Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[CH2:10]1.Cl[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34].C1(C)C=CC=CC=1>C1COCC1>[OH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][C@@H:9]([NH:8][C:33](=[O:34])[O:35][CH:36]([CH3:38])[CH3:37])[CH2:10]2)[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[N:17]=1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: -70 °C
Yield: 38 %

Procedure:
At RT under an N2 atmosphere, triethylamine (23 mL, 0.31 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg, 0.16 mmol) in THF (1.5 mL), and the reaction was cooled to −70° C. A 1.0 M solution of isopropyl chloroformate in toluene (133 μL, 0.15 mmol) was added, and the mixture was warmed to RT. The reaction was quenched with H2O and extracted with CH2Cl2. The combined organic extracts were washed twice with H2O, dried over Na2SO4, and concentrated. Purification via silica gel chromatography using 0-20% EtOAc in a 1:1 mixture of CH2Cl2 and hexanes gave (R)-isopropyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 12) (23 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (dd, J=8.1, 1.6 Hz, 1H), 8.17 (d, J=8.6 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J=5.9 Hz, 1H), 7.38-7.32 (m, 2H), 6.94-6.90 (m, 2H), 4.81-4.74 (m, 1H), 4.25-4.11 (m, 3H), 4.06-4.01 (m, 1H), 3.85 (dd, J=11.1, 3.5 Hz, 1H), 2.49 (s, 3H), 2.25-2.17 (m, 1H), 2.05-1.99 (m, 1H), 1.20-1.15 (m, 6H) ppm. LC/MS: m/z 407.5 (M+H)+ at 2.44 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH2:11])[C:9]=1[Cl:10])[C:5]#[N:6].Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19]>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:11][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:9]=1[Cl:10])[C:5]#[N:6]
Reactant: N#Cc1cc(N)c(Cl)c(N)c1
Reactant: COCCOCCBr
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCCOCCNc1cc(C#N)cc(N)c1Cl
Temperature: 100 °C
Yield: 28.2 %

Procedure:
To a solution of 3,5-diamino-4-chlorobenzonitrile (220 mg, 1.313 mmol) in DMF (3 mL) was added IIlunig's Base (2.75 mL, 15.75 mmol) followed by 1-bromo-2-(2-methoxyethoxy)ethane (1442 mg, 7.88 mmol). The resulting solution was heated at 100° C. for 16 h. LC-MS indicated ca. 30% conversion. It was diluted with EtOAc and water. After separating the layers, the aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over MgSO4, filtered and concentrated. Purification via silica gel chromatography (0-70% EtOAc in Hexanes, 24 g) gave 3-amino-4-chloro-5-((2-(2-methoxyethoxy)ethyl)amino)benzonitrile (100 mg) as an orange oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15]([NH:17][C:18]1[CH:49]=[CH:48][C:21]([C:22]([N:24]([CH3:47])[C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=3[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)=[O:39])=[O:23])=[CH:20][C:19]=1[O:50][CH3:51])=[O:16])[CH:11]=[CH:10][CH:9]=2)=[O:5])C.Cl.CO>[OH-].[Na+].C(O)C>[C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15]([NH:17][C:18]1[CH:49]=[CH:48][C:21]([C:22]([N:24]([CH3:47])[C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=3[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)=[O:39])=[O:23])=[CH:20][C:19]=1[O:50][CH3:51])=[O:16])[CH:11]=[CH:10][CH:9]=2)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)cccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 72.9 %

