Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:23])([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=1)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8](Br)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=O)C>CN(C)C=O>[CH3:1][C:2]([CH3:23])([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=1)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:7]=1
Reactant: CCOc1ccc(C(C)(C)COCc2ccc(F)c(Br)c2)cc1
Reactant: CC(=O)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(C)(C)COCc2ccc(F)c(Nc3ccccc3)c2)cc1
Temperature: 140 °C
Reaction time: 40 h

Procedure:
2.37 Grams of 3-bromo-4-fluorobenzyl 2,2-dimethyl-2-(4-ethoxyphenyl)ethyl ether, 0.95 g of potassium carbonate, 1.01 g of acetanilide, 10 ml of dimethylformamide and 250 mg of cuprous chloride were mixed and stirred at 140° C. for 40 hours in a nitrogen stream. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous sodium chloride liquor, and after removing the solvent by evaporation, the residual oil was dissolved in a 20% ethanol solution of potassium hydroxide (2 times by mole) and refluxed for 30 minutes. The reaction solution was then poured into ice water and extracted with ether. The ether layer was washed with an aqueous sodium chloride liquor and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation. The residual oil was separation-purified by column chromatography on silica gel to obtain 1.05 g of 3-anilino-4-fluorobenzyl 2,2-dimethyl-2-(4-ethoxyphenyl)ethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([OH:26])[CH3:25])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([OH:26])[CH3:25])=[CH:21][CH:22]=2)[CH:7]=1
Reactant: CC(O)Cc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Product: CC(O)Cc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2[N+](=O)[O-])cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 2,4-dichloro-5-nitrobenzotrifluoride and 1-(4-aminophenyl)-2-propanol (step 1 of Example 6).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13](=[O:14])[N:12]([CH3:15])[CH:11]=[C:10]2[C:16](=[O:32])[N:17]([CH2:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[C:18](=[O:19])[C:9]=12>CCO>[CH3:15][N:12]1[C:13](=[O:14])[C:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[C:9]2[C:18](=[O:19])[N:17]([CH2:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[C:16](=[O:32])[C:10]2=[CH:11]1
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Reactant: C1COCCN1
Solvent: CCO
Product: Cn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Temperature: 90 °C
Reaction time: 16 h
Yield: 123 %

Procedure:
Morpholine (0.355 ml, 4.08 mmol) was added to a solution of 7-chloro-5-methyl-2-(2-quinolin-2-yl-ethyl)-5H-pyrrolo[3,4-c]pyridine-1,3,6-trione (0.5 g, 1.36 mmol, see Example c1)) in EtOH (30 ml) and the reaction was stirred at 90° C. for 16 h. The solvent was removed to give the title compound (0.7 g, 123% yield), which was used in the next steps without further purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[S:10](=[O:13])(=[O:12])[NH2:11])[NH2:6].[Cl:16][CH2:17][C:18](Cl)=[O:19]>>[Cl:16][CH2:17][C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([S:10](=[O:12])(=[O:13])[NH2:11])=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=1)=[O:19]
Reactant: Nc1ccc(S(N)(=O)=O)c(C(F)(F)F)c1
Reactant: O=C(Cl)CCl
Product: NS(=O)(=O)c1ccc(NC(=O)CCl)cc1C(F)(F)F

Procedure:
3-Trifluoromethyl-4-sulphamoylaniline (24.0g) and α-chloroacetyl chloride (20 ml) were refluxed together 30 mins and the mixture worked up as in Example 2(a) to yield 28 g, m.p. 185°-190°
Reaction SMILES: [CH:1]1[N:5]([C@@H:6]2[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]2[OH:14])[N:4]=[C:3]([C:15]([NH2:17])=[O:16])[N:2]=1.O.P(Cl)(Cl)(Cl)=O.[P:24](OC)([O:28]C)([O:26]C)=[O:25]>>[CH:1]1[N:5]([C@@H:6]2[O:10][C@H:9]([CH2:11][O:12][P:24]([OH:28])([OH:26])=[O:25])[C@@H:8]([OH:13])[C@H:7]2[OH:14])[N:4]=[C:3]([C:15]([NH2:17])=[O:16])[N:2]=1
Reactant: COP(=O)(OC)OC
