Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[C:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:15][N:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[C:27](Cl)(=[O:31])[O:28][CH2:29][CH3:30].C(N(CC)CC)C.[OH-].[Na+]>N1C=CC=CC=1.O1CCCC1>[CH:17]1([C:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:27](=[O:31])[O:28][CH2:29][CH3:30])=[CH:3][C:4]=4[O:25][CH3:26])=[N:13][C:12]=3[N:14]([CH3:23])[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(N)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(-c2nc3c(c(C4CCCCC4)nn3C)c(=O)[nH]2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
To a 6 ml tetrahydrofuran suspension of 100 mg (0.283 mmol) of the compound obtained in Example 44, 48 μl (0.50 mmol) of ethyl chlorocarbonate and 98 μl (0.707 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 3 hours. Further, 48 μl (0.50 mmol) of ethyl chlorocarbonate and 1 ml of pyridine were added, and the mixture was stirred at room temperature for 18 hours. Then, a 1M aqueous solution of sodium hydroxide was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1˜2/1) to obtain 68 mg (57%) of the captioned compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[C:21]([Cl:23])[N:20]=[C:19]([C:24]([OH:26])=O)[CH:18]=3)[CH2:13][CH2:12]2)=[O:9])[NH:5][C:6]=1[CH3:7].[NH3:27]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]3[N:22]=[C:21]([Cl:23])[N:20]=[C:19]([C:24]([NH2:27])=[O:26])[CH:18]=3)[CH2:15][CH2:16]2)=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: N
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(Cl)n3)CC2)cc1Br
Solvent: CO
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)nc(Cl)n3)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Example 8 by coupling 6-(4-{[(4-bromo-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-chloropyrimidine-4-carboxylic acid (Example 31) with 2 M ammonia in MeOH.
Reaction SMILES: CN([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])C.[C:12]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[O:17]=[C:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11]
Reactant: O=C1CCCC1
Reactant: CN(C)CC1CCCCC1=O
Product: O=C1CCCCC1CC1CCCC1=O
Yield: 80 %

Procedure:
2-(oxo-cyclopentyl)methyl cyclohexanone is prepared from 2-(dimethylaminomethyl)-cyclohexanone and cyclopentanone according to the method described in Ann.Chim., 1963, 53 (6), 819 and is isolated as a colourless oil in 80% yield b.p. 92°/0.05 mm. 5,6,7,8-Tetrahydro-2,3-dihydro-1H-cyclopenta[b]quinoline is prepared from 2-(2-oxocyclopentyl)methylcyclohexanone according to the method described in Ann.Chim., 1963, 53, (6), 819 and is isolated in 65% yield as a colourless oil b.p. 80°/0.05 mm. The hydrochloride is prepared for characterisation by treating an ethereal solution of the base with ethereal HCl and is isolated as the hemihydrate as colourless needles from ethanol-ether m.p. 104° C (Found: C, 65.7; H, 7.8; N, 6.6. C12H16N.HCl.1/2H2O requires: C, 65.8; H, 7.8; N, 64%. 5,6,7,8-Tetrahydro-2,3-dihydro-1H-cyclopenta[b]-quinoline is converted to methyl 5,6,7,8-tetrahydro-2,3-dihydro-1H-cyclopenta[b]quinoline-5-carboxylate following the method described in Example 19 and this is converted to 5,6,7,8-tetrahydro-2,3-dihydro-1H-cyclopenta[b]-quinoline-5-carboxamide following the method described in Example 22. The amide is converted to the title compound, following the procedure of Example 23, and is recrystallised from isopropanol, dissolved in ether and treated with an excess of ethereal HCl. The resultant solid is recrystallised from ethanol-ether to give the hydrochloride of the title compound as the monohydrate m.p. 118° C. (Found: C, 54.6; H, 6.3; N, 10.0. C13H16N2S.HCl H2O requires: C, 54.4; H, 6.6; N, 9.8%)
Reaction SMILES: CC#C.[Mg].C(Br)CBr.[O:9]([C:16]1[CH:23]=[CH:22][C:19](C=O)=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.[O:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:27]([CH:26]([OH:25])[C:22]1[CH:19]=[CH:18][CH:17]=[C:16]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:23]=1)#[C:28][CH3:29]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: C1CCOC1
Agent: C#CC
Agent: Cl
Agent: [Mg]
Solvent: BrCCBr
Product: CC#CC(O)c1cccc(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 8 g of methyl acetylene in 100 ml of tetrahydrofurane is slowly added at 0° C. a Grignard solution freshly prepared from 4 gof magnesium and 20 g of ethylene bromide in 20 ml of tetrahydrofurane. Themixture is stirred for 15 minutes under argon and a solution of 27 g of p-phenoxybenzaldehyde in 100 ml of tetrahydrofurane is added dropwise at 0° to 5° C. After stirring for 14 hours at room temperature,the reaction mixture is cooled to 0° C. with 50 g of ice and, after the slow addition of 25 ml of conc. hydrochloric acid, extracted with ether. The ethereal extract is washed twice with water and twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The product is chromatographed over silica gel with ethyl acetate/hexane (1:4) as eluant, affording the compound of the formula ##STR4##with a refractive index of nD20° =1.5898.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]1[CH2:24][CH:23]([OH:25])[CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[C:14]([Si:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:18][CH2:19][CH2:20][CH:21]1[CH2:24][CH:23]([O:25][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)[CH2:22]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](OCCC1CC(O)C1)(c1ccccc1)c1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCC1CC(OC2CCCCO2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 105 %

