Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9](SC)[NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)[CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:28].CO>>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[NH:28])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)[CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSC(=Nc1cccc(F)c1)Nc1ccc(C(C(C)C)n2ccnc2)cc1
Reactant: N
Solvent: CO
Product: CC(C)C(c1ccc(NC(=N)Nc2cccc(F)c2)cc1)n1ccnc1
Temperature: 40 °C
Yield: 46 %

Procedure:
A solution of methyl N′-(3-fluorophenyl)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-phenyl]carbamimidothioate (0.0094 mol) in NH3/CH3OH (60 ml) was stirred and heated in autoclave at 40° C. for 3 days. The solvent was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 94/6/0.2 to 90.10/0.5). The pure fractions were collected and evaporated. The residue was crystallized from 2-propanone and (C2H5)2O and filtered off, yielding 0.89 g (46%) N′-(3-fluorophenyl)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]guanidine (compound 744).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]1=[O:16])[O:6][CH2:7][CH3:8])[CH3:2].N1C(C)=CC(C)=CC=1C.[C:27]1([CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:6][CH2:7][CH3:8])[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:34]([CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:36])=[O:35])[C:10]1=[O:16])[CH3:2]
Reactant: CCOC(=O)C(OCC)n1cccc(N)c1=O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: C1CCOC1
Product: CCOC(=O)C(OCC)n1cccc(NS(=O)(=O)Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a stirred, cooled (0° C.) solution (RS)-(3-amino-2-oxo-2H-pyridin-1-yl)-ethoxy-acetic acid ethyl ester (428 mg) and 2,4,6-collidine (0.47 ml) in THF (3 ml) under an argon atmosphere was added dropwise a solution of alpha-toluenesulphonylchloride (340 mg) in THF (2 ml) over 10 min. When addition was complete, stirring at 0° C. was continued for 2 h. The mixture was diluted with EtOAc, washed with 1.0 N HCl and brine, dried (MgSO4), filtered and concentrated to give (RS)-ethoxy-(2-oxo-3-phenylmethanesulfonylamino-2H-pyridin-1-yl)-acetic acid ethyl ester (592 mg) as light brown solid. MS 393.0 ([M−H]−)
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[C:6]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39].[H-].[Na+].[Br:42][C:43]1[CH:44]=[N:45][C:46](Cl)=[N:47][CH:48]=1.CN(C=O)C>C1COCC1>[Br:42][C:43]1[CH:44]=[N:45][C:46]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=3)[C:6]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH3:39])=[N:47][CH:48]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCO
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCOc1ncc(Br)cn1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
4-i-Propyl-phenyl sulfamic acid-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (60 mg, Example 3) was dissoved in THF (8 ml). Sodium hydride (14 mg, 60% dispersion in mineral oil) was added and stirring continued for 10 min. 5-Bromo-2-chloro-pyrimidine (37 mg) was added and the mixture was heated to 60° C. for 120 min. DMF (0.5 ml) was added and the solution was stirred at r.t. for 48 h. The solvents were evaporated, water (12 ml) and a 10% solution of citric acid was added until the pH was 3. The precipitate was filtered off and washed with water and purified by chromatography through silica gel with EtOAc/Hex=1:1 to give 4-i-propyl-phenyl sulfamic acid-[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(o-methoxy-phenoxy)-2-(4-pyridyl)pyrimidin-4-yl]-amide (55.4 mg). tR=5.30 min, (LC); [M+H]+=710.35 (ES+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)O[C:9]1[CH:14]=[CH:13][CH:12]=CC=1.[OH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:26]=[O:27].C(Cl)(Cl)Cl>ClCCl>[CH2:6]([N:1]([CH2:12][CH2:13][CH2:14][CH3:9])[CH2:2][CH2:20][NH:25][C:26]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:26]=[O:27])=[O:27])[CH2:5][CH2:4][CH3:3]
Reactant: CCCCCCCCCCCCCCCCCCN(C=O)c1ccccc1CO
Reactant: c1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(C=O)c1ccccc1COC(=O)NCCN(CCCC)CCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyridine (0.30 ml) and phenyl chlorocarbonate (0.35 ml) were added to a suspension of [2-(hydroxymethyl)phenyl]-N-octadecylformamide (1.38 g) in dichloromethane (10 ml) while being cooled with ice. After being stirred for 1 hours at room temperature, the reaction mixture, with chloroform added thereto, was washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and then concentrated. N,N-Di-n-butylethylenediamine (0.57 ml) was added to the residue. After being stirred for 3 hours at 70° C., the reaction mixture was purified by silica gel column chromatography (silica gel 40 g, chloroform:methanol=50:1), thereby yielding 1.31 g of the aimed compound as white solid.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:23][C@@H:22]2[C@:9]([CH3:27])([CH2:10][C@H:11]([OH:26])[C@H:12]3[C@H:21]2[CH2:20][CH2:19][C:18]2[C@:13]3([CH3:25])[CH:14]=[CH:15][C:16](=[O:24])[CH:17]=2)[C@H:4]1[C:5](=[O:8])[CH2:6]O)#[N:2].[O:28]1[CH:33]=[CH:32][CH2:31][CH2:30][CH2:29]1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[CH2:6][C:5](=[O:8])[C@@H:4]1[C@:9]2([CH3:27])[C@H:22]([C@H:21]3[C@H:12]([C@@H:11]([OH:26])[CH2:10]2)[C@:13]2([CH3:25])[C:18](=[CH:17][C:16](=[O:24])[CH:15]=[CH:14]2)[CH2:19][CH2:20]3)[CH2:23][C@H:3]1[C:1]#[N:2]
Reactant: C1=COCCC1
Reactant: C[C@]12C[C@H](O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1C[C@@H](C#N)[C@@H]2C(=O)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: C[C@]12C[C@H](O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1C[C@@H](C#N)[C@@H]2C(=O)CC1CCCCO1

