Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[CH:17]1([NH:16][C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=4)[C:22]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)[N:24]=4)=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Brc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: c1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 46.8 %

Procedure:
To a solution of 2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (100 mg, 0.19 mmol) in toluene (10 mL) was added tributyltin hydride (112 mg, 0.39 mmol) and 2,2′-azobisisobutyronitrile (9.4 mg, 0.057 mmol). After heating at reflux for 4 hours, the reaction mixture was allowed to cool to room temperature. Concentration, followed by purification with flash chromatography (40:60 ethyl acetate:hexanes) gave N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-phenylpyrazolo[1,5-a]pyridin-7-amine as a yellow foam (39 mg, 46%). 1H NMR (CDCl3): δ 7.98 (d, 1H), 7.78 (d, 1H), 7.64 (m, 2H), 7.45 (m, 2H), 7.33–7.26 (m, 2H), 6.27 (d, 1H), 6.04 (m, 2H), 5.12 (d, 1H), 4.35 (m, 1H), 4.00 (m, 1H), 2.09–2.03 (m, 4H), 1.81–1.59 (m, 12H). MS m/z 439 (M+1).
Reaction SMILES: [I-:1].[Na+].[CH:3]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1)=[CH2:4]>CC(C)=O>[CH:3]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][I:1])=[CH:7][CH:6]=1)=[CH2:4]
Reactant: [I-]
Reactant: C=Cc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: C=Cc1ccc(CI)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
Sodium iodide (1.2 equiv., 59 g, 0.39 mol) was dissolved in acetone (200 ml) and 4-vinylbenzyl chloride (50 g, 0.33 mol) was added to a reaction flask. The mixture was stirred at room temperature overnight. The reaction mixture was filtered and acetone removed under reduced pressure. The resulting product was dissolved in hexane, filtered, and the solvent removed under reduced pressure. The monomer was isolated as a red, slightly viscous liquid (68 g, yield 84%). 1H NMR (CDCl3) δ (ppm) 4.47 (s, 2H), 5.25 (d, 1H), 5.74 (d, 1H), 6.65 (dd, 1H), 7.34 (m, 4H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([F:14])[C:12]=1[CH3:13])[C:7]([OH:9])=O)=[N+:2]=[N-:3].[NH2:15][C:16]1[C:17]([O:31][CH3:32])=[C:18]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1.N(C1C=C(C=CC=1C)C(NC1C=C(C(C)(C)C)C=C(NS(C)(=O)=O)C=1OC)=O)=[N+]=[N-]>>[N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([F:14])[C:12]=1[CH3:13])[C:7]([NH:15][C:16]1[CH:21]=[C:20]([C:22]([CH3:24])([CH3:25])[CH3:23])[CH:19]=[C:18]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:17]=1[O:31][CH3:32])=[O:9])=[N+:2]=[N-:3]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Cc1c(F)cc(C(=O)O)cc1N=[N+]=[N-]
Agent: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2cc(F)c(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
3-Azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-5-fluoro-4-methyl-benzamide was prepared from 3-azido-5-fluoro-4-methyl benzoic acid (U.S. Ser. No. 04/102,492) and N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in the same manner as 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide (Example 15).
Reaction SMILES: [CH3:1][N:2]([C:19]1[CH:20]=[N:21][C:22]([N:32](C)[C:33](=O)C(F)(F)F)=[CH:23][C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][N:2]([C:19]1[CH:20]=[N:21][C:22]([NH:32][CH3:33])=[CH:23][C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])[C:3](=[O:18])[C:4]1[CH:5]=[C:6]([C:14]([F:16])([F:17])[F:15])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: Cc1ccccc1-c1cc(N(C)C(=O)C(F)(F)F)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CNc1cc(-c2ccccc2C)c(N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1

