Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[N:13][N:14]=[CH:15][C:16]3[NH:20][C:19]([CH3:21])=[C:18]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=O)=[O:23])[C:17]=3[CH3:33])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.O[C:49]1[C:57]2[N:56]=N[NH:54][C:53]=2[CH:52]=[CH:51][CH:50]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[N:13][N:14]=[CH:15][C:16]3[NH:20][C:19]([CH3:21])=[C:18]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH:54][C:53]4[CH:52]=[CH:51][CH:50]=[CH:49][C:57]=4[NH2:56])=[O:32])=[O:23])[C:17]=3[CH3:33])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3cc(C(F)(F)F)ccc32)c(C)c1C(=O)NCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3cc(C(F)(F)F)ccc32)c(C)c1C(=O)NCCCCCC(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
6-(5-(((6-trifluoromethyl-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-hexanoic acid (491 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (384 mg, 66% yield) as a red solid. LC-MS (m/z) 582 (M+1).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]([O:21][CH2:22][C:23]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:24][OH:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CC(C)=O>[CH2:37]([O:36][CH2:35][C:23]([CH2:22][O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([CH2:26][O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:24]([OH:3])=[O:25])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: OCC(COCc1ccccc1)(COCc1ccccc1)COCc1ccccc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C(COCc1ccccc1)(COCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A Jones reagent (0.984 mmol) was added to 5 mL of a solution of 3-benzyloxy-2,2-bis(benzyloxymethyl)propan-1-ol (200 mg, 0.492 mmol) obtained in the Step A in acetone under ice-cooling, and the mixture was stirred at room temperature for one hour. Water was added to the mixture, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3-benzyloxy-2,2-bis(benzyloxymethyl)propionic acid (206 mg, 100%) as a colorless solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[O:11][C:10]2=[O:28])=[CH:5][CH:4]=1>ClCCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH2:16][CH2:17][CH:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:19][CH2:20]3)[O:11][C:10]2=[O:28])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CC(CN3CCC(Cc4ccccc4)CC3)OC2=O)cc1
Solvent: ClCCCl
Product: O=C1OC(CN2CCC(Cc3ccccc3)CC2)CN1c1ccc(O)cc1
Reaction time: 0.5 h

Procedure:
A suspension of 3.8 g of 3-p-methoxyphenyl-5-(4-benzyl-piperidino-methyl)-oxazolidin-2-one in 50 ml of 1,2-dichloroethane is added dropwise to a boiling solution of 15.6 g of dimethyl sulfide/boron tribromide complex in 50 ml of 1,2-dichloroethane; the mixture is boiled for another 30 minutes and worked up in a conventional manner to give 3-p-hydroxyphenyl-5-(4-benzyl-piperidino-methyl)-oxazolidin-2-one.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][OH:16].CC([O-])(C)C.[K+].Cl>>[F:8][C:7]1[C:2]([NH2:1])=[N:3][C:4]([O:16][CH2:15][C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)=[N:5][CH:6]=1
Reactant: Nc1nc(Cl)ncc1F
Reactant: OCc1cccs1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: Nc1nc(OCc2cccs2)ncc1F
Temperature: 100 °C
Yield: 137.1 %

Procedure:
To a mixture of 4-amino-2-chloro-5-fluoropyrimidine (2.00 g, 13.5 mmol) and thiophen-2-ylmethanol (1.92 g, 16.9 mmol) with a magnetic stir bar in a 20 mL Biotage Initiator microwave reaction vessel was added t-BuOK (17.0 mL of 1M in t-BuOH, 17.0 mmol). The resulting mixture was sealed with a Biotage Initiator microwave septa cap and heated in a Biotage Initiator microwave to 100° C. for 30 min. The heating cycle was repeated (2×) for a total reaction time of 90 min. The contents were poured into ice-water and the pH was adjusted to neutral with 2N HCl. The resulting solid was filtered and washed with water (2×) and then 20% ether/hexanes (100 mL). The remaining solid was dried overnight at 50° C. under vacuum to give 4.17 g (68%) of 5-fluoro-2-(thiophen-2-ylmethoxy)pyrimidin-4-ylamine as a pale yellow powder: mp 92-94° C.; 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J=2.7 Hz, 1H), 7.29 (m, 1H), 7.13 (d, J=3.6 Hz, 1H), 6.97 (m, 1H), 5.46 (s, 2H), 5.17 (br s, 2H); MS (ESI) m/z 226 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH2:24]([OH:29])[CH2:25][CH2:26][C:27]#[CH:28]>>[NH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]2[C:11]([C:28]#[C:27][CH2:26][CH2:25][CH2:24][OH:29])=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=1
Reactant: C#CCCCO
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Product: COc1c(C)cnc(Cn2cc(C#CCCCO)c3c(Cl)nc(N)nc32)c1C

