Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@:3]12[CH2:28][C:27](=[O:29])[CH2:26][CH2:25][C@:24]1([CH3:30])[C:23]1[CH2:22][CH2:21][C@@:20]3([CH3:31])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@H:11]([CH3:19])[CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=1[CH2:5][CH2:4]2)#[N:2].[BH4-].[Na+]>>[C:1]([C@:3]12[CH2:28][C@@H:27]([OH:29])[CH2:26][CH2:25][C@:24]1([CH3:30])[C:23]1[CH2:22][CH2:21][C@@:20]3([CH3:31])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@H:11]([CH3:19])[CH2:12][CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:6]=1[CH2:5][CH2:4]2)#[N:2].[C:1]([C@:3]12[CH2:28][C@H:27]([OH:29])[CH2:26][CH2:25][C@:24]1([CH3:30])[C:23]1[CH2:22][CH2:21][C@@:20]3([CH3:31])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@H:11]([CH3:19])[CH2:12][CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:6]=1[CH2:5][CH2:4]2)#[N:2]
Reactant: C[C@H](CC1CCCCC1)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C[C@]1(C#N)CC3
Agent: [BH4-]
Agent: [Na+]
Product: C[C@H](CC1CCCCC1)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@@H](O)C[C@]1(C#N)CC3
Product: C[C@H](CC1CCCCC1)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@]1(C#N)CC3

Procedure:
90 mg (20R)-5-cyano-21-cyclohexyl-20-methyl-5α-pregn-8-en-3-one were treated with 33 mg sodium borohydride as described in example 58b. After column chromatography, 15 mg (20R)-5-cyano-21-cyclohexyl-20-methyl-5α-pregn-8-en-3β-ol and 25 mg (20R)-5-cyano-21-cyclohexyl-20-methyl-5α-pregn-8-en-3α-ol were isolated.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=O.P(Cl)(Cl)(Cl)=O>>[CH:4]1[N:3]=[CH:1][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: O=CNCc1ccccn1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccn2cncc2c1
Temperature: 25 °C

Procedure:
To 13.6 g. of 2-formamidomethylpyridine in a round-bottom flask is added 25 ml. of phosphorous oxychloride. Following the exothermic reaction, the reaction mixture is cooled to room temperature, and quenched on crushed ice. The aqueous mixture is treated with sufficient 20% aqueous sodium hydroxide solution to provide a pH of 9-10, and the liberated product extracted into chloroform (3×300 ml.). The extracts are combined, dried over sodium sulfate and concentrated to give imidazo[1,5-a]pyridine as a light brown oil, 14.0 g.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([CH2:27][C:28]([NH2:30])=[O:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].OC(C(F)(F)F)=O.N1CC(C2C=CC3C4N=C(C5N(C(C)C)N=CN=5)SC=4[CH2:51][CH2:52][O:53][C:44]=3[CH:43]=2)C1.ClCC(N1CCOCC1)=O>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:24][N:25]([CH2:27][C:28]([N:30]6[CH2:43][CH2:44][O:53][CH2:52][CH2:51]6)=[O:29])[CH2:26]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Agent: O=C(CCl)N1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(=O)N4CCOCC4)C3)ccc1-2

Procedure:
Following the procedure of 319, a suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) and 4-(2-chloroacetyl)morpholine gave 471 isolated as a yellow solid (79 mg, 22%). LCMS: RT=3.17 min, [M+H]+=495. 1H NMR δ (ppm) (DMSO-d6): 8.25 (1 H, d, J=8.17 Hz), 8.05 (1 H, s), 7.17 (1 H, dd, J=8.24, 1.82 Hz), 7.03 (1 H, d, J=1.77 Hz), 5.82-5.73 (1 H, m), 4.35-4.29 (2 H, m), 3.67-3.56 (2 H, m), 3.58-3.45 (5 H, m), 3.44-3.34 (6 H, m), 3.31 (2 H, s), 3.16 (2 H, t, J=6.11 Hz), 1.50 (6 H, d, J=6.59 Hz)
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)O.C(N(CC)CC)C>C1COCC1>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[Cl:27])[C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1)=[O:11])[CH2:3]2
Reactant: OC(c1ccc(Cl)cc1)c1ccccc1Cl
Reactant: O=C(O)C1CN2CCC1CC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: C1CCOC1
Product: O=C(OC(c1ccc(Cl)cc1)c1ccccc1Cl)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (0.1 g, 0.52 mmol), EDC (150 mg, 0.78 mmol), and HOBT (120 mg, 0.78 mmol) were dissolved in dry THF (3 ml). (2-Chlorophenyl)(4-chlorophenyl)methanol (145 mg, 0.57 mmol) was dissolved in dry THF (2 ml) and then added to the reaction mixture. Triethylamine (253 μl, 1.83 mmol) was added, and the resulting reaction was stirred at room temperature overnight. The mixture was evaporated, and the crude was taken up with EtOAc and washed with water and brine. The organic phase was separated, dried (sodium sulfate), filtered, and evaporated under vacuum. The crude was purified by flash chromatography (DCM/MeOH=95/5) to afford (2-chlorophenyl)(4-chlorophenyl)methyl quinuclidine-3-carboxylate (40 mg, mixture of diastereoisomers). The compound was used as such in the next step.
