Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][OH:10])=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:19]([C:21]([CH2:28][CH3:29])([C:25](Cl)=[O:26])[C:22](Cl)=[O:23])[CH3:20]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[C:22](=[O:23])[C:21]([CH2:28][CH3:29])([CH2:19][CH3:20])[C:25](=[O:26])[O:10]2)=[O:8])=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)NO)cc1
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1(CC)C(=O)ON(C(=O)c2ccc(OC)cc2)C1=O
Yield: 70.3 %

Procedure:
A mixture consisting of 1.67 g (0.0107 mol) of 4-methoxybenzohydroxamic acid, mp 158°-15920 C. (dec.)(lit. mp 156°-157° C. (dec.), Beilstein Handbook of Organic Chemistry, series H, vol 10, p. 170), 5 ml of pyridine, and 100 ml of methylene chloride was prepared in a 250 ml round bottom flask. The mixture was cooled in an ice bath, and 2.107 g (0.0107 mol) of diethylmalonyl chloride was added dropwise over a 15 minute period with stirring. The reaction mixture was stirred for 2 hours at room temperature after which time all the hydroxamic acid had dissolved. The solution was extracted two times with 50 ml portions of water, three times with 50 ml portions of 5% hydrochloric acid, and two times with 50 ml portions of 5% sodium carbonate. The methylene chloride was dried (MgSO4) and evaporated to dryness under reduced pressure to give 2.19 g (70.4%) of crude 2-(4-methoxybenzoyl)-4,4-diethylisoxazolidine-3,5-dione as a solid residue. Recrystallization of the solid from absolute ethanol gave pure 2-(4-methoxybenzoyl)-4,4-diethylisoxazolidine-3,5-dione as a white solid: mp 116°-118° C.; IR (Nujol) 1810 (s,C=O), 1750 (s, C=O), 1690 cm-1 (s, C=O); 1H NMR (400 MHz, CDCl3) 7.83 (d, 2H), 6.98 (d, 2H), 3.89 (t, 3H), 1.95 (q, 4H), 1.01 (t, 6H); High resolution MS, calc'd for: C15H17NO5 : 291.1102. Found: 291.1106. Anal. Calc' d for: C15H17NO5 : C, 61.84; H, 5.88; N, 4.81. Found: C, 61.83; H, 5.76; N, 4.76.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([CH2:12]C(O)=O)#[N:11].N1C=CC=CC=1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[CH:12]/[C:10]#[N:11]
Reactant: N#CCC(=O)O
Reactant: O=Cc1cccc(Cl)c1
Solvent: CC(C)O
Solvent: c1ccncc1
Product: N#C/C=C/c1cccc(Cl)c1

Procedure:
m-Chlorobenzaldehyde (210.75 g; 1.5 m), cyanoacetic acid (127.5 g; 1.5 m) and pyridine (150 ml.) were refluxed for two days. The solution was evaporated to give an oil which was distilled to give a mixture of isomers (72% trans/23% cis; 5% aldehyde), Yield (129 g; 53%), b.p. 70°-85°C. at 0.8 mm. The material was dissolved in isopropanol and allowed to fractionally crystallise at 0°C. The solid was filtered and freeze-dried. Yield of pure trans isomer was 15 g (6.1%) b.p. 104°-106°C. at 1 mm; m.p. 26°-28°C.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl.[F:35][CH:36]([F:42])[CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:39]4[CH2:40][CH2:41][CH:37]([CH:36]([F:42])[F:35])[CH2:38]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: FC(F)C1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CCC(C(F)F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and 3-Difluoromethyl-pyrrolidine hydrochloride. 1H NMR (400 MHz, DMSO-d6): δ 8.75 (t, J=5.81 Hz, 1H), 7.75 (dd, J=9.31, Hz, 1H), 7.51-7.58 (m, 2H), 7.01 (d, J=9.01 Hz, 1H), 6.05-6.34 (m, 1H), 3.67-3.76 (m, 2H), 3.51-3.57 (m, 2H), 3.22-3.24 (m, 2H), 2.84-2.93 (m, 1H), 2.13-2.21 (m, 1H), 1.99-2.06 (m, 3H), 1.73-1.86 (m, 5H), 1.23-1.32 (m, 2H). m/z: 458.2 [M+H]+
Reaction SMILES: [CH:1]1([CH2:11][C:12](O)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:15][O:16][C:17]1[C:18]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:19][C:20]2[O:24][CH2:23][CH2:22][C:21]=2[CH:25]=1>>[CH3:15][O:16][C:17]1[C:18]([N:26]2[CH2:27][CH2:28][N:29]([CH2:12][CH2:11][CH:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)[CH2:30][CH2:31]2)=[CH:19][C:20]2[O:24][CH2:23][CH2:22][C:21]=2[CH:25]=1
Reactant: O=C(O)CC1CCCc2ccccc21
Reactant: COc1cc2c(cc1N1CCNCC1)OCC2
Product: COc1cc2c(cc1N1CCN(CCC3CCCc4ccccc43)CC1)OCC2

