Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)=[N:4][N:3]=1.[NH:25]1[CH2:37][CH2:36][CH:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:26]1.O>CN1CCCC1=O>[C:32]([O:31][C:29]([CH:28]1[CH2:36][CH2:37][N:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=3)[C:5]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=3)=[N:4][N:3]=2)[CH2:26][CH2:27]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)C1CCNCC1
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nnc(N3CCC(C(=O)OC(C)(C)C)CC3)c3ccc(C#N)cc23)cc1Cl
Temperature: 170 °C
Yield: 56.6 %

Procedure:
1-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine (2 g) prepared in Example 1 and t-butyl isonipecotate (2 g) were dissolved in 20 ml of N-methyl-2-pyrrolidone. The obtained solution was heated at 170° C. for 5 hours and cooled, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The obtained residue was subjected to silica gel column chromatography and eluted with toluene/tetrahydrofuran (10:1) to give 1.6 g of 1-(4-tert-butoxycarbonyl-piperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].[C:9]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[C:14]([CH2:20][CH2:21][CH3:22])[C:13]=1[OH:23])(=[O:11])[CH3:10]>O>[C:9]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8])=[C:14]([CH2:20][CH2:21][CH3:22])[C:13]=1[OH:23])(=[O:11])[CH3:10]
Reactant: OCCCCO
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCc1c(COCCCCO)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 9.6 g. of a 50% oil dispersion of sodium hydride in 100 ml. of 1,4-butanediol were added 11.3 g. of 4-acetyl-3-hydroxy-2-propylbenzyl chloride. The reaction was stirred overnight at room temperature and then heated to 60° C. for six hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The ethyl acetate solution was evaporated to dryness and the residue was purified by chromatography over silica gel to provide 4.1 g. of the desired title product. NMR.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([O:17]CC)=[O:16])#[N:2].[OH-:20].[K+]>O>[C:15]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:1]([NH2:2])=[O:20])([OH:17])=[O:16]
Reactant: CCOC(=O)c1cnn(-c2ccc(C)cc2)c1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(-n2ncc(C(=O)O)c2C(N)=O)cc1
Reaction time: 72 h

Procedure:
To 10 g. of ethyl 5-cyano-1-(4-methylphenyl)-4-pyrazolecarboxylate was added 5.6 g. of potassium hydroxide and 200 ml. of water followed by enough water to cause solution. The mixture was stirred under reflux for 8hours and allowed to stand for 3 days. It was then poured over ice, made acid and filtered. The solids from the filtration were heated in 100 ml. of ethyl acetate, and the undissolved solid was separated, dried and identified as 4.25 g. of the desired product, m.p. 260° dec. The product was identified by nuclear magnetic resonance analysis in DMSOd6. δ2.36 (s, 3), methyl; 7.32 (d, 2), aromatic; 7.45 (d, 2), aromatic; 8.01 (s, 1), pyrazole; 7.91 (s, 1), carboxamide; 8.33 (s, 1), carboxamide.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[Cl:14][C:15]1[C:23]2[O:22][CH2:21][C:20](=O)[C:19]=2[CH:18]=[CH:17][CH:16]=1>C1COCC1>[Cl:14][C:15]1[C:23]2[O:22][CH:21]=[C:20]([CH2:5][C:3]#[N:4])[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1COc2c(Cl)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCc1coc2c(Cl)cccc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.1 %

