Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:10][C:11]1[N:16]=[C:15]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]([C:27]([O:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[CH2:24]3)=[CH:19][CH:18]=2)[CH:14]=[C:13]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[N:12]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[NH2:10][C:11]1[N:16]=[C:15]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]([C:27]([O:29][CH:30]4[CH2:35][CH2:34][N:33]([C:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:7])[CH2:32][CH2:31]4)=[O:28])[CH2:24]3)=[CH:19][CH:18]=2)[CH:14]=[C:13]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[N:12]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCN(C(=O)C5CCCC5)CC3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclopentanecarbonyl chloride (2.0 uL, 0.016 mmol) was added to a mixture of piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate HCl salt (6.0 mg, 0.011 mmol) and N,N-diisopropylethylamine (9.3 uL, 0.054 mmol) in acetonitrile (0.4 mL). The reaction mixture was stirred at r.t. for 30 min., purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=548.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:19])[C:16]#[C:17][CH3:18].[H-].[Na+].O>CN(C)C=O>[F:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([O:19][CH2:15][C:16]#[C:17][CH3:18])[N:3]=[CH:4][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC#CCO
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(-c2cccc(F)c2)ncn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.7 %

Procedure:
In 7 ml of N,N-dimethylformamide were dissolved 204 mg of 4-chloro-6-(3-fluorophenyl)pyrimidine and 82 mg of 2-butyn-1-ol, to which 47 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 6 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 151 mg of 4-(3-fluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (57)).
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH3:2].[CH3:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([C@H:20]([NH:27][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([CH2:1][CH3:2])=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:5]=2)[CH3:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCc1ccc(C=O)cc1-c1ccc(OC)cc1
Product: CCc1ccc(CN[C@H](C)c2ccccc2)cc1-c1ccc(OC)cc1

Procedure:
The title compound (0.2 g, white solid as HCl salt) was prepared from 4-ethyl-3-(4-methoxyphenyl)benzaldehyde (0.5 g) and (R)-α-methylbenzylamine (0.265 mL) analogously to Example 66, step 3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1nc(-c2ccc(OC)cc2)cc(C(=O)OCC)c1=O
Yield: 84.5 %

Procedure:
Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and ethyl bromoacetate as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 84.5%.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:2]([C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:7][CH2:8]2)[CH3:1])=[O:21])=[CH:18][CH:17]=1
Reactant: CN[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
from trans-N-methyl-4-phenylcyclohexylamine and 4-chlorobenzoylchloride. Melting point: 138°-140° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)([CH3:14])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:21]I>CN(C=O)C.O>[CH3:21][N:6]([CH2:5][C:4]([CH3:3])([N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)[CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCC(C)(C)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CC(C)(C)N1CCOCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 120 h
Yield: 119.5 %

