Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH:4][C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[CH3:8])[CH3:3].Cl.[OH-].[NH4+:13]>>[O:10]=[C:5]1[CH2:6][C:7]([CH3:9])([CH3:8])[NH:13][C:2]([CH3:3])([CH3:1])[CH2:4]1
Reactant: CC(C)=CC(=O)C=C(C)C
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: CC1(C)CC(=O)CC(C)(C)N1
Yield: 60 %

Procedure:
In a 500 mL erlenmeyer flask, 25 gm (0.182 moles) of phorone (Aldrich Chemical Company) and 250 mL of ammonium hydroxide are stirred in a water bath at 50° C. for 14 hours. Upon cooling in an ice bath, the reaction is acidified with conc. HCl and extracted (four times) with ether. The remaining water solution is first made basic with ammonium hydroxide, then saturated with NaCl and finally, extracted with ether. The ether solution is dried over anhydrous MgSO4 and evaporated to dryness, giving a pale yellow solid (I), (17 gm, 60%). A small portion of this material is recrystallized from cyclohexane, mp 34°-36° C. (lit. ref. 1) mp 35.5°-36° C.). The NMR and i.r. (1750 cm-1) confirm the presence of 4-oxo-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]1=2.[H-].[Na+].[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22]Cl>CN(C=O)C>[O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]([CH2:22][O:21][CH2:20][CH2:19][Si:18]([CH3:25])([CH3:24])[CH3:17])[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]1=2
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1cc2c([nH]1)CCCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(n1COCC[Si](C)(C)C)CCCC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of methyl 4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (500 mg, 2.6 mmol) in DMF (3 mL) was added to a cooled (0° C.) suspension of sodium hydride (114 mg, 60% in oil, 2.8 mmol) in DMF (2 mL). After 10 min, 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) (550 μl, 3.1 mmol) was added. The mixture was stirred at rt for 2 h and was then poured into ice-water and extracted with EtOAc. After concentration, methyl 4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate was obtained as a crude oil (930 mg).
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=O.Cl.[CH:23]1([NH:29][NH2:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C1C=CN=CC=1)C>[CH:23]1([N:29]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)cc1
Reactant: NNC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: COc1ccc(-c2nn(C3CCCCC3)c3c(C(F)(F)F)cccc23)cc1

Procedure:
Prepared according to Method C step A (2-fluoro-3-trifluoromethyl-phenyl)-(4-methoxyphenyl)-methanone (0.149 g, 0.5 mmol), cyclohexylhydrazine hydrochloride (0.90 g, 0.6 mmol) and DMAP (0.061 g, 0.5 mmol) to give the title compound.
Reaction SMILES: Cl.[C:2]([O:6][CH2:7][C@@H:8]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]#[N:18])=[O:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].[C:19](=O)([O:27]C1C=CC([N+]([O-])=O)=CC=1)[O:20][CH:21]([O:23][C:24](=[O:26])[CH3:25])[CH3:22].C(N(CC)CC)C>ClCCl>[C:24]([O:23][CH:21]([O:20][C:19]([NH:9][C@H:8]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]#[N:18])=[O:11])[CH2:7][O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:27])[CH3:22])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC[C@H](N)C(=O)N1CCC[C@H]1C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(C)OC(=O)N[C@@H](COC(C)(C)C)C(=O)N1CCC[C@H]1C#N
Yield: 34.5 %

Procedure:
A solution of (2S)-1-(O′-tert-butylserinyl)pyrrolidine-2-carbonitrile hydrochloride (30 mg, 0.11 mmol; prepared according to Jenkins et al., WO95/15309), α-acetoxyethyl p-nitrophenyl carbonate (32 mg, 0.12 mmol; prepared according to Alexander et al., J. Med. Chem. 31, 318, 1988) and triethylamine (20 mg, 0.20 mmol) in dichloromethane (25 ml) was stirred at room temperature for 18 hours. After this time the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (eluant EtOAc:Pet. Ether 60–80° C.; 4:6) yielding a white solid identified as the title compound (14 mg, 0.038 mmol, 35%).
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:12][CH2:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)=[O:22])=[CH:16][CH:15]=1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(Cc1ccc(O)cc1)OCC12CC3CC(CC(C3)C1)C2
Reaction time: 8 h