Procedure:
Prepared as described in Example 9, starting from 1,2,3,4-tetrahydronaphthalen-1-ylacetic acid and 4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. The fumarate of the title compound melts at 219°-220° C. after recrystallisation from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]=[C:9]=[O:10])[CH:5]=[C:4]([F:11])[CH:3]=1.[F:12][C:13]1[C:14](=[NH:21])[N:15]([CH3:20])[C:16](=[O:19])[NH:17][CH:18]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([N:17]2[CH:18]=[C:13]([F:12])[C:14](=[NH:21])[N:15]([CH3:20])[C:16]2=[O:19])=[O:10])[CH:5]=[C:4]([F:11])[CH:3]=1
Reactant: O=C=Nc1cc(F)cc(F)c1
Reactant: Cn1c(=O)[nH]cc(F)c1=N
Solvent: CN(C)C=O
Product: Cn1c(=N)c(F)cn(C(=O)Nc2cc(F)cc(F)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,3-Difluoro-5-isocyanatobenzene (119 mg, 0.769 mmol) was added to a solution of 5-fluoro-4-imino-3-methyl-3,4-dihydropyrimidin-2(1H)-one (100 mg, 0.699 mmol) in DMF (1.8 mL) and stirred overnight at room temperature. The solution was then concentrated under vacuum and the resulting residue stirred in dichloromethane (2 mL) for 30 min. The solids were filtered and washed with dichloromethane (2×3 mL) and dried under vacuum to afford the title compound; mp 203.0-204.5° C.; 1H NMR (400 MHz, CDCl3) δ 11.03 (s, 1H), 9.87 (s, 1H), 7.68 (d, J=6.2 Hz, 1H), 7.25 (d, J=7.4 Hz, 2H), 6.80 (s, 1H), 3.25 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 163.77, 163.62, 161.36, 161.21, 158.57, 149.14, 146.14, 145.90, 142.72, 142.58, 142.44, 138.68, 136.41, 122.85, 122.52, 101.05, 100.76, 97.32, 97.06, 96.79, 29.43; ESIMS m/z 299.0 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[CH:22](OCC)=[O:23]>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]3[C@H:14]([NH:15][CH:22]=[O:23])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: CCOC=O
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Product: O=CN[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Yield: 100 %

Procedure:
trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (10 mg, 0.03 mmol) was dissolved in 1 mL of ethyl formate. The resulting mixture was heated to reflux for 18 h. The cooled mixture was evaporated to give trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)formamide (12.0 mg, 100%). Data: (m/z)=329 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[CH:21]=1>>[C:20]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:1]2[CH:2]([C:10]3[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=3[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:21]=1
Reactant: COC(=O)CCCC(N)c1c(OC)ccnc1OC
Reactant: O=Cc1cccc(-c2ccccc2)c1
Product: COc1ccnc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,4-dimethoxypyridin-3-yl)pentanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC the target compound. LC-MS (conditions A): tR=0.83 min.; [M+H]+: 403.34 g/mol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[C:15]2=[CH:16][C:17]3[O:21][CH2:20][O:19][C:18]=3[CH:22]=[C:14]2[O:13][CH2:12]1.[CH3:23][N:24](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:11]=[C:8]1[C:7]2([C:15]3=[CH:16][C:17]4[O:21][CH2:20][O:19][C:18]=4[CH:22]=[C:14]3[O:13][CH2:12]2)[C:6]2[C:10](=[C:2]([C:23]#[N:24])[CH:3]=[CH:4][CH:5]=2)[NH:9]1
Reactant: CN(C)C=O
Reactant: O=C1Nc2c(Br)cccc2C12COc1cc3c(cc12)OCO3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc2c1NC(=O)C21COc2cc3c(cc21)OCO3
Yield: 76 %

