Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[N:4]([CH2:23][CH3:24])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:14]=1[CH2:21][CH3:22].C(O)(=O)[CH2:27][C:28]([OH:30])=[O:29].Cl>N1CCCCC1.N1C=CC=CC=1>[Cl:1][C:2]1[C:3](=[O:25])[N:4]([CH2:23][CH3:24])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:27][C:28]([OH:30])=[O:29])=[CH:15][C:14]=1[CH2:21][CH3:22]
Reactant: O=C(O)CC(=O)O
Reactant: CCc1cc(C=O)ccc1OCCCNc1cnn(CC)c(=O)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCc1cc(C=CC(=O)O)ccc1OCCCNc1cnn(CC)c(=O)c1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture comprising 1.34 g of 4-chloro-5-[3-(2-ethyl-4-formylphenoxy)propylamino]-2-ethyl-3(2H) pyridazinone (Compound No. 92), 0.73 g of malonic acid, one drop of piperidine and 12 ml of pyridine, were heated under stirring at 100° C. for 3 hours. After cooling, the reaction solution was acidified with hydrochloric acid, and extracted with ethyl acetate. The extract was washed twice with water, and dried over sodium sulfate. Then, the solvent was distilled off, and the residue thereby obtained was crystallized from ethyl acetate-ethyl ether to obtain 1.2 g of the above identified compound as pale yellow crystals having a melting point of from 145° to 147° C.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:22])[C:11](=[O:21])[N:12]2[CH2:15][C:16]([O:18]CC)=[O:17])=[CH:7][CH:6]=1)(=O)C.[N+:23]([O-])([O-:25])=[O:24].[K+].N>S(=O)(=O)(O)O>[NH2:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:22])[C:11](=[O:21])[N:12]2[CH2:15][C:16]([OH:18])=[O:17])=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2ccc(NC(C)=O)cc21
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Nc1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c(=O)n2CC(=O)O
Temperature: 0 °C
Yield: 69.3 %

Procedure:
57.5 g (0.19 mol) of 7-acetamido-1-(ethoxycarbonylmethyl)quinoxaline-2,3(1H,4H)-dione were dissolved in 575 ml of concentrated sulfuric acid. The solution was cooled to 0° C., and 19.0 g (0.19 mol) of potassium nitrate were added in portions. The cooling was then removed, and the mixture was stirred. After reaction was complete, the mixture was poured into 2 l of ice-water and heated on a waterbath for 2 h. The pH was then adjusted to about 4-5 with aqueous ammonia solution, and the precipitate was filtered off with suction. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (mobile phase: methanol:tetrahydrofuran:water=5:4:1+2.5% glacial acetic acid). The resulting product was combined with the first precipitate to afford 36.9 g (70%) of product.
Reaction SMILES: [C:1]([CH:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[OH:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.C1OCCOCCOCCOCCOCCOC1.[N+:34]([C:37]([CH3:39])=[CH2:38])([O-:36])=[O:35]>C(#N)C.O1CCCC1>[N+:34]([CH:37]([CH3:39])[CH2:38][O:6][CH:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:1]([CH3:4])([CH3:3])[CH3:2])([O-:36])=[O:35]
Reactant: C=C(C)[N+](=O)[O-]
Reactant: CC(C)(C)C(O)C(C)(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(COC(C(C)(C)C)C(C)(C)C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Di-t-butylmethanol is added to a dry flask under argon at 0+ C. Dry tetrahydrofuran is added with a syringe. Sec-Butyl lithium (1.5M in Hexanes) is added quickly in one portion and the contents of the flask are stirred for one hour at room temperature. A 10 mM solution of 18-crown-6-ether in acetonitrile is added with a syringe and the flask cooled to 0° C. A tetrahydrofuran solution of 2-nitropropene is added with vigorous stirring over a 10 minute period. After completion of the reaction as judged by thin layer chromatography, it is quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield 2-nitro 1-[di-(t-butyl)methoxy]propane.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[OH:17])=[N:8][C:7]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:32]1(Br)[CH2:36][CH2:35][CH2:34][CH2:33]1>O>[CH:32]1([O:17][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:11]=2[C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:18][C:7]=3[N:8]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: BrC1CCCC1
Reactant: Oc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3OC3CCCC3)nc2c1
Temperature: 60 °C
Yield: 83.3 %