Procedure:
The process of claim 9 which additionally comprises reacting (VI) with 2,3-dihydropyran and pyridinium tosylate to produce (VII) 21-tetrahydropyranyl-16α-cyano-11β-hydroxy-3,20-dioxo-1,4-pregnadiene.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[Br:18][C:14]1[C:15]([OH:17])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CNCCc2cc(O)c(Br)cc21
Temperature: 20 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.655 g, 1.89 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (20 mL), and stirred overnight at 20° C. The product mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.460 g of a clear oil. 1H NMR (400 MHz, DMSO-d6) δ 7.11 (s, 1H), 6.65 (s, 1H), 2.90 (m, 1H), 2.73 (m, 5H), 2.55 (m, 1H), 1.19 (d, J=7 Hz, 3H). MS calculated for C11H14BrNO+H: 256, observed: 256.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([C:7]1[CH:23]=[CH:22][C:10]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3[O:19][CH:20]=[CH:21][C:15]=3[CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:6].[CH3:28][NH:29][CH3:30].[CH2:31]=O>C(O)(=O)C>[CH3:28][N:29]([CH2:31][C:20]1[O:19][C:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:10]3[CH:22]=[CH:23][C:7]([C:5](=[O:6])[C:4]4[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=4[O:2][CH3:1])=[CH:8][CH:9]=3)[CH2:14][C:15]=2[CH:21]=1)[CH3:30]
Reactant: COc1ccccc1C(=O)c1ccc(C(=O)N2CCc3occc3C2)cc1
Reactant: C=O
Reactant: CNC
Solvent: CC(=O)O
Product: COc1ccccc1C(=O)c1ccc(C(=O)N2CCc3oc(CN(C)C)cc3C2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.230 g (0.636 mmol) of 5-[4-(2-methoxybenzoyl)benzoyl]-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 10 ml of acetic acid, 0.086 ml (0.95 mmol) of 50% aqueous dimethylamine and 0.077 ml (0.95 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 60 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform/methanol=50/1) to yield the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=S(Cl)Cl.O.C([O-])([O-])=O.[Na+].[Na+].[CH3:26][CH2:27]O>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([O:14][CH2:26][CH3:27])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc2cc(O)ccc2c1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cnc2cc(O)ccc2c1
Yield: 64 %

Procedure:
To a solution of the compound obtained in stage A (15 g, 79 mmol) in EtOH (500 ml) was added dropwise SOCl2 (40 mL). The resulting mixture was stirred under reflux during 12 hours. After adding water (200 mL), the pH was adjusted to 7.0 with 20% aqueous Na2CO3. The aqueous solution was extracted with CH2Cl2 (3×200 mL). The combined organic layers were dried over MgSO4, filtered and evaporated to afford 11 g (yield: 64%) of the product of molecular formula C12H11NO3. Aspect: pale brown powder.
Reaction SMILES: [Li+].C[CH:3]([N-:5][CH:6]([CH3:8])C)[CH3:4].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:12][CH:11]=1.[CH2:22]([O:24]CC)[CH3:23]>>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([CH2:17][CH:18]([CH3:19])[CH3:20])[C:8]3[CH:6]=[N:5][CH:3]=[CH:4][C:23]=3[C:22](=[O:24])[O:21]2)=[CH:14][CH:15]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)CC(=O)c1ccc(F)cc1
Reactant: CCOCC
Agent: [Li+]
Product: CC(C)CC1(c2ccc(F)cc2)OC(=O)c2ccncc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 7 %

