Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:12]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]2[NH:10][N:9]=[N:8][C:7]=2[CH:11]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1ccc2[nH]nnc2c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc2nn[nH]c2cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
5-Nitro-1H-benzotriazole was dissolved in conc. sulphuric acid (60 ml) and cooled to 0° C. in an ice bath. Nitric acid (60 ml, excess) was added drop wise to the cooled solution over a period of 20 minutes. Stirring was continued for another 15 minutes at 0° C. and then at 115° C. overnight, by which time TLC (A) indicated the conversion of starting material. The solution was cooled to room temperature and poured over ice to precipitate a pale yellow solid and a clear yellow solution. The solid was collected by filtration and washed with copious amounts of water until neutral to afford [19] in 67% yield. Rf (A) 0.34; δH(400 MHZ; DMSO-d6) 9.02 (2H, s, BT); m/z (FAB) 210.02695 [(M+H)+ calc. for C6H4N5O4 210.02633].
Reaction SMILES: [N:1]([CH:4]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:33]=[N:34][NH:35][N:36]=2)[CH:27]=1)[C:5]1[CH:25]=[CH:24][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[C:13]([OH:20])[C:12]=2[CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH:4]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[NH:36][N:35]=[N:34][N:33]=2)[CH:27]=1)[C:5]1[CH:25]=[CH:24][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[C:13]([OH:20])[C:12]=2[CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1
Reactant: CCCc1c(OCc2ccc(C(N=[N+]=[N-])c3cccc(-c4nn[nH]n4)c3)cc2)ccc(C(C)=O)c1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCc2ccc(C(N)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.5 %

Procedure:
A mixture of 1-[4-(4-{azido-[3-(2H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (340 mg, 0.703 mmol), triphenylphosphine (195 mg, 0.74 mmol), water (0.5 mL), and tetrahydrofuran (5 mL) is stirred at room temperature 48 hr. The mixture is filtered, the cake is washed with tetrahydrofuran (2 mL) and dried under vacuum to give the title compound 169 mg, 52%, as a white solid. 1H NMR (DMSO-d6) δ 12.86 (s, 1H), 8.9 (bs, 2H), 8.18 (s, 1H), 7.98 (d, 1H), 7.80 (d, 1H), 7.35-7.58 (m, 6H), 6.72 (d, 1H), 5.74 (s, 1H), 5.28 (s, 2H), 2.58-2.62 (m, 5H), 1.46-1.54 (m, 2H), 0.88 (t, 3H). LCMS M−1 456.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]#[N:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=[CH:30][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25](=[N:35][OH:36])[NH2:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=[CH:30][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C#N)cc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(N)=NO)cc32)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbonitrile (0.60 g, 1.23 mmol, intermediate 54) in ethanol (6 mL) at rt was added hydroxylamine (0.24 mL of a 50% aqueous solution), and potassium carbonate (0.02 mL of a 0.8 M aqueous solution). After stirring at rt for 45 min, the reaction mixture was heated at 105° C. for 65 min in a microwave reactor. After cooling to rt, the precipitate was collected by filtration to provide the title compound. LC/MS: m/e 520.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][N:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:59][N:60]1[CH:64]=[CH:63][C:62]([NH2:65])=[N:61]1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:12][O:11][CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:65][C:62]2[CH:63]=[CH:64][N:60]([CH3:59])[N:61]=2)=[N:3][CH:4]=1
Reactant: Cn1ccc(N)n1
Reactant: COCCOc1ccc(Br)nc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCCOc1ccc(Nc2ccn(C)n2)nc1
Yield: 35 %

