Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C@@H:9]([CH2:25][OH:26])[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[S:34](Cl)([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C@@H:9]([CH2:25][O:26][S:34]([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35])[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)CC[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H](CCC(=O)OC(C)(C)C)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-5-tert-butoxy-2-(hydroxymethyl)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate (244 mg, 0.63 mmol) in anhydrous DCM (6 mL) was added pyridine (2 mL) and catalytic amount of DMAP, the solution was chilled to 0° C. TsCl (360 mg, 1.88 mmol) was added and stirred at rt overnight. The reaction mixture was diluted with EtOAc (40 mL) and washed with 1 N HCl (two times, 50 ml+20 ml), followed by H2O, aq. NaHCO3, brine, dried over Na2SO4, and filtered. After evaporation, the residue was purified on silica gel column, eluted with 0-20% EtOAc in hexane to afford (S)-tert-butyl 4-((R)-5-tert-butoxy-5-oxo-2-(tosyloxymethyl)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (317 mg, yield 93%). MS ESI +ve m/z 564 (M+Na).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([NH2:22])=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:23](O)([C:25](F)(F)F)=O>C(OC)(OC)(OC)C>[CH3:23][C:25]1[N:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:22]=1
Reactant: Nc1ccc(OCc2ccccc2)nc1Nc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: COC(C)(OC)OC
Product: Cc1nc2ccc(O)nc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(Benzyloxy)-N2-phenylpyridine-2,3-diamine (68 mg, 0.23 mmol) was dissolved in trimethyl orthoacetate (5.0 mL) and TFA (10 μL) was added. The mixture was stirred at room temperature for 2 h and concentrated in vacuo. The benzyl group of the residue was then removed as described in Example 1.11, Step B to give the title compound as a white solid (15 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.35 (s, 1H), 6.51 (d, J=8.6 Hz, 1H), 7.48-7.55 (m, 3H), 7.57-7.63 (m, 2H), 7.84 (d, J=8.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4](=[O:31])[CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[N:10](C(OC(C)(C)C)=O)[C:9]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4](=[O:31])[CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[NH:10][C:9]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccccc2F)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccccc1F

Procedure:
Dissolve 3-[(o-fluorophenacyl)methylamino]-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride (5 mL). Add trifluoracetic acid (3 mL) and stir for 5 hours. Concentrate the reaction in vacuo, dilute with ethyl acetate (100 mL), wash with saturated sodium carbonate, dry over magnesium sulfate, filter and concentrate in vacuo. Recrystallize the residue from ethyl acetate/hexane to yield the title compound (650 mg).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:18]=[C:17]([C:27]([O:29]CC)=[O:28])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=O)C.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:26][C:22]1[CH:21]=[C:20]([N:19]2[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][OH:4])[CH:10]=3)=[CH:16][C:17]([C:27]([OH:29])=[O:28])=[N:18]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc(-c2cccc(OCCCOC(C)=O)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: O=C(O)c1cc(-c2cccc(OCCCO)c2)n(-c2cccc(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 67A in analogy to the synthesis of the compound of Example 71A. 99 mg of the title compound with 65% purity (70% of theory) are obtained.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:19][C:20]2[CH:21]=[N:22][C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3C)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[OH-].[Na+].[CH2:35]1COCC1.CO>>[CH3:17][CH:16]([CH3:18])[CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:32])=[O:31])=[CH:9][CH:10]=1)[NH:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[C:25]([CH3:35])[CH:24]=2
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Nc2cnc3c(C)cccc3c2)cc1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2cc(NC(CC(C)C)c3ccc(C(=O)NCCC(=O)O)cc3)cnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a mixture of 3-{4-[3-Methyl-1-(8-methyl-quinolin-3-ylamino)-butyl]-benzoylamino}-propionic acid methyl ester (12) (49 mg, 0.11 mM) in 1:1 mixture of THF/MeOH (1 mL) was added 1N NaOH solution (0.283 mL, 0.283 mM). The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated to remove organic solvent. The aqueous solution was diluted with DCM (5 mL), acidified by 1N HCl solution to pH=3-4. The organic solution was separated and the aqueous solution was extracted with 10% i-PrOH-DCM (3×5 mL). The combined organic solution were dried (Na2SO4) and concentrated to give a yellow solid product (˜78%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.93 (d, J=6.59 Hz, 3H) 0.98 (d, J=6.59 Hz, 3H) 1.53-1.60 (m, 1H) 1.70 (dt, J=13.72, 6.68 Hz, 1H) 1.76-1.83 (m, 1H) 2.43 (s, 3H) 2.47 (t, J=7.07 Hz, 2H) 3.35-3.46 (m, 2H) 4.65 (t, 1H) 7.23 (br. s., 1H) 7.37 (d, J=8.54 Hz, 1H) 7.41 (br. s., 1H) 7.54 (d, J=8.29 Hz, 2H) 7.59-7.67 (m, 2H) 7.76 (d, J=8.29 Hz, 2H) 8.43 (t, J=5.49 Hz, 1H) 8.61 (d, J=2.68 Hz, 1H), one proton was exchanged. LC-MS: m/z 420.2 (M+1).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:20]C(N[C@H](C(O)=O)CO)=O)(C)(C)C.NCC(OC(C)(C)C)=O>C(Cl)Cl>[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Dicyclohexylcarbodiimide (6.81 g) is added to a solution, cooled to 5° C., of N-t-butoxycarbonyl-L-serine (6.16 g) and t-butyl glycinate (3.93 g) in methylene chloride (100 cc). The reaction mixture is stirred for 30 minutes at 5° C. and then for 18 hours at about 20° C. The precipitate of dicyclohexylurea formed is filtered off and washed twice with methylene chloride (40 cc in total). The combined organic phases are washed successively 3 times with a saturated solution of sodium bicarbonate (90 cc in total) and twice with water (60 cc in total), dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields an oil (10.22 g) which is chromatographed on neutral silica gel (0.04-0.063 mm) (100 g) contained in a column of diameter 3.4 cm. Elution is carried out successively with a cyclohexane/ethyl acetate mixture (1/1 by volume) (500 cc) and a cyclohexane/ethyl acetate mixture (1/3 by volume) (600 cc), 100 cc fractions being collected. Fractions 5 to 8 are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. This yields t-butyl N-t-butoxycarbonyl-L-seryl-glycinate (2.64 g) in the form of an oil which crystallises slowly.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][CH2:18][C:19](Br)=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[B-](F)(F)F.[K+].C(N(CC)CC)C.C(Cl)Cl>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(O)C>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][CH2:18][C:19]([C:31]2[C:30]([F:29])=[CH:35][CH:34]=[CH:33][C:32]=2[F:36])=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(F)c1[B-](F)(F)F
Reactant: O=C(N[C@H]1CC[C@H](OCC(Br)=Cc2ccccc2)CC1)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H](OCC(=Cc2ccccc2)c2c(F)cccc2F)CC1)OCc1ccccc1

Procedure:
A stirred mixture of 1.8 g of trans-[4-(2-bromo-3-phenyl-allyloxy)-cyclohexyl]-carbamic acid benzyl ester, 0.9 g of potassium 2,6-difluorophenyltrifluoroborate (G. A. Molander and B. Biolatto, Journal of Organic Chemistry, (2003), 68, 4302-4314), 1.8 mL of triethylamine, 0.30 g of PdCl2(dppf).CH2Cl2, 50 mL of ethanol was heated to reflux for 12 h. The mixture was cooled and partitioned between 10 mL of water and 50 mL of chloroform The chloroform extract was washed with 50 mL of saturated sodium carbonate, 50 mL of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. Chromatography over silica gel eluting with a gradient of 10%-25% ethyl acetate in hexane gave 1.1 g of product as a white crystalline solid: MS (m+1)=478.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]3[C:20]4[C:27]5[CH2:28][CH2:29][CH2:30][CH2:31][C:26]=5[S:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:14][CH2:13]2)([CH3:11])[C:9]#N)[CH:5]=[CH:6][CH:7]=1.C[Mg+].[Br-].C(OCCCC)CCC.[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]([N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19]3[C:20]4[C:27]5[CH2:28][CH2:29][CH2:30][CH2:31][C:26]=5[S:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:16][CH2:17]2)([CH3:11])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C#N)(c1cccc(F)c1)N1CCC(Nc2ncnc3sc4c(c23)CCCC4)CC1
Agent: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Solvent: CCCCOCCCC
Solvent: C1CCOC1
Product: CC(C)(c1cccc(F)c1)N1CCC(Nc2ncnc3sc4c(c23)CCCC4)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
2-(3-Fluorophenyl)-2-(4-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl amino)piperidin-1-yl)propanenitrile (435 mg, 1 mmol) was dissolved in dry THF (20 mL) and was added 1 M solution of MeMgBr in butyl ether (1.7 mL, 12 mmol) at 0° C. The reaction was stirred at room temperature for 3 h. The mixture was poured into a cold saturated NH4Cl solution (10 mL) and extracted with DCM (2×25 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4 and evaporated under reduced pressure. Purification by silica chromatography (2% MeOH-DCM) afforded the title compound (331 mg, 78%). 1H NMR (400 MHz, CDCl3): δ 7.94 (s, 1H), 7.29-7.21 (m, 3H), 6.83 (t, 1H), 3.81-3.72 (m, 1H), 3.08-3.01 (m, 2H), 2.81 (t, 2H), 2.36-2.20 (m, 4H), 1.96-1.95 (m, 4H), 1.31 (s, 3H), 1.30 (s, 3H). MS (ESI) m/z: Calculated: 424.5; Observed: 425.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:9][C:10](O)=[O:11])[N:7]=[N:8][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[CH:17]=1.C(Cl)(=O)C(Cl)=O.[F:31][C:32]([F:41])([F:40])[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[NH2:39]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:9][C:10]([NH:39][C:38]3[CH:37]=[CH:36][N:35]=[CH:34][C:33]=3[C:32]([F:41])([F:31])[F:40])=[O:11])[N:7]=[N:8][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[CH:17]=1
Reactant: Nc1ccncc1C(F)(F)F
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)Nc2ccncc2C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
To a suspension of [5-chloro-4-(3-chloro-5-cyanophenoxy)-1H-1,2,3-benzotriazol-1-yl]acetic acid (15 mg, 0.041 mmol) (see step 2 in Example 16) in DCM (0.5 mL) was added oxalyl chloride (58 mg, 0.454 mmol), followed by addition of DMF (1 drop) and then, following bubbling cessation, by addition of 3-(trifluoromethyl)pyridin-4-amine (201 mg, 1.239 mmol). After 10 minutes, the reaction mixture was concentrated, taken up in MeOH/DMSO, and purified by reverse phase chromatography eluting with 30-95% MeCN/H2O+0.1% TFA. Product fractions were lyophilized to yield the title compound. 1H NMR (CDCl3) δ 8.1 (m, 3H), 8.50 (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.55 (m, 2H), 7.41 (m, 1H), 7.27 (m, 1H), 7.07 (s, 1H), 5.60 (s, 2H). HRMS (M+1)=507.0363
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH3:11]I.[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:11])[C:9]#[N:10]
