Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][CH:33]([CH2:36][CH3:37])[CH2:34][NH2:35].[BH4-].[Na+]>ClCCl.CO.C(O)(=O)C>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:35][CH2:34][CH:33]([CH3:32])[CH2:36][CH3:37])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCC(C)CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(C)CNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (44 mg, 0.1 mmol) in dichloromethane (2 mL) and methanol (1 mL) was added 2-methyl-1-butanamine (52 mg, 0.6 mmol) and 1 drop of acetic acid. This mixture was stirred for 2 h then sodium tetrahydridoborate (22.8 mg, 0.6 mmol) was added. The resulting mixture was stirred for 1 h. It was then concentrated and again dissolved in dimethyl sulfoxide (3 mL). It was then purified by Gilson Preparatory HPLC to give 28.4 mg of the title compound (55.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:16]([CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]([OH:19])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C:39]([CH3:42])([OH:41])[CH3:40])[N:34]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:16]([CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][C:39]([OH:41])([CH3:40])[CH3:42])[N:34]=2)=[O:19])[CH:5]=[CH:6][C:7]=1[S:8]([CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)(=[O:9])=[O:10]
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(S(=O)(=O)C2CCCC2)c(Cl)c1
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(=O)(=O)C3CCCC3)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (R)-2-(3-chloro-4-cyclopentanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (0.15 mmol) is dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution is added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 1.2 equiv.) and it is then allowed to warm to 25° C. and stirred 1 h at 25° C. After this time, the reaction is concentrated in vacuo to ⅓ of the original volume. In a separate flask, a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 1.5 equiv.), 2,6-lutidine (2.0 equiv.) and methylene chloride (5 mL) is cooled to 0° C. in an ice bath. To this solution is added the solution of the prepared acid chloride, diluted with another portion of methylene chloride (2 mL) dropwise. After the addition is complete the reaction is then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction mixture is diluted with methylene chloride (10 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (silica gel column) will afford (R)-2-(3-chloro-4-cyclopentanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[CH:24]=1.C(OC(N1CC[C:43]2C=C(OCC3C=CC(C(OC)=O)=CC=3)C=C[C:42]=2[CH2:41][CH2:40]1)=O)(C)(C)C.COC(=O)C1C=CC(COC2C=CC3CCNCCC=3C=2)=CC=1>>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:19][C:16]2[CH:17]=[CH:18][C:11]3[CH2:10][CH2:9][N:8]([CH:6]4[CH2:43][CH2:42][CH2:41][CH2:40]4)[CH2:14][CH2:13][C:12]=3[CH:15]=2)[CH:24]=1
Reactant: COC(=O)c1ccc(COc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Agent: COC(=O)c1ccc(COc2ccc3c(c2)CCNCC3)cc1
Product: COC(=O)c1cccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)c1

Procedure:
Example 94 (E94) was prepared in an analogous manner to Example 88 (E88) from 7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (WO 02/40471) and 3-bromomethyl-benzoic acid methyl ester using the methods highlighted in Description 3 (D3), Description 4 (D4) and Example 88 (E88); MS (ES+), m/e 380 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:32])[CH:5]([NH:18][S:19]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)(=[O:21])=[O:20])[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([NH2:17])=[N:12][CH:11]=[CH:10]2.Cl.Cl.[CH3:35][O:36]C(=O)C(N)CC1C=C2C(=CC=1)C(N)=NC=C2.COC1C=C2C(C=CC(S(Cl)(=O)=O)=C2)=CC=1>>[CH3:2][O:3][C:4](=[O:32])[CH:5]([NH:18][S:19]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26]([O:36][CH3:35])=[CH:27][CH:28]=2)[CH:23]=1)(=[O:21])=[O:20])[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([NH2:17])=[N:12][CH:11]=[CH:10]2
Reactant: COC(=O)C(N)Cc1ccc2c(N)nccc2c1
Reactant: COC(=O)C(Cc1ccc2c(N)nccc2c1)NS(=O)(=O)c1ccc2ccccc2c1
Agent: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Agent: Cl
Product: COC(=O)C(Cc1ccc2c(N)nccc2c1)NS(=O)(=O)c1ccc2ccc(OC)cc2c1