Procedure:
2-Bromo-5-(2-methoxy-ethoxy)-pyridine (0.42 mmol), sodium-tert.-butylate (1.4 eq.), tris-(dibenzylidene-aceton)-dipalladium (0.1 eq.), BINAP [=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl] (0.1 eq.) and 1-methyl-1H-pyrazole-3-amine (1.4 eq.) are filled under nitrogen in a microwave reaction vessel. Degassed toluene (45 eq.) is added. The reaction suspension is heated for 100 min to 120° C. and for 30 min to 150° C. Ethyl acetate is added to the reaction suspension and filtrated over celite. The solvent of the filtrate is removed in vacuo. [5-(2-Methoxy-ethoxy)-pyridine-2-yl]-(1-methyl-1H-pyrazole-3-yl)-amine (“A22”) is obtained after reversed phase column chromatography (Water/acetonitrile+0.1% TFA) as yellow oil in a yield of 35%: HPLC (method C): 1.16 min; LC-MS (method A): 0.43 min, 249.15 (M+H+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 10.803 (s, 1H), 7.900 (d, 1H, J=2.8 Hz), 7.802 (dd, 1H, J=2.8 Hz, J=9.4 Hz), 7.739 (d, 1H, J=2.3 Hz), 7.314 (d, 1H, J=9.4 Hz), 6.103 (d, 1H, J=2.3 Hz), 4.149-4.131 (m, 2H), 3.861 (s, 3H), 3.688-3.670 (m, 2H), 3.323 (s, 3H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.C(N(CC)CC)C.[CH3:13][C:14]1[C:23]([CH3:24])=[C:22]([O:25][C:26](=[O:28])[CH3:27])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N+:15]=1[O-]>C(Cl)Cl>[Cl:3][CH2:13][C:14]1[C:23]([CH3:24])=[C:22]([O:25][C:26](=[O:28])[CH3:27])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Oc1c(C)c(C)[n+]([O-])c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1c(C)c(CCl)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
A solution of 1.38 g (9.04 mmols) of phosphorus oxychloride in 5 ml of methylene chloride and a solution of 913 mg (9.04 mmols) of triethylamine in 5 ml of methylene chloride were, respectively, dropped almost simultaneously in 15 minutes into a solution of 1.85 g (8.00 mmols) of the crude product of 2, 3-dimethyl-4-acetoxyquinoline oxide in 5 ml of methylene chloride, followed by stirring at room temperature for 10 minutes. The reaction solution was washed with a saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution, and dried with sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product, followed by purification by silica gel column chromatography (Wako (solvent: n-hexane : ethyl acetate=5:1) to obtain 700 mg (yield 36%) of 2-chloromethyl-3-methyl-4-acetoxyquinoline.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[N:7][NH:8][C:9]2=[O:14])([O-])=O.C(N(CC)CC)C.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[N:7][NH:8][C:9]2=[O:14]
Reactant: O=c1[nH]ncc2c([N+](=O)[O-])cccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1cccc2c(=O)[nH]ncc12
Yield: 100.5 %

Procedure:
980 mg of 5-nitro-phthalazin-1-one (Example 66) and 100 mg of palladium on activated carbon are suspended in 50 ml of ethyl acetate and 1 ml of triethylamine and hydrogenated with hydrogen under normal pressure. It is filtered through diatomaceous earth, and the solvent is removed in a vacuum. As a crude product, 830 mg of 5-amino-phthalazin-1-one is obtained as a solid.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)[C:3](Cl)=[S:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)[C:3](=[S:4])[O:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([CH3:21])[CH:16]=1
Reactant: Cc1cc(O)ccc1Cl
Reactant: Cc1cccc(N(C)C(=S)Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1cccc(N(C)C(=S)Oc2ccc(Cl)c(C)c2)n1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A mixture of 2.01 g of N-methyl-N-(6-methyl-2-pyridyl)thiocarbamoylchloride, 1.43 g of 4-chloro-3-methylphenol, and 1.38 g of potassium carbonate in 50 ml of methyl ethyl ketone was refluxed for 48 hours. After the reaction mixture was cooled to room temperature, it was poured into cold water and the product was extracted with benzene. The benzene solution, successively washed with water and brine, was dried over anhydrous magnesium sulfate. The residue obtained by the removal of benzene under reduced pressure was chromatographed through silica gel column using hexane-ethyl acetate (3/1, V/V) as an eluent to give 1.07 g of pure O-4-chloro-3-methylphenyl N-methyl-N-(6-methyl-2-pyridyl)thiocarbamate as solid in the yield of 35%. A part of the solid was recrystallized from benzene-hexane and crystalls having melting point of 134° to 136° C. were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH2:11])[CH:5]=[CH:6][CH:7]=1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:21][C:16]3[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]2=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCCc1cccc(Br)c1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1CCCc1cccc(Br)c1
Reaction time: 1.5 h
Yield: 72.7 %

