Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C@@H:13]([C:14]([NH:16][C@H:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH3:18])=[O:15])[CH2:12][CH:11]3[CH:9]2[CH2:10]3)=[CH:5][CH:4]=1.O[Li].O>>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C@@H:13]([C:14]([NH:16][C@H:17]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[CH3:18])=[O:15])[CH2:12][CH:11]3[CH:9]2[CH2:10]3)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC3CC3N2Cc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li]O
Solvent: O
Product: C[C@H](NC(=O)[C@H]1CC2CC2N1Cc1ccc(C(F)(F)F)cc1)c1ccc(C(=O)O)cc1
Yield: 88.9 %

Procedure:
The title compound (E33) (62 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-((1S)-1-((3R)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamido)ethyl)benzoate (single diastereoisomer 1) (D150) (72 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[N:26]=[N:27][C:28]([CH:31]2[CH2:33][CH2:32]2)=[CH:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[N:26]=[N:27][C:28]([CH:31]4[CH2:33][CH2:32]4)=[CH:29][CH:30]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Clc1ccc(C2CC2)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ccc(C3CC3)nn2)CC1

Procedure:
The title compound is prepared by reacting N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 3-chloro-6-cyclopropyl-pyridazine in the presence of K2CO3 in N-methylpyrrolidinone at 200° C. in a microwave vessel. LC (method 15): tR=1.26 min; Mass spectrum (ESI+): m/z=430 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C@H:20]([CH2:21][CH:22]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])C(O)=O)[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl-].[Na+].O>CS(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C@H:20]([CH2:21][CH2:22][C:26]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[O:27])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C[C@H]2CC(C(=O)O)C(=O)N2CCOCC2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C[C@H]2CCC(=O)N2CCOCC2)cc1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
To a solution of 7.80 g (16.51 mmol) of the compound obtained in Step C in 100 mL of DMSO there are added 1.16 g (19.83 mmol) of solid sodium chloride (NaCl) and then, dropwise, 5 mL of water. The batch is stirred at 130° C. for 1 hour and then the solution is concentrated to 3/4. The reaction mixture is then diluted with dichloromethane and washed successively with saturated aqueous lithium chloride solution and then with brine. The organic phase is then dried over MgSO4, filtered and concentrated to dryness. After purification by chromatography over silica gel using cyclohexane and ethyl acetate as eluants, the expected product is obtained in the form of an oil.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH:34]([CH3:36])[CH3:35])[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:39][N:38]=[N:37][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH:34]([CH3:35])[CH3:36])[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(C(C)C)cn3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3cn(C(C)C)cn3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]#[C:20][CH2:21][O:22][CH3:23])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:24]([C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[CH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:26]1([CH:25]=[C:24]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([C:19]#[C:20][CH2:21][O:22][CH3:23])[CH:18]=[C:13]3[CH:12]=2)[C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COCC#Cc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCC#Cc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 99.3 %

Procedure:
A solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine (400 mg, 0.70 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 4 mL, 4 mmol) was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine (302 mg, quant.) as a light yellow solid: LC/MS m/e calcd for C25H26N2O3S [M+H]+ 435.56, observed 435.0.
Reaction SMILES: [C:1](=[O:40])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C@@H:3]1[CH2:19][C@@H:18]2[C@@:6]([CH3:29])([C@@H:7]3[C@@H:15]([CH2:16][CH2:17]2)[C@:14]2([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]4[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=4)[CH2:12][CH2:13]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[O:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][NH2:49])[CH2:43][CH2:42]1>C(Cl)Cl>[O:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][NH:49][C:1](=[O:40])[O:2][C@@H:3]2[CH2:19][C@@H:18]3[C@@:6]([CH3:29])([C@@H:7]4[C@@H:15]([CH2:16][CH2:17]3)[C@:14]3([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]5[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=5)[CH2:12][CH2:13]3)[CH2:9][CH2:8]4)[CH2:5][CH2:4]2)[CH2:43][CH2:42]1
Reactant: C[C@]12CC[C@H](OC(=O)Oc3ccc([N+](=O)[O-])cc3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Reactant: NCCN1CCOCC1
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)NCCN3CCOCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Yield: 61.4 %

