Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:37])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:25][CH:24]=3)[C@@H:14]([CH3:38])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[CH:39](=O)[CH3:40].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:37])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]4[CH2:36][CH2:35][N:34]([CH2:39][CH3:40])[CH2:33][CH2:32]4)=[CH:25][CH:24]=3)[C@@H:14]([CH3:38])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCC3CCNCC3)cc2)c2ccccc21
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CCC(COc2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)CC1
Yield: 55 %

Procedure:
The piperdine was reacted with acetaldehyde, Na(OAc)3BH in dichloromethane at room temperature overnight. Then washed with 1N NaOH, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (10% methanol/90% dichloromethane) to afford the product (55%).
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24]C)[C:17]([NH2:19])=[O:18])C>>[CH3:11][O:13][C:14]1[CH:15]=[C:16]([C:17]2[O:18][CH:10]=[C:8]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:19]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: CCOc1ccc(C(N)=O)cc1OCC
Reactant: CCOC(=O)C(Cl)C(C)=O
Product: CCOC(=O)Cc1coc(-c2ccc(OC)c(OC)c2)n1

Procedure:
Using ethyl 2-chloroacetoacetate and 16 g of 3,4-diethoxybenzamide and following the procedure of Reference Example 5, 3.8 g of ethyl [2-(3,4-dimethoxyphenyl)oxazol-4-yl]acetate was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]([CH3:11])[C:8]([OH:10])=O.[CH3:12]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:36][O:37][C:38](=[O:46])[C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[CH3:12][N:45]([C:42]1[CH:43]=[CH:44][C:39]([C:38]([O:37][CH3:36])=[O:46])=[CH:40][CH:41]=1)[C:8](=[O:10])[CH:7]([N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH3:11]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C(=O)O)N1CCCC1=O
Reactant: COC(=O)c1ccc(N)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(N(C)C(=O)C(C)N2CCCC2=O)cc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
To 2-(2-oxopyrrolidin-1-yl)propanoic acid (942 mgs, 6.0 mmol) in DMF (8 mL), was added HATU (2.4 g, 6.4 mmol), 4-Amino-benzoic acid methyl ester (660 mg, 4.0 mmol) and NMM (1.8 mL, 16.0 mmol) and stirred at 55° C. for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 1 N HCl, saturated NaHCO3, water, brine and dried over MgSO4. Filtration and concentration gave methyl 4-(N-methyl-2-(2-oxopyrrolidin-1-yl)propanamido)benzoate.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[C:10]2[C:11]([O:13][C:14](=[O:15])[C:9]=2[CH:8]=[C:7]2[C:16]([O:18][C:19](=[O:20])[C:6]=12)=[O:17])=[O:12].[CH3:21][CH:22]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)[CH:40]([CH3:42])[CH3:41])(C)C.Cl>CCCCCCC.C(OCC)(=O)C.ClCCCl>[CH3:21][CH:22]([CH2:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:19]([C:6]2[CH:5]=[C:10]([C:11]([OH:13])=[O:12])[C:9]([C:14](=[O:15])[C:28]3[CH:27]=[CH:26][C:25]([CH2:24][CH2:23][CH:40]([CH3:41])[CH2:42][C:32]([CH3:31])([CH3:34])[CH3:33])=[CH:30][CH:29]=3)=[CH:8][C:7]=2[C:16]([OH:18])=[O:17])=[O:20])=[CH:27][CH:26]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(CCc1ccccc1)CC(C)(C)C
Reactant: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(CCc1ccc(C(=O)c2cc(C(=O)O)c(C(=O)c3ccc(CCC(C)CC(C)(C)C)cc3)cc2C(=O)O)cc1)CC(C)(C)C
Temperature: 15 °C

