Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8](OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:9])[C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:35]=O)=[CH:27][CH:26]=1.[F:37][C:38]([F:50])([F:49])[S:39]([C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40]>>[F:37][C:38]([F:50])([F:49])[C:5]([OH:7])=[O:6].[CH3:5][C@H:2]1[N:1]([CH2:35][C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:25]=[CH:26][CH:27]=2)[C:8](=[O:9])[N:46]([C:45]2[CH:47]=[CH:48][C:42]([S:39]([C:38]([F:49])([F:37])[F:50])(=[O:40])=[O:41])=[CH:43][CH:44]=2)[C:3]1=[O:4]
Reactant: O=Cc1ccnc2ccccc12
Reactant: O=C(N[C@H](CO)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Product: C[C@@H]1C(=O)N(c2ccc(S(=O)(=O)C(F)(F)F)cc2)C(=O)N1Cc1ccnc2ccccc12
Product: O=C(O)C(F)(F)F

Procedure:
The compound is prepared from 0.04 mmol of resin, 0.12 mmol of N-Fmoc-D-Ala(OH), 0.20 mmol of 4-quinolinecarboxaldehyde and 0.10 mmol of 4-(trifluoromethanesulfonyl)aniline, in the same way as in Example 1. After purification by preparative LC-MS, 10 mg of expected product are obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)[CH2:3]1.[C:17]([O:21][C:22]([NH:24][C@H:25]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH2:26][C:27](O)=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[NH:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=[C:8]1[CH:4]1[CH2:5][CH2:6][CH2:7][N:2]([C:27](=[O:28])[CH2:26][C@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Cl)cc1
Reactant: c1ccc2[nH]c(C3CCCNC3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCCC(c2nc3ccccc3[nH]2)C1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a flask containing 2-(piperidin-3-yl)-1H-benzo[d]imidazole hydrochloride (200.0 mg, 0.841 mmol) and (R)-3-(tert-butoxycarbonylamino)-4-(4-chlorophenyl) butanoic acid (282.5 mg, 0.900 mmol) was added dichloromethane (5 mL) and triethylamine (0.23 mL, 1.683 mmol); the reaction mixture was stirred at room temperature until all the components dissolved. To the solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (193.5 mg, 1.010 mmol) followed by N-hydroxybenzotriazole (142.1 mg, 1.052 mmol). The solution was stirred at ambient temperature for 12 hrs and diluted with excess DCM (5 mL). The solution was washed with water (2×8 mL) and brine (lx 5 mL), and then the organic layer was collected, dried with Na2SO4, and concentrated to yield tert-butyl (2R)-4-(3-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(4-chlorophenyl)-4-oxobutan-2-ylcarbamate (3A) as an amorphous solid (415.9 mg, 99.5% yield). ESI-MS: m/z 497.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])=[O:14])[N:10]=[C:9]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[C:4]([Cl:28])[CH:3]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31].C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.O>[Cl:28][C:4]1[CH:3]=[C:2]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:38]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH:12]=[C:11]([C:13]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])=[O:14])[N:10]=[C:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(CO)NC(=O)c1cn(-c2ccc(Br)cc2Cl)c(-c2ccccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(C)(CO)NC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2Cl)c(-c2ccccc2Cl)n1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
To a 100 mL round bottom flask attached with condenser column and magnetic stir bar was added 1-(4-bromo-2-chlorophenyl)-2-(2-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-1H-imidazole-4-carboxamide (956 mg, 1.98 mmol), 3-methylsulfonylphenyl boronic acid (435 mg, 2.18 mmol), PdCl2dppf (150 mg, 10 mol %), K2CO3 (830 mg, 6.00 mmol), 1,2-dimethoxyethane (50 mL) and H2O (13 mL). The reaction solution was allowed to stir at 80° C. for 2.5 hrs. The reaction solution was diluted with EtOAc (150 mL) and filtered through a Celite padded Buchner funnel to remove spent Pd. The filtrate was transferred to a separatory funnel and washed with aq NH4Cl (100 mL) and aq NaCl (100 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 5% EtOAc to 100% EtOAc to afford 885 mg (80% yield) of the title compound. MS (ESI) 556.3, 558.3, 560.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (t, J=1.7 Hz, 1H), 8.06-8.13 (m, 2H), 8.03 (s, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.82 (dd, J1=7.3 Hz, J2=1.5 Hz, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.38-7.48 (m, 3H), 5.18 (br s, 1H), 3.45 (s, 2H), 3.36 (br s, 1H), 3.31 (s, 3H), 1.37 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]3[CH2:14][CH2:13]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[N:3]=1.Cl[C:23]1N=C2C(N=C(I)N2CC)=C(N2CCOC[C@@H]2C)N=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]3[CH2:13][CH2:14]3)[N:8]2[CH2:11][CH3:23])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[N:3]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1CC1)n2C
Reactant: CCn1c(I)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Product: CCn1c(C2CC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21

