Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][C@@H:24]([CH3:27])[CH2:25][CH3:26])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.NN.C(O)COCCO.[OH-].[K+]>O>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C@@H:24]([CH3:27])[CH2:25][CH3:26])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)C[C@@H](C)CC)cc2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCCCCCCOc1ccc(-c2ccc(CC[C@@H](C)CC)cc2)cc1
Reaction time: 4 h
Yield: 56.7 %

Procedure:
4-Octyloxy-4'-((S)-3-methyl-pentanoyl)biphenyl (24.6 g, 0.065 mol) obtained in Example 23 described later, 80% hydrazine hydrate (50 ml) and diethylene glycol (85 ml) were placed in a 500 ml three-neck flask, followed by heating with stirring, keeping the mixture at 120° C. for one hour, then cooling, adding, at a stroke, a solution of potassium hydroxide (8.8 g, 0.157 mol) in water (5 ml) while keeping the temperature at 50° C., distilling off so that the temperature of the system might become 200° C., reacting at 200° C. for 4 hours, then cooling, adding water (200 ml) and toluene (50 ml), transferring the contents into a separating funnel, water-washing the organic layer till the washing liquid became neutral, distilling off the solvent, distilling under reduced pressure to collect a fraction having a boiling point of 210°-213° C./3 mmHg, and recrystallizing it from ethyl alcohol (20 ml) and ethyl acetate (5 ml) to obtain 4-octyloxy-4'-((S)-3-methyl-pentyl)biphenyl (IIIb1) (13.5 g) which was a smectic liquid crystal exhibiting SC* phase and SH* phase, and whose phase transition points were as follows as shown in Table 2, column of Example 24: C-S1 point, 43.0° C.; Sl-SH* point, 57.9° C.; SH*-SC* point, 62.5° C; SC*-I point, 65.1° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[Br:11][C:12]1[C:13]([CH3:25])=[CH:14][C:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17](=O)[C:16]=2[C:23]=1[CH3:24].[OH-].[Na+]>O.C1COCC1>[Br:11][C:12]1[C:13]([CH3:25])=[CH:14][C:15]2[O:19][C:18]([CH3:20])([CH3:21])[CH2:17][C:16]=2[C:23]=1[CH3:24]
Reactant: Cc1cc2c(c(C)c1Br)C(=O)C(C)(C)O2
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(c(C)c1Br)CC(C)(C)O2
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
Lithium aluminium hydride (2.33 mg, 61.5 mmol) was added to a suspension of THF (70 mL) containing aluminium chloride (8.20 g, 6.15 mmol) under ice-cooling condition, and the mixture was stirred for 15 minutes. After that, a solution of THF (30 mL) containing 5-bromo-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one (6.63 g, 24.6 mmol) synthesized in Reference Example 119 was added thereto, and the mixture was stirred under heated reflux for 2.5 hours. The reaction solution was iced, and after that, water was added dropwise thereto. 0.5N sodium hydroxide aqueous solution was further added thereto, and the mixture was stirred at room temperature for 10 minutes. Insolubles were removed by filtration. The filtrate was subjected to extraction using a mixed solvent of ethyl acetate-diethyl ether (1:1). The extract was washed with saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate 9:1). Crystallization was performed using methanol-ethyl acetate to give 5.29 g of the title compound (yield: 84%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:5][NH:6]2>C(O)C.[Pd]>[CH3:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:5][NH:6]2
Reactant: Cc1c([N+](=O)[O-])ccc2[nH]cc(CCCO)c12
Agent: [Pd]
Solvent: CCO
Product: Cc1c(N)ccc2[nH]cc(CCCO)c12
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
To a solution of 4-methyl-5-nitro-3-(3-hydroxypropyl)indole (0.365 g, 1.56 mmol) in 20 mL of absolute ethanol was added 10% palladium-on-charcoal (0.150 g) and the mixture was hydrogenated on a Parr shaker at 50 psi for 0.5 h. The mixture was then filtered through a plug of Celite, the catalyst was washed with additional ethanol and the filtrate was evaporated to give the title compound (0.280 g, 88%) as a solid. An analytical sample was crystallized from ethyl acetate to give cream-coloured needles, mp 141°-142° C.: IR (KBr) 3388, 3180, 1618 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ 10.20 (br s, 1H), 6.87 (d, J=8.8 Hz, 1H), 6.83 (s, 1H), 6.50 (d, J=8.3 Hz, 1H), 4.43 (t, J=5.2 Hz, 1H), 4.12 (s, 2H), 3.47 (dt, J=6.4, 5.3 Hz, 2H), 2.79 (t, J=7.7 Hz, 2H), 2.31 (s, 3H), 1.73 (m, 2H). Anal. Calcd for C12H16N2O: C, 70.55; H, 7.90; N, 13.72. Found: C, 70.41; H, 7.89; N, 13.55.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC=C(C#N)C#N
Reactant: NCc1ccccc1
Product: N#CC(C#N)=CNCc1ccccc1

Procedure:
{[Benzylamino]methylene}methane-1,1-dicarbonitrile was synthesized in the same manner using (ethoxymethylene)methane-1,1-dicarbonitrile and benzylamine. The NMR data for this compound are shown below.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.[C:29](Cl)(=[O:31])[CH3:30]>N1C=CC=CC=1>[CH3:18][S:17][C:13]1[N:12]=[C:11]([C:8]2[CH:9]=[C:10]3[C:2]([NH:1][C:29](=[O:31])[CH3:30])=[N:3][NH:4][C:5]3=[N:6][C:7]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CSc1nccc(-c2cc3c(N)n[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CSc1nccc(-c2cc3c(NC(C)=O)n[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Yield: 35.1 %

Procedure:
A solution of 3-amino-5-[2-(methylsulfanyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine (200 mg, 0.5 mmol, obtained in example 123) and acetyl chloride (39 mg, 0.5 mmol) in pyridine (10 mL) was stirred at room temperature for 3 h. It was concentrated and the residue was taken up in a mixture of EtOAc and 1 N NaOH. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 78 mg of the title compound (yield: 37%)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([O:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](OCC)=[O:28])=[CH:21][CH:20]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].Cl>O1CCCC1>[C:11]([O:15][C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][OH:28])=[CH:23][CH:24]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(CCCO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
Diisobutylaluminium hydride(l.5 M in toluene, 30.5 ml, 45.8 mmol) was added dropwise to a stirred solution of ethyl 3-(4-tert-butoxycarbonylaminophenyl)propionate (6.10 g, 20.8 mmol) in tetrahydrofuran (60 ml) at 0° C. and the mixture was stirred at 0° C. for 1 hour. 2N-hydrochloric acid was added to the mixture and the mixture was extracted with ethyl acetate. The extract was successively washed with water, saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (100 g) with hexane-ethyl acetate (3:2) to give 3-(4-tert-butoxycarbonylaminophenyl)propanol as a colorless oil (2.66 g, 51%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH3:17])[N:3]=1.B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:17])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:6]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[N:7]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Temperature: 90 °C
Yield: 39.1 %

Procedure:
To a suspension of mixture of methyl 2-(2,4-dichloro-6-methylpyrimidin-5-yl)pentanoate (2.56 g, 7.18 mmol) in a degassed mixture of 1,2-dimethoxyethane-water (3:1, 60 mL) were added p-tolylboronic acid (1.51 g; 10.77 mmol), tetrakis(triphenylphosphine)palladium (0.846 g; 0.732 mmol) and diisopropylethylamine (5 mL; 28.70 mmol). The resulting mixture was heated at 90° C. for 2 h. After cooling, the reaction mixture was partitioned between brine and ethyl acetate, the phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (3-20%) in heptane furnished 0.935 g (27%) of the title compound as an oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:13][C:14]([O:17][C:18]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:19])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CS(C)=O>[C:14]([O:17][C:18](=[O:19])[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:23][CH2:22]1)([CH3:16])([CH3:13])[CH3:15]
Reactant: Cc1cc(F)cc(N)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc(N)c1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 3 h

Procedure:
5-Fluoro-3-methyl-2-nitro-phenylamine (0.97 g, 5.7 mmol), 4-N-BOC-aminopiperidine (1.60 g, 8.0 mmol), diisopropylethylamine (2.5 ml, 14 mmol) and DMSO (10 ml) are combined and stirred at 85° C. for 3 hours. The reaction mixture was poured on saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layers were washed with water (3×) and brine, dried over Na2SO4 and concentrated. Flash column chromatography on silica (eluent hexanes-ethyl acetate-triethylamine 50-50-1, then 33-66-1) gave the tiitle compound as a yellow solid. (1.57 g, 79%). LCMS (M+H)+ m/z 351 (t=1.55 min.). 1H NMR (500 MHz, CD3OD) δ 6.70 (1H, broad s), 6.22 (1H, d, J=2.5 Hz)), 6.13 (1H, d, J=2.5 Hz), 3.88 (2H, d, J=13.3 Hz), 3.58 (1H, broad s), 2.98 (2H, t, J=11.8 Hz), 2.48 (3H, s), 1.92 (2H, d, J=11.3 Hz), 1.48 (2H, m), 1.45 (9H, s). Procedure for the Preparation of 3-methyl-5-(2-morpholin-4-ethoxy)-2-nitro phenylamine
Reaction SMILES: [OH:1][C:2]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:20]1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1.CN(C)C=O>O>[CH3:29][O:28][C:22]1[CH:23]=[C:24]([O:26][CH3:27])[N:25]=[C:20]([O:1][C:2]2[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[N:21]=1
Reactant: COC(=O)c1ccc(C)nc1O
Reactant: COc1cc(OC)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C)nc1Oc1nc(OC)cc(OC)n1
Yield: 8 %

Procedure:
5.0 g (0.03 mol) of methyl 2-hydroxy-6-methylnicotinate, 5.0 g (0.03 mol) of potassium carbonate, 5.7 g (0.03 mol) of 2-chloro-4,6-dimethoxypyrimidine and 50 ml of N,N-dimethylformamide were weighed, and were reacted at 100° C. for 4 hours. The reaction mixture was then poured into water, and was extracted with 100 ml of ethyl acetate. The organic layer was then washed with water and a saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 0.73 g of the aimed product.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5])[CH3:2]>C1COCC1.CCOC(C)=O.[Pd]>[NH2:19][C:15]1[CH:14]=[C:13]([C:9]2[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=2[CH3:12])[CH:18]=[CH:17][CH:16]=1
Reactant: CCNC(=O)Nc1nc(C)c(-c2cccc([N+](=O)[O-])c2)s1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc(C)c(-c2cccc(N)c2)s1
Reaction time: 2 h

Procedure:
A stirred solution of 1-Ethyl-3-[4-methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-urea (98c) (0.55 g, 1.8 mmol) in THF (25 ml) and EtOAc (50 ml) under Argon is treated with 10% palladium on carbon (1.0 g). The reaction mixture was placed under an atmosphere of hydrogen for 2 hours. The mixture was then filtered through Celite™ filter material and the solvent removed in vacuo to yield the titled compound.
Reaction SMILES: CC1(C)CO[CH:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)OC1.[CH3:20][NH:21][S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:29]([C:28]3[CH:30]=[CH:31][C:25]([S:22]([NH:21][CH3:20])(=[O:24])=[O:23])=[CH:26][CH:27]=3)[CH:5]=[CH:8][CH:9]=2)=[CH:17][CH:16]=1
Reactant: CC1(C)COC(CCC(=O)c2ccc(F)cc2)OC1
Reactant: CNS(=O)(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CNS(=O)(=O)c1ccc(-n2cccc2-c2ccc(F)cc2)cc1
Yield: 40 %

Procedure:
A mixture of 3-(5,5-dimethyl-1,3-dioxan-2-yl)-1-(4-fluorophenyl)propan-1-one (Step 4) (400 mg, 1.5 mmol), 4-[(N-methylamino)sulfonyl]aniline (Step 6) (308 mg, 1.65 mmol) and p-toluenesulfonic acid (40 mg) in toluene (80 ml) was heated to reflux for 48 hr. The reaction mixture was cooled, filtered and concentrated. The crude yellowish solid (760 mg) was chromatographed (silica gel, hexane/ethyl acetate 7/3) to give 4-[2-(4-fluorophenyl)-1H-pyrrol-1-yl]-N-methylbenzenesulfonamide (198 mg, 40%) as a white solid: mp (DSC) 174° C. Anal Calc'd. for C17H15N2FO2S 0.25 H2O: C, 60.97; H, 4.67; N, 8.37. Found: C, 60.86; H, 4.56; N, 8.01.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:30]=[C:31]([Br:35])[C:32]([Cl:34])=[CH:33][C:8]1=2)=[O:6])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:42](OC(=O)C)(=[O:44])[CH3:43]>C(OCC)(=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:42](=[O:44])[CH3:43])[CH2:15][C:16]2[CH:17]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:19]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:21]=2)[C:9]2[CH:30]=[C:31]([Br:35])[C:32]([Cl:34])=[CH:33][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(Br)c(Cl)cc21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)c(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of crude 5-(3,5-Bis-trifluoromethyl-benzylamino)-7-bromo-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (1.40 g, 2.38 mmol) and pyridine (5.00 ml) was treated with acetic anhydride (5.00 ml) via dropwise addition. The mixture was stirred at room temperature overnight and then diluted with ethyl acetate (50.0 ml), washed with 1.00N HCl (2×50.0 ml) and brine (3×150 ml). Dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (gradient eluent, 0-40% ethyl acetate in hexane) provided the titled compound (1.28 g, 85%) as white foamy solid. MS (ES+): 629, 631 (M+H).
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([F:19])=[CH:5][C:6]2[N:15]=[C:14]([NH2:16])[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1.[CH3:20][O:21][CH2:22][CH2:23][C@H:24]1[CH2:29]N[CH2:27][CH2:26][NH:25]1>CS(C)=O.C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[F:2][C:3]1[C:4]([F:19])=[CH:5][C:6]2[N:15]=[C:14]([N:16]3[CH2:27][CH2:26][NH:25][C@@H:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:29]3)[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1
Reactant: Cc1cc2c(s1)Nc1cc(F)c(F)cc1N=C2N
Reactant: COCC[C@H]1CNCCN1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COCC[C@H]1CN(C2=Nc3cc(F)c(F)cc3Nc3sc(C)cc32)CCN1
Temperature: 130 °C
Yield: 37.8 %

Procedure:
Dissolve 6,7-difluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (1.7 g, 5.66 mmol) and (S)-2-(2-methoxy-ethyl)-piperazine (2.45 g, 17.0 mmol) in dimethylsulfoxide/toluene (1:2)(21 ml), stir under nitrogen and heat in an oil bath at 130° C. for 43 hours. Cool to ambient temperature. Dilute the mixture with one volume water and two volumes ethyl acetate, separate layers and extract the aqueous layer with ethyl acetate. Basify the aqueous layer with ammonium hydroxide and extract with ethyl acetate. Combine all ethyl acetate extracts and wash with water and brine. Dry the organic phase (Na2SO4), filter and concentrate under reduced pressure. Purify by silica gel chromatography (eluent: 0-10% 2N ammonia in methanol/dichloromethane) to give the title compound (840 mg, 38%): Mass Spectrum (ESMS) 393 (M+1); 391 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>ClCCl>[Si:16]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1)([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1COc2cc(O)ccc21
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
To a solution of 6-hydroxybenzofuran-3(2H)-one (30.0 g, 200 mmol) in dichloromethane (500 mL) was added TBSCl (36.0 g, 240 mmol) and imidazole (16.3 g, 240 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure to afford 6-(tert-butyldimethylsilyloxy)benzofuran-3(2H)-one (40.0 g, 80% yield), that was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[S:25][C:24]([CH3:26])=[C:23]4[C:19]=3[CH2:20][C@H:21]3[C:27]([CH3:29])([CH3:28])[C@H:22]34)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][OH:8].CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:1][C:2]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[S:25][C:24]([CH3:26])=[C:23]4[C:19]=3[CH2:20][C@H:21]3[C:27]([CH3:28])([CH3:29])[C@H:22]34)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][S:41]([CH3:40])(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
At 0° C., a solution of 3-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-propan-1-ol (170 mg, 0.40 mmol) and DIPEA (0.11 mL, 0.64 mmol) in DCM (5 mL) is treated with methanesulfonyl chloride (0.04 mL, 0.48 mmol). The reaction mixture is stirred at 0° C. for 30 min, then at rt for 1 h before it is diluted with DCM (15 mL) and washed with 0.1 N aq. NaOH (20 mL) followed by 10% aq. citric acid solution (20 mL). The organic layer is dried over Na2SO4 and evaporated to dryness to give methanesulfonic acid 3-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-propyl ester (185 mg) as a beige resin; LC-MS: tR=1.23 min, [M+1]+=503.20.
Reaction SMILES: C([O-])([O-])=O.[K+:5].[K+].[CH2:7]([N:14]1[C:21]2[CH:20]=[C:19]([C:22]([OH:24])=[O:23])[NH:18][C:17]=2[CH:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.CO>[K+:5].[CH2:7]([N:14]1[C:21]2[CH:20]=[C:19]([C:22]([O-:24])=[O:23])[NH:18][C:17]=2[CH:16]=[CH:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1cc2c(ccn2Cc2ccccc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C([O-])c1cc2c(ccn2Cc2ccccc2)[nH]1
Reaction time: 0.58 h
Yield: 196.5 %

Procedure:
To a suspension of K2CO3 (24 mg, 0.17 mmol) in H2O (0.2 mL) and MeOH (1 mL) was added a solution of 4-benzyl-1,4-dihydropyrrolo[3,2-b]pyrrole-2-carboxylic acid 13 (82 mg, 0.34 mmol) in MeOH (2 mL). The solution was stirred for 35 min and then concentrated in vacuo to give potassium 4-benzyl-1,4-dihydro-pyrrolo[3,2-b]pyrrole-2-carboxylate 13a as a grey solid (93 mg, 98%). 1H NMR (400 MHz, (CD3)2SO) δ (ppm) 9.61 (s, 1H) 7.27-7.33 (m, 2H) 7.19-7.26 (m, 3H) 6.74 (d, J=2.9 Hz, 1H) 5.90 (s, 1H) 5.73 (dd, J=2.9, 0.8 Hz, 1H) 5.04 (s, 2H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[F:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:43](=[O:44])[C:42]3[CH:46]=[CH:47][C:39]([F:38])=[CH:40][CH:41]=3)=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccc(F)cc2)cc1
Yield: 93 %

Procedure:
The title compound was prepared in 93% yield by reaction of 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C) with 4-fluorobenzoyl chloride according to the procedure of Example 13, Step C. Column chromatography on silica gel (gradient elution with 0.5-5% MeOH in CH2Cl2) provided the material as cream-colored crystals, mp 120°-122° C.; satisfactory purity by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 691 (M+K)+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([OH:21])=O)=[O:5].[NH2:30][CH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][O:33]1>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([NH:30][CH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][O:33]1)=[O:21])=[O:5]
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Reactant: NC[C@H]1CCCO1
Product: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)NC[C@H]1CCCO1

Procedure:
The title compound was prepared from the product of Example 45A and commercially available (R)-2-aminomethyltetrahydrofuran using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.45 (s, 6H), 1.48 (s, 6H), 1.50-1.58 (m, 2H), 1.66-0.191 (m, 3H), 3.13-3.29 (m, 2H), 3.39-3.46 (m, 1H), 3.60-3.67 (m, 1H), 3.85-3.94 (m, 1H), 7.69-7.82 (m, 3H), 8.03 (t, J=5.8 Hz, 1H), 11.42 (br s, 1H). MS (ESI+) m/z 515 (M+H)+.