Procedure:
To a suspended mixture of 7′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.44 g, 1.2 mmol) and zinc cyanide (0.28 g, 2.4 mmol) in anhydrous N,N-dimethylformamide (12 mL) was added tetrakis(triphenylphosphine)palladium (0.14 g, 0.12 mmol). The reaction mixture was refluxed for 3 h. The solid was filtered and washed with ethyl acetate (40 mL). The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (20% to 30% gradient) to afford 2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile (0.28 g, 76%) as a colorless solid: mp 205-207° C.; 1H NMR (300 MHz, DMSO-d6) δ11.55 (s, 1H), 7.62 (dd, J=8.0 Hz, 1.1 Hz, 1H), 7.41 (d, J=7.0 Hz, 1H), 7.12-7.07 (m, 1H), 6.69 (s, 1H), 6.44 (s, 1H), 5.93 (dd, J=3.4, 0.8 Hz, 2H), 4.78 (d, J=9.5 Hz, 1H), 4.67 (d, J=9.5 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ178.4, 155.4, 148.3, 145.2, 141.7, 133.8, 131.6, 128.3, 122.5, 118.9, 115.9, 103.2, 101.3, 93.1, 92.6, 79.6, 57.5; MS (ES+) m/z 307.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=1[O:25][CH3:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([Li])CCC>>[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]([OH:22])[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:19][C:18]=1[O:25][CH3:26])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: Cc1ccc(Br)cc1
Agent: [Li]CCCC
Product: COc1cc(C(O)c2ccc(C)cc2)ccc1OCc1ccccc1

Procedure:
The synthesis is based essentially on the reaction of 4-bromotoluene with 4-(benzyloxy)-3-methoxybenzaldehyde in the presence of butyllithium to give 4-(benzyloxy)-3-methoxy-4'-methylbenzhydrol. By oxidation to 4-(benzyloxy)-3-methoxy-4'-methylbenzophenone and subsequent debenzylation there is obtained 4-hydroxy-3-methoxy-4'-methylbenzophenone. After regioselective nitration to 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenone and subsequent hydrolysis of the methoxy group there is obtained the aforementioned inhibitor 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:18][CH2:17]2)=[O:15])=[C:8]([N+:30]([O-:32])=[O:31])[CH:7]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:13][O:12][C:11]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:44]2[CH2:43][CH2:42][N:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[O:34][CH3:33])[CH2:46][CH2:45]2)=[CH:7][C:8]([N+:30]([O-:32])=[O:31])=[C:9]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:18][CH2:17]2)=[O:15])[CH:10]=1
Reactant: COc1cc(C(=O)N2CCN(c3ccccc3OC)CC2)c([N+](=O)[O-])cc1OCCCBr
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(=O)N2CCN(c3ccccc3OC)CC2)c([N+](=O)[O-])cc1OCCCN1CCN(c2ccccc2OC)CC1
Reaction time: 16 h
Yield: 93 %

Procedure:
To a stirred suspension of [4-(3-bromopropyloxy)-5-methoxy-2-nitrophenyl][4-(2-methoxyphenyl)piperazino]methanone (9) (500 mg, 1.65 mmol), 1-(2-methoxyphenyl)piperazine (316 mg 15.6 mmol) and K2CO3 (816 mg 26.6 mmol) in acetone (30 mL) and the stirring was continued for 16 h. The acetone was evaporated in vacuum and the aqueous layer was washed with ethyl acetate and extracted with ethyl acetate and washed with brine, dried over Na2SO4 and evaporated in vacuum to afford the crude product to (5-methoxy-4-3-[4-(2-methoxyphenyl)-piperazino]propoxy-2-nitrophenyl)[4-(2-methoxyphenyl)piperazino]methanone (10) in 93% yield (670 mg, 85% yield). 1H NMR (CDCl3): δ 1.60-2.15 (m, 2H), 2.98-3.12 (t, 2H, J=7.31 Hz), 3.18-3.36 (m, 8H), 3.38-3.60 (m, 10H), 3.85 (m, 3H), 3.95 (s, 3H), 4.00-4.15 (m, 3H) 6.85-7.00 (m, 8H), 7.20-7.40 (m, 1H), 7.70-7.80 (d, 1H, J=6.81 Hz); FABMS: 619 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[S:18](O)=O>CS(O)(=O)=O>[Br:1][C:2]1[C:3]2[S:8][C:9]3[C:10](=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)[S:18][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccccc2Br)c(S(=O)O)c1
Agent: CS(=O)(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)Sc1cccc(Br)c1S2
Temperature: 50 °C
Yield: 60.7 %

