Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].O.S(=O)(=O)(O)[OH:26]>C(O)CO>[C:1]([C:3]1([NH:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)(=[O:11])=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)(=[O:26])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: C#CC1(NS(=O)(=O)Cc2ccc(S(C)(=O)=O)cc2)CCCCC1
Solvent: OCCO
Solvent: O
Product: CC(=O)C1(NS(=O)(=O)Cc2ccc(S(C)(=O)=O)cc2)CCCCC1
Temperature: 175 °C

Procedure:
N-(1-Ethynylcyclohexyl)-4-methanesulfonyl-phenylmethane sulfonamide (19.6 g, 55 mmol) was suspended in ethylene glycol (250 ml). 10 ml Water, 2 g HgO and 2 ml conc. sulfuric acid were added and the mixture was heated at 175° C. for 3 hours, then poured warm into 1 l crushed ice, decanted from mercury salts, stirred and the precipitate was filtered off, washed with water and dried under vacuum at 70° C. to yield N-(1-acetylcyclohexyl)-4-methanesulfonyl-phenylmethanesulfonamide, shown below, as a solid (14.4 g, 70%). 1H-NMR (CDCl3) δ 7.95 (d, 2H), 7.68 (d, 2 H), 4.68 (s, 1 H), 4.42 (s, 2 H), 3.06 (s, 3 H), 2.29 (s, 3 H), 2.00-1.25 (m, 10 H); MS (IS): 372.1 [M−H]−
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[F:26][C:27](=[CH2:31])[C:28](Cl)=[O:29]>C(OCC)C>[F:26][C:27](=[CH2:31])[C:28]([O:18][C:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)([C:10]([F:11])([F:12])[F:13])[C:14]([F:17])([F:15])[F:16])=[O:29]
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Reactant: C=C(F)C(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)OC(c1ccc(C)c(C)c1)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 51.4 %

Procedure:
A solution of 27.3 g (0.1 mol) Of 2-(3,4-dimethylphenyl)hexafluoro-2-propanol and 10.1 g (0.1 mol) of triethylamine in 50 ml of dry diethyl ether was added dropwise with stirring at a temperature of 20° C. to a solution of 20 g (0.184 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 50 ml of dry diethyl ether in the course of 35 minutes. The reaction mixture was then stirred at a temperature of 20° C. for a further 3.5 hours. The resulting solid was filtered off. The filtrate was distilled under reduced pressure after addition of 0.01 g of hydroquinone monomethyl ether. 17.7 g (51 percent of theory) of 2-(3,4-dimethylphenyl)-hexafluoro-2-propyl α-fluoroacrylate having a boiling point of 72° to 73° C. (under 0.4 mbar) were obtained.
Reaction SMILES: O.[NH2:2][NH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:15][C:16]1[CH:33]=[CH:32][C:31]2[C@@H:30]3[C@H:21]([C@H:22]4[C@@:26]([CH2:28][C@@H:29]3[C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][S:46]([CH2:49][CH2:50][CH2:51][C:52]([F:58])([F:57])[C:53]([F:56])([F:55])[F:54])(=[O:48])=[O:47])=[CH:36][CH:35]=3)([CH3:27])[C:25](=O)[CH2:24][CH2:23]4)[CH2:20][CH2:19][C:18]=2[CH:17]=1.C(=O)(O)[O-].[Na+]>CO>[OH:15][C:16]1[CH:33]=[CH:32][C:31]2[C@@H:30]3[C@H:21]([C@H:22]4[C@@:26]([CH2:28][C@@H:29]3[C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][S:46]([CH2:49][CH2:50][CH2:51][C:52]([F:58])([F:57])[C:53]([F:56])([F:55])[F:54])(=[O:48])=[O:47])=[CH:36][CH:35]=3)([CH3:27])[C:25](=[N:2][NH2:3])[CH2:24][CH2:23]4)[CH2:20][CH2:19][C:18]=2[CH:17]=1
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@]12C[C@H](c3ccc(OCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=NN
Reaction time: 16 h

