Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:36](O)=[O:37])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:39]([O:46][CH2:47][CH2:48][NH:49][CH:50]([CH3:52])[CH3:51])([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].[Si](OCCN(C(C)C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N=1)=O)(C(C)(C)C)(C)C>>[CH2:1]([O:8][C:9]1[C:10]([C:36]([N:49]([CH2:48][CH2:47][O:46][Si:39]([C:42]([CH3:44])([CH3:43])[CH3:45])([CH3:40])[CH3:41])[CH:50]([CH3:51])[CH3:52])=[O:37])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[C:24]([C:32]([F:34])([F:33])[F:35])[CH:25]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(CC2(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Agent: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-(Benzyloxy)-2-((1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methyl)-N-(2-((tert-butyl-dimethylsilyl)oxy)ethyl)-6-hydroxy-N-isopropylpyrimidine-4-carboxamide (463) was synthesized from 5-(benzyloxy)-2-((1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylic acid (462) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (245).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]([O:16]CC)=[O:15].[OH-].[K+].C(O)C.S([O:34][CH2:35][C:36]1([CH2:40][CH3:41])[CH2:39][O:38][CH2:37]1)(C1C=CC(C)=CC=1)(=O)=O>C1(C)C=CC=CC=1.O>[CH2:40]([C:36]1([CH2:35][O:34][C:7]2[CH:2]=[C:3]([C:14]([OH:16])=[O:15])[C:4]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:5][CH:6]=2)[CH2:39][O:38][CH2:37]1)[CH3:41]
Reactant: CCOC(=O)c1c(O)cccc1-c1ccccc1
Reactant: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCC1(COc2ccc(-c3ccccc3)c(C(=O)O)c2)COC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
12 g of ethyl hydroxybiphenylcarboxylate and 15 g of potassium hydroxide were added to 100 mL of ethanol, and stirred at 60° C. for 1 hour. After decreasing the temperature to 45° C., 15 g of 3-((tosyloxy)methyl)-3-ethyloxetane was added dropwise thereto, and then refluxed for 2 hours. Water and toluene were added thereto, and the toluene layer was separated. The toluene layer was washed with 3% hydrochloric acid, a saturated sodium carbonate solution and water, and then toluene was distilled off. 20 g of sodium hydroxide, 500 mL of ethanol and 100 mL of water were added to the resulting residue, and refluxed for 2 hours. A residue obtained by distilling ethanol off was put in 300 mL of 5% hydrochloric acid to obtain crystals. The crystals thus obtained by filtering were recrystallized from ethanol to obtain 8 g of 4-(3-ethyloxetane-3-ylmethoxy)biphenylcarboxylic acid (OX2), which had a melting point of 222 to 225° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[C:17](O)(=[O:28])[CH2:18][NH:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:20]([NH:19][CH2:18][C:17]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH2:5][CH2:4]1)=[O:28])(=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1ccccc1)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 125 %

Procedure:
A solution of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (50 mg, 0.21 mmol) in CH2Cl2 (1 mL) was treated with hippuric acid (38 mg, 0.21 mmol), EDCI (48 mg, 0.24 mmol), HOBt (31 mg, 0.23 mmol) and Et3N (38 μL, 0.27 mmol). The reaction mixture was stirred for 16 h at 25° C., diluted with 1 mL of CH2Cl2, washed with 2 N aqueous NaOH solution (2×0.75 mL), dried (MgSO4) and concentrated. Chromatography (SiO2, 6 to 8% CH3OH/CH2Cl2 gradient elution) afforded 4-{(N-benzoylglycyl)amino)methyl-1-(compound No. 458) which was treated with TFA to give a TFA salt(105 mg, 97%): The purity was determined by RPLC/MS (85%); ESI/MS m/e 400 (M++H, C22H26ClN3O2)
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3OS(C(F)(F)F)(=O)=O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:39][C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([F:47])[C:41]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>CN(C=O)C.ClCCl.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:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3[C:41]3[C:40]([F:39])=[CH:45][C:44]([F:46])=[CH:43][C:42]=3[F:47])=[O:16])=[CH:13][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: OB(O)c1c(F)cc(F)cc1F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3c(F)cc(F)cc3F)ccc2c1
Temperature: 100 °C
Yield: 33.3 %

