Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[C:26]([C:30]([O:32]CC)=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1.[OH-].[Na+].Cl>CO>[CH3:1][S:2][C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:13][CH:14]=2)[C:6]2[C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1
Reactant: CCOC(=O)c1cccc2nc(SC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 90.4 %

Procedure:
A solution of ethyl 2-methylthio-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.2 g) in a methanol (5 ml) solution containing 1N NaOH (1.3 ml) was heated under reflux for 2 hours. The reaction mixture was adjusted to about pH 4 with dilute hydrochloric acid to give crystals. The crystals were collected by filtration, and recrystallized from ethyl acetate-hexane to give colorless crystals (0.17 g, 81%), m.p. 223-225° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:13][C:12]=1[CH3:25].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[CH3:25]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a stirred solution of tert-butyl 4-[N′-(2-fluorophenyl)ureido]-3-methylphenylacetate (1.25 g, 3.49 mmol) in CH2Cl2 (10 ml) was added TFA (10 ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to a small volume and poured into ice-H2O. The resulting precipitate was collected under a reduced pressure and the crude solid was recrystallized from MeOH—CHCl3—IPE to give 4-[N′-(2-fluorophenyl)ureido]-3-methylphenylacetic acid (830 mg, 79%) as white needles. 1H-NMR (DMSO-d6) δ2.23 (s, 3 H), 3.47 (s, 2 H), 6.96-7.30 (m, 5 H), 7.74-7.76 (m, 1 H), 8.17-8.20 (m, 1 H), 8.33 (s, 1 H), 8.94 (s, 1 H), 12.27 (br s, 1 H); Anal. Calcd. for C16H15FN2O3: C, 63.57; H, 5.00; N, 9.27; F, 6.28. Found: C, 63.28; H, 5.00; N, 9.14; F, 6.43.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]3[O:15]C[O:13][C:10]=3[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].B(Br)(Br)Br.[OH-].[K+]>O>[OH:15][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[OH:13])[N:3]([CH2:1][CH3:2])[CH:4]=[C:5]([C:17]([OH:19])=[O:18])[C:6]2=[O:16]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3c(cc21)OCO3
Agent: BrB(Br)Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(O)c(O)cc21
Yield: 84.1 %

Procedure:
1.4-Dihydro-1-ethyl-6,7-methylenedioxy-4-oxoquinoline-3-carboxylic acid (3.9 g) and boron tribromide (15 ml) were heated at 50° C. for 15 hours. The reaction mixture was cooled and added slowly to water (100 ml) at 0° C. The pH was adjusted to 11 with concentrated potassium hydroxide, the mixture was filtered and the filtrate taken to pH1, whereupon the precipitate was collected by filtration, washed with water and dried to give 1,4-dihydro-6,7-dihydroxy-1-ethyl-4-oxoquinoline-3-carboxylic acid (3.13 g); δ ((CD3)2SO) 1.42(3H,t); 4.46(2H,q); 7.23(1H,s); 7.66(1H,s); 8.82(1H,s)ppm.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:26]1[CH:35]=[CH:34][C:33]2[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=2[CH:27]=1.Cl>O1CCCC1>[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:26]1[CH:35]=[CH:34][C:33]2[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=2[CH:27]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCO)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(C(=O)O)cc4)ccc3OCCCCO)ccc21
Temperature: 40 °C
Reaction time: 48 h
Yield: 89.9 %

