Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([I:14])[CH:13]=1)[C:8](O)=[O:9])=[O:4].C(N(CC)CC)C.ClC(OCC(C)C)=O>O1CCCC1>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:13]=[C:12]([I:14])[CH:11]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(I)cc(CO)c1
Reaction time: 0.75 h

Procedure:
To a solution of 3-methoxycarbonyl-5-iodobenzoic acid (1 g) in tetrahydrofuran (10 ml) was added at -40° C. to -30° C. triethylamine (0.55 ml) followed by slow addition of isobutyl chloroformate (0.51 ml) under nitrogen atmosphere. The reaction mixture was stirred below -20° C. for 45 minutes. Then, triethylamine hydrochloride was filtered off and washed with cold tetrahydrofuran, and the filtrate was added as quickly as possible to a suspension of sodium borohydride (0.37 g) in tetrahydrofuran-water (8:1, 8 ml) at 0° C. with vigorous stirring. The stirring was continued at ambient temperature for 4 hours, followed by acidification of the solution to pH 5. The tetrahydrofuran was removed under reduced pressure, and the product was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. Ethyl acetate was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (30:1). The fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-hydroxymethyl-5-iodobenzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N+:6]([O-])=[C:5]([CH3:12])[C:4]=1[CH3:13].C(OC(=O)C)(=[O:16])C>>[OH:16][CH2:12][C:5]1[C:4]([CH3:13])=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][N:6]=1
Reactant: COc1c[n+]([O-])c(C)c(C)c1OC
Reactant: CC(=O)OC(C)=O
Product: COc1cnc(CO)c(C)c1OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
4.5 g of 4,5-dimethoxy-2,3-dimethylpyridine 1-oxide are warmed to 110° C. in 20 ml of acetic anhydride in the course of 30 minutes and the mixture is then concentrated on a rotary evaporator. The oily residue, which consists of the intermediate 2-acetoxymethyl-4,5-dimethoxy-3-methylpyridine, is stirred in 30 ml of 3N sodium hydroxide solution at 80° C. for 2 hours, the mixture is extracted, after cooling, five times with 30 ml of methylene chloride each time, the combined organic phases are washed twice with 2N sodium hydroxide solution, dried and concentrated and the residue is stirred with petroleum ether, filtered off with suction and dried. 4.0 g (89% of theory) of 2-hydroxymethyl-4,5-dimethoxy-3-methylpyridine of m.p. 91°-92° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:36])[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:28]=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])[C:3]=12.[H-].[Na+].Cl[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[N:9]=2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:36])[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[N:29]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:28]=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])[C:3]=12
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(-c3cc[nH]n3)ncc(F)c12
Reactant: ClCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(-c3ccn(CCN4CCOCC4)n3)ncc(F)c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.7 %

Procedure:
1-(4-fluoro-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (40 mg, 0.08 mmol) in DMF (1 mL) was treated with sodium hydride (60% in oil, 33 mg, 0.8 mmol) and stirred at room temperature for 5 min. 4-(2-chloroethyl)morpholine (149 mg, 0.8 mmol) was added and the mixture was stirred at rt for 1 h. Reaction was quenched with H2O and concentrated under reduced pressure. The residue was dissolved in DMF and purified using reverse phase prep HPLC to afford the title compound as a white solid (20 mg, 67%). 1H NMR (500 MHz, MeOD) δ ppm 3.43 (s, 1H) 3.77 (s, 5H) 3.81 (s, 5H) 4.08 (s, 2H) 4.28 (s, 3H) 4.37 (s, 4H) 5.27 (s, 6H) 7.56 (s, 1H) 8.06-8.12 (m, 2H) 8.13 (s, 2H) 8.38 (s, 1H) 8.70 (s, 1H) 8.85 (s, 1H). LCMS: m/e 600 (M+H)+, ret time 1.22 min (method 3).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](Cl)=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[CH3:14][O:15][C:16](=[O:23])[C@@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18]>>[O:3]1[C:4]2[CH:9]=[C:8]([C:10]([NH:18][C@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16]([O:15][CH3:14])=[O:23])=[O:11])[CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: COC(=O)[C@H](N)CC(C)C
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Agent: Cl
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1ccc2c(c1)OCO2
Yield: 83 %

