Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([S:33]([C:36]2[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:45].O1CCOCC1>C(OCC)C>[ClH:45].[C:11]1([C@H:9]([NH:8][CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][N:24]([S:33]([C:36]3[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH2:23]2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(S(=O)(=O)c2ccc(C(=O)O)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@@H](NC[C@H]1CN(S(=O)(=O)c2ccc(C(=O)O)cc2)C[C@@H]1c1ccccc1)c1cccc2ccccc12

Procedure:
A 320 mg portion of 4-{[(3S,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]sulfonyl}benzoic acid was dissolved at room temperature in 3.0 ml of 4 M hydrogen chloride/1,4-dioxane solution and stirred for 24Hours. The reaction solution was diluted with diethyl ether and then concentrated under a reduced pressure, the thus obtained residue was dissolved in THF and mixed with diisopropyl ether, and the thus precipitated solid was collected by filtration and dried under a reduced pressure to obtain 183 mg of 4-{[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]sulfonyl}benzoic acid hydrochloride as a colorless solid.
Reaction SMILES: NO.CC[N:5]([CH2:8][CH3:9])[CH2:6]C.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.CS(Cl)(=O)=O.[Na+].[Cl-]>C(Cl)Cl.O>[CH3:11][C:10]([C@:8]1([CH3:9])[CH2:6][N:5]1[S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])([CH3:20])[CH3:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: NO
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2C[C@@]2(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 96.4 %

Procedure:
A solution of the amino alcohol from Step 2 (4.98 g, 38.0 mmol) in CH2Cl2 (200 mL) at 0° C. was treated with Et3N (26 mL, 190 mmol) followed by a solution of p-toluenesulfonyl chloride (8.7 g, 45.6 mmol) in CH2Cl2 (50 mL) over 40 min. The reaction mixture was stirred at room temperature for 4 days. The mixture was cooled to 0° C. after which Et3N (8.50 mL, 60.8 mmol) and methanesulfonyl chloride (5.88 mL, 76.0 mmol) were added. The mixture was stirred at 0° C. for 4 h. The reaction mixture was poured into a 1:1 mixture of saturated aqueous NaCl and water and was extracted with CH2Cl2. The organic layer was washed with saturated aqueous NaCl, dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography, elution with 0-50% EtOAc in heptane, to provide the title compound (5.88 g, 58%) as a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1([C:13](=O)[CH2:14][C:15]2[CH:16]=[C:17]([N:21]3[CH:25]=[C:24]([C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[NH:28][N:27]=4)[N:23]=[N:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.O.CCOC(C)=O>C1COCC1>[N:7]1([CH2:13][CH2:14][C:15]2[CH:16]=[C:17]([N:21]3[CH:25]=[C:24]([C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[NH:28][N:27]=4)[N:23]=[N:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1
Reactant: O=C(Cc1cccc(-n2cc(-c3n[nH]c4ccccc34)nn2)c1)N1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: c1cc(CCN2CCOCC2)cc(-n2cc(-c3n[nH]c4ccccc34)nn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
LAH (1M in THF, 107 μl; 0.26 mmol; 2.0 eq.) was added dropwise to a cooled (0° C.) solution of 3-{1-[3-(2-morpholin-4-yl-2-oxoethyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole (50 mg, 0.13 mmol, 1 eq.) in dry THF (1 mL). The reaction mixture was allowed to warm to RT and stirred overnight. Water was added and the reaction mixture was extrated three times with EtOAc. Combined organic phases were dried over magnesium sulfate, filtered and concentratd. The crude was purified by preparative HPLC to give the title compound as a beige powder. 1H NMR (300 MHz, DMSO-d6) δ 13.37 (brs, 1H), 9.31 (s, 1H), 8.37 (dt, J=8.2 Hz, 1.0 Hz, 1H), 7.96 (t, J=1.5 Hz, 1H), 7.90-7.87 (m, 1H), 7.61 (dt, J=1.0, 8.4 Hz, 1H), 7.53 (t, J=7.9 Hz, 1H), 7.47-7.41 (m, 1H), 7.40-7.38 (m, 1H), 7.28-7.23 (m, 1H), 3.59 (t, J=4.6 Hz, 4H), 2.91-2.86 (m, 2H), 2.64-2.59 (m, 2H), 2.47 (t, J=4.6 Hz, 4H). HPLC (Condition A): Rt 2.47 min (purity 95.5%). MS (ESI+): 375.2, MS (ESI−): 373.3.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[Cl-].[NH4+]>C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)[CH:7]=1
Reactant: Clc1ccnc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(Cl)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-4-chloropyridine (C2) (1.00 g, 5.20 mmol) in CH2Cl2 (10 mL) cooled to −78° C. was added n-butyllithium (1.6 M in hexanes, 3.57 mL, 5.72 mmol) dropwise. After 15 min, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (C1) (1.14 g, 5.72 mmol) in CH2Cl2 (3 mL) was added dropwise. After 1 h, saturated aqueous ammonium chloride (5 mL) was added. The mixture was warmed to ambient temperature, diluted with CH2Cl2 and washed with saturated aqueous sodium bicarbonate and brine. The organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified via silica gel chromatography eluting with 0-20% ethyl acetate in hexanes to provide tert-butyl 4-(4-chloropyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (C3).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[C:13]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+].O>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[C:13]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(C)CN(C(=O)OCc2ccccc2)CC1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C1(C)CN(C(=O)OCc2ccccc2)CC1O
Reaction time: 0.33 h
Yield: 56.5 %