Procedure:
N-Methyl-N-(4-o-tolyl-6-(2,2,2-trifluoro-N-methylacetamido)pyridin-3-yl)-3,5-bis (trifluoromethyl)benzamide (70 mg, 0.12 mmol) was stirred in CH3OH (1.5 mL) with potassium carbonate (75 mg, 0.54 mmol) for 1 h. The reaction mixture was then filtered and all volatiles removed under reduced pressure. The residue was dissolved in EtOAc and washed twice with water and twice with brine. The aqueous phases were back-extracted twice with EtOAc and washed with brine. The combined organic layers were dried over Na2SO4. Filtration followed by removal of volatiles under reduced pressure gave a waxy residue. N-Methyl-N-(6-methylamino-4-o-tolyl-pyridin-3-yl)-3,5-bis-trifluoromethyl-benzamide was isolated from this residue by flash chromatography on silica gel (50-67% EtOAc in n-hexane) as a white foam (40 mg, 69%). MS (ESI): m/z=468.0 [M+H]+.
Reaction SMILES: CS([CH:5]([OH:15])[CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])(=O)=O.[I:16][C:17]1[CH:18]=[C:19](O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.CCCCCC>[I:16][C:17]1[CH:22]=[C:21]([CH:20]=[CH:19][CH:18]=1)[O:15][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14]
Reactant: Oc1cccc(I)c1
Reactant: COCCOCCOCC(O)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOCCOCCOc1cccc(I)c1
Temperature: 68 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
To a solution of 1-[(methanesulfonyl)-oxyl-3,6,9-trioxadecane (11.6 g, 47.9 mmol) in dry DMF (145 ml) was added 3-iodophenol (10.6 g, 48.2 mmol) and potassium carbonate (6.6 g, 47.8 mmol). The reaction was immersed in an oil bath which was warmed to 68° C. over a period of 0.5 hr. The reaction was stirred at this temperature under an N2 atmosphere for 16 hrs and then at 82° C. for an additional 2 hrs. At the end of this period, the reaction was cooled, diluted with DMF, filtered through a pad of celite and evaporated in vacuo. The resulting residue was taken up into ethyl acetate (500 ml), washed with water (200 ml), 1 N aqueous sodium hydroxide (200 ml) and brine (200 ml), dried (Na2SO4), filtered and evaporated in vacuo to provide a light brown oil. Flash column chromatography (silica, 1:3 to 1:2; EtOAc:hexane) provided 1 -(3-iodophenoxy)-3,6,9-trioxadecane as a light yellow oil (10.8 g, 37.1%).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[C:10]([Cl:22])[CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28]Cl)[CH3:25].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:25][CH2:24][N:26]([CH2:30][CH3:31])[CH2:27][CH3:28])[C:15]=2[C:14]2[C:9]1=[C:10]([Cl:22])[CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc2c1c1cccc(Cl)c1n2Cc1ccccc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc2c1c1cccc(Cl)c1n2Cc1ccccc1
Yield: 61.4 %

Procedure:
9-Benzyl-8-chloro-9H-carbazol-4-ol (0.0826 g, 0.27mmol), 2-diethylaminoethylchloride hydrochloride (0.0719 g, 0.42 mmol), potassium carbonate (0.1157 g, 0.84 mmol), sodium iodide (0.0031 g, 0.021 mmol) and DMF (1 mL) are heated at 85° C. for 4 h. After the mixture had cooled, it is partitioned between water and ether. The combined organic layers are dried over magnesium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (30 mL) using methanol/dichloromethane (1/99 to 2/98 to 4/96) to give 0.0675 g (62%) of the title compound: mp 73.5-75° C.; MS (ESI+) for C25H27ClN2O m/z 407.3 (M+H)+; IR (drift) 2966, 1588, 1499, 1454, 1413, 1355, 1337, 1266, 1124, 1027, 789, 732, 727, 717, 697 cm−1; 1H NMR (CDCl3) δ1.13, 2.72, 3.10, 4.33, 5.99, 6.71, 6.96, 7.10, 7.15-7.26, 7.33, 8.33. Anal. Calcd for C25H27ClN2O: C, 73.79; H, 6.69; N, 6.88. Found: C, 73.47; H, 6.81; N, 6.76.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([CH3:14])[O:11][CH:10]([CH3:15])[CH2:9]1)C1C=CC=CC=1.[C:16]([OH:19])(=[O:18])[CH3:17]>C(O)C.[OH-].[OH-].[Pd+2]>[C:16]([OH:19])(=[O:18])[CH3:17].[CH3:15][CH:10]1[O:11][CH:12]([CH3:14])[CH2:13][NH:8][CH2:9]1
Reactant: CC1CN(Cc2ccccc2)CC(C)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1CNCC(C)O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
4-Benzyl-2,6-dimethylmorpholine (10.72 mg, 45.76 mmol) was dissolved in acetic acid (10 mL) and ethanol (200 mL), and 10% palladium hydroxide/carbon (5 g) was added thereto. The mixture was stirred for two days at room temperature under a hydrogen stream at normal pressure. The catalyst was separated by filtration, and then the reaction liquor was concentrated under reduced pressure and dried, to obtain the title compound (7.36 g, 92%) as an oily matter. This compound was used in the subsequent reaction without performing further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9](Br)[CH:8]=[N:7][C:6]=1[NH:12][CH3:13])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O1CCOCC1>O>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=[N:7][C:6]=1[NH:12][CH3:13])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)cnc1NC
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)cnc1NC
Yield: 44 %

