Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]#[N:19])[C:5]2[C:6]([CH3:17])=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:9]=2[CH:10]=1>[Ni].N.CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:17])=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([CH2:18][NH2:19])[CH:3]=1
Reactant: Cc1nn(C2CCCCO2)c2cc(Cl)cc(C#N)c12
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1nn(C2CCCCO2)c2cc(Cl)cc(CN)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
A mixture of 6-chloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile (150 mg, 0.545 mmol) and Raney nickel (20 mg) in NH3/MeOH (7 N, 10 mL) was stirred under hydrogen at RT overnight. The reaction mixture was filtered through Celite® and the filtrate concentrated to afford (6-chloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methanamine (123) as an oil (130 mg, 72.3%). MS (ESI): m/z=280 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)([CH3:6])[CH3:5].C(N(CC)CC)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3](=[O:14])[C:4]([CH3:6])([C@H:7]1[CH2:8][CH2:9][C@H:10]([O:13][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:11][CH2:12]1)[CH3:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@H](O)CC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)[C@H]1CC[C@H](OS(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
0.400 g trans-2-(4-hydroxy-cyclohexyl)-2-methyl-propionic acid methyl ester (residue HH) are dissolved in 10 ml of dichloromethane. Triethylamine (0.42 ml) and 4-dimethylamino pyridine (0.012 g) are added and the solution is cooled to 0° C. 0.419 g of para-toluenesulfonyl chloride are added portionwise and the reaction mixture is then stirred at room temperature for 16 hours. The reaction mixture is poured onto saturated aqueous sodium hydrogencarbonate solution and the layers are separated. The aqueous layer is extracted with dichloromethane and the combined organics are dried over sodium sulphate and concentrated. Flash chromatography (SiO2 60F) of the residue provides the title compound which is identified on the basis of its Rf-value.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:17]12[NH:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][C:19](=[O:25])[CH2:18]2>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:24]2[CH:17]3[CH2:23][CH2:22][CH:21]2[CH2:20][C:19](=[O:25])[CH2:18]3)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=C1CC2CCC(C1)N2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CC2CCC(C1)N2Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A stirred solution of 1-bromo-4-bromomethylbenzene (0.39 g, 1.56 mmol), triethylamine (0.45 mL, 3.20 mmol) and 8-azabicyclo[3.2.1]octan-3-one (0.33 mL, 2.32 mmol) in THF (10 mL) was heated under reflux for 5 h. The reaction mixture was allowed to cool to ambient temperature and the solid removed by filtration. The filtrate was concentrated under reduced pressure to afford a residue that was purified by flash chromatography (silica, 50 g column, Biotage, 0-100% DCM in ethyl acetate) to afford the title compound as an off-white solid (400 mg, 90%). 1H NMR (CDCl3, 300 MHz): 7.48-7.43 (m, 2H), 7.32-7.28 (m, 2H), 3.69 (s, 2H), 3.49-3.43 (m, 2H), 2.66 (dd, J=16.0, 4.3 Hz, 2H), 2.26-2.17 (m, 2H), 2.14-2.06 (m, 2H), 1.66-1.56 (s, 2H). LCMS (Method B): RT=1.86 min, M+H+=294/296.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)[N:31]2[CH2:34][CH:33]([CH2:35][S:36]([NH:39][C:40]3[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=3)[C:43]([OH:45])=O)(=[O:38])=[O:37])[CH2:32]2)=[CH:26][CH:25]=1.Cl.[NH2:57][CH2:58][C:59]([N:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1)=[O:60]>O1CCCC1.ClCCl.C(N(CC)CC)C>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]([C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)[N:31]2[CH2:34][CH:33]([CH2:35][S:36]([NH:39][C:40]3[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=3)[C:43]([NH:57][CH2:58][C:59]([N:61]3[CH2:66][CH2:65][O:64][CH2:63][CH2:62]3)=[O:60])=[O:45])(=[O:37])=[O:38])[CH2:32]2)=[CH:28][CH:29]=1
