Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br)=[CH:4][CH:3]=1.[CH3:17][C@H:18]1[O:23][C@@H:22]([CH3:24])[CH2:21][NH:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:20]2[CH2:19][C@H:18]([CH3:17])[O:23][C@H:22]([CH3:24])[CH2:21]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: BrCCCCCCCOc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(CCCCCCCOc2ccc(Br)cc2)C[C@H](C)O1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 1-bromo-4-(7-bromoheptyloxy)benzene (4.405 g), cis-2,6-dimethylmorpholine (1.55 ml) and potassium carbonate (2.09 g) in N,N-dimethylformamide (22 ml) was stirred for 1 hour at 70° C. To the reaction mixture was added cis-2,6-dimethylmorpholine (7.75 ml) and stirred for 1 hour at 70° C. Ethyl acetate (100 ml) was added, and the mixture washed with water (50 ml×2) and brine. The separated organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give a crude pale yellow oil (5.30 g). The crude oil was purified by silica gel chromatography (20:1-1:2 hexane-ethyl acetate) to give 4-[7-(4-bromophenoxy)heptyl]-cis-2,6-dimethylmorpholine (4.43 g) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:10](=O)[CH:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[CH3:12])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[N:9][N:8]=2)[N:7]=1
Reactant: CC(C(=O)NNc1ccc(Cl)nn1)c1ccc2ncccc2c1
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccc2ncccc2c1)c1nnc2ccc(Cl)nn12

Procedure:
A solution of N′-(6-chloropyridazin-3-yl)-2-(quinolin-6-yl)propanehydrazide (4300 mg, 13119 μmol) in TFA (40 mL) was heated to 120° C. with microwaves for 40 min. LCMS suggests very good converson. Solvents removed under reduced pressure and residue partitioned between 9:1 CHCl3/IPA (75 mL) and 1M NaOH (100 mL). Aqueous further extracted with 9:1 CHCl3/IPA (2×25 mL). Combined organics dried over MgSO4, concentrated, and oily residue dissolved in ACN/MeOH (2 mL). Resulting solid after 2 h was isolated by filtration and washed with ACN (5 mL). 6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline isolated as a white solid. MS (ESI pos. ion) m/z: 310 (MH+). Calc'd exact mass for C16H12ClN5: 309.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[C:13](C(OCC)=O)[C:12]2=[O:30])=[CH:2]1>CN(C)C=O.CC(O)CC>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:30])[CH:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccccc2OC)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: CN(C)C=O
Solvent: CCC(C)O
Product: COc1ccccc1NC1=CC(=O)C(=Cc2c[nH]c3ncccc23)O1
Temperature: 25 °C
Yield: 12.1 %

Procedure:
A solution of the compound (0.099 g, 0.24 mmol) of Example 7 in N,N-dimethylformamide (2.0 mL) was refluxed for 9 h. Cooled to ambient temperature, the reaction mixture was diluted with 2-butanol and washed with 4M sodium hydroxide solution. The organic layer was concentrated then purified by chromatography on silica gel(chloroform/methanol) to afford the titled compound as solid (0.0097 g, y. 12%).
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[Cl:5][C:6]1[C:15]2[C:14](=[O:16])[NH:13][C@H:12]3[CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][C@@H:11]3[C:10]=2[CH:9]=[C:8]([CH2:27][CH3:28])[CH:7]=1>>[ClH:5].[Cl:5][C:6]1[C:15]2[C:14](=[O:16])[N:13]([CH2:2][CH2:3][CH3:4])[C@H:12]3[CH2:17][NH:18][CH2:19][C@@H:11]3[C:10]=2[CH:9]=[C:8]([CH2:27][CH3:28])[CH:7]=1
Reactant: CCCI
Reactant: CCc1cc(Cl)c2c(c1)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC2=O
Product: CCCN1C(=O)c2c(Cl)cc(CC)cc2[C@H]2CNC[C@@H]21
Product: Cl

