Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:38]=[CH:37][C:19]([CH2:20][N:21]2[CH:25]=[C:24]([C:26]([O:28]CC)=[O:27])[C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:22]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][N:21]2[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:22]2)=[CH:37][CH:38]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C(=O)O)c(-c3ccccc3)n2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (2.42 g), ethyl 1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-carboxylate (3.40 g), potassium carbonate (2.51 g) and N,N-dimethylformamide (50 ml) was stirred overnight at 80° C. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. A mixture of the residue, potassium hydroxide (1.78 g) and ethanol (50 ml) was refluxed for 5 hours. After the reaction solvent was removed under reduced pressure, water was added to the reaction mixture, then the mixture was acidified with 1N hydrochloric acid. The crystals obtained were collected by filtration to yield 1-[4-(5-methyl-2 phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-carboxylic acid (3.66 g, yield: 75%). This was recrystallized from acetone-hexane. Melting point: 165–166° C.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C)[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH2:27][CH2:28][OH:29])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CN(C)CCNC(=O)c1cccc2nc3ccc4c(OCCO[Si](C)(C)C(C)(C)C)cccc4c3nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4c(OCCO)cccc4c3nc12
Reaction time: 1.5 h
Yield: 24.6 %

Procedure:
To a solution of 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (125 mg) in tetrahydrofuran (5 mL) was added a 1.0M solution of tetrabutyl ammonium fluoride (1.2 mL). After stirring for 1.5 hours the reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield crude product which was purified using flash chromatography to yield the title compound as an orange solid (24 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:46]N1C(=O)CCC1=O>C1C=CC=CC=1>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:46])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCOC(=O)c1ncc2ccc(S(=O)(=O)c3ccccc3)cc2c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCCCOC(=O)c1nc(Br)c2ccc(S(=O)(=O)c3ccccc3)cc2c1O
Yield: 75.4 %

Procedure:
To a mixture of 6-benzenesulfonyl-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (100 mg, 0.26 mmol; see U.S. Patent Application Publication No. 2004/0254215) and benzene (4.5 mL) was added benzoyl peroxide (6.3 mg, 0.026 mmol). Resulting mixture was refluxed for 15 min. prior to the addition of N-bromosuccinimide (51 mg, 0.29 mmol). Reaction mixture was refluxed overnight. It was concentrated and the crude product was purified by silica gel chromatography (eluting with 20%-80%) ethyl acetate/hexanes to provide the title compound (91 mg). MS-(+)-ion: M+1=466.18, 464.14.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:8]2[CH3:11])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[H-].[Na+].I[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C)C=O>[C:30]([O:29][C:28]([NH:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:8]2[CH3:11])=[C:4]([C:17]([F:20])([F:18])[F:19])[CH:3]=1)=[O:34])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCCCI
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)cc(O)cc2n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C(F)(F)F)cc(OCCCNC(=O)OC(C)(C)C)cc2n1C

Procedure:
The reaction was carried out in a manner similar to Reference Example 5 except for using 1.00 g (3.48 mmol) of ethyl 6-hydroxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate, 0.14 g (3.48 mmol) of 60% sodium hydride, 0.99 g (3.48 mmol) of tert-butyl N-(3-iodopropyl)carbamate and 40 ml of dimethylformamide. Ethyl 6-(3-tert-butoxycarbonylaminopropoxy)-1-methyl-4-trifluoromethyl-2-indolecarboxylate was thus obtained in an amount of 1.28 g.
Reaction SMILES: [CH2:1]1[C@@H:3]2[C:4](=[O:22])[CH:5]=[C:6]3[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH:8]=[CH:7]3.[OH-:23].[Na+]>>[CH2:1]1[C@@H:3]2[C:4](=[O:22])[CH:5]3[O:23][C:6]43[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH:8]=[CH:7]4
Reactant: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Reactant: [OH-]
Agent: [Na+]
Product: C[C@]12CC[C@H]3[C@@H](C=CC45OC4C(=O)[C@H]4CC4[C@]35C)[C@@H]1CCC2=O
Reaction time: 20 h
Yield: 85 %

