Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([NH:15][NH:16][C:17]([C@@:19]2([CH3:33])[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[N:20]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:18])=[O:14])=[CH:11][C:10]=1[C:36]([F:39])([F:38])[F:37])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([NH:15][NH:16][C:17]([C@@:19]2([CH3:33])[CH2:23][O:22][C:21]([CH3:24])([CH3:25])[N:20]2[C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])=[O:18])=[O:14])=[CH:11][C:10]=1[C:36]([F:38])([F:39])[F:37]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)NNC(=O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)NNC(=O)c1ccc(O)c(C(F)(F)F)c1
Yield: 99 %

Procedure:
A solution of benzyl protected acyl-benzohydrazide 5b (1.0 equiv) in MeOH was subjected to hydrogenation in the presence of Pd/C (10% w) for 1 h. The reaction mixture was filtered through celite and concentrated to give compound 5c (6.86 g, 99% yield). MS (ESI, M+Na+): 484.0; TLC (2:1, Hex/EtOAc), Rf=0.20; 1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H,), 7.95 (d, 1H, J=8.8 Hz), 7.01 (d, 1H, J=8.8 Hz), 4.28 (br s, 1H), 3.91 (br s, 1H), 1.69 (s, 3H,), 1.64 (s, 3H), 1.58 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:36][CH2:35][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)[CH:23]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4].[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:36][CH2:35][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]6[CH2:30][CH2:31][N:32]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:33][CH2:34]6)[CH:23]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5cccc(CN6CCNCC6)c5)cc4c3C2)nc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5cccc(CN6CCN(S(C)(=O)=O)CC6)c5)cc4c3C2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.3 %

Procedure:
To a stirred solution of methyl-2-{8-[3-(piperazin-1-ylmethyl)phenyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (800 mg, 1.65 mmol) in dry DCM (50 mL) was added 4-dimethylaminopyridine (1.012 g, 8.29 mmol), then methanesulfonyl chloride (0.155 mL, 1.99 mmol) was added at 0° C. and stirred for 10 min. The reaction mass was maintained at room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC and after completion the reaction mass was diluted with water and extracted with DCM. The DCM layer dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give methyl-2-{8-[3-((4-(methylsulfonyl)piperazin-1-yl)methyl)phenyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (900 mg, 95.40%) with HPLC purity 95.40%. 1HNMR (200 MHz, CD3OD) δ: 2.62 (t, 4H, 2×CH2), 2.85 (s, 3H, CH3) 3.0 (t, 2H, CH2), 3.22 (t, 4H, 2×CH2), 3.7 (s, 2H, CH2) 3.95 (s, 3H, OCH3), 4.4 (t, 2H, CH2), 5.18 (s, 2H, CH2), 7.2-7.8 (m, 7H, Ar—H), 8.9 (s, 2H, Pyrimidine-H); m/e=561 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:15])[C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12])N.N(OCCC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:6]=[C:7]([Cl:15])[C:8]=1[O:9][CH2:10][C:11]([F:12])([F:13])[F:14]
Reactant: Nc1cc(Cl)c(OCC(F)(F)F)c(Cl)c1
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: FC(F)(F)COc1c(Cl)cccc1Cl

Procedure:
3,5-Dichloro-4-(2,2,2-trifluoroethoxy)aniline (1.60 g, 6.15 mmol) in THF (20 mL) was added isopentyl nitrite (2.94 g, 17.22 mmol) dropwise. The resulting solution was refluxed for 6 h and the solvent was removed under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE to provide 1,3-dichloro-2-(2,2,2-trifluoroethoxy)benzene as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[F:19][C:20]([F:28])([F:27])[C:21](=[O:26])[CH2:22][C:23](=O)[CH3:24]>C(O)(=O)C.S(=O)(=O)(O)O>[F:19][C:20]([F:28])([F:27])[C:21]([C:22]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[S:6][C:2]2=[N:1][C:23]=1[CH3:24])=[O:26]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1sc2ccccc2c1C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3ccccc3c2c(-c2ccccc2)c1C(=O)C(F)(F)F
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 16.6 %

Procedure:
To a stirred solution of 32 mg (0.13 mmol) (2-amino-benzo[b]thiophen-3-yl)-phenyl-methanone (the preparation of which is described in example 11) in 2 ml acetic acid was added 0.016 ml (0.13 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 20:1) afforded 8 mg (17%) 2,2,2-trifluoro-1-(2-methyl-4-phenyl-benzo[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a light yellow solid. ES-MS m/e (%): 372 (M+H+, 100).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:5]1=[O:25])(=O)C.[CH3:26][N:27]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[CH3:28][N:27]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:35][CH:36]=1)[CH3:26]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2cccc(Cl)c2)c2cc([N+](=O)[O-])ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2cccc(Cl)c2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(3-chlorophenyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[N:21][CH:22]=1>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:16][C:17]1[CH:22]=[N:21][C:20]([N:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[N:19][CH:18]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)(=[O:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(N)cn2)CC1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Yield: 44.7 %

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (300 mg, 1.06 mmol) was reacted with tert-butyl 4-(5-aminopyrimidin-2-yl)piperazine-1-carboxylate (495 mg, 1.59 mmol) to afford the desired product (250 mg, 44%) as a yellow solid: ESI MS m/z 527, [C24H27BrN6O3+H]+
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4](C(O)=O)[C:3]=1[C:14]([OH:16])=[O:15]>O.O.O.S([O-])([O-])(=O)=O.[Ca+2]>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(F)c1F

Procedure:
Decarboxylation of 150 g of 3,4,5,6-tetrafluorophthalic acid in 500 g of water was effected by following the procedure of Example 1, except that 54.2 g (0.315 mole) of calcium sulfate dihydrate was used as a catalyst and the heating and stirring were carried out at 170° C. for 14 hous [pH 1.37 at 70° C. at the time of charging]. After completion of the reaction, the reaction product was separated by following the procedure, to produce 2,3,4,5-tetrafluorobenzoic acid in a yield of 86.4 mole % as found by the same calculation.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH:12]1[CH2:11][CH2:10][CH:9]([N:6]2[C:5]3[CH:22]=[CH:23][C:2]([NH2:1])=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc3cc(N)ccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc2c(c1)ncn2C1CCNCC1
Yield: 128.5 %

Procedure:
tert-Butyl 4-(5-amino-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (3.75 mmol, 1.187 g) was stirred in dichloromethane (5 mL)/trifluoroacetic acid (5 mL) for 1 hour at room temperature. The reaction was concentrated under vacuum and passed down an SCX column to afford the title compound (1.042 g). MS (ESI) m/z 217.1 [M+H]+
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:15](=[O:31])[NH:16][C@@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:30])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][CH2:50][C@@H:51]([CH2:52][O:53][CH3:54])[N:43]2[C:42]1=[O:55]>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:15]([NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]1=[O:30])=[O:31])[C:9]([NH:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][CH2:50][C@@H:51]([CH2:52][O:53][CH3:54])[N:43]2[C:42]1=[O:55])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@@H]1CCCCN(c2ccccc2)C1=O)Cc1ccccc1
Reactant: COC[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Agent: Cl
Product: COC[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4ccccc4)C3=O)Cc3ccccc3)C(=O)N12

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((4S,7S,10aS)-7-(methoxymethyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-N6-((S)-2-oxo-1-phenylazepan-3-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 24 (10 mg, 0.020 mmol) and Intermediate 66 (6.6 mg, 0.023 mmol) to give a white solid (7.6 mg, 53% yield). Anal. Calcd. for C43H54N4O5S m/z 738.7. found: 739.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.38 (2H, t, J=7.8 Hz), 7.30-7.18 (3H, m), 7.18-7.09 (8H, m), 6.91 (1H, d, J=6.4 Hz), 6.83 (1H, d, J=6.4 Hz), 5.29-5.19 (1H, m), 4.96-4.87 (1H, m), 4.76 (1H, dd, J=9.9, 6.6 Hz), 4.71-4.64 (1H, m), 3.95 (1H, dd, J=15.1, 11.9 Hz), 3.70 (1H, t, J=9.4 Hz), 3.60 (1H, dd, J=15.1, 4.6 Hz), 3.40-3.31 (4H, m), 3.22-3.12 (1H, m), 2.90-2.78 (2H, m), 2.75-2.60 (3H, m), 2.40-2.30 (2H, m), 2.06-1.92 (4H, m), 1.91-1.79 (3H, m), 1.79-1.43 (9H, m), 1.36-1.24 (2H, m).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([O:7][CH2:8]SC1C=CC=CC=1)=[O:6])[CH3:2].S(Cl)([Cl:19])(=O)=O.C1CCCCC=1>C(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]([O:7][CH2:8][Cl:19])=[O:6])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOCC(=O)OCSc1ccccc1
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CCOCC(=O)OCCl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.7 %

Procedure:
To a solution of (phenylthio)methyl 2-ethoxyacetate (17.28 g, 76 mmol) in CH2Cl2 (200 mL) at 0° C. was added a solution of sulfuryl chloride (7.36 mL, 92 mmol) in CH2Cl2 (50 mL) over a period of 15 min, and the reaction was stirred at room temperature for 90 min. The reaction was again cooled to 0° C. and treated with a second portion of sulfuryl chloride (7.36 mL, 92 mmol) in CH2Cl2 (50 mL) over a period of 15 min. The reaction was then warmed to 30° C., stirred for 1 hour, and then cooled back to 0° C. A solution of cyclohexene (24.5 mL, 242 mmol) in CH2Cl2 (50 mL) was added over a period of 10 min, during which gas evolution was observed. The reaction was stirred at room temperature for 90 min, stored at −20° C. overnight, and purified by vacuum distillation to give the target compound as a slightly yellow oil (11.33 g, 97%): by 58° C. at 6.8 mm Hg; 1H NMR (400 MHz, CDCl3) δ 5.77 (s, 2H), 4.16 (s, 2H), 3.62 (q, J=7.0 Hz, 2H), 1.27 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 168.81, 68.59, 67.77, 67.48, 14.96.
Reaction SMILES: [CH2:1]([N:4]([CH2:13][CH:14]=[CH2:15])[CH:5]=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:2]=[CH2:3].C(N)C=C.C(N)(=[O:23])C=C.NC=CC=C(C#N)C#N>C(O)C.Cl.CC(C)=O>[C:9]([NH2:10])(=[O:23])[C:8]([CH3:11])=[CH2:7].[CH2:1]([N:4]([CH:5]=[CH:6][CH:7]=[C:8]([C:9]#[N:10])[C:11]#[N:12])[CH2:13][CH:14]=[CH2:15])[CH:2]=[CH2:3]
Reactant: C=CC(N)=O
Agent: C=CCN(C=CC=C(C#N)C#N)CC=C
Agent: Cl
Agent: N#CC(C#N)=CC=CN
Solvent: C=CCN
Solvent: CCO
Solvent: CC(C)=O
Product: C=C(C)C(N)=O
Temperature: 90 °C
Reaction time: 20 h

Procedure:
40 g of intermediate (A) and 10.6 g of allylamine in 580 ml of ethanol and 19.6 ml of 37% hydrochloric acid were dissolved in a flask provided with a stirrer and reflux condenser. Under stirring and raising the mixture temperature up to 90° C., a solution of 107.7 g of acrylamide and 4.2 g of 2.2'-azobisisobutyrronitrile in 648 ml of ethanol was added thereto. The reaction mixture was kept at 90° C. for 20 hours and then poured into 2 liters of acetone; the precipitated product was grinded and washed upon decantation with one liter of acetone, filtered and dried. 108.6 g of a water soluble product were obtained, containing about 10% w/w of aminoallylidenmalononitrile moieties.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: C1CCNCC1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: CCO
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCCCC1
Reaction time: 1 h
Yield: 67.1 %

Procedure:
2-Chloro-5-nitrobenzonitrile (20 g) and piperidine (9.34 g) were added to ethanol (100 ml) and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give 5-nitro-2-piperidinobenzonitrile (17 g), melting point 75° C.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([O:30][CH3:31])[CH:5]=1)=[S:3].Cl[CH:33]([C:38](C)=O)[C:34]([O:36][CH3:37])=[O:35]>CCO>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@H:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]3[CH:28]=[CH:29][C:4]([C:2]4[S:3][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][N:1]=4)=[CH:5][C:6]=3[O:30][CH3:31])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH3:27]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cc3OC)ccc21
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4ncc(C(=O)OC)s4)cc3OC)ccc21
Temperature: 70 °C
Yield: 49.5 %

Procedure:
Ethyl ((1S)-5-{3-[4-(aminocarbonothioyl2-methoxyphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (90 mg, 0.2 mmol) (Example 146) and methyl 2-chloroacetoacetate (37 mg, 0.24 mmol) were dissolved in EtOH (8 mL), and the mixture was heated at 70° C. for 6 h. The reaction was cooled to rt, and then concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc:hexane (v/v)=1:2) provided 52 mg (48%) of the title compound as a clear oil. LC-MS: RT=4.18 min, (M+H)+ 540.1.
Reaction SMILES: [CH:1]1([CH:4]([O:20][CH3:21])[CH:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([C:16]([OH:18])=O)=[C:8]2[CH3:19])[CH3:6])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:47][CH2:48][C:49]1[C:50](=[O:58])[NH:51][C:52]([CH3:57])=[CH:53][C:54]=1[O:55][CH3:56]>ClCCl>[CH:1]1([CH:4]([O:20][CH3:21])[CH:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([C:16]([NH:47][CH2:48][C:49]3[C:50](=[O:58])[NH:51][C:52]([CH3:57])=[CH:53][C:54]=3[O:55][CH3:56])=[O:18])=[C:8]2[CH3:19])[CH3:6])[CH2:3][CH2:2]1
Reactant: COc1cc(C)[nH]c(=O)c1CN
Reactant: COC(C1CC1)C(C)n1c(C)c(C(=O)O)c2cccnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C(OC)C2CC2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 1-(1-cyclopropyl-1-methoxypropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (100 mg, 0.35 mmol) in dichloromethane (2 mL) was added HATU (192 mg, 0.52 mmol), TEA (105.28 mg, 1.04 mmol). After stirred for 50 min at room temperature, 3-(aminomethyl)-4-methoxy-6-methylpyridin-2(1H)-one hydrochloride (87.5 mg, 0.52 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction completed, the solution was partitioned between EtOAc and H2O. The organic was separated, dried over Na2SO4 and evaporated under vacuum.
Reaction SMILES: [CH2:1]([C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[C:11]([NH:22][C:23]([C:25]2[NH:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=2)=[O:24])[CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>FC(F)(F)C(O)=O>[CH2:1]([C:9]1[CH:21]=[CH:20][C:12]([C:13]([OH:15])=[O:14])=[C:11]([NH:22][C:23]([C:25]2[NH:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=2)=[O:24])[CH:10]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NC(=O)c1cc(-c2ccccc2)n[nH]1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(CCc2ccccc2)ccc1C(=O)O)c1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 4-phenethyl-2-(3-phenyl-1H-pyrazole-5-carboxamido)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; ethyl acetate] to obtain 2.6 mg of 4-phenethyl-2-(3-phenyl-1H-pyrazole-5-carboxamido)benzoic acid as white solid.
Reaction SMILES: COC1C=CC=CC=1S[C:10]1[S:14][C:13]([C:15]([NH2:17])=[NH:16])=[CH:12][C:11]=1[C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:22]=1.[CH3:29][O:30]C1C=CC=CC=1SC1SC(C(OC)=O)=CC=1C1SC=C(C2C=CC=CC=2)N=1>>[CH3:29][O:30][C:10]1[S:14][C:13]([C:15]([NH2:17])=[NH:16])=[CH:12][C:11]=1[C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:22]=1
Reactant: COc1ccccc1Sc1sc(C(=N)N)cc1-c1nc(-c2ccccc2)cs1
Reactant: COC(=O)c1cc(-c2nc(-c3ccccc3)cs2)c(Sc2ccccc2OC)s1
Product: COc1sc(C(=N)N)cc1-c1nc(-c2ccccc2)cs1
Yield: 91 %

Procedure:
5-(Methoxyphenylthio)-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine: Methyl 5-(methoxyphenylthio)-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate (100 mg, 0.22 mmol) was treated in a manner similar to that for Example 10, step (b), to give 5-methoxy-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine (94 mg, 91%) as an orange solid. 1H-NMR (DMSO-d6; 300 MHz) δ 9.49 (br s, 2H), 9.15 (br s, 2H), 8.70 (s, 1H), 8.26 (s, 1H), 8.07 (m, 2H), 7.49 (m, 2H), 7.40 (m, 1H), 7.35 and 6.90 (AB quartet, 2H, J=8.7 Hz), 4.41 (s, 2H), 3.73 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C22H19N3OS3 438.5 (M+H), found 438.1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])O.[Na+].[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>C(O)C>[CH:25]1([NH:31][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1NC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.6 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.19 mmol) in ethanol (5 mL) was added sodium hydrogen carbonate (295 mg, 2.32 mmol) and cyclohexylamine (288 mg, 2.32 mmol), and this was heated to reflux with stirring for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and this was extracted with ethyl acetate. The organic layer obtained was dried over anhydrous sodium sulfate, filtered, and concentrated to give crystals that were purified by silica gel column chromatography to yield the title compound (191 mg, 48% yield) as orange crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]([CH3:27])[C:24]([NH2:26])=[O:25])=[N:4][C:5](NC2C=NN(C)C=2)=[N:6][CH:7]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[N:33][CH:34]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:3]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]([CH3:27])[C:24]([NH2:26])=[O:25])=[N:4][C:5]([NH:28][C:29]2[CH:34]=[N:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(N)cn1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C)c2)ncc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1ccc(Nc2ncc(Cl)c(CCc3ccccc3C(C)C(N)=O)n2)cn1
Temperature: 120 °C
Yield: 33 %

Procedure:
A mixture of 2-(2-(2-(5-chloro-2-(1-methyl-1H-pyrazol-4-ylamino)pyrimidin-4-yl)ethyl)phenyl)propanamide WAK-011-06-05 (0.080 g, 0.25 mmol), 5-amino-2-methylpyridine (0.053 g, 0.49 mmol), Xantphos (0.0057 g, 0.010 mmol) and Cs2CO3 (0.24 g, 0.74 mmol) in 1,4-dioxane (3 mL) was bubbled with nitrogen for 10 minutes. Palladium (II) acetate (0.0011 g, 0.0049 mmol) was added and the mixture was heated at 120° C. under microwave irradiation for 20 minutes. The volatiles were removed in vacuo and the residue was purified by silica gel column chromatography (Combiflash Rf, 0-10% MeOH in DCM) to give the title compound 41 as a light yellow solid (0.032 g, 33%). LCMS-C: rt 4.24 min; m/z 396 [M+H]+.
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[I-:11].[Na+].[CH2:13]([N:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>CC(C)=O>[I-:11].[I:11][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N+:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:5][CH:4]=1
Reactant: CCCCN(CCCC)CCCC
Reactant: Cc1ccc(C(Cl)Cl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCC[N+](CCCC)(CCCC)Cc1ccc(CI)cc1
Temperature: 25 °C

Procedure:
To a mixture of α,α-dichloro-p-xylene (50 g, 28.6 mmol) and sodium iodide (8.6 g, 57 mmol) in acetone (100 mL) was added tri-n-butylamine (3.7 g, 20.0 mmol). The reaction mixture was stirred at room temperature under argon for several days after which time TLC examination showed completion of the reaction. The reaction mixture was filtered and the solvent was removed under reduced pressure to give an oily residue. The residue was washed with pentane several times and dried to give a yellow solid. The product was used without further purification.