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: NC(=O)c1ncn([C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The manufacture and synthesis Ribavirin (ICN Pharmaceuticals, Costa Mesa Calif.) are described in U.S. Pat. No. 4,211,771, incorporated herein by reference. A dry 1 L ml 3-neck round bottom flask, equipped with a stir bar, gas inlet adapter, and thermometer, was charged with 50 g Ribavirin (0.204 moles), 500 ml trimethyl phosphate, and 0.367 ml de-ionized water (0.0204 moles). The mixture was cooled under nitrogen with an ice/water bath. When the temperature reached 10° C., 23.3 ml phosphorous oxychloride was added, the flask was removed from the ice bath, and the mixture was stirred under nitrogen. After 30 min., the flask was cooled in the ice/water bath. When the temperature reached 10° C., the mixture was poured into a 2 L beaker containing 1000 ml ice water. The pH was adjusted to pH=9.0 using 4 M LiOH and the mixture was stirred overnight. After final adjustment to pH 9, the white precipitate that has formed is filtered away using a 0.2 mm filter. The mixture was evaporated at 40° C. under reduced pressure to 1 L. The solution was added to 1 L hot ethanol dropwise. The white precipitate was collected on a 2 L glass fritted funnel, coarse grade, washing the solid with two 100 ml portions of ethanol, re-suspending the solid each time. The product was dried under vacuum overnight, yield: 89 g. The solid was dissolved in 200 ml de-ionized water, and 5 g activated carbon was added. The mixture was filtered through a 0.2 mm filter, washing the carbon with 50 ml de-ionized water. The filtered solution was added dropwise to 1200 ml hot ethanol The mixture was cooled to room temperature, and the precipitate was collected on the 2 L glass fritted funnel. The solid was washed with 2×100 ml ethanol in the funnel, and dried under vacuum. Yield: 66.6 g. The dried product was dissolved in 200 ml de-ionized water. Amberlite IR-120 H.C.P. resin (H+ form) was added until the pH of the mixture reached pH=2.18. The resin was filtered off using a 0.2 mm filter, and the final solution was lyophilized. Yield: 54.8 g (0.160 moles), 78.5%, Ribavirin 5'-monophosphate. Elemental analysis indicates the product contains 1 mole water/mol ribavirin 5'-monophosphate.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:20]=[CH:19][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[C:21](=[O:23])=[O:22]>C1COCC1.O>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH2:11][C:10]1[CH:19]=[CH:20][C:7]([C:21]([OH:23])=[O:22])=[CH:8][CH:9]=1
Reactant: Brc1ccc(COc2ccccn2)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(COc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6 M in hexane, 11.4 ml) was added to a solution of 2-(4-bromobenzyloxy)pyridine (4.2 g) in THF (120 ml) at −78° C. After 15 minutes, dry ice (7 g) was added. After warming to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The aqueous phase was acidified and again extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The product with the molecular weight of 229.24 (C13H11NO3); MS (ESI): 230 (M+H+) was obtained in this way.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>O1CCCC1>[N:16]1([S:13]([C:10]2[CH:11]=[CH:12][C:7]([B:21]([OH:26])[OH:22])=[CH:8][CH:9]=2)(=[O:15])=[O:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(B(O)O)cc1)N1CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
n-Butyllithium (20 mL, 31 mmol) was added dropwise over 30 min to a cooled (−78° C.) solution of 1-[(4-bromophenyl)sulfonyl]pyrrolidine (3.0 g, 10.3 mmol) and triisopropyl borate (7.2 mL, 30.9 mol) in anhydrous tetrahydrofuran (10 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 1 h at −78° C. whereafter the temperature was allowed to reach room temperature over 3 h. Silica gel was added and the solvent was evaporated. Chromatography on a silica gel column using a gradient methylene chloride (100%) to methylene chloride/ethanol, (1:1), gave 1.85 g (70% yield) of the title compound as a white solid: 1H NMR (CD3OD, 400 MHz) δ 7.90 (d, J=7 Hz, 2H), 7.75 (d, J=8 Hz, 2H), 3.21 (m, 4H), 1.72 (m, 4H); 13C NMR (CDCl3/CD3OD (1:1), 100 MHz) δ 136.79, 133.50, 125.48, 47.19, 24.30; MS (ES) m/z 256 (M++1).