Procedure:
Following the procedures described in Example 24, Parts A and B, except that iodopropane was used instead of iodomethane, (3aR,9bS)-tert-butyl 6-chloro-5-oxo-8-ethyl-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the first eluting compound from the OD column separation of N-BOC intermediate enantiomers in Example 29 and 30 (the first eluting compound gave Example 29), was converted to the title compound of Example 42 as an off-white solid. 1H NMR (CD3OD): δ 7.37 (s, 1H), 7.32 (s, 1H), 4.48 (q, 1H, J=6.8 Hz), 3.98-3.92 (m, 1H), 3.80-3.69 (overlapping m, 4H), 3.41-3.35 (m, 1H), 3.35-3.30 (m, 1H), 2.71 (q, 2H, J=7.5 Hz), 1.72-1.60 (m, 2H), 1.27 (t, 3H, J=7.7 Hz), 0.96 (t, 3H, J=7.4 Hz). LRMS (ESI): 293.2/295.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:8]=[CH:7][C:4]=1[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:21]([CH3:24])([O-:23])=[O:22]>>[CH2:12]([N:11]([C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[CH:24][N+:21]([O-:23])=[O:22])=[C:3]([O:2][CH3:1])[CH:10]=1)[CH2:14][CH3:15])[CH3:13]
Reactant: CCN(CC)c1ccc(C=O)c(OC)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCN(CC)c1ccc(C=C[N+](=O)[O-])c(OC)c1
Temperature: 100 °C
Yield: 44 %

Procedure:
A solution was prepared by dissolving 30 grams (0.14 mol) of 2-methoxy-4-(N,N-diethylamino)benzaldehyde in 150 ml of nitromethane, and added with 4 grams of ammonium acetate. The mixture wa heated at 100° C. for 5 hours under agitation. The reaction solution was then cooled on a dry ice-acetone bath until crystallization had been completed. The separated solid (crystal) was filtered off and dried in vacuum. The obtained product was recrystallized from acetonitrile for two times. An amount of 16 grams of red crystals was obtained. The yield was 44%.
Reaction SMILES: N12CCCN=C1CCCCC2.[CH3:12][C:13]1[N:18]2[N:19]=[C:20]([CH2:22][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:21]=[C:17]2[C:16]([CH3:42])=[N:15][CH:14]=1.[Cl-].[C:44]1([C:50]2[NH:51][CH:52]=[C:53]([CH:55]=O)[N:54]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1COCC1>[CH3:12][C:13]1[N:18]2[N:19]=[C:20]([CH2:22][CH2:55][C:53]3[N:54]=[C:50]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[NH:51][CH:52]=3)[N:21]=[C:17]2[C:16]([CH3:42])=[N:15][CH:14]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ncc(C)n2nc(CCc3c[nH]c(-c4ccccc4)n3)nc12

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.087 mL, 0.58 mmol) was added to a stirred suspension of (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylmethyl)-triphenyl-phosphonium; chloride (0.27 g, 0.58 mmol) and 2-Phenyl-1H-imidazole-4-carbaldehyde (0.100 g, 0.581 mmol) in dry THF (8 mL) and the mixture was stirred at room temperature under an atmosphere of Argon overnight. Some solid was filtered off and the solvent was removed in vac. The remanens was dissolved in DCM, and purified by silica gel chromatography (Eluent: 0-100% EtOAc in n-heptane). Yield: 97 mg of the intermediate as a cis/trans mixture as an oil (53%).
Reaction SMILES: [O-:1][Mn](=O)(=O)=O.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[OH2:15]>>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:1])=[O:15])=[CH:10][CH:9]=1
Reactant: O
Reactant: Cc1ccc(Br)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1ccc(Br)cc1
Temperature: 60 °C
Yield: 41 %

