Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1.[S:35]1[CH:39]=[CH:38][N:37]=[C:36]1[NH2:40].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:40][C:36]4[S:35][CH:39]=[CH:38][N:37]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: Nc1nccs1
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A vial was charged with perfluorophenyl 1-(4-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE NNN) (82.4 mg, 0.160 mmol), thiazol-2-amine (17.60 mg, 0.176 mmol), and THF (799 μl) to give a clear, colorless solution. The vial was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (335 μl, 0.335 mmol) was added drop wise. After 30 min, the mixture was warmed to room temperature and loaded onto a 5-g silica gel loading column with the aid of DCM. The column was dried under vacuum for 5 min then eluted onto a pre-equilibrated 12-g column with 0 to 10% MeOH/DCM to give 1-(4-chloro-2-methoxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (54 mg, 0.125 mmol, 78% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=13.21-11.96 (m, 1H), 8.73-8.62 (m, 1H), 8.52 (d, J=1.8 Hz, 1H), 8.17-8.02 (m, 1H), 7.85 (dd, J=1.9, 8.9 Hz, 1H), 7.75-7.66 (m, 1H), 7.36-7.25 (m, 3H), 7.18 (dd, J=2.0, 8.0 Hz, 1H), 6.85 (d, J=4.6 Hz, 1H), 3.67 (s, 3H); m/z (ESI) 432.2 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][N+:14]([O-:25])=[CH:15][CH:16]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1cc[n+]([O-])cc1

Procedure:
To a stirred solution of 28.8 g of 4-(tert-butyl-dimethysilyloxyethyl)-pyridine in 300 ml of methylene chloride is added 24 g of m-chloroperbenzoic acid. After 4 hours the solution is washed with aqueous sodium carbonate solution and water. The solution is dried over sodium sulfate, filtered and concentrated in vacuo to yield 4-(tert-butyl-dimethylsilyloxyethyl)-pyridine-N-oxide.
Reaction SMILES: C([O:4][C:5]1[C:10]2[C:11]([CH3:21])=[C:12](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)C=C.C(O[C:25]([C:27]1OC2C=CC=C(OCC=C)C=2[C:31]=1C)=O)C>>[CH2:31]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]([CH3:21])[C:10]=2[C:5]=1[OH:4])[CH:27]=[CH2:25]
Reactant: C=CCOc1cccc2oc(C(=O)OCC)c(C)c12
Reactant: C=CCOc1cccc2oc(/C=C/C(=O)OCC)c(C)c12
Product: C=CCc1ccc2oc(/C=C/C(=O)OCC)c(C)c2c1O

Procedure:
Following the procedure of Example 134 but substituting an equivalent amount of the title compound of Example 167 for ethyl-4-allyloxy-3-methylbenzofuran-2-carboxylate, there was obtained the title compound, m.p. 125°-127° C.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH:7]([N:15]([C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[Cl:38])[CH2:16][C:17]1[S:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:38][C:32]1[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:31]=1[C:30]([N:15]([CH2:16][C:17]1[S:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:23]=[C:24]([F:29])[CH:25]=[C:26]([F:28])[CH:27]=1)[CH:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:6]([OH:40])=[O:5])=[O:39]
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1)N(Cc1sccc1-c1cc(F)cc(F)c1)C(=O)c1ccc(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(Cc1ccccc1)N(Cc1sccc1-c1cc(F)cc(F)c1)C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a stirred solution of 2-{(2,4-Dichloro-benzoyl)-[3-(3,5-difluoro-phenyl)-thiophen-2-ylmethyl]-amino}-3-phenyl-propionic acid tert-butyl ester (37.63 mg, 0.0625 mmol.) in dichloromethane (1 ml.), was added trifluoroacetic acid (1 ml.). The reaction mixture was stirred at room temperature during 1 hr. TLC monitored the progress of the reaction. When the reaction was completed, the mixture was concentrated under reduced pressure on a rotary evaporator, followed by silica chromatography using 90% ethylacetate, 10% methanol and 1 drop of acetic acid, afforded 2-{(2,4-Dichloro-benzoyl)-[3-(3,5-difluoro-phenyl)-thiophen-2-ylmethyl]-amino}-3-phenyl-propionic acid in 85% yield. 1H NMR (Varian 400 MHz, CDCl3) δ(ppm), 7.22 (m, 8H, ArH), 7.00 (m, 2H, ArH), 6.82 (m, 2H, ArH), 6.50 (m, 1H, ArH), 4.95 (m, 0.5H, NCH2), 4.65 (m, 0.5H, NCH2), 4.10 (m, 1H, NCH2), 3.60 (m, 1H, CHCH2), 3.20 (m, 1H, CHCH2), 3.05 (m, 1H, CHCH2). MS, 546.00 found.
Reaction SMILES: [NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24](O)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH2:31][C:32]([NH:34][CH2:35][C:36]1[CH:37]=[C:38]([CH2:42][NH2:43])[CH:39]=[CH:40][CH:41]=1)=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:31][C:32]([NH:34][CH2:35][C:36]1[CH:37]=[C:38]([CH2:42][NH:43][C:24](=[O:25])[C@@H:7]([CH2:6][CH2:5][CH2:4][NH:3][C:2]([NH2:1])=[N:27][N+:28]([O-:30])=[O:29])[NH:8][C:9](=[O:23])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:39]=[CH:40][CH:41]=1)=[O:33]
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)O
Reactant: NCc1cccc(CNC(N)=O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: NC(=O)NCc1cccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)c1
Yield: 50 %