Procedure:
100 μl of hydrazine hydrate and 3 mg of paratoluenesulphonic acid are added to 300 mg of the product obtained in Example 73 in 3 cm3 of methanol. Agitation is carried out for 16 hours at ambient temperature, 50 cm3 of an aqueous solution of sodium bicarbonate is added, extraction is carried out with methylene chloride, the solvent is evaporated off, the residue is chromatographed on silica (eluant: ethyl acetate) and 190 mg of expected product is obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.I[CH2:13][CH2:14][O:15][CH3:16]>CN(C=O)C>[CH3:16][O:15][CH2:14][CH2:13][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: COCCI
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
To a slurry of sodium hydride (0.932 g, 23.0 mmol) in DMF (30 mL) was added indole (2.52 g, 21 mmol) portionwise at 10-20° C. over 5 minutes. The reaction mixture was stirred at rt for 1.5 h, and 2-iodoethylmethylether (4.8 g, 26 mmol) in DMF (10 mL) was added over 5 minutes. The mixture was stirred at rt for 2 h, quenched with ice/water, and extracted with tert-butylmethylether. The organics were washed, dried, and concentrated. The residue was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain 1-(2-methoxy-ethyl)-1H-indole (3.40 g) as a yellowish liquid. MS (ISP): m/e 176.4 (M+H)+
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[CH3:19][CH:20]([NH2:24])[CH:21]([CH3:23])[CH3:22]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:24][CH:20]([CH3:19])[CH:21]([CH3:23])[CH3:22])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1Cl
Reactant: CC(C)C(C)N
Product: CC(C)C(C)Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Yield: 111.2 %

Procedure:
2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.20 g, 0.66 mmol) and 1,2-dimethyl-propylamine (0.11 g, 1.32 mmol) were treated substantially as described in Part D of Example 9 to produce 0.26 g (100%) of [4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1,2-dimethyl-propyl)-amine. MS (AP) m/z 354.2 [(M+H)+, 100].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH:16]1[O:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]3[N:28]=[C:27]([CH3:29])[O:26][C:23]3=2)[O:18][CH2:17]1.[CH:30](=O)[CH3:31].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:30]([N:14]([CH2:13][CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1)[CH2:15][CH:16]1[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]3[N:28]=[C:27]([CH3:29])[O:26][C:23]=3[C:24]=2[O:25]1)[CH3:31]
Reactant: Cc1nc2ccc3c(c2o1)OC(CNCCCc1c[nH]c2ccc(F)cc12)CO3
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CCCc1c[nH]c2ccc(F)cc12)CC1COc2ccc3nc(C)oc3c2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [3-(5-fluoro-1H-indol-3-yl)-propyl]-(2-methyl-7,8-dihydro-1,6,9trioxa-3-aza-cyclopenta[a]napthalen-8-ylmethyl)-amine (0.13 g, 0.32 mmol) and acetaldehyde (0.18 mL, 3.2 mmol) in methanol (20 mL) was added sodium cyanoborohydride (0.07 g, 0.57 mmol) and acetic acid (0.04 mL, 0.32 mmol) at room temperature. The mixture was stirred at room temperature under nitrogen overnight, then quenched with 1N NaOH (5 mL). The mixture was extracted with methylene chloride (3×50 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. The crude oil was column chromatographed on silica gel (5% methanol-methylene chloride). The product-containing fractions were concentrated in vacuum to give 145 mg of the (S)-enantiomer of the title compound as a yellow oil. The dihydrochloride salt was prepared in ethyl acetate as a white solid, m.p. 115° C. d.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6]O.S(Cl)(Cl)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[Na+].C([O-])(=O)C.[K+]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: OCc1nccs1
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cc1nccs1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 11 h