Procedure:
The compound (f-1) was prepared in an analogous fashion to (S)-4-(2-chloro-8-cyclopropyl-9-methyl-9H-purin-6-yl)-3-methylmorpholine, using (S)-4-(2-chloro-9-ethyl-8-iodo-9H-purin-6-yl)-3-methylmorpholine as the starting material. 1H NMR (CDCl3, 400 MHz) δ ppm 5.31 (broad s, 1H), 5.00 (broad s, 1H), 4.26 (q, J=7.2 Hz, 2H), 3.97 (dd, J=11.3, 3.4 Hz, 1H), 3.74 (m, 2H), 3.58 (td, J=12.2, 2.7, 1H), 3.43 (broad t, 1H), 1.92 (m, 1H), 1.41 (t, J=7.2 Hz, 3H), 1.34 (d, J=6.2 Hz, 3H), 1.12 (m, 2H), 1.06 (m, 2H); LC-MS m/z (method A)=322 [M+H]+, RT=2.81 min.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=1)#[N:18]>>[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: N#Cc1ccc(CO)cc1
Reactant: COC(=O)c1ccnc(-n2nccc2O)c1
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C#N)cc2)c1

Procedure:
The title compound was prepared from methyl 2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6) and (4-cyanophenyl)methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C18H14N4O3, 335; Found, 335.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12]([Cl:18])=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.O.O.O.O.O.O.O.O.O.O.O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[CH:39]1([NH2:42])[CH2:41][CH2:40]1>CC1C=CC=CC=1C.O>[Cl:18][C:12]1[C:11]([NH:10][C:8]([C:7]2[C:2]([NH:42][CH:39]3[CH2:41][CH2:40]3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[C:16]([CH3:17])[CH:15]=[CH:14][N:13]=1
Reactant: NC1CC1
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1ccnc(Cl)c1NC(=O)c1cccnc1NC1CC1
Temperature: 135 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (15 g), trisodium phosphate dodecahydrate (20.21 g), cyclopropylamine (12.12 g) were suspended in o-xylene (45 ml) and heated to 130-140° C. for 6-8 h in S.S. Bomb with occasional shaking. Then the reaction mass was cooled to 70-75° C., diluted with o-xylene (75 ml) and DM water (45 ml) and stirred for 10 min at 70-80° C. The aqueous layer was separated and washed the organic layer with DM water (45 ml) at 70-80° C. The organic layer was concentrated at 60-65° C. under reduced pressure. The concentrated mass was cooled to 5-10° C. and stirred for 30 min. Filtered the solid obtained and washed with chilled o-xylene (15 ml, 5-10° C.). Dried the obtained solid at 55-60° C. under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([CH3:33])[CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][C:26]=2[CH3:33])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccccc2)c1Cl
Reactant: Cc1cc(F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccccc2)c1-c1ccc(F)cc1C
Temperature: 75 °C
Reaction time: 15 h
Yield: 84.5 %

Procedure:
A solution of 1-benzyl-4-chloro-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (4.56 g, 0.0144 mol) in toluene (80 mL) and EtOH (40 mL) was degassed 3 times before Pd(PPh3)4 (0.834 g, 0.722 mmol), 4-fluoro-2-methylphenylboronic acid (2.67 g, 0.0173 mol) and an aqueous solution of Na2CO3 (2N, 14.4 mL, 0.0288 mol) were added. The reaction mixture was stirred at 75° C. for 15 hours, cooled down to RT, filtered and the volatiles evaporated under vacuo. The residue was taken up in EtOAc and washed with aqueous NaOH (1N). The organic phase was dried over Na2SO4, concentrated under vacuo, before a purification on column chromatography (SiO2, EtOAc/Heptane, 1/4) yielded 4.74 g (84%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH3:12].ClC1C=CC(O[CH2:19][C:20]#[N:21])=CC=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[C:7]([CH2:19][C:20]#[N:21])[CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])cc1C
Reactant: N#CCOc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CC#N)c([N+](=O)[O-])cc1C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
To a solution of 1-methoxy-2-methyl-4-nitrobenzene (0.4 g) and (4-chlorophenoxy)acetonitrile (0.4 g) in N,N-dimethylformamide (10 mL) was added potassium tert-butoxide (0.3 g) under ice cooling and this mixture was stirred at the same temperature for 1 hours. This mixture was poured into water and the resulting mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.2 g).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][CH2:14][CH2:15][B:16]3[O:20]C(C)(C)C(C)(C)[O:17]3)[C@:10]([NH:29]C(=O)C(F)(F)F)([C:25]([O:27]C)=[O:26])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.O.[OH-].[Li+].[ClH:41]>C1COCC1.O>[ClH:41].[NH2:29][C:10]1([C:25]([OH:27])=[O:26])[CH:11]([CH2:13][CH2:14][CH2:15][B:16]([OH:20])[OH:17])[CH2:12][N:8]([C:6](=[O:7])[C:5]2[CH:36]=[CH:37][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: COC(=O)[C@]1(NC(=O)C(F)(F)F)CN(C(=O)c2ccc(F)cc2)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC1(C(=O)O)CN(C(=O)c2ccc(F)cc2)CC1CCCB(O)O
Yield: 30 %