Procedure:
Using the procedure described for 11a, the reaction of methyl ester 1j and sulfonyl chloride 12a gave 3-(1-amino-6-isoquinolinyl)-2-[[(7-methoxy-2-naphthalenyl)sulfonyl)amino]propionic acid methyl ester. This ester was saponified and subsequently coupled with 4-methylpiperidine using the procedure described for the previous example to give the title compound 12b. 1H-NMR 200 MHz (CD3OD) δ: 0.18-0.85 (5H, m), 1.22-1.58 (3H, m), 1.78-3.18 (4H, m), 3.80-4.26 (2H, m), 3.88 (3H, s), 4.57-4.72 (1H, m), 6.97-7.04 (1H, m), 7.20-7.79 (8H, m) 8.01-8.14 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:26][O:27][C:28](=[O:29])[C:30]1[CH:35]=[CH:34][C:33]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH:10]([CH3:25])[C:11]([OH:16])([C:17]3[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:12]([F:15])([F:13])[F:14])=[C:2]([Cl:1])[C:7]=2[Cl:8])=[CH:32][CH:31]=1
Reactant: CC(c1ccc(O)c(Cl)c1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2Cl)cc1

Procedure:
In analogy to Example 151, step 8, 5-[2-(2,3-dichloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one was reacted with 4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=528.2 [M−H+].
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:15]OC)([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.O>CC#N.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[NH2:15][C:5]1([CH2:12][CH2:13][CH3:14])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:19]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=3[S:21](=[O:35])(=[O:34])[N:20]=2)[C:4]1=[O:18]
Reactant: CCCC1(NOC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Mo]
Agent: [C-]#[O+]
Solvent: O
Solvent: CC#N
Product: CCCC1(N)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 69.7 %

Procedure:
To a solution of the product of Example 9 (20 mg, 0.038 mmol) in CH3CN (1.5 mL) was added H2O (100 uL) and molybdenum hexacarbonyl (7 mg, 0.027 mmol) and the solution was refluxed for 2 hours. After cooling to room temperature the solvent was removed in vacuo and the crude product was purified by column chromatography on C-1 8 silica gel (70:30:0.1 methanol:H2O:trifluoroacetic acid) to give the title compound as a colorless solid (13 mg, 69%): 1H NMR (d6-DMSO) δ 14.47 (s, 1H), 9.94 (s, 1H), 8.61 (s, 2H), 8.14, 8.11 (d, 1H), 7.70-7.42 (m, 5H), 7.37, 7.34 (d, 1H), 3.01 (s, 3H), 2.03-1.93 (m, 1H), 1.87-1.75 (m, 1H), 1.29-1.14 (m, 1H), 0.96-0.83 (m, 1H), 0.76-0.67 (t, 3H); MS (ESI) m/z 491 (M+H+).
Reaction SMILES: C(N1C[C:8](=O)[N:7]([CH:11]([CH3:13])[CH3:12])[CH2:6][C:5]1=[O:14])(C)C.Cl.[P:16]([OH:19])([OH:18])[OH:17].C=[O:21]>O>[CH:11]([N:7]([CH2:8][P:16]([OH:19])([OH:18])=[O:17])[CH2:6][C:5]([OH:14])=[O:21])([CH3:12])[CH3:13]
Reactant: C=O
Reactant: OP(O)O
Reactant: CC(C)N1CC(=O)N(C(C)C)CC1=O
Agent: Cl
Solvent: O
Product: CC(C)N(CC(=O)O)CP(=O)(O)O
Temperature: 105 °C
Yield: 70.7 %

