Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.[Li]CCCC.CN(C)[CH:19]=[O:20]>O1CCCC1>[O:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:19]=[O:20])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: Ic1ccc2c(c1)CCCO2
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 6-iodochroman (13.8 g, 53.1 mmol) in tetrahydrofuran (THF) (143 mL) was cooled to −78° C. in a dry ice/acetone bath and then treated with n-BuLi, 2.5M solution in hexanes (23.35 mL, 58.4 mmol). The mixture was stirred for 10 minutes before being treated with N,N-dimethylformamide (6.16 mL, 80 mmol) and the resultant was warmed to ambient temperature and stirred for 10 minutes. The mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford the crude chroman-6-carbaldehyde as a yellow solid which was used without further purification. LC/MS (m/z) ES+=163.22 (M+1). A solution of the crude chroman-6-carbaldehyde, methyl 3-oxobutanoate, piperidine (0.263 mL, 2.66 mmol) and AcOH (0.152 mL, 2.66 mmol) in Benzene (113 mL) was refluxed (DS-trap) overnight. The mixture was concentrated and diluted with ethyl acetate. The dilution was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-30% hexanes/ethyl acetate) the afford methyl 2-(chroman-6-ylmethylene)-3-oxobutanoate (mixture of E and Z isomers, 8.352 g, 32.08 mmol, 60.47% yield) as a thick yellow oil. 1H NMR (400 MHz, CHLOROFORM-d, major isomer) δ ppm 7.48 (s, 1 H), 7.22-7.12 (m, 2 H), 6.78 (d, J=8.6 Hz, 1 H), 4.27-4.18 (m, 2 H), 3.92-3.81 (m, 3 H), 2.77 (t, J=6.3 Hz, 2 H), 2.39 (s, 3 H), 2.06-1.99 (m, 2 H); 1H NMR (400 MHz, CHLOROFORM-d, minor isomer) δ ppm 7.58 (s, 1 H), 7.16-7.08 (m, 2 H), 6.79-6.71 (m, 1 H), 4.23-4.18 (m, 2 H), 3.84-3.78 (m, 3 H), 2.76 (t, J=6.4 Hz, 2 H), 2.38 (s, 3 H), 2.03-1.96 (m, 2 H); LC/MS (m/z) ES+=261.2 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][S:6][C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1>S(=O)(=O)(O)O>[CH3:5][S:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:1]([O-:4])=[O:2])[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: O=[N+]([O-])O
Reactant: CSc1nc2ccccc2s1
Agent: O=S(=O)(O)O
Product: CSc1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 5 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
See FIG. 4A. Fuming nitric acid (1.93 g) was added dropwise to a solution of 2-(methylthio)benzothiazole (5 g) in concentrated sulfuric acid (16.8 g) cooled in an ice bath. After stirring at 5° C. for 3 h the solution was poured onto ice and filtered to provide a yellow solid (5.7 g, 25 mmol, 91%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[O-2:10].[Ca+2:11]>O>[C:1]([O:9][OH:10])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[Ca+2:11].[Ca+2:11].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: [O-2]
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])CC(O)C(=O)OO

Procedure:
A large batch of dicalciumhydroxy malate is produced by mixing 19.16 kg of malic acid in 68.19 L of water. In a separate tank, 16.33 kg of calcium oxide is mixed in 68.19 L of water. These two aqueous solutions are slowly mixed together and stirred continuously. A milky solution containing the product resulted, which is spray dried to obtain a powdered product of dicalciumhydroxy malate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@H:10]([CH2:26][C:27](O)=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C@H:10]([CH2:26][C:27]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reactant: CS(N)(=O)=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)C[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
To a solution of 2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic acid (Example 41) (83 mg, 0.192 mmol), methanesulfonamide (22.59 mg, 0.230 mmol) and 4-dimethylaminopyridine (1.057 mg, 0.00865 mmol) in DCM (2 mL) was added diisopropylethylamine (80 μL, 0.461 mmol). The reaction mixture was stirred at room temperature for one minute before adding bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (125 mg, 0.269 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with 1N HCl and the aqueuos layer was extracted with DCM (10 mL). The combined organic layers were washed with 1N HCl, 1N NaOH, sat. aq. NaCl solution and concentrated under reduced pressure. The residue was purified by reversed phase preparatory HPLC (column: Gemini-NX C18 5 μm column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) to afford the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[C:8](OC)(=[O:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13]([O-:15])=[O:14])=[CH:11][CH:10]=1>ClCCl.Cl>[N:1]1([C:8]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)c1ccc(C(=O)N2CCCCC2)cc1
Reaction time: 2 h

