Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.C[Mg]Cl.[CH3:11][C:12]([OH:15])([CH3:14])[CH3:13].[Cl:16][C:17]1[N:22]=C(C(OC)=O)[CH:20]=[CH:19][N:18]=1>C1COCC1.CCOC(C)=O>[Cl:16][C:17]1[N:22]=[C:11]([C:12]([OH:15])([CH3:14])[CH3:13])[CH:20]=[CH:19][N:18]=1
Reactant: CC(C)(C)O
Reactant: COC(=O)c1ccnc(Cl)n1
Agent: C[Mg]Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccnc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of THF (0.25 mL) and toluene (1 mL) at −20° C. under a nitrogen atmosphere was added methyl magnesium chloride (3.0 M in THF, 1 mL, 2.90 mmol) followed by t-BuOH (0.050 mL in 0.750 mL THF, 0.579 mmol) and left to stir for 30 min at 0° C. The solution was cooled back down to −20° C. and methyl 2-chloropyrimidine-4-carboxylate (100 mg, 0.58 mmol) in THF (1 mL) was added. The solution was warmed to room temperature and stirred for an additional 30 min. The solution was diluted with EtOAc, washed with brine, dried with MgSO4, filtered, and concentrated to dryness to afford 2-(2-chloropyrimidin-4-yl)propan-2-ol (71 mg, 0.41 mmol, 71% yield. MS ESI: [M+H]+ m/z 173.1. 1H NMR (500 MHz, CDCl3) δ 8.60 (dd, J=1.8, 5.1, 1H), 7.44 (d, J=5.1 1H), 1.56 (d, J=1.8, 6H).
Reaction SMILES: Br.C(C1C=CC(C[N:9]2[C:13](CC3SC=C(C4C=CC=CN=4)N=3)=[CH:12][N:11]=[CH:10]2)=CC=1)#N.C(N(CC)CC)C.[C:35]1([C:41](Br)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C[CH2:56][O:57][C:58]([CH3:60])=[O:59]>CN(C=O)C.O>[CH3:56][O:57][C:58](=[O:59])[CH2:60][C:13]1[N:9]=[CH:10][N:11]([C:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:12]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1ccc(Cn2cncc2Cc2nc(-c3ccccn3)cs2)cc1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 24 h

Procedure:
To a solution of the product from Step A (24.85 g, 0.141 mol) in DMF (115 mL) was added triethylamine (57.2 mL, 0.412 mol) and triphenylmethyl bromide (55.3 g, 0.171 mol) and the suspension was stirred for 24 hours. After this time, the reaction mixture was diluted with EtOAc and water. The organic phase was washed with sat. aq. NaHCO3, dried, (Na2 SO4) and the solvent evaporated in vacuo. The residue was purified by chromatography (Silica gel, 0-100% EtOAc in hexanes) to provide the title compound as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.35(1H,s),7.31(9H,m),7.22(6H,m), 6.76(1H,s),3.68(3H,s) and 3.60(2H,s) ppm.
Reaction SMILES: C(O[C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1OC(=O)C)(=O)C.[O:17]=[C:18]1[CH:27]=[CH:26][C:25](=[O:28])[C:24]2[CH2:23][CH:22]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][CH2:20][C:19]1=2>C1(C)C(C)=CC=CC=1>[O:17]=[C:18]1[C:27]2[C:26](=[CH:6][C:7]3[C:8]([CH:5]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:25](=[O:28])[C:24]2[CH2:23][CH:22]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][CH2:20][C:19]1=2
Reactant: COC(=O)C1CCC2=C(C1)C(=O)C=CC2=O
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Solvent: Cc1ccccc1C
Product: COC(=O)C1CCC2=C(C1)C(=O)c1cc3ccccc3cc1C2=O
Yield: 81.2 %