Procedure:
To a mixture of 0.28 g of 4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-ol, 0.28 g of potassium carbonate and 2 ml of DMF, a mixture of 0.29 g of cyclopentyl bromide and 2 ml of DMF was added at room temperature. The reaction mixture was stirred while heating at 60° C. for four hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.29 g of 2-(3-cyclopentyloxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 115”).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][C:11]2=[O:12])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[N:10]1([C:7]2[CH:8]=[CH:9][C:4]([C:1]([Cl:23])=[O:2])=[CH:5][CH:6]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:11]1=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(N2C(=O)CCc3ccccc32)cc1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc(N2C(=O)CCc3ccccc32)cc1

Procedure:
To a solution of 1-(4-carboxyphenyl)-3,4-dihydrocarbostyril (0.2 g) in chloroform (5 ml) is added thionyl chloride (0.8 ml) and the mixture is refluxed with heating for 1 hour. Then, chloroform and thionyl chloride are distilled off under reduced pressure to give 4-(3,4-dihydrocarbostyril-1-yl)benzoic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].O[CH2:13][CH:14]([CH2:16]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O.O>>[Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]2[C:6]([CH:13]=[CH:14][CH:16]=[N:5]2)=[CH:7][CH:8]=1
Reactant: OCC(O)CO
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c(Cl)ccc2cccnc12
Yield: 40.5 %

Procedure:
In a similar fashion using route 10 general procedure 20, 3-chloro-2-nitroaniline (1.0 g, 5.8 mmol), glycerol (1.65 g, 18.0 mmol), 3-nitrobenzensulfonic acid sodium salt (1.66 g, 7.5 mmol) and H2SO4/H2O (12 ml, 7:5) gave the title compound (490 mg, 40%) which was used in the next step without purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC([O-])(C)C.[K+].CN(C=O)C>[Cu]I.C(OCC)(=O)C>[C:11]1([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccccc1
Reactant: c1ccc2ocnc2c1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(-c2nc3ccccc3o2)cc1
Yield: 16.9 %

Procedure:
Copper(I) iodide (19.1 mg, 0.1 mmol), benzoxazole (119 mg, 10.0 mmol), bromobenzene (471 mg, 3.0 mmol), t-BuOK (224 mg, 2.0 mmol), and DMF (1.0 mL). After column chromatography (hexanes, then 10% ethyl acetate in hexanes) and preparative HPLC (5% ethyl acetate in hexanes) 99 mg (51%) of 2-phenylbenzoxazole is obtained. Table I, entry 2.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH2:7][N:8]([CH2:18][CH3:19])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[CH3:22][S:23]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:8]([CH2:18][CH3:19])[CH2:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:21][CH:20]=2)=[CH:12][CH:13]=1)(=[O:25])=[O:24]
Reactant: CCN(CCc1ccc(N)cc1)CCc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Product: CCN(CCc1ccc(NS(C)(=O)=O)cc1)CCc1ccc(NS(C)(=O)=O)cc1

