Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(NC1C=CC=CC=1N1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][N:35]([C:38](=[O:68])[C@H:39]([NH:48][C:49]([C@@H:51]2[CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][N:52]2C(OC(C)(C)C)=O)=[O:50])[CH2:40][C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[CH2:34][CH2:33]1.N1C=CC=CC=1.[N+:75]([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][C:79]=1[CH2:84][S:85](Cl)(=[O:87])=[O:86])([O-:77])=[O:76].Cl>C(Cl)CCl.CCOC(C)=O>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][C@@H:39]([NH:48][C:49]([C@@H:51]2[CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][NH:52]2)=[O:50])[C:38]([N:35]2[CH2:36][CH2:37][N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[NH:25][S:85]([CH2:84][C:79]3[CH:80]=[CH:81][CH:82]=[CH:83][C:78]=3[N+:75]([O-:77])=[O:76])(=[O:86])=[O:87])[CH2:33][CH2:34]2)=[O:68])=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N)CC1
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2NS(=O)(=O)Cc2ccccc2[N+](=O)[O-])CC1)[C@@H]1Cc2ccccc2CN1
Yield: 6.3 %

Procedure:
Following the procedure for the synthesis of Preparation III, the title compound was prepared from tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperazinyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Preparation IX) (250 mg, 0.40 mmol) in ClCH2CH2Cl (1.5 mL), pyridine (0.040 mL, 0.44 mmol), and 2-nitro-α-toluenesulfonyl chloride (Aldrich) (104 mg, 0.44 mmol). The crude was treated with a soln of HCl satd EtOAc, which resulted in the precipitation of the salt. This material was collected by filtration, dried in vacuo, and recrystallized from MeOH to afford the product as the HCl salt (18 mg). MS (ESI, pos. ion) m/z: 717 (M+H). Calc'd for C36H37ClN6O4S: 716.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][C:20]([C:22](O)=[O:23])=[CH:21][C:12]2=3)(=[O:10])=[O:9])[CH:7]=1.[NH2:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1>>[CH2:35]([O:34][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:22]([C:20]2[CH:19]=[CH:18][C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:25][CH3:26])(=[O:9])=[O:10])[C:12]=3[CH:21]=2)=[O:23])=[CH:38][CH:37]=1)[CH3:36]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCCCc2ccc(C(=O)O)cc21
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCCC3)cc1

Procedure:
1-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-8-carboxylic acid was reacted with ethyl 4-aminobenzoate in analogy to example 62, step 4, yielding 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-8-carbonyl]-amino}-benzoic acid ethyl ester. Light brown solid, MS (ISP) 543.2 (M+H).
Reaction SMILES: Cl[C:2]1[CH:14]=[C:6]2[N:7]([CH:11]3[CH2:13][CH2:12]3)[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:15])[N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][C:32]=1[F:33])[O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][C:22]=1[F:29]>>[CH:11]1([N:7]2[CH2:8][CH2:9][CH2:10][N:5]3[C:4](=[O:15])[N:3]=[C:2]([O:28][CH2:27][C:24]4[CH:25]=[CH:26][C:21]([O:20][C:19]5[CH:30]=[CH:31][C:32]([F:33])=[C:17]([F:16])[CH:18]=5)=[C:22]([F:29])[CH:23]=4)[CH:14]=[C:6]23)[CH2:13][CH2:12]1
Reactant: OCc1ccc(Oc2ccc(F)c(F)c2)c(F)c1
Reactant: O=c1nc(Cl)cc2n1CCCN2C1CC1
Product: O=c1nc(OCc2ccc(Oc3ccc(F)c(F)c3)c(F)c2)cc2n1CCCN2C1CC1

Procedure:
The title compound was prepared by a procedure similar to that described for E2 starting from 8-chloro-1-cyclopropyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (4-(3,4-difluorophenoxy)-3-fluorophenyl)methanol.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22]O)=[O:16])=[CH:11][CH:10]=1.CS(Cl)(=O)=O.C(=O)([O-])O.[Na+].[C:34]([O-:37])(=[S:36])[CH3:35].[K+]>C(Cl)(Cl)Cl.CN(C)C=O>[C:34](=[O:37])([S:36][CH2:22][C@@H:18]1[CH2:19][CH2:20][CH2:21][N:17]1[C:15](=[O:16])[C:12]1[CH:11]=[CH:10][C:9]([Br:8])=[CH:14][CH:13]=1)[CH3:35]
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CO
Reactant: CC([O-])=S
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)SC[C@@H]1CCCN1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.5 %

Procedure:
Triethylamine (0.2 ml, 1.41 mmol) was added to a solution of 200 mg (0.704 mmol) of (S)-(4-bromophenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone synthesized in step (i) of Reference Example 8 in chloroform (2 ml), and the mixture was stirred at room temperature for 10 min. Thereafter, 0.11 ml (1.41 mmol) of methanesulfonyl chloride was added thereto, and the mixture was stirred at room temperature for 10 min. The reaction was stopped by adding a saturated aqueous sodium hydrogencarbonate solution, and the reaction solution was extracted with chloroform. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate, and was then filtered. The filtrate was concentrated under the reduced pressure and was then dried. Potassium thioacetate (160.8 mg, 1.41 mmol) was added to a solution of the crude product in N,N-dimethylformamide (4 ml), and the mixture was stirred at 100° C. for 2 hr. The reaction was stopped by adding a saturated aqueous sodium hydrogencarbonate solution, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate, and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was then purified by preparative thin layer chromatography (hexane:ethyl acetate=1:2) to give 100 mg (yield 42%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[CH:4][N:3]=1.[C:10]([C@@H:14]1[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[C:10]([C@@H:14]1[CH2:15][CH2:16][C@H:17]([NH:20][C:2]2[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[CH:4][N:3]=2)[CH2:18][CH2:19]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)[C@H]1CC[C@@H](N)CC1
Reactant: CCc1cc(Cl)ncn1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCc1cc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)ncn1

