Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[C:15]([F:18])([F:17])[F:16])(=O)=O.[I-:26].[Na+]>CC(C)=O.C(Cl)Cl>[F:16][C:15]([F:18])([F:17])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[CH2:5][I:26]
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCc2c([N+](=O)[O-])cccc2C(F)(F)F)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1CI
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A 200 mL round bottomed flask was charge under dry nitrogen with 35.08 g of 2-(trifluoromethyl)-6-nitrobenzyl tosylate dissolved in 100 mL of dry acetone. To this was added slowly with cooling 28.06 g of anhydrous sodium iodide dissolved in 75 mL of dry acetone. This reaction mixture was stirred overnight at room temperature. The mixture was stripped of acetone under vacuum redissolved in methylene chloride and filtered. The filtrate was extracted with 50 mL of distilled water, dried over anhydrous magnesium sulfate, filtered and the solvent removed under vacuum. By this procedure 29.92 g (97% yield) of product was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:13](=[O:14])[CH2:12][C:11]([CH3:10])=[O:15])=[C:4]([CH3:9])[CH:3]=1
Reactant: C=C1CC(=O)O1
Reactant: Cc1cc(Br)ccc1N
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1ccc(Br)cc1C
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-2-methylaniline (25 g) and diketene (11.8 cm3) in toluene (100 cm3) was heated with stirring under reflux for 5 hours. On cooling to room temperature the precipitated solid was filtered off and recrystallised from hexane/ethyl acetate to afford N-[4-bromo-2-methylphenyl]-acetoacetamide, m.p. 109° (14.0 g).
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>O.O1CCCC1>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4])(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: O=C(O)CNCC(=O)O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)N(CC(=O)O)CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3.3 Parts of iminodiacetic acid and 3.2 parts of sodium hydroxide are dissolved in 50 parts of water. Into the resulting aqueous solution, 20 parts of tetrahydrofuran containing 5 parts of p-methoxybenzenesulfonyl chloride was dropped. The resulting mixture is suspending at first, but becomes transparent when stirred at room temperature for about 1.5 hours. The mixture is further stirred at 50° C. for about 20 minutes to terminate the reaction. After completion of the reaction, the reaction liquid is freed from the tetrahydrofuran and then acidified with hydrochloric acid to precipitate crystals. The crystals are collected by filtration and then recrystallized from water to obtain 3.8 parts of N-p-methoxybenzenesulfonyl-iminodiacetic acid, m.p. 177°-178.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:22]1[N:26]2[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[N:30][C:25]2=[N:24][CH:23]=1)CCC>>[F:16][C:5]1[CH:4]=[CH:3][C:2]([C:22]2[N:26]3[CH:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[N:30][C:25]3=[N:24][CH:23]=2)=[CH:7][C:6]=1[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: COc1ccnc(-c2cc(Br)ccc2F)c1
Product: COc1ccnc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)c1

Procedure:
2-(5-Bromo-2-fluorophenyl)-4-methoxypyridine (50 mg, 0.2 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.3 mmol) by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane containing 1% methanol gave 3-[4-fluoro-3-(4-methoxypyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 3.93 (3H, s), 6.86 (1H, dd, J 5 and 2), 7.26 (1H, d, J 7), 7.38 (1H, dd, J 11 and 9), 7.42 (1H, s), 7.54-7.58 (1H, m), 8.12 (1H, s), 8.26 (1H, dd, J 7 and 2), 8.54 (1H, d, J 5), 8.86 (1H, d, J 7); m/z (ES+) 388 (M++H).
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]#[CH:3].Br[CH2:7]/[CH:8]=[C:9](\[CH3:19])/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl>Cl[Cu].C(OCC)C>[CH3:19]/[C:9](/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8]\[CH2:7][CH2:3][C:2]#[CH:1]
Reactant: CCCCCCCCC/C(C)=C/CBr
Reactant: C#CC[Mg]Br
Agent: Cl[Cu]
Agent: Cl
Solvent: CCOCC
Product: C#CCC/C=C(\C)CCCCCCCCC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A diethyl ether solution (100 ml) of propargyl bromide (22.4 g, 190 mmols) was added dropwise to magnesium (5.20 g, 210 mmols) and HgCl2 (360 mg, 1.33 mmols) to obtain propargyl magnesium bromide (Grignard reagent). CuCl (200 mg, 2.02 mmols) was added to this Grignard reagent, and the resulting solution was ice-cooled. After a diethyl ether (100 ml) solution of (E)-1-bromo-3-methyl-2-dodecene (4′) (18.8 g, 72.0 mmols) was added dropwise, the mixture was stirred for 3 hours at 0° C. The reaction mixture was poured into ice water, acidified with diluted hydrochloric acid, and extracted several times with diethyl ether. The organic layers were combined, and washed with water and a saturated aqueous solution of sodium chloride. A small amount of allene type impurities was removed by silica gel column chromatography (elution with hexane) to obtain pure (E)-6-methyl-5-pentadecen-1-yne (5′) (12.7 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9](O)[CH3:10].FC(F)(F)C(O)=O.[NH:19]=[N+:20]=[N-:21]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([N:19]=[N+:20]=[N-:21])[CH3:10]
Reactant: [N-]=[N+]=N
Reactant: CC(O)c1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Product: CC(N=[N+]=[N-])c1c(F)cccc1F
Reaction time: 24 h

