Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[NH:11][C@H:10]([CH2:12][O:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([N:11]2[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C@H:10]2[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45]
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reaction time: 8 h
Yield: 103.7 %

Procedure:
To a stirred solution of methyl 4-[5-(R)-phenyl-2-(S)-pirrolidinylmethoxy]benzoate (135 mg, 0.43 mmol), 4-[N′-(2-methylphenyl)ureido]-3-methoxyphenylacetic acid (136 mg, 0.43 mmol) and N,N-dimethylaminopyridine (52.9 mg, 0.43 mmol) in DMF (10 ml) was added EDC.HCl (90.8 mg, 0.48 mmol) at rt, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:5) as eluent to give methyl 4-[1-[4-[N′-(2-methylphenyl)ureido]-3-methoxyphenyl acetyl]-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (271 mg, quant.) as a colorless amorphous solid. 1H-NMR (CDCl3) δ 2.00–2.18 (m, 3 H), 2.31–2.41 (m, 1 H), 2.27 (s, 3 H), 3.31 (s, 2 H), 3.67 (s, 3 H), 3.89 (s, 3 H), 4.35–4.48 (m, 2H), 4.60 (br s, 1 H), 4.92 (t, J=6.8 Hz, 1 H), 6.51 (d, J=8.4 Hz, 1 H), 6.62 (s, 1 H), 6.96 (d, J=8.8 Hz, 1 H), 7.11–7.40 (series of m, 8 H), 7.51 (d, J=8.0 Hz, 1 H), 7.97–8.00 (m, 2 H); MS (ESI) m/z, 608 (M++H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([OH:19])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O[CH2:25][CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([O:19][CH2:25][CH2:26][O:27][C:28]3[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=3)=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CS(=O)(=O)OCCOc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCOc2cnc(-c3ccccc3)c(-c3ccccc3)n2)cc1
Temperature: 0 °C
Yield: 85.4 %

Procedure:
To a mixture containing 5,6-diphenyl-2-pyrazinol (2.45 g), 4-[2-(methanesulfonyloxy)ethoxy]benzaldehyde (2.44 g), and potassium carbonate (1.8 g), dimethylformamide (100 mL) was added. The resultant mixture was heated at 100° C. on an oil bath for two hours under stirring, and the reaction mixture was poured into an ice-water mixture. The thus-formed organic matter was separated through extraction by use of ethyl acetate, followed by washing sequentially with water and saturated saline. The washed product was dried over sodium sulfate anhydrate, and the residual solvent was removed through distillation under reduced pressure. The thus-yielded residue was purified by means of a silica gel column and crystallized from n-hexane, to thereby yield 3.34 g of the title compound (yield 85.4%).
Reaction SMILES: [C:1]([N:8]([CH3:40])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:42]1[CH:47]=[CH:46][C:45]([N:48]([CH3:52])[C:49](=[O:51])[CH3:50])=[CH:44][CH:43]=1>>[C:49]([N:48]([CH3:52])[C:45]1[CH:46]=[CH:47][C:42]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:29]([CH2:28][N:15]([C:16]([C:18]3[S:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[C:19]=3[Cl:27])=[O:17])[CH:12]3[CH2:11][CH2:10][CH:9]([N:8]([CH3:40])[C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:7])[CH3:5])[CH2:14][CH2:13]3)[CH:30]=2)=[CH:43][CH:44]=1)(=[O:51])[CH3:50]
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)N(C)c1ccc(Br)cc1
Product: COc1ccc(-c2ccc(N(C)C(C)=O)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 5 (200 mg, 0.34 mmol) is coupled to aryl bromide 62 (93 mg, 0.41 mmol) using Method B to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13]([C:20]3[NH:28][C:27]4[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=4[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[N:11]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([C:20]4[NH:28][C:27]5[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=5[CH:21]=4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Nc5ccc(Cl)cc5)nc34)cc21
Reaction time: 3 h
Yield: 17.5 %