Procedure:
A mixture of 240 mg (1.1 mmol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 220 mg (1.0 mmol) of methyl rac-1,2,3,4,5,8-hexahydro-5,8-dioxonaphthalene-2-carboxylate in 20 ml of dry xylene was stirred and heated under reflux under an atmosphere of nitrogen for 18 hours. The solution was evaporated to dryness, the yellow residue was stirred with 10 ml of diethyl ether and the mixture was subsequently filtered to give 260 mg (81%) of methyl rac-1,2,3,4,5,12-hexahydro-5,12-dioxonaphthacene-2-carboxylate in the form of a bright yellow solid of melting point 173°-174° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:3])[CH3:2].[F:14][C:15]([F:28])([F:27])[C:16]([F:26])([F:25])[C:17]([F:24])([F:23])[C:18](OCC)=[O:19]>>[F:23][C:17]([F:24])([C:16]([F:25])([F:26])[C:15]([F:14])([F:27])[F:28])[C:18](=[O:19])[CH2:2][C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)=[O:3]
Reactant: CCOC(=O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(=O)c1ccc2ccccc2c1
Product: O=C(CC(=O)C(F)(F)C(F)(F)C(F)(F)F)c1ccc2ccccc2c1

Procedure:
The compound was synthesized according to example 1 using 2-acetylnaphthalene and ethyl heptafluorobutyrate as starting materials. The product was crystallized from petroleum ether. 1H NMR (CDCl3): 6.76 (s, 1 H); 7.57-7.66 (m, 2H); 7.90 (bd, 1 H); 7.93-7.94 (m, 2H); 7.98 (bd, 1 H); 8.53 (s, 1H). IR (film): 1602 (C═O); 1232 (C—F).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl[CH2:7][CH:8]1[CH2:12][S:11][C:10]2([CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]2)[S:9]1>CN(C=O)C.O>[C:1]([S:3][CH2:7][CH:8]1[CH2:12][S:11][C:10]2([CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]2)[S:9]1)(=[O:4])[CH3:2]
Reactant: CCOC(=O)CC1CCC2(C1)SCC(CCl)S2
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCC2(C1)SCC(CSC(C)=O)S2
Yield: 103.5 %

Procedure:
A mixture of potassium thioacetate (5.4 g, 0.047 mole) and a solution of the product of Example E (4.0 g, 0.013 mole) in DMF (40 ml) was stirred under nitrogen for 2 days at room temperature. The reaction mixture was diluted with water (200 ml) and extracted twice with ethyl acetate. The organic phase was washed with brine and dried (Na2SO4). The drying agent was filtered and the filtrate stripped on the rotary evaporator to give 4.5 g of the titled compound. This material was a single spot on TLC.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](=O)[CH2:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.[Cl:15][C:16]1[C:17]([NH:23][NH2:24])=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=1>C(O)(=O)C>[Cl:15][C:16]1[C:17]([N:23]2[C:5]([C:7]3[O:8][CH:9]=[CH:10][CH:11]=3)=[CH:4][C:3]([C:2]([F:14])([F:13])[F:1])=[N:24]2)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Reactant: NNc1ncc(Cl)cc1Cl
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(-c2ccco2)n(-c2ncc(Cl)cc2Cl)n1
Yield: 60.9 %