Procedure:
A mixture of 5-bromo-2-methylamino-nicotinic acid ethyl ester (100 mg, 0.39 mmol), potassium carbonate (160 mg, 1.16 mmol), dichloro[1,1′-bis(diphenylphosphine)ferrocene]palladium(II); (28 mg, 39 μmol) and phenylboronic acid (146 mg, 1.16 mmol), 1,4-dioxane (0.9 mL), and water (0.11 mL) was heated at reflux for 3 h, then partitioned between ethyl acetate and sat. aq. ammonium chloride solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (44 mg, 44%). Yellow liquid, MS (EI): 256.2 (M+).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:8]2[CH2:9][C:10]3[S:14][C:13]([SH:15])=[N:12][C:11]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1)C.[C:21]1([CH:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:29]I)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:28][CH2:29][S:15][C:13]2[S:14][C:10]3[CH2:9][C:8]4[C:7]([O:6][CH2:5][C:4]([OH:3])=[O:20])=[CH:19][CH:18]=[CH:17][C:16]=4[C:11]=3[N:12]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ICCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1Cc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1Cc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 34 %

Procedure:
Using ethyl[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and 3,3-diphenylpropyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 34%.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].FC(F)(F)C(O)=O.[CH2:37]1[C:40]2([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:39][O:38]1.COC(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:43]4[CH2:44][CH2:45][C:40]5([CH2:37][O:38][CH2:39]5)[CH2:41][CH2:42]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: C1CC2(CCN1)COC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC4(CC3)COC4)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.075 g, 0.19 mmol), 2-oxa-7-azaspiro[3.5]nonane trifluoroacetate (0.05 g, 0.20 mmol) in DCE (2 mL), trimethoxymethane (0.204 mL, 1.9 mmol) and acetic acid (0.011 mL, 0.2 mmol) was stirred for 2 h at room temperature. Sodium triacetoxyborohydride (0.061 g, 0.29 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was partitioned between DCM and water, the organic layer was separated, washed with brine, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM gradient 0:100 to 10:90) to give 324 as a white solid (0.066 g, 70%). LCMS (Method G): RT=5.88 min, [M+H]+ 503.2. 1H NMR (CDCl3, 400 MHz) δ 8.03-7.99 (m, 1 H); 7.83-7.79 (m, 1 H); 7.33-7.29 (m, 2 H); 4.48-4.37 (m, 4 H); 4.34-4.30 (m, 4 H); 3.90-3.84 (m, 7 H); 3.76-3.72 (m, 2 H); 3.40 (d, J=8.3 Hz, 2 H); 2.49-2.44 (m, 4 H); 1.95-1.91 (m, 4 H); 1.48 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.C(Cl)(=O)C([Cl:36])=O>ClCCl.CN(C)C=O>[O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH:25]([C:28]([Cl:36])=[O:29])[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(C(=O)O)C3)c2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(C(=O)Cl)C3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
To a cooled solution of 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidine-3-carboxylic acid (120 mg, 0.26 mmol) in dichloromethane (20 mL) was added two drops of N,N-dimethylformamide followed by oxalyl chloride (30.6 μL, 0.39 mmol) at 0° C. After being stirred for 16 hours at room temperature, the reaction mixture was concentrated in vacuo to afford 100 mg of the crude product which was used for the next step without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[N:14]=[C:13](O)[N:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:17]=1.N1C2C3C=CC=CC=3CCC=2C=NC=1O.O=P(Cl)(Cl)[Cl:35]>>[Cl:35][C:13]1[N:12]=[CH:11][C:10]2[CH2:9][CH2:8][C:7]3[CH:17]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[C:15]=2[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(c1)CCc1cnc(O)nc1-2
Agent: Oc1ncc2c(n1)-c1ccccc1CC2
Product: COc1ccc2c(c1)CCc1cnc(Cl)nc1-2
Temperature: 100 °C
Yield: 86 %

