Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=2)=[O:14])[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:25]([C:31]1[CH:32]=[N:33][C:34]([OH:37])=[N:35][CH:36]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:37][C:34]3[N:33]=[CH:32][C:31]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:36][N:35]=3)=[O:21])=[CH:18][CH:17]=2)=[O:14])[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cnc(O)nc1
Reactant: CCCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(C(=O)Cl)cc2)CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCc1cnc(OC(=O)c2ccc(OC(=O)[C@H]3CC[C@H](CCCCCC)CC3)cc2)nc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of p-(trans-4-hexylcyclohexylcarbonyloxy)-benzoyl chloride (3.9 g) dissolved in toluene was added to a solution of 5-hexylpyrimidin-2-ol (1.0 g) in pyridine (10 ml), followed by stirring at 60° C. for 2 hours, allowing the mixture to stand at room temperature overnight, adding water and toluene to the reaction mixture, separating the toluene layer containing the reaction product, washing the toluene solution twice with 6NHCl (30 ml), washing with water, washing 5 times with 2N NaOH (100 ml), finally washing with water till the washing water became neutral, drying the resulting toluene solution, distilling off low boiling mixture of solvent, etc. under reduced pressure, and recrystallizing crystals obtained from the residue from n-heptanol solvent to obtain the objective compound (2.0 g) (yield 73%), which had a C-N point of 53.3° C. and a N-I point of 125.3° C.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:8]=2[N:7]=[C:6]1[NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1)[CH:2]([CH3:4])[CH3:3].CN.[CH3:34][N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][NH:35][C:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:29])([F:31])[F:30])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:7][C:8]=2[CH:13]=1)=[O:16]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CC(C)C
Yield: 38.9 %

Procedure:
1-Isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methylamide (40.0 mg) was prepared by following General Procedure F starting from 1-isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (100.0 mg), methylamine (2.0 M solution in THF, 0.5 mL), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 465; and 1H NMR (DMSO-d6, 400 MHz): δ 8.40 (1H, m), 8.09 (1H, m), 7.91 (1H, m), 7.72 (1H, m), 7.54 (1H, m), 7.35 (1H, m), 4.00-3.99 (2H, m), 2.81-2.80 (3H, d), 1.23 (1H, m), 0.95-0.92 (6H, m), 2 —NH proton signals were not observed.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]2[O:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:13]1[C:21]2[C:16](=[C:17]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>>[F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]([OH:10])[CH2:9][N:25]2[CH2:26][CH2:27][N:22]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:16]=3[CH:15]=[CH:14][NH:13]4)[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(OCC2CO2)cc1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Product: OC(COc1ccc(F)cc1)CN1CCN(c2cccc3[nH]ccc23)CC1
Yield: 99.3 %

Procedure:
A methanolic solution (50 ml) of 1-(4-fluorophenoxy)-2,3-epoxypropane (0.50 g, 3.0 mmole) and 1-(indol-4yl)-piperazine (0.6 g, 3.0 mmole) was refluxed for 1 hr under an atmosphere of nitrogen. The mixture was concentrated in vacuo, and the product purified by silica gel chromatography (EtOAc) to afford a white solid (1.1 g, 99%). Treatment with a 0.25M ethanolic fumaric acid solution gave the required salt, which was recrystallized from ethanol to afford the title compound as a white solid. m.p. 234-235° C.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:5]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:4]=2[N:3]=1.[C:21](OC)(=[O:24])[C:22]#[CH:23]>CO>[F:20][C:17]1[CH:18]=[CH:19][C:4]2[N:3]3[CH:23]=[CH:22][C:21](=[O:24])[N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:5]=2[CH:16]=1
Reactant: NC1=Nc2ccc(F)cc2C(c2ccccc2F)=NC1
Reactant: C#CC(=O)OC
Solvent: CO
Product: O=c1ccn2c(n1)CN=C(c1ccccc1F)c1cc(F)ccc1-2

