Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([CH:18]=C)=[CH:14][N:13]3[CH:20]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:22].[Na+].C(O)(C)(C)C.O>C1COCC1.[Os](=O)(=O)(=O)=O>[CH:18]([C:15]1[CH:16]=[CH:17][C:12]2[N:13]([CH:20]=[C:10]([C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[N:11]=2)[CH:14]=1)=[O:22]
Reactant: C=Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 20 °C
Reaction time: 20 h
Yield: 66.2 %

Procedure:
A suspension of 150 mg of N-phenyl-6-vinylimidazo[1,2-a]pyridine-2-carboxamide, 232 μL of osmium tetroxide and 167.5 mg of sodium periodate in a mixture of 6 mL of THF, 3 mL of t-butanol and 3 mL of water is stirred for 20 hours at 20° C. and then for a further 48 hours while adding in four portions 100 μL of osmium tetroxide and 80 mg of sodium periodate. The reaction mixture is poured into 50 mL of water and the resulting mixture is extracted twice with 50 mL of ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride solution, separated by settling, dried and concentrated to dryness under reduced pressure. The residue is chromatographed on silica, eluting with a mixture of cyclohexane and ethyl acetate (gradient from 0 to 50%) to give 100 mg of 6-formyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:33]=[CH:32][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:31])[C:15]([CH3:30])([CH2:24][CH2:25][C@@H:26]([CH3:29])[CH2:27][CH3:28])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:34](Cl)([CH3:37])(=[O:36])=[O:35].N1C=CC=CC=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:30])([CH2:24][CH2:25][C@@H:26]([CH3:29])[CH2:27][CH3:28])[C:14](=[O:31])[C:13]=1[C:8]1[NH:7][C:6]2[CH:32]=[CH:33][C:3]([NH:2][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@H](C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC[C@H](C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 43F (0.119 g, 0.240 mmol), mesyl chloride (0.075 mL, 0.970 mmol), and pyridine (0.157 mL, 1.94 mmol) in acetone (3 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=3)=[N:19][CH:20]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:30]1([C:25]([C:24]2[CH:28]=[CH:29][C:21]([C:18]3[N:19]=[CH:20][C:15]([O:14][CH2:13][CH:10]4[CH2:9][CH2:8][N:7]([C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[O:6])[CH2:12][CH2:11]4)=[CH:16][CH:17]=3)=[CH:22][CH:23]=2)=[O:27])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C1CCNC1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)O)cc3)nc2)CC1
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: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.6 %

Procedure:
4-(5-{[(1-{[(1-Methylethyl)oxy]carbonyl}-4-piperidinyl)methyl]oxy}-2-pyridinyl)benzoic acid (0.05 g, 0.13 mmol) was added to a solution of pyrrolidine (0.01 g, 0.13 mmol) in DMF (2 mL), followed by addition of HATU (0.05 g, 0.13 mmol), and diisopropylethylamine (0.02 g, 0.13 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The reaction was then purified by reverse-phase preparative HPLC using CH3CN:H2O gradient (0:100 to 90:10) with 0.05% TFA as a modifier. The resultant lyophilized material was converted to its free base by dissolving the solid in CH2Cl2, washing with saturated aqueous NaHCO3 and concentrating in vacuo to give the title compound (15 mg, 25%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.44 (d, 1H, J=2.9 Hz), 7.93 (d, 2H, J=8.4 Hz), 7.65 (d, 1H, J=8.6 Hz), 7.68 (d, 2H, J=8.4 Hz), 7.27-7.20 (m, 1H), 4.95-4.85 (m, 1H), 4.29-4.12 (m, 2H), 3.87 (d, 2H, J=6.4 Hz), 3.68-3.59 (m, 2H), 3.47-3.41 (m, 2 H), 2.78-2.72 (m, 2H), 2.04-1.78 (m, 7H), 1.34-1.28 (m, 2H), 1.22 (d, 6H, J=6.2 Hz); LRMS (ESI), m/z 452 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[O-:12][C:13]#[N:14].[K+]>O>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH:11][C:13]([NH2:14])=[O:12]
Reactant: N#C[O-]
Reactant: NNc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NNc1ccc(Cl)cc1Cl
Reaction time: 4 h

