Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13]2>C(N(CC)CC)C.C1(C)C=CC=CC=1>[O:21]=[C:11]1[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:9][C:8]([CH2:7][O:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])=[C:17]2[N:12]1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][S:18][C:16]=12
Reactant: CCN=C=O
Reactant: O=c1c(-c2ccccc2)cc(CO)c2n1CCc1ccsc1-2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCNC(=O)OCc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Reaction time: 2 h

Procedure:
A few drops of triethylamine and three 0.24 ml portions of ethyl isocyanate were added to a suspension of 1.02 g of 4,5-dihydro-10-(hydroxymethyl)-8-phenyl-7H-thieno[2,3-a]quinolizin-7-one in 11.5 ml of toluene, whereby the mixture was stirred at 85° for about 2 hours between each of the addtions. After the reaction was finished, the mixture is evaporated in vacuo. By recrystallization of the residue from ethanol, there was obtained pure (4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizin-10-yl)methyl-ethylcarbamate of m.p. 136°-137°.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15]2[N:16]=[C:17](I)[C:18]3[C:23]([CH3:25])([CH3:24])[C:22](=[O:26])[NH:21][C:19]=3[N:20]=2)=[N:6]1>CN(C=O)C.[Pd]>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15]2[N:16]=[CH:17][C:18]3[C:23]([CH3:25])([CH3:24])[C:22](=[O:26])[NH:21][C:19]=3[N:20]=2)=[N:6]1
Reactant: Cc1ncc2c(-c3nc(I)c4c(n3)NC(=O)C4(C)C)nn(Cc3cccc(F)c3F)c2n1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1ncc2c(-c3ncc4c(n3)NC(=O)C4(C)C)nn(Cc3cccc(F)c3F)c2n1
Yield: 28.5 %

Procedure:
44 mg (0.05 mmol) of 2-[1-(2,3-difluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one were dissolved in 8 ml of absolute DMF, 11 mg (0.01 mmol) of 10% palladium on charcoal were added and hydrogenation was effected under standard hydrogen pressure for 4 h. The reaction mixture was filtered and purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 20:80→100:0). 6 mg of the target compound were obtained (purity 81%; 21% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH3:34])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][CH:20]([CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[C:13]3=[CH:12][C:11]=2[CH:10]=1)[CH3:2].[Li+].[OH-].CCOC(C)=O.Cl>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH3:34])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:13]3=[CH:12][C:11]=2[CH:10]=1)[CH3:2]
Reactant: CCOc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1OCC
Temperature: 70 °C
Yield: 86.3 %

Procedure:
tert-Butyl 2-(7-(3,4-diethoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (173.1 mg) was taken up in dioxane (4 mL) and 1.0 M aqueous LiOH (1.11 mL) was added. The reaction was stirred at 70° C. 16 h, and stirred at 80° C. for an additional 5 h. The mixture was cooled to room temperature and poured into a separatory funnel containing EtOAc and 1.0 M HCl. The water layer was removed and the EtOAc layer was washed with water. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give title compound (131.4 mg). LCMS m/z=410.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.28-1.34 (m, 6H), 2.15-2.26 (m, 1H), 2.54 (dd, J=16.3, 7.9 Hz, 1H), 2.68 (dd, J=16.3, 6.7 Hz, 1H), 2.72-2.82 (m, 1H), 3.53-3.62 (m, 1H), 3.91-4.93 (m, 6H), 4.95 (s, 2H), 6.0 (s, 1H), 6.73 (dd, J=8.7, 2.4 Hz, 1H), 6.90-6.96 (m, 2H), 7.02-7.06 (m, 2H), 7.17 (d, J=9.0 Hz, 1H), 12.3 (bs, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11](NC)=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:34]([O:35][CH3:36])=[CH:33][C:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][OH:32])[CH2:28][CH2:29][C:23]=2[CH:22]=1.C(N)(=O)C1C=CC=CC=1.[CH3:46][O:47][CH2:48][CH2:49][OH:50]>>[CH3:46][O:47][CH2:48][CH2:49][O:50][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[NH:8][C:6]1[C:5]([Cl:19])=[CH:4][N:3]=[C:2]([NH:20][C:21]2[C:34]([O:35][CH3:36])=[CH:33][C:24]3[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][OH:32])[CH2:28][CH2:29][C:23]=3[CH:22]=2)[N:7]=1
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCO
Agent: NC(=O)c1ccccc1
Product: COCCOC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CCO)CC3)ncc1Cl

