Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C([O-])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)=O>>[Br:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Br)(Cc1ccccc1)C(=O)[O-]
Agent: O=C=O
Product: CCOC(=O)C(Br)Cc1ccccc1

Procedure:
Ethyl bromo-(phenylmethyl)propandioate (XXVI, Example 60, 130 g.) is heated under reduced pressure to 140° with vigorous evolution of carbon dioxide. When decarboxylation is complete (about 5 minutes), the mixture is distilled to give ethyl 2-bromo-3-phenylpropionate, b.p. 120°/30 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>C1COCC1>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:1][C:20](=[O:23])[CH2:21][CH3:22])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCC(=O)Cl
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Yield: 42 %

Procedure:
To a solution of 7-amino-4-[(3-bromophenyl)amino]-quinazoline (163 mg, 0.52 mmol) in dry THF (3 mL) stirred under N2 at 25° C. was added dropwise propionyl chloride (0.05 mL, 0.58 mmol). A yellow solid formed at once. After 1 hour the solid was collected by Buchner filtration and washed with ether then dried. Recrystallized from wet methanol afforded the desired product as bright yellow solid (81 mg, 38%), mp 282-283° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[F:11].[CH2:12](I)C>C(O)C.O>[F:11][C:3]1[CH:4]=[C:5]([S:8][CH2:9][CH3:12])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: N#CSc1ccc(N)c(F)c1
Reactant: CCI
Solvent: CCO
Solvent: O
Product: CCSc1ccc(N)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A solution of the product of Example 26, Step A, 4-amino-3-fluorophenyl thiocyanate (500 mg, 2.97 mmol), in ethanol (7 mL) was added dropwise to a solution of Na2S.9H2O (714 mg, 2.97 mmol) in water (1.5 mL) and the resulting mixture stirred at 50° C. for 1 hour. A solution of ethyl iodide (510 mg, 3.27 mmol) in ethanol (1 mL) was then added and the reaction stirred at 50° C. for a further 6 hours. The mixture was diluted with water (30 mL) and extracted with Et2O (4×10 mL), then the combined Et2O extracts washed with water (3×20 mL), saturated NaCl (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded a pale yellow oil which was purified by dry flash column chromatography on silica (5% Et2O/hexanes as eluant) to afford 2-fluoro-4-ethylthioaniline as a colourless oil (470 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.08 (dd, J=11.3, 2.0 Hz, 1 H), 7.01 (ddd, J=8.2, 2.0, 0.9 Hz, 1 H), 6.71 (dd, J=9.3, 8.2 Hz, 1 H), 3.81 (br s, 2 H), 2.80 (q, J=7.3 Hz, 2 H), 1.24 (t, J=7.3 Hz, 3 H). Step B: Preparation of 3,4-difluoro-2-[[2-fluoro-4-(ethylthio)phenyl]amino]-benzoic acid
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15](CCC3C=C(C=CC=3)N)[CH2:14][CH2:13]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][C:35]([C:37]1[CH:38]=[C:39]([NH:43][C:44](=[O:46])[CH3:45])[CH:40]=[CH:41][CH:42]=1)=[O:36]>CN(C=O)C.O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:34][C:35]([C:37]3[CH:38]=[C:39]([NH:43][C:44](=[O:46])[CH3:45])[CH:40]=[CH:41][CH:42]=3)=[O:36])[CH2:14][CH2:13]2)[N:3]=1
Reactant: CC(=O)Nc1cccc(C(=O)CCl)c1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(C(=O)CN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Reaction time: 1.5 h
Yield: 42 %