Procedure:
A mixture of 694.76 grams of aluminum chloride, 270.6 grams of benzene-1,2,4,5-tetracarboxylic acid dianhydride (pyromellitic dianhydride), and 1722.0 grams of 1,2-dichloroethane was stirred at 15° C. A mixture of 507.04 grams of (3,5,5-trimethylhexyl)benzene, 173.17 grams of N,N-diisopropylethylamine and 676.4 mL of 1,2-dichloroethane was added to the reaction over a period of 3.5 hours keeping the reaction temperature between 15° C. and 20° C. The mixture was allowed to stir overnight at room temperature and then added to 1200 g of ice and 1200 mL concentrated hydrochloric acid and stirred for 3 hours. The mixture was extracted with ethyl acetate and the ethyl acetate was washed several times with water. The organic phase was dried with magnesium sulfate and stripped to give a clear thick yellow slurry. To this was added 200 mL ethyl acetate followed by 600 mL of heptane and stirred for 15 minutes. The solid was collected by filtration to give 2,5-bis(4-(3,5,5-trimethylhexyl)benzoyl)terephthalic acid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:8])[CH3:7].[C:24]([O-])(=[O:26])C.[Na+]>CN(C)C=O>[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:23])[C:17]1[CH:18]=[CH:19][C:20]([CH:24]=[O:26])=[CH:21][CH:22]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)OCCCCCCN(C)c1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)OCCCCCCN(C)c1ccc(C=O)cc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Phosphorous oxychloride (145 g, 0.95 mol) was added dropwise at 5° C. to 280 mL of stirred N,N-dimethylformamide (DMF), and the mixture was stirred at 5° C. for 2 hours. N-(6-Acetoxyhexyl)-N-methylaniline (230 g, 0.93 mol) was added slowly, and the reaction mixture was heated at 90° C. for 3 hours. After cooling, the solution was poured onto 500 g of ice and the resulting mixture was neutralized to pH 5 with sodium acetate. The mixture was extracted with dichloromethane (4×200 mL), the combined extracts were dried (MgSO4), and the solvent was removed at reduced pressure. The brown residue was distilled in vacuo the provide 186 g (73%) of a yellow oil, bp 195° C. (0.15 mm).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:19]2)=[CH:14][CH:13]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[CH:1]([NH:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:19]2)=[CH:14][CH:13]=1)=[O:2]
Reactant: CCOC(=O)C1CCc2ccc(N)cc2O1
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCc2ccc(NC=O)cc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Mixed anhydride is prepared by stirring 1.25 equivalents of formic acid and 1 equivalent of acetic anhydride at 60° C. for 2 h. A solution of ethyl 7-amino-2-chromancarboxylate (1.25 g; 5.6 mmol) in THF is treated with triethylamine (0.78 mL; 5.6 mmol) and the previously prepared mixed anhydride (1.6 mL), stirred at ambient temperature for 1 h, poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl ether. The combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title compound as a straw colored oil (1.4 g; 100%), identified by NMR spectral analysis.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=1[Cl:28])[CH2:10][C:9]2([CH3:30])[CH3:29])=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:28][C:17]1[CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:21][C:16]=1[CH:11]1[CH2:10][C:9]([CH3:29])([CH3:30])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(N3CCOCC3)ccc1Cl)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CC(c2cc(N3CCOCC3)ccc2Cl)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 16 h
Yield: 92.1 %

Procedure:
To a stirred mixture solution of 2-(2-chloro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.8 g, 6.5 mmol) in methanol (50 mL) and tetrahydrofuran (50 mL) was added 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60° C. for 16 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (100 mL×2), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(2-chloro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2.4 g, 92%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=401.1.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[C:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.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>[Cl:1][C:2]1[C:7]([C:12]#[C:11][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1
Reactant: C#Cc1cccnc1
Reactant: Cc1nc(N)nc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(Cl)c1C#Cc1cccnc1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 4.0 g (15 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin-2-ylamine (GP3) and 2.0 g (19 mmol) 3-ethynyl-pyridine using 282 mg (1.5 mmol) CuI, 1.0 g (1.5 mmol) PdCl2(PPh3)2 and 21 mL (148 mmol) triethylamine in 200 mL dry DMF. For the work-up the reaction mixture is concentrated in vacuo before water is added. The precipitate is collected, dried at 40° C. and crystallized from MeOH/H2O. Yield: 3.0 g (83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13](OC(=O)C)[C:14]([N:16]([CH3:30])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[O:26][CH:27]([CH3:29])[CH3:28])=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O>ClCCl>[CH3:30][N:16]1[C:14](=[O:15])[CH:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[C:23]2[C:18](=[C:19]([O:26][CH:27]([CH3:29])[CH3:28])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[CH2:17]1
Reactant: COc1cccc(CN(C)C(=O)C(OC(C)=O)c2cc(OC)c(OC)c(OC)c2)c1OC(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C2C(=O)N(C)Cc3c2ccc(OC)c3OC(C)C)cc(OC)c1OC