Procedure:
The solution of 4-[(2-ethoxycarbonylindol-4-yl)-carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (100 mg) in a mixture of 1 N aqueous sodium hydroxide solution (0.43 ml) and ethanol (4.0 ml) was stirred at ambient temperature for 5.5 hours. The resulting solution was neutralized with 1 N hydrochloric acid and methanol was removed in vacuo. The residue was diluted with water and the aqueous layer was extracted with chloroform. Drying, filtering and removal of solvents afforded 4-[(2-carboxyindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (70 mg) as a yellow amorphous.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH3:2].CCN(C(C)C)C(C)C.[C:20]1([CH3:31])[CH:25]=[CH:24][C:23]([NH:26][CH2:27][C:28](O)=[O:29])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[C:28](=[O:29])[CH2:27][NH:26][C:23]1[CH:24]=[CH:25][C:20]([CH3:31])=[CH:21][CH:22]=1)[CH3:2]
Reactant: Cc1ccc(NCC(=O)O)cc1
Reactant: CCNCc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCN(Cc1ccccn1)C(=O)CNc1ccc(C)cc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
A suspension of ethyl-pyridin-2-ylmethyl-amine (29.0 mmol) and DIPEA (78.0 mmol) in DMF (50 mL) was cooled to −20° C. and added to a cold (−20° C.) solution of p-tolylamino-acetic acid (26.0 mmol) and TBTU (34.0 mmol) in DMF (100 mL). The reaction mixture was stirred for 15 min at −20° C. Water (300 mL) and ethyl acetate (400 mL) were added, the layers were separated and the organic layer washed with water (4×100 mL). The combined aqueous layers were extracted with ethyl acetate (200 mL). The combined organic layers were washed with NaOH solution (1.0 mol/L, 100 mL) and brine (100 mL) and dried with Na2SO4. The solvents were removed in vacuo and the obtained solid was dissolved in ethanol. By addition of a solution of hydrogen chloride in ether a byproduct precipitated which was filtered off. Dilution of the remaining solution with ether led to precipitation of the desired acetamide, which was obtained as a white solid (5.3 g).
Reaction SMILES: [N:1]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24][C@H:2]1[C:3]([NH:5][C@@H:6]([C:12]([NH:14][C@H:15]([C:20]([O:22]C)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[C:7]([S:10][CH3:11])([CH3:9])[CH3:8])=[O:4].[OH-].[Na+]>CO>[N:1]1([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:26][CH2:25][CH2:24][C@H:2]1[C:3]([NH:5][C@@H:6]([C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[C:7]([S:10][CH3:11])([CH3:9])[CH3:8])=[O:4]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(C)(C)SC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSC(C)(C)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O
Temperature: 25 °C
Yield: 103 %

Procedure:
To a solution of Boc-Pro-DPen(Me)-Leu-OMe (0.94 g, prepared in Example (9-e)) in methanol (2.5 mL) was added 1N NaOH (2.5 mL) under ice-cooling. The mixture was stirred under ice-cooling for 30 min and at room temperature for 1 h. The mixture was evaporated under reduced pressure to remove methanol and water (20 mL) was added to the residue. The mixture was extracted with diethyl ether (20 mL). The aqueous layer was acidified with 10% aq. citric acid and extracted with ethyl acetate (10 mL×3). The combined ethyl acetate extracts were washed with brine (10 mL), dried over MgSO4 and evaporated under reduced pressure to give the product (0.94 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][CH:9]=3.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(OCC)(=O)C.CCCCCC>[CH2:26]([N:7]1[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([O:17][CH3:18])[CH:12]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: COc1ccc2c(c1)Sc1cc(OC)ccc1N2
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCN1c2ccc(OC)cc2Sc2cc(OC)ccc21

Procedure:
A suspension of 15.0 g (57.8 mmol) of 3,7-dimethoxy-phenothiazine, 31.9 g (0.231 mmol) of powdered potassium carbonate, 61.29 g (0.289 mol) of 1-iodohexane and 1.6 g (5.0 mmol) of tris-[2-(2-methoxymethoxy)ethyl]amine was heated to 110° for 64 hours. The working up was effected analogously to that described in Example 4.1.1.b. After chromatography on silica gel with ethyl acetate/hexane (1:4) 18.33 g (91.8%) of 10-hexyl-3,7-dimethoxy-phenothiazine were obtained as a brownish oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=3)=[CH:25][N:24]=2)=[CH:19][CH:18]=1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:44]1[CH2:48][CH2:47][C@H:46]([C:49]([O:51][CH3:52])=[O:50])[CH2:45]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[CH:25][C:26]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][CH:34]=3)=[CH:27][N:28]=2)=[CH:19][CH:18]=1)[C:13]([N:44]1[CH2:48][CH2:47][C@H:46]([C:49]([O:51][CH3:52])=[O:50])[CH2:45]1)=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CCNC1
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)O)cc3)nc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)N4CC[C@H](C(=O)OC)C4)cc3)nc2)cc1
Reaction time: 4 h
Yield: 52 %

Procedure:
Prepared using General Procedure 7. To a stirring solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid INT-22 (2082 mg, 2.75 mmol), methyl (S)-pyrrolidine-3-carboxlate HCl (545 mg, 3.30 mmol), and DIEA (1523 μl, 8.25 mmol) in DMF (6 mL) cooled to 0° C. was slowly added a solution of HATU (1254 mg, 3.30 mmol) in DMF (5 mL) in a drop-wise fashion The reaction mixture was allowed to warm slowly and stirring continued for 4 h. The reaction mixture was poured onto ice-water and the solid was filtered. The solid was dissolved in EA (50 mL), dried over MgSO4, evaporated and purified by chromatography (EA/hexane) to provide 932 mg (52%) of methyl (S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate. LCMS-ESI (m/z) calculated for C40H46N4O6: 678.3. found 679.3 [M+H]+, tR=4.50 min (Method 16).
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:16])([CH3:15])[C:5](=[O:14])[NH:6]2.[H-].[Na+].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1.[Cl-].[NH4+]>CN(C=O)C>[CH:21]1([CH2:20][N:6]2[C:7]3[C:3](=[C:2]([F:1])[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=3)[C:4]([CH3:16])([CH3:15])[C:5]2=[O:14])[CH2:23][CH2:22]1
Reactant: BrCC1CC1
Reactant: CC1(C)C(=O)Nc2ccc([N+](=O)[O-])c(F)c21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(CC2CC2)c2ccc([N+](=O)[O-])c(F)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one (300 mg) in DMF (10 mL) were added sodium hydride (69.6 mg) and (bromomethyl)cyclopropane (0.193 mL) at 0° C., and the mixture was allowed to be warmed to room temperature, and stirred overnight under a nitrogen atmosphere. The reaction mixture was cooled to 0° C., saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (317 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[N:38]=2)[N:3]=1.[ClH:44].[H][H]>CO.C(O)(C)C.[Pd]>[ClH:44].[ClH:44].[ClH:44].[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[N:38]=2)[N:3]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(C6=CCN(C(=O)OC(C)(C)C)CC6)ccn45)cccc32)n1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(C6CCNCC6)ccn45)cccc32)n1
Yield: 17 %

Procedure:
tert-Butyl 4-(3-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Example 51; 0.037 g, 0.064 mmol) was dissolved in 6 mL of methanol and 1.3 mL of 6N HCl in isopropyl alcohol. 10% Pd/C (0.075 g) was added and the mixture hydrogenated under a balloon of hydrogen for 2 hours. Celite was added and the mixture was then filtered through GF/F filter paper and the filtrate concentrated under reduced pressure. The crude material was purified by reverse phase chromatography, followed by treatment of the isolated material with 4M HCl/dioxane to provide the title compound (17% yield). MS (APCI), positive scan, m/z=480.3 (M+H).
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([OH:24])(C)[CH2:19]C(C)C)=[O:10].C(OC)(OC)OC.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.S(=O)(=O)(O)O>[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:9]([C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[F:1])=[O:10])(=[O:24])[CH3:19]
Reactant: Cc1nn(C)c(F)c1C(=O)Nc1ccccc1C(C)(O)CC(C)C
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: Cc1ccccc1
Product: CC(=O)c1ccccc1NC(=O)c1c(C)nn(C)c1F
Reaction time: 1 h

Procedure:
14 g (80% pure, 33.6 mmol) of 5-fluoro-N-[2-(1-hydroxy-1,3-dimethylbutyl)phenyl]-1,3-dimethyl-1H-pyrazole-4-carboxamide and 4.28 g (40.3 mmol) of trimethyl orthoformate are dissolved in 420 ml of toluene, and 5 drops of concentrated sulphuric acid are added. The solution is boiled for 1 h, treated with sodium sulphate and filtered off, and the filtrate is concentrated under reduced pressure. The residue is treated with 300 ml of heptane. This results in the N-(2-acetylphenyl)-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide still present in the starting material precipitating out. The filtrate is concentrated using a rotary evaporator, giving 10.7 g of a yellow oil. Examination by GC/MS shows the following composition: 24% A, 25% B, 29% C and 7% of a methanol adduct.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH:10]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][C:24]=3[O:33][CH3:34])[CH2:15][CH2:14]2)=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.CCOCC.N>[F:41][C:38]1[CH:37]=[CH:36][C:35]([CH:10]([CH:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]2)[CH2:11][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][C:24]=3[O:33][CH3:34])[CH2:15][CH2:14]2)=[CH:40][CH:39]=1
Reactant: COc1ccc2ccccc2c1CCCCN1CCN(C(=O)C(c2ccc(F)cc2)C2CCN(C(C)C)CC2)CC1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2ccccc2c1CCCCN1CCN(CC(c2ccc(F)cc2)C2CCN(C(C)C)CC2)CC1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
0.14 g of 1-Isopropyl-4-(1-(4-fluorophenyl)-2-{4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazin-1-yl}-2-oxoethyl)piperidine was dissolved in 5 ml of tetrahydrofuran, and 10 ml of lithium aluminum hydride was added, followed stirring at 50° C. for 15 minutes. The reaction solution was cooled to room temperature and diluted with ether, and 25% aqueous ammonia solution was added dropwise. The precipitate was removed by Celite filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=4:1) to give 0.13 g of 1-[2-(4-fluorophenyl)-2-(1-isopropylpiperidin-4-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:14]([CH3:22])C(=O)OC(C)(C)C)=[C:11](I)[N:12]=2)[CH:5]=[N:6][CH:7]=1.[C:23]([Cu])#[N:24]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([NH:14][CH3:22])=[C:11]([C:23]#[N:24])[N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)c1sc(-c2cncc(F)c2)nc1I
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNc1sc(-c2cncc(F)c2)nc1C#N
Temperature: 120 °C

Procedure:
To a nitrogen-purged solution of tert-butyl 2-(5-fluoropyridin-3-yl)-4-iodothiazol-5-yl(methyl)carbamate (1.0 g, 2.298 mmol) in DMF (8 mL) was added CuCN (288 mg, 3.22 mmol) and the mixture was heated in a microwave at 120° C. for 80 min. The mixture was diluted with ethyl acetate (75 mL) and successively washed with an aqueous solution (15 mL) of ethylene diamine (5% v/v), and brine, dried over MgSO4 filtered, and concentrated on a rotary evaporator under vacuum to give a yellow solid, 2-(5-fluoropyridin-3-yl)-5-(methylamino)thiazole-4-carbonitrile. The solid was used in the preparation of N-(4-cyano-2-(5-fluoropyridin-3-yl)thiazol-5-yl)-N-methyl-3-(methylthio)propanamide. To a solution of crude 2-(5-fluoropyridin-3-yl)-5-(methylamino)thiazole-4-carbonitrile (200 mg, 0.83 mmol) in CH2Cl2 (2 mL) were added K2CO3 (178 mg, 1.28 mmol) and 3-(methylthio)propanoyl chloride (130 mg, 0.94 mmol) followed by dimethylaminopyridine (21 mg, 0.17 mmol). The mixture was stirred at room temperature for 36 h and diluted with ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (5 mL). The organic phase was separated and washed with brine, dried over MgSO4 and concentrated in vacuo to give a brown gummy residue. This residue was purified by silica gel chromatography (6:4 hexane/ethyl acetate) to give N-(4-cyano-2-(5-fluoropyridin-3-yl)thiazol-5-yl)-N-methyl-3-(methylthio)propanamide as a pale yellow solid (164 mg, 57% yield): mp 97-98° C.; 1H NMR (300 MHz, CDCl3) δ 8.98 (bs, 1H), 8.72 (d, J=2.7 Hz, 1H), 8.27 (dt, J=9.6, 1.8 Hz, 1H), 2.73 (t, J=7.5 Hz, 2H), 2.62 (t, J=7.62, 2H), 2.09 (s, 3H), 2.03 (s, 3H): ESIMS m/z 337.2 (M+1).
Reaction SMILES: [Cl:1][CH2:2][Si:3]([Cl:6])(Cl)[Cl:4].[C:7]1([Li])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[Cl:1][CH2:2][Si:3]([Cl:6])([Cl:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [Li]c1ccccc1
Reactant: ClC[Si](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: ClC[Si](Cl)(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
A solution of 25.1 ml (36.8 g, 0.200 mol) of chloromethyltrichlorosilane in 400 ml dry tetrahydrofuran was cooled to -78° under nitrogen and stirred vigorously while 48.0 ml (0.100 mol) of 2.1 molar phenyllithium was slowly dripped in over 1 hour. After stirring another 30 minutes at -78° the solution was allowed to warm to room temperature and evaporated to about 200 ml. Addition of 500 ml ether, filtration to remove precipitated lithium chloride, and evaporation of the filtrate left 25.0 g of liquid. Distillation gave 6.5 g (29%) of the title compound as a colorless liquid: bp 62°-82° (0.15 mm); nmr (CDCl3): δ3.3 (s, 2) and 7.1-7.9 (m, 5).
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:13])[CH2:4][C@H:5]([NH:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:6]O.[C:14](=[S:16])=[S:15].C([O-])([O-])=O.[Cs+].[Cs+]>CC(=O)CC>[CH2:9]([N:8]1[C@@H:5]([CH2:4][CH:3]([CH3:13])[CH3:2])[CH2:6][S:16][C:14]1=[S:15])[CH:10]([CH3:12])[CH3:11]
Reactant: S=C=S
Reactant: CC(C)CN[C@H](CO)CC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CC(C)C[C@H]1CSC(=S)N1CC(C)C
Yield: 47.5 %

Procedure:
To a mixture of (2S)4-methyl-2-(isobutylamino)pentan-1-ol HCl salt (Method B4c; 0.21 g, 1.0 mmol) and CS2 (0.30 mL, 5.0 mmol, 5.0 equiv.) in 2-butanone (20 mL) was added Cs2CO3 (0.72 g, 2.20 mmol, 2.2 equiv.) and the resulting mixture was heated at the reflux temp. overnight. The resulting orange solution was concentrated under reduced pressure and the residue was triturated with EtOAc (25 mL). The remaining solids were washed with EtOAc (25 mL), and the combined EtOAc phases were concentrated under reduced pressure. The residue was absorbed onto SiO2 and purified by MPLC (Biotage 40 S silica gel column; 5% EtOAc/hex) to give (4S)-3,4diisobutyl 1,3-thiazolidin-2-thione as a yellow oil (0.11 g, 52%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[I:17]Cl>C(Cl)Cl>[I:17][C:11]1[S:10][C:9]([NH2:12])=[N:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClI
Reactant: Nc1nc(-c2ccccc2)cs1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1nc(-c2ccccc2)c(I)s1
Reaction time: 0.5 h

Procedure:
4-Phenyl-thiazol-2-ylamine (0.881 g, 5.00 mmol) was dissolved in 10 mL of CH2Cl2 and 2 mL of acetic acid and treated at 0° C. with iodine monochloride (5.25 mL of 1M in CH2Cl2, 1.05 eq.) and kept at this temperature for 0.5 h. Pouring onto crashed ice/Na2CO3, twofold extraction with ethyl acetate, washing with water and brine, drying over sodium sulfate, and evaporation to dryness produced 1.60 g of the title compound as dark brown gum, sufficiently pure to be used for the next step.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH2:19][CH:20]([CH2:27][C:28]2([CH3:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:21]3=[O:26])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].C1COCC1>C(O)C>[C:13]([C:11]1[CH:10]=[C:9]([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH2:19][CH:20]([CH2:27][C:28]2([CH3:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:21]3[OH:26])[CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:12]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CC1(CC2Cc3c(cccc3-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)C2=O)CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(CC2Cc3c(-c4cc(C(C)(C)C)cc(C(C)(C)C)c4)cccc3C2O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Sodium borohydride (1.32 g, 34.83 mmol, 1.5 equiv) was added in portions at 0° C. to a solution of compound 13 (10.0 g, 23.22 mmol, 1.0 equiv), THF (100 mL) and ethanol (100 mL). The reaction mixture was stirred at room temperature overnight, when LCMS indicated that the reaction was complete. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (300 mL) and water (50 mL). 1M HCl was added dropwise to quench the reaction. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated brine (500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound 14 (10.0 g, >99% yield) as a pale-yellow oil. This material was used subsequently.