Procedure:
To a chloroform (15 ml) solution of thiazole-2-methanol (171 mg, 1.49 mmol) was added thionyl chloride (0.33 ml, 4.47 mmol) and the resulting mixture was stirred at 50° C. for 11 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in butanol (10 ml). To the resulting solution were added sodium 4-chlorobenzenesulfinate (296 mg, 1.49 mmol) and potassium acetate (292 mg, 2.98 mmol). The mixture was stirred at 70° C. for 24 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed successively with water and brine and then, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column. The fraction obtained from the hexane:ethyl acetate (=1:1) eluate was concentrated under reduced pressure, whereby the title compound (169 mg, 41%) was obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:26])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([Cl:23])[CH:12]=3)[O:8][C:7](=[O:24])[C:6]=2[CH:25]=1.[CH3:27][NH2:28]>O1CCCC1>[Cl:23][C:13]1[CH:12]=[C:11]([C:9]([NH:10][C:5]2[C:6]([C:7]([NH:28][CH3:27])=[O:24])=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:26])=[O:8])[N:15]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[N:14]=1
Reactant: CN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(Cl)nn1-c1ncccc1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 6-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Example 3, Step E) (6.32 g, 15.47 mmol) in tetrahydrofuran (50 mL) was added methylamine (2.0 M solution in THF, 38 mL, 77.38 mmol), and the reaction mixture was heated to 60° C., stirred for 1 hour and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (4.57 g) melting at 225–226° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:9][CH2:8][CH2:7][C:6]2=1.[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[NH:9][CH2:8][CH2:7][C:6]2=1
Reactant: COc1ccc2[nH]c3c(c2c1)CCN=C3CCc1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2[nH]c3c(c2c1)CCNC3CCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 91 mg (0.24 mmol) 6-methoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-4,9-dihydro-3H-β-carboline and 27.7 mg (0.73 mmol) sodium borohydride in 5 mL ethanol was stirred for 2 h at room temperature. The mixture was filtered and evaporated to dryness. Trituration with ethyl acetate yielded after drying 90 mg (98%) of the title compound as light yellow solid.
Reaction SMILES: Br.C(O)(=O)C.C(OC([NH:16][CH2:17][C:18]([N:20]([CH2:22][CH2:23][CH2:24][P:25](=[O:28])([OH:27])[OH:26])[OH:21])=[O:19])=O)C1C=CC=CC=1.C(OCC)C>C(O)(=O)C>[NH2:16][CH2:17][C:18]([N:20]([CH2:22][CH2:23][CH2:24][P:25](=[O:26])([OH:28])[OH:27])[OH:21])=[O:19]
Reactant: O=C(NCC(=O)N(O)CCCP(=O)(O)O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NCC(=O)N(O)CCCP(=O)(O)O
Temperature: 25 °C
Yield: 32.6 %

Procedure:
48% Hydrogen bromide-acetic acid (1 ml) was added under ice-cooling to a solution of 3-[N-(N-benzyloxycarbonylaminoacetyl)-N-hydroxyamino] propylphosphonic acid (200 mg) in acetic acid (1 ml) and the reaction mixture was stirred at an ambient temperature for an hour. To the resultant mixture was added dry ethyl ether (20 ml) to precipitate an oil. The oil was separated, washed twice with dry ethyl ether (10 ml) and then dissolved in water (0.5 ml). The solution was adjusted to pH 4 with pyridine and ethanol (5 ml) was added thereto to give precipitates. The upper layer was removed by decantation and the precipitates was pulverized with ethyl ether (10 ml) to give 3-(N-aminoacetyl-N-hydroxyamino)propylphosphonic acid (40 mg) in the form of powder.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([Br:21])[C:19]=1[OH:20])[C:13](=[N:15]O)[NH2:14]>N1C=CC=CC=1>[Br:9][C:10]1[CH:11]=[C:12]([C:13]2[N:15]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:8][N:14]=2)[CH:17]=[C:18]([Br:21])[C:19]=1[OH:20]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC(=NO)c1cc(Br)c(O)c(Br)c1
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2cc(Br)c(O)c(Br)c2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
Ethyl 2-chloro-2-oxoacetate (12.3 g, 82 mmol) was added dropwise to a stirred solution of 3,5-dibromo-N′,4-dihydroxybenzimidamide (25.5 g, 82 mmol) in pyridine (120 mL) and the mixture was stirred at room temperature for 1 hour and then at 60° C. for 2 hours. The resulting suspension was poured onto water (1.5 L) and extracted with ethyl acetate (2×400 mL). The combined extracts were washed with saturated sodium chloride, dried (MgSO4) and evaporated in vacuo to give an oily solid that was purified by flash chromatography to give a colourless powder. Crystallisation from toluene (400 mL) gave the title compound (14.7 g, 46%) as colourless crystals. 1H NMR δ (ppm) (DMSO-d6): 1.14 (3 H, t), 4.49 (2 H, q), 8.14 (2 H, s), 10.93 (1 H, br s).
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[CH:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]1([C:17](Br)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[I:1]/[CH:2]=[CH:3]/[CH:4]([O:10][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCC(O)/C=C/I
Solvent: c1ccncc1
Product: CCCCCC(/C=C/I)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 7.62 g. (0.03 mole) of 1-iodo-trans-1-octen-3-ol with 10.67 g. (0.033 mole) of triphenylmethyl bromide in pyridine in the manner described in Example 728 gave 13.448 g. (90%) of a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][CH:5]([CH2:7]CS([O-])(=O)=O)[CH2:4][O:3]1.[NH2:14][CH2:15][CH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:13][C:2]1([CH3:1])[CH2:6][CH:5]([CH2:7][NH:14][CH2:15][CH2:16][NH2:17])[CH2:4][O:3]1
Reactant: CC1(C)CC(CCS(=O)(=O)[O-])CO1
Reactant: NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1(C)CC(CNCCN)CO1
Temperature: 80 °C
Reaction time: 3 h
Yield: 41.5 %

