Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([C:38]1[C:39]([N:47]2[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43])[CH3:37].Cl.O1CCOCC1.N>CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH2:36][CH3:37])[C:39]([N:47]4[CH2:48][CH2:49][CH:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:51][CH2:52]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCc1cc(N)c(OC)cc1N1CCC(CCS(C)(=O)=O)CC1
Agent: Cl
Agent: N
Solvent: CO
Solvent: C1COCCO1
Product: CCc1cc(Nc2nccc(-c3c(-c4ccc(OC)c(C(=O)Nc5c(F)cccc5F)c4)nc4ccccn34)n2)c(OC)cc1N1CCC(CCS(C)(=O)=O)CC1
Temperature: 180 °C
Yield: 56.2 %

Procedure:
In a microwave vial with septum cap, 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.131 g, 0.267 mmol) and 5-ethyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}aniline (0.091 g, 0.27 mmol) were taken up in 1,1,1-trifluoroethanol (1.5 mL) and 4M HCl in dioxane (0.134 mL, 0.535 mmol) was added. The vial was sealed and heated in the microwave at 180° C. for 40 min. Reaction was complete by MS, it was cooled to rt, neutralized with 7N ammonia in MeOH, and concentrated in vacuo onto silica gel and flash chromatographed. The desired fractions were combined and concentrated and the resulting solid was triturated with diethyl ether, filtered and air dried to give the title compound (0.12 g, 0.15 mmol, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1H), 9.23-9.40 (m, 1H), 8.44 (s, 1H), 8.21 (d, J=5.2 Hz, 1H), 8.08 (s, 1H), 7.75 (dd, J=8.4, 1.6 Hz, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.49 (s, 1H), 7.29-7.45 (m, 2H), 7.21-7.29 (m, 1H), 7.07-7.21 (m, 2H), 6.91 (t, J=6.8 Hz, 1H), 6.78 (s, 1H), 6.54 (d, J=5.1 Hz, 1H), 3.95 (s, 3H), 3.76 (s, 3H), 3.06-3.20 (m, 2H), 2.86-3.01 (m, 5H), 2.57-2.72 (m, 2H), 2.51 (q, J=7.5 Hz, 2H), 1.75 (dd, J=11.6, 0.6 Hz, 2H), 1.60-1.71 (m, 2H), 1.40-1.55 (m, 1H), 1.20-1.39 (m, 2H), 1.06 (t, J=7.5 Hz, 3H). MS (M+H, ES+) 796.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[Br:24][CH2:25][CH2:26]O>>[Br:24][CH2:25][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: OCCBr
Product: CC1(C)c2cc(OCCBr)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-bromoethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[CH:21]=[C:20]([Si](C)(C)C)[C:11]3[C:12]4[C:13]([NH:19][C:10]=3[C:9]2=[O:26])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=4)=[CH:5][CH:4]=1.[I:29]I>C(O)C.C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[I:29][C:20]1[C:11]2[C:12]3[C:13]([NH:19][C:10]=2[C:9](=[O:26])[N:8]([CH2:7][C:6]2[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:21]=1)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3
Reactant: COc1ccc(Cn2cc([Si](C)(C)C)c3c([nH]c4ncc(C)cc43)c2=O)cc1
Reactant: II
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(Cn2cc(I)c3c([nH]c4ncc(C)cc43)c2=O)cc1
Reaction time: 0.25 h

Procedure:
In a 2 L round bottom flask, 7-(4-methoxybenzyl)-3-methyl-5-trimethylsilyl-7,9-dihydro-8H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-8-one (18.6 g, 47.505 mmol) was suspended in ethanol (1 L) and DCM (150 mL), then cooled in an ice bath. To the cooled mixture was added silver tetrafluoroborate (AgBF4, 10.17 g, 52.255 mmol) and after 15 minutes of stirring, iodine (18.08 g, 71.257 mmol) was added. The reaction was stirred at 0° C. for one hour followed by five hours at ambient temperature. The crude yellow solid was collected by filtration, suspended in 10% wt Na2S2O3 (700 mL) and stirred for 1 h. The solid was collected by filtration and again washed with 10% wt Na2S2O3. The product (light yellow solid) was collected by filtration, washed with water and diethyl ether and dried under high vacuum. The material was taken forward without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.59 (s, 3H) 3.81 (s, 3H) 5.26 (s, 2H) 6.90 (d, J=8.84 Hz, 2H) 7.34 (d, J=8.59 Hz, 2H) 7.44 (s, 1H) 8.51 (s, 1H) 8.92 (s, 1H). ESI-MS: m/z 446.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[C:8]([CH:10]=[CH:11][C:12]([O:14][CH3:15])=[O:13])[CH:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][CH:27]=1)#[N:19].O>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:18]#[N:19])=[CH:31][CH:30]=2)[CH:7]=[C:8]([CH:10]=[CH:11][C:12]([O:14][CH3:15])=[O:13])[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1cc(C=CC(=O)OC)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1cc(C=CC(=O)OC)cn1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
Methyl 3-[2-(n-butyl)pyrrol-4-yl]acrylate (AE) (6.2 g) (prepared, e.g., as described in Preparation 21), in DMF (200 ml) was treated with sodium hydride (1.8 g of 60% mineral oil dispersion) at 0° C., and the resulting mixture was stirred for 30 minutes at 0° C. 2'-(Cyano)biphenyl-4-ylmethyl bromide (9.8 g) was added, and the mixture allowed to come to room temperature. Water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with 25% ethyl acetate/hexane, affording methyl 3-[2-(n-butyl)-1-(2"-cyanobiphenyl-4'-ylmethyl)pyrrol-4-yl]acrylate (9.17 g), a compound of Formula AF, as an oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[F:15].C(=O)(O)[O-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl.O>[CH2:25]([O:24][C:22]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]1[F:15])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
(3R,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (300 mg, 1.374 mmol) was taken up in DCM (8 mL) and a solution of sodium bicarbonate (346 mg, 4.12 mmol) in water (1 mL) was added. The reaction mixture was cooled to 0° C. and benzyl chloroformate (0.235 mL, 1.649 mmol) was added dropwise. The reaction was stirred at 0° C. for 30 min, then brought to rt and stirred overnight. The reaction mixture was diluted with DCM and water, and the organic layer was collected. The aqueous layer was reextracted with DCM and the organic layers were combined, dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography, eluting with 0-30% EtOAc/Hex. The fractions were combined and concentrated to give (3R,4S)-tert-butyl 4-(((benzyloxy)carbonyl)amino)-3-fluoropiperidine-1-carboxylate (450 mg) as a colorless glass.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:10][C:11]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](Cl)(=[O:25])[CH3:24]>C1COCC1.[Cl-].[Na+].O>[C:23]([N:20]1[CH2:21][CH2:22][CH:17]([C:9]2[S:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:18][CH2:19]1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1sc(C2CCNCC2)nc1-c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1sc(C2CCN(C(C)=O)CC2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To prepare compound 90, the procedure was followed as outlined in Scheme 10, Step 2 replacing compounds 77 and 78 with compounds tent-butyl 4-carbamothioylpiperidine-1-carboxylate and ethyl 2-bromo-3-oxo-3-phenylpropanoate to afford compound 90 (0.790 g, 21% yield) as a white solid. To a stirring solution of ethyl 4-phenyl-2-(piperidin-4-yl)thiazole-5-carboxylate 90 (0.235 g, 0.743 mmol) in THF (8 mL) was added acetyl chloride (1.11 mL, 0.891 mmol) and the reaction was stirred at room temperature for 2 h. The solution was diluted with brine and extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to afford ethyl 2-(1-acetylpiperidin-4-yl)-4-phenylthiazole-5-carboxylate 91 as a light yellow oil (0.196 g, 74% yield) after purification by flash chromatography (0 to 10% MeOH in ethyl acetate). LRMS (ESI): (calc) 358.45 (found) 359.3 (MH)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:19])[CH:14]=[C:15]2[CH2:18][CH2:17][CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:19])[CH2:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)C=C2CCC2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)CC2CCC2)C1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
Add palladium on carbon (50 mg, catalytic) to 3-(2-cyclobutylidene-acetyl)pyrrolidine-1-carboxylic acid tert butyl ester (850 mg, 3.20 mmol) in ethyl acetate (25 mL) and stir under nitrogen at room temperature. Install a balloon of hydrogen gas and stir overnight. Filter the reaction over celite, rinse with ethyl acetate and concentrate to dryness to afford 391 mg (46%) of the desired compound. MS (m/z)=212.0 (M−55)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:16]=1)(=[O:12])=[O:11]
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: Cc1cc(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)c(Cl)cc1Cl
Yield: 24.5 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting with 2,4-dichloro-5-methylbenzene sulfonyl chloride (14.3 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) yielding 4.7 mg (24%) of the title compound. MS (ESI+) calcd for C14H11Cl2N5O2S 383.001051, found 383.000871.
Reaction SMILES: C([CH:3]([C:14]1[C:19]([CH:20]([CH3:22])[CH3:21])=[C:18]([O:23][CH3:24])[N:17]=[C:16]([O:25][CH3:26])[N:15]=1)[C:4]1[CH:5]=[C:6]([C:12]#[N:13])[CH:7]=[C:8]([CH:11]=1)[C:9]#[N:10])#N.[H-].[Na+].CN(C=[O:33])C>>[CH:20]([C:19]1[C:14]([C:3]([C:4]2[CH:5]=[C:6]([C:12]#[N:13])[CH:7]=[C:8]([CH:11]=2)[C:9]#[N:10])=[O:33])=[N:15][C:16]([O:25][CH3:26])=[N:17][C:18]=1[O:23][CH3:24])([CH3:22])[CH3:21]
Reactant: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(C#N)cc(C#N)c2)n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C#N)cc(C#N)c2)n1
Reaction time: 0.5 h
Yield: 8 %

Procedure:
To a solution of 5-[cyano-(5-isopropyl-2,6-dimethoxy-pyrimidin-4-yl)-methyl]-isophthalonitrile (0.2457 g, 0.707 mmol) in DMF (2.4 mL) was added 60% sodium hydride (0.031 g, 0.778 mmol) and stirred for 30 min. Oxygen was bubbled into reaction mixture for 4 h. The reaction was quenched with saturated ammonium chloride solution and pH was adjusted to ˜6.0 with 1N HCl. Mixture was extracted with ethyl acetate and organic layer was washed with water (2×), dried (MgSO4) and concentrated. The resulting residue was purified by flash column chromatography (silica gel, 10 to 50% ethyl acetate/hexane) to give a white foam (0.018 g, 8%). 1H NMR (300 MHz, CDCl3): δ 8.32 (s, 2H); 8.08 (s, 1H), 4.05 (s, 3H), 3.89 (s, 3H), 3.0-2.8 (m, 1H), 1.19 (s, 3H), 1.42 (s, 3H). Mass spectrum: 337.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:31]4[CH:30]=[N:29][N:28]([CH2:27][C:26]([OH:43])([CH3:42])[CH3:25])[CH:32]=4)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(-c3cnn(CC(C)(C)O)c3)cc1-2
Yield: 7.8 %

Procedure:
Following the procedure for 277, 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (225 mg, 0.547 mmol) and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazol-1-yl)propan-2-ol (174.7 mg, 0.656 mmol) were reacted to give 331 (20.0 mg, 8% yield, M+1 471.2).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Br[C:24]([CH3:36])([CH3:35])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>CC#N.CCOC(C)=O>[CH3:35][C:24]([N:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=2)[CH2:14][CH2:13]1)([CH3:36])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]
Reactant: CC(C)(Br)C(=O)OCc1ccccc1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C(=O)OCc1ccccc1)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
To a solution of 1-[5-(trifluoromethyl)pyrid-2-yl]piperazine (554 mgs, 2.4 mmol) in CH3CN (5 mL) and K2CO3 (1.1 g, 8.0 mmol) was added benzyl 2-bromo-2-methylpropanoate (512 mgs, 2.0 mmol). The reaction mixture was heated to 80° C. After 14 hours, the reaction mixture was cooled to room temperature, diluted with EtOAc, stirred and filtered. The filtrate was then concentrated and purified by flash chromatography on silica gel with elution using 3% MeOH/CH2Cl2 to give Benzyl 2-methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propanoate.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:11][C:12]2[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[C@@H:20]([CH3:22])[NH2:21])=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:22][C@H:20]1[NH:21][C:32](=[O:34])[N:18]([C:15]2[CH:16]=[N:17][C:12]([O:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH:2]([CH3:1])[CH3:3])[CH:6]=3)=[CH:13][CH:14]=2)[C:19]1=[O:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)Oc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1cccc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a solution of N1-[6-({3-[(1-methylethyl)oxy]phenyl}oxy)-3-pyridinyl]-D-alaninamide (Intermediate 32, 229 mg) and triethylamine (442 mg, 4.38 mmol) in dichloromethane (20 mL) was added a solution of triphosgene (216 mg, 0.73 mmol) in dichloromethane (10 mL) dropwise at 0° C. during 5 minutes. The resulting mixture was stirred at room temperature for 2 hours. The solvent was distilled off and the residue was partitioned between dichloromethane (3 times 50 mL) and water (50 mL). The combined organic layers were washed with brine (3 times 10 mL), dried over sodium sulphate, filtered and concentrated to afford a grey solid, which was purified by silica gel chromatography (PE:EtOAc=2:1) to afford the title compound as a white solid (120 mg).
Reaction SMILES: [C:1]([S:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]([O:17][CH3:18])=[O:16])=[S:13])=[C:7]([N+:19]([O-])=O)[CH:6]=1)(=[O:3])[NH2:2].CO>[Fe].O>[NH2:19][C:7]1[CH:6]=[C:5]([S:4][C:1](=[O:3])[NH2:2])[CH:10]=[CH:9][C:8]=1[NH:11][C:12]([NH:14][C:15]([O:17][CH3:18])=[O:16])=[S:13]
Reactant: COC(=O)NC(=S)Nc1ccc(SC(N)=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CO
Product: COC(=O)NC(=S)Nc1ccc(SC(N)=O)cc1N

Procedure:
1.5 G. of 4-carbamoylthio-1-(3-methoxycarbonyl-2-thioureido)-2-nitrobenzene is treated for four hours in a refluxing mixture of 160 ml. methanol and 40 ml. water and with 4 g. iron powder (added in two portions) and 1 g. ferrous sulfate. The mixture is filtered, and the filtrate concentrated. The residue is dissolved in chloroform and washed with water, then the solvent evaporated affording 2-amino-4-carbamoylthio-1-(3-methoxycarbonyl-2-thioureido)-benzene.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15][C:16](O)=[O:17])\[CH3:13])[C:5]([OH:19])=[C:4]2[C:20]([O:22][CH2:23][C:3]=12)=[O:21].CN(C)C=O.S(Cl)([Cl:31])=O>ClCCl>[OH:19][C:5]1[C:6]([CH2:10][CH:11]=[C:12]([CH3:13])[CH2:14][CH2:15][C:16]([Cl:31])=[O:17])=[C:7]([O:8][CH3:9])[C:2]([CH3:1])=[C:3]2[C:4]=1[C:20](=[O:21])[O:22][CH2:23]2
Reactant: O=S(Cl)Cl
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C)c2c(c(O)c1CC=C(C)CCC(=O)Cl)C(=O)OC2

Procedure:
A solution of mycophenolic acid (320 g, 1 mol) and dimethylformamide (0.1 g) in dichloromethane (3.2L) at reflux was treated dropwise with thionyl chloride (82 mL, 1.12 mol). After one hour additional heating at reflux, the volatiles were distilled at reduced pressure leaving a gray solid residue of (E) 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl -3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoyl chloride which was cooled and dissolved in anhydrous tetrahydrofuran (1L).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[H][H]>C(O)C.C1COCC1.[Pd]>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][CH:8]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(C2CCN(CC3CC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(C2CCN(CC3CC3)CC2)cc1

Procedure:
3.3 g (12.5 mmol) 1-cyclopropylmethyl-4-(4-nitro-phenyl)-piperidine are dissolved in a mixture of 40 ml of ethanol and 40 ml THF, combined with 1.3 g palladium/charcoal (10%) and hydrogenated at 1 bar hydrogen. Then the reaction mixture is suction filtered and the filtrate is concentrated by evaporation. Yield: 2.7 g
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].Cl[C:23]1C(C2CC2)=NC=C(CC)N=1>>[CH:1]1([C:3]2[C:4]([NH:11][C@@H:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][C@@H:13]3[OH:21])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=2)[CH2:23][CH2:2]1
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: CCc1cnc(C2CC2)c(Cl)n1
Product: CCc1cnc(C2CC2)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3-chloro-2-cyclopropyl-5-ethylpyrazine and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.93-1.02, 1.24-1.30, 1.72-1.81, 2.61-2.68, 3.06-3.30, 4.79-4.84, 5.36, 5.58, 7.24-7.35, 7.66; MS (ESI+) for C18H21N3O m/z 296 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].[CH:20]1([CH2:25][CH2:26][C:27](O)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([CH2:25][CH2:26][C:27]([CH2:2][CH2:1][NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=2)[OH:8])=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reactant: O=C(O)CCC1CCCC1
Product: CS(=O)(=O)Nc1ccc(C(O)CCCNCCC(=O)CCC2CCCC2)cc1
Yield: 42.8 %

Procedure:
The product from Example 7, Step II was condensed with 3-cyclopentylpropionic acid according to Procedure E (Example 7, Step III). The product was recrystallized from EtOAc-hexane to give N-[4-[4-[(2-Cyclopentylethylcarbonyl)ethylamino]-1-hydroxybutyl]phenyl]methanesulfonamide (42.8%): mp 101°-102° C.; NMR (CDCl3) δ1.13 (m, 5H), 1.63 (m, 13H), 2.3 (m, 2H), 2.99 (d, 3H), 3.39 (m, 4H), 4.72 (m, 1H), 7.07 (s, 1H), 7.24 (m, 4H); MS m/z (relative intensity) 410 (M+, 2.8), 392 (3.2), 331 (11.5), 223 (29.0), 207 (6.3), 200 (2.9), 189 (19.4); IR (Nujol) 3397, 3190, 1591 cm-1. Anal. calc'd for C21H34N2O4S: C, 61.43 ; H, 8.35; N, 6.82; S, 7.81. Found: C, 61.21; H, 8.56; N, 6.59; S, 7.77.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:11]2[CH:10]=[C:9]([C:12]([O:14]C)=[O:13])[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.O.[OH-].[Li+].O>CO>[F:16][C:2]([F:1])([F:17])[C:3]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc2c(C(F)(F)F)cccc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2c(C(F)(F)F)cccc2s1
Temperature: 75 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
A mixture of 290 mg of methyl 4-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 60 mg of lithium hydroxide monohydrate, 2 ml of water and 6 ml of methanol was stirred at 75° C. for 1 hour. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. To the residue was added water, and then washed with tert-butyl methyl ether 3 times. To the aqueous layer was added concentrated hydrochloric acid, and then extracted with chloroform 3 times. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 240 mg of 4-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid (the present compound 3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.Cl.[SH:18][C:19]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:20]=1[NH2:21]>CO.O>[CH:12]1([O:11][C:4]2[CH:5]=[C:6]([C:7]3[S:18][C:19]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:20]=4[N:21]=3)[CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1cc(F)ccc1S
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(-c2nc3cc(F)ccc3s2)cc1OC1CCCC1
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of (440 mg, 2 mmoles) 4-methoxy-3-cyclopentyloxy benzaldehyde and (400 mg, 2.1 mmoles) 2-mercapto-5-fluoroaniline hydrochloride was heated on a steam bath for 15 minutes. The resulting thick orange oil was cooled and dissolved in 5 ml of 10% FeCl3 in methanol and allowed to stir overnight. The reaction was diluted with water and extracted with CH2Cl2. The CH2Cl2 layer was dried and evaporated to give 760 mg of crude product which was purified on silica gel with CH2 Cl2 to give 500 mg of product. Recrystallization from isopropanol gave 140 mg of product. M.P.: 96°-97° C. Elemental Analysis Calc'd for C19H18O2NSF : Calc'd: C, 66.45; H, 5.28; N, 4.08. Found: C, 66.44; H. 5.13; N. 4.06.