Procedure:
Dissolve trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-methoxy-naphthalen-2-yl ester (990 mg, 1.8 mmol), 2,4,6-trifluorophenylboronic acid (634 mg, 3.6 mmol), potassium phosphate (2.2 g, 10.8 mmol), tetrakis(triphenylphosphine)palladium (416 mg, 0.4 mmol) in dry DMF (25 mL) and heat at 100° C. for 3 hours. Purify reaction by SCX column and by silica gel chromatography using a 1-3% gradient of methanol in dichloromethane to yield 320 mg (35%) of the title compound: mass spectrum (ion spray) m/z=534 (M+H).
Reaction SMILES: [Na:1].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][O:13][CH2:14][CH2:15][O:16]C(=O)C2C=CC=CC=2)=[C:5](Cl)[N:4]=1.O.[CH2:27]([OH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Na:1].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][O:13][CH2:14][CH2:15][OH:16])=[C:5]([O:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:4]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(Cl)c2ncn(COCCOC(=O)c3ccccc3)c2n1
Agent: [Na]
Solvent: O
Product: Nc1nc(OCc2ccccc2)c2ncn(COCCO)c2n1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A solution of sodium benzylate in benzyl alcohol was prepared from sodium (2.58 g) and benzyl alcohol (28 ml). The solution was heated to 120° C. and 2-amino-6-chloro-9-(2-benzoyloxyethoxymethyl)purine (3.47 g) was added over a 10 minute period. The reaction mixture was headed overnight with stirring at 120°-130° C. and then poured into a mixture of ice and water. The resulting mixture was extracted thoroughly with chloroform. The aqueous phase was neutralized with acetic acid, giving a white precipitate which was recrystallized from methanol and then from water to give analytically pure 2-amino-6-benzyloxy-9-(2-hydroxyethoxymethyl)purine, m.p. 291°-292° C. (dec.) in 50% yield.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:10][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([O:24]CC)=O)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:37][NH2:38]>C(O)C>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:10][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([NH:37][NH2:38])=[O:24])=[N:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NN
Reactant: CCOC(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 80 °C
Yield: 103.9 %

Procedure:
To a solution of ethyl 5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)nicotinate (Example 43) (0.2 g, 0.43 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.1 mL, 2.1 mmol). The reaction mixture was heated to reflux at 80° C. for 16 h. The ethanol was evaporated under reduced pressure and the residue was dissolved in DCM and washed with water. The organic layer was dried and concentrated to provide 5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)nicotinohydrazide (0.2 g, crude), which was used without further purification. LCMS Method E: retention time 1.8 min; [M+1]=447.50.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH3:35].CO>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH2:35])=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([C:25]([F:27])([F:26])[F:28])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: O=C(O)Cc1ccc(Cc2cc(-c3cccc(Cl)c3)nc(C(F)(F)F)c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)Cc1ccc(Cc2cc(-c3cccc(Cl)c3)nc(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 21 %

Procedure:
An 100-mL round bottom flask was charged with 2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetic acid (0.17 g, 0.42 mmol) in dichloromethane (10 ml). To this solution at 0° C. was added oxalyl chloride (0.18 mL, 2.10 mmol) followed by DMF (1 drop). After stirring for 5 h the volatile material was removed under reduced pressure to afford crude acid chloride. The residue was dissolved in dichloromethane (10 mL), cooled to 0° C., and 7N ammonia in methanol (10.0 mL, 70 mmol) was added. After stirring for 0.5 h, the volatile material was removed under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent followed by chromatography on silica using dichloromethane/methanol (10:0 to 9:1) as eluent to afford the title compound (0.079 g, 21%) as an off-white solid. MW=404.81. M.p. 148-160° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.33 (s, 1H), 8.17-8.15 (m, 1H), 8.11-8.05 (m, 1H), 7.76 (d, J=0.5 Hz, 1H), 7.60-7.55 (m, 2H), 7.41 (br s, 1H), 7.31 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 6.82 (br s, 1H), 4.11 (s, 2H), 3.32 (s, 2H); APCI MS m/z 405 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)=[O:6])#[N:2].[Br:16][C:17]1[C:18](I)=[N:19][C:20]([I:23])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Br:16][C:17]1[C:18]([C:10]2[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:6])=[CH:8][CH:9]=2)=[N:19][C:20]([I:23])=[N:21][CH:22]=1
Reactant: Brc1cnc(I)nc1I
Reactant: N#CCNC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCNC(=O)c1ccc(-c2nc(I)ncc2Br)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 50.2 %