Procedure:
Prepared in a similar manner to example 1 using benzo[d][1,3]dioxole-5-carbonyl chloride and D-leucine methyl ester hydrochloride. Yield: 83%. 1H NMR (500 MHz, CDCl3): δ 0.98 (m, 6H); 1.63-1.67 (m, 1H); 1.71-1.76 (m, 2H); 3.76 (s, 3H); 4.83 (m, 1H); 6.03 (s, 2H); 6.38 (d, 1H); 6.83 (d, 1H); 7.32 (s, 1H); 7.33 (d, 1H). MS (M+H, 294). m.p: 89-90° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH:18]([CH3:20])[CH3:19].S(Cl)([Cl:24])(=O)=O.O>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:18]([CH3:20])[CH3:19])[Cl:24]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)C1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C1(Cl)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reaction time: 16 h

Procedure:
(1-Oxo-2-isopropyl-6,7-dichloro-5-indanyloxy)acetic acid (60 g., 0.189 mole) is dissolved in acetic acid (400 ml.). Sulfuryl chloride (18 ml., 0.216 mole) is added dropwise to the stirred solution. The resulting clear yellow solution is then heated at 80°-85° C. for 3/4 hour, cooled and poured slowly, with stirring, into water (3 l.). The gum that separates solidifies after 16 hours to yield 55.5 g. of (1-oxo-2-isoporpyl-2,6,7-trichloro-5-indanyloxy)acetic acid, m.p. 158°-159° C., after recrystallization from acetic acid water (1:1).
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH2:23]([O:25][C:26](=[O:49])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]2[O:38][N:37]=[C:36]([CH2:39][O:40]C3C=CC(OC)=CC=3)[N:35]=2)=[CH:29][CH:28]=1)[CH3:24]>C(#N)C.O>[CH2:23]([O:25][C:26](=[O:49])[C:27]1[CH:28]=[CH:29][C:30]([CH2:33][C:34]2[O:38][N:37]=[C:36]([CH2:39][OH:40])[N:35]=2)=[CH:31][CH:32]=1)[CH3:24]
Reactant: CCOC(=O)c1ccc(Cc2nc(COc3ccc(OC)cc3)no2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc(Cc2nc(CO)no2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 528 %

Procedure:
Add half of the ammonium cerium(IV) nitrate (285 mg, 0.52 mmol) to a solution of 4-[3-(4-methoxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acid ethyl ester (193 mg, 0.52 mmol) in acetonitrile (9 mL) and water (2.3 mL) at room temperature. Stir the reaction mixture at room temperature for one hour and add the second half of the ammonium cerium(IV) nitrate (285 mg, 0.52 mmol). Stir at room temperature for an additional hour, dilute the reaction is with saturated aqueous sodium hydride CO3, stir for 5 minutes, dilute with water, and extract with ethyl acetate (3×). Wash the combined organic layers with brine, dry over MgSO4, and concentrate. Purify the residue by flash column chromatography using 50% ethyl acetate/hexane to give the title compound (720 mg, 81%). LC-MS (m/e): 263 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8]O)=[NH:7])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:18])[C:16]#[CH:17])[CH3:13]>CO>[CH2:12]([O:14][C:15]([C:16]1[NH:7][C:6]([C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:8][CH:17]=1)=[O:18])[CH3:13]
Reactant: N=C(NO)c1ccc(Cl)cc1
Reactant: C#CC(=O)OCC
Solvent: CO
Product: CCOC(=O)c1cnc(-c2ccc(Cl)cc2)[nH]1
Temperature: 190 °C