Procedure:
A 100 ml 3-necked flask was equipped with a magnetic stir bar, thermometer, condenser and an addition funnel. To this flask were added 1,4-diisopropyl-2,5-diketopiperazine (1.98 g; 10.0 mmol), water (25 ml), concentrated hydrochloric acid (10 ml), and phosphorous acid (1.72 g; 21 mmol). The resulting mixture was heated rapidly to 105° C. At this point, a solution of 37% formaldehyde in water (1.95 g; 24 mmol) was added slowly drop-wise to the mixture. Upon completion of the addition of formaldehyde, the reaction mixture was heated at 104°-105° C. for 17 hours. Analysis of the reaction mixture by HPLC indicated the presence of 1.49 g (70.7% yield) of N-isopropyl-N-phosphonomethylglycine.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][C:14]([OH:16])=[O:15]>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: Sc1ccc(Br)cc1
Reactant: O=C(O)CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCSc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
8.5 g (0.211 mol) of sodium hydroxide was added to 45 mL of water, 20.0 g (0.106 mol) of 4-bromothiophenol (purchased from Aldrich Chemical Company) was then added and the mixture was cooled to about 0° C. 18.0 g (0.116 mol) of 3-bromopropionic acid (purchased from Aldrich Chemical Company) was added in portions while keeping the temperature below 5° C. The mixture was warmed to room temperature, stirred for 1 h under nitrogen, and was then washed with diethyl ether (3×100 mL). The aqueous layer was acidified with 1N HCl, and then filtered to yield 27.95 g of the title compound of Step A as a solid melting at 101-103° C. 1H NMR (CDCl3): δ2.66 (t,2H), 3.14 (t,2H), 7.2 (m,2H), 7.4 (m,2H).
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(OC(=O)C)(=O)C.[CH3:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[C:8]([C:7]1[C:2]([C:21]2[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)#[N:9]
Reactant: N#Cc1cccnc1Br
Reactant: Cc1ccc(B(O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(-c2ncccc2C#N)cc1

Procedure:
Synthetic Scheme XXV shows the 8-step preparation of the alkylating reagent 2-(4-bromomethylphenyl)-3-cyanopyridine (57) from 2-amino-3-picoline (58) (Aldrich). In step 1, the aminopicoline 58 was converted to the bromopicoline 59 by reaction with bromine, concentrated hydrobromic acid, and sodium nitrite at 0° C. In step 2, the picoline 59 was oxidized with KMNO4 to give the corresponding carboxylic acid 60. In step 3, the acid 60 was reduced to the alcohol 61 with borane/THF. In step 4, the alcohol 61 was oxidized to the aldelyde 62 under Swern conditions or by using MnO2. In step 5, the aldehyde 62 was reacted with hydroxylamine to give the oxime 63. In step 6, the oxime 63 was converted to 2-bromo-3-cyanopyridine (64) with acetic anhydride at reflux. In step 7, the nitrile 64 was coupled with 4-methylphenylboronic acid (56) (Scheme XXIV) using Snieckus conditions (Scheme XIII) to give 3-cyano-2-(4-methylphenyl)pyridine (65). In step 8, 65 was brominated with NBS/AIBN in carbon tetrachloride at reflux to give the desired alkylating reagent 57. ##STR88##
Reaction SMILES: C(Cl)(=[O:3])C.[Br:5][C:6]1[C:7]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:8]=2[S:9][C:10]=1[CH:11]([O:14][Si](C)(C)C)C#N.[CH3:24][OH:25]>>[Br:5][C:6]1[C:7]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:8]=2[S:9][C:10]=1[CH:11]([OH:14])[C:24]([OH:3])=[O:25]
Reactant: CC(=O)Cl
Reactant: CO
Reactant: Cc1cccc2sc(C(C#N)O[Si](C)(C)C)c(Br)c12
Product: Cc1cccc2sc(C(O)C(=O)O)c(Br)c12
Temperature: 25 °C
Yield: 74 %

Procedure:
Acetyl chloride (2.6 mL, 36.3 mmol) was dropped at 0° C. in methanol (20 mL). After minutes, a solution of (3-bromo-4-methyl-benzo[b]thiophen-2-yl)-trimethylsilanyloxy-acetonitrile (428 mg, 1.21 mmol) in methanol (5 mL) was added at 0° C. to the reaction. The mixture was warmed at room temperature for 2 hours and then concentrated under vacuum. The residue was diluted with ethyl acetate (30 mL). The organic layer was washed with an aqueous solution of sodium hydroxyde 1M for 2 hours and was then acidified to pH 2 with an hydrochloric acid solution 1N. The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to afford the desired acid (23g) as a white solid (270 mg, 0.9 mmol, 74%) without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([O:10][CH3:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.[I:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[N+:22]([O-:24])=[O:23])[NH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[I:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[N+:22]([O-:24])=[O:23])[N:15]([CH2:2][C:3]2[C:4]([O:10][CH3:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=2)[N:14]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: COc1nc(C)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nc(C)ccc1Cn1nc(I)c2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.9 %