Procedure:
To a suspension of 60% NaH in mineral oil (238 mg, 5.96 mmol) in dry DMF (5 mL) was added dropwise a solution of tert-butyl 2-methyl-2-morpholinopropylcarbamate (770 mg, 2.98 mmol) in dry DMF (5 mL). After 30 min MeI (0.928 mL, 14.9 mmol) was added dropwise. The mixture was stirred at room temperature for 5 d, poured in H2O and extracted with Et2O (30 mL). The organic layer was dried (Na2SO4) and concentrated to yield the desired crude product (970 mg,) as a light yellow oil.
Reaction SMILES: [NH3:1].[N:2]1([CH:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[C:16]4[C:17]5[C:22]([S:23][C:24]=4[N:25]=[CH:26][N:27]=3)=[CH:21][CH:20]=[C:19]([CH2:28][C:29]([O:31]CC)=O)[CH:18]=5)[CH2:10][CH2:9]2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1>C(O)C>[N:2]1([CH:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15]3[C:16]4[C:17]5[C:22]([S:23][C:24]=4[N:25]=[CH:26][N:27]=3)=[CH:21][CH:20]=[C:19]([CH2:28][C:29]([NH2:1])=[O:31])[CH:18]=5)[CH2:12][CH2:13]2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: N
Reactant: CCOC(=O)Cc1ccc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c2c1
Solvent: CCO
Product: NC(=O)Cc1ccc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Into a saturated solution of ammonia (gas) in ethanol (50 mL) was added ethyl 2-(3-[[4-(morpholin-4-yl)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0 [2,7]]trideca-1(13),2(7),3,5,9,11-hexaen-12-yl)acetate (100 mg, 0.22 mmol, 1.00 equiv) and the resulting solution was sealed and stirred overnight at room temperature. After completion, the solvent was removed under reduced pressure. The residue was applied onto a silica gel column with dichloromethane/methanol/NH4OH (15:1:0.05) to provide the resulted 2-(3-[[4-(morpholin-4-yl)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0 [2,7]]trideca-1(13),2(7),3,5,9,11-hexaen-12-yl)acetamide (38.5 mg, 41%) as a off-white solid. LC/MS: (ES, m/z) 426 [M+H]+. 1H-NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.93-7.91 (d, 1H), 7.75 (s, 1H), 7.45-7.40 (t, 1H), 5.46-5.42 (d, 2H), 5.35-5.32 (d, 2H), 4.31-4.16 (m, 1H), 3.81-3.79 (m, 6H), 2.64-2.60 (d, 3H), 2.46-2.40 (d, 3H), 2.07-1.98 (m, 2H), 1.58-1.55 (m, 2H), 1.48-1.42 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][N:10]([CH2:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=1)[C:11](=[O:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(O[N:66]1[C:71](=[O:72])[CH2:70][CH2:69][C:67]1=[O:68])=[N+](C)C)C>C1COCC1>[O:68]=[C:67]1[CH2:69][CH2:70][C:71](=[O:72])[N:66]1[O:40][C:39](=[O:41])[C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:10]([CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:11](=[O:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)Cc1ccc(C(=O)O)cc1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)Cc1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Temperature: 0 °C
Yield: 86.8 %

Procedure:
4-{[(2-tert-Butoxycarbonylethyl)-(15-tert-butoxycarbonyl-pentadecanoyl)amino]methyl}benzoic acid (70 mg, 0.12 mmol) was dissolved in THF (5 mL). The mixture was cooled with an ice bath. Diisopropylethylamin (0.024 mL, 0.14 mmol) and O—(N-succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (42 mg, 0.14 mmol) was added. The mixture was stirred under nitrogen at 0° C. After 30 minutes the ice cooling was removed and the mixture was stirred for an additional 3 hours. Solvent removed in vacuo flowed by reevaporation from toluene. The crude product was dissolved in ethyl acetate (25 mL), washed with water (10 mL). The organic phase dried (Na2SO4), solvent removed in vacuo to yield the title compound (73 mg, 87%) which was used in subsequent step.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH3:7][Si:8]([C:11]#[CH:12])([CH3:10])[CH3:9].C(NCC)C>C1COCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[CH3:7][Si:8]([C:11]#[C:12][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1)([CH3:10])[CH3:9]
Reactant: Ic1cn[nH]c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cn[nH]c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Iodo-1H-pyrazole (20.0 g, 103 mmol) is dissolved in anhydrous THF (150 ml) and trimethylsilyl acetylene (72.8 ml, 515 mmol) is added under an inert atmosphere. Diethyl-amine (150 ml), bis-(triphenylphosphine) palladium (II) chloride (10.8 g, 15 mmol) and copper iodide (2.9 g, 15 mmol) are added and the reaction mixture is left to stir at room temperature for 3 hours. The solvent is removed under reduced pressure. The residue is dissolved in diethyl ether and the insoluble impurities are filtered off. The solvent is removed under reduced pressure. The residue is dissolved in methanol and the insoluble impurities removed. The solvent is removed under reduced pressure. The residue is purified by dry flash chromatography on silica gel eluting with a gradient system of diethyl ether: iso-hexane (20:80 to 100:0) to afford the title compound [MH+] 165.07 1H NMR (DMSO): 0.00 (s, 9H), 7.45 (s, 1H), 7.90 (s, 1H), 12.90 (br s, 1H)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[N:10]([CH3:11])[C:9]([CH3:12])=[C:8]([CH3:13])[C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:17].C(Cl)Cl.[OH-].[Na+]>O>[Cl:17][C:4]1[C:5]2[N:10]([CH3:11])[C:9]([CH3:12])=[C:8]([CH3:13])[C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1nc2c(C)c(C)n(C)c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1nc(Cl)c2c(n1)c(C)c(C)n2C
Temperature: 100 °C
Reaction time: 17 h