Procedure:
A suspension of 8-Methoxy-5,6-dihydro-benzo[h]quinazolin-2-ol as a 1:1 urea complex from preparation 1 (20 g, 69.0 mM) in POCl3 (350 ml) was heated under nitrogen atmosphere at 100° C. for 20 hr. The POCl3 was removed under reduced pressure and the residue was suspended in dichloromethane (300 ml) and cooled in an ice bath and then concentrated sodium bicarbonate (500 ml) was carefully added followed by 1 N NaOH (200 ml) and the phases separated. The aqueous phase was extracted with dichloromethane (3×500 ml) and the pooled organic phases were dried over Na2SO4, filtered and the filtrate evaporated under reduced pressure to give 2-Chloro-8-methoxy-5,6-dihydro-benzo[h]quinazoline (2, 14.46 g, 86% yield) as a yellow solid. ES-MS MH+ 247.1. 1H NMR (300 MHz, ppm, DMSO-d6): 8.54 (s, 1H), 8.09 (d, 1H), 6.99 (m, 3H) 3.84 (s, 3H), 2.91 (m, 4H).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:27]([CH3:30])([CH3:29])[CH3:28])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:26])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][Si](C)(C)C)[CH:15]=[CH:14][C:13]=1[O:24][CH3:25])[CH2:2][CH2:3][CH3:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[CH2:1]([C:5]1=[CH:6][N:7]([C:27]([CH3:28])([CH3:30])[CH3:29])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:26])[C:12]1[CH:17]=[C:16]([C:18]#[CH:19])[CH:15]=[CH:14][C:13]=1[O:24][CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(C#C[Si](C)(C)C)ccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(OC)c(C(=O)/N=c2\sn(C(C)(C)C)cc2CCCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
The product from Example 62A (300 mg, 0.68 mmol) in THF (10 mL) was treated with TBAF (1M) (1.7 mL, 1.7 mmol), stirred at rt for 1 hr, diluted with H2O and extracted with EtOAc (2×). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 183 mg (73%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 0.98 (t, J=7.36 Hz, 3 H) 1.36-1.50 (m, 2 H) 1.65 (s, 9 H) 1.67-1.77 (m, 2 H) 2.83 (dd, J=7.98 Hz, 2 H) 2.99 (s, 1 H) 3.94 (s, 3 H) 6.93 (d, J=8.59 Hz, 1 H) 7.52 (dd, J=8.59, 2.15 Hz, 1 H) 7.93 (s, 1 H) 8.28 (d, J=2.15 Hz, 1 H); MS (DCI/NH4+) m/z 371 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][C:7]([N:9]1[CH2:14][C@H:13]([CH3:15])[N:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11][C@H:10]1[CH3:24])=[O:8].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.C([O:48][C:49](=[O:56])[CH:50]([S:52](Cl)(=[O:54])=[O:53])[CH3:51])C>O1CCCC1.C(OCC)(=O)C>[Cl:29][C:27]1[CH:26]=[CH:25][C:4]([O:5][CH2:6][C:7]([N:9]2[CH2:14][C@H:13]([CH3:15])[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:11][C@H:10]2[CH3:24])=[O:8])=[C:3]([CH:28]=1)[CH2:2][NH:1][S:52]([CH:50]([CH3:51])[C:49]([OH:56])=[O:48])(=[O:54])=[O:53]
Reactant: CCOC(=O)C(C)S(=O)(=O)Cl
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CN
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C(=O)O)S(=O)(=O)NCc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C

