Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:16])=[O:6]
Reactant: O=C(O)c1ccccc1C(F)(F)F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccccc1C(F)(F)F

Procedure:
A solution of 2.0 g of o-trifluoromethylbenzoic acid in 21 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is concentrated from toluene three times and dried under vacuum to give 2.1 g of the desired product as a residue.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:24][CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[C:12](=O)[CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])(=O)C.[NH4+:34].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:12]2[NH:34][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:14][CH:13]=2)[CH2:24][CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)CCC(=O)c2ccccn2)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOC2)c2ccc(-c3ccccn3)[nH]2)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of 5-[4-(methylsulfonyl)phenyl]-1-(pyridin-2-yl)-6-(tetrahydrofuran-3-yl)hexane-1,4-dione (43.5 mg) in acetic acid (0.53 mL) was added ammonium acetate (129 mg), and the mixture was stirred at 110° C. for 2 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (27.4 mg, yield 66%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([NH:15][C:16]3[C:17]4[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[S:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[NH3:29]>CO.CN(C=O)C>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([O:8][C:9]2[C:14]([NH:15][C:16]3[C:17]4[C:24]([CH3:25])=[C:23]([C:26]([NH2:29])=[O:27])[S:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:7]1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](O)CC3)c12
Reactant: N
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](O)CC3)c12

Procedure:
Prepared analogously to 1.4 from 0.1 g 4-[2-(trans-4-hydroxy-cyclohexyloxy)-pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia in methanol (7M) in DMF. Separated from cis isomer by chromatography.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:15]([C:18]1[C:26]2[O:25][N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=2[CH:21]=[CH:20][C:19]=1[O:31][CH2:32][CH2:33][CH2:34]Br)[CH2:16][CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:7])[N:4]([CH2:34][CH2:33][CH2:32][O:31][C:19]2[CH:20]=[CH:21][C:22]3[C:23]([C:27]([F:29])([F:30])[F:28])=[N:24][O:25][C:26]=3[C:18]=2[CH2:15][CH2:16][CH3:17])[C:3]1=[O:8]
Reactant: CC1(c2ccncc2)NC(=O)NC1=O
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCCCN2C(=O)NC(C)(c3ccncc3)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
A mixture of crude rac-5-methyl-5-(4-pyridyl)-imidazolidinedione (29 mg), 7-propyl-3-trifluoromethyl-6-(3-bromopropyloxy)-1,2-benzisoxazole (27 mg) from Example 7, and Cs2CO3 (71 mg) in DMF (3.0 mL) was allowed to react overnight. Water (0.4 mL) was added and the resulting mixture separated by HPLC to yield the title compound as a clear oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15]1([NH:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[NH:21]([N:22]1[C:5](=[O:13])[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:2]([Br:1])[C:3]1=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Br
Reactant: NNc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)=C(c2ccccc2)C(=O)N1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.3 g (17 mmol) of 3-bromo-4-phenylfuran-2,5-dione were initially charged in 40 ml of chloroform and, at room temperature, admixed dropwise with stirring with 1.84 g (17 mmol) of phenylhydrazine in 15 ml of chloroform, and the mixture was stirred at room temperature overnight. The mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using ethyl acetate/cyclohexane. Yield: 1.9 g, m.p. 146-147° C.
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[N+:20]([O-])([OH:22])=[O:21]>>[CH3:7][CH:2]1[CH:3]=[C:4]([N+:20]([O-:22])=[O:21])[CH:5]=[CH:6][N:1]1[OH:8]
Reactant: Cc1cccc[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC1C=C([N+](=O)[O-])C=CN1O
Temperature: 5 °C