Procedure:
10 g (63 millimoles) of 1-(2,6-difluorophenyl)ethanol are dissolved in 150 ml of hydrazoic acid (1.2N in toluene). To this solution are added 22.8 g (200 millimoles) of trifluoroacetic acid and the reaction mixture is allowed to stand for 24 hours at room temperature. After dilution with 300 ml of hexane, the reaction solution is washed first with water, then with sodium bicarbonate solution until free of acid and dried over sodium sulfate. The solvent is subsequently removed at 40°-50° C. under reduced pressure. The residue is dissolved in 100 ml of hexane and the solution is filtered through 50 g of silica gel and concentrated by evaporation once more, affording 1-(2,6-difluorophenyl)ethyl azide as a colourless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[CH2:12][CH3:13]>[Pt].C(C(CC)=O)C>[CH2:12]([C:4]1[CH:5]=[CH:6][C:7]([NH:9][CH:3]([CH2:8][CH3:7])[CH2:4][CH3:5])=[CH:8][C:3]=1[CH3:2])[CH3:13]
Reactant: CCc1ccc([N+](=O)[O-])cc1CCl
Agent: [Pt]
Solvent: CCC(=O)CC
Product: CCc1ccc(NC(CC)CC)cc1C
Yield: 237.7 %

Procedure:
A mixture of α-chloro-2-ethyl-5-nitrotoluene (5.0 g; 0.025 mol), diethyl ketone (30 ml) and 5% platinum on carbon catalyst (Pt/C; 0.50 g) is charged to a pressure vessel. Next, the vessel is sealed, evacuated and purged with nitrogen and is then pressurized with hydrogen gas to 40 to 60 psig. The reaction mixture is agitated until the theoretical amount of hydrogen is taken up (2.5 hours). The vessel is then vented, the reaction mixture diluted with methylene chloride and filtered. The filtrate is concentrated under vacuum to yield an off-white solid (6.1 g). This solid is dissolved in 0.5 N hydrochloric acid (200 ml) at 90° C. The aqueous solution is then cooled to room temperature, extracted with ether (3x) and made alkaline. An oil separates and is removed by extraction with ether. The ether phase is washed with water, dried and concentrated under vacuum to afford 3.82 g (74.5%) of crude product, a brown oil, found to be 73.7% pure by glc.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15](=O)[NH:14][C:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>C(N(CC)C1C=CC=CC=1)C>[Cl:26][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][S:10][C:11]=2[N:12]=[C:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:14]=1
Reactant: CCOC(=O)Cc1nc2scc(-c3ccc(F)cc3)c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CCOC(=O)Cc1nc(Cl)c2c(-c3ccc(F)cc3)csc2n1
Reaction time: 8 h

