Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:7]([OH:15])[CH2:8][CH:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH2:11])=[O:4].C(N(C(C)C)C(C)C)C.[CH2:35]([CH:42]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:43](O)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[CH2:46]([CH:42]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:43]([NH:1][C@@H:2]([CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:7]([OH:15])[CH2:8][C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH2:11])=[O:4])=[O:44])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: C=CC(C[C@H](O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Reactant: O=C(O)C(Cc1ccccc1)Cc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1ccccc1)Cc1ccccc1)C(C)C
Yield: 16 %

Procedure:
0.65 g of (S)-α-amino-N-[(1S,2S,4RS)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]imidazole-4-propionamide in 20 ml of acetonitrile were added together with 0.36 ml of ethyldiisopropylamine to a solution of 0.45 g of 2-benzyl-3-phenylpropionic acid (which was prepared according to the method described in J. Am. Chem. Soc. 71 1863 (1949)) and 0.8 g of BOP in 30 ml of acetonitrile and the mixture was stirred at room temperature for 20 hours. Subsequently, the reaction mixture was evaporated under reduced pressure, the residue was dissolved in 50 ml of ethyl acetate and the organic solution was washed twice with 100 ml of water each time, dried over sodium sulfate and evaporated. The residue Was separated by flash chromatography on 100 g of silica gel with a 250:15 mixture of methylene chloride and methanol as the eluting agent, to obtain there was obtained 0.17 g of (S)-α-(2,2-dibenzylacetamido)-N-[(1S,2S,4S)-2 -hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]imidazole-4-propionamide as a white powder, melting point 120°. This compound corresponds to the less polar isomer and has a Rf value of 0.14.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2>>[ClH:1].[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: COc1cc2c(Nc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCN(C)CC1
Product: Cl
Yield: 99.3 %

Procedure:
Using an analogous procedure to that described in Example 37, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (50 mg, 0.155 mmol), (prepared as described for the starting material in Example 10), was reacted with 5-amino-2-methylindole (0.171 mmol) to give 6-methoxy-4-(2-methylindol-5-ylamino)-7-(1-methylpiperidin 4-ylmethoxy)quinazoline hydrochloride (72 mg, quant.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:26]3[CH2:29][CH2:28][CH2:27]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:11]=3)=[CH:4][C:3]=1[Cl:30].Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>C(Cl)Cl.N1C=CC=CC=1.C1(C)C=CC=CC=1.Cl>[CH:35]([O:34][C:32](=[O:33])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:26]3[CH2:29][CH2:28][CH2:27]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:25]=2)[CH:11]=3)=[CH:4][C:3]=1[Cl:30])([CH3:37])[CH3:36]
Reactant: CC(C)OC(=O)Cl
Reactant: N#Cc1c(-c2ccc(N)c(Cl)c2)n(C2CCC2)c2cc(Oc3ncccn3)ccc12
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(Oc4ncccn4)cc3n2C2CCC2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To 2-(4-amino-3-chloro-phenyl)-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile (0.26 g, 0.6 mmol) in CH2Cl2 (0.5 mL) and pyridine (0.5 mL) was added a solution of isopropyl chloroformate in toluene (1.0M, 0.8 mL) and the mixture was stirred at room temperature overnight. The mixture was diluted with aq. HCl (1N) and extracted with CH2Cl2. The organic layer was washed with water and brine, dried, concentrated and purified on silica gel (40% EtOAc/hexane) to provide {2-chloro-4-[3-cyano-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (0.29 g, 93%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:37][C:38]1[CH:42]=[C:41]([CH3:43])[O:40][N:39]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:37][C:38]2[CH:42]=[C:41]([CH3:43])[O:40][N:39]=2)=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Reactant: Cc1cc(CBr)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Cn2nc(-c3cnc4c(n3)c(C(=O)NC(C)C)cn4COCC[Si](C)(C)C)c3ccc(Cl)cc32)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 165 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (10.6 mg, 264 μmol) was added and the mixture was allowed to stir for 30 min. 3-(Bromomethyl)-5-methylisoxazole (31.9 mg, 181 μmol) was added and the mixture was warmed to room temperature. After 15 h, the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 40 g Analogix column, 20%-50% ethyl acetate in hexanes 15 min) to give 2-(6-chloro-1-((5-methylisoxazol-3-yl)methyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (89 mg, 153 μmol, 93.0%) as a yellow powder. MS (M+Na)+=602; 1H NMR (CDCl3) δ: 9.23-9.32 (m, 1H), 8.48 (s, 2H), 8.18-8.30 (m, 1H), 7.54-7.61 (m, 1H), 7.27 (m, 2H), 5.70-5.76 (m, 2H), 5.65-5.69 (m, 2H), 4.38-4.56 (m, 1H), 3.52-3.65 (m, 2H), 2.31-2.41 (m, 3H), 1.35-1.47 (m, 6H), 0.89-1.00 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][C:6]1=2.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:24]1([NH:30][C:31](=[O:32])[NH:1][CH2:2][CH2:3][S:4][CH:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][O:8][C:7]3[CH:16]=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][C:6]2=3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc2c(c1)C(SCCN)c1ccccc1CO2
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(SCCNC(=O)Nc1ccccc1)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound f, 2.0 g, obtained in Reference Example 6 was dissolved in 100 ml of methylene chloride and 0.7 ml of phenyl isocyanate was added to the solution. The mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The residue was extracted with 200 ml of ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate=2:1) to give 2.2 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:18][C@H:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[CH3:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:10]=1)[C:7]([NH:18][C@H:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[CH3:20])=[O:9]
Reactant: CC(C)COCc1ccc(Cl)cc1C(=O)O
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COCC(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-(isobutoxymethyl)benzoic acid (step 1) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[N+:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=O)([O-:13])=[O:12].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][NH2:29].C([O-])(=O)C.[Na+].C(O)(=O)C>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C@@H:4]1[N:29]([CH2:28][CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[C:17](=[O:19])[CH2:16][CH2:15][C@H:14]1[N+:11]([O-:13])=[O:12]
Reactant: O=Cc1cc(F)ccc1F
Reactant: COC(=O)CCC[N+](=O)[O-]
Reactant: NCCc1ccccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1CC[C@@H]([N+](=O)[O-])[C@H](c2cc(F)ccc2F)N1CCc1ccccn1
Reaction time: 0.08 h

Procedure:
To a solution of 2,5-difluorobenzaldehyde (2.29 mL, 21.1 mmol) in ethanol (42 mL) was added methyl 4-nitrobutyrate (2.51 mL, 21.1 mmol) and the mixture stirred for 5 min. To the reaction mixture was added 2-pyridin-2-ylethanamine (2.61 mL, 21.1 mmol) and the mixture stirred for 10 min. To the mixture was added sodium acetate (1.73 g, 21.1 mmol) followed by glacial acetic acid (2.42 mL, 42.2 mmol) and the mixture heated at reflux temperature for 48 h. The solvent was removed in vacuo and to the yellow oil was added saturated aqueous sodium hydrogen carbonate (25 mL) and the aqueous phase extracted with ethyl acetate (4×25 mL). The combined organic phases were washed with saturated aqueous brine (1×25 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo. The yellow oil was purified by column chromatography (silica gel Biotage 40S™) eluting with ethyl acetate/hexane (gradient from 0% to 100%) to give the racemic trans title compound as a yellow gum. LC/MS 362.2 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH2:13]([N:15]([CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:16][CH3:17])[CH3:14].[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25]>C(#N)C>[OH2:5].[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[CH2:13]([N:15]([CH2:16][CH3:17])[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:14]
Reactant: O=S(=O)(CCCl)c1ccccc1
Reactant: CCN(CC)CCCCN
Agent: O=C(O)C(=O)O
Solvent: CC#N
Product: CCN(CC)CCCCNCCS(=O)(=O)c1ccccc1
Product: O
Temperature: 25 °C
Reaction time: 16 h
Yield: 164.4 %

Procedure:
A mixture of 28.2 g (0.138 mole) of [(2-chloroethyl)sulfonyl]benzene and 20.0 g (0.139 mole) of 4-(N,N-diethylamino)-1-butanamine in 700 ml of acetonitrile was stirred at room temperature for 16 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was dissolved in methanol, a solution of 25.0 g (0.278 mole) of oxalic acid was added and a precipitate was collected to give 47.69 g (68.9%) of title compound, a white crystalline solid, mp 158°-165° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@@H:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([O:29]C)=[O:28])[C:22]3[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=3[O:20][C@@H:19]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[OH-].[Li+].CO.Cl>C1COCC1.O>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@@H:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([OH:29])=[O:28])[C:22]3[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=3[O:20][C@@H:19]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:16])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)[C@@H](c2ccccc2)Oc2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)N(CC(=O)O)c2ccccc2O[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a stirred solution of methyl [(2R,3S)-3-({N-[(3,5-difluorophenyl)acetyl]-L-alanyl}amino)-4-oxo-2-phenyl-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate (70) (133 mg, 0.241 mmol) in THF (4 mL) was added a solution of lithium hydroxide (11 mg, 0.262 mmol) in water (1 mL). Several small drops of methanol were then added until a clear homogeneous solution was achieved. The mixture was stirred for 1 h at ambient temperature then acidified with 1N aqueous HCl and extracted with ethyl acetate. The organic solution was dried, filtered and evaporated. The glass-like solid residue was dissolved in dichloromethane (2 mL) then precipitated by addition of hexanes to afford the title compound (124 mg, 96%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ1.08 (d, 3H, J=7.0 Hz), 3.41 and 3.48 (AB quartet, 2H, J=14.5 Hz), 4.21 (m, 1H), 4.58 (s, 2H), 5.02 (t, 1H, J=7.0 Hz), 5.55 (d, 1H, J=7.0 Hz), 6.94 (m, 2H), 7.08 (m, 1H), 7.24-7.49 (m, 10H), 8.33 (d, 1H, J=7.0 Hz), 12.94 (br, 1H). MS APCI, m/z=538 (M+1). LC/MS: 2.27 min.
Reaction SMILES: [CH:1]12[CH2:11][CH:7]([C:8](=O)[CH2:9]1)[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1.[NH3:12].[H][H]>CO.[Ni]>[CH2:3]1[CH:2]2[CH:6]([CH:7]3[CH2:11][CH:1]2[CH2:9][CH:8]3[NH2:12])[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: O=C1CC2CC1C1CCCC21
Reactant: N
Agent: [Ni]
Solvent: CO
Product: NC1CC2CC1C1CCCC21

Procedure:
A solution of 15 g of tricyclo[5,2,1,02,6]decan-8-one in 60 ml of methanol, which had been saturated beforehand at 10° C. with NH3, was, after addition of Raney nickel, hydrogenated in an autoclave at 90° C. and a hydrogen pressure of 100 bar for 10 hours. The catalyst was filtered off and the solvent was distilled off under reduced pressure, and the mixture was then made strongly alkaline using 10 N NaOH and extracted 2-3 times with ethyl acetate or with diisopropyl ether. The combined organic phases were dried and subjected to fractional distillation under reduced pressure. Bp6-7mm 86-88° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.[CH2:23]([NH:30][CH2:31][C@@H:32]([C:34]1[CH:45]=[CH:44][C:37]2[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=2[CH:35]=1)[OH:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>C(#N)C.C(OCC)C>[CH2:23]([N:30]([CH2:31][C@@H:32]([C:34]1[CH:45]=[CH:44][C:37]2[O:38][C:39]([CH3:42])([CH3:43])[O:40][CH2:41][C:36]=2[CH:35]=1)[OH:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NS(=O)(=O)c1cccc(CCCCOCCCCCCBr)c1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCc3ccccc3)ccc2O1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC1(C)OCc2cc([C@@H](O)CN(CCCCCCOCCCCc3cccc(S(N)(=O)=O)c3)Cc3ccccc3)ccc2O1
Temperature: 25 °C
Yield: 113.1 %

Procedure:
A stirred mixture of 3-{4-[(6-bromohexyl)oxy]butyl}benzenesulfonamide (11.1 g), (1R)-2-(benzylamino)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (9 g) and diisopropyl ethylamine (8.9 ml) in acetonitrile (28 ml) was heated at reflux for 18 h. The resulting mixture was cooled to room temperature, diluted with diethyl ether (250 ml) and washed with water (2×100 ml) and brine (100 ml) before being dried over anhydrous Na2SO4. The suspension was filtered and concentrated under reduced pressure to give the title compound (20 g) as an oil. LC RT=4.68 min, δ (CDCl3) 7.70 (2H, m), 7.38 (2H, m), 7.29 (5H, m), 7.02 (1H, d, J 8.3 Hz), 6.91 (1H, s), 6.73 (1H, d, J 8.3 Hz), 4.79 (2H, s), 4.53 (1H, m), 3.87 (1H, m), 3.40 (5H, m), 2.69 (2H, t, J 7.2 Hz), 2.54 (2H, m), 2.43 (2H, m), 1.70 (2H, m), 1.60 (2H, m), 1.51 (10H, m), 1.25 (4H, m)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](Br)=[CH:4][N:3]=1.[N:10]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[S:37](Cl)(=[O:39])=[O:38]>>[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[CH:29][C:28]=1[S:37]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:25][C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)(=[O:18])=[O:17])=[CH:24][CH:23]=2)=[CH:4][N:3]=1)(=[O:39])=[O:38]
Reactant: Cc1cc(N)ncc1Br
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCCCC1
Product: Cc1cc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1

Procedure:
Prepared from 2-amino-5-bromo-4-methylpyridine and 4-(N-piperidinylsulfonyl)thiophenol according to General Method 11 step 1 followed by reaction with 2-chloro-4-trifluoromethylphenylsulfonyl chloride according to General Method 11 step 2. 1H NMR (CDCl3): 13.39 (1H, br s, NH), 8.39 (1H, s, A-ring CH ortho to Cl), 8.31 (1H, d, J 11 Hz, A-ring CH ortho to SO2NH), 7.67 & 7.18 (2×1H, 2×s, pyridyl CH's), 7.61 (1H, d, J 11 Hz, A-ring CH ortho to CF3), 7.53 & 7.04 (2×2H, 2×d, 2×J 10 Hz, Ar CH's of C-ring), 2.91-2.82 (4H, m, CH2NCH2), 2.22 (3H, s, CH3), 1.62-1.46 (4H, m, CH2CH2CH2CH2CH2), 1.39-1.28 (2H, m, CH2CH2CH2CH2CH2). Hplc (Luna 2, Gradient 5): rt=6.47 minutes. LC/MS rt=7.13 minutes, 606 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][Br:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(CBr)cc1
Yield: 99.9 %

Procedure:
p-tert-butyltoluene (14.8 g; 0.10 mol) was dissolved in carbon tetrachloride, and N-bromosuccinimide (17.8 g; 0.10 mol) and benzoyl peroxide (200 mg) were added thereto. The mixture was refluxed for 2 hours, and then cooled. Insoluble matter was filtered off, followed by washing with carbon tetrachloride. The filtrate was concentrated under reduced pressure, and the residue was dissolved in n-hexane, followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure, to thereby yield 22.7 g of p-tert-butylbenzyl bromide (yield: 100%). The thus-obtained product was analyzed by 1H-NMR, and was found to be a mixture of the target compound, starting compounds, and a dibromo compound (10:1:1). Sodium carbonate (10.6 g; 0.10 mol) was added to 40% solution of methylamine in methanol (200 ml). While the mixture was cooled in an ice bath, p-tert-butyl benzyl bromide (22.7 g; 0.10 mol) in methanol (20 ml) was added dropwise thereto. The mixture was removed from the ice bath, and stirred for 41 hours at room temperature. Methanol was removed under reduced pressure, and the residue was taken up in water, followed by extraction with ether (400 ml). The ether layer was extracted with 1N hydrochloric acid twice (200 ml and 100 ml), and the aqueous layer was extracted with ethyl acetate. The aqueous layer was alkalinized with aqueous 2N sodium hydroxide solution, and extracted with ether (400 ml), followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=200:1→100:1→20:1), to thereby yield 9.51 g of the target compound (yield: 53.7%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][NH2:25])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](Cl)=[O:42])=[CH:36][CH:35]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][NH:25][C:41](=[O:42])[CH2:40][C:37]1[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NN)c(OCc1ccccc1)c2=O
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OCCn2c1nc(C(=O)NNC(=O)Cc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To stirred solution of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbohydrazide (0.170 g, 0.49 mmol) and Et3N (0.14 mL, 1 mmol) in CH2Cl2 (10 mL) was added 2-(4-fluorophenyl)acetyl chloride (69 mL, 0.5 mmol) and the mixture stirred 2 h at room temperature. The reaction mixture was purified by preparative HPLC on a C18 column using water/MeOH containing 0.1% TFA as eluent to afford the title compound (0.078 g, 33% yield) as a white solid. 1HNMR (500 MHz, CDCl3) δ: 9.97 (1H, d, J=7.0 Hz), 8.42 (1H, d, J=6.7 Hz), 7.54 (2H, d, J=6.7 Hz), 7.35-7.27 (5H, m), 7.05 (2H, t, J=8.6 Hz), 5.36 (2H, s), 4.04-3.98 (4H, m), 3.64 (2H, s), 1.60 (6H, s). HRMS (M+H) calcd for C25H26N4O5F: 481.1887. found: 481.1866.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=2)[C:10]([I:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:23]=C=NCCCN(C)C.Cl>CN(C=O)C>[C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=[C:10]2[I:20])(=[O:18])[NH2:23]
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cc(C(=O)O)ccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc(I)c2cc(C(N)=O)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To solution of 1-(tert-butoxycarbonyl)-3-iodo-1H-indole-5-carboxylic acid (1 g, 2.57 mmol) in DMF (10 mL) at 0° C. was added EDC.HCl (741 mg, 3.86 mmol) and HOBT-NH3 complex (825 mg, 5.15 mmol). The reaction mixture was stirred at RT for 3 h and then extracted with DCM (15 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by column chromatography to obtain title compound as an off white solid (550 mg, 50%). MS (ESI, Neg. ion) m/z: 286.9 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][Zn]Cl>C1COCC1>[C:1]1([C:7]2[C:8]([C:16]3[CH:17]=[CH:18][C:19]([CH:20]([OH:21])[CH3:24])=[CH:22][CH:23]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Reactant: C[Zn]Cl
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Temperature: 100 °C

Procedure:
100 mg 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde (prepared as described for example 1) are dissolved in 2 ml THF and 1 ml of a 2M solution of MeZnCl is added. The mixture is heated (100° C., microwave) for 2 h, cooled to room temperature and extracted with a mixture of dichloromethane and water. The organic layers are dried over sodium sulphate and the solvent is evaporated.