Procedure:
A suspension of 4.00 g of [(2,2-dimethyl-4-tetrahydrofuryl) methyl]methanesulfonate, 10.4 g of 1,2-diaminoethane and 2.87 g of potassium carbonate in 40 ml of acetonitrile was stirred at 80° C. for 3 hours. The mixture was cooled to room temperature, and water was then added thereto, followed by extraction with dichloromethane, The organic layer was dried over magnesium sulfate, anhydrous, and then concentrated under a reduced pressure to obtain 1.38 g of N-[(2,2-dimethyl-4-tetrahydrofuryl) methyl]-1,2-diaminoethane as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][CH:4]=1.[Br-:9].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C([O-])(O)=O.[Na+]>CO.O>[Br:9][C:4]1[CH:5]=[N:6][N:7]([CH3:8])[C:3]=1[O:2][CH3:1]
Reactant: [Br-]
Reactant: COc1ccnn1C
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: COc1c(Br)cnn1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
A solution of 5-methoxy-1-methyl-1H-pyrazole (0.500 g, 4.46 mmol) in MeOH (50.0 mL) was cooled to 0° C. and charged with pyridinium tribromide (1.43 g, 4.46 mmol) in portions. The solution was stirred for 1 h at 0° C. then for an additional 16 h at rt. The reaction mixture was charged with sat. NaHCO3 (2.5 mL) and diluted with H2O and extracted with CHCl3 (3×). The combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo resulting in 647 mg, 76% yield of the title compound as a red oil. This material was used in the next step without further purification. 1H NMR (400 MHz, CD3OD): δ=3.66 (s, 3H), 4.07 (s, 3H), 7.30 (s, 1H). MS (ES+): m/z 190.98, 192.99 (49.5/50.5) [MH+]. HPLC: tR=3.33 min (polar—5 min, ZQ3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][OH:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:21]([O:25][C:26]1(OCCCC)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:22][CH2:23][CH3:24]>>[CH2:21]([O:25][C:26]1([O:17][CH2:16][C:13]2[N:14]([CH3:15])[C:10]([S:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)=[C:11]([CH:18]([CH3:20])[CH3:19])[N:12]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOC1(OCCCC)CCCCC1
Reactant: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: CCCCOC1(OCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCC1
Yield: 30.9 %

Procedure:
The compound 14 (3.1 mg, 0.1 mmol) was converted to the acetal with 1,1-dibutoxycyclohexane (228 mg, 1 mmol) in the same manner as the example 14 to give the compound 16 (15 mg, 30%) as oil. Rf 0.44 (Al2O3 60, Type E, toluene).
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([C:11]#[C:12][CH2:13]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C.N1C=CC=CC=1>[C:5]1([C:11]#[C:12][CH2:13][Br:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCC#Cc1ccccc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: BrCC#Cc1ccccc1
Temperature: 40 °C
Yield: 248.9 %