Procedure:
A 20 g portion of 2,4-dichlorophenylhydrazine hydrochloride was added to 200 ml of water and the solution was heated to 80°. Then 6.8 g of potassium cyanate was dissolved in 75 ml of water, and that solution was added dropwise to the first solution. The mixture was stirred for 4 hours at 80°, and it was then cooled. The product was collected by filtration, dried, and recrystallized from ethanol to obtain 11.8 g of the desired intermediate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][OH:30])=[C:22]([Br:31])[CH:21]=1)[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][S:33](Cl)(=[O:35])=[O:34].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:32][S:33]([O:30][CH2:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:21][C:22]=1[Br:31])(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCO)c(Br)c1)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCOS(C)(=O)=O)c(Br)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.8 %

Procedure:
To a solution of the product of Example 1A (300 mg, 0.598 mmol) dissolved in anhydrous CH2Cl2 (6.0 mL) was added MsCl (55.8 μL, 0.718 mmol), DMAP (87.7 mg, 0.718 mmol) and Et3N (0.125 mL, 0.897 mmol). The reaction mixture was stirred at room temperature for 45 min then concentrated to yield an oil. The crude material was directly purified using silica gel chromatography (4:1 hexanes:EtOAc) to yield a colorless oil (245.6 mg, 71% yield). 1H NMR (CDCl3, 300 MHz): δ 9.35 (brs, 2H), 7.56 (d, J=3.0 Hz, 1H), 7.26 (m, 1H). 6.84 (d, J=9.0 Hz, 1H), 5.09 (brs, 2H), 4.53 (t, J=6.0 Hz, 2H), 4.15 (t, J=6.0 Hz, 2H), 3.01 (s, 3H), 2.29 (m, 2H), 1.52 (s, 9H), 1.43 (s, 9H); 13C(CDCl3, 150 MHz): δ 160.7, 154.9, 154.1, 133.3, 133.1, 128.0, 132.2, 113.2, 110.7, 128.3, 84.7, 80.5, 66.9, 64.6, 46.7, 29.9, 28.5, 28.2.
Reaction SMILES: CC([O-])(C)C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:26])=[C:12]([C:14]([NH:21][C:22](=[O:25])[CH2:23]Cl)([CH:18]([F:20])[F:19])[CH2:15][CH2:16][OH:17])[CH:13]=1>CC(O)(C)C.C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:26])=[C:12]([C:14]2([CH:18]([F:20])[F:19])[CH2:15][CH2:16][O:17][CH2:23][C:22](=[O:25])[NH:21]2)[CH:13]=1
Reactant: O=C(CCl)NC(CCO)(c1cc(Br)ccc1F)C(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: O=C1COCCC(c2cc(Br)ccc2F)(C(F)F)N1

Procedure:
To a refluxing solution of potassium tert-butylate (1.63 g, 14.52 mmol) in 555 ml t-BuOH was added dropwise a solution of) N-[1-(5-bromo-2-fluoro-phenyl)-1-difluoromethyl-3-hydroxy-propyl]-2-chloro-acetamide (2.72 g, 7.26 mmol) in 45 ml THF over a period of 40 minutes. The reaction mixture was cooled down and quenched with 1N HCl. EtOAc was added and the organic layer was washed with brine, dried with Na2SO4 and evaporated. The crude product was crystallized from DCM/TBME to provide the title compound as white crystals.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([S:8][C:9]1[S:10][C:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)C=O)C.Br>C(O)(=O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:13]=[C:9]([S:8][CH2:5][CH:4]=[O:3])[S:10][C:11]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(C=O)Sc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Agent: Br
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(SCC=O)sc2-c2ccc(OC)cc2)cc1