Procedure:
6 ml of piperidine was stirred in dichloromethane at 0° C., and a solution of 3 g (15 mmol) of monomethyl terephthalate chloride in dichloromethane was added to the resultant mixture. The temperature was elevated to room temperature, and they were stirred for 2 hours and then diluted with 1 N hydrochloric acid. After the extraction with dichloromethane, the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated aqueous NaCl solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was stirred in ethanol. 30 ml of 1 N aqueous sodium hydroxide solution was added to the resultant mixture, and they were stirred at room temperature overnight. The solvent was evaporated, and the reaction liquid was concentrated and then diluted with 1 N hydrochloric acid. After the extraction with ethyl acetate, the organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.CCCCCC.[Br:19][CH2:20][CH2:21][C:22](OC)=[O:23].Cl>C1COCC1>[Br:19][CH2:20][CH2:21][C:22]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)=[O:23]
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)CCBr
Agent: C[Al](C)C
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(CCBr)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
5.75 ml of 4-fluoroaniline (6.65 g, 59.88 mmol, 1 equivalent) were initially charged in 65 ml of THF, 33 ml of 2 M trimethylaluminium solution in hexane (65.87 mmol, 1.1 equivalents) were added at −78° C. and the mixture was stirred for 20 min, slowly warming to RT. At −20° C., this solution was added dropwise to a solution of 6.54 ml (10 g, 59.8 mmol, 1 equivalent) of methyl 3-bromopropanoate in 65 ml of THF and then stirred at RT for 3 h. At 0° C., the reaction solution was acidified carefully with 1 N aqueous hydrochloric acid solution and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. This gave 12.6 g (67% of theory; purity 78%) of the title compound which was reacted further without purification.
Reaction SMILES: [O:1]=[C:2](Cl)[O:3][C:4](Cl)(Cl)Cl.[NH2:9][C@@H:10]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)CO.CCN(CC)CC.C>C1COCC1>[CH:13]1([C@H:10]2[CH2:4][O:3][C:2](=[O:1])[NH:9]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N[C@H](CO)C1CCCCC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1N[C@@H](C2CCCCC2)CO1
Temperature: 50 °C
Yield: 87.9 %

Procedure:
Diphosgene (0.704 mL, 6.05 mmol) was added dropwise to a stirred suspension of (S)-2-amino-2-cyclohexylethanol (1.02 g, 7.12 mmol), Et3N (6.95 mL, 49.9 mmol) and activated charcoal (40 mg) in THF (20 mL) at 0° C. under N2. The reaction mixture was heated at 50° C. overnight. After cooling, the suspension was filtered through Celite. To the filtrate was added sat. aq. NaHCO3 solution. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by silica gel flash column chromatography (1:1 hexane/EtOAc) to give (S)-4-cyclohexyloxazolidin-2-one (0.900 g, 75%) as a white solid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:12](N(CC)CC)C.IC>C(Cl)Cl>[CH3:12][S:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCN(CC)CC
Reactant: Oc1ccc2nc(S)sc2c1
Solvent: CI
Solvent: ClCCl
Product: CSc1nc2ccc(O)cc2s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
To the ice cooled solution of 2-mercapto-benzothiazol-6-ol from step 1 (3.80 g, 20.76 mmol, 1.0 eq) in DCM (40 mL, 0.5M) at 0° C., was added triethylamine (7.29 mL, 51.91 mmol, 2.5 eq) followed by iodomethane (1.93 mL, 31.14 mmol, 1.5 eq). The reaction was stirred from 0° C. to −10° C. for 3 hours. The solvent was removed in vacuo. Water (ca. 200 mL) was added and the aqueous layer was extracted with ethyl acetate (3×150 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo to yield 2-methylsulfanyl-benzothiazol-6-ol as light green powder (3.76 g, 92%). The crude product was used in the next step without purification. M+H=198.0
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH2:13][CH2:14][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:17])[CH3:16].[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27]>>[CH3:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:17])[CH2:14][CH2:13][N:12]1[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[NH:1][C:26]1=[O:27]
Reactant: CC(C)(CCNc1ccc(C(F)(F)F)cc1N)NC(=O)OC(C)(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CC(C)(CCn1c(=O)[nH]c2cc(C(F)(F)F)ccc21)NC(=O)OC(C)(C)C