Procedure:
Prepared analogously to Example 4b) from (R)-N5 -[amino(nitroimino]methyl]-N2 -(diphenylacetyl)-ornithine, 3-(amino-carbonylaminomethyl)benzenemethanamine and TBTU in a yield of 50% of theory. Colourless amorphous substance.
Reaction SMILES: [CH2:1]([C:7]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:12]2[S:13][CH2:14][CH2:15][C:11]=2[C:10]2[C:16](O)=[CH:17][C:18](C)=[CH:19][C:9]=2[O:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[BrH:28].[N:29]1([CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1>>[BrH:28].[CH2:22]([C:7]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:12]2[S:13][CH2:14][CH2:15][C:11]=2[C:10]2[C:16]([O:38][C:37](=[O:39])[CH2:36][CH2:35][CH2:34][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:17][CH:18]=[CH:19][C:9]=2[O:8]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)CCCN1CCCC1
Reactant: CCCCCCC1(CCCCCC)Oc2cc(C)cc(O)c2C2=C1SCC2
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCCC1(CCCCCC)Oc2cccc(OC(=O)CCCN3CCCC3)c2C2=C1SCC2

Procedure:
By reacting 1,2-dihydro-9-hydroxy-7-methyl-4-oxo-4H-thieno[2,3-c][1]benzopyran with n-hexyl magnesium bromide, using the procedure described in Example 8, there is obtained 4,4-di(1-hexyl)-1,2-dihydro-9-hydroxy-7-methyl-4H-thieno[2,3-c][1]benzopyran. The benzopyran is then reacted with γ-pyrrolidinobutyric acid, hydrobromide salt and dicyclohexylcarbodiimide according to the method of Example 10 to yield the desired ester.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][OH:5].C(N(CC)CC)C.[N:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1>C(Cl)Cl>[OH:5][CH2:4][CH:3]([NH:2][S:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][C:20]2[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=2)=[CH:29][CH:28]=1)(=[O:31])=[O:32])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccncc2)cc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CO)NS(=O)(=O)c1ccc(Oc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled mixture of 6.84 g (44 mmol) of D, L-serine, methyl ester hydrochloride and 21.4 (144 mmol) of triethylamine in 90 ml of CH2Cl2 was added a solution of 10.78 g (40 mmol) of 4-(4-pyridinyloxy)benzenesulfonyl chloride in 50 ml of CH2Cl2. The mixture was stirred at room temperature overnight, diluted with 50 ml of CH2Cl2 and the solution washed with H2O, 1N NaHCO3, 2N citric acid, brine and dried (with Na2SO4). The solvent was removed under vacuum to give a solid. The aqueous 2N citric acid wash was made basic with saturated NaHCO3 and then extracted with CH2Cl2. The solvent was removed to give a solid. The two crops of solid were combined, washed with H2O and then hexane. The solid was dried at 80° C. to give 10.95 g of methyl 3-hydroxy-2-[4-(4-pyridinyloxy)-benzenesulfonylamino]propionate as white crystals, mp. 137-139° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: N#Cc1ccc(N)cc1
Product: Cc1cc(Nc2cc3ccccc3c(Nc3ccc(C#N)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-amino-benzonitrile to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ylamino]-benzonitrile. LC-MS m/e 341(MH+). 1H NMR(DMSO): δ 2.26(s, 3H), δ 5.82(s, 1H), δ 6.52(m, 1H), δ 7.25(t, 1H), δ 7.35(br, 1H), δ 7.55(m, 2H), δ 7.71(d, 2H), δ 8.22(d,2H), δ 8.32(d, 1H), δ 8.79(s, 1H), δ 9.47(s,1H), δ 11.75(s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[N:14]([CH3:15])[CH:13]=[CH:12][C:7]=2[C:8](Cl)=[N:9][CH:10]=1)=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].CS(O)(=O)=O>O1CCOCC1.CO>[CH3:1][O:2][C:3]([C:5]1[C:6]2[N:14]([CH3:15])[CH:13]=[CH:12][C:7]=2[C:8]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:17]([Cl:16])[CH:18]=2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(Cl)c2ccn(C)c12
Reactant: Nc1cccc(Cl)c1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cnc(Nc2cccc(Cl)c2)c2ccn(C)c12