Procedure:
A mixture of 3-(3-bromophenyl)-propylamine (7.86 g, 36.7 mmol), 2-bromomethyl-benzoic acid methyl ester (8.45 g, 36.7 mmol), and K2CO3 (6.91 g, 50 mmol) in toluene (100 mL) was heated at reflux with stirring for 1.5 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-[3-(3-bromophenyl)-propyl]-2,3-dihydroisoindol-1-one (8.81 g, 73%). GC/MS gave: m/z (rel.int.) 331 (M+, 10), 329 (M+, 10), 147-(100), 146 (72) 119 (25), and 91 (38). 1H NMR (300 MHz, CDCl3): δ 2.00 (dt, 2H), 2.67 (t, 2H), 3.67 (t, 2H), 4.36 (s, 2H), 7.14 (dd, 2H), 7.31 (m, 1H), 7.35 (br s, 1H), 7.45 (m, 2H), 7.51 (dt, 1H), 7.85 (d, 1H). 13C NMR (300 MHz, CDCl3): δ 29.9, 32.8, 42.0, 49.9, 122.4, 122.7, 123.6, 127.1, 128.0, 129.1, 130.0, 131.2, 131.3 132.8, 141.1, 143.7, 168.6.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]([CH3:17])[C:10]=1[C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:23]([N:20]([CH2:21][CH3:22])[C:18]([C:10]1[N:11]([CH3:17])[C:12]([CH3:16])=[CH:13][C:14](=[O:15])[C:9]=1[OH:8])=[O:19])[CH3:24]
Reactant: [H][H]
Reactant: CCN(CC)C(=O)c1c(OCc2ccccc2)c(=O)cc(C)n1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)C(=O)c1c(O)c(=O)cc(C)n1C
Yield: 90.8 %

Procedure:
Pd(OH)2 on charcoal (0.1 g) was added to a solution of 3-(benzyloxy)-N,N-diethyl-1,6-dimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide(1.0 g, 3.05 mmol) in ethanol (100 ml) under nitrogen. The mixture was hydrogenated at 50 psi hydrogen for 4 hrs. The Pd(OH)2 was removed by filtration through Celite and the Celite cake was washed with ethanol (3×10 ml). The ethanol filtrate was evaporated to give a slightly red solid (0.66 g, 94%). Melting point: 128 to 130° C. H-NMR (CDCl3) σ:1.19 (t, J=7.11 Hz, 3H, Me), 1.30 (t, J=7.00 Hz, 3H, Me), 2.36 (s, 3H, Me), 3.36 (m, 2H, CH2), 3.38 (s, 3H, NMe), 3.64 (q, J=6.90 Hz, 2H, CH2), 6.35 (s, 1H, CH), Mass spect. 239 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[C:9]([F:12])([F:10])[F:11]
Reactant: O=[N+]([O-])[O-]
Reactant: Fc1ccc(C(F)(F)F)c(Br)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1F
Temperature: 0 °C
Yield: 101.6 %

Procedure:
A stirred solution of 2-bromo-4-fluorobenzotrifluoride (1.0 g, 4.1 mmole) in concentrated sulphuric acid (10 ml) at 0° C. was treated portionwise with KNO3 (0.46 g, 4.6 mmole) and maintained at 0° C. for 0.5 hr before warming to room temp. over 2 hr. The mixture was added to well stirred ice/water (100 ml) and then extracted with ethyl acetate. The extract was dried and concentrated under vacuum to afford the title compound as a yellow solid (1.2 g, 100%). 1H NMR (400 MHz, CDCl3) δ: 7.75 (1H, d), 8.45 (1H, d).
Reaction SMILES: [C:1]1(=[O:5])[O:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:12]=[C:11]([C:13]2[C:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[S:25][C:21]=3[C:20]([Br:30])=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[CH:18]3)[CH:10]=[C:9]([Br:31])[C:8]=1[OH:32].CC(C)([O-])C.[K+].Cl>C1COCC1.O>[Br:6][C:7]1[CH:12]=[C:11]([C:13]2[C:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[S:25][C:21]=3[C:20]([Br:30])=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[CH:18]3)[CH:10]=[C:9]([Br:31])[C:8]=1[O:32][CH:2]([CH3:3])[C:1]([OH:4])=[O:5]
Reactant: O=C1CCO1
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br)C(=O)O
Yield: 44.3 %

