Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[CH2:25]([O:27][C:28]([CH:30]1[NH:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]1)=[O:29])[CH3:26].C(N(CC)CC)C>C(O)C>[CH2:25]([O:27][C:28]([CH:30]1[N:35]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:6]3[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:31]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
6-Chloro-9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purine I-(4A-7)c (103 mg, 0.27 mmol), piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (Chiu, C. K.-F. and Griffith, D. A., EP 1004583 A2; 156 mg, 0.60 mmol), and triethylamine (95 μl, 0.68 mmol) were combined in ethanol (1.5 ml) and heated at 60° C. until complete by TLC (3 days). The reaction mixture was concentrated under reduced pressure and then purified on a Biotage™ Flash 12M column using 20 to 30% ethyl acetate in hexanes as eluant to afford title compound I-(8A-1)a (78 mg, 48%): +ESI MS (M+1) 597.3; 1H NMR (400 MHz, CD3OD) δ 8.298 (br s, 1H), 7.57 (br s, 1H), 7.48–7.25 (m, 7H), 5.60 (v br s, 1H), 4.67 (d, J=13.7 Hz, 1H), 4.23–4.05 (br m, 3H), 3.43–3.00 (br m, 2H), 1.46 (s, 9H), 1.22 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:18]([Cl:21])=[CH:19][CH:20]=1)[NH2:17]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[C:18]([Cl:21])=[CH:19][CH:20]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: COc1ccc(Cl)c(Nc2ccccc2CC(=O)O)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-methoxy-6-chloroaniline to yield 2-[(3-methoxy-6-chlorophenyl)amino]phenylacetic acid.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OCC3C=CC=CC=3)=O)[CH2:8][C@@H:9]([O:10][S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:10][C@@H:9]2[CH2:8][NH:7][C@@H:6]3[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OCc3ccccc3)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reaction time: 1.75 h
Yield: 89 %

Procedure:
Preparation of (3R,3aR,6R,6aS)-Benzyl 3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (34b). Ethanol (1.5 mL) was added dropwise to a mixture of 10% palladium on charcoal (10 mg) and anti-(33b) (12.0 mg, 0.028 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 1.75 hours before filtering the mixture through celite in vacuo. The filter cake was washed with ethanol (7.5 mL) then the solvents removed in vacuo from the filtrate. The residue was azeotroped with toluene (2 mL) to obtain (3R, 3aR,6R,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl 4-methylbenzenesulfonate (7.6 mg, 89%) as a pale yellow oil which was used without further purification. TLC (Rf=0.01, EtOAc:heptane 1:1), HPLC-MS 300.1 [M+H]+, 621.2 [2M+Na]+.
Reaction SMILES: C(N(CC)[C:4]([CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH2:17][C@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[O:5])C.[OH-:30].[K+]>O.C(O)C>[C:23]([O:22][C:21]([NH:20][C@H:18]([CH3:19])[CH2:17][C:13]1[C:12]2[C:16](=[C:8]([O:7][CH2:6][C:4]([OH:30])=[O:5])[CH:9]=[CH:10][CH:11]=2)[NH:15][CH:14]=1)=[O:27])([CH3:24])([CH3:26])[CH3:25]
Reactant: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)NC(=O)OC(C)(C)C)c[nH]c12
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[C@H](Cc1c[nH]c2c(OCC(=O)O)cccc12)NC(=O)OC(C)(C)C
Yield: 99 %

Procedure:
A solution of tert-butyl (R)-[2-(7-diethylcarbamoylmethoxy-1H-indol-3-yl)-1-methylethyl]carbamate (0.35 g, 0.87 mmol) and potassium hydroxide (0.39 g, 7 mmol) in water (4 mL) and ethanol (6 mL) is stirred at 60° C. for 8 hours. After cooling, the mixture is concentrated and acidified by addition of water (30 mL) and acetic acid. The resultant is extracted with chloroform, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give the desired (R)-[3-(2-(tert-butoxycarbonylamino)propyl)-1H-indol-7-yloxy]acetic acid (0.30 g, yield: 100%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([O:13]CC)=O.[CH3:16][NH2:17]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:17][CH3:16])=[O:13]
Reactant: CN
Reactant: CCOC(=O)c1cc2ccccc2n1C
Product: CNC(=O)c1cc2ccccc2n1C
Temperature: 80 °C