Procedure:
To a stirred suspension of NaH 50% dispersion in mineral oil, washed with hexane; 1.82 g, 0.0378 mol) in THF (70 mL) was added a solution of diethyl cyanomethylphosphonate (6.7 g, 0.0378 mol) in THF (30 mL) dropwise over 20 minutes. After 20 minutes, the mixture was cooled to 0° C. and a solution of 7-chlorobenzofuran-3-one (5.8 g, 0.0344 mol) in THF (80 mL) was added dropwise over 30 minutes. The cooling bath was removed and stirring was continued at room temperature overnight. H2O (400 mL) and ether were added. The organic phase was washed with saturated aqueous NaCl, dried (MgSO4), and concentrated to give a red solid (6.4 g, 97%).
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[CH3:14].[C:15](=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])=O.[Na+].[Na+].CI>O.C(Cl)CCl>[Br:6][C:7]1[CH:12]=[C:11]([S:2]([CH3:15])(=[O:5])=[O:3])[C:10]([CH3:13])=[CH:9][C:8]=1[CH3:14]
Reactant: O=S(=O)(O)Cl
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(Br)c(C)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: ClCCCl
Product: Cc1cc(C)c(S(C)(=O)=O)cc1Br
Temperature: 25 °C

Procedure:
6 g of common salt was added to 25 ml of 1,2-dichloroethane (EDC), and 40 g of chlorosulfonic acid was added dropwise thereto at room temperature under stirring and 20 ml of EDC was further added thereto. To the resultant mixture, was dropwise added 18.5 g (0.1 mol) of 4-bromo-m-xylene at room temperature over one hour period. After dropwise added, the resultant mixture was stirred continuously for 30 minutes, and was then heated to 70° C., and was stirred continuously for one hour, and was thereafter standed to cool to room temperature. After dropping the resultant reaction liquor to 65 ml of water, the mixture was stirred for 30 minutes and EDC layer was taken out. To a solution having 17 g of sodium carbonate and 13 g of sodium sulfite dissolved in 85 ml of water, was dropwise added the EDC layer thus obtained at 65° C. over one hour period, and the resultant mixture was stirred at the same temperature for 4 hours to take the aqueous layer out. 14.2 g of methyl iodide was added dropwise to the aqueous layer thus obtained, and the resultant mixture was heated to 65° C. to react for 4 hours.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH3:23])[CH:21]=3)[NH:16][CH:15]=2)=[CH:10][CH:9]=1.[NH2:24]OS([O-])(=O)=O.[K+].NOS(O)(=O)=O>CN(C=O)C>[NH2:24][N:16]1[C:17]2[C:22](=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:14]([C:11]2[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=2)=[CH:15]1
Reactant: Cc1ccc2[nH]cc(-c3ccc(F)cc3)c2c1
Reactant: NOS(=O)(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: NOS(=O)(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(-c1ccc(F)cc1)cn2N

Procedure:
Potassium tert-butoxid (7.5 g) was added to a solution of 3-(4-fluorophenyl)-5-methyl-1H-indole 1c (15 g) in DMF during 15 min at 0°-5° C. Then a suspension of potassium hydroxylamine-O-sulphonate in DMF (prepared by addition of potassium tert-butoxid (7.5 g) to a suspension of hydroxylamine-O-sulphonic acid (7.6 g) in DMF (100 ml) during 0.5 h at 0°-5° C.) was added slowly at 0°-5° C. After reaction at 0° C. for 1 h the mixture was poured into ice, and extracted with diethyl ether (2×250 ml). The combined organic phases were washed with brine (3×250 ml) and dried (Na2SO4). Evaporation of the solvents afforded the title compound which was purified by column chromatography on silica gel (eluted with ethyl acetate/heptane 1:3) and crystallized from diethylether. Yield: 4.3 g, mp 116°-120° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:13][NH2:14].Cl.[C:16]1(NN)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C(N)=O)C2C(=CC=CC=2)CC1.C1(C)C=CC=CC=1CC(N)=O.[CH:47]([NH:49][C:50](=O)[CH2:51][C:52]1C=CC=C[CH:53]=1)=O>>[Cl:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[N:13]1[C:50]([CH:51]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:53][CH2:52]2)=[N:49][CH:47]=[N:14]1
Reactant: NNc1ccccc1
Reactant: O=CNC(=O)Cc1ccccc1
Reactant: NNc1cccc(C(F)(F)F)c1Cl
Agent: Cc1ccccc1CC(N)=O
Agent: Cl
Agent: NC(=O)C1CCc2ccccc21
Product: FC(F)(F)c1cccc(-n2ncnc2C2CCc3ccccc32)c1Cl

