Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:1][CH:2]([CH2:12][NH:13][C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[CH2:3][NH:4][C:5]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Reaction time: 1.5 h

Procedure:
To a solution of di-tert-butyl (2-hydroxy-1,3-propanediyl)biscarbamate (200 g) in methylene chloride (1.2 L) was added triethylamine (384 ml) under cooling on an ice-water bath and then a solution of methanesulfonyl chloride (64 ml) in methylene chloride (300 ml) was dropwise added at a temperature below 15° C. The mixture was stirred at the same temperature for 1.5 hours and quenched with saturated aqueous sodium hydrogencarbonate solution (200 ml). The organic layer was made acidic (pH=3) with diluted hydrochloric acid, and washed with saturated aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave a residue, which was triturated with ethyl acetate (100 ml)—hexane (500 ml) to give 2-[(tert-butoxycarbonyl)amino]-1-{[(tert-butoxycarbonyl)amino]methyl}ethyl methanesulfonate (202 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C@@H:7]([NH:20][C:21](=[O:40])[NH:22][C@@H:23]([CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:8][CH2:9][C:10](ON1C(=O)CCC1=O)=[O:11])([CH3:4])([CH3:3])[CH3:2].[NH2:42][C@@H:43]([CH2:47][CH2:48][CH2:49][CH2:50][N:51]([CH2:78][C:79]1[N:80]([CH2:84][C:85]([N:87]([CH2:96][C:97]([O:99][C:100]([CH3:103])([CH3:102])[CH3:101])=[O:98])[CH2:88][C:89](=[O:95])[O:90][C:91]([CH3:94])([CH3:93])[CH3:92])=[O:86])[CH:81]=[CH:82][N:83]=1)[CH2:52][C:53]1[N:54]([CH2:58][C:59](=[O:77])[N:60]([CH2:69][C:70](=[O:76])[O:71][C:72]([CH3:75])([CH3:74])[CH3:73])[CH2:61][C:62](=[O:68])[O:63][C:64]([CH3:67])([CH3:66])[CH3:65])[CH:55]=[CH:56][N:57]=1)[C:44]([OH:46])=[O:45].CCN(C(C)C)C(C)C>CN(C=O)C>[C:100]([O:99][C:97](=[O:98])[CH2:96][N:87]([CH2:88][C:89](=[O:95])[O:90][C:91]([CH3:94])([CH3:93])[CH3:92])[C:85](=[O:86])[CH2:84][N:80]1[CH:81]=[CH:82][N:83]=[C:79]1[CH2:78][N:51]([CH2:52][C:53]1[N:54]([CH2:58][C:59](=[O:77])[N:60]([CH2:69][C:70](=[O:76])[O:71][C:72]([CH3:75])([CH3:74])[CH3:73])[CH2:61][C:62](=[O:68])[O:63][C:64]([CH3:65])([CH3:67])[CH3:66])[CH:55]=[CH:56][N:57]=1)[CH2:50][CH2:49][CH2:48][CH2:47][C@H:43]([NH:42][C:10](=[O:11])[CH2:9][CH2:8][C@@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:41])[NH:20][C:21](=[O:40])[NH:22][C@H:23]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:31][CH2:32][C:33](=[O:34])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:44]([OH:46])=[O:45])([CH3:103])([CH3:102])[CH3:101]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCC(=O)N[C@@H](CCCCN(Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 84.3 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-5-(2,5-dioxopyrrolidin-1-yloxy)-1,5-dioxopentan-2-yl)ureido)pentanedioate (82 mg, 0.14 mmol), ((S)-2-amino-6-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (98 mg, 0.11 mmol) and DIPEA (0.50 mL) in DMF (2.0 mL) was stirred at rt for overnight. The Solvent was removed under reduced pressure to give a residue, which was purified by biotage eluting with 1% to 40% MeOH in DCM to afford (2S,7S,11S)-2-(4-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)butyl)-7,11-bis(tert-butoxycarbonyl)-16,16-dimethyl-4,9,14-trioxo-15-oxa-3,8,10-triazaheptadecan-1-oic acid (125 mg, 84%) as a white solid. MS (ESI), 674.6 (M/2+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:29])([CH3:28])[CH2:12][C@:13]([CH2:19]SC2C=CC(C)=CC=2)([OH:18])[C:14]([F:17])([F:16])[F:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.F[B-](F)(F)F.C[O+](C)C.