Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Br[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]([C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:31]=1[CH3:32])[C:25]([O:27][CH3:28])=[O:26])[C:15]2=[O:33]>>[CH3:32][C:31]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[N:16]1[C:15](=[O:33])[C:14]2[C:19](=[CH:20][CH:21]=[C:12]([N:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:6][CH2:7]3)[CH:13]=2)[N:18]=[CH:17]1
Reactant: COCCN1CCNCC1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(Br)cc3c2=O)c1
Product: COCCN1CCN(c2ccc3ncn(-c4cc(C(=O)OC)ccc4C)c(=O)c3c2)CC1

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1 which is concerned with the preparation of starting material N-(2-methoxyethyl)piperazine was reacted with methyl 3-(6-bromo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate to give methyl 4-methyl-3-[6-(4-(2-methoxyethyl)piperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoate; NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 2.55 (t, 2H), 2.60 (m, 4H), 3.25 (s, 3H), 3.27 (m, 4H), 3.50 (t, 2H), 3.88 (s, 3H), 7.47 (s, 1H), 7.62 (m, 3H), 7.97 (s, 1H), 8.01 (m, 1H), 8.09 (s, 1H); Mass Spectrum: M+H+ 437.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[N:21]=[C:20]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].CO>C1COCC1.CS(C)=O.CC(O)=O>[NH2:11][CH2:10][CH2:9][CH:8]([C:12]1[N:21]=[C:20]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: Cc1cc(Nc2nc(C(CC#N)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Cc1cc(Nc2nc(C(CCN)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 3-(4-fluorophenyl)-3-(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)propanenitrile from Example 68 (80 mg, 0.21 mmol) in THF (3 mL) at 0° C. was added lithium aluminum hydride (20 mg) and the mixture was stirred for 5 min, then allowed to warm to rt and stir for 2-3 h. An additional amount of lithium aluminum hydride (40 mg) was then added and stirring was continued for 45 min. To the solution was slowly added 1 N NaOH (0.5 mL) followed by MeOH (2 mL). The mixture was stirred for 5 min and then AcOH (0.5 mL) was added, followed by DMSO (2 mL). The resulting solution was purified by preparative HPLC (Varian Diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 2-(3-amino-1-(4-fluorophenyl)propyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine as the acetate salt (21 mg, 25%). 1H NMR (300 MHz, DMSO-d6) δ 1.81 (s, 3H) 2.2-2.6 (m, 7H) 4.26 (t, 1H) 6.46 (s, 1H) 7.12 (t, 2H) 7.46-7.51 (m, 3H) 7.73-7.78 (m, 2H) 8.57 (d, 1H); LC-MS (ESI) m/z 377 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](O)=[O:19])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:26][CH2:27][C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[OH:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:26][CH2:27][C@@H:28]([OH:29])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:19])=[O:14])[CH2:9][CH2:8]2)=[CH:24][CH:25]=1
Reactant: O=C(O)c1cccc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Reactant: NC[C@@H](O)c1ccccc1
Product: O=C(NC[C@@H](O)c1ccccc1)c1cccc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Yield: 51 %

Procedure:
The title compound was prepared in 51% yield (10.1 mg) prepared from 3-(4-(4-chlorophenoxy)piperidine-1-carbonyl)benzoic acid (Step-2) according to the procedure similar to that described in Step-2 of Example 349, using (S)-2-amino-1-phenylethanol instead of 25% ammonium water.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:12][OH:13])=[CH:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]1([C:7]2[C:8]([CH:12]=[O:13])=[CH:9][O:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cocc1-c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: O=Cc1cocc1-c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
Prepare a solution of (4-phenylfuran-3-yl)methanol (2.3 g, 13.2 mmol) in methylene chloride (20 mL). Add N-methylmorpoline N-oxide (2.2 g, 18.5 mmol) and powdered 4 Å molecular sieves. Cool the mixture to 0° C. and add tetra-n-propyl ammonium perruthenate. Warm the mixture to room temperature and stir for an additional 3 hours. Filter the reaction mixture through Celite® and concentrate the filtrate. Perform flash chromatography on silica gel eluting with 10% diethyl ether/hexane to afford 1.36 g of 4-phenyl-3-formylfuran. 1H NMR (CDCl3) δ 10.01 (s, 1H), 8.15 (s, 1H), 7.60 (s, 1H), 7.35-7.54 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](OB(O)O)=[CH:11][C:10]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[N:22]=[C:23]([N:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]2)[C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:37]([N:34]1[CH2:33][CH2:32][N:31]([C:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:30]=[C:21]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:10]([F:19])[CH:11]=3)[N:22]=2)[CH2:36][CH2:35]1)[CH3:38]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: OB(O)Oc1ccc(OCc2ccccc2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN1CCN(c2nc(-c3ccc(OCc4ccccc4)c(F)c3)cc3ccccc23)CC1
Yield: 96.1 %