Procedure:
To a stirred solution of 2-methyl-5-(1-piperazinyl)quinoline (D6, 0.14 g, 1 eq) in dry DMF (5 mL) were added potassium carbonate (0.11 g, 1.2 eq) and a solution of N-[3-(2-chloroacetyl)phenyl]acetamide (J. Chem. Soc., 1949, 552, 553, 0.17 g, 1.2 eq) in DMF (3 mL) under an inert atmosphere. The reaction was stirred for 1.5 hrs. The mixture was diluted with water (8 mL) and extracted with DCM (3×15 mL). The organic phase was washed with brine (25 mL), dried over sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified on SPE cartridge (Silica) using as eluant DCM-methanol (95:5), affording the title compound in 42% yield (0.104 g).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([C:44]([OH:46])=O)[CH2:19][S:20][CH2:21][C@H:22]([O:34][C:35](=[O:43])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:23][O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])C3C(=CC=CC=3)C=2C=CC=1.[NH2:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][P:60](=[O:67])([O:64]CC)[O:61]CC>>[NH2:17][C@@H:18]([CH2:19][S:20][CH2:21][C@H:22]([O:34][C:35](=[O:43])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:23][O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:44](=[O:46])[NH:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][P:60](=[O:61])([OH:67])[OH:64]
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Reactant: CCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCC
Product: CCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(O)O)OC(=O)CCCCCCC

Procedure:
The title product was prepared from (5R,9R)-1-(9H-fluoren-9-yl)-9-(octanoyloxy)-3,12-dioxo-2,11-dioxa-7-thia-4-azanonadecane-5-carboxylic acid (1 eq) and diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.3 eq, from example 18, step 4) by following the procedure described for example 20, step 6-8. 1H NMR (DMSO-d6): δ 8.18 (t, 1H), 5.04-5.11 (m, 1H), 4.27 (dd, 1H), 4.10 (dd, 1H), 3.46-3.56 (m, 8H), 3.38-3.56 (m, 4H), 3.27-3.36 (m,1H), 3.18-3.25 (m, 2H), 2.74-2.83 (m, 2H), 2.68 (dd, 1H), 2.57 (dd, 1H), 2.21-2.33 (m, 4H), 1.55-1.67 (m, 2H), 1.44-1.55 (m, 4H), 1.16-1.32 (m, 16H), 0.85 (t, 6H). LRMS [M+H]=687.4.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:8]2.[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl>>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:20]3[CH2:21][O:22]3)=[CH:15][CH:16]=1)[CH2:10]2
Reactant: Oc1ccc(C2C3CC4CC(C3)CC2C4)cc1
Reactant: ClCC1CO1
Product: c1cc(C2C3CC4CC(C3)CC2C4)ccc1OCC1CO1

Procedure:
The title compound was prepared from 4-tricyclo[3.3.1.13,7]decan-2-yl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]([O:31]C)=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:33](O)(=O)C>[OH-].[Na+]>[CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[CH2:12][CH:11]([CH3:33])[CH2:10][CH2:9][C:8]=2[N:7]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:24]([C:29]([OH:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)OC)cc2)c2c(c1=O)CCCC2
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2c(c1=O)CC(C)CC2
Temperature: 60 °C

Procedure:
Using the procedure of Example 31, 0.4 g of product A of Example 32 in 10 ml of 2N sodium hydroxide were reacted. The mixture was stirred over-night at about 60° C. and the medium was cooled to ambient temperature, acidified with glacial acetic acid, decanted, impasted in a solution of 2N hydrochloric acid, separated, dried and crystallized from 50 ml of an ethanol-water 49-1 mixture to obtain 0.220 g of the expected product melting at 255° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([OH:14])=O)=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:17])=O>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([Cl:17])=[O:14])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)COc1nc(Cl)c(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)COc1nc(Cl)c(Cl)cc1Cl

Procedure:
To a stirred slurry of 30 g (0.1237 mole) 3,5,6-trichloro-2-pyridyloxyacetic acid in 500 ml methylene chloride, 1 ml N,N-dimethylformamide was added. Then 16.2 g [10 m' (0.136 mole)] thionyl chloride was added dropwise. The mixture was refluxed 31/2 hours. The solvent was stripped in vacuo to give the 3,5,6-trichloro-2-pyridyloxyacetyl chloride as an oil, which was used in step (b) without further isolation.
Reaction SMILES: C(O[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2(O)[CH2:19][CH:18]([CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.CS(O)(=O)=O>CCO.[Pd]>[C:10]1([CH3:9])[CH:11]=[CH:12][C:13]([CH:16]2[CH2:17][CH:18]([CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:19]2)=[CH:14][CH:15]=1
Reactant: OC1(c2ccc(COCc3ccccc3)cc2)CC(CN2CCCC2)C1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CCO
Product: Cc1ccc(C2CC(CN3CCCC3)C2)cc1
Yield: 77 %