Procedure:
To 4-chloroaniline (Alfa Aesar, Ward Hill, Mass.; 0.225 g, 1.763 mmol) and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added LHMDS (1.0 M solution in THF; 1.763 ml, 1.763 mmol). After 3 h, the reaction mixture was partitioned between saturated aq. NH4Cl and DCM. The aq. layer was extracted with DCM (3×), and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. EtOAc was added, the layers were separated, and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The solid was suspended in MeOH and filtered, rinsing 1× MeOH to give 2-(2-((4-chlorophenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.017 g, 0.044 mmol, 17% yield) as a dull-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.96 (1H, br. s), 9.62 (1H, s), 8.12 (1H, d, J=9.0 Hz), 7.89 (1H, dt, J=7.2, 0.8 Hz), 7.72-7.81 (2H, m), 7.61 (1H, dt, J=7.8, 0.9 Hz), 7.36-7.46 (2H, m), 7.31 (1H, t, J=7.6 Hz), 7.08 (1H, d, J=9.0 Hz), 6.88-7.00 (2H, m), 3.37-3.52 (2H, m), 2.70 (2H, t, J=6.9 Hz). m/z (ESI, +ve) 389.0 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[C-:9]#[N:10].[Na+]>CS(C)=O.CCOC(C)=O>[F:8][C:4]1[N:3]=[C:2]([C:9]#[N:10])[CH:7]=[CH:6][CH:5]=1
Reactant: [C-]#N
Reactant: Fc1cccc(F)n1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(F)n1
Temperature: 100 °C

Procedure:
2,6 Difluoropyridine (12 g, 100 mmol) was dissolved in DMSO (3 mL) and sodium cyanide (1.3 g, 26 mmol) in DMSO (100 mL) was added dropwise via syringe pump over 16 h. The reaction was then heated at 100° C. for 16 h. The crude mixture was then diluted with EtOAc (500 mL) and washed with a mixture of brine (200 mL) and H2O (500 mL). The organic phase was dried (MgSO4), filtered, and concentrated in vacito. The residue was chromatographed on silica gel eluting with hexanes:EtOAc (4:1) to afford 6-fluoropyridine-2-carbonitrile. MS (ESI) 122.0 (M++H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:15][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc(CBr)c2ccccc12
Yield: 111.8 %

Procedure:
A mixture of 4-methylnaphthoic acid (10 g, 54 mmol), N-bromosuccinimide (10 g, 56 mmol) and AIBN (100 mg) in CCl4 (250 mL) was refluxed for 3 hr. The reaction mixture was concentrated and dissolved in ethyl acetate. The organic layer was washed with water, brine and dried over MgSO4. Evaporation of the solvent gave the desired product (16 g, 80%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6](=[O:18])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[C:14]([F:17])([F:16])[F:15])[CH3:3].[Cl:25][C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[C:30](Cl)[CH:29]=[CH:28][N:27]=1.C(N(CC)CC)C>CCO>[Cl:25][C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[C:30]([NH:1][C@H:2]([C:4]2[N:5]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:6](=[O:18])[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[C:14]([F:15])([F:16])[F:17])[CH3:3])[CH:29]=[CH:28][N:27]=1
Reactant: C[C@H](N)c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@H](Nc1ccnc(Cl)c1[N+](=O)[O-])c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of (S)-3-(1-aminoethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-one III-1 (1.0 g, 3.0 mmol, 1.0 eq) and 2,4-dichloro-3-nitropyridine (578 mg, 3.0 mmol, 1.0 eq) in EtOH (10 mL), triethylamine (608 mg, 6.0 mmol, 2.0 eq) was added and the resulting mixture was stirred at reflux overnight. The mixture was allowed to cool to RT and then concentrated in vacuo. The resultant residue was purified by flash column chromatography on silica gel (1% MeOH-DCM) to afford the product, (S)-3-(1-(2-chloro-3-nitropyridin-4-ylamino)ethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-one III-33.
Reaction SMILES: [OH:1][CH:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:12])(=[O:11])[NH:4][CH2:3]1.[H-].[Na+].[N:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1>CN(C=O)C>[OH:1][CH:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:12])(=[O:11])[N:4]([CH2:21][C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)[CH2:3]1
Reactant: ClCc1ccncc1
Reactant: O=S1(=O)NCC(O)c2ccsc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2sccc2C(O)CN1Cc1ccncc1
Temperature: -10 °C
Reaction time: 0.67 h
Yield: 84.8 %

Procedure:
The product from Step C of Example 2 (4.0 g, 19.5 mmol) was dissolved in anhydrous DMF (20 mL) and cooled to -10° C. and sodium hydride (21.5 mmol) was added. After stirring for 40 min at room temperature, a solution of 4-picolyl chloride (3.7 g, 29.2 mmol) in DMF (15 mL) was added to the chilled (0° C.) reaction mixture. The mixture was allowed to warm to room temperature and stir for 18 h. The solution was concentrated and the residue was suspended in saturated sodium bicarbonate (50 mL) and the desired subject was collected by filtration. Recrystallization from ethanol gave a beige solid (4.9 g, 85%): mp 183°-185° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([OH:14])=[O:13])[CH2:4][CH2:3]1.[BH4-].[Na+].[CH3:17][Si](C=[N+]=[N-])(C)C>C1COCC1.Cl>[OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([O:14][CH3:17])=[O:13])[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C1CCC(C(=O)O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CCC(O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Oxo-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (3.50 g, 18.4 mmol) in THF (18.4 ml) was added to a dry flask and the solution was purged and then evacuated with argon. Sodium borohydride (1.74 g, 46.0 mmol) was added in one portion and the mixture was stirred at room temperature overnight. The reaction was diluted with aqueous HCl and the mixture was extracted with EtOAc (3×). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily solid was taken-up in methanol/dichloromethane (1:1, 20 ml). Trimethylsilyldiazomethane (18.4 ml, 36.8 mmol) was added drop wise until the solution turned bright yellow and then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 100% EtOAc/hexanes) to afford methyl 4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxylate as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1([CH2:28][CH2:29][C:30]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: OCCCSc1cccc2nccn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)OCCCSc1cccc2nccn12
Temperature: 25 °C
Yield: 83.8 %

Procedure:
To a solution of 5-[3-(hydroxy)propylthio]imidazo[1,2-a]pyridine (1.00 g, 4.80 mmoles) and triethylamine (0.80 ml, 5.74 mmoles) in methylene chloride (25 ml) was added 3-phenylpropionyl chloride (1.01 g, 5.99 mmoles) with stirring at room temperature and the mixture was further stirred at room temperature for 2 hours. The reaction mixture was washed with an aqueous 1N sodium hydroxide solution and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent: hexane/acetone (1:1)] to obtain 1.37 g of the desired product (84.2%, yellow oily product).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13].O>N1C=CC=CC=1>[CH3:19][C:18]1[CH:20]=[CH:21][C:15]([S:12]([O:11][CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M) (99.8 g, 0.63 mol) in pyridine (450 mLs) at 0° C. under nitrogen was added tosylchloride (132.4 g, 0.69 mol) portionwise such that T<2° C. On complete addition, the mixture was allowed to warm slowly to room temperature and stirred at room temperature overnight. Treated with water (750 mL) and extracted with EtOAc (500 mL then 2×250 mL). Combined extracts were washed with 3N HCl (3×300 mL), brine (300 mL) and dried over Na2SO4. Filtered and evaporated to yield a pale yellow oil (200 g crude). This oil was treated with petroleum ether (40-60°) (200 mL) and scratched to induce solid formation. 1,4-dioxaspiro[4.5]dec-8-yl 4-methyl-1-benzenesulfonate was filtered, washed with petroleum ether (40-60°) (200 mL) and dried in vacuo. Yield=181.0 g, 92%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[N:30]=[CH:29]1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:33]([C:31]2[N:30]=[CH:29][N:28]([CH3:27])[CH:32]=2)(=[O:35])=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cn(C)cn2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A of Example 11o, and 1-methyl-1H-imidazole-4-sulfonyl chloride following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 1H), 7.70 (s, 1H), 7.54 (m, 3H), 7.39 (d, 1H), 7.24 (m, 2H), 7.14 (m, 1H), 7.04-6.97 (m, 3H), 6.45 (m, 1H), 4.43 (s, 2H), 4.40 (s, 2H), 3.74 (s, 3H), 3.65 ), 2.83 (t, 2H), 2.53 (t, 2H); MS 494 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][N:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]([CH3:33])=[N:26]1>CN1CCCC1=O.O>[CH:21]1([C:19]([NH:18][C:16]2[N:17]=[C:12]3[CH:11]=[CH:10][C:9]([S:8][C:4]4[CH:3]=[C:2]([NH:1][C:30]([C:29]5[N:25]([CH3:24])[N:26]=[C:27]([CH3:33])[CH:28]=5)=[O:31])[CH:7]=[CH:6][CH:5]=4)=[N:14][N:13]3[CH:15]=2)=[O:20])[CH2:22][CH2:23]1
Reactant: Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc(Sc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To a solution of N-{6-[(3-aminophenyl)sulfanyl]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (195 mg, 0.6 mmol) in N-methylpyrrolidone (3.0 mL) was added 1,3-dimethylpyrazole-5-carbonyl chloride (159 mg, 1.0 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30) and precipitated from methanol to give the title compound (245 mg, 91%) as a white powder.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1)=[O:2].[CH2:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:21][CH2:22][C:23]#[CH:24]>CCCCCCC.C(Cl)Cl>[C:25]1([CH2:20][CH2:21][CH2:22][C:23]#[C:24][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C=O)cc2)cc1
Reactant: C#CCCCc1ccccc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=Cc1ccc(C#CCCCc2ccccc2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-formyl-phenyl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/DCM 1:1; yield (100 mg, 58%); 1H NMR δ (CDCl3): 9.98 (s, 1H), 8.02 (d, J=8.61 Hz, 2H), 7.81 (d, J=8.63 Hz, 2H), 7.57-7.47 (m, 4H), 2.79 (t, J=7.18 Hz, 2H), 2.48 (t, J=7.17 Hz, 2H), 1.93 (p, J=7.23 Hz, 2H); LCMS m/z: 248.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[S:13]1[CH2:17][CH:16](C(O)=O)[NH:15][CH2:14]1>C1(C)C=CC=CC=1>[N:15]12[CH2:14][S:13][CH2:17][CH:16]1[CH2:3][CH:2]1[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]1
Reactant: O=C(O)C1CSCN1
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC3CSCN3C2C1

Procedure:
17.2 g (0.1 mol) of ethyl N-allyl-N-(2-oxoethyl)-carbamate are heated under reflux overnight with 13.5 g (0.1 mol) of thiazolidine-4-carboxylic acid in 300 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:13][CH:14]([F:24])[O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>CO>[S:7]([NH:10][N:11]=[CH:4][C:3]1[CH:2]=[CH:1][CH:6]=[CH:5][C:20]=1[C:19]1[CH:22]=[CH:23][C:16]([O:15][CH:14]([F:24])[F:13])=[CH:17][CH:18]=1)([C:4]1[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=1)(=[O:8])=[O:9]
Reactant: O=Cc1ccc(OC(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NN=Cc2ccccc2-c2ccc(OC(F)F)cc2)cc1
Yield: 25.9 %

Procedure:
4-Tolylsulfonyl hydrazine (6.03 g, 182 mmol) was added to a stirred solution of 4-difluoromethoxy-benzaldehyde (5 g, 172 mmol) in methanol (6 ml). Everything dissolved. After two hours the solvent was evaporated to yield 9.8 g (99%) of a white solid.
Reaction SMILES: C([O:8][C:9](=[O:49])[CH2:10][CH:11]([NH:21][C:22]([CH:24]1[N:28]2[C:29](=[O:48])[CH:30]([NH:35][C:36]([C:38]3[CH:47]=[CH:46][C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:39]=3)=[O:37])[CH2:31][CH:32]=[CH:33][CH2:34][CH:27]2[CH2:26][CH2:25]1)=[O:23])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])C1C=CC=CC=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:17]([Si:14]([CH3:16])([CH3:15])[O:13][CH2:12][CH:11]([NH:21][C:22]([CH:24]1[N:28]2[C:29](=[O:48])[CH:30]([NH:35][C:36]([C:38]3[CH:47]=[CH:46][C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:39]=3)=[O:37])[CH2:31][CH:32]=[CH:33][CH2:34][CH:27]2[CH2:26][CH2:25]1)=[O:23])[CH2:10][C:9]([OH:49])=[O:8])([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCC(CC(=O)OCc1ccccc1)NC(=O)C1CCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC(CC(=O)O)NC(=O)C1CCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.3 %

Procedure:
A solution containing 4-(tert-Butyl-dimethyl-silanyloxy)-3-({6-[(naphthalene-2-carbonyl)-amino]-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carbonyl}-amino)-butyric acid benzyl ester (590 mg, 0.86 mmol) in MeOH (10 mL) is treated with 1N NaOH (2.5 mL) and stirred at rt for 12 hrs. The solution was poured into water, acidified to pH=3 with 10% citric acid, and extracted with EtOAc. The combined organic extracts are washed with brine and dried over Na2SO4. The solution is filtered and concentrated to yield 492 mg of desired product that was used without further purification. MS (ESI) 594 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:8](O)([CH3:10])[CH3:9])[CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.Cl>CCOCC>[F:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:12][CH3:13])([CH3:10])[CH3:9])[CH:16]=1
Reactant: COc1ccc(F)cc1C(C)(C)O
Reactant: Oc1ccc(F)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)c1cc(F)ccc1O
Reaction time: 8 h
Yield: 43 %

Procedure:
2-(5-fluoro-2-methoxyphenyl)propan-2-ol (6 g) was added in small portions to a melt of 4-fluorophenol (12 g) and concentrated hydrochloric acid (10 days) at 90° C. The mixture was stirred at this temperature overnight and was then cooled and dissolved in ether. The excess of p-fluorophenol was removed by extraction with 5% aqueous sodium hydroxide solution. The alkali insoluble material crystallised from hexane to give 2-(5-fluoro-2-hydroxyphenyl)-2-(5-fluoro-2-methoxyphenyl) propane (3.9 g) as colourless prisms; m.p. 90° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18]([NH:21][C:22]1[C:27](Cl)=[N:26][C:25]([Cl:29])=[CH:24][N:23]=1)(=[O:20])=[O:19]>>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18]([NH:21][C:22]1[C:27]([O:9][CH2:8][C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:26][C:25]([Cl:29])=[CH:24][N:23]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Reactant: Cc1ncccc1CO
Product: Cc1ncccc1COc1nc(Cl)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using (2-methyl-3-pyridinyl)methanol (0.15 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.15 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[F:13][C:14]1[N:18]([CH3:19])[N:17]=[C:16]([CH3:20])[C:15]=1[C:21](Cl)=[O:22].C(N(CC)CC)C>O1CCCC1>[F:13][C:14]1[N:18]([CH3:19])[N:17]=[C:16]([CH3:20])[C:15]=1[C:21]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][CH2:3][CH:2]([CH3:12])[CH3:1])=[O:22]
Reactant: CC(C)CCc1ccccc1N
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(F)c1C(=O)Nc1ccccc1CCC(C)C
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
326.5 mg (2.0 mmol) of [2-(3-methylbutyl)phenyl]amine (III-1) are added to a solution comprising 388.5 mg (2.2 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride and 0.45 ml (3.2 mmol) of triethylamine in 20 ml of tetrahydrofuran. The reaction solution is stirred at 60° C. for 90 min, filtered through silica gel and concentrated. Column chromatography (cyclohexane/ethyl acetate gradient) gives 592 mg (98% of theory) of 5-fluoro-1,3-dimethyl-N-[2-(3-methylbutyl)phenyl]-1H-pyrazole-4-carboxamide of logP (pH 2.3)=3.12.