Procedure:
N,N-Bis-(4-aminophenethyl)ethylamine (0.3 g) was acylated with methanesulphonyl chloride in a similar fashion to Example 19(C) to provide the title compound as a foam, yield 0.12 g, m.p. <60°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:15]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:28])[C:18]2=[CH:29][CH:30]=[C:31]([Cl:32])[N:17]2[N:16]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:41]1([CH3:50])[CH:46]=[CH:45][C:44]([C:47](Cl)=[O:48])=[CH:43][CH:42]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:28])[C:18]2=[CH:29][CH:30]=[C:31]([Cl:32])[N:17]2[N:16]=1)[CH2:13][CH3:14])[C:47](=[O:48])[C:44]1[CH:45]=[CH:46][C:41]([CH3:50])=[CH:42][CH:43]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
To a solution of (±)-N-{3-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-propylamino]-propyl}-carbamic acid tert-butyl ester (0.51 g, 1.08 mmol) and Et3N (0.25 mL, 1.79 mmol) in CH2Cl2 (10 mL) at rt was added p-toluoyl chloride (0.21 mL, 1.58 mmol) under N2 and stirred at rt for 3 hr. The reaction mixture was diluted with CH2Cl2 to 100 mL, washed with aq. NaHCO3 solution (30 mL), dried over MgSO4. Concentration and purification of the crude product by flash column chromatography (SiO2, EtOAc/hexane 1.5:8.5 to 1:3) gave the title compound as pale oil (0.43 g, 67%): 1H NMR (CDCl3) δ 7.30 (m, 2H), 7.24 (m, 1H), 7.15 (m, 2H), 7.10 (d, 1H, J=4.4 Hz), 6.53 (d, 1H, J=4.4 Hz), 5.91 (m, 1H), 4.95 (m, 1H), 3.35 (m, 2H), 2.70 (m, 1H), 2.36 (s, 3H), 2.05 (m, 1H), 1.95 (m, 1H), 1.43 (m, 3H), 1.35 (s, 9H), 0.67 (m, 3H); MS (ESI+) 592.15 (M++H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>C(OCC)(=O)C.CN(C)C=O>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22]([CH2:21][O:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5])=[O:23]
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Reactant: O=C(CCl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)OC(C)(C)C
Reaction time: 3.5 h
Yield: 90.2 %

Procedure:
To a suspension of tert-butyl 2-hydroxyimino-3-oxobutyrate (46.8 g) and potassium carbonate (51.8 g) in ethyl acetate (70 ml) and N,N-dimethylformamide (70 ml) was added 2,2,2-trichloroethyl chloroacetate (56.5 g), and the mixture was stirred at 45° to 48° C. for 3.5 hours. After the insoluble inorganic substance was filtered off, to the filtrate were added water and ethyl acetate. The separated ethyl acetate solution was washed with water and a saturated aqueous sodium chloride, followed by drying over magnesium sulfate. Removal of the solvent gave tertbutyl 2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyrate (84.9 g).
Reaction SMILES: C([O:4][C:5]1[C:6]([O:11][C:12]2[CH:17]=[C:16]([N:18]3[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]3=[O:30])[C:15]([F:31])=[CH:14][C:13]=2[Cl:32])=[N:7][CH:8]=[CH:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>C(O)(=O)C>[Cl:32][C:13]1[CH:14]=[C:15]([F:31])[C:16]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:17][C:12]=1[O:11][C:6]1[C:5]([OH:4])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CC(=O)Oc1cccnc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ncccc3O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
A mixture of 100 mg of 3-acetoxy-2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyridine, 15 mg of potassium carbonate and 1 ml of methanol was stirred for 3 hours at room temperature. The reaction solution was poured into ice water, then, to this was poured acetic acid. The precipitated crystals were collected by filtration to obtain 65 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxypyridine
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[O:6][CH2:7][C:8](=[O:29])[CH2:9][N:10]([C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])C(=O)OCC1C=CC=CC=1)([O-:3])=[O:2].[BrH:34]>O1CCOCC1.C(O)(=O)C>[BrH:34].[N+:1]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[O:6][CH2:7][C:8]([CH2:9][NH:10][C@@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22])=[O:29])([O-:3])=[O:2]
Reactant: C[C@H](c1ccccc1)N(CC(=O)COc1ccccc1[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: C[C@@H](NCC(=O)COc1ccccc1[N+](=O)[O-])c1ccccc1
Reaction time: 0.5 h

