Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11](O)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:31]([NH2:39])[C:32]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:33].C(Cl)(Cl)Cl.CO>C(#N)C>[NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:15])[C@H:2]([C:11]([NH:39][CH2:31][C:32]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:33])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: NCC(=O)NCC(=O)O
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: CC#N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
FMOC-Tyr-gly-gly was coupled to ADR as in Section 7.1.1. for gly-ADR. Yield of FMOC-tyr-gly-gly-ADR was 95%; melting point 150°-153° C.; Rf: 0.63 [chloroform/methanol 8:2 (silica); Rf: 0.68 [acetonitrile/0.1% aqueous TFA 1:1 (reverse phase)]. Elemental analysis for C55H54N4O17H2O; calculated: C,62.25; H, 5.32; N, 5.30; observed: C, 62.17; H, 5.92; N, 5.09. The protecting FMOC moiety removed from the product as described in Section 7.1.1. for gly-ADR. Yield of the product tyr-gly-gly-ADR.HOAc was 68 mg (80%); melting point, 165.C (dec.); Rf: 0.10 [chloroform/methanol 8:2 (silica)]; Rf: 0.53 [acetonitrile 0.1% aqueous TFA 1:1 (reverse phase)]. Elemental analysis for C42H48N4O17.2H2O; calculated: C, 55.01; H, 5.72; observed: C, 55.15; H, 5.54.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH2:11]([NH:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1)=[S:17])[CH:12]([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([NH:18][C:16]([NH:15][CH2:11][CH:12]([CH3:14])[CH3:13])=[S:17])[CH:20]=2)=[CH:4][CH:3]=1
Reactant: CC(C)CNC(=S)Nc1cccc(N)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)CNC(=S)Nc1cccc(NC(=O)Nc2ccc(Cl)cc2)c1

Procedure:
A solution of freshly distilled p-chlorophenyl isocyanate (1.38 g.) in 10 ml. chloroform is added at room temperature in one portion to a solution of 1-isobutyl-3-(m-aminophenyl)thiourea (2.0 g.) in chloroform (30 ml.). The product precipitates rapidly and is filtered off after several hours. The filter cake is washed with chloroform and dried to give 1-(3-p-chlorophenylureido)-3-(3-isobutylthioureido)-benzene, m.p. 195°-196° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][C@@H:9]1[C:18](OC)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:10][C@@H:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.4 %

Procedure:
To a solution of (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine (3.96 g: 12.2 mmole) in a mixture of tetrahydrofuran (12 ml) and ethanol (18 ml), sodium borohydride (1.85 g: 48.8 mmole) is added in a nitrogen atmosphere under ice cooling. The mixture is stirred for 45 minutes at room temperature to give (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (2.97 g). Yield: 83%. Colorless crystals. mp. 95° to 96° C. NMR δ(CDCl3) ppm: 1.49(s, 9H), 1.7 to 2.1(m, 1H), 2.3 to 2.5(m, 1H), 3.06(s, 3H), 3.4 to 3.7(m, 2H), 3.7 to 4.0(m, 2H), 4.0 to 4.3(m, 1H), 5.2(m, 1H). IR ν (KBr) cm-1 : 3400, 3420, 1648.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]=[N:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([F:16])[CH:3]=1.C([N-]C(C)C)(C)C.CN([CH:27]=[O:28])C.O>C1COCC1>[Br:1][C:2]1[C:3]([CH:27]=[O:28])=[C:4]([F:16])[C:5]([N:9]=[N:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(Br)cc(F)c1N=NN1CCCC1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1c(Br)cc(F)c(N=NN2CCCC2)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
In a 200 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, (4-bromo-2,6-difluoro-phenyl)-pyrrolidin-1-yl-diazene a8 (6.06 g, 0.021 mol.) in THF (50 ml) is added to a solution of diisopropylamide (2 M in THF, 12.5 ml) cooled at −78° C. After 2 h at this temperature, dry DMF (3.2 ml) is added to the green solution. After 1 h, it is poured into water (200 ml), extracted with ether (3×200 ml) and the organic phase is dried over MgSO4, filtered and concentrated in vacuo to give the crude aldehyde a9 (6.62 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=2)=[N:14]1>>[NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=3)=[N:14]2)=[O:9])[N:6]=1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Nc1nc(C(=O)O)co1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(N)n1
Yield: 35.7 %