Procedure:
2-Picoline-N-oxide (14)(21.9 g, 0.2 mmol) was added to a concentrated sulphuric acid (76 mL), maintaining the temperature below 40° C. The mixture was cooled to 5° C.; fuming nitric acid (60 mL) was the added dropwise over 15 minutes, maintaining reaction temperature below 10° C. After the addition was complete the reaction mixture was heated to 100° C. for 1.5 hours. The reaction was then cooled to rt and poured over ice (ca 500 g), the resultant green/yellow solution was neutralised by addition of sodium carbonate (ca 205 g over 1 hour). The mixture was then filtered and washed with water (2 L). The solid cake was then dissolved in DCM (500 mL) and dried over Na2SO4. Hexane (100 mL) was added to the DCM solution resulting in a yellow suspension which was filtered off and dried. Single peak in LC-MS analysis, (25.40 g 82.5%) no purification performed and taken through crude to next step.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[NH:14][CH:13]=[C:12]2[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22]CCCl.O=P(Cl)(Cl)Cl>C(OCC)(=O)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([Cl:22])=[N:14][CH:13]=[C:12]2[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCl
Reactant: COc1c[nH]c(=O)c2ccc(SCc3ccccc3)cc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cnc(Cl)c2ccc(SCc3ccccc3)cc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A vial was charged with 6-(benzylthio)-4-methoxyisoquinolin-1(2H)-one (0.933 g, 3.14 mmol) and DCE (15.69 ml). POCl3 (0.585 ml, 6.27 mmol) was added and the reaction was stirred overnight at 90° C. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford crude 6-(benzylthio)-1-chloro-4-methoxyisoquinoline (Intermediate VVV) as a brown solid. (ESI) 316.3 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([F:26])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[CH:37]=O.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([F:26])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:37][C:29]3[N:28]([CH3:27])[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1c(C=O)nc2ccccc21
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ccccc4n3C)C(=O)O2)cc1F

Procedure:
The title compound was prepared by coupling 6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione from Step 1 of Example B(14), to 1-Methyl-1H-benzoimidazole-2-carbaldehyde using the AlCl3/reduction procedure described for Example B(13). 1H NMR (CDCl3): δ 1.32 (d, J=6 Hz, 6H), 1.45-1.91 (brm, 8H), 2.05 (m, 2H), 2.44-2.88 (m, 8H), 2.91 (s, 3H), 4.48 (m, 1H), 6.75-6.92 (m, 3H) 7.22-7.45 (m, 3H) 7.66 (s, 1H). ESIMS (MH+): 507.2
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=1.CO[CH:16]=[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([I:27])[CH:25]=2)[C:20](=[O:28])[NH:19][C:18]1=[O:29]>CN(C)C=O>[OH:9][C:7]1[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=[C:3]([CH2:2][NH:1][CH:16]=[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([I:27])[CH:25]=3)[C:20](=[O:28])[NH:19][C:18]2=[O:29])[CH:8]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: CCCOc1cnc(CN)cc1O
Solvent: CN(C)C=O
Product: CCCOc1cnc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1O

Procedure:
A mixture of 2-aminomethyl-5-propoxy-pyridin-4-ol (137 mg, 0.75 mmole) in 10 mL of N,N-dimethylformamide is stirred, then 4-methoxymethylene-6-iodo-4H-isoquinoline-1,3-dione (247 mg, 0.75 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, triturated with 5% methanol in chlororform, filtered washed with fresh 5% methanol in chloroform, washed with acetonitrile and dried to give a pink solid, 313 mg, (87%); MS (ES+): m/z 479.9 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([F:43])=[C:14]([CH:42]=2)[C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[N:28]2[CH2:33][CH2:32][CH2:31][C@@H:30]([O:34][Si](C(C)(C)C)(C)C)[CH2:29]2)=[O:16])=[CH:4][N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([F:43])=[C:14]([CH:42]=2)[C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][C:19]=2[N:28]2[CH2:33][CH2:32][CH2:31][C@@H:30]([OH:34])[CH2:29]2)=[O:16])=[CH:6][N:7]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(C#Cc3cnc(N)nc3)ccc2F)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncc(C#Cc2ccc(F)c(C(=O)Nc3cc(C(F)(F)F)ccc3N3CCC[C@@H](O)C3)c2)cn1
Reaction time: 6 h

