Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([OH:24])[CH3:23])=[CH:14][CH:13]=3)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:24][C@H:22]([C:15]1[N:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C@H:10]1[N:18]2[C@H:19]([CH3:21])[CH2:20][NH:8][CH2:9]1)[CH3:23]
Reactant: CC(O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](O)c1ccc2c(n1)N1[C@@H](CNC[C@H]1C)C2

Procedure:
A solution of 3.09 g (9.27 mmol) (4R,9aR)-6-(1-(RS)-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 38, intermediate) in 33 ml dichloromethane was cooled to 0 deg C. and treated with 8.8 ml (12.7 g, 0.11 mol) trifluoroacetic acid. The cooling bath was removed and the volatile components were removed on a rotary evaporator. The residue was chromatographed on silica gel (0.032–0.063 mm) with dichloromethane:methanol:ammonia (19:1:0.1). The remaining oil was dissolved in dichloromethane and saturated aqueous sodium bicarbonate solution and extracted until all product was extracted from the aqueous phase. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The remaining light brown oil was chromatographed on a Chiralpak-AD column with 7% ethanol/n-heptane yielding the two diastereomers, the R-diastereomer being eluted first.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Br[CH2:11][C:12]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[CH:13][C:14](OCC)=[O:15]>C(O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:12]2[CH2:11][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:14](=[O:15])[CH:13]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)C=C(CBr)c1ccc(F)cc1
Reactant: COc1ccc(N)cc1
Solvent: CCO
Product: COc1ccc(N2CC(c3ccc(F)cc3)=CC2=O)cc1
Reaction time: 24 h

Procedure:
p-Anisidine (1793 g, 14.6 mol) and ethyl 4-bromo-3-(4-fluorophenyl)-2-butenoate (1393 g, 4.9 mol) are combined in ethanol (6 L), and the mixture is stirred for 24 hr. The precipitate which forms is collected by filtration, washed with ethanol, and dried under vacuum for 24 hr at 60° C. to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[F:26][C:27]([F:46])([F:45])[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=1)=[O:29].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[CH:5]=[CH:4][C:3]([CH3:25])=[C:2]([C:32]5[CH:33]=[CH:34][CH:35]=[C:30]([C:28](=[O:29])[C:27]([F:46])([F:45])[F:26])[CH:31]=5)[N:7]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: CC1(C)OB(c2cccc(C(=O)C(F)(F)F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)C(F)(F)F)c1
Temperature: 120 °C

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (163 mg, 0.444 mmol) was dissolved in 1,2-dimethoxyethane (4.0 mL) in a reaction tube. 2,2,2-Trifluoro-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone (200 mg, 0.666 mmol), aqueous 2 M sodium carbonate (0.444 mL), and (Ph3P)4Pd (26 mg, 0.022 mmol) were added and the reaction mixture was heated at 120° C. under N2 atmosphere for 30 minutes in the microwave. The resulting material was cooled to room temperature, filtered, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(3-(2,2,2-trifluoroacetyl)phenyl)-pyridin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 522.1. found 523.5 (M+1)+. Retention time 1.92 minutes.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:40][CH2:39][C:15]3([O:19][N:18]=[C:17]([C:20]4[C:21]([NH:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[C:22]5[C:28]([CH3:29])=[N:27][N:26]([CH2:30][CH3:31])[C:23]5=[N:24][CH:25]=4)[CH2:16]3)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[C-:41]#[N:42].[Na+].O>CN(C)C=O>[CH:33]1([NH:32][C:21]2[C:20]([C:17]3[CH2:16][C:15]4([CH2:14][CH2:13][CH:12]([C:41]#[N:42])[CH2:40][CH2:39]4)[O:19][N:18]=3)=[CH:25][N:24]=[C:23]3[N:26]([CH2:30][CH3:31])[N:27]=[C:28]([CH3:29])[C:22]=23)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: [C-]#N
Reactant: CCn1nc(C)c2c(NC3CCCCC3)c(C3=NOC4(CCC(OS(=O)(=O)c5ccc(C)cc5)CC4)C3)cnc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(C)c2c(NC3CCCCC3)c(C3=NOC4(CCC(C#N)CC4)C3)cnc21
Temperature: 62.5 °C
Reaction time: 8 h

Procedure:
3-[4-(Cyclohexylamino)-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl 4-methylbenzenesulfonate (0.0018 mole) (example 39) is taken in dimethylformamide. Sodium cyanide (0.0036 mole) is added and the reaction mixture is stirred at 60-65° C. overnight. Water is added and extraction is done with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure to give crude compound, which is purified by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[O:17]=[C:18]([C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)[CH2:19][C:20](OC(C)(C)C)=[O:21]>>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[C:2]([NH:1][C:20](=[O:21])[CH2:19][C:18](=[O:17])[C:27]2[CH:32]=[N:31][CH:30]=[CH:29][N:28]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cnccn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(Br)cc1NC(=O)CC(=O)c1cnccn1