Procedure:
KMnO4 was added in three portions according to the following procedure: KMnO4 (1.515 g, 9.59 mmol) was suspended in water (20 mL). 4-bromotoluene was added dropwise while the reaction stirred vigorously at 60° C. The mixture was allowed to reflux overnight with a loosely placed septum. A second portion of KMnO4 (0.773 g, 4.795 mmol) was added and reaction allowed to continue reflux for 8.5 hr. A final portion of KMnO4 was added and the reaction allowed to reflux for an additional 48 hr, until deemed complete by the consumption of KMnO4 and the formation MnO2. The reaction was filtered under vacuum and precipitate was rinsed with hot water. The aqueous solution was extracted with EtOAc and then acidified to pH 2-3 (as indicated by pH paper). The aqueous layer extracted again with 2× equal volume EtOAc. Pooled organic layers from the second extraction were dried over anhydrous Na2SO4 and evaporated to dryness to afford 4-bromobenzoic acid (0.673 g, 3.3 mmol, 41%). 1H-NMR (CD2Cl2, 500 MHz) δ (ppm): 7.63 (d, J=14.1 Hz, 2H); 7.94 (d, J=17.2 Hz, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)[C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18]C)=[O:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-].[Li+]>CO.O>[CH2:36]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([N:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:27][CH2:28]2)[C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([OH:18])=[O:17])=[CH:10][CH:11]=1)=[O:5])[CH3:37]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(C(=O)OC)c2)N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(C(=O)O)c2)N2CCN(Cc3ccccc3)CC2)cc1

Procedure:
To a solution of INTERMEDIATE 8 (1.66 g, 3.3 mmol) in methanol (15 mL) and water (5 mL) was added lithium hydroxide (0.69 g, 16.5 mmol). After 5 hours at room temperature the methanol was removed and INTERMEDIATE 9 was precipitated from the aqueous solution by the addition of 2M hydrochloric acid.
Reaction SMILES: C(OC([O:6][CH2:7][C:8]#[C:9][C:10](=[O:25])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1)C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C.O1CCCC1.O>[OH:6][CH2:7][C:8]#[C:9][C:10](=[O:25])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1
Reactant: CCOC(C)OCC#CC(=O)/C=C/c1cc(OC)c(OC)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1cc(/C=C/C(=O)C#CCO)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 4 g (11.5 mmol) of (E)-6-(1-ethoxy-ethoxy)-1-(3,4,5-trimethoxyphenyl)-1-hexen-4-yn-3-one in 40 ml of ethanol/tetrahydrofuran (1:1) was treated at room temperature with 0.4 g (1.6 mmol) of pyridinium (toluene-4-sulphonate) and was stirred at room temperature for 20 hours. The reaction mixture was diluted with water and extracted twice with ether. The combined organic phases were dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 200 g of silica gel (elution agent methylene chloride/ether 4:1) and was subsequently crystallized from methylene chloride/ether. There was obtained (E)-6-hydroxy-1-(3,4,5-trimethoxyphenyl)-1-hexen-4-yn-3-one of melting point 113°-115°.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:36])[CH:13]([C:20]2[N:21]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:22]=[C:23]3[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]3)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:7]([F:37])[CH:6]=1)C.[OH-].[Li+]>C1COCC1.CO>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([N:21]2[C:20]([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:38])=[O:3])=[CH:6][C:7]=3[F:37])=[O:36])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[CH:27]3)=[N:22]2)=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)C(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 7.2, 4-{2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid ethyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as yellow oil. MS: m/e=506.2 [M+H+].
Reaction SMILES: C([Li])CCC.[C:6]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:32]1[CH2:36][CH2:35][N:34]=[C:33]1[C:37]1[CH:51]=[CH:50][C:40]([CH2:41]P(=O)(OCC)OCC)=[CH:39][CH:38]=1>CCCCCC.O1CCCC1>[O:32]1[CH2:36][CH2:35][N:34]=[C:33]1[C:37]1[CH:38]=[CH:39][C:40]([CH:41]=[C:28]2[CH2:27][CH2:26][N:25]([C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)=[CH:50][CH:51]=1
Reactant: CCOP(=O)(Cc1ccc(C2=NCCO2)cc1)OCC
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C(=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1)c1ccc(C2=NCCO2)cc1
Temperature: -60 °C
Reaction time: 0.42 h