Procedure:
To a 250 mL flask, 4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione (5.50 g, 26.7 mmol), 3,5-dichloro-2-hydrazinylpyridine (4.75 g, 26.7 mmol) and glacial acetic acid (100 mL) were added. The reaction mixture was heated to reflux. When the reaction completed, the reaction mixture was concentrated by rotary evaporator. Then ethyl acetate (300 mL) and water (150 mL) was added, the organic extracts were washed with saturated sodium bicarbonate solution (150 mL) and brine (150 mL) in sequence, dried over anhydrous magnesium sulfate and concentrated by rotary evaporator. The residue was purified by silica gel column chromatography (Fluent: ethyl acetate/petroleum ether=1/5) to give the product (5.66 g) as a yellow oil in 61% yield. 1H NMR (300 MHz, CDCl3): 8.514 (d, 1H), 7.974 (d, 1H), 7.362 (d, 1H), 6.917 (s, 1H), 6.388 (dd, 1H), 6.148 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19]/[C:20](=[N:27]/[S:28][C:29]([CH3:32])([CH3:31])[CH3:30])/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[CH3:33][C:34](=[CH2:38])[CH2:35][Mg]Cl.C1C[O:42]CC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][C:20]([NH:27][S@@:28]([C:29]([CH3:31])([CH3:30])[CH3:32])=[O:42])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:35][C:34]([CH3:33])=[CH2:38])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH3:9])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: C[C@@H](c1ccc(Br)cc1)N(CC/C(=N/SC(C)(C)C)c1ccccc1)C(=O)OC(C)(C)C
Reactant: C=C(C)C[Mg]Cl
Product: C=C(C)CC(CCN(C(=O)OC(C)(C)C)[C@@H](C)c1ccc(Br)cc1)(N[S@](=O)C(C)(C)C)c1ccccc1
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of (S,Z)-tert-butyl 1-(4-bromophenyl)ethyl(3-(tert-butylthioimino)-3-phenylpropyl)carbamate (20 g, 0.037 mol) in THF (200 mL) was added (2-methylallyl)magnesium chloride (5.0 g, 0.044 mol) under nitrogen at −78° C. The mixture was stirred for 2 h. The reaction was quenched with satd aq NH4Cl. The organic phase was separated and concentrated to give crude tert-butyl(S)-1-(4-bromophenyl)ethyl(3-((R)-1,1-dimethylethylsulfinamido)-5-methyl-3-phenylhex-5-enyl)carbamate (6.5 g, 30%), which was purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH2:13]([Mg]Cl)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCCCCC[Mg]Cl
Product: CCCCCCC(O)c1ccc(C(=O)OC)cc1

Procedure:
This compound is made from 4-formyl-benzoic acid methyl ester and n-hexylmagnesium chloride following the general method of Preparation 1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[N:12]([S:15]([O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[C:21]([O:23][CH2:24][CH2:25][Cl:26])=[O:22])(=[O:17])=[O:16])=[C:13]=[O:14].CCCCCCC>ClCCl>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:13](=[O:14])[NH:12][S:15]([O:18][C:19]2[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=2[C:21]([O:23][CH2:24][CH2:25][Cl:26])=[O:22])(=[O:16])=[O:17])[N:7]=1
Reactant: O=C=NS(=O)(=O)Oc1ccccc1C(=O)OCCCl
Reactant: COc1cc(OC)nc(N)n1
Solvent: CCCCCCC
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Oc2ccccc2C(=O)OCCCl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.8 %