Procedure:
In an analogous manner to Example 1534, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol. The 2-methoxyethanol solvent reacted with the benzamide resulting in the product (40 mg, 37%). mp: 125-131° C., MS (ESI+): 542 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 11.03 (s, 1H), 8.85 (d, J=8.6 Hz, 1H), 8.16 (s, 2H), 8.15 (s, 1H), 7.53 (t, J=8.1 Hz, 1H), 7.49 (s, 2H), 7.11 (t, J=7.2 Hz, 1H), 6.68 (s, 1H), 4.55 (t, J=8.6 Hz, 2H), 3.90 (s, 3H), 3.79 (m, 2H), 3.66 (m, 2H), 3.46 (s, 3H), 2.91 (m, 2H), 2.83 (m, 2H), 2.69 (m, 6H).
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:21]=[N:22][N:23]([CH3:25])[CH:24]=4)=[CH:16][CH:15]=3)=[C:8]([CH3:12])[C:9]=2[CH3:11])[C:4](=[O:26])[N:3]1[CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][O:29]1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:11][C:9]1[C:8]([CH3:12])=[C:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:18][CH:19]=2)[CH:6]=[C:5]2[C:10]=1[CH2:2][N:3]([CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][O:29]1)[C:4]2=[O:26]
Reactant: Cc1c(Cc2ccc(-c3cn(C)nn3)cc2)cc2c(c1C)C(O)N(C[C@@H]1CCCO1)C2=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cc2ccc(-c3cn(C)nn3)cc2)cc2c(c1C)CN(C[C@@H]1CCCO1)C2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.5 %

Procedure:
To a solution of 3-hydroxy-4,5-dimethyl-6-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2-(((2S)-tetrahydrofuran-2-yl)methyl)isoindolin-1-one (0.11 g) in trifluoroacetic acid (1.50 mL) was added triethylsilane (0.08 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.08 g).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:19](Cl)(=[O:23])/[CH:20]=[CH:21]/[CH3:22]>C1COCC1.CCOCC>[C:19]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])(=[O:23])/[CH:20]=[CH:21]/[CH3:22]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: C/C=C/C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C/C=C/C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 109.2 %

Procedure:
A solution of (4S)-4-benzyl-2-oxazolidinone (1.0 g, 5.6 mmol) in anhydrous THF (20 ml) was cooled to −78° C. n-BuLi (1.6 M solution in hexanes, 3.5 ml, 5.6 mmol) was added dropwise to the cooled solution. After 30 minutes, crotonyl chloride (0.59 ml, 6.2 mmol) was added to the mixture. The reaction was stirred for 30 minutes at −78° C., then warmed slowly to room temperature. The reaction mixture was quenched by addition of 4 ml saturated aqueous ammonium chloride. The resultant reaction mixture was diluted with ether, and washed with water and brine. The organic layer was dried using anhydrous Na2SO4 and evaporated under reduced pressure. Flash chromatography on a silica gel column using ethyl acetate/hexane (1/3) as eluent provided compound 1, i.e., (4S)-3-((E)-2-butenoyl)-4-benzyl-2-oxazolidinone, (1.50 g, 87%) as a white solid. m.p.: 83° C. IR (KBr): 3027, 2922, 2539, 1772, 1682, 1351, 1209 cm−1. 1H NMR (400 MHz, CDCl3): 7.36-7.15 (m, 7H, aromatic H's, CH═CH); 4.75-4.70 (m, 1H, CHN); 4.23-4.15 (m, 2H, CH2O); 3.33 (dd, 1H, J=3.3, 13.4 Hz, CHHPh); 2.79 (dd, 1H, J=9.5, 13.4 Hz, CHHPh); 1.98 (dd, 3H, J=1.0, 6.2 Hz, CH3). 13C NMR (100 MHz, CDCl3): δ 164.69, 153.51, 146.95, 135.28, 129.37, 128.86, 127.23, 121.74, 66.01, 55.20, 37.79, 18.50.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([N+:13]([O-])=O)[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[H][H]>CO.[Pt]>[NH2:13][C:4]1[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[CH3:16]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: COc1c(C(C)=O)cc(Cl)c(C)c1N