Procedure:
6.25 ml of a 1.6M solution of n-butyllithium in hexane followed, after stirring for 20 minutes, by 3.4 g of N-trityl-4-piperidone (prepared from 4-piperidone hydrochloride hydrate and trityl chloride) in 20 ml of tetrahydrofuran are added dropwise at -60° C. to 2.97 g of diethyl 4-(2-oxazolin-2-yl)benzylphosphonate. The mixture is stirred at -60° C. for 25 minutes. The reaction solution is then allowed to warm to ambient temperature and is stirred for a further 1.5 hours at this temperature. The reaction solution is then stirred into 150 ml of ice-water, the mixture is extracted three times with 150 ml of ethyl acetate, and the organic phase is dried and evaporated down. The residue is purified by column chromatography on Silica gel (petroleum ether/ethyl acetate=1:1, v/v). 1.7 g of the title compound of melting point 110°-115° C. are obtained.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][C:23]1[CH:31]=[C:30](F)[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].C[N:34]([CH3:37])C=O>O.ClCCl>[Br:22][C:23]1[CH:31]=[C:30]([N:34]2[CH:37]=[CH:9][C:8]([CH3:15])=[N:7]2)[CH:29]=[CH:28][C:24]=1[C:25]([N:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11]1)=[O:26]
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: CN(C)C=O
Reactant: O=C(Cl)c1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(Br)c2)n1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 59.5 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (5.15 g, 26.1 mmol) in dimethylformamide (70 mL) under nitrogen was added potassium carbonate (7.95 g, 57.51 mmol). The mixture was cooled and treated dropwise with a solution of crude 2-bromo4-fluorobenzoyl chloride of Step A (31.37 mmol) in dimethylformamide (30 mL). After stirring at room temperature for 75 minutes the mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness to give a brown solid foam. The crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with a hexane-ethyl acetate gradient (from 95:5 to 75:25) provided the pure title compound (6.18 g, 59.5%) along with some impure material (1.2 g). The pure material was triturated with hexane to provide an off-white solid foam, which was used as such in the next step.
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].[N:5]1([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=2)[CH:9]=[CH:8][CH:7]=[N:6]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH3:4][O:3][N:2]([CH3:1])[C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:10]([N:5]2[CH:9]=[CH:8][CH:7]=[N:6]2)=[N:11][CH:12]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(-n2cccn2)nc1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(-n2cccn2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,O-Dimethylhydroxylamine (1.03 g, 10.6 mmol) was added to an ambient temperature solution of 6-(1H-pyrazol-1-yl)nicotinic acid (2 g, 10.6 mmol), EDC (2.4 g, 12.7 mmol), HOBt (1.94 g, 12.7 mmol) and NMM (5.2 mL, 47.6 mmol) in methylene chloride (100 mL). After stirring at ambient temperature overnight, the reaction mixture was diluted with methylene chloride and washed successively with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded N-methoxy-N-methyl-6-(1H-pyrazol-1-yl)nicotinamide.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][C:11]1([C:14](=[O:16])[NH2:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[CH2:1]([O:8][C:9](=[O:17])[NH:10][C:11]1([C:14](=[O:16])/[N:15]=[CH:20]/[N:21]([CH3:23])[CH3:22])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C1(NC(=O)OCc2ccccc2)CC1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=N/C(=O)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a round bottom flask was added (1-carbamoyl-cyclopropyl)-carbamic acid benzyl ester (935 mg, 4 mmol) in N,N-dimethylformamide dimethyl acetal (15 mL). The reaction mixture was stirred at 100° C. for 1 h. The solvent was concentrated in vacuo. The residue was dissolved in EtOAc/sat. NaHCO3. The organic phase was separated, washed with brine, dried over anhydrous Na2SO4, filtered, concentrated and dried under high vacuum to afford 1.11 g of (1-{[1-dimethylamino-meth-(E)-ylidene]-carbamoyl}-cyclopropyl)-carbamic acid benzyl ester as a light brown oil, m/z 290.9 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[N:19]=1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][C:18]2[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]3[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=3[N:19]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: CC(C)n1c(CBr)nc2ccccc21
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2nc3ccccc3n2C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (746 mg, 5.2 mmol) was dissolved in anhydrous DMF (30 mL), then potassium carbonate (2.18 g, 15.8 mmol) and 2-(bromomethyl)-1-(propan-2-yl)-1H-benzimidazole (1.99 g, 7.9 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 12% DCM in MeOH to afford 6-methyl-2-({[1-(propane-2-yl)-1H-benzimidazol-2-yl]methyl}sulfanyl)pyrimidin-4-ol (1.01 g, 41% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.55 (s, 3H), 1.56 (s, 3H), 2.20 (s, 3H), 4.76 (s, 2H), 4.84-4.92 (m, 1H), 6.06 (bs, 1H), 7.13-7.20 (m, 2H), 7.54-7.57 (m, 1H), 7.68-7.71 (m, 1H); LRMS (ES+) m/z 315 (100%, M+1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>CN(C)C(=O)C>[F:11][C:2]([F:1])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)nc1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(trifluoromethyl)pyridine-3-amine (1.00 g, 6.15 mmol) and pyridine (1.50 ml, 18.5 mmol) in N,N-dimethylacetamide (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.17 ml, 8.51 mmol) with ice-cooling, and the mixture was stirred for 1 hour with ice-cooling. The reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate and the desired product (1.83 g, 88.0%) as a solid was collected by filtration.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=[C:9]([CH:13]=1)[C:10](O)=[O:11])([OH:4])(=[O:3])=[O:2].[OH:17][OH:18].[O-:19]S([O-])(=O)=O.[Na+].[Na+].C(OC)(C)(C)C>S(=O)(=O)(O)O>[S:1]([C:5]1[CH:6]=[C:7]([C:14]([O:16][OH:19])=[O:15])[CH:8]=[C:9]([CH:13]=1)[C:10]([O:17][OH:18])=[O:11])([OH:4])(=[O:3])=[O:2]
Reactant: O=S(=O)([O-])[O-]
Reactant: O=C(O)c1cc(C(=O)O)cc(S(=O)(=O)O)c1
Reactant: OO
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COC(C)(C)C
Product: O=C(OO)c1cc(C(=O)OO)cc(S(=O)(=O)O)c1
Temperature: 15 °C
Reaction time: 2 h