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:28])([CH3:29])[CH2:12][C@:13]2([C:14]([F:17])([F:15])[F:16])[CH2:19][O:18]2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc(SC[C@](O)(CC(C)(C)c2cc(Cl)cc3c2OCC3)C(F)(F)F)cc1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C[C@]1(C(F)(F)F)CO1)c1cc(Cl)cc2c1OCC2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 94.6 %

Procedure:
To a solution of (S)-4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-p-tolylsulfanylmethylpentan-2-ol (1.43 g, 3.21 mmol) in 10 mL of anhydrous dichloromethane was added trimethyloxonium tetrafluoroborate (713 mg, 4.82 mmol). The resulting suspension was stirred at room temperature for 4.5 hours. A solution of potassium carbonate (1.33 g, 9.64 mmol) in 10 mL of water was then added. After 13 hours, the reaction mixture was poured into 40 mL of saturated aqueous sodium bicarbonate solution and extracted with three 50 mL portions of dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography with silica gel (eluted with 0%-2% EtOAc/hexanes) afforded the title compound as a clear oil (974 mg, 95%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:11][CH:12]=2)[CH2:7]1.Cl.[NH2:25][C:26]1[CH:36]=[CH:35][C:29](/[CH:30]=[CH:31]/[C:32](O)=[O:33])=[CH:28][CH:27]=1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1>ClCCl>[NH2:25][C:26]1[CH:27]=[CH:28][C:29](/[CH:30]=[CH:31]/[C:32]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][C:10]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:11][CH:12]=3)[CH2:7]2)=[O:33])=[CH:35][CH:36]=1
Reactant: NCCCCN1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Reactant: Nc1ccc(/C=C/C(=O)O)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccc(/C=C/C(=O)NCCCCN2CCc3ccc(OS(=O)(=O)C(F)(F)F)cc3C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
A mixture of 2-(4-aminobutyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline (440 mg, 1.25 mmol), trans-4-aminocinnamic acid hydrochloride (250 mg, 1.25 mmol), triethylamine (0.174 ml, 1.25 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240 mg, 1.25 mmol) and 1-hydroxybenzotriazole (100 mg, 0.74 mmol) in dichloromethane (50 ml) was stirred at room temperature for 18 h. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate (50 ml) and the organic layer dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica using 10-100% ethyl acetate-hexane gradient elution to afford the title compound (280 mg, 45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.OC1C=C(C(=O)/C=C/C2C=CC=CC=2)C=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:10](=[O:11])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(F)cc1)c1cccc(O)c1
Agent: O=C(/C=C/c1ccccc1)c1cccc(O)c1
Product: O=C1CC(c2ccc(F)cc2)c2ccc(O)cc21
Reaction time: 120 h
Yield: 47 %

Procedure:
The procedure of Step 2 of Example 1 was repeated except for using (E)-3-(4-fluorophenyl)-1-(3-hydroxyphenyl)prop-2-en-1-one obtained in Step 1 as a starting material instead of (E)-1-(3-hydroxyphenyl)-3-phenylprop-2-en-1-one, being stirred for 5 d, and removing TFA by rotary evaporation to obtain the title compound (47%).