Procedure:
5.00 g (13.8 mmol) tert-butyl [3-(2-amino-4-trifluoromethyl-phenylamino)-1,1-dimethyl-propyl]-carbamate and 6.73 g (41.5 mmol) 1,1′-carbonyldiimidazole are reacted and worked up analogously to method 2c). White solid. Yield: 4.18 g (78%); mass spectroscopy: [M−H]+=386.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13](O)[CH2:14][OH:15].B(F)(F)F.CCOCC>C(O)(=O)C>[CH2:14]1[O:15][CH:4]([C:3]2[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=2[F:1])[O:5][CH2:13]1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: OCCO
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(F)c(C2OCCO2)c1
Temperature: 45 °C

Procedure:
A solution of 2-fluoro-5-nitro-benzaldehyde (25.0 g, 148 mmol), ethylene glycol (160 mL, 2.87 mol) in acetic acid (625 mL) was heated to 55° C. for 15 min. The temperature was then adjusted to 45° C., at which time BF3 --Et2O (20 mL, 20 mmol) was added dropwise (30 min). After an additionl 60 min at 45° C. the solution was cooled to room temperature, and poured onto ice (1 L). The resulting solid was filtered, pressed dry, and dried in vacuo to afford the title compound as white flakes (18.81 g, 60%). MS(ES) m/e 213 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][O:26][CH3:27].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][O:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Reactant: O=C(Cl)c1ccccc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNC(=O)c1ccccc1
Yield: 44.6 %

Procedure:
Using the general method of Example 186 1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.84 g, 2.27 mmol) was reacted with benzoyl choride (260 μL, 2.27 mmol) to provide 0.48 g of N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}benzamide as a tan powder, m.p. 133.4-137.5° C.
Reaction SMILES: [C:1]([C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1)#[N:2].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Br.[Br:46][C:47]1[N:48]=[C:49]2[C:54]([NH:55][C@H:56]3[C@@H:60]([CH3:61])[CH2:59][NH:58][CH2:57]3)=[C:53]([C:62]([NH2:64])=[O:63])[CH:52]=[N:51][N:50]2[CH:65]=1>C(Cl)Cl>[Br:46][C:47]1[N:48]=[C:49]2[C:54]([NH:55][C@H:56]3[C@@H:60]([CH3:61])[CH2:59][N:58]([C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)=[O:8])[CH2:57]3)=[C:53]([C:62]([NH2:64])=[O:63])[CH:52]=[N:51][N:50]2[CH:65]=1
Reactant: C[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)nc12
Reactant: N#CC1(C(=O)O)CC1
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a solution of 1-cyanocyclopropanecarboxylic acid (0.264 g, 2.380 mmol) in DCM (15.9 ml) were added DIEA (2.079 ml, 11.90 mmol), and BOP (1.263 g, 2.86 mmol). The solution was stirred at room temperature for 10 minutes, and 2-bromo-8-(((3S,4S)-4-methylpyrrolidin-3-yl)amino) imidazo[1,2-b]pyridazine-7-carboxamide, hydrobromide (from Step 2 of Example 1, 1.00 g, 2.380 mmol) was added. The reaction was stirred for 1 hr. After removal of the solvent, the crude product was purified by flash chromatography (ISCO, prepacked silica gel column eluting with 0-5% EtOAc/MeOH over 15 column volumes) to afford 2-bromo-8-(((3S,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-yl)amino)imidazo[1,2-b]pyridazine-7-carboxamide as a white solid, 1.01 g, 2.336 mmol, 98% yield. ESI-MS (Method B): m/z 434.1 ([M+H]+). HPLC (Method B) Rt: 2.505 min.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH:3][CH3:4].[NH:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.C(=O)(O)[O-].[Na+]>CO>[CH2:1]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCCl
Reactant: c1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC=CCn1ccnc1

