Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:10][CH2:9][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])[CH2:11][CH:12]([CH3:13])[CH3:14])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 78.1 %

Procedure:
To a stirred solution of (S)-tert-butyl(1-hydroxy-4-methylpentan-2-yl)carbamate (1.6 g, 7.36 mmol) in dichloromethane (15 mL) was added triethyl amine (2.052 mL, 14.73 mmol) at 0° C. and the solution was stirred for 5 min. To this mixture at 0° C. was added methanesulfonyl chloride (0.574 mL, 7.36 mmol) dropwise and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (15 mL) and extracted with DCM (2×15 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulphate, concentrated under reduced pressure to yield (S)-2-((tert-butoxycarbonyl)amino)-4-methylpentyl methanesulfonate (1.7 g, 5.75 mmol, 78% yield) as a yellow solid which was carried on without further purification. 1H NMR (400 MHz, CDCl3) δ 4.55 (m, 1 H), 4.25 (m, 1 H), 4.16 (m, 1 H), 3.92 (m, 1 H), 3.05 (s, 3 H), 1.66 (m, 2 H), 1.56 (m, 10 H), 0.92 (m, 6 H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[S:33](Cl)(=[O:35])=[O:34]>O1CCCC1.C(OCC)(=O)C>[S:1]1[CH:5]=[C:4]([N:6]([S:33]([C:26]2[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:25]=2[F:24])(=[O:35])=[O:34])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)Nc1cscn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(F)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of tert-butyl thiazol-4-ylcarbamate (3.46 g, 17.3 mmol) in tetrahydrofuran (150 mL) at −78° C. was treated with lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 20.8 mL, 20.8 mmol). The resulting mixture was stirred at −78° C. for 0.5 h, allowed to warm to ambient temperature and stirred for a further 0.5 h. The reaction mixture was cooled to −78° C. and treated with a solution of 2,4,5-trifluorobenzene-1-sulfonyl chloride (3.99 g, 17.3 mmol) in tetrahydrofuran (30 mL). The resulting mixture was stirred at −78° C. for 4 h, allowed to warm to ambient temperature and stirred for a further 16 h. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with saturated aqueous ammonium chloride (2×150 mL) and brine (2×150 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes to afford tert-butyl thiazol-4-yl((2,4,5-trifluorophenyl)sulfonyl)carbamate as a beige solid in 62% yield (4.23 g): 1H NMR (300 MHz, CDCl3) δ 8.79-8.75 (m, 1H), 8.06-7.96 (m, 1H), 7.53-7.48 (m, 1H), 7.15-7.04 (m, 1H), 1.34 (s, 9H); MS (ES+) m/z 394.7 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[CH2:18]([N:25]1[CH2:29][CH2:28][C@H:27](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(C)([O-])C.[K+].O>C1COCC1>[CH2:18]([N:25]1[CH2:29][CH2:28][C@@H:27]([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCN(Cc3ccccc3)C2)cc1
Reactant: COc1cccc(C(C#N)c2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(C#N)(c2ccccc2)[C@@H]2CCN(Cc3ccccc3)C2)c1
Temperature: 80 °C
Yield: 77.3 %

Procedure:
To a stirred solution of (3-methoxyphenyl)phenylacetonitrile (5.2 g, 23 mmol; prepared as described in Preparation 6) in THF (100 mL) was added toluene-4-sulfonic acid (S)-1-benzylpyrrolidin-3-yl ester (7.2 g, 22 mmol), followed by the addition of potassium t-butoxide (4.0 g, 36 mmol). The mixture was heated to 80° C. for 1 hour, then allowed to cool and H2O (10 mL) was added. The mixture was filtered through a pad of Celite®. The mixture was washed with a saturated aqueous NaCl solution (100 mL) and the organic phase was separated, dried over MgSO4, and filtered. The solvent was removed under reduced pressure. The crude material was purified via silica gel chromatography to afford the title compound (6.2 g, 17 mmol). MS m/z: {M+H+] calcd for C26H26N2O, 382.5; found 383.4.
Reaction SMILES: [Mg].[CH:2]1[CH2:6][CH:5]=[CH:4][CH:3]=1.F[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1Br>C1COCC1>[F:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[CH:4]1[CH2:5][CH:6]2[CH:2]=[CH:3]1
Reactant: C1=CCC=C1
Reactant: Fc1ccc(F)c(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)C1C=CC2C1
Reaction time: 0.25 h