Procedure:
A mixture of ethyl 1-methylindole-2-carboxylate (4.06 g, 20 mmol) and methylamine (50 mL) was heated at 80° C. in a sealed glass vessel overnight. The reaction was cooled and the title compound (2.4 g, 64%) was collected by filtration as a colorless solid. MS (ES) m/e 189.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])([O-])=O.CO>O=[Pt]=O.C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][N:15]1[C:16](=[O:25])[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]1=[O:24]
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
Combine a mixture of 2-(2-(5-nitro-1H-indol-3-yl)ethyl)isoindole-1,3-dione (1.8 g, 5.4 mmol), PtO2 (500 mg), 100 mL MeOH and 100 mL THF and hydrogenate at atmospheric pressure overnight. Filter the reaction through a pad of celite and concentrate to dryness. Redissolve the residue in 50/50 chloroform/dichloromethane and refilter through a pad of celite. Concentration under vacuum give the title compound as a dark solid: ISMS 306 (M+1); Analysis for C18H13N3O4 0.1C7H8 0.2 dichloromethane: calcd: C, 68.70; H, 4.89; N, 12.58; found: C, 69.08; H, 4.75; N, 12.69; 1H NMR (CDCl3) 7.9–7.8 (m, 3H), 7.75–7.65 (m, 2H), 7.2–7.1 (m, 1H), 7.05–7.0 (m, 2H), 6.7–6.6 (m, 1H), 4.0–3.9 (m, 2H), 3.4 (bs, 2H), 3.1–3.0 (m, 2H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([C:10]#[N:11])=[CH:8][N:7]=[C:6]([Cl:12])[N:5]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]=[C:22]=[O:23].Cl>C(OCC)(=O)C.CN(C)C=O>[Cl:12][C:6]1[N:5]=[C:4]2[NH:3][C:22](=[O:23])[N:21]([C:15]3[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:20])[C:10](=[NH:11])[C:9]2=[CH:8][N:7]=1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: N#Cc1cnc(Cl)nc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.1 %

Procedure:
1.12 g of sodium hydride was added to an N,N-dimethylformamide (35 mL) solution of 3.0 g of 4-amino-2-chloropyrimidine-5-carbonitrile, and stirred at room temperature for 5 minutes. 4.38 g of 2,6-dichlorophenyl isocyanate was added to the reaction liquid, and stirred at room temperature for 1 hour. Ethyl acetate and aqueous 1 N hydrochloric acid solution were added to the reaction solution, and the organic layer was separated. This was washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The precipitated solid was solidified with a mixed solvent of methanol/ethyl acetate and taken out through filtration to obtain 3.8 g of the entitled compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[Cl-].[Li+]>C1(C)C=CC=CC=1>[CH2:14]([C:2]1[CH:11]=[CH:10][C:9]2[C:7](=[O:8])[O:6][CH2:5][C:4]=2[CH:3]=1)[CH:13]=[CH2:12]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1OCc2cc(Br)ccc21
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1)COC2=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A 4-neck, 22-L, round bottom flask equipped with a mechanical stirrer, thermocouple, nitrogen bubbler, and condenser was charged with 5-bromophthalide (650 g, 3.0 mol), allyltri-n-butyltin (1200 g, 3.6 mol), palladium tetrakis triphenylphosphine (100 g, 0.089 mol), lithium chloride (250 g, 5.9 mol) and toluene (8.8 L). The mixture was evacuated and flushed with nitrogen 3 times and then was stirred at 100° C. for 4 hours. After slowly cooling to ambient temperature, the mixture was filtered and concentrated. The resulting solid was purified by silica gel column chromatography (heptane:ethyl acetate, 0→40%) to provide 5-(prop-2-en-1-yl)-2-benzofuran-1(3H)-one.
Reaction SMILES: [P:1](Cl)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:17]([CH2:20][CH3:21])CC>C(Cl)Cl>[P:1]([N:17]([P:1]([N:17]([P:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20][CH3:21])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCN(P(c1ccccc1)c1ccccc1)P(c1ccccc1)N(CC)P(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 130 %