Procedure:
2 ml (2.0 mmol) of an aqueous solution of sodium hydroxide (1 M) are added to a solution of 0.20 g (0.40 mmol) of ethyl 4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate in 8 ml of tetrahydrofuran. The reaction mixture is stirred for 48 h while heating at 40° C. The reaction mixture is placed under a stream of nitrogen in order to eliminate the tetrahydrofuran and then 2.4 ml (2.4 mmol) of a solution of hydrochloric acid (1 M) are added. The product precipitates in the form of a white solid. After filtration, the product is washed twice with 5 ml of diethyl ether and then dried in an oven under vacuum overnight. 0.17 g of 4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid is obtained (white solid, Mp 235° C., yield=90%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10])(=[O:5])=[O:4].[F:16][C:17]1[CH:18]=[C:19]([C:24](=[O:35])[CH:25]=[C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[NH:27]2)[CH:20]=[C:21]([F:23])[CH:22]=1.C(N(CC)CC)C.COCCOCCOC>O>[F:16][C:17]1[CH:18]=[C:19]([C:24](=[O:35])[C:25](=[C:26]2[NH:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[NH:30]2)[C:9]([C:8]2[CH:7]=[C:6]([S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4])[CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: O=C(C=C1Nc2ccccc2N1)c1cc(F)cc(F)c1
Reactant: CN(C)S(=O)(=O)c1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: COCCOCCOC
Product: CN(C)S(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
3-[(dimethylamino)sulfonyl]benzoyl chloride (1.97 g) was added to a mixture of 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)ethanone (865 mg), triethylamine (1.6 mL) and 2-methoxyethyl ether (10 mL), followed by heating with stirring at 110° C. for 30 minutes. Water (0.06 mL) was added, followed by further heating under reflux for 30 minutes. After cooling, water was added, followed by extraction with ethyl acetate. The organic layer was washed with water, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1), and recrystallized from ethyl acetate/n-hexane to obtain 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-N,N-dimethylbenzenesulfonamide (391 mg).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:2]2[C:3]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Product: COc1ccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)cc1OC
Yield: 44.6 %

Procedure:
The ester product was obtained via a Suzuki coupling reaction using the method previously shown in Example 13, Step 6, with methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 3,4-dimethoxyphenylboronic acid (80 mg, 0.44 mmol, 1.50 equiv) as reactants. Purification by Prep-TLC (silica gel) yielded 50 mg (44%) of 3-(3,4-dimethoxyphenyl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:24][CH2:25][O:26][CH2:27][CH3:28])=[C:16]([CH:18]=[CH:19][C:20]([O:22]C)=[O:21])[CH:17]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5].P([O-])([O-])([O-])=O>O1CCCC1.CO.O>[C:4]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:24][CH2:25][O:26][CH2:27][CH3:28])=[C:16]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])[CH:17]=1)=[O:10])([CH3:6])([CH3:7])[CH3:5]
Reactant: CCOCOc1ccc(NC(=O)OC(C)(C)C)cc1C=CC(=O)OC
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOCOc1ccc(NC(=O)OC(C)(C)C)cc1C=CC(=O)O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
2.53 g (0.06 mol) of lithium hydroxide monohydrate was added at 0° C. to a solution of 6.3 g (0.018 mol) of methyl 3-(5-tert.butoxycarbonylamino-2-ethoxymethoxyphenyl)acrylate from step D in 50 mL of tetrahydrofuran, 15 mL of methanol and 30 mL of water. The mixture was allowed to agitate 24 hours at 60° C. The reaction mixture was then poured onto a phosphate buffer solution (pH 7.0) and extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous sodium chloride solution and then dried over sodium sulfate. The organic phase was partially evaporated to incipient formation of a precipitate, and hexane was then added. The precipitate was filtered off and washed with 50 mL of hexane. This gave 5.4 g (89% of the theoretical) of 3-(5-tert.butoxycarbonylamino-2-ethoxymethoxyphenyl)acrylic acid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:20])([CH3:19])[C:17]#[CH:18].N1CCCCC1>O.[Cu](I)I>[CH3:15][C:16]([CH3:20])([CH3:19])[C:17]#[C:18][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: C#CC(C)(C)C
Agent: I[Cu]I
Solvent: O
Solvent: C1CCNCC1
Product: CC(C)(C)C#Cc1ccc(S(=O)(=O)n2cccc2)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
A mixture of N-(5-bromothiophene-2-sulfonyl)pyrrole (600 mg, 2.05 mmol), 3,3-dimethyl-1-butyne (338 mg, 4.1 mmol), copper iodide (39 mg, 0.21 mmol), tetrakistriphenylphosphine palladium [Pd(PPh3)4 ] (118 mg, 0.1 mmol) and piperidine (5 ml) was stirred at room temperature for a period of 24 hours under a nitrogen atmosphere. The mixture was then diluted with water (10 ml) and extracted with 3×25 ml portions of ether. The combined ether extracts are washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and crude product purified by column chromatography using 2% ethyl acetate/hexanes to give 423 mg N-[5-(3,3-dimethylbutyn-1-yl)thiophene-2-sulfonyl]pyrrole as a yellow powder (70% yield).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:12]/[C:13](/[CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:28])/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:14]\[CH2:15][CH2:16][OH:17].O>N1C=CC=CC=1>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O:17][CH2:16][CH2:15]/[CH:14]=[C:13](\[CH3:12])/[CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:28])/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])(=[O:3])=[O:2]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCOS(=O)(=O)c1ccc(C)cc1

