Azzindani/Open_Reaction_Data huggingface dataset:
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].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:38][CH2:37][C@H:36]([F:39])[CH2:35]2)[CH2:31]1.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:30]4[CH2:33][CH:32]([N:34]5[CH2:38][CH2:37][C@H:36]([F:39])[CH2:35]5)[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: F[C@H]1CCN(C2CNC2)C1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CC[C@H](F)C4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.6 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.245 g, 0.627 mmol), (S)-1-azetidin-3-yl-3-fluoropyrrolidine (0.109 g, 0.752 mmol) and 4 Å molecular sieves (0.5 g) in DCE (5 mL). The reaction mixture was stirred for 90 min at room temperature. Sodium triacetoxyborohydride (0.266 g, 1.254 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 20:80) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 586 as an off-white solid (0.204 g, 63%). LCMS (Method I): RT=2.46 min, [M+H]+ 520.2 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.99 (m, 1 H), 7.65-7.61 (m, 1 H), 7.27-7.21 (m, 2 H), 5.19 (dt, J=55.8, 5.4 Hz, 1 H), 4.50-3.95 (m, 4 H), 3.87 (s, 2 H), 3.81-3.72 (m, 7 H), 3.40 (dd, J=7.1, 6.1 Hz, 2 H), 3.26 (q, J=7.4 Hz, 2 H), 3.21-3.12 (m, 1 H), 3.12-3.03 (m, 2 H), 2.79-2.65 (m, 2 H), 2.64-2.51 (m, 1 H), 2.34-2.25 (m, 1 H), 2.15-2.03 (m, 1 H), 1.76-1.95 (m, 1 H), 1.33 (t, J=7.4 Hz, 3 H)
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:11]([Br:12])=[CH:10][C:9]([CH:13]([CH2:17][CH2:18][OH:19])[CH2:14][CH2:15][OH:16])=[CH:8][C:5]=2[C:6]=1[CH3:7].[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>N1C=CC=CC=1>[CH3:20][S:21]([O:19][CH2:18][CH2:17][CH:13]([C:9]1[CH:10]=[C:11]([Br:12])[C:4]2[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[C:5]=2[CH:8]=1)[CH2:14][CH2:15][O:16][S:21]([CH3:20])(=[O:23])=[O:22])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1oc2c(Br)cc(C(CCO)CCO)cc2c1C
Agent: Cl
Solvent: c1ccncc1
Product: Cc1oc2c(Br)cc(C(CCOS(C)(=O)=O)CCOS(C)(=O)=O)cc2c1C
Temperature: 0 °C