Procedure:
3-(2-{[Tert-butyl(diphenyl)silyl]oxy}ethyl)cyclobutanol (3.58 g, 10.1 mmol) was dissolved in dry tetrahydrofuran (50 mL) and 2,3-dihydro-4H-pyran and 4-toluenesulfonic acid pyridine salt were added and the reaction was stirred at room temperature for 48 hours. The reaction was concentrated in vacuo and purified on silica gel with a heptane-ethyl acetate gradient (5% ethyl acetate, then 20% ethyl acetate) to give crude tert-butyl(diphenyl){2-[3-(tetrahydro-2H-pyran-2-yloxy)cyclobutyl]ethoxy}silane (4.66 g, 105%) as a milky oil. Partial 1H NMR indicated a ˜4:1 mix of unknown cis-trans isomers. (CDCl3, δ ppm, key peaks are 4.05 (m, 0.80H), 4.30 (m, 0.20H), 4.52 (m, 0.20H), 4.56 (m, 0.80H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(C)C=O>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([CH:13]=[CH2:14])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CN(C)C=O
Product: C=Cc1ncc(Cl)cc1C(=O)OC
Temperature: 80 °C
Yield: 99.1 %

Procedure:
A sealable vial was charged with methyl 2,5-dichloronicotinate (100 mg, 0.49 mmol, Bionet Research), tributyl(vinyl)stannane (156 μl, 0.53 mmol) and N,N-dimethylformamide (1 mL) at RT under nitrogen atmosphere. 2,6-Ditert-butyl-4-methylphenol (Aldrich, 5 mg) was added, followed by dichlorobis(triphenylphosphine)palladium(II) (Strem, 68 mg, 0.10 mmol) and the reaction mixture was heated to 80° C. for 1 hour. The reaction mixture was cooled to RT and partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was separated and washed with water (2×25 mL) and brine (30 mL), The combined organic layers were dried over anhydrous magnesium sulfate and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (5-35% EtOAc/hexanes) to obtain the title compound as a colorless oil (96 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[C:18]([C:22](Cl)=[O:23])[CH:17]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:22](=[O:23])[C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH3:25])[CH:17]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: Cc1cccc(C(=O)NC2CCCc3c2[nH]c2ccc(Br)cc32)c1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methylbenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and m-toluoyl chloride in a similar manner as described above to give a tan solid (51% yield). 1H-NMR (CDCl3): δ 8.95 (s, 1H), 7.63-7.59 (m, 2H), 7.55 (m, 1H), 7.33 (m, 2H), 7.23 (m, 1H), 7.17 (d, 1H), 6.38 (d, 1H), 5.32 (m, 1H), 2.72 (m, 2H), 2.40 (s, 3H), 2.31 (m, 1H), 1.98 (m, 3H); MS m/z 383 (M−1).
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.[C:25]1(C2C=CC=CC=2)[CH:30]=[CH:29][C:28]([C:31]2[N:32]=[C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]3[C:40]=2[CH2:41]Cl)=[CH:27][CH:26]=1.[NH:49]1[CH:53]=[CH:52][N:51]=[N:50]1>>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]2[N:34]([C:40]([CH2:41][N:49]3[CH:53]=[CH:52][N:51]=[N:50]3)=[C:31]([C:28]3[CH:27]=[CH:26][CH:25]=[CH:30][CH:29]=3)[N:32]=2)[CH:35]=1
Reactant: c1c[nH]nn1
Reactant: ClCc1c(-c2ccc(-c3ccccc3)cc2)nc2ccc(Cl)cn12
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: Clc1ccc2nc(-c3ccccc3)c(Cn3ccnn3)n2c1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 2-(biphenyl-4-yl)-6-chloro-3-(chloromethyl)imidazo[1,2-a]pyridine hydrochloride and 1H-1,2,3-triazole. (m, 3H), 7.62 (dd, J=0.7, 9.5 Hz, 1H), 7.52 (m, 2H), 7.46 (m, 2H), 7.26 (m, 1H), 5.99 (s, 2H) ppm.
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:8]3[C:9]=2[C:4](=[CH:5][CH:6]=[CH:7]3)[C:3]1=[O:18].[Br:19]N1C(=O)CCC1=O>C(O)(=O)C>[Br:19][C:14]1[C:15]([O:16][CH3:17])=[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]2=[C:10]([CH:13]=1)[C:11](=[O:12])[N:2]([OH:1])[C:3]3=[O:18]