Procedure:
4.0 g of 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]-2-formylacetic acid ethyl ester are dissolved in 50 ml of acetic acid, 10 ml of 43% strength hydrobromic acid are added and the mixture is heated at 80° for 4 hours. The mixture is concentrated to dryness by evaporation under reduced pressure, and the residue is dissolved in 200 ml of ethyl acetate, washed twice with 50 ml of saturated sodium bicarbonate solution each time and with water, dried over magnesium sulphate and concentrated to dryness by evaporation. The crude product is recrystallised from hexane/diethyl ether (55 ml+10 ml). 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]-acetaldehyde having a melting point of 75°-76° is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].O[NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=[NH:15].N1C=CC=CC=1>O1CCOCC1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]2[O:8][N:15]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:24][CH:23]=4)=[CH:20][CH:21]=3)[N:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: N=C(NO)c1ccc(-c2ccc(OCCCC(=O)O)cc2)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2nc(-c3ccc(-c4ccc(OCCCC(=O)O)cc4)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
A solution of 4-cyanobenzoyl chloride (2.29 g, 13.8 mmol) in dioxane (10 ml) was added to a suspension of 4-(4′-(N-hydroxycarbamimidoyl)biphenyl-4-yloxy)butyric acid (3.23 g, 9.6 mmol) in dioxane (50 ml) and pyridine (2.5 ml, 31.6 mmol). The mixture was stirred at room temperature for 4 h, and then heated to 100° C. for 22 h. The mixture was concentrated to ½ of its original volume, diluted with water (100 ml), and acidified by addition of concentrated hydrochloric acid (3 ml). The product was isolated by filtration and washed with water (50 ml). The solid was suspended in MeCN (70 ml), heated to reflux, allowed to cool, filtered off, and dried under reduced pressure to yield 3.17 g (54%) of 4-(4′-{5-[4-cyanophenyl]-[1,2,4]oxadiazol-3-yl}biphenyl-4-yloxy)butyric acid as a solid.
Reaction SMILES: [CH:1]1([S:6](Cl)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:11][C:12]1[N:17]=[C:16]([C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][N:24]([C:28]([O:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[O:29])[CH2:25]3)=[CH:20][CH:19]=2)[CH:15]=[C:14]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)[N:13]=1>>[NH2:11][C:12]1[N:17]=[C:16]([C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][N:24]([C:28]([O:30][CH:31]4[CH2:36][CH2:35][N:34]([S:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)(=[O:8])=[O:7])[CH2:33][CH2:32]4)=[O:29])[CH2:25]3)=[CH:20][CH:19]=2)[CH:15]=[C:14]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)[N:13]=1
Reactant: O=S(=O)(Cl)C1CCCC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCN(S(=O)(=O)C5CCCC5)CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 67, Step 4 starting from cyclopentanesulfonyl chloride (Aldrich, Cat. #656607) and piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate HCl salt. Analytic LCMS (M+H)+: m/z=584.2.
Reaction SMILES: [K].[CH3:2][S:3]([NH:6][C:7](=O)[CH3:8])(=[O:5])=[O:4].[N+:10]([C:13]1[CH:20]=[CH:19]C(CBr)=[CH:15][CH:14]=1)([O-:12])=[O:11].[OH-].[Na+]>CN(C=O)C.O>[N+:10]([C:13]1[CH:20]=[CH:19][C:8]([CH2:7][NH:6][S:3]([CH3:2])(=[O:5])=[O:4])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: CC(=O)NS(C)(=O)=O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [K]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 86 %

