Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][CH:15]=[C:14]([CH:17]=[CH:18][C:19]([OH:21])=O)[C:13]=3[CH:22]=2)[S:3]1.CCN(C(C)C)C(C)C.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C1COCC1>[O:21]=[C:19]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH:18]=[CH:17][C:14]1[C:13]2[CH:22]=[C:9]([CH:8]=[C:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])[CH:10]=[CH:11][C:12]=2[O:16][CH:15]=1
Reactant: O=C(O)C=Cc1coc2ccc(C=C3SC(=O)NC3=O)cc12
Reactant: C1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1NC(=O)C(=Cc2ccc3occ(C=CC(=O)N4CCCCC4)c3c2)S1
Reaction time: 1 h

Procedure:
180 mg (0.57 mmol) of 3-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-acrylic acid (example 72) was suspended in THF (25 ml). To this suspension was added DIEA (2 eq.) and piperidine (3 eq.). Under stirring was added PyBOP (1.5 eq.). After 30 min the reaction mixture became clear, after an additional 1 h a precipitate was formed. The reaction was stirred overnight. The precipitate was filtered off and washed with THF and 1N HCl affording the title compound in high purity.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([F:36])[CH:35]=1)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[C:12](/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25]C(=O)OC(C)(C)C)=[O:17])[CH:11]=[N:10]1>O1CCOCC1.CCOC(C)=O>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][C:16](=[O:17])/[CH:15]=[CH:14]/[C:12]1[CH:11]=[N:10][N:9]([CH2:8][CH2:7][O:6][C:5]2[CH:33]=[C:34]([F:36])[CH:35]=[C:3]([Cl:2])[CH:4]=2)[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1cnn(CCOc2cc(F)cc(Cl)c2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ccccc1NC(=O)/C=C/c1cnn(CCOc2cc(F)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 107.4 %

Procedure:
A 4 M solution of HCl in dioxane (2 mL) was added to a solution of (E)-tert-butyl (2-(3-(1-(2-(3-chloro-5-fluorophenoxy)ethyl)-1H-pyrazol-4-yl)acrylamido)phenyl)carbamate (118 mg, 0.23 mmol) in dioxane (3 mL) and the mixture was stirred for 6 h at room temperature under a nitrogen atmosphere. The reaction mixture was then diluted with EtOAc (15 mL). The salt was filtered, washed with EtOAc and dried overnight to give 99 mg of the hydrochloric acid salt of (E)-N-(2-aminophenyl)-3-(1-(2-(3-chloro-5-fluorophenoxy)ethyl)-1H-pyrazol-4-yl)acrylamide as an off-white solid. MS: ES+(M+Na)+: 423
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)=[CH:4][C:3]=1[N:20]1[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[N:22]([CH2:28][C:29]([OH:31])=[O:30])[C:21]1=[O:32].S(=O)(=O)(O)O.[CH3:38]O>>[CH3:38][O:30][C:29](=[O:31])[CH2:28][N:22]1[C:23]([CH3:26])([CH3:27])[C:24](=[O:25])[N:20]([C:3]2[CH:4]=[C:5]([CH2:8][C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](=[O:19])[NH:11][N:10]=3)[CH:6]=[CH:7][C:2]=2[F:1])[C:21]1=[O:32]
Reactant: CC1(C)C(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)N1CC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CN1C(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)C1(C)C
Temperature: 70 °C