Reactant: NCC(=O)N1CCOCC1
Reactant: O=C(O)c1cccc(NS(=O)(=O)CC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(=O)N1CCOCC1)c1cccc(NS(=O)(=O)CC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
67 mg of 1-hydroxybenzotriazole, 0.14 cm3 of triethylamine and 270 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added successively to a solution of 500 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)benzoic acid and 215 mg of 2-amino-1-morpholin-4-ylethanone hydrochloride in 15 cm3 of tetrahydrofuran. The reaction mixture is left stirring overnight at a temperature in the region of 20° C. After concentration of the reaction medium to dryness under reduced pressure, the residue obtained is taken up with dichloromethane. The organic phase is washed with water, dried, and concentrated to dryness under reduced pressure, to give a reaction crude which is purified by flash chromatography on a Merck 30 g silica cartridge (elution gradient: 100/0 to 95/5 dichloromethane/methanol). After concentration of the fractions under reduced pressure, a white foam is obtained which crystallizes after trituration with diethyl ether. After filtration and drying using a vane pump, 470 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-N-(2-morpholin-4-yl-2-oxoethyl)benzamide are thus obtained in the form of white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])=[C:4]([CH3:10])[CH:3]=1
Reactant: BrCCCCCCCBr
Reactant: Cc1cc(Br)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C)c1OCCCCCCCBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4-bromo-2,6-dimethylphenol (2.00 g) and 1,7-dibromoheptane (5.10 g) in N,N-dimethylformamide (20 ml) was treated with potassium carbonate (2.06 g), and the mixture was stirred for 5 hours at ambient temperature. To the reaction mixture was added water and methylene chloride, and the organic layer was separated and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting successively with the following solvents: (1) n-hexane, (2) n-hexane:ethyl acetate=4:1, (3) n-hexane:ethyl acetate=1:1. The fractions containing the object compound were concentrated in vacuo to give crude 5-bromo-2-(7-bromoheptyloxy)-1,3-dimethylbenzene, that was used in the next reaction directly, as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[N:20]=[C:21](/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])[O:22][CH:23]=2)[CH:14]=[CH:13][C:3]=1[CH2:4][S:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[N:9]1.ClC1C=CC=C(C(OO)=[O:42])C=1>ClCCl.C(OCC)(=O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:26](/[CH:25]=[CH:24]/[C:21]2[O:22][CH:23]=[C:19]([CH2:18][O:17][C:15]3[CH:14]=[CH:13][C:3]([CH2:4][S:5]([CH2:6][CH2:7][N:8]4[CH:12]=[CH:11][N:10]=[N:9]4)=[O:42])=[C:2]([CH3:1])[CH:16]=3)[N:20]=2)=[C:27]([F:33])[CH:28]=1
Reactant: Cc1cc(OCc2coc(/C=C/c3ccc(Cl)cc3F)n2)ccc1CSCCn1ccnn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(OCc2coc(/C=C/c3ccc(Cl)cc3F)n2)ccc1CS(=O)CCn1ccnn1
Temperature: -30 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
To a solution of 710 mg (1.46 mmol) 1-[2-(2-methyl-4-{2-[2-(E)-(4-chloro-2-fluorophenyl)-vinyl]-oxazol-4-ylmethoxy}-benzylsulfanyl)-ethyl]-1H-[1,2,3]triazole in 35 ml dichloromethane at −30° C. were added dropwise during 20 min. 493 mg (2.20 mmol) 3-chloro-perbenzoic acid (77% peracid) dissolved in 20 ml ethyl acetate. After 1 hour stirring at −30° C. the mixture was allowed to warm up over night, stirred another 48 hours at room temperature, diluted with dichloromethane, washed with sodium bicarbonate solution, then with water, dried and evaporated. Elution from silica with ethyl acetate (1–10% methanol gradient) gave as the second fraction 199 mg (27%) title compound as white solid.
