Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:14]C[C:16](Cl)=[O:17].[C:19]([CH2:21][CH2:22][NH:23][CH3:24])#[N:20].[ClH:25].Cl.COCC(NC(=O)CN1CCNCC1)C>>[ClH:14].[ClH:25].[C:19]([CH2:21][CH2:22][N:23]([CH3:24])[C:16](=[O:17])[CH2:6][N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)#[N:20]
Reactant: CNCCC#N
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)CCl
Agent: COCC(C)NC(=O)CN1CCNCC1
Agent: Cl
Product: CN(CCC#N)C(=O)CN1CCNCC1

Procedure:
N-(2-Cyano-ethyl)-N-methyl-2-piperazin-1-yl-acetamide dihydrochloride was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and N-(2-cyanoethyl)-N-methylamine in an analogous manner as described for the preparation of N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide dihydrochloride (example 40).
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:14][CH2:15][CH3:16]>>[CH2:18]([N:17]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCC1CO1
Reactant: CCCCNCCCCCCNCCCC
Product: CCCCCCCCCC(O)CN(CCCC)CCCCCCN(CCCC)CC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and N,N'-dibutylhexamethylenediamine affords N,N'-(1,6-hexylene)-bis[N-butyl-2-hydroxyundecylamine] (I: R= CH3 (CH2)8, R' = CH3 (CH2)3, X= (CH2)6, Z= H).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[NH:5][CH:6]=[N:7]2.[CH3:16][NH2:17]>CO>[CH3:16][NH:17][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[NH:5][CH:6]=[N:7]2
Reactant: O=c1[nH]cnc2ccc([N+](=O)[O-])c(Cl)c12
Reactant: CN
Solvent: CO
Product: CNc1c([N+](=O)[O-])ccc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-Chloro-6-nitroquinazolin-4-one, from Example 3 (0.26 g, 1.15 mmol) was suspended in MeOH (3 mL) at −20° C. Methylamine gas was passed into the mixture for a few minutes, resulting in a clear solution. The solution was stirred at room temperature for 5 h and evaporated to give 5-methylamino-6-nitroquinazolin-4-one in quantitative yield. The above amine (350 mg, 1.6 mmol) was hydrogenated over platinum oxide (30 mg) in MeOH (200 mL) at 60 psi for 4 h. The mixture was filtered through diatomaceous earth and the solvent evaporated, to give 6-amino-5-methylaminoquinazolin-4-one, which was immediately suspended in EtOAc (20 mL) and THF (10 mL). A solution of 2,6-dichlorophenylisothiocyanate (340 mg, 1.67 mmol) in EtOAc (5 mL) was added, and the mixture stirred for 16 h. The reaction mixture was concentrated to half the volume, filtered, and the solid washed with EtOAc to yield the thiourea (400 mg, 64% over 2 steps.)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]2.CCN(C(C)C)C(C)C.[CH2:27]([SH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:27]([S:34][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]2)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: SCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(Br)cc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2ccc(SCc3ccccc3)cc2C1
Temperature: 90 °C
Yield: 92.1 %

Procedure:
To a solution of tert-butyl 5-bromoisoindoline-2-carboxylate (2 g, 6.71 mmol) in 1,4-dioxane (17.1 mL) in a round bottom flask was added Pd2(dba)3 (0.154 g, 0.168 mmol), xantphos (0.194 g, 0.335 mmol), DIPEA (2.343 mL, 13.41 mmol) and benzyl mercaptan (0.873 mL, 7.38 mmol) and the resulting mixture was stirred and heated at 90° C. under nitrogen for overnight. The reaction mixture was filtered through celite, rinsed with ethyl acetate and the filtrate concentrated in vacuo. The residue was purified on silica gel, eluting with ethyl acetate in cyclohexane (0-20%) to afford the title compound (2.11 g). LCMS (A): m/z [(M-tBu)+H]+ 286, C20H23NO2S requires 341 (acidic).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:17][CH2:18][OH:19])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:33]([O:37][C:38](=O)[CH2:39][OH:40])(=O)[CH2:34][OH:35].C[OH:43]>C(Cl)Cl>[CH2:10]([NH+:15]([CH2:20][CH3:21])[CH2:16][CH3:17])[CH3:9].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:17][CH2:18][O:19][C:34]([CH2:33][O:37][CH2:38][C:39]([O-:40])=[O:43])=[O:35])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccccc2N(CCCO)c2ccccc2)cc1
Reactant: O=C(CO)OC(=O)CO
Reactant: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[NH+](CC)CC
Product: COc1ccc(-c2ccccc2N(CCCOC(=O)COCC(=O)[O-])c2ccccc2)cc1
Reaction time: 2 h