Procedure:
2.02 g (0.013 mole) of 2-amino-4,6-dimethoxypyrimidine are dissolved in 80 ml of dichloromethane, and 4.28 g (0.014 mole) of 2-chloroethyl 2-isocyanatosulfonyloxybenzoate, dissolved in 20 ml of dichloromethane, are added at 0° C. The reaction mixture is stirred at room temperature for 18 hours and is then stirred into 600 ml of n-heptane. In this manner, 4.72 g (79% of theory) of 2-chloroethyl 2-[3-(4,6-dimethoxypyrimidin-2-yl)ureidosulfonyloxy]-benzoate of melting point 148°-150° C. are obtained.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[OH:8][C:9]1[C:19]([CH:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][C:30]3[O:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[C:21]2=[O:39])=[CH:18][C:12]2[N:13]([CH3:17])[CH2:14][CH2:15][O:16][C:11]=2[CH:10]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:17][N:13]1[C:12]2[CH:18]=[C:19]3[C:20]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH2:29][C:30]5[O:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=5)[C:21]4=[O:39])[CH2:2][O:8][C:9]3=[CH:10][C:11]=2[O:16][CH2:15][CH2:14]1
Reactant: O=C(O)C(F)(F)F
Reactant: CN1CCOc2cc(O)c(C3C(=O)N(Cc4ccc(C(F)(F)F)o4)c4ccccc43)cc21
Agent: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: CN1CCOc2cc3c(cc21)C1(CO3)C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one trifluoroacetate salt to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one was obtained. To a suspension of 1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1H)-one (0.59 g, 1.3 mmol) in methanol (8.5 mL) was added 4 M hydrochloric acid in 1,4-dioxane (1.5 mL, 6.0 mmol) and the resulting solution was stirred at ambient temperature for 35 min. The solvent was removed and the residue was dried under reduced pressure. The residue was then precipitated by addition of hexanes, sonicated and the solvent was removed under reduced pressure. This process was repeated several times, until the solid formed a fine suspension in hexanes. The material was then collected by filtration and air-dried to afford 1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one hydrochloride (0.60 g, 94%) as a pale gray powder: mp 105° C. (dec.) (hexanes); 1H NMR (300 MHz, DMSO-d6) δ7.33 (ddd, J=7.8, 7.5, 0.9 Hz, 1H), 7.22-7.17 (m, 3H), 7.07 (dd, J=7.5, 7.5 Hz, 1H), 6.74 (d, J=3.3 Hz, 1H), 6.48 (s, 1H), 6.25-6.19 (m, 1H), 5.10 (d, J=16.2 Hz, 1H), 5.02 (d, J=16.2 Hz, 1H), 4.76 (d, J=9.3 Hz, 1H), 4.65 (d, J=9.3 Hz, 1H), 4.33-4.22 (m, 2H), 3.27-3.18 (m, 2H), 2.68 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ176.4, 157.2, 153.2, 147.9, 141.9, 139.6 (q, J=42.0 Hz), 131.3, 129.0, 123.9, 123.4, 121.5, 119.0 (q, J=267 Hz), 114.2 (q, J=2.8 Hz), 112.4, 109.9, 109.3, 98.8, 79.9, 62.7, 57.1, 48.8, 48.6, 41.5, 36.6; MS (ES+) m/z 457.1 (M+1); Anal. Calcd. for C24H19FN2O4.HCl: C, 58.49; H, 4.09; N, 5.68. Found: C, 58.85; H, 3.74; N, 5.37.
Reaction SMILES: [CH3:1][N:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[C:4]([C:10]([O:12]C)=[O:11])[C:3]1=[O:14].O.[OH-].[Li+]>C1COCC1.O>[CH3:1][N:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[C:4]([C:10]([OH:12])=[O:11])[C:3]1=[O:14]
Reactant: COC(=O)c1ccc(SC)n(C)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(C(=O)O)c(=O)n1C
Temperature: 25 °C
Yield: 81.9 %

Procedure:
Methyl 1,2-dihydro-1-methyl-6-methylthio-2-oxopyridine-3-carboxylate (2.1 g, 9.8 mmol) and lithium hydroxide monohydrate (0.50 g, 12 mmol) were dissolved in a mixed solvent of THF (30 mL) and water (2 mL), and stirred for a day at room temperature. The reaction mixture was concentrated under reduced pressure. To thus obtained residue, a mixed solution of aqueous saturated sodium bicarbonate and ethyl acetate was added, and then liquid separation and extraction were subjected. The obtained liquid layer was added with diluted hydrochloric acid to give a pH of 3 to 4, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, to obtain 1.6 g of a desired product (yield: 82%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C:4](Br)([CH3:6])[CH3:5].[CH3:9][N:10]1[C:18]([CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:32]1[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[N:34]=[C:33]1[CH3:41])=[N:14][C:15]=2[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:5][C:4]([N:23]1[CH2:22][CH2:21][CH:20]([CH2:19][C:18]2[N:10]([CH3:9])[C:11]3[C:16]([N:17]=2)=[C:15]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:14]=[C:13]([N:32]2[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:34]=[C:33]2[CH3:41])[N:12]=3)[CH2:25][CH2:24]1)([CH3:6])[C:3]([O:2][CH3:1])=[O:8]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Reactant: COC(=O)C(C)(C)Br
Product: COC(=O)C(C)(C)N1CCC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1