Reaction SMILES: C(OC([N:11]1[C:20]2[C:15](=[CH:16][C:17]([CH3:22])=[N:18][C:19]=2[CH3:21])[C:14](=[O:23])[CH2:13][CH:12]1[CH2:24][CH3:25])=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH2:24]([CH:12]1[CH2:13][C:14](=[O:23])[C:15]2[C:20](=[C:19]([CH3:21])[N:18]=[C:17]([CH3:22])[CH:16]=2)[NH:11]1)[CH3:25]
Reactant: CCC1CC(=O)c2cc(C)nc(C)c2N1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCC1CC(=O)c2cc(C)nc(C)c2N1

Procedure:
This compound can be obtained by reacting a solution of 2-ethyl-6,8-dimethyl-4-oxo-3,4-dihydro-2H-[1,7]naphthyridine-1-carboxylic acid benzyl ester in methanol, under nitrogen atmosphere, with ammonium formate (2.5 eqv) and 10% Pd—C (50% water wet), at about 40° C. for a time period of about 1 h, followed by a typical workup.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12](=O)(OC)OC.[Mg].[Al]>>[CH3:12][O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCO
Reactant: COC(=O)OC
Agent: [Al]
Agent: [Mg]
Product: CCCCCCCCCCOC
Reaction time: 1.1 h

Procedure:
A mixture of 1-decanol (1 mole) and dimethyl carbonate (3 mole) was passed through 11.5 grams of a magnesium:aluminum mixed metal oxide (3/16 inch pellets, Mg/Al 3:1) at a temperature of 250° C. and at a liquid feed rate of 0.34 milliliters/minute. After a period of 1.1 hour, a total of 36.5 grams of liquid was collected. Analysis was performed by capillary gas chromatography (FID) using a DB-1701 column. The results were (area %) as follows:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](=O)[CH2:7][CH3:8])=[CH:2]1.[Cl:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=O)=[CH:16][CH:15]=1>>[Cl:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH2:7][CH3:8])=[CH:16][CH:15]=1
Reactant: CCC(=O)c1ccsc1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccsc1
Yield: 94.7 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, 1-(thiophen-3-yl)propan-1-one (0.5 g, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (1.5 g, 1.5 eq) to give 1.3 g desired product (95% yield, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.10-7.14 (m, 1H), 7.02-7.09 (m, 2H), 6.76-6.92 (m, 5H), 6.68-6.71 (m, 1H), 6.60-6.66 (m, 1H), 6.55-6.59 (m, 1H), 4.62 (s, 1H), 4.49 (s, 1H), 4.24 (t, J=6.0 Hz, 1H), 4.14 (t, J=6.0 Hz, 1H), 3.82 (t, J=6.0 Hz, 1H), 3.76 (t, J=6.0 Hz, 1H), 2.43-2.49 (m, 2H), 0.98 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:27]12[CH2:35][C:31]([CH2:36][NH2:37])([CH2:32][CH2:33][CH2:34]1)[CH2:30][CH2:29][CH2:28]2>O1CCCC1.CO>[N:27]12[CH2:35][C:31]([CH2:36][NH:37][C:7](=[O:9])[C:6]3[CH:10]=[C:2]([Cl:1])[C:3]([NH:13][CH3:14])=[CH:4][C:5]=3[O:11][CH3:12])([CH2:32][CH2:33][CH2:34]1)[CH2:30][CH2:29][CH2:28]2
Reactant: NCC12CCCN(CCC1)C2
Reactant: CNc1cc(OC)c(C(=O)O)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(OC)c(C(=O)NCC23CCCN(CCC2)C3)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
A solution of 5-chloro-2-methoxy-4-(methylamino)benzoic acid (1.08 g, 5 mmol) in anhydrous tetrahydrofuran (7 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (0.90 g, 5.5 mmol), stirred one hour, degassed under a stream of nitrogen for 10 minutes, and cooled (0° C.). A solution of 1-azabicyclo[3.3.1]nonane-5-methanamine (0.82 g, 5.3 mmol) in tetrahydrofuran (3 mL) was added dropwise, and stirring was continued at room temperature for 18 hours. The suspension was diluted with enough methanol to dissolve the solid, then the solution was filtered through a short column of alumina (eluted with 20% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo, triturated from cold ether, and recrystallized from acetonitrile to afford 1.29 g (73%) of colorless crystals; mp 188°-190° C. (second phase), first phase melting point 175° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[Cl:9][C:10]([Cl:15])([Cl:14])[CH:11](O)O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:9][C:10]([Cl:15])([Cl:14])[C@@H:11]1[N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3](=[O:5])[O:4]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Yield: 62.5 %

Procedure:
A suspension of L-proline (10.0 g, 87.0 mmol) and chloral hydrate (21.6 g, 130 mmol) in chloroform (100 mL) was heated at reflux for 6 h under a soxlet adapter charged with sodium sulfate. The cooled mixture was washed with water (2×), dried (MgSO4) and concentrated in vacuo. The product was recrystallised from boiling absolute ethanol to give the title compound as white needles (13.3 g, 63%). 1H NMR (400 MHz, CDCl3): 1.65-1.83 (1H, m), 1.86-2.01 (1H, m), 2.04-2.31 (2H, m), 3.06-3.18 (1H, m), 3.36-3.49 (1H, m), 4.12 (1H, dd, J 4.6, 4.0), 5.16 (1H, s).