Procedure:
A mixture of 2,5,6,7-tetramethyl-3H,4H,5H-pyrrolo[3,2-d]pyrimidin-4-one N9b (0.334 g, 1.75 mmol) and POCl3 (4 ml) is stirred at 100° C. for 17 hours. At 0° C. DCM (30 ml) and aqueous sodium hydroxide (1 mol/1, 20 ml) is added under vigorous stirring. The water phase is made basic with an aqueous solution of sodium hydroxide (1 mol/l) and extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is used without further purification. Yield: 330 mg (90%). HPLC-MS: M+H=210; tR=0.92 min (METHOD—1).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].FC1C=CC(C[N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=CC=1.C(O)(=O)C>CO>[N:4]1[CH:5]=[CH:6][N:7]=[CH:8][C:3]=1[CH2:1][CH2:2][N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:18]2[NH:17][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=2)[CH2:32][CH2:31]1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: C=Cc1cnccn1
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc2[nH]c(NC3CCN(CCc4cnccn4)CC3)nc2c1

Procedure:
A mixture of 1.27 parts of 2ethenylpyrazine, 6.48 parts of 1-[(4 fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine, 0.3 parts of acetic acid and 40 parts of methanol was stirred and refluxed for 48 hours. The solvent was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (88:12 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was washed with 2,2'-oxybispropane and crystallized from 27 parts of methylbenzene, yielding 2.4 parts of 1-)4-fluorophenylmethyl)-N-[1-[2-(2-pyrazinyl)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 165.3° C. (compound 101).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]=2[CH3:21])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C(OCC)(=O)C.CCCCCC>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]3[O:10][C:9]([CH3:21])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:12]=3[C:13]=2[CH3:20])=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1oc2c(C)c(C)c(NC(=O)c3ccc(F)cc3)c(C)c2c1-c1ccc(F)cc1
Yield: 75 %

Procedure:
By using 3-(4-fluorophenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 75%. Melting point: 232-234° C. (Ethyl acetate-hexane).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH2:10][C:11]1[S:15][C:14]([CH2:16][O:17][CH2:18][C:19]([NH2:21])=O)=[CH:13][CH:12]=1)[CH3:9].CCOCC>O1CCCC1>[CH3:9][N:8]([CH2:10][C:11]1[S:15][C:14]([CH2:16][O:17][CH2:18][CH2:19][NH2:21])=[CH:13][CH:12]=1)[CH3:7]
Reactant: CN(C)Cc1ccc(COCC(N)=O)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(COCCN)s1
Yield: 74.8 %

