Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[S:6].Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[S:6][CH:12]=[C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=S)c1cccc(Br)c1
Product: CCOC(=O)Cc1csc(-c2cccc(Br)c2)n1
Yield: 74.8 %

Procedure:
3-Bromothiobenzamide (10.8 g) and ethyl 4-chloroacetoacetate (8.3 g) were dissolved in 50 ml of alcohol. The reaction was stirred and heated under reflux for 4 hours. When cooled, the crystalline solid was filtered yielding 12.2 g of product, mp 65°-70° C. When recrystallized from ether-petroleum ether, it melted 68°-70° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:24])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]=1[CH3:23]>C1COCC1.CO>[CH2:16]([N:9]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]([CH2:6][C:5]([OH:24])=[O:4])=[C:8]1[CH3:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)Cc1c(C)n(Cc2ccccc2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccccc1
Reaction time: 5.5 h

Procedure:
1M Aqueous NaOH (364 μL, 0.364 mmol) is added to a stirring solution of (1-benzyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid methyl ester (65 mg, 0.22 mmol) in 5:1 THF/MeOH (2.4 mL). After 5.5 hours, the reaction is evaporated, and partitioned between water and EtOAc. The aqueous layer is acidified to pH 3, and the resulting precipitate collected by filtration to furnish 1-benzyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid; MH+=281.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([OH:15])=O)[N:10]=[C:9]([C:16]3[N:17]=[CH:18][NH:19][CH:20]=3)[CH:8]=2)=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([OH:29])[CH2:24]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:23]3[CH2:28][CH2:27][CH2:26][C@@H:25]([OH:29])[CH2:24]3)=[O:15])[N:10]=[C:9]([C:16]3[N:17]=[CH:18][NH:19][CH:20]=3)[CH:8]=2)=[CH:21][CH:22]=1
Reactant: O[C@@H]1CCCNC1
Reactant: O=C(O)Cn1nc(-c2c[nH]cn2)cc1Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2c[nH]cn2)cc1Cc1ccc(F)cc1)N1CCC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
A mixture of [5-(4-fluorobenzyl)-3-(1H-imidazol-4-yl)-1H-pyrazol-1-yl]acetic acid (0.5 g, 1.67 mmol), (R)-piperidin-3-ol (0.30 g, 2.50 mmol), EDCI (0.58 g, 3.0 mmol), HOBt (0.40 g, 3.0 mmol) and NMM (1.0 mL, 10.0 mmol) in DMF (15 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was diluted with water (5 mL). The mixture was extracted with CH2Cl2 (3×5 mL) and the organics combined, washed with 1 N aq. NaOH (3×10 mL), water (3×5 mL) and brine (25 mL), dried over MgSO4 and evaporated. The residue was purified via column chromatography (silica gel, EtOAc/Petroleum ether 1:4) to yield crude material (201.0 mg), which was further purified via prep. HPLC to yield the title compound (100 mg, 15%) as a white solid. 1H NMR (400 MHz, MeOD): δ ppm 8.837 (s, 1H), 7.699 (s, 1 H), 7.303 (m, 2 H), 7.078 (m, 2 H), 6.337 (s, 1 H), 3.992-3.039 (m, 7 H), 1.994-1.400 (m, 4 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:16][C:17]1[C:18]([O:20][C:21](=O)[C:22]=1[CH3:23])=[O:19].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[F:14][C:12]([F:15])([F:13])[O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:1]3[C:18](=[O:19])[C:17]([CH3:16])=[C:22]([CH3:23])[C:21]3=[O:20])[S:3][C:4]=2[CH:10]=1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: CC1=C(C)C(=O)OC1=O
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC1=C(C)C(=O)N(c2nc3ccc(OC(F)(F)F)cc3s2)C1=O
Yield: 74.6 %

