane (2.1 ml) was added at a dropwise. The mixture was stirred for 4 hours. Again, (bromomethyl)cyclohexane (2.1 ml) was added at a dropwise thereto. The mixture was stirred for 25 hours at room temperature. After the concentration of reaction mixture, the residue was diluted with 1N—HCl and extracted with ethyl acetate. The extract solution was washed by water and saturated solution of sodium chloride successively, dried over anhydrous sodium sulfate and concentrated. The residue was purified with column chromatography on silica gel (chloroform:methanol=97:3) to obtain the title compound (2.52 g) having the following physical data.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][O:16][CH3:17])[C:9]=1[C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:4])[CH3:3].[C:27]1(C)C=CC=CC=1>O.C(OCC)(=O)C>[CH2:22]([O:21][C:19](=[O:20])[C:18]([C:9]1[C:10]([O:14][CH2:15][O:16][CH3:17])=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][O:6][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:26])[CH3:25])=[CH2:27])[CH3:23]
Reactant: CCOC(=O)C(=O)c1c(CO[Si](C)(C)C(C)(C)C)cccc1OCOC
Reactant: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C(=O)OCC)c1c(CO[Si](C)(C)C(C)(C)C)cccc1OCOC
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl (2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-6-{[(methyloxy)methyl]oxy}phenyl)(oxo)acetate (Intermediate 130, 1.4 g) in dry toluene (8 ml) dimethyl titanocene 9% w/w in toluene (Intermediate 131, 30 ml) was added and the reaction mixture was stirred for 1.5 hours at 90° C. After cooling the reaction was diluted with water (20 ml) and ethyl acetate (30 ml). Two phases were separated and the organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 9:1 as eluents. This afforded the title compound as a yellow pale oil (865 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15].[CH2:16]([Sn](CCCC)(CCCC)C=C)[CH2:17]CC>ClCCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:16]=[CH2:17])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=Cc1nc(C(=O)OC)c(OC)c(N)c1F
Yield: 97.1 %

Procedure:
A mixture of methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (405 mg, 1.73 mmol), tributyl(vinyl)stannane (1.097 g, 3.46 mmol), and PdCl2(PPh3)2 (181 mg, 0.26 mmol) in 1,2-dichloroethane (3.5 mL) was heated at 120° C. in a Biotage microwave for 30 min Column chromatography (0-40% EtOAc/hexanes) of the crude reaction mixture provided the title compound as a yellow oil (0.38 g, 97%): 1H NMR (400 MHz, CDCl3) δ 6.88 (ddd, J=17.5, 11.1, 1.4 Hz, 1H), 6.33 (dd, J=17.5, 1.6 Hz, 1H), 5.57 (ddd, J=11.1, 1.6, 0.7 Hz, 1H), 4.47 (s, 2H), 3.97 (s, 3H), 3.91 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −143.2; ESIMS m/z 227 ([M+H]+).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][CH:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:4]([C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:7][CH:6]=1)#[CH:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#C[Si](C)(C)C)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(NC(=O)OC(C)(C)C)cn1
Reaction time: 0.67 h
Yield: 98.2 %

Procedure:
A solution of tert-butyl 6-(2-(trimethylsilyl)ethynyl)pyridin-3-ylcarbamate (62 mg, 0.21 mmol) in THF (5 mL) was cooled to −15° C. and treated with 1.0 M tetrabutylammonium fluoride (Aldrich, 0.25 mL, 0.25 mmol) and stirred for 40 min. The mixture was concentrated in vacuo and partitioned between EtOAc and saturated aqueous NaHCO3 solution. The EtOAc phase was washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (45 mg, 100%) as an off-white solid. 1H NMR (DMSO-d6) δ 9.78 (s, 1H), 8.58 (d, 1H, J=2.5 Hz), 7.92-7.84 (m, 1H), 7.46 (d, 1H, J=8.6 Hz), 4.17 (s, 1H), 1.47 (s, 9H); MS (ESI+): m/z 219.20 (M+H)+.
Reaction SMILES: Cl.[O:2]1[C:7]2=[CH:8][CH2:9][CH2:10][CH:6]2[NH:5][CH2:4][CH2:3]1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][N:16]2[C:21](=[O:31])[CH2:22][C:23]1[NH:28][C:27](=[O:29])[CH:26]=[C:25](Cl)[N:24]=1.O>C(N(C(C)C)CC)(C)C>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][N:16]2[C:21](=[O:31])[CH2:22][C:23]1[NH:28][C:27](=[O:29])[CH:26]=[C:25]([N:5]2[CH:6]3[CH2:10][CH2:9][CH2:8][CH:7]3[O:2][CH2:3][CH2:4]2)[N:24]=1
Reactant: O=C(Cc1nc(Cl)cc(=O)[nH]1)N1CCc2c(F)cccc21
Reactant: C1=C2OCCNC2CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Cc1nc(N2CCOC3CCCC32)cc(=O)[nH]1)N1CCc2c(F)cccc21
Temperature: 100 °C
Yield: 23.2 %

