Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[O:2][CH:3]=[C:4]2[C:9]([CH2:10][C:11]([N:13]([CH:15]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=3)[CH2:16][CH:17]3[CH2:21][CH2:20][CH:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:18]3)[CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][C:5]=12.C(=O)([O-])[O-].[K+].[K+].[C:43]([O:47][C:48](=[O:51])[CH2:49]Br)([CH3:46])([CH3:45])[CH3:44].O>CN(C)C=O>[C:43]([O:47][C:48](=[O:51])[CH2:49][O:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([CH:15]([N:13]([C:11](=[O:12])[CH2:10][C:9]2[C:4]3[CH:5]=[CH:1][O:2][C:3]=3[CH:6]=[CH:7][CH:8]=2)[CH3:14])[CH2:16][CH:17]2[CH2:21][CH2:20][CH:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:18]2)[CH:31]=1)([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(C(=O)Cc1cccc2cocc12)C(CC1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)Cc1cccc2occc12)C(CC1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(OCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of Example 35 1.63 g, 3.2 mmol) in dimethylformamide (22 mL) was added potassium carbonate (1.37 g, 9.9 mmol) and, under argon, t-butylbromoacetate (0.47 mL, 3.2 mmol). After stirring at room temperature for 23 hours, the reaction was poured into water (160 mL), extracted with dichloromethane (160 mL), dried (MgSO4), and the solvent removed in vacuo. Purification by column chromatography (dichloromethane:methanol 39:1 followed by ethyl acetate:heptane 4:1) gave the product as a clear oil, 1.4 mmol, 45%.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:5]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:4]=2[N:3]=1.[C:21](OC)(=[O:24])[C:22]#[CH:23]>CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:4]2[N:3]3[CH:23]=[CH:22][C:21](=[O:24])[N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[C:5]=2[CH:16]=1
Reactant: C#CC(=O)OC
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Solvent: CO
Product: O=c1ccn2c(n1)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
In the manner given in Example 1, 2-amino-7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepine, methyl propiolate and methanol were refluxed. The mixture was chromatographed to give 9-chloro-7-(o-chlorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[Si:15]([O:22][CH:23]1[CH2:28][CH2:27][C:26](=[CH:29][C:30]#[N:31])[CH2:25][CH2:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N12CCCN=C1CCCCC2>C(#N)C>[Si:15]([O:22][CH:23]1[CH2:24][CH2:25][C:26]([CH2:29][C:30]#[N:31])([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:27][CH2:28]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=CC#N)CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(C3(CC#N)CCC(O[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.09 g, 0.0159 mol) in acetonitrile (39.8 mL) was added (4-(tert-butyl(dimethyl)silyl)oxycyclohexylidene)acetonitrile (4.80 g, 0.0191 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.19 mL, 0.00797 mol). The resulting mixture was stirred at room temperature overnight, then evaporated to dryness. The mixture was purified on silica gel, eluting with 0 to 20% EtOAc in hexanes, to give the desired product as cis- and trans-mixture (2.33 g, 33%). LCMS (M+H) 446.3.
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=[S:9])[NH:2]1.[OH-].[Na+].I[CH3:15]>C(O)C.O>[CH3:15][S:9][C:3]1[C:4]2=[CH:8][S:7][CH:6]=[C:5]2[S:1](=[O:10])(=[O:11])[N:2]=1
Reactant: CI
Reactant: O=S1(=O)NC(=S)c2cscc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSC1=NS(=O)(=O)c2cscc21
Yield: 36.3 %

Procedure:
To a mixture of 0.9 g (0.0044 mole) of thieno[3,4-d]isothiazol-3(2H)-thione 1,1-dioxide in 4 ml of ethanol is added a solution of 0.35 g (0.0044 mole) of 50% sodium hydroxide in 3 ml of water. To this thick mixture is added 0.62 g (0.0044 mole) of iodomethane. The mixture is heated under reflux for 5 minutes, and then filtered to give 0.35 g of product. On cooling, a second crop of 0.1 g of material is obtained. A small amount of the first crop is recrystallized from ethanol to afford an analytical sample, m.p. 184°-6° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH:10][C:11]1[NH:16][C:15](=[O:17])[C:14]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][N:12]=1.[I-].[CH3:26][N+:27]([CH3:29])=[CH2:28]>CN(C)C=O>[CH3:26][N:27]([CH2:29][C:5]1[S:1][C:2]([CH2:6][S:7][CH2:8][CH2:9][NH:10][C:11]2[NH:16][C:15](=[O:17])[C:14]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][N:12]=2)=[CH:3][CH:4]=1)[CH3:28]
Reactant: C=[N+](C)C
Reactant: O=c1[nH]c(NCCSCc2cccs2)ncc1Cc1cccnc1
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(CSCCNc2ncc(Cc3cccnc3)c(=O)[nH]2)s1