Reactant: COc1ccc2c3c(cccc13)C(=O)N(O)C2=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: COc1c(Br)cc2c3c(cccc13)C(=O)N(O)C2=O
Reaction time: 24 h
Yield: 31 %

Procedure:
A mixture of 2-hydroxy-6-methoxy-benzo[de]isoquinoline-1,3-dione (0.12 g, 0.5 mmol, from Example 17) and N-bromosuccinimide (0.13 g, 0.7 mmol) in acetic acid (20 mL) was sonicated at 60° C. for 24 hours. The mixture was transferred to a preheated oil bath at 100° C. with vigorous stirring for another 24 hours. The precipitate was filtered, washed with water, dried, and recrystallized from methanol to give 0.05 g of the title compound, mp 223-227° C.;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][CH2:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([S:25]([NH:14][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][O:6][CH2:5][C:4]3[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=3)[N:13]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(COCc2cccc(F)c2)n1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: O=S(=O)(Nc1cccc(COCc2cccc(F)c2)n1)c1cccc(Cl)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(3-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.06 g) and 3-chloro-benzenesulfonyl chloride (0.06 g) as a yellow gum (0.07 g). MS (ESI−): 405.1 ([M−H]−).
Reaction SMILES: [C:1]([CH2:4][S:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][C:27]([Cl:33])=[CH:28][CH:29]=4)[N:24]=3)=[CH:20][C:7]1=2)([OH:3])=O.[C:34]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[C:34]1([S:40]([NH:43][C:1]([CH2:4][S:5][CH:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][O:9][C:8]3[CH:17]=[CH:18][C:19]([O:21][CH2:22][C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][C:27]([Cl:33])=[CH:28][CH:29]=5)[N:24]=4)=[CH:20][C:7]2=3)=[O:3])(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)CSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(CSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 28.7 %

Procedure:
0.27 g of 11-carboxymethylthio-2-(7-chloroquinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine obtained in Example 21, 0.9 g of benzenesulfonamide and 0.14 g of 4-dimethylaminopyridine and 0.11 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride dissolved in 10 ml of methylene chloride were stirred at room temperature for 7 days. After 10 ml of water and 1.13 ml of 1N-hydrochloric acid were added to the reaction mixture, the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The residue obtained by removing the solvent was applied to silica gel column chromatography to obtain 0.1 g of the title compound as light brown powder.
Reaction SMILES: C([O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1)(C)C.O.[OH-].[Li+]>O1CCCC1CO.O>[F:20][C:18]([F:19])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([OH:22])=[O:4])=[N:13][CH:14]=1
Reactant: CC(C)OC(=O)c1ccccc1-c1ccc(C(F)(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: OCC1CCCO1
Solvent: O
Product: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(5-Trifluoromethyl-pyridin-2-yl)-benzoic acid isopropyl ester was dissolved in 10 ml of a 3:1:1 mixture of tetrahydrofuran-methanol-water, and lithium hydroxide monohydrate (161 mg, 3.84 mmol) was added. After stirring for 3 h at room temperature, the volatiles were removed under vacuum and 5 ml of water were added to the mixture, which was brought to pH 6 with 1N HCl. The resulting slurry was extracted with ethyl acetate, the combined organic layers were dried (magnesium sulfate), filtered and concentrated under vacuum to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])(=[O:21])[CH3:20]
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 60 h
Yield: 55.6 %