Procedure:
16.4 g (0.05 mol) of 3-(2,3-dimethyl-7-bromo-5-benzofuranyl)-1,5-pentanediol are dissolved in 200 ml of pyridine. The solution is cooled to -8° to -10° and 8.5 ml (=12.6 g, 0.11 mol) of methanesulfonyl chloride are added dropwise at this temperature in the course of 30 minutes. The reaction mixture is allowed to react at -8° to -10° for 11/2 hours and is then poured onto 500 g of ice and the pH value is adjusted to about 1 by adding 5 N hydrochloric acid. This acid mixture is extracted 3 times with methylene chloride and the extracts are washed twice with 2 N hydrochloric acid and 3 times with water. The combined extracts are dried over sodium sulfate and the solvent is evaporated off under a waterpump vacuum. A crude product which crystallises spontaneously and has a melting point of 154°-156° is thereby obtained. Recrystallisation from methylene chloride/hexane gives 3-(2,3-dimethyl-7-bromo-5-benzofuranyl)-1,5-pentanediyl dimethanesulfonate as white crystals of melting point 158°-159°.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].C(O[C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:26])C.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+].C(O)C>CN(C)C=O.C(O)(=O)C>[OH:26][C:25]1[C@H:27]2[C@H:28]([CH2:29][CH2:30][CH2:31]2)[N:32]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:17](=[O:18])[C:16]=1[C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=2[S:13](=[O:15])(=[O:14])[N:12]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C1CCCC1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(c3ccccc3)C1=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.7 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4] thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol) and 2-phenylamino-cyclopentanecarboxylic acid ethyl ester (0.070 g, 0.300 mmol) in N,N-dimethylformamide (1.5 mL) was treated with N-methylmorpholine (72.8 mg, 0.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbo-diimide hydrochloride (69.0 mg, 0.36 mmol) and stirred at 25° C. for 4 h. The solvent was removed in vacuo. The crude material was redissolved in ethyl acetate (75 mL) and washed twice with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The crude intermediate was redissolved in ethanol (5 mL) and treated with a 21% w/w solution of sodium ethoxide in ethanol (448 μL, 1.2 mmol) and stirred for 2 h at 60° C. The reaction was allowed to cool to 25° C., treated with glacial acetic acid (0.4 mL), the solvents were removed in vacuo, and the residue was and purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-N-[3-(4-Hydroxy-2-oxo-1-phenyl-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (25 mg, 0.050 mmol, 16.6%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.65-1.72 (1H, m), 1.76-1.88 (2H, m), 1.93-2.00 (1H, m), 2.26-2.31 (2H, m), 3.04 (3H, s), 3.26 (1H, dd, J1=15.5 Hz, J2=7.7 Hz), 4.26 (1H, dd, J1=13.1 Hz, J2=5.4 Hz), 7.10 (1H, d, J=8.5 Hz), 7.22-7.29 (2H, m), 7.39 (1H, t, J=7.4 Hz), 7.49 (2H, t, J=8.0 Hz), 7.56-7.59 (1H, m), 7.69 (1H, d, J=2.5 Hz). LC-MS (ESI) calcd for C22H22N4O6S2 502.10, found 503.2 [M+H+].
Reaction SMILES: Cl[C:2]1[C:3]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:4]=2[N:5]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:6](=[O:18])[CH:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[Cl:17])[N:8]=1.[Cl-].[Li+].O.[OH-].[Cs+].[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43](B2OC(C)(C)C(C)(C)O2)=[CH:42][C:41]=1[CH3:55]>O1CCOCC1.O.C(OCC)(=O)C>[Cl:32][C:30]1[CH:29]=[CH:28][C:4]2[N:5]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:6](=[O:18])[CH:7]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[Cl:17])[N:8]=[C:2]([C:43]3[CH:44]=[CH:45][C:40]([O:39][CH3:38])=[C:41]([CH3:55])[CH:42]=3)[C:3]=2[CH:31]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C
Reactant: COc1ccc(CN2C(=O)C(Cc3ccc(F)cc3Cl)N=C(Cl)c3cc(Cl)ccc32)cc1
Agent: [Cl-]
Agent: [Cs+]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN2C(=O)C(Cc3ccc(F)cc3Cl)N=C(c3ccc(OC)c(C)c3)c3cc(Cl)ccc32)cc1
Temperature: 160 °C

