Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5]2.[Cl:16][C:17]1[CH:22]=[C:21]([N+]([O-])=O)[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-:27].[K+].[K+].O>CS(C)=O>[Cl:16][C:17]1[CH:22]=[C:21]([O:27][C:6]2[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]3[C:4]([CH:5]=2)=[CH:3][CH:2]=[CH:11][CH:10]=3)[CH:20]=[CH:19][N:18]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccc2cc(O)ccc12
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(Oc2ccnc(Cl)c2)cc2ccccc12
Temperature: 70 °C

Procedure:
A stirred mixture of 6-hydroxy-1-naphthalenecarboxylic acid, methyl ester (0.202 g, 1.0 mmol), 2-chloro-4-nitropyridine (0.174 mg, 1.1 mmol) and potassium carbonate (0.276 g, 2 mmol) in dimethylsulphoxide (5 mL) is heated at 70° C. for 1 h. The mixture is poured into water and the crude product is filtered off, washed with water. The crude product is dissolved in ethyl acetate, washed with brine, dried (Na2SO4) and the solvent is evaporated off under reduced pressure to give a residue which is recrystallized from ethylacetate-hexane to afford the title compound as a beige crystalline solid, m.p.: 103-104° C.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:6]2=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:4]=1[CH:23]([CH2:29][CH2:30][CH3:31])[C:24]([O:26]CC)=[O:25])[CH3:2].[OH-].[Na+]>CO.C(O)C>[CH2:1]([C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:6]2=[C:5]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:4]=1[CH:23]([CH2:29][CH2:30][CH3:31])[C:24]([OH:26])=[O:25])[CH3:2]
Reactant: CCCC(C(=O)OCC)c1c(CC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCC(C(=O)O)c1c(CC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 90 °C
Yield: 67.4 %

Procedure:
To a suspension of ethyl 2-[2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.322 g; 0.739 mmol) in a mixture methanol-ethanol (2:1) (22.5 mL) was added a solution of sodium hydroxide 5% (18 mL; 22.5 mmol) and the reaction mixture was heated at 90° C. for 4 h. The organic volatiles were removed under reduced pressure and the remaining basic solution was acidified until pH 2 with a solution of hydrochloric acid 1N. The aqueous layer was extracted with ethyl acetate, the organics were combined, dried over sodium sulphate and concentrated under reduced pressure to furnish 0.203 g (68%) of the title compound as a white solid.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C@@H:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])[CH2:10]1)(C(C)(C)C)(C)C.[ClH:30].O1CCOCC1>C(Cl)Cl>[ClH:30].[F:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH3:29])=[C:21]([CH:11]2[NH:12][CH2:13][C@H:9]([OH:8])[CH2:10]2)[CH:26]=1
Reactant: COc1ccc(F)cc1[C@H]1CC(O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(F)cc1C1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To solution of (R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-carboxylate (1.01 g, 2.37 mmol) in CH2Cl2 (10 mL) at 0° C. was added 4 M HCl in dioxane (5.93 mL, 23.7 mmol). The resulting mixture was warmed to ambient temperature and stirred for 8 hours. The reaction mixture was concentrated under reduced pressure to give the crude material that was triturated with ether. The resulting solids were filtered and dried under reduced pressure to afford (R)-5-(5-fluoro-2-methoxyphenyl)pyrrolidin-3-ol hydrochloride (0.577 g, 2.33 mmol, 98.2% yield). MS (APCI) m/z=212.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1(C)C[CH:6]([OH:8])[CH2:5][C:4](C)(C)N1.[OH:12][CH2:13][CH2:14][N:15]1[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[NH:18][C:17]([CH3:25])([CH3:24])[C:16]1=[O:26]>>[CH2:1]=[CH2:2].[C:6]([O:12][CH2:13][CH2:14][N:15]1[C:20](=[O:21])[C:19]([CH3:22])([CH3:23])[NH:18][C:17]([CH3:25])([CH3:24])[C:16]1=[O:26])(=[O:8])[CH:5]=[CH2:4]
Reactant: CC1(C)NC(C)(C)C(=O)N(CCO)C1=O
Reactant: CC1(C)CC(O)CC(C)(C)N1
Product: C=C
Product: C=CC(=O)OCCN1C(=O)C(C)(C)NC(C)(C)C1=O

