Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:28]1[C:32]([CH3:34])([CH3:33])[C:31](=[O:35])[N:30]([C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[C:38](C(F)(F)F)[CH:37]=2)[C:29]1=[O:49])[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16](C(F)(F)F)[CH:15]=2)[C:7]1=[O:27].CC1(C)NC(=O)N(C2C=CC([N+]([O-])=O)=C([C:66]([F:69])([F:68])[F:67])C=2)C1=O>>[CH2:1]([N:28]1[C:32]([CH3:33])([CH3:34])[C:31](=[O:35])[N:30]([C:36]2[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][C:41]=2[C:66]([F:69])([F:68])[F:67])[C:29]1=[O:49])[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[C:66]([F:69])([F:68])[F:67])[C:7]1=[O:27]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCN1C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C1(C)C
Reactant: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])cc2C(F)(F)F)C(=O)N1CCCCCN1C(=O)N(c2ccc([N+](=O)[O-])cc2C(F)(F)F)C(=O)C1(C)C
Yield: 12 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 2, intermediate 11.1 replacing 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-imidazolidine-2,4-dione. The expected compound is obtained in the form of a light yellow foam with a yield of 12%.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=2)=[C:4]([CH3:18])[C:3]=1[CH3:19].CO.[BH4-].[Na+].Cl>O1CCCC1>[OH:17][CH2:16][C:12]1[CH:11]=[C:10]([C:5]2[C:4]([CH3:18])=[C:3]([CH3:19])[C:2]([OH:1])=[C:7]([CH3:8])[C:6]=2[CH3:9])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1c(C)c(-c2cccc(C=O)c2)c(C)c(C)c1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C)c(-c2cccc(CO)c2)c(C)c(C)c1O
Reaction time: 2 h
Yield: 92.7 %

Procedure:
A solution of 4′-hydroxy-2′,3′,5′,6′-tetramethylbiphenyl-3-carbaldehyde (2.03 g, 8.00 mmol) in a mixed solvent of methanol (10 mL) and tetrahydrofuran (20 mL) was ice-cooled, sodium borohydride (90%, 0.336 g, 8.00 mmol) was added, and the mixture was stirred for 2 hr under nitrogen atmosphere. The reaction mixture was treated with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (1.90 g, yield 93%) as colorless crystals. melting point 152-153° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([OH:12])=[CH:7]2.S(Cl)(Cl)(=O)=O.[CH2:18]([N:36]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[C:37](=[O:48])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:39]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl>N1C=CC=CC=1>[CH2:49]([N:36]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:37](=[O:48])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44](=[O:45])(=[O:46])[NH:1][C:2]2[C:3]3[C:8](=[CH:7][C:6]([OH:12])=[CH:5][CH:4]=3)[CH:9]=[CH:10][CH:11]=2)[CH:39]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1cccc2cc(O)ccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cccc(S(=O)(=O)Nc2cccc3cc(O)ccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a stirred solution of 5-amino-2-naphthol (8.0 g, 0.05 mol) in pyridine (80 ml) was added the sulfonyl chloride, N,N-dioctadecyl-3-chlorosulfonylbenzamide (Example 5) (36.2 g, 0.05 mol). The reaction was stirred overnight at room temperature and then poured into excess dilute hydrochloric acid. The mixture was extracted with dichloromethane, washed with water, dried over magnesium sulfate and suction-filtered through a pad of decolorizing carbon. The filtrate was concentrated to an oil which was crystallized from acetonitrile to yield 26.5 g of product.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].N1[CH2:17][C@H:15]([OH:16])[CH2:14][C@H:10]1C(O)=O.N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1>>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:6][C:7]1[CH:8]=[CH:17][C:15]([OH:16])=[CH:14][CH:10]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
proline (Pro) (pyrrolidin-2-yl), hydroxyproline (4-hydroxy-2-pyrrolidinyl), tryptophan (Trp)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]#[N:13])[CH:11]=1)=[O:5])[CH3:2].Cl.[NH2:15][OH:16].C(N(CC)CC)C>CO>[NH2:13][C:12](=[N:15][OH:16])[C:10]1[CH:9]=[N:8][CH:7]=[C:6]([CH:11]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: NO
Reactant: CCOC(=O)c1cncc(C#N)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cncc(C(N)=NO)c1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Ethyl-(5-cyano-3-pyridyl)carboxylate) (WO 96/30372) (1.8 g, 10.2 mmol) was dissolved in methanol (50 mL), the solution was cooled to 0° C. then hydroxylamine hydrochloride (0.71 g, 10.2 mmol) and triethylamine (1.4 mL, 10.2 mmol) were added and the mixture was stirred at room temperature for 72 hours. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel (graded elution of dichloromethane/methanol 95:5 to 93:7) to give the title compound as a white solid which contained 0.3 equivalents of triethylamine hydrochloride (2.5 g).
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25].[Na+].[I-]>>[N:1]1([C:10]2[N:18]=[C:17]([NH:20][C:21]3[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reactant: CCOC(=O)c1cccc(N)c1
Agent: [I-]
Agent: [Na+]
Product: CCOC(=O)c1cccc(Nc2nc(-n3cnc4ccccc43)c3nc[nH]c3n2)c1
Temperature: 140 °C