Reaction SMILES: [C:1]12([CH:11]([OH:13])C)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)C1)[CH2:8]2.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N([CH2:30][CH3:31])CC)C>ClCCl.Cl>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:13][CH2:11][CH2:1][CH:10]2[CH:5]3[CH2:6][CH:7]4[CH2:9][CH:3]([CH2:30][CH:31]2[CH2:8]4)[CH2:4]3)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCN(CC)CC
Reactant: CC(O)C12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: ClCCl
Product: O=S(=O)(OCCC1C2CC3CC(C2)CC1C3)c1ccc(Br)cc1
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of 1-adamantylethanol (5.8 g, 32 mmol) in triethylamine (6.7 ml) and dichloromethane (50 ml) was added 4-bromobenzenesulphonyl chloride (8.9 g, 35 mmol) at room temperature. The solution was stirred for 16 h, diluted with aqueous hydrochloric acid (2M, 100 ml) and extracted with dichloromethane (100 ml). The extract was washed with saturated aqueous sodium hydrogen carbonate solution (100 ml) and brine (100 ml), dried (MgSO4), and concentrated in vacuo to give the title compound as a white crystalline solid (11.2 g, 88%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:23]([NH:25][CH:26]([C:35](=[O:38])[CH2:36]Br)[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16].[F-].[K+].[F:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([F:50])[C:43]=1[OH:51].CCCCCC.CCOC(C)=O>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:23]([NH:25][CH:26]([C:35](=[O:38])[CH2:36][O:51][C:43]1[C:44]([F:50])=[C:45]([F:49])[CH:46]=[C:47]([F:48])[C:42]=1[F:41])[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16]
Reactant: Oc1c(F)c(F)cc(F)c1F
Reactant: CC(C)Cc1c(C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CBr)n(C)c2ccccc12
Agent: [F-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Cc1c(C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc2c(F)c(F)cc(F)c2F)n(C)c2ccccc12
Yield: 72.4 %

Procedure:
The titled product (47.6 mg, 72%, white solid) was prepared as described in Example 82 using the product of Example 88 (57.6 mg, 0.097 mmol), potassium fluoride (18.5 mg, 0.24 mmol), and 2,3,5,6-tetrafluorophenol (21.1 mg, 0.097 mmol) in DMF (2.0 ml). TLC (hexane/EtOAc, 50/50): Rf=0.55.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[CH:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][CH:16]=1.[N+](C1C=C([N+]([O-])=O)C=CC=1C(O)=O)([O-])=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[CH2:1]([O:8][CH2:9][C@@H:10]([C:19]1[C:18]2[C:22](=[CH:23][C:15]([Cl:14])=[CH:16][CH:17]=2)[NH:21][CH:20]=1)[CH2:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: O=CC=CCOCc1ccccc1
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: ClCCl
Product: O=CC[C@@H](COCc1ccccc1)c1c[nH]c2cc(Cl)ccc12
Yield: 75.7 %

Procedure:
Prepared according to the general procedure from 4-benzyloxy-but-2-enal (143 mg, 0.750 mmol), 6-chloro-1H-indole (75.8, 0.500 mmol), 2,4-dinitrobenzoic acid (21.2 mg, 0.100 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.90 mL) and isopropanol (0.10 mL) at −60° C. for 12.75 h to provide, after silica gel chromatography (CH2Cl2), the title compound as a colorless oil (124 mg, 73% yield, 97% ee) after silica gel chromatography in CH2Cl2. IR (film) 3383, 2953, 2930, 2834, 2734, 1718, 1623, 1603, 1548, 1453, 1403, 1378, 1273, 1184, 1104, 1069, 1019, 909, 804, 774, 714 cm−1; 1HNMR (300 MHz, CDCl3) δ 9.77 (dd, J=1.8, 1.8 Hz, 1H, CHO), 8.15 (s, 1H, NH), 8.02-7.99 (m, 2H, ArH), 7.65 (dd, J=0.6, 8.7 Hz, 1H, ArH), 7.58 (tt, J=1.5, 6.6 Hz, 1H, ArH), 7.48-7.42 (m, 2H, ArH), 7.37 (d, J=1.8 Hz, 1H NCH), 7.12 (dt, J=2.1, 8.7 Hz, 2H, ArH), 4.70 (dd, J=5.1, 10.8 Hz, 1H, CH2O), 4.42 (dd, J=8.4, 11.1 Hz, 1H, CH2O), 4.08 (m, 1H, ArCH), 3.06 (ddd, J=1.8, 6.3. 16.8 Hz, 1H, CH2CO); 2.95 (ddd, J=2.1, 7.8, 16.5 Hz, 1H, CH2CO); 13C NMR (75 MHz, CDCl3) δ 200.9, 166.5, 136.7, 135.4, 133.2, 129.9, 129.6, 128.5. 125.1, 122.3, 120.7, 119.8, 115.0, 111.4, 67.8, 46.5, 31.0; HRMS (CI) exact mass calcd for (C19H16ClNO3) requires m/z 341.0819, found m/z 341.0814.[α]D=−3.3 (c=1.0 CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AD and AD guard column (10:90 ethanol/hexanes, 1 mL/min); S isomer tr=38.8 min and R isomer tr=43.3 min.