Procedure:
To a solution of 2-(2-aminomethyl-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.05 g, 0.119 mmol) in tetrahydrofuran (1 ml) at −40° C. was added triethylamine (0.021 ml, 0.151 mmol), catalytic dimethylaminopyridine and finally a solution of 2-chlorosulfonyl-propionic acid ethyl ester (for preparation, see: Helv. Chim. Acta., (1997) 80, 671 and Bull. Soc. Chim. Fr. (1975), 807) (0.029 g, 0.145 mmol) in tetrahydrofuran (0.25 ml), added over 5 minutes. The reaction was allowed to warm to ambient temperature. After 23 hours the reaction was diluted with ethyl acetate and washed with pH 7 phosphate buffer (0.5 M). The organic layer was dried over magnesium sulfate, filtered and concentrated. The desired product was isolated via silica gel chromatography (0.047 g). This ester (0.07 mmol) was dissolved in 1:1 tetrahydrofuran:water (1 ml) and lithium hydroxide hydrate (5.8 mg, 0.138 mmol) was added. After 21 hours the reaction was concentrated and the title compound obtained after silica gel chromatography (0.039 g, LRMS: 556.1).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])O.[Na+].[Cl:16][CH2:17]OS(Cl)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.ClCCl.ClCCl>[C:1]([O:10][CH2:17][Cl:16])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)O
Reactant: O=S(=O)(Cl)OCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: ClCCl
Product: CCCCCCCC(=O)OCCl
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
Compound 43 was prepared by a procedure similar to that of Harada and co-workers (Harada, N. et al. Synth. Commun. 1995, 25, 767-772). To a vigorously stirring solution of octanoic acid (4.50 g, 31.2 mmol), sodium hydrogen carbonate (10.48 g, 124.8 mmol) and tetra-n-butylammonium hydrogen sulfate (1.06 g, 3.12 mmol) in water-dichloromethane (125 mL, 1:1 v/v) at 0° C. was added chloromethylchlorosulfate (5.15 g, 31.2 mmol) in dichloromethane (15 mL), and the reaction stirred at room temperature for a further 18 h. The mixture was diluted with dichloromethane (150 mL) and washed with brine (150 mL), dried over anhydrous magnesium sulfate and the solvent removed in vacuo. Purification by flash chromatography (hexane/ethyl acetate 9:1) afforded 43 as a yellow oil (5.28 g, 27.3 mmol, 88%). 1H NMR (400 MHz, CDCl3) δ 0.86-0.90 (3H, m, Me), 1.24-1.37 (8H, m, CH3(CH2)4), 1.60-1.71 (2H, m, CH2CH2COO), 2.36-2.40 (2H, m, CH2CH2COO), 5.71 (2H, s, CH2Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1([C:20]2[N:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][CH:21]=2)[CH:19]=[N:18][CH:17]=[N:16]1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:26]([C:23]2[CH:24]=[N:25][C:20]([N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)=[CH:21][CH:22]=2)=[O:27])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(-n2cncn2)nc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(-n2cncn2)nc1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (40 mg) and 6-(1H-1,2,4-triazol-1-yl)pyridine-3-carboxylic acid to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(1H-1,2,4-triazol-1-yl)pyridine-3-carboxamide. MS (Q1) 377.0 (M)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.N1C=CC=CC=1.[C:39]1([S:49](Cl)(=[O:51])=[O:50])[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][CH:40]=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:49]([C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)(=[O:51])=[O:50])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4cccc5ccccc45)ccc3N2)=C(O)c2ccccc21
Yield: 101.6 %

Procedure:
A mixture of Example 39H (23.8 mg, 0.050 mmol), pyridine (31.6 mg, 0.80 mmol), and 1-naphthalenesulfonyl chloride (45.3 mg, 0.20 mmol) in acetone (1.5 mL) was stirred at rt for 72 h. The reaction mixture was evaporated in vacuo and partitioned between ethyl acetate and 1 N HCl. The organic phase was separated, dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with 99:1 dichloromethane/methanol to provide the title compound (32.0 mg, quant. yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[N:19]=[CH:20][NH:21][C:22]=1[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[CH:20]=[N:21][C:22]([C:23]#[N:24])=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1[nH]cnc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Yield: 38.4 %

Procedure:
Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251 mg, 1.0 mmol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (124 mg, 38%). MS (ISP) 323.1 [(M+H)+]; mp 205° C.