Procedure:
To a mixture of 4-(cyanomethylcarbamoyl)phenylboronic acid (see example 3) (185 mg, 0.9 mmol) and 5-bromo-2,4-diiodopyrimidine (410 mg,1.0 mmol) in 1,4-dioxane (10 mL), was added 2M aqueous potassium carbonate (100 μL). The resulting mixture was stirred under nitrogen for 5 minutes then tetrakis(triphenylphophine)palladium(0) (52 mg, 0.045 mmol) was added under a nitrogen atmosphere. The mixture was heated at 80° C. overnight. The cooled reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with water then brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product as a brown solid. The crude material was purified by flash chromatography, eluting with 50% ethyl acetate/petroleum spirit to give 4-(5-bromo-2-iodopyrimidin-4-yl)-N-(cyanomethyl)benzamide (200 mg, 35% over 2 steps). LC-ESI-MS (method B): rt 6.2 min.; m/z 443.0/445.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[NH4+:14].[OH-]>CN(C)C=O.O>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:14])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: [NH4+]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(Br)n1
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc([N+](=O)[O-])cc(Br)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
1.3 g (0.00526 mol) of 6-bromo-4-nitropyridine-2-carboxylic acid were dissolved in 10 ml of dimethylformamide, treated at 5° C. with 0.94 g (0.0058 mol) of 1,1-carbonyldiimidazole and subsequently stirred at room temperature for 3 hrs. Then, 40 ml of 25% NH4OH in water was added thereto and the mixture was stirred at room temperature for 1 hr. The reaction mixture was partitioned in water and dichloromethane and the organic phase was washed with water and sat. sodium chloride solution, dried over MgSO4 and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:1. There were obtained 1.1 g (85%) of 6-bromo-4-nitropyridine-2-carboxamide as white crystals; m.p.: 179-180° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][NH:13][NH2:14].[OH-].[Na+]>>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([N:13]([CH3:12])[NH2:14])=[N:3][CH:4]=1
Reactant: CNN
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Product: CN(N)c1ccc(C(F)(F)F)cn1
Temperature: 90 °C