Procedure:
To 3-(bromomethyl)-2-methoxy-6-methylpyridine (500 mg, 2.314 mmol) and 3-iodo-4-nitro-1H-indazole (668.8 mg, 2.314 mmol) in DMF (10 mL) was added K2CO3 (479.7 mg, 3.471 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with EtOAc, washed with water, brine and concentrated under reduced pressure to give the product (1.0 g).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[CH3:25])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 71.5 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2-methylphenylboronic acid (available from Combi-Blocks Inc.; 54 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-methyl-biphenyl-2-carboxylic acid (63 mg, 72%). 1H NMR (400 MHz, DMSO-d6) δ 12.92 (br s, 1H), 8.46 (d, J=4.8 Hz, 2H), 8.34 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.17-7.32 (m, 3H), 7.09 (d, J=7.0 Hz, 1H), 2.08 (s, 3H).
Reaction SMILES: C(O)(=[O:3])C.O=P[O:7][P:8]=[O:9].O[CH2:11][NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CC(C)=O>[C:13]([NH:12][CH2:11][P:8]([OH:9])(=[O:3])[OH:7])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(NCO)c1ccccc1
Reactant: O=POP=O
Reactant: CC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: O=C(NCP(=O)(O)O)c1ccccc1
Temperature: 25 °C

Procedure:
50 ml of acetic acid were cooled to 10° C. with stirring and under a nitrogen atmosphere. 11 g (0.1 mol) of diphosphorus trioxide (P2O3) were then added dropwise with further cooling, during the course of which the temperature fell to 0° to 5° C. 30.2 g (0.2 mol) of N-hydroxymethylbenzamide were then added in portions at 5°-10° C. during the course of 60 minutes. The mixture was then stirred without cooling until room temperature was reached. It was then heated to reflux for 31/2 hours. It was then cooled. 2 g (0.11 mol) of water were then added dropwise with stirring, the temperature rising to 35° C. The mixture was then allowed to cool and 25 ml of acetone were added. It was then additionally stirred and filtered with suction. 31.5 g of benzoylaminomethanephosphonic acid having a melting point of 165° to 170° C. were obtained. A further 2 g were isolated from the mother liquor. Altogether, 33.5 g (78% of theory) were thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.BrC[C:32]1[CH:37]=[CH:36][C:35]([C:38]([OH:47])([C:43]([F:46])([F:45])[F:44])[C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(#N)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:32]3[CH:37]=[CH:36][C:35]([C:38]([OH:47])([C:43]([F:44])([F:46])[F:45])[C:39]([F:42])([F:40])[F:41])=[CH:34][CH:33]=3)[CH2:12][CH2:13]2)=[O:7])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)cc2)CC1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reaction time: 8 h
Yield: 54.4 %

Procedure:
tert-Butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate (4.98 mmol, 1.520 g) was dissolved in dichloromethane and trifluoroacetic acid added. The reaction was left overnight and then treated to SCX purification. The intermediate amine was combined with 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4.98 mmol, 1.678 g) and potassium carbonate (4.98 mmol, 0.688 g) in acetonitrile (30 mL) and stirred overnight. The reaction was concentrated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure. Purification by SCX column chromatography and silica chromatography (eluting with ethyl acetate) gave the title compound (1.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:23])=[C:17]([C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:16]=3)[CH:13]=2)[N:8](COC(=O)C(C)(C)C)[N:7]=1.[OH-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[O:23])=[C:17]([C:30](=[O:34])[N:31]([CH3:32])[CH3:33])[CH:16]=3)[CH:13]=2)[NH:8][N:7]=1
Reactant: CN(C)C(=O)c1cc(-c2cnc3c(c2)c(Cc2cccc(Cl)c2)nn3COC(=O)C(C)(C)C)ccc1NC(=O)N1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)c1cc(-c2cnc3[nH]nc(Cc4cccc(Cl)c4)c3c2)ccc1NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.2 %