Procedure:
A solution of PPh (NHEt)2 (0.301 g, 1.5 mmol) in CH2CH2 (20 cm3) was added to PPh2Cl (0.677 g, 3.0 mmol) dissolved in CH2Cl2 (5 cm3) containing NEt3 (0.466 g, 4.6 mmol) and stirred for two hours. The solvent was removed in vacuo affording an off white solid. The solid was washed with 3×20 cm3 aliquots of diethylether, the washings combined and the solvent then removed in vacuo yielding a white solid characterised as Ph2PN(Et)P(Ph)N(Et)PPh2 (0.540 g, 1.3 mmol) 31P [H] NMR (CD2Cl2)=53.5 [d, PPh2, 2P, J (PP)25]. 105.1 [t, PPh, J(PP) 25 Hz] ppm.
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)=[O:14])=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:33]=[N:34][NH:35][N:23]=3)[CH:17]=2)=[O:14])=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2cccc(C(=O)Nc3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCc2cccc(C(=O)Nc3cccc(-c4nn[nH]n4)c3)c2)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
Heat a mixture of 3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-N-(3-cyano-phenyl)-benzamide, sodium azide (1.12 g, 17.3 mmol), and ammonium chloride in dimethylformamide at 110 C for 24 hours. Cool to room temperature and dilute with water. Filter and wash several times with water. Dry filtered material and dissolve in hot acetone. Purify the resulting solution via chromatography, eluting with hexanes:acetone with 1% acetic acid to afford the title compound. 1H NMR (DMSO-d6) δ 0.88 (t, 3H), 1.52 (sextet, 2H), 2.58 (s, 3H), 2.62 (t, 2H), 5.37 (s, 2H), 6.76 (d, 1H), 7.57 (d, 1H), 7.61 (d, 1H), 7.68 (d, 1H), 7.74 (d, 1H), 7.82 (d, 1H), 7.97 (m, 2H), 8.09 (m, 1H), 8.59 (s, 1H), 10.56 (s, 1H), 12.85 (s, 1H); MS (APCI-neg mode) m/z (rel intensity) 470 (100).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8]>CCO>[Br:3][C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Sodium borohydride (7.1 g, 186.1 mmol) in several portions was added to a solution of 3-bromobenzaldehyde (114.8 g, 620.4 mmol) in EtOH (650 mL) at 25° C. Then the mixture was stirred for 1 h at room temperature. The reaction was quenched with water (200 mL). After removing EtOH, the residue was dissolved in AcOEt (500 mL), and filtered. The filtrate was washed with water (150 mL), brine (150 mL), and dried over Na2SO4. After removing the solvent, 115.8 g of the title compound was obtained (yield: 99.8%).
Reaction SMILES: [NH2:1]/[C:2](=[N:16]\[OH:17])/[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH3:18][CH2:19]N(C(C)C)C(C)C.C(Cl)(=O)C>C(#N)C>[CH3:18][C:19]1[O:17][N:16]=[C:2]([CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[N:1]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCCC1/C(N)=N/O
Solvent: CC(=O)Cl
Solvent: CC#N
Product: Cc1nc(C2CCCCN2C(=O)OC(C)(C)C)no1
Temperature: 0 °C
Yield: 33.2 %

