Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:13]CCCO2)[CH:5]=[CH:6][CH:7]=1.[CH:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:16])[CH3:15].C(O[Na])(C)(C)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:14]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=2)[CH:8]=[O:13])[CH2:19][CH2:18]1)([CH3:16])[CH3:15]
Reactant: Brc1cccc(C2OCCCO2)c1
Reactant: CC(C)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(c2cccc(C=O)c2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
A mixture of 2-(3-bromophenyl)-1,3-dioxane (2, 1.58 g, 6.5 mmol), 1-isopropylpiperazine (1.0 g, 7.8 mmol), rac-BINAP (60 mg, 0.096 mmol), and tert-BuONa (1.06 g, 11.1 mmol) in toluene (15 mL) was degassed under vacuum and flushed with nitrogen. Pd2(dba)3 (30 mg, 0.033 mmol) was added. The reaction mixture was degassed again and flushed with nitrogen and was heated at 100° C. under nitrogen for 16 h. The reaction mixture was poured into cold 1N HCl (30 mL) and stirred for 2 h. It was adjusted to pH 8 with 6N NaOH and extracted with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and purified by silica gel chromatography eluting with 0-100% EtOAc (containing 5% v/v Et3N) in hexanes to afford the title compound as a viscous yellow oil (1.32 g, 87%): 1H NMR (500 MHz, CDCl3) δ 9.96 (s, 1H), 7.44-7.37 (m, 2H), 7.34-7.30 (m, 1H), 7.21-7.16 (m, 1H), 3.28 (t, J=5.0 Hz, 4H), 2.73 (sept, J=6.5 Hz, 1H), 2.69 (t, J=5.0 Hz, 4H), 1.10 (d, J=6.5 Hz, 6H); ESI MS m/z 233 [M+H]+.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[CH2:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[CH2:5]([NH:4][C:1](=[O:3])[CH3:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(N)=O
Reactant: ClCc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccccc1
Reaction time: 4 h
Yield: 72.6 %

Procedure:
To 200 ml of N,N-dimethylformamide, were added 12 g of acetamide, 105 g of LEVATIT MP-500, which was also used in Example 68, and 32 g of benzylchloride. They were .reacted at 50° C. for 4 hours with stirring. After the reaction, the reaction solution was treated in the same manner as in Example 69, the resulting distillation residue was recrystallized from benzene, thereby providing 22 g of N-benzylacetamide having a melting point of 61°-62° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C1C(=O)N(Br)C(=O)C1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)(Cl)Cl.CCO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: Cc1ccc(I)cc1F
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Fc1cc(I)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a solution of 2-fluoro-4-iodotoluene (23.60 g, 0.10 mol) in CHCl3 (1000 mL) was added BPO (0.55 g, 2.27 mmol) and NBS (24.92 g, 0.14 mol) under N2. The reaction mixture was refluxed for 6 h, then cooled and filtered. The filtrate was concentrated in vacuo. The residue was added to a solution of morpholine (43.56 g, 0.50 mol) in EtOH (1000 mL) under N2. The resulting mixture was stirred at rt overnight, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:1) to give the title compound as a white solid (4.82 g, 15%).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH3:15])=[O:11])=[C:6]([O:16][CH3:17])[C:5]([O:18][CH:19]([F:21])[F:20])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[C:41](=[O:45])[NH:40][CH2:39]3)O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:20][CH:19]([F:21])[O:18][C:5]1[C:6]([O:16][CH3:17])=[C:7]([C:2]([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[C:41](=[O:45])[NH:40][CH2:39]3)=[CH:3][CH:4]=1)[O:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH3:15])=[O:11]
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Reactant: CCCNC(=O)COc1c(Br)ccc(OC(F)F)c1OC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCNC(=O)COc1c(-c2ccc3c(c2)CNC3=O)ccc(OC(F)F)c1OC
Temperature: 85 °C

Procedure:
A stirring solution of 2-(6-bromo-3-difluoromethoxy-2-methoxy-phenoxy)-N-propyl-acetamide (100 mg, 0.271 mmol) in dimethylformamide (10 mL) was purged with argon for 1 h, to this cesium carbonate (266 mg, 0.813 mmol), tetrakis(triphenylphosphine) palladium(0) (22 mg, 0.019 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (105.5 mg, 0.407 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a solid. (20 mg, 18%).