Procedure:
The product from Example 1D (19 g, 42.4 mmol) in 1,4-dioxane (100 mL) at 10° C. was treated with 30% HBr in acetic acid (30 mL), stirred for 30 minutes, purged with nitrogen, poured into diethyl ether (600 mL), triturated, and filtered to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ1.60 (d, 3H), 3.98 (d, 1H), 4.20 (d, 1H), 4.38 (q, 1H), 5.14 (s, 2H), 7.16 (t, 1H), 7.25 (d, 1H), 7.40-7.55 (m, 5H), 7.63 (t, 1H), 7.91 (d,1H), 9.20-9.60 (bs, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:12]([Mg]Cl)[C:13]([CH3:16])([CH3:15])[CH3:14]>C1COCC1.CCCCCC>[CH3:12][C:13]([CH3:16])([CH3:15])/[CH:14]=[CH:8]/[C:7]1[CH:10]=[CH:11][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CC(C)(C)C[Mg]Cl
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)/C=C/c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) and well stirred suspension of 4-carboxy benzaldehyde (2.0 g, 13.32 mmol) in anhydrous THF (90 mL) is added 33.3 mmol of neopentyl magnesium chloride in hexane during 20 minutes and the mixture is stirred at the same temperature for an additional two hours before being quenched with satyrated ammonium chloride solution. Most of the THF is evaporated and the aqueous mixture is treated with conc. HCl (50 mL) and the mixture is heated to reflux for 2 hours. The mixture is then cooled to ambient temperature and extracted with methylene chloride (2×100 mL), the organic layer is dried over sodium sulfate and concentrated to obtain the desired compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.[OH-].[Na+]>N1C=CC=CC=1>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:18][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Nc1nc2ccc(O)cc2n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1nc2ccc(O)cc2n1Cc1ccccc1