Procedure:
1-Adamantanemethanol (8.31 g, 0.05 mol), 4-hydroxyphenylacetic acid (7.6 g, 0.05 mol) and p-toluenesulfonic acid (1 g, 0.006 mol) were refluxed in benzene (100 mL) with continuous water separation for 8 hours. The reaction mixture was allowed to cool with stirring overnight, then was washed, first with water (100 mL), then with aqueous 5% NaHCO3 solution (100 mL), then twice more with water (100 mL). Drying over anhydrous MgSO4, filtering and concentrating in vacuo afforded (adamant-1-yl)methyl 4-hydroxyphenylacetate, which was then combined with epichlorohydrin (50 mL) and refluxed for 2 hours in the presence of DBU (1 mL, 0.007 mol). Excess epichlorohydrin was removed in vacuo. The oily residue was dissolved in acetonitrile (100 mL) and combined with isopropylamine (20 mL, 0.23 mol). The resultant reaction mixture was refluxed for 4 hours. The oily brown residue was partitioned between ethyl ether (100 mL) and 1M aqueous KOH solution (100 mL ). The ether layer was separated and to it was added 1N HCl (30 mL). The resultant acid layer was separated and to it were added ethyl ether (100 mL) and 1M aqueous KOH solution (30 mL). The resultant ether layer was separated, dried over anhydrous MgSO4, filtered and evaporated in vacuo to give the free amine base as a crude product. The crude product (5.16 g, 72.5% yield) was dissolved in acetone (25 mL), and oxalic acid (1.8 g) in acetone (25 mL) was added dropwise, with stirring. The mixture was allowed to stir for 24 hours with additional acetone. The acetone solution was evaporated and the oily residue was partitioned between ether (100 mL) and 1M aqueous KOH solution (100 mL). The ether solution was dried over anhydrous MgSO4, filtered and concentrated. The oily residue was dissolved in acetone and an equivalent amount of oxalic acid in acetone was added dropwise. The oxalate salt of (adamant-1-yl)methyl 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate which separated was removed and dried. It melted at 55°-57° C. NMR and elemental analysis were consistent with structure. The free base has the formula: ##STR298##
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][CH2:38][C:39]([OH:41])=O)=[O:36])=[CH:33][C:32]=2[O:44][CH3:45])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:80][CH2:81][CH2:82][O:83][CH2:84][CH2:85][O:86][CH2:87][CH2:88][O:89][CH2:90][CH2:91][OH:92]>O1CCCC1>[OH:92][CH2:91][CH2:90][O:89][CH2:88][CH2:87][O:86][CH2:85][CH2:84][O:83][CH2:82][CH2:81][NH:80][C:39]([CH2:38][O:37][C:35](=[O:36])[C:34]1[CH:42]=[CH:43][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:46])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:44][CH3:45])[CH:33]=1)=[O:41]
Reactant: NCCOCCOCCOCCO
Reactant: COc1cc(C(=O)OCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)OCC(=O)NCCOCCOCCOCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 0.5 h
Yield: 10.6 %

Procedure:
In a 20 mL round-bottomed flask, 2-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)-acetic acid (Example 69, 150 mg, 152 μL, 222 μmol), HATU (84.6 mg, 222 μmol) and Hunig's base (86.2 mg, 117 μL, 667 μmol) were combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred for 30 min and the solution became clear. 2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethanol (43.0 mg, 222 μmol) was added. After stirring at room temperature overnight, the reaction mixture was concentrated. The residue was reconstituted with ethyl acetate. It was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was absorbed on small amount of silica gel and loaded on a 24 g pre-packed silica gel column. Eluting the column with 0-10% methanol in ethyl acetate over 20 min gave 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid (2-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-ethylcarbamoyl)-methyl ester as an off-white solid (20 mg, 10% yield). LCMS (ES+) m/z calcd. for C41H48Cl2F2N4O9 [(M+H)+]: 849. found: 849.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 57 %