Procedure:
The above-named copolymer was prepared by the general procedure of Example 1 by substituting for the 2,2,6,6-tetramethylpiperidin-4-ol an equivalent amount of 1-(2-hydroxyethyl)-3,3,5,5-tetramethylpiperazine-2,6-dione. The reaction was run at 210° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]2([CH3:21])[C@@H:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:12][O:11][C:10]([NH2:20])=[N:9]2)[CH:7]=1.[Cl:23][C:24]1[C:25]([C:31](O)=[O:32])=[N:26][CH:27]=[C:28]([Cl:30])[CH:29]=1>>[NH2:20][C:10]1[O:11][CH2:12][C@H:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:25]3[C:24]([Cl:23])=[CH:29][C:28]([Cl:30])=[CH:27][N:26]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:22])([CH3:21])[N:9]=1
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F
Product: C[C@]1(c2cc(NC(=O)c3ncc(Cl)cc3Cl)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.4) and 3,5-dichloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=495.1 [M+H]+ and 497.2 [M+2+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:19][CH2:18][C@H:17]2[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:20])[CH2:3]1.[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCOC(C)=O.CCCCCC>C1C=CC=CC=1.CCOC(C)=O>[CH2:22]1[O:23][C:11]2([CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@@H:17]2[C@@H:4]([CH2:3][CH:2]([OH:1])[CH2:19][CH2:18]2)[CH2:5][CH2:6]4)[O:20][CH2:21]1
Reactant: OCCO
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@@H]4CC(O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CC[C@@H]4CC(O)CC[C@@H]43)[C@@H]1CCC21OCCO1
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Compound 4(10 g, 36.2 mmol) was dissolved in dry benzene (150 ml) mixed with ethylene glycol (25 ml, 280 mmol) and pyridinium p-toluenesulfonate (1 g, 3.9 mmol) and refluxed using a Dean-stark separator overnight till no starting material was detected by TLC. The cold solution was diluted with EtOAc (100 ml), washed twice with brine, dried on Na2SO4 and the solvents removed under reduced pressure. Flash-chromatography on silica gel with EtOAc: Hexane 4:6 as eluant to give 11.0 g (94.5% yield) the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([O:11][CH3:12])[O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[F:13].C([Li])CCC.[CH:19](N1CCOCC1)=[O:20].[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[CH3:10][O:9][CH:8]([O:11][CH3:12])[C:6]1[CH:5]=[CH:4][C:3]([F:13])=[C:2]([CH:7]=1)[CH:19]=[O:20]
Reactant: COC(OC)c1ccc(F)c(Br)c1
Reactant: O=CN1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COC(OC)c1ccc(F)c(C=O)c1
Temperature: -60 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
6.2 g of 2-Bromo-4-dimethoxymethyl-1-fluorobenzene was dissolved in 65 ml of tetrahydrofuran, and the solution was cooled to −60° C. under a nitrogen gas flow. 18 ml of 1.6M n-Butyl lithium in hexane was added dropwise and the mixture was stirred at −60° C. for 1 hour. 3.3 ml of N-Formylmorpholine was added thereto, and the reaction mixture was allowed to warm to room temperature. The mixture was stirred for 1 hour, then ice-cooled, and treated with water and ammonium chloride solution, then extracted with ethylacetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was subjected to silica gel column chromatography, to give 2.8 g of the title compound (8% ethyl acetate-hexane).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].CO.Br[CH2:9][CH2:10][CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>O>[OH:3][NH:2][CH2:9][CH2:10][CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]
Reactant: NO
Reactant: CCOP(=O)(CCCBr)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOP(=O)(CCCNO)OCC
Yield: 62.8 %