Procedure:
Ethyl 2-[5-(4-fluorophenyl)-4-oxo-4-H-thieno[2,3-d]pyrimidin-2-yl]acetate (10 g, 0.0301 mol) in N,N-diethylaniline (50 mL) and phosphorous oxychloride (150 mL) was heated to 115° C. for 4.5 hrs. The mixture was concentrated in vacuo and the residue poured into ice-water and allowed to stand overnight. The aqueous solution was neutralized with sodium bicarbonate, filtered, then extracted with DCM. The reaction was repeated on a further 10 g of ethyl 2-[5-(4-fluorophenyl)-4-oxo-4-H-thieno[2,3-d]pyrimidin-2-yl]acetate and the DCM extract combined with that of the first batch. The solvent was removed in vacuo and the residue purified by silica column chromatography eluting first with petroleum ether/DCM 50:50 v/v, then petroleum ether/DCM 25:75 v/v, followed by DCM (100%). Further fractions were eluted from the column with 25% diethyl ether in DCM. Fractions were analysed by TLC, combined and concentrated to give ethyl 2-[4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2-yl]acetate as a brown solid (14 g). LCMS RT=4.83 min, M+1=351.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([N:13]([CH3:33])[C:14](=[O:32])[C:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)([CH3:17])[CH3:16])=[C:9]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])[CH:8]=2)[CH2:3]1.C(N(CC)C(C)C)(C)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>ClCCl.CN(C1C=CN=CC=1)C>[F:27][C:24]([F:25])([F:26])[C:22]1[CH:23]=[C:18]([C:15]([CH3:16])([CH3:17])[C:14]([N:13]([C:10]2[CH:11]=[N:12][C:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][S:52]([CH3:51])(=[O:54])=[O:53])[CH2:3]3)=[CH:8][C:9]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:33])=[O:32])[CH:19]=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:21]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CC[C@H](N)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)ccc1-c1cc(N2CC[C@H](NS(C)(=O)=O)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
To a solution of 600 mg (1.03 mmol) (S)-N-[6-(3-amino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 6 ml dichloromethane were added 6 mg (0.05 mmol) 4-(N,N-dimethylamino)pyridine, 266 mg (2.06 mmol) N,N-diisopropylethylamine and 153 mg (1.34 mmol) methanesulfonyl chloride. After stirring at room temperature for 18 h the reaction mixture was diluted with 20 ml dichloromethane and washed with 20 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated and purified by flash chromatography to give 553 mg (81%) of the title compound as an off-white foam.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:38])=[N:4][O:5][C:6]=1[N:7]([CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:20](O)[C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH3:30])(=[O:10])=[O:9].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:38])=[N:4][O:5][C:6]=1[N:7]([CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH3:30])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2cc3c(cc2C)OCO3)sc2ncccc12
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2cc3c(cc2C)OCO3)sc2ncccc12
Yield: 82 %

Procedure:
The title compound was prepared by the method of Example 5(A), using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-[α-hydroxy-2-methyl-4,5-(methylenedioxy)benzyl]thieno[2,3-b]pyridine-3-sulfonamide (0.16 g, 0.28 mmoles), CH2Cl2 (3 ml), triethylsilane (0.45 ml, 2.8 mmoles) and boron trifluoride etherate (0.17 ml, 1.4 mmoles). Flash chromatography (40% EtOAc/hexanes) provided 0.13 g (82%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCC(CCCN)CCc1cccnc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCC(CCCNS(=O)(=O)c1ccc(Cl)cc1)CCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.127 g (9.045 mmol) of methyl 8-amino-5-[2-(3-pyridyl)ethyl]-octanoate in 5 ml methylene chloride are added a few crystals of 4-dimethylaminopyridine followed by 0.1 ml (0.7 mmol) triethylamine and 0.112 g p-chlorophenylsulfonyl chloride, and the solution is stirred at room temperature for 16 h. The reaction mixture is diluted with 10 ml methylene chloride and washed with saturated aqueous sodium bicarbonate solution. The organic phase is dried (MgSO4), filtered and evaporated to obtain an oil which is purified by preparative thin layer chromatography to give methyl 8-(p-chlorophenylsulfonamido)-5-[2-(3-pyridyl)ethyl]-octanoate as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][CH:19]([F:30])[O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH:19]([F:30])[F:18])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ccc(OC(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ccc(OC(F)F)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-difluoromethoxy-pyridine-2-carboxylic acid (CAS 1174323-34-2) following procedure I yielded the title compound as a white foam. MS (ISP): m/z=413.3 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:12])(=[O:11])NC1.[H-].[Na+].[CH3:15]I.C[N:18]([CH:20]=O)[CH3:19]>>[CH3:15][O:1][CH:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:12])(=[O:11])[N:18]([CH3:19])[CH2:20]1
Reactant: CI
Reactant: CN(C)C=O
Reactant: O=S1(=O)NCC(O)c2ccsc21
Agent: [H-]
Agent: [Na+]
Product: COC1CN(C)S(=O)(=O)c2sccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product from Step C. (2.75 g, 13.4 mmol) in anhydrous DMF (40 mL) cooled to 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.18 g, 29.5 mmol), followed by methyl iodide (2.5 mL, 40.2 mmol). The reaction mixture stirred at ambient temperature for 4 h and was poured onto ice and extracted with ethyl acetate (3×80 mL). Evaporation gave 3.35 g of an orange liquid which was chromatographed (silica, eluting with 50% ethyl acetate-hexane) to give the desired product (2.42 g, 77%): mp 61°-63° C.
Reaction SMILES: Cl[C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5](Cl)=[N:4][N:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][CH2:18][NH:17][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([NH:17][CH2:18][CH2:19][CH2:20][OH:21])=[N:4][N:3]=1
Reactant: Clc1nnc(Cl)c2cc3ccccc3cc12
Reactant: NCCCO
Product: OCCCNc1nnc(NCCCO)c2cc3ccccc3cc12
Temperature: 130 °C

Procedure:
A mixture of 1,4-dichloro-2,3-diaza-anthracene (4.84 g) and dry 1-amino-3-propanol (48 ml) is heated at 130° C. for 24 hours in an autoclave. After cooling to room temperature and dilution of the reaction mixture with a solution of potassium carbonate (96 g) in water (240 ml) a crystalline solid separates which is filtered and recrystallized from aqueous ethanol to give 6.09 g of 1,4-bis[N-(3-hydroxypropyl)amino]-2,3-diaza-anthracene, m.p. 225°-228° C.
Reaction SMILES: [CH2:1](Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]1([CH:16]2[CH2:21][NH:20][CH2:19][C:18]3[CH:22]=[CH:23][S:24][C:17]2=3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:1]([N:20]1[CH2:21][CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17]2[S:24][CH:23]=[CH:22][C:18]=2[CH2:19]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(C2CNCc3ccsc32)cc1
Reactant: BrCCc1ccccc1
Product: c1ccc(CCN2Cc3ccsc3C(c3ccccc3)C2)cc1

Procedure:
Phenethyl bromide is condensed with 7-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (Example 4) according to the procedure of Example 8.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:11]=2[CH:12]=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[CH:25]=[C:24]1[CH3:33]>>[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[C:25]([CH2:12][C:11]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:10]=2[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[C:24]1[CH3:33]
Reactant: O=Cc1ccc(Cl)cc1S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2ccc(Cl)cc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 2-benzenesulfonyl-4-chlorobenzaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCN(CC1)CC2.[C:26](#[N:29])[CH:27]=[CH2:28]>>[C:2]1([CH2:1][O:8][C:9]2[CH:16]=[CH:15][C:12]3[CH:13]=[C:27]([C:26]#[N:29])[CH2:28][O:17][C:11]=3[CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC#N
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: C1CN2CCN1CC2
Product: N#CC1=Cc2ccc(OCc3ccccc3)cc2OC1
Yield: 45.6 %

Procedure:
A mixture of 1.14 g of 4-benzyloxy-2-hydroxybenzaldehyde, 0.125 g of 1,4-diazabicyclo[2,2,2]octane and 0.65 g of acrylonitrile was stirred and heated at 80°-85° C., under argon, for 2 hours. After removal of the solvent, the residual product was dissolved in tetrahydrofuran-ether(1:1), washed with 1N-sodium hydroxide, water, dried, and the solvents evaporated in vacuo. The crude material (1.10 g) was purified by column chromatography on silica gel to afford 0.6 g (45.7%) of 7-(phenylmethoxy)-2H-1-benzopyran-3-carbonitrile, as a colorless solid mp 95°-98° C. (from ethyl acetatehexane).
Reaction SMILES: [CH2:1]=[C:2]([O:5][Si](C)(C)C)[CH:3]=[CH2:4].[CH3:10][S:11]([CH:14]=[CH2:15])(=[O:13])=[O:12]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:10][S:11]([CH:14]1[CH2:4][CH2:3][C:2](=[O:1])[CH2:5][CH2:15]1)(=[O:13])=[O:12]
Reactant: C=CC(=C)O[Si](C)(C)C
Reactant: C=CS(C)(=O)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.5 %