Procedure:
To a solution of 4-diisopropylamidopyridine (3.2 g, 15.54 mmol) in anhydrous diethyl ether (160 mL) at −78° C. was added a 1M solution of LDA in diethyl ether (23.27 mL) and the reaction mixture stirred at −78° C. for 2 hours. A solution of 1-(4-fluorophenyl)-3-methylbutan-1-one (3.5 g, 19.42 mmol) in anhydrous diethyl ether (5 mL) was added dropwise, and the reaction was stirred at −78° C. for 30 min. The reaction mixture was quenched with brine (100 mL), extracted with ethyl acetate (3×50 mL), dried (MgSO4), and concentrated. The crude mixture was stirred with 6 N HCl (50 mL) for 12 hours, then cooled to 0° C. Sodium hydroxyde (15 g, 37.5 mmol) was added in 3 portions, the reaction mixture was stirred at 0° C. for 30 min, then extracted with ethyl acetate (3×100 mL). The organic layers were dried (MgSO4), concentrated and purified by column chromatography (40 g, SiO2, 0 to 40% ethyl acetate in hexanes) to provide 3-(4-fluorophenyl)-3-isobutylfuro[3,4-c]pyridin-1(3H)-one (296 mg, 7%) as an off-white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.80-0.91 (m, 6H), 1.54-1.66 (m, 1H), 2.06 (dd, J=14.88, 6.97 Hz, 1H), 2.48 (dd, J=15.07, 5.27 Hz, 1H), 7.04-7.14 (m, 2H), 7.46-7.56 (m, 2H), 7.77 (dd, J=5.09, 0.94 Hz, 1H), 8.85 (d, J=4.90 Hz, 1H), 9.01 (s, 1H); MS m/z 286 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][O:1][C:2]2[C:11]3[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)[N:8]4[CH2:21][CH2:22][N:23]=[C:7]4[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:27][CH:28]=1)(=[O:33])=[O:34]
Reactant: O=C(NC1=Nc2c(O)cccc2C2=NCCN12)c1cccnc1
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Product: CS(=O)(=O)c1ccc(COc2cccc3c2N=C(NC(=O)c2cccnc2)N2CCN=C32)cc1

Procedure:
The procedure used for the preparation of Example 1 was used to prepare the title compound from N-(7-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Intermediate C) and 1-(chloromethyl)-4-(methylsulfonyl)benzene. High vacuum drying at 60° C. gave the title compound (50 mg, 43%): HPLC MS RT=2.05 min, MH+=476.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 3.24 (3H, s), 4.28-4.34 (2H, m), 4.59-4.66 (2H, m), 5.62 (2H, s), 7.61 (1H, t), 7.79-7.88 (4H, m), 7.98-8.05 (3H, m), 8.98-9.02 (2H, m), 9.53 (1H, s).
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C@H:5]([C@@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1)[CH3:6].C(N(C(C)C)CC)(C)C.[CH:21]1([N:24]2[C:33]3[C:28](=[CH:29][C:30]([F:37])=[C:31](F)[C:32]=3[O:34][CH3:35])[C:27](=[O:38])[C:26]3[C:39]([OH:44])=[C:40]([C:42]#[N:43])[S:41][C:25]2=3)[CH2:23][CH2:22]1.Cl>CS(C)=O.CO>[CH:21]1([N:24]2[C:33]3[C:28](=[CH:29][C:30]([F:37])=[C:31]([N:9]4[CH2:10][CH2:11][C@@H:7]([C@@H:5]([NH:4][CH2:3][CH2:2][F:1])[CH3:6])[CH2:8]4)[C:32]=3[O:34][CH3:35])[C:27](=[O:38])[C:26]3[C:39]([OH:44])=[C:40]([C:42]#[N:43])[S:41][C:25]2=3)[CH2:22][CH2:23]1
Reactant: COc1c(F)c(F)cc2c(=O)c3c(O)c(C#N)sc3n(C3CC3)c12
Reactant: C[C@H](NCCF)[C@@H]1CCNC1
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(N2CC[C@@H]([C@H](C)NCCF)C2)c(F)cc2c(=O)c3c(O)c(C#N)sc3n(C3CC3)c12
Temperature: 110 °C
Yield: 30.7 %

Procedure:
2-Fluoro-N—((S)-1-((R)-pyrrolidin-3-yl)ethyl)ethanamine (0.14 g, 0.87 mmol) and diisopropylethylamine (0.38 mL, 2.18 mmol) are added to a mixture of 9-cyclopropyl-6,7-difluoro-3-hydroxyl-8-methoxy-4-oxo-4,9-dihydrothieno[2,3-b]quinoline-2-carbonitrile (0.15 g, 0.44 mmol) in DMSO (2 mL). The reaction mixture is heated at 110° C. for 18 h, and cooled to rt. The resulting solution is purified by preparative HPLC using mass-based fraction collection to provide the desired mass only fractions. The fractions containing product were combined and lyophilized. The resulting solid was treated with a solution of 1.25 M HCl in methanol (3 mL), evaporated, and triturated with diethyl ether. This step was repeated three times. The brown solid was dissolved in water and lyophilized to afford the desired product (66.1 mg, 29%, HCl salt) as a brown solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH:16]=[CH:15][C:13]([OH:14])=[CH:12][CH:11]=1)[OH:10]>>[CH2:1]([O:10][C:9]1[CH:16]=[CH:15][C:13]([OH:14])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(O)cc1
Product: Oc1ccc(OCc2ccccc2)cc1

Procedure:
Benzylbromide and hydroquinone are reacted to obtain 4-benzyloxyphenol (i),which is reacted with optical active perfluoro-2-(perfluoroalkoxy) propionic chloride in pyridine as a solvent to obtain 4-benzyloxyphenyl-perfluoro-2-(Perfluoroalkoxy) propionate (ii), which is then subjected to the hydrogenation in the presence of a palladium/carbon catalyst to obtain 4-hydroxyphenyl-perfluoro-2-(perfluoropropoxy) propionate (iii), which is reacted to 4-alkyloxybenzoic acid and thionyl chloride in pyridine as a solvent to obtain an objective optically active compound, 4-[perfluoro-2-(perfluoropropoxy)propionyloxy]phenyl4'-n-octyloxybenzoate.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].CN(C)C=O.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O>[CH3:2][CH2:1][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH:5][C:17]([CH3:18])=[O:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cccc(CC)c1N
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cccc(CC)c1NC(C)=O
Reaction time: 1 h

Procedure:
A solution of 74.5 parts of 2,6-diethylaniline in 200 parts of dimethylformamide is treated with 56 parts of acetic anhydride at 10°C. The mixture is stirred at 40° for one hour, poured into ice and water and stirred. The solid 2,6-diethylacetanilide is filtered, washed with water and dried.
Reaction SMILES: F[C:2]1[CH:10]=[C:9](F)[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([OH:15])=[O:14].[F:16]C1C=C(F)C=C2C=1CCC2(CC(O)=O)O>>[F:16][C:10]1[CH:2]=[C:3]2[C:7](=[CH:8][CH:9]=1)/[C:6](=[CH:12]/[C:13]([OH:15])=[O:14])/[CH2:5][CH2:4]2
Reactant: O=C(O)/C=C1\CCc2c(F)cc(F)cc21
Reactant: O=C(O)CC1(O)CCc2c(F)cc(F)cc21
Product: O=C(O)/C=C1\CCc2cc(F)ccc21
Yield: 68 %

Procedure:
This compound was prepared in an analogous manner to (E)-2-(4,6difluoro-1-indanylidene)acetic acid in Example 5e by substituting 2-(5-fluoro-1-hydroxy-1-indanyl)acetic acid(14.70 g, 0.069 mol) for 2-(4,6-difluoro-1-hydroxy-1-indanyl)acetic acid. Recrystallization from acetonitrile: 2-propanol mixtures gave 9.05 g (68%) of (E)-2-(5-fluoro-1-indanylidene)acetic acid as a white solid: m.p., 240°-242° C.;
Reaction SMILES: Br[C:2]1[C:21]([F:22])=[CH:20][C:5]2[O:6][CH2:7][CH:8]([N:17]([CH3:19])[CH3:18])[C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([OH:33])([C:31]#[CH:32])[CH3:30]>>[CH3:18][N:17]([CH3:19])[CH:8]1[C:9]2[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=2[C:4]2[CH:3]=[C:2]([C:32]#[C:31][C:29]([OH:33])([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[CH3:30])[C:21]([F:22])=[CH:20][C:5]=2[O:6][CH2:7]1
Reactant: CN(C)C1COc2cc(F)c(Br)cc2-c2nc(C(N)=O)sc21
Reactant: C#CC(C)(O)c1ccccn1
Product: CN(C)C1COc2cc(F)c(C#CC(C)(O)c3ccccn3)cc2-c2nc(C(N)=O)sc21