Procedure:
A 100 ml flask was charged with 2-amino-6-trifluoromethoxybenzothiazole (7.03 g), 2,3-dimethylmaleic anhydride (4.16 g) and diphenyl ether (50 ml), and a Dean-Stark separator was attached to the flask. The reaction materials were refluxed for about 5 minutes. After allowing the reaction mixture to cool, it was poured into hexane (200 ml). The resulting crystals were collected by filtration and washed with a small amount of diethyl ether to give N-(6-trifluoromethoxy-2-benzothiazolyl)-dimethymaleimide (7.66 g). m.p. 196°-198° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:26][CH2:25][C:20]4(OCCO4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[N:9][N:8]=[N:7]1)[CH3:2].[NH2:28][CH2:29][C@@H:30]([C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1)[OH:31]>>[OH:31][C@H:30]([C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1)[CH2:29][NH:28][CH:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:10]3[N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:27])[N:7]=[N:8][N:9]=3)=[CH:12][CH:13]=2)[CH2:26][CH2:25]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)Cn1nnnc1-c1ccc(N2CCC3(CC2)OCCO3)cc1
Product: CCOC(=O)Cn1nnnc1-c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from ethyl{5-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-1H-tetraazol-1-yl}acetate (which was obtained in Example 48) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedures of Example 34 and Example 73 as a white solid; mp >140° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.17 (t, J=7.1 Hz, 3H), 1.20-1.40 (m, 2H), 1.80-1.95 (m, 2H), 2.50-3.50 (m, 5H), 2.89 (s, 3H), 3.70-3.90 (m, 2H), 4.11 (q, J=7.1 Hz, 2H), 4.47 (dd, J=7.8, 4.4 Hz, 1H), 5.60 (brs, 2H), 6.79 (d, J=8.2 Hz, 1H), 6.96 (dd, J=8.2, 2.0 Hz, 1H), 7.07 (d, J=8.9 Hz, 2H), 7.16 (d, J=2.0 Hz, 1H), 7.56 (d, J=8.9 Hz, 2 H); MS (ES) m/z: 560.2 (MH+); HRMS Calcd. for C21H28N7O4S(MH+): 560.2286. Found: 560.2282.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]([CH2:29][OH:30])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]([CH:29]=[O:30])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C=O)C(c2ccccc2)C1
Reaction time: 0.08 h
Yield: 83.7 %

Procedure:
To a solution of 13.1 mL (26.25 mmol) of oxalyl chloride (2M in DCM) in 13 mL of anhydrous DCM were added 3.72 mL (52.5 mmol) of DMSO at −78° C. After 5 minutes of stirring, 3 g (10.5 mmol) of 3-(RS)-hydroxymethyl-4-(SR)-phenylpyrrolidine-1-carboxylic acid tert-butyl ester, previously dissolved in 15 mL of anhydrous DCM, were added dropwise. After 30 minutes additional agitation at −78° C., 18.5 mL (105 mmol) of DIPEA were added dropwise. An additional 30 minutes of agitation at 0° C. and the reaction mixture was quenched with 10 mL of water. 100 mL of water were again added and the solution was extracted with DCM (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated in vacuo. The crude yellow oil was purified by flash chromatography on silica gel (ethyl acetate/hexanes 0:100 to 20:80) yielding 2.42 g (83.7%) of 3-(RS)-formyl-4-(SR)-phenylpyrrolidine-1-carboxylic acid tert-butyl ester as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH2:27][C:28]5([CH2:44][CH2:45][C:46]=4[C:47]4[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=4)[CH2:33][CH2:32][N:31](C(OCC4C=CC=CC=4)=O)[CH2:30][CH2:29]5)[CH2:21][CH2:20]3)[CH:12]=[CH:13][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:4][C:3]=1[Cl:54]>C(O)C.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([N:19]3[CH2:20][CH2:21][N:22]([CH2:25][C:26]4[CH2:27][C:28]5([CH2:44][CH2:45][C:46]=4[C:47]4[CH:48]=[CH:49][C:50]([Cl:53])=[CH:51][CH:52]=4)[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]5)[CH2:23][CH2:24]3)[CH:12]=[CH:13][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:4][C:3]=1[Cl:54]
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCN(C(=O)OCc5ccccc5)CC4)C3)CC2)cc1Oc1cnc(N)c(Cl)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCNCC4)C3)CC2)cc1Oc1cnc(N)c(Cl)c1
Reaction time: 5 h

Procedure:
To a solution of EXAMPLE 391G (1.02 g) in ethanol (20 mL) was added Pd/C (10%, 150 mg). The mixture was stirred for 5 hours. The mixture was filtered and the filtrate was concentrated to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[F:18])=[CH:9][N:10]=2)[CH:7]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:30]4[N:26]([C:23]5[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=5)[N:27]=[CH:28][CH:29]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[C:12]([F:18])[CH:13]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(Cl)cc2)OC1(C)C
Reactant: Fc1cc(Cl)ccc1-c1cnc2ccc(Br)cn12
Product: Fc1cc(Cl)ccc1-c1cnc2ccc(-c3ccnn3-c3ccc(Cl)cc3)cn12