Procedure:
4-Benzyloxy-3-fluorophenylboric acid (1.97 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (2.57 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.09 g) in toluene (250 ml) and a 10% aqueous solution of sodium carbonate (150 ml) in nitrogen atmosphere for 2 hr. 4-Benzyloxy-3-fluorophenylboric acid (0.99 g) was additionally added thereto, and the mixture was heated under reflux for 30 min. 4-Benzyloxy-3-fluorophenylboric acid (1.43 g) was again added thereto, and the mixture was heated under reflux overnight. The organic layer was separated and extracted with 2N hydrochloric acid twice, and the resulting aqueous layer was washed with ethyl acetate. Then, it was adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give obtain 1-(4-ethylpiperazin-1-yl)-3-(4-benzyloxy-3-fluorophenyl)isoquinoline (3.19 g) as a brown viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:65]([O:67][C:68](=[O:76])[C:69]1[CH:74]=[CH:73][C:72]([NH2:75])=[CH:71][CH:70]=1)[CH3:66]>C(Cl)Cl>[CH2:65]([O:67][C:68](=[O:76])[C:69]1[CH:74]=[CH:73][C:72]([NH:75][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:29])=[CH:71][CH:70]=1)[CH3:66]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 4-amino benzoic acid ethyl ester (43 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 20% EtOAc/hexanes) to give a white solid. 37 mg.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:25][CH2:24][C@H:23]([CH2:26]O)[O:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:46]=[N+:47]=[N-:48].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.CS(C)=O>[CH2:1]([O:8][C:9](=[O:29])[NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:25][CH2:24][C@H:23]([CH2:26][N:46]=[N+:47]=[N-:48])[O:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](Cn1ncc2ccc3c(c21)O[C@@H](CO)CO3)NC(=O)OCc1ccccc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: C[C@@H](Cn1ncc2ccc3c(c21)O[C@@H](CN=[N+]=[N-])CO3)NC(=O)OCc1ccccc1
Temperature: 95 °C
Yield: 63.6 %

Procedure:
To a ° C. stirred solution of the alcohol from Step B of Example 1 (0.43 g, 1.08 mmol) in anhydrous tetrahydrofuran (30 mL) was added triethylamine (0.88 g, 8.6 mmol) and methanesulfonic anhydride (0.76 g, 4.4 mmol) under nitrogen atmosphere. After 1 h the volatiles were evaporated. To the residue was added anhydrous DMSO (30 mL) and sodium azide (0.7 g, 11 mmol). The resulting mixture was heated at 85° C. for 3 h, 95° C. for 1 h, cooled, mixed with a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (50 mL×3). Chromatography on silica eluting with a gradient of 15% to 60% ethyl acetate/hexane gave an oil (0.29 g, 63%): LCMS (+APCI) 423 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[O:18])=[CH:12][CH:11]=2)[CH:4]=1.[CH2:27](C1C=CC(N=C=O)=CC=1)C>>[CH2:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][C:5]3[CH:4]=[C:3]([NH:2][CH3:1])[N:8]=[CH:7][N:6]=3)=[CH:15][CH:14]=2)=[O:18])=[CH:25][CH:24]=1)[CH3:27]
Reactant: CNc1cc(Cc2ccc(NC(=O)Nc3ccc(C)cc3)cc2)ncn1
Reactant: CCc1ccc(N=C=O)cc1
Product: CCc1ccc(NC(=O)Nc2ccc(Cc3cc(NC)ncn3)cc2)cc1
Reaction time: 6 h

Procedure:
The title compound Is prepared as described in Example 102 but using [6-(4-amino-benzyl)-pyrimidin-4-yl]-methyl-amine (Example 119) and 4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 6 h. The title compound is obtained as a white solid: ES-MS: 362.0 [M+H]+; single peak at tR=7.14 min (System 2).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[O:11])=[C:8]([CH3:23])[N:7]=[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=3)[N:5]=2)[CH2:3][CH2:2]1.CN([C:38]([O:42]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.Cl.N1CCC(N2CCC[C@H]2CO)CC1>CN(C=O)C>[CH:1]1([C:4]2[C:9]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:19][CH2:20][CH2:21][C@H:22]4[CH2:38][OH:42])[CH2:14][CH2:13]3)=[O:11])=[C:8]([CH3:23])[N:7]=[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:32])([F:33])[F:34])[CH:25]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1nc(-c2cccc(OC(F)(F)F)c2)nc(C2CC2)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: OC[C@@H]1CCCN1C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cccc(OC(F)(F)F)c2)nc(C2CC2)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for intermediate 2,4-cyclopropyl-6-methyl-2-(3-trifluoromethoxy-phenyl)-pyrimidine-5-carboxylic acid (example 36) was reacted with HATU, triethylamine and ((S)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanol di-hydrochloride (intermediate 9) in DMF. Subsequent purification by preparative HPLC afforded the title compound as a gum. MS: 505.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:15])[C:12]([OH:14])=[O:13].[C:21]([O-])(=O)[CH3:22].[Na+].C(Br)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:15])[C:12]([O:14][CH2:21][CH3:22])=[O:13]
Reactant: CC(=O)[O-]
Reactant: O=C(O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Solvent: O
Solvent: CCBr
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 78.4 %