Procedure:
In the manner given in Example 1, 2-amino-7-fluoro-5-(o-fluorophenyl)-3H-1,4-benzodiazepine, methyl propiolate and methanol were refluxed. The mixture was chromatographed to give 9-fluoro-7-(o-fluorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:23])=[CH:3]\[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:9]([C:19]([F:22])([F:21])[F:20])[CH:8]=1)=[O:5].[C:24](OCC)(OCC)(OCC)[CH3:25]>>[F:20][C:19]([F:22])([F:21])[C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[CH:3]=[C:2]([CH3:23])[N:1]=[C:24]2[CH3:25])[CH:12]=[CH:11][C:10]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CCOC(C)(OCC)OCC
Reactant: C/C(N)=C/C(=O)Nc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(C(F)(F)F)c2)c(C)n1
Temperature: 150 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A mixture of (Z)-3-amino-N-(3-trifluoromethyl-4-morpholinophenyl)but-2-enamide (4.0 g, 12.1 mmol) and triethyl orthoacetate (10 mL) was stirred at 150° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale yellow solid (3.00 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Br.C(O[CH2:6][CH2:7][N:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]1=[NH:18])(=O)C.P(Br)(Br)([Br:21])=O.C(#N)CC.C(=O)(O)[O-].[Na+]>>[Br:21][C:6]1[N:18]=[C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][N:8]2[CH:7]=1
Reactant: O=P(Br)(Br)Br
Reactant: CC(=O)OCCn1cc(C(F)(F)F)ccc1=N
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC#N
Product: FC(F)(F)c1ccc2nc(Br)cn2c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 61.6 %

Procedure:
A mixture of 1.63 g of (2-imino-5-trifluoromethyl-2H-pyridin-1-yl)ethyl acetate hydrobromide, 2.84 g of phosphorus oxybromide and 2 ml of propionitrile was stirred at 100° C. for 2.5 hours. The cooled reaction mixture was neutralized in a saturated aqueous sodium bicarbonate solution and a 5 M aqueous sodium hydroxide solution, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane to obtain 808 mg of 2-bromo-6-trifluoromethyl-imidazo[1,2-a]pyridine.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([OH:14])[CH2:9][O:10][CH2:11][CH2:12][OH:13]>>[C:1]([OH:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:10])=[O:5].[CH2:8]([OH:14])[CH2:9][O:10][CH2:11][CH2:12][OH:13]
Reactant: O=C1C=CC(=O)O1
Solvent: OCCOCCO
Product: O=C(O)/C=C\C(=O)O

Procedure:
Into the similar reaction vessel as used in Manufacturing Example 1, were placed 98 parts of maleic anhydride and 106 parts of diethylene glycol and the mixture was, while stirring and introducing a nitrogen gas thereto, heated at 190° to 200° C. for 6 hours to obtain diethylene glycol maleate having an acid value of 30.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([OH:25])[CH2:22][C:23]#[CH:24].N1C=CC=CC=1>ClCCl>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:25][CH2:21][CH2:22][C:23]#[CH:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
Triphenylmethyl chloride (122 g, 0.44 mol) is added to a solution of but-3-yne-1-ol (25 g, 0.36 mol) in dichloromethane (400 ml) containing pyridine (50 ml) and stirred overnight at room temperature. The reaction mixture is filtered and washed with cold dilute hydrochloric acid, aqueous sodium bicarbonate and water. The dried solution is concentrated to a solid which is crystallized from ether-petroleum ether to give 4-triphenylmethyloxybut-1-yne (60 g), m.p. 97°-99° (ether-petroleum ether).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[O:26]CC=C)=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]1(OC2C=CC=CC=2)[CH:35]=CC=C[CH:31]=1>>[CH2:35]([C:21]1[C:20]2[O:26][C:16]([CH2:15][C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:8]=3)=[N:18][C:19]=2[CH:24]=[C:23]([Cl:25])[CH:22]=1)[CH:30]=[CH2:31]
Reactant: C=CCOc1ccc(Cl)cc1NC(=O)Cc1ccc(OC)c(OC2CCCC2)c1
Reactant: c1ccc(Oc2ccccc2)cc1
Product: C=CCc1cc(Cl)cc2nc(Cc3ccc(OC)c(OC4CCCC4)c3)oc12
Yield: 52 %

Procedure:
A solution of N-(3-cyclopentyloxy-4-methoxyphenylacetyl)-2-allyloxy-5-chloroaniline (38.1 g, 0.092 mol) in 200 ml of diphenyl ether was heated under nitrogen at 180° for 8 hours. Protracted heating resulted in reduced yields. The reaction mixture was diluted with 500 ml of petroleum ether, applied to a column packed with 500 g of flash chromatography silica gel and eluted with petroleum ether followed by methylene chloride. Fractions of 800 ml were collected. The material from fractions 9-14 weighed 30 g (80% of theoretical). This material was recrystallized from hexane to give 19 g (52%) of the title compound, mp 43°-44° C., which was greater than 98.3% pure by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH3:16])=[C:6]([N+:17]([O-])=O)[CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH3:16])=[C:6]([NH2:17])[CH:5]=1
Reactant: COC(=O)c1ccc(NC2CCCC2C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(NC2CCCC2C)c(N)c1
Reaction time: 16 h
Yield: 71.9 %