Procedure:
In a 16 mL vial, tert-butyl 2-[(Z)-amino(hydroxyimino)methyl]piperidine-1-carboxylate (150 mg, 0.62 mmol; which may be prepared as described in Step 1) was dissolved in acetonitrile (6.2 mL) and cooled at 0° C. under nitrogen. DIPEA (324 μL, 1.86 mmol) and acetyl chloride (88 μL, 1.24 mmol) were added dropwise and the reaction mixture was allowed to warm to room temperature then heated to 100° C. for 4 h, cooled and concentrated. The residue was taken up in EtOAc and water. The two layers were separated and the aqueous phase extracted with EtOAc. The combined organics were dried on Na2SO4 and concentrated. The residue was taken up in o-xylene (7 mL) and heated to 150° C. for 3 h then concentrated. The crude mixture was purified on column chromatography (eluent: Pentane/EtOAc 7/3) to give the product (55 mg, 33%) as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24](=[O:38])[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)[CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1.[CH3:39][N:40]=[C:41]=[O:42]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24](=[O:38])[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]2)[CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[C:41]([NH:40][CH3:39])=[O:42])=[CH:2]1
Reactant: COc1ccccc1CNCC(Cc1c[nH]c2ccccc12)NC(=O)CN1CCN(c2ccccc2)CC1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)N(Cc1ccccc1OC)CC(Cc1c[nH]c2ccccc12)NC(=O)CN1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a room temperature solution of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane (0.40 g, 0.78 mmole) in 10 ml of anhydrous tetrahydrofuran was added dropwise methyl isocyanate (140μl, 2.3 mmoles). The resulting mixture was then stirred for 16 hours at room temperature. The tetrahydrofuran was removed in vacuo. The title product was isolated by consecutive washes with ethyl acetate, water, and brine, and then dried over sodium sulfate. Flash chromatography using silica gel and a methanol/methylene chloride (5/95) eluant provided 396 mg of the homogeneous product as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH:10]([N:23]1[C:19](=[O:29])[C:20]2[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:22]1=[O:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCC(O)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C

Procedure:
To a solution of (3-hydroxy-3-phenyl-propyl)-carbamic acid tert-butyl ester (10.4 g, 41.4 mmol), phthalimide (5.2 g, 36.6 mmol), and PPh3 (14.6 g, 55.5 mmol) in THF (204 mL) was added dropwise DEAD (8.9 mL, 55 mmol) with stirring at 0° C. Then the resulting mixture was warmed to room temperature for an additional 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate, 3:1) to give [3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propyl]-carbamic acid tert-butyl ester. (Yield 10.5 g, 66.8%). 1H NMR (300 MHz, CDCl3): δ 7.81-7.75 (m, 2H), 7.69-7.64 (m, 2H), 7.53-7.50 (m, 2H), 7.34-7.23 (m, 3H), 5.44-5.38 (m, 1H), 4.74 (brs, 1H), 3.29-3.07 (m, 2H), 2.83-2.75 (m, 1H), 2.51-2.42 (m, 1H), 1.42 (s, 9H). LC-MS: [M-Boc+H]+ 281.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][N:12]=[CH:11]2)=[CH:5][CH:4]=1)#[N:2].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>C(#N)C>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:9]([N:10]2[CH:11]=[N:12][N:13]=[CH:14]2)[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: BrCc1ccc(Br)cc1
Solvent: CC#N
Product: N#Cc1ccc(N(Cc2ccc(Br)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
40 Milliliters of acetonitrile was added to 3.15 g of 4-[N-(4-cyanophenyl)amino]-4H-1,2,4-triazole, 4.25 g of 4-bromobenzyl bromide and 3.52 g of anhydride potassium carbonate and the mixture was stirred for 2 hours at room temperature. The solvent was removed by distillation under reduced pressure, and water was added to the residue formed, which was then extracted with chloroform. The chloroform layer separated was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography to give crude crystals from the chloroform/methanol (100/1) eluate. The crude crystals were recrystallized from ethanol to give 3.92 g of 4-[N-(4-bromobenzyl)-N-(4-cyanophenyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:29][S:30]([O:26][C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:17]1[S:18][C:14]2[CH:13]=[C:12]([CH2:11][N:8]3[C:5]4=[N:6][CH:7]=[C:2]([F:1])[CH:3]=[C:4]4[N:10]=[CH:9]3)[CH:28]=[CH:27][C:15]=2[N:16]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Reaction time: 15 h
Yield: 44.3 %