Reaction SMILES: N1C=CC=CC=1.[F:7][C@:8]12[C@@H:27]([OH:28])[CH2:26][C@@:25]3([CH3:29])[C@@H:18]([CH2:19][CH:20]=[C:21]3[C:22](=[O:24])[CH3:23])[C@@H:17]1[CH2:16][CH2:15][C:14]1[C@:9]2([CH3:31])[CH2:10][CH2:11][C:12](=[O:30])[CH:13]=1>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[F:7][C@:8]12[C:27](=[O:28])[CH2:26][C@@:25]3([CH3:29])[C@@H:18]([CH2:19][CH:20]=[C:21]3[C:22](=[O:24])[CH3:23])[C@@H:17]1[CH2:16][CH2:15][C:14]1[C@:9]2([CH3:31])[CH2:10][CH2:11][C:12](=[O:30])[CH:13]=1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8.5 ml of dry pyridine in 220 ml of dry dichloromethane is added 5.1 g of chromium trioxide in small portions. When all the solid has dissolved, 25 g of dry Celite is added followed (with stirring) by a solution of 3.0 g of 9-fluoro-11β-hydroxypregna-4,16-diene-3,20-dione. The mixture is then stirred at room temperature for 30 minutes, filtered and the solids are washed with a small amount of dichloromethane. The filtrate and the washings are combined, washed with 5% hydrochloric acid, a dilute sodium bicarbonate solution and water, dried and evaporated to afford the product as a solid. One crystallization from acetone-hexane gives 2.65 g of the title compound, melting point 208°-211°C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]#[C:8][C:9]([OH:11])=O.ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][C:32]([C:38]#[N:39])=[C:31]2[NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Br:47])[CH:42]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:47][C:43]1[CH:42]=[C:41]([NH:40][C:31]2[C:30]3[C:35](=[CH:36][CH:37]=[C:28]([NH:27][C:9](=[O:11])[C:8]#[C:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:29]=3)[N:34]=[CH:33][C:32]=2[C:38]#[N:39])[CH:46]=[CH:45][CH:44]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: COCCOCC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCCOCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.5 %

Procedure:
To a solution of 0.56 g (3.54 mmol) of 4-(2-methoxy-ethoxy)-but-2-ynoic acid and 0.46 g (3.4 mmol) of isobutyl chloroformate in 12 ml of tetrahydrofuran was added at 0° C. with stirring 0.36 g (3.54 mmol) of N-methylmorpholine. After 15 min, 1.0 g (2.95 mmol) of 6-amino-4-[(3-bromophenyl)amino]-quinoline-3-carbonitrile was added. After stirring 3 hr at 0° C. and 17 hr at room temperature, the mixture was poured into a saturated solution of sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic layer was dries over magnesium sulfate. The solvent was remove and the residue was purified by chromatography on silica gel eluting with chloroform-ethyl acetate mixtures to give 0.53 g of 4-(2-Methoxy-ethoxy)-but-2-ynoic acid[4-(3-bromo-phenylamino)-3-cyano-quinolin-6-yl]-amide as a yellow powder: mass spectrum (electrospray, m/e,): M+H 480.9.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH2:17][NH:18][C:19]5[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=5[C:21]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([S:34]([N:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[C:21]3[C:11]4[CH:10]=[N:9][NH:8][C:12]=4[N:13]=[CH:14][C:15]=3[CH2:16][CH2:17]2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CCNc2ccccc2-4)cc1
Product: O=S(=O)(c1ccccc1)N1CCc2cnc3[nH]ncc3c2-c2ccccc21

Procedure:
The compound 8-(phenylsulfonyl)-3,6,7,8-tetrahydropyrazolo[4′,3′:5,6]pyrido[3,4-d][1]benzazepine was prepared using 3-(4-methoxybenzyl)-3,6,7,8-tetrahydropyrazolo[4′,3′:5,6]pyrido[3,4-d][1]benzazepine and phenylsulfonyl chloride as described in the 2 step procedure K. The desired compound was obtained as an off-white solid (0.040 g, 18%); 1H NMR (CDCl3, 400 MHz) δ: 8.52 (s, 1H), 8.29 (m, 2H), 7.73 (m, 2H), 7.67-7.50 (m, 6H), 7.00 (dd, J1=1.2 Hz, J2=8.8 Hz, 2H), 6.51 (dd, J1=J2=8.0 Hz, 2H), 6.20 (dd, J1=J2=8.0 Hz, 1H), 4.20 (m, 1H), 3.65 (m, 1H), 2.70 (m, 2H); LCMS [M+H]: 377