Procedure:
300 mg of product obtained in stage 1 above are mixed with 0.83 ml (5 equivalents) of ethyl 3-aminobenzoate and 0.166 mg of NaI, and the mixture is then heated at 140° C. for approximately 4 days.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:23]N(C=O)C>>[CH3:23][NH:15][C:14]1[CH:16]=[CH:17][C:11]([O:10][C:9]2[CH:21]=[CH:22][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=2)=[CH:12][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CNc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a mixture of NaH (60% oily, 320 mg, 8.0 mmol) in DMF (30 mL) was added a solution of 4-(4-nitrophenoxy)-2-nitroaniline (Intermediate 8A-2.00 g, 7.3 mmol) in DMF (30 mL) at 0° C. followed by an excess amount of Mel (2.0 mL). The mixture was stirred at 0° C. for 1.5 hrs then at room temperature overnight. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2column chromatography gave the title compound (2.10 g, quant). ): 1H NMR (CDCl3-d1) δ 3.08 (d, 3H), 6.94 (d, 1H), 7.00 (d, 2H), 7.30 (dd, 1H), 7.97 (d, 1H), 8.08 (brs, 1H), 8.22 (d, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH2:22][CH:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:24]([N:26]([CH3:28])[CH3:27])=[O:25]>>[CH3:27][N:26]([CH3:28])[C:24]([CH:23]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25]
Reactant: CN(C)C(=O)C(N)c1ccccc1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: CN(C)C(=O)C(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 2-amino-N,N-dimethyl-2-phenylacetamide hydrochloride (CAN 1214036-19-7) as starting materials. MS (EI): m/e=445.1 [M+H]+.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][CH:1]=[O:3])=[CH:30][CH:31]=1
Reactant: O=CO
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NC=O)cc3)c2cc1OC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Formic acid (0.13 ml) was added to acetic anhydride (0.27 ml), and the admixture was stirred at 60° C. for 2 hours. A solution of 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (303 mg) in tetrahydrofuran (8 ml) was added to the reaction mixture, and the admixture was stirred at room temperature for 45 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 327 mg of 6,7-dimethoxy-4-(4-formylaminophenoxy)quinoline.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:23][C:24]1[C:25]([F:31])=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>O1CCOCC1.C(#N)C>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[C:24]([Cl:23])[C:25]=3[F:31])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Nc1cccc(Cl)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
4.0 M HCl in Dioxane (4.0 ml) was added to a stirred suspension of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline (CAS Registry No162364-72-9, prepared as described in WO98/13354, Example 1) (60 g, 0.2 mol) and 3-chloro-2-fluoroaniline (31.96 g, 0.22 mol) in acetonitrile (1200 ml). The reaction mixture was heated at 80° C. for 1 hour then left to stand overnight. Acetonitrile (500 ml) was added and the resulting precipitate filtered, washed with acetonitrile (3×500 ml) and dried under vacuum to give 7-(benzyloxy)-N-(3-chloro-2-fluorophenyl)-6-methoxyquinazolin-4-amine hydrochloride as a beige solid (85.45 g, 96%); 1H NMR Spectrum: (DMSO d6) 4.02 (s, 3H), 5.35 (s, 2H), 7.30-7.60 (m, 9H), 7.65 (m, 1H), 8.38 (s, 1H), 8.85 (s, 1H), 11.8 (s, 1H); Mass Spectrum: (M+H)+ 410.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:22])[CH2:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[OH-].[Na+].[C:25]([Cl:28])(=[O:27])[CH3:26].Cl>CC(C)=O.O>[ClH:28].[C:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:22])[CH2:16][NH:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)NCC(O)COc1ccc(O)c2c1CCC(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(OCC(O)CNC(C)(C)C)c2c1NC(=O)CC2
Yield: 45.5 %