Procedure:
To a solution of {3-[2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-phenyl]-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl}-acetic acid (36B)(0.044 g, 0.10 mmol) in methanol (2 ml) was added concentrated sulfuric acid (0.25 ml) and heated at 70° C. for 90 minutes before being cooled to rt. The reaction mixture was then concentrated in vacuo, diluted with water (5 ml) an extracted with ethyl acetate (2×10 ml). The organic layer was then dried over magnesium sulfate and concentrated in vacuo to afford a colourless oil. Single peak in LC-MS, (42 mg, 91% purity) and required no further purification; m/z (LC-MS, ESP), RT=3.31 mins (M+H) 453;
Reaction SMILES: [Si]([O:18][C:19]1[CH:59]=[CH:58][C:22]([O:23][CH2:24][C@@H:25]([OH:57])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:56]=[CH:55][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=4[C:51]([F:54])([F:53])[F:52])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:53][C:51]([F:52])([F:54])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[CH2:44][NH:43][C:41]([N:38]1[CH2:39][CH2:40][CH:35]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:57])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:59][CH:58]=3)=[CH:56][CH:55]=2)[CH2:36][CH2:37]1)=[O:42]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4ccccc4C(F)(F)F)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccccc1C(F)(F)F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 58.3 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-[2-(trifluoromethyl)benzyl]-1-piperidinecarboxamide (0.211 g, 0.24 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.085 g, 0.14 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)(=[O:15])=[O:14])=[O:11])[N:3]=1.[H][H]>[Pd].C(O)C>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:10]([NH:9][C:4]1[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)=[O:11])(=[O:14])=[O:15]
Reactant: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2[N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2N)n1
Reaction time: 1 h

Procedure:
A suspension containing 1 g of N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-2-nitrobenzenesulfonamide, 0.2 g of 5% palladium on carbon and 50 ml of ethanol was shaken in a Paar apparatus under 40 p.s.i.g. hydrogen at ambient temperature. After one hour, the reaction mixture was filtered and the solids thereby recovered, which contained catalyst and desired product, was stirred with 10% aqueous sodium hydroxide. Filtration of that mixture and acidification of the filtrate with hydrochloric acid to pH 3 caused the desired product to precipitate. After removal by filtration and drying, the desired product melted at 212°-216° and showed infrared absorption peaks at 3200 and 3300 cm-1, consistent for the desired amino-containing compound. Mass spectrometry showed two particles of mass 198 and 123 units, equivalent to aminobenzenesulfonyl isocyanate and 2-amino-4,6-dimethylpyrimidine respectively, as expected for the desired compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2=[O:23])[C@H:15]2[C@H:6]1[C@@H:7]1[C:12]([CH2:13][C@H:14]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][Si](C(C)(C)C)(C)C)=[CH:11][C:10](=[O:41])[CH2:9][CH2:8]1)(=[O:3])[CH3:2].S(=O)(=O)(O)O>CO.C(OCC)(=O)C>[C:1]([O:4][C@@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2=[O:23])[C@H:15]2[C@H:6]1[C@@H:7]1[C:12]([CH2:13][C@H:14]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])=[CH:11][C:10](=[O:41])[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2[C@H](CCCCCCCCCO[Si](C)(C)C(C)(C)C)CC3=CC(=O)CC[C@@H]3[C@H]21
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)O[C@@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2[C@H](CCCCCCCCCO)CC3=CC(=O)CC[C@@H]3[C@H]21
Reaction time: 2.5 h
Yield: 98.6 %

Procedure:
19.9 g of 11α-acetoxy-7α-(9-tert-butyldimethylsilyloxynonyl)-estr-4-ene-3,17-dione in 90 ml of methanol is mixed at room temperature with 20 ml of 8% sulfuric acid. After 2.5 hours, it is diluted with ethyl acetate, washed neutral with saturated sodium bicarbonate solution and water and dried. The chromatography of the crude product on silica gel with a methylene chloride-acetone gradient yields 15.8 g of 11α-acetoxy-7α-(9-hydroxynonyl)-estr-4-ene-3,17-dione as a foam.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([NH:16][C@H:17]([C:22]([O:24]C)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH:8]=[CH:7]2)([O-])=O.[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:1][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH2:13][C:14]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])=[O:15])[CH:8]=[CH:7]3)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)Cn1ccc2cc([N+](=O)[O-])ccc21
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)C[C@H](NC(=O)Cn1ccc2cc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ccc21)C(=O)O

Procedure:
The title compound was prepared from methyl N-[(5-nitro-1H-indol-1-yl)acetyl]-L-leucinate and 4-tert-butylphenyl sulfonyl chloride following the procedures of Example 10 Step 4 and Step 5: MS (ESI) m/z 500; MS (ESI) m/z 498.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)[C:11]([O:21][CH3:22])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:23](=[O:25])[CH3:24])[CH:15]=3)[C:11]([O:21][CH3:22])=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cnc(-c2ccc(F)cc2)nc1-c1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: COc1cnc(-c2ccc(F)cc2)nc1-c1cccc(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 73 %