Procedure:
1-Benzyl-6-hydroxy-2-amino-1H-benzimidazole was treated with BOC2O in pyridine, followed by hydrolysis with NaOH (aq) to give the title compound; MS m/e 340 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24](Cl)[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:30]([CH:24]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[C:16]([Cl:23])=[CH:17][C:18]([Cl:22])=[CH:19][C:20]=4[Cl:21])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[C:25]([F:27])([F:28])[F:26])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)C(Cl)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of 9-chloro-6-(1-chloro-2,2,2-trifluoroethyl)-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (290 mg, 0.576 mmol) and sodium azide (74.9 mg, 1.15 mmol) in dimethylsulfoxide (2.8 mL) was stirred at 100° C. for 2 h. After the mixture was diluted with ethyl acetate, the resultant mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous solid (286 mg, 0.560 mmol, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH:15]4[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:30][CH2:29][C:26]3[CH:25]=[N:24][C:23]([C:22]([F:32])([F:21])[F:31])=[CH:28][CH:27]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH:15]4[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: OC1CCC(N2CCc3[nH]c4ccc(Cl)cc4c3C2)C1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: OC1CCC(N2CCc3c(c4cc(Cl)ccc4n3CCc3ccc(C(F)(F)F)nc3)C2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(8-chloro-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)cyclopentanol (300 mg, 1.03 mmol), 2-trifluoromethyl-5-vinylpyridine (140 mg, 0.809 mmol) and potassium hydroxide (310 mg, 5.5 mmol) in 0.6 ml of NMP was heated to 60 deg C. for 2 h. The reaction mass was cooled at RT and diluted with 20 ml of ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate and concentrated under vacuum. It was purified on 230-400 silica gel (flash) deactivated with triethylamine using ethyl acetate/methanol (5-10%) as eluant, followed by isolation of 3-(8-chloro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)cyclopentanol by PREP HPLC. Yield: 70 mg as TFA salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[NH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]
Reactant: NCCCN1CCCC1=O
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and 1-(3-aminopropyl)pyrrolidin-2-one (35.6 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a beige solid, 63.5 mg, (65% yield) MS (ES+): 392.2, (M+H).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:12][CH2:13]/[CH:14]=[C:15](/[CH3:22])\[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3]\[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.O.BrN1C(=[O:30])CCC1=O>C(COC)OC>[CH3:20][C:19]([CH:18]([OH:30])[CH2:17][CH2:16]/[C:15](/[CH3:22])=[CH:14]\[CH2:13][CH2:12]/[C:2](/[CH3:1])=[CH:3]/[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)=[CH2:21]
Reactant: CC(C)=CCC/C(C)=C\CC/C(C)=C/COC1CCCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: COCCOC
Solvent: O
Product: C=C(C)C(O)CC/C(C)=C\CC/C(C)=C/COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2 g (0.0065 mol) of tetrahydro-2-[[(2E,6Z)-3,7,11-trimethyl-2,6,10-dodecatrienyl]oxy]-2H-pyran dissolved in 13 ml of monoglyme and 2.6 ml of water is treated portionwise at -10° with 1.3 g of N-bromosuccinimide. The mixture is subsequently stirred at 0° for 1/4 hour and at room temperature for 2 hours. The reaction solution is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution. After drying and removing the solvent the residue, containing tetrahydro-2-[[(2E,6Z)-10-bromo-11-hydroxy-3,7,11-trimethyl-2,6,10-dodecatrienyl]oxy]-2H-pyran, is dissolved in 18 ml of methanol and treated with 600 mg of potassium carbonate. The suspension is stirred at room temperature for 1.5 hours under argon. After removing the methanol on a rotary evaporator the residue is treated with 500 ml of ether and 200 ml of water. The organic phase is washed with saturated sodium chloride solution. After drying and removing the solvent the residue, containing (6Z,10E)-2,3-epoxy-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)-oxy]-6,10-dodecadiene, is dissolved in 30 ml of toluene and treated with 1.35 g of aluminum isopropylate. The reaction mixture is boiled at reflux for 17 hours. After cooling to room temperature the reaction mixture is poured into 200 ml of an ice-water mixture. After acidification with 1N hydrochloric acid the mixture is extracted with 3×150 ml of hexane. The organic phase is washed with 500 ml of saturated sodium chloride solution. After drying and removing the solvent the residue is chromatographed on silica gel with a 1:2 ether-hexane mixture which additionally contains 0.1% triethylamine. There is obtained (6Z,10E)-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-1,6,10-dodecatrien-3-ol which has the following bands in the IR spectrum: 3447 cm-1, 1644 cm-1, 1443 cm-1, 1379 cm-1, 909 cm-1.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:7])[CH:2]=1.[F:13][C:14]([C:17]1[N:22]=[C:21]([C:23]2[S:27]C(N)=NC=2C)[CH:20]=[CH:19][N:18]=1)([CH3:16])[CH3:15]>C(Cl)Cl>[F:13][C:14]([C:17]1[N:22]=[C:21]([C:23]2[S:27][C:4]([NH:3][C:6]([N:8]3[CH:9]=[CH:10][N:11]=[CH:12]3)=[O:7])=[N:5][C:1]=2[CH3:2])[CH:20]=[CH:19][N:18]=1)([CH3:16])[CH3:15]
Reactant: Cc1nc(N)sc1-c1ccnc(C(C)(C)F)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccnc(C(C)(C)F)n1
Reaction time: 56 h

Procedure:
CDI (0.10 g) was added to a stirred solution of 5-[2-(1-fluoro-1-methyl-ethyl)-pyrimidin-4-yl]-4-methyl-thiazol-2-ylamine (Step 9.2) (0.15 g) in CH2Cl2 (4 mL) at rt. The reaction mixture was then stood for 56 h at 25° C. and the title compound isolated by filtration.