Procedure:
0.7 g of 8-hydroxy-5-(3-t-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril was suspended in 20 ml of acetone, and 3.0 ml of 1 N sodium hydroxide was added thereto to form a homogeneous solution. 0.2 g of acetyl chloride dissolved in a small amount of acetone was added dropwise to the solution under cooling with water, followed by allowing the mixture to stand under water-cooling for 30 minutes. 2 ml of 1 N hydrochloric acid was added thereto, and the solvent evaporated under reduced pressure. The residue was purified by silica gel column chromatography using chloroformmethanol (8:1 by volume) as an eluent. The solvent was evaporated, and the residue was recrystallized from methanol-diethyl ether to obtain 0.4 g of 8-acetoxy-5-(3-t-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril hydrochloride as colorless flake-like crystals having a melting point of 247°-248° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:9]=2)[CH:5]=[C:4]([CH2:19]O)[CH:3]=1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCC>[Br:22][CH2:19][C:4]1[CH:3]=[C:2]([CH3:1])[C:10]2[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:9]=2)[CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(CO)cc2cn(COCC[Si](C)(C)C)nc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1cc(CBr)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)methanol (138 mg, 0.472 mmol) and carbon tetrabromide (235 mg, 0.708 mmol) in tetrahydrofuran (1 mL) at 0° C. was added triphenylphosphine (186 mg, 0.708 mmol). The resulting solution was stirred at room temperature for 30 min. The reaction was diluted with several volumes of pentane and filtered to remove undissolved solids. The organics were concentrated and purified by column chromatography (5→12% EtOAc/Hex) to give 114 mg (68%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 8.03 (s, 1H), 7.48 (s, 1H), 7.06 (s, 1H), 5.68 (s, 2H), 4.55 (s, 2H), 3.61 (m, 2H), 2.59 (s, 3H), 0.91 (m, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 148.8, 131.6, 129.0, 126.6, 123.3, 121.6, 118.1, 81.7, 67.3, 35.4, 17.7, 17.1, −1.5.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C:14]2=[O:17])=[CH:10][CH:9]=1.Br[CH2:19][CH2:20][O:21][CH2:22][CH2:23]Br>CC(O)(C)C.CC1CCCO1>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][C:13]3([C:14]2=[O:17])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:10][CH:9]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: BrCCOCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC1CCCO1
Product: O=C1c2cc(Br)ccc2CC12CCOCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.2 %

Procedure:
A solution of potassium tert-butoxide (3.94 g, 35.1 mmol) in t-BuOH (35 mL) was added dropwise over 15 min to a solution of 6-bromo-1-indanone (3.53 g, 16.73 mmol) in 2-methyl-tetrahydrofuran (350 mL) at r.t. under a nitrogen atmosphere. After 15 min bis(2-bromoethyl)ether (2.102 mL, 16.73 mmol) was added and the resulting mixture was stirred at r.t. for 5 h. Potassium tert-butoxide (0.938 g, 8.36 mmol) was added and the mixture was stirred at r.t. overnight. The mixture was quenched with saturated aq. NH4Cl (150 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (3×50 mL) and Et2O (50 mL). The combined organics were washed with brine (100 mL), dried over MgSO4, filtered and concentrated. The resulting residue was taken up in DCM, concentrated onto silica gel and purified on a silica gel column eluted with 0-40% EtOAc in heptane to give 1.14 g (24% yield) of the title compound; MS (ES+) m/z 281 [M+H]+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[C:17]([OH:19])=O)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O.CN(C)C=O>C(Cl)Cl>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[C:17]([Cl:22])=[O:19])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C(=O)O)c(SCc2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)Cl)c(SCc2ccccc2)c1

Procedure:
To a solution containing 23.2 g of 3-benzylmercapto-4-carboxy benzaldehyde in 250 ml of methylene chloride is added 15 ml of thionyl chloride and 0.5 ml of dimethylformamide. The reaction mixture is refluxed for 6-7 hours, then evaporated to dryness. Crystallization from 100 ml of ether yielded 27.0 g of 3-benzylmercapto-4-chlorocarbonyl benzaldehyde (a).
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]([O:10][C@@H:11]([C@@H:14]([C@@H:23]([CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:24])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:12]=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O1CCCC1>[NH:1]([C:12]([C@H:11]([C@@H:14]([C@@H:23]([CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[OH:24])[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:13])[NH2:2]
Reactant: NN
Reactant: O=C[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: NNC(=O)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1