Procedure:
3.48 g (10 mmol) of Compound 27 obtained in Example 27 was dissolved in 100 ml of dimethylformamide under argon atmosphere, 1.32 ml of ethyl bromoacetate and 1.23 g of potassium tert-butoxide were added under ice-cooling and the mixture was stirred at room temperature for 25 minutes. The reaction solution was cooled on ice, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was triturated with ethyl acetate to give 3.20 g (57%) of 2-[4-(N-acetyl-N-ethoxycarbonylmethylamino)-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].Cl.[CH:23]1([CH2:29][NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:23]1([CH2:29][N:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:12](=[O:14])[CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCCCCCCNCC1CCCCC1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCN(CC1CCCCC1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.108 g, 0.36 mmol) in methylene chloride (3.6 mL) were added N-(cyclohexylmethyl)-N-heptylamine hydrochloride (0.090 g, 0.36 mmol) and DMAP (0.098 g, 0.80 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.070 g, 0.36 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (25 mL) and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL) and brine (25 mL), dried over Na2SO4 and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 5 g Si/25 mL) with methanol (0-1% gradient) in methylene chloride as the eluent yielded 0.103 g (58%) of a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]([CH3:15])=[C:7]([C:9](N(OC)C)=[O:10])[O:8][C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]([CH3:15])=[C:7]([CH:9]=[O:10])[O:8][C:4]=2[CH:3]=1
Reactant: CON(C)C(=O)c1oc2cc(F)ccc2c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C=O)oc2cc(F)ccc12
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution (50 mL) of 6-fluoro-N-methoxy-N,3-dimethyl-1-benzofuran-2-carboxamide (3.65 g) synthesized above in tetrahydrofuran was added lithium aluminum hydride (292 mg) at 0° C., and the mixture was stirred for 1 hr. Water (300 μL) was added to quench the reaction, 1N aqueous sodium hydroxide solution (600 μL) was added, and the mixture was stirred at room temperature for 1 hr. The resulting insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title object compound (1.88 g, 69%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[CH:4]=1.[N:11]([O-])=[O:12].[Na+]>C(O)(=O)C.O>[N:11]([C:4]1[C:5]([NH2:10])=[N:6][C:7]([NH2:9])=[N:8][C:3]=1[O:2][CH3:1])=[O:12]
Reactant: O=N[O-]
Reactant: COc1cc(N)nc(N)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1nc(N)nc(N)c1N=O
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a stirred solution of 7.0 g (0.05 mol) 6-methoxy-2,4-diaminopyrimidine in 100 ml acetic acid (10% conc. in water) at 50-60° C. was added dropwise over a period of 30 min a solution of 4.55 g (0.07 mol) sodium nitrite in 20 ml water. The solution was stirred at this temperature for a further 30 min and then stirred at room temperature overnight. The filtrate was filtered off with suction, washed with water and dried. 5-Nitroso-2,4-diamino-6-methoxypyrimidine (7.80 g, 92%) was obtained as a violet solid.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[C:7]=1[OH:17])([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1CCCCC1>CCCCCCC>[C:1]([C:6]1[C:7](=[O:17])[C:8]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])=[CH:9][C:10](=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCC(C)(C)c1cccc(C(C)(C)CC)c1O
Solvent: CCCCCCC
Solvent: C1CCNCC1
Product: CCC(C)(C)C1=CC(=Cc2ccccc2)C=C(C(C)(C)CC)C1=O
Yield: 41.7 %

Procedure:
6.0 g (0.026 Mol) of 2,6-di-tert-amylphenol, 2.75 g (0.026 mol) of benzaldehyde and 4.37 g (0.05 1 mol) of piperidine are refluxed under nitrogen in 50 ml of heptane on a Dean-Stark trap for 24 hours. The solution is then evaporated in vacuo and the residue chromatographed twice on silica gel with hexane and then with hexane:ethyl acetate (9:1 ) to give 3.5 g of the title compound as a thick yellow oil.
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].C(N(CC)C(C)C)(C)C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([CH3:44])[C:31]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([Cl:43])[CH:38]=2)([OH:36])[C:32]([F:35])([F:34])[F:33])=[C:26]([Cl:45])[CH:25]=1.ClC(C1C=CC(C([O-])=O)=CC=1)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:4]([C:2]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:44])[C:31]([C:37]3[CH:42]=[CH:41][N:40]=[C:39]([Cl:43])[CH:38]=3)([OH:36])[C:32]([F:33])([F:34])[F:35])=[C:26]([Cl:45])[CH:25]=2)=[O:3])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CC(c1ccc(N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C([O-])c1ccc(C(=O)Cl)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(=O)Nc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 4-chlorocarbonylbenzoate (CAS Reg. No. 7377-26-6, 30 mg) and N,N-diisopropylethylamine (0.05 ml) in DCM (5 ml) was added to a solution of 3-(4-amino-2-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (50 mg) in DCM (1 ml). The mixture was stirred for 2 h at room temperature. Additional 4-chlorocarbonylbenzoate (CAS Reg. No. 7377-26-6, 54 mg) and N,N-diisopropylethylamine (0.1 ml) were added. The mixture was stirred for 4 h at room temperature. The mixture was poured on a saturated aqueous NaHCO3 solution (20 ml) and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 30% EtOAc/heptane) to give the title compound (57 mg) as a white foam. MS (m/e)=527.0 [M+H+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl.C(N(CC)CC)C>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)cc1)N1CCC2(C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Spiro(1H-indene-1,4'-piperidine) (15 mg, 81.1 μmol) and p-bromobenzenesulfonyl chloride (21 mg, 81.1 μmol) were combined in CH2Cl2 and treated with triethylamine (2 drops). The mixture was stirred at ambient temperature for 15 min, then poured onto a silica gel column and eluted with 1:1 CH2Cl2 : hexane. The product fractions were combined and evaporated to dryness in vacuo to provide the title compound as a solid which was dried in vacuo overnight at ambient temperature: (m.p. 177°-178°).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:7][CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15]
Reactant: COc1ccc(CN)cc1OC
Reactant: O=S1(=O)CCCO1
Solvent: CC(C)=O
Product: COc1ccc(CNCCCS(=O)(=O)O)cc1OC
Temperature: 25 °C
Yield: 42.4 %