Procedure:
Magnesium turnings (0 66 g, 27.2 mmol) were stirred in anhydrous THF (10 mL) in a flame dried 75 mL 3 neck round bottom flask equipped with a non-equalizing addition funnel with a N2 flow adapter, magnetic stirrer and efficient condenser equipped with a N2 flow adapter. The flask was stirred and warmed to relux by a removable heating mantle. 2,5-Difluorobromobenzene (0.1 g) was added followed by of 3N EtMgBr in THF (0.1 mL). The addition funnel was charged with an intimate mixture of cyclopentadiene (1.71 g, 25.9 mmol) and 2,5-difluorobromobenzene (5.0 g, 25.9 mmol). Small portions (˜0.2 mL) of the intimate mixture were introduced to assist initiation (˜4×). After ˜15 minutes, the reaction initiated (exotherm, and vapor condensation) and heating was maintained as necessary during the addition of the contents of the addition funnel. The reaction was then maintained at reflux for 1 hour.
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([CH3:16])[CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:16][N:11]1[CH2:10][CH:9]2[CH:13]([CH2:14][CH2:15][NH:8]2)[CH2:12]1
Reactant: CN1CC2CCN(Cc3ccccc3)C2C1
Agent: [Pd]
Solvent: CCO
Product: CN1CC2CCNC2C1

Procedure:
10.3 g (47.6 mmol) of 2-benzyl-7-methyl-2,7-diazabicyclo[3.3.0] octane in 200 ml of ethanol are hydrogenated at 100° C. and 100 bar on 2.5 g of palladium-active carbon (10% Pd). The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:7]=[C:6]([OH:19])[CH:5]=1)([CH3:3])[CH3:2].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:19][C:6]2[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=3)[N:7]=2)=[CH:23][CH:22]=1
Reactant: CC(C)c1cc(O)nc(-c2cccc([N+](=O)[O-])c2)n1
Reactant: Fc1ccc(CBr)cc1
Product: CC(C)c1cc(OCc2ccc(F)cc2)nc(-c2cccc([N+](=O)[O-])c2)n1

Procedure:
The title compound was prepared from 6-isopropyl-2-(3-nitro-phenyl)-pyrimidin-4-ol (which was obtained in Intermediate 8) and 4-fluorobenzyl bromide according to Method A; LC retention time 4.01 min: MS: m/z (ESI) 368 (M+H)
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([NH2:30])[CH3:29]>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:30][CH2:28][CH3:29])=[O:24])=[CH:21][CH:20]=3)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)cc1
Product: CCNC(=O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)cc1
Yield: 15 %