Reaction SMILES: N[C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1.N([O-])=O.[Na+].C(OCC)(=O)C.O.[ClH:24]>O1CCCC1>[Cl:24][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1
Reactant: Cl
Reactant: COC(=O)c1nc(Cl)cnc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nc(Cl)cnc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a mixture of 14 mL of 12 mol/L hydrochloric acid and 14 mL of tetrahydrofuran was suspended 8.0 g of methyl 3-amino-6-chloro-2-pyrazinecarboxylate. After adding 5.9 g of sodium nitrite at 5-12° C., the mixture thus obtained was stirred at an ice-cooled temperature for 50 minutes. Then, 8.4 g of cuprous (I) chloride suspended in 6 mol/L hydrochloric acid was added and stirred at the same temperature as above for 10 minutes. The reaction mixture was poured into a mixture of 100 mL of ethyl acetate and 100 mL of water, and the organic layer was separated. The organic layer thus obtained was washed successively with 50 mL of water and 50 mL of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography [eluent: n-hexane:ethyl acetate=6:1] to obtain 6.0 g of methyl 3,6-dichloro-2-pyrazinecarboxylate as a colorless oily product.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]2[CH:11]=[C:12]([CH3:22])[N:13]=[C:14]([C:19]([OH:21])=O)[C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:30][NH:31][O:32][CH3:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[NH:1]([C:8]1[N:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]2[CH:11]=[C:12]([CH3:22])[N:13]=[C:14]([C:19]([N:31]([O:32][CH3:33])[CH3:30])=[O:21])[C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(c(C(=O)O)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CON(C)C(=O)c1nc(C)cc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridine-5-carboxylic acid (80 mg, 0.22 mmol), N,O-dimethylhydroxylamine hydrochloride (64 mg, 0.66 mmol), HOBT (89 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol) were dissolved in CH2Cl2 (9 mL). To this solution was added TEA (120 uL, 0.88 mmol). The reaction was stirred for 1 h and was diluted with CH2Cl2, washed with 0.5N HCl, saturated NaHCO3, and brine. The organic layer was collected, dried over Na2SO4, and concentrated in vacuo. The solid obtained was triturated with Et2O and dried to give 2-anilino-N-methoxy-N,7-dimethyl-4-oxo-1-phenyl-1,4-dihydro-1,6 naphthyridine-5-carboxamide as a light yellow solid (50 mg, 55%): LCMS RT: 2.08 min, MH+: 414.9. This transformation can also be accomplished by coupling the appropriate amine with the corresponding acid chloride.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:23]([O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29]Br)[CH3:24].C(N(CC)CC)C>C(#N)C>[CH2:23]([O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29][N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][C:13]([S:10](=[O:12])(=[O:11])[NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=3)=[CH:14][CH:15]=2)[CH2:20]1)[CH3:24]
Reactant: CCOC(=O)CCCBr
Reactant: O=S(=O)(Nc1cccc(Cl)c1)c1ccc2c(c1)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CCCN1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1
Yield: 16.9 %

Procedure:
A mixture of 7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.05 g, 8 mmol), ethyl-4-bromobutyrate (1.56 g), and triethylamine (0.81 g, 8 mmol) in acetonitrile (35 ml) was heated at 55°-60° for 4 hr. The mixture was filtered, the filtrate concentrated and chromatographed (silica gel, ether) to give ethyl-4-[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]butyrate (0.59 g, 17%) as an oil.