Procedure:
532 mg of hexahydrocyclopenta[1,4]oxazine hydrochloride are added to a solution of 100 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-chloro-3H-pyrimidin-4-one in 5 ml of diisopropylethylamine. The reaction medium is heated at 100° C. for 2 hours. The reaction medium is taken up with 10 ml of water. The solid formed is filtered off and washed with water and then dried so as to give 30 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(hexahydrocyclopenta[1,4]oxazin-4-yl)-3H-pyrimidin-4-one in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:16][C:17]1[CH:25]=[C:24]([O:26][CH2:27][C@@H:28]2[CH2:33][N:32]([CH3:34])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[O:29]2)[CH:23]=[C:22]([CH3:39])[C:18]=1[C:19](Cl)=[O:20].OC1C=C(C)C(C(OC)=O)=C(C)C=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11])=[CH:3][C:2]=1[NH:1][C:19](=[O:20])[C:18]1[C:17]([CH3:16])=[CH:25][C:24]([O:26][CH2:27][C@@H:28]2[CH2:33][N:32]([CH3:34])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[O:29]2)=[CH:23][C:22]=1[CH3:39]
Reactant: COC(=O)C(C)(C)c1ccc(Cl)c(N)c1
Reactant: Cc1cc(OC[C@@H]2CN(C)c3ccccc3O2)cc(C)c1C(=O)Cl
Agent: COC(=O)c1c(C)cc(O)cc1C
Product: Cc1cc(OC[C@@H]2CN(C)c3ccccc3O2)cc(C)c1C(=O)Nc1cc(C(C)(C)C(=O)O)ccc1Cl
Yield: 47.5 %

Procedure:
By the same procedures as a series of Example 18 and Example 19 using the compound (121 mg) prepared in Example 16 and 2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoylchloride (211 mg) (the compound prepared by the same procedures as a series of Example 8→Example 9→Example 10 using methyl 4-hydroxy-2,6-dimethylbenzoate.), the title compound (132 mg) having the following physical data was obtained.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=2[O:19][CH3:20])[CH2:11]1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K]>CN(C=O)C.C(OCC)(=O)C>[CH3:26][O:25][C:13]1[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]([O:19][CH3:20])=[C:17]2[C:12]=1[CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]1[C:30](=[O:32])[C:29]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]3[C:27]1=[O:37])[CH2:18]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCI)C2
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN1C(=O)c3ccccc3C1=O)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.5 %

Procedure:
To a solution of 2-(8-iodooctyl)-4,5,6,7-tetramethoxyindan (1.98 g) in DMF (10 ml) was dropwise added potassium phthalimide (924 mg). After being stirred at room temperature for 12 hr, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo and the residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=10:1) and then recrystallized from hexane gave the entitled compound (1.74 g) as crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([F:11])=[C:4]2[CH:10]=[CH:9][N:8]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Fc1c(Br)cnc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2c(F)c(Br)cnc21
Reaction time: 0.33 h
Yield: 59.3 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (5.3 g, 24.7 mmol) was placed in DMF (53 mL) at 0° C. NaH (1.18 g, 29.6 mmol) was then added and stirred for 20 minutes. Benzenesulfonyl chloride (3.47 mL, 27.1 mmol) was then added next, and the reaction was stirred at 0° C. for 30 minutes. Water was then added, and the resulting solid was filtered and dried. The crude solid was then triturated in 1:1 hexane:EtOAc to give 5-bromo-4-fluoro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (5.2 g, 59.4% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[C:6]2(SCCCS2)[C:5]1=[O:19]>C(O)C.O1CCCC1.[Ni]>[Cl:1][CH2:2][CH2:3][N:4]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[CH2:6][C:5]1=[O:19]
Reactant: O=C1N(CCCl)c2ccc(F)cc2C12SCCCS2
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C1Cc2cc(F)ccc2N1CCCl
Reaction time: 3 h