Procedure:
2.72 g (7.83 mmol) of the alcohol (26) was dissolved in 20 mL of methylene chloride with 1.3 mL (9.4 mmol) of triethylamine and 1.1 g (9.5 mmol) of glycolic anhydride. The mixture was stirred for 2 h (became homogeneous). TLC showed clean reaction (Rf=0.35 in 9:1/methylene chloride:methanol). The solvents were removed by evaporation and the residue was chromatographed on a 1.5×18 inch silica gel column packed with 93% methylene chloride, 5% methanol, and 2% triethylamine. The fractions containing product were combined and solvent was removed by evaporation. Co-evaporation with dry DMF ensured removal of traces of water and of residual volatile solvents. Yield of the colorless syrup (27) was assumed to be 100%. The syrup was dissolved in dry DMF to give a final volume of 23.4 mL (˜0.33 M solution).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC(C)(C)C)=O)[CH:6]=[C:5]2[C:18]1[CH:19]=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:35]1[S:39][C:38]([NH:40]C(=O)OC(C)(C)C)=[N:37][CH:36]=1)CCC>CN(C=O)C.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>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:35]4[S:39][C:38]([NH2:40])=[N:37][CH:36]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cnc3ccccc3c2)c2cc(Br)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc3[nH]cc(-c4cnc5ccccc5c4)c3c2)s1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 5-bromo-3-(quinolin-3-yl)-1H-indole-1-carboxylate (104 mg, 0.246 mmol), Pd(PPh3)4 (14 mg, 0.012 mmol), Lithium chloride (83 mg, 1.965 mmol) and DMF (2.0 ml, 0.246 mmol) in a microwave reaction vessel was sealed and heated at 100° C. for 5 min. A solution of tert-butyl 5-(tributylstannyl)thiazol-2-ylcarbamate (240 mg, 0.491 mmol) in DMF (1.0 mL) was then added and the reaction was heated at 100° C. for additional 17 h. The mixture was filtered through a pad of Celite and the filtrate was evaporated to dryness. The above crude product was dissolved in DCM (0.5 mL) followed by the addition of TFA (0.5 mL). The reaction was stirred at RT for 1 h then evaporated in vacuo to dryness. The residue was purified by silica gel chromatography to 5-(3-(quinolin-3-yl)-1H-indol-5-yl)thiazol-2-amine (6.7 mg, 8.0%) as a yellow solid. MS (ESI, pos. ion) m/z: 343 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 6.98 (s, 2H), 7.32 (d, J=9.0 Hz, 1H), 7.38 (s, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 7.70 (t, J=7.3 Hz, 1H), 7.98 (s, 1H), 8.00-8.05 (m, 2H), 8.10 (d, J=8.0 Hz, 1H), 8.62 (s, 1H), 9.29 (d, J=2.0 Hz, 1H), 11.65 (s, 1H).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:26])[CH2:6][CH2:7][CH2:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([CH2:23]CO)[CH2:20][CH2:21]O)=[CH:18][C:11]=2[N:10]=1)([CH3:3])[CH3:2].Cl[CH2:28][Cl:29].S(Cl)([Cl:32])=O.O>CCCCCCC>[CH:1]([O:4][C:5](=[O:26])[CH2:6][CH2:7][CH2:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([CH2:23][CH2:28][Cl:29])[CH2:20][CH2:21][Cl:32])=[CH:18][C:11]=2[N:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)CCCc1nc2cc(N(CCO)CCO)ccc2n1C
Reactant: ClCCl
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CCCCCCC
Product: CC(C)OC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 2.5 °C
Reaction time: 7 h

