Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][NH:6][C:7](=[O:24])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][C:17]=2[CH3:23])=[CH:10][CH:9]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][NH:6][C:7](=[O:24])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:18][C:17]=2[CH3:23])=[CH:10][CH:9]=1
Reactant: COC(=O)CCNC(=O)c1ccc(OCc2ccc(Br)cc2C)cc1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CCNC(=O)c1ccc(OCc2ccc(-c3ccccc3)cc2C)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 101.2 %

Procedure:
A mixture of 3-[4-(4-bromo-2-methyl-benzyloxy)-benzoylamino]-propionic acid methyl ester (0.20 g, 0.49 mmol), phenyl boronic acid (0.09 g, 0.78 mmol), and Na2CO3 (0.11 g, 1.08 mmol) in toluene/water (3 mL: 1 mL) is degassed (2×). Pd(PPh3)4 (0.05 g, 0.04 mmol) is added, and the mixture is stirred at 100° C. for 12 h. The mixture is filtered through Celite. Water is added, and the mixture is extracted with EtOAc. The organics are dried with MgSO4 and concentrated. The crude material is purified by flash chromatography to yield 0.20 g (100%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=O)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.[CH3:24][C:25]([S@:28]([NH2:30])=[O:29])([CH3:27])[CH3:26]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:30][S@@:28]([C:25]([CH3:27])([CH3:26])[CH3:24])=[O:29])[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1
Reactant: O=C(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: CC(C)(C)[S@](N)=O
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N=C(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1

Procedure:
(3-Fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methanone (3.3 g, 9.88 mmol) was stirred in anhydrous THF (20 mL) at r.t. under N2. (R)-(+)-2-Methylpropane-2-sulfinamide (1.21 g, 10 mmol, 1.01 eq) was added as one single portion, followed by addition of Ti(OEt)4 (3.09 mL, 14.91 mmol, 1.51 eq). The resulting solution was heated at reflux for 48 hours. The cooled mixture was evaporated. H2O (100 mL) was added, followed by the addition of EtOAc (100 mL). The mixture was filtered through celite, and washed with EtOAc (200 mL). The filtrate was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel flash chromatography and was eluted with hexanes and EtOAc (0-30% EtOAc in hexanes) to give (R)—N-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide as yellowish viscous oil which solidified after drying under vacuum as light yellow solids (3.50 g, yield: 81.0%). LC-MS ESI 437.88 (M+H), retention time=3.83 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min gradient); 1H NMR (400 MHz, CDCl3) δ ppm 7.82-6.99 (br, m, 7H), 5.90 (tt, J=52, 4 Hz, 1H), 1.31 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1cc(Cl)c(Cc2cc3ccccc3cn2)c(Cl)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Cc2cc3ccccc3cn2)c(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichloro-N-(3,5-dichloro-4-isoquinolin-3-ylmethyl-phenyl)-benzenesulfonamide was synthesized (63%) from 3,5-dichloro-4-isoquinolin-3-ylmethyl-phenylamine (236), 2,4-dichlorobenzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.30 (br s, 1H), 9.19 (s, 1H), 8.14 (d, J=8.6 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.93 (d, J=2.1 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.74-7.68 (m, 2H), 7.60 (td, J=7.5, 1.0 Hz, 1H), 7.31 (s, 1H), 7.20 (s, 2H), 4.42 (s, 2H). MS (EI): m/z 509 (M−H).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].[C:9]([C:11]1[N:12]([C:16]2[CH:17]=[C:18]([C:26]([O:28]C)=O)[CH:19]=[C:20]([CH:25]=2)[C:21]([O:23]C)=O)[CH:13]=[CH:14][CH:15]=1)#[N:10].O>CO.CN(C)C=O>[C:9]([C:11]1[N:12]([C:16]2[CH:25]=[C:20]([CH:19]=[C:18]([C:26]([N:5]=[C:6]([NH2:8])[NH2:7])=[O:28])[CH:17]=2)[C:21]([N:7]=[C:6]([NH2:8])[NH2:5])=[O:23])[CH:13]=[CH:14][CH:15]=1)#[N:10]