Procedure:
To a solution of ethyl 1-benzyloxycarbonyl-3-methyl-4-oxopyrrolidine-3-carboxylate (1.0 g, 3.28 mmol) in methanol (20 mL), sodium borohydride (0.19 g, 4.92 mmol) was added at −20° C., and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture were added saturated aqueous solution of ammonium chloride (20 mL) and water (20 mL), and the mixture was extracted by ethyl acetate (20 mL×3). The extract was washed with saturated aqueous solution of sodium chloride (20 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 3:1) to obtain 0.57 g (57%) of the title compound as a colorless oily product.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23]C(OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42][CH2:43][C:44]([CH3:47])([OH:46])[CH3:45].[OH-].[K+]>O1CCCC1.CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:42][CH2:43][C:44]([OH:46])([CH3:47])[CH3:45])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(O)CCBr
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](SCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a solution of 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (81.6 mg, 0.140 mmol) and 4-bromo-2-methyl-2-butanol (117 mg, 0.700 mmol) in tetrahydrofuran (1 ml) was added 1M KOH solution in methanol (1 ml), and the mixed solution was stirred at room temperature for 30 minutes, then concentrated under reduced pressure. The residue was diluted with hexane, washed with brine and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethyl acetate=8:1, developed once) to give the title compound as a colorless oil (60.3 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH2:13]([O:15][C:16](=[O:28])[CH:17]([NH2:27])[CH:18]([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])[CH3:14].N1C=CC=CC=1>ClC(Cl)C>[CH2:13]([O:15][C:16](=[O:28])[CH:17]([NH:27][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:12])[CH:4]=1)(=[O:10])=[O:9])[CH:18]([C:19]([F:22])([F:20])[F:21])[C:23]([F:25])([F:26])[F:24])[CH3:14]
Reactant: CCOC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(F)c1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCOC(=O)C(NS(=O)(=O)c1ccc(Cl)c(F)c1)C(C(F)(F)F)C(F)(F)F
Reaction time: 18 h
Yield: 62.5 %

Procedure:
To a vial containing a solution of 4-chloro-3-fluorobenzenesulfonyl chloride (181 mg, 0.79 mmol) and 2-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl ester (200 mg, 0.79 mmol) in anhydrous dichloroethane (3 mL) was added pyridine (192 μL). The vial was capped and shaken for 18 h. The solvent was removed in vacuo and the residue transferred to a separatory funnel with EtOAc (100 mL) and washed with distilled water (100 mL×2). The organic layer was removed and the combined aqueous washings were extracted with EtOAc (100 mL×2). The organic extracts were combined, washed with brine (100 mL), dried (MgSO4), filtered, and evaporated to give a yellow solid (220 mg). This material was adsorbed onto silica gel and purified by column chromatography, eluent: HCCl3, to afford a white solid (186 mg, 53%). Mass Spectrum (+ESI): 446 [M−H]+.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[CH2:11][C:10]2[CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18](=[O:32])[N:19]([CH3:31])[CH2:20][C:21]3[N:22]([CH3:30])[C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:14]=[N:15][C:9]=2[NH:8][C:7]1=[O:33])C.[OH-].[Na+:36]>CO>[CH3:31][N:19]([CH2:20][C:21]1[N:22]([CH3:30])[C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18](/[CH:17]=[CH:16]/[C:13]1[CH:14]=[N:15][C:9]2[NH:8][C:7](=[O:33])[N:6]([CH2:5][C:4]([O-:34])=[O:3])[CH2:11][C:10]=2[CH:12]=1)=[O:32].[Na+:36]
Reactant: CCOC(=O)CN1Cc2cc(/C=C/C(=O)N(C)Cc3cc4ccccc4n3C)cnc2NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)CN(CC(=O)[O-])C(=O)N2
Yield: 76.8 %