Procedure:
4-Chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid methyl ester (1.04 g), 3-chloroaniline (0.97 ml) and methanesulfonic acid (0.60 ml) in 1,4-dioxan (10 ml) were irradiated at 180° C. for 30 minutes with microwaves. The solid mass obtained was dissolved in methanol and the solvent evaporated. The residue was dissolved in ethyl acetate and washed with water followed by saturated brine solution then dried (MgSO4)), filtered and evaporated to yield a brown oil (1.6 g). The brown oil was purified by column chromatography on a Biotage® 40M column eluting in 20% ethyl acetate/iso-hexane, to give the title compound as an off-white solid (0.62 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C(COC3C=C(C(O)=O)N(C)N=3)=C(CO)O[N:34]=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([NH2:34])=[O:23])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)O
Reactant: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)O
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(N)=O
Yield: 25 %

Procedure:
As described for example 93b, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.28 mmol), instead of 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid, was converted to the title compound (25 mg, 25%) which was obtained as a white solid. MS: m/e=363.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[C:6]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39].[H-].[Na+].[F:42][C:43]([F:52])([F:51])[C:44]1[CH:45]=[CH:46][C:47](Cl)=[N:48][CH:49]=1>C1COCC1>[F:42][C:43]([F:52])([F:51])[C:44]1[CH:45]=[CH:46][C:47]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=3)[C:6]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH3:39])=[N:48][CH:49]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCOc1ccc(C(F)(F)F)cn1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 64.9 %

Procedure:
4-i-Propyl-phenyl sulfamic acid-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (50 mg, Example 3) was dissolved in THF (8 ml). Sodium hydride (12 mg, 60% dispersion in mineral oil) was added and stirring continued for 10 min. 5-Trifluoromethyl-2-chloro-pyridine (28 mg) was added and the mixture was heated to 60° C. for 180 min. The solvents were evaporated, water (12 ml) and a 10% solution of citric acid was added until the pH was 3. The precipitate was filtered off, washed with water and purified by recrystallization with diethylether to give 4-i-propyl-phenyl sulfamic acid-[6-[2-(5-trifluoromethyl-pyridin-2-yloxy)-ethoxy]-5-(o-methoxy-phenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (41 mg). tR=5.81 min, (LC); [M+H]+=697.17 (ES+).
Reaction SMILES: C(Cl)Cl.Cl[CH:5]1[NH:10][CH:9]=[CH:8][N:7]2[C:11]([CH:30]3[CH2:33][CH2:32][CH2:31]3)=[N:12][C:13]([C:14]3[CH:23]=[C:22]4[C:17]([N:18]=[CH:19][C:20]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:21]4)=[CH:16][CH:15]=3)=[C:6]12.[N:34]#N.N>CC(O)C>[CH:30]1([C:11]2[N:7]3[CH:8]=[CH:9][N:10]=[C:5]([NH2:34])[C:6]3=[C:13]([C:14]3[CH:23]=[C:22]4[C:17](=[CH:16][CH:15]=3)[N:18]=[CH:19][C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:21]4)[N:12]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: ClC1NC=Cn2c(C3CCC3)nc(-c3ccc4ncc(-c5ccccc5)nc4c3)c21
Reactant: N#N
Agent: N
Solvent: ClCCl
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4ncc(-c5ccccc5)nc4c3)c12
Temperature: 100 °C