Procedure:
One drop of 96% sulfuric acid was added to a mixture of 1.2 g of 2-(4-fluorophenyl)-4-(3-hydroxyphenyl)-5-methoxypyrimidine and 0.5 g of acetic anhydride, and the resulting mixture was stirred for 20 hours at room temperature. After completion of the reaction, ice-cold water was added to mixture. Subsequently, the mixture was extracted with ethyl acetate. The solvent was evaporated off, and the residue was purified by column chromatography on silica gel thereby obtaining 1.0 g of 2-(4-fluorophenyl)-4-(3-acetoxyphenyl)-5-methoxypyrimidine (Compound 55).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33]>C1COCC1>[O:33]=[C:24]1[C:25]2[C:26](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:28])[N:23]1[CH2:22][CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: COC(=O)Cc1ccsc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1ccsc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To pure methyl 2-(thiophen-3-yl)acetate in THF cooled to −78° C. was added LiHMDS and the solution stirred at −78° C. for 30 min. Then N-(bromomethyl)phthalimide was added directly and the solution was allowed to warm to 0° C. The mixture was poured into NaHCO3(sat) extracted with EtOAc, dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 0-40% EtOAc/Hex) gave pure methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(thiophen-3-yl)propanoate (E429).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]#[C:10][CH2:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:39]I>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]#[C:10][CH2:11][CH2:12][CH2:13][I:39]
Reactant: II
Reactant: OCCCC#Cc1cc(Cl)ccc1Cl
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Clc1ccc(Cl)c(C#CCCCI)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
5-(2,5-Dichlorophenyl)pent-4-yn-1-ol (13.7 g, 59.8 mmol), triphenylphosphine (20.4 g, 77.8 mmol), and imidazole (5.71 g, 83.8 mmol) in a mixed solvent (100 ml acetonitrile-150 ml ether) was stirred under nitrogen at 0° C., and to this was slowly added iodine (21.3 g, 83.8 mmol). The solution was allowed to warm to room temperature and stirring was continued for 18 hours. This was chromatographed on silica gel with hexane to give the title compound (14.7 g, 72%), MS m/z 337.9 In the manner described in Example 30, above, the following alcohols in Table III were converted to the corresponding bromides:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:34])[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:20][CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14].I[CH3:36]>CN(C=O)C>[CH3:3][O:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:34])[S:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])=[CH:20][CH:19]=1)([O:17][CH3:36])[C:13]([F:15])([F:14])[F:16]
Reactant: COCCn1cccc1C(O)(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1cccc1C(OC)(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a suspension of 3.8 mg of NaH (0.10 mmol) in 3 mL of DMF at 0° C. was added 32 mg of N-(4-{-[1-(2-methoxyethyl)-1H-pyrrol-2-yl]-2,2,2-trifluoro-1-hydroxyethyl}-phenyl)-N-methyl-benzenesulfonamide (Example 79, 0.068 mmol) and the reaction mixture was stirred at 0° C. for 35 min. 6 μL of iodomethane (0.089 mmol) was added and the reaction mixture allowed to warm to room temperature and stirred for 2.5 h. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:EtOAc, 9:1) to give the title compound.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.Cl.[CH3:20][O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]1>>[CH3:20][O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH:28][C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[CH2:24][CH2:23]1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: CO[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CO[C@H]1CC[C@H](Nc2ncc(C#Cc3ccccc3)cn2)CC1

