Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:12][C:13]=2[CH3:14])=[C:5]([O:24][CH3:25])[CH:4]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:35])=O>C(OCC)(=O)C>[Cl:35][CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:12][C:13]=2[CH3:14])=[C:5]([O:24][CH3:25])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)/C=C/c1nc(COc2ccc(CO)cc2OC)c(C)o1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1nc(COc2ccc(CCl)cc2OC)c(C)o1
Yield: 89.1 %

Procedure:
To mixture of ethyl (2E)-3-{4[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (5.0 g) and toluene (100 mL) was added thionyl chloride (1.88 g), and the mixture was heated under reflux for 1 hr. After concentration of the reaction mixture, ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl(2E)-3-{4[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (4.69 g, yield 89%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 107-108° C.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].[Cl:13][C:14]1[C:15]2[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=2[S:17][C:18]=1[C:19](Cl)=[O:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH2:2]([N:6]1[C:10]([CH3:11])=[CH:9][S:8]/[C:7]/1=[CH:12]\[C:19]([C:18]1[S:17][C:16]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=2[C:14]=1[Cl:13])=[O:20])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: CCCC[n+]1c(C)csc1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: CCCCN1C(C)=CS/C1=C\C(=O)c1sc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 3-chlorobenzo[b]thiophene-2-carbonyl chloride (37.0 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.98 (t, 3 H) 1.39-1.48 (m, 2 H) 1.70-1.80 (m, 2 H) 2.31-2.37 (m, 3 H) 4.00-4.09 (m, 2 H) 6.67-6.70 (m, 1 H) 6.85-6.89 (m, 1 H) 7.49-7.56 (m, 2 H) 7.85-7.92 (m, 1 H) 8.01-8.07 (m, 1 H); MS (ESI) positive ion 364 (M+H).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[C:25](I)[CH:24]=[CH:23][C:22]=1[OH:28]>C(Cl)Cl>[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[C:25]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)[CH:24]=[CH:23][C:22]=1[OH:28]
Reactant: COC(=O)c1cc(I)ccc1O
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: ClCCl
Product: COC(=O)c1cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)ccc1O

Procedure:
rac-5-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)ethynyl]-2-hydroxybenzoic acid methyl ester was prepared by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 2-hydroxy-5-iodobenzoic acid methyl ester [M. Covello, Chim. Ther. 2, 73 (1967)] as described in Example 4. The compound was isolated by chromatography over silica gel using methylene chloride and was crystallized from ethyl acetate/hexane to yield colorless crystals with m.p. 151°-153° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][C:5]([C:7]#[N:8])=[CH:4][C:3]1=[O:9].[BH4-].[Na+].C(O)(=O)C>CO>[OH:9][CH:3]1[C:2]([CH3:10])([CH3:1])[CH2:6][C:5]([C:7]#[N:8])=[CH:4]1
Reactant: CC1(C)CC(C#N)=CC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)CC(C#N)=CC1O
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4,4-dimethyl-3-oxocyclopent-1-enecarbonitrile (Step 1, 6 g, 44.4 mmol) in methanol (50 ml) was added sodium borohydride (2.52 g, 66.6 mmol) at 0° C. under nitrogen atmosphere. Reaction mixture was stirred at same temperature for 20 mins. Progress of reaction was monitored by TLC. After completion of reaction, distilled the reaction mixture was concentrated under reduced pressure. To crude reaction mass water (10 ml) was added followed by addition of 1 ml acetic acid. Aqueous reaction mixture was extracted in ethyl acetate (2×25 ml). Combined organic layer was dried on sodium sulphate and concentrated under reduced pressure to get oily compound which was directly used for next reaction without further purification (3.9 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:11]=1)=[CH2:5])C.C1C(=O)N([Br:23])C(=O)C1>C1COCC1.O>[Br:23][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:11]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1ccc(C(=O)OC)nc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(=O)CBr)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of step 1 product (780 mg, 3.76 mmol) in THF (37.5 ml) and H2O (2.5 ml) was added NBS (670 mg, 3.76 mmol) in one portion. The solution was stirred at rt for 10 min, solvent was removed and purified on silica gel column eluting a gradient of 8-75% EtOAc in hexane to afford methyl 5-(bromoacetyl)pyridine-2-carboxylate (0.92 g) LCMS: [M+H]+=258.1, 260.1.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1([CH3:31])[O:9][C:8](=[O:10])[CH:7]([CH:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[C:12]#[C:13][CH3:14])[C:6](=[O:30])[O:5]1.O.Cl>CC(O)=O>[CH3:3][C:4]1([CH3:31])[O:9][C:8](=[O:10])[CH:7]([CH:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[O:1])=[CH:17][CH:16]=2)[C:12]#[C:13][CH3:14])[C:6](=[O:30])[O:5]1
Reactant: CC#CC(c1ccc(SCc2ccccc2C)cc1)C1C(=O)OC(C)(C)OC1=O
Reactant: OO
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC#CC(c1ccc(S(=O)Cc2ccccc2C)cc1)C1C(=O)OC(C)(C)OC1=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
Hydrogen peroxide (20 μL, 0.05 mmol) was added to a 0° C. solution of 28.3 (20 mg, 0.05 mmol) in AcOH (2 mL). The reaction was stirred at 80° C. for 1.5 hours, then cooled to room temperature and stirred for 16 hours. The reaction mixture was poured into cold water and the resulting solution was acidified to pH=2 with 6N HCl(aq). The aqueous layer was extracted with ethyl acetate and sec-butanol. The combined organic layers were concentrated to yield 10 mg (50%) of 2,2-Dimethyl-5-[1-(4-o-tolylmethanesulfinyl-phenyl)-but-2-ynyl]-[1,3]dioxane-4,6-dione (29.1). LC/MSD m/e: 383.0 (consistent with di-acid-H).
Reaction SMILES: [CH2:1]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[ClH:34]>O1CCOCC1>[CH2:1]([N:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)[CH2:21][CH2:22]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[ClH:34]
Reactant: CCCCCCCCCCCCCCCCN1CCN(Cc2ccc(C(=O)OC)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCN1CCN(Cc2ccc(C(=O)O)cc2)CC1