Procedure:
2,2-Dimethyl-propionic acid 3-(3-chloro-benzyl)-5-{3-dimethylcarbamoyl-4-[(morpholine-4-carbonyl)-amino]-phenyl}-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (180 mg, 0.284 mmol) was dissolved in tetrahydrofuran (10 ml). 1 M sodium hydroxide in methanol (3.0 ml) was added to the mixture, and the reaction was stirred for 2 hours at room temperature. The reaction was quenched with sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried, filtered, and concentrated. The crude material was purified by mass-triggered reverse-phase HPLC to give 18 mg (12%) of morpholine-4-carboxylic acid {4-[3-(3-chloro-benzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-2-dimethylcarbamoyl-phenyl}-amide. 1H-NMR (250 MHz, DMSO-d6) δ 13.48 (s, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.77 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 7.79-7.71 (m, 2H), 7.64 (s, 1H), 7.47 (s, 1H), 7.34-7.20 (m, 3H), 4.35 (s, 2H), 3.66-3.56 (m, 4H), 3.43-3.35 (m, 4H), 2.98 (s, 6H); MS: m/z 519.2 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][C@@H:16]([C:18]3[CH:32]=[CH:31][C:21]([O:22][CH2:23][C@@H:24]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[CH3:25])=[CH:20][CH:19]=3)[C@@H:15]([C:33]3[CH:38]=[CH:37][C:36]([O:39][Si](C(C)C)(C(C)C)C(C)C)=[CH:35][CH:34]=3)[S:14][C:13]=2[CH:50]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.CCOC(C)=O.O.[Pd]>[OH:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:15]2[S:14][C:13]3[CH:50]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=3[O:17][C@H:16]2[C:18]2[CH:32]=[CH:31][C:21]([O:22][CH2:23][C@@H:24]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH3:25])=[CH:20][CH:19]=2)=[CH:34][CH:35]=1
Reactant: CC(C)[Si](Oc1ccc([C@H]2Sc3cc(OCc4ccccc4)ccc3O[C@H]2c2ccc(OC[C@H](C)N3CCCC3)cc2)cc1)(C(C)C)C(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@@H](COc1ccc([C@@H]2Oc3ccc(O)cc3S[C@@H]2c2ccc(O)cc2)cc1)N1CCCC1
Temperature: 80 °C

Procedure:
A stirred mixture of 102 mg (0.14 mmol) of compound 10a, generated in Example 10, Step A, 30.6 mg (0.29 mmol) of palladium black and 181.2 mg (0.29 mmol) ammonium formate in 3 mL of EtOH/EtOAc/H2O (7:2:1) was heated at 80° C. for 2 h. The reaction mixture was filtered through a pad of Celite® to remove the catalyst, washed thoroughly with EtOH/EtOAc/H2O (7:2:1), and the filtrate was partitioned between water and EtOAc. The organic phase was separated, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give the crude product which was used without purification.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14]C)=[O:13])=[N:10][CH:11]=1)[CH:3]([OH:5])[CH3:4].Cl>O.[OH-].[Li+]>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1)[CH:3]([OH:5])[CH3:4]
Reactant: COC(=O)c1ccc(C(O)C(C)O)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(O)C(O)c1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-(1,2-dihydroxypropyl)-2-pyridinecarboxylate (5 mg) in water (0.1 ml), 1N lithium hydroxide (50 μl) was added at room temperature. After stirring for 1 hour at room temperature, the reaction mixture was neutrized with 1N HCl. The solution was applied to a Diaion HP20 (Mitsubishikasei trademark) column and eluted with methanol-water (1:1) to give 5-(1,2-dihydroxypropyl)-2-pyridinecarboxylic acid: white amorphous powder; molecular formula C9H11NO4; LRFAB-MS m/z 196 [M−H]−; 1H-NMR (D3O) δ 8.74 (1 H, d, J=2.2 Hz),8.47(1 H,d, J=8.1 Hz),8.28(1H,dd,J=8.1 and2.2 Hz),4.88(1 H,d,J=4.3 Hz), 4.12 (1 H, dq, J=6.5 and 4.3 Hz), 1.21 (3H, d, J=6.5 Hz).