Procedure:
1-(5-Chloro-2-methoxy-4-methyl-3-nitrophenyl)ethanone (5.0 g, 20 mmol) was hydrogenated in 100 mL of methanol in the presence of 0.5 g of 10% Pt/C, under a balloon pressure of hydrogen overnight. The catalyst was filtered off and the filtrate was concentrated. The residue was dissolved in dichloromethane and dried over sodium sulfate and then evaporated to dryness. The crude product was used directly in next step (4.4 g, 100%). LCMS calculated for C10H13ClNO2 (M+H)+: m/z=214.1. found: 214.1.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrBr.C(Cl)(Cl)[Cl:14]>>[Cl:14][C:6]1[C:1]2[N:7]=[C:8]([NH2:10])[S:9][C:2]=2[CH:3]=[CH:4][CH:5]=1
Reactant: ClC(Cl)Cl
Reactant: NC(=S)Nc1ccccc1
Agent: BrBr
Product: Nc1nc2c(Cl)cccc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The phenylthiourea (6.00 g, 32.16 mmol) was dissolved in CHCl3 (150 mL) and cooled to 0° C. with an ice bath. To this mixture was added a solution of Br2 (1.6 mL, 32.2 mmol) in CHCl3 (100 mL) dropwise over 30 min. After the addition, the mixture was stirred at 0° C. for 1 h, then allowed to warm to rt. the reaction was refluxed for 3 h to 4 h than allowed to cool to room temperature. The organic solvent was removed and the residue was washed with sulfurous acid. The residue was then neutralized with liquid ammonia. The solid was filtered off, washed with watyer and recrystallized from EtOH.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[NH4+].[NH4+].S(O)(O)(=O)=[O:9].C1(N)CCCCC1.C1(N)CCCCC1.S(O)(O)(=O)=[O:28].[CH:32]1([NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[CH:45]1([NH:51][CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH:39]1([N:38]([CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[OH:28])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1.[CH:52]1([N:51]([CH:45]2[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]2)[OH:9])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]1
Reactant: O=S(=O)([O-])[O-]
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: NC1CCCCC1
Product: ON(C1CCCCC1)C1CCCCC1

Procedure:
It can be seen from the NMR spectrum which is then measured that DCHAS has been formed. Traces of oxime, ammonium sulfate, CHAS, cyclohexylamine hemisulfate and dicyclohexylamine hemisulfate can be discerned as impurities in the NMR spectrum.
Reaction SMILES: C(OC[CH:10]([OH:23])[CH:11]([CH2:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1)[C:12]([O:14][CH2:15]C)=[O:13])C1C=CC=CC=1.[ClH:24]>C(O)C.[Pd]>[ClH:24].[OH:23][CH:10]1[CH2:15][O:14][C:12](=[O:13])[CH:11]1[CH2:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1
Reactant: CCOC(=O)C(Cc1c[nH]cn1)C(O)COCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C1OCC(O)C1Cc1c[nH]cn1

Procedure:
93.9 g (0.295 mole) of ethyl 4-benzyloxy-3-hydroxy-2-[(1H-imidazol-4-yl)methyl]-butanoate dissolved in 500 ml of absolute ethanol and 65 ml of a 6.8N ethanolic solution of hydrochloric acid, are subjected to hydrogenolysis in the presence of 5 g of 10% palladium on carbon under a hydrogen pressure of 3.5 bars. The catalyst is then filtered off and the solvent is eliminated at 65° C. under reduced pressure. 67.1 g of 4-hydroxy-3-[(1H-imidazol-4-yl)methyl]-dihydro-2(3H)-furanone hydrochloride are obtained (mixture of diastereoisomers). Practically quantitative yield. The product obtained is used as such in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][OH:7].C(O[CH:14](OCC)[CH2:15][CH2:16][Cl:17])C>[Ti](Cl)(Cl)(Cl)Cl.[N+](C)([O-])=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:14]([CH2:15][CH2:16][Cl:17])[O:7][CH2:6][CH2:5]2
Reactant: CCOC(CCCl)OCC
Reactant: OCCc1cccc(Cl)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C[N+](=O)[O-]
Product: ClCCC1OCCc2cc(Cl)ccc21

Procedure:
A mixture of 3-chlorophenethyl alcohol (XLV, 5.9055 g, 0.0398 mol), 3-chloropropionaldehyde diethyl acetal (LXII, 7.2 ml, 0.0430 mol) and nitromethane (3 ml) is cooled in an ice/water bath. Titanium tetrachloride (1M in dichloromethane, 88 ml, 0.088 mol) is added dropwise and the mixture is heated at 45° for 3 hr. After cooling, the mixture is poured onto ice/aqueous hydrochloric acid (1N) and extracted with dichloromethane. The combined organic layers are backwashed with hydrochloric acid (1N) and filtered through a pad of Celite topped with sodium sulfate. The filtrate is concentrated and chromatographed twice on silica gel eluting with ethyl acetate/hexane (5/95). The appropriate fractions are pooled and concentrated to give 6-chloro-1-(2-chloroethyl)isochroman (LXIV), NMR (CDCl3) 2.23, 2.70, 2.93, 3.75, 4.09, 4.89, 7.01 and 7.16 δ.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[O:12][C:11](=[O:27])[CH:10]=1.C([Sn](CCCC)(CCCC)[C:34]([O:36][CH2:37][CH3:38])=[CH2:35])CCC>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.C1(C)C=CC=CC=1>[Cl:28][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:34]([O:36][CH2:37][CH3:38])=[CH2:35])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[O:12][C:11](=[O:27])[CH:10]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Br)cc(=O)oc2c1OC1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1cncc(Cl)c1Nc1cc(=O)oc2c(OC3CCCC3)c(OC)ccc12
Temperature: 80 °C