Reaction SMILES: N1C=C2C(N=CN2)=NC=1.[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([NH:15][CH:16]=[N:17]2)=[C:13](Cl)[N:12]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([NH:15][CH:16]=[N:17]2)=[C:13]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:12]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: C1COCCN1
Agent: c1ncc2[nH]cnc2n1
Product: Clc1nc(N2CCOCC2)c2[nH]cnc2n1

Procedure:
As shown in Scheme 4, a purine compound of the invention can be prepared by using commercially-available 2,6-dichloro-7H-purine as a starting material. The two chloro groups can be displaced by various substituents. More specifically, for example, the first chloro group (e.g., at position 6) can be displaced by morpholine to give a 2-chloro-6-(morpholin-4-yl)-7H-purine. The second chloro group can then be displaced by a nucleophile, e.g., hydrazine, and the primary amine of the coupled hydrazine moiety can be further reacted with an aldehyde, e.g., 3-methyl-6-methoxy-benzaldehyde, 3-methyl-6-amino-benzaldehyde, or 1H-indole carbaldehyde to form a hydrazone linkage.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5](Br)=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C>[N:15]1([C:5]2[S:4][C:3]([NH2:2])=[N:7][CH:6]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Nc1ncc(Br)s1
Reactant: C1COCCN1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncc(N2CCOCC2)s1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a mixture of 2-amino-5- bromothiazole monohydrobromide (2 gm, 7.69 mmol) and powdered potassium carbonate (2.1 gm, 15.38 mmol) in DMF (20 mL) was added morpholine (1.34 ml, 15.38 mmol) under argon atmosphere and heated at 60° C. for 3 hr. Reaction mixture was cooled to rt and poured over ice cold water (100 ml), extracted with ethylacetate (3×100 ml), washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To the residue, diisopropyl ether (50 mL) was added, after stirring for 30 minutes product precipitated out, which was filtered and dried under vacuum to provide 5-morpholin-4-yl-thiazol-2-ylamine (0.95 gm).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[Br:12][CH:13](Br)[CH3:14]>O.CCOC(C)=O>[Br:12][CH2:13][CH2:14][O:11][C:6]1[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([Cl:10])[CH:7]=1
Reactant: CC(Br)Br
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1cc(Cl)cc(OCCBr)c1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To a solution of NaOH (2.45 g, 61.3 mmol) in water (20 mL) was added 3,5-dichlorophenol (5 g, 30.7 mmol). The solution was heated at reflux for 1 h and was cooled to room temperature. Dibromoethane (11.52 g, 61.3 mmol) was added and the reaction was heated at reflux for 24 h. The cooled solution was diluted with EtOAc and the organic solution was washed sequentially with HCl (1N, 1×), water (1×), and brine (1×). The organic solution was dried (MgSO4), filtered, and concentrated. Purification by flash chromatography (hexanes to 5% EtOAc in hexanes) provided the title compound (3.79 g). 1H NMR (400 MHz, CDCl3) δ 6.98 (m, 1H), 6.82 (m, 2H), 4.25 (t, 2H), 3.61 (t, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH:16](=O)[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([C:2]2[O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[CH:16]=2)=[O:4])=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: O=Cc1ccccc1O
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(C(=O)c2cc3ccccc3o2)ccc1Cl

Procedure:
4 g 2-Bromo-4'-chloro-3'-sulfamoylacetophenone and 1.63 g salicylaldehyde are maintained for 2 hours with agitation and with exclusion of moisture at a temperature of 80° C. in 50 ml anhydrous dimethyl formamide, in the presence of 2.9 g potassium carbonate ground under anhydrous conditions. After cooling, the batch is poured into a mixture of icewater and excess hydrochloric acid, extracted with ethyl acetate and dried over sodium sulfate. After having distilled off the solvent, crystallization is carried out from di-isopropyl ether and isopropanol. M.p. 152°-156° C. Recrystallization from glacial acetic acid after clarification with active charcoal gives colorless crystals having a melting point of 167°-170° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](#[N:14])[CH:12]=[CH2:13]>C(O)C>[C:11]([CH2:12][CH2:13][NH:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)#[N:14]