Procedure:
To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrophenyl carbonate (29 mg, 0.054 mmol) in CH2Cl2 was added 2-morpholinoethanamine (70.2 mg, 0.54 mmol). The resultant mixture was stirred at rt for 16 h and then purified via preparative TLC to afford (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl)carbamate (18 mg, 61.4%) as a white solid. LRMS (M+H+) m/z 543.4. 1H NMR (CD3OD, 400 MHz) δ 7.89 (dd, J=9.6, 2.4 Hz, 1H), 7.33 (m, 1H), 6.18 (d, J=9.6 Hz, 1H), 4.82 (m, 1H), 3.59 (m, 4H), 3.16 (m, 2H), 2.46 (m, 2H), 2.41 (m, 5H), 1.08-2.15 (m, 21H), 0.87 (s, 3H), 0.61 (s, 3H).
Reaction SMILES: C(OO)(=[O:3])C.[CH2:6]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)=[O:10])[CH3:7]>>[CH2:6]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N+:18]=2[O-:3])=[CH:13][CH:12]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1ccc(-c2ccccn2)cc1
Reactant: CC(=O)OO
Product: CCOC(=O)c1ccc(-c2cccc[n+]2[O-])cc1
Temperature: 25 °C

Procedure:
8.9 ml of 40% peracetic acid is added dropwise to 14.08 g of 2-(p-ethoxycarbonylphenyl)pyridine so as to maintain the reaction temperature between 80° and 85°. After the addition is complete the reaction mixture is heated at 90° for 3 h, and allowed to cool to room temperature. The excess peracetic acid is destroyed with aqueous sodium sulfite solution. The solvent is evaporated and the residue taken up in methylene chloride and refiltered through Celite®. Evaporation yields 2-(p-ethoxycarbonylphenyl)pyridine-N-oxide which is treated with 8.66 g dimethyl sulfate in 62 ml of toluene at 90° for 3 h. The solvent is evaporated and the residue redissolved in an ice-cold mixture of 8 ml of water and 9.3 ml of 1N sodium hydroxide. A solution of 13.64 g of potassium cyanide in 10 ml of water is added slowly and the reaction mixture is maintained at 0° for 24 h. Extraction with methylene chloride, drying over sodium sulfate and evaporation of solvent yields the title compound (a); IR (CH2Cl2) 2200 cm-1.
Reaction SMILES: [C:1]([OH:16])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:17][C:18]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:19]=1[OH:20].B(F)(F)F.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:17][C:18]1[CH:24]=[C:23]([C:22]([C:1](=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:21][C:19]=1[OH:20])[OH:25]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: Cc1cc(O)ccc1O
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCC(=O)c1cc(O)c(C)cc1O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
228 g (1 mole) of myristic acid and 136 g (1.1 mole) of monomethylhydroquinone were melted together whilst stirring a 100° C. and saturated with boron trifluoride for 4 h. After being stirred for 2 h at 100° C. the mixture was poured into 3 l of water. The product formed was pulverized under water and neutralized with a solution of 110 g of sodium carbonate in 400 ml of water, suction-filtered, washed with water, dried, and recrystallized from benzine. Yield: 305 g of compound Y1a. Melting point: 83° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:6]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)[CH3:3].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:55]1[CH2:60][CH2:59][CH:58]([N:61]2[CH2:64][C:63]([CH2:87][C:88]#[N:89])([N:65]3[CH:69]=[C:68]([C:70]4[C:71]5[CH:78]=[CH:77][N:76](COCC[Si](C)(C)C)[C:72]=5[N:73]=[CH:74][N:75]=4)[CH:67]=[N:66]3)[CH2:62]2)[CH2:57][CH2:56]1>CN(C)C=O>[CH3:3][N:2]([CH2:4][C:5]1[N:6]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([N:55]1[CH2:56][CH2:57][CH:58]([N:61]2[CH2:62][C:63]([CH2:87][C:88]#[N:89])([N:65]3[CH:69]=[C:68]([C:70]4[C:71]5[CH:78]=[CH:77][NH:76][C:72]=5[N:73]=[CH:74][N:75]=4)[CH:67]=[N:66]3)[CH2:64]2)[CH2:59][CH2:60]1)=[O:12])[CH3:1]
Reactant: CN(C)Cc1cc(C(=O)O)c(F)c(C(F)(F)F)n1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)Cc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)c(F)c(C(F)(F)F)n1
Reaction time: 1 h