Procedure:
To a stirring solution of Example 212, (1-(4-benzyloxymethyl-phenyl)-3-pyrrolidin-1-ylmethyl-cyclobutanol) (200 mg, 0.57 mmol) in EtOH (10 mL) was added methane sulfonic acid (370 uL, 5.7 mmol), followed by 10% Pd/C (200 mg). The reaction vessel was purged with N2, and then pressurized with 45 psi H2. After 30 minute the reaction vessel was purged with nitrogen. The reaction was filtered through a plug of Celite and then concentrated under reduced pressure. The residual was dissolved in EtOAc and a solution of HCl (2 N in ether) was added. The solution was decanted and the residual was purified. Purification of this material was accomplished by dry pack flash column chromatograpy using a 40 g ISCO column, eluting with a gradient of 5%–15% MeOH/CH2Cl2 with 0.2% NH4OH. The product containing fractions were collected and concentrated to give the title compound (100 mg, 77% yield) as a colorless oil. The HCl salt of the title compound was made by dissolving the title compound in ethyl acetate and then adding a solution of HCl (2N in ether), the resulting colorless solid was collected and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.C(O)(=O)C.[N+:15]([CH3:18])([O-:17])=[O:16]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:18]/[N+:15]([O-:17])=[O:16])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C=O
Reactant: C[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Cl)ccc1/C=C/[N+](=O)[O-]
Temperature: 140 °C
Yield: 64.9 %

Procedure:
Under an atmosphere of nitrogen was added to a solution of 4-chloro-2-methylbenzaldehyde (10.0 g, 64.9 g) in acetic acid (70 mL) ammonium acetate (11.5 g, 149 mmol) and nitromethane (10.0 ml, 185 mmol). The solution was stirred at reflux (oil bath 140° C.) for 2 h. After cooling to ambient temperature water (70 mL) was added and extracted twice with ethyl acetate (70 mL). The organic layers were washed with water (70 mL) and brine (70 mL) and were dried over sodium sulfate. The filtrated was concentrated and the resulting solid was suspended in methanol (30 mL), at 0° C. filtered off and was washed with cold methanol (10 mL) affording the title compound (8.30 g, 65%) as a yellow solid. MS m/e: 197.0 [M]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21]([NH2:30])=[C:20]([OH:31])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][C:21]([NH:30][CH:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)=[C:20]([OH:31])[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(O)c(N)cc3-c3ccccc3)cc2)CCC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(O)c(NC4CCOCC4)cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl(1-(4-(5-amino-6-hydroxy-3-phenylpyridin-2-yl)phenyl)cyclobutyl)carbamate (200 mg, 0.46 mmol) in dry DCE (2 ml) was added dihydro-2H-pyran-4(3H)-one (88 mg, 0.88 mmol), AcOH (0.16 ml, 2.78 mmol), sodium triacetoxyborohydride (275 mg, 1.30 mmol) under nitrogen. The resulting mixture was stirred for 3 h at room temperature. A saturated solution of NaHCO3 was added and the mixture was extracted with AcOEt (3×10 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was used in the next step without any purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([OH:29])=O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33]1([CH2:39][CH2:40][NH2:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[C:33]1([CH2:39][CH2:40][NH:41][C:27](=[O:29])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([CH2:23][C@@H:19]3[CH2:20][CH2:21][CH2:22][C@H:18]3[C:9]3[O:10][C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH:25]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCCc1ccccc1
Reactant: O=C(O)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccccc1)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.7 %