Reaction SMILES: O[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]([OH:20])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1[C:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18](=[O:20])[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1c(-c2ccccc2)c(O)nc2ccccc12
Product: O=C1c2ccccc2-c2c(Cl)nc3ccccc3c21
Temperature: 150 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
2.65 g (10 mmol) of 2-hydroxy-3-phenylquinoline-4-carboxylic acid (3a) was added into POCl3 (30 mL) and heated at 150° C. for 48 hrs (TLC monitoring). After cooling, the mixture was poured into ice-water (150 mL) to result in precipitation, followed by filtration. The resultant filter cake was poured into 5% NaHCO3(aq) (200 mL) with vigorous stirring for 1 hr, washed with H2O, and dried to give a brown solid, which was recrystallized with EtOH to give the title compound 4a as a red solid (2.31 g, 87% yield).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:14][CH2:15][CH2:16][OH:17])[CH3:13])=[O:4].[BH4-].[Na+]>CN(C)C=O>[OH:17][CH2:16][CH2:15][N:14]1[CH:12]([CH3:13])[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][C:3]1=[O:4]
Reactant: CC(=NCCO)c1ccccc1NC(=O)C(Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1c2ccccc2NC(=O)N1CCO
Reaction time: 8 h

Procedure:
To 135 parts of N,N-dimethylforamide are added first 16.2 parts of 2,2,2-trichloro-N-[2-[1-[(2-hydroxyethyl)imino]ethyl]phenyl]acetamide and then portionwise 5.7 parts of sodium borohydride while stirring: exothermic reaction. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto water and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 8.5 parts of 3,4-dihydro-3-(2-hydroxyethyl)-4-methyl-2(1H)-quinazolinone as a solid residue.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:16]([CH2:24][CH:25]=[CH:26][Cl:27])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].CCCC[SnH](CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Cl:27][CH2:26][CH:25]1[C:2]2[C:11]3[CH:10]=[CH:9][C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:16]([C:17]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:23])[CH2:24]1
Reactant: CC(C)(C)OC(=O)N(CC=CCl)c1ccc2cc(S(C)(=O)=O)ccc2c1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CC(CCl)c2c1ccc1cc(S(C)(=O)=O)ccc21
Yield: 78.7 %

Procedure:
A mixture of 163 (5.38 g, 11.33 mmol), Bu3SnH (3.05 mL, 11.34 mmol) and AIBN (0.25 g, 1.5 mmol) in dry benzene (80 mL) under N2 was stirred at reflux for 2 h, then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and the solution was diluted with excess hexane and refrigerated. The precipitated semisolid was purified by chromatography on silica gel, eluting with CH2Cl2/EtOAc (19:1), to give tert-butyl 1-(chloromethyl)-7-(methylsulfonyl)-1,2-dihydro-3H-benzo[e]indole 3-carboxylate (164) (3.53 g, 79%) as a white solid: mp (iPr2O) 125-126° C.; 1H NMR [(CD3)2SO] δ 8.54 (d, J=1.8 Hz, 1H), 8.25-8.05 (m, 3H), 7.91 (dd, J=8.9, 1.9 Hz, 1H), 4.36-4.27 (m, 1H), 4.23 (t, f=10.5 Hz, 1H), 4.10 (dd, J=11.4, 2.9 Hz, 1H), 4.05 (dd, J=11.1, 3:2 Hz, 1H), 3.94 (dd, J=11.1, 6.7 Hz, 1H, 3.21 (after D2O exchange, s, 3H, 1.56 (s, 9H). Anal. (C19H22ClNO4S) C, H, N.