Procedure:
The title compound was prepared using the procedure as described in Example 80 substituting 2-chloro-3-trifluoromethylphenylhydrazine hydrochloride for phenylhydrazine hydrochloride and substituting N-formyl-2,3-dihydro-1H-indene-1-carboxamide (prepared using the procedure as described in Example 76A, substituting from indan-1-carboxamide [Seidl Tetrahedron 1964, 20, 633] for 2-o-tolylacetamide) for N-formylphenylacetamide. The residue was purified by flash chromatography (40% ethyl acetate/hexanes) to provide the title compound. MS (ESI) m/e: 364 (M+H)+; 1H NMR (DMSO-d6) δ 2.05-2.45 (m, 2H), 2.8-3.05 (m, 2H), 4.29-4.35 (t, 1H), 6.95-7.05 (bs, 1H), 7.03-7.1 (t, 1H), 7.1-7.21 (t, 1H), 7.2-7.3 (d, 1H), 7.78-7.82 (t, 2H), 8.0-8.01 (bs, 0.5H), 8.18 (s, 1H), 8.22 (bs, 0.5H); Anal. calcd. for C, 59.43; H, 3.60; N, 11.55. Found C, 59.20; H, 3.34; N, 11.48
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][CH:21]([CH:58]([F:60])[F:59])[CH2:22][O:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([N:30]2[C:35](=[O:36])[C:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:40][CH:39]=3)=[C:33]([CH2:52][CH2:53][CH3:54])[N:32]3[N:55]=[CH:56][N:57]=[C:31]23)[CH2:26][CH2:25]1)(C(C)(C)C)(C)C>O.C(OCC)(=O)C>[F:60][CH:58]([F:59])[CH:21]([OH:20])[CH2:22][O:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([N:30]2[C:35](=[O:36])[C:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[C:50]4[NH:51][C:4](=[O:7])[O:5][N:3]=4)=[CH:40][CH:39]=3)=[C:33]([CH2:52][CH2:53][CH3:54])[N:32]3[N:55]=[CH:56][N:57]=[C:31]23)[CH2:28][CH2:29]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O[Si](C)(C)C(C)(C)C)C(F)F)CC2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C(F)F)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.18 g), sodium hydrogen carbonate (0.24 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(2-{[tert-butyl(dimethyl)silyl]oxy}-3,3-difluoropropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.12 g) was added, and the mixture was stirred at 90° C. for 21 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.035 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.032 mL) were added, and the mixture was stirred at room temperature for 2 hr. Thereafter, tetrabutylammonium fluoride (0.44 mL, 1.0 M tetrahydrofuran solution) was added, and the mixture was stirred at 70° C. for 2 hr. To the reaction mixture was added 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.080 g, 73%).
Reaction SMILES: [NH:1]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:46][CH2:45][CH2:44][C@H:28]1[C:29]([NH:31][C@H:32]([C:34]([O:36]CC1C=CC=CC=1)=[O:35])[CH3:33])=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.CO.N(C(OC(C)(C)C)=O)[C@H](C(N[C@H](C(N1CCC[C@H]1C(N[C@H](C(N[C@H](C(OCC1C=CC=CC=1)=O)CCCCNC(OCC1C=CC=CC=1Cl)=O)=O)C)=O)=O)CCCNC(=N)NS(C1C=CC(C)=CC=1)(=O)=O)=O)CC(=O)N>CO>[NH:1]([C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48])[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:46][CH2:45][CH2:44][C@H:28]1[C:29]([NH:31][C@H:32]([C:34]([OH:36])=[O:35])[CH3:33])=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=1)(=[O:16])=[O:15])=[O:5])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
At 0° C. to the solution of 550 mg (0.726 mmol) of Boc-Ala-Arg(Tos)-Pro-Ala-OBzl (SEQ ID NO: 7) in 20 ml of methanol 8 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 15:1) indicated complete disappearance of Boc-Asn-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 17). The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 330 mg (67%) of the title compound as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([N:39]3[CH2:38][CH2:37][N:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[F:29])[CH2:41][CH2:40]3)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)O
Reactant: Fc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccccc2F)CC1
Yield: 76.6 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(3-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (562 mg, 1.41 mmol, 76%) was obtained.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[F:42][C:43]([F:53])([F:52])[CH2:44][N:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1.Cl>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:51][CH:48]5[CH2:49][CH2:50][N:45]([CH2:44][C:43]([F:53])([F:42])[F:52])[CH2:46][CH2:47]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCN(CC(F)(F)F)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(CC(F)(F)F)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.20 mL (1.1 mmole) of ethyldiisopropyl amine and 0.068 g (0.26 mmole) of 1-(2,2,2-trifluoro-ethyl)-piperidin-4-ylamine; hydrochloride in 4.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate solution, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexane-ethylacetate (gradient, 80:20-0:100) gave 0.11 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-[1-(2,2,2-trifluoro-ethyl)-piperidin-4-yl]-benzamide (I-77) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16](=[O:17])[C:15]([F:22])([F:21])[F:14])=[N:3][CH:4]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Br)cn1)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
2,5-Dibromopyridine (7.11 g, 30 mmol) was dissolved in dry toluene (200 mL) and cooled to −78° C. n-BuLi (14.4 mL, 2.5 M in THF, 36 mmol) was added dropwise. The mixture was stirred at −78° C. for 2 hours and ethyl trifluoroacetate (6.39 g, 45 mmol) was added. The resulting mixture was allowed to warm to room temperature slowly and stirred at room temperature for 30 min. The reaction was quenched with NH4Cl (aq.) and extracted with EtOAc. The organics were dried and concentrated and the resulting residue was purified by column chromatography (silica gel, 0-30% EtOAc/Hexane) to give the product 1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethanone (5.87 g).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[CH2:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[CH2:4][C:3]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:21]2[N:22]([CH:2]=1)[CH:23]=[CH:24][CH:25]=[CH:26]2
Reactant: O=C(CBr)Cc1c(F)cccc1Cl
Reactant: c1ccc(Cc2ccccn2)cc1
Solvent: CC(C)=O
Product: Fc1cccc(Cl)c1Cc1cn2ccccc2c1-c1ccccc1
Yield: 76.3 %