Procedure:
A mixture of N-(methylsulphonyl)acetamide potassium salt (23 g) and 4-nitrobenzyl bromide (24 g) in dry DMF (160 ml) was stirred in an oil bath at 130° for 2 h. After standing overnight at room temperature, a solution of sodium hydroxide (8 g) in water (50 ml) was added and the mixture stirred under nitrogen for 0.75 h. The mixture was diluted with water (900 ml) and the product extracted into ethyl acetate (2×400 ml). The combined extract was washed with brine (3×200 ml), dried (Na2SO4) and evaporated in vacuo to leave an orange solid (22 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([Cl:17])[N:11]=1.O>O1CCCC1>[Cl:9][C:10]1[N:11]=[C:12]([Cl:17])[CH:13]=[C:14]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[N:15]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Cc1ccc(N)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Nc2cc(Cl)nc(Cl)n2)cc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
6.4 g of p-toluidine was dissolved in 50 ml of tetrahydrofuran, and 5.5 g of 2,4,6-trichloropyrimidine was dropwise added thereto with stirring at room temperature. After being stirred for 1 hour, 200 ml of water was added to the reaction mixture. The crystal thus precipitated was taken out by filtration and dried to obtain 6.6 g of 2,4-dichloro-6-p-toluidinopyrimidine, which had a m.p. of 162° to 166° C. Next, 2.4 g of phenol and 8.6 g of potassium carbonate were dispersed in 30 ml of N,N'-dimethylimidazolin-2-one, and 2.54 g of the previously prepared 2,4-dichloro-6-p-toluidinopyrimidine was added thereto with stirring and then heated at 150° C. for 2 hours. After the reaction solution was cooled, 100 ml of ethyl acetate was added thereto. The solution was then washed with water and extracted. The resulting ethyl acetate extract was concentrated, and methanol was added to the residue for crystallization. Accordingly, 3.4 g of the intended Coupler (12) was obtained, which had a m.p. of 151° to 152° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CON(C)[C:30](=[O:46])[CH:31]([O:44][CH3:45])[C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1>C1COCC1>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[C:12]([C:30](=[O:46])[CH:31]([O:44][CH3:45])[C:32]3[CH:33]=[CH:34][C:35]([N:38]4[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)=[CH:36][CH:37]=3)[S:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(-c2cscn2)cc(OC)c1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2csc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)n2)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
To a −78° C. solution of 4-(4-bromo-3,5-dimethoxyphenyl)thiazole (0.096 g, 0.32 mmol) in anhydrous THF (2 mL) under argon was added a solution of LiHMDS (1.0 M in THF, 0.35 mmol) dropwise. After stirring for 30 min, a solution of N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide (0.121 g, 0.41 mmol) in anhydrous THF (1.5 mL, 1.0 mL) was added dropwise. After stirring for 35 min, the cold bath was removed and the reaction was allowed to warm to room temp. The mixture was quenched with brine and diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried over Na2SO4 and concentrated. Purification by chromatography (25-45% EtOAc-hexanes) gave 1-(4-(4-bromo-3,5-dimethoxyphenyl)thiazol-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone as a yellow solid (0.050 g, 29% yield). MS: m/z 533.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](Cl)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=1.N1C=CC=CC=1.O>C(Cl)Cl>[Cl:1][C:2]1[C:11]([C:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=2)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(=O)c1ccc(N)cn1
Reactant: O=C(Cl)c1cc2ccccc2nc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(NC(=O)c2cc3ccccc3nc2Cl)cn1
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A solution of 2-chloroquinoline-3-carbonyl chloride (2.72 g, 12.04 mmol) in methylene chloride (37.7 mL) was added dropwise to a mixture of methyl 5-aminopyridine-2-carboxylate (1.83 g, 12.04 mmol), pyridine (2.9 mL, 36.12 mmol) and methylene chloride (25.1 mL) at 0° C. The mixture was stirred and allowed to warm up to room temperature over 1.5 hours. To the reaction slurry, water (30 mL) was added and a precipitate formed. The solid was filtered, washed with water (2×30 mL), hexanes (2×50 mL), and a small amount of dichloromethane. The solid from the filtrate was isolated and washed with water (1×15 mL) and hexanes (1×20 mL). This solid obtained was dried in the vacuum oven to yield methyl 5-(2-chloroquinoline-3-carboxamido)picolinate (3 g, 73%). ESI-MS m/z calc. 341.06, found 342.2 (M+1)+; Retention time: 1.18 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.95 (d, J=2.5 Hz, 1H), 8.85 (s, 1H), 8.42 (dd, J=8.6, 2.5 Hz, 1H), 8.21-8.12 (m, 2H), 8.07 (dd, J=8.6, 1.1 Hz, 1H), 8.02-7.89 (m, 1H), 7.82-7.72 (m, 1H), 3.89 (s, 3H) ppm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.Cl[C:10]1[N:15]=[C:14]([Cl:16])[N:13]=[C:12]2[N:17]([CH3:20])[N:18]=[CH:19][C:11]=12>>[Cl:16][C:14]1[N:13]=[C:12]2[N:17]([CH3:20])[N:18]=[CH:19][C:11]2=[C:10]([N:1]2[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]2)[N:15]=1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Reactant: O=S1(=O)CCNCC1
Product: Cn1ncc2c(N3CCS(=O)(=O)CC3)nc(Cl)nc21