Procedure:
12.74 g 4-(2-Methyl-cyclopentylamino)-3-nitro-benzoic acid methyl ester were dissolved in 80 ml methanol, 0.39 g of palladium on carbon (10%) were added and the mixture was hydrogenated at 5 bar for 16 h. The catalyst was removed by filtration over celite, the filtrate was concentrated and the residue purified by chromatography (silica, ethyl acetate/hexane) to obtain 8.17 g (72%) of 3-Amino-4-(2-methyl-cyclopentylamino)-benzoic acid methyl ester.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:7])[CH:4]=[CH:5][CH:6]=1.[OH-].[Na+].Br[C@@H:11]([CH3:15])[C:12]([OH:14])=[O:13].Cl>>[O:7]=[C:3]1[N:2]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])[N:1]=[CH:6][CH:5]=[CH:4]1
Reactant: O=c1cccn[nH]1
Reactant: C[C@H](Br)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)n1ncccc1=O
Temperature: 90 °C

Procedure:
To 3(2H)-pyridazinone (1.19 g, 12.3 mmol) was added 5 N sodium hydroxide solution (4.9 ml) followed by (2S)-2-bromopropanoic acid (1.11 ml, 12.3 mmol). The reaction mixture was heated at 90° C. for 1 h. After cooled downed to ambient temperature, 2 N hydrochloric acid (6.2 ml) was added and the reaction mixture was directly purified by reverse phase HPLC (TMC Pro-Pac C18; 0-40% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were collected and the solvent was removed in vacuo to afford the title compound as pale yellow solid. 2-[6-Oxopyridazin-1(6H)-yl]propanoic acid: 1H NMR (D2O): δ 8.07 (dd, J=4.1, 1.6 Hz, 1H), 7.53 (dd, 9.3, 3.9 Hz, 1H), 7.09 (dd, J=9.4, 1.6 Hz, 1H), 5.46 (m, 1H), 1.64 (d, J=7.3 Hz, 3H).
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH2:13][C:12]=3[C:25](=[O:27])[O:26][C:5]=2[CH:4]=1>Br>[OH:2][C:3]1[C:8]([OH:9])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[CH2:13][C:12]=3[C:25](=[O:27])[O:26][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CCN1CCOCC1)C3
Agent: Br
Product: O=c1oc2cc(O)c(O)cc2c2c1CN(CCN1CCOCC1)CC2
Yield: 68.3 %

Procedure:
A solution of 8.7 g of 1,2,3,4-tetrahydro-8,9-dimethoxy-3-(2-morpholinoethyl)-5H[1]benzopyrano[3,4-c]-pyridin-5-one in 60 cc of 48% HBr was refluxed for 17 hr then cooled. Crystallization of precipitate from water afforded 5.5 g of product; mp 299°-302° C.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39](=[O:47])[NH:40][S:41]([CH:44]([CH3:46])[CH3:45])(=[O:43])=[O:42])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[N:25]([CH2:26][CH3:27])[N:24]=[CH:23][C:22]=4[C:28]([O:30]CC)=[O:29])=[CH:18][C:17]4[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Na+]>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39](=[O:47])[NH:40][S:41]([CH:44]([CH3:46])[CH3:45])(=[O:42])=[O:43])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[N:25]([CH2:26][CH3:27])[N:24]=[CH:23][C:22]=4[C:28]([OH:30])=[O:29])=[CH:18][C:17]4[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1cnn(CC)c1C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)C(C)C)cc3n2C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1ncc(C(=O)O)c1C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)C(C)C)cc3n2C1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
Ethyl 5-(13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1-ethyl-1H-pyrazole-4-carboxylate was dissolved in THF (14 mL) and methanol (14 mL) then sodium hydroxide (15 mL, 15.00 mmol) (1.0N aqueous) was added to the reaction. The reaction was placed under a nitrogen atmosphere and stirred at room temperature for 16.5 hrs. The reaction was concentrated in vacuo using a rotary evaporator (bath temp equal to less than 26 C) then partitioned between ethyl acetate and 1.0N aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the organic extracts combined, washed with brine and dried over magnesium sulfate. The organic solution was filtered and solvents removed in vacuo to give amorphous amber-orange solid (902 mg) after drying at room temperature in vacuo.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]([CH3:30])([C:24]1[N:28]=[C:27]([CH3:29])[O:26][N:25]=1)[NH2:23]>>[CH3:21][C:22]([NH:23][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:24]1[N:28]=[C:27]([CH3:29])[O:26][N:25]=1)[CH3:30]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: O=C(O)c1ccc(C2CCOCC2)c(OCC2CC2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CCOCC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (Example 9 f) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e 401.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:16])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][CH3:14].[Cl:17]N1C(=O)CCC1=O>C(#N)C>[CH3:1][O:2][N:3]([CH3:16])[C:4](=[O:15])[C:5]1[CH:10]=[C:9]([Cl:17])[C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][CH3:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(C(=O)N(C)OC)c(OC)c1
Solvent: CC#N
Product: COc1cc(OC)c(C(=O)N(C)OC)cc1Cl
Temperature: 50 °C
Yield: 62.5 %

