Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].Cl.[CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18]Cl)([CH3:15])[CH3:14].[H-].[Na+]>C1(C)C=CC=CC=1.CN(C)C=O>[CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])([CH3:15])[CH3:14]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Temperature: 80 °C

Procedure:
2.94 Grams of isatin and 4.00 g of 2-diisopropylaminoethyl chloride hydrochloride were suspended in a mixture of 50 ml of dry toluene and 10 ml of dry N,N-dimethylformamide, and 1.60 g of sodium hydride (60% dispersion in mineral oil) was added to the suspension with stirring under ice-cooling. The mixture was stirred for 30 minutes at room temperature, and then heated at 80° C. for 19 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with benzene, and the benzene layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 4.62 g of 1-(2-diisopropylaminoethyl)isatin having a melting point of 60°-61° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][C:24]4=[CH:27][CH:28]=[C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[N:36]([S:38]([CH3:41])(=[O:40])=[O:39])[CH3:37])[N:23]4[N:22]=3)=[C:16]([O:42][CH3:43])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl>[CH3:43][O:42][C:16]1[CH:15]=[C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)[CH:19]=[CH:18][C:17]=1[NH:20][C:21]1[N:26]=[CH:25][C:24]2=[CH:27][CH:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:36]([CH3:37])[S:38]([CH3:41])(=[O:40])=[O:39])[N:23]2[N:22]=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]
Reactant: COc1cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C2=CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Hydroxy-4-(4-{7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-3-methoxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (41 mg) was dissolved in dichloromethane (1 ml), and trifluoroacetic acid (1 ml) was added. The solution was stirred 2 hours at room temperature, and then concentrated. Purification on Gilson reverse phase chromatograph (15% to 45% acetonitrile/water gradient) and lyophilization afforded N-(2-{2-[2-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-N-methyl-methanesulfonamide, compound with trifluoroacetic acid as an orange solid, 16 mg. mp 204-205° C. LCMS (E/I+) 505 (M+H). NMR 1H (DMSO-d6) 9.01 (s, 1H), 8.85 (br s, 1H), 7.98-8.05 (m, 2H), 7.80 (s, 1H), 7.64-7.70 (m, 1H), 7.51-7.62 (m, 2H), 7.24-7.48 (m, 1H), 7.11 (s, 1H), 6.98-7.05 (m, 2H), 6.91-6.96 (d, J=4.56, 1H), 6.21 (s, 1H), 3.88 (s, 3H), 3.65-3.82 (m, 2H), 3.39-3.48 (m, 2H), 3.12 (s, 3H), 2.87 (s, 3H), 2.55-2.64 (m, 2H), 2.32 (s, 1H).
Reaction SMILES: [CH2:1]=[C:2]1[CH:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][C:5]2([C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)[CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]1[CH:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][C:5]2([C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: C=C1CCC2(c3c[nH]cn3)Cc3ccccc3C12
Agent: [Pd]
Solvent: CCO
Product: CC1CCC2(c3c[nH]cn3)Cc3ccccc3C12

Procedure:
4-(3-Methylene-2,3,3a,8-tetrahydro-1H-cyclopenta[a]inden-8a-yl)-1H-imidazole (0.23 g) was dissolved in 20 ml of ethanol and the mixture was hydrogenated at 50-55° C. with 10% palladium on carbon as catalyst until no more hydrogen was consumed. The catalyst was filtered off and the solvent removed under reduced pressure. The residue was crystallized from ethyl acetate. The yield was 0.14 g, m.p. 168-172° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([OH:12])[CH3:11].Br[C:14]1[C:15]([NH2:21])=[N:16][CH:17]=[C:18]([Br:20])[N:19]=1>>[Br:20][C:18]1[N:19]=[C:14]([O:12][CH:10]([C:3]2[C:4]([F:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[C:15]([NH2:21])=[N:16][CH:17]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CC(O)c1c(F)ccc(F)c1Cl
Product: CC(Oc1nc(Br)cnc1N)c1c(F)ccc(F)c1Cl