Procedure:
Tosylchloride (3.51 g, 9 mmol) was added to a stirred solution of (E,E)-4,8,12-trimethyl-3,7,11-tridecatrienol (1.66 g, 7 mmol) in pyridine (30 mL) at 0° C. The resulting mixture was placed in a refrigerator overnight, then poured into cold water and extracted with ether. The ethereal extract was washed with diluted hydrochloric acid to remove pyridine. After drying and filtration, the filtrate was evaporated to afford the title compound as an oil which was used in the next step without purification.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)[CH:13]=[CH:12]2)(C(C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>C(O)C>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)[CH:13]=[CH:12]2
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O[Si](C)(C)C(C)(C)C)ccc3n2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
To a solution of ethyl 1-((6-((tert-butyldimethylsilyl)oxy)quinolin-2-yl)methyl)piperidine-4-carboxylate (6.5 g, 15.2 mmol) in ethanol (100 mL) was added concentrated HCl (13 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 3 h. The mixture was neutralized by sat. NaHCO3 and the solvent was removed. Then the mixture was extracted with DCM (3×30 mL). The combined organic layers were washed by brine (30 mL), dried over Na2SO4 and concentrated to give crude product ethyl 1-((6-hydroxyquinolin-2-yl)methyl)piperidine-4-carboxylate as a white solid (3.9 g, yield: 80%). ESI-MS (M+H)+: 315.2. 1H NMR (400 MHz, CDCl3) δ: 7.88 (d, J=8.8 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.22 (dd, J=9.2, 2.4 Hz, 1H), 7.04 (s, 1H), 4.11 (q, J=7.2 Hz, 2H), 3.80 (s, 2H), 2.93-2.90 (m, 2H), 2.28-2.16 (m, 3H), 1.89-1.76 (m, 4H), 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(OC)cc1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)c1c(F)cc(O)cc1F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
To a solution of diethyl 2-(2,6-difluoro-4-methoxyphenyl)malonate (2.11 g, 7.0 mmol) in 60 mL of methylene chloride at −78° C. is added boron tribromide (2.65 mL, 28 mmol) dropwise. The mixture is then stirred at −78° C. for 10 minutes, warmed to 0° C., and stirred at 0° C. for 1 h. A 5% aqueous solution of sodium bicarbonate is added slowly to quench the reaction. The product is extracted with ethyl acetate. The combined organic extracts are washed with saturated sodium chloride, dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of 10% ethyl acetate in hexanes to 30% ethyl acetate in hexanes. Concentration provides diethyl 2-(2,6-difluoro-4-hydroxyphenyl)malonate as a colorless oil (1.91 g). MS: m/z 287.2 (M−H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:12])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[CH:13](OCC)(OCC)OCC.[CH3:23][C:24]1([CH3:32])[O:29][C:28](=[O:30])[CH2:27][C:26](=[O:31])[O:25]1>C(O)C>[Br:1][C:2]1[C:3]([NH:12][CH:13]=[C:27]2[C:28](=[O:30])[O:29][C:24]([CH3:32])([CH3:23])[O:25][C:26]2=[O:31])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Nc1cc2c(cc1Br)OCCO2
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: CC1(C)OC(=O)C(=CNc2cc3c(cc2Br)OCCO3)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A mixture of 7-Bromo-2,3-dihydro-benzo[1,4]dioxin-6-ylamine (14.8 g, 64.3 mmol, 1 eq), triethyl orthoformate (12.7 cm3, 77.2 mmol, 1.2 eq) and 2,2-dimethyl-[1,3]dioxane-4,6-dione (Meldrum's acid) (11.1 g, 77.2 mmol, 1.2 eq) in ethanol (70 mL) was heated to reflux. After 1 hour the mixture was allowed to cool to room temperature then filtered, washing with ethanol then ether, to afford a white solid (22.9 g, 93%). LC/MS (ES) m/z 384 (MH+ 100%); 1H-NMR (400 MHz, d4-DMSO), 11.43 (1H, br d, J=20, NH), 8.6 (1H, d, J=12, NCH═C), 7.49 (1H, s, CHCBr), 7.28 (1H, s, CHCN), 4.30-4.27 (4H, m, 2×(CH2O)), 1.68 (6H, s, (CH3)2C)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[OH2:11].[C-:12]#[N:13].[Na+].Cl>C(OCC)C>[OH:4][C:1]([CH2:2][CH3:3])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:12]([NH2:13])=[O:11]
Reactant: [C-]#N
Reactant: CCC(=O)c1ccccc1
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: CCC(O)(C(N)=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
In a 1000 ml, two-opening ball matrass equipped with a separating funnel and a thermometer, 89.9 grams (0.67 moles) propiophenone, 100 ml water and 80 ml ethyl ether were added. The matrass was immersed in an ice and salt bath and 82 grams (1.67 moles) granulated sodium cyanide was added. The mixture was shaken vigorously for 20 minutes, and when the mixture temperature had dropped to 5° C., 140 ml (1.7 moles) concentrated hydrochloric acid from the separating funnel was added at such a speed that the temperature of the reaction stayed between 5° C. and 10° C. The addition took nearly two hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH:14]=1)[O:7][C@H:8]([CH3:13])[C:9](OC)=[O:10]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:15][C:9](=[O:10])[C@@H:8]([CH3:13])[O:7][C:6]=2[CH:14]=1
Reactant: COC(=O)[C@@H](C)Oc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@H]1Oc2cc(Br)ccc2NC1=O
Temperature: 25 °C
Yield: 96 %