Procedure:
1.0 g (5.9 mmol) of 4-chloro-N-hydroxy-benzamidine and 776 mg (7.96 mmol) of propynoic acid ethyl ester were dissolved in methanol and the resulting solution was boiled under reflux for 15 h. The solvent was removed under reduced pressure, and the residue was dissolved in Dowtherm A. This solution was heated to 190° C. for 2.5 h, allowed to cool, then poured into n-heptane. The precipitated product was filtered off and washed with n-heptane.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:7]=[C:8]=[S:9])=[CH:4][S:5][CH:6]=1.[Cl:10][C:11]1[C:12]([NH2:18])=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1>>[NH2:18][C:12]1[C:11]([Cl:10])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:17][C:8]([NH:7][C:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)=[S:9]
Reactant: Cc1cscc1N=C=S
Reactant: Nc1cccc(Cl)c1N
Product: Cc1cscc1NC(=S)Nc1cccc(Cl)c1N

Procedure:
is obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 3-chloro-1,2-diaminobenzene (prepared by catalytic hydrogenation of 3-chloro-2-nitroaniline using Pt on activated carbon under atmospheric pressure at room temperature). Crystalline solid, m.p. 298-305° C.,
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]O>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=3)=[CH:15][CH:16]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CC(=O)N(c2ccc(O)cc2)C1
Reactant: OCc1cccc(Cl)c1
Product: COC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(Cl)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 28b), the alkylation of the (R)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester [Example 28a)] with 3-chlorobenzylalcohol yields the (R)-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid. MS: m/e=360 (M+H)+.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([C:12]([O:14][CH3:15])=[O:13])[NH:3]1.C(N(CC)CC)C.N#N.Cl.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[CH:34]=[C:33]([S:40]([NH:43][C@H:44]([C:52](Cl)=[O:53])[CH2:45][CH2:46][CH2:47][NH:48][C:49](=[NH:51])[NH2:50])(=[O:42])=[O:41])[CH:32]=[CH:31]2>C(Cl)(Cl)Cl>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[CH:34]=[C:33]([S:40]([NH:43][C@H:44]([C:52]([N:3]1[CH:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:2]1)=[O:53])[CH2:45][CH2:46][CH2:47][NH:48][C:49](=[NH:50])[NH2:51])(=[O:41])=[O:42])[CH:32]=[CH:31]2
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2cc1OC
Reactant: COC(=O)C1Cc2ccccc2CN1
Agent: Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1Cc2ccccc2CN1C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Reaction time: 8 h

Procedure:
To a stirred solution of 1.8 g of methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride and 8 ml of triethylamine in 50 ml of chloroform which was cooled in an ice bath, there was carefully added N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl chloride hydrochloride obtained above. The reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was washed twice with 50 ml of saturated sodium chloride solution and evaporated to dryness. The residue was dissolved in water-ethanol and ajusted to pH 12 with 5N NaOH solution at a temperature below 0° C to precipitate a solid. This was collected by filtration to give 3 g of methyl 2-[N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=[O:38])[NH:17][C:18]2[CH:19]=[C:20]3[C:36](=[O:37])[NH:35][N:34]=[CH:33][C:22]4=[C:23]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[NH:24][C:25]([CH:26]=2)=[C:21]34)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[O:37]=[C:36]1[C:20]2[C:21]3[C:22](=[C:23]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:24][C:25]=3[CH:26]=[C:18]([NH:17][C:16](=[O:38])[CH2:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=2)[CH:33]=[N:34][NH:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)Nc2cc3c4c(c(-c5ccccc5)[nH]c4c2)C=NNC3=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCC1CCNCC1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 82 %