Procedure:
(S)-2-amino-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-amino-1,3-oxazole-4-carboxylic acid (0.037 g, 0.288 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.05 g, 0.192 mmol). Yield 35.7%. 1H-NMR (400 MHz; MeOD): δ 1.23 (d, 3H), 4.30 (dd, 1H), 4.37 (dd, 1H), 4.46-4.54 (m, 1H), 6.77 (d, 1H), 7.65 (s, 1H), 7.69 (d, 1H), 7.79 (dd, 1H), 7.91 (dd, 1H), 8.05 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][CH2:8][C@@H:7]1[C:12]([OH:14])=O.[NH2:18][CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:20]([OH:24])[C:21]([NH2:23])=[O:22].O[NH-].O=[N-]>>[NH2:23][C:21](=[O:22])[C:20](=[O:24])[CH:19]([NH:18][C:12]([C@H:7]1[CH2:8][CH2:9][C:10](=[O:11])[N:6]1[CH2:5][C:4]1[CH:15]=[CH:16][CH:17]=[C:2]([Cl:1])[CH:3]=1)=[O:14])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1cccc(Cl)c1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1cccc(Cl)c1

Procedure:
Coupling of (R)-1-(3-chloro-benzyl)-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN([CH:9]=[O:10])C.[CH3:11][C:12]1[CH:16]=[C:15](O)[N:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:13]=1>>[Cl:3][C:15]1[N:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:13]=[C:12]([CH3:11])[C:16]=1[CH:9]=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: Cc1cc(O)n(-c2ccccn2)n1
Product: Cc1nn(-c2ccccn2)c(Cl)c1C=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
In a 1.0-liter egg plant-type flask, POCl3 (56 mL, 0.60 mL) was dropwise added to a DMF (17.4 mL, 0.23 mol) solution of 3-methyl-1-pyridin-2-yl-1H-pyrazol-5-ol with cooling with ice, and stirred overnight at 80° C. The reaction solution was poured onto crushed ice, and stirred at room temperature. The formed precipitate was filtered, and dried under reduced pressure to obtain the title compound as a pale brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]([CH3:13])[C:8]([O:10]CC)=[O:9])[NH:4][N:3]=1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[CH:6]=[C:5]([CH:7]([CH3:13])[C:8]([OH:10])=[O:9])[NH:4][N:3]=1
Reactant: CCOC(=O)C(C)c1cc(C)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(C)C(=O)O)[nH]n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.3 %

Procedure:
To a solution of 1.24 g (6.8 mmol) of ethyl 2-(3-methyl-1H-pyrazol-5-yl)propanoate from step B in 20 mL of methanol and 5 mL of water was added 1.5 mL (7.5 mmol) of an aq. 5.0 M sodium hydroxide solution. The resulting mixture was stirred at ambient temperature for 2.5 h and then evaporated in vacuo to remove the methanol. The aqueous phase was extracted with ethyl acetate (2×75 mL) then acidified with a 2 N hydrochloric acid solution until a pH of 4 was achieved. The aqueous solution was extracted with ethyl acetate (5×50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated to yield the title compound as a yellow gum (0.80 g, 76%). 1H NMR (CDCl3, 500 MHz) δ 10.23 (br s, 1H), 7.26 (s, 1H), 5.97 (s, 1H), 3.87 (q, J=7.3 Hz, 1H), 2.26 (s, 3H), 1.59 (d, J=7.3 Hz, 3H). LC-MS: m/z (ES) 155 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[NH:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH3:8])[N:28]=2)=[CH:19]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Cc1ccccc1N
Product: Cc1ccccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 33.2 %

Procedure:
Using the procedure of example 1, o-toluidine (87 mg) was reacted with compound 1f (100 mg) to provide compound 8 (27 mg, 33%). 1H NMR (400 MHz, CD3OD) δ 8.55 (d, J=8.0 Hz, 1H), 8.24 (d, J=5.2 Hz, 1H), 8.12 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.29 (q, J=7.6 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.11 (d, J=5.6 Hz, 1H), 7.11 (dd, J=7.6 Hz, 4.8 Hz, 1H), 2.35 (s, 3H). MS (ESI) m/z: 302 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[C:17]([C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])[CH:18]=[CH:19][CH:20]=1)([O-])=O.C1CCC=CC=1>CCO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[C:17]([C:21]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(c1cccc(CNCCNc2ccccc2[N+](=O)[O-])c1)N1CCCCC1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCC=C1
Product: Nc1ccccc1NCCNCc1cccc(C(=O)N2CCCCC2)c1
Temperature: 100 °C
Yield: 60.3 %