Procedure:
Iron powder (1.91 g, 34.15 mmol) and (R)-methyl 2-(5-bromo-2-nitrophenoxy)propanoate (R)-A-16 (525.0 mg, 1.71 mmol) were heated at 50° C. in glacial acetic acid (10.5 mL) for 5 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (80 mL), filtered over a pad of celite, and rinsed with ethyl acetate (80 mL). The filtrate was successively washed with water (2×30 mL), a saturated aqueous solution of sodium bicarbonate (40 mL), then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The resulting white crystalline solid (R)-7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (R)-A-17 (399.4 mg, Yield=96%) was used as such for next step without purification. MS (ESI) [M+1]+ 242, 244.
Reaction SMILES: [F:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:19][CH3:20].[F:21][C:22]1[C:38]([O:39][CH3:40])=[C:37]([F:41])[C:25]2[S:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[CH:28][C:24]=2[CH:23]=1.C1C(=O)N([Br:49])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.C(Cl)Cl>[Br:49][C:10]1[C:6]2[CH:5]=[CH:4][C:3]([O:19][CH3:20])=[C:2]([F:1])[C:7]=2[S:8][C:9]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[Br:49][C:28]1[C:24]2[CH:23]=[C:22]([F:21])[C:38]([O:39][CH3:40])=[C:37]([F:41])[C:25]=2[S:26][C:27]=1[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1
Reactant: COc1ccc(-c2cc3cc(F)c(OC)c(F)c3s2)cc1
Reactant: COc1ccc(-c2cc3ccc(OC)c(F)c3s2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(-c2sc3c(F)c(OC)c(F)cc3c2Br)cc1
Product: COc1ccc(-c2sc3c(F)c(OC)ccc3c2Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.6 %
Yield: 24.62 %