Procedure:
To a stirred mixture of (1R,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (517 mg, 1.3 mmol) from Example 162, TEA (194 μL, 1.4 mmol), and CH2Cl2 (15 mL) at rt under argon was added methanesulfonyl chloride (152 μL, 2.0 mmol). After stirring the mixture for 15 h, additional TEA (194 μL, 1.4 mmol) and methanesulfonyl chloride (152 μL, 2.0 mmol) were added. After stirring for an additional 18 h, the mixture was diluted with CH2Cl2 and stirred with saturated aq NaHCO3 (50 mL) for 30 min. The layers were separated and the organic layer was washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with a gradient of 100% hexanes to 100% EtOAc, to afford (1S,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl methanesulfonate (274 mg, 44%) as a clear oil. 1H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.39 (t, J=1.8 Hz, 1H), 8.16 (d, J=7.4 Hz, 1H), 8.04 (dd, J=2.6, 9.5 Hz, 1H), 7.66 (d, J=1.0 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.22 (dd, J=1.4, 8.2 Hz, 1H), 5.46 (s, 2H), 4.98 (m, 1H), 4.06 (m, 1H), 2.99 (s, 3H), 2.01 (m, 1H), 1.54-1.72 (m, 4H), 1.34-1.50 (m, 3H); LCMS (ESI) m/z 476 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])=O.[NH4+]>C(O)C.O.[C].[Pd]>[CH3:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)=Cc1ccccn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)Cc1ccccn1
Yield: 90.9 %

Procedure:
Ethyl 2-methyl-3-(2-pyridyl)acrylate (7.8 g, 41.0 mmol) was dissolved in ethanol (80 ml), and 10% palladium-carbon (1.0 g) and a solution of ammonium formate (11.2 g, 178 mmol) in water (20 ml) was added thereto. The mixture was refluxed for 2 hrs. Palladium-carbon was filtered off. The reaction mixture was combined with water, concentrated under reduced pressure to the half amount and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (7.2 g, 91%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[NH2:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:13])[CH3:12]>[OH-].[Na+]>[CH2:5]([O:4][C:2]([NH:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:3])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
11.2 ml (85.3 mmol) of isobutyl chloroformate are added to a solution of 10 g (85.3 mmol) of (L)-valine in 100 ml of 2N sodium hydroxide solution and the solution is stirred at RT for 18 h. The reaction solution is washed with methylene chloride, acidified with 4N hydrochloric acid and extracted with methylene chloride. The organic extracts are washed with brine and filtered through cotton wadding to yield the title compound in the form of a colourless resin after concentration by evaporation. 1H-NMR (200 MHz, CD3OD): 0.95 (m, 12H), 1.9 (m, 1H), 2.15 (m, 1H), 3.85 (d, J=7 Hz, 2H), 4.05 (d broad, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]12[CH2:11][O:10][CH2:9][CH:8]1[S:7][C:6]([NH2:12])=[N:5]2)[CH3:2].Br[CH2:14][CH2:15][O:16][CH3:17]>>[CH2:1]([O:3][C:4]12[CH2:11][O:10][CH2:9][CH:8]1[S:7][C:6](=[NH:12])[N:5]2[CH2:14][CH2:15][O:16][CH3:17])[CH3:2]
Reactant: COCCBr
Reactant: CCOC12COCC1SC(N)=N2
Product: CCOC12COCC1SC(=N)N2CCOC

Procedure:
The product from Example 125B and 1-bromo-2-methoxyethane were processed using the method described in Example 12A to afford the title compound. MS (ESI+) m/z 247 (M+H)+.