Procedure:
The title compound was prepared by Sonogashira coupling of 4-chloro-5-iodo-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (see Example 1) with 4-pentyn-1-ol according to the General Procedure A. tR: 4.71 min. 1H-NMR (DMSO-d6) δ 8.04 (s, 1H), 7.22 (s, 1H), 6.69 (br. s, 2H), 5.25 (s, 2H), 4.48 (d, 1H), 3.71 (s, 3H), 3.50 (q, 2H), 2.42 (t, 2H), 2.23 (s, 3H), 2.14 (s, 3H), 1.65 (5, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[O:18][CH:19]=[CH:20][N:21]=1)CCC>O1CCOCC1.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:11][C:4]1[CH:3]=[C:2]([C:17]2[O:18][CH:19]=[CH:20][N:21]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Clc1cc(-c2ncco2)nc2c1CCC2
Temperature: 110 °C
Yield: 34.1 %

Procedure:
To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.152 g, 0.81 mmol) in dioxane (3 mL) was added 2-(tributylstannyl)oxazole (0.318 g, 0.89 mmol) and tetrakis(triphenylphosphine)palladium (0.046 g, 0.040 mmol). The mixture was purged with nitrogen and then heated to 110° C. under sealed conditions for 16 h. After this time, the mixture was diluted with water and extracted with ethyl acetate. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.061 g, 34%) as a white solid. MW=220.66. 1H NMR (CDCl3, 500 MHz) δ 7.94 (s, 1H), 7.78 (s, 1H), 7.29 (s, 1H), 3.19 (t, J=7.5 Hz, 2H), 3.06 (t, J=7.5 Hz, 2H), 2.22 (quin, J=7.5 Hz, 2H); APCI MS m/z 221 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[NH:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=3)=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)[N:16]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[NH:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=3)=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)[N:16]=2)=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(C(=O)O)c3)nc2-c2ccc3ncccc3c2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(CO)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
To a suspension of 2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzoic acid (Example 104) (75 mg, 0.171 mmol) in THF (1 mL) was added LAH (1M solution in THF, 342 uL, 0.342 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by addition of ethyl acetate (1 mL) and H2O (3 drops), and the mixture was stirred for 30 min. The mixture was dried over Na2SO4, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by MPLC (MeOH:CH2Cl2=1:50 (v/v) to 1:20 (v/v)) to afford the title compound (16.9 mg, 23%). (300 MHz, CDCl3) δ 2.50 (3H, s), 4.09 (2H, s), 6.64-6.72 (2H, m), 6.91-6.98 (2H, m), 7.31 (1H, d), 7.39 (1H, t), 8.13 (2H, d), 8.41 (1H, s), 8.84 (2H, dd), MS (ESI) m/z 411 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:26][C@@H:27]([OH:31])[C:28]([OH:30])=[O:29])[NH:16][C:17]([C:19]3[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.Cl[CH2:34][O:35][C:36](=[O:46])[C@@H:37]([NH:41][C:42]([O:44][CH3:45])=[O:43])[CH:38]([CH3:40])[CH3:39].[Na+].[I-].N1C=CC=CC=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][N:15]([CH2:26][C@@H:27]([OH:31])[C:28]([O:30][CH2:34][O:35][C:36](=[O:46])[C@@H:37]([NH:41][C:42]([O:44][CH3:45])=[O:43])[CH:38]([CH3:40])[CH3:39])=[O:29])[NH:16][C:17]([C:19]3[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=3)=[O:18])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Reactant: COC(=O)N[C@H](C(=O)OCCl)C(C)C
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)N[C@H](C(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(OC)no1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
A mixture of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (200 mg, 430 mmol), (S)-2-methoxycarbonylamino-3-methylbutyric acid chloromethyl ester (193 mg, 860 mmol), NaI (129 mg, 860 μmol) and pyridine (136 mg, 1.7 mmol) in DMF (5.0 mL) was stirred at 25° C. overnight. The mixture was then poured into water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=1:1) to yield the title compound as a colorless liquid (7 mg). LC-MS: 651.1 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 0.95-0.97 (m, 6H), 2.06-2.14 (m, 1H), 3.34-3.39 (m, 2H), 3.69 (s, 3H), 3.98 (s, 3H), 4.08-4.11 (m, 1H), 4.22-4.24 (m, 2H), 4.38-4.40 (m, 1H), 5.78-5.91 (m, 2H), 6.54 (s, 1H), 7.18-7.22 (m, 1H), 7.34-7.36 (m, 1H), 7.46-7.55 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)(O)[CH2:11][S:10][C:9]2=[S:24])[CH:5]=[CH:6][CH:7]=1>C(O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([NH2:23])(=[O:21])=[O:22])=[CH:18][CH:19]=3)=[CH:11][S:10][C:9]2=[S:24])[CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(C2(O)CSC(=S)N2c2cccc(Cl)c2)cc1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-c2csc(=S)n2-c2cccc(Cl)c2)cc1