Procedure:
To a cooled solution of 1,2β-methylenandrosta-4,6-diene-3,17-dione (2.964 g, 10 mmol) in 120 ml methanol ice cold 36% H2O2 (10 ml) and 2% NaOH (5 ml) is added gradually under stirring and then the mixture allowed to stand at 0°-5° C. for about 20 hours. Then the reaction mixture is poured onto ice, the raw product filtered off, washed with water, dried and purified by column chromatography on silica gel, using CHCl3 as eluant. Thus 2.655 g (85%) of pure title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][N:11]3[CH:23]=2)[CH:5]=[CH:6][CH:7]=1.ClS([N:33]=[C:34]=O)(=O)=O.CN(C)C=O.[OH-].[Na+]>ClCCl>[C:34]([C:23]1[N:11]2[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:15][C:10]2=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)#[N:33]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(-c2cccc(F)c2)cn2c1CN(C(=O)OC(C)(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2cccc(F)c2)c(C#N)n2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a solution, under argon and cooled to 10° C., of 2.52 g (6.49 mmol) of 2-tert-butyl 8-ethyl 7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate in 20 ml of dichloromethane is added dropwise 0.62 ml (7.14 mmol) of chlorosulfonyl isocyanate (CAS 1189-71-5) and the mixture is left stirring at 0° C. for 1 hour. 3.3 ml (65 mmol) of dimethylformamide are then added dropwise to the mixture, cooled to −10° C. After stirring for 5 hours at room temperature, the mixture is poured into 60 ml of aqueous 1N sodium hydroxide solution and the product is extracted with dichloromethane. The solution is dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give a yellow oil, which is chromatographed on a column of g of silica gel, eluting with a mixture of 20% ethyl acetate in cyclohexane, to give 1.24 g of 2-tert-butyl 8-ethyl 6-cyano-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate in the form of a white powder after crystallizing from diisopropyl ether, filtering off and drying.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35]Br)/[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([O:41][C:42](=[O:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[SH:49])([CH3:40])([CH3:39])[CH3:38]>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35][S:49][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:50])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1S
Reactant: CCOC(=O)/C(=N\OCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: CC(C)(C)OC(=O)c1ccccc1SCCO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
The starting material may be prepared by reaction of ethyl 2-(2-tritylaminothiazol-4-yl)-2-((Z)-bromoethoxyimino)acetate (UK Patent Application No. 2017702) with t-butyl-2-mercaptobenzoate and hydrolysis of the resulting ester to give 2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2-(2-t-butoxycarbonylphenylthio)ethoxyimino]acetic acid, n.m.r. in solvent C:-1.6(s, 9H); 3.3(t, 2H); 4.4(t, 2H); 6.67(s, 1H); 7.0-8.0(m, 4H); 7.34;L (s, 15H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[C:17]([C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[C:24]([O:29]C)[CH:25]=5)[CH:20]=4)[CH:16]=[C:15]([O:31]C)[CH:14]=3)[CH:9]=2)[CH:4]=1.B(Br)(Br)Br>>[OH:31][C:15]1[CH:16]=[C:17]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([OH:29])[CH:23]=[CH:22]3)[CH:18]=[C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([OH:2])[CH:4]=3)[CH:9]=2)[CH:14]=1
Reactant: COc1cc(-c2ccc3cc(OC)ccc3c2)cc(-c2ccc3cc(OC)ccc3c2)c1
Agent: BrB(Br)Br
Product: Oc1cc(-c2ccc3cc(O)ccc3c2)cc(-c2ccc3cc(O)ccc3c2)c1
Yield: 99 %

Procedure:
The compound is prepared by reaction of 2-methoxy-6-[3-methoxy-5-(6-methoxy-2-naphthyl)phenyl]naphthalene (100 mg, 0.24 mmol, 1 eq) with boron tribromide solution (3.6 ml, 3.6 mmol, 15 eq) according to method G. Purification by column chromatography with hexane/ethyl acetate 9/1 yielded the desired product in a yield of 99%, 90 mg.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:30]([CH3:32])[CH3:31])[C:17]4[CH2:23][O:22][CH2:21][CH:20]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:33][CH3:34])[CH:6]=1>C(=O)=O.CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:30]([CH3:31])[CH3:32])[C:17]4[CH2:23][O:22][CH2:21][C@H:20]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:33][CH3:34])[CH:6]=1
Reactant: COc1cc(Nc2nc3c(c(N(C)C)n2)COCC3c2ccccc2)ccc1-n1cnc(Cl)c1
Agent: O=C=O
Solvent: CO
Product: COc1cc(Nc2nc3c(c(N(C)C)n2)COC[C@@H]3c2ccccc2)ccc1-n1cnc(Cl)c1