Reactant: C=CC#N
Reactant: NCCCc1ccccc1
Solvent: CCO
Product: N#CCCNCCCc1ccccc1

Procedure:
A mixture of 3-phenylpropylamine (0.95 g, 7 mmol) and acrylonitrile (0.55 ml, 8.4 mmol) in ethanol (30 ml) was refluxed for 2 hours to give N-(2-cyanoethyl)-3-phenyl-propylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:29]=[CH:30][CH:31]=3)[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:39][C:40]1[C:41]([OH:51])=[C:42]([S:47](Cl)(=[O:49])=[O:48])[CH:43]=[C:44]([Cl:46])[CH:45]=1>ClCCl>[Cl:39][C:40]1[C:41]([OH:51])=[C:42]([S:47]([N:15]([CH2:16][C:17]2[CH:18]=[C:19]([CH:29]=[CH:30][CH:31]=2)[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)(=[O:49])=[O:48])[CH:43]=[C:44]([Cl:46])[CH:45]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNCc2ccc(-c3ccc(F)cc3)cc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
tert-Butyl 3-(((4′-fluorobiphenyl-4-yl)methylamino)methyl)benzylcarbamate (1.8 g, 4.28 mmol, 1.0 eq) was dissolved in dichloromethane and cooled 0° C. Triethylamine (1.85 mL, 12.8 mmol, 3.0 eq) was added slowly over 5-10 minutes and the mixture was stirred for 10 minutes at 0° C. 3,5-Dichloro-2-hydroxybenzene-1-sulfonyl chloride (1.2 g, 4.7 mmol, 1.1 eq) was dissolved in DCM and added slowly to the above mixture at 0° C. After 2 h, the reaction mixture was concentrated under vacuum at low temperature and the white precipitate that formed was removed. The solution was purified by silica gel (60-120) column chromatography using 15-20% ethyl acetate/hexane as the eluent to afford the desired product (2.3 g, 85%). 1H NMR (400 MHz, CD3OD) δ 1.45 (d, 9H), 4.11-4.15 (d, 2H) 4.49-4.52 (d, 4H), 7.07-7.19 (m, 8H), 7.42-7.44 (d, 2H), 7.56-7.59 (m, 3H), 7.65-7.66 (d, 1H). MS (ESI): 644.0 (M−H)−.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1(S([N:51]2[C:59]3[CH:58]=[CH:57][N:56]=[C:55](Br)[C:54]=3[CH:53]=[CH:52]2)(=O)=O)C=CC=CC=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:40][C:36]([N:33]1[CH2:32][CH2:31][N:30]([CH2:29][C:27]2[S:28][C:8]3[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11]([C:55]4[C:54]5[CH:53]=[CH:52][NH:51][C:59]=5[CH:58]=[CH:57][N:56]=4)=[N:10][C:9]=3[CH:26]=2)[CH2:35][CH2:34]1)([CH3:41])[C:37]([NH2:39])=[O:38]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)nccc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4nccc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 140 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
A mixture of 2-((4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (150 mg, 0.22 mmol), 1-benzenesulfonyl-4-bromo-1H-pyrrolo[3,2-c]pyridine (90 mg, 0.27 mmol), Pd(PPh3)4 (25 mg, 10 mol %) and CuI (50 mg, 0.25 mmol) in dioxane (2.5 mL) was purged with argon gas then heated at 140° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH. The resulting residue was dissolved in IMS/dioxane (1:1 mL) and 12.5 M aqueous NaOH solution (0.1 mL) added. After stirring for 1 h the reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 05:95) to give 106 (28 mg, 24%) as a pale yellow solid. LCMS (Method F) RT 4.86 min; [M+H]+ 521.3. 1H NMR (CDCl3, 400 MHz): δ 9.11 (s, 1 H); 8.54 (d, J=5.6 Hz, 1 H); 7.45 (s, 1 H); 7.41 (dd, J=3.3, 0.9 Hz, 1 H); 7.38 (dd, J=5.6, 0.95 Hz, 1 H); 7.36 (d, J=3.3 Hz, 1 H); 7.10 (d, J=5.3 Hz, 1 H); 5.25 (d, J=5.2 Hz, 1 H); 4.10 (t, J=4.75 Hz, 4 H); 3.91 (t, J=4.7 Hz, 4 H); 3.85 (s, 2 H); 2.60 (s, 8 H); 1.25 (s, 6 H)
Reaction SMILES: [Cl:1][CH:2]([CH2:6][CH3:7])[C:3](Cl)=[O:4].[NH2:8][C:9]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12]>C1(C)C=CC=CC=1>[Cl:1][CH:2]([C:3]1[O:4][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([F:19])([F:20])[F:21])[C:9]=2[N:8]=1)[CH2:6][CH3:7]
Reactant: CCC(Cl)C(=O)Cl
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CCC(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A suspension of 20.3 g of 2-chloro-butyryl chloride and 12.3 g of 2-amino-3-trifluoromethyl-benzoic acid in toluene was refluxed under reduced pressure for one hour and was then evaporated to dryness under reduced pressure. The oil residue was added to 100 ml of iced water and the mixture was stirred for one hour and was vacuum filtered. The product was washed with water and dried under reduced pressure at 50° C. to obtain 17 g of 2-(1-chloropropyl)-8-trifluoromethyl-4H-3,1-benzoxazine-4-one melting at 65°-70° C.