Procedure:
To a solution of (3-{[2-(2-nitro-phenylamino)-ethylamino]-methyl}-phenyl)piperidin-1-yl-methanone (Example 11; 0.060 g, 0.16 mmol) in EtOH (1.6 mL) was added cyclohexadiene (0.55 mL) followed by Pd/C (10 wt %, 0.02 g), and the resulting suspension was heated to 100° C. for 45 min. The suspension was filtered (diatomaceous earth), and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (0-5% CH3OH/CH2Cl2) to provide the desired product as a colorless oil (0.034 g, 61%). MS (ESI): mass calculated for C21H28N4O, 352.23; m/z found, 353.2 [M+H]+, 375.2 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.38-7.32 (m, 3H), 7.26-7.24 (m, 1H), 6.80 (d t, J=5.4, 1.9 Hz, 1H), 6.72-6.64 (m, 3H), 3.84 (br s, 2H), 3.70 (br s, 2H), 3.32 (br s, 2H), 3.21 (t, J=5.7 Hz, 2H), 2.94 (t, J=5.7 Hz, 2H), 1.67 (br s, 4H), 1.50 (br s, 1H). 13C NMR (100 MHz, CDCl3): 170.3, 140.7, 137.7, 136.7, 134.6, 129.1, 128.4, 126.5, 125.3, 120.5, 118.7, 116.3, 112.0, 53.3, 48.1, 43.8, 29.7, 26.5, 24.6.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22](=S)[S:23]C)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>C(O)C>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22](=[S:23])[NH:27][NH2:28])=[CH:18][CH:19]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NN
Reactant: CSC(=S)NCc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CNC(=S)NN)cc1

Procedure:
A mixture of 1.53 g (4.1 mmole) of methyl N-[[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl]dithiocarbamate, 796 μl (820 mg, 16.4 mmole) of hydrazine hydrate, and 10 ml of absolute ethanol was stirred at reflux under N2. After 2 hours the resulting solution was cooled and concentrated. The residual oil was chromatographed on a column of silica gel (elution with 99:1 and the 98:2 CH2Cl2) to give (after concentration and vacuum-drying) 1.15 g (79%) of a stiff, white foam, mp>45° C. (gradual); homogeneous by TLC in 19:1 CH2Cl2 -MeOH; mass spectrum (FAB) m/e 358 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(Cl)Cl>C1COCC1>[Cl:1][C:2]1[C:3]([F:21])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(Cl)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1c(Cl)cnc2[nH]ccc12
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
5-Chloro-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.0 g, 9.2 mmol) in THF (15 mL) at 0° C. was treated dropwise with TBAF (10.1 mL, 10.1 mmol). After 30 minutes, the reaction was quenched with saturated aqueous NaHCO3 and extracted into CH2Cl2. The combined organic fractions were dried (MgSO4), filtered, and concentrated in vacuo. The crude was purified by flash chromatography on silica gel using 1.2% MeOH:CH2Cl2 to provide 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridine (1.4 g, 89% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8](=[O:22])(=[O:21])[N:9]=[C:10]([N:14]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH:16]=[N:15]2)[NH:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[NH:23]C(=O)C(F)(F)F.C(=O)([O-])[O-].[K+].[K+].O>CO>[NH2:23][C:3]1[CH:4]=[CH:5][C:6]([S:8]([N:9]=[C:10]([N:14]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH:16]=[N:15]2)[NH:11][CH2:12][CH3:13])(=[O:22])=[O:21])=[CH:7][C:2]=1[Br:1]
Reactant: CCNC(=NS(=O)(=O)c1ccc(NC(=O)C(F)(F)F)c(Br)c1)N1CC(C)(C)C=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCNC(=NS(=O)(=O)c1ccc(N)c(Br)c1)N1CC(C)(C)C=N1
Yield: 1 %

Procedure:
7.0 g (1 mol equiv.) N-(2-Bromo-4-{[(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-sulfamoyl}-phenyl)-2,2,2-trifluoro-acetamide was dissolved in 225 mL methanol; 10.3 g (5 mol equiv.) potassium carbonate and 30 mL water were added and the reaction mixture was refluxed for 2.5 hours. Volatiles were evaporated under reduced pressure, and the residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and concentrated on silica gel. Purification by flash chromatography on silica gel (Et2O) afforded 4.1 g (73%) 4-amino-3-bromo-N-[(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 1.17 (t, J=7.3 Hz, 3H), 1.21 (s, 6H), 3.43-3.52 (m, 2H), 3.74 (br.s., 2H), 4.45 (br.s., 2H), 6.73 (s, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.83-6.92 (br.s., 1H), 7.65 (dd, J=8.4, 2.0 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]([NH:29][C:30]2[C:35]([CH:36]([CH3:38])[CH3:37])=CC=[C:32](O)[C:31]=2[CH:40]([CH3:42])[CH3:41])=[O:28])[CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][N:20]1[CH2:21][CH2:22][N:23]([CH2:26][C:27]([NH:29][C:30]2[C:31]([CH:40]([CH3:41])[CH3:42])=[CH:32][CH:6]=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:35]=2[CH:36]([CH3:38])[CH3:37])=[O:28])[CH2:24][CH2:25]1
Reactant: CC(C)c1ccc(O)c(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(C)C)c(NC(=O)CN2CCN(CCSc3nc4ccccc4o3)CC2)c1C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
Acetic anhydride (2 ml) was added to a solution of 2-[4-[2-(benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-(2,6-d iisopropyl-3-hydroxyphenyl)acetamide (176 mg, 0.354 mmol) in pyridine (1 ml) and the mixture was stirred at room temperature for 90 minutes. The reaction solution was neutralized with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (20 g of silica gel; developing solvent, chloroform:methanol=30:1→20:1) and the resulting crude crystals were recrystallized from acetone-hexane to provide 140 mg (yield 73%) of the desired compound as colorless needles.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:8](O)(=[O:16])[CH:9]([CH:11]([C:13](O)=[O:14])[OH:12])[OH:10]>C1(C)C=CC=CC=1>[CH2:1]([N:7]1[C:13](=[O:14])[CH:11]([OH:12])[CH:9]([OH:10])[C:8]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN
Reactant: O=C(O)C(O)C(O)C(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCN1C(=O)C(O)C(O)C1=O
Temperature: 100 °C

Procedure:
N-hexyl DL-tartarimide was prepared by the reaction of n-hexyl amine with DL-tartaric acid. DL-Tartaric acid (10.026 g, 66.80 mmole) and toluene (17.327 g) were weighed into a 250 mL 3-necked round-bottomed flask equipped with a teflon-coated magnetic stir bar. A Claisen adapter was placed in the center neck, a Dean-Stark trap was placed on top of the Claisen adapter, and a condenser was placed in the neck of the Dean-Stark trap. A nitrogen inlet adapter was placed on the condenser. In the left neck was placed a pressure-equalizing addition funnel containing n-hexyl amine (6.760 g, 66.80 mmole) and toluene (7.936 g, added to ensure complete transfer of the amine). In the right neck was placed a rubber septum which held a thermocouple. The apparatus was purged with nitrogen for 10-15 minutes and then heated to ˜100° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1ccncc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccncc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-pyridine-4-carbaldehyde (0.500 g, 2.68 mmol) in MeOH (5 mL) at 0° C. is added sodium borohydride (0.122 g, 3.22 mmol). The mixture is stirred at room temperature for 1 h followed by removal of the solvent in vacuo. The residue is redissolved in DCM and washed with water twice. The organic layer is dried over sodium sulfate and concentrated in vacuo to afford (3-bromo-pyridin-4-yl)-methanol as a yellow oil. MS (ESI) m/z 189.9 (M+H)+
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[C:9]([C:17](O)=[O:18])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>>[C:4]([C:3]1[C:2]([C:7]#[N:8])=[N:1][C:17]([OH:18])=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1)#[N:5]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: N#C/C(N)=C(/N)C#N
Agent: Cl
Product: N#Cc1nc(O)c(-c2ccccc2)nc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Diaminomaleonitrile (5.40 g; 0.05 mole) and 7.50 g (0.05 mole) of benzoylformic acid were put into 50 ml of a 2 N aqueous solution of hydrochloric acid. The mixture was stirred at 20° to 30° C. for 30 minutes, and further stirred at 70° to 80° C. for 2 hours. The mixture was then cooled to room temperature. The precipitate formed was collected by filtration, washed thrice with 40 ml of water, and dried under reduced pressure to afford 10.0 g (yield 90%) of 2,3-dicyano-5-hydroxy-6-phenylpyrazine.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C([O-])([O-])=O.[Na+].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:34]3[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=3[NH:32][C:31](=O)[C@H:30]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[N:29]=2)=[CH:24][CH:23]=1>ClCCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:34]3[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=3[NH:32][C:31](=[S:2])[C@H:30]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[N:29]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2NC1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2NC1=S
Temperature: 70 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A suspension of P4S10 (36.1 g, 81.1 mmol) and Na2CO3 (8.6 g, 81.1 mmol) in 1,2-DCE (700 mL) at room temperature was stirred for 2 h before Methyl [(3S)-5-(4-chlorophenyl)-7-(methyloxy)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]acetate (for a preparation see Reference compound D) (16.8 g, 45.1 mmol) was added. The resulting mixture was stirred at 70° C. for 2 h before being cooled and filtered. The solid was washed twice with DCM and the filtrate washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash-chromatography on silica gel (DCM/MeOH: 99/1) to afford the title compound (17.2 g, 98% yield) as a yellowish solid. LC/MS (Method D): m/z 389 [M(35Cl)+H]+, Rt 2.64 min
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:9][C:10]1[S:11][CH:12]=[C:13]([CH3:20])[C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:15]1[C:14]2[C:13]([CH3:20])=[CH:12][S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[N:2]=1
Reactant: CCOC(=O)c1c(C)csc1N
Reactant: N#Cc1cccnc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1csc2nc(-c3cccnc3)nc(Cl)c12

Procedure:
With the procedure of Example 477, the reaction of 3-cyanopyridine and 2-amino-4-methyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])(O)[CH2:4][CH2:3]1.[CH3:26][CH2:27]N(C(C)C)C(C)C.[OH:35][CH2:36][C@H:37]1[CH2:41][CH2:40][N:39](CC)[CH2:38]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][CH:37]([CH2:36][OH:35])[C@@H:38]4[CH2:26][CH3:27])=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:4][CH2:3]1
Reactant: CCN1CC[C@H](CO)C1
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CCN(C(C)C)C(C)C
Product: CC[C@H]1C(CO)CCN1c1ccc2c(C(=O)NCC3CCC(F)(F)CC3)c(Cl)ccc2n1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and (S)-3-hydroxymethyl-ethyl-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 4.72 (1H), 3.66 (m, 2H), 3.49 (m, 2H), 3.32 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.30 (m, 2H). m/z: 466 [M+H]
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][CH3:12])[N:3]=1.C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.[B:41](OC(C)C)([O:46]C(C)C)[O:42]C(C)C.FC1N=C(OCCOC)C(B(O)O)=CC=1>C1COCC1>[F:1][C:2]1[C:7]([B:41]([OH:46])[OH:42])=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][CH3:12])[N:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCCOc1cccc(F)n1
Agent: CC(C)[N-]C(C)C
Agent: COCCOc1nc(F)ccc1B(O)O
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: COCCOc1ccc(B(O)O)c(F)n1
Temperature: -60 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
2-Fluoro-6-(2-methoxyethoxy)pyridine (1.13 g, 6.60 mmol) in THF (5 mL) was cooled to −60° C. and treated with lithium diisopropylamide, 2.0 M solution in heptane/tetrahydrofuran/ethylbenzene (4.95 mL, 9.90 mmol) (Aldrich) and stirred at −60° C. for 1 h. The mixture was then treated with triisopropyl borate (2.277 mL, 9.90 mmol) (Aldrich) and allowed to warm to RT over 30 min. It was then quenched by the addition of a saturated solution of ammonium chloride and stirred for 30 min. The reaction mixture was extracted with EtOAc (3×25 mL), dried over MgSO4, filtered and concentrated. Purification on the ISCO (12 g column, 5-100% EtOAc) gave a mixture of 2-fluoro-6-(2-methoxyethoxy)pyridin-3-ylboronic acid (226 mg, 1.051 mmol, 15.92% yield) and 6-fluoro-2-(2-methoxyethoxy)pyridin-3-ylboronic acid as a semi-crystalline solid. m/z (ESI, +ve ion) 216.1 (M+H)+.