Reaction SMILES: CC(C)(C[N:6]1[C:10]2[N:11]=[C:12]([NH:15]C3C=CC(N4CCNCC4)=CN=3)[N:13]=[CH:14][C:9]=2[C:8]2[CH:28]=[CH:29]N=[CH:31][C:7]1=2)CO.[CH3:33][O:34][C:35]1[C:40](B(O)O)=[CH:39][CH:38]=[C:37]([O:44][CH3:45])[N:36]=1.C1(P(C2CCCCC2)C2C(OC)=CC=CC=2OC)CCCCC1>C(O)CCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:7]1([NH:6][C:10]2[C:9]([C:40]3[C:35]([O:34][CH3:33])=[N:36][C:37]([O:44][CH3:45])=[CH:38][CH:39]=3)=[CH:14][N:13]=[C:12]([NH2:15])[N:11]=2)[CH2:8][CH2:28][CH2:29][CH2:31]1
Reactant: CC(C)(CO)Cn1c2cnccc2c2cnc(Nc3ccc(N4CCNCC4)cn3)nc21
Reactant: COc1ccc(B(O)O)c(OC)n1
Agent: [Pd]
Agent: COc1cccc(OC)c1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Product: COc1ccc(-c2cnc(N)nc2NC2CCCC2)c(OC)n1
Temperature: 100 °C
Yield: 52.6 %

Procedure:
Compound 2 (2.00 g, 7.78 mmol), 2,6-dimethoxypyridin-3-ylboronic acid (2.13 g, 11.7 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.214 g, 0.233 mmol), and dicyclohexyl(2,6-dimethoxyphenyl)phosphine (0.156 g, 0.467 mmol), were dissolved in n-butanol (2.5 mL). The reaction was purged with argon and heated at 100° C. for 19 hours. The resulting solution was added to 80 mL water and extracted with ethyl acetate (2×150 mL). The combined organics were dried (MgSO4) and evaporated to give an orange oil. Silica gel chromatography (gradient elution dichloromethane+2.5% TEA/0-5% methanol) afforded compound 267 as an off-white solid (1.29 g, 53%).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=C[O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH:32]1([NH:38][CH3:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[CH2:40](Cl)Cl>>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:39]\[N:38]([CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[CH3:40])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: CNC1CCCCC1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N(C)C2CCCCC2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 27.2 mg (0.24 mmol) cyclohexyl-methyl-amine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 30 mg (46%) product as an orange powder. MS (ESI) m/z 544.25 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:4][N:5]([CH2:7]O)[CH:6]=1.S(Cl)([Cl:15])=O>ClCCl>[ClH:15].[Br:1][C:2]1[C:3]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:4][N:5]([CH2:7][Cl:15])[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1nn(CO)cc1Br
Solvent: ClCCl
Product: CC(C)(C)c1nn(CCl)cc1Br
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.79g of 4-bromo-3-t-butyl-1H-pyrazole-1-ylmethanol was dissolved to 45 ml of dichloromethane. 3.4 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure. The solid obtained was washed with hexane and chloroform to obtain 3.69 g of 4-bromo-3-t-butyl-1-(chloromethyl)-1H-pyrazole hydrochloride.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Li+].[O:7]1[C:9]([CH3:11])([CH3:10])[CH2:8]1.[Br:12][C:13]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].O>C(OCC)C>[Br:12][C:13]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][CH2:8][C:9]([CH3:11])([OH:7])[CH3:10]
Reactant: CC1(C)CO1
Reactant: Cc1cccc(N)c1Br
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: O
Product: Cc1cccc(NCC(C)(C)O)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of lithium perchlorate (2.13 g, 20 mmol) in diethyl ether (4 mL) was added 1,2-epoxy-2-methylpropane (0.195 mL, 2.2 mmol), followed by 2-bromo-3-methylaniline (0.250 mL, 2 mmol) under an atmosphere of nitrogen gas. The reaction mixture was stirred overnight at RT. Water was added dropwise, and the product was extracted from the reaction mixture with DCM. The organic phase was dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (10-40% hexanes/EtOAc). 1-(2-bromo-3-methylphenylamino)-2-methylpropan-2-ol was obtained as a clear colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH2:14])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26].O>O1CCCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:14][C:11]2[C:12]3[CH2:13][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH2:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)=[O:24])=[CH:18][C:17]=1[C:25]([F:26])([F:27])[F:28]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCOC1=CCc2cccc(N)c2C1