Procedure:
The compound of step 1 (1.17 g, 4.41 mmol) and 2-benzyl-pyridine (1.49 g, 8.82 mmol) were dissolved in acetone (15 ml) and the mixture was stirred under reflux overnight. The mixture was concentrated to dryness and the residue was purified by chromatography on silica gel (DCM/MOH, 100:0, then 95:5) to give 1.13 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:24]3[CH2:26][CH2:25]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:11]=3)=[CH:4][CH:3]=1.C1C([N+]([O-])=O)=CC=C([Cl-][C:37]([O-])=[O:38])C=1.[CH:40]1([CH:43]([OH:45])[CH3:44])[CH2:42][CH2:41]1>N1C=CC=CC=1.O.C(Cl)Cl>[CH:40]1([CH:43]([O:45][C:37](=[O:38])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]([CH:24]4[CH2:26][CH2:25]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:11]=4)=[CH:4][CH:3]=2)[CH3:44])[CH2:42][CH2:41]1
Reactant: CC(O)C1CC1
Reactant: COCCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CC3)c2c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COCCOc1ccc2c(C#N)c(-c3ccc(NC(=O)OC(C)C4CC4)cc3)n(C3CC3)c2c1
Temperature: 35 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
A mixture of 2-(4-aminophenyl)-1-cyclopropyl-6-(2-methoxyethoxy)indole-3-carbonitrile (35 mg, 0.1 mmol), 4-nitrophenylchloroformate (50 mg, 0.25 mmol) in pyridine (2.0 mL) is stirred at 35° C. for 2 h, followed by the addition of 1-cyclopropylethanol (98 μL, 1.0 mmol). The mixture is then stirred at 60° C. overnight and diluted with water (10 mL) and DCM (5 mL). The organic is washed with water (3×5 mL), HCl (2N, 3×5 mL), saturated NaHCO3 (3×5 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the title compound, {4-[3-cyano-1-cyclopropyl-6-(2-methoxyethoxy)indol-2-yl]phenyl}carbamic acid 1-cyclopropylethyl ester (22 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)c1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)c1ccccc1Nc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A round-bottomed flask was charged with 2,4-dichloro-5-fluoropyrimidine (2.5 g, 15 mmol), ethyl 2-aminobenzoate (4.9 g, 30 mmol), N,N-diisopropylethylamine (5.2 mL, 3.9 g, 30 mmol) and isopropanol (50 mL). The flask was fitted with a reflux condenser and the mixture was heated to reflux and stirred for 18 h. After cooling the reaction mixture to room temperature a precipitate appeared. The solid was collected and washed sparingly with isopropanol then copiously with ethyl ether to afford the title compound as a white solid; yield, 1.8 g (41%). MS: M(C13H13ClFN3O2)=295.70 (M+H)+=296.0 and 298.0.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH2:9]([I:11])[CH3:10].CC(C)=O.C(OCC)C>C(Cl)(Cl)Cl>[I-:11].[CH2:9]([N+:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2)[CH3:10]
Reactant: CCI
Reactant: C1CN2CCC1CC2
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC[N+]12CCC(CC1)CC2
Product: [I-]

