Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.CO[BH-](OC)OC.[Na+]>ClCCl.O>[CH:5]1([CH2:6][NH:26][CH2:25][C:24]([C:15]2[NH:16][C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:13]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=3)[N:14]=2)([CH3:28])[CH3:27])[CH2:10][CH2:11][CH2:12][CH2:3][CH2:4]1
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Agent: CO[BH-](OC)OC
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2cc(-c3nc(C(C)(C)CNCC4CCCCC4)[nH]c3-c3ccncc3)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
A solution of the product of Example 2 (20 mg, 0.05 mmol) in dichloromethane (2 mL) was treated with cyclohexaldehyde (3 mg, 0.07 mmol) and sodium trimethoxyborohydride (9 mg, 0.07 mmol). The solution was stirred at room temperature for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The aqueous layer was separated and extracted with additional ethyl acetate, the organic layers were combined, dried over anhydrous magnesium sulphate, filtered and concentrated at reduced pressure. The residue was chromatographed on a Gilson HPLC to give the title compound (10 mg, 40%) as a yellow solid; MS(ES) m/e 469 [M+H]+.
Reaction SMILES: [Si]([O:8][CH:9]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:10][CH:11]([OH:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(C(C)(C)C)(C)C.[SiH3]O[SiH3]>Cl.CO.CCO>[CH3:47][CH2:46][CH2:45][CH2:44][CH2:43]/[CH:42]=[CH:41]\[CH2:40]/[CH:39]=[CH:38]\[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH:9]([OH:8])[CH2:10][CH:11]([OH:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CC(CCCCCCC/C=C\C/C=C\CCCCC)O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [SiH3]O[SiH3]
Solvent: CCO
Solvent: CO
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CC(O)CCCCCCC/C=C\C/C=C\CCCCC
Reaction time: 0.75 h
Yield: 76.1 %

Procedure:
The silyl ether (6Z,9Z,29Z,32Z)-21-((tert-butyldimethylsilyl)oxy)octatriaconta-6,9,29,32-tetraen-19-ol (6) (2.44 g, 3.62 mmol) was dissolved in HCl—CH3OH (1%, 100 mL) and EtOH (40 mL). After stirring (45 min) the solution was concentrated and subjected to chromatography (10%→15% EtOAc-hexanes) to yield (6Z,9Z,29Z,32Z)-octatriaconta-6,9,29,32-tetraene-18,20-diol (7) (1.54 g, 76%) as a clear colorless oil. Rf 0.12 (10% EtOAc-hexanes), FW 558.96, C38H70O2.
Reaction SMILES: CO[CH:3](OC)[CH:4](Cl)[CH3:5].Cl.CC([O-])=O.[Na+].[NH2:15][C:16]1[NH:21][C:20](=[O:22])[NH:19][C:18](=[O:23])[CH:17]=1>O>[CH3:5][C:4]1[C:17]2[C:18]([OH:23])=[N:19][C:20]([OH:22])=[N:21][C:16]=2[NH:15][CH:3]=1
Reactant: COC(OC)C(C)Cl
Reactant: Nc1cc(=O)[nH]c(=O)[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1c[nH]c2nc(O)nc(O)c12
Temperature: 95 °C
Yield: 92.3 %

Procedure:
To a mixture of 2-chloropropionaldehyde dimethyl acetal (5.84 g, 42.1 mmol) in H2O (26 mL) was added conc. HCl (1 mL). After heating at 95° C. for 15 min (or until the solution turns homogenous), NaOAc (5.2 g) was added to neutralize the excess HCl. The resulting solution was then transferred to a separate flask containing a suspension of 6-aminouracil (4 g, 31.5 mmol) and NaOAc (2.6 g) in H2O (52 mL). After heating the mixture at reflux overnight, the reaction was cooled and the precipitates were collected by filtration to give 5-methyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (4.8 g, 94% yield).
Reaction SMILES: Br[CH:2]1[CH2:19][CH2:18][C:5]2=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:7][C:8]([S:9][CH2:10][CH2:11][CH3:12])=[C:4]2[C:3]1=O.[C:21]([NH2:29])(=[S:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C>O>[C:22]1([C:21]2[S:28][C:2]3[CH2:19][CH2:18][C:5]4=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:7][C:8]([S:9][CH2:10][CH2:11][CH3:12])=[C:4]4[C:3]=3[N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCSc1sc(C(=O)OCC)c2c1C(=O)C(Br)CC2
Reactant: NC(=S)c1ccccc1
Solvent: O
Solvent: CCO
Product: CCCSc1sc(C(=O)OCC)c2c1-c1nc(-c3ccccc3)sc1CC2
Yield: 34.9 %