Procedure:
Crotyl chloride (3.2 g; 35 m mole) in methanol (35 ml) was added dropwise with stirring during 3.5 hours to a refluxing mixture of imidazole (11.9 g; 175 m mole) and sodium bicarbonate (2.95 g; 35 m mole) in methanol (35 ml). When the addition was complete the reaction mixture was refluxed for 24 hours, the solvent evaporated and the residue dissolved in water (60 ml) and extracted with chloroform (3×20 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (25 ml), dried over magnesium sulphate and concentrated under reduced pressure. The residue was fractionally distilled to yield 1-crotylimidazole as a colourless oil, b.p. 123°-124° C./18 mmHg.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=1)=[S:4].[N-:13]=[N+:14]=[N-:15].[Na+]>O1CCCC1.O>[N:13]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=1)=[S:4])=[N+:14]=[N-:15]
Reactant: Cc1cc(C(=S)CBr)ccc1O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=S)CN=[N+]=[N-])ccc1O
Reaction time: 5 h

Procedure:
To a solution of the product of Step A (150.5 g, 0.576 mole) in tetrahydrofuran (1 liter) cooled to 20° C., add dropwise sodium azide (37.4 g, 0.576 mole) in water (450 ml) and stir for five hours. Partially evaporate the solvent and extract the concentrated reaction mixture with chloroform. Dry the organic phase and evaporate in vacuo to obtain 2-azido-4'-hydroxy-3'-methylthioacetophenone, mp. 124°-129° C.
Reaction SMILES: [C:1]1([N:7]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18]OC)=[N:15][C:14]=3[CH:21]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)[Br:30]>ClCCl>[C:1]1([N:7]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][Br:30])=[N:15][C:14]=3[CH:21]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrB(Br)Br
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(COC)nc2c1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2sc(CBr)nc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2.05 g (5.14 mmol) of 2-methoxymethylbenzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide and 5.7 ml (5.7 mmol) of a 1M solution of boron tribromide in dichloromethane was dissolved in a further 60 ml of dichloromethane and stirred for 16 hours at room temperature. Then the mixture was washed with 40 ml of saturated sodium hydrogen carbonate solution, the organic phase was dried with sodium sulfate, and the solvent was distilled off. The crude 2-bromomethylbenzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide thus obtained (2.4 g) was taken up in 5.0 ml of N,N-diisopropylethylamine and mixed with 0.64 g (5.4 mmol) of 4-aminobenzonitrile. After 1 hour's heating to 130° C., the solvent was distilled off in vacuo and the crude product obtained was purified by flash chromatography (silica gel; gradient: ethyl acetate/petroleum ether=1:3 to 1:1), whilst an orange foam was obtained when the eluates were evaporated down.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6](=[O:9])[NH:7][CH:8]=1.[BrH:10]>>[Br:10][CH2:2][C:3]1[CH:4]=[CH:5][C:6](=[O:9])[NH:7][CH:8]=1
Reactant: Br
Reactant: O=c1ccc(CO)c[nH]1
Product: O=c1ccc(CBr)c[nH]1
Temperature: 100 °C