Procedure:
Preparation of example 92 from title compound of Example 88 (52 mg, 0.101 mmol) and 45% TFA in CH2Cl2 (1 mL) was carried out analogously to Example 20. Isolation, also in an analogous manner, afforded the title compound 50 mg, 0.084 mmol) as a yellow powder in 82% yield.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].O=CCC[CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:2]([CH:14]1[CH2:15][CH2:10][CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)[CH2:3][CH:4]=[CH2:5]
Reactant: CC(C)(C)OC(=O)N1CCCC(CCC=O)C1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CCCC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A 1 L oven-dried round-bottom flask was charged with methyltriphenylphosphonium bromide (9.30 g, 26.0 mmol) and THF (250 mL) and cooled to −70° C. A solution of BuLi (2.5 M in hexanes, 10.4 mL, 26.0 mmol) was added dropwise, and the reaction mixture was stirred for 1 h. A solution of tert-butyl 3-(3-oxopropyl)piperidine-1-carboxylate (4.19 g, 17.4 mmol) in THF (15 mL) was added, and the reaction mixture was slowly warmed to RT and stirred for 3 days. The reaction mixture was quenched with water and concentrated to remove THF. The mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried with anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (95 hexane/5 EtOAc) to give the title compound as a colorless oil. 1H NMR (CDCl3): δ 5.83-5.77 (m, 1H), 5.0{tilde over (4)} 4.95 (m, 2H), 3.9{tilde over (2)} 3.88 (m, 2H), 2.77 (s, br, 1H)), 2.6{tilde over (0)} 2.35 (m, 1H), 2.1{tilde over (1)} 2.07 (m, 2H), 1.81 (m, 1H), 1.6{tilde over (4)} 1.58 (m, 1H), 1.5{tilde over (0)} 1.20 (m, 13H), 1.2{tilde over (5)} 1.00 (m, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)[N:11]3[C:28](=[O:32])[N:29]([CH3:31])[N:30]=[C:10]3[C:9]=2[C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][NH:18][CH2:17]3)[N:11]3[C:28](=[O:32])[N:29]([CH3:31])[N:30]=[C:10]3[C:9]=2[C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(NC[C@@H]3CCN(C(=O)OC(C)(C)C)C3)n2c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(NC[C@@H]3CCNC3)n2c1=O
Temperature: 25 °C

Procedure:
A solution of (S)-tert-butyl 3-((7,8-bis(4-chlorophenyl)-2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-ylamino)methyl)pyrrolidine-1-carboxylate (85 mg, 0.15 mmol) in a mixture of TFA (0.1 mL) and CH2Cl2 (0.5 mL) was stirred at room temperature until HPLC/MS indicated complete conversion to the title compound. The reaction mixture was then partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried, and evaporated. The residue was purified by preparative reverse phase HPLC (without TFA) to obtain the title compound as a pale yellow solid. HPLC/MS: retention time 3.475 min, [M+H]30 =469.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=[N:15][CH:16]=1.[H-].[Na+].Cl[CH2:26][CH2:27][O:28][Si](C)(C)C.Cl>CN(C=O)C>[OH:28][CH2:27][CH2:26][N:17]([C:13]1[CH:14]=[N:15][CH:16]=[C:11]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=1)[S:18]([CH2:21][CH3:22])(=[O:20])=[O:19]
Reactant: C[Si](C)(C)OCCCl
Reactant: CCS(=O)(=O)Nc1cncc(-c2cc3ccccc3n2C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(CCO)c1cncc(-c2cc3ccccc3n2C)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A flask is charged with ethanesulfonic acid [5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide (Example 226, 200 mg, 0.634 mmol) and DMF (3 mL). The reaction is cooled to 0° C. and sodium hydride (38.0 mg, 0.951 mmol) is added. The reaction is stirred at room temperature for 10 min, then 2-chloro-ethoxytrimethylsilane (0.154 mL, 0.951 mmol) is added. The reaction is stirred at 100° C. for 16 h then cooled to room temperature. Aqueous 1M HCl (1 mL) is added and stirring is continued for 30 min. The mixture is purified using an Xbridge C18 eluting with a 10 to 100% acetonitrile-water gradient to afford ethanesulfonic acid (2-hydroxy-ethyl)-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide. MS (ESI) m/z 360.1 (M+H)+. 1H NMR (400 MHz, MeOD) δ ppm 1.42 (t, J=7.3 Hz, 3H), 3.29 (t, 2H), 3.70 (t, J=5.6 Hz, 2H), 3.84 (s, 3H), 3.96 (t, J=5.6 Hz, 2H), 6.75 (s, 1H), 7.14 (td, J=7.5, 0.9 Hz, 1H), 7.28 (td, J=7.7, 1.0 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 8.18 (t, J=2.1 Hz, 1H), 8.71 (d, J=2.3 Hz, 1H), 8.75 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 360.1383 [(M+H)+ Calcd for C18H12N3O3S 360.1376].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][CH:27]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][CH:27]=1)=[O:25])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.7 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (71.0 mg, 62%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH2:14]([NH:21][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: O=C(O)c1cccc(S(=O)(=O)NCc2ccccc2)c1
Yield: 99.7 %