Procedure:
1-(2-chloro-1-ethyl)-1,3-dihydro-5-fluoro-2-oxo-2H-indole-3-spiro-2'-1,3 dithiane was dissolved in a mixture of ethanol/tetrahydrofuran (3:2). Raney nickel was added and the mixture was heated under reflux with vigorous stirring for 3 h. The cooled solution was filtered, evaporated under reduced pressure and triturated with ether to give 1-(2-chloro-1-ethyl)-5-fluoro-1,3-dihydro-2H-indole-2-one as a white solid, melting point 127° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([NH:15][CH2:16][B:17]([OH:19])[OH:18])(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4].OC(C(O)(C)C)(C)C.Cl>O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][S:12]([NH:15][CH2:16][B:17]([OH:18])[OH:19])(=[O:14])=[O:13])=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(CS(=O)(=O)NCB(O)O)cc1
Agent: CC(C)(O)C(C)(C)O
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc(CS(=O)(=O)NCB(O)O)cc1
Yield: 85.4 %

Procedure:
A mixture of 8 (67 mg, 0.18 mmol) and HCl 3 N degassed (3 mL) was allowed to react at reflux for 1 h 30 min. After cooling, the reaction mixture was diluted with water (15 mL) and washed twice with diethyl ether (2×20 mL). The aqueous phase was concentrated in vacuo, affording 9 as a yellow solid (42 mg, 86% yield). Mp 118-122° C. (dec). 1H-NMR (400 MHz, DMSO): δ 2.5 (2H, d, J 4.9, BCH2), 4.42 (2H, s, PhCH2), 6.22 (1H, t, J 4.9, SO2NH), 7.49 (2H, d, J 8.6, H2, H6), 7.93 (2H, d, J 8.6, H3, H5), 7.94 (1H, s, COOH). 13C-NMR (100 MHz, DMSO): δ 31.3 (CB), 55.7, 129.7, 130.7, 131.4, 136.0, 167.6. EI-MS and elemental analysis were not obtainable, but exposure of 9 to an equimolar amount of pinacol in anhydrous THF afforded the corresponding pinacol boronate in quantitative yield and satisfactory elemental analysis; Anal. Calcd. for C15H22BNO6S: C, 50.72; H, 6.24; N, 3.94; S, 9.03. Found: C, 50.88; H, 6.41; N, 3.80; S, 8.77.
Reaction SMILES: [CH2:1]([N:8]1[C:12](O)=[C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[CH2:1]([N:8]1[C:12]([Cl:23])=[C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CCc1nnn(Cc2ccccc2)c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCOC(=O)CCc1nnn(Cc2ccccc2)c1Cl
Reaction time: 2 h

Procedure:
To a solution of 1.0 g. (4 mmol.) of 1-benzyl-4-(2-carbethoxyethyl)-5-hydroxy-1,2,3-triazole in 2 ml. of phosphorus oxychloride is added 0.5 g. (5 mmol.) of phosphorus pentachloride. The reaction mixture is stirred at 25° for two hours, then warmed on a steam bath for 10 minutes and evaporated to dryness. The residue is dissolved in 0.5 ml. of phosphorus oxychloride and the solution is heated to reflux for 30 minutes, cooled and evaporated to dryness to give 1-benzyl-4-(2-carbethoxyethyl)-5-chloro-1,2,3-triazole.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:13][O:14][CH:15]2[CH2:17][CH2:16]2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:3]=1.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:15]1([O:14][N:13]=[C:7]([C:4]2[N:3]=[C:2]([NH:1][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[S:6][N:5]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:17][CH2:16]1
Reactant: CCOC(=O)C(=NOC1CC1)c1nsc(N)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)C(=NOC1CC1)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 4 h
Yield: 107.5 %