Procedure:
To a mixture of 3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzoic acid (140 mg, 0.331 mmol) and 2-phenylethylamine (0.046 ml, 0.364 mmol) in DMF (5 ml) was added 1-hydroxybenzotrioxazole (49 mg, 0.364 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (95 mg, 0.495 mmol). After stirring the mixture at room temperature for 2.5 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with water, saturated sodium hydrogencarbonate solution, water, and brine. The resultant mixture was dried over magnesium sulfate, and evaporated in vacuo. The resultant residue was purified by silica gel column chromatography (hexane:EtOAc, 2:1 elution) to give N-(2-phenylethyl)-3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzamide (172.1 mg, 99%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:33][CH2:32][C:26]4([O:31][CH2:30][CH2:29][CH2:28][O:27]4)[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:13]=1>>[CH3:21][N:18]1[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][C:26]3([O:27][CH2:28][CH2:29][CH2:30][O:31]3)[CH2:32][CH2:33]2)=[N:16][C:15]2[C:19]1=[N:20][C:12]([N:3]1[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]1[CH3:1])=[N:13][C:14]=2[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: Cn1c(CN2CCC3(CC2)OCCCO3)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC4(CC3)OCCCO4)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 9-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-1,5-dioxa-9-azaspiro[5.5]undecane were reacted to give 400. LCMS m/z: 519.2 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[N+:35]([O-])=O)[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])=[O:7]>C(O)C.C(OCC)(=O)C.[Fe]>[NH2:35][C:34]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1N
Temperature: 25 °C
Yield: 80.5 %

Procedure:
A mixture of 3-methoxy-4-nitro-N-methyl-N-[4-methyl-2-[5-(4methylpiperazin-1-ylcarbonyl)pent-1-yloxy]phenyl]benzamide (6.2 g) and iron powder (3.43 g) in a mixture of ethanol (65 ml) and ethyl acetate (6 ml) was refluxed for 2 hours. After being cooled to ambient temperature, the solution was filtered through a bed of Celite and the filtrate was evaporated in vacuo. The residue was diluted with ethyl acetate and the solution was washed with saturated sodium hydrogen carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 4-amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-ylcarbonyl)pent-1-yloxy]phenyl]benzamide (4.7 g ).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:13][N:14]([CH3:19])[S:15](Cl)(=[O:17])=[O:16]>C1C=CC=CC=1>[CH3:13][N:14]([CH3:19])[S:15]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:17])=[O:16]
Reactant: c1c[nH]cn1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Imidazole (1) (20.0 g, 0.29 mol), triethylamine (41.0 mL, 0.29 mol) and N,N-dimethylsulfamoyl chloride (31.6 mL, 0.29 mol) were added to 320 mL of benzene. The reaction was stirred for 48 h at room temperature (rt) and then filtered. The filtrate was collected and concentrated under reduced pressure. Vacuum distillation of the crude product (˜0.5 mmHg, 115°-118° C.) afforded 38.7 g (76%) of a clear and colorless oil. Upon cooling the product solidifies to give white crystals (2). 1-(Dimethylsulfamoyl) imidazole (2) (18.8 g, 0.11 mol) was added to 430 mL of tetrahydrofuran (THF). The solution was cooled to −78° C. A solution of n-butyl lithium (n-BuLi) in hexane (1.6M, 70.9 mL, 0.11 mol) was added dropwise to the reaction flask. Upon completion, the reaction was stirred for 1 h at −78° C. t-Butyldimethylsilylchloride (17.8 g, 0.12 mol) in 50 mL of THF was added via cannula to the reaction. After the addition was completed the reaction mixture was warmed slowly to rt and then stirred for 24 h. The reaction was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography (20% ethyl acetate/hexane as eluant) afforded a light yellow solid. Recrystallization from pentane gave 30 g (94%) of white crystals (3). 1-Dimethylsulfamoyl-2-t-butyldimethylsilyl imidazole (3) (5.0 g, 17.3 mmol) was added to 100 mL of THF. The solution was cooled to −20° C. A solution of secondary butyl lithium (s-BuLi) in hexane (1.3M, 14.6 mL, 19 mmol) was added dropwise to the reaction flask. Upon completion the reaction was stirred for 1 h at −20° C. 8 mL of dimethylformamide (DMF) was added to the reaction and then stirred at rt for 3.5 h. The reaction was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography (20% ethyl acetate/hexane) afforded a light yellow oil. Upon cooling the product solidifies to give yellow crystals of 1-dimethylsulfamoyl-2-t-butyldimethylsilyl -5-imidazolecarboxaldehyde (4).
Reaction SMILES: ClC1C=CC(C2(C3C=CC(Cl)=CC=3)[O:12][C:11]3[CH:13]=[CH:14][C:15]([CH2:17][C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:21]=4)=[O:19])=[CH:16][C:10]=3[O:9]2)=CC=1>C(O)(=O)C.O>[OH:9][C:10]1[CH:16]=[C:15]([CH2:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:21]=2)=[O:19])[CH:14]=[CH:13][C:11]=1[OH:12]
Reactant: CCOC(=O)CCCn1cc(C(=O)Cc2ccc3c(c2)OC(c2ccc(Cl)cc2)(c2ccc(Cl)cc2)O3)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCn1cc(C(=O)Cc2ccc(O)c(O)c2)c2ccccc21
Yield: 76.3 %