Procedure:
5-bromo-3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-ylamine was prepared following procedure 2 from 1-(2-chloro-3,6-difluoro-phenyl)-ethanol and 3,5-dibromo-pyrazin-2-ylamine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6]
Reactant: BrCCCCCBr
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cccc(OCCCCCBr)c1
Yield: 71.2 %

Procedure:
A mixture of 3-hydroxybenzamide (0.5 g, 3.65 mmol), 1,5-dibromopentane (1.82 g, 1.1 ml, 7.3 mmol) and potassium carbonate (500 mg, 3.65 mmol) was refluxed (2h) in acetonitrile (18 ml) until the reaction was complete by TLC. The solvent was then removed by rotary evaporation to leave a white sticky solid which was chromatographed (10% methanol in dichloromethane on silica) to give a white solid. This was recrystallised from a mixture of petrol and ethyl acetate to give white flaky crystals (0.744 g, 2.6 mmol, 70% yield). mp 98°-99° C.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:9])(=[NH:8])[CH2:6][CH3:7].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>C1C=CC=CC=1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:8][C:5](=[NH:9])[CH2:6][CH3:7])=[O:19])=[CH:13][CH:12]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC(=N)NC(=O)Nc1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
To a stirred, cooled mixture of 10.8 g. sodium methoxide in 100 ml. dry benzene was added 21.6 g. propionamidine hydrochloride in one portion and stirring was continued for twenty minutes. To this mixture at room temperature was added a solution of 30.6 g. of 4-chlorophenyl isocyanate in 100 ml. benzene dropwise during 15 minutes and stirring was continued for 18 hours. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. A solution of the resulting residue in either was chilled and treated with ethereal hydrogen chloride until acidic. The solid was collected by filtration to give after recrystallization from acetonitrile 22 g. of the hydrochloride of 1-(4-chlorophenyl)-3-(propanimidoyl)urea; m.p. 191°-192°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[N:3]=1.Cl.[CH:14]12[O:21][CH:18]([CH2:19][CH2:20]1)[CH2:17][NH:16][CH2:15]2.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:15][CH:14]3[O:21][CH:18]([CH2:19][CH2:20]3)[CH2:17]2)[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([Cl:8])[N:7]=1
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1Cl
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(Cl)nc(Cl)nc1N1CC2CCC(C1)O2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,4,6-Trichloro-5-nitropyrimidine (45, 1.43 g, 6.26 mmoles) was dissolved in dichloromethane and cooled to 0° C. A solution of 8-oxa-3-azabicyclo[3.2.1]octane (2, 0.934 g, 6.26 mmoles) in dichloromethane and triethylamine (0.873 mL, 6.26 mmoles) was slowly added over 1 hour. The solution was allowed to stir at 0° C. for 2 hours, then warmed to room temperature and stirred for an additional 16 hours. The reaction mixture was filtered, the filtrate was concentrated, dissolved in ethyl acetate, washed with 1N hydrochloric acid, saturated sodium bicarbonate, brine, dried, and concentrated to provide 3-(2,6-dichloro-5-nitropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (46). Yield: 1.53 g (80%). HRMS; [M+H]+ Obs'd=305.0200, [M+H]+ Calc'd=305.0203.
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O.Cl>[OH:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
The product from (c) (1.7 g) and excess of pyridine hydrochloride were heated together for 8 hours at 180° C. The mixture was cooled, diluted with water and 2-molar hydrochloric acid, and extracted with ether. The extracts were dried and evaporated to yield an oil identified as the required hydroxy compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][S:23]([C:26]4[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=4)[C:29](O)=[O:30])(=[O:25])=[O:24])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.Cl.[NH2:36][CH2:37][C:38]1[C:43]([CH2:44][CH3:45])=[N:42][C:41]2[N:46]([CH2:49][CH3:50])[N:47]=[CH:48][C:40]=2[C:39]=1[NH:51][CH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH2:49]([N:46]1[C:41]2=[N:42][C:43]([CH2:44][CH3:45])=[C:38]([CH2:37][NH:36][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([S:23]([NH:22][CH2:21][C:17]4[CH:16]=[C:15]([C:11]5[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][CH:5]6[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]6)[CH:10]=5)[CH:20]=[CH:19][CH:18]=4)(=[O:25])=[O:24])[CH:27]=3)[C:39]([NH:51][CH:52]3[CH2:53][CH2:54][O:55][CH2:56][CH2:57]3)=[C:40]2[CH:48]=[N:47]1)[CH3:50]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CN1CCC(Cc2cccc(-c3cccc(CNS(=O)(=O)c4cccc(C(=O)O)c4)c3)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(S(=O)(=O)NCc2cccc(-c3cccc(CC4CCN(C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
To a solution of 3-{[({3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)amino]sulfonyl}benzoic acid (0.086 g, 0.102 mmol) in THF (1 mL) was added 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (0.042 g, 0.122 mmol), HBTU (0.048 g, 0.133 mmol), and TEA (0.036 mL, 0.255 mmol) and the reaction was stirred at room temperature for 18 h. The reaction mixture was concentrated on Glas-Col evaporator, purified using a Gilson HPLC (with 0.1% TFA), concentrated, basified with amino cartridge to afford 0.0458 g (59%) of the title compound. LC-MS m/z 764 (M+H)+.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][CH:6]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][CH2:8]O>>[Br:2][CH2:8][CH2:7][CH:6]([CH3:5])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(C)CCO
Reactant: BrP(Br)Br
Product: CCCCC(C)CCBr
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Phosphorus tribromide (10.44 g, 38.5 mmol) is added dropwise to 95% 3-methyl-1-heptanol (7.7 g, 56.3 mmol) at 0° C. and the mixture is stirred for 5 h at 100° C. The mixture is allowed to cool, poured onto ice, and extracted several times with hexane. The extract is washed with sodium carbonate solution, dried over magnesium sulfate, and evaporated down.
Reaction SMILES: [H-].[Na+].Br[C@H:4]1[C@H:9](O)[C:8]2[C:11]([O:15][CH3:16])=[CH:12][CH:13]=[CH:14][C:7]=2[O:6][CH2:5]1.[O:17]1CCCC1>>[CH3:16][O:15][C:11]1[C:8]2[CH2:9][C:4](=[O:17])[CH2:5][O:6][C:7]=2[CH:14]=[CH:13][CH:12]=1
Reactant: C1CCOC1
Reactant: COc1cccc2c1[C@@H](O)[C@H](Br)CO2
Agent: [H-]
Agent: [Na+]
Product: COc1cccc2c1CC(=O)CO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5.0 g sodium hydride in 100 ml of dry tetrahydrofuran is added with stirring a solution of 13 g of trans-3-bromo-4-hydroxy-5-methoxy-3,4-dihydro-2H-[1]-benzopyran in 150 ml of dry tetrahydrofuran in a dropwise fashion. After 30 minutes stirring at room temperature, the reaction mixture is filtered through filter-cel and the solvent is removed in vacuo. The residue is dissolved in 150 ml of toluene, 1.0 g of anhydrous zinc iodide is added and the mixture is refluxed for 15 minutes. The reaction mixture is filtered through 120 g of silica gel with methylene chloride as the eluent to afford 5-methoxy-3,4-dihydro-2H-[1]-benzopyran-3-one (5-methoxychroman-3-one) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]=O>C(O)=O>[CH3:14][N:12]=[S:10]([CH3:13])([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:11]
Reactant: C=O
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: O=CO
Product: CN=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 22 h