Procedure:
The title compound, MS: m/e=308.5 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and trans-4-methoxycyclohexanamine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])=[C:5]([CH3:17])[N:4]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]OS(C)(=O)=O)=[CH:20][CH:19]=2)[N:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[N:31]([CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([N:4]2[C:5]([CH3:17])=[C:6]([C:7]3[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=3)[C:10]([O:12][CH3:13])=[O:11])[C:2]([CH3:1])=[N:3]2)=[CH:19][CH:20]=1)=[N+:32]=[N-:33]
Reactant: COC(=O)c1cccc(-c2c(C)nn(-c3ccc(CCOS(C)(=O)=O)cc3)c2C)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(-c2c(C)nn(-c3ccc(CCN=[N+]=[N-])cc3)c2C)c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of methyl 3-[3,5-dimethyl-1-(4-{2-[(methylsulfonyl)oxy]ethyl}phenyl)-1H-pyrazol-4-yl]benzoate (step 2, 2.0 mmol) and KI (330 mg, 2.0 mmol) in N,N-dimethylformamide (10 mL) was added sodium azide (260 mg, 4.0 mmol), and then the resulting mixture was stirred for 1.5 h at 100° C. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate/toluene (4:1). The organic layer was washed with water (50 mL) and brine (50 mL), then dried (Na2SO4). After removal of the solvent, the crude product was purified by TLC with hexane/ethyl acetate (1:1) to give the title compound as yellow oil (quant.): 1H-NMR (CDCl3) δ 8.01 (2H, s), 7.53-7.34 (6H, m), 3.95 (3H, s), 3.55 (2H, t, J=7.1 Hz), 2.96 (2H, t, J=7.1 Hz), 2.33 (3H, s), 2.30 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClC(OCC)=O.[OH-].[NH4+:23]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH2:23])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCC(=O)O)cc1OC
Reactant: [NH4+]
Agent: CCOC(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(CCC(N)=O)cc1OC
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-(3,4-dimethoxy-phenyl)-propionic acid (10.0 g, 47.6 mmol) in dry THF (175 mL), under nitrogen, is added TEA (7.3 ml, 52.4 mmol). The resulting mixture is cooled to −10° C. before ethyl chloroformate (5.0 ml, 52 mmol) is added dropwise. After stirring at −10° C. (20 min), ammonium hydroxide (25% in water, 105 ml) in THF (105 mL) is added and the mixture is stirred at −15° C. for 30 min and then at rt for 1.5 h. The reaction mixture is concentrated in vacuo, extracted three times with CH2Cl2 and the combined organic extracts are washed with saturated aqueous NaHCO3 and brine. The organic phase is dried over anhydrous MgSO4, filtered and concentrated to give the title compound as a colorless solid.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:18][C:19]([C@@H:21]([NH:28][C:29]([C@H:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:32][C:33]([O:35]CC)=O)=[O:30])[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[O:20])[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:46][NH2:47]>CO>[CH:1]1([CH2:7][C@H:8]([NH:18][C:19]([C@@H:21]([NH:28][C:29]([C@H:31]([CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:32][C:33]([NH:46][NH2:47])=[O:35])=[O:30])[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[O:20])[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:15])[CH3:16])[CH:12]=[CH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NN
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)OCC)Cc1ccccc1)C(C)C
Solvent: O
Solvent: CO
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)NN)Cc1ccccc1)C(C)C

Procedure:
100 mg (0.164 mmol) of ethyl (R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyrate were stirred at room temperature for 3 hours in a solution of 30% hydrazine hydrate in methanol. Thereafter, the reaction mixture was evaporated and the residue was chromatographed on silica gel with a 14:1:0.1 mixture of methylene chloride, methanol and ammonia. Crystallization of the crude product from methanol/methylene chloride/ether yielded (R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]4-phenylbutyrohydrazide as white crystals, melting point 109°.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:3]1.[CH3:12][C:13]1[CH:20]=[C:19]([N:21]([CH3:23])[CH3:22])[CH:18]=[C:17]([CH3:24])[C:14]=1[CH:15]=[O:16]>O1CCOCC1>[CH3:23][N:21]([CH3:22])[C:19]1[CH:20]=[C:13]([CH3:12])[C:14]([CH:15]2[O:16][C:2]([CH3:1])([CH3:11])[N:3]=[C:4]2[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[C:17]([CH3:24])[CH:18]=1
Reactant: CC1(C)N=C1c1ccccc1
Reactant: Cc1cc(N(C)C)cc(C)c1C=O
Solvent: C1COCCO1
Product: Cc1cc(N(C)C)cc(C)c1C1OC(C)(C)N=C1c1ccccc1