Procedure:
20 grams of Quinuclidine (1 Aza bicyclo [2.2.2]octane, Aldrich) were dissolved in 100 ml of chloroform with stirring and cooling in an ice bath. 28.08 Grams of ethyl iodide (Aldrich) were added dropwise. The mixture became cloudy and was stirred overnight, slowly coming to room temperature. Acetone was added to the solution and then, with stirring, diethyl ether was added dropwise until crystals formed. The filtered solids were washed with acetone and dried under vacuum. The product had the correct microanalysis for C, H, and N.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[S:10].CN(C=O)C.[CH:16]([NH:18][NH2:19])=O.[H-].[Na+]>O>[N:19]1[N:18]=[CH:16][N:8]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[S:10][C:9]=12
Reactant: S=C=Nc1ccccc1Cl
Reactant: NNC=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)sc1nncn12
Temperature: 160 °C

Procedure:
Five grams (30.0 mmoles) of o-chlorophenylisothiocyanate were dissolved in 50 ml. of dry DMF. A solution of 1.8 g. (30.0 mmoles) of formylhydrazine in 50 ml. of dry DMF was added dropwise rapidly to the stirred reaction mixture. The temperature of the reaction rose to about 45° C. The temperature was maintained between 60° C. and 100° C. for 24 hours. Thirty millimoles, 1.5 g., of sodium hydride as a 50% mineral oil suspension was added to the reaction mixture. The reaction was completed by heating at reflux temperature (160° C.) for about 185 hours. The cooled mixture was poured into water. The aqueous mixture was extracted with n-hexane to remove mineral oil. The product was extracted with ethyl acetate. The ethyl acetate extract was washed (water), dried (MgSO4) and evaporated in vacuo to a residual oil. The oil was covered with dry ether and the product crystallized upon standing. The yield of s-triazolo[3,4-b]benzothiazole, m.p. about 175-176° C., was 200 mg.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][CH3:10]>>[CH:9]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])([CH3:10])[CH3:8].[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC
Solvent: Oc1ccccc1
Product: CC(C)c1ccccc1O

Procedure:
Phenol is treated with propylene in the presence of an alkylation catalyst to produce an isopropyl phenol-phenol mixture (in the manner described, for instance, in U.S. Pat. No. 3,576,923) which is then distilled at approximately 7 mm over a temperature range of 70°-120° C. to give a water white liquid distillate; gas chromatography of the distillate indicates the following composition: