Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16](=O)[CH2:17][N:18]2[C:22]([C:23]([O:25]CC)=O)=[CH:21][CH:20]=[N:19]2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]>C(O)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[NH:5][C:23](=[O:25])[C:22]3[N:18]([N:19]=[CH:20][CH:21]=3)[CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: [NH4+]
Reactant: CCOC(=O)c1ccnn1CC(=O)c1ccc(OC)c(OC)c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc(-c2cn3nccc3c(=O)[nH]2)cc1OC
Temperature: 110 °C

Procedure:
Ammonium acetate (4.16 g, 54.0 mmol) was added to a solution of ethyl 1-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-1H-pyrazole-5-carboxylate 5.01 (195 mg, 0.61 mmol) in Acetic Acid (5.4 mL) at room temperature. Mixture was heated at 110° C. overnight. An additional 900 mg of ammonium acetate was added and mixture was heated at 110° C. for 3.5 hours, and then cooled to room temperature. Acetic acid was concentrated and residue was taken up in ethyl acetate and washed with 1:1 water/saturated NaHCO3 (aq). Layers were separated and aqueous was extracted with ethyl acetate. Combined organic layers were washed with 1:1 brine/saturated NaHCO3 (aq), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 6-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrazin-4(5H)-one 5.02, which was used without further purification.
Reaction SMILES: [C:1]([O:4][CH:5]([C:8]1[C:13]([S:14]([NH:17]C(C)(C)C)(=[O:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:6][F:7])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([O:4][CH:5]([C:8]1[C:13]([S:14]([NH2:17])(=[O:15])=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:6][F:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CF)c1ncccc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC(CF)c1ncccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
5.3 g of 2-(1-acetoxy-2-fluoroethyl)-N-t-butyl-3-pyridinesulfonamide is added to 20 ml of trifluoroacetic acid and allowed to stir at room temperature for 12 hours. The acid is evaporated and the residual oil is taken up in CH2Cl2. The solution is washed with sat. aq. NaHCO3, dried (MgSO4), evaporated and the crude solid product is crystallized from ethyl acetate and n-haxane; 3.1 g (Yield: 71%).
Reaction SMILES: [F:1][C:2]([F:33])([S:29]([CH3:32])(=[O:31])=[O:30])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[O:19]C(C)(C)[N:17]([C:22](=[O:26])[CH:23]([F:25])[F:24])[C@@H:16]3[CH2:27][F:28])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>Cl.O1CCOCC1.O>[F:33][C:2]([F:1])([S:29]([CH3:32])(=[O:30])=[O:31])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([OH:19])[C@H:16]([NH:17][C:22](=[O:26])[CH:23]([F:25])[F:24])[CH2:27][F:28])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(C(F)(F)S(C)(=O)=O)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)C(F)(F)c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
1-((4S,5R)-5-(4-(6-(difluoro(methylsulfonyl)methyl)pyridin-3-yl)phenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidin-3-yl)-2,2-difluoroethanone (30 mg, 0.06 mmol) is suspended in 4N hydrochloric acid in dioxane, cooled to 5° C. then treated with 2 drops of water, stirred 30 minutes then purified by HPLC to give the title compound (13 mg). 1H NMR (400 MHz, DMSO-d6) δ: 3.40 (s, 3H), 4.25-4.50 (m, 3H), 4.92 (m, 1H), 6.20 (t, J=56 Hz, 1H), 7.52 (d, J=8.2, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.93 (d, J=8.2, 1H), 8.38 (dd, J=8.2 Hz and 2.1 Hz, 1H), 8.83 (d, J=8.6 Hz, 1H), 9.13 (d, J=1.8 Hz, 1H). m/z (Cl) 453 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:26]([O-])=O)=[C:6]([CH:25]=1)[C:7]([NH:9][C:10]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:11]=1)=[O:8]>C(O)(=O)C.[Zn]>[NH2:26][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][C:6]=1[C:7]([NH:9][C:10]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)[N:11]=1)=[O:8]
Reactant: O=C(Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 5-chloro-2-nitro-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide (400 mg, 0.98 mmol, 1.00 equiv) in acetic acid (5 mL), and Zn (640 mg, 9.85 mmol, 10.00 equiv). The resulting solution was stirred for 1 h at 70° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The solution was adjusted to pH 8 with ammonia (2 mol/L). The resulting solution was extracted with 2×50 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 300 mg (81%) of product as a yellow solid.
Reaction SMILES: C[O:2][Si:3][O:4]C.[CH:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:12]3[N:44]=[C:43]4[N:45]=[C:36]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=54)[N:35]=[C:33]4[NH:34][C:26]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=54)=[N:25][C:23]4=[N:24][C:16]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=54)=[N:15][C:14]=2[NH:13]3)[CH:11]=1.O>CN1CCCC1=O>[OH:2][Si:3][OH:4].[CH:7]1[CH:6]=[CH:11][C:10]2[C:9](=[C:14]3[N:15]=[C:16]4[N:24]=[C:23]([C:22]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=54)[N:25]=[C:26]4[NH:34][C:33]([C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=54)=[N:35][C:36]4=[N:45][C:43]([C:42]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=54)=[N:44][C:12]=2[NH:13]3)[CH:8]=1
Reactant: CO[Si]OC
Agent: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Solvent: O
Solvent: CN1CCCC1=O
Product: O[Si]O
Temperature: 25 °C

Procedure:
10 g of dimethoxysilicon phthalocyanine synthesized in Synthesis Example 2 was added to 5 g of water and 95 g of N-methylpyrrolidone (95% NMP aqueous solution) and reacted at 148° C. for 3 hours. The reaction product was thermally filtrated and washed with NMP and acetone in the order named. After the product was stirred in 100 ml of acetone at room temperature, crystals were separated by filtration and dried to obtain 8.0 g of dihydroxysilicon phthalocyanine. When structural analysis was carried out by mass spectral (negative measurement) and IR (KBr method) methods, the same spectrum as that of Example 1 was obtained. Therefore, it was confirmed that the product was dihydroxysilicon phthalocyanine. When the structural analysis of the obtained dihydroxysilicon phthalocyanine was carried out in accordance with the method of Itoh, it was found to be monoclinic and have lattice constants a=12.79Å, b=14.61Å, c=6.79Å and β=94.4°. According to the X-ray spectrum (FIG. 10), it is a dihydroxysilicon phthalocyanine having the crystal form of the present invention and a main peak at a 2 θ of 9.2° and other peaks at 12.2, 14.0, 15.3, 19.7, 23.4 and 27.1°, respectively.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].[H-].[Na+].[CH3:18][C:19]1([CH3:29])[C:23]([CH3:24])=[CH:22][CH2:21][CH:20]1[CH2:25][C:26](=O)[CH3:27].CC1C(C)(C)C(CC=O)CC=1>C1COCC1>[CH2:2]([O:3][C:4](=[O:5])[C:6]([CH3:7])=[C:26]([CH3:27])[CH2:25][CH:20]1[CH2:21][CH:22]=[C:23]([CH3:24])[C:19]1([CH3:29])[CH3:18])[CH3:1]
Reactant: CC(=O)CC1CC=C(C)C1(C)C
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: CC1=CCC(CC=O)C1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=C(C)CC1CC=C(C)C1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
47.6 g (0.20 mol) of triethyl 2-phosphonopropionate was added dropwise under nitrogen to a cooled and stirred suspension of 4.8 g (0.20 mol) of sodium hydride in 300 ml of THF and stirring continued for 30 min. at room temperature. After addition of 30 g (0.18 mol) of 1-(2,2,3-trimethylcyclopent-3-enyl)propan-2-one, prepared from campholenic aldehyde as known per se, and 46 hours of more stirring, the reaction mixture was poured into 400 ml of ice-cold 1N hydrochloric acid and extracted with 2×300 ml of MTBE. The extract was washed with 5×350 ml of brine, dried (MgSO4) and concentrated in vacuo. The distillation at 90-97° C./0.065-0.075 Torr yielded 13 g of the product which was further purified by flash chromatography on silica gel (eluent: hexane/MTBE 15:1) to give 6.4 g (14% yield) of2,3-dimethyl-4-(2,2,3-trimethylcyclopent-3-enyl)but-2-enoic acid ethyl ester.
Reaction SMILES: [I:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].F[C:13]1[C:21]2[CH:20]=[C:19]([C:22]#[N:23])[S:18][C:17]=2[C:16](O)=[CH:15][CH:14]=1>C1COCC1>[I:1][CH2:2][CH2:3][C@H:4]([O:5][C:16]1[C:17]2[S:18][C:19]([C:22]#[N:23])=[CH:20][C:21]=2[CH:13]=[CH:14][CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O[C@H](CCI)c1ccccc1
Reactant: N#Cc1cc2c(F)ccc(O)c2s1
Solvent: C1CCOC1
Product: N#Cc1cc2cccc(O[C@@H](CCI)c3ccccc3)c2s1
Reaction time: 18 h
Yield: 90.5 %

Procedure:
4,4-(Dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenyl phosphonium (383 mg, 0.93 mmol) was added in one portion to a stirred solution of (R)-3-iodo-1-phenyl-1-propanol (Ref: Molander, Gary A.; Shakya, Sagar R.; J. Org. Chem.; EN; 59; 12; 1994; 3445–3452.) (182 mg, 0.69 mmol) and 4-fluoro-7-hydroxy-benzo[b]thiophene-2-carbonitrile (112 mg, 0.58 mmol) in dry THF (12 mL) under an inert atmosphere on nitrogen. The resulting suspension was allowed to stir for a further 18 hrs before the solvent was removed in vacuo. The residue was purified by flash chromatography with a gradient of 0–4% diethyl ether in hexane to give the title compound as a colourless oil (0.22 g, 88%); δH (300 MHz, CDCl3) 7.83 (1H, s, 3-ArH), 7.36–7.12 (5H, m, ArH), 6.85–6.75 (1H, m, ArH), 6.65–6.57 (1H, m, ArH), 5.40–5.30 (1H, m, CHO), 3.47–3.28 (1H, m, CH2CHHI), 3.23–3.12 (1H, m, CH2CHHI), 2.60–2.42 (1H, m, CHHCH2I) and 2.34–2.19 (1H, m, CHHCH2I).
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH2:15][CH2:16][CH3:17])=[C:9]([CH3:14])[C:10]=1[CH2:11][CH2:12][CH3:13])(OCC)=O.C=O>>[CH3:1][C:6]1[NH:7][C:8]([CH2:15][CH2:16][CH3:17])=[C:9]([CH3:14])[C:10]=1[CH2:11][CH2:12][CH3:13]
Reactant: CCCc1[nH]c(C(=O)OCC)c(CCC)c1C
Agent: C=O
Product: CCCc1[nH]c(C)c(CCC)c1C

Procedure:
2-Carbethoxy-3,5-di(n-propyl)-4-methyl-pyrrole was reductively alkylated with paraformaldehyde to yield 2,4-dimethyl-3,5-di(n-propyl)-pyrrole. ##STR104##
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[NH2:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][C:38]=1[Br:39])[C:35](=[O:40])[CH2:34][CH2:33]2>CO.O.ClCCl>[CH2:1]([O:8][CH2:9][C:10]([NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][C:38]=1[Br:39])[C:35](=[O:40])[CH2:34][CH2:33]2)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COCc1ccccc1
Reactant: Nc1cc2c(cc1Br)C(=O)CC2
Agent: CCOP(=O)(Cl)OCC
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C(COCc1ccccc1)Nc1cc2c(cc1Br)C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
A 15 mL, 1 neck flask was equipped with a magnetic stirrer, a reflux condenser and a N2 inlet. The flask was charged with benzyloxyacetic acid (166 mg, 0.001 mol) and dry dichloromethane (4 mL). To the solution was added diethyl chlorophosphate (0.36 mL, 0.0025 mol) followed by the dropwise addition of triethylamine (0.35 mL, 0.0025 mol). The reaction mixture was allowed to stir at room temperature for one hour and then 5-amino-6-bromo-1-indanone (226 mg, 0.001 mol), (weight uncorrected for a purity of about 90%) and triethylamine (0.35 mL, 0.0025 mol) was added. The reaction was refluxed for 24 hours and an aliquot was removed and analyzed by HPLC. The reaction was approximately 80% complete. The solvent was removed on the rotary evaporator affording a brown viscous residue. To the residue was added 4 mL of a 20% methanol/water mixture. A free flowing solid formed which was filtered off, washed with 4 mL of cold (0° C.) methanol and dried without heating in the vacuum oven. 220 mg (59%) of the desired benzyloxyacetamide 9 was obtained as a tan powder after drying. TLC Analysis: Rf 0.68 (50% EtOAc/hexanes). HPLC 10:90 to 90:10 CH3CN:H2O over 15 min. Hold at 90:10 for 2 min, 0.025% TFA Buffer, 1.5 mL/min, UV at 220 nm, Phenomenex Jupiter C18 column 4.6 mm×250 mm at 29° C.: (11.17 min, 94.3 A %)1H NMR (CDCl3, 400 MHz): 2.65-2.75 (m, 2H), 3.05-3.15 (m, 2H), 4.17 (s, 2H), 4.72 (s, 2H), 7.30-7.50 (m, 5H), 7.95 (s, 1H), 8.65 (s, 1H), 9.39 (br, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][N:28]([CH3:35])[C:29]2=[O:34].[BH4-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:17])([F:18])[F:19])[CH2:14][NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][N:28]([CH3:35])[C:29]3=[O:34])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(F)cc2c1OCC2
Reactant: Cn1ccc2c(N)cccc2c1=O
Agent: [BH4-]
Agent: [Na+]
Product: Cn1ccc2c(NCC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)cccc2c1=O

Procedure:
Analogously to Example 1, 4-(2,3-dihydro-5-fluoro-7-benzofuranyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal is converted with 5-amino-2-methylisoquinol-1(2H)-one into the corresponding imine. After reaction with sodium borohydride, the title compound is obtained.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[CH:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:38][S:39]([CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:41])=[O:40]>>[ClH:25].[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:49][CH2:48]3)=[O:34])[C@H:16]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
cis-4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 20) was reacted with 1-(2-methanesulfonyl-ethyl)piperazine dihydrochloride (example 3) to give cis-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C33H41N6O4SCl2 [(M+H)+] 687.2282, observed 687.2286.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.O1CCCC1.[F:16][C:17]1[CH:18]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>C(N(CC)CC)C>[F:16][C:17]1[CH:18]=[C:19]([S:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[CH:5]3)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc2[nH]ncc2c1)c1cccc(F)c1
Yield: 36.6 %

Procedure:
3-Fluoro-N-(1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 1 from 0.4 g of 5-amino-1H-indazole, 20 ml of tetrahydrofuran, 0.83 ml of triethylamine and 0.88 g of 3-fluorobenzenesulfonyl chloride. 0.32 g of 3-fluoro-N-(1H-indazol-5-yl)-benzenesulfonamide is thus obtained in the form of a cream solid.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH2:19]([N:22]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](B(O)O)=[CH:29][CH:28]=1)[CH2:23][CH:24]1[CH2:26][CH2:25]1)[CH2:20][CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:30]4[C:31]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:27]([N:22]([CH2:19][CH2:20][CH3:21])[CH2:23][CH:24]5[CH2:25][CH2:26]5)=[CH:28][CH:29]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CCCN(CC1CC1)c1ccc(B(O)O)c2ccccc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCN(CC1CC1)c1ccc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)c2ccccc12
Yield: 63.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 4-(N-propyl,N-cyclopropylmethylamino)-1-naphthylboronic acid (249 mg, 0.78 mmol), 1.8 mL of 2M sodium carbonate solution and 2 mL of THP, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×50 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 193 mg (64%) of the title compound as an oil. FDMS: m/e=466. α[D]589 =+50.52 (c=0.95, chloroform).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:44][O:45][NH:46][CH3:47]>CN(C=O)C>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([N:46]([O:45][CH3:44])[CH3:47])=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-Amino-5-bromonicotinic acid (1 g, 4.6 mmol) in DMF (15 ml) is added EDC hydrochloride (1.06 g, 5.53 mmol), HOBt (0.747 g, 5.53 mmol), diisopropylethylamine (2 ml, 11.5 mmol) and N-methoxy-N-methylamine hydrochloride (0.54 g, 5.53 mmol), and the resulting solution is stirred at room temperature overnight. The reaction is concentrated in vacuo, and the residue is dissolved in EtOAc, washed with sat. aq. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (SiO2, 0-10% ethanol in DCM) yields 2-Amino-5-bromo-N-methoxy-N-methyl-nicotinamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[CH3:17][C:16]([CH3:19])([CH3:18])[C:15]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:20]
Reactant: Nc1ccncc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccncc1

Procedure:
To a mixture of 20 g of 4-Aminopyridine and 37 mL of triethylamine in 380 mL of methylene chloride is added 28.8 mL of pivaloyl chloride in a dropwise fashion. After 1 hour at room temperature the reaction mixture is washed with water and sodium bicarbonate solution, dried over magnesium sulfate and the solvent is removed in vacuo. The residue is triturated with hexane to afford 4-trimethylacetamidopyridine as a white solid.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[N:7]([NH:11]C(=O)OCC)[CH:8]=[CH:9][CH:10]=1)=[O:5].NN1C=CC=C1CC1C=CC=CC=1F.ClC(OCC)=O.[OH-].[K+]>C(O)C.O>[CH:10]1[CH:9]=[CH:8][N:7]2[C:6]=1[C:4](=[O:5])[C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[NH:11]2
Reactant: CCOC(=O)Nn1cccc1C(=O)c1ccccc1F
Agent: CCOC(=O)Cl
Agent: Nn1cccc1Cc1ccccc1F
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=c1c2ccccc2[nH]n2cccc12

Procedure:
A solution of [2-(2-fluorobenzoyl)-1H-pyrrol-1-yl]carbamic acid, ethyl ester (60.0 g, prepared from 1-amino-2-(2-fluorobenzyl)pyrrole and ethyl chloroformate in substantially the same manner as in Example 3) in 250 ml of ethanol was treated with a solution of potassium hydroxide (51 g) in 150 ml of water and then the mixture was heated at reflux for 1 hour. The ethanol was evaporated and the aqueous layer washed with 3×500 ml of ether The aqueous phase was then adjusted to pH 5 with 6N HCl and the product collected by filtation. Oven drying yielded 20 g of a yellow powder, mp >300° C.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:10])=[C:3](/[CH3:9])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(#N)C>[NH2:1][CH:2]([CH3:10])[CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)/C(C)=C(/C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)C(C)C(C)N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.1 %

Procedure:
To (Z)-ethyl 3-amino-2-methylbut-2-enoate (Org. Lett. 2003, 5(25) 4779-4782, 1.1 g, 7.68 mmol) in acetonitrile (15 mL) was added sodium triacetoxyborohydride (4.88 g, 23.05 mmol) in one lot at RT. After the addition of acetic acid (2.0 mL, 34.9 mmol) (pH of reaction mixture ˜6.0), the contents were stirred at RT for 2.5 h. The reaction mixture was concentrated and partitioned between dichloromethane (60 mL) and 20% NaOH (10 mL). The dichloromethane layer is dried over sodium sulfate and concentrated to yield the title compound (1.05 g, 7.23 mmol, 94% yield) as an oil, which was used as such for the subsequent step without further purification. MS found: (M+H)+=146.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([C:14]1[N:19]=[C:18](C(O)=O)[CH:17]=[C:16]([CH3:23])[N:15]=1)[CH2:12][CH3:13].[N:24]1([C:30](N)=O)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.B.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([C:14]1[N:19]=[C:18]([CH2:30][N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:17]=[C:16]([CH3:23])[N:15]=1)[CH2:12][CH3:13]
Reactant: CCN(c1nc(C)cc(C(=O)O)n1)c1ccc(C(C)C)cc1Br
Reactant: NC(=O)N1CCOCC1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCN(c1nc(C)cc(CN2CCOCC2)n1)c1ccc(C(C)C)cc1Br
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of 2-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-6-methylpyrimidine-4-carboxylic acid, morpholine amide (750 mg, 1.72 mmol) in anhydrous tetrahydrofuran (1.4 mL) at ambient temperature under a nitrogen atmosphere was added a solution of borane in tetrahydrofuran (1M, 3.6 mL, 3.6 mmol) dropwise and the reaction mixture was heated at reflux temperature for 20 h. After cooling to room, acetic acid (3.5 mL) was slowly added and the mixture was heated at reflux for 30 min. After being cooled to ambient temperature, the reaction mixture was poured into a 3N NaOH solution and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography (ethyl acetate) afforded the title compound as an oil (300 mg, 39% yield, Rf 0.3): NMR (CDCl3, 300 MHz) 7.5 (s, 1H), 7.2 (d, 1H, J=7), 7.15 (d, 1H, J=7), 6.5 (s, 1H), 4.3-4.1 (m, 1H), 3.8-3.6 (m, 7H), 3.5-3.3 (m, 2H), 2.9 (septet, 1H, J=7), 1.2 (t, 3H, J=7); CI-HRMS: calcd: 433.1603 (M+H), found: 433.1586.