Procedure:
2-[2-(2-Thienylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone is reacted with an excess of dimethyl(methylene)ammonium iodide in dimethylformamide at room temperature to give 2-[2-(5-dimethylaminomethyl-2-thienylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[C:5]([C:13]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:14]=1[NH:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[C:5]([C:13]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:14]=1[NH:15][C:16](=[O:23])[C:17](=[N:1][OH:3])[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 50 g. of sodium nitrite is added dropwise to a solution of 34.6 g. of ethyl 2'-benzoyl-4'-chloro-malonanilate in 250 ml. of glacial acetic acid. After 11/2 hours stirring at room temperature, the oxime crystallizes out and is filtered off by suction, washed with water and dried in vacuum. Ethyl 2'-benzoyl-4'-chloro-mesoxalanilate 2-oxime, m.p. 98°-105° is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[F:11][C:12]([F:16])([F:15])[CH2:13]I.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:13][C:12]([F:16])([F:15])[F:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: FC(F)(F)CI
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OCC(F)(F)F
Yield: 838.3 %

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (3.1 g, 2 mmol), 1,1,1-trifluoro-2-iodo-ethane (2.4 mL, 24 mmol), K2CO3 (5.5 g, 40 mmol) and KI (0.1 g) were mixed in DMF (20 mL). Then the mixture was irradiated under microwave at 180° C. for 1 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1N NaOH. Then the organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give title compound as a yellow solid (Yield: 4 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8].[C:11]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12]1>I.C(OC(=O)C)(=O)C.[PH2](O)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: O=C1CCCC1
Reactant: CC(=O)c1c(C)c[nH]c1C
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1c(C)[nH]c(C2CCCC2)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,4-Dimethyl-3-acetyl-pyrrole (0.548 g) was dissolved in a mixture of hydriodic acid (10 ml), acetic anhydride (10 ml) and hypophosphorous acid (2 ml). The solution was stirred at 40° while cyclopentanone (1.5 ml) was added in three portions over 3/4 hr. After stirring an additional 1/2 hr., the solution was poured into ice water (125 ml) and the pale yellow product (95%), m.p. 161.5°-163.5° after changing to prisms at ca 140°, separated. For analysis it was recrystallized successively from hexane, from aqueous methanol and again from n-hexane as pale pink prisms m.p. 167.5°-168° (lit20), 164.5°-165.5°). Anal. Calc. for C13H19NO: C, 76.05, H, 9.33; N, 6.82. Found: C, 76.12; H, 9.21; N, 6.65.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C:11]2=[O:14])=[CH:7][CH:6]=1)=[O:4].[CH3:15][CH:16](O)[CH:17]=[CH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:15]([CH:10]1[CH2:9][C:8]2[C:12](=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[C:11]1=[O:14])[CH:16]=[CH:17][CH3:18]
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC2
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(C(=O)OC)cc2C1=O
Yield: 83 %

Procedure:
A solution of 8 g of 6-methoxycarbonyl-1-indanone, 8 ml of 3-buten-2-ol and 100 mg of p-toluenesulfonic acid in 80 ml of 2,2-dimethoxy-propane was boiled under reflux for 28 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 3:1). In addition to 1.3 g of educt, there were obtained 8.5 g (83%) of (RS)-2-(2-buten-1-yl)-6-methoxycarbonyl-1-indanone as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[CH3:11][C:12]1([CH3:30])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=2)[NH:15][CH:14]([C:23]2[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=2)[CH2:13]1.N1C=CC=CC=1>ClCCl>[CH3:11][C:12]1([CH3:30])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=2)[NH:15][CH:14]([C:23]2[CH:24]=[C:25]([NH:29][S:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)(=[O:9])=[O:8])[CH:26]=[CH:27][CH:28]=2)[CH2:13]1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(NS(=O)(=O)c3cccnc3)c1)N2
Reaction time: 8 h
Yield: 13.6 %