Procedure:
A solution of the amide from step 2 above (6.2 g) in dichloromethane (60 ml) and trifluoroacetic acid (20 ml) was refluxed for 6 hours. The reaction mixture was concentrated to dryness and the residue was crystallized from methanol, giving 2-methyl-4-(3,4,5-trimethoxyphenyl)-8-isopropoxy-7-methoxy-1,4-dihydro-3(2H)-isoquinolinone (4.8 g), m.p. 128-129° C.
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].Cl.[NH2:19][C@@H:20]([C:33]([NH:35][C@H:36]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:34])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH:31]=[O:32])[CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(Cl)Cl>[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([NH:19][C@@H:20]([C:33]([NH:35][C@H:36]([C:44]([O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:45])[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:34])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH:31]=[O:32])[CH:23]=1)=[O:10])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Reactant: N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
To a solution of Boc-Gln-OH (2.10 g), HCl.H-D-Trp(CHO)-Phe-OBzl (4.70 g) and HOBT (1.15 g) in a mixed solvent of methylene chloride (60 ml) and DMF (10 ml), was added WSC (1.41 g) under ice cooling. The reaction mixture was stirred for 1.5 hours at the same temperature and for additional 1.5 hours at room temperature and concentrated under reduced pressure. Water was added to the residue and the resulting precipitates were collected and washed successively with water, diluted sodium hydrogencarbonate solution and water. After drying, the crude product (5.84 g) was stirred in hot ethyl acetate (60 ml) in water bath. After cooling, the precipitates were collected by filtration and dried to give Boc-Gln-D-Trp(CHO)-Phe-OBzl (5.70 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH2:25])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:27]([N:34]=[C:35]=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][NH:25][C:35]([NH:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:36])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN)c1
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: (2′-aminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [OH:1][N:2]([CH2:6][C:7]1[CH:30]=[CH:29][C:10]([O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([OH:28])[C:25]([NH2:27])=[O:26])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)[C:3]([NH2:5])=[O:4].[OH-].[Na+].Cl[C:34](OCC)=[O:35].Cl.[O:40]1CCC[CH2:41]1>>[O:26]=[C:25]1[NH:27][C:34](=[O:35])[O:28][N:24]1[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15]/[CH:14]=[CH:13]\[CH2:12][O:11][C:10]2[CH:29]=[CH:30][C:7]([CH2:6][N:2]3[C:3](=[O:4])[NH:5][C:41](=[O:40])[O:1]3)=[CH:8][CH:9]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cl
Reactant: C1CCOC1
Reactant: NC(=O)N(O)Cc1ccc(OC/C=C\COc2ccc(CN(O)C(N)=O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(=O)n(Cc2ccc(OC/C=C\COc3ccc(Cn4oc(=O)[nH]c4=O)cc3)cc2)o1
Temperature: 25 °C
Reaction time: 49 h

Procedure:
To the solution of (Z)-1,4-Bis[4-[(1-hydroxyureido)methyl]phenoxy]-2-butene (0.75 g) in tetrahydrofuran (20 ml) was added 2N sodium hydroxide aqueous solution (6.9 ml) and then, with ice-cooling, ethyl chloroformate (0.66 ml) was added dropwise to the mixture. After 49 hours of stirring at room temperature, the reaction mixture was adjusted to pH 1 with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate and then the solvent was evaporated under a reduced pressure. The resulting residue was subjected to silica gel column chromatography with chloroform-methanol (10:1) elution, and the obtained crude product was recrystallized from methanol to obtain (Z)-1,4-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-2-butene (0.31 g).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1I)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[B:22]([OH:27])[OH:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1ccc(OCc2ccccc2)c(I)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Temperature: -78 °C
Yield: 52.6 %