Reaction SMILES: [CH3:1][S:2]([N:5]([CH2:11][CH2:12][Cl:13])[NH:6][S:7]([CH3:10])(=[O:9])=[O:8])(=[O:4])=[O:3].[C:14](Cl)(=[O:17])[CH2:15][CH3:16].C(N(CC)CC)C>CC(C)=O>[CH3:1][S:2]([N:5]([CH2:11][CH2:12][Cl:13])[N:6]([S:7]([CH3:10])(=[O:9])=[O:8])[C:14](=[O:17])[CH2:15][CH3:16])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)NN(CCCl)S(C)(=O)=O
Reactant: CCC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O
Reaction time: 20 h
Yield: 46.3 %

Procedure:
To a stirred solution of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (1.25 g, 0.005 mol) and propionyl chloride (3.20 g, 0.035 mol) in dry acetone (20 mL), triethylamine (0.014 mol) was added dropwise at room temperature. A precipitate was formed immediately. After an additional 20 h, the reaction mixture was filtered and the filtrate evaporated in dryness in vacuo. The residue was taken up in ethyl acetate (100 mL) and washed with dilute hydrochloric acid (3×15 mL), followed by water (2×10 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated to dryness in vacuo. The residue was triturated with petroleum ether to give a solid which, on recrystallization from absolute ethanol, afforded 0.71 g (46.4%) of the title compound: mp 97°-98° C.; 1H NMR (acetone-d6) δ 3.8-4.2 (m, 4 H, CH2CH2), 3.5 and 3.3 (2 s, 6 H, 2 CH3SO2), 2.8 (q, 2 H, COCH2), 1.1 (t, 3 H, COCCH3). Anal. (C7H15C1N2O5S2) C, H, N.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].CCN(CC)CC.[C:17]([N:27]1[CH2:34][CH2:33][CH2:32][C@@H:28]1[C:29](O)=[O:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[OH:8][CH2:7][C@H:5]([NH:6][C:29]([C@H:28]1[CH2:32][CH2:33][CH2:34][N:27]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:30])[C:4]([O:3][CH3:2])=[O:9]
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a solution of L-Serine methyl ester hydrochloride (Aldrich, 5.0 g, 32.0 mmoles), in CH2Cl2 (150 mL) at 0° C., were added Et3N (4.88 mL, 35.2 mmoles), Cbz-D-Proline (8.01 g, 32.0 mmoles) and DCC (7.26 g, 35.2 mmoles) sequentially. The reaction was allowed to warm to room temperature and stirred overnight. All the solvent was evaporated and the residue was triturated with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated under low pressure and chromatographed on silica gel (70% ethyl acetate/30% chloroform) to yield 8.5 g of (R)-benzyl 2-((S)-3-hydroxy-1-methoxy-1-oxopropan-2-ylcarbamoyl)pyrrolidine-1-carboxylate.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[C:19]([CH3:26])[CH:18]=1>ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:15][NH:14][C:12](=[O:13])[CH2:11][C@@H:8]2[CH2:9][CH2:10][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:7]2)=[O:25])=[C:19]([CH3:26])[CH:18]=1
Reactant: Cc1cc(Br)ccc1N=C=O
Reactant: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Solvent: ClCCl
Product: Cc1cc(Br)ccc1NC(=O)NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (800 mg, 3.79 mmol) in dry dichloromethane (5 mL) was added 4-bromo-1-isocyanato-2-methylbenzene (803 mg, 3.79 mmol). The reaction was allowed to progress for 1 h at room temperature (became a thick suspension that could not be stirred). The reaction mixture was diluted with dichloromethane (10 mL) and the precipitate was collected by filtration. A second crop was obtained by filtration and the two crops were combined, rinsed with minimal dichloromethane and dried to constant weight under high vacuum to provide the title product (1.54 g, 3.64 mmol, 96% yield) as a white solid. MS(ES)+ m/e 422.9 [M+H]+. This material was 76% pure by LCMS (UV214) and was used as is in the next step.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:19][CH2:20][CH3:21].B(Br)(Br)Br.C(Cl)Cl>>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:19][CH2:20][CH3:21]
Reactant: CCCc1cc2c(OC)cccc2n1Cc1ccccc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 71.1 %

Procedure:
By the method used in Example 1, Part D, 1.16 g (3.27 mmol) of 1-([1,1′-biphenyl]-2-ylmethyl)-4-methoxy-2-propyl-1H-indole was O-demethylated by treating it with 13 mL of 1M BBr3/CH2Cl2. The crude product was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 794 mg (71% yield) of 1-([1,1′-biphenyl]-2-ylmethyl)-4-hydroxy-2-propyl-1H-indole as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:7]=3[C:6]=2[N:18]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOCC>N1C=CC=CC=1>[I:17][C:15]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[CH2:11][C:5]3[CH:4]=[N:3][C:2]([NH:1][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:18][C:6]=3[C:7]=2[CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncc2c(n1)-c1cc(I)ccc1NC(=O)C2
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C1Cc2cnc(NC(=O)c3ccccc3)nc2-c2cc(I)ccc2N1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
2-Amino-10-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-51) (69.7 mg, 0.20 mmol) was dissolved in pyridine (800 μL) and benzoyl chloride (23 mL, 0.20 mmol). The mixture was stirred at 110° C. for 1 h, then cooled to 22° C. Et2O was added and the product was filtered from the solution to give I-83 (37%): MS (FA) Rt=1.49 min, m/z=457 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:18][C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1O
Reactant: OCc1cccs1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)ccc1OCc1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
Methyl 5-bromosalicylate [prepared by treating methyl 5-bromosalicyclic acid with methanol and sulphuric acid] (4.62 g, 20 mmol) was dissolved in THF (150 mL) and treated with thiophene methanol (2.28 g, 20 mmol) and triphenyl phosphine (10.4 g, 40 mmol). The reaction was cooled in an ice bath and treated with DEAD (6.96 g, 20 mmol). The resultant orange solution was allowed to stir at ambient temperature under argon for 18 hours. The reaction mixture was evaporated and the residue subjected to chromatography (eluant: diethyl ether/hexane) to give methyl 5-bromo-2-(2-thienylmethoxy)benzoate as a pink oil (3.6 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH2:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>CCOC(C)=O>[Cl:1][C:2]1[C:3]([N:30]2[CH2:31][CH2:32][CH:28]([NH2:27])[CH2:29]2)=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1CCNC1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Solvent: CCOC(C)=O
Product: NC1CCN(c2c(Cl)cnc3nc(-c4ccc(OCCN5CCOCC5)cc4)[nH]c23)C1
Yield: 61 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (40 mg, 110 μmol) and 3-aminopyrrolidine (0.5 ml) were heated at 195° C. for 15 min and then allowed to cool. The reaction mixture was diluted with EtOAc (5 ml) and extracted with 4M HCl (4 ml). The aqueous phase was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc (4 ml). The organic phase was evaporated in vacuo and the residue dissolved in acetonitrile (2 ml) and subjected to semi-preparative HPLC-C18. The appropriate fractions were pooled and evaporated in vacuo. The residue was dissolved in EtOAc (5 ml). This solution was washed with saturated aqueous NaHCO3 (5 ml) and brine (2 ml). The organic phase was dried (MgSO4) and evaporated in vacuo to afford the pure product (30 mg, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([OH:15])(=[O:14])=[O:13])[CH:8]=[CH:7]2.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20](Cl)=[O:21]>N1C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([OH:15])(=[O:13])=[O:14])[CH:8]=[CH:7]2)=[O:21]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1cccc2ccc(S(=O)(=O)O)cc12
Solvent: c1ccncc1
Product: O=C(Nc1cccc2ccc(S(=O)(=O)O)cc12)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.8 %

Procedure:
8-Amino-2-naphthalenesulfonic acid (Aldrich, 1.00 g, 4.48 mmol) and 3,4-dichlorobenzoyl chloride (938 mg, 4.48 mmol) were dissolved in pyridine (10.0 mL), and the resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then concentrated in vacuo, and the residue was dissolved in 1N HCl. The solution was extracted with EtOAc (5×), and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (1.70 g, 91%). 1H NMR (DMSO-d6) δ 11.30 (s, 1H), 8.93 (d, J=2.0 Hz, 1H), 8.83 (s, 1H), 8.65 (dd, J=8.0, 1.9 Hz, 1H), 8.58-8.50 (m, 1H), 8.50-8.43 (m, 2H), 8.34 (dd, J=8.6, 1.5 Hz, 1H), 8.19-8.14 (m, 2H), 6.14 (br s, 1H); MS(ESI−) m/z 394.2 (M−H)−.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[NH:33][C:34]([SH:37])=[N:35][N:36]=2)[CH:27]=1>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:37][C:34]3[NH:33][C:32]([C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[N:36][N:35]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Sc1nnc(-c2cccnc2)[nH]1
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nnc(-c4cccnc4)[nH]3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 5-(3-pyridinyl)-4H-1,2,4-triazole-3-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.53-1.69 (m, 8H) 2.03 (m, 1H) 2.11 (m, 1H) 2.35 (m, 1H) 2.57 (m, 1H) 2.63 (m, 1H) 2.82 (d, J=17.6 Hz, 1H) 2.96 (d, J=15.0 Hz, 1H) 3.77 (s, 3H) 6.95 (d, J=8.5 Hz, 1H) 7.09 (d, J=8.5 Hz, 1H) 7.23 (d, J=1.4 Hz, 1H) 7.41 (m, 1H) 8.13 (s, 1H) 8.60 (d, J=4.1 Hz, 1H) 9.03 (s, 1H). MS (APCI) calcd for C26H27ClN4O4S: 527.04; found M=527.0.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:10]3[CH2:12][CH2:13][CH2:14][CH:15]([C:16]#[N:17])[C:9]=3[CH:8]=[CH:7][C:6]=2[NH:5][CH:4]=1.CO.[CH2:20](N)[CH2:21][NH2:22]>C(Cl)Cl>[NH:17]1[CH2:20][CH2:21][N:22]=[C:16]1[CH:15]1[C:9]2[CH:8]=[CH:7][C:6]3[NH:5][CH:4]=[C:3]([S:2][CH3:1])[C:11]=3[C:10]=2[CH2:12][CH2:13][CH2:14]1
Reactant: CSc1c[nH]c2ccc3c(c12)CCCC3C#N
Reactant: NCCN
Solvent: ClCCl
Solvent: CO
Product: CSc1c[nH]c2ccc3c(c12)CCCC3C1=NCCN1

Procedure:
The product from Example 123 (1.9 g) was dissolved in methylene chloride (35 ml) and methanol (1.5 ml) and reacted with ethylenediamine (3.5 ml) as in Example 35 giving the desired product (1.38 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[Si:29]([O:36][CH2:37][CH2:38][C@@H:39]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[C:57]([Cl:63])[C:56]=1[CH3:64])[C:40]([NH:42][NH:43][C:44](=O)[C:45]1[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[CH:47][CH:46]=1)=[O:41])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl>[Si:29]([O:36][CH2:37][CH2:38][C@@H:39]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[C:57]([Cl:63])[C:56]=1[CH3:64])[C:40]1[O:41][C:44]([C:45]2[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[CH:47][CH:46]=2)=[N:43][N:42]=1)([C:32]([CH3:34])([CH3:33])[CH3:35])([CH3:31])[CH3:30]
Reactant: Cc1c(N[C@H](CCO[Si](C)(C)C(C)(C)C)C(=O)NNC(=O)c2ccc(C#N)cc2)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(N[C@H](CCO[Si](C)(C)C(C)(C)C)c2nnc(-c3ccc(C#N)cc3)o2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
To a 25 mL round bottom flask equipped with a magnetic stir bar and septum was added triphenylphosphine (polymer bound, 3.0 mmol/g loading) (1 g, 3 mmol) under an atmosphere of nitrogen. To this was added methylene chloride (60 mL) followed by addition of solid iodine (688 mg, 2.71 mmol). This was allowed to stir at room temperature for a period of 10 min followed by slow addition of triethylamine (1 mL, 7.24 mmol). (R)—N′-(4-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-cyanobenzohydrazide (950 mg, 1.81 mmol) was taken up in methylene chloride (15 mL) and slowly added to the stirred reaction mixture. After a period of 30 min, the solid polymer was filtered out and washed with additional methylene chloride (50 mL). The organic filtrate was then washed with 10% sodium thiosulfate/water (2×25 mL), brine (1×30 mL) and dried (Na2SO4). The solution was then filtered and concentrated under reduced to reveal a brown solid (1.03 g). Purification by flash column chromatography [EtOAc-hexanes (1:2) as eluent] afforded the title compound as a white crystalline solid (900 mg, 98%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.19 (d, J=9 Hz, 2H), 8.00 (d, J=9 Hz, 2H), 7.53 (d, J=9 Hz, 1H), 6.98 (d, J=9 Hz, 1H), 6.05 (d, J=9 Hz, 1H), 5.4 (m, 1H), 4.00-3.95 (m, 1H), 3.94-3.89 (m, 1H), 2.57-2.40 (m, 2H), 2.38 (s, 3H), 0.88 (s, 9H), 0.04 (s, 3H) and 0.00 (s, 3H).