Procedure:
Ethyl 4-(3-[(2,2-di[4-chlorophenyl]-1,3-benzodioxolan-5-yl)methylcarbonyl]indol-1-yl)butanoate (9.5 g) (see Preparation 9) was dissolved in acetic acid/water (9:1 ) (100 ml) and heated under reflux for one hour. The reaction mixture was cooled, evaporated to dryness and partitioned between ethyl acetate and brine. The organic layer was separated, dried (MgSO4) and evaporated to a brown oil. Flash chromatography (silica, eluant=10:1 dichloromethane/ethanol) gave the title compound as a pale tan solid (4.5 g). LRMS m/z=382 (m+1)+.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([NH2:8])=[O:7])(N)=[O:2].[CH2:9](N)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Cl>CN1CCCC1=O>[CH2:9]([N:8]1[C:6](=[O:7])[NH:5][NH:4][C:1]1=[O:2])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NC(=O)NNC(N)=O
Reactant: CCCCCCN
Agent: Cl
Solvent: CN1CCCC1=O
Product: CCCCCCn1c(=O)[nH][nH]c1=O

Procedure:
60 g of hydrazodicarbonamide and 56 g of n-hexylamine are stirred in 100 ml of N-methy pyrrolidone for 6 hours at 150° C., for 20 hours at 175° C. and for 20 hours at 180° C. The solvent is then distilled off in vacuo and the residue is triturated with 100 ml of 10% sodium hydroxide solution. The deposit is isolated by filtration under suction and the filtrate is neutralised with 10% hydrochloric acid. A deposit is precipitated and is isolated by filtration under suction, washed with water and dried in vacuo, giving 75 g (81% of the theoretical yield) of 4-(n-hexyl)-1,2,4-triazolidine-3,5-dione in the form of colourless crystals melting at 144° C. to 145° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][N:38]=1)[C:33](O)=[O:34].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[CH3:15][C:4]1[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[N:17]=[C:18]([NH:21][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][N:38]=[C:30]([F:29])[CH:31]=2)[S:19][CH:20]=1
Reactant: O=C(O)c1ccnc(F)c1
Reactant: Cc1cc(Sc2cnccn2)cc(C)c1-c1csc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Sc2cnccn2)cc(C)c1-c1csc(NC(=O)c2ccnc(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-(pyrazin-2-ylthio)phenyl)thiazol-2-amine (11-5, 200 mg, 0.60 mmol) in CH2Cl2 (2.0 mL) was added triethylamine (0.20 mL, 1.9 mmol) followed by 2-fluoroisonicotinic acid (107.7 mg, 1.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (243.9 mg, 1.27 mmol) and hydroxybenzotriazole (172.0 mg, 1.27 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered, and dried under vacuum to give N-{4-(2,6-dimethyl-4-(pyrazin-2-ylthio)phenyl)thiazol-2-yl}-2-fluoroisonicotinamide (19, 68.4 mg) as yellow solids in 25% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.10 (s, 1 H), 8.47-8.50 (m, 2 H), 8.36-8.41 (m, 2 H), 7.96 (s, 1 H), 7.80 (s, 1 H), 7.41 (s, 2 H), 7.33 (s, 1 H), 2.13 (s, 6 H); ESI-MS: m/z 438.1 (M+H)+.