Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:18][C@H:19]([C:29]([NH:31][C@H:32]([C:41]([NH:43][C@H:44]([C:54]([NH:56][C@H:57]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:58][O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:55])[CH2:45][CH2:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:42])[CH2:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:30])[CH2:20][CH2:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:17])[CH3:15])=[O:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]>C(O)C>[NH2:1][C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:18][C@H:19]([C:29]([NH:31][C@H:32]([C:41]([NH:43][C@H:44]([C:54]([NH:56][C@H:57]([C:64]([O:66][C:67]([CH3:68])([CH3:70])[CH3:69])=[O:65])[CH2:58][O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:55])[CH2:45][CH2:46][C:47](=[O:53])[O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:42])[CH2:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:30])[CH2:20][CH2:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:17])[CH3:15])=[O:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: C[C@H](NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCO
Product: C[C@H](NC(=O)CNC(=O)[C@@H](N)CC(N)=O)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
6.47 g. (5.7 mmoles) of Z-25-31-OtBu are dissolved in a mixture of 220 ml. of ethanol and 20 ml. of DMF, and gaseous hydrogen is bubbled into the mixture for 1 hour in the presence of 1 g. of palladium-on-carbon. The catalyst is removed by filtration, the filtrate is evaporated to dryness, and the gelly residue is triturated with ether. The solid is filtered off and washed. 4.9 g. (86.2 %) of H-25-31 -OtBu are obtained. M.p.: 174°-176° C (under decomposition, Rf3 = 0.2.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@@H:2]4[NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4N)no2)cc1C#N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4NS(C)(=O)=O)no2)cc1C#N
Reaction time: 1 h
Yield: 44.7 %

Procedure:
Prepared using General Procedure 8A: To a stirred solution of (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 50 (18 mg, 0.05 mmol) in DCM (1 mL) was added TEA (13.9 μL, 0.1 mmol) and methanesulfonyl chloride (19 mg, 0.1 mmol). After 1 h, additional TEA (13.9 μL, 0.1 mmol) and methanesulfonyl chloride (19 mg, 0.1 mmol) were added. After an additional 1 h of stirring the solvent was evaporated and purified by preparative HPLC to afford 9.8 mg (45%) of (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl) methane sulfonamide 69. LCMS-ESI (m/z) calculated for C22H22N4O4S: 438.1. found 439.1 [M+H]+, tR=3.70 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.2 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 8.12 (d, J=7.7 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 5.07 (dd, J=16.5, 7.8 Hz, 1H), 4.78 (hept, J=6.1 Hz, 1H), 4.48 (d, J=9.3 Hz, 1H), 3.51 (ddd, J=17.5, 8.8, 3.4 Hz, 1H), 3.29-3.12 (m, 1H), 3.09 (s, 3H), 2.74 (dtd, J=12.9, 8.0, 3.5 Hz, 1H), 2.07-1.92 (m, 1H), 1.46 (d, J=6.1 Hz, 6H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][N:11](C)C=O.[Cu](C#N)C#N>>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:10]#[N:11])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)cnc1Br
Agent: N#C[Cu]C#N
Product: Cc1cc(Br)cnc1C#N
Temperature: 120 °C
Reaction time: 12 h
Yield: 49.4 %

Procedure:
To a solution of 2,5-dibromo-3-methylpyridine (5.0 g, 20. mmol) in N,N-dimethylformamide (20.0 mL, 259 mmol) was added copper cyanide (1.8 g, 20. mmol) and the reaction was stirred at 120° C. for 12 h. The reaction was partitioned between EtOAc and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated and purified by combi-flash chromatography to afford 1.94 g (49% yield) of the desired product as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].CCOC(C)=O>C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Oc1ccccc1F
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Fc1ccccc1Oc1cncc(Cl)n1
Yield: 80 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (250 mg, 1.69 mmol) and 2-fluorophenol (166 μL, 1.86 mmol, d=1.26 g/mL), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (302 mg). Yield: 80%. 1H NMR (250 MHz, DMSO-d8) δ 7.31-7.45 (m, 4H, Harom), 8.56 (s, 1H, HPz 5), 8.67 (s, 1H, HPz 3).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[C:15]2[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]=2[S:9][C:8]=1[C:23](OC)=[O:24]>O1CCCC1>[OH:24][CH2:23][C:8]1[S:9][C:10]2[CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:14][C:15]=2[N:7]=1
Reactant: COC(=O)c1nc2c(s1)CN(C(=O)OC(C)(C)C)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nc(CO)sc2C1
Reaction time: 1 h
Yield: 66 %

Procedure:
To a suspension of lithium aluminium hydride (3.986 mmol) in dry tetrahydrofuran (12 ml) was added 5-tert-butyl 2-methyl 6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-dicarboxylate (3.22 mmol) in tetrahydrofuran (10 ml) at 0° C. and the resulting reaction mixture was stirred at the same temperature for 1 h. It was quenched with saturated aqueous sodium sulfate solution, diluted with ethyl acetate and filtered. The filtrate was evaporated under reduced pressure to give the crude product which was used in the next step without further purification. Yield: 66%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: COc1ccc(B(O)O)cc1
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: [I-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(Cc2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)cc1
Yield: 33.2 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(4-methoxybenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.075 g; 0.216 mmol), 4-methoxyphenylboronic acid (0.034 g; 0.220 mmol), tetrakis(triphenylphosphine)palladium(0) (0.013 g; 0.011 mmol), sodium carbonate (0.045 g; 0.431 mmol), sodium iodide (0.064 g; 0.431 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.030 g (32%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[C:34]([Cl:35])=[CH:33][C:32]([Cl:36])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[C:34]([Cl:35])=[CH:33][C:32]([Cl:36])=[CH:31][N:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: N[C@@H](Cc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(3,5-dichloro-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[CH3:19][C:20]1[O:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][NH:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[N:24]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:33]1[CH:34]=[CH:35][N:31]([C:28]2[CH:29]=[CH:30][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][CH:22]=3)=[CH:26][CH:27]=2)[C:32]1=[O:36])[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: Cc1nc(-c2ccc(-n3cc[nH]c3=O)cc2)co1
Product: Cc1nc(-c2ccc(-n3ccn([C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)c3=O)cc2)co1

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 1-[4-(2-methyl-4-oxazolyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2-methyl-4-oxazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 37).
Reaction SMILES: N1CC[CH2:3][CH2:2]1.C1(=O)CCCC1.[C-]#N.[K+].[CH3:15][C:16]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:19])[C:17]#[N:18]>O>[N:20]1([C:16]2([C:17]#[N:18])[CH2:19][CH2:3][CH2:2][CH2:15]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNC1
Reactant: CC(C)(C#N)N1CCCC1
Agent: [C-]#N
Agent: [K+]
Solvent: O=C1CCCC1
Solvent: O
Product: N#CC1(N2CCCC2)CCCC1
Yield: 76 %

Procedure:
The title compound (2.50 g, 76%) was prepared from pyrrolidine (1.42 g, 20 mmol), cyclopentanone (1.68 g, 20 mmol) and potassium cyanide (1.30 g, 20 mmol) in water (10 ml) in a similar manner to that described in D4. 1H NMR (CDCl3) δ: 1.80-1.90 (10H, m), 2.15 (2H, m), 2.71 (4H, m).
Reaction SMILES: [CH2:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)(=O)C(Cl)=O.O[C:25]1[CH:60]=[CH:59][C:28]([CH2:29][N:30]([CH2:51][C:52]([O:54]C(C)(C)C)=[O:53])[C:31](=[O:50])[C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:49])[CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)=[CH:34][CH:33]=2)=[CH:27][CH:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][C:39]([NH:38][C:35]2[CH:34]=[CH:33][C:32]([C:31]([N:30]([CH2:51][C:52]([OH:54])=[O:53])[CH2:29][C:28]3[CH:27]=[CH:26][C:25]([O:14][C:13](=[O:15])[C:12]4[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:17][CH:16]=4)=[CH:60][CH:59]=3)=[O:50])=[CH:37][CH:36]=2)=[O:49])=[CH:46][CH:45]=1
Reactant: CCCCCCCCc1ccc(C(=O)O)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc(C(=O)Oc2ccc(CN(CC(=O)O)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
Prepared using General Procedures 2 and 8: To a stirring solution of 4-octylbenzoic acid (42 mg, 0.178 mmol) in DCM (0.5 mL) were added DMF (1 drop) and oxalyl chloride (0.016 mL, 0.190 mmol). The reaction mixture was stirred at room temperature for 2 h. To this mixture was added a solution of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-7 (60 mg, 0.119 mmol) and TEA (0.050 mL, 0.357 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 18 h then TFA (1 mL) was added. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to provide to afford 15.3 mg (19%) of 2-(4-(2-(4-methoxyphenyl)acetamido)-N-(4-((4-octylbenzoyl)oxy)benzyl)benzamido)acetic acid 40. LCMS-ESI (m/z) calculated for C40H44N2O7: 664; found 665 [M+H]+, tR=10.33 min (Method 4). 1H NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 8.04 (d, J=8.2 Hz, 2H), 7.65 (d, J=8.5 Hz, 2H), 7.50-7.21 (m, 10H), 6.89 (d, J=8.4 Hz, 2H), 4.63 (d, J=36.7 Hz, 2H), 3.95 (d, J=33.1 Hz, 2H), 3.73 (s, 3H), 3.58 (s, 2H), 2.76-2.64 (m, 2H), 1.61 (s, 2H), 1.36-1.10 (m, 10H), 0.86 (t, J=6.8 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:11][C:12]1[CH:17]=[C:16]([I:18])[CH:15]=[CH:14][C:13]=1[F:19])C(OCC)=O)C.O.[OH-].[Na+]>CCO>[C:24]([O:23][C:21]([NH:20][CH:5]([CH2:11][C:12]1[CH:17]=[C:16]([I:18])[CH:15]=[CH:14][C:13]=1[F:19])[C:4]([OH:28])=[O:3])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)C(Cc1cc(I)ccc1F)(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(Cc1cc(I)ccc1F)C(=O)O
Temperature: 40 °C

Procedure:
A suspension of 2-tert-butoxycarbonylamino-2-(2-fluoro-5-iodo-benzyl)-malonic acid diethyl ester G-22 in EtOH (113 mL) was heated to 40° C. and water (50 mL) was then added giving an easily stirrable emulsion. 1M aq. NaOH (93 mL) was carefully added and reaction mixture was heated to 100° C. for 16 h. The reaction mixture was cooled to RT and the volatiles were removed in vacuo. The remaining aqueous phase was extracted once with TBME and this extract was discarded. The aqueous layer was acidified with 25% aq. HCl and extracted with TBME (2×). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated in vacuo to give the crude product that was purified by flash chromatography (eluting with a gradient of 25% to 50% EtOAc in hexane) to give the title compound as a white solid. LC-MS B: tR=0.80 min; [M-Me]+=394.95.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[C:5]([Cl:17])=[CH:4][N:3]=1.[CH2:18]([N:20]1[C:24]([NH2:25])=[CH:23][C:22]([CH3:26])=[N:21]1)[CH3:19].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:7][C:2]([NH:25][C:24]2[N:20]([CH2:18][CH3:19])[N:21]=[C:22]([CH3:26])[CH:23]=2)=[N:3][CH:4]=1
Reactant: N#Cc1ccccc1Nc1cc(Cl)ncc1Cl
Reactant: CCn1nc(C)cc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCn1nc(C)cc1Nc1cc(Nc2ccccc2C#N)c(Cl)cn1
Temperature: 120 °C
Yield: 45.5 %

Procedure:
To a 50 mL tube was added 2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile (738 mg, 2.80 mmol), 1-ethyl-3-methyl-1H-pyrazol-5-amine (350 mg, 2.80 mmol), BINAP (696 mg, 1.118 mmol), cesium carbonate (2733 mg, 8.39 mmol) and palladium(II) acetate (62.8 mg, 0.280 mmol) in 1,4-dioxane (15 mL). The reaction mixture was heated to 120° C. for 18 hr. Solid was filtered off and discarded and the solution was concentrated. Product was then dissolved in 1 M HCl (1 mL) and extracted with EtOAc. The organic layer was discarded. The water layer was neutralized with 1 M NaOH (to pH 8) and extracted with EtoAc. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated. The solid was the dissolved in 20 mL of EtOAc and 20 mL of water and 1 mL of acetic acid were added. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated. 2-({5-Chloro-2-[(1-ethyl-3-methyl-1H-pyrazol-5-yl)amino]-4-pyridinyl}amino)benzonitrile (450 mg, 1.275 mmol, 45.6% yield) was isolated as orange foam. This product was used in the next step without further purification. LCMS (M+H)+=353.1; 1H NMR (400 MHz, DMSO-d6) ppm 1.19 (t, J=7.20 Hz, 3 H) 1.91 (s, 3 H) 3.84 (q, J=7.24 Hz, 2 H) 5.92 (s, 1 H) 6.03 (s, 1 H) 7.41 (td, J=7.64, 0.88 Hz, 1 H) 7.48 (d, J=8.08 Hz, 1 H) 7.76 (td, J=7.83, 1.52 Hz, 1 H) 7.91 (dd, J=7.83, 1.52 Hz, 1 H) 7.96 (s, 1 H) 8.47 (d, J=7.07 Hz, 1 H) 11.98 (br. s., 1 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[CH:7]=[N:6]2.[H-].[Na+].CS(O[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>CC(C)=O>[C:35]([O:34][C:32](=[O:33])[NH:31][CH:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][N:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:7][C:8]2=[O:15])[CH2:26][CH2:27]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: COc1cc2ncc(=O)[nH]c2cc1OC
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2cc1OC
Yield: 27.6 %

Procedure:
6,7-Dimethoxyquinoxalin-2(1H)-one (Intermediate 158, 540 mg, 2.60 mmol) was deprotonated with sodium hydride (60% in oil, 2.90 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (3.9 mmol) as described for Intermediate 2. Chromatography on silica gel with 20-50% acetone in hexanes gave 310 mg (28%) of the product as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH2:20][CH3:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[CH3:23][O:24][CH2:25][CH2:26][C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:20]([N:4]1[C:3](=[O:22])[C:2]([NH:1][C:27](=[O:28])[CH2:26][CH2:25][O:24][CH3:23])=[C:7]([CH3:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=2)[C:5]1=[O:19])[CH3:21]
Reactant: CCn1c(=O)c(N)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: COCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(=O)c(NC(=O)CCOC)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
A solution of 5-amino-3-ethyl-6-methyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 239) (200 mg), 3-methoxypropionic acid (0.15 ml), HATU (487 mg), HOAT (174 mg) and diisopropylethyl amine (0.21 ml) in DMF (5.0 ml) was stirred at room temperature for two hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford the above-mentioned N-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methoxypropaneamide (222 mg). UPLC/MS 400 (M+H)/0.754 min. (measurement condition 9)
Reaction SMILES: FC(F)(F)S(OC1C=C[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([OH:45])([C:21]3[N:22]=[CH:23][N:24](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:25]=3)[CH:18]([CH3:20])[CH3:19])[CH:13]=2)C=1)(=O)=O.[C:48]1(B(O)O)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[Cl-].[Li+].C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[NH:24]1[CH:25]=[C:21]([C:17]([C:12]2[CH:11]=[CH:10][C:9]3[C:14](=[CH:14][CH:9]=[C:10]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[CH:11]=3)[CH:13]=2)([OH:45])[CH:18]([CH3:19])[CH3:20])[N:22]=[CH:23]1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)C(O)(c1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: COCCOC
Product: CC(C)C(O)(c1ccc2cc(-c3ccccc3)ccc2c1)c1c[nH]cn1
Temperature: 80 °C
Yield: 287.7 %

Procedure:
6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-naphthyl trifluoromethanesulfonate (2.0 g), phenylboronic acid (446 mg), tetrakis(triphenylphosphine)-palladium (0) (115 mg) and lithium chloride (259 mg) were dissolved in dimethoxyethane (DME, 20 mL). Ag.Na2CO3 (2M, 4.5 mL) was added to the mixture, and whole was heated at 80° C. for 20 h. Water was added, the mixture was extracted with AcOEt. The extract was washed with brine, dried and concentrated. The residue was purified by column chromatography (eluent, hexane:THF=2:1) to give the titled compound (1.50 g) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:20])(=[O:19])[NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.S(Cl)([Cl:23])=O.Cl.C(OC(C)C)(C)C>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:23])=[O:7])=[CH:4][C:3]=1[S:11](=[O:20])(=[O:19])[NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)NC2CCCCC2)c1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CC(C)OC(C)C
Product: O=C(Cl)c1ccc(Cl)c(S(=O)(=O)NC2CCCCC2)c1

Procedure:
30 g of 4-chloro-3-cyclohexylsulfamoylbenzoic acid were reacted as prescribed in Example 74a) with thionyl chloride and worked up analogously after HCl had finished to develop. Colorless crystals, melting point 119° C (from diisopropyl ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[OH:18])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:13][C:12]=2[OH:18])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1
Reactant: COc1ccc(N=Nc2ccc(O)cc2O)c([N+](=O)[O-])c1
Reactant: C[Si](C)(C)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N=Nc2ccc(OCCC[Si](C)(C)C)cc2O)c([N+](=O)[O-])c1
Temperature: 75 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-(4-methoxy-2-nitrophenylazo)benzene-1,3-diol (2.5 g, i.e. 0.0086 mol) and potassium carbonate (1.24 g) in 30 ml of dimethylformamide was brought to 70-75° C. 3-Chloropropyltrimethylsilane (1.24 g, i.e. 0.0086 mol) was added thereto over 20 minutes. The mixture was stirred at 75° C. for 6 hours. The reaction mixture was then poured into 50 ml of water and extracted with diisopropyl ether. The organic phase was dried, concentrated and purified by column chromatography (eluent: 50/50 heptane/CH2Cl2) to give compound (9) in the form of a red powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].Cl.[OH:15][NH2:16].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)[C:5](=[N:16][OH:15])[NH2:6]
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=NO)c1cc(F)cc(C(F)(F)F)c1
Yield: 40.5 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-19 by using 3-fluoro-5-(trifluoromethyl)benzonitrile (2.00 g, 10.0 mmol), hydroxyl amine HCl (1.09 g, 15 mmol) and potassium carbonate (2.2 g, 15 mmol), ethanol (20 mL) to afford 0.900 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 6.10 (s, 2H), 7.69 (d, J=7.8 Hz, 1H), 7.79 (d, J=10.2 Hz, 1H), 10.03 (s, 1H); MS (m/z): 223.17 (M+H)+.