Procedure:
Following General Procedure C, 2-bromo-2-methyl-propionoic acid methyl ester and 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine were reacted to give 507. LCMS m/z: 274.2 (2M+H)
Reaction SMILES: N[C:2]1[C:3]([CH3:25])=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([C@@H:21]4[CH2:23][C@@H:22]4[F:24])=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:5]=[N:6][CH:7]=1.FC(F)(F)C(O)=[O:29].CCCCCON=O>>[F:24][C@H:22]1[CH2:23][C@H:21]1[C:19]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([OH:29])[C:3]=1[CH3:25])[CH:17]=2)=[O:20]
Reactant: Cc1c(N)cncc1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Reactant: O=C(O)C(F)(F)F
Agent: CCCCCON=O
Product: Cc1c(O)cncc1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.2 %

Procedure:
To a solution of (1S,2S)-N-(7-(5-amino-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide (46.2 mg; 0.137 mmol) in trifluoroacetic acid (1.0 mL; 13 mmol) at 0° C. was added N-amyl nitrite (29 μL; 0.21 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and then partitioned between dichloromethane and 2 M aqueous sodium carbonate. The aqueous layer was neutralized to pH 7 with citric acid, and then extracted twice more with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-10% methanol in dichloromethane) followed by preparatory reverse-phase HPLC to yield 8.4 mg (18%) of the title compound. LCMS (ESI): RT (min)=3.583, M+H=338.1, method=E; 1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 9.94 (broad s, 1H), 9.19 (s, 1H), 8.52 (s, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 4.95 m, 1H), 2.27 (m, 1H), 2.12 (s, 3H), 1.70 (m, 1H), 1.20 (m, 1H).
Reaction SMILES: ClC1C=CC(C2(C[Br:17])CCC(CCC)O2)=CC=1.[CH3:18][C:19]([OH:33])([CH2:21][CH2:22][C:23]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)=[CH:24][CH3:25])[CH3:20].BrBr.N1C=CC=CC=1>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]2([CH:24]([Br:17])[CH3:25])[CH2:22][CH2:21][C:19]([CH3:20])([CH3:18])[O:33]2)=[CH:27][CH:28]=1
Reactant: CC=C(CCC(C)(C)O)c1ccc(Cl)cc1
Reactant: CCCC1CCC(CBr)(c2ccc(Cl)cc2)O1
Agent: BrBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Br)C1(c2ccc(Cl)cc2)CCC(C)(C)O1
Yield: 94 %

Procedure:
By the method described in Example 1 for the preparation of 2-(4-chlorophenyl)-2-bromomethyl-5-prop-1-yltetrahydrofuran, 2-methyl-5-(4-chlorophenyl)hept-5-en-2-ol (3.2 g), bromine (2.35 g), and pyridine (1.18 g) in dry dichloromethane (40 ml) gave 2-(4-chlorophenyl-2-(1-bromoethyl)-5,5-dimethyltetrahydrofuran (4.4 g, 94%), a mixture of diastereomers, as an orange oil.
Reaction SMILES: P(=O)(O)(O)O.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[N:8]=1.[CH3:14][CH2:15][C:16](=O)[CH2:17][C:18](=O)[CH2:19][CH3:20]>>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]2[C:9](=[N:13][C:16]([CH2:15][CH3:14])=[CH:17][C:18]=2[CH2:19][CH3:20])[N:8]=1
Reactant: CCC(=O)CC(=O)CC
Reactant: Nc1cccc(N)n1
Agent: O=P(O)(O)O
Product: CCc1cc(CC)c2ccc(N)nc2n1