Procedure:
2-Chloro-5-trifluoromethylpyridine (44.3 g; 0.24 mol) was treated with several portions of methyl hydrazine (33.9 g; 0.74 mol) at room temperature under nitrogen. The mixture was heated at 90° C. for 6 hr. The resulting solid was treated with 3M aqueous NaOH and extracted with ethyl acetate. The organic extracts were dried and evaporated to leave an oil/solid. Distillation of the crude product to remove excess hydrazine gave 1-[5-trifluoromethylpyrid-2-yl]-1-methyl hydrazine as a white solid (44.0 g; 94%), m.pt. 52°-55° C. ##STR14##
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)[O:8]C1.[C:32]([C:34]1[C:35]([CH:45]([CH3:47])[CH3:46])=[N:36][S:37][C:38]=1[N:39]=[C:40](Cl)[N:41]([CH3:43])[CH3:42])#[N:33]>C(#N)C>[C:1]([N:39]([C:38]1[S:37][N:36]=[C:35]([CH:45]([CH3:47])[CH3:46])[C:34]=1[C:32]#[N:33])[C:40](=[O:8])[N:41]([CH3:43])[CH3:42])(=[O:4])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Reactant: CC(C)c1nsc(N=C(Cl)N(C)C)c1C#N
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N(C(=O)N(C)C)c1snc(C(C)C)c1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4.9 g of potassium acetate, and a catalytic amount of 2,3,11,12-dibenzo-1,4,7,10,13,16-hexaoxacyclooctadeca-2,11-diene in 60 ml of acetonitrile was stirred vigorously during 45 minutes. Then 12.8 grams of N'-(4-cyano-3-isopropyl-5-isothiazolyl)-N,N-dimethylchloroformamidine in acetonitrile were added. The reaction mixture stood at ambient temperature for 16 hours. Thin layer chromatographic analysis indicated that the reaction had not gone to completion. The reaction mixture was stirred at ambient temperature for 3 days, at which time thin layer chromatographic analysis indicated the reaction to be complete. The reaction mixture was filtered and the filtrate evaporated, under reduced pressure. The residue was slurried in diethyl ether to give a solid. The solid was collected by filtration, then slurried in water to give 10.8 g of N'-acetyl-N'-(4-cyano-3-isopropyl-5-isothiazolyl)-N,N-dimethylurea; mp 128°-130°. The nmr and the ir spectra were consistent with the assigned structure. The uv spectrum confirmed the structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C@H:20]([C@@H:28]([OH:34])[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([NH:19][C@H:20]([C@@H:28]([OH:34])[CH2:29][CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:18])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CC(C)CC[C@H](O)[C@@H](N)CC1CCCCC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a solution of N-t-butoxycarbonyl-L-histidine (363 mg) and 2(S)-amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (294 mg) in dry N,N-dimethylformamide (30 ml) which was cooled to 0° C., were added a solution of diphenyl phosphorylazide (390 mg) in dry N,N-dimethylformamide (5 ml) and triethylamine (144 mg). The mixture was stirred overnight at ambient temperature. After evaporation of the solvent, the residue was dissolved in ethyl acetate (30 ml) and the solution was washed with 10% citric acid solution, saturated sodium bicarbonate solution and water successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (chloroform as eluent) to give 2(S)-(N-t-butoxycarbonyl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (384 mg) as an amorphous powder.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18](Cl)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CC(O)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O>[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Cl)nc3Cl)c(C)nn12
Reactant: C1COCCN1
Solvent: O
Solvent: CC(C)O
Product: CCC(CC)c1cc(C)nc2c(-c3sc(N4CCOCC4)nc3Cl)c(C)nn12
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 94.1 %

Procedure:
7-(1-ethyl-propyl)-3-(2,4-dichloro-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (11.64 mmoles) is charged into a 100 mL 3-necked round bottomed flask followed by addition of 2-propanol (16 mL, 3.72 volumes). The yellowish brown slurry is stirred at about 20° C. for 5 min. Then morpholine (3.3 g, 37.84 mmoles) is added over 2-5 minutes. Contents are refluxed for 6 hr. The slurry is cooled to 25° C. 2-Propanol (32 mL, 7.44 volumes) and water (8.6 mL, 2.0 volumes) are added and the mixture warmed to 70-75° C., filtered and concentrated to ˜9 volumes at atmospheric pressure. The clear solution is gradually cooled to 55° C., seeded with 0.06 g of crystalline 7-(1-ethyl-propyl)-3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine slurried in 0.5 mL 2-propanol, rinsed with additional 0.5 mL 2-propanol and added to crystallization flask. The slurry is cooled to 0-5° C., maintained for 1 hr., filtered and the product rinsed with 2-propanol (9 mL, 2.1 volumes). Suctioned dried under vacuum at 60° C. to afford 4.6 g of dry 7-(1-ethyl-propyl)-3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (88.8% yield, purity by HPLC assay is 99.88%). MS (ES)=420 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([NH:17]C(=O)OCC3C=CC=CC=3)[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C([O-])=O.[NH4+]>[Pd].CO>[NH2:17][C:12]1[CH:13]=[C:14]2[C:9]([C:8]3[C:7]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[CH:6][CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]=3[NH:15]2)=[CH:10][CH:11]=1
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(NC(=O)OCc3ccccc3)ccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(N)ccc12
Temperature: 25 °C