Procedure:
A mixture of N-methoxy-N-methyl-2,4-dimethoxybenzamide (7.2 g, 32 mmol), prepared as in Example 4, N-chlorosuccinimide (4.8 mL, 36 mmol) and acetonitrile (100 mL) was heated 16 hours at 50° C. The mixture was concentrated and the residue was partitioned between ethyl acetate (300 mL) and saturated sodium bicarbonate (150 mL). The mixture was filtered and the organic layer was separated, washed with water (4×) and brine (1×), dried (K2CO3), filtered through a short column of silica-gel and concentrated to give N-methoxy-N-methyl-5-chloro-2,4-dimethoxybenzamide (5.3 g, 20 mmol), m.p. 97°-99° C.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH3:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@H:27]3[CH2:29][O:28]3)=[CH:21][C:19]=2[N:20]=1>C(O)C>[OH:28][C@H:27]([CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:18]2[S:17][C:16]([CH3:15])=[N:20][C:19]=2[CH:21]=1)[CH2:29][N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@@H:2]1[CH3:1]
Reactant: Cc1nc2cc(OC[C@H]3CO3)ccc2s1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCO
Product: Cc1nc2cc(OC[C@@H](O)CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)ccc2s1

Procedure:
A solution of tert-butyl (3S)-3-methylpiperazinecarboxylate (3 g, 15 mmol) and 2-(2R)-methyl-5-(oxiran-2-ylmethoxy)benzothiazole, (3.3 g, 15 mmol), a compound of formula (5), was refluxed in ethanol for 24 hours. The solvent was removed under reduced pressure, and the residue was chromatographed on silica gel, eluting with methanol/dichloromethane 1/15, to yield tert-butyl (3S)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinecarboxylate, a compound of formula (8).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2]>O>[C:6]1([C:5]2[O:12][CH2:2][CH2:3][N:4]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(NCCO)c1ccccc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Sn+2]
Solvent: O
Product: c1ccc(C2=NCCO2)cc1
Temperature: 230 °C
Yield: 58 %

Procedure:
N-(2-Hydroxyethyl)benzamide (200 parts by weight) and stannous octoate (1 part by weight) were charged to the standard reaction vessel as one lot. The mixture was heated to 230° C. at 250 mm Hg (33 kPa) and maintained at these conditions for 4 hours by when water had ceased to distil over. The residues were distilled under vacuum to give 2-phenyl-2-oxazoline (yield 58%), b.p. 115° C./1 mm Hg (0.13 kPa).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Cl:7][C:8]1[NH:9][C:10]2[C:15]([CH2:16][C:17]=1[CH:18]=[O:19])=[CH:14][C:13]([F:20])=[C:12]([Cl:21])[CH:11]=2.S(S([O-])=O)([O-])=[O:23].[Na+].[Na+]>O.[OH-].[K+]>[Cl:7][C:8]1[C:17]([C:18]([OH:23])=[O:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([Cl:21])=[C:13]([F:20])[CH:14]=2)[N:9]=1
Reactant: O=S([O-])S(=O)[O-]
Reactant: O=CC1=C(Cl)Nc2cc(Cl)c(F)cc2C1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2cc(F)c(Cl)cc2nc1Cl
Reaction time: 0.5 h
Yield: 115.9 %