Procedure:
A mixture of 4-(3-bromo-5-chloropyridin-4-ylamino)-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (0.206 g, 0.441 mmol, Example 11), PdCl2(PPh3)2 (31 mg, 0.044 mmol), tributyl(1-ethoxyvinyl)tin (0.20 mL, 0.57 mmol), and toluene (5 mL) was heated at 80° C. under N2 for 4 h. After allowing to cool to rt, the mixture was filtered through Celite and washed with EtOAc. The filtrate was washed with aqueous KF, dried, filtered, concentrated, and purified by silica gel chromatography (0→50% EtOAc/hexanes) to give 4-(3-chloro-5-(1-ethoxyvinyl)pyridin-4-ylamino)-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 8.80 (s, 1H), 8.65 (s, 1H), 7.94 (d, 1H), 7.16 (d, 1H), 4.83 (m, 1H), 4.53 (m, 2H), 4.41 (d, 1H), 3.90 (s, 3H), 3.61 (m, 2H), 1.85-1.52 (m, 8H), 0.89 (t, 3H); MS (ESI): 457.1.
Reaction SMILES: [C:1]1([CH:7]=[N+:8]=[N-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:25])[C:18]#[C:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:13]([N+:26]([O-:28])=[O:27])[CH:12]=1>C1COCC1>[C:1]1([C:7]2[C:18]([CH:17]([C:14]3[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][C:13]=3[N+:26]([O-:28])=[O:27])[OH:25])=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C#CC(O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: [N-]=[N+]=Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]nc(-c2ccccc2)c1C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.1 %

Procedure:
A solution of freshly generated phenyldiazomethane (2.44 g, 20.7 mmol) in 10 mL of anhydrous THF was added to ethyl 4-(4-chloro-2-nitrophenyl)-4-hydroxy-2-butynoate (5.86 g, 20.7 mmol) in 10 mL THF and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with excess ethereal acetic acid and concentrated via rotary evaporation to an oil (12.24 g) which solidified on cooling. This was filtered to yield the title compound as a pale yellow solid (2.42 g). The filtrate was concentrated via rotary evaporation to an oil which was triturated with hexane:ethyl acetate (4:1) to yield an additional 1.52 g of the title compound (48% combined yield).
Reaction SMILES: B.[CH3:2][N:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C@@H:13]4[CH2:18][N:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16][CH2:15][C@@H:14]4[N:6]([C:7]=23)[CH2:5][C:4]1=O.Cl>O1CCCC1>[CH3:2][N:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C@@H:13]4[CH2:18][N:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16][CH2:15][C@@H:14]4[N:6]([C:7]=23)[CH2:5][CH2:4]1
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3C
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCN3C
Yield: 92.9 %

Procedure:
A solution of borane in tetrahydrofuran (1M, 33 mL, 33 mmol) was added dropwise to a stirred solution of ethyl (6bR, 10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (5.24 g, 16.6 mmol) in anhydrous tetrahydrofuran (25 mL) under nitrogen. After the addition was complete, the mixture was stirred and heated at reflux for 1 h, cooled and treated with 6N hydrochloric acid (15 mL). It was then heated under reflux for 30 min, cooled and evaporated to dryness under reduced pressure. The residue was dissolved in a minimum quantity of water and the solution basified with 1N sodium hydroxide and extracted with dichloromethane (2×). The extract was washed with water, dried over magnesium sulfate, and concentrated to yield 4.65 g (93%) of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate as a viscous liquid. 1H NMR (CDCl3, 300 MHz) δ 1.28 (t, J=7 Hz, 3H), 1.68-1.78 (m, 1H), 1.78-1.93 (m, 2H), 2.81-2.90 (m, 2H), 2.86 (s, 3H), 3.05-3.26 (m, 2H), 3.26-3.38 (m, 2H), 3.56-3.75 (m, 2H), 3.79-3.87 (m, 1H), 4.16 (q, J=7 Hz, 2H), 6.41 (d, J=8.1 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 6.67 (t, J=8.1 Hz, 1H) ppm. MS (CI): 302 (M+H+).
Reaction SMILES: [N:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[CH:3][C:2]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[CH:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=O.C1([SiH3])C=CC=CC=1>C1COCC1.C([Sn](Cl)(Cl)CCCC)CCC>[N:1]1[C:6]([NH:7][CH2:14][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)=[CH:5][CH:4]=[CH:3][C:2]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Nc1cccc(-c2cccnc2)n1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNc2cccc(-c3cccnc3)n2)cc1
Reaction time: 108 h
Yield: 98.3 %