Procedure:
To a solution of 6.2 g of 2-(2,6-dichloroanilino)-phenylglyoxylic acid in 30 ml of dimethylformamide were added 3.3 g of anhydrous sodium acetate and then dropwise added 3 ml of ethyl bromide under ice-cooling. The mixture was stirred at room temperature for 10 hours. Thereafter, the reaction mixture was poured into 300 ml of water and the whole mixture was extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and then concentrated. The residue was subjected to column chromatography with silica gel (Wacogel C 200), using etherhexane (1:2) as a developing solvent, to give 5.3 g of ethyl 2-(2,6-dichloroanilino)phenylglyoxylate as yellow crystals. m.p. 84°-85° C. Yield: 78% of theoretical amount
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:14]2[C@@H:13]3[CH2:15][C@@H:12]3[CH2:11][C:10]=2[C:9]([C:16]([OH:18])=O)=[N:8]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[Cl-].[C:51]([NH:55][NH3+:56])([CH3:54])([CH3:53])[CH3:52]>C(#N)C>[C:51]([NH:55][NH:56][C:16]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:15][C@H:13]3[C:14]=2[N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1)=[O:18])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)N[NH3+]
Reactant: O=C(O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)NNC(=O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a suspension of (1aR,5aR)-2-(pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1.211 g, 5.0 mmol) and HATU (2.091 g, 5.50 mmol) in acetonitrile (100 mL) was added triethylamine (1.771 g, 17.50 mmol) at room temperature. 2-tert-Butylhydrazinium chloride (0.748 g, 6.00 mmol) was added to the solution and the reaction was stirred for 12 at room temperature. The mixture was concentrated. The residue was diluted with EtOAc (150 mL) and washed with NaHCO3 solution (100 mL). The organic layer was concentrated and purified by silica gel column chromatography to give the title compound (1.42 g) as a glassy solid. LCMS m/z=313.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.49 (dd, J=8.0 and 4.7 Hz, 1H), 1.18 (s, 9H), 1.24-1.29 (m, 1H), 2.29-2.34 (m, 1H), 2.75-2.80 (m, 1H), 2.94 (d, J=16.9 Hz, 1H), 3.03 (dd, J=16.5 and 6.2 Hz, 1H), 4.75 (bs, NH, 1H), 805 (bs, NH, 1H), 8.41 (dd, J=2.5 and 1.5 Hz, 1H), 8.51 (d, J=2.6 Hz, 1H), 9.26 (d, J=1.4 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=[N:19]O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CS(Cl)(=O)=O.C(N(CC)CC)C.C(OCC)(=O)C>C(COC)OC.[Fe](Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[N:13]3[N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(Cc2cccc(Cl)n2)=NO)cc1Br
Agent: Cl[Fe]Cl
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: COc1ccc(-c2cc3cccc(Cl)n3n2)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.1 %

Procedure:
To a solution of 1-(3-bromo-4-methoxyphenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime (1.00 g, 2.8 mmol) in dimethoxyethane (30 mL) at 0° C. was added slowly methylsulfonyl chloride (0.24 mL, 3.08 mmol). The reaction was stirred for 15 minutes and then triethylamine (1.7 mL, 12.3 mmol) in dimethoxyethane (3 mL) was added to the reaction. Upon addition of the triethylamine a precipitate formed. Once the addition of the triethylamine solution had been completed the reaction mixture was allowed to warm to room temperature and was stirred for 1 hour. The precipitate was removed by filteration and the precipitate was washed with dimethoxyethane. To the combined filtrate was added iron (II) chloride (14 mg, 0.12 mmol) and the resulting mixture was heated at 80° C. for 15 hours. The reaction mixture was allowed to cool to room temperature. Ethyl acetate was added to dilute the mixture and the organic phase was washed with water, brine and dried (magnesium sulfate). Filtration and concentration of the filtrate, followed by flash chromatography (4:6 ethyl acetate:hexanes) gave 2-(3-bromo-4-methoxyphenyl)-7-chloropyrazolo[1,5-a]pyridine (86 mg, 9%). 1H NMR (CDCl3): δ 8.21 (d, 1H), 7.95 (d, 1H), 7.48 (d, 1H), 7.10 (t, 1H), 6.98 (d, 1H), 6.88 (d, 1H), 6.84 (s, 1H), 3.96 (s, 3H); MS m/z 337 (M+1).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=3)[NH:12][C:11]=2[C:20]([OH:22])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[N:27]1([CH2:26][CH2:25][CH2:24][NH:23][C:20]([C:11]2[NH:12][C:13]3[C:18]([C:10]=2[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[O:22])[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Product: O=C(NCCCn1ccnc1)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1