Procedure:
2-(2-Bromo-phenylsulfanyl)-5-nitro-benzenesulfinic acid (208.5 g, 557 mmol) thinly ground was dissolved slowly in methanesulfonic acid (2 litre) with stirring. The mixture was stirred and heated at 50° C. for 17 hours. The solution was poured onto ice (5 L) with stirring, then filtered and the solid collected. The residue was suspended in water (500 ml) and then basified to pH 8 with concentrated ammonia. The solid was then filtered, suspended into methanol (1 L) and filtered again. The solid was then dried in a desiccator under vacuum to give the title compound (115 g, 61%). m/z (LC-MS, ESP), RT=5.53 min (no ionisation). 1HNMR (300 MHz, CDCl3): δH=7.15 (1H, t), 7.45 (1H, dd), 7.58 (1H, dd), 7.67 (1H, d), 8.11 (1H, dd), 8.31 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N+:13]([O-:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].I[CH2:17][CH2:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:13]([O-:15])=[O:14])[CH2:17][CH2:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(CCI)CCc1ccccc1
Reactant: COc1ccc(CC[N+](=O)[O-])cc1OC
Solvent: C1CCOC1
Product: COc1ccc(CC(CCC(=O)CCc2ccccc2)[N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 113.2 %

Procedure:
To a solution of 36 g (0.17 mole) of 2-(3,4-dimethoxyphenyl)-1-nitroethane in 300 mL of dry tetrahydrofuran was added 71 g (0.17 mole) of 40% Triton B. The solution was stirred at room temperature for 10 min. 55.3 g (0.19 mole) of 1-iodo-5-phenyl-3-pentanone in a minimum amount of dry tetrahydrofuran was added dropwise. The mixture was stirred at room temperature for 30 min, at 50° C. for 3 hr., then allowed to stir at room temperature overnight. Solvent was removed in vacuo and the residue taken up in ether and extracted twice with water. The organic layer was dried over anh Mg SO4, and concentrated at reduced pressure to give 71.5 g of crude oil. This crude material was passed through HPLC to give 46.4 g. of purified material.
Reaction SMILES: CS(O[CH2:6][CH:7]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=O)=O.[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.[K]>CN(C)C=O>[CH2:25]([O:24][CH:7]([CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6][N:43]1[C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]2[C:39]1=[O:49])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCCCCCCCCCCCOCC(COS(C)(=O)=O)OCCCCCCCCCCCCCC
Agent: [K]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOCC(CN1C(=O)c2ccccc2C1=O)OCCCCCCCCCCCCCC
Temperature: 70 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Crude O-(2,3-dimyristyloxypropyl) methanesulphonate 3 (14.2 g, 25.3 mmol) and potassium phthalimide (13.9 g, 75.0 mmol) were flushed with nitrogen and dissolved in anhydrous N,N-dimethylformamide (250 ml). The reaction was left to stir at 70° C. overnight under a constant stream of nitrogen. The N,N-dimethylformamide was removed on the rotary evaporator using a high vacuum pump instead of the usual aspirator. The residue was dissolved in chloroform (300 ml) and transferred to a separatory funnel with a chloroform rinse (50 ml), then washed with distilled water and ethanol (3×300 ml distilled water, 50 ml ethanol). The combined aqueous washes were back-extracted with chloroform (2×100 ml). The combined organic layers were dried with magnesium sulfate and the chloroform was removed on the rotary evaporator. TLC (30% ether-hexane, developed in Molybdate) indicated that the starting material had reacted to form product. This reaction yielded 13.5 g of crude N-(2,3-dimyristyloxypropyl)phthalimide 4.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2].C[O:21][C:22]([CH:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23].[OH-].[K+]>CO>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([C:27]3[CH2:28][CH2:29][CH:24]([C:22]([OH:23])=[O:21])[CH2:25][CH:26]=3)=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: CCc1cccc(CC)c1-c1cc2cc[nH]c2cn1
Reactant: COC(=O)C1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCc1cccc(CC)c1-c1cc2c(C3=CCC(C(=O)O)CC3)c[nH]c2cn1
Yield: 40.1 %