Procedure:
Phosphorous tribromide (2.62 mL, 27.6 mmol) was added to a solution of 3-phenyl-2-propyn-1-ol (10.0 g, 76 mmol) and pyridine (0.14 mL, 1.77 mmol) in diethyl ether (22 mL) at a rate to maintain reflux. After addition, the mixture was heated at 40° C. for 2 h. The mixture was cooled and poured onto ice. The organic layer was separated and diluted with diethyl ether (100 mL), washed with saturated sodium bicarbonate (2×50 mL) and saturated sodium chloride (50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford 1-phenyl-3-bromo-1-propyn (13.4 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:17][C:18]3[N:23]=[C:22]([C:24]([O:26]C)=[O:25])[CH:21]=[CH:20][CH:19]=3)=[C:8]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:17][C:18]3[N:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[CH:20][CH:19]=3)=[C:8]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(Cc2c(-c3ccsc3)[nH]c3cc(OC)ccc23)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3cccc(C(=O)O)n3)c(-c3ccsc3)[nH]c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a solution of methyl 6-(6-methoxy-2-thiophen-3-yl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (936 mg) in tetrahydrofuran/methanol (14.7 mL/6.3 mL) was added 2 mol/L aqueous sodium hydroxide solution (3.71 mL) at room temperature, and this mixture was stirred at 60° C. for 2 hours. The reaction mixture was left to be cooled and concentrated under reduced pressure. The residue was suspended in water (30 mL) and the resulting mixture was acidified by the addition of 1 mol/L hydrochloric acid (7.8 mL). After stirring at room temperature for 1 hour, the precipitate was collected by filtration, washed with water, and then dried under reduced pressure. The suspension of the solid in ethanol was heated under reflux to give a solution. The solution was left to be cooled. The precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (547 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 4.37 (2H, s), 6.64 (1H, dd, J=2.3, 8.8 Hz), 6.85 (1H, d, J=2.3 Hz), 7.37 (1H, dd, J=1.5, 7.3 Hz), 7.42 (1H, d, J=8.8 Hz), 7.57 (1H, dd, J=1.3, 5.0 Hz), 7.67 (1H, dd, J=2.8, 5.0 Hz), 7.77-7.88 (2H, m), 8.09 (1H, dd, J=1.3, 2.8 Hz), 11.13 (1H, s), 12.60-13.70 (1H, br).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>C1COCC1.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[C:2]1=[O:10]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: O=C1Cc2cccnc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(C3C(=O)Nc4ncccc43)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 151.3 %

Procedure:
A solution of 7-azaoxindole (268 mg, 2 mmol) in THF (3 ml) was added to a suspension of sodium hydride (80 mg, 2 mmol, prewashed with THF) in THF (4 ml). After stirring for 20 minutes at ambient temperature a solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (180 mg, 0.7 mmol) in a mixture of THF (3 ml) and DMF (1 ml) was added. After stirring for 30 minutes at ambient temperature followed by 1 hour at 65° C., the volatiles were removed by evaporation. The residue was partitioned between water and ether. The aqueous layer was separated and adjusted to pH4 with 2M hydrochloric acid. The precipitate was collected by filtration and dried under vacuum, it was then suspended in methylene chloride/methanol (1/1) and 3M hydrogen chloride in ether was added. The solid was collected by filtration, washed with methanol followed by ether and dried under vacuum to give 4-(7-azaoxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (388 mg, 68%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]([OH:16])=[O:15].[CH2:17](O)[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCO
Reactant: Cc1[nH]c(-c2ccccc2)nc1CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)Cc1nc(-c2ccccc2)[nH]c1C

Procedure:
About 40 g of 5-methyl-2-phenylimidazole-4-acetic acid, 100 ml of absolute ethanol, 1 g of p-toluenesulfonic acid and 650 ml of benzene is heated under reflux with azeotropic removal of water overnight (about 15 hours). The reaction mixture is filtered, washed with sodium bicarbonate solution, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo to yield the product, ethyl 5-methyl-2-phenylimidazole-4-acetate.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].N.[OH:21]O>C(O)C>[NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:5]=[CH:4][C:3]=1[C:18]([NH2:19])=[O:21]
Reactant: CC(CCCc1ccccc1)n1ncc(C#N)c1N
Reactant: OO
Agent: N
Solvent: CCO
Product: CC(CCCc1ccccc1)n1ncc(C(N)=O)c1N

Procedure:
512 mg (2.02 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-pyrazole-4-carbonitrile are stirred for 3 hours at room temperature with 25 ml of concentrated aqueous NH3, 20 ml of ethanol and 5 ml of 30% strength H2O2. The non-aqueous solvent is removed in vacuo, and the solid which has precipitated is filtered off with suction and dried.