Procedure:
To a round bottom flask, an unseparated mixture of 7-fluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and 5,7-difluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (380 mg, 1.318 mmol) was dissolved in THF (10 mL) and the solution was cooled to 0° C. To the solution was added NBS (237 mg, 1.331 mmol). The reaction mixture was stirred at 0° C. for 1 h then warmed to room temperature and stirred for an additional 2 h. The reaction mixture was concentrated to afford the crude product. The crude product was diluted with DCM and set. Na2S2O3 (sodium thiosulfate). The organic layer was collected (phase separator) and concentrated. The reaction mixture was diluted with water and DCM. The organic phase was collected (phase separator) and concentrated to afford the crude product. The crude material was purified by column chromatography (SiO2, 0-5% Heptanes/EtOAc) to afford 3-bromo-7-fluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (211 mg, 0.575 mmol 43.6% yield) and 3-bromo-5,7-difluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (125 mg, 0.324 mmol, 24.62% yield). 3-bromo-7-fluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene: 1H NMR (400 MHz, CDCl3) δ ppm=7.56-7.66 (m, 2H), 7.46 (dd, J=1.01, 8.59 Hz, 1H), 7.11 (dd, J=7.58, 8.59 Hz, 1H), 6.90-6.97 (m, 2H), 3.92 (s, 3H), 3.79 (s, 3H), 3-bromo-5,7-difluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene: 1H NMR (400 MHz, CDCl3) δ ppm=7.53-7.68 (m, 2H), 7.48 (d, J=8.59 Hz, 1H), 7.15-7.27 (m, 1H), 7.07 (dt, J=2.53, 8.59 Hz, 1H), 3.98 (s, 3H), 4.02 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][OH:24])(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][OH:24])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=S(=O)(NCCO)c1ccc(F)cc1
Product: O=S(=O)(NCCO)c1ccc(N2CCC3(CC2)OCCO3)cc1

Procedure:
The title compound was prepared according to the procedure of Intermediate 24 from 2.28 g (15.6 mmol) of 1,4-dioxa-8-aza-spiro[4.5]decane and 2.85 g (13.0 mmol) of 4-fluoro-N-(2-hydroxyethyl)-benzenesulfonamide, yielding 3.0 g of a colorless gum; MS (ES) m/z 343.2 (MH+); HRMS (EI) Calcd. for C15H22N2O5S (M+): 342.1249, Found: 342.1235.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:13][CH2:14][CH:15]([NH:29][CH2:28][CH:25]4[CH2:27][CH2:26]4)[CH2:16][CH2:17]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: NCC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(NCC4CC4)CC3)cc2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 43.5 %

Procedure:
To a solution of 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-one (0.2 g, 0.545 mmol) in 1,2-dichloroethane (3 mL) were added cyclopropanemethylamine (71 μL, 0.812 mmol) and sodium triacetoxyborohydride (0.15 g, 0.71 mmol). The resulting suspension was stirred at RT for 17 h, then diluted with water and DCM. The aqueous layer was separated and extracted with DCM. The combined organic layers were dried (Na2SO4), then concentrated in vacuo to give the title compound as an off-white solid (0.10 g, 44%).
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]([CH2:7][CH2:8]C=O)[C:4](=[O:11])[CH:3]=1.[CH:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(O)C>[CH2:20]([O:19][CH:12]([O:16][CH2:17][CH3:18])[CH2:8][CH2:7][N:5]1[C:4](=[O:11])[CH:3]=[C:2]([Cl:1])[S:6]1)[CH3:21]
Reactant: O=CCCn1sc(Cl)cc1=O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(CCn1sc(Cl)cc1=O)OCC

Procedure:
A solution of compound 5 (2.5 g, 0.013 mole), triethyl orthoformate (3.87 g, 0.026 mole) in 20 ml ethanol and p-toluenesulfonic acid (35 mg) was refluxed for 18 hours. Upon cooling, the mixture was treated with 0.2 ml of triethylamine and extracted with diethyl ether. The extract was then washed successively with NaHCO3 solution, water and brine. After drying (MgSO4), the solvent was removed in vacuo. The residual brown oil was purified by column chromatography on silica gel, using diethyl ether/hexane (4/1) as eluant. The product was obtained as a light brown oil; 2.2 g; IR (neat) 1625 cm-1 ; NMR (CDCl3) δ6.3 (s, 1H); 4.6 (t, 1H); 3.85 (t, 2H); 3.4-3.8 (m, 4H); 2.0 (q, 2H); 1.2 (t, 6H).