Procedure:
To a solution of hydroxylamine hydrochloride (55.6 g.) in water (100 ml.) were added solution of sodium hydroxide (32.0 g.) in water (75 ml.) under ice-cooling and then methanol (75 ml.). To this solution was added dropwise diethyl 3-bromopropylphosphonate (25.5 g.), whereafter the mixture was warmed at 40°-45° C. for 3 hours with stirring. The methanol was distilled off under reduced pressure. The resultant aqueous solution was adjusted to pH 8 with sodium bicarbonate, washed three times with benzene which were discarded (once with 150 ml. and twice with 100 ml. portions) and then extracted with three 150 ml. portions of chloroform. The chloroform extracts were combined, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give oily diethyl 3-(N-hydroxyamino)propylphosphonate (13.05 g.).
Reaction SMILES: [OH:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:4]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[N:3]1.[CH3:29][N:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:31](Cl)=[O:32]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:5]2[C:4]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[N:3][N:2]([O:1][C:31](=[O:32])[N:30]([CH3:29])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:16][CH:17]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: COc1ccc(-c2c(-c3ccc(F)cc3)c(-c3ccc(C)cc3)nn2O)cc1
Product: COc1ccc(-c2c(-c3ccc(F)cc3)c(-c3ccc(C)cc3)nn2OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-4-(4-fluorophenyl)-5-(4-methoxyphenyl)-3-(4-methylphenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (11%, crystals).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14]CC)=O)[N:9]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:6]2=[N:7][CH:8]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[CH:37]=1>>[CH3:36][C:34]1[S:35][C:31]2[CH:30]=[CH:29][C:28]([NH:27][C:12]([C:10]3[N:9]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[C:6]4=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:26])[F:25])[CH:4]=[C:5]4[CH:11]=3)=[O:14])=[CH:37][C:32]=2[N:33]=1
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Reactant: Cc1nc2cc(N)ccc2s1
Product: Cc1nc2cc(NC(=O)c3cc4cc(C(F)(F)F)cnc4n3Cc3cccc(F)c3)ccc2s1
Yield: 73.1 %

Procedure:
The process is performed according to the method described in step 13.5 of Example 13, starting with 0.35 g (0.96 mmol) of ethyl 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Example 13.4) and 0.17 g (1.06 mmol) of 5-amino-2-methylbenzothiazole. 0.34 g of expected compound is isolated.
Reaction SMILES: CC1C=CC(S([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([OH:28])[CH:24]=4)[CH:19]=3)=[C:14]([O:29][CH3:30])[CH:13]=2)(=O)=O)=CC=1.[OH-].[K+].O>C(O)C>[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21]3)=[C:14]([O:29][CH3:30])[CH:13]=1
Reactant: COc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1-c1ccc2cc(O)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(O)ccc1-c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A solution of 4-(6-hydroxy-2-naphthyl)-3-methoxyphenyl 4-methylbenzenesulfonate (1.74 g, 4.05 mmol), potassium hydroxide (5 g), water (85 mL), and ethanol (85 mL) was stirred at 90° C. for 2 hr. The reaction was cooled to room temperature and concentrated to 50% volume, neutralized with acetic acid, and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, evaporation of the solvent, and purification by silica column (25% ethyl acetate-hexanes) yielded 1.01 g (94%) of the title compound as a tan solid. A sample was further purified by preparative reverse phase HPLC to yield a tan solid: mp 152–154° C.;
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][N:10](C)[CH3:11].[C]=O>>[CH2:1]([N:10]([CH3:11])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C
Reactant: OCc1ccccc1
Agent: [C]=O
Product: CN(C)Cc1ccccc1
Temperature: 200 °C
Reaction time: 5 h