Procedure:
Reaction of the 3-phenylsulfonyl-5-chloroindole-2-carboxylic acid with 1-(3-aminopropyl)imidazole under the conditions of Example 37 gave the title compound, mp 216°-217.5° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([CH2:5][C:6](=[O:22])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:13][C@:12]12[CH2:14][CH2:15][C@H:16]3[C@@H:7]([C:6](=[O:22])[CH2:5][CH:4]4[C@:17]3([CH3:20])[CH2:18][CH2:19][C:2](=[O:1])[CH2:3]4)[C@@H:8]1[CH2:9][CH2:10][C:11]2=[O:21]
Reactant: C[C@]12CC[C@H](O)CC1CC(=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: C[C@]12CCC(=O)CC1CC(=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
To a stirred solution of 3β-hydroxyandrostane-7,17-dione (1.65 g), TPAP (0.100 g), NMNO (1.40 g) under N2 in CH2Cl2 (90 mL), molecular sieve type 4 Å powder (2.6 g) was added. After 0.5 h the mixture was filtered and the filtrate was purified by flash chromatography (SiO2, CH2Cl2) to give the title compound II-bp (1.32 g, 81%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 2.82-1.12 (m, 20H), 1.39 (s, 3H), 0.88 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=3)[N:3]=[CH:4]2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccc(Cn2cnc(N)c2C(N)=O)cc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Product: CC(C)(C)c1ccc(Cn2cnc(NC(=O)c3cccc(C(F)(F)F)c3)c2C(N)=O)cc1
Yield: 70 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 1, using 1.91 g (7.01 mmol) of 4-amino-1-(4-t-butylbenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 57 and 3-trifluoromethylbenzoyl chloride instead of benzoyl chloride to obtain 2.17 g of 1-(4-t-butylbenzyl)-4-(3-trifluoromethylbenzoylamino)-5-imidazolecarboxamide (yield 70%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:25][CH:14]2[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH:13]2[CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:25][CH:14]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:17][CH:13]3[CH2:12]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC2CC(N)CC2C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cnc(Cl)nc1NC1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (2.00 g, 12.3 mmol) and tert-butyl 5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (4.64 g, 20.5 mmol) in EtOH (25 mL) was added Et3N (2.62 g, 25.9 mmol). The reaction mixture was stirred at 50° C. overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as yellow oil (2.42 g, 55.9%).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][NH:22][CH2:23][CH2:24][OH:25].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:9][CH:10]([C:12](=[O:14])[N:22]([CH2:23][CH2:24][OH:25])[CH3:21])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNCCO
Reactant: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CN(CCO)C(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A mixture of 1-diphenylmethylazetidine-3-carboxylic acid (see Preparation 58) (1.8 g, 6.73 mmol), 2-methylaminoethanol (0.76 g, 1.5 mol. equiv.), 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide hydrochloride (1.27 g, 1.1 mol. equiv.), 1-hydroxybenzotriazole hydrate (1.08 g, 1.05 mol. equiv.) and N-methylmorpholine (1.5 g, 2.2 mol. equiv.) in dry dichloromethane (50 ml) was stirred at room temperature for sixteen hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate solution (50 ml). The layers were separated and the aqueous layer further extracted with ethyl acetate (30 ml). The combined organic layers were dried over anhydrous sodium sulphate. The solution was filtered, the solvent removed from the filtrate under reduced pressure and the residue chromatographed using silica gel eluting with methanol:dichloromethane (7:93, by volume) to give the title compound (1.76 g). TLC Rf 0.3 (silica, methanol:dichloromethane, 7:93, by volume). LRMS m/z=325(m+1)+. Found C, 71.99; H, 7.60; N, 8.47. C20H24N2O2.0.13 CH2Cl2 requires C, 72.14; H, 7.30; N, 8.36%.