Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](O)=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)N3CCOCC3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, morpholine (10 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-morpholin-4-yl-3-oxo-propyl)-1H-pyrazol-3-yl]-propionamide (17 mg, 30%) as a white solid: ESI-LRMS m/e calcd for C25H33ClN4O5S [M+] 536.2, found 537.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.22 (m, 2H, CH2), 1.44-1.93 (m, 8H, 4×CH2), 2.12-2.30 (m, 1H, CH), 2.79 (t, J=6.6 Hz, 2H, COCH2), 3.26 (s, 3H, SO2CH3), 3.31-3.41 (m, 2H, CH2), 3.53 (t, J=7.6 Hz, 1H, CH), 3.55-3.66 (m, 6H, 3×CH2), 4.35 (t, J=6.6 Hz, 2H, NCH2), 6.60 (d, J=2.3 Hz, 1H, Ar), 7.35 (d, J=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 7.75 (s, 1H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[CH2:5][NH:6][C:7]([C:9]1[C:14]([O:15]CC2C=CC=CC=2)=[C:13]([CH3:23])[N:12]=[C:11]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][C:40]([CH2:43][OH:44])=[CH:39][CH:38]=4)=[C:33]([Cl:45])[CH:32]=3)[CH2:27][CH2:26]2)[N:10]=1)=[O:8])[CH3:2].[F:47][C:48]([F:53])([F:52])[C:49](O)=[O:50].C(=O)([O-])O.[Na+]>ClCCl>[Cl:45][C:33]1[CH:32]=[C:31]([N:28]2[CH2:29][CH2:30][CH:25]([CH2:24][C:11]3[N:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:46])=[O:8])[C:14]([OH:15])=[C:13]([CH3:23])[N:12]=3)[CH2:26][CH2:27]2)[CH:36]=[CH:35][C:34]=1[C:37]1[CH:42]=[CH:41][C:40]([CH2:43][O:44][C:49](=[O:50])[C:48]([F:53])([F:52])[F:47])=[CH:39][CH:38]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(-c4ccc(CO)cc4)c(Cl)c3)CC2)nc(C)c1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(-c4ccc(COC(=O)C(F)(F)F)cc4)c(Cl)c3)CC2)nc(C)c1O
Temperature: 25 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
Ethyl({[5-(benzyloxy)-2-({1-[2-chloro-4′-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.96 g, 1.5 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (20 mL) was added under a nitrogen atmosphere, followed by stirring at room temperature for 7 hours. An aqueous sodium hydrogencarbonate solution was added to the reaction solution for neutralization, followed by extraction with dichloromethane, and subsequently the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: dichloromethane/ethyl acetate), and a fraction corresponding to the Rf value=0.80 (dichloromethane/ethyl acetate=4/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.74 g, 1.3 mmol) as a yellow oil (yield 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:5]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12](Cl)[CH:11]=2)=[O:9])[CH:7]=1.[CH3:22][O-:23].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:5]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:23][CH3:22])[CH:11]=2)=[O:9])[CH:7]=1
Reactant: CS(=O)(=O)Nc1cc(Br)cc(C(=O)c2ccnc(Cl)c2)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)c2cc(Br)cc(NS(C)(=O)=O)c2)ccn1
Temperature: 80 °C
Yield: 43.3 %

Procedure:
To a mixture of 0.080 g (0.21 mmol) of N-[3-bromo-5-(2-chloro-pyridine-4-carbonyl)-phenyl]-methanesulfonamide in 10.0 mL of anhydrous methanol in a pressure tube was added 0.007 g (0.21 mmol) of sodium methoxide. The tube was sealed and the reaction was heated at 80° C. for 18 hours. The methanol was removed under vacuum and water was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate, washed with water and brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to give 0.035 g of N-[3-bromo-5-(2-methoxy-pyridine-4-carbonyl)-phenyl]-methanesulfonamide. The Suzuki reaction and removal of the triisopropylsilyl protecting group were carried out as described in Example 35. 1H NMR (400 MHz, CD3COCD3): δ 10.49 (s, 1H), 8.96 (s, 1H), 8.38 (d, J=5.1 Hz, 1H), 8.07 (t, J=1.9 Hz, 1H), 7.90 (t, J=1.6 Hz, 1H), 7.83 (t, J=1.9 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.45 (t, J=2.8 Hz, 1H), 7.30 (dd, J=5.1, 1.3 Hz, 1H), 7.26-7.18 (m, 2H), 7.10 (s, 1H), 6.75-6.72 (m, 1H), 3.96 (s, 3H), 3.15 (s, 3H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9](S(C)(=O)=O)[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:6]=1)(=O)=O.[H-].[Na+].[OH:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>>[N:36]1[CH:37]=[CH:38][C:33]([O:32][C:5]2[N:10]=[C:9]([O:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[C:8]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:7]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:6]=2)=[CH:34][CH:35]=1