Procedure:
To a glass-lined, stainless steel microreactor were charged 2 ml of benzyl alcohol, 1 ml of trimethylamine, and carbon monoxide (900 psi). The reactor was shaken 5 hours at 200° C. A large yield of benzyldimethylamine was obtained.
Reaction SMILES: [C:1]([C:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:27]([O:26][C:24](=[O:25])[C:23]([C:21]#[N:22])=[C:1]([CH3:2])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:28]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)C(C(C)=O)(C(=O)OCC)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=C(C)C(C(=O)OCC)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of diethyl 2-acetyl-2-phenylmalonate (50 mmol, Example 32, Part A), ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether.
Reaction SMILES: C(N(CC)CC)C.CS([Cl:12])(=O)=O.O[CH2:14][C:15]1[C:16]([CH3:60])=[N:17][C:18]([CH3:59])=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:36]=[N:37][N:38]([C:40]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:39]=2)=[CH:25][CH:24]=1>ClCCl.O>[Cl:12][CH2:14][C:15]1[C:16]([CH3:60])=[N:17][C:18]([CH3:59])=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:36]=[N:37][N:38]([C:40]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:39]=2)=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CO)c(C)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CCl)c(C)n1
Reaction time: 20 h

Procedure:
Triethylamine (2.2 ml) and methanesulphonyl chloride (1.24 ml) were added to a solution of compound B (10.0 g) in dichloromethane (150 ml). The solution was left to stand for 20 hours and then diluted with water (150 ml). The organic phase was separated, washed with saturated sodium chloride solution (150 ml), and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with a mixture of methanol and dichlormethane (1:19 v/v) to give 3-chloromethyl-2,6-dimethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine (C) (8.5 g), as a white solid, m.p. 110°-112° C.; NMR (d6 -DMSO/d4 -acetic acid): 2.5(s,3H), 2.65(s,3H), 4.75(s,2H), 5.45(s,2H), 6.9-7.9 (complex m,24H).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].O.C(=O)(O)[O-].[Na+].[CH:25]1([C:28](O)=O)[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][NH:3][C:4]2[S:5][CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:27][CH2:26]1
Reactant: O=C(O)C1CC1
Reactant: CCOC(=O)c1csc(N)c1C(=O)OCC
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1csc(NCC2CC2)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium borohydride (12.5 g) was added portionwise over 3 hours to a stirred solution of diethyl 2-aminothiophene-3,4-dicarboxyate (Example 36a, 25 g) in cyclopropane carboxylic acid (125 ml). The mixture was stirred at room temperature for 18 hours then further sodium borohydride (5 g) was added and stirring was continued at 50° C. for 16 hours. Further sodium borohydride (5 g) was again added and stirring was continued at 50° C. for 16 hours and then at room temperature for 3 days. Water (500 ml) was added, the mixture was neutralised with sodium bicarbonate and extracted with ether (2×250 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography over silica, eluting with ether/isohexane (2:3) to give the subtitle compound (12.10 g) as an oil.
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=12.[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:21])=[O:20].N1C=CC=CC=1>ClCCl.CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([N:2]2[CH:3]=[C:4]3[C:5]([CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]3)=[N:1]2)=[CH:24][CH:23]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2c[nH]nc2CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(S(C)(=O)=O)cc3)nc2CC1