Reactant: COC(=O)c1cc(C(=O)OC)cc(-n2cccc2C#N)c1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1cccn1-c1cc(C(=O)N=C(N)N)cc(C(=O)N=C(N)N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.8 %

Procedure:
28% Sodium methoxide in methanol (8.6 ml) was added to guanidine hydrochloride (4.7 g) in dry N,N-dimethylformamide (14 ml), and the mixture was stirred for 20 minutes at ambient temperature. To the mixture was added dimethyl 5-(2-cyanopyrrol-1-yl)isophthalate (1.4 g) and the mixture was stirred for 4 hours at the same temperature. The reaction mixture was poured into a water (150 ml) under stirring. The isolated precipitate was collected by filtration, washed with water and dried to give 2-[3-(2-cyanopyrrol-1-yl)-5-(diaminomethyleneaminocarbonyl)benzoyl]guanidine (0.88 g).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:7][C:4]1[CH:3]=[C:2]([CH3:1])[N:6]([CH2:15][C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:22][CH2:23]2)=[O:17])[N:5]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: Cc1cc(N)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(N)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 5-methyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): 7.12–7.18 (m, 3H), 7.0–7.08 (t, 2H), 4.8 (s, 2H), 5.1 (s, 2H), 3.78–3.88 (m, 4H), 3.18–3.38 (m, 4H), 2.28 (s, 3H). MS (ES) M+H expected 317.37, found 318.1
Reaction SMILES: [OH:1][CH:2]([CH2:6][O:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH2:3][C:4]#[N:5].[ClH:12].[H][H]>CO.[Pd]>[ClH:12].[OH:1][CH:2]([CH2:6][O:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH2:3][CH2:4][NH2:5]
Reactant: [H][H]
Reactant: CS(=O)(=O)OCC(O)CC#N
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)OCC(O)CCN

Procedure:
To a solution of (RS)-3-hydroxy-4-(methanesulfonyloxy)butyronitrile (14.6 g) in methanol (60 ml), 10 wt. % Pd on carbon (2.5 g) and conc. hydrochloric acid (15 ml) were added. The mixture was stirred in a hydrogen atmosphere of 4.0 kg/cm2 at room temperature for 8 hours. After filtering off the catalyst, the mixture was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (Wako Gel C200, an eluent: methanol/acetone (volume ratio of 1/9) to obtain pure (RS)-3-hydroxy-4-(methanesulfonyloxy)butylamine hydrochloride (15.4 g). Yield, 85 %.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C:3](=[O:22])[CH2:4][C:5](=[O:21])[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)=[CH:7][N:8]([CH3:10])[CH3:9].COC(OC)N(C)C.CN>O1CCCC1>[CH3:10][N:8]1[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[C:5](=[O:21])[C:4]([C:3](=[O:22])[C:2]([CH3:24])([CH3:23])[CH3:1])=[CH:9]1
Reactant: CN(C)C=C(C(=O)CC(=O)C(C)(C)C)c1cccc(C(F)(F)F)c1
Agent: CN
Agent: COC(OC)N(C)C
Solvent: C1CCOC1
Product: Cn1cc(C(=O)C(C)(C)C)c(=O)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The product of Preparation 3 above, 3.6 g. of impure 6,6-dimethyl-1-dimethylamino-2-(3-trifluoromethylphenyl)-1-heptene-3,5-dione, was dissolved in 17 ml. of N,N-dimethylformamide dimethyl acetal and stirred under reflux at about 100° overnight using a sub-surface nitrogen bubbler. The mixture was then evaporated under vacuum to obtain 3.5 g. of a dark oil, which was dissolved in 120 ml. of tetrahydrofuran and reacted with 15 ml. of 40% aqueous methylamine at ambient temperature for 1 hour. The mixture was then evaporated under vacuum, and the resulting oil was chromatographed on a 300 g. silica gel column with 2:3 ethyl acetate:dichloromethane as the eluting solvent. The product-containing fractions was combined and evaporated under vacuum, and the residue was triturated under hexane to obtain 0.6 g. of the desired product, m.p. 86°-88°, showing the following peaks on nmr analysis in DMSOd6 : δ7.6-8.2 (m, 6H, aromatic); 3.8 (s, 3H, N--CH3); 1.2 (s, 9H, C(CH3)3).
Reaction SMILES: 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.[CH2:34]([N:41]1[C:45]([C:46]([F:49])([F:48])[F:47])=[C:44]([CH3:50])[C:43]([Br:51])=[C:42]1[C:52]([OH:54])=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>CN(C=O)C.CCOC(C)=O.O>[CH2:34]([N:41]1[C:45]([C:46]([F:47])([F:48])[F:49])=[C:44]([CH3:50])[C:43]([Br:51])=[C:42]1[C:52]([N:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1)=[O:54])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Cc1c(Br)c(C(=O)O)n(Cc2ccccc2)c1C(F)(F)F
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(Br)c(C(=O)N2CCOCC2)n(Cc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
HATU (12.59 g 33.14 mmol) and DIPEA (12.3 mL, 33.14 mmol) were added to the ice cold solution of 1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid (10 g, 27.62 mmol) in DMF (110 mL) and it was stirred for 10 min at same temperature and then morpholine (2.8 mL, 33.14 mmol) was added to the reaction mixture warmed to RT and then stirred for 14 h. The reaction mixture was diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×300 mL), washed with water (2×300 mL) and brine (2×300 mL), organic layer was dried over anhydrous Na2SO4, combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield crude mass which was then purified by column chromatography (100-200 mesh Silica gel; 30% ethyl acetate/hexane; Rf-value 0.6) to afford title compound (10 g, 84% yield, white color solid).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:8]([CH3:15])=[C:9]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:20][O:19][C:17](=[O:18])[CH2:16][C:7]1[C:8]([CH3:15])=[C:9]([C:12]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[O:14])[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=2)[CH:6]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)O)c1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)N2CCN(c3ccc(F)cc3)CC2)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
To a solution of 7-fluoro-3-methoxycarbonylmethyl-2-methyl-naphthalene-1-carboxylic acid (27.6 mg, 0.10 mmol) and 1-(4-fluoro-phenyl)-piperazine (19.8 mg, 0.11 mmol) in N,N-dimethylformamide (2 mL) was added bromo-tris-pyrrolidino phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and N,N-diisopropylethylamine (34.7 μL, 0.20 mmol). After being stirred at room temperature for 24 hours, the resulting mixture was diluted with ethyl acetate (10 mL), and washed with 1N hydrochloric acid (10 mL), a saturated aqueous solution of sodium carbonate (10 mL), and brine (10 mL). The resulting organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 20-40% ethyl acetate in petroleum ether) to afford {6-fluoro-4-[4-(4-fluoro-phenyl)-piperazine-1-carbonyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (36.2 mg, 83%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[O-:25]S([O-])(=S)=O.[Na+].[Na+].C(O)(=O)C>C(O)C.OO.O>[CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:6][CH:5]=[N:4][C:3]=1[CH2:14][S+:15]([O-:25])[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
0.5 g of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazole was suspended in 7 ml of ethanol at room temperature. 0.025 g of Na2WO4·2H2O oxidation catalyst was dissolved in 0.141 g H2O2 (35% aqueous solution), and further diluted with 2 ml of water. The oxidant/catalyst solution was added to the reactant suspension dropwise so that the addition was completed in about 30 minutes while stirring at room temperature. The reaction was continued for additional 8 hours while stirring. 2 ml of 10% Na2S2O3 aqueous solution was then added, and the resulting mixture was subjected to a reduced pressure to remove ethanol therefrom. Finally, a precipitate was formed after adding a diluted acetic acid aqueous solution to a pH value of about 8, which was filtered, water washed, and dried in vacuo to obtain Lansoprazole with a yield of about 63% (LC purity>80%).
Reaction SMILES: [F:1][C:2]1[C:3]([O:14][C@H:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH3:16])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl.O.CC#N>CO>[F:1][C:2]1[C:3]([O:14][C@H:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH3:16])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(F)c(O[C@@H](C)c2ccncc2)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: COc1cc(O[C@@H](C)c2ccncc2)c(F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 5-fluoro-2-methoxy-4-[1-(S)-(4-pyridyl)ethoxy]benzoate (290 mg, 0.95 mmol) in methanol (5 mL) was added aqueous NaOH (396 μL, 3.6M). The reaction was stirred at ambient temperature overnight and then heated to 45° C. in an oil bath for another 24 h. The reaction pH was lowered to pH 3 using 1N HCl and the reaction mixture stripped down under reduced pressure. The white foam was lyophilized from H2O/CH3CN to afford the 5-fluoro-2-methoxy-4-[1-(S)-(4-pyridyl)ethoxy]benzoic acid as a white powder.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4]3[C:5]([C:20](=[O:30])[N:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[N:22]=3)=[CH:6][N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3I)[C:8]=2[CH:9]=[CH:10][CH:11]=1.[CH3:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(B(O)O)=CN=1.B(O)O.C(=O)(O)[O-].[Na+]>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[Cu]Cl.O>[OH:1][C:2]1[C:3]2[C:4]3[C:5]([C:20](=[O:30])[N:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[N:22]=3)=[CH:6][N:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:35]4[CH:34]=[N:33][C:32]([CH3:31])=[CH:37][CH:36]=4)=[CH:15][CH:14]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1ccccc1-n1nc2c3c(O)cccc3n(Cc3ccccc3I)cc-2c1=O
Reactant: Cc1ccc(B(O)O)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl[Cu]
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(Cn3cc4c(=O)n(-c5ccccc5C)nc-4c4c(O)cccc43)cc2)cn1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
9-Hydroxy-5-[(iodophenyl)methyl]-2-(2-methylphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 728, 0.28 g, 0.56 mmol) was dissolved in tetrahydrofuran (5 mL) and treated with bis(tri-tert-butylphosphine)palladium(0) (57 mg, 0.11 mmol, 0.2 equiv), copper(I) chloride (55 mg, 0.56 mmol, 1 equiv), 2-methyl-5-pyridinylboronic acid (0.15 g, 1.1 mmol, 2 equiv) and an aqueous solution (2 mL) of cesium carbonate (0.45 g, 1.4 mmol, 2.5 equiv). The mixture was placed into a preheated oil bath at 70° C. for 2 hours, charged with additional boronic acid 2-methyl-5-pyridinylboronic acid (75 mg, 0.56 mmol, 1 equiv) and bis(tri-tert-butylphosphine)palladium(0) (27 mg, 0.056 mmol, 0.1 equiv). The mixture was heated for an additional 3 hours at 70° C., cooled to ambient temperature, poured into sodium bicarbonate (50 mL, aqueous saturated) and water (100 mL) and extracted with ethyl acetate (2×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 10% methanol), providing the titled compound as a light yellow solid: 1H-NMR (400 MHz, CDCl3) δ 9.72 (1H, br s), 8.70 (1H, d, J=2.1 Hz), 8.45 (1H, s), 7.74 (1H, dd, J=8.0, 2.3 Hz), 7.58 (2H, d, J=8.0 Hz), 7.50-7.21 (4H, br m), 7.46 (1H, br m), 7.33 (2H, d, J=8.2 Hz), 7.23 (1H, d, J=8.0 Hz), 7.01 (1H, br s), 5.46 (2H, s), 2.60 (3H, s), 2.35 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 473.1985 [(M+H)+; calculated for C30H25N4O2: 473.1972].