Procedure:
To a suspension of 4-amino-3-methylbenzoic acid (60 g, 0.40 mol) in methylene chloride (800 mL) was added triethylamine (121 g, 1.19 mol). The solution became clear. Then, acetic anhydride (81 g, 0.79 mol) was added and the reaction mixture was stirred for 60 h at room temperature. The solvent was evaporated. The residue was diluted with water (400 mL) and extracted with ethyl acetate (3×600 mL). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to give the title compound as a tan solid (43 g, 56% yield). 1H-NMR (d6-DMSO, 300 MHz) δ 9.36 (s, 1H), 7.77 (s, 1H), 7.10 (s, 2H), 2.27 (s, 3H), 2.10 (s, 3H). LC/MS: tR=1.22 min, 194 (MH)+.
Reaction SMILES: [F:1][C:2]1([F:54])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:34][C@@H:35]5[CH2:39][O:38]C(C)(C)[O:36]5)=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:42]([F:53])[C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)[CH2:4][CH2:3]1.Cl.[OH-].[Na+].[Cl-].[Na+]>CO>[F:54][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:34][C@@H:35]([OH:36])[CH2:39][OH:38])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:42]([F:53])[C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:50])([F:52])[F:51])=[CH:45][CH:44]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(OC[C@@H]5COC(C)(C)O5)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OC[C@@H](O)CO)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 93.6 %

Procedure:
To a solution of 86.7 mg (0.114 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-2-[1-(5-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}pyrimidin-2-yl)piperidin-4-yl]-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 24, in 2 ml of methanol, 0.5 ml of 2 N hydrochloric acid was added, and the mixture was stirred at 50° C. for 2.5 hours. After completion of the reaction, 0.5 ml of 2 N sodium hydroxide aqueous solution was added to the reaction solution, then saturated sodium chloride aqueous solution was poured thereinto, and the reaction solution was extracted with ethyl acetate. The obtained organic phases were combined, washed with saturated sodium chloride aqueous solution, dried with magnesium sulfate and then filtered, and the solvent was distilled off under reduced pressure to provide 77.1 mg of the title compound as a white solid (yield: 94%).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1>ClCCl>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:19]1[CH2:20][CH2:21][CH2:22][C@H:18]1[CH3:17])=[O:12])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
BOC proline (CAS 15761-39-4) and 2-(R)Methyl-pyrrolidine hydrochloride (CAS 135324-85-5) are coupled in a manner substantially analogous to Procedure B′ in dichloromethane to give 2(S)-(2(R)-Methyl-pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. The material is deprotected by stirring in dichloromethane at 5-10° C. while trifluoroacetic acid (10 eq,) is added and then stirred at room temperature for 18 hours. Reaction is concentrated, is dissolved in H2O, pH is adjusted to 8-9 with K2CO3, and is extracted several times with CH2Cl2. The extracts are combined, dried (Na2SO4) and concentrated in vacuo to give (2(R)-Methyl-pyrrolidin-1-yl)-pyrrolidin-2-yl-methanone. A 1 M Lithium Aluminum Hydride/THF solution (3 eq.) is diluted with an equal volume of THF and stirred under N2 as a THF solution of (2(R)-methyl-pyrrolidin-1-yl)-pyrrolidin-2-yl-methanone is added dropwise, allowing the reaction to mildly exotherm. The reaction mixture is stirred at 40° C. for 45 minutes, then at room temperature 18 hours. The mixture is cooled in an ice bath and is quenched with H2O (3 eq.), 4 N NaOH (3 eq.), then H2O (9 eq.) while keeping reaction temperature less than 15° C. The mixture is stirred overnight, filtered and the precipitate is washed three times with THF. The filtrate and washes are combined and concentrated to give 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 169.3 (M+H)+ The title compound is used as such or is purified by SCX chromatography or distillation.
Reaction SMILES: O1CCCC1.CS(Cl)(=O)=O.OC(C(F)(F)F)=O.Br[C:19]1[CH:20]=[C:21]2[C:26](N[C@@H]3C[C@@H]4CNC[C@@H]4[C@H]3C)=[C:25]([C:37]([NH2:39])=[O:38])[CH:24]=[N:23][N:22]2[CH:40]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:23]1[N:22]2[CH:40]=[CH:19][CH:20]=[C:21]2[CH:26]=[C:25]([C:37]([NH2:39])=[O:38])[CH:24]=1
Reactant: C[C@@H]1[C@H]2CNC[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cnn2cccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 213.6 %