Procedure:
A mixture of ethyl 5-bromo-4,5,6,7-tetrahydro-4-oxo-3-propylthiobenzo[c]thiophene-1-carboxylate (9.43 g), thiobenzamide (6.86 g) and ethanol (190 ml) was refluxed under heating for 4 hours, after which it was poured over water (600 ml) and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:10, v/v) to yield ethyl 4,5-dihydro-2-phenyl-8-propylthiothieno[3,4-e]benzothiazole-6-carboxylate (3.63 g, 34.9%), which was then recrystallized from ethyl acetate-hexane. Yellow prisms. Melting point 125-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.C[O-].[Na+].[C:13](OCC)(=[O:15])C.O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:15][CH3:13])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(Cl)nc(Cl)c1
Reaction time: 12 h

Procedure:
To a solution of 2,4,6-trichloropyridine (4.5 g) in methanol was added sodium methoxide (25% in methanol, 6.8 mL) at room temperature. The mixture was stirred for 12 h then poured into ethyl acetate/water and separated. The organic layer was washed with water, brine and dried over magnesium sulfate. Upon evaporating, the residue was purified by crystallization (100% hexanes) to give title compound as solid (3.1 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1O)#[N:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]#[N:16])[CH2:12][CH2:13]1
Reactant: N#Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-Boc-4-hydroxypiperidine (20 g, 99.35 mmol) and 2-cyanophenol (11.82 g, 99.35 mmol) were added to mixture of triphenylphosphine (26.06 g, 99.35 mmol) and di-tert-butyl azodicarboxylate (19.56 mL, 99.35 mmol) in tetrahydrofuran (800 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was taken up in hydrochloric acid (4M in dioxane, 300 mL). The reaction mixture was stirred at room temperature for 18 hours and was then concentrated in vacuo. The residue was partitioned between water and ethyl acetate and the aqueous layer was separated and washed with ethyl acetate (2×100 mL). The aqueous solution was then basified with 2M sodium hydroxide solution and then extracted with diethyl ether (3×100 mL). The combined organic solution was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a white solid in quantitative yield. LRMS ESI m/z 203 [M+H]+
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>CCOCC>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOCC
Product: O=C(Nc1cccc(Cl)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.56 g of phenyl chloroformate in 50 ml of ether was added dropwise to a stirred solution of 2.55 g of 3-chloroaniline in 35 ml of ether. The mixture was stirred for one hour at room temperature and then filtered. The filtrate was evaporated and the residue crystallized from hexane to yield phenyl N-(3-chlorophenyl)carbamate.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[S:5][C:6]([CH2:9][OH:10])=[CH:7][N:8]=1.Cl[C:12]1[C:17]([CH3:19])([CH3:18])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[C:14](=[O:23])[CH:13]=1.Cl>O1CCCC1.O>[Br:3][C:4]1[S:5][C:6]([CH2:9][O:10][C:12]2[C:17]([CH3:18])([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[C:14](=[O:23])[CH:13]=2)=[CH:7][N:8]=1
Reactant: OCc1cnc(Br)s1
Reactant: CC1(C)C(=O)C=C(Cl)C(C)(C)C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C(=O)C=C(OCc2cnc(Br)s2)C(C)(C)C1=O
Yield: 53.8 %