Procedure:
DCM solution of 7-(8-chloro-3-cyclobutyl-7,8-dihydroimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoxaline (61 mg, 0.15 mmol) was evaporated to dryness by passing a stream of N2. The residue was suspended in anh. i-PrOH (4 mL) and the suspension was saturated with gaseous NH3 at 0° C. (2 min). The reaction vessel was sealed and heated to 100° C. (external temperature) for 63 h. Then the reaction was cooled to rt, concentrated under reduced pressure and purified by flash chromatography (silica gel, 0-5% MeOH in DCM) and then preparative TLC (4% MeOH in CH3CN) to afford the title compound as a light yellow solid; 1H NMR (400 MHz, CDCl3) δ 9.36 (d, J=4 Hz, 1H), 8.43 (s, 1H), 8.30-8.25 (m, 4H), 7.65-7.50 (m, 3H), 7.15 (m, 2H), 5.26 (br, 2H), 3.86 (quintet, J=8 Hz, 1H), 2.75-2.60 (m, 2H), 2.60-2.45 (m, 2H), 2.20 (q, J=8 Hz, 1H), 2.07 (br, 1H). MS (ES+): m/z 393.1 (100) [MH+]; HPLC: tR=2.30 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1([C:9]([O:11]C(C)(C)C)=[O:10])[CH2:6][CH:5]([CH2:7][NH2:8])[CH2:4][O:3]1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN1CCOCC1>>[CH3:1][C:2]1([C:9]([OH:11])=[O:10])[CH2:6][CH:5]([CH2:7][NH:8][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:4][O:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)C1(C)CC(CN)CO1
Solvent: CN1CCOCC1
Product: CC1(C(=O)O)CC(CNC(=O)c2ccccc2)CO1

Procedure:
At room temperature, to a solution of 2-methyl-4-aminomethyl-2-tetrahydrofuroic acid, tert-butyl ester (30 mg, 0.139 mmole) was added benzoyl chloride (0.167 mmol, 24 mg) and N-methylmorpholine (0.334 mmol, 34 mg). After being stirred at room temperature for 2.5d, volatiles were removed and the residue was flash chromatographed through silica gel. The title compound was obtained in quantitative yield (47 mg). TLC: Rf=0.45 (1:1 hexane:ethyl acetate); Mass Spectrum: ESI m/e 320 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C(C)(C)C)[C:5]([I:15])=[CH:4][CH:3]=1>Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([I:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)ccc1I
Agent: Cl
Product: Nc1nc(Cl)ccc1I
Temperature: 25 °C

Procedure:
A suspension of N-(6-chloro-3-iodopyridin-2-yl)-2,2-dimethyl propionamide (Preparation 108, 5.0 g, 14.8 mmol) in 1M HCl was heated to reflux for 4.5 h. The reaction was cooled to rt and then extracted with diethyl ether (2×50 mL). The organics were washed with Na2CO3 solution (2×50 mL) before being dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (SiO2, CH2Cl2) afforded the title compound. δH (CDCl3): 7.76 (1H, d), 6.46 (1H, d), 5.43–5.20 (2H, br s).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH2:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20](Cl)(=[O:23])[CH:21]=[CH2:22].C(N(CC)CC)C>ClCCl>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([NH:19][C:20](=[O:23])[CH:21]=[CH2:22])([CH3:17])[CH3:18])=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(N)c1ccc(OCc2ccccc2)cc1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)NC(C)(C)c1ccc(OCc2ccccc2)cc1

Procedure:
1-(4-Benzyloxyphenyl)-1-methylethylamine hydrochloride (25.0 g) was treated with acryloyl chloride (8.43 ml) in dichloromethane (250 ml) containing triethylamine (14.4 ml) to give N-[1-(4-benzyloxyphenyl)-1-methylethyl]acrylamide, m.p. 116-117° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH:16]([N:18]([CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH2:36][CH3:37])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].C(O)(=O)C>C(O)C>[C:22]([O:21][C:19]([N:18]([CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH2:36][CH3:37])[CH:16]([CH3:17])[CH2:15][C:9]1[CH:8]=[C:7]2[C:12](=[C:11]([C:13]#[N:14])[CH:10]=1)[NH:4][CH2:5][CH2:6]2)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc(C#N)c2c(c1)CCN2C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc(C#N)c2c(c1)CCN2
Yield: 86.8 %