Procedure:
4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (43 mg) was coupled with ethylamine as in General Procedure 8 to give the title compound as a tan solid (15% yield). M.p.=195° C., LCMS: m/z=387.31 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.24 (3H, t, J=7.3 Hz), 3.44 (2H, quartet, J=7.3 Hz), 4.51 (2H, s), 5.26 (2H, s), 7.33 (8H, m), 7.76 (1H, d, J=8.6 Hz), 7.81 (2H, d, J=8.1 Hz), 8.05 (1H, d, J=8.3 Hz).
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B.C1COCC1>C1COCC1>[C:1]([N:8]1[CH2:16][CH2:15][CH:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
1-Boc-isonipecotic acid (10.0 g, 214 mmol) was dissolved in THF (400 mL) and cooled to 0° C. A solution of BH3-THF (180 mL, 1 N in THF, 180 mmol) was added slowly. The mixture stirred for 1 h at 0° C. and was allowed to warm to room temperature for 12 h. The mixture was carefully quenched with water and diluted with ethyl acetate. The water layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated to provide l-Boc-piperidine-4-methanol (7.98 g, 85%) as a white solid.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4([CH3:34])[C:26](=[O:27])[NH:25][C:24]([C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)=[N:23]4)[CH2:17][CH2:16]3)[C:9]=2[O:8][CH2:7][CH2:6]1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>O1CCCC1>[CH2:1]([N:25]1[C:26](=[O:27])[C:22]([CH2:21][N:18]2[CH2:17][CH2:16][N:15]([C:14]3[C:9]4[O:8][CH2:7][CH2:6][O:5][C:10]=4[CH:11]=[CH:12][CH:13]=3)[CH2:20][CH2:19]2)([CH3:34])[N:23]=[C:24]1[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: CC1(CN2CCN(c3cccc4c3OCCO4)CC2)N=C(c2cccnc2)NC1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCN1C(=O)C(C)(CN2CCN(c3cccc4c3OCCO4)CC2)N=C1c1cccnc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of allyl bromide (0.7 ml) in dry tetrahydrofuran (5 ml) was added dropwise at 0° C. under nitrogen to a stirred mixture of 4-[4-(1,4-benzodioxan-5-yl)piperazin-1-ylmethyl]-4-methyl-2-(3-pyridyl)-2-imidazolin-5-one (2.86 g; prepared in a similar manner to that described in Example 40), powdered potassium hydroxide (0.57 g) and 18-Crown-6 (0.18 g) in dry tetrahydrofuran (60 ml). The mixture was stirred at ambient temperature for 17 hours then poured onto ice-water (30 ml) and the product extracted into ether. The extracts were dried (MgSO4) and the solvents removed in vacuo to yield a foam which was triturated with ether. The precipitate was collected by filtration to yield 1-allyl-4-[4-(1,4-benzodioxan-5-yl)piperazin-1-ylmethyl]-4-methyl-2-(3-pyridyl)-2-imidazolin-5-one as a solid (0.53 g), m.p. 102-105° C.
Reaction SMILES: [CH3:1][N:2]([CH3:48])[C:3]([C:5]1[S:6][C:7]([C:10]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([C:24]5[S:25][CH:26]=[CH:27][N:28]=5)=[CH:22][N:23]=4)[CH:20]=3)=[CH:13][N:12](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:11]=2)=[CH:8][CH:9]=1)=[O:4].[ClH:49]>O1CCCC1.CO>[ClH:49].[ClH:49].[CH3:1][N:2]([CH3:48])[C:3]([C:5]1[S:6][C:7]([C:10]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([C:24]5[S:25][CH:26]=[CH:27][N:28]=5)=[CH:22][N:23]=4)[CH:20]=3)=[CH:13][NH:12][N:11]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: CN(C)C(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4nccs4)n3c2)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)c1ccc(-c2n[nH]cc2-c2ccc3ncc(-c4nccs4)n3c2)s1
Reaction time: 3 h

Procedure:
29 mg 5-[4-(3-thiazol-2-yl-imidazo[1,2-a]pyridin-6-yl)-1-trityl-1H-pyrazol-3-yl]-thiophen-2-carboxylic acid dimethylamide obtained in Example 444 was dissolved in 8.0 mL solvent mixture of tetrahydrofuran and methanol (1:1), then 3.0 mL of 5 N hydrochloric acid was added thereto, and the mixture was left at room temperature for 3 hours. The reaction solution was neutralized, then extracted with ethyl acetate and purified by NH silica gel column chromatography (ethyl acetate/hexane) The product was converted into the corresponding hydrochloride by 4 N hydrogen chloride in ethyl acetate and recrystallized from methanol/ethyl acetate to give 20 mg of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]([OH:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.[CH3:14][Si:15]([CH3:29])([CH3:28])[CH2:16][CH2:17]N=C(O)N(C(C)C)C(C)C>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([OH:11])[C:8]([O:10][CH2:17][CH2:16][Si:15]([CH3:29])([CH3:28])[CH3:14])=[O:9])=[CH:12][CH:13]=1
Reactant: CC(C)N(C(O)=NCC[Si](C)(C)C)C(C)C
Reactant: COc1ccc(C(O)C(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(C(O)C(=O)OCC[Si](C)(C)C)cc1
Yield: 72 %