Procedure:
A suspension of lithium aluminium hydride (0.38 g) and [[5-(N,N-dimethylaminomethyl)2-thienyl]methoxy]acetamide (2.28 g) in a mixture of dry ether (25 ml) and dry tetrahydrofuran (5 ml) was heated at reflux for 4 hr. The reaction was then quenched with water and evaporated. The residue was extracted with chloroform. The organic phase was dried and distilled to afford a colourless oil (1.6 g) b.p. 110°-120° (0.1 mm). NMR (CDCl3), 8.43, s, (2H); 7.72, s, (6H); 7.12, t, (2H); 6.46 t, (2H); 6.38, s, (2H); 5.32, s, (2H), 3-3.3, m, (2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:23]=[CH:22][C:13]([O:14][CH2:15][CH:16]3[O:20][C:19]([NH2:21])=[N:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:3]1.C1O[C@H]1CCl.CC1(C)CC(C)(C)C[CH:33]([C:39]2C=C[C:42]([OH:45])=[CH:41][CH:40]=2)C1.C(OCC)(=O)C#CCC>C(O)C>[CH2:39]([C:40]1[N:18]2[CH2:17][C@@H:16]([CH2:15][O:14][C:13]3[CH:12]=[CH:11][C:10]([CH:4]4[CH2:5][C:6]([CH3:8])([CH3:9])[CH2:7][C:2]([CH3:24])([CH3:1])[CH2:3]4)=[CH:23][CH:22]=3)[O:20][C:19]2=[N:21][C:42](=[O:45])[CH:41]=1)[CH3:33]
Reactant: CC1(C)CC(c2ccc(OCC3CN=C(N)O3)cc2)CC(C)(C)C1
Reactant: CC1(C)CC(c2ccc(O)cc2)CC(C)(C)C1
Agent: CCC#CC(=O)OCC
Agent: ClC[C@H]1CO1
Solvent: CCO
Product: CCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3CC(C)(C)CC(C)(C)C3)cc1)O2
Temperature: 25 °C

Procedure:
To a solution of 5-[4-(3,3,5,5-tetramethyl-cyclohexyl)-phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine (0.15 g, 0.454 mmol), prepared in accordance with the procedures described in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-(3,3,5,5-tetramethyl-cyclohexyl)-phenol (prepared using the same procedure as in step 1 of Example 74), in ethanol (5 mL) was added ethyl 2-pentynoate (0.086 g, 0.681 mmol). The reaction mixture was heated at reflux for 14 hrs and then cooled to room temperature. The reaction mixture was concentrated, loaded onto a silica gel column, and eluted with 4% methanol/methylene chloride to afford 23 mg of (S)-5-ethyl-2-[4-(3,3,5,5-tetramethyl-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)[N:4]=1.C(N(CC)CC)C.[CH:29]([S:32](Cl)(=[O:34])=[O:33])([CH3:31])[CH3:30]>C(Cl)Cl>[F:21][C:2]([F:1])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][S:32]([CH:29]([CH3:31])[CH3:30])(=[O:34])=[O:33])=[CH:14][CH:13]=2)[N:4]=1
Reactant: NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
A mixture of ({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)amine (100 mg, 0.339 mmol), triethylamine (0.07 ml, 0.51 mmol) in DCM (10 ml) was stirred in an ice bath under argon. Then isopropylsulfonyl chloride was added (148 mg in total, 1 mmol) in DCM (1 ml) dropwise with stirring. The reaction mixture was allowed to stir at room temperature for 16 hr. Then the reaction mixture was washed with water (20 ml), separated the organic layer and dried with sodium sulphate. Solvent was removed by rotary evaporation and the sample purified by MDAP to give the title compound as an off white solid (51 mg, 37%).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[CH3:12].[N:13]#[C:14][NH2:15]>C(O)C>[ClH:1].[NH:2]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[CH3:12])[C:14]([NH2:15])=[NH:13]
Reactant: N#CN
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1NC(=N)N
Temperature: 60 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To 140 ml of ethanol, was added 22.6 g of 4-amino-3-methylbenzoic acid hydrochloride followed by 7.6 g of cyanamide. After having been stirred overnight at 60° C., the reaction mixture was freed from the solvent by distillation under reduced pressure and mixed with acetone to collect the crystals by filtration. The crystals were washed with acetone and recrystallized from a mixture of ethanol and ethyl acetate to obtain 8.9 g of white granular crystals of 4-guanidino-3-methylbenzoic acid hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl[CH2:12][C:13]#[C:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[C:19]([O:18][C:17](=[O:23])[NH:16][CH2:15][C:14]#[C:13][CH2:12][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC#CCCl
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC#CCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.51 g), tert-butyl (4-chlorobut-2-yn-1-yl)carbamate (2.60 g), cesium carbonate (4.80 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 2 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→33:67) to give the title compound (2.61 g) as an orange oil.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[CH2:13][CH:12]([NH2:21])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)C(N)(CO)CO>ClCCCl>[CH2:3]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[CH2:13][CH:12]([NH:21][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1Cc2cc(Cl)ccc2N(Cc2ccccc2)C1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: O=S(=O)(NC1Cc2cc(Cl)ccc2N(Cc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was synthesized as part of library using the following procedure in a parallel synthesis fashion using 48 well red and blue minireactors. Typical procedure: To a solution of 22B (14 mg, 0.05 mmol) in DCE (0.5 mL) at RT was added NMM (0.109 mL, 0.1 mmol), followed by addition of benzene sulfonylchloride (17.6 mg, 0.1 mmol) in DCE (0.5 uL). The reaction mixture was shaken at RT for 24 h, and treated with 100 mg of PS-Trisamine (4 mmol/g loading) for 2 h to remove excess sulfonyl chloride. Contents were filtered into a synthesis tube rack (STR) and the solvent was dried in a speed vac. The resulting residue was chromatographed using Prep HPLC (conditions: Xterra MS-C18 (30×50 mm); Eluted with 10% to 100% B, 6 min gradient. (A=100% water−0.1% TFA and B=acetonitrile with 0.1% TFA); Flow rate at 30 mL/min. UV detection at 220 nm) to give compound 50 (13.8 mg, 69%). HPLC: 99% at 1.74 min (retention time) (Conditions: Xterra MS-C18 (2.1×50 mm); Eluted with 0% to 100% B, 2.75 min gradient. (A=100% water−0.1% TFA and B=acetonitrile with 0.1% TFA); Flow rate at 1 mL/min. UV detection at 220 nm). MS (ES): m/z 413 [M+H]+.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([OH:6])[C:4]#[CH:5].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[H-].[Na+].O>O1CCCC1>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([O:6][C:3]([CH2:7][F:8])([C:4]#[CH:5])[CH2:2][F:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: C#CC(O)(CF)CF
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CC(CF)(CF)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.2 %

Procedure:
An amount (6.6 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol and p-toluenesulfonyl chloride (9.5 g) were dissolved in tetrahydrofuran (100 ml); to the solution under cooling with ice, 60% oily sodium hydride (2.4 g) was added under a nitrogen atmosphere. After the end of the addition, the mixture was stirred for 5 hours while its temperature was raised to room temperature. To the reaction mixture, water was added followed by extraction with ether. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane/methylene chloride=1/1) to give the titled compound (11.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:16][CH3:17])(=[N:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:4][CH:3]=1.[Br:18][C:19]1[C:20]([O:26][C@H:27]([CH3:31])[C@H:28]([OH:30])[CH3:29])=[N:21][C:22](Cl)=[N:23][CH:24]=1.Cl>C(#N)C.O1CCOCC1>[Br:18][C:19]1[C:20]([O:26][C@H:27]([CH3:31])[C@H:28]([OH:30])[CH3:29])=[N:21][C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH2:16][CH3:17])(=[N:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:4][CH:3]=2)=[N:23][CH:24]=1
Reactant: C[C@@H](O)[C@@H](C)Oc1nc(Cl)ncc1Br
Reactant: CCOC(=O)N=S(=O)(CC)c1ccc(N)cc1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CCOC(=O)N=S(=O)(CC)c1ccc(Nc2ncc(Br)c(O[C@H](C)[C@@H](C)O)n2)cc1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
128 mg (0.51 mmol) of (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-ethyl sulfoximide and 150 mg (0.53 mmol) of (2R,3R)-3-[(5-bromo-2-chloropyrimidin-4-yl)oxy]-butan-2-ol in 2 ml of acetonitrile are mixed with 0.12 ml of a 4N solution of HCl in dioxane. The batch is stirred for 2 days at 60° C. The solvent is removed, and the residue is purified by chromatography (DCM/EtOH 95:5). 43 mg (0.09 mmol, corresponding to 17% of theory) of the product is obtained.