Reaction SMILES: NC1N=C(N2CCC3(CN[C@H](C(O)=O)C3)CC2)C=C(O[C@H](C2C=C([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]([O:47][CH2:48][CH3:49])=[O:46])C=CC=2N2C=CC(C)=N2)C(F)(F)F)N=1.[NH2:50][C:51]1[N:56]=[C:55]([N:57]2[CH2:79][CH2:78][C:60]3([CH2:64][N:63](C(OCC4C=CC=CC=4)=O)[C@H:62]([C:75]([OH:77])=[O:76])[CH2:61]3)[CH2:59][CH2:58]2)[CH:54]=[C:53]([O:80][C@H:81]([C:86]2[CH:91]=[CH:90][C:89]([Cl:92])=[CH:88][C:87]=2Br)[C:82]([F:85])([F:84])[F:83])[N:52]=1>>[NH2:50][C:51]1[N:56]=[C:55]([N:57]2[CH2:79][CH2:78][C:60]3([CH2:64][NH:63][C@H:62]([C:75]([OH:77])=[O:76])[CH2:61]3)[CH2:59][CH2:58]2)[CH:54]=[C:53]([O:80][C@H:81]([C:86]2[CH:91]=[CH:90][C:89]([Cl:92])=[CH:88][C:87]=2[C:42]2[CH:43]=[CH:44][CH:39]=[C:40]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:41]=2)[C:82]([F:83])([F:85])[F:84])[N:52]=1
Reactant: CCOC(=O)c1ccccc1-c1ccc(-n2ccc(C)n2)c([C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)c1
Reactant: Nc1nc(O[C@H](c2ccc(Cl)cc2Br)C(F)(F)F)cc(N2CCC3(CC2)C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C3)n1
Product: CCOC(=O)c1cccc(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)c1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(2′-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 20) starting with (S)-8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13]([C:16]([OH:28])([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17](OC)=[O:18])=[N:14][N:15]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[OH-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([C@H:38]([N:40]=[C:41]=[O:42])[CH3:39])=[CH:34][CH:33]=1>C1COCC1.C(OCC)(=O)C>[CH2:21]([C:16]1([C:13]2[NH:12][C:11]([C:5]3[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:15][N:14]=2)[O:28][C:41](=[O:42])[N:40]([C@@H:38]([C:35]2[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=2)[CH3:39])[C:17]1=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@@H](N=C=O)c1ccc(F)cc1
Reactant: COC(=O)C(O)(Cc1ccccc1)c1nnc(-c2cc(OC)cc(OC)c2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(-c2nnc(C3(Cc4ccccc4)OC(=O)N([C@H](C)c4ccc(F)cc4)C3=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[5-(3,5-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-2-hydroxy-3-phenylpropanoate (7 mg) in 1 mL of THF was added NaOH (4 mg) and (R)-1-fluoro-4-(1-isocyanatoethyl)benzene (15 mg). The resulting mixture was stirred at ambient temperature overnight. The resulting mixture was diluted with ethyl acetate, and then quenched with water. The organic layer was concentrated and purified by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 30% to 100% acetonitrile/water with 0.1% TFA) to give the title compound. LC/MS 517.2 (M+1). IC50 value=C rating.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[F:26][C:27]([F:39])([F:38])[S:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1.Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:36]([NH:35][C:32]4[CH:33]=[CH:34][C:29]([S:28][C:27]([F:38])([F:26])[F:39])=[CH:30][CH:31]=4)=[O:37])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc(SC(F)(F)F)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(SC(F)(F)F)cc4)ccc3C2=O)C(=O)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
TEA (0.28 g, 2.8 mmol) was added to a mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) and 4-(trifluoromethylthio)phenyl isocyanate (0.31 g, 1.4 mmol) in acetonitrile (30 mL) at 0° C. The reaction was stirred at 0° C. for 2 h and then 4% aqueous HCl (30 mL) was added. The solid precipitate was filtered and dried in vacuo providing 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(4-trifluoromethylsulfanyl-phenyl)-urea as a white solid (0.34 g, 51% yield); mp 218-220° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 3.18 (97.19%); 1H NMR (DMSO-d6) δ 1.97-2.02 (m, 1H), 2.31-2.46 (m, 1H), 2.57-2.63 (m, 1H), 2.87-2.98 (m, 1H), 4.28-4.48 (m, 4H), 5.11 (dd, 1H, J=13.2 Hz, J=5.1 Hz), 6.92 (t, 1H, J=6.0 Hz), 7.45 (d, 1H, J=8.1 Hz), 7.52-7.64 (m, 5H), 7.70 (d, 1H, J=7.8 Hz), 9.08 (s, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.8, 47.1, 51.5, 113.0, 118.4, 121.9, 122.9, 126.9, 129.6 (q, J=306 Hz), 130.3, 137.3, 142.4, 143.6, 144.5, 154.8, 167.9, 171.0, 172.8; LCMS: MH=493; Anal. Calcd for C22H19F3N4O4S+0.2H2O: C, 53.27; H, 3.94; N, 11.29. Found: C, 53.06; H, 3.59; N, 11.12.