Procedure:
A suspension of (E)-(6-{2-[methyl-(1-methyl-1H-indol-2-ylmethyl)carbamoyl]vinyl}-2-oxo, 1,4-dihydro-2H-pyrido[2,3-d]pyrimidin-3-yl)acetic acid ethyl ester (0.19 g, 0.40 mmol) in methanol (20 mL) was treated with 1N NaOH (0.80 mL, 0.80 mmol). The mixture was heated at reflux for 2 h. After cooling, the solid was collected by filtration to give the title compound (140 mg, 77%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6+D2O) δ 8.30-8.25 (m, 1H), 7.97-7.86 (m, 1H), 7.55-7.42 (m, 3H), 7.17-7.05 (m, 3H), 6.46-6.22 (m, 1H), 5.03-4.86 (m, 2H), 4.55 (s, 1H), 4.48 (s, 1H), 3.76-3.67 (m, 5H), 3.13-3.05 (m, 3H); MS (ESI) m/e 434 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C:16]([OH:18])=[O:17])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[CH3:19]O>>[NH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(O)Cc1ccc2c(c1)NCCC2
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc2c(c1)NCCC2
Temperature: 70 °C

Procedure:
Thionyl chloride (13 g; 1.5 equiv.) was added dropwise at 0° C., in the course of 5-10 minutes, to a solution of crude 2-(1,2,3,4-tetrahydroquinolin-7-yl)acetic acid (stage 5; 14 g; 1 equiv.) in 140 ml of methanol, and the resulting reaction mixture was then heated for 6 hours at reflux (70° C.). When the conversion was complete, the reaction solution was concentrated under reduced pressure and the residue was taken up in 150 ml of water, rendered basic (pH 7-8) with sodium carbonate and finally extracted with 2×150 ml of chloroform. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 10-12% ethyl acetate/-hexane). Methyl 2-(1,2,3,4-tetrahydroquinolin-7-yl)acetate (4 g) was obtained in the form of a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[N:10][C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1.[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([F:33])[CH:32]=1)#[N:26].[Cl-].[NH4+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:24][C:20]1[CH:19]=[C:18]([C:9]2[N:10]=[C:11]([C:13]([OH:15])=[O:14])[S:12][C:8]=2[C:29]2[CH:30]=[C:31]([F:33])[CH:32]=[C:27]([C:25]#[N:26])[CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1nc(-c2cccc(Cl)c2)c(Br)s1
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: N#Cc1cc(F)cc(-c2sc(C(=O)O)nc2-c2cccc(Cl)c2)c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
At room temperature, 7.2 ml of an aqueous 2M sodium carbonate solution and 167 mg (0.144 mmol) of tetrakis(triphenylphosphine)palladium are added to 1.00 g (2.89 mmol) of the compound from Example 5A and 714 mg (4.33 mmol) of the boronic acid from Example 22A in 40 ml of DME, and the mixture is subsequently stirred at 80° C. for 24 h. A saturated aqueous ammonium chloride solution is added, and the reaction mixture is subsequently extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 606 mg (53% of theory) of the title compound having a purity of 90% are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[C:9]([CH3:12])[C:10]=1[NH2:11])=[O:4].[N:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[C:9]([CH3:12])[C:10]=1[NH:11][S:32]([C:29]1[CH:28]=[CH:27][C:26]([O:25][C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)=[CH:31][CH:30]=1)(=[O:33])=[O:34])=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccncc2)cc1
Reactant: COC(=O)c1cc(-c2ccccc2)cc(C)c1N
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cc(-c2ccccc2)cc(C)c1NS(=O)(=O)c1ccc(Oc2ccncc2)cc1
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of 1.43 g (5.93 mmol) of the product of Example 40 in 20 mL of pyridine was added 1.98 g (6.52 mmol) 4-(pyridin-4-yloxy)-benzenesulfonyl chloride and the reaction was stirred overnight. Additional 4-(pyridin-4-yloxy)-benzenesulfonyl chloride (0.5 g, 1.6 mmol) was added twice over the next two days. The reaction was then diluted with water and extracted three times with dichloromethane. The organics were combined, washed with brine, dried over Na2SO4, concentrated in vacuo and chromatographed on silica gel using gradient elution (100% hexane to 100% ethyl acetate) to provide 5-methyl-4-[4-(pyridin-4-yloxy)-benzenesulfonylamino]-biphenyl-3-carboxylic acid methyl ester 2.54 g (90%) as a white solid. Electrospray Mass Spec: 475.2 (M+H)+
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH2:5][C:6]1[C:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH:4]2[C:3](=[O:2])[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[CH:11][C:6]=3[CH2:5]2)=[CH:27][CH:28]=1
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1ccc(OC)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(C2Cc3cnc(Nc4ccccc4)nc3N(c3ccccc3)C2=O)cc1
Temperature: 80 °C