Procedure:
5,7-Dichloro-3-(2-chloro-4-fluorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.3 g, 0.61 mmol) was combined with lithium chloride (0.078 g, 1.83 mmol), cesium hydroxide hydrate (0.31 g, 1.83 mmol) and 2-(4-methoxy-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.151 g, 0.61 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) and the mixture was purged with nitrogen. [Tetrakis(triphenylphosphine)]palladium(0) (0.07 g, 0.061 mmol) was added and the mixture was heated in a CEM Discover microwave reactor at 160° C. for 20 minutes. The mixture was allowed to cool and diluted with ethyl acetate then washed with water then brine. The organic layer was concentrated onto silica gel and chromatographed on a silica gel column eluting with 10-35% ethyl acetate in hexanes to give 7-chloro-3-(2-chloro-4-fluorobenzyl)-5-(4-methoxy-3-methylphenyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:27])[CH3:26])[N:17]=2)=[O:15])[CH2:10][C@H:9]1[CH2:28][C:29](O)=[O:30])=O)(C)(C)C.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:25]([N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:14]([NH:13][C@H:11]2[CH2:10][C@@H:9]([CH2:28][C:29](=[O:30])[N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[NH:8][CH2:12]2)=[O:15])=[N:17]1)([CH3:27])[CH3:26]
Reactant: C1CCNCC1
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Product: CC(C)n1nc(C(=O)N[C@@H]2CN[C@H](CC(=O)N3CCCCC3)C2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 7 from ((2S,4S)-1-(tert-butoxycarbonyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidin-2-yl)acetic acid (step 1 of Example 13) and piperidine.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@@H:12]1[CH2:17][CH2:18][CH:19]([OH:32])[C:20]1[O:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[CH:23][CH:24]=1)C.[OH-].[Na+].Cl.C(OCC)(=O)C>CO>[OH:32][CH:19]([C:20]1[O:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[CH:23][CH:24]=1)[CH2:18][CH2:17][C@H:12]1[CH2:13][CH2:14][C:15](=[O:16])[N:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)CCCCCCN1C(=O)CC[C@@H]1CCC(O)c1ccc(-c2ccccc2C)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccccc1-c1ccc(C(O)CC[C@H]2CCC(=O)N2CCCCCCC(=O)O)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
The ester (54 mg) was dissolved in methanol (3 mL) and treated with 5 M aqueous solution of sodium hydroxide (0.5 mL) and stirred at ambient temperature for 1 hour. 7-{(S)-2-[3-hydroxy-3-(5-o-tolyl-furan-2-yl)-propyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid (54) (71) (45 mg, 0.10 mmol) resulted upon treatment with 1 M aqueous hydrochloric acid and extraction with ethyl acetate: MS: 428 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][CH2:29][N:30]([CH3:41])[S:31]([C:34]1[S:38][C:37]([NH2:39])=[N:36][C:35]=1[CH3:40])(=[O:33])=[O:32]>>[OH:27][CH2:28][CH2:29][N:30]([CH3:41])[S:31]([C:34]1[S:38][C:37]([NH:39][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])=[N:36][C:35]=1[CH3:40])(=[O:32])=[O:33]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)N(C)CCO
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)N(C)CCO

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-ethyl)-methyl-amide (example B.20) according to general procedure II.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].[CH3:18][N:19]1[C:23](=[O:24])[CH:22]=[CH:21][C:20]1=[O:25]>C(O)(C)(C)C.C1(C)C=CC=CC=1.CCCCCCC.C(OCC)(=O)C>[C:13]([C:9]1[CH:10]=[C:11]([CH:21]2[CH2:22][C:23](=[O:24])[N:19]([CH3:18])[C:20]2=[O:25])[CH:12]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:8]=1[OH:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CN1C(=O)C=CC1=O
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CN1C(=O)CC(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 9.5 %

Procedure:
This compound is prepared by the procedure of Example 1 from 2.40 g (0.1 mol) of sodium hydride, 20.63 g (0.1 mol) of 2,6-di-tert-butylphenol, and 11.11 g (0.1 mol) of N-methylmaleimide in tert-butyl alcohol. The residue is recrystallized from petroleum ether to give 13.2 g (42%) of crude product. The analytical sample is prepared by flash chromatography (1:1 heptane:ethyl acetate eluent) followed by trituration with a mixture of heptane and toluene to give 3.0 g of a white solid: mp 164°-166° C.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][NH:12][C:11](=[O:16])[C:10]=3[N:9]=[C:8]2[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:30][C:31]([F:46])([F:45])[S:32]([NH:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39])(=[O:34])=[O:33]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:17]([C:8]1[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=3[NH:35][S:32]([C:31]([F:46])([F:30])[F:45])(=[O:34])=[O:33])=[CH:22][CH:21]=2)[C:15]2[CH:14]=[CH:13][NH:12][C:11](=[O:16])[C:10]=2[N:9]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCc1nc2c(=O)[nH]ccc2n1Cc1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1NS(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(=O)[nH]ccc2n1Cc1ccc(NC(=O)c2ccccc2NS(=O)(=O)C(F)(F)F)cc1
Reaction time: 16 h

Procedure:
A mixture of 2.96 g of 1-p-aminobenzyl-2-butyl-4,5-dihydro-4-oxo-1H-imidazo [4,5-c ]pyridine, 3 ml of triethylamine, 0.5 g of 4-dimethylaminopyridine and 120 ml of CH2Cl2 is cooled to 5° and a solution of 2.88 g of o-trifluoromethanesulphonamidobenzoyl chloride in 20 ml of CH2Cl2 is added dropwise. The mixture is stirred at 20° for a further 16 hours, evaporated and worked up in conventional manner to give 2-butyl-4-oxo-1-[4-(2-trifluoromethanesulphonamidobenzamido)benzyl]-4,5-dihydro-1H-imidazo[4,5-c]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10](=O)[CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[N:9][CH:8]=2)[CH:7]=1
Reactant: O=C(CCC(F)(F)C(F)(F)F)NCc1ccc(Cl)cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: FC(F)(F)C(F)(F)CCc1ncc2ccc(Cl)cn12
Temperature: 25 °C