Procedure:
To a solution of 4-methoxymandelic acid (2.00 g, 10.978 mmol) in 55 mL of dioxane at 90° C. is added 2-trimethylsilylethyl-N,N-diisopropyl-pseudourea. The resulting solution is refluxed for about 8 hours. After cooling the mixture is diluted with 50 mL of ethyl acetate, filtered, washed with saturated aqueous sodium bicarbonate followed by brine, dried over magnesium sulfate, and concentrated. The resulting residue is chromatographed on silica gel (9/1 hexanes/ethyl acetate) to give the title compound as an oil: 2.24 g, 72% yield. 1H NMR (300 MHz, CDCl3): 7.32 (d, J=8.8, 2 H), 6.89 (d, J=8.8, 2 H), 5.08 (d, J=5.6, 1 H), 4.38-4.17 (m, 2 H), 3.81 (s, 3 H), 3.41 (d, J=5.6, 1 H), 0.96 (m, 2 H), 0.01 (s, 9 H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Br:9][C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[N:19]([C:22]1[N:27]=[C:26]([C:28](OC)=[O:29])[CH:25]=[C:24]([CH3:32])[N:23]=1)[CH2:20][CH3:21].[OH-].[Na+]>C1COCC1.CCOCC>[Br:9][C:10]1[CH:15]=[C:14]([CH:16]([CH3:17])[CH3:18])[CH:13]=[CH:12][C:11]=1[N:19]([CH2:20][CH3:21])[C:22]1[N:23]=[C:24]([CH3:32])[CH:25]=[C:26]([C:28]([N:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[O:29])[N:27]=1
Reactant: C1COCCN1
Reactant: CCN(c1nc(C)cc(C(=O)OC)n1)c1ccc(C(C)C)cc1Br
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(c1nc(C)cc(C(=O)N2CCOCC2)n1)c1ccc(C(C)C)cc1Br
Temperature: 25 °C
Reaction time: 26 h
Yield: 39.4 %

Procedure:
To sodium hydride (60% in oil, 0.24 g, 6.0 mmol) suspended in anhydrous THF (10 mL) was added morpholine (0.52 g, 6.0 mmol) with stirring; the reaction mixture was warmed to reflux temperature and stirred for 1 hour. The reaction mixture was then cooled to ambient temperature and 2-(N-(2-bromo-4-(2-propyl)-phenyl)-N-ethylamino)-4-carbomethoxy-6-methyl-pyrimidine (2.0 g, 5.1 mmol) was added. Stirring was continued for 26 hours. The reaction mixture was then poured onto a 1 N NaOH solution, stirred and extracted three time with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Column chromatography (Et2O) afforded the title compound as a solid (900 mg, 39% yield): mp 145° C.; NMR (CDCl3, 300 MHz): d 7.5 (d, 1H, J=1), 7.2 (dd, 1H, J=7.1), 7.1 (d, 1H, J=7), 6.8 (br s, 1H), 4.3-4.15 (m, 1H), 3.9-3.3 (m, 11H), 3.1-3.0 (m, 1H), 2.9 (septet, 1H, J=7), 1.3 (d, 6H, J=7), 1.15 (t, 3H, J=7); Anal. (C21H27BrN4O2) Calcd: C, 56.38, H, 6.08, N, 12.52, Br, 17.86; Found: C, 56.07, H, 6.05, N, 12.29, Br, 18.08.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)cc1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 4-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (79 mg, 71%). MS (ISP) 449.3 [(M+H)+]; mp 225-228° C.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:15][CH2:14][CH2:13][N:12]([S:16]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=2[CH2:29][CH2:30][F:31])[C:22]([O:24]C)=[O:23])(=[O:18])=[O:17])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.O>[CH2:1]([O:8][CH:9]1[CH2:15][CH2:14][CH2:13][N:12]([S:16]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=2[CH2:29][CH2:30][F:31])[C:22]([OH:24])=[O:23])(=[O:17])=[O:18])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CCF)c(S(=O)(=O)N2CCCC(OCc3ccccc3)CC2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CCF)c(S(=O)(=O)N2CCCC(OCc3ccccc3)CC2)c1
Temperature: 37.5 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
To a solution of methyl 3-(4-benzyloxyazepan-1-yl)sulfonyl-4-(2-fluoroethyl)benzoate (180.00 mg, 400.42 umol, 1.00 Eq) in THF (5 mL) and H2O (1 mL). The formed mixture was stirred at 25-50° C. for 3 hr. The reaction mixture was neutralized with 1N HCl solution and concentrated to give the crude product 3-(4-benzyloxyazepan-1-yl)sulfonyl-4-(2-fluoroethyl)benzoic acid (160.00 mg, 367.39 umol, 91.75% yield).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([NH:23][CH:24]=[C:25]([C:29]([OH:31])=[O:30])[C:26](O)=[O:27])[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32]1(OC2C=CC=CC=2)C=CC=C[CH:33]=1>C(O)C>[O:27]=[C:26]1[C:12]2[C:11](=[CH:10][C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:13]=2)[NH:23][CH:24]=[C:25]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)C(=CNc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)O
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2cc(OCc3ccccc3)c(OCc3ccccc3)cc2c1=O