Procedure:
To 5-hydroxymethyl-2-pyridone-(114.9 mg, 0.9 mmol) was added 3.0 ml of 48% hydrobromic acid. The mixture was heated at 100° C. for 20 minutes. The excess hydrobromic acid was then evaporated in vacuo to give the corresponding 5-bromomethyl-2-pyridone. This compound was used without purification. HRMS: m/e, M+ found; 186.9626, 7.4% Calc. for C6H6BrNO: 186.9633, −3.9 ppm.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[CH3:14])(=[O:3])[CH3:2].[OH-].[Na+].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[CH3:26].Cl>CCO.O>[OH:17][C:18]1[CH:25]=[CH:24][C:21](/[CH:22]=[CH:2]/[C:1]([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=2[CH3:14])=[O:3])=[CH:20][C:19]=1[CH3:26]
Reactant: CC(=O)Nc1ccc(C(C)=O)c(C)c1
Reactant: Cc1cc(C=O)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)/C=C/c2ccc(O)c(C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of N-(4-acetyl-3-methylphenyl)acetamide (1.3 g, 7.0 mmol) and NaOH (1.4 g, 36 mmol) in 25 mL of absolute EtOH was added 4-hydroxy-3-methylbenzaldehyde (1.0 g, 7.3 mmol). The reaction mixture was stirred at room temperature for 18 hr. 5 mL of water was added and the reaction mixture was acidified with concentrated HCl to pH 5-6. The aqueous layer was extracted with two 25 mL portions of EOAc, and the layers were separated. The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The resulting product was submitted to the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=O)[CH3:2].[CH:17]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)C.[BH4-].[Na+]>O>[CH:17]1([NH:24][CH:1]([C:4]2[CH:16]=[CH:15][C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7][C:6]=3[CH:5]=2)[CH3:2])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCCCCC1
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(NC1CCCCCC1)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
2-Acetylfluorene (4.17 g, 20 mmol) and cycloheptylamine (2.38 g, 21 mmol) were heated together at 130° C. for 14 hrs and, then, distilled under reduced pressure. To the residue were added ethanol (20 ml) and sodium borohydride (0.76 g, 20 mmol) and the mixture was stirred at room temperature overnight. The mixture was then diluted with water (100 ml) and extracted with chloroform (80 ml×2 times). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was then purified by silica gel column chromatography to give 1.58 g of the amine compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:12][N:11]=[C:10]([C:13]2[N:14]=[C:15]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[S:16][CH:17]=2)[CH2:9]1.[ClH:31]>C(O)C.CCOCC>[ClH:31].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:12][N:11]=[C:10]([C:13]2[N:14]=[C:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:16][CH:17]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4F)C3)cs2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Fc1ccccc1C1CC(c2csc(C3CCNCC3)n2)=NO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(4,5-dihydro-5-(2-fluorophenyl)-3-isoxazolyl)-2-thiazolyl]-1-piperidinecarboxylate (i.e. the product of Step B) (1.05 g, 2.43 mmol) in ethanol (20 mL) was added a solution of hydrogen chloride in ether (2 M, 12.2 mL). The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure to provide the title compound as colorless solid (0.807 g)
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH2:17][CH2:18][CH3:19])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][CH2:22][CH2:23][Cl:24].C(N(CC)CC)C>C(#N)C>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:21][CH2:22][CH2:23][Cl:24])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH2:17][CH2:18][CH3:19])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCCBr
Reactant: CCCc1cc(N2CCNCC2)nc(C(C)(C)C)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1cc(N2CCN(CCCCl)CC2)nc(C(C)(C)C)n1

Procedure:
15 g of 2-tert-butyl-4-piperazin-1-yl-6-propyl-pyrimidine (57.2 mmol), 9 g of 1-bromo-3-chloropropane (57.2 mmol), 8.7 g of triethylamine (86.2 mmol) in 200 ml of acetonitrile were heated to reflux for 3 h. The precipitate was filtered off and the remaining filtrate evaporated to dryness. The thus obtained crude product was purified by chromatography on silica gel with dichloromethane/methanol (0-5%). Yield: 6 g (31%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[F:10][C:11]1[C:17]([F:18])=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][C:12]=1[NH2:13]>>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:13][C:12]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[C:17]([F:18])[C:11]=1[F:10])=[O:9]
Reactant: COc1ccc(N)c(F)c1F
Reactant: O=C(O)c1sccc1Br
Product: COc1ccc(NC(=O)c2sccc2Br)c(F)c1F
Yield: 100.3 %

Procedure:
Following Step 1 from General Procedure A, 3-bromothiophene-2-carboxylic acid (1.3 g, 6.3 mmol) was reacted with 2,3-difluoro-4-methoxyaniline (960 mg, 7.5 mmol) to afford the desired product (2.2 g, >99%): ESI MS m/z 349 [C12H8BrF2NO2S+H]+.