Procedure:
A solution of 6-[(dimethylamino)methyl]-3-fluoro-2-(trifluoromethyl)isonicotinic acid (0.0776 g, 0.291 mmol, from Step C) in N,N-dimethylformamide (1 mL) was treated with N,N-diisopropylethylamine (0.3 mL, 2 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.15 g, 0.35 mmol). This mixture was pre-stirred for 1 hour, followed by the addition of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (0.158 g, 0.320 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base). After 3 hours, additional N,N-diisopropylethylamine (0.507 mL, 2.91 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.26 g, 0.58 mmol) were added and the mixture was stirred for 48 hours. The SEM-protected product was purified by preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Solvent was removed from fractions containing desired product by rotary evaporation. The product was deprotected by stirring with a 1:1 mixture of TFA:DCM for 1 hour, followed by evaporation, and stirring with ethylenediamine (0.2 mL) in methanol for 30 minutes. The product was purified by preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Fractions containing desired product were frozen and lyophilized. Yield: 0.006 g (3%); LC-MS: 611.2 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 8.69 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 7.77 (d, 1H), 7.51 (d, 1H), 6.98 (d, 1H), 4.33-4.21 (m, 1H), 3.87-3.71 (m, 4H), 3.68 (s, 2H), 3.59-3.45 (m, 3H), 3.44-3.10 (m, 2H), 2.71-2.58 (m, 1H), 2.31 (s, 6H), 1.97-1.85 (m, 1H), 1.85-1.72 (m, 1H), 1.56-1.24 (m, 2H). 19F NMR (300 MHz, CD3OD): δ −67.26 (d, 3F), −132.8 (m, 1F).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7](F)=[CH:8][CH:9]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:8][CH:9]=1
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Reactant: C1CCNCC1
Solvent: CN1CCCC1=O
Product: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(N3CCCCC3)ccc21
Yield: 20.8 %

Procedure:
In a similar fashion using route 51 general procedure 118, 12-chloro-9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 503 (200 mg, 0.6 mmol), piperidine (195 mg, 2.3 mmol) and NMP (2 ml) gave title compound (50 mg, 21%) after purification by column chromatography using DCM/MeOH (99.5:0.5) as the eluent.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].Cl[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1>CS(C)=O>[OH:12][C:11]1[C:4]([O:3][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: CC1(C)CCC(C)(C)c2cc(CCl)ccc21
Reactant: O=Cc1cccc(O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(COc3c(O)cccc3C=O)ccc21
Reaction time: 1 h
Yield: 55.5 %