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:13])([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].O>CN(C)C=O>[CH3:12][Si:3]([CH2:2][N:18]1[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]2[C:14]1=[O:24])([CH3:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[Si](C)(CCl)Cc1ccc(F)cc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Yield: 94.9 %

Procedure:
Chloromethyl-dimethyl-4-fluorobenzylsilane (2.01 g, 9.33 mmol) and potassium phthalimide (1.90 g), 10.27 mmol) were heated in dry dimethylformamide (30 ml) at 70° C. for 5 hours and then the mixture was poured into water and extracted with ether. The ether solution was washed with water, brine, dried and evaporated. Chromatography (silica gel, ether/hexane-20/80) afforded N[(dimethyl-4-fluorobenzylsilyl)methyl]phthalimide as a white powder (2.90 g, 95% yield) 1H NMR (CDCl3, TMS) δ: 0.20 (s,6H), 2.25 (s,2H), 3.27 (s,2H), 6.83-7.13 (m,4H), 7.67-7.97 (m,4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=2)[N:12]=1)[C:5]([NH2:7])=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.CCN(CC)CC>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=2)[N:12]=1)[C:5]#[N:7]
Reactant: NC(=O)c1ccc(-c2ccc3cc(O)ccc3n2)c(Cl)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(-c2ccc3cc(O)ccc3n2)c(Cl)c1
Temperature: 30 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of crude 3-chloro-4-(6-hydroxyquinolin-2-yl)benzamide (360 mg), TFAA (505 mg, 2.40 mmol) and Et3N (364 mg, 3.62 mmol) in DCM (20 mL) was stirred at 30° C. overnight. The resulting mixture was suspended in water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EtOAc=10/1) to give the product (250 mg, 3-step yield 67%) as a solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].C([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=O)C.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+].C(O)C>CN(C)C=O.C(O)(=O)C>[OH:24][C:25]1[C@H:27]2[C@H:28]([CH2:29][CH2:30][CH2:31]2)[N:32]([CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:17](=[O:18])[C:16]=1[C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=2[S:13](=[O:15])(=[O:14])[N:12]=1
Reactant: CCOC(=O)C1CCCC1NCCc1ccccc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(CCc3ccccc3)C1=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.7 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol) and 2-phenethylamino-cyclopentanecarboxylic acid ethyl ester (0.078 g, 0.300 mmol) in N,N-dimethylformamide (1.5 mL) was treated with N-methylmorpholine (63.7 mg, 0.63 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60.4 mg, 0.315 mmol) and stirred at 25° C. for 4 h. The solvent was removed in vacuo. The crude material was redissolved in ethyl acetate (75 mL) and washed twice with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The crude intermediate was redissolved in ethanol (5 mL) and treated with a 21% w/w solution of sodium ethoxide in ethanol (448 μL, 1.2 mmol) and stirred for 2 h at 60° C. The reaction was allowed to cool to 25° C., treated with glacial acetic acid (0.4 mL), the solvents were removed in vacuo, and the residue was and purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-N-[3-(4-hydroxy-2-oxo-1-phenethyl-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (35.9 mg, 0.068 mmol, 22.6%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.48-1.65 (3H, m), 1.97-2.26 (3H, m), 2.83-2.99 (4H, m), 3.06 (3H, s), 3.88 (2H, bs), 7.21-7.34 (8H, m), 7.50-7.83 (5H, m), 10.17 (1H, bs). LC-MS (ESI) calcd for C24H26N4O6S2 530.13, found 531.3 [M+H+].