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:19][C:20]([NH2:22])=[S:21].O>C(O)C>[NH2:22][C:20]1[S:21][CH:2]=[C:3]([C:4](=[N:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:19]=1
Reactant: CCOC(=O)C(=NOC1CCCCC1)C(=O)CCl
Reactant: NC(N)=S
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NOC1CCCCC1)c1csc(N)n1
Yield: 12 %

Procedure:
Ethyl 4-chloro-2-cyclohexyloxyimino-3-oxobutyrate (syn isomer, 27.8 g.), thiourea (7.7 g.), sodium acetate 3-hydrate (13.7 g.), water (70 ml.) and ethanol (140 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetate (syn isomer, 3.6 g.), mp. 125° to 126° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[S:15]([O-:18])(=[O:17])=[O:16].[Na+:19].[Cl-].[NH4+]>O>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:7]([S:15]([O-:18])(=[O:17])=[O:16])[CH:8]=1.[Na+:19]
Reactant: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: COCCOc1ccc(N)cc1S(=O)(=O)[O-]
Reaction time: 2 h

Procedure:
A mixture solution of 30 g of sodium 2-(2-methoxyethoxy) -5-nitrobenzenesulfonate, 30 g of reduced iron, 0.6 g of ammonium chloride and 60 ml of water was heated at 80° to 85° C. with stirring for 2 hours. After completion of the reaction, the insoluble materials were removed by filtration, 200 ml of isopropyl alcohol was added to the filtrate and the mixture was cooled with ice. The crystals thus precipirated were collected by filtration, washed with 50 m of isopropyl alcohol and air-dried. Yield: 23 g. Melting Point: over 250° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:3]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](B2OC(C)(C)C(C)(C)O2)=[N:24]1>O>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]4[C:26]=3[CH:25]=[N:24][NH:23]4)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=23)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COc1ccc(Nc2nc(Cl)nc3c2cnn3C)cc1OC
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Solvent: O
Product: COc1ccc(Nc2nc(-c3cccc4[nH]ncc34)nc3c2cnn3C)cc1OC

Procedure:
(6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(3,4-dimethoxy-phenyl)-amine was reacted with indazole boronic acid pinacol ester in General Procedure A. Addition of water gave a solid which was purified by preparative HPLC to give 132. NMR: (CDCl3): 3.81 (s, 3H, CH3), 3.89 (s, H, ArH), 4.07 (s, 3H, CH3), 6.88 (d, H, ArH, J=8.52 Hz), 7.00 (dd, H, ArH, J=2.41 Hz, 8.46 Hz), 7.15-7.18 (m, 2H, 2×ArH), 7.43-7.47 (m, H, ArH), 7.54-7.56 (m, H, ArH), 8.33 (d, H, ArH, J=7.26 Hz), 9.08 (s, H, ArH), 10.1 (sbr, H, NH). MS: (ESI+) MH+=402.14
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33].C[O-].[Na+:37]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O-:34])=[O:33].[Na+:37]
Reactant: O=C(NCCc1ccc(Cl)cc1Cl)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NCCc1ccc(Cl)cc1Cl)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-Chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)-chroman-4-carboxylic acid (4.50 g, 8.64 mmol) was dissolved in 25 mL of MeOH and cooled to 0° C. A 0.5 M solution of sodium methoxide in methanol (17.3 mL, 8.64 mmol) was then added and the cooling bath removed. After stirring at ambient temperature for 1 hour, the solution was concentrated to a residue. The residue was mixed with 50 mL of hexanes and stirred for 1 hour. The resulting precipitates were collected by filtration and dried under high vacuum to provide the title compound. The hexane treatment was repeated and the resulting white powder was dried under high vacuum at 65° C. to give sodium 6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylate (4.7 g, 100% yield). MS (apci) m/z=518 (M+2H—Na).