Procedure:
A mixture of ethyl 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(cyclopropyloxyimino)acetate (syn isomer)(5.26 g), trityl chloride (12.9 g) and 4-dimethylaminopyridine (224 mg) in pyridine (25 ml) was stirred at 50°-60° C. for 4 hours. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic solution was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated in vacuo to give a crystal. The crystal was washed with n-hexane and diisopropyl ether, heated in methanol (80 ml) under reflux, and finally cooled to give ethyl 2-cyclopropyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetate (syn isomer) (11 g) as a crystal.
Reaction SMILES: [I:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26]>C(O)C>[CH2:10]([N:9]([CH2:26][CH2:25][C:24]([O:28][CH2:29][CH3:30])=[O:27])[CH2:8][CH2:7][O:6][C:5]1[CH:22]=[CH:23][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C=CC(=O)OCC
Reactant: CCCCCCCCCCCCNCCOc1ccc(I)cc1
Solvent: CCO
Product: CCCCCCCCCCCCN(CCOc1ccc(I)cc1)CCC(=O)OCC
Yield: 85.9 %

Procedure:
A mixture of N-2-[4-iodophenoxy]ethyldodecylamine (1.0 g, 2.3 mmol), ethyl acrylate (1.2 g, 12 mmol) and ethanol (3 ml) was stirred and refluxed for 6 h, and then concentrated in vacuo . The residue was chromatographed on silica gel (hexane/ethyl acetate 8:1) to afford the title compound (1.05 g, 86%) as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][OH:8])[CH2:2]1.C(C1OC1)Cl.[CH2:14](NCCO)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][OH:8])[CH2:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCC1CNCCO1
Reactant: OCCNCc1ccccc1
Solvent: ClCC1CO1
Product: OCC1CN(Cc2ccccc2)CCO1

Procedure:
The first steps (B1 and B2) in the synthesis of the morpholin-2-yl methanol intermediates (compounds 54 and 56) of general reaction Scheme B, is to react epichlorohydrin with N-benzylethanolamine to form (4-benzylmorpholin-2-yl)methanol. (R) or (S) stereoisomers as appropriate, are formed using either the (R) or (S) form of epichlorohydrin. The reaction may take place in solution or in an organic solvent, such as a mixture of water and isopropanol. A preferred solvent is 1:1 water/isopropanol. Beneficially, epichlorohydrin may be dissolved in a pre-formed solution of N-benzylethanolamine. Conveniently, the reaction may be performed at room temperature (e.g. between 20 and 25° C.; preferably between 23 and 25° C.), and optionally may be continued at a lower temperature, such as −20° C. At −20° C. the reaction may be continued overnight (e.g. for a further 8 to 16 hours).
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:17]3[CH:18]=[N:19][C:20]([C:23]([CH:25]4[CH2:30][CH2:29][C@@H:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C@@H:27]([CH3:36])[CH2:26]4)=[CH2:24])=[N:21][CH:22]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)[N:4]=1>[Pd].C1COCC1>[F:37][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:17]3[CH:22]=[N:21][C:20]([CH:23]([CH:25]4[CH2:30][CH2:29][C@@H:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C@@H:27]([CH3:36])[CH2:26]4)[CH3:24])=[N:19][CH:18]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)[N:4]=1
Reactant: C=C(c1ncc(-c2cc(C)cc(Nc3nccc(C(F)F)n3)c2)cn1)C1CC[C@@H](C(=O)OCC)[C@@H](C)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCC(C(C)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)F)n4)c3)cn2)C[C@@H]1C
Temperature: 30 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethenyl}-2-methylcyclohexanecarboxylate (592 mg, 1.17 mmol) and palladium on carbon (50 mg) in THF (10 mL) was stirred at 30° C. for 16 hours under a hydrogen atmosphere (45 psi). The mixture was then filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (ethyl acetate/petroleum ether) to give ethyl rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylate. MS ESI calc'd for C28H34F2N5O2[M+H]+ 510. found 510. 1H NMR: (400 MHz, CD3OD) δ 8.98 (d, J=1.0 Hz, 2H), 8.64 (d, J=4.8 Hz, 1H), 7.99 (s, 1H), 7.60 (s, 1H), 7.19 (s, 1H), 7.04 (d, J=5.0 Hz, 1H), 6.58 (t, J=54.4 Hz, 1H), 4.15-4.06 (m, 2H), 2.87-2.75 (m, 2H), 2.44 (s, 3H), 2.02 (br s, 2H), 1.90-1.58 (m, 4H), 1.37-1.30 (m, 5H), 1.24-1.19 (m, 3H), 1.00-0.86 (m, 3H).