Procedure:
To a solution of 3,4-dimethoxybenzylamine (2.2 mL, 15.0 mmol) in acetone (20 mL) was added 1,3-propane sultone (1.97 g, 15.8 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. The crude product was suspended in 90% acetone/MeOH (75 mL). The suspension was stirred at reflux for 30 sec., the solid material was collected by filtration, and dried in vacuo. Compound S (1.84 g, 43%) was isolated as a white solid. 1H NMR (D2O, 500 MHz) δ ppm 6.96 (m, 3H), 4.06 (s, 2H), 3.74 (s, 6H), 3.07 (t, 1H, J=7.8 Hz), 2.86 (t, 1H, J=7.8 Hz), 2.01 (m, 2H). 13C NMR (D2O, 125 MHz) δ ppm 149.23, 148.50, 123.63, 123.37, 55.90, 55.86, 50.96, 48.06, 45.62, 21.39. ES-MS 290 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)[CH:22]=3)=[CH:16][C:15]=2[F:33])=[O:12])[N:7]([C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[CH2:40][N:39](C(OCC2C=CC=CC=2)=O)[CH2:38][CH2:37]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)[CH:22]=3)=[CH:16][C:15]=2[F:33])=[O:12])[N:7]([C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[CH2:40][NH:39][CH2:38][CH2:37]3)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc5c(c4)CCN(C(=O)OCc4ccccc4)C5)c(F)c3)ccn2)cn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc5c(c4)CCNC5)c(F)c3)ccn2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of benzyl 6-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 0.14 mmol) in methanol/EtOAc (1:1, 10 mL) was added 10% Pd/C. The solution was stirred overnight under H2 (1 atm) at RT. The solution was filtered and concentrated in vacuo to obtain 1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (73 mg, 90% yield) 1H NMR (400 MHz, DMSO-d6) δ 9.00 (brs, 1H), 8.02 (m, 1H), 8.35 (d, J=5.6 Hz, 1H), 8.25 (s, 1H), 8.15 (dt, J=2.4, and 8.8, 1H), 7.95 (s, 1H), 7.1-7.3 (m, 3H), 7.99 (m, 1H), 6.65 (m, 1H), 6.36 (d, J=2.8 Hz, 1H), 3.95 (m, 1H), 3.84 (s, 3H), 3.53 (m, 1H), 3.01 (m, 1H), 2.88 (m, 1H), 2.79 (m, 1H), 2.60 (m, 1H), 1.25 (s, 9H); MS (ESI) m/z: 581.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][N:44]1[CH2:49][CH2:48][N:47]([CH2:50][CH2:51]O)[CH2:46][CH2:45]1>>[CH3:43][N:44]1[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:46][CH2:45]1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CN1CCN(CCO)CC1
Product: COc1cc(C(=O)OCCN2CCN(C)CC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2-(4-methylpiperazin-1-yl)ethanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-(4-methyl-piperazin-1-yl)-ethyl ester. MS (ES+) m/z calcd. for C38H44Cl2F2N5O4: [(M+H)+]: 742. found: 742.