Procedure:
2.25 g of 2,2-dimethyl-3-phenyl-2H-azirine and 2 g of 2,6-dimethyl-4-(dimethylamino)benzaldehyde were exposed to light for 3 hours in 350 ml of 1,4-dioxane (with the light source described in Example 2). After purification as described in Example 11 and crystallization from n-pentane, there was obtained 5-[4-(dimethylamino)-2,6-xylyl]-2,2-dimethyl-4-phenyl-3-oxazoline which melted at 105° C. after drying for 4 hours at 60° C. and 13 Torr.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[N:6]=[C:5]([CH3:14])[CH:4]=1.[Cl:16][C:17]1[N:22]=[C:21](Cl)[N:20]=[C:19]([Cl:24])[N:18]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:16][C:17]1[N:18]=[C:19]([Cl:24])[N:20]=[C:21]([NH:13][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([CH3:14])[CH:4]=[C:3]3[N:2]([CH3:15])[CH3:1])[N:22]=1
Reactant: Cc1cc(N(C)C)c2cc(N)ccc2n1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(N(C)C)c2cc(Nc3nc(Cl)nc(Cl)n3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution containing 3 g of 4-dimethylamino-2-methylquinolin-6-amine, 2.75 g of 2,4,6-trichloro-s-triazine and 4 g of potassium carbonate in 300 ml of tetrahydrofuran is stirred overnight at room temperature, in a 1 l three-necked flask. The reaction medium is filtered, and then the filtrate is concentrated under reduced pressure; 5.1 g (98%) of 4,6-dichloro-2-(4-dimethylamino-2-methylquinolin-6-yl)amino-[1,3,5]triazine are thus obtained in the form of a brown solid whose characteristics are the following:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:5])[CH3:4].[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16](F)[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CS(C)=O>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[C:20]([NH:1][CH2:2][C@H:3]([OH:5])[CH3:4])[CH:21]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(OCc2ccccc2)cc1F
Reactant: C[C@@H](O)CN
Solvent: CS(C)=O
Product: C[C@@H](O)CNc1cc(OCc2ccccc2)ccc1C#N
Temperature: 125 °C
Reaction time: 48 h

Procedure:
A solution of (R)-(−)-1-amino-propan-2-ol (389 g, 5.19 mol) in dimethyl sulfoxide (600 mL) was added to a solution of the product from Step A (786 g, 3.46 mol), basic alumina (786 g), and 4A molecular sieves (131 g). The stirred mixture was heated at 110-140° C. for 24 h, cooled and filtered, the filter-aide was washed with 10 L of 4:1 ether-ethyl acetate followed by 4 L of 3:2 ethyl acetate-hexane. The organic washes were extracted with water (5 L) and the aqueous phase was extracted with 25% ethyl acetate-hexane (4×2 L). The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated to about 3 L and allowed to stand for 48 h. The precipitated solid was collected by filtration, washed with hexane, and vacuum-dried to provide the desired product in two crops (619 g and 86 g). The concentated supernatant was applied to a 5 kg silica gel pad and eluted with a gradient of 10-50% ethyl acetate-hexane to give, after concentration in vacuo, additional product (119 g): total yield was 791 g (81%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:9]=2)[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:3]1[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[N:14]1([CH2:13][CH2:12][O:11][C:8]2[CH:9]=[C:10]3[C:5]([C:4]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[C:3]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[C:2]3=[O:1])=[CH:6][CH:7]=2)[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C(c2cccnc2)=C(c2ccccc2)c2ccc(OCCN3CCNCC3)cc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75 %

Procedure:
To a solution of tert-butyl 4-(2-(1-oxo-3-phenyl-2-(pyridin-3-yl)-1H-inden-6-yloxy)ethyl)piperazine-1-carboxylate (0.38 mmol, 200 mg) obtained in Step 2 of Example 44 in CH2Cl2 (0.3M) was added TFA (20 eq). The resulting mixture was stirred at room temperature for 40 min and diluted with CH2Cl2. The solution was basicified to pH 9 by the addition of 3N NaOH. The mixture was washed with H2O, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (acetone/hexanes=1:1) to obtain the title compound (75%).