Solvent: C1CCOC1
Solvent: O
Product: CCOC1=CCc2cccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
To a stirred solution of 7-ethoxy-5,8-dihydronaphthalen-1-ylamine (0.16 g, 0.84mmol) in tetrahydrofuran (15 mL) was added 4-chloro-3-trifluoromethyl-phenylisocyanate (0.22 g, 1.0 mmol). The mixture was stirred at room temperature for 1.5 hours and was poured into water. The product was extracted with ethylacetate, and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford N-(4-chloro-3-trifluoromethyl-phenyl)-N′-(7-ethoxy-5,8-dihydro-naphthalen-1-yl)urea (0.31 g, 89% yield). Next, to a solution of N-(4-chloro-3-trifluoromethyl-phenyl)-N′-(7-ethoxy-5,8-dihydro-naphthalen 1-yl)-urea (0.21 g, 0.51 mmol) in tetrahydrofuran (20 mL) was added a solution of aqueous 1N hydrochloric acid (5 mL), and the mixture was stirred at 40° C. for 45 minutes. The mixture was neutralized with addition of 10% aqueous sodium bicarbonate solution, and extracted with ethylacetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford N(4-chloro-3-tri-fluoromethyl-phenyl)-N′-(7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)urea (0.16 g, 85% yield). Next, to N-(4-chloro-3-trifluoromethyl-phenyl)-N′-7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)urea (0.07 g, 0.18 mmol) in methanol (10 mL) was added sodium borohydride (0.04 g, 0.09 mmol) at 0° C., and the mixture was stirred for 30 minutes. The mixture was poured into water, and the product was extracted with ethylacetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure, and the obtained product was recrystalized from a mixture of ethylacetate/hexane (1/2) solution to give N-[4chloro-3-(trifluoromethyl)phenyl]-N′-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea (41 mg, 59% yield)
Reaction SMILES: [OH-].[Na+:2].[O:3]=[S:4]1(=[O:36])[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[C:31]([NH:33][CH3:34])=[O:32])=[O:21])[C:17]([OH:35])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2.CC(C)=O.C(#N)C>O>[O:36]=[S:4]1(=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[C:31]([NH:33][CH3:34])=[O:32])=[O:21])[C:17]([O-:35])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2.[Na+:2]
Reactant: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydroxide (150 μL, 0.15 mmol, 1N solution) was added to a cloudy solution of 5-(1,1-dioxido-1,2-thiazinan-2-yl)-N-{4-fluoro-2-[(methylamino)carbonyl]benzyl}-8-hydroxy-1,6-naphthyridine-7-carboxamide (73 mg, 0.15 mmol) in a 2 mL mixture of acetone, acetonitrile and water. The homogeneous bright yellow solution was allowed to stir at room temperature for 30 minutes. The solvent was removed in vacuo and dried overnight on the high vac with gentle heating to give the desired product as a bright yellow solid.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])=[S:2].[CH3:9]OS(F)(=O)=O.C(N(CC)CC)C.[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[CH3:22][O:23][CH:24]1[CH:1]([S:2][CH3:9])[N:3]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:25]1=[O:26]
Reactant: COC(=O)CNC=S
Reactant: COS(=O)(=O)F
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN1C(=O)C(OC)C1SC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl thioformylglycinate (266 mg.) in methylene chloride (3 ml.) was added magic methyl (methyl fluorosulphonate, 170 μl.). The resulting mixture was stirred at room temperature for 3 hours and then cooled with ice. Triethylamine (574 μl.) and methoxyacetyl chloride (192 μl.) were added to the above mixture, which was then stirred at that temperature for 45 minutes and then at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, washed with water and dried over magnesium sulphate. The solvent was then distilled off. The resulting residue was purified by preparative thin layer chromatography eluted with a 4:1 by volume mixture of methylene chloride and ethyl acetate, to afford 27 mg. of the desired product.