Procedure:
To the solution of 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester (227.3 mg, 0.5 mmol) (from Example 1e supra) in glacial acetic acid (15 mL) was added concentrated sulfuric acid (0.2 mL) in one portion. The reaction mixture was heated at 80° C. overnight. The reaction mixture was then diluted with ethyl acetate (50 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude products which was crystallized from ethyl acetate-hexanes to give 6-(4-methoxy-phenyl)-8-phenyl-2-phenylamino-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one as brown crystalline solid. (Yield 174.2 mg, 82.4%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH2:10][CH:11]([CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].O>CS(C)=O>[O:34]1[CH2:33][CH2:32][N:31]([CH2:30][C:9](=[O:8])[CH2:10][CH:11]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)C(Cc1cccc2ccccc12)CC(O)CN1CCOCC1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(CC(=O)CN1CCOCC1)Cc1cccc2ccccc12
Reaction time: 6 h
Yield: 66.6 %

Procedure:
2.3 g (14.7 mmole) of a sulfur trioxide/pyridine complex and 2.1 ml of triethylamine were added at room temperature to a solution of 1.96 g (4.91 mmole) of t-butyl 4-hydroxy-5-morpholino-2-(1-naphthylmethyl)pentanoate (prepared as described in Preparation 12) dissolved in 20 ml of anhydrous dimethyl sulfoxide. The mixture was stirred for 6 hours, allowed to stand overnight and then mixed with water, after which it was extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. It was then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent: a 10: 90 by volume mixture of methanol and methylene chloride), to afford 1.30 g (66.7%) of the title compound as a pale brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[C:10]=2[F:18])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([NH2:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.CN(C1C=CC=CN=1)C.CN1CC[O:44][CH2:43][CH2:42]1>ClCCl.C(OC(=O)C)(=O)C>[C:43]([NH:30][S:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:19])[C:9]3[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[C:10]=3[F:18])=[CH:6][N:5]=2)[CH2:22][CH2:23]1)(=[O:28])=[O:29])(=[O:44])[CH3:42]
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(N)(=O)=O)CC2)nc1N
Reactant: CN1CCOCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)NC(C)=O)CC2)nc1N
Reaction time: 2 h

Procedure:
4-[4-Amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-sulfonic acid amide (50 mg, Example 285) in dichloromethane (10 mL), N-methyl morpholine (0.1 mL, Aldrich) and dimethylaminopyridine (1 mg, Aldrich) was chilled in ice and added acetic anhydride (5 drops). The mixture was stirred cold for two hours and quenched with methanol. The mixture was evaporated to dryness and chromatographed on silica gel (dichloromethane, then ethyl acetate). Fractions corresponding to product were combined and crystallized from dichloromethane/ethyl ether to give 45 mg of colorless material, MP 153° C. (dec). MS(ES) MH+485
Reaction SMILES: [CH2:1]([C:3]1[N:8]([CH2:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:18])[C:6]2[C:19]([N:36](CC)[C:37](=O)[C:38](F)(F)F)=[C:20]([C:23]([NH:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33][OH:34])[CH2:28][CH2:27]3)=[O:24])[N:21]([CH3:22])[C:5]=2[CH:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:1]([C:3]1[N:8]([CH2:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:18])[C:6]2[C:19]([NH:36][CH2:37][CH3:38])=[C:20]([C:23]([NH:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33][OH:34])[CH2:28][CH2:27]3)=[O:24])[N:21]([CH3:22])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(c(N(CC)C(=O)C(F)(F)F)c(C(=O)NC3CCN(C(=O)CO)CC3)n2C)c(=O)n1CC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCNc1c(C(=O)NC2CCN(C(=O)CO)CC2)n(C)c2cc(CC)n(CC(=O)c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
A mixture of the compound of Reference Example 25 (50 mg, 0.10 mmol), 2-(4-aminopiperidin-1-yl)-2-oxoethanol hydrochloride (24 mg, 0.13 mmol), HOBt (21 mg, 0.16 mmol), WSCD (30 mg, 0.16 mmol) and triethylamine (21 mg, 0.21 mmol) in DMF (2 ml) was stirred at room temperature for 2 days. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted twice with ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluate, ethyl acetate) to give 6-ethyl-3-[ethyl(trifluoroacetyl)amino]-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide (40 mg, 65%) as a colorless amorphous solid. A mixture of the 6-ethyl-3-[ethyl(trifluoroacetyl)amino]-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide (40 mg, 0.065 mmol) and potassium carbonate (18 mg, 0.13 mmol) in methanol (3 mL) was stirred at room temperature for 3 hr. Water (10 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (22 mg, 65%) as beige crystals.