Procedure:
Pyridine-3-sulfonyl chloride (96 mg, 0.54 mmol) was added dropwise a mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (120 mg, 0.45 mmol) and pyridine (60 mg, 0.76 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. The mixture was filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=4:1) to afford pyridine-3-sulfonic acid [3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide as off-white solid (25 mg, yield: 13.7%). MS (ESI+APCI) M+1=408.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.CN.C[CH2:20][N:21](CC)CC>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:21][CH3:20])=[CH:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)nc1
Agent: CN
Solvent: CCO
Product: CNc1ccc(C(=O)c2ccc(Cl)cc2)cn1
Temperature: 80 °C
Yield: 54.4 %

Procedure:
A mixture of compound B (23.4 g, 93.22 mmol), methylamine (88 mL, 932 mmol, 33% solution in ethanol) and Et3N (37.51 mL, 280 mmol) in EtOH (100 mL) was heated in a sealed tube at 80° C. for 3 h. EtOH was removed under reduced pressure and the residue was dissolved in DCM (150 mL), washed with water and brine. The organic layer was dried (Na2SO4), filtered and evaporated. The crude product was purified by triturating with diethyl ether to obtain 12.5 g (55%) of compound C as off-white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][NH:14]1.C(N(CC)CC)C.N1C2C(=CC=CC=2)C=NC=1>O1CCOCC1>[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][N:14]1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: c1ccc2c(c1)CNC2
Agent: c1ccc2ncncc2c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Ic1ccc2ncnc(N3Cc4ccccc4C3)c2c1
Yield: 87.2 %

Procedure:
0.50 g of 4-chloro-6-iodoquinazoline, 0.27 g of 2,3-dihydro-1H-isoindole, 0.42 ml of triethylamine in 4 ml of dioxane are heated at 80° C. in a flask until the quinazoline has reacted virtually completely (HPLC check, about 3 hours). The cooled reaction solution is evaporated to dryness in a rotary evaporator. The residue is suspended in EA. The undissolved solid is filtered off, rinsed with water and dried, giving 0.56 g of 4-(1,3-dihydroisoindol-2-yl)-6-iodoquinazoline as slightly yellowish solid (yield 93%, content 94%); MS-FAB (M+H+)=373.8; Rf (polar method): 1.73 min. This is employed for the next step without further purification.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][O:25][C:26]([C:28]1[C:37]2[O:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[C:34]([CH3:44])[C:33](=[O:45])[C:32]=2[CH:31]=[CH:30][CH:29]=1)=[O:27].O>CN(C)C=O>[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH2:24][O:25][C:26]([C:28]2[C:37]3[O:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[C:34]([CH3:44])[C:33](=[O:45])[C:32]=3[CH:31]=[CH:30][CH:29]=2)=[O:27])[CH2:11][CH2:10]1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)OCCCBr)cccc2c1=O
Reactant: Clc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)OCCCN3CCN(c4ccccc4Cl)CC3)cccc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2.8 g of 1-(2-chlorophenyl)-piperazine hydrochloride and 4.2 g of anhydrous potassium carbonate in 25 ml of dimethylformamide was stirred at ambient temperature for 15 minutes. 4.81 g of Intermediate I was added, and stirring was continued for 2 days. The reaction mixture was then poured into 200 ml of cold water, and extracted with diethyl ether and ethyl acetate. The organic extracts were washed in turn with aqueous sodium chloride solution, 0.1N aqueous acetic acid solution, aqueous sodium chloride solution, aqueous 4% sodium carbonate solution and water, and were then dried on anhydrous sodium sulfate. After evaporation to dryness in vacuo, the residue was dissolved in 160 ml of acetonitrile and excess hydrogen chloride in diethyl ether was added. The insoluble title compound was recrystallized from acetonitrile. Yield 3.6 g, m.p. 138°-143° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:30]=[CH:29][C:8]([O:9][CH:10]([CH3:28])[C:11](=[O:27])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:38][S:39]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:28])[C:11](=[O:27])[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])=[CH:18][CH:19]=2)=[CH:29][CH:30]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Oc1ccc(CCCO)cc1)C(=O)COc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(CCCOS(C)(=O)=O)cc1)C(=O)COc1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.75 h
Yield: 83.1 %