Procedure:
The title compound, white solid (46 mg, 46%), MS (ISP) m/z=423.5 [(M+H)+], mp 148° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-chloro-2-fluoro-phenyl)-imidazo[1,2-a]pyridine (intermediate I) (0.1 g, 0.31 mmol) and 1-(4-chloro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (intermediate B) (0.11 g, 0.37 mmol).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33].Cl>C(O)(C)C>[CH3:33][N:32]([CH3:34])[CH2:31][CH2:30][CH2:29][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:18]1[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=1)=[CH:8][C:7]2=[N:6][OH:5].[ClH:28].[CH3:33][N:32]([CH3:34])[CH2:31][CH2:30][CH2:29][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:18]1[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=1)=[CH:8][C:7]2=[N:6][OH:5]
Reactant: CN(C)CCCCl
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Agent: Cl
Solvent: CC(C)O
Product: CN(C)CCCOc1ccc2oc(-c3cc4cccn4cn3)cc(=NO)c2c1

Procedure:
6-(3-Dimethylamino-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime was prepared in 22% overall yield using the procedure described in example 42A, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 81A) and (3-Chloro-propyl)-dimethyl-amine hydrochloride. The compound was treated with a 1.25 N solution of hydrogen chloride in isopropanol to yield 6-(3-Dimethylamino-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime hydrochloride as an orange solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH:7]=[CH:6][NH:5]1.C(O)C>O>[CH3:3][CH:4]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH2:7][CH2:6][NH:5]1
Reactant: CC1NC=Cc2ccsc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1NCCc2ccsc21
Reaction time: 1 h
Yield: 97.2 %

Procedure:
Sodium borohydride(4.4 g, 116 mmol) was added portionwise at room temperature to a mixture solution of 7-methyl-6,7-dihydrothieno[2,3-c]pyridine(10.5 g, 69.4 mmol) prepared in the above Step 2 and ethanol(100 ml). After stirring for 1 hour, the reaction mixture was diluted with water, and extracted with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate and concentrated to give 10.34 g of the titled compound. (Yield: 97%)
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:26][CH:27]1[NH:31][C:30](=[O:32])[CH2:29][CH2:28]1>>[CH3:26][CH:27]1[N:31]([C:2]2[CH:3]=[CH:4][C:5]([C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:6]([CH3:8])[N:7]=2)[C:30](=[O:32])[CH2:29][CH2:28]1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3C)CC2)nc1C
Reactant: CC1CCC(=O)N1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)nc3C)CC2)nc1C
Yield: 85.8 %

Procedure:
Using (6-bromo-2-methylpyridin-3-yl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (145 mg) described in Preparation Example 248 and 5-methylpyrrolidin-2-one (54 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (130 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14]CC)=[O:13])[C:6]=2[CH:23]=1.[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[C:27]([C:28](O)=[O:29])[C:26]=1[OH:36]>>[C:17]1([CH:10]([N:7]2[C:6]3[CH:23]=[C:2]([NH:1][C:28](=[O:29])[C:27]4[C:26]([OH:36])=[C:25]([Cl:24])[CH:33]=[C:32]([Cl:34])[C:31]=4[Cl:35])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH2:11][C:12]([OH:14])=[O:13])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Reactant: O=C(O)c1c(O)c(Cl)cc(Cl)c1Cl
Product: O=C(O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3c(O)c(Cl)cc(Cl)c3Cl)cc21