Procedure:
To a solution of the intermediate from Step F (7.1 g, 22.42 mmol) in 1,2-dichloroethane (30 mL) was added phosphorous oxychloride (10.45 mL, 112 mmol). The resulting mixture was refluxed for 18 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between water and ethyl acetate. The aqueous layer was neutralized with solid sodium bicarbonate and then extracted with ethyl acetate (3×). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give a light yellow solid. m/z=298.9 (M+H).
Reaction SMILES: Cl[C:2](OC)=[O:3].[NH2:6][CH2:7][C:8]1[C:14]([O:15][CH2:16][CH:17]([OH:31])[CH2:18][N:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10]>C(O)(C)C.O>[CH2:20]([N:19]([C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:18][CH:17]([OH:31])[CH2:16][O:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:9]2[C:8]=1[CH2:7][NH:6][C:2](=[O:3])[NH:10]2)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)N(Cc1ccccc1)CC(O)COc1cccc(N)c1CN
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)N(Cc1ccccc1)CC(O)COc1cccc2c1CNC(=O)N2

Procedure:
5.3 g of methyl chloroformate are added dropwise to a solution of 16.2 g of 2-aminomethyl-3-[2-hydroxy-3-(N-benzyl-tert.-butylamino)-propoxy]-aniline in a mixture of 150 ml of isopropanol and 150 ml of water, at 15°-20°, whilst stirring and cooling with ice. The reaction mixture is stirred at room temperature for a further 2 hours and then evaporated. The residue is dissolved in 100 ml of water, the solution is extracted with 50 ml of ether and the aqueous phase is rendered alkaline with concentrated ammonia and extracted 3 times with, in each case, 200 ml of ethyl acetate. The residue which remains after evaporating the organic phase is dissolved in 50 ml of methanol and boiled with 4.86 g of sodium methylate under reflux for 3 hours. The crystalline precipitate which gradually forms is filtered off after cooling the reaction mixture in an ice bath, whereupon 5-[3-(N-benzyl-tert.-butylamino)-2-hydroxy-propoxy]-3,4-dihydro-1H-quinazolin-2-one with a melting point of 215°-217° is obtained.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([NH2:14])=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.CS(O)(=O)=O.[N:20](OCCC(C)C)=O>C(O)C.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]2[C:6]3[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=3[N:14]=[N:20]2)[CH2:2][CH2:3]1
Reactant: CC(C)CCON=O
Reactant: COc1ccc(NCC2CC2)c(N)c1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2c(c1)nnn2CC1CC1
Reaction time: 0.25 h

Procedure:
N1-(Cyclopropylmethyl)-4-methoxybenzene-1,2-diamine (10.8 g, 56.2 mmol) was dissolved in ethanol (80 mL) and treated with methanesulfonic acid (3.65 ml, 56.2 mmol) followed by isoamyl nitrite (7.56 ml, 56.2 mmol). The mixture was stirred for 15 minutes, diluted with ethyl acetate (1500 mL) and washed with saturated bicarbonate solution (500 mL×2). The organic extracts were concentrated in vacuo. The residue was purified by silica gel gradient chromatography (5-50% ethyl acetate in heptanes), providing the titled compound as a tan solid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[N:34]1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:35]3[NH:34][N:33]=[CH:37][CH:36]=3)[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1-c1ccn[nH]1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 26 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((2-hydroxyethyl)(methyl)amino)nicotinamide (Stage 23.1) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford a yellow resin. UPLC-MS (Condition 3) tR=0.97 min, m/z=438.1 [M+H]+, m/z=436.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.77 (s, 3H) 3.37-3.49 (m, 2H) 3.49-3.65 (m, 2H) 4.62 (br. s, 1H) 6.47 (d, J=1.96 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.72-7.85 (m, 1H) 7.85-7.96 (m, 2H) 8.14 (br. s, 1H) 8.71 (d, J=1.96 Hz, 1H) 10.26 (s, 1H) 12.58-13.18 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1>C(O)C>[C:11]1([C:10]2[C:3]3[C:2]([C:27]4([CH2:30][OH:31])[CH2:28][CH2:29][NH:24][CH2:25][CH2:26]4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCC1CCNCC1
Reactant: Clc1ncnc2scc(-c3ccccc3)c12
Solvent: CCO
Solvent: CCN(CC)CC
Product: OCC1(c2ncnc3scc(-c4ccccc4)c23)CCNCC1
Temperature: 50 °C
Yield: 93.3 %