Procedure:
A racemic mixture of N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,N4-dimethyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine (80.1 mg, 0.130 mmol) (Example 53) was purified using chiral SFC to afford peak A (21.2 mg, 0.044 mmol) (Example 53A) and peak B (24.2 mg, 0.051 mmol) (Example 53B). SFC Method: Chiralpak OJ-H (30×250 mm, 5 μM), 35% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 70 mL/min for 13 min, absorbance 268 nm, injection 5 μL of 27 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=4.5 min, tR (peak B) 9.5 min. The absolute stereochemistry of individual enantiomers (Examples 53A and 53B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 53).
Reaction SMILES: CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C.[N:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][CH:23]=1.O[CH2:32][N:33]1[C:37](=[O:38])[C:36]([C:39]2[C:47]3[C:42](=[CH:43][C:44]([N+:48]([O-:50])=[O:49])=[CH:45][CH:46]=3)[N:41]([CH3:51])[CH:40]=2)=[C:35]([C:52]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[N:54]([CH3:61])[CH:53]=2)[C:34]1=[O:62]>C(Cl)Cl>[CH3:61][N:54]1[C:55]2[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:52]([C:35]2[C:34](=[O:62])[N:33]([CH2:32][O:29][C:28](=[O:30])[C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)[C:37](=[O:38])[C:36]=2[C:39]2[C:47]3[C:42](=[CH:43][C:44]([N+:48]([O-:50])=[O:49])=[CH:45][CH:46]=3)[N:41]([CH3:51])[CH:40]=2)=[CH:53]1
Reactant: O=C(O)c1ccncc1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)N(CO)C2=O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)N(COC(=O)c3ccncc3)C2=O)c2ccccc21
Yield: 76 %

Procedure:
To a solution of dimethylaminopyridine (1.5 equivalents) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.5 equivalent) in CH2Cl2 was added 4-picolinic acid (1.2 equivalents) and the reaction mixture was stirred a few minutes. 1-Hydroxymethyl-3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione, prepared as in example 1a, was added and the reaction mixture was stirred at room temperature for several hours. The mixture was diluted with dichloromethane, washed with aqueous HCL, saturated NaHCO3, water, dried over MgSO4 and evaporated. The residue was purified by column chromatography to afford isonicotinic acid 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl ester (yield—76%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[F:26][C:27]1([F:35])[CH2:30][C:29]([CH2:33][NH2:34])([CH2:31][NH2:32])[CH2:28]1>>[NH2:32][CH2:31][C:29]1([CH2:33][NH:34][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:30][C:27]([F:35])([F:26])[CH2:28]1
Reactant: NCC1(CN)CC(F)(F)C1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(CN)CC(F)(F)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3,3-difluorocyclobutane-1,1-diyl)dimethanamine. MS obsd. (ESI+) [(M+H)+] 487, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (dd, J=7.83, 1.01 Hz, 1 H), 8.08 (s, 1 H), 7.89 (d, J=7.07 Hz, 1 H), 7.80-7.68 (m, 2 H), 7.68-7.56 (m, 2 H), 6.15 (s, 1 H), 5.37 (s, 2 H), 4.55 (brs, 2 H), 3.80 (s, 2 H), 3.79-3.67 (m, 2 H), 3.44 (s, 2 H), 2.76 (t, J=12.25 Hz, 4 H), 2.51 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH:19](OC)[O:20]C)[NH:11][C:10]2=[N:24][NH:25][CH:26]=[C:9]12.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH:19]=[O:20])[NH:11][C:10]2=[N:24][NH:25][CH:26]=[C:9]12
Reactant: CCOC(=O)C1=C(C(OC)OC)Nc2n[nH]cc2C1c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C=O)Nc2n[nH]cc2C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.3 %

Procedure:
To a solution of ethyl 4-(2-chlorophenyl)-6-dimethoxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate (463 mg) in tetrahydrofuran (5 ml) was added 1 N hydrochloric acid (10 ml) and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give the title compound (290 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COc1cccc(OC)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(OC)cccc1OC
Temperature: 30 °C
Reaction time: 20 h
Yield: 91.6 %

Procedure:
To a solution of 2,6-dimethoxyphenol (1.54 g, 10 mmol) and ethyl bromoacetate (2.00 g, 12 mmol) in 15 mL of anhydrous DMF, was added 2.76 g (20 mmol) of K2CO3. The reaction mixture was stirred at 30° C. for 20 hours. The mixture was concentrated in vacuo to remove volatiles. The resulting residue was extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacou to give 2.2 g (91.6%) of ethyl 2-(2,6-dimethoxyphenoxy)acetate. The obtained ester (1.2 g, 5 mmol) was dissolved in a suspension of Silica Gel (2.0 g) in 20 mL of DCM. To this was dropwise added of a solution of concentrated HNO3 (20 mL) in 20 mL of DCM at rt. After being stirred at room temperature for 1 hour, it was transferred into a separatory funnel and then brown bottom layer was discarded into 100 g of ice. The remaining top organic layer was washed with brine, dried over anhydrous sodium sulfate, and then concentrated in vacou to give 1.4 g (98%) of ethyl 2-(2,6-dimethoxy-4-nitrophenoxy)acetate as a brown solid. The obtained nitrophenoxy ester (1.34 g, 4.7 mmol) was dissolved in anhydrous THF (20 mL). To this, was slowly added of 1M DIBAL solution (10.3 mL, 10.3 mmol) in toluene with ice bath cooling. After 1 hour at rt, the reaction was quenched by addition of 1N-NaOH solution, and then extracted with EtOAc. The obtained organic layer was dried over anhydrous sodium sulfate, and passed through Silica Gel pad. The resulting filtrate was concentrated in vacuo to afford 2-(2,6-dimethoxy-4-nitrophenoxy)ethanol (1.01 g, 88%) as a pale yellow solid; MS (ESI) m/z 326 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH3:17])([O-])=O.[CH2:18](OC(OCC)N(C)C)C.N1CCCC1>CN(C)C=O>[O:10]([C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[NH:1][CH:18]=[CH:17]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(OCC)N(C)C
Reactant: Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: c1ccc(Oc2ccc3[nH]ccc3c2)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
A solution of 2-nitro-5-phenoxytoluene (2.06 g) in dimethylformamide (30 ml) containing dimethylformamide diethylacetal (1.57 g) and pyrrolidine (0.77 g) was heated at 120° C. for 2 hours. Solvent was removed at reduced pressure and the residue dissolved in methanol. Raney Nickel (one spatula measure) was added followed by hydrazine hydrate (3×0.5 ml portions, one portion every 30 minutes). The mixture was stirred for a further 1 hour after the final portion of hydrazine hydrate was added, the mixture filtered and solvent removed at reduced pressure. The residue was partitioned between water (100 ml) and diethyl ether (100 ml), the organic phase separated and dried (MgSO4), solvent removed at reduced pressure and the residue column chromatographed (silica gel, hexane →10% ethyl acetate/hexane eluant) to give 5-phenoxyindole (0.52 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]([NH:10][C:11]1([C:17]([OH:19])=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9].[NH2:20][C@H:21]([CH2:25][OH:26])[CH:22]([CH3:24])[CH3:23]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]([NH:10][C:11]1([C:17]([NH:20][C@H:21]([CH2:25][OH:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:9]
Reactant: O=C(NC1(C(=O)O)CCCCC1)OCc1ccco1
Reactant: CC(C)[C@H](N)CO
Product: CC(C)[C@@H](CO)NC(=O)C1(NC(=O)OCc2ccco2)CCCCC1

Procedure:
2.00 g (7.48 mmol) of 1-[[(2-furanylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid was used instead of 2-benzothiophenecarboxylic acid and 772 mg (7.48 mmol) of L-valinol was used instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in the process according to Reference example 188 to obtain 2.64 g (quantitative) of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH2:13][C:12](=O)[CH2:11][CH2:10]2)(=[O:3])[CH3:2].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1.CN(C=O)C.CC1C=CC(S(O)(=O)=O)=CC=1>[C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH:12]([NH:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CC(=O)CC2
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc2c1CC(NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
A solution of 8-acetamido-2-tetralone (15.5 g. 76 mmol), benzylamine (16.3 g, 150 mmol) and tosic acid (0.2 g) in benzene (200 mL) and DMF (50 mL) was refluxed with a Dean-Stark trap attached for 18 h. The solvent was evaporated and the residue dissolved in 1:1 methanol:THF (250 mL). After cooling in an ice bath, sodium cyanoborohydride was added and the mixture warmed to room temperature and stirred for 5 h. The mixture was basified with 12.5% NaOH and the solvent concentrated. The residue was dissolved in methylene chloride:water and filtered through a celite pad. The aqueous layer was extracted with methylene chloride, and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The dark residue was purified by column chromatography (9:1 EtOAc:methanol) to give the product (15 g).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][C:14]1[C:15]([N:23]2[C:27](=[O:28])[C:26]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]3[C:24]2=[O:33])=[N:16][CH:17]=[C:18]([CH:20]([Cl:22])[Cl:21])[N:19]=1>ClCCl>[CH:13]([C:14]1[C:15]([N:23]2[C:24](=[O:33])[C:25]3=[CH:32][CH:31]=[CH:30][CH:29]=[C:26]3[C:27]2=[O:28])=[N:16][CH:17]=[C:18]([CH:20]([Cl:21])[Cl:22])[N:19]=1)=[O:12]
Reactant: O=C1c2ccccc2C(=O)N1c1ncc(C(Cl)Cl)nc1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1nc(C(Cl)Cl)cnc1N1C(=O)c2ccccc2C1=O
Reaction time: 0.67 h
Yield: 78 %

Procedure:
5.1 g of pyridinium chlorochromate were added a little at a time to a solution of 4 g of 3-hydroxymethyl-5-dichloromethyl-2-phthalimidopyrazine in 80 ml of dichloromethane at 35° C., after which the mixture was stirred for 40 minutes and filtered over silica gel, and the filtrate was evaporated down. 3.1 g (76%) of colorless crystals of 3-formyl-5-dichloromethyl-2-phthalimidopyrazine of melting point 145°-146° C. (from ethyl acetate) were obtained. 1H-NMR (270 MHz, CDCl3): δ6.9 (s, 1H), 8.0 (m, 4H), 9.3 (s, 1H), 10.1 (s, 1H).