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Reactant: Oc1ccncc1
Agent: [H-]
Agent: [Na+]
Product: Clc1ccc(-c2c(Oc3ccncc3)nc(Oc3ccncc3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2,4-Bis-(methylsulfonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Reference Example 5 (500 mg, 1.02 mmol) was reacted with 1.1 equivalents each of sodium hydride (60% in oil, 45 mg, 1.12 mmol) and 4-hydroxy-pyridine (106.4 mg, 1.12 mmol) by the general procedure described in Example 16 to afford the title compound: 1H-NMR 400 MHz (CDCl3): δ 6.38 (d, J=8 Hz, 2H), 7.17-7.21 (m, 4H), 7.25-7.31 (m, 4H), 7.42 (d, J=2 Hz, 1H), 8.53 (d, J=8 Hz, 2H), 8.75 (d, J=5 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Difluoronitrobenzene (3.7 g, 23.2 mmol)was dissolved in ethyl acetate (10 mL). Morpholine (2.2 mL, 25 mmol), and N,N-diisopropylethylamine (4 mL, 23 mmol) were added and the mixture stirred overnight at room temperature. At 17 h, additional ethyl acetate (150 mL) was added and the combined mixture was washed with water (50 mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was used without further purification.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:20]([C:21]#[N:22])=[C:19]([N:23]=[CH:24]OCC)[NH:18][N:17]=2)=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>C(O)C>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:20]3[C:21](=[NH:22])[N:32]([C:31]4[CH:33]=[CH:34][CH:35]=[C:29]([Cl:28])[CH:30]=4)[CH:24]=[N:23][C:19]=3[NH:18][N:17]=2)=[CH:13][CH:14]=1)([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CCOC=Nc1[nH]nc(Nc2ccc(NC(=O)OC(C)(C)C)cc2)c1C#N
Reactant: Nc1cccc(Cl)c1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2n[nH]c3ncn(-c4cccc(Cl)c4)c(=N)c23)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 7 g (18.9 mmol) of 3-[4-(N-BOC-amino)-phenylamino]-4-cyano-5-(ethoxy-methyleneamino)-pyrazole, 3.97 ml (37.78 mmol) of 3-chloro-aniline and 150 ml of ethanol is heated under reflux for 9 hours and stirred at room temperature for a further 15 hours. Filtering and washing the filter residue with cold ethanol yield the title compound; m.p. 229-234° C. (decomp.); FAB-MS: (M+H)+ =452.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([C:16]2[C:17]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])=[C:8]([F:30])[CH:7]=1)C.[OH-].[Li+]>O1CCCC1.O>[F:30][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([OH:31])=[O:3])[CH:11]=[CH:10][C:9]=1[CH2:12][NH:13][C:14]([C:16]1[C:17]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:15]
Reactant: CCOC(=O)Cc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1
Temperature: 55 °C
Yield: 51.7 %

Procedure:
[3-Fluoro-4-({[2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-acetic acid ethyl ester (1.45 g) was combined with lithium hydroxide (0.59 g) in a 30 mL solution of tetrahydrofuran:water (2:1). The reaction mixture was heated to 55° C. in an oil bath for 1 h. The reaction mixture was allowed to cool to ambient temperature, and the organic solvent was removed in vacuo. The remaining portion of the reaction mixture was brought to pH=3 with 3N hydrochloric acid. The mixture was extracted with ethyl acetate (5×40 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by recrystallization (ethyl acetate) to yield the pure product (0.700 g).