Procedure:
4-Chloro-5-phenyl-thieno[2,3-d]pyrimidine (1 g, 4.05 mmol) was dissolved in ethanol (15 ml) to give a yellow solution. To this was added triethylamine (1.7 ml, 12.2 mmol) and 4-piperidinemethanol (0.58 g, 5 mmol). The reaction mixture was heated to 50° C. and stirred for 1.5 hours until no 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine was present by TLC. The reaction mixture was allowed to cool to room temperature before being poured over ice water (50:50 mix). The resultant precipitate was collected by filtration to give the product as a pale yellow solid (1.23 g, yield 90%). LCMS: RT=4.05 min, M+1=326.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15](OCC)=[O:16])[N:12]=[C:11]([C:20](OCC)=[O:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[BH4-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:20][OH:21])[N:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)cc(C(=O)OCC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(OCc2ccccc2)cc(CO)n1
Temperature: 40 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
Over a solution of 5 (3.8 g, 11 mmol) in anhydrous EtOH, NaBH4 was carefully added (2.61 g, 68 mmol). The resulting solution was stirred at 40° C. for 24 h. then the reaction was quenched with H2O. EtOH was rotovaped down half the total volume, extracted with EtOAc (5×) dried with NaSO4 and the solvent was evaporated to obtain 90% of a white solid as the product.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:18][N:13]3[CH2:14][CH2:15][NH:16][CH2:17][C@@H:12]3[CH2:11]2)=[N:7][CH:8]=1.C(N(CC)CC)C.[CH2:28]([CH:30]([CH2:34][CH3:35])[C:31](Cl)=[O:32])[CH3:29]>ClCCl>[CH2:28]([CH:30]([CH2:34][CH3:35])[C:31]([N:16]1[CH2:15][CH2:14][N:13]2[CH2:18][C@@H:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][N:7]=3)[CH2:11][C@H:12]2[CH2:17]1)=[O:32])[CH3:29]
Reactant: FC(F)(F)c1ccc(N[C@H]2C[C@H]3CNCCN3C2)nc1
Reactant: CCC(CC)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)C(=O)N1CCN2C[C@@H](Nc3ccc(C(F)(F)F)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 20 (286 mg, 1 mmol) and triethylamine (202 mg, 2 mmol) in dichloromethane (5 mL) was added 2-ethylbutanoyl chloride (141 mg, 1.05 mmol) in dichloromethane (1 mL). The mixture was stirred room temperature for 2 hours, and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=10:1) to give the title compound. 1H NMR(400 MHz, DMSO-d6) δ ppm 0.80 (m, 6H), 1.35 (m, 3H), 1.50 (m, 3H), 1.80-2.00 (m, 2H), 2.35 (m, 3H), 2.60-3.07 (m, 3H), 4.02-4.10 (m, 1H), 4.33 (m, 1H), 4.48-4.60 (m, 1H), 6.60 (d, 1H, J=7 Hz), 7.56 (m, 1H), 7.60 (d, 1H, J=7 Hz), 8.28 (s, 1H); MS (ESI) m/z 385 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25](OCC)=[O:26])=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:32][NH2:33]>O1CCCC1>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([NH:33][CH3:32])=[O:26])=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nc2)CC1
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nc2)CC1

Procedure:
The procedure described in Example 1 (step 1.4.) is used. Starting with 0.60 g (1.37 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{6-[3-(trifluoromethyl)phenyl]-3-pyridyl}-1-piperazinecarboxylate, obtained in step 7.5, and 3.40 ml (6.86 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, eluting with a 98/2 and then 97/3 mixture of dichloromethane and methanol, followed by washing with diisopropyl ether, 0.36 g of pure product is obtained in the form of a white solid.