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[N:19]=[C:18]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]=[C:16]([NH2:28])[C:15]=1[NH2:29].C(N(CC)CC)C>C(Cl)Cl>[Cl:13][C:14]1[N:19]=[C:18]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]=[C:16]2[C:15]=1[NH:29][C:2](=[O:4])[NH:28]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1nc(SCc2ccccc2)nc(Cl)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2nc(SCc3ccccc3)nc(Cl)c2[nH]1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 47.5 %

Procedure:
A solution of triphosgene (0.92 g) in DCM (25 ml) was added dropwise to a solution of the product from example 2, step (e) (0.69 g) and triethylamine (0.55 ml) in DCM (25 ml) at −10° C. The cooling bath was then removed and the suspension stirred for 2.5 h. Upon cooling to 0° C. NaHCO3 (20 ml) was added with vigorous stirring before recovering the organics by extracting with DCM (3×50 ml). The organic extracts were combined, dried (MgSO4) and concentrated in vacuo to yield a crude yellow solid. This material was triturated with EtOAc and filtered to afford a pink solid (360 mg, 48%). The filtrate was concentrated and again triturated with EtOAc to provide a second crop (170 mg, 70% overall)
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH2:9][CH2:10][CH2:11][CH:12]([NH2:17])[C:13](OC)=[O:14])[C:5](OC)=[O:6].C(O)CCCC>C(N(CC)CC)C>[CH:12]12[NH:17][C:5](=[O:6])[CH:4]([NH:3][C:13]1=[O:14])[CH2:9][CH2:10][CH2:11]2
Reactant: COC(=O)C(N)CCCC(N)C(=O)OC
Agent: Cl
Solvent: CCCCCO
Solvent: CCN(CC)CC
Product: O=C1NC2CCCC1NC2=O
Yield: 69.3 %

Procedure:
A solution of 39.0 g (0.134 M) of 2,6-diaminoheptanedioic acid, dimethyl ester, dihydrochloride, 56 ml (0.4 M) of triethylamine, and 3 L of 1-pentanol was heated under reflux for 4 days. The solution was evaporated to dryness and the residue was recrystallized from chloroform to give 14.3 g of the title compound, mp 280°-3° (69%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O.[C:20]([CH:23]1[CH2:28][CH2:27][C:26]([O:29][CH3:30])=[CH:25][CH2:24]1)(=[O:22])[CH3:21].C[O-].[Na+]>C1C=CC=CC=1.O>[CH3:30][O:29][C:26]12[CH2:27][CH2:28][CH:23]([CH2:24][CH2:25]1)[C:20](=[O:22])[CH2:21]2
Reactant: COC1=CCC(C(C)=O)CC1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC12CCC(CC1)C(=O)C2

Procedure:
A mixture of 13.2 g. of p-toluenesulfonic acid and 0.9 g. of hydroquinone in 540 ml. of benzene was heated at reflux under a Dean Stark trap until no more water was evolved. A solution of 90.6 g. of 1-Acetyl-4-methoxy-3-cyclohexene in 750 ml. of benzene was then added to the refluxing solution over 6 hrs. Following an additional hr's heating the mixture was cooled and treated with 16 ml. of 4.64 N methanolic sodium methoxide. The mixture was washed twice with water and the solvent evaporated in vacuum. The residual oil was distilled at 0.45 mm to afford 64.2 g. of bicyclic ketone 4-Methoxybicyclo[2,2,2]-octan-2-one, bp 77°-82°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[N:7]=[C:8]([C:12]([O:14]CC)=[O:13])[S:9][C:10]=1[CH3:11].O[Li].O.Cl>C1COCC1.CO.O.CCOC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[N:7]=[C:8]([C:12]([OH:14])=[O:13])[S:9][C:10]=1[CH3:11]
Reactant: CCOC(=O)c1nc(Cc2cccc(Br)c2)c(C)s1
Agent: Cl
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1sc(C(=O)O)nc1Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl 4-(3-bromobenzyl)-5-methylthiazole-2-carboxylate (20 mg, 0.06 mmol) was treated with LiOH.H2O (7.5 mg, 0.18 mmol) in 2 mL of THF/MeOH/H2O (2:1:1) and stirred at RT for 2 h. The reaction was diluted with EtOAc and H2O and then acidified by 6N HCl. The organic layer was separated and concentrated to give a crude which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH2:10][OH:11])=[CH:8][N:7]=[C:6]([S:12][CH3:13])[N:5]=1)[CH3:2]>O=[Mn]=O>[CH2:1]([NH:3][C:4]1[C:9]([CH:10]=[O:11])=[CH:8][N:7]=[C:6]([S:12][CH3:13])[N:5]=1)[CH3:2]
Reactant: CCNc1nc(SC)ncc1CO
Agent: O=[Mn]=O
Product: CCNc1nc(SC)ncc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
Activated MnO2 (52 g, 0.6 mol) was added to a solution of (4-(ethylamino)-2-(methylthio)pyrimidin-5-yl)methanol (15 g, 0.075 mol) in CH2CL2 (300 mL) and the reaction mixture was stirred overnight at RT. The reaction solution was filtered and the filtrate was concentrated to give 4-(ethylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (14 g, 93% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.71 (s, 1 H), 8.67 (br s, 1 H), 8.49 (s, 1 H), 3.51 (m, 2 H), 2.48 (s, 3 H), 1.17 (t, J=7.2 Hz, 3 H).