Procedure:
A solution of (3R and 3S)-3-[4-(3-hydroxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone (0.092 g, 0.22 mmol) in dry dichloromethane (5 ml) was cooled to 0° C. and treated with triethylamine (0.07 ml, 0.5 mmol) followed by methanesulfonyl chloride (0.03 ml, 0.39 mmol). After 45 minutes at 0° C., the reaction mixture was quenched by addition of ethyl acetate (100 ml) and water. The organic phase was washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation and chromatography of the residue on silica gel (elution toluene and ethyl acetate, 9:1) gave 0.090 g (82%) of the title material as an oil.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH:4]([C:6]([OH:8])=[O:7])[CH3:5].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O>[C:9]([NH:3][C@H:4]([C:6]([OH:8])=[O:7])[CH3:5])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@H](NC(=O)c1ccccc1)C(=O)O
Temperature: 75 °C
Yield: 90.4 %

Procedure:
To a solution of sodium hydroxide (8.98 g, 224.49 mmol) in water (112.25 mL), was added at rt DL-Alanine (10 g, 112.25 mmol). The resulting solution was heated at 75° C. and the benzoyl chloride (15.77 g, 112.25 mmol) was slowly added. The reaction was heated for 30 minutes, and cooled down to 0° C. with an ice bath. Conc. HCl was added to adjust the pH to 1, then the white solid was filtrated through a fritted glass funnel and vacuum dried with P2O5 overnight. No purification was needed. This gave N-benzoylalanine (19.6 g, 90.4% yield) as white solid. 1H NMR (DMSO-d6) δ 12.61 (s br, 1H), 8.64 (d, 1H), 7.87-7.85 (m, 2H), 7.52-7.43 (m, 3H), 4.40 (q, 1H), 1.39 (d, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.Cl.[F:37][CH:38]([F:41])[CH2:39][NH2:40].C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:40][CH2:39][CH:38]([F:41])[F:37])[N:3]=3)[N:25]=2)=[CH:30][CH:31]=1
Reactant: NCC(F)F
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCC(F)F)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
140 mg (0.260 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), 61 mg (0.519 mmol) of 2,2-difluoroethylamine hydrochloride and 67 mg (0.519 mmol) of N,N-diisopropylethylamine were dissolved in 2 ml of tetrahydrofuran and stirred at room temperature overnight. Without further work-up, the reaction mixture was purified by preparative HPLC. 77 mg (yield: 51% of theory) of the target compound were obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH3:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25](COCC[Si](C)(C)C)[C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:20])=[O:28]
Reactant: Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 56.9 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-methylbenzonitrile (0.053 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.050 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was recrystallized from boiling IPA, cooled in an ice bath and filtered to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-methylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.043 g, 0.103 mmol, 56.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br. s., 1H), 8.25 (m, 1H), 7.78 (s, 1H), 7.50 (m, 1H), 7.44 (s, 1H), 7.36 (t, J=8.03 Hz, 1H), 7.22 (s, 1H), 7.13 (s, 1H), 4.54 (d, J=5.36 Hz, 2H), 2.33 (s, 3H). LC-MS (ES−) m/z 417.04, 419.01 [M−1]. LC-MS (ES+) m/z 418.79, 420.06 [M+H].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=2[Br:39])[C:10](=[O:40])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:39][C:16]1[CH:17]=[CH:18][C:19]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:20][C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2Br)C(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1ccc(Br)c(CN2CCNCC2=O)c1)(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of product from Step D (2.30 g, 3.69 mmol) in methylene chloride (16 mL) was added trifluoroacetic acid (4 mL). The resulting solution was stirred for 3 hours, then poured onto saturated aqueous sodium bicarbonate, and extracted with methylene chloride (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title product as a yellow oil which was sufficiently pure for use in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][O:36][CH2:35]1>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:38][CH2:37][O:36][CH2:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCC3CCOC3)c2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt, (200 mg) and potassium carbonate (236 mg) in dry DMF (2 mL) were heated at 60° C. with stirring for 1 h. 3-(2-Bromoethyl)tetrahydrofuran, Intermediate 83 (123 mg) was added and the reaction was continued for 2 h at 60° C. The mixture was quenched with water and extracted with EtOAc (×3). The combined organics were washed with water and brine, dried using a hydrophobic frit and evaporated to an oil (261 mg). This material was purified by flash chromatography (silica, 5-20% methanol:ethyl acetate) and the appropriate fractions combined and evaporated to give the title compound, yield 181 mg.