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)[O:14][C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)=O.C(OCC)(=[O:25])C>ClCCl>[OH:25][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)c1ccc(O)cc1
Yield: 56 %

Procedure:
To prepare 22, a solution of 3 (Srinivasan et al., PLoS Biol. 10:e1001237 (2012), which is hereby incorporated by reference in its entirety) (181.5, 413 μmol) in dry tetrahydrofuran (0.5 mL) was added to a mixture of LiOH (8.9 mg, 371 μmol) and water (0.2 mL) in 1,4-dioxane (1 mL). After stirring at 67° C. for 40 minutes the solution was acidified with few drops of glacial acetic acid and concentrated in vacuo. Flash column chromatography on silica using a gradient of 10-40% ethyl acetate in hexanes afforded 20 (48.5 mg, 145 μmol, 35%) as a colorless oil. A solution of 20 (48.5 mg, 145 μmol) in dry dichloromethane (2 mL) was treated with Dess-Martin periodinane (88 mg, 208 μmol). After 5 hours the solution was diluted with 10 mL dichloromethane and washed three times with a solution of 5% Na2S2O3 in H2O. The organic layer was dried over Na2SO4 and concentrated in vacuo. Flash column chromatography on silica using a gradient of 0-30% ethyl acetate in hexanes afforded 21 (26.8 mg, 81 μmol, 56%) as a colorless oil. A solution of 21 (24.5 mg, 74 μmol) in 1:1 dichloromethane:methanol (0.7 mL) was treated with NaBH4 (12 mg, 317 μmol). After 10 minutes the solution was acidified with glacial acetic acid and diluted with dichloromethane and concentrated in vacuo. Flash column chromatography on silica using a gradient of 0-40% ethyl acetate in hexanes afforded (2S,3R,5S,6R)-6-((R)-hex-5-en-2-yloxy)-5-hydroxy-2-methyltetrahydro-2H-pyran-3-yl benzoate (22) (18.2 mg, 54 μmol, 74%) as a colorless oil. 1H NMR (600 MHz, acetone-d6): δ (ppm) 8.04-8.01 (m, 2H), 7.67-7.63 (m, 1H), 7.55-7.50 (m, 2H), 5.89 (ddt, J=17.1 Hz, J=10.3 Hz, J=6.6 Hz, 1H), 5.09-5.04 (m, 1H), 4.99-4.95 (m, 1H), 4.84 (d, J=3.7, 1H), 4.69 (ddd, J=11.4 Hz, J=9.8 Hz, J=4.6 Hz, 1H), 4.04-3.98 (m, 1H), 3.89-3.82 (m, 1H), 3.78-3.71 (m, 1H), 2.29-2.16 (m, 3H), 1.93-1.86 (m, 1H), 1.79-1.72 (m, 1H), 1.65-1.58 (m, 1H), 1.19 (d, J=6.1 Hz, 3H), 1.16 (d, J=6.3 Hz, 3H). 13C NMR (151 MHz, acetone-d6): δ (ppm) 165.9, 139.6, 134.1, 131.1, 130.2, 129.5, 114.9, 96.4, 73.7, 72.9, 67.8, 66.8, 37.3, 34.3, 30.7, 19.5, 17.9. See FIGS. 94A-B.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9]C)=O.[NH2:11][C:12](N)=[O:13]>>[S:5]1[C:6]2[C:7](=[O:9])[NH:11][C:12](=[O:13])[NH:1][C:2]=2[N:3]=[CH:4]1
Reactant: COC(=O)c1scnc1N
Reactant: NC(N)=O
Product: O=c1[nH]c(=O)c2scnc2[nH]1
Temperature: 190 °C

Procedure:
A mixture of methyl 4-aminothiazole-5-carboxylate 40 (WO 2006/096338; WO 2005/049613) and urea is heated at 190° C. for 2 hours. The hot reaction mixture is poured onto sodium hydroxide solution and any insoluble material is removed by filtration. The mixture is acidified (HCl, 2N) to yield thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione 41 (Baker et al (1970) Jour. of the Chem. Soc. 18:2478-84; U.S. Pat. No. 3,277,093; Childress and McKee (1951) J. Am. Chem. Soc. 73:3862-64; Erlenmeyer and Furger (1943) Helv. Chem. Acta 26:366-68) as a white precipitate, which was collected by filtration and air dried.