Procedure:
A solution of potassium permanganate (89.3 g) in water (1.4 liters) is added in the course of 1 hour to a stirred suspension, cooled to 10° C., of 2,7-dichloro-6-fluoro-3-formyl-1,4-dihydroquinoline (69.5 g) in 2 N aqueous potassium hydroxide (282 cc) and water (282 cc) while the temperature is maintained at between 10° and 14° C. The temperature is allowed to rise to approximately 20° C. and the mixture is stirred for a further 30 minutes at this temperature. Sodium dithionite (26 g) is added and the mixture is stirred for 10 minutes at a temperature in the region of 20° C., filtered through diatomaceous silica for filtration and washed with water (2×250 cc). The filtrate and the aqueous washing phases are combined and treated with 35% strength aqueous hydrochloric acid solution (90 cc). The precipitate formed is extracted with ethyl acetate (4×500 cc). The combined organic extracts are washed with water (3×500 cc), dried over magnesium sulphate, filtered and concentrated under reduced pressure (20 kPa) at 50° C. The residue is taken up with ethyl ether (350 cc), drained and washed with ethyl ether (2×200 cc). 2,7-Dichloro-6-fluoro-3-quinolinecarboxylic acid (45 g) is obtained in the form of a beige solid, m.p. 230° C., which is used without further purification for the subsequent steps.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(c2ccc(N)cc2)C1
Reaction time: 18 h

Procedure:
A suspension of 10% Pd/C (0.320 g) and tert-butyl-3-(4-nitrophenyl)azetidine-1-carboxylate (I6) (2.14 g, 7.68 mmol) in EtOAc (16 mL) was stirred under a hydrogen atmosphere for 18 hours. Additional 10% Pd/C (1.00 g) was added and stirring continued for a further 20 hours. The resulting mixture was filtered through a pad of Celite, washing with EtOAc, and the filtrate concentrated in vacuo to give the title compound I7 as a light yellow/cream solid (1.80 g, 94%); 1H NMR (300 MHz, CDCl3) δ 7.12 (d, J=8.3 Hz, 2H), 6.69 (dd, J=6.5, 1.9 Hz, 2H), 4.29 (t, J=8.7 Hz, 2H), 3.93 (dd, J=8.4, 6.1 Hz, 2H), 3.65 (brs, 2H), 1.55-1.68 (m, 1H), 1.48 (s, 9H). LCMS-B: rt 4.964 min; m/z 249 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:12])[CH2:7][C:8]([CH2:10]Cl)=[O:9])[CH3:4].[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][C:8](=[O:9])[CH2:10][O:17][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:4]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)COC(C)(C)C
Temperature: 0 °C

Procedure:
A suspension of sodium hydride (4.44 g, 60% dispersion in mineral oil) in dimethyl formamide (50 ml), at 0° C., was treated dropwise with ethyl-4-chloroacetoacetate (5 ml) and then with tert-butyl alcohol (7.08 ml). This mixture was maintained at 0° C. for 2 hours, then a further 2 hours at ambient temperature and then poured onto 2N hydrochloric acid/ice and then extracted four times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium hydrogen carbonate solution, then with water, then with brine, then dried over magnesium sulfate and then evaporated. The resulting yellow oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petrol (1:9, v/v) to give 4-tert-butoxy-3-oxo-butyric acid ethyl ester (5.20 g) as a yellow oil. TLC (silica, 1:4, v/v ethyl acetate/petrol): RF=0.51. NMR (400 MHz, CDCl3): δ 1.21 (9H, s), 1.28 (3H, t), 3.55 (2H, s), 4.19 (2H, q).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[C:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH:19]=[CH:18][C:17]4[CH:26]=[CH:27][CH:28]=[CH:29][C:16]3=4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[C:33]([O:35][CH3:36])=[O:34]>>[CH:25]1[C:20]2[CH:19]=[CH:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[C:15](=[C:12]3[CH2:11][CH2:10][N:9]([CH2:8][CH:7]=[CH:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=4)[CH2:14][CH2:13]3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Reactant: COC(=O)Cl
Product: COC(=O)Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Yield: 97.5 %

Procedure:
This compound was prepared from 1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) and methyl chloroformate. Yield 97.5%