Procedure:
To a suspension of sodium hydride, 60% dispersion in mineral oil solution (1.6 g, 40 mmol) in tetrahydrofuran (50 ml) is added a solution of (2-bromothiazol-5-yl)methanol (6.75 g, 35 mmol) in tetrahydrofuran (50 ml) at 0° C. A solution of 5-chloro-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (7.0 g, 35 mmol) in tetrahydrofuran (50 ml) is then added and the reaction mixture is heated to reflux for 18 hours. The reaction mixture is poured into water, acidified to pH4 with dilute aqueous hydrochloric acid and extracted with ethyl acetate (4×50 ml). The combined organic layers are dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated to a brown oil. The crude product is purified by flash chromatography on silica gel to give 5-(2-bromothiazol-5-ylmethoxy)-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (6.75 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][CH:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]([CH3:17])[CH:8]2[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1CCC(NCc2ccc(Cl)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(Cc1ccc(Cl)cc1)C1CCC(O)CC1

Procedure:
7.2 g (30 mMol) of 4-[N-(4-chloro-benzyl)-amino]-cyclohexanol are dissolved in 30 ml of dimethyl-formamide, and after the addition of 2.2 g (16 mMol) of potassium carbonate, 4.26 g (30 mMol) of methyliodide are added dropwise. When the slightly exothermic reaction has ended, the mixture is concentrated by evaporation, mixed with water and extracted with chloroform. The concentrated extracts are chromatographed on silica gel to purify them (eluant; methylene chloride/methanol=20/1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>ClCCl>[CH2:23]([O:22][C:20]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)/[C:6](=[CH:12]/[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)/[C:7]1=[O:11])=[O:21])[CH3:24]
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/C1CCCCC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C(=O)/C(=C\C2CCCCC2)c2ccc(Cl)cc21
Yield: 95.1 %

Procedure:
In a manner similar to the method described in example 4b, E/Z-6-chloro-3-cyclohexylmethylene-1,3-dihydro-indol-2-one (2.71 g, 10.4 mmol) was reacted with ethyl chloroformate (1.47 mL, 15.6 mmol) and triethylamine (2.89 mL, 20.7 mmol) in dichloromethane to give E/Z-6-chloro-3-cyclohexylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as a brown solid (Yield 3.3 g, 95%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]1[CH2:11][CH2:10][C@H:9](O)[CH2:8]1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]1[CH2:11][CH2:10][C@H:9]([N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])[CH2:8]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O[C@H]1CC[C@@H](c2ccccn2)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](c2ccccn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
A solution of cis-3-(2-pyridyl)cyclopentanol (1.86 g, 11.4 mmol) in THF (100 mL) was cooled to 0° C. and treated with phthalimide (1.85 g, 12.5 mmol), diethylazodicarboxylate (2.2 M in toluene, 5.7 mL, 11.4 mmol) and triphenylphosphine (3.29 g, 12.5 mmol). The reaction mixture was stirred at room temperature for overnight. The solvent was removed, and the crude product was purified by column chromatography (Hexane/EtOAc=3/1→2/1→1/1) to yield trans-N-[3-(2-pyridyl)cyclopentyl]phthalimide (1.52 g, 41%) as a colorless powder.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)(=[O:24])=[O:23])[CH:19]=3)[CH2:15]2)[CH2:11][O:10][C@@H:9]1[C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])CCC.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[C@@H:9]1[C@@H:8]([NH2:7])[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)(=[O:23])=[O:24])[CH:19]=3)[CH2:15]2)[CH2:11][O:10]1
Reactant: CCCCOC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CCCC4)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CCCC4)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Reaction time: 1.5 h