Procedure:
A 1 mL tetrahydrofuran solution of methanesulfonyl chloride (41.9 mg, 0.366 mmol) was added to a solution of 6-bromo-4-((3aS,4R,5R,6aS)-4-methyloctahydrocyclopenta[c]pyrrol-5-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide TFA salt (150 mg, 0.305 mmol) and N,N-diisopropylethylamine (0.266 mL, 1.523 mmol) in N,N-dimethylformamide (2 mL) at 0° C. After stirring for 1 h at 0° C., the mixture was quenched with saturated sodium bicarbonate (5 mL), diluted with ethyl acetate (80 ml), washed with water, brine, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography to provide 6-bromo-4-((3aS,4R,5R,6aS)-4-methyl-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (105 mg, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.44-11.18 (1 H, m), 8.25 (1 H, s), 7.88 (1 H, d, J=1.76 Hz), 7.13 (1 H, d, J=1.76 Hz), 3.87-4.11 (1 H, m), 3.15-3.24 (3 H, m), 3.02-3.08 (1 H, m), 2.92 (3 H, s), 2.77-2.85 (1 H, m), 2.53-2.64 (1 H, m), 2.27-2.39 (1 H, m), 1.51-1.72 (1 H, m), 1.23-1.33 (1 H, m), 1.06 (3 H, d, J=6.38 Hz); MS (ES+) m/z: 439.2, 441.2 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](O)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3]>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(CCO)cc1
Temperature: -10 °C
Yield: 79.7 %

Procedure:
10 g (47 mmole) 4-(methylsulfonyl)phenyl acetic acid was dissolved in 40 ml tetrahydrofuran and the solution was cooled to −10° C. At this temperature 4-(methylsulfonyl)phenyl acetic acid precipitates. 47 ml 1 M borane-tetrahydrofuran complex was added slowly. The reaction mixture was allowed to reach room temperature and the reaction was followed by TLC. After completion 100 ml methanol was added and the solvents were evaporated. The residue was dissolved in dichloromethane and washed with sodium hydroxide. The organic phase was dried, filtered and evaporated in vacuo to give 7.5 g (yield 79.7%) of 2-[4-(methylsulfonyl)phenyl]-1-ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH:9]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>CN(C)C(=O)C.[Cu-]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:20]2[C:21]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: O=[Cu-]
Solvent: CC(=O)N(C)C
Product: Brc1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C

Procedure:
9-(4-bromophenyl) carbazole was prepared through the Ullmann Reaction following the procedures reported in the literature (Macromolecules 2004, 37, 5531-5537). Briefly, a mixture of 1-bromo-4-iodobenzene (2.83 g, 10 mmol), copper (I) oxide (2.86 g, 20 mmol) and carbazole (0.84 g, 5 mmol) in 10 ml N,N-dimethylacetamide (DMAC) was heated to reflux in an oil bath for 24 h under N2 atmosphere. The reaction mixture was cooled to room temperature and then filtered to remove excess copper complex. The filtrate was evaporated to dryness and went through silica gel column to give product, yielding 1.22 g (76%). 1H NMR (400 MHz, CDCl3): δ(ppm) 8.132-8.122 (d, J=8.0 Hz, 2H), 7.715-7.695 (t, J=8.0 Hz, 2H), 7.476-7.247 (m, 8H).