Procedure:
500 mg (2.5 mmol) (RS)—S-(4-nitrophenyl)-S-methylsulfoximide in 4 ml formaldehyde (aqueous, 37%) and 20 ml formic acid (98-100%) are stirred in the open flask at 100° C. After 22 hours, the solvent is evaporated, the mixture is treated again with 4 ml formaldehyde (aqueous, 37%) and 20 ml formic acid (98-100%) and stirred for a further 22 hours at 100° C. Residues of the solvent are removed on the rotary evaporator. The remaining residue is dissolved with 2N HCl and extracted with dichloromethane. The aqueous phase is basified with NaHCO3 and extracted with dichloromethane. The combined organic phases are dried (Na2SO4), filtered and concentrated. 448 mg (2.1 mmol, corresponding to 85% of theor.) of the product is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:24][CH:23]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[N:20]=[CH:19][C:18](Br)=[CH:17][N:16]=1)=[CH:10][CH:9]=2)=[O:5])C.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)O1>>[CH:29]1([O:28][C:25]2[CH:26]=[CH:27][C:22]([N:7]3[C:8]4[C:13](=[CH:12][C:11]([C:15]5[N:20]=[CH:19][C:18]([C:43]6[CH:42]=[CH:47][CH:46]=[CH:45][N:44]=6)=[CH:17][N:16]=5)=[CH:10][CH:9]=4)[CH:14]=[C:6]3[C:4]([OH:3])=[O:5])=[CH:23][CH:24]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)c1cc2cc(-c3ncc(Br)cn3)ccc2n1-c1ccc(OC2CCCC2)cc1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Product: O=C(O)c1cc2cc(-c3ncc(-c4ccccn4)cn3)ccc2n1-c1ccc(OC2CCCC2)cc1