Procedure:
A mixture of 40 mmole methyl 4-[1-(n-hexadecyl)-piperazin-4-ylmethyl]-benzoate, 100 ml. 6N hydrochloric acid and 20 ml. dioxan is maintained at reflux temperature for 16 hours, then concentrated, cooled and suction filtered. After recrystallisation from a DMF-water mixture, there is obtained a yield of 62% of theory of the desired product as a hydrochloride; m.p. 245° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:10]3[S:14][C:13]([NH2:15])=[N:12][C:11]=3[CH:16]=2)[CH:2]=1.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1(C)C=CC=CC=1>[CH2:34]([O:33][C:31](=[O:32])[NH:15][C:13]1[S:14][C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:8][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:16][C:11]=2[N:12]=1)[CH3:35]
Reactant: CCOC(=O)Cl
Reactant: Nc1nc2cc(-c3cccnc3)cc(-c3ccccn3)c2s1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3ccccn3)c2s1
Temperature: 40 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
To a solution of 5-pyridin-3-yl-7-pyridin-2-yl-benzothiazol-2-ylamine (0.10 g, 0.33 mmol) in toluene (5 mL) was added triethylamine (0.10 ml, 0.07 mmol) at room temperature. The reaction mixture was heated to 40° C. followed by the addition of ethyl chloroformate (0.17 g, 0.16 mmol). The resulting reaction mixture was stirred under nitrogen atmosphere at 70° C. for 16 h. After the completion of reaction (TLC monitoring) toluene was evaporated under reduced pressure. The crude solid residue was washed with water and was purified by chromatography over silica gel (230-400 M) using ethyl acetate:hexane (60:40) to provide the title compound as white solid (0.046 g, 38%). M.P. 235° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8](Cl)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2].[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8]([C:21]2[CH:22]=[CH:23][S:19][CH:20]=2)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: OB(O)c1ccsc1
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1-c1ccsc1
Yield: 68 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (100 mg, 0.357 mmol) was reacted with 3-thienyl boronic acid (2 eq) to give 3-(2-thien-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (80 mg, 68%).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:42][C:43](=[O:49])[C@H:44]([CH:46]([CH3:48])[CH3:47])[NH2:45]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]([NH:45][C@H:44]([C:43]([OH:42])=[O:49])[CH:46]([CH3:48])[CH3:47])=[O:34])=[CH:36][CH:37]=2)=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCC(=O)N[C@H](C(=O)O)C(C)C)cc2)cc1