Procedure:
The title compound was prepared from the reaction of tert-butyl 2-amino-4-bromophenylcarbamate (Example B1; 1 mmol) and tert-butyl 3-oxo-3-(pyrazin-2-yl)propanoate (Example C3; 1 mmol) according to the general procedure D. Obtained as a yellow solid (81%), MS (EI) 435 [(M+1)+].
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:28][CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:9]=3[N+:8]([O-])=[CH:7][C:6]=2[N:27]=1)[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:47]>ClCCl>[NH2:47][C:7]1[C:6]2[N:27]=[C:3]([CH2:1][CH3:2])[N:4]([CH2:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:5]=2[C:14]2[CH:13]=[CH:12][C:11]([O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[CH:10][C:9]=2[N:8]=1
Reactant: CCc1nc2c[n+]([O-])c3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC1CCOCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCc1nc2c(N)nc3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC1CCOCC1
Reaction time: 16 h

Procedure:
tert-Butyl 2-{[2-ethyl-5-oxido-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate (wet from above) was slurried in dichloromethane (25 mL) and ammonium hydroxide (25 mL). p-Toluenesulfonyl chloride (0.810 g, 4.25 mmol) was added in one portion and the reaction was stirred for 16 hours. The layers were separated and the aqueous fraction was extracted with dichloromethane. The combined organic fractions were washed with water, then saturated aqueous sodium chloride. The organic fraction was dried over anhydrous sodium sulfate, filtered and concentrated. The material was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-20% CMA in chloroform) to afford 1.8 g of tert-butyl 2-{[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate as a white foam. Recrystallization from acetonitrile of a small portion provided an analytical sample as a white solid, mp 200-201° C.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:26]=[N:27][C:28]2[C:33]([C:34]=1[N:35]1[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41]C(=O)OC(C)(C)C)[CH2:36]1)=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:23])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:26]=[N:27][C:28]2[C:33]([C:34]=1[N:35]1[CH2:40][CH2:39][CH2:38][C@H:37]([NH2:41])[CH2:36]1)=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:23]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2ccccc2c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2ccccc2c1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.1 %

Procedure:
To a solution of tert-butyl {(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)quinolin-4-yl]piperidin-3-yl}carbamate (115.8 mg, 0.17 mmol) in DCM (2.0 mL) was added TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.15% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (20.5 mg, 25%). LCMS calc. for C24H23F2N6OS (M+H)+: m/z=481.2. found 481.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:18]1([CH2:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:24]([NH:25][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
Combined 6-chloronicotinoyl chloride (1.76 g, 10.00 mmol) and DCM (20 mL) and cooled in an ice-bath then triethylamine (2.09 mL, 15.0 mmol) and phenylmethanamine (1.072 g, 10.00 mmol) were added. The reaction was then stirred at room temperature for 3 hours before being diluted in DCM (30 ml), washed with 1N aqueous HCl (50 ml), saturated aqueous sodium bicarbonate (50 ml), brine (50 ml), dried over Na2SO4, and concentrated to give the title compound (2.19 g, 89%) as a light beige solid which was used without further purification. MS m/z [M+H]+ 247.1.
Reaction SMILES: [CH2:1]([CH:8]([C:14]([O:16]CC)=[O:15])[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[CH2:1]([CH:8]([C:9]([OH:11])=[O:10])[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(Cc1ccccc1)C(=O)O