Procedure:
A solution of 1,1-dimethylethyl 4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 9) (75 mg, 0.32 mmol), [4-(methylsulfonyl)phenyl]boronic acid (128 mg, 0.64 mmol), copper acetate (116 mg, 0.64 mmol), molecular sieves (4 Å, 0.2 g) and pyridine (52 μl, 0.64 mmol) in dichloromethane (2.5 ml) was stirred at room temperature open to atmosphere for 60 hours. The mixture was then diluted with methanol and filtered through a celite pad washing with methanol. The solvent was evaporated in vacuo. Residue was taken up into ethyl acetate and washed with water and 5% aq. sodium hydrogen carbonate, then dried over magnesium sulphate and evaporated in vacuo. The resulting residue was purified by MDAP to afford the title compound (D32). MS (ES+) m/e 392 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)([O-])=O.[CH2:13]([NH2:16])[CH2:14][CH3:15].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C1COCC1.C1COCC1.O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:16][CH2:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCN
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCNC(=O)Nc1ccc(N)cc1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with N-4-aminophenyl-N'-propylurea to generate the title compound. The N-4-aminophenyl-N'-propylurea was prepared by sequentially treating commercial 4-nitrophenyl isocyanate with PrNH2 in THF at 20° C. followed by reduction with Na2S2O4 in THF/H2O at 100° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:15](=[O:16])[C:14]3[C:9](=[C:10]([OH:18])[CH:11]=[CH:12][C:13]=3[OH:17])[C:7](=[O:8])[C:5]=2[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].S([O-])(O[CH2:29][CH3:30])(=O)=O.[CH2:32](C(C)=O)[CH3:33]>>[CH2:32]([O:18][C:10]1[C:9]2[C:7](=[O:8])[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[C:15](=[O:16])[C:14]=2[C:13]([O:17][CH2:29][CH3:30])=[CH:12][CH:11]=1)[CH3:33]
Reactant: CCOS(=O)(=O)[O-]
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(OCC)c2c1C(=O)c1ccccc1C2=O
Reaction time: 8 h

Procedure:
A mixture of quinizarin (20.0 g, 83.5 mmol), potassium carbonate (76 g, 550 mmol) and ethyl sulfate (38.6 g, 250 mmol) was refluxed in methyl ethyl ketone (MEK, 950 mL) for 24 hrs. The reaction was filtered hot through Celite using additional hot MEK. The solution was evaporated on a rotary evaporator until crystallization began, then the reaction was allowed to sit overnight. After cooling in an ice bath, the crystals were filtered, rinsed with Et2O, sucked dry, then dried overnight in a vacuum oven at 70° C. The yield was 14.0 g (57%) of yellow/orange crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[C:18](=O)[CH:17]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH:18]=[C:17]([CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cccc3c2C(=O)C(CC2CCCCC2)C3)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(-c2cccc3c2C=C(CC2CCCCC2)C3)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
82.3 g (229 mmole) 7-(4′-tert-Butyl-phenyl)-2-cyclohexylmethyl-indan-1-one were dissolved in 292 ml toluene in a 1 l-roundbottom flask equipped with a reflux condenser. 9.5 g (1.1 eq.) sodium borohydride were added. Then 40 ml (4.3 eq.) methanol were added at 50° C. and the mixture was stirred for 3 h at 50° C. An additional 1 g of sodium borohydride and 5 ml methanol were added and the mixture was stirred another 2 h at 50° C. 2M sulphuric acid was added until the gas evolution ceased. After addition of 100 ml water the layers were separated and the organic layer was washed two times with 2M sulphuric acid and once with a saturated sodium chloride solution. The solvent was evaporated and the crude indanol was dissolved in approx. 350 ml of toluene. After addition of 0.7 g p-toluene sulfonic acid the mixture was heated to reflux using a Dean-Stark-trap until TLC showed complete conversion (90 min). The solution was washed twice with a saturated NaHCO3-solution, once with water and once with a saturated sodium chloride solution. Drying over magnesium sulphate, evaporation of the solvent and crystallization from 800 ml ethanol afforded 67.3 g (86%) of the desired indene as white crystals. 1H-NMR (400 MHz, CDCl3): δ=7.45, 7.33, 7.25, 7.14 (4×m, 7H, aromatic), 6.69 (s, 1H, ═CH), 3.35 (s, 2H, benzylic), 2.34 (d, 2H, aliphatic), 1.71-1.50 (m, 6H, aliphatic), 1.39 (s, 9H, C(CH3)3), 1.24-0.87 (m, 5H, aliphatic) ppm.