Procedure:
Sodium hydride (0.139 g., 4.60 mmol, 1.1 equiv.; 80% in oil washed with pentane) is suspended in 6 mL of DMSO. 2,3-Dihydroxybenzaldehyde (0.580 g., 4.20 mmol, 1 equiv.) dissolved in 2.8 mL of DMSO is added dropwise via cannula, and the mixture is allowed to stir for 1 hour. 2-Chloromethyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene) (18a) (1.00 g., 4.20 mmol, 1 equiv.) dissolved in 8 mL of DMSO is added dropwise via cannula, and the mixture allowed to stir 26.5 hours. The mixture is partitioned between saturated aqueous ammonium chloride solution and EtOAc. Salt is added to the aqueous phase, which is then extracted twice with EtOAc. The combined extracts are washed with brine, dried (MgSO4), and treated with charcoal before filtering through a pad of silica gel. The filtrate is evaporated, and the crude material is chromatographed on silica gel using EtOAc/hexane to afford 3-hydroxy-2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]methoxy benzaldehyde (45) (0.786 g., 2.33 mmol, 56%) as an oil: 1H NMR (300 MHz, CDCl3) δ 10.14 (s, 1H, CHO), 7.35 (m, 2H, ArH), 7.22-7.09 (m, 4H, ArH), 5.77 (s, 1H, OH), 5.00 (s, 2H, ArCH2O), 1.67 (s, 4H, CH2CH2), 1.27 (s, 6H, 2×CH3), 1.22 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ 189.40 (C=0), 149.74, 148.00, 146.20, 145.64, 132.58, 129.63, 127.36, 127.11, 126.00, 125.12, 121.64, 121.34, 79.18, 34.92, 34.90, 34.27, 31.80, 31.75; IR (KBr) 3226, 2958, 2926, 1662, 1604, 1580, 1470, 1294, 1284, 1222, 934, 786 cm-1 ; MS (DCI) m/e 339 (MH+), 201 (C15H21+).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:14])=[N:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-])=O.[H][H]>CO>[N:6]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[C:4]([NH2:1])[C:5]=1[NH2:14]
Reactant: Nc1nc2c(cc1[N+](=O)[O-])CCCC2
Reactant: [H][H]
Solvent: CO
Product: Nc1cc2c(nc1N)CCCC2
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
A mixture of intermediate (9) (0.0658 mol) in NH3/CH3OH 7N (60 ml) was stirred at 120° C. for 12 hours in an autoclave. The solvent was evaporated till dryness. The residue was taken up in 2-propanone. The precipitate was filtered off and dried, yielding 8.6 g 5,6,7,8-tetrahydro-3-nitro-2-quinolinamine (intermediate 10). d) A mixture of intermediate (10) (0.031 mol) in methanol (100 ml) was hydrogenated at room temperature under a 3.105 Pa (3 bar) pressure for 30 minutes in a Parr apparatus. After uptake of hydrogen (3 equivalents), the catalyst was filtered through celite, rinced with methanol and the filtrate was evaporated till dryness. The product was used with further purification, yielding 5.07 g 5,6,7,8-tetrahydro-2,3-quinolinediamine (intermediate 11).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=1.[Cl:13][C:14]1[C:15]([C:31]#[N:32])=[C:16]([CH:28]=[CH:29][CH:30]=1)[O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[Cl:13][C:14]1[C:15]([C:31]#[N:32])=[C:16]([CH:28]=[CH:29][CH:30]=1)[O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:1][C:2]2[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=2)(=[O:25])=[O:26])=[CH:22][CH:23]=1
Reactant: COC(=O)Cc1nc(N)sc1C
Reactant: N#Cc1c(Cl)cccc1Oc1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)Cc1nc(NS(=O)(=O)c2ccc(Oc3cccc(Cl)c3C#N)cc2)sc1C

Procedure:
The title compound was prepared from methyl 2-(2-amino-5-methyl-1,3-thiazol-4-yl)acetate and 4-(3-chloro-2-cyanophenoxy)benzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (28.3 mg) with purity >90%. LCMS (pos) m/z 478.2.
Reaction SMILES: [C:1]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[C:5]([C:7]([O-:9])=O)[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=1.Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN1CCOCC1.C(Cl)CCl>>[C:22]1([CH2:21][O:28][NH:29][C:7]([C:5]2[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=[C:1]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=2)=[O:9])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NOCc1ccccc1
Reactant: CCOC(=O)c1cc(C(=O)[O-])cc(C(=O)OCC)c1
Agent: Cl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)c1cc(C(=O)NOCc2ccccc2)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.9 %