Reaction SMILES: [OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][N:4]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH:28]1([NH:34][C:35]2[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:40]=2[C:41]([NH:43][S:44]([CH2:47][CH2:48][CH2:49][OH:50])(=[O:46])=[O:45])=[O:42])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1(C)C=CC=CC=1.C(O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[CH:28]1([NH:34][C:35]2[CH:36]=[C:37]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][N:4]([CH2:3][C@H:2]([OH:1])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:16][CH:17]=3)[CH:38]=[CH:39][C:40]=2[C:41]([NH:43][S:44]([CH2:47][CH2:48][CH2:49][OH:50])(=[O:46])=[O:45])=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(NS(=O)(=O)CCCO)c1ccc(B(O)O)cc1NC1CCCCC1
Reactant: CC(C)(C)OC(=O)N(CCOc1ccc(I)cc1)C[C@H](O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CCOc1ccc(-c2ccc(C(=O)NS(=O)(=O)CCCO)c(NC3CCCCC3)c2)cc1)C[C@H](O)c1ccccc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
To a solution of tert-butyl [(2R)-2-hydroxy-2-phenylethyl][2-(4-iodophenoxy)ethyl]carbamate (250 mg) and [3-(cyclohexylamino)-4-[[[(3-hydroxypropyl)sulfonyl]amino]-carbonyl]phenyl]boronic acid (258 mg) in toluene (3.0 ml) and ethanol (750 μl) were added 1,1′-bis(diphenylphosphino)ferrocene (29 mg), sodium carbonate aqueous solution (2M, 830 μl) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (38 mg) at room temperature under nitrogen and stirred at 75° C. for 2 hours. The reaction mixture was poured into 0.5N hydrochloric acid (20 ml) and ethyl acetate (20 ml), added active carbon and stirred at room temperature for 30 minutes. The mixture was filtered and separated the organic layer. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified with silica gel column chromatography to give tert-butyl [2-[[3′-(cyclohexylamino)-4′-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-4-biphenylyl]oxy]ethyl][(2R)-2-hydroxy-2-phenylethyl]-carbamate (127 mg).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[S:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>O1CCCC1>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[S:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CSC(CCCCOC1CCCCO1)CCCc1cccnc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CSC(CCCCO)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.241 g (0.59 mmol) ethyl 8-(2-tetrahydropyranyloxy)-4-[3-(3-pyridyl)propyl]-3thia-octanoate in 1 ml tetrahydrofuran is added 1 mL of 1N hydrochloric acid. After stirring for 1 hour at room temperature, thin layer chromatography indicates incomplete conversion. Another 0.35 mL of 6N hydrochloric acid is added and the mixture is stirred for 1 hour. The pH of the reaction mixture is then adjusted to 8.0 and the resulting solution is extracted with methylene chloride. The organic layer is washed with brine, dried, filtered and evaporated to give yellow oil which is purified by preparative thin layer chromatography over silica gel using ether/ethyl acetate (4:1) as eluent to give ethyl 8-hydroxy-4-[3-(3-pyridyl)propyl]-3-thia-octanoate; IR (CH2Cl2) 3679, 1730 cm-1.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9](OC)=[O:10])[C:6]([C:13](OC)=[O:14])=[CH:5][CH:4]=1)#[N:2].[BH4-].[Li+].C([O-])(O)=O.[Na+]>CCO.C1COCC1>[OH:14][CH2:13][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[N:8][C:7]=1[CH2:9][OH:10]
Reactant: COC(=O)c1ccc(C#N)nc1C(=O)OC
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc(CO)c(CO)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of dimethyl 6-cyanopyridine-2,3-dicarboxylate from Step A (13.0 g, 59.0 mmol) in EtOH (295 mL) was added lithium borohydride (29.5 mL of a 2 M solution in THF, 59.0 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 4 h, and then cooled to 0° C. Saturated aqueous NaHCO3 (200 mL) was added slowly and the quenched mixture was extracted with EtOAc (9×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH-100:0 to 85:15, to give the title compound. MS: m/z=165 (M+1).