Procedure:
Reaction of thiomorpholine-1,1-dioxide with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave 6-chloro-4-(1,1-dioxo-thiomorpholin-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([O:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18]Br)[CH:14]=2)[N:9]=[CH:8]1)=[O:4].[CH2:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][CH:27]=1)[C:23]#[CH:24].C(=O)([O-])[O-].[Ca+2]>CC(N(C)C)=O>[CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([O:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][N:25]([C:26]3[CH:27]=[CH:28][C:29]([C:32](=[O:34])[CH3:33])=[CH:30][CH:31]=3)[CH2:22][C:23]#[CH:24])[CH:14]=2)[N:9]=[CH:8]1)=[O:4]
Reactant: CC(C)(C)C(=O)OCn1cnc2ccc(CBr)cc2c1=O
Reactant: C#CCNc1ccc(C(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)N(C)C
Product: C#CCN(Cc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(C)=O)cc1
Temperature: 80 °C
Yield: 186.8 %

Procedure:
A suspension of 5.79 g (12.5 mmol) of 75% pure 2,2-dimethylpropanoic acid, [6-(bromomethyl)-4-oxo-3(4H)-quinazolinyl]methyl ester (European patent application 204,529), 2.89 g (16.7 mmol) of 1-[4-(2-propynylamino)phenyl]ethanone (see Example A), and 3.34 g (33.4 mmol) of dry calcium carbonate in 100 ml of dimethylacetamide (DMA) is stirred at 80° C. for eighteen hours. The suspension is poured into a water-ice mixture and stirred. The suspension is extracted with ethyl acetate. The ethyl acetate solution is dried (magnesium sulfate) and concentrated to give 10.4 g of a yellow oil. This is dissolved in a minimum amount of dichloromethane and applied to a column of 1 kg of flash silica gel packed in dichloromethane/methanol (100:1). Elution with the same solvent gives 2.83 g (50.8%) of impure product as a yellow gum followed by 2.34 g (42.0% assuming 75% pure bromomethyl compound) of the product as a cream colored foam. This is used as is without characterization in the next reaction.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Reactant: Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3cccc(C)c3)CC2)cc1
Yield: 96.9 %

Procedure:
The title compound (D27) (63 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 4-(1-(piperidine-2-carboxamido)cyclopropyl)benzoate (D13) (50 mg, 0.16 mmol) and 3-methyl benzyl bromide (0.033 ml, 0.25 mmol). (Na2CO3: 2.5 eq; reaction time: 6 hrs; 60° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)=[CH:4][CH:3]=1.C1COCC1.C[CH2:39][CH2:40][CH2:41][N+:42](CCCC)(CCCC)CCCC.[OH-].C(#N)C=C>C(Cl)Cl.O.C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:39][CH2:40][C:41]#[N:42])[C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=2)=[CH:31][CH:32]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C=CC#N
Product: Cn1c(=O)n(CCC#N)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.215 mmol, Intermediate 9) in a mixed solution of THF (3 mL) and acetonitrile (5 mL) was added TBAH (0.05 ml, 0.193 mmol) and acrylonitrile (40 mg, 0.642 mmol). The mixture was stirred at 60° C. overnight. Then the mixture was diluted with DCM and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product. This crude material was purified by silica gel chromatography eluting with petroleum/ethyl acetate (3:1 to 1:1) to give 3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanenitrile (75 mg, 68.8%) as white solid. 1H-NMR (DMSO-d6) δ 7.63-7.59(t, 1H), 7.50(s, 1H), 7.45-7.40(m, 5H), 7.35-7.33(d, 1H), 5.45(s, 2H), 4.16-4.13(t, 2H), 3.31(s, 3H), 2.89-2.86(t, 2H). LCMS retention time 3.248 min; LCMS MH+ 520.