Procedure:
The compound of title 4 (2.55 g, 5.36 mmol) was added under stirring to 21 mL boiling diphenylether. The mixture was heated to reflux for 15 minutes while the resulting ethanol was distilled off. After cooling, ether was added to the resulting suspension. The precipitate (the title compound) was filtered off and dried in vacuo.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6]([O:8][C:9]([C:11](=[CH:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][CH:18]=1)[CH2:12][C:13](O)=O)=[O:10])[CH3:7]>C(OC(=O)C)(=O)C.ClCCl>[C:1]([O:4][C:13]1[C:18]2[O:19][C:20]([CH3:22])=[CH:21][C:17]=2[CH:16]=[C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=Cc1coc(C)c1)CC(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc(OC(C)=O)c2oc(C)cc2c1
Yield: 81 %

Procedure:
Sodium acetate (15 g, 0.18 mol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(5-methyl-3-furyl)but-3-enoic acid (14 g, 58 mmol) in 150 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 300 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 250 mL of dichloromethane. The combined solutions were washed by 350 mL of a saturated aqueous solution of NaHCO3 and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (250×150 mm) with hexane/ethyl acetate mixture (3:1) as eluent to give the desired product 12.5 g (47 mmol, 81%) as a solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[CH:12]3[CH2:14][CH2:15][CH2:16][CH2:17][CH:11]3[O:10][C:9]=2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=1[Cl:22])(=[O:3])[CH3:2]>C1C=CC=CC=1>[C:1]([NH:4][C:5]1[C:13]2[C:12]3[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=3[O:10][C:9]=2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=1[Cl:22])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OC1CCCCC21
Solvent: c1ccccc1
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2c3c(oc12)CCCC3
Temperature: 80 °C

Procedure:
A mixture of 1 g methyl 1-acetylamino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate and 1 g of dichlorodicyanoquinone in 15 ml of benzene is stirred and heated at 80° C. in a sealed tube for 8 hours. The coooled reaction mixture is then diluted with benzene, filtered and evaporated to dryness. Purification by recrystallization from ethyl acetate/hexane gives pure methyl 1-acetylamino-2-chloro-6,7,8,9-tetrahydrodibenzofuran-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5](/[C:9](=[N:11]/[NH2:12])/[CH3:10])=[C:4](F)[CH:3]=1.C([O-])(O)=O.[Na+]>C(O)CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:9]([CH3:10])=[N:11][NH:12]2)=[CH:6][C:7]=1[F:8]
Reactant: C/C(=N\N)c1cc(F)c(Br)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Product: Cc1n[nH]c2cc(Br)c(F)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (E)-[1-(4-bromo-2,5-difluorophenyl)ethylidene]hydrazine in ethylene glycol (3 mL) was heated at 165° C. for 3 hours in a sealed tube. The mixture was cooled to RT and saturated NaHCO3 was added (3 mL) and stirred for 10 minutes. The mixture was filtered and solid was washed with water (5 mL×2) to obtain the desired product brown solid (163 mg, 62%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[C:15](B(O)O)=[C:14]([O:19][CH3:20])[CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[C:14]([O:19][CH3:20])=[CH:13][CH:12]=[CH:11][C:10]=2[F:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1cccc(F)c1B(O)O
Solvent: ClCCl
Product: COc1cccc(F)c1Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Into a 100 mL round bottom flask was added 4-bromophenol (2.04 g, 11.8 mmol), 6-fluoro-2-methoxyphenylboronic acid (1.00 g, 5.88 mmol), cupric acetate (1.4 g, 7.70 mmol) and DCM (50 mL). TEA (4.0 mL, 29.0 mmol) was then added followed by 4 A° molecular sieves and the reaction mixture was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane.