Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:21])[CH2:8][N:9]2[C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:4][CH:3]=1.ClCCCl.C(N(CC)C(C)C)(C)C.[C:35](Cl)(=[O:37])[CH3:36]>C(OCC)(=O)C>[O:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:12]([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=3)[N:6]([C:35](=[O:37])[CH3:36])[C@@H:7]([CH3:21])[CH2:8]2)=[N:13]1
Reactant: CC(=O)Cl
Reactant: C[C@H]1CN(c2noc3ccccc23)c2cc(Br)ccc2N1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(Br)cc2N(c2noc3ccccc23)C[C@@H]1C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A reaction vial was charged with (S)-3-(7-bromo-3-methyl-3,4-dihydroquinoxalin-1(2H)-yl)benzo[d]isoxazole (10.33 mg, 0.03 mmol) and 1,2-dichloroethane (0.30 mL). N,N-Diisopropylethylamine (0.026 mL, 0.150 mmol) and acetyl chloride (6.4 μl, 0.090 mmol) were added, and the mixture stirred at 50° C. for 1.5 h. The reaction was diluted with ethyl acetate and washed with brine. The aqueous layer was separated and washed with ethyl acetate, and the combined organic layers were concentrated under a stream of nitrogen to afford (S)-1-(4-(benzo[d]isoxazol-3-yl)-6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.012 g, 0.03 mmol) which was used without purification. MS (ESI, pos. ion) m/z 386
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C@:15]3([C@@H:14]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=4[F:40])[C@H:13]([C:11]([NH:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:41])=[O:2])=[CH:9][CH:8]=4)=[O:12])[NH:17][C@H:16]3[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid methyl ester prepared in Example 5 (57 mg, 0.095 mmol) in tetrahydrofuran (9 mL) was added an aqueous solution (1N) of NaOH (9 mL, 9 mmol) and methanol (3 mL). The reaction mixture was heated at 80° C. for 1 h, and then cooled to room temperature. The “pH” of the mixture was adjusted to 5-6 by aqueous HCl solution, then concentrated to a small volume. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgSO4, and concentrated to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid as a off white solid (46 mg, 83%).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:20](=O)[CH3:21])[CH2:6][C:7](=O)[CH2:8][C@@H:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:10])C.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([CH3:32])[CH:26]=1.O>C(O)(=O)C>[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([N:29]2[C:7]([CH2:8][C@@H:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH3:10])=[CH:6][C:5]([C:4]([OH:3])=[O:23])=[C:20]2[CH3:21])=[C:27]([CH3:32])[CH:26]=1
Reactant: CCOC(=O)C(CC(=O)C[C@H](C)OCc1ccccc1)C(C)=O
Reactant: Cc1cc(Cl)ccc1N
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Cl)ccc1-n1c(C[C@H](C)OCc2ccccc2)cc(C(=O)O)c1C
Temperature: 110 °C
Reaction time: 15 h
Yield: 74.1 %

Procedure:
To a solution of (6S)-2-acetyl-6-(benzyloxy)-4-oxoheptanoic acid ethyl ester (2.5 g, 7.8 mmol) in acetic acid (8 ml), 4-chloro-2-methylaniline (1.1 g, 7.8 mmol) was added, and the mixture was stirred at 110° C. for 15 hours. 15 ml of water was poured to the reaction mixture, and after the organic layer was extracted with diethyl ether, it was washed with 1N aqueous sodium hydroxide solution, water, a saturated aqueous ammonium chloride solution and saturated brine, and dried with sodium sulfate. The solvent was distilled off under reduced pressure and the residue was crudely purified by silica gel column chromatography. Subsequently, the product was dissolved in a 5M aqueous sodium hydroxide solution (30 mL) and methanol (40 mL), and the mixture was stirred at 100° C. for 4 hours. After the reaction, 2M hydrochloric acid (80 mL) was added under ice-cooling to neutralize it, and it was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (2.3 g, 73%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)[Cl:21].[CH3:25][O:26][CH2:27][O:28][C:29]1[C:30]([CH3:44])=[C:31]2[C:36](=[C:37]([CH3:40])[C:38]=1[CH3:39])[O:35][C:34]([CH3:43])([CH:41]=O)[CH2:33][CH2:32]2>C(Cl)Cl.[Zn]>[Cl:21][C:20]([Cl:24])=[CH:41][C:34]1([CH3:43])[CH2:33][CH2:32][C:31]2[C:36](=[C:37]([CH3:40])[C:38]([CH3:39])=[C:29]([O:28][CH2:27][O:26][CH3:25])[C:30]=2[CH3:44])[O:35]1
Reactant: COCOc1c(C)c(C)c2c(c1C)CCC(C)(C=O)O2
Reactant: ClC(Cl)(Cl)Cl
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCOc1c(C)c(C)c2c(c1C)CCC(C)(C=C(Cl)Cl)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A mixture of triphenylphosphine (524 mg, 2.0 mmol), carbon tetrachloride (193 ul, 2.0 mmol), Zinc dust (130 mg, 2.0 mmol) and 6-methoxymethoxy-2,5,7,8-tetramethyl-chroman-2-carbaldehyde (0.25 gram, 0.95 mmol) in 4 ml of DCM was stirred overnight at room temperature. The mixture was rinsed with hexane times and the combined solutions were dried over MgSO4. The solution was concentrated and the residue was purified via flash column chromatography on silica gel (10% ethyl acetate in hexane) to afford 320 mg of 2-(2,2-dichloro-vinyl)-6-methoxymethoxy-2,5,7,8-tetramethyl-chroman.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH2:12]([OH:16])[C@H:13]([OH:15])[CH3:14].N1C=CN=C1>CN(C=O)C>[CH:1]([Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[O:16][CH2:12][C@H:13]([OH:15])[CH3:14])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)CO
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OC[C@@H](C)O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.7 %

Procedure:
Triisopropylsilyl chloride (83.8 mL, 390 mmol) was added slowly over 15 minutes to a solution of (2R)-propane-1,2-diol (29.7 g, 390 mmol) in DMF at 0° C. (100 mL) keeping the internal temperature below 15° C. This was followed by addition of imidazole (66.4 g, 975 mmol) and the reaction mixture was allowed to warm to RT and stirred under argon for 20 hours. The reaction was quenched with 1M hydrochloric acid/diethyl ether (300 mL/800 mL). The organic layer was separated and washed with 1M hydrochloric acid followed by saturated brine solution. The organic layer was dried (MgSO4), filtered and evaporated. Purification by distillation at 110 mmHg, 90-104° C., afforded the title compound as colourless oil (69.5 g). 1H NMR δ (CDCl3): 1.05 (s, 18H), 1.05-1.1 (m, 3H), 1.05 (d, 3H), 2.55 (s, 1H), 3.45 (dd, 1H), 3.7 (dd, 1H), 3.85 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.[CH:13]1([C:18]2([CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([CH2:34][CH3:35])[C:31]([OH:36])=[C:30]([CH2:37][CH3:38])[CH:29]=3)[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][C:21]3[C:22](=[O:24])[O:23][C:18]([CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)([CH2:26][CH2:27][C:28]4[CH:33]=[C:32]([CH2:34][CH3:35])[C:31]([OH:36])=[C:30]([CH2:37][CH3:38])[CH:29]=4)[CH2:19][C:20]=3[OH:25])[N:10]=2)[CH:7]=1
Reactant: O=Cc1nc2ncc(Cl)cn2n1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(CC)c1O
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncc(Cl)cn4n3)C(=O)O2)cc(CC)c1O

Procedure:
The title compound was prepared analogously to Example A(224) where 6-chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used in place of 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-cyclopentyl-6-[2-(3,5-diethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione (Example A(235)) was used in place of 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione in that example. 1H NMR (DMSO): δ 1.15 (t, J=3.89 Hz, 6H), 1.30-1.80 (brm, 8H), 2.00-2.20 (brm, 5H), 2.43 (q, J=20.06 Hz 4H), 2.85 (m, 4H), 3.55 (m, 3H), 6.70 (s, 2H), 8.76 (s, 1H), 8.82 (s, 1H). Anal. Calcd. For C28H33O4N4Cl, C, 64.05; H, 6.34; N, 10.67. Found: C, 64.35; H, 6.50; N, 10.75.
Reaction SMILES: O.O[C:3]1[C:11]2[N:10]=[N:9]NC=2C=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[F:33][C:34]1[CH:35]=[C:36]([C:41]2[C:45]([CH2:46][O:47][C:48]3[CH:56]=[CH:55][C:51]([C:52]([OH:54])=O)=[CH:50][N:49]=3)=[C:44]([CH2:57][OH:58])[O:43][N:42]=2)[CH:37]=[CH:38][C:39]=1[F:40].NN1CCCC1>C1COCC1>[F:33][C:34]1[CH:35]=[C:36]([C:41]2[C:45]([CH2:46][O:47][C:48]3[CH:56]=[CH:55][C:51]([C:52]([NH:9][N:10]4[CH2:5][CH2:4][CH2:3][CH2:11]4)=[O:54])=[CH:50][N:49]=3)=[C:44]([CH2:57][OH:58])[O:43][N:42]=2)[CH:37]=[CH:38][C:39]=1[F:40]
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN1CCCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NN1CCCC1)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Reaction time: 8 h
Yield: 85 %

Procedure:
Hydroxybenzotriazole hydrate (64.7 mg; 0.41 mmol), N-ethyldiisopropylamine (181 μL, 1.04 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (81 mg, 0.41 mmol) were added to a mixture of 6-[3-(3,4-difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (150 mg, 0.41 mmol) and 1-aminopyrrolidine (51.8 mg, 0.41 mmol) in THF (15 mL) at room temperature. After stirring overnight the solvent was removed by distillation and the residue was purified by chromatography (silica, dichloromethane:methanol=98:2 to 95:5) afforded the title compound (150 mg, 84%) as a white solid. MS: m/e=429.1 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]2OC(=O)[S:15][N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:21]([C:27]([O:29][CH3:30])=[O:28])#[C:22][C:23]([O:25][CH3:26])=[O:24]>ClC1C=CC=CC=1Cl>[F:19][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([C:27]([O:29][CH3:30])=[O:28])[S:15][N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=c1oc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ns1
Reactant: COC(=O)C#CC(=O)OC
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1snc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1C(=O)OC
Yield: 65.9 %

Procedure:
A solution of 20.7 g (0.0657 mol) of 5-(α,α,α,α',α',α'-hexafluoro-3,5-xylyl)-1,3,4-oxathiazol-2-one and 18.7 g (0.131 mol) of dimethyl acetylenedicarboxylate in 52 g of o-dichlorobenzene was held at reflux for 10 hours (gas chromatography assay revealed the product had formed in 77% yield) and was concentrated under vacuum to 90° at 0.5 torr. The residue was crystallized from methanol to give 17.9 g of solid, m.p. 71°-74°. The solid was recrystallized to give 14.3 g (53% yield) of white solid, m.p. 73°-75°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1>C(O)(=O)C.C(O)(C)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:6]2[CH:15]=[CH:16][CH:3]=[CH:4][CH:5]=2)[OH:8])([C:9]2[CH:14]=[CH:13][C:12]([O:2][CH3:1])=[CH:11][CH:10]=2)[OH:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COc1ccc(C(O)(c2ccc(OC)cc2)C(O)(c2ccccc2)c2ccccc2)cc1
Reaction time: 140 h

Procedure:
To a one neck, one liter round bottom glass flask equipped with a stirrer and condenser was charged 10 g of 4-methoxybenzophenone, 300 cc of isopropanol, and 1 drop of glacial acetic acid. The solution was exposed to radiation through the flask wall for 140 hours from a 275 watt U.V. sunlamp situated 4 inches from the side of the flask. The solvent was stripped off under vacuum and the residue crystallized from ethyl alcohol to give 4,4'-dimethoxybenzopinacol with, after drying, a melting point of 163°-165° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].N1[CH:21]=[CH:20][CH:19]=[CH:18]C=1.[O:22]=[C:23](Cl)[O:24]C(Cl)(Cl)Cl.C1(CO)CC1>C(#N)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[N:15]([C:23]([O:24][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[O:22])[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: c1ccncc1
Reactant: Cc1cccc([C@H](C)c2ncc[nH]2)c1C
Agent: OCC1CC1
Solvent: CC#N
Product: Cc1cccc([C@H](C)c2nccn2C(=O)OCC2CC2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a mixture of the compound of Example 58 (100 mg, 0.5 mmol) and pyridine (90 μl, 1.1 mmol) in anhydrous acetonitrile (1 ml), at 0° C. and under nitrogen, was added diphosgene (33 μl, 0.28 mmol). The mixture was stirred at 0° C. for 30 min, before addition of cyclopropylmethanol (43 μl, 0.55 mmol). The reaction mixture was stirred at room temperature for 1 h and then filtered. The filtrate was purified by automated preparative liquid chromatography (Gilson system, 150 mm×22.4 mm LUNA C18(2) 5 μm column, 20 ml/min) using an acetonitrile:water gradient [15:85 (3 min) to 98:2 (16 min)]. The appropriate fractions were combined and concentrated to give the title compound (30 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=O.C1(C)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=C(O)[CH:27]=[CH:28][CH:29]=1.S(=O)(=O)(O)O>CO>[OH:1][C:2]1[CH:3]=[C:4]([C:5]2[C:27]3[C:11](=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)[O:10][C:8](=[O:9])[CH:7]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(O)c1
Reactant: COC(=O)CC(=O)c1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc2c(-c3cccc(O)c3)cc(=O)oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
The solution of methyl 3-hydroxybenzoylacetate (about 4.0 kg) and toluene (total weight of solution 5.6 kg) from the step above was charged to a reaction vessel along with 3-methoxyphenol (2.55 kg). The mixture was stirred vigorously at 0° C. while 27 M sulfuric acid (5.55 L) was added over 5 minutes. The resulting dark solution was warmed to 25° C. When the reaction began to thicken (40 minutes), methanol (21.8 L) was added. The addition was exothermic. Continued stirring (15 minutes) yielded a smooth, brown slurry which was cooled to 5° C. over 25 minutes, stirred for one hour, then filtered. The filter cake was washed with methanol (5.50 L) and dried under vacuum at 45-50° C. to give 3.70 kg (13.8 mol, 70% yield for two steps) of 4-[3′-(hydroxy)phenyl]-7-methoxycoumarin (a compound of Formula (b)).
Reaction SMILES: [CH:1]1([C:5]2[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC3C=CC=CC=3)[N:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[O:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>>[CH:1]1([C:5]2[CH:9]=[C:8]([NH:10][C:11]([NH:44][C:43]3[CH:45]=[CH:46][CH:47]=[C:41]([O:40][C:31]4[C:30]5[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=5)[N:34]=[CH:33][N:32]=4)[CH:42]=3)=[O:19])[N:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C2CCC2)nn1-c1ccccc1)Oc1ccccc1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5CCC5)nn4-c4ccccc4)c3)c2cc1OC

Procedure:
1-(3-cyclobutyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea was prepared from phenyl 3-cyclobutyl-1-phenyl-1H-pyrazol-5-ylcarbamate and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) according to the procedure given in Example 352B. 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.55 (s, 1H), 8.49 (s, 1H), 7.51-7.55 (m, 6H), 7.34-7.42 (m, 3H), 7.18 (m, 1H), 6.92 (m, 1H), 6.36 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 3.35 (m, 1H), 2.08-2.26 (m, 4H), 1.84-1.99 (m, 2H); LC-MS (ESI) m/z 537 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:10][C@@H:9]1[CH:11]=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18]N(C)C(=N)N(C)C.[N+:26]([CH3:29])([O-:28])=[O:27]>>[C:1]([O:5][C:6]([C@H:8]1[CH2:10][C@@H:9]1[CH:11]([CH2:18][CH2:29][N+:26]([O-:28])=[O:27])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=N)N(C)C
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=C[C@H]1C[C@@H]1C(=O)OC(C)(C)C
Product: CCOC(=O)CC(CC[N+](=O)[O-])[C@H]1C[C@@H]1C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 87.2 %

Procedure:
To 150 ml of a nitromethane solution of 17.33 g (72.1 mmol) of ethyl 3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl)-acrylate was added 14.47 ml (115.4 mmol) of tetramethylguanidine at room temperature, and the mixture was stirred at 70° C. for 3.5 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=85:15) to give 18.95 g (87.2%) of the title compound as a colorless oily substance.
Reaction SMILES: CC1C=CC=C(C)C=1NC#N.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[NH:20][C:21]([NH2:23])=S.CC(C)([O-])C.[K+].[Cl:30][CH2:31][C:32]([NH:34][C:35]1[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:36]=1[CH3:42])=[O:33]>CN(C)C=O.O>[ClH:30].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[N:20]1[CH2:31][C:32](=[O:33])[N:34]([C:35]2[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:36]=2[CH3:42])[C:21]1=[NH:23]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: Cc1cccc(C)c1NC(N)=S
Agent: CC(C)(C)[O-]
Agent: Cc1cccc(C)c1NC#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1N1CC(=O)N(c2c(C)cccc2C)C1=N
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
6.3 g (0.0443 moles) of 2,6-dimethylphenyl-cyanamide [m.p.: 120°-122° C.; prepared from 1-(2',6'-dimethylphenyl)-thiourea according to the method of Rathke (Ber. 12, 773 /1879/; Beilstein's Handbuch der organischen Chemie 12 H, 368 /1929/)] are dissolved in 100 ml of dry dimethylformamide, 4.8 g (0.0048 moles) of potassium tert.-butoxide are added, and the mixture is stirred at room temperature for 0.5 hours. Thereafter 8.7 g (0.0443 moles) of N-chloroacetyl-2,6-dimethyl-aniline (m.p.: 145°-146° C.; prepared by acylating 2,6-dimethylaniline with chloroacetyl chloride) are introduced, and the resulting mixture is stirred at 100° C. for 2 hours. The mixture is cooled, poured into water, the separated crystalline product is filtered off, washed with water and dried. This crude product is dissolved in 10% isopropanolic hydrochloric acid, and the salt is precipitated with diethyl ether. 1.7 g (12.5%) of pure 1,3-bis(2',6'-dimethylphenyl)-2-imino-4-oxo-imidazolidine hydrochloride are obtained; m.p.: 219°-221° C.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([C:29]#[N:30])[CH:19]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:18]2)=[O:16])=[N:10]1)(C)(C)C.C(O)(=O)C.O>CCOC(C)=O>[OH:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:20]([C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)([C:29]#[N:30])[CH:19]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:18]2)=[O:16])=[N:10]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO)n2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.2 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-amide (65.2 mg, 0.0995 mmol), acetic acid (2.0 mL, 31 mmol), water (1 mL) and stirred at RT over the weekend (48 h). Reaction complete by 50%. The mixture was then diluted with EtOAc and washed with NaHCO3(s). The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated under reduced vacuum and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-amide (21.6 mg, 40.22%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1c(C)ccnc1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccnc(C)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The product from Step 4 above (60 mg, 0.1 mmol) was dissolved in 4 M HCI in dioxane (4 mL). Water (1 mL) was added and the mixture was refluxed for 2 h. The solvent was evaporated and the residue was dissolved 20% aqueous acetonitrile and lyophylization yielded 4-chloro-N-[5-chloro-2-(2,4-dimethyl-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide as the hydrochloride salt. 1H NMR: (400 MHZ, DMSO-d6) δ 8.55 (d, J=6 Hz, 1 H), 8.45 (d, J=2 Hz, 1 H), 8.32 (d, J=2 Hz, 1 H), 8.18-8.15 (m, 1 H), 8.05 (d, J=2 Hz, 1 H), 7.95 (d, J=8.4 Hz, 1 H), 7.53 (m, 1 H), 2.20 (s, 3 H), 2.03 (s, 3 H). MS: (M+H)/z=504.
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:34])([F:33])[C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[CH2:20][N:21]1[CH2:25][C@H:24]2[C@H:26]([NH2:29])[CH2:27][CH2:28][C@H:23]2[CH2:22]1.[CH2:35](N1C[C@H]2C(N)CC[C@H]2C1)[C:36]1C=CC=CC=1>>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12]([NH:29][C@H:26]2[C@H:24]3[C@H:23]([CH2:22][N:21]([CH2:20][C:19]4[CH:30]=[CH:31][CH:32]=[C:17]([C:16]([F:33])([F:15])[F:34])[CH:18]=4)[CH2:25]3)[CH2:28][CH2:27]2)=[O:14])[CH:10]=[CH:9][CH:8]=[CH:36][CH:35]=1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: O=C(N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by substituting 2,2-diphenylacetic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4R*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 2: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.94 (d, J=6.8, 1H), 7.74 (s, 2H), 7.64 (d, J=7.8, 4H), 7.47-7.40 (m, 1H), 7.38-7.29 (m, 5H), 7.28-7.23 (m, 3H), 4.45-4.37 (m, 1H), 3.57 (d, J=13.5, 1H), 3.42 (d, J=13.5, 1H), 2.76 (dd, J=3.0, 9.1, 1H), 2.54-2.47 (m, 1H), 2.47-2.42 (m, 1H), 2.39 (dd, J=7.3, 9.0, 1H), 2.23 (d, J=3.0, 2H), 2.06 (dq, J=6.2, 12.2, 1H), 1.83-1.74 (m, 1H), 1.59 (dt, J=6.9, 14.5, 1H), 1.33 (dt, J=6.3, 19.6, 1H); MS (ESI+) m/z 479 (M+H)+.