Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[N:24]=[C:25]=[O:26])([CH3:14])[CH3:13].N1C=CC=CC=1>ClCCl>[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25]([NH:11][CH:8]1[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]1)=[O:26])([CH3:13])[CH3:14]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(C)(C)C1CCC(N)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NC1CCC(C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.5 %

Procedure:
To a solution of 1.6 g of 4-tert-butylcyclohexylamine in 15 ml of dichloromethane was added a solution of 2.2 g of 2,6-diisopropylphenylisocyanate in dichloromethane dropwise in the presence of pyridine at 0° C. Thereafter the mixture was stirred for 1.5 hours at room temperature and concentrated. The residue was partitioned between isopropyl ether and water, and the organic layer was successively washed with 0.5N hydrochloric acid, water and sodium sulfate solution. The organic layer was dried over magnesium sulfate and then distilled away. The resulting residue was crystallized from ethyl acetate to give 2.2 g of N-(2,6-diisopropylphenyl)-N'-(4-tert-butylcyclohexyl)urea, melting at 270° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[I:11]
Reactant: O=C(O)c1cc(F)ccc1I
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)ccc1I
Temperature: 65 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
To a 500 mL round-bottomed flask was added 5-fluoro-2-iodo-benzoic acid (23 g, 86.5 mmol) in methanol (230 mL). To the resulting solution was added conc. sulfuric acid (2.3 mL, 43.2 mmol). The reaction mixture was warmed to 65° C. and stirred for 15 h. The resulting mixture was concentrated under reduced pressure to give crude product which was then was partitioned between EtOAc (250 mL) and a half sat. Na2CO3(aq) solution (250 mL). The layers were thoroughly mixed and then separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil (23 g, 95% yield). 1H NMR (400 MHz, CDCl3): 7.94 (dd, J=8.7, 5.4 Hz, 1H), 7.54 (dd, J=9.0, 3.1 Hz, 1H), 6.93 (m, 1H), 3.94 (s, 3H).
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([OH:15])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:22]1([Mg]Cl)C=CC=CC=1.CC1C=CC2C(=O)C3C(C=2C=1)=CC=CC=3>>[CH3:22][C:3]1[C:4]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)([OH:15])[C:5]=2[CH:13]=[CH:14][CH:2]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: Cc1ccc2c(c1)-c1ccccc1C2(O)c1ccccc1
Agent: Cc1ccc2c(c1)-c1ccccc1C2=O
Product: Cc1cccc2c1-c1ccccc1C2(O)c1ccccc1

Procedure:
3-methyl-9-phenyl-9H-fluoren-9-ol: from phenylmagnesium chloride and 3-methyl-9-fluorenone;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44](O)=[O:45])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:45]
Reactant: Cc1ccc(F)c(-c2nc(C(=O)O)c(NC(=O)OC(C)(C)C)s2)c1
Reactant: Cn1ncc(N)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Product: Cc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C)c3N3CC[C@@H](F)[C@@H](N)CC3)c(N)s2)c1

Procedure:
Following the procedure for Example 221 starting from N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonyl-amino)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxylic acid gave, after purification via silica gel column chromatography (5% MeOH/DCM with 1% 7 N ammonia in MeOH), 294 as a cream solid (107 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 7.90-7.84 (m, 1H), 7.82 (s, 1H), 7.17-7.11 (m, 1H), 7.04 (dd, J=11.1, 8.4 Hz, 1H), 6.10 (s, 2H), 4.95-4.78 (m, 1H), 3.74 (s, 3H), 3.49-3.33 (m, 3H), 3.24-3.11 (m, 2H), 2.40 (s, 3H), 2.40-2.26 (m, 1H), 2.09-1.91 (m, 2H), 1.87-1.77 (m, 1H). Alkyl NH2 not seen. LCMS (ES+) m/z 462 (M+1)
Reaction SMILES: [CH3:1][N:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][C:4]([NH2:15])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.[CH3:16][O:17][C:18]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([S:31][CH3:32])[C:19]=1[C:20](Cl)=[O:21]>>[CH3:1][N:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][C:4]([NH:15][C:20](=[O:21])[C:19]2[C:23]([S:31][CH3:32])=[CH:24][C:25]([C:27]([F:30])([F:28])[F:29])=[CH:26][C:18]=2[O:17][CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Reactant: CC1CCC(N)(c2ccccc2)CN1C
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(c2ccccc2)CCC(C)N(C)C1

Procedure:
In analogy to the procedure described for the synthesis of example 16, the title compound was prepared from 1,6-Dimethyl-3-phenyl-piperidin-3-ylamine and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6). MS (m/e): 453.2 (M+H).
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:28]=[CH:27][C:22]([C:23](OC)=[O:24])=[CH:21][N:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[NH2:37][CH3:38].CO>>[OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([NH:37][CH3:38])=[O:24])=[CH:21][N:20]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CN
Reactant: COC(=O)c1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nc1
Solvent: CO
Product: CNC(=O)c1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
Methyl 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate (150 mg, 0.307 mmol) was dissolved in NH2Me/MeOH (10 mL). The mixture was stirred at rt overnight. The solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC and chiral HPLC to afford 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-N-methylnicotinamide (54 mg, 36%). LC-MS Method 2 tR=1.117 min, m/z=430.1; 1H NMR (CD3OD) 0.93 (s, 3H), 1.27 (s, 3H), 1.59 (d, 3H), 2.16 (s, 2H), 2.22-2.37 (m, 1H), 2.41-2.60 (m, 2H), 2.99 (s, 3H), 3.11 (m, 1H), 5.60 (m, 1H), 7.12 (d, 1H), 7.29 (m, 5H), 7.80 (m, 2H), 8.01 (d, 1H), 8.41 (d, 1H), 9.03 (s, 1H).
Reaction SMILES: C[C:2]1([C:9]2[C@H:10]([C:14]([N:16]3[C@@H:20]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:19][O:18][C:17]3=[O:28])=[O:15])[NH:11][CH2:12]C=2)[CH2:7][C:6](=O)[CH:5]=[CH:4][CH2:3]1.CC1(C2[C@@H](C(N3[C@@H](CC4C=CC=CC=4)COC3=O)=O)NCC=2)CC(=O)C=CC1.[CH3:57][CH2:58][OH:59]>[Pd].CCOC(C)=O>[CH3:12][N:11]1[C:58](=[O:59])[CH2:57][C@H:9]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@@H:10]1[C:14]([N:16]1[C@@H:20]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:19][O:18][C:17]1=[O:28])=[O:15]
Reactant: CC1(C2=CCN[C@H]2C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)CC=CC(=O)C1
Reactant: CCO
Agent: [Pd]
Agent: CC1(C2=CCN[C@@H]2C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)CC=CC(=O)C1
Solvent: CCOC(C)=O
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 48 h

Procedure:
To a slurry of 10% palladium on carbon (7.0 g) in EtOAc (700 mL) was added a solution of diastereomers 3-[((2R)-1-methyl-5-oxo-3-phenyl(3-pyrrolin-2-yl)carbonyl](4S)-4-benzyl-1,3-oxazolidin-2-one and (4S)-3-[((2S)-1-methyl-5-oxo-3-phenyl(3-pyrrolin-2-yl))carbonyl]-4-benzyl-1,3-oxazolidin-2-one (78.5 g, 0.208 mol) in EtOH (100 mL) and the reaction mixture was stirred under a H2 atmosphere (1 Atm) for 2 days. The reaction mixture was filtered through a pad of Celite® with the aid of EtOAc. The filtrate was concentrated under reduced pressure and purified by flash chromatography (gradient from 15% to 65% EtOAc/hex) to give diastereomer 3-[((2R,3R)-1-methyl-5-oxo-3-phenylpyrrolidin-2-yl)carbonyl](4S)-4-benzyl-1,3-oxazolidin-2-one as a single diastereomer (41.02 g, 52%): TLC (15% i-PrOH/hex) Rf0.25; 1H NMR (CDCl3) δ 1.39 (dd, J=11.4, 13.6 Hz, 1H), 2.45-2.51 (dd, J=3.3, 13.6 Hz, 1H), 2.87-2.91 (m, 5H), 3.91 (dd, J=9.2, 2.9 Hz, 1H), 4.03-4.23 (m, 3H), 4.36-4.43 (m, 1H), 5.75 (d, J=9.2 Hz, 1H), 7.01-7.03 (m, 2H), 7.21-7.39 (m, 8H); HPLC ES-MS m/z (rel abundance) 377 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:21])[NH:11][C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:61][O:62][C:63]1[CH:68]=[C:67]([O:69][CH3:70])[CH:66]=[CH:65][C:64]=1[CH2:71]O>C(OCC)(=O)C.O1CCCC1>[CH3:61][O:62][C:63]1[CH:68]=[C:67]([O:69][CH3:70])[CH:66]=[CH:65][C:64]=1[CH2:71][N:11]1[C:10](=[O:21])[C:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:3][C:2]=2[F:1])=[C:14]([CH2:15][CH2:16][CH3:17])[N:13]2[N:18]=[CH:19][N:20]=[C:12]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)[nH]c2ncnn12
Reactant: COc1ccc(CO)c(OC)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(Cc2ccc(OC)cc2OC)c2ncnn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.9 %

Procedure:
A mixture of 3′-fluoro-4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.3 g), tributylphosphine (1.6 mL), (2,4-dimethoxyphenyl)methanol (0.58 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.36 g, 26%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:24])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[C:25]([O:29][C:30]([N:32]1[CH2:39][CH2:38][CH2:37][C@H:33]1C(O)=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>Cl.O1CCOCC1>[C:25]([O:29][C:30]([N:32]1[CH2:39][CH2:38][CH2:37][C@H:33]1[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:24])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[O:7])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
(2S)-1-(tert-Butoxycarbonyl)-2-[1-hydroxy-2-(4-methoxyphenoxy)ethyl]pyrrolidine (1.57 g) was dissolved in 4N hydrochloric acid/1,4-dioxane (23 ml), and the mixture was stirred at room temperature for 1 hour. The residue obtained by concentration and drying of the reaction mixture was dissolved in DMF (15 ml), and subjected to the condensation reaction using N-(tert-butoxycarbonyl)-L-proline (1.00 g), N-methylmorpholine (0.51 ml), HOBt (0.75 g) and DCC (0.96 g) in the same manner as in Example 46-C) to give 1.41 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.Cl.CCN(C(C)C)C(C)C.[C:42]([Cl:45])(=[O:44])[CH3:43]>CN1C(=O)CCC1>[C:42]([N:25]1[CH2:26][CH2:27][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[CH:31][C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1)(=[O:44])[CH3:43].[ClH:45]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1ccccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCC(c2ccc(Nc3cc(NCc4ccccc4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Compound 4-(2-fluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 106) HCl salt (100 mg, 0.2 mmol) was stirred in 5 mL NMP. To the solution were added DIEA (0.18 mL, 1.0 mmol) and acetyl chloride (0.022 mL, 0.3 mmol). The mixture was stirred at RT for 15 min and quenched with Me2NH. The mixture was concentrated in vacuo and subjected to reverse phase prep HPLC to isolate the title compound as HCl salt. UV=259 nm. M+H found for C26H28FN5O2: 462.5. NMR (CD3OD): 8.12 (1H, s), 7.37 (1H, m), 7.34 (2H, d, J=8.4 Hz), 7.28 (1H, m), 7.18 (1H, m), 7.15-7.10 (3H, m), 5.88 (1H, s), 4.69 (1H, m), 4.51 (2H, s), 4.06 (1H, m), 3.24 (1H, m), 2.89 (1H, m), 2.73 (1H, m), 2.15 (3H, s), 1.92 (2H, m), 1.66 (2H, m) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:13][C:14](Cl)=[CH2:15])[C:10]([NH2:12])=[S:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>O>[NH:12]=[C:10]1[N:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[CH:13]=[C:14]([CH3:15])[S:11]1
Reactant: C=C(Cl)CN(C(N)=S)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cn(-c2cc(Cl)cc(Cl)c2)c(=N)s1
Temperature: 90 °C
Yield: 60.8 %

Procedure:
N-(3,5-dichlorophenyl)-N-(2-chloro-2-propenyl)thiourea (0.30 g) was added to 90% sulfuric acid (3.5 g) at room temperature with stirring, and the mixture was heated to 90° C. and stirred at the same temperature for 1.0 hour. After cooling, water was added to the reaction mixture, which was then neutralized by addition of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water. The solvent was removed by distillation under reduced pressure, and the residual oily material was subjected to column chromatography on silica gel, which afforded 0.16 g of 2-imino-3-(3,5-dichlorophenyl)-5-methyl-4-thiazoline (62% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([C:27]2[N:28]=[C:29]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:30][CH:31]=2)[CH:24]=[CH:25][CH:26]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:35]2[CH2:34][CH2:33][CH:32]([C:29]3[S:30][CH:31]=[C:27]([C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[CH:22]=4)[N:28]=3)[CH2:37][CH2:36]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Fc1cccc(-c2csc(C3CCNCC3)n2)c1
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(NC(=O)N2CCC(c3nc(-c4cccc(F)c4)cs3)CC2)cn1
Temperature: 70 °C
Reaction time: 12 h
Yield: 57.6 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (274 mg, 0.839 mmol), 4-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperidine (200 mg, 0.762 mmol) and diisopropylethylamine (0.266 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 12 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (193 mg, 57.5%) as a solid.
Reaction SMILES: [CH:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:2].[CH2:16]([N:18](CC)CC)C.CN>C(Cl)(Cl)Cl>[CH3:16][NH:18][S:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:3]([CH:1]=[O:2])[CH2:4][CH2:5]2)(=[O:14])=[O:13]
Reactant: CCN(CC)CC
Reactant: O=CN1CCc2cc(S(=O)(=O)Cl)ccc21
Agent: CN
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1ccc2c(c1)CCN2C=O
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a solution of 31.07 g (0.126 mol) of N-formyl-5-chlorosulfonylindoline in 400 ml of ice-cold methylene chloride was added 37 ml (0.252 mol) of triethylamine and 30 ml (0.252 mol) of 40% aqueous methylamine solution, portionwise over twenty minutes. The mixture was allowed to warm to room temperature and then heated to reflux in an oil bath for one hour while stirred mechanically. Thin layer chromatography with chloroform showed the reaction was complete. The aqueous layer was removed. The methylene chloride layer was washed with water and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue allowed to air dry to give 23.74 g (0.0988 mol) (75% by weight yield) of 5-methylsulfamoyl-N-formylindoline.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:6][C:7]1[O:11][C:10]([CH2:12][S:13][CH2:14][CH2:15][NH2:16])=[CH:9][CH:8]=1)[CH3:5].[O-:17][C:18]#[N:19].[K+].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:5][N:4]([CH2:6][C:7]1[O:11][C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:18]([NH2:19])=[O:17])=[CH:9][CH:8]=1)[CH3:3]
Reactant: N#C[O-]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(C)Cc1ccc(CSCCNC(N)=O)o1

Procedure:
A solution of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine dihydrochloride (2.8 g) and potassium cyanate (3.75 g) in water (50 ml) was heated on a steam bath for 8 hr. Excess solid sodium carbonate was added and organic material continually extracted with diethyl ether. The extracts were evaporated and the residue after column chromatography yielded N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]urea as a waxy solid (1.28 g). Analysis Found: C, 48.22; H, 7.50; N, 15.61. C11H19N3O2S.H2O requires: C, 48.00; H, 7.63; N, 15.27%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:7]=1.[H-].[Na+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:18]1([S:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([C:2]3[N:3]([S:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:34])=[O:33])[CH:4]=[CH:5][N:1]=3)=[CH:7]2)(=[O:17])=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ncc[nH]2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccnc1-c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of 3-(1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (9ya) (20 mmol) in anhydrous THF (300 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.2 equiv, 24 mmol) and stirred for 20 min Benzenesulfonyl chloride (1.2 equiv, 24 mmol) was added and the reaction mixture was stirred overnight. After dilution by 200 mL of saturated NaHCO3 solution (aqueous), the reaction mixture was extracted by ethyl acetate (600 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 5:1) to give a white solid. Yield: 40%. 1H NMR (CDCl3, 300 MHz) δ 8.02-8.08 (m, 4H), 7.72 (d, J=1.5 Hz, 1H), 7.35-7.60 (m, 8H), 7.23 (d, J=1.5 Hz, 1H), 7.10-7.16 (m, 3H). MS (ESI) calcd for C23H17N3O4S2 463.1. found 486.01[M+Na]+.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]=O>[CH2:12]1[O:10][C:9]2[C:2](=[C:3]([CH:6]=[CH:7][CH:8]=2)[CH:4]=[O:5])[O:1]1
Reactant: O=Cc1cccc(O)c1O
Reactant: BrCBr
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc2c1OCO2
Yield: 85.6 %

Procedure:
A mixture containing 2,3-dihydroxybenzaldehyde, (50 g) dibromomethane (188 g), potassium carbonate (150 g) and copper (II) oxide (1.4 g) in dimethylformamide (2 L) was heated at reflux for 4 hours. The reaction mixture was cooled, filtered and evaporated. The residue was dissolved in toluene and the organic layer was washed with staurated sodium bicarbonate and brine. The layer was then dried, filtered and evaporated to yield 46.5 g of 2,3-methylenedioxybenzaldehyde mp 32°-33° C.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:80])[CH2:15][C@@H:16]([NH:69]C(OCC1C=CC=CC=1)=O)[CH2:17][CH2:18][CH2:19][NH:20][C:21]([C@H:23]1[N:41]([CH2:42][CH3:43])[C:40](=[O:44])[C@H:39]([CH2:45][CH2:46][CH2:47][NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[NH:38][C:37](=[O:56])[C@@H:36]([NH:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:35][C:34]2[CH:65]=[C:30]([CH:31]=[CH:32][C:33]=2[OH:66])[C:29]2=[CH:67][C:25](=[C:26]([OH:68])[CH:27]=[CH:28]2)[CH2:24]1)=[O:22])C1C=CC=CC=1>C(O)C.[Pd]>[C:52]([O:51][C:49](=[O:50])[NH:48][CH2:47][CH2:46][CH2:45][C@@H:39]1[NH:38][C:37](=[O:56])[C@@H:36]([NH:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:35][C:34]2[CH:65]=[C:30]([CH:31]=[CH:32][C:33]=2[OH:66])[C:29]2=[CH:67][C:25](=[C:26]([OH:68])[CH:27]=[CH:28]2)[CH2:24][C@@H:23]([C:21]([NH:20][CH2:19][CH2:18][CH2:17][C@H:16]([NH2:69])[CH2:15][C:14]([NH:13][CH2:12][CH2:11][NH2:10])=[O:80])=[O:22])[N:41]([CH2:42][CH3:43])[C:40]1=[O:44])([CH3:53])([CH3:54])[CH3:55]
Reactant: CCN1C(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H]1C(=O)NCCC[C@@H](CC(=O)NCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCN1C(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H]1C(=O)NCCC[C@H](N)CC(=O)NCCN
Reaction time: 15 h

Procedure:
14.5 mg (0.013 mmol) of benzyl(2-{[(3S)-3-{[(benzyloxy)carbonyl]amino}-6-({[(8S,11S,14S)-14-[(tert-butoxycarbonyl)amino]-11-{3-[(tert-butoxycarbonyl)amino]propyl}-9-ethyl-5,17-dihydroxy-10,13-dioxo-9,12-diazatricyclo[14.3.1.12,6]henicosa-1(20),2(21),3,5,16,18-hexaen-8-yl]carbonyl}amino)hexanoyl]amino}ethyl)carbamate (Example 176A) are dissolved in 3 ml of ethanol. 15 mg of palladium on activated carbon (10%) are added thereto, and the mixture is then hydrogenated under atmospheric pressure for 15 h. The reaction mixture is filtered through prewashed kieselguhr, and the filtrate is concentrated on a rotary evaporator in vacuo. The crude product is reacted without further purification.
Reaction SMILES: [F:1][C:2]1(F)[C:15](F)([F:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[NH4+].[OH-]>C1COCC1.[Zn]>[F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=1[F:16])=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: FC1(F)c2ccccc2-c2ccccc2C1(F)F
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: C1CCOC1
Product: Fc1c(F)c2ccccc2c2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.2 %

Procedure:
A solution of the 9,9,10,10-tetrafluoro-9,10-dihydrophenanthrene (1.96 g, 7.75 mmol) in THF (15 ml) was treated with 30% aqueous NH4OH (30 ml) and zinc (2.52 g, 38.75 mmol) and stirred under N2 for 24 hours at room temperature. The reaction was monitored by GC/MS for disappearance of the starting material and found to be complete. The solution was filtered, extracted with hexane (30 ml), and filtered through a short silica column (20 g). The hexane solution was evaporated in vacuo to afford an oil. This crystallized on cooling to room temperature to afford 1.58 g (95% yield) of product.