Procedure:
Diethyl benzylmalonate (100 g, 400 mmol) was dissolved in ethanol (300 mL) and treated with a solution of potassium hydroxide (134.4 g, 2.4 mol) in water (500 mL). The mixture was heated under reflux for 5 hours and then allowed to cool. Ethanol was removed under reduced pressure and the remaining aqueous solution cooled in ice and acidified to pH 1 with concentrated HCl. The product was extracted with ethyl acetate (3×200 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield benzylmalonic acid as a white crystalline solid. The solid was taken-up in ethanol (250 mL) and treated portionwise with piperidine (33 g, 397 mmol) followed by an aqueous solution of formaldehyde (37%, 150 mL) which resulted in formation of a white precipitate. The reaction mixture was heated and treated with methanol (50 mL) to give a homogeneous solution. Following dissolution the reaction mixture was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure. The aqueous residue was acidified to pH 1 with 1 M HCl and the product extracted with ethyl acetate (3×150 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 2-benzyl-acrylic acid as a colorless oil which crystallized on standing (45 g, 75%). 1H-NMR; δ (CDCl3), 7.32-7.17 (5 H, m), 6.36 (1 H, s), 5.54 (1 H, d, J=1.3 Hz), 3.61 (2 H, s).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[C:9]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:14][C:10]=2[N:11]=[CH:12][N:13]=1>CN(C=O)C.O>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[C:9]3[C:8]([O:5][CH2:4][CH2:3][OH:6])=[N:13][CH:12]=[N:11][C:10]=3[O:14][C:15]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCO)c23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
Add, at 0° C., 59 mg (1.5 mmol) of 60% sodium hydride to a solution of 461 mg (7.4 mmol) ethylene glycol in 10 ml DMF. After warming to room temperature, continue stirring for 1 h. Then add 0.50 g (1.5 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and stir the mixture for 3 h at room temperature. Next, dilute with water and extract with ethyl acetate. Wash the organic phase with saturated sodium chloride solution, dry over magnesium sulphate and concentrate by evaporation. The raw product thus obtained is purified by RP-HPLC (column: Gromsil 250 mm×30 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-50 min 5%→98% acetonitrile, 50-55 min 98% acetonitrile). In this way, 412 mg (77% of theor.) 2-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}ethanol is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])=[CH:4][CH:3]=1.[C:14](Cl)(=[O:24])[C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17](Cl)=[O:18]>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:14](=[O:24])[C:15]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])=[CH:12][CH:13]=2)=[O:18])=[CH:13][CH:12]=1)=[O:7])[CH2:10][CH3:11]
Reactant: CCCOC(=O)c1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Product: CCCOC(=O)c1ccc(OC(=O)c2ccccc2C(=O)Oc2ccc(C(=O)OCCC)cc2)cc1

Procedure:
Propyl p-hydroxybenzoate and phthalic dichloride are allowed to react and treated in a similar procedure to Example 4. The residue obtained is recrystallized from hexane and recrystallized from ethyl acetate-chloroform (1:1) to yield di(p-propoxycarbonylphenyl)phthalate, m.p. 87°-89° C., as white crystals.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15]C)=[O:14])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>CN(C=O)C>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: Nc1ccccn1
Reactant: COC(=O)c1ccc(CBr)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(CNc2ccccn2)c2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 9.5 %

Procedure:
The compound obtained in Example 17-2 (1.6728 g) was dissolved in DMF (33 ml). After the addition of potassium carbonate (1.66 g) and 2-aminopyridine (0.68 g), the mixture was stirred for 15 hours at room temperature. After the reaction, the solvent was removed by distillation and the residue was dissolved in chloroform. The organic layer was washed with 1 mol/l aqueous solution of hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. Then, the solvent was removed by distillation. The residue was dissolved in DMF (44 ml). Triethylamine. (1.58 ml) and di-t-butyldicarbonate (2.60 ml) were added and the mixture was stirred for 6 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was dissolved in ethyl acetate. The solution was washed with 0.5 mol/l aqueous solution of hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation. The residue was dissolved in methanol (6 ml), and 1 mol/l aqueous solution of sodium hydroxide (6 ml) was added. After the reaction for one day, the reaction solution was concentrated. The residue was dissolved again in methanol and neutralized with ion-exchange resin CG50. The resin was removed by filtration. The filtrate was concentrated. The residue was purified by silica gel column chromatography (15 g, chloroform/methanol=5/1) to obtain the title compound (159 mg) as a colorless viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:10][CH:11]([C:15](=[O:26])[CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[OH:18])[C:12](=O)[N:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:18][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH2:16][C:15](=[O:26])[C:11]2=[CH:10][C:9]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1
Reactant: O=C(CC(O)c1cccc(F)c1)C1C=C(c2ccc(Cl)cc2)C(c2ccccc2Cl)=NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccc(F)c2)Oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc21
Temperature: 120 °C