Reaction SMILES: C[O-].[Na+].[Na].[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[N+:25]=[N-:26]>CO.O>[N:24](/[C:27](=[CH:17]\[C:16]1[CH:19]=[CH:20][C:13]([O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=1)/[C:28]([O:30][CH3:31])=[O:29])=[N+:25]=[N-:26]
Reactant: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: COC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)/C(=C/c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 5 h
Yield: 58.7 %

Procedure:
Under argon, to a sodium methoxide solution (prepared from 2.5 g (108.7 mmol) of sodium and 70 ml of methanol) a mixture of 6.1 g (23.7 mmol) of 4-benzyloxy-3-nitrobenzaldehyde and 11.2 g (97.3 mmol) of methyl azidoacetate in 100 ml of methanol is added at 0° C. The mixture is stirred at 0° C. for 5 h, then diluted with 350 ml of water, the precipitated crystalls were filtered off, washed with water and dried to yield 4.93 g (59%) of the title compound. Mp.: 95-96° C. (water).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](OCC)(=[O:15])[C:12]([CH3:14])=[CH2:13]>COC(C)(C)C>[CH3:13][CH:12]1[CH2:14][N:6]2[C:2](=[N:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=32)[NH:1][C:11]1=[O:15]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: C=C(C)C(=O)OCC
Solvent: COC(C)(C)C
Product: CC1Cn2c(nc3ccccc32)NC1=O
Temperature: 130 °C
Reaction time: 7 h

Procedure:
5.326 g (40 mmol) 2-aminobenzimidazole and 4.56 g (40 mmol) ethyl methacrylate were dissolved in 25 ml Proglyde DMM. The reactionmixture is heated to 130° C. The reaction is allowed to continue for 7 hours at 130° C. The reactionmixture is allowed to cool down to room temperature and is added to 250 ml tert-butyl methyl ether. The precipitated 3,4-dihydro-3-methyl-pyrimidino[1,2-a]benzimidazol-2(1H)-one was isolated by filtration and recrystallized from 1-methoxy-2-propanol. 2.7 g (33%) of 3,4-dihydro-3-methyl-pyrimidino[1,2-a]benzimidazol-2(1H)-one was isolated (m.p. >260° C.).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2].[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[C:10]([O:9][C:7]([N:5]1[CH2:6][C:3]([C:1]#[N:2])([CH3:14])[CH2:4]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C#N)CN(C(=O)OC(C)(C)C)C1
Temperature: -76 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
In a 100 mL 2-neck round-bottomed flask, tert-butyl 3-cyanoazetidine-1-carboxylate (1.5 g, 8.2 mmol) was dissolved in THF (30 mL). The colorless solution was cooled to −76° C. and lithium bis(trimethylsilyl)amide (1.0M solution in THF, 9.0 mL, 9.0 mmol) was added dropwise over 25 min. The yellow solution was stirred at −76° C. for 30 min then iodomethane (0.78 mL, 12.5 mmol) was slowly added. The reaction mixture was stirred at −76° C. for 30 min and then warmed to room temperature over 1 h. The reaction mixture was quenched with 10 mL of saturated NH4Cl and diluted with 10 mL of water then extracted with ˜100 ml EtOAc (2×). The combined organic layers were washed with ˜10 mL water and ˜10 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 40 g silica gel with EtOAc/hexanes, (gradient: 0-30% EtOAc). All fractions containing product were combined and concentrated to afford 1.44 g (89%) of 3-cyano-3-methyl-azetidine-1-carboxylic acid tert-butyl ester as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[O:37]1C2C=CC(C(=O)C)=CC=2[O:39][CH2:38]1.[OH-].[K+]>C(O)C>[O:37]1[C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:18]5[N:22]([CH:23]6[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]6)[C:21]6[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=6[N:19]=5)[CH:14]=4)[N:9]=3)=[CH:7][C:2]=2[O:39][CH2:38]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc5c(c4)OCO5)ccc3c1)n2C1CCCCC1
Yield: 24 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-benzo[1,3]dioxol-5-yl-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (30 mg, 24% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])[CH:5]=[C:4]([Cl:13])[N:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>O1CCCC1>[CH3:14][S:15]([O:11][CH2:10][C@@H:9]([NH:8][C:6]1[CH:5]=[C:4]([Cl:13])[N:3]=[C:2]([Cl:1])[N:7]=1)[CH3:12])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CO)Nc1cc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](COS(C)(=O)=O)Nc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-((2,6-dichloropyrimidin-4-yl)amino)propan-1-ol (2.10 g, 9.46 mmol), MsCl (1.19 g, 10.4 mmol) and triethylamine (2.87 g, 28.4 mmol) in tetrahydro-furan (THF) (60 mL) was added dropwise methanesulfonyl chloride (1.19 g, 10.4 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h, then filtered and concentrated. The crude was used into next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:19][C:18]3[CH:20]=[CH:21][C:15]([Br:14])=[CH:16][CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(Nc3ccc(Br)cc3)c2cn1