Procedure:
A mixture of benzyl 8-carbamoyl-5-(2-fluorophenyl)-9H-carbazol-2-ylcarbamate (Example 50-1, 400 mg, 0.882 mmol), 10% palladium on charcoal (94 mg, 0.088 mmol) and ammonium formate (334 mg, 5.29 mmol) in methanol (20 mL) was heated at reflux for 1 h. The mixture was cooled to rt, diluted with methanol and filtered through a Celite pad. The filtrate was concentrated to give 7-amino-4-(2-fluorophenyl)-9H-carbazole-1-carboxamide in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1 H) 8.11 (br. s., 1 H) 7.78 (d, J=7.78 Hz, 1 H) 7.51 (d, J=2.01 Hz, 2 H) 7.35-7.47 (m, 3 H) 6.93 (d, J=7.78 Hz, 1 H) 6.79-6.84 (m, 1 H) 6.72 (d, J=8.03 Hz, 1 H) 6.24 (dd, J=8.41, 1.88 Hz, 1 H) 5.22 (s, 2 H). Mass spectrum m/z 320.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:8]2[CH:9]=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[N:6]([CH3:17])[C:5](=[O:18])[CH2:4][N:3]=1.[C:19]1(B(O)O)C=CC=C[CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:8]2[CH:9]=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[N:6]([CH2:17][CH2:19][CH3:20])[C:5](=[O:18])[CH2:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc2c(cc1OC)N(C)C(=O)CN=C2Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1C(=O)CN=C(Cl)c2cc(OC)c(OC)cc21
Temperature: 115 °C
Yield: 55.6 %

Procedure:
Heat at 115° C. for 12 hours under an inert atmosphere a mixture of 200 mg (0.74 mmol) of 5-chloro-7,8-dimethoxy-1-methyl-1,3-dihydro-1,4-benzodiazepin-2-one XVIIIaa, 109 mg (0.89 mmol) of benzene boronic acid, 182 mg (0.86 mmol) of K3PO4, 23 mg (0.020 mmol) of tetrakis(triphenylphosphine)Pd(0) in 5 ml of DMF. Allow to cool to room temperature. Add 80 ml of H2O and extract three times with 50 ml of Et2O. Dry the organic fractions on Na2SO4. Purify by chromatography (AcOEt). Recrystallize in EtOH. One obtains 122 mg of the abovenamed product in the form of colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[H-].[Na+].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CN(C=O)C>[C:16]([O:15][C:13](=[O:14])[CH2:12][N:4]1[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]1=[O:8])([CH3:19])([CH3:18])[CH3:17]
Reactant: CN1CCCNC1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCN(CC(=O)OC(C)(C)C)C1=O
Reaction time: 8 h
Yield: 15.2 %

Procedure:
A solution of 0.30 g (2.6 mmol) of 1-methyltetrahydropyrimidin-2(1H)-one from step A above in 5 mL of anhydrous DMF was added to a 10 mL round bottom flask containing 0.16 g (4.2 mmol) of a 60% sodium hydride suspension in mineral oil under an atmosphere of nitrogen. After stirring for 10 min 0.62 g (3.2 mmol) of tert-butyl bromoacetate was added in one portion and the reaction mixture was allowed to stir overnight. The reaction mixture was then quenched with 5 mL of a saturated aqueous ammonium chloride solution and then diluted with 20 mL of water. The resulting suspension was extracted with ethyl acetate (3×10 mL) and the combined organics were washed with water (2×3 mL), brine (1×3 mL) and dried over magnesium sulfate. The mixture was filtered, evaporated and purified by silica gel chromatography eluting with a 0-5% methanol in ethyl acetate gradient to afford the title compound as a clear oil (0.090 g, 15%). 1HNMR (500 MHz, CDCl3) δ: 3.88 (s, 2H), 3.23 (t, J=6 Hz, 2H), 3.20 (t, J=6 Hz, 2H), 2.84 (s, 3H), 1.94-1.89 (m, 2H), 1.37 (s, 9H). LC-MA: m/z (ES) 229 (MH)+.