Procedure:
4-{5-[Bis-(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl}-butyric acid isopropyl ester (5 g) and dichloromethane (75 mL) are charged into a round bottom flask and cooled to 0-5° C. Thionyl chloride (4 mL, 4.0 M) is slowly added at the same temperature. The temperature is allowed to rise to 25-30° C. and the mixture is stirred for about 7 hours. Water (100 mL) is slowly added and the mixture is stirred for about 20 minutes, then the layers are separated. The dichloromethane layer is washed with saturated sodium bicarbonate solution (100 mL), dried over sodium sulfate, and is concentrated under vacuum at 30-33° C. to obtain 10-15 mL of a concentrated mass. n-Heptane (100 mL) is added to the concentrated mass slowly at 27° C., stirred for about 1 hour, filtered, and the collected solid is washed with n-heptane (15 mL) and dried under vacuum to give the title compound. Yield: 3.4 g (61%).
Reaction SMILES: [N+:1](=[CH:3][C:4]([C:6]1([C:11]([F:14])([F:13])[F:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=O)=[N-:2].NN1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:33].CN1CCCC1=[O:40]>ClCCCl.CCOC(C)=O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:33])[N:2]([NH:1][C:3](=[O:40])[CH2:4][C:6]3([C:11]([F:14])([F:13])[F:12])[CH2:10][CH2:9][CH2:8][CH2:7]3)[N:25]=2)=[CH:27][CH:28]=1
Reactant: [N-]=[N+]=CC(=O)C1(C(F)(F)F)CCCC1
Reactant: CN1CCCC1=O
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(CC1(C(F)(F)F)CCCC1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
A solution of the above crude 2-diazo-1-(1-(trifluoromethyl)cyclopentyl)ethanone and the product from Example 86A in 1,2-dichloroethane and 1-methyl-2-pyrrolidinone was microwaved at 200° C. for 15 minutes, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (1-2% acetone/dichloromethane) to give the title compound as a white solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.50-8.58 (m, 1H), 8.47-8.50 (bs, 1H), 7.78-7.86 (m, 2H), 7.67-7.75 (m, 1H), 7.52-7.57 (m, 2H), 7.48-7.52 (m, 2H), 2.67 (s, 2H), 2.07-2.18 (m, 2H), 1.94-2.04 (m, 2H), 1.67-1.84 (m, 4H); MS (ESI−) M/Z 448 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=1[O:26]CC1C=CC=CC=1)(=[O:16])=[O:15])[C:9]([NH:11][CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].C1COCC1>[Pd].CO>[C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[OH:26])(=[O:15])=[O:16])[C:9]([NH:11][CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1O
Yield: 109.4 %

Procedure:
A mixture of 1.0 g (1.91 mmol) 3-(2-benzyloxy-4-nitro-benzenesulfonylamino)-N-methyl-succinamic acid tert-butyl ester from Route D, 0.2 g 20% Pd/C, and 75 mL of a 1:1 mixture of THF:MeOH was shaken under 50 psi H2 gas for 4.5 h. TLC analysis showed reaction complete. The reaction was filtered to remove catalyst and the solvent evaporated under reduced pressure to give 3-(4-amino-2-hydroxy-benzenesulfonylamino)-N-methyl-succinamic acid tert-butyl ester 0.78 g (100%) as a light yellow foam. MS (APCI) m/z 402 (M−1).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[C:23]([O-])(=O)C.[Na+].C=O>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[CH2:19][CH2:18]1
Reactant: CC(=O)[O-]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: c1cnc2[nH]ccc2c1
Agent: C=O
Agent: [Na+]
Product: Fc1ccccc1N1CCN(Cc2c[nH]c3ncccc23)CC1

Procedure:
1H-pyrrolo[2,3-b]pyridine (47 mg, 0.40 mmol), 1-(2-flurophenyl)piperazine (72.0 mg, 0.48 mmol), sodium acetate (72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were processed as described in Example 18 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.62 (m, 4H) 3.14 (m, 4H) 4.03 (s, 2H) 5.60 (s, 1H) 7.09 (m, 3H) 7.14 (m, 2H) 8.06 (dd, J=8.31, 1.53 Hz, 1H) 8.20 (dd, J=4.75, 1.70 Hz, 1H). (ESI) m/z 311 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([NH2:36])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([NH:36][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 86.5 %

Procedure:
A suspension of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (15.3 g, 45.4 mmol), 3-amino-piperidine-1-carboxylic acid tert-butyl ester (10.00 g, 49.9 mmol), and diisopropylethylamine (25 ml, 140 mmol) in propan-2-ol (200 ml) was heated at 80° C. for 20 h. The mixture was then cooled to 25° C. and stirred for 12 h. The resulting yellow solid was collected by vacuum filtration, washed with propan-2-ol (1×30 ml), and was air-dried to afford 3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (19.7 g, 87%). LCMS (Method G, ESI): RT=1.25 min, m+H=502.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:19](=[O:32])[NH:20][C:21](=[O:31])[C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:13][CH:12]=1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl.C(OCC)(=O)C>[NH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[C:19](=[O:32])[NH:20][C:21](=[O:31])[C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:15][CH:16]=1
Reactant: COc1ccccc1C1=C(Nc2ccc(CCNC(=O)OC(C)(C)C)cc2)C(=O)NC1=O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1C1=C(Nc2ccc(CCN)cc2)C(=O)NC1=O

Procedure:
A solution of 3-[4-[2-(t-butoxycarbonylamino)ethyl]phenylamino]-4-(2-methoxyphenyl)-1H-pyrrole-2,5-dione (0.060 g. 0.13 mmol) and trifluoroacetic acid (4 drops) in dry DCM (5 mL) was stirred for 18 hours at room temperature. The suspension was diluted with ethyl acetate (10 mL), poured onto sodium bicarbonate (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic solutions were washed with brine, dried with magnesium sulfate, evaporated and the residue triturated with a mixture of hexane-dichloromethane (95:5 v/v) to afford the tide compound as an orange solid.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])(=[O:22])=[O:21]>>[CH2:6]([N:8]([CH2:9][CH3:10])[C:3](=[O:4])[CH2:2][N:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH3:11])[S:20]([C:23]1[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH3:7]
Reactant: CCNCC
Reactant: COc1ccccc1NS(=O)(=O)c1ccccc1C
Reactant: O=C(Br)CBr
Product: CCN(CC)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of 2-bromoacetyl bromide with diethylamine and N-(2-methoxy-phenyl)-2-methyl-benzenesulfonamide
Reaction SMILES: O[C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH2:15][C:16]([CH3:18])=[CH2:17])[CH2:3][CH2:4][N:5]([C:10]([CH3:14])([C:12]#[CH:13])[CH3:11])[C:6](=[O:9])[O:7]C.Br[C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[C:31](=[O:37])[CH:30]=[CH:29]2>>[CH3:14][C:10]([N:5]1[CH2:4][CH2:3][C:2]([CH2:15][C:16]([CH3:18])=[CH2:17])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:7][C:6]1=[O:9])([C:12]#[C:13][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[C:31](=[O:37])[CH:30]=[CH:29]2)[CH3:11]
Reactant: C#CC(C)(C)N(CCC(O)(CC(=C)C)c1ccccc1)C(=O)OC
Reactant: Cn1c(=O)ccc2cc(Br)ccc21
Product: C=C(C)CC1(c2ccccc2)CCN(C(C)(C)C#Cc2ccc3c(ccc(=O)n3C)c2)C(=O)O1

Procedure:
The title compound was prepared from methyl 3-hydroxy-5-methyl-3-phenylhex-5-enyl(2-methylbut-3-yn-2-yl)carbamate and 6-bromo-1-methylquinolin-2(1H)-one following procedures analogous to those described in Example 1 Steps 3 and 4. LC-MS Method 1 tR=1.92 min, m/z=455; 1H NMR (CDCl3) 1.64 (s, 3H), 1.69 (s, 3H), 1.82 (s, 6H), 2.26 (m, 1H), 2.40 (m, 1H), 2.61 (AB quartet, 2H), 3.08 (m, 1H), 3.64 (m, 1H), 3.71 (s, 3H), 4.64 (s, 1H), 4.83 (s, 1H), 6.77 (d, 1H), 7.25-7.65 (9H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:9]=[N+:10]=[N-:11].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:9]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:10]=[N-:11]
Reactant: BrCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1ccccc1
Reaction time: 24 h
Yield: 79.5 %

Procedure:
To a solution of benzylbromide (350 μL, 2.92 mmol) in anhydrous dimethylformamide (7 mL), under argon, was added sodium azide (288 mg, 6.43 mmol). After 24 h at room temperature, the reaction mixture was diluted with ethyl acetate and then washed three times with brine. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was diluted with water and extracted with pentane, dried over sodium sulfate, filtered and evaporated to afford the title compound (309 mg, 80%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[CH:18]([CH3:33])[C:19]([OH:32])([C:24]1[CH:29]=[CH:28][C:27](=[O:30])[N:26]([CH3:31])[CH:25]=1)[C:20]([F:23])([F:22])[F:21])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#N)=[CH:8][C:7]=1[F:14].O1CCOCC1.[OH2:40].Cl.[OH-:42].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[CH:18]([CH3:33])[C:19]([OH:32])([C:24]1[CH:29]=[CH:28][C:27](=[O:30])[N:26]([CH3:31])[CH:25]=1)[C:20]([F:22])([F:23])[F:21])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:42])=[O:40])=[CH:8][C:7]=1[F:14]
Reactant: [OH-]
Reactant: CC(c1ccc(Oc2ccc(C#N)cc2F)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: O
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: CC(c1ccc(Oc2ccc(C(=O)O)cc2F)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-propyl]-phenoxy}-3-fluoro-benzonitrile (100 mg) in 2 M aqueous KOH solution (5.2 ml) was added dioxane (1 ml). The mixture was stirred at 90° C. for 30 minutes. Water was added and the mixture was acidified with 2 M aqueous HCl. The solid was collected by filtration, washed with water and dried to give the title compound (99 mg) as a colorless solid. MS (m/e, ISP neg. ion)=498.1 [M−H+].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11](O)=[O:12])=[C:9]([CH3:14])[N:8]([C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:6]=2[N:7]=1.ON1C2C=CC=CC=2N=N1.Cl.C(C(N=C=NCCCN(C)C)C)C.C(N(CC)CC)C.[NH2:54][CH2:55][C:56]1[C:57]([OH:64])=[N:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62]>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:54][CH2:55][C:56]3[C:57]([OH:64])=[N:58][C:59]([CH3:63])=[CH:60][C:61]=3[CH3:62])=[O:12])=[C:9]([CH3:14])[N:8]([C@@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[C:6]=2[N:7]=1
Reactant: Cc1c(C(=O)O)c2cnc(Cl)nc2n1[C@H](C)c1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCC(C)N=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(Cl)ncc23)c(O)n1
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To a solution of (R)-2-chloro-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (100 mg, 0.32 mmol) in dichloromethane (10 mL) was added with 1-hydroxybenzotriazole (65 mg, 0.48 mmol), 1-Ethyl-3-(3-dimethylaminopropyl)ethyl-carbodiimide hydrochloride (92 mg, 0.48 mmol) and triethylamine (97 mg, 0.96 mmol). After stirred for 30 minutes, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (49 mg, 0.32 mmol) was added and the reaction mixture was stirred at room temperature for 12 hours. The solution was concentrated, diluted with water (20 mL), extracted with ethyl acetate (20 mL). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to afford (R)-2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (100 mg, 70%). LRMS (M+H+) m/z: calcd 449.16. found 449.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:5][NH:6][C:7](=[O:11])[CH2:8][C:9]#[N:10].CO[CH:18]=[CH:19][C:20](=O)[CH3:21].N12CCN(CC1)CC2>COCCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:5][N:6]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:8]([C:9]#[N:10])[C:7]1=[O:11]
Reactant: N#CCC(=O)NCc1ccc(Cl)c(Cl)c1
Reactant: COC=CC(C)=O
Agent: C1CN2CCN1CC2
Solvent: COCCO
Product: Cc1ccc(C#N)c(=O)n1Cc1ccc(Cl)c(Cl)c1
Yield: 62 %

Procedure:
A solution of 49.7 g. (0.204 mole) of N-(3,4-dichlorobenzyl)-2-cyanoacetamide, 48.0 g (0.48 mole) of 4-methoxy-3-buten-2-one, and 4 g. of 1,4-diazabicyclo (2.2.2)octane (DABCO) in 160 ml. of 2-methoxyethanol is refluxed for 4 hr. The dark reaction mixture is then concentrated in vacuo and the crude solid is isolated by filtration from the resulting slurry and washed with ether. The crude product is dissolved in methylene chloride and the organic solution is washed with water, 2N--HCl and finally with more water. The methylene chloride is removed and the product is obtained in 62% yield by ether tirituration.