Procedure:
5.4 g of the product of Example 7 are dissolved in 50 ml of ethanol to which 1 ml of concentrated hydrochloric acid has been added. The reaction mixture is refluxed for 1 h, then filtered. The solid obtained is washed with ethanol, then with pentane.
Reaction SMILES: [C@@H:1]12[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]1[CH2:4][N:3](C(OCC1C=CC=CC=1)=O)[CH2:2]2>CO.[Pd]>[C@@H:1]12[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]1[CH2:4][NH:3][CH2:2]2
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN(C(=O)OCc3ccccc3)C[C@H]21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]21
Temperature: 25 °C
Reaction time: 10 h
Yield: 92 %

Procedure:
The product of Example 38I (2.3 g, 6.92 mmol) in methanol (30 mL) was treated with 10% palladium on carbon (0.23 g) and stirred at room temperature under H2 (1 atm) for 10 hours. The catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated to provide the title compound as a yellow oil. (1.27 g, 92% yield). 1H NMR (MeOH-d4, 300 MHz) δ 1.46 (s, 9H), 2.47 (dd, J=12.9, 3.7 Hz, 1H), 2.64 (dd, J=12.2, 5.7 Hz, 1H), 2.95 (m, 1H), 3.05 (d, J=12.2 Hz, 1H), 3.24 (d, J=12.5 Hz, 1H), 3.46 (m, 1H), 3.95 (m, 1H), 4.64 (dd, J=6.1, 3.8 Hz, 1H), MS (DCI/NH3) m/z 216 (M+NH4)+, 199 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[N:22]=[C:21]2[C:33]1[CH:38]=[N:37][CH:36]=[C:35](Cl)[N:34]=1>CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[N:22]=[C:21]2[C:33]1[N:34]=[C:35]([O:3][C@@H:4]2[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH:36]=[N:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: Clc1cncc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
NaH (60% in mineral oil, 0.081 g, 2.032 mmol) was added to a solution of (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (0.245 g, 1.219 mmol, Astatech, Inc.) in DMF (2.50 mL) at 0° C. The mixture was stirred for 15 min then 5-bromo-3-(6-chloropyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 1c (0.400 g, 1.016 mmol, Pharmacore) was added and the heterogenous mixture was warmed to RT. After 60 min at RT, ice was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide tert-butyl (3R)-3-((6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-pyrazinyl)oxy)-1-piperidinecarboxylate (0.562 g, 1.006 mmol, 99% yield) as a light-yellow foam. MS (ESI, pos. ion) m/z: 558.0, 560.0 (M+1).
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7]([O:9]C)=[O:8]>C1COCC1.O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccc(N2CCCCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1N1CCCCC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 88.6 %

Procedure:
Lithium hydroxide (2.5 g; 103 mmol; 5 eq.) was added to a solution of methyl 3-methyl-4-piperidin-1-ylbenzoate (4.8 g; 20.6 mmol; 1 eq.) in THF (100 mL) and water (5 mL) and the reaction mixture was stirred at 50° C. for 12 hours. The solvent was removed in vacuo, the residue diluted with water and the aqueous layer washed with DCM (2×50 mL). The aqueous layer was acidified to pH 4 with conc. HCl and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound (4.0 g, 89%) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N+:8]([O-])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].P(Br)(Br)([Br:16])=O>ClCCCl>[Br:16][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=[CH:7][N:8]=1
Reactant: CC(C)(C)c1cc[n+]([O-])cc1
Reactant: O=P(Br)(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CC(C)(C)c1ccnc(Br)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
In a round-bottomed flask, phosphorous oxybromide (5.0 g, 17.4 mmol and 4-tert-butylpyridine N-oxide (0.85 g, 5.34 mmol) were dissolved in 1,2-dichloroethane (35 mL). The reaction mixture was stirred at 70° C. overnight then cooled to room temperature and slowly poured onto ice. Sodium hydroxide (50% solution in water) was added slowly until pH˜10. The mixture was then extracted three times with ˜100 mL dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on 4 g SiO2 and chromatographed over 24 g SiO2 with EtOAc/Hexanes (gradient: 0-10% EtOAc). All fractions containing product were combined and concentrated to give 157 mg (14%) of 2-bromo-4-tert-butyl pyridine as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=3[Cl:20])=[N:8][C:5]2=[N:6][CH:7]=1.O.O.Cl[Sn]Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=3[Cl:20])[NH2:17])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(-c2nc3ncc(Br)cc3[nH]2)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cl)c(-c2nc3ncc(Br)cc3[nH]2)c1
Yield: 73 %