Procedure:
To 50 ml. of 85% phosphoric acid is added with stirring 2,6-diaminopyridine (6.55 g., 0.06 mole) followed by 3,5-heptanedione (7.7 g., 0.06 mole). The mixture is heated on the steam bath under nitrogen atmosphere for 16 hours. The reaction mixture is poured into crushed ice and neutralized with concentrated ammonium hydroxide and extracted with methylene chloride (3×250 ml.). The combined extracts are dried, filtered and concentrated in vacuo. Crystallization of the residue from ethyl acetate affords 2-amino-5,7-diethyl-1,8-naphthyridine melting at 187°-189° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH2:12][C:13]2[N:14]=[C:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:16][CH:17]=2)=[CH:6][CH:5]=1.[O:27]([CH2:34][C@@H:35]1[CH2:37][O:36]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(O)C>[CH2:19]([NH:18][C:15]1[S:16][CH:17]=[C:13]([CH2:12][C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][CH2:37][C@H:35]([OH:36])[CH2:34][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:5][CH:6]=2)=[O:26])[N:14]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCc1ccc(NC(=O)Cc2csc(NCc3ccccc3)n2)cc1
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Solvent: CC(C)O
Product: O=C(Cc1csc(NCc2ccccc2)n1)Nc1ccc(CCNC[C@H](O)COc2ccccc2)cc1
Yield: 26.5 %

Procedure:
A solution of 670 mg of N-[4-(2-aminoethyl)phenyl]-2-(2-benzylaminothiazol-4-yl)acetamide and 300 mg of (S)-2-[(phenoxy)methyl]oxirane in 20 ml of 2-propanol was heated under refluxing for three hours. The solvent was evaporated off in vacuo and the residue was purified by means of silica gel column chromatography (eluate: chloroform/methanol=10/1). The resulting solid was recrystallized from methanol to obtain 250 mg of (S)-2-(2-benzylamino-4-thiazolyl)-4′-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethyl]acetanilide.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][C:17]1[S:21][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:19][CH:18]=1.[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[CH3:16][C:17]1[S:21][C:20]([S:22]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:5])[N:33]([C:32]4[CH:34]=[CH:35][C:29]([O:28][C:27]([F:26])([F:36])[F:37])=[CH:30][CH:31]=4)[CH2:13][CH2:12]3)[CH2:11][CH2:10]2)(=[O:24])=[O:23])=[CH:19][CH:18]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: Cc1ccc(S(=O)(=O)N2CCC3(CCN(c4ccc(OC(F)(F)F)cc4)C3=O)CC2)s1

Procedure:
Off-white solid. MS (ESI): 475.07 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 5-methylthiophene-2-sulphonyl chloride and 4-(trifluoromethoxy)-aniline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:21]([CH3:23])[CH3:22])[CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)CC)C.[CH:54]([O:57][C:58]1[C:59]([N:67]2[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]2)=[C:60]2[CH:66]=[CH:65][NH:64][C:61]2=[N:62][CH:63]=1)([CH3:56])[CH3:55]>C(Cl)Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:10]([C:11]([N:70]2[CH2:71][CH2:72][N:67]([C:59]3[C:58]([O:57][CH:54]([CH3:56])[CH3:55])=[CH:63][N:62]=[C:61]4[NH:64][CH:65]=[CH:66][C:60]=34)[CH2:68][CH2:69]2)=[O:12])[CH2:9][N:8]([CH:21]([CH3:23])[CH3:22])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:15][CH:16]=1
Reactant: CC(C)Oc1cnc2[nH]ccc2c1N1CCNCC1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)Oc1cnc2[nH]ccc2c1N1CCN(C(=O)[C@H](CN(C(=O)OC(C)(C)C)C(C)C)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
(S)-3-(tert-Butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (59 mg, 0.17 mmol, see Example H), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (44 mg, 0.23 mmol), HOBt-H2O (35 mg, 0.23 mmol) and triethylamine (12 mg, 0.12 mmol) were added to 5-isopropoxy-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (30 mg, 0.12 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 18 hours. The reaction was then diluted with DCM (50 mL) and washed with 1N HCL, 10% K2CO3 and brine. After drying over MgSO4, the residue was concentrated to dryness and purified by chromatography (SP4, 12+M, water/ACN 90/10→0/100, 20 CV) to yield (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-isopropoxy-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (42 mg, 62% yield) as a solid.