Procedure:
To a solution of 3.8 g (119 mmoles) of anhydrous hydrazine in 10 ml of absolute methanol a solution of 5 g (11.9 mmoles) of 2,3,5-tri-O-benzyl-D-arabinose in 10 ml of absolute tetrahydrofuran (THF) is added dropwise while stirring and cooling in an ice bath at a moderate speed. After 10 minutes the ice bath is removed and the solution is stirred for 6 hours at room temperature. Then the solvent is removed with the superfluous hydrazine, and the remaining yellowish oil is dried for removal of the last traces of hydrazine for one day under a continuous oil pump vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][OH:13])[C@@H:7]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:28]([O:35][CH2:36]Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][O:13][CH2:36][O:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:7]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2]
Reactant: ClCOCc1ccccc1
Reactant: CCOC(=O)[C@H]1[C@@H](CCO)CCN1C(=O)OCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1[C@@H](CCOCOCc2ccccc2)CCN1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6 g of cis 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol in 75 ml of methylene chloride containing 7.3 ml of diisopropylethylamine, to which is added 5.1 ml of 85% benzyloxymethyl chloride, is stirred 31/2 hours at room temperature. The solution is washed with water and saturated aqueous sodium bicarbonate. The solution is then dried over sodium sulfate, filtered, concentrated and purified by flash chromatography using ethyl acetate/hexane (1:4) to yield cis ethyl 1-ethoxycarbonyl-3-[2-(benzyloxymethoxy)-ethyl]-pyrrolidine-2-carboxylate.
Reaction SMILES: [C:1](O)(=O)[CH:2]([CH:4]([C:6](O)=O)[OH:5])[OH:3].[NH2:11][C:12]1[CH:13]=[C:14]([CH3:19])[CH:15]=[CH:16][C:17]=1[NH2:18].Cl.P(=O)(O)(O)O>O.C(O)C>[CH3:19][C:14]1[CH:15]=[CH:16][C:17]2[N:18]=[C:1]([CH:2]([OH:3])[CH:4]([OH:5])[C:6]3[NH:11][C:12]4[CH:13]=[C:14]([CH3:19])[CH:15]=[CH:16][C:17]=4[N:18]=3)[NH:11][C:12]=2[CH:13]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: Cl
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: O
Product: Cc1ccc2nc(C(O)C(O)c3nc4ccc(C)cc4[nH]3)[nH]c2c1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of 15.0 g (0.10 mole) tartaric acid, 29.32 g (0.24 mole) 3,4-diaminotoluene, 25 ml water, 15 ml ethanol, 25 ml hydrochloric acid (conc.) and 10 ml 85% phosphoric acid was heated at 120° C. for 40 hours, poured into water and the mixture acidified with concentrated hydrochloric acid. After extraction with chloroform and making the aqueous phase alkaline with sodium hydroxide, a precipitate formed and was collected by filtration. The solid was washed with a small amount of acetone and held in vacuo for 18 hours. The residual moisture was removed by azeotropic distillation of its mixture with benzene.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([C:9]1[CH2:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].C(O)C.[OH-].[K+]>CCOCC>[C:5]([C:9]1[CH:13]=[CH:12][C:11](=[C:2]([CH3:4])[CH3:1])[CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)=O
Reactant: CC(C)(C)C1=CC=CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)=C1C=CC(C(C)(C)C)=C1

Procedure:
Dry acetone (99.3 mmol, 5.77 g, 7.3 mL) and t-butylcyclopentadiene (50.6 mmol, 6.17 g) were mixed in a dropping funnel and added at room temperature to an ethanol solution (10 mL) of KOH (10.3 mmol, 0.58 g) stirring under nitrogen. After stirring overnight, the golden solution was diluted with ether, washed with 2 N HCl, water, and dried over sodium sulfate. A sample of the crude organic fraction (7.4 g) was taken for analysis (GCMS) showing 90% conversion to the title compound. The product was submitted to distillation. 1H-NMR (CDCl3): δ 1.38 (s, 9H), 2.28 (s, 6H), 6.24 (m, 1H), 6.63 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[Cl:19][C:20]1[C:21]([F:31])=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[F:26].N12CCN(CC1)CC2>C1COCC1>[Cl:19][C:20]1[C:21]([F:31])=[C:22]([S:27]([N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1F
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(F)c(Cl)c2F)c(OC)c1
Yield: 53 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (1.00 g, 4.07 mmol) prepared in Example 14a, 3-chloro-2,4-difluorobenzenesulfonyl chloride (1.51 g, 6.11 mmol), 1,4-diazabicyclo[2.2.2]octane (0.69 g, 6.11 mmol) and THF (20 mL), to yield the title compound (0.983 g, 53%) as a colorless amorphous solid.