Procedure:
A stirred solution of racemic methyl (3R,4S)-1-(4-fluorobenzoyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]-3-[(trifluoroacetyl)amino]pyrrolidine-3-carboxylate (200 mg, 0.377 mmol) in THF (4.2 mL) and water (3.7 mL) was sparged with nitrogen for 5 min. Lithium hydroxide monohydrate (33.2 mg, 0.792 mmol) was added, and the mixture was sparged with nitrogen for 10 min and stirred under nitrogen at room temperature for 4 days, during which additional lithium hydroxide monohydrate (39.6 mg, 0.943 mmol) was added. The mixture was diluted with water (5 mL) and acidified to pH<1 with 3 M aqueous HCl. The resulting solution was washed with ethyl acetate (2×20 mL) and methylene chloride (2×20 mL). The aqueous phase was concentrated under reduced pressure and purified by reverse phase HPLC. Product fractions were pooled, concentrated, re-dissolved in 1M aqueous HCl, concentrated and lyophilized to give racemic (3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]-1-(4-fluorobenzoyl)pyrrolidine-3-carboxylic acid hydrochloride (42 mg, 30%) as a white amorphous solid. MS (ESI+) m/z 321 (M−H2O+H+), 303 (M−2H2O+H+) and MS (ESI−) m/z 319 (M−H2O−H+).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3].[CH:18]1([CH2:24][C:25](=O)[C:26]([OH:28])=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([BH3-])#N.[Na+]>>[C:26]([CH:25]([NH:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3])[CH2:24][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([OH:28])=[O:27]
Reactant: O=C(O)C(=O)CC1CCCCC1
Reactant: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(CC1CCCCC1)C(=O)O)C(=O)N1C2CCCCC2C[C@H]1C(=O)O

Procedure:
Condense 1-[(S)-alanyl]octahydroindole-2(S)-carboxylic acid (prepared as described in Example 1) and 3-cyclohexyl-2-oxopropionic acid with sodium cyanoborohydride as described in Example 5 to obtain the title compound,
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([OH:14])[CH2:11][CH2:12][CH3:13].S([O-])([O-])(=O)=O.[Mg+2]>>[CH2:6]([O:9][CH:8]([O:14][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:1][CH2:2][CH3:3]
Reactant: O=CCc1ccccc1
Reactant: CCCCO
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CCCCOC(Cc1ccccc1)OCCCC
Temperature: 100 °C
Reaction time: 6 h
Yield: 172.1 %

Procedure:
In a 100-ml three-necked flask, 24 g (0.2 mole) of phenylacetaldehyde, 18 g (0.24 mole) of n-butanol, 10 g of anhydrous magnesium sulfate and 0.1 mg of stannous chloride dihydrate were charged. The resulting mixture was stirred at 100° C. under atmospheric pressure for 6 hours in a nitrogen atmosphere. After the removal of magnesium sulfate, the residue was purified by chromatography on a silica gel column to give 43.1 g of phenylacetaldehyde dibutyl acetal [R1 =a benzyl group, R2 =a hydrogen atom and R3 =an n-butyl group] (yield: 86.3%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:11]=[CH:12][C:13]([N+:25]([O-:27])=[O:26])=[C:14]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=1.[H-].[Na+]>CN1CCCC1=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:10]2[CH:11]=[CH:12][C:13]([N+:25]([O-:27])=[O:26])=[C:14]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NCc1cc(Oc2ccc(Cl)nc2)ccc1[N+](=O)[O-]