Procedure:
To a solution of diethyl 1,3,5-benzenetricarboxylate (3.192 g, 20 mol) and O-benzylhydroxyamine hydrochloride (4.789 g, 19 mmol) in 40 mL were added N-methylmorpholine (2.2 mL, 20 mmol) and EDC (3.834 g, 20 mmol) at 0° C., and the mixture was stirred at room temperature for 20 hours. The solvent was removed by evaporator and the residue was dissolved in EtOAc (150 mL). The organic solution was washed with 1 N HCL (150 mL), washed with saturated aqueous NaHCO3 (50 mL), dried over Na2SO4, and concentrated to give white solid. This material was recrystallized from EtOAc to give 4.154 g of white powder (59% yield).
Reaction SMILES: [OH:1][C:2]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[O:29])[CH:20]=[CH:21]2)[CH:16]=[CH:15]3)[CH2:12][CH2:11]1)[CH3:9])([CH3:4])[CH3:3].[OH-:30].[K+].OO>C(O)C.O>[O:30]1[C@H:20]2[C:19](=[O:29])[CH:18]=[C:17]3[C@:22]([CH3:23])([C@@H:21]12)[C@@H:24]1[C@H:14]([C@H:13]2[C@:27]([CH3:28])([CH2:26][CH2:25]1)[C@@H:10]([C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][C:2]([OH:1])([CH3:3])[CH3:4])[CH2:11][CH2:12]2)[CH:15]=[CH:16]3
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The trienone from (a) (1.3 gms) in ethanol (50 mls) was treated with 10% aqueous potassium hydroxide (0.5 ml) and 30% aqueous H2O2 (3 ml). After storage overnight at room temperature, the solution was diluted with water and the solid product collected. Recrystallization from aqueous methanol gave the title compound which after one further crystallization had melting point 162°-163°.
Reaction SMILES: [CH2:1]([C@H:8]([NH:20][C:21](=[O:31])[O:22][C@@H:23]1[C@H:30]2[C@H:26]([O:27][CH2:28][CH2:29]2)[O:25][CH2:24]1)[C@H:9]([OH:19])[CH2:10][NH:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41](Cl)(=[O:43])=[O:42])=[CH:40][C:35]=2[O:34][CH2:33]1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41]([N:11]([O:12][CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:10][C@@H:9]([OH:19])[C@@H:8]([NH:20][C:21](=[O:31])[O:22][C@@H:23]3[C@H:30]4[C@H:26]([O:27][CH2:28][CH2:29]4)[O:25][CH2:24]3)[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)(=[O:42])=[O:43])=[CH:40][C:35]=2[O:34][CH2:33]1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc2c(c1)OCO2)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
A mixture of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.230), 1,3-benzodioxole-5-sulfonyl chloride (Eur. Pat. Appl. 583960, 23 Feb. 1994, 56 mg, 0.253 mmol) and diisoproylethylamine (0.042 mL, 0.242 mmol) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature under an Argon atmosphere for 16 hours. A catalytic quantity of dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately 2 hours. An additional quantity of 1,3-benzodioxole-5-sulfonyl chloride (11 mg, 0.050 mmol) was added and the reaction was heated for an additional hour. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. After separating the phases, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 μM) eluting with 1:1 ethyl acetate:hexane. The product band was removed, eluted with 3:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate (123 mg, 87%) as a white solid. H1-NMR (chloroform-D3): 1.32 (m, 6H), 1.70 (m, 5H), 2.14 (m, 2H), 3.00 (m, 4H), 3.18 (b, 1H), 3.74 (m, 2H), 3.97 (m, 4H), 4.27 (m, 1H), 4.90 (m, 1H), 5.07 (m, 1H), 5.70 (d, 1H), 6.15 (s, 2H), 6.95 (d, 1H), 7.30 (m, 7H). MS(ESI): 641(M+Na).