Procedure:
A solution of the intermediate obtained in Step A above (90 mg, 0.16 mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (3 mL) at room temperature. After 1.5 h, the reaction mixture was concentrated to give the title compound. 1H NMR (500 MHz, CD3OD): δ 1.61-1.74 (m, 4H); 1.92-2.08 (m, 4H); 2.11 (q, 1H, J=12 Hz); 2.78-2.84 (m, 1H); 3.68 (td, 1H, J=12, 4 Hz); 3.78 (t, 1H, J=12 Hz); 3.88-3.96 (m, 1H); 4.02-4.10 (m, 1H); 4.49-4.67 (m, 5H); 4.71 (d, 1H, J=12 Hz); 7.19-7.27 (m, 2H); 7.28-7.33 (m, 1H); 8.09 (s, 1H). LC-MS: 453.04 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4].[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=2)[N:13]=[CH:12][N:11]=1.C(NC(C)C)(C)C>C1COCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2[Cl:9])=[O:4]
Reactant: C#CCNC(=O)CCl
Reactant: Clc1ncnc2ccc(I)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(CCl)NCC#Cc1ccc2ncnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-Chloro-N-prop-2-ynyl-acetamide (385 mg; 2.93 mmol) and 4-chloro-6-iodoquinazoline (850 mg; 1 equiv.) were dissolved in dry THF and diisopropylamine (296 mg; 0.41 mL; 1 equiv.). To this mixture was added 0.04 equivalents of copper iodide (22+mg) and Pd(PPh3)2Cl2 (82 mg). The reaction was stirred at room temperature under a nitrogen atmosphere overnight (˜20 hrs). The solvent was then removed in vacuo and the residue dissolved in CH2Cl2. This solution was transferred to a separatory funnel and washed with 1× saturated NH4Cl, brine, dried over Na2SO4 and the solvent removed in vacuo. The product was purified by silica gel chromatography eluting with 1:1 Hexanes/EtOAc and collecting fractions with an Rf=0.25. 2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide was obtained as an off white solid (454 mg; 53%). 1H NMR (400 MHz; CDCl3) δ 4.12 (2H, s), 4.40 (2H, d, J=5.2 Hz), 7.91-7.93 (1H, dd, J=2, 6.8 Hz), 8.00 (1H, d, J=8.4 Hz), 8.34 (1H, d, J=1.6 Hz), 9.03 (1H, s). Irms (M+): 294.0, 296.0, 298.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8]Cl.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[N:31]=[C:19]2[N:20]=[C:21]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:22]=[C:23]([NH2:24])[N:18]2[N:17]=1.CCN(CC)CC>CC#N>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8][N:28]1[CH2:27][CH2:26][N:25]([C:21]2[N:22]=[C:23]([NH2:24])[N:18]3[N:17]=[C:16]([C:12]4[O:11][CH:15]=[CH:14][CH:13]=4)[N:31]=[C:19]3[N:20]=2)[CH2:30][CH2:29]1
Reactant: ClCc1c(Cl)cncc1Cl
Reactant: Nc1nc(N2CCNCC2)nc2nc(-c3ccco3)nn12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1nc(N2CCN(Cc3c(Cl)cncc3Cl)CC2)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3,5-Dichloro-4-chloromethyl-pyridine (1.5 eq.) was added to a solution of 2-furan-2-yl-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.14 mmol; see Example 1(a) above) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H-NMR (DMSO-d6) δ 8.9 (s, 2H), 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 3.8 (br s, 2H), 2.2-3.2 (m, 8H). MS: m/z: 447 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C@H:10]([CH3:15])[C:11]([CH3:14])([OH:13])[CH3:12])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:16][C:17]1[CH:18]=[C:19]([S:23]([CH3:26])(=[NH:25])=[O:24])[CH:20]=[CH:21][CH:22]=1.Cl>C(#N)C.O1CCOCC1>[Br:1][C:2]1[C:3]([NH:9][C@H:10]([CH3:15])[C:11]([OH:13])([CH3:14])[CH3:12])=[N:4][C:5]([NH:16][C:17]2[CH:18]=[C:19]([S:23]([CH3:26])(=[NH:25])=[O:24])[CH:20]=[CH:21][CH:22]=2)=[N:6][CH:7]=1
Reactant: CS(=N)(=O)c1cccc(N)c1
Reactant: C[C@@H](Nc1nc(Cl)ncc1Br)C(C)(C)O
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: C[C@@H](Nc1nc(Nc2cccc(S(C)(=N)=O)c2)ncc1Br)C(C)(C)O