Procedure:
The reaction and post-treatment were carried out according to Example (1a) using 6-chloropyridin-3-ol (10 g, 77 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (19 g, 66 mmol), sodium hydride (56%, 3.1 g, 77 mmol) and N-methylpyrrolidinone (80 mL) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([N:9]([CH3:19])[C@H:10]([CH3:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[F:20][C:21]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:6]1[N:7]=[C:2]([C:27]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:20])[CH:28]=2)[CH:3]=[C:4]([N:9]([CH3:19])[C@H:10]([CH3:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: C[C@H](Cc1ccccc1)N(C)c1cc(Cl)nc(N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Cc1ccccc1)N(C)c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 80.1 %

Procedure:
To a mixture of 6-chloro-N4-methyl-N4-[(1R)-1-methyl-2-phenylethyl]-2,4-pyrimidinediamine (0.4 g, 1.45 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.46 g, 1.88 mmol) and Na2CO3 (0.38 g, 3.63 mmol) in 1,4-dioxane (6 mL) and water (3 mL) was added Pd(PPh3)4 (16 mg, 0.015 mmol), the reaction mixture was heated at 140° C. under microwave conditions with stirring for 40 minutes. The mixture was filtered and concentrated, and the resulting residue was purified by reverse phase chromatography using CH3CN in water from 45% to 55% (0.5% ammonium hydrogen carbonate in water) to afford the title compound (0.42 g) as a yellow solid. LC-MS (ES) m/z=362 [M+H]+.
Reaction SMILES: [CH3:1][O:2][P:3]([O:7]C)([O:5][CH3:6])=[O:4].[CH3:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>>[CH3:1][O:2][P:3]([O-:7])([O:5][CH3:6])=[O:4].[CH3:9][N+:10]1([CH3:1])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: COP(=O)(OC)OC
Reactant: Cn1ccnc1
Product: COP(=O)([O-])OC
Product: C[N+]1(C)C=CN=C1
Temperature: 140 °C
Reaction time: 3 h
Yield: 197.8 %

Procedure:
Trimethylphosphate (127.6 g, 0.883 mole) was added dropwise over a period of 1 hour to a 300 ml flask containing 72.2 g (99%, 0.87 mole) N-methylimidazole at room temperature. The temperature of the reaction mixture was slowly increased to 140° C. As the reaction mixture approached 140° C., there was an acceleration in the rate at which the temperature increased. The reaction mixture was stirred at the same temperature for an additional 3 hours. The mixture was cooled and moved to a rotary evaporator and dried at 150° C./5 mm Hg for 4 hours. The product (194 g, yield 100%) was pure, judged from NMR and liquid at room temperature. 1H-NMR (CDCl3, 300.13 MHz, δ): 10.40 (s, 1H, —N—CH═N—), 7.43 (s, 2H, —N—CH═CH—N—), 3.91 (s, 6H, N—CH3), 3.46 (d, 6H, —OCH3). 31P-NMR (CDCl3, 81.015 MHz, δ): 3.01 [s, (RO)2—P(═O)—O−].
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([CH2:39][C:40]2[S:41][C:42]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:43]=3[CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([CH2:39][C:40]2[S:41][C:42]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:43]=3[CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cc2cc3cc(C)ccc3s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cc3cc(C)ccc3s2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
A mixture of hydroxylammonium chloride (1.28 g), sodium hydrogen carbonate (2.07 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-2-methyl-1-[(5-methyl-1-benzothien-2-yl)methyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.63 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.25 g, 35%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].[CH2:25]([N:27]1[CH:31]=[CH:30][C:29](I)=[N:28]1)[CH3:26]>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:29]3[CH:30]=[CH:31][N:27]([CH2:25][CH3:26])[N:28]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Reactant: CCn1ccc(I)n1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3ccn(CC)n3)c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 1-ethyl-3-iodo-1H-pyrazole.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH:20]([CH3:22])[CH3:21])[NH:16][S:15]2(=[O:24])=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>C1COCC1>[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH:20]([CH3:21])[CH3:22])[N:16]([CH3:1])[S:15]2(=[O:23])=[O:24])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)C1NS(=O)(=O)N(Cc2ccccc2)C1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)C1C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of potassium t-butoxide (3.53 g, 29 mmol) in THF was added a solution of 2-phenylmethyl-4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (7.7 g, 29 mmol) in THF at 0° C. and the mixture was stirred at this temperature for 1 hour. To the mixture was added methyl iodide (20.38 g, 0.143 mol) and the resulting mixture was allowed to stir at room temperature for 2.5 hours. The resulting mixture was quenched with brine, extracted with ether, and the organic layer was washed with brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 7.1 g (88%) of 2-phenylmethyl-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula XI: R1 =H; R2 =isopropyl; R3 =CH3) as a solid.