Procedure:
A solution containing (buta-1,3-dien-2-yloxy)(trimethyl)silane (12.5 ml, 70.7 mmol) in toluene (50 ml), was treated with (methylsulfonyl)ethene (4.1 ml, 47.1 mmol) and heated under reflux for 76 hours. After which time, the reaction mixture was cooled to room temperature and concentrated in-vacuo to give a yellow oil. The oil was dissolved in CH2Cl2 (120 ml) and filtered through Celite®. The filtrate was concentrated in-vacuo and the resulting residue was then dissolved in MeOH (8 ml) with cooling (ice/water). It was then treated with TFA (2.0 ml). The reaction mixture was stirred at 0° C. for a further 10 minutes and then at room temperature for 25 hours. The reaction mixture was concentrated in-vacuo and the residue was purified by flash column chromatography (0-10% MeOH/CH2Cl2) 100 g SNAP cartridge on the Biotage Isolera to give the title compound 1.2 g (14%) as a thick yellow oil. LC-MS 94%, 0.39 min (3.5 minute LC-MS method), m/z=177.0 (ELS visible only). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 3.24-3.32 (m, 1H) 2.94 (s, 3H) 2.62-2.70 (m, 2H) 2.50-2.56 (m, 2H) 2.38-2.45 (m, 2H) 2.07-2.18 (m, 2H).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH:14][C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([O:25][C@@H:26]([CH3:30])[CH2:27][O:28][CH3:29])[CH:24]=1)[C:18]([O:20]C)=[O:19]>>[N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:14][C:15]3[CH:16]=[C:17]([CH:22]=[C:23]([O:25][C@@H:26]([CH3:30])[CH2:27][O:28][CH3:29])[CH:24]=3)[C:18]([OH:20])=[O:19])=[CH:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)OC)c1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)O)c1

Procedure:
3-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoic acid was prepared in an analogous fashion from 2-(azetidin-1-ylcarbonyl)-5-bromopyridine and methyl 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][NH:28][CH3:29])=[CH:17][CH:16]=3)[C:10](=[O:30])[C:9]=2[N:8]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:7]=1)=O)C.C([NH2:41])=O.CO[Na].O>CN(C=O)C.CO>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([N:8]2[C:9]3[C:10](=[O:30])[N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[CH2:27][NH:28][CH3:29])=[CH:17][CH:16]=4)[CH2:12][CH2:13][C:14]=3[C:6]([C:4]([NH2:41])=[O:3])=[N:7]2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(-c3ccccc3CNC)cc1)C2=O
Reactant: NC=O
Agent: CO[Na]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CNCc1ccccc1-c1ccc(N2CCc3c(C(N)=O)nn(-c4ccc(OC)cc4)c3C2=O)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 1-(4-methoxy-phenyl)-6-(2′-methylaminomethyl-biphenyl-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (57, 13.5 g, 26.4 mmol) in DMF (50 mL) was treated with formamide (8.32 g, 6.2 mL, 184.8 mmol, 7.0 equiv) at room temperature, and the resulting reaction mixture was cooled down to 0-5° C. before being treated dropwise with a solution of MeONa (8.6 g, 9.05 mL, 39.6 mmol, 1.5 equiv) in methanol at 0-5° C. The resulting reaction mixture was stirred at 0-5° C. for 30 min before being gradually warmed up to room temperature for an additional 3 h. When HPLC and TLC showed the reaction was complete, the reaction mixture was slowly poured into water (600 mL). The resulting mixture was then stirred at room temperature for 1 h to precipitate the desired product. The solids were collected by filtration, washed with water (2×100 mL) and methyl tert-butyl ether (2×100 mL), dried in vacuo at 40-45° C. for 12 h to afford crude desired 1-(4-methoxy-phenyl)-6-(2′-methylaminomethyl-biphenyl-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide (58, 10.55 g, 12.71 g theoretical, 83%). This crude solids were subsequently recrystallized in a mixture of ethanol and methanol to afford the pure product. For 58, CIMS m/z 482 (M++H, C28H27N5O3).