Procedure:
The product from Example 95C and L-valine methyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.36-13.13 (br.s, 1 H), 8.94 (s, 1 H), 7.99 (d, 1 H), 7.23 (m, 7 H), 7.03 (t, 1 H), 6.95 (m, 6 H), 6.82 (d, 2 H), 4.58 (d, 2 H), 4.21 (dd, 1 H), 4.05 (s, 2 H), 4.00 (s, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.10 (m, 1 H), 0.87 (dd, 6 H); MS (ESI+) m/z 646 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:12](=[O:37])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]1[S:27][C:28]([C:32]([O:34]CC)=[O:33])=[C:29]([CH3:31])[N:30]=1)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>O1CCCC1.C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:12](=[O:37])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]1[S:27][C:28]([C:32]([OH:34])=[O:33])=[C:29]([CH3:31])[N:30]=1)=[CH:15][CH:14]=2)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1sc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of ethyl 2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylate (0.69 g, 1.2 mmol) in tetrahydrofuran (10 ml) and ethanol (10 ml) was added 1N sodium hydroxide solution (3 ml). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-n-hexane to give 2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylic acid (0.61 g, 93.8%) as crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(O)cc1
Product: CS(=O)(=O)c1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-methanesulfonylphenol: 1H NMR (300 MHz, CDCl3) δ 7.67 (app. d, J=8.8 Hz, 2H), 7.67 (d, J=8.6 Hz, 1H), 7.19 (d, J=2.5 Hz, 1H), 7.05-6.95 (m, 3H), 4.29 (t, J=5.3 Hz, 2H), 4.20 (q, J=8.6 Hz, 2H), 4.05 (t, J=5.1 Hz, 2H), 3.01 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:14]([C:15](O)=[O:16])[C:13]=2[C:21]([OH:23])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:25][CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28]>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:14]3[C:13]=2[C:21](=[O:23])[N:25]([CH:26]2[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]2=[O:28])[C:15]3=[O:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(Nc2cccc(C(=O)O)c2C(=O)O)cc1
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Yield: 92 %

Procedure:
A mixture of 3-(4-tert-butylphenylamino)phthalic acid (0.50 g, 1.6 mmol) and rac-α-aminoglutarimide hydrochloride (0.26 g, 1.6 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), and evaporated. The residue was chromatographed in 1:1 hexanes-ethyl acetate, eluting 0.60 g of the product, in 92% yield: mp 228-230° C.; 1H NMR (CDCl3) δ 1.34 (s, 9H), 2.14-2.19 (m, 1H), 2.73-2.96 (m, 3H), 4.96 (dd, J=11.9 Hz, J=5.1 Hz, 1H), 7.16-7.22 (m, 3H), 7.33-7.49 (m, 4H), 7.98 (s, 1H), 8.07 (s, 1H); 13C NMR (CDCl3) δ 22.8, 31.3, 31.4, 34.5, 49.0, 111.2, 113.4, 118.6, 122.7, 126.5, 132.5, 135.8, 136.1, 144.4, 148.1, 167.4, 168.4, 169.3, 171.1; Anal. calcd for C23H23N3O4.0.25H2O: C, 67.39; H, 5.78; N, 10.25. Found: C, 67.42; H, 5.65; N, 10.15.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C:9]12([C:19](Cl)=[O:20])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.C(OCC)C>C(N(CC)CC)C>[C:9]12([C:19]([C:5]3[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=3)=[O:20])[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:12][CH:11]([CH2:17]3)[CH2:10]1)[CH2:18]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: NC(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: NC(=O)c1n[nH]c(C(=O)C23CC4CC(CC(C4)C2)C3)n1

Procedure:
To a cooled, stirred mixture of 2 g. of 1,2,4-triazole-3-carboxamide and 5.4 g. of adamantylcarbonyl chloride in 125 ml. of anhydrous diethyl ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred at room temperature for 23.5 hours. The mixture is filtered and the solid is washed successively with diethyl ether, cold water, diethyl ether and dried in vacuo for 3 hours yielding 4.5 g. of colorless solid. This solid is extracted with hot dry acetonitrile, cooled and washed with acetonitrile yielding 0.4 g. of colorless crystals. The remaining 3.5 g. of acetonitrile insoluble solid is further extracted with acetonitrile, yielding an additional 0.6 g. of product, m.p. 213°-216° C. (dec.).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:26][C:27]1([CH3:33])[O:31][C:30](=[O:32])[NH:29][CH2:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[CH:7][C:2]([N:29]5[CH2:28][C:27]([CH3:33])([CH3:26])[O:31][C:30]5=[O:32])=[N:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(Br)cn2)CC1
Reactant: CC1(C)CNC(=O)O1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(N3CC(C)(C)OC3=O)cn2)CC1
Yield: 17.8 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 243 and 5,5-dimethyloxazolidin-2-one (52 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (29 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[C:19](Cl)(Cl)=[O:20]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:3]=1[N:4]=[C:19]=[O:20]
Reactant: COc1cc(N)c(Br)cc1OC
Reactant: O=C(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc(Br)c(N=C=O)cc1OC
Temperature: 90 °C