Procedure:
To a yellow solution of (R)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide (0.162 g, 0.264 mmol) was added tetrabutylammonium fluoride, 1.0 M in THF (0.688 ml, 2.38 mmol). The reaction was allowed to stir for 6 h, at which point it was found by TLC analysis to be complete. The reaction was diluted with EtOAc and washed once with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give a yellow oil, which was purified by silica gel chrmatography, 0-10% MeOH/MC to give (R)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluoro-N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide as an off-white solid. MS m/z=500 [M+H]+. Calc'd for C25H21F4N5O2: 499.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9][CH2:10][CH2:11][C:12]#[N:13])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24]([CH3:25])=[O:37])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9][CH2:10][CH2:11][C:12]#[N:13])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(CCCC#N)c3ccc(Cl)cc3)c[nH]c12
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(CCCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.14 mmol) of the compound from Example 49 were introduced into 9 ml of dichloromethane while cooling in ice, 33.4 mg (0.14 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. 2 ml of methanol were added, and the residue after concentration was taken up in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases were separated, the organic phase was washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 33 mg (63% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH:14]=2)=[C:5]([CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])[CH:4]=1>C(OCC)(=O)C.C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]=2)=[C:5]([CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])[CH:4]=1
Reactant: COC(=O)C(C)c1cc(Cl)ccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(C)c1cc(Cl)ccc1C1=CCNCC1
Reaction time: 1 h
Yield: 112.6 %

Procedure:
A saturated solution of hydrogen chloride in ethyl acetate (6 mL) was added to a solution of tert-butyl 4-[4-chloro-2-(2-methoxy-1-methyl-2-oxoethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (0.730 g, 1.92 mmol) in methylene chloride (6 mL) at 0° C. After 1 h, the volatiles were evaporated in vacuo, and the crude residue triturated twice with dry diethyl ether to give 2-3 (0.605 g) (m/z (ES) 280 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=3)[CH:19]=2)[CH2:15][CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([Cl:41])[CH:35]=1>>[Cl:41][C:36]1[CH:35]=[C:34]([CH2:33][CH2:32][NH:31][C:26]2[N:25]=[C:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][N:14]([CH2:15][CH3:16])[CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:19]=3)[CH:29]=[CH:28][N:27]=2)[CH:39]=[CH:38][C:37]=1[OH:40]
Reactant: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NCCc1ccc(O)c(Cl)c1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C1CCNCC1

Procedure:
Intermediate 84 was coupled with 4-(2-amino-ethyl)-2-chloro-phenol following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 467. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.27 (m, 2H), 7.69 (m, 2H), 7.26 (d, 1H), 7.19 (m, 1H), 7.04 (s, 1H), 7.01 (d, 1H), 6.80 (d, 1H), 4.48 (m, 2H), 3.53 (m, 4H), 3.09 (m, 4H), 2.85 (t, 2H), 2.39 (d, 2H), 2.03 (m, 3H), 1.32 (t, 3H).
Reaction SMILES: [Na].[C:2]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=O)([O:4]CC)=O.[F:14][C:15]([F:20])([F:19])[C:16]([NH2:18])=[NH:17]>C(O)C>[F:14][C:15]([F:20])([F:19])[C:16]1[NH:18][C:2](=[O:4])[C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:17]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: N=C(N)C(F)(F)F
Agent: [Na]
Solvent: CCO
Product: O=c1[nH]c(C(F)(F)F)nc2c1CCCC2
Temperature: 25 °C

Procedure:
To 10 mL of absolute ethanol under a nitrogen atmosphere was added 0.15 g of sodium metal. After all the sodium had reacted, 1.00 g of 2-carboethoxycyclohexanone was added followed by 0.78 g of 85% trifluoroacetamidine. The reaction was refluxed gently overnight. The reaction was cooled to room temperature and all solvents were removed by evaporation. The pH of the residue was adjusted to 6 with dilute hydrochloric acid and refluxed briefly and allowed to cool. The resulting solid was collected. (0.73 g, 57%): 1H NMR (DMSO-d6, 300 MHz) δ 13.0 (s, 1H), 2.78 (m, 2H), 2.45 (m, 2H), 1.78 (m, 4H).
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[S:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH2:34]O>C1(C)C=CC=CC=1>[N:15]([CH2:34][C:30]1[S:29][CH:33]=[CH:32][N:31]=1)=[N+:16]=[N-:17]
Reactant: OCc1nccs1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
Diphenylphosphoryl azide (3.25 mL, 0.015 mol) and 1,8-diazabicyclo[5.4.0] undec-7-ene (2.25 mL, 0.025 mol) were added to a solution of thiazol-2-yl-methanol (1.44 g, 0.013 mol) in toluene (20 mL) at 0° C. After 1 hour, the reaction was warmed to room temperature and stirred overnight. The mixture was diluted with toluene (20 mL) and washed with H2O (3×) brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (30% ethyl acetate/hexanes) to afford the azide as a tan oil (1.1 g, 63%). IR: 2098 cm-1.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH:20]([CH3:22])[CH3:21])(O)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].Cl.[H][H]>[Pd].CO>[C:1]([N:6]1[CH2:7][CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH:20]([CH3:21])[CH3:22])[CH2:10][CH2:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: [H][H]
Reactant: CCOC(=O)N1CCC(O)(c2ccccc2OC(C)C)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)N1CCC(c2ccccc2OC(C)C)CC1
Yield: 86 %

Procedure:
A crude solution of XV (36 g), 10% palladium on carbon (1.80 g), 5 mL of concentrated HCl and 125 mL of MeOH was shaken on a Parr apparatus under 55.5 psig of hydrogen at 22° C. for 3 d. The reaction was filtered over Celite, and concentrated to a residue. This material was partitioned between ether and water. The organic solution was dried (MgSO4), filtered, and concentrated to yield 29.34 g of XVI as a light yellow oil which was carried forward without further purification. The structure was supported by MS and 1H NMR.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C#C)[CH2:2]CC.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([C@@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:26][CH:27]=2)=[CH:19][CH:18]=1.[Li+].[Cl-]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:24][C:25]([C@@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[N:26][CH:27]=2)=[CH:19][CH:18]=1)#[CH:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C#Cc1ccc(-c2cnc([C@@H]3CCCN3C(=O)OC(C)(C)C)[nH]2)cc1
Temperature: 80 °C

Procedure:
Pd(Ph3P)4 (0.115 g, 0.099 mmol) was added to a mixture of tributyl(ethynyl)stannane (1.539 g, 4.88 mmol), (S)-tert-butyl 2-(4-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.965 g, 2.46 mmol; for its preparation, see PCT Publication No. WO 2008/021927) and LiCl (0.277 g, 6.53 mmol) in dioxane (20 mL) in a sealed pressure tube. The mixture was purged with nitrogen, sealed and heated at 80° C. for 3 hr. After it was allowed to cool to ambient temperature, the volatile component was removed in vacuo and the residue was partitioned between CH3CN and hexanes (2:1 ratio in volume). The hexane layer was washed with an equal volume of CH3CN. The combined CH3CN phase was rotervaped, and the resultant crude material was purified with a BIOTAGE® (100 g silica gel; 40-50% EtOAc/hexanes) to afford Intermediate M1a as a dull orange solid (591 mg). 1H NMR (DMSO-d6, δ=2.50 ppm, 400 MHz): 12.21/11.95/11.88 (three ‘br s’, 1H), 7.74 (d, J=8.3, 1.6H), 7.66-7.47 (m, 1.66H), 7.41 (d, J=8.3, 1.6H), 7.32 (m, 0.14H), 4.84-4.75 (m, 1H), 4.19/4.12 (two ‘s’, 1H), 3.52 (m, 1H), 3.39-3.29 (m, 1H), 2.28-1.77 (m, 4H), 1.39/1.15 (two ‘s’, 9H). LC/MS: Anal. Calcd. for (M+H)+ C20H24N3O2: 338.18. Found, 338.28.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH:8]=[C:7]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][O:27][C:26]4=[O:30])[CH2:19][CH2:18]3)[C:6]=2[CH:31]=1.[BH4-].[Na+].C(O)(=O)C(O)=O>COCCOCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][O:27][C:26]4=[O:30])[CH2:21][CH2:22]3)[C:6]=2[CH:31]=1
Reactant: Cc1ccc2c(c1)C=C(N1CCN(CCN3CCOC3=O)CC1)c1cc(Cl)ccc1S2
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: Cc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1cc(Cl)ccc1S2
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1.0 G. of 3-{2-[4-(8-chloro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone is stirred at room temperature with 50 ml. of diethyleneglycol dimethyl ether (diglyme) and 0.6 g. of sodium borohydride for 30 minutes under an atmosphere of argon. Thereafter, a solution of 2.8 g. of oxalic acid (C2H2O4 . 2H2 o) in 15 ml. of diglyme is added dropwise at 20°-30° C. The mixture is stirred at 100° C. for 4 hours, and subsequently evaporated under reduced pressure. The residue is taken up in 2N sodium hydroxide and water, and extracted three times with 100 ml. of benzene each time. The combined benzene phases are washed with water, dried over magnesium sulfate, filtered and concentrated. the crystalline residue is recrystallized from ethyl acetate/petroleum ether (low boiling), whereby there is obtained 3-{2-[4-(8-chloro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1 -piperazinyl]-ethyl}-2-oxazolidinone, having a melting point of 184°-186° C. The maleate crystallizes from methanol/ether and melts at 174°-175° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[C:6]([Br:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.I([Cl:28])(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[C:6]([Br:20])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]([CH:17]([CH3:19])[CH3:18])[C:12]([OH:15])=[C:13]([Cl:28])[CH:14]=1
Reactant: COc1ccc(Oc2c(Br)cc(CC(=O)O)cc2Br)cc1C(C)C
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)c1cc(Oc2c(Br)cc(CC(=O)O)cc2Br)cc(Cl)c1O
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a stirred solution of 3,5-dibromo-4-(3-isopropyl-4-methoxyphenoxy)phenylacetic acid (1.5 g, 3.4 mmol) in acetic acid (40 mL) at room temperature was added benzyltrimethylammonium tetrachloroiodate (1.42 g, 3.4 mmol). The reaction mixture was stirred for one hour and was filtered. The filtrate was concentrated, and the product was extracted with ethyl acetate, washed with saturated NaHCO3 (aq), NaCl (aq), and dried over MgSO4 and concentrated in vacuo. The residue was purified on column (silica gel, chloroform/methanol/acetic acid 98:2:0.3) to give 802 mg (50%) of 3,5-dibromo-4-(3-chloro-4-hydroxy-5-isopropylphenoxy)phenylacetic acid.
Reaction SMILES: N[N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[NH:4][C:3]1=[O:12].N([O-])=O.[Na+]>C(O)(=O)C.O>[NH:4]1[C:5]2[CH:11]=[CH:10][S:9][C:6]=2[C:7](=[O:8])[NH:2][C:3]1=[O:12]
Reactant: Nn1c(=O)[nH]c2ccsc2c1=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2sccc2[nH]1
Temperature: 60 °C
Yield: 49.2 %

Procedure:
To a solution of 3-amino-1H-thieno[3,2-d]pyrimidine-2,4-dione (1.70 g, 9.3 mmol) in a 1:1 mixture of acetic acid/H2O (155 mL) was added sodium nitrite (1.92 g, 27.8 mmol) portion-wise. The reaction mixture was heated to 60° C. until the evolution of brown gas ceased (2 h). Acetic acid was removed under reduced pressure and the solution was cooled to 0° C. The resulting white solid was collected by filtration to afford 0.77 g of the desired product. MS: 167.3. 1H NMR (400 MHz, d6-N,N-dimethylsulfoxide (d6-DMSO)) δ ppm 11.40 (br s, 1H), 8.04 (d, J=5.2 Hz, 1H), 6.91 (d, J=5.3 Hz, 1H), 3.34 (br s, 1H).