Procedure:
4.00 g (0. 0149 mol) 5-sulfo isophtalic acid was dissolved in 11.00 g 98% sulfuric acid at 35° C. during 1 hour and was then cooled to 15° C. 3.58 g (0.895 mol) 85% hydrogen peroxide was added by drops, the temperature not exceeding 25° C. After 2 hours reaction at 35° C., 200 ml saturated Na2SO4 solution and a few grams of solid Na2SO4 were added. The solution was poured into cold tert.butylmethyl ether and was allowed to stand for 2 hours under agitation. The tert.butyl-methyl ether phase was separated and dried over Na2SO4, whereupon the solvent was evaporated and 5-sulfo diperoxy isophtalic acid precipitated as crystals. The yield of active oxygen was 80.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.S(=O)(=O)(O)O.O.[CH3:21]COCC>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:21])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Cl)ccc2c1
Reactant: CCOCC
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2cc(Cl)ccc2c1
Reaction time: 72 h

Procedure:
A suspension of the 6-chloro-2-naphthoic acid (41.2 g.) in a mixture of methanol (500 ml.) and concentrated sulphuric acid (50 ml.) is heated under reflux for 3 hours, stored at ambient temperature for 3 days, then warmed until a solution is obtained. Water (2 1.) and ether (1 1.) are added. The ethereal layer is separated, and is washed in turn with water, N-aqueous sodium hydroxide, and water, dried with magnesium sulphate, and evaporated to give methyl 6-chloro-2-naphthoate (38.8 g.) m.p. 97°-98° C., which may be further purified by recrystallisation from light petroleum (b.p. 40°-60° C.) to give material of m.p. 100°-101° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1C(=O)C3=CC=CC=C3C1=O)[CH2:7]2.O.NN>C(O)C>[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[CH2:7][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:5]2
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN1C(=O)c3ccccc3C1=O)C2
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN)C2
Temperature: 25 °C
Yield: 91.8 %

Procedure:
The mixture of N-[8-(4,5,6,7-tetramethoxyindan-2-yl)octyl]phthalimide (384 mg), hydrazine monohydrate (194 mg) in ethanol (8 ml) was heated under reflux for 6 hr. The reaction mixture was cooled to room temperature and solid was filtered off and the filtrate was concentrated. The residue was diluted with ethyl acetate, washed with 1M aqueous potassium carbonate, water, and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo to yield the entitled compound (260 mg) as an oil.