Procedure:
A solution of 5-(2,6-diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (200 mg, 0.8 mmol) in MeOH (5 mL) is added to a stirring solution of 4-oxo-cyclohexanecarboxylic acid methyl ester (204 mg, 1.2 mmol) and KOH (163 mg, 2.9 mmol) in MeOH (10 mL) at room temperature. The mixture is heated at reflux for 24 hours. The solvent is removed to dryness in vacuo. The residue is mixed with water and adjusted pH to 7. The mixture is extracted with CH2Cl2 (2×10 mL). The organic layer is washed with brine, dried, and evaporated under reduce pressure to give 120 mg of crude product. The crude product is used for next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[CH:16](O)=[O:17]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:16]=[O:17])=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1
Reactant: Nc1ccc(Br)cc1Oc1ccccc1
Reactant: O=CO
Product: O=CNc1ccc(Br)cc1Oc1ccccc1

Procedure:
Using the general procedure of J. Chem. Soc., Perkin I 1976, 1279-1285, 4-bromo-2-(phenoxy)aniline, prepared as described in J. Chem. Soc., 1930, 1202-1208, is heated with formic acid to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])[C:5]([NH:7][C:8]1[C:16]2[NH:15][C:14](=O)[NH:13][C:12]=2[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=1)=[O:6].O=P(Cl)(Cl)[Cl:29]>>[Cl:29][C:14]1[NH:15][C:16]2[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:3]=[C:2]([F:1])[C:24]([F:25])=[C:23]([F:26])[CH:22]=3)=[CH:9][C:10]([C:18]([F:21])([F:20])[F:19])=[CH:11][C:12]=2[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(Nc1cc(C(F)(F)F)cc2[nH]c(=O)[nH]c12)c1cc(F)c(F)c(F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc2nc(Cl)[nH]c12)c1cc(F)c(F)c(F)c1

Procedure:
3,4,5-Trifluoro-N-(2-oxo-6-trifluoromethyl-2,3-dihydro-1H-benzoimidazol-4-yl)-benzamide from step (c) above (1.12 g, 3.0 mmol) reacted with POCl3 (5 mL, Aldrich) under the conditions of Example 1c to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 393.7 (M+1), (ESI, neg. ion) m/z: 392 (M−1).
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)[N:7]=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=1>C(Cl)Cl.O=[Mn]=O>[F:21][CH:2]([F:1])[O:3][C:4]1[N:8]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=2)[N:7]=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=1
Reactant: OCc1ccc(-n2nc(C(F)(F)F)cc2OC(F)F)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1ccc(-n2nc(C(F)(F)F)cc2OC(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.3 %

Procedure:
A solution of [4-(5-difluoromethoxy-3-trifluoromethyl-pyrazol-1-yl)-phenyl]-methanol (380 mg, 1.2 mmol) in DCM (20 mL) was treated with excess amount of MnO2 was stirred at room temperature for 24 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by chromatography (SiO2, 6:1 hexane/EtOAc) gave 4-(5-difluoromethoxy-3-trifluoromethyl-pyrazol-1-yl)-benzaldehyde (350 mg, 93% yield) as a syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH3:17][CH:18](O)[CH:19]=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:17]([CH:8]1[C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:18]=[CH:19][CH3:20]
Reactant: C=CC(C)O
Reactant: CCC1(CC)CC(=O)c2cc(OC)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1C(=O)c2cc(OC)ccc2C1(CC)CC
Yield: 15 %

Procedure:
A solution of 22.0 g of 6-methoxy-3,3-diethyl-1-indanone, 20.8 ml of 3-buten-2-ol and 220 mg of p-toluenesulfonic acid in 220 ml of 2,2-dimethoxypropane was boiled under reflux for 87 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 6:1). In addition to 15.7 g of educt, there were obtained 4.1 g (15%) of (RS)-2-(2-buten-1-yl)-6-methoxy-3,3-diethyl-1-indanone as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:31](O)=[O:32])[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl.[CH3:45][NH:46][O:47][CH3:48]>ClCCl>[CH3:48][O:47][N:46]([CH3:45])[C:31]([C:17]1[C:18]2[C:23]([CH3:24])=[N:22][N:21]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[C:19]=2[N:20]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[F:34])[CH:16]=1)=[O:32]
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)O)c12
Reactant: CNOC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2F)nc2c1c(C)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
6-(4-Benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3.00 g) was dissolved in dichloromethane (50 mL), DIPEA (3.34 mL), N,O-dimethylhydroxylamine hydrochloride (0.63 g) and finally BEP (3.92 g) were added. The mixture was stirred at r.t. overnight, then extracted with sat. sodium carbonate solution, washed with 1N HCl and finally again with sodium carbonate solution. The solvent was evaporated and the residue was crystallized from methanol and filtered off giving 6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid methoxy-methyl-amide (2.28 g, 70%) as a solid.