Procedure:
The title compound was prepared in accordance with Example 8(b) from 5-(5-bromopyrimidin-2-yl)-1-(4-cyclopentoxyphenyl)-1H-indole-2-carboxylic acid ethyl ester (see Example 48(g)) and 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine, followed by ester hydrolysis in accordance with the procedure described in Example 35, Method 3, step (b).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.[OH:24][C:25]([CH3:30])([CH3:29])[C:26](O)=O>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH:17][CH2:26][C:25]([OH:24])([CH3:30])[CH3:29])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CC(C)(O)C(=O)O
Product: CC(C)(O)CNc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (50 mg) was reacted with 2-hydroxyisobutyric acid via General Procedure I to give N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxy-2-methylpropanamine. 62 mg of the crude N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxy-2-methylpropanamine was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 16.2 mg of 112. MS (Q1) 515 (M)+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=4[O:33][CH3:34])=[CH:21][CH:20]=3)[CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C>CO>[F:32][C:28]1[C:29]([F:31])=[CH:30][C:25]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:14]3[CH:15]=[C:16]4[C:11]([CH:10]=[CH:9][NH:8]4)=[CH:12][CH:13]=3)=[CH:20][CH:21]=2)=[C:26]([O:33][CH3:34])[CH:27]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3ccn(C(=O)OC(C)(C)C)c3c2)cc1
Solvent: CO
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3cc[nH]c3c2)cc1
Yield: 100.7 %

Procedure:
To 6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indole-1-carboxylic acid tert-butyl ester (232 mg, 0.5 mmol) was added methanol and the mixture was microwaved at 150° C. for 30 min. The reaction was concentrated and dried from dichloromethane to yield 6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole as a white solid (184 mg, 99%). LC-MS (ES) calculated for C22H17F2NO2, 365.2; found m/z 366 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6][S:7][C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]([O-:15])=[O:14])=[C:2]1[C:16]([O:18]C)=[O:17].Cl>[OH-].[Na+].C(O)C>[S:1]1[CH:5]=[CH:4][C:3]([S:6][S:7][C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]([OH:15])=[O:14])=[C:2]1[C:16]([OH:18])=[O:17]
Reactant: COC(=O)c1sccc1SSc1ccsc1C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1sccc1SSc1ccsc1C(=O)O

Procedure:
aaa) 38.9 g of methyl 3,3'-dithiobis-thiophene-2-carboxylate were suspended in 1500 ml of 1N sodium hydroxide solution and 700 ml of ethanol, whereupon the suspension was heated under reflux until the reaction finished. After cooling, in an ice-bath the mixture was acidified with 25 percent hydrochloric acid, whereby the product crystallized out. By recrystallization from water, there was obtained 3,3'-dithiobis-thiophene-2-carboxylic acid as colorless crystals of m.p. 256°-257°.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[CH3:7].Br[CH2:19][CH:20]1[CH2:22][CH:21]1[CH3:23]>>[CH3:1][C:2]1[N:3]([CH2:19][CH:20]2[CH2:22][CH:21]2[CH3:23])[C:4]([C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[CH3:7]
Reactant: Cc1cc(C(=O)CCc2ccccc2)[nH]c1C
Reactant: CC1CC1CBr
Product: Cc1cc(C(=O)CCc2ccccc2)n(CC2CC2C)c1C
Yield: 99.1 %

Procedure:
The title compound was prepared as a yellow oil in 99.1% yield in a similar procedure to that described in Referential Example 97 by using 2,3-dimethyl-5-(3-phenylpropionyl)pyrrole and 1-bromomethyl-2-methylcyclopropane.
Reaction SMILES: C([O:8][CH2:9][C:10]#[C:11][CH2:12][C@H:13]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)C1C=CC=CC=1>CO.[Pd]>[F:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C@@H:13]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:21][CH:20]=1
Reactant: COCCOCO[C@@H](CC#CCOCc1ccccc1)COc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: COCCOCO[C@@H](CCCCO)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.1 %

Procedure:
To a solution of (2S)-6-benzyloxy-1-(4-fluorophenoxy)-2-(methoxyethoxymethyloxy)-hex-4-yne (2.2 g, 5.4 mmol) in dry methanol (20 ml) was added 10% Pd/C (250 mg) and the mixture stirred under H2 at room temperature for 4 h. The reaction mixture was filtered through celite, washed with excess methanol. Evaporation of the solvent afforded a crude product which was purified by silica gel column using ethyl acetate-light petroleum (2:3) as eluent to give (2S)-1-(4-fluorophenoxy)-2-(methoxyethoxymethyloxy)-hexan-6-ol (1.3 g, 76%) as a colourless liquid. TLC:ethyl acetate-light petroleum (2.3), Rf=0.3. 1H NMR (CDCl3, 200 MHz) δ 1.5-1.7 (m, 6H), 3.35 (s, 3H), 3.5 (t, J=4.8 Hz, 2H), 3.65 (t, J=4.8 Hz, 2H) 3.7-3.8 (m, 2H), 3.85-3.95 (s, 3H), 4.75-4.95 (dd, J=12.6, 6.0 Hz, 2H), 6.75-7.0 (m, 4H).
Reaction SMILES: [F:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4][CH2:3]1.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[F:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]([C:18]([C:17]2[CH:21]=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=2[O:15][CH:12]([CH3:14])[CH3:13])=[O:19])[CH2:3]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: FC1CNCc2ccccc21
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccccc2C(F)C1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-1,2,3,4-tetrahydro-isoquinoline (CA [537033-79-7]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 392.0 (M+H+).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[OH:19][CH2:20][CH2:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH2:21][CH2:20][OH:19])=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCc1ncc[nH]1
Reactant: ICCCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCCc1nccn1CCCc1ccc(OCc2ccccc2)cc1
Yield: 55.1 %

Procedure:
Using benzyl 4-(3-iodopropyl)phenyl ether (5.28 g), 2-(2-hydroxyethyl)imidazole (5.05 g) and potassium carbonate (2.07 g), the same reaction as Reference Example 12-(i) was carried out to yield the titled compound (2.78 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:16]COC(C)=O>CO>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(N)cc1
Yield: 93 %

Procedure:
Into a 1000 mL 3-necked round bottom flask, was placed a solution of 4-aminobenzoic acid (20 g, 145.99 mmol) in methanol (600 mL). To the above was added H2SO4 (30 mL) dropwise with stirring. The resulting solution was stirred at reflux overnight. The reaction progress was monitored by TLC (EtOAc/PE=1:5). After completion, the volatile components were removed under reduced pressure and the residue was dissolved in 300 mL of water. Adjustment of the pH to 9 was accomplished by the addition of and aqueous sat. Na2CO3 solution. The resulting solution was extracted three times with 600 mL of EtOAc and the organic layers were combined and dried over Na2SO4. Removal of the volatile components under reduced pressure afforded the crude product methyl 4-aminobenzoate (vii) (20.4 g, 93% yield) as a yellow solid which was used directly in the next step without further purification.