Temperature: 200 °C
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido [4,3-d]pyrimidine (261 mg, 1.36 mmole) and 4-bromoaniline (1.00 g, 5.81 mmole) is stirred under N2 at 200° C. for 15 min. The resulting product is chromatographed on silica gel (10-15% EtOH/EtOAc) to give 7-amino-4-(4-bromoanilino)pyrido[4,3-d]pyrimidine (200 mg, 46%) as a pale yellow solid. 1H NMR (DMSO) δ 9.88 (1H, brs). 9.34 (1H, s), 8.40 (1H, s), 7.83 (2H, d, J=8.8 Hz 7.55 (2H, d, J=8.8 Hz), 6.64 (2H, brs), 6.44 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12](CC(O)=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[C:25](OCC)(=[O:27])[CH3:26]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[CH2:26][CH2:25][OH:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1CCO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(t-butoxycarbonylamino)-benzeneacetic acid (2.9 g, 11.4 mmoles) is dissolved in 10 ml of anhydrous THF at 0° C. and added to a suspension of LiAlH4 (0.52 g, 13.6 mmoles) in 30 ml of THF. The reaction mixture is agitated at ambient temperature for 1.5 hours. 50 ml of ethyl acetate then 20 ml of 2N soda are added to the medium. The expected product is extracted from the organic phase, which is then washed with 3 times 15 ml of water. The organic phase is dried and the solvent evaporated off under reduced pressure. Then the reaction product is purified on silica gel in a dichloromethane/methanol mixture (95/5). 1.1 g (40%) is thus obtained in the form of a colourless oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].C(N(CC)CC)C>ClCCl>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: OCCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(CCO)CC2)cc1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 415 μL (3.38 mmol) of 1-piperazineethanol in 20 mL of dichloromethane were added 500 mg (2.26 mmol) of 4-nitrobenzenesulfonyl chloride and 472 μL (3.38 mmol) of triethylamine under ice cooling, and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was diluted with dichloromethane and the organic layer was washed with water, saturated sodium bicarbonate aqueous solution and saturated saline solution and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=30/1) to give 670 mg (94%) of the title compound.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: NCCc1ccccc1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-phenethylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].C([Li])CCC.[CH2:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC.C1COCC1>[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][OH:9])([OH:27])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: OCc1ccccc1I
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCc1ccccc1C1(O)CCN(Cc2ccccc2)C1
Temperature: -4 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of (2-iodophenyl)methanol (5.88 g, 0.0251 mol) in tetrahydrofuran (40 mL, 0.5 mol) at −78 Celsius was added 1.600 M of n-butyllithium in hexane (31.7 mL). The mixture was stirred at −4 Celsius for 1 hour, then cooled to −78 Celsius. A solution of 1-benzylpyrrolidin-3-one (3.67 mL, 0.0228 mop in THF (2 mL) was added to the above mixture, and the resulting mixture was stirred at −78 Celsius for 2 hours. The reaction was quenched with small amount of brine, then extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel column with 70% AcOEt in hexanes to give the desired compound (3.5 g, 54% yield). MS (ESI): 284.1 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][N:29]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[N:30]1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:33]3[N:29]([CH3:28])[N:30]=[CH:31][CH:32]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: Cn1nccc1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1N1CC[C@@H](O)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 2.1 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 9.2) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford a white powder. HPLC (Condition 4) tR=5.25 min, UPLC-MS (Condition 3) tR0.98 min, m/z=464.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.89 (m, 2H) 2.87-3.00 (m, 1H) 3.09-3.29 (m, 3H) 3.59 (s, 3H) 4.19 (br. s, 1H) 4.87 (d, J=3.13 Hz, 1H) 6.39 (s, 1H) 7.27-7.36 (m, 2H) 7.50 (dd, J=1.76, 0.98 Hz, 1H) 7.78-7.88 (m, 2H) 8.00 (d, J=2.35 Hz, 1H) 8.78 (dd, J=2.35, 1.17 Hz, 1H) 10.15 (s, 1H).