Reaction SMILES: C([N:8]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]1[CH:10]=[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])[CH2:20][CH2:19]2)[CH:12]=[CH:13][C:14]=1[N:15]([CH3:17])[CH3:16])C1C=CC=CC=1>C(O)C.[Pd]>[CH3:16][N:15]([CH3:17])[C:14]1[CH:13]=[CH:12][C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])[CH2:20][CH2:19]2)=[CH:10][C:9]=1[NH:8][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN(C)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1N(Cc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirred solution of (4-(3-(benzyl(phenyl)amino)-4-(dimethylamino)phenyl)piperazin-1-yl)(phenyl)methanone (0.49 g, 1 mmol) in ethanol (10 ml), 10% Pd—C was added under argon. The resulting mixture was stirred under H2 atmosphere at room temperature for 10 h. After completion of reaction (by TLC) it was filtered through celite, evaporated under vacuum to get the crude product. Flash chromatography gave (4-(4-(dimethylamino)-3-(phenylamino)phenyl)piperazin-1-yl)(phenyl)methanone which was isolated finally as trihydrochloride salt (0.39 g), 86% yield. 1H NMR (500 MHz, DMSO): δ 3.26 (s, 6H), 3.4 (bs, 4H), 4.2 (bs, 2H), 4.4 (s, 2H), 7.15 (t, J=7, 7.5 Hz 2H), 7.26 (d, J=7.6 Hz 2H), 7.29 (s, 2H), 7.42 (t, J=7.5, 8 Hz, 2H), 7.51 (m, 7H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:10])=[O:9])=[CH:5][CH:4]=1.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:12]([NH:11][S:8]([C:6]1[S:7][C:3]([CH2:2][NH:1][CH2:30][C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=2)=[CH:4][CH:5]=1)(=[O:9])=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCCCCCNS(=O)(=O)c1ccc(CN)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCCCCCCCCCNS(=O)(=O)c1ccc(CNCc2ccc(C(F)(F)F)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of 5-(aminomethyl)-N-dodecylthiophene-2-sulfonamide (797 mg, 2.21 mmol) and 4-trifluoromethyl-benzaldehyde (350 mg, 2.01 mmol) in DCE (50 mL) was added at once NaBH(OAc)3 (596 mg, 2.81 mmol) and the resulting mixture was stirred overnight at rt. 30 mL of a saturated aqueous solution of NaHCO3 were added to the reaction mixture, the aqueous layer was separated and washed with DCM (3×200 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford a yellowish oil. This crude product was purified by column chromatography over silica gel (AcOEt/c-Hex 1/4 to 1/2 in about 1 h) to give the title compound as a colorless oil (675 mg, 64%). 1H NMR (CDCl3, 300 MHz) δ 7.60 (m, 2H), 7.46 (m, 2H), 7.37 (d, 0.7H, J=8.0 Hz), 6.88 (d, 1H, J=3.8 Hz), 4.00 (s, 2H), 3.90 (s, 2H), 3.02 (m, 2H), 1.85-1.55 (m, 2H), 1.5 (m, 2H), 1.22 (s, 18H), 0.87 (t, 3H, 6.6 Hz). M−(LC/MS (ESI)): 517.2; M+(LC/MS (ESI)): 519.2 HPLC (Condition A), Rt: 5.27 min (HPLC purity: 97.2%).