Procedure:
127 mg (0.43 mmol) of (R)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-methyl-butan-2-ol in 1 ml of acetonitrile is added to 74 mg (0.43 mmol) of (RS)-S-(3-aminophenyl)-S-methyl sulfoximide in 0.5 ml of acetonitrile. It is mixed with 0.1 ml of a 4N solution of HCl in dioxane, and the batch is refluxed overnight. The solvent is drawn off, and the remaining residue is purified by chromatography (DCM/EtOH 9: 1). 37 mg (0.09 mmol, corresponding to 20% of theory) of the product is obtained.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[C:34]([O:36][C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])[CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]>>[Cl:14][C:15]1[CH:35]=[C:34]([CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](=[O:28])[NH:13][C@H:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=3)[CH3:12])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31])[O:36][C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)[C@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c(Cl)c1
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c(Cl)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(2-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14](=[O:30])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:8][CH:7]=1)[OH:5].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14](=[O:30])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:8][CH:7]=1)[O:5][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: COC(=O)C(O)c1ccc(C=CC(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(OS(C)(=O)=O)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Yield: 105.2 %

Procedure:
To a solution of {4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-hydroxy-acetic acid methyl ester (9.00 g, 21.1 mmol) and triethylamine (3.20 g, 31.6 mmol) in CH2Cl2 (135 mL) cooled to −5 degrees Celcius was added dropwise methanesulfonyl chloride (3.14 g, 27.4 mmol) under N2 atmosphere. The reaction was stirred at 0 degrees Celcius until the starting material had been consumed according to TLC (about 1 hour). The mixture was washed with water (90 mL) and brine (90 mL), dried with MgSO4, filtered, and evaporated in vacuo to obtain 11.2 g (quantitative yield) of light yellow crystal which was used without further purification. MS: calc'd 505 (MH+), exp 505 (MH+).
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([CH2:14][OH:15])[CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[F:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@@H:4]([CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1COS(C)(=O)=O
Temperature: 2.5 °C

Procedure:
7.5 3.2 g of tert-butyl (2R,4S)-4-fluoro-2-hydroxymethylpyrrolidine-1-carboxylate are dissolved in 50 ml of CH2Cl2 with stirring, 3.1 ml of triethylamine are added, the mixture is cooled to 0-5° C., and a solution of 1.4 ml of methane-sulfonyl chloride in 10 ml of CH2Cl2 is subsequently added dropwise. The mixture is subsequently stirred at RT for 4 h. After aqueous work-up, the 4.1 g of tert-butyl (2R,4S)-4-fluoro-2-methanesulfonyloxymethylpyrrolidine-1-carboxylate) obtained are reacted further directly.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][CH:10]=[N:9][C:8]=2[NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](Cl)=[O:24]>ClCCCl>[C:26]1([C:22]2[N:9]3[CH:10]=[N:11][N:12]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:8]3=[N:13][C:23]=2[OH:24])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ncnnc1-c1ccccc1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Oc1nc2c(-c3ccccc3)nncn2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 42.2 %

Procedure:
To a solution of 6-phenyl-[1,2,4]triazin-5-ylamine (1.1 g, 6.4 mmol) and triethylamine (891 μl, 6.4 mmol) in anhydrous 1,2-dichloroethane (75 ml) under an atmosphere of nitrogen was added dropwise 2-chloro-2-phenylacetyl chloride (1.01 ml, 6.4 mmol). The reaction mixture was stirred at 0° C. for 90 min, then triethylamine (891 μl, 6.4 mmol) was added, and the resulting mixture heated under reflux for 30 min. The cooled reaction mixture was partitioned between CH2Cl2 (100 ml) and water (100 ml). The organic layer was separated, dried over MgSO4 and evaporated in vacuo. The solid residue was triturated with a 1:1 mixture of CH2Cl2 and MeOH (10 ml), filtered and dried to give 780 mg (2.7 mmol, 42%) of 3,8-diphenylimidazo[1,2-d][1,2,4]triazin-2-ol as a pale yellow solid. δH (360 MHz; DMSO-d6) 7.41 (1H, t, J 7.3 and 7.2, aromatic), 7.50-7.63 (5H, m, aromatics), 7.82 (2H, d, J 7.8, aromatics), 8.57 (2H, m, aromatics), 9.65 (1H, s, imidazotriazine H5), 11.72 (1H, br s, OH); m/z (ES+) 289 (M++H, 100%).