Procedure:
To a suspension of 6-bromo-2-(2-chloro-5-nitrophenyl)-1H-imidazo[4,5-b]pyridine I-2a (18 g, 50.91 mmol, 1.00 equiv) in ethanol (200 mL) was added SnCl2.2H2O (17.3 g, 76.55 mmol, 1.50 equiv) and heated to reflux overnight. The resulting mixture was concentrated under vacuum and the residue was diluted with 200 mL of H2O. The pH value of the mixture was adjusted to 8 with sodium carbonate (sat.). A filtration was performed and the solids were applied on a silica gel column and eluted with ethyl acetate/PE (1/1) to give 12 g (73%) of 3-[6-bromo-1H-imidazo[4,5-b]pyridin-2-yl]-4-chloroaniline (I-2b) as a yellow solid. 1H-NMR (DMSO, 400 MHz): 13.00-13.53 (m, 1H), 8.46 (s, 1H), 8.30 (brs, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.05 (brs, 1H), 6.76 (dd, J=8.4, 2.8 Hz, 1H), 5.57 (brs, 2H). MS M/Z=325 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)Cl.CO[CH:26](OC)[CH2:27][NH2:28].C(O)(C)C>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:26]=[CH:27][N:28]=[C:10]2[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COC(CN)OC
Reactant: COc1ccc(NC(=O)c2ccncc2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(C)O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-n2ccnc2-c2ccncc2)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
Preparation 87 (N-(4-methoxyphenyl)isonicotinamide, 1 g, 4.39 mmol) was dissolved in phosphorous oxychloride (POCl3) (5 mL) then phosphorous pentachloride (913 mg, 4.39 mmol) was added. The mixture was heated at 120° C. for 4 h. The POCl3 was removed in vacuo, aminoacetaldehyde dimethyl acetal (9.5 mL, 87.8 mmol) and isopropanol (10 mL) were added, and the mixture was stirred at 23° C. for ca. 16 h. The reaction mixture was concentrated in vacuo and concentrated hydrochloric acid (36.5%, 25 mL) in isopropanol (15 mL) was added. The reaction mixture was heated at 90° C. for 24 h. After cooling to 23° C., aqueous sodium hydroxide (1N) and aqueous sodium bicarbonate were added to obtain pH=8. The mixture was extracted with methylene chloride, was dried (MgSO4), and was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/hexanes/methanol (80:20:0 to 76:19:5) to afford 811 mg (74% yield) of the title compound; diagnostic 13C NMR signals (100 MHz, CDCl3) δ 160.069, 149.952, 144.142, 137.853, 131.004, 129.882, 127.414, 124.977, 122.195, 115.114, 55.808; MS (AP/CI) 252.4 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[C:8]([Cl:14])[CH:7]=1)=[O:5].[OH-].[Na+].Cl>C1(C)C=CC=CC=1>[Cl:14][C:8]1[CH:7]=[C:6]([C:4](=[O:5])[C:3]([OH:15])=[O:2])[CH:11]=[CH:10][C:9]=1[S:12][CH3:13]
Reactant: COC(=O)C(=O)c1ccc(SC)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CSc1ccc(C(=O)C(=O)O)cc1Cl
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
A solution of (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid methyl ester (61.7 g, 252 mmol) in toluene (120 mL) was heated at 50° C. This heated solution was then treated dropwise with a 3M aqueous sodium hydroxide solution (105 mL, 313 mmol) via a dropping funnel, taking care to keep the temperature below 60° C. After the addition was complete, the reaction mixture was stirred at 50° C. for another 1.5 h, during which time, a yellow precipitate began to form. After this time, the heat was removed, and the warm solution was treated dropwise with concentrated hydrochloric acid (10.6 mL, 290 mmol). The resulting reaction mixture was allowed to cool to 25° C. and then was stirred at 25° C. for 16 h. The solid was filtered and then washed with water (50 mL) and toluene (50 mL). The solid was dried by suction for 1 h and then dried in a high vacuum desiccator to afford (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid (57.22 g, 98%) as a white solid: mp 166° C. (dec); FAB-HRMS m/e calcd for C9H7ClSO3 (M+Na)+ 252.9702, found 252.9700.