Procedure:
To a solution of 1-acetyl-5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carbonitrile (167 mg) in ethanol (2.2 ml) was added a 5N-sodium hydroxide solution (1.1 ml), and the mixture was reacted at room temperature for 2.5 hours. The reaction mixture was neutralized by adding acetic acid, and extracted with methylene chloride. The extract was washed with water and a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 133 mg of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carbonitrile as an oil.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]2[C:8]([CH3:13])=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[N:5]=[C:4]1[CH3:14].[I:15][C:16]1[CH:21]=[C:20](I)[N:19]=[CH:18][N:17]=1>C(O)CCC>[I:15][C:16]1[N:17]=[CH:18][N:19]=[C:20]([NH:12][C:10]2[CH:9]=[C:8]([CH3:13])[C:7]3[N:3]([CH3:2])[C:4]([CH3:14])=[N:5][C:6]=3[CH:11]=2)[CH:21]=1
Reactant: Cc1cc(N)cc2nc(C)n(C)c12
Reactant: Ic1cc(I)ncn1
Agent: Cl
Solvent: CCCCO
Product: Cc1cc(Nc2cc(I)ncn2)cc2nc(C)n(C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
150 mg (0.700 mmol) 1,2,7-trimethyl-1H-benzimidazol-5-ylamine hydrochloride, 260 mg (0.800 mmol) 4,6-diiodopyrimidine, 0.300 mL (2.00 mmol) TEA and 5.0 mL 1-butanol were combined and stirred for 1 h at RT. The reaction mixture was evaporated down and the residue was extracted with DCM and 1N aqueous sodium hydroxide solution. The organic phase was dried on sodium sulphate, filtered and evaporated down.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Br[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6][OH:7]
Reactant: BrCCc1ccccc1
Reactant: OCCNCCO
Product: OCCN(CCO)CCc1ccccc1

Procedure:
2-[(2-Hydroxy-ethyl)-(2-phenyl-ethyl)-amino]ethanol was prepared according to the general method as outlined in example 1. Starting from diethanolamine (6.0 g, 57), and 2-bromo-ethylbenzene (9.0 g, 48.3 mmol). Yield 9 g, (90%); yellow oil; MS: 210 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:11]2[CH:16]=[C:15]([Cl:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:11]3[CH:16]=[C:15]([Cl:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1OC
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(Cl)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2,6-dichloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-chloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[N:6]([C@H:9]3[CH2:14][C@H:13]([OH:15])[C@@H:12]([CH2:16][OH:17])[O:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.CN(C=O)C.N1C=CN=C1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>O>[Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[N:6]([C@H:9]3[CH2:14][C@H:13]([OH:15])[C@@H:12]([CH2:16][O:17][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[O:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H]1OC[C@@H](n2cnc3cc(Cl)c(Cl)cc32)C[C@@H]1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1OC[C@@H](n2cnc3cc(Cl)c(Cl)cc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a stirred suspension of (3S,5S,6R)-5,6-dichloro-1-(tetrahydro-5-hydroxy-6-(hydroxymethyl)-2H-pyran-3-yl)-1H-benzimidazole (example 36, 1.50 g, 4.73 mmol) in 15 ML of dry DMF at 0° C. was added imidazole (0.40 g, 5.68 mmol) followed by tert-butyldimethylsilyl chloride (0.81 g, 5.20 mmol). The reaction was allowed to warm to room temperature, stirred overnight then diluted with water (100 ML) and extracted with chloroform (100 ML). The organic layer was dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. Purification by flash chromatography on silica gel 60 eluting with 50% ethyl acetate-hexanes afforded the title compound as a white solid (1.00 g, 50%) along with 0.40 g recovered starting material; m.p. 143-155° C.; 1H-NMR (DMSO-d6, 200 MHz) δ: 8.51, 8.09, 8.00 (s, each 1H), 4.90 (d, J=5.6 Hz, 1H), 4.89 (m, 1H), 4.26 (m, 1H), 3.91 (m, 1H), 3.86 (m, 1H), 3.55-3.42 (m, 1H), 3.32-3.24 (m, 2H), 2.29-2.19 (m, 1H), 1.97-1.83 (m, 1H), 0.91 (s, 9H), 0.97, 0.78 (s, each 3H).