Procedure:
2-Bromo-4,5-dimethoxyaniline (464 mg, 2.0 mmol) was dissolved in 10 ml of toluene at room temperature. DMAP (1 eq, 245 mg), and pyridine (1.3 eq, 0.22 ml) were added followed by phosgene (1.33 eq, 1.33 ml of a 20% solution in toluene). The mixture was heated to 90° C. for 4 hours. Upon cooling, the mixture was filtered and the filtrate was concentrated in vacuo to give 1-bromo-2-isocyanato-4,5-dimethoxy-benzene (542 mg, quantitative) as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])=[C:17]([O:26][CH3:27])[CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])=[C:17]([O:26][CH3:27])[CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C(C)(C)CO)c(OC)c3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)ccc1C(C)(C)CO
Temperature: 70 °C
Reaction time: 24 h
Yield: 75.2 %

Procedure:
A mixture of the methyl 6-chloro-5-(4-(1-hydroxy-2-methylpropan-2-yl)-3-methoxyphenyl)-1H-indole-3-carboxylate (25 mg, 0.064 mmol), 2.4 ml of methanol (2.4 mL), and 0.8 mL of 1 M aqueous solution of sodium hydroxide (0.8 mL, 0.8 mmol) was stirred at 70° C. for 24 hours—the starting material is consumed by TLC and LCMS. The reaction mixture was cooled to room temperature, diluted with 1 M solution of potassium bisulfate (1 mL) and the obtained mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over anhydrous magnesium sulfate and loaded on silica gel. A silica gel column was equilibrated with 30% ethyl acetate in heptane. Chromatography on this column, eluting with a solution of 3% of acetic acid and 30% of ethyl acetate in heptane gave the title compound (18 mg, 73% yield). MS (ES−) 372.1 (M−H)−. Retention time: 3.00 min Column: Phenomenex Gemini-NX, 4.6 mm×50 mm, C18, 3 μm, 110A; Column Temperature 60° C. Mobile Phase A: 0.1% formic acid in water (v/v); Mobile Phase B: 0.1% formic acid in acetonitrile (v/v) Gradient Profile: Flow-1.5 mL/min. Initial conditions: A-95%, B-5%; Linear Ramp to A-0%, B-100% over 0.0-4.10 min; hold at A-0%, B-100% from 4.10-4.50 min; return to initial conditions 4.60-5.0 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([NH:30][CH2:31][CH2:32][CH3:33])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([NH:30][CH2:31][CH2:32][CH3:33])(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCNS(=O)(=O)c1ccc(C)c(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CCCNS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-4-methyl-N-propyl-benzenesulfonamide (Intermediate 150), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[NH2:15][CH2:16][CH:17]1[CH2:19][CH2:18]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: NCC1CC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(NCCO)nc1NCC1CC1

Procedure:
In analogy to the procedure described in example 38b, 4,6-dichloro-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with aminomethyl-cyclopropane in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-chloro-6-(cyclo-propylmethyl-amino)-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=268.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5]2.[CH3:18][N:19]1C(=O)CCC1>>[C:18]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5]2)#[N:19]
Reactant: CN1CCCC1=O
Reactant: CCOC(=O)c1cc2cc(Br)c(OC)cc2[nH]1
Product: CCOC(=O)c1cc2cc(C#N)c(OC)cc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of ethyl 5-bromo-6-methoxy-1H-indole-2-carboxylate obtained in step 1 (300 mg; 1.01 mmol) and cuprous cyanide (108 mg; 1.21 mmol) in NMP (10 mL) was heated under microwave irradiations at 200° C. for 30 minutes. The dark solution was filtered through a short pad of silica, which was washed with DCM. The obtained dark red solution was concentrated in vacuo and the oily residue was precipitated in water. The solid was collected by filtration, washed thoroughly with water and dried under high vacuum. Purification by silica column chromatography (DCM then DCM/MeOH, 99/1) gave the title compound as a slightly pink solid. HPLC (Method A), Rt 3.45 min (Purity: 97.4%). LC/MS (Method B): 243.2 (M+H)+.