Reactant: N#CCc1ccccc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)c1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18.9 g (96.41 mmol) of (2-bromophenyl)-acetonitrile and 31.41 g (221.74 mmol) of methyl iodide are dissolved in 150 ml of N,N-dimethylformamide. At 0° C., 8.87 g (221.74 mmol) of sodium hydride (as 60% suspension in oil) is added in portions, and the batch is stirred overnight at room temperature. The reaction mixture is poured into ice water and worked up as usual. Since the compound that is isolated after chromatography (20.9 g) still contains 2-(2-bromophenyl)-propionitrile in addition to the desired product, the entire amount is reacted another time with the same amounts of reagent. This reaction also yields only material that still contains mono-methyl compound. After another alkylation with 15 g of methyl iodide and 4.45 g of sodium hydride in 150 ml of N,N-dimethylformamide, 18.57 g of the desired compound is isolated.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(OCC)(=O)C>[CH3:17][S:18]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1cccc(O)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.8 %

Procedure:
To a mixture of 3-hydroxybenzaldehyde (25.31 g), triethylamine (23.07 g) and ethyl acetate (500 mL) was added methanesulfonyl chloride (26.12 g) at 0° C. The mixture was stirred at room temperature for 15 hrs. The reaction mixture was washed successively with water, 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-formylphenyl methanesulfonate as a pale-yellow oil (41.40 g, yield 100%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:44][CH2:45][C:46]1[N:47]=[CH:48][N:49]([C:51]2[CH:56]=[CH:55][C:54]([N:57]3[CH2:62][CH2:61][CH2:60][CH2:59][C:58]3=[O:63])=[CH:53][CH:52]=2)[CH:50]=1>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:44][CH2:45][C:46]2[N:47]=[CH:48][N:49]([C:51]3[CH:52]=[CH:53][C:54]([N:57]4[CH2:62][CH2:61][CH2:60][CH2:59][C:58]4=[O:63])=[CH:55][CH:56]=3)[CH:50]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1cn(-c2ccc(N3CCCCC3=O)cc2)cn1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1cn(-c2ccc(N3CCCCC3=O)cc2)cn1)c1ccc(Cl)s1
Reaction time: 0.08 h
Yield: 60.3 %

Procedure:
To a solution of 5-chloro-thiophene-2-carboxylic acid 1-5 (43 mg, 0.26 mmol) and triethylamine (0.200 mL, 1.43 mmol) in DMF (2 mL), BOP (130 mg, 0.29 mmol) was added. After 5 min of stirring, the solution was added to a solid sample of 1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)piperidin-2-one (54 mg, 0.18 mmol) in a flask. After being stirred at room temperature for 2 h, the mixture was purified by HPLC to give the titled compound (45 mg). MS 415.1 and 417.1 (M+H, Cl pattern).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([O:23]CC)=[O:22])=[CH:14][C:12]=2[CH:13]=1.[OH-].[Na+]>C(O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([OH:23])=[O:22])=[CH:14][C:12]=2[CH:13]=1
Reactant: CCOC(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C(=O)O)c3)ccc2o1
Temperature: 55 °C

Procedure:
The product from Example 143C (755 mg, 2 mmol) was dissolved into ethanol (20 mL) and treated with 2 M aqueous NaOH (2 mL). The mixture was heated at 55° C. for 40 minutes, cooled to room temperature, concentrated, and partitioned between isopropanol and a mixture of 1 M aqueous potassium dihydrogen phosphate and brine. The aqueous phase was separated and extracted with isopropanol, and the combined organic phases were washed with a mixture of pH 6 potassium phosphate buffer and brine. The aqueous phase was separated and extracted with isopropanol, and the combined organic phases were washed with brine. Again, the aqueous phase was separated and extracted with isopropanol, and the combined organic phases were diluted with EtOAc, and filtered. The filtrate was dried (Na2SO4) and concentrated. The residue was chromatographed on silica with 50% EtOAc/CH2Cl2, followed by 10% MeOH/45% EtOAc/CH2Cl2, followed by 30% MeOH/CH2Cl2. The appropriate fractions were concentrated and the residue dissolved into EtOAc/CH2Cl2, and the solids which precipitated were washed with additional EtOAc/CH2Cl2 to provide the title compound as a white powder. MS (ESI APCI) m/z 350 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.39 (s, 3H), 1.58-1.76 (m, 1H), 1.91-2.10 (m, 2H), 2.16-2.31 (m, 1H), 2.89-3.04 (m, 1H), 3.08-3.3 (m, 4H), 3.50-3.71 (m, 2H), 6.70 (s, 1H), 7.39-7.59 (m, 3H), 7.69 (d, 1H), 7.79 (s, 1H), 7.92 (d, 1H), 8.23 (s, 1H).]
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([CH3:18])[C:15]([CH3:17])=[CH:16][C:8]=3[NH:7][C:6]=2[N:19]=1.[H-].[Na+].[CH3:22]I>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:22])[C:9]3[CH:13]=[C:14]([CH3:18])[C:15]([CH3:17])=[CH:16][C:8]=3[NH:7][C:6]=2[N:19]=1
Reactant: CI
Reactant: Cc1ccc2c(n1)Nc1cc(C)c(C)cc1NC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)Nc1cc(C)c(C)cc1N(C)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture consisting of 38 gm (0.15 mol) of 6,11-dihydro-2,8,9-trimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 300 ml of dimethyl formamide and 8.4 gm (0.18 mol) of 50% sodium hydride in mineral oil was stirred at room temperature in a nitrogen atmosphere for 30 minutes. Then, a solution of 31.4 gm (0.22 mol) of methyl iodide in 50 ml of dimethyl formamide was added dropwise, and the mixture was heated on an oil bath at 100° C. for 2 hours while stirring. The mixture was then evaporated in vacuo, ice was added to the oily residue, and the mixture was stirred until the residue crystallized. The crystals were collected by suction filtration and recrystallized from n-propanol, yielding 65% of theory of the compound named in the heading, which had a melting point of 217°-219° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[N:21][C:20]([CH3:23])=[CH:19][N:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13]>Br>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([OH:16])([C:17]1[CH:22]=[N:21][C:20]([CH3:23])=[CH:19][N:18]=1)[C:12]([F:15])([F:13])[F:14]
Reactant: COc1ccc(C(C)C(O)(c2cnc(C)cn2)C(F)(F)F)c(Cl)c1
Agent: Br
Product: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Temperature: 0 °C
Yield: 74.6 %

Procedure:
A solution of 3-(2-chloro-4-methoxy-phenyl)-1,1,1-trifluoro-2-(5-methyl-pyrazin-2-yl)-butan-2-ol (Example 1, 60 mg, 0.17 mmol) in aqueous HBr (48%, 2 mL) was refluxed for 3 h. The reaction mixture was poured into ice/water, and extracted (ethyl acetate). The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was taken up in methanol and purified (reversed-phase, preparative HPLC, Agilent Zorbax XdB-C18 column, solvent gradient 5-95% CH3CN in 0.1% TFA[aq]) to give the title compound (44 mg). MS (m/e)=347.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[N:6][CH:7]=1.CO[CH:34]1[CH:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:37][CH:36](OC)O1>C(O)(=O)C>[C:15]([C:12]1[N:13]=[CH:14][C:9]([NH:8][C:5]2[CH:4]=[C:3]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]3)[C:2]([N:1]3[CH:36]=[CH:37][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:34]3)=[CH:7][N:6]=2)=[N:10][CH:11]=1)#[N:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)C1
Reactant: CCOC(=O)C1CC(OC)OC1OC
Solvent: CC(=O)O
Product: CCOC(=O)c1ccn(-c2cnc(Nc3cnc(C#N)cn3)cc2NCC2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 80 °C
Reaction time: 6.5 h

Procedure:
tert-Butyl 3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (163 mg, 0.384 mmol) (Synthesis 101-C) and ethyl 2,5-dimethoxy-tetrahydrofuran-3-carboxylate (196 mg, 0.96 mmol) were dissolved in acetic acid (4 mL) and the solution was stirred at 80° C. for 6.5 h. The reaction mixture was evaporated to dryness and the residue was used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=1>>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: Cc1ccc(CO)cc1
Product: Cc1ccc(COc2ccnn2-c2cc(C#N)ccn2)cc1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.36 (3H, s), 5.20 (2H, s), 5.74 (1H, s, J=1.6 Hz), 7.19-7.32 (4H, m), 7.38 (1H, dd, J=1.2 Hz, J=4.8 Hz), 7.56 (1H, s, J=1.2 Hz), 8.02 (1H, s), 8.70 (1H, s, J=4.8 Hz). [M+H] Calc'd for C17H14N4O, 291; Found, 291.