Procedure:
Similar to as described in General Procedure G, racemic 9-bromo-4-(dimethylamino)-8-fluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with racemic 2-(pyridin-2-yl)but-3-yn-2-ol to give an isomeric mixture of the titled compound. The mixture (80 mg) was separated by Chiral-Prep-HPLC with the following conditions (2#-Gilson Gx 281(HPLC-09)): Column, CHIRALPAK AD-H SFC, 5*25 cm, 5 um; mobile phase, Hex (0.2% TEA) and ethanol (0.2% TEA) (hold 30.0% ethanol (0.2% TEA) in 30 min); Detector, UV 220/254 nm to give 1st 3.7 mg (2%) of Compound 1, then 10.2 mg (4%) of Compounds 2 and 18.6 mg (8%) Compound 3. The stereochemistry of these compounds has not been assigned.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:13]O>>[C:3]([CH:2]1[CH2:6][CH2:7][CH2:8][NH:1]1)([O:5][CH3:13])=[O:4]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCCN1
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of L-proline (2.23 g) in dry methanol (15 ml) was cooled to −5° C. and thionyl chloride (4.52 g) was added dropwise, while stirring and maintaining the temperature of the reactants below 0° C. The reaction was continued at 25° C. for 2 h. The solvent was distilled and the residue stored in ice-chest for 12 h. The solid mass was added to aqueous solution of potassium carbonate (50%, 20 ml) at 0° C. and the separated oily layer was extracted into ether (15 ml×3). The ethereal layer was dried over anhydrous sodium sulfate and distilled to afford 2.3 g of 2-(carbomethoxy)-pyrrolidine (85%), [MS (m/z) M+129 (1%), 114 (0.5), 70(100), 68(50), 43(80), 41(90)]. It was taken in dry diethyl ether (15 ml), cooled to 0° C. and t-butylhypochlorite (2.16 g) added dropwise. The reaction was monitored on silica gel thin layer using chloroform as the eluant. After completion of the reaction (15 min.), potassium t-butoxide (2.24 g) was added gradually over 10 min. and the reactants stirred at 25° C. for 5 h. The solution was filtered and the solvent distilled under reduced pressure to afford 2-(carbomethoxy)-1-pyrrroline (2 g), [MS (m/z) M+ 127(1%), 112(0.5), 97 (15), 69 (100), 54 (50), 41 (75)]. To a suspension of magnesium turnings (0.43 g) in dry ether, iodine (0.01 g) was added followed by dropwise addition of a solution of methyl iodide (3.08 g) in ether (5 ml) at 35° C. The mixture was stirred until the disappearance of magnesium turnings (15 min), then cooled to 0° C. To it, a solution of 2-(carbomethoxy)-1-pyrrroline (2 g) in dry ether (5 ml) was added over 5 min. and the mixture was stirred at room temperature. On completion of the reaction (2 h) the product was worked up by the addition of dilute hydrochloric acid (5%, 10 ml) and the organic layer separated. The aqueous layer was further extracted with ether (10 ml×2) and the combined organic layers dried over anhydrous sodium sulphate and distilled to afford pure 2-acetyl-1-pyrroline [1.3g, 95% purity, MS (m/z) M+ 111 (5%), 96 (0.1), 83 (15), 69(8), 68 (10), 55 (2), 52 (0.2), 43 (100),42 (25), 41 (50)].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24](F)[C:25]([CH3:31])=[N:26]3)=[CH:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36].O.CCOC(C)=O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])[C:25]([CH3:31])=[N:26]3)=[CH:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(N)CO
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(F)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)CO)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 71.9 %

Procedure:
A mixture of ethyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (302b) (250 mg, 0.57 mmol) and 2-amino-2-methyl-1-propanol (Sigma-Aldrich) (0.11 mL, 1.13 mmol) in DMSO (2 mL) was heated at 70° C. for 18 h. The reaction mixture was cooled to RT and water and EtOAc was added. The layers were separated and the aq. layer was extracted with EtOAc (2×). The combined organic layers were washed with water and brine and dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by chromatography (0-100% EtOAc in hexanes) to provide ethyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(34(1-hydroxy-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (302c) (208 mg, 0.41 mmol, 72% yield) as a yellow oil. m/z (ESI, +ve) 512.2 (M+H)+.