Procedure:
Butyllithium (11.5 ml, 28.7 mmol, 2.5 M) was added, under nitrogen, over 10 minutes, to a solution of 2-benzyloxy-5-chloro-iodobenzene (9 g, 26.2 mmol) in THF (40 ml) at −100° C. The reaction mixture was then warmed up at −78° C. and stirred for 1 hour (at −78° C.) before triisopropyl borate (18 ml, 78.4 mmol) was added over 10 minutes. The reaction mixture was then warmed to room temperature before a solution of HCl (60 ml, 1M) was added. The mixture was vigorously stirred for 1½ hours. The organic phase was separated, washed sequentially with water and brine, dried (MgSO4) filtered and concentrated. The residue was triturated with a 30% solution of ether in iso-hexane and filtered to give the title compound (3.62 g, 53%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]3[NH:11][C:12]([CH:17]=O)=[C:13]([O:15][CH3:16])[CH:14]=3)[N:5]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:4]=2[CH:3]=1.[CH3:26][C:27]1[NH:28][CH:29]=[C:30]([CH3:32])[CH:31]=1.Cl>CO.CCOCC>[Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]3[CH:14]=[C:13]([O:15][CH3:16])/[C:12](=[CH:17]/[C:29]4[NH:28][C:27]([CH3:26])=[CH:31][C:30]=4[CH3:32])/[N:11]=3)[N:5]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:4]=2[CH:3]=1
Reactant: COc1cc(-c2cc3sc(Cl)cc3n2C(=O)OC(C)(C)C)[nH]c1C=O
Reactant: Cc1c[nH]c(C)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC1=CC(c2cc3sc(Cl)cc3n2C(=O)OC(C)(C)C)=N/C1=C\c1[nH]c(C)cc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
To a solution of tert-butyl 2-chloro-5-(5-formyl-4-methoxy-1H-pyrrol-2-yl)-4H-thieno[3,2-b]pyrrole-4-carboxylate (11 mg) and 2,4-dimethyl-1H-pyrrole (3.5 mg) in 1 mL of MeOH was added 2 small drops of a solution of 2 N HCl in ether. The dark-red reaction solution was stirred at r.t. for 10 min and then quenched with 3 mL of pH 7 sodium phosphate buffer solution. The product was extracted with 2×5 mL of EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by Combiflash on a silica gel column eluted with a gradient up to 60% EtOAc/hexanes to give 10 mg of the title compound as a dark solid.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][N:7]=1.[CH3:15]O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:15][O:13][C:12](=[O:14])[C:10]1[CH:9]=[CH:8][N:7]=[C:6]([Cl:5])[CH:11]=1
Reactant: CO
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
To a solution of thionyl chloride (13.85 mL, 190.38 mmol) in toluene (50 mL) was added 2-chloropyridine-4-carboxylic acid (15 g, 95 mmol). The solution was heated to reflux for 3 hours. The resulting brown color solution was cooled to room temperature, and methanol (11.56 mL, 285.6 mmol) was added slowly dropwise. The mixture was brought to reflux for 15 minutes and became clear. The solution was then cooled to room temperature and poured into water (150 mL), basified with 50 percent sodium hydroxide and extracted with ethyl acetate (2×200 ml). The organic layer was separated and washed with brine, dried with magnesium sulfate, filtered and concentrated to yield the titled compound (11.93 g, 73%) as a brown color solid. This was used in the next step without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31](/[C:44](=[CH:48]\[CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)/[C:45](O)=[O:46])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([C:40]([F:43])([F:42])[F:41])=[N:38][N:37]=[N:36]1.[NH2:55][C:56]1[S:57][CH:58]=[CH:59][N:60]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31](/[C:44](=[CH:48]\[CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)/[C:45]([NH:55][C:56]2[S:57][CH:58]=[CH:59][N:60]=2)=[O:46])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([C:40]([F:43])([F:42])[F:41])=[N:38][N:37]=[N:36]1
Reactant: O=C(O)/C(=C/C1CCCCC1)c1ccc(-n2nnnc2C(F)(F)F)c(Cl)c1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)/C(=C/C1CCCCC1)c1ccc(-n2nnnc2C(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.5 %

Procedure:
A solution of triphenylphosphine (772 mg, 2.96 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (526 mg, 2.96 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylic acid (594 mg, 1.48 mmol) in methylene chloride (5 mL). The reaction mixture was then stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (444 mg, 4.44 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (70 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 5/1 to 3/2 hexanes/ethyl acetate) afforded (E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl] -3-cyclohexyl-N-thiazol-2-yl-acrylamide (82 mg, 11%) as an amorphous solid: EI-HRMS m/e calcd for C20H18ClF3N6OS (M+) 482.0903, found 482.0906.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC1(C)C(C)(C)OB([C:54]2[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=2)O1>ClCCCl>[CH3:19][N:20]([CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([C:54]3[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=3)=[N:7][C:6]=2[CH:8]=1)[CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1
Reactant: CNC1CCN(C)CC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCC(N(C)Cc2cc3nc(-c4cccnc4)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (0.5 g, 1.8 mmol) in 1,2-dichloroethane (10 mL) was added N,1-dimethylpiperidin-4-amine (0.3 g, 2.3 mmol) and AcOH (100 μL, 1.8 mmol). After stirring 10 min at room temperature, Na(OAc)3BH (0.5 g, 2.1 mmol) was added and the resulting mixture stirred overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3 and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by silica gel chromatography (95:5; CH2Cl2: 2 M NH3 in MeOH). A portion of the purified intermediate (0.3 mmol) was coupled following General Procedure A with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to provide 213 after reverse phase HPLC purification (27 mg). MS (Q1) 439 (M)+.