Procedure:
The product of step A (200 mg, 0.42 mmol) was dissolved in toluene (2 mL) and p-toluenesulfonic acid (30 mg, 0.16 mmol) was added. The reaction was heated at 120° C. for 4 h and allowed to cool overnight. The reaction was diluted with EtOAc and washed with a saturated solution of NaHCO3, brine, dried (Na2SO4), filtered and concentrated The residue was purified by flash chromatography on silica gel gradient eluted with 0-30% EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 464.2 (M+1), 466.2 (M+3); Rt=2.61 min.
Reaction SMILES: N1C=CC=CC=1.[FH:7].[Br:8][C:9]1[CH:15]=[C:14]([CH3:16])[C:12](N)=[C:11]([I:17])[CH:10]=1.N([O-])=O.[Na+]>>[Br:8][C:9]1[CH:15]=[C:14]([CH3:16])[C:12]([F:7])=[C:11]([I:17])[CH:10]=1
Reactant: F
Reactant: Cc1cc(Br)cc(I)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc(Br)cc(I)c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
A PFA plastic round bottom flask was charged with a solution of hydrogen fluoride pyridine (70 wt % HF, 100 ml, 1150 mmol). The solution was cooled to 0° C. and 4-bromo-2-iodo-6-methylaniline (9.2 g, 29.5 mmol, Organic Letters 2009, 11, 249-251) was added portion wise. After 15 minutes, sodium nitrite (1.032 ml, 32.4 mmol) was added and the reaction mixture was stirred at 0° C. for additional 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 15 minutes, followed by heating at 90° C. for 3 hour. The reaction mixture was then cooled to room temperature and quenched with water and diethyl ether. The organic layer was separated, washed with brine and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure. The crude material was purified via silica gel chromatography eluting with hexanes to afford the title compound (8.45 g, 26.8 mmol, 91% yield) as a brown solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.29 (s, 3H) 7.27-7.34 (m, 1H) 7.64-7.75 (m, 1H)
Reaction SMILES: CN(C)C=O.[C:6]1([N:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[N:22]=[CH:23][NH:24][C:14]=3[C:13]2=[S:25])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[CH2:28]([S:25][C:13]1[N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:14]=1[N:24]=[CH:23][N:22]=2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: S=c1c2[nH]cnc2c2cccnc2n1-c1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(CSc2c3ncnc-3c3cccnc3n2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
Into 30 ml of dimethylformamide was dissolved 0.79 g (2.5 mmol) of Compound 1 obtained in Example 1. Furthermore, 0.13 g (3.4 mmol) of 60% sodium hydride was added thereto with stirring at room temperature. The mixture was stirred for 1 hour. Then, 0.41 ml (3.4 mmol) of benzyl bromide was added thereto, followed by further stirring for 1 hour. The mixture was cooled with ice and then water was added thereto. The precipitated solid was collected by filtration. The solid was dried, dissolved into chloroform and purified by silica gel column chromatography (eluent: chloroform) to give 0.25 g (24%) of Compound (II) as the first fractions and 0.40 g (38%) of Compound 3 as the second fractions.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:18]#[N:19])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[ClH:27].[NH2:28][CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1.C([BH3-])#N.[Na+]>C(O)C>[ClH:27].[CH2:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:37][CH:29]1[NH:28][CH:14]1[CH2:15][CH2:16][C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([C:18]#[N:19])[CH2:12][CH2:13]1
Reactant: NC1Cc2ccccc2C1
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#N)CCC(NC3Cc4ccccc4C3)CC2)cc1OC

Procedure:
A solution of 4-(3,4-dimethoxyphenyl)-4-cyanocyclohexanone (0.71 g, 2.74 mmol), triethylamine (0.38 ml, 2.74 mmol), 2-amino-2,3-dihydro-1H-inden hydrochloride (0.46 g, 2.74 mmol) and sodium cyanoborohydride (0.17 g, 2.7 mmol) in 10 ml ethanol was stirred at 25° C. for 3 days, filtered and the volatiles were removed in vacuo. The residue was diluted with ethyl acetate, washed with water, 1N NaOH and brine and dried (MgSO4). The volatiles were removed in vacuo. The residue was treated with ethyl acetate and anhydrous HCl. The volatiles were removed in vacuo. Recrystallization of the residue with aqueous ethanol gave the product, m.p. >250° C. ##STR20##
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])([C:6]2[S:7][CH:8]=[CH:9][C:10]=2[CH3:11])O)[CH2:3][CH2:2]1.[Br:20][Si](C)(C)C.O>ClCCl>[Br:20][CH2:3][CH2:2][CH:1]=[C:4]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19])[C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccc(C(O)(c2sccc2C)C2CC2)c(C)c1
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=CCCBr)c2sccc2C)c(C)c1
Temperature: 10 °C

Procedure:
A solution of cyclopropyl(2,4-dimethylphenyl)(3-methyl-2-thienyl)methanol (7.0 g, 0.026 mole; obtained by the method described in Example 7) in dichloromethane (125 ml) was cooled to 10° C. and bromotrimethylsilane (4.0 g, 0.026 mole) in dichloromethane (50 ml) was added dropwise keeping the temperature at about 10° C. When addition was complete, water was added (250 ml) and the phases were separated. The aqueous phase was extracted with dichloromethane (25 ml). The combined organic phases was washed with a saturated sodium bicarbonate solution, brine and dried over sodium sulphate. The solvent was removed in vacuo leaving 1-bromo-4-(2,4-dimethylphenyl)-4-(3-methyl-2-thienyl)but-3-ene (8.7 g) as an oil. This bromide was converted by the method described in Example 7 into the title acid hydrochloride, M.p.=200°-201° C. (i-Propanol).