Procedure:
Using a similar procedure to that described in Preparation 21, the title compound (19 mg) was prepared from ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and 3,5,6-trichlorosalicylic acid (HATU was substituted for TBTU), and purified by RP-HPLC. [LCMS (Method A, Mobile Phase I) RT=4.54 min, MH+ 506].
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li]CCCC.[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.OS(O)(=O)=O>C1COCC1>[CH3:11][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:21]2([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]1=2
Reactant: O=C1CCCCC1
Reactant: CN(c1ccccc1)c1ccccc1Br
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1c2ccccc2C2(CCCCC2)c2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A flame-dried two-necked flask was charged with 2-bromo-N-methyl-N-phenylaniline (1.0 g, 3.8 mmol) and 100 mL dry THF under argon and cooled to −78° C. in a dry ice-acetone bath. 2.6 mL of a 1.6 M solution of n-BuLi in hexanes (4.16 mmol) was added dropwise over 5 minutes and the reaction stirred at −78° C. under argon for 1 h. Cyclohexanone (0.43 mL, 0.412 g, 4.2 mmol) was added in one portion to the reaction mixture at −78° C., the reaction allowed to warm to room temperature and stirred overnight under argon. After quenching with saturated ammonium chloride, the reaction was extracted with Et2O, the organic layers combined, washed with brine and water and dried over anhydrous MgSO4 and the solvent evaporated under reduced pressure. To the neat residue thus obtained was added 2 mL of concentrated H2SO4 under argon and the mixture stirred at room temperature for 1 h under argon. After dilution with 30 mL DI H2O, the reaction was extracted with Et2O (5×50 mL), the organic layers were combined, washed with brine and water and dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using hexanes as the eluent to yield 0.3 g (30%) of the desired compound as a clear oil. 1H NMR (400 MHz, CHCl3) δ 1.53 (m, 4H), 2.10 (m, 4H), 3.12 (s, 3H), 5.65 (m, 1H), 6.66 (m, 3H), 7.18 (m, 6H). 13C NMR (100 MHz, CHCl3) δ 22.0, 23.0, 25.6, 28.2, 39.2, 113.7, 116.9, 125.6, 126.3, 127.7, 128.2, 128.5, 130.3, 137.9, 142.8, 145.6, 149.0. HRMS (ESI) calc for C19H21N [M+H]+ 264.1747, found 264.1758. IR (KBr plate) 693 (m), 747(m), 1069 (s), 1155 (m), 1263 (m), 1345 (m), 1499 (s), 1602(s), 2853 (m), 2921 (s) cm−1.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])C>ClC1C=CC=CC=1>[CH3:14][O:13][C:8]1[C:7]2[S:6][CH:5]=[CH:4][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(CSc1ccccc1OC)OCC
Solvent: Clc1ccccc1
Product: COc1cccc2ccsc12
Temperature: 155 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
A solution of 1-[(2,2-diethoxyethyl)thio]-2-methoxybenzene (18 g, 70.3 mmol) in dry chlorobenzene (100 mL) was added slowly to a stirred solution of polyphosphoric acid (50 g) in dry chlorobenzene (300 mL) at 145° C. After addition was complete the resulting black solution was stirred at 155° C. for a further 18 hrs. After this time the reaction was allowed to cool to room temperature before being filtered through a pad of CELITE™, the solid cake was washed with dichloromethane (200 mL) and the combined organic extracts were concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane:ethyl acetate [95:5] to give a pale yellow oil (8.7 g, 75%); δH (300 MHz, CDCl3) 7.45–7.29 (4H, m, Ar), 6.75 (1H, d, Ar), 4.00 (3H, s, OCH3).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].[CH2:15]([O:17][P:18]([C:23]([C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)([O:26][CH2:27][CH3:28])[PH2:24]=[O:25])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:16].CCN(C(C)C)C(C)C>CCO>[CH2:15]([O:17][P:18]([C:23]([O:26][CH2:27][CH3:28])([C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:2]2[N:10]=[C:9]([I:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]([CH3:14])[CH3:13])=[CH:33][CH:34]=1)[PH2:24]=[O:25])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:16]
Reactant: CC(C)n1cnc2c(Cl)nc(I)nc21
Reactant: CCOC([PH2]=O)(c1ccc(N)cc1)P(=O)(OCC)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC([PH2]=O)(c1ccc(Nc2nc(I)nc3c2ncn3C(C)C)cc1)P(=O)(OCC)OCC
Temperature: 105 °C

Procedure:
6-Chloro-2-iodo-9-isopropyl-9H-purine (1.7 g, 5.2 mmol), [(4-amino-phenyl)-ethoxy-phosphinoylmethyl]-phosphonic acid diethyl ester (2.6 g, 7.7 mmol), and DIPEA (2.7 mL, 15.5 mmol) were dissolved in EtOH (27 mL) and heated in a sealed tube at 105° C. for 48 h. After cooling, the EtOH was evaporated. The residue was poured into water and extracted with EtOAc. The combined extracts, were washed with water, sat'd NaCl, then dried over MgSO4 and filtered. Concentration yielded an oil which was purified by silica gel chromatography (11% MeOH/EtOAc) to a glassy solid (1.8 g, 53%): MS [M+H]+ 621.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:39](Cl)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:28]=[N:29][N:30]([C:39]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:31]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of E3174 (234.58 g, 0.54 mol) in DCM (4500 mL) was added triethylamine (85 mL, 0.59 mol) followed by a solution of trityl chloride (159 g, 0.56 mol) in DCM (800 mL) and the reaction mixture was stirred at rt overnight. The reaction mixture was washed with water, dried (MgSO4), filtered, and concentrated in vacuo. Chromatography over silica eluting with 20-80% acetone/heptane afforded the title compound as an orange solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[C:14]([Cl:17])[N:13]=[CH:12][C:11]=2[C:10]([CH:18]=[O:19])=[C:9]1[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:23]Cl=O.[Na+]>CC(O)(C)C.CC(=CC)C.O>[CH2:1]([N:8]1[C:16]2[CH:15]=[C:14]([Cl:17])[N:13]=[CH:12][C:11]=2[C:10]([C:18]([OH:23])=[O:19])=[C:9]1[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1c(C=O)c2cnc(Cl)cc2n1Cc1ccccc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)c1c(C(=O)O)c2cnc(Cl)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-benzyl-6-chloro-2-isopropyl-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde (Compound 14, 146 mg, 0.47 mmol) in t-BuOH (15 ml) and 2-methyl-2-butene (10 ml) was added a solution of NaH2PO4 (1.41 g, 11.8 mmol) and NaClO2 (80%, 1.05 g, 9.3 mmol) in H2O (10 ml). The mixture was stirred at room temperature for 16 h and was extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes, then 0→30% MeOH—CH2Cl2) to yield the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]([C:5]1(C(OCC)=O)[O:9][NH:8][CH:7]=[CH:6]1)([CH3:4])[CH3:3].[BH4-].[Na+].O.[CH2:18]([OH:20])C>>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH2:18][OH:20])[CH:6]=1)([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1(C(C)(C)O)C=CNO1
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(C)(O)c1cc(CO)no1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
9.96 g of ethyl 5-(1-hydroxy-1-methylethyl)isoxazole-5-carboxylate was dissolved in 200 ml of ethanol, and 3.78 g of sodium borohydride was then added. The mixture was stirred at room temperature for 10 hours. After 50 ml of water was added, the reaction mixture was concentrated to 50 ml under reduced pressure. The concentrated solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced-pressure. The residue was subjected to silica gel column chromatography to obtain 6.17 g of [5-(1-hydroxy-1-methylethyl)isoxazol-3-yl]methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH:9]=[CH:10][C:11]([NH:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.OO.C(O)(=[O:21])C=C.CN>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:9]2[O:21][CH:10]2[C:11]([NH:13][CH3:14])=[O:12])=[O:15])=[CH:6][CH:7]=1
Reactant: C=CC(=O)O
Reactant: CNC(=O)C=CC(=O)c1ccc(Cl)cc1
Agent: CN
Agent: OO
Product: CNC(=O)C1OC1C(=O)c1ccc(Cl)cc1

Procedure:
3 was prepared as a white solid, m.p.: 160°-161° C, from 4-(4-chlorophenyl)-N-methyl-4-oxo-2-butenamide (3A) by hydrogen peroxide oxidation by the procedure described in Example 1, 3A having been prepared from the corresponding acrylic acid and monomethylamine by the procedure described in Example 2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](OC)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CC(C[AlH]CC(C)C)C>CCOCC>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Product: OCc1ccc2[nH]ccc2c1

Procedure:
96 g (0.548 mole) of 6b are treated analogously to Example 1a in 1,800 ml of ether and 1,391 ml (1.67 moles) of DIBAL (1.2 molar in toluene). After chromatography on silica gel with gradient elution with petroleum ether/ethyl acetate (3:1) and petroleum ether/ethyl acetate (1:1), 39.3 g (49%) of pure product are obtained. C9H9NO (147.2)