Procedure:
β-Propiolactone (0.186 mL, 2.66 mmol) was added to a stirred, room temperature solution of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen- 11 -yl)-phenol (1.5 g, 2.66 mmol), potassium tert-butoxide (0.314 g, 2.66 mmol) in THF (33 mL) under a dry nitrogen atmosphere. After 2 days the reaction mixture was added to water, acidified with 10% aqueous HCl and extracted with ethyl acetate. To the ethyl acetate phase was added acid washed (2% phosphoric acid in methanol) silica gel and the solvent was removed. The adsorbate was flash chromatographed (2% phosphoric acid in methanol treated silica gel ; eluent: gradient: 9:1 to 8:2 petroleum ether:ethyl acetate) to provide the title compound as an off-white solid (0.748 g, 44%): mp 218-220° C.: NMR (DMSO-d6);δ12.48 (broad s, 1H), 8.28 (d, J=8 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 7.83 (s, 2 H), 7.79 (ddd, J=7, 6, 1 Hz, 1 H), 7.64-7.57 (m, 2 H), 7.52 (ddd, J=8, 7, 1 Hz, 1H), 7.31 (ddd, =8, 7, 1 Hz, 1 H), 6.69 (d, J=8 Hz, 1 H), 4.44 (t, J=6 Hz, 2 H), 2.89 (t, J=6 Hz, 2 H); MS (+FAB): [M+], 3 bromine isotope pattern, 632 (30%), 634 (70%) 636 (80%) 638 (40%); Anal. Calc. for C25H15Br3O3S: C, 47.27, H, 2.38, N, 0.00. Found: C, 47.68, H, 2.36, N, 0.01.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:11](/[CH:12]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2cc(/C=N/[S@](=O)C(C)(C)C)c(Cl)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a solution of 2-chloro-8-methylquinoline-3-carboxaldehyde (2.05 g, 10 mmol) in dry THF (20 mL) under nitrogen was added titanium isopropoxide (5.68 g, 20 mmol) and the mixture stirred at r.t. for 10 minutes. (R)-(+)-2-Methyl-2-propanesulfinamide (1.21 g, 10 mmol) was added to the reaction which was stirred at r.t. for 72 h. Water (20 mL) was added and the mixture was extracted with DCM (150 mL). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo to afford the title compound (2.4 g, 72%) as a pale yellow solid. δH (CDCl3) 9.12 (s, 1H), 8.79 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.67 (d, J=6.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 2.79 (s, 3H), 1.32 (s, 9H). LCMS (ES+) 309, 311 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH2:10])[CH2:5][CH2:4]1.C(C1C=CC=CC=1C#N)#N>>[NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1
Reactant: NCC1CCC(CN)CC1
Agent: N#Cc1ccccc1C#N
Product: NCc1ccc(CN)cc1

Procedure:
It is known to prepare 1,4-bis(aminomethyl)cyclohexane from dicyanobenzene in a two stage process as disclosed, e.g., in DE-A 3,003,730. In the first stage dicyanobenzene is catalytically hydrogenated to produce 1,4-bis(aminomethyl)benzene, which is then catalytically hydrogenated to produce 1,4-bis(aminomethyl)cyclohexane. One disadvantage is that the starting material must be produced with hydrogen cyanide.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]([CH:13]=[O:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.[CH3:17][C:18]([CH:20]=[CH2:21])=[O:19]>C(N(CC)CC)C.C(OCC)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8]([CH:13]=[O:14])([CH2:21][CH2:20][C:18](=[O:19])[CH3:17])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CC1(C)CC(C=O)C(=O)c2cc(Br)ccc21
Reactant: C=CC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)CCC1(C=O)CC(C)(C)c2ccc(Br)cc2C1=O
Temperature: 0 °C
Yield: 87.2 %

Procedure:
7-Bromo-4,4-dimethyl-2-formyl-1-oxo- 1,2,3 ,4-tetrahydronaphthalene (1.0 g, 3.56 mmol) was dissoved in methylvinylketone (dist., 0.468 g, 6.7 mmol) and this mixture was cooled down to 0° C. Triethylamine (3 drops) was then added and the mixture was stirred at 0° C. for an hour and then at room temperature overnight. The reaction mixture was dissolved in ethyl ether and concentrated to give the title material (1.09 g, 87%) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[N:2]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[CH:23][CH:24]=[O:25])=[CH:9][CH:8]=2)[N:2]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2cccnn2)cc1
Product: O=CC=Cc1ccc(-c2cccnn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(3-pyridazinyl)benzaldehyde (prepared as described in Reference Example 16) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](N)([NH:11][CH3:12])[CH:6]([CH:10]=1)[C:7]([O-:9])=[O:8].C(NC1C=CC(C(O)=O)=C(N[CH2:28][C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)C=1)(=O)C.CC1OC(C=O)=CC=1>ClCCCl.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH2:12][C:31]2[O:30][C:29]([CH3:28])=[CH:33][CH:32]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(=O)Nc1ccc(C(=O)O)c(NCc2ccco2)c1
Reactant: CNC1(N)C=CC(Cl)=CC1C(=O)[O-]
Agent: Cc1ccc(C=O)o1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1ccc(CNc2ccc(Cl)cc2C(=O)O)o1

Procedure:
Reductive amination of 5-chloro-2-amino-methylanthranilate carried out as described for compound 1 using 5-methyl furaldehyde in DCE for 4 hrs. After workup, the product was isolated by FC using 10-30% acetone/hexanes to afford a light yellow solid. The ester was subsequently taken up in THF and saponified using 1N at 60° C. for 12 hrs. The solution was cooled, acidified and the product collected as an off-white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>O1CCCC1.O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1cccnc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(=O)(=O)NCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
Ex-17A: To a solution of 4-acetylbenzenesulfonyl chloride (0.50 g, 2.3 mmol) in tetrahydrofuran (10 mL) was added 3-(aminomethyl)pyridine (0.58 g, 5.7 mmol) and the reaction was stirred for 30 min at room temperature. The mixture was then diluted with water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2×25 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting solid was dried in vacuo to afford 0.67 g (99%) of 4-acetyl-N-pyridin-3-ylmethylbenzenesulfonamide as a white solid, mp 143–144° C. 1H-NMR (300 MHz, CDCl3) δ 8.50–8.52 (m, 1H), 8.41 (d, 1H, J=2.7 Hz), 8.06 (d, 2H, J=8.7 Hz), 7.95 (d, 2H, J=8.4 Hz), 7.6–7.63 (m, 1H), 7.21–7.25 (m, 1H), 5.05 (brs, 1H), 4.22 (d, 2H, J=5.7 Hz), 2.66 (s, 3H). HRMS (EI) Calcd. for C14H14N2O3S: 290.0725 (M+); Found: 290.0726.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1.O>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([C:17]2[CH:16]=[N:15][N:14]([CH3:13])[CH:18]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C)ccc1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Temperature: 100 °C

Procedure:
A mixture of methyl 2-bromo-5-methylbenzoate (1.01 g, 4.41 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.1 g, 5.28 mmol), Pd(PPh3)4 (0.764 g, 0.66 mmol), K2CO3 (1.83 g, 13.23 mmol) and dioxane/H2O (4:1, 15 mL) was degassed for 10 min and then heated overnight at 100° C. The mixture was cooled, diluted with brine, and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3 and dried over Na2SO4. The solvent was removed in vacuo to obtain the crude material, which was purified by silica gel chromatography to obtain the title compound. ESI-MS (m/z): 231 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[N:5]([CH2:11][CH3:12])[C:4]1=[O:13])[CH3:2].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Sn](Cl)(Cl)(Cl)Cl.ClC1C=CC=CC=1>CCOC(C)=O>[C:14]([C:7]1[C:6](=[O:10])[N:5]([CH2:11][CH3:12])[C:4](=[O:13])[N:3]([CH2:1][CH3:2])[C:8]=1[CH3:9])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCn1c(C)cc(=O)n(CC)c1=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: CCn1c(C)c(C(=O)c2ccccc2)c(=O)n(CC)c1=O
Temperature: 25 °C

Procedure:
1,3-Diethyl-6-methylpyrimidine-2,4(1H,3H)-dione (step 1)(680 mg, 3.73 mmol), benzoyl chloride (1.299 mL, 11.20 mmol) and tin(IV) chloride (1.314 mL, 11.20 mmol) were combined in chlorobenzene (30 mL, 295 mmol) and the mixture heated at reflux for 16 h. The reaction mixture was cooled to RT and diluted with EtOAc. The mixture was washed with 2M NaOH(aq) until basic. The organic phase was washed with brine, dried over sodium sulphate and evaporated under vacuum. The residue was dissolved in DCM and evaporated onto silica. The silica was deposited onto a 10 g silica cartridge and the system eluted with 10% EtOAc/hexane, 20% EtOAc/hexane, 40% EtOAc/hexane and 50% EtOAc/hexane. Product elutes at 40% EtOAc/hexane. Fractions were concentrated under vacuum to yield the title compound as an off white solid;