Procedure:
3-Chlorosulfonyl-benzoic acid (300 mg, 1.36 mmol), and benzylamine (0.60 mL, 5.49 mmol) were stirred at room temperature in anhydrous CH2Cl2 (10 mL) overnight under N2. The reaction mixture was concentrated in vacuo. Purification of the residue on IR-120 ion exchange resin column (elution with methanol) afforded the title compound (395 mg, 100%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:22]([CH3:24])=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(OC)c(F)cc3OCC3CC3)ncnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(OC)c(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester (example D.a10) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([CH:8]=O)=[CH:6][CH:7]=1.[C:10]1([CH2:16][CH2:17][CH2:18][NH:19][S:20]([CH2:23][C:24]#[N:25])(=[O:22])=[O:21])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:1][S:2][C:3]1[S:4][C:5](/[CH:8]=[C:23](/[S:20]([NH:19][CH2:18][CH2:17][CH2:16][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:22])=[O:21])\[C:24]#[N:25])=[CH:6][CH:7]=1
Reactant: CSc1ccc(C=O)s1
Reactant: N#CCS(=O)(=O)NCCCc1ccccc1
Product: CSc1ccc(/C=C(\C#N)S(=O)(=O)NCCCc2ccccc2)s1

Procedure:
Reaction of 2-methylmercaptothiophen-5-carboxaldehyde and (3-phenyl-n-propyl)aminosulfonylacetonitrile as in Example 1 gave (E)-3-(2-methylmercaptothien-5-yl)-2-[(3-phenyl-n-propyl)aminosulfonyl]acrylonitrile
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[N-:10]=[N+:11]=[N-:12].[Na+].C(N(CC)CC)C>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:10]=[N:11][NH:12][N:9]=2)[CH:7]=1
Reactant: N#Cc1cncc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Brc1cncc(-c2nn[nH]n2)c1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-5-cyanopyridine (1 eq), sodium azide (1.2 eq), triethylamine (1.2 eq) and AcOH (1.2 eq) was stirred at 100C for 14 h. The reaction mixture was cooled to rt, diluted with aqueous acetic acid solution and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=O)[CH3:13]>>[Br:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[O:5][C:12]([CH3:13])=[N:1][C:2]=2[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Br)ccc1C(=O)O
Product: Cc1nc2cc(Br)ccc2c(=O)o1
Temperature: 130 °C
Reaction time: 4 h
Yield: 49.2 %

Procedure:
2-amino-4-bromobenzoic acid (825 mg, 3.82 mmol) was taken up in acetic anhydride (5.2 mL, 55.01 mmol) and mixture was heated at 130° C. After 4 hours, reaction mixture was cooled to rt and left there for two hours. The solid that precipitated was filtered and washed with cold ether, and dried in-vacuo to yield 7-bromo-2-methyl-4H-benzo[d][1,3]oxazin-4-one 7.25 (451 mg), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]Cl)=[C:6]([F:10])[CH:5]=[CH:4][CH:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CS(C)=O>[Cl:1][C:2]1[C:7]([CH2:8][N:11]=[N+:12]=[N-:13])=[C:6]([F:10])[CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cccc(Cl)c1CCl
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
123 g of (0.687 mole) of 6-chloro-2-fluorobenzyl chloride are added dropwise at 20°-40° C. to a suspension of 47 g (0.722 mole) of sodium azide in 400 ml of dimethylsulfoxide. The mixture is stirred for 4 hours at room temperature, then diluted with ice-water and extracted with cyclohexane. The solvent is removed by distillation and the residue is distilled, affording 6-chloro-2-fluorobenzyl azide; bp15 =99°-100° C.