Procedure:
To a stirred suspension of a mixture of 11 (3.00 g, 17.52 mmol), methyl 4-formylbenzoate (4.62 g, 28.11 mmol, 1.5-2.0 equiv.) and dibutyl tin dichloride 160 mg, 0.53 mmol) in anhydrous THF (15 mL) at room temperature was added phenylsilane (2.34 mL, 19.28 mmol) in three portions over two days. After stirring for 2 to 7 days the reaction mixture was filtered, filtrate was concentrated and purified by flash chromatography on silica gel (MeOH/CH2Cl2, 2/98→10/90) to afford the title compound 12 (5.50 g, 17.22 mmol, 98% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.11 (dd, J=2.3, 0.7 Hz, 1H), 8.55 (dd, J=4.7, 1.8 Hz, 1H), 8.29-8.24 (m, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.57-7.40 (m, 5H), 7.18 (d, J=7.2 Hz, 1H), 6.59 (d, J=8.2 Hz 1H), 4.69 (d, J=6.1 Hz, 2H), 3.85 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[C:9]=2[CH2:27][CH3:28])=[CH:4][CH:3]=1.BrC1C=CC(C2N([C:41]3C=C[C:44]([S:47](N)(=O)=O)=[N:45][CH:46]=3)N=C(C(F)(F)F)C=2Cl)=CC=1>>[CH2:27]([C:9]1[C:10]([C:23]([F:26])([F:25])[F:24])=[N:11][N:12]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:46]2[N:45]=[CH:44][S:47][CH:41]=2)=[CH:3][CH:4]=1)[CH3:28]
Reactant: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(Br)cc1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Br)cc2)cn1
Product: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(-c2cscn2)cc1

Procedure:
The title compound was prepared according to the procedure of step 3 in the Example 4 using 5-[5-(4-bromophenyl)-4-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide, instead of 5-[5-(4-bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[C:12]([F:25])[CH:11]=2)C=CC=CC=1.C(N(CC)CC)C.[CH2:34]([CH2:36][NH2:37])[OH:35]>CN(C=O)C>[F:25][C:12]1[CH:11]=[C:10]([NH:9][C:8]([NH:37][CH2:36][CH2:34][OH:35])=[O:26])[CH:15]=[CH:14][C:13]=1[B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:23])([CH3:24])[O:17]1
Reactant: NCCO
Reactant: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2F)OC1(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2F)OC1(C)C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of phenyl(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (intermediate 12) (1.0 g, 2.8 mmol) in DMF (2 mL) was added triethylamine (1.3 mL, 9.0 mmol) followed by ethanolamine (0.84 mL, 14.0 mmol) and stirred at 50° C. for 2 hours. The reaction mixture was concentrated in-vacuo to afford a white solid (1.84 g, quantitative).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]4[CH2:32][O:31]C5(CCCCC5)[O:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[N:4]1)[CH3:2].O.Cl>CCO>[CH2:1]([N:3]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]([OH:29])[CH2:32][OH:31])[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)CO)ns1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (S)-N-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (1.24 g, 2.31 mmol) in EtOH (25 ml) and H2O (1.09 ml, 2.31 mmol) was added concentrate HCl (0.480 ml, 5.77 mmol) and the reaction was heated at reflux for 8 hours. The reaction was allowed to cool to ambient temperature and stirred overnight. The mixture was concentrated to a residue that was dissolved in EtOAc and saturated aqueous NaHCO3. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (3% MeOH/CH2Cl2) to afford (S)-1-(5-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol as cream solids. The solids were dissolved in CH2Cl2 (25 ml) and 1N HCl in Et2O (20 ml) was added. The mixture was concentrated to dryness and dried in the vacuum oven to afford (S)-1-(5-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol hydrochloride (0.569 g, 49.9% yield) as an off-white solid. Mass spectrum (apci) m/z=458.1 (M+H—HCl).