Procedure:
14.3 g of 4-chloro-6-ethylpyrimidine and 17.1 g of cis-4-tert-butylcyclohexylamine were heated to 80 to 90° C. with 15.2 g of triethylamine in 75 ml of toluene for 8 hours. After cooling, the mixture was stirred with water and the organic phase was dried and concentrated. For purification, the mixture was chromatographed over silica gel (ethyl acetate). This gave the title product as a colourless oil.
Reaction SMILES: [C:1]([C:3]([CH3:30])([CH3:29])[C:4]1[CH:27]=[CH:26][C:7]([CH2:8][NH:9][C:10](=[O:25])[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=2[O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:6]([F:28])[CH:5]=1)#[N:2].[N:31]([Si](C)(C)C)=[N+:32]=[N-:33].C[Sn](=O)C>C1(C)C=CC=CC=1>[F:28][C:6]1[CH:5]=[C:4]([C:3]([CH3:30])([C:1]2[NH:33][N:32]=[N:31][N:2]=2)[CH3:29])[CH:27]=[CH:26][C:7]=1[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C#N)c1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1
Agent: C[Sn](C)=O
Solvent: Cc1ccccc1
Product: CC(C)(c1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1)c1nnn[nH]1
Temperature: 100 °C
Reaction time: 168 h

Procedure:
To N-[4-(cyano-dimethyl-methyl)-2-fluoro-benzyl]-2-(4-fluoro-phenoxy)-nicotinamide (2.36 g) in a 50 mL sealable tube were added anhydrous toluene (2 mL), azidotrimethylsilane (1.42 mL), and dimethyl tin oxide (0.19 g). The reaction was stirred at 100° C. for seven days. The solvent was removed in vacuo. The residue was then taken up in acetone, and the precipitate was filtered and rinsed with water, giving a brown solid (1.13 g). The filtrate was concentrated, then taken up in satd. aq. sodium bicarbonate, (50 mL) and washed with ethyl acetate (50 mL). The aqueous was acidified to pH 3, and extracted with ethyl acetate (3×100 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The combined recovered solids were recrystallized with ethanol, yielding the title compound (1.26 g).
Reaction SMILES: O[CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH2:4][CH2:3]1.S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[Cl:17][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cccc2c1CCC2O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc2c1CCC2Cl

Procedure:
In 6 ml. of chloroform is dissolved 5.7 g. of methyl 1-hydroxyindan-4-carboxylate and, under cooling with ice, the solution is stirred. Then, 3 ml. of thionyl chloride is added dropwise and, after the dropwise addition has been completed, the mixture is further stirred under cooling with ice for one hour. Then, the solvent and the excess thionyl chloride are distilled off under reduced pressure. The residue obtained is purified by column chromatography on silica gel (500 g. silica gel; eluant: chloroform). The procedure gives methyl 1-chloroindan-4-carboxylate as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].II>C(OCC)C.C1C=CC=CC=1.[Zn]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[OH:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(F)cc21
Reactant: CCOC(=O)CBr
Agent: II
Agent: [Zn]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)CC1(O)CCc2ccc(F)cc21
Yield: 95.8 %

Procedure:
A mixture of 6-fluoro-1-indanone (5.0 g, 33.3 mmol), ethyl bromoacetate (8.3 g, 50.0 mmol, Aldrich), activated zinc powder (3.2 g, 50.0 mmol, Mallinckrodt; Org. Synth., Coll. Vol. 6, 290, 1988) and a few crystals of iodine in diethyl ether-benzene (1:1, 100 mL) was heated at reflux under nitrogen for 24 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue in diethyl ether was vigorously stirred with excess dilute ammonium hydroxide, dried and concentrated to give ethyl 2-(6-fluoro-1-hydroxy-1-indanyl)acetate as an amber oil (7.6 g, 97%);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]([O:28][CH3:29])[N:20]=1.C(N(CC)CC)C>C(O)C>[CH3:29][O:28][C:21]1[N:20]=[C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(Nc2ccc3[nH]cc(CC4CCCN4C)c3c2)n1
Yield: 54 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 2-chloro-6-methoxy-3-nitropyridine were used. Triethylamine was used as base, absolute ethanol was used as solvent, and the reaction was heated at reflux for 5.5 hours. Column chromatography afforded the title compound (54%) as a red amorphous solid: 1H NMR (CDCl3) δ 8.80 (br s, NH), 8.37 (d, J=9.1 Hz, 1H), 7.85 (s, 1H), 7.34-7.28 (m, 2H), 7.03 (d, J=2.0 Hz, 1H), 6.14 (d, J=9.1 Hz, 1H), 3.85 (s, 3H), 3.19-3.11 (m, 2H), 2.61 (dd, J=13.8 and 9.5 Hz, 1H), 2.54-2.45 (m, 1H), 2.45 (s, 3H), 2.24 (dd, J=17.1 and 9.3 Hz, 1H), 1.91-1.54 (m, 4H); 13C NMR (CDCl3) δ 166.9, 151.3, 138.2, 134.0, 129.6, 127.8, 123.3, 122.0, 118.6, 114.1, 113.3, 111.1, 102.0, 66.5, 57.5, 54.7, 40.8, 31.6, 29.9, 21.9; HRMS calculated for C20H23N5O3 381.1803, found 381.1799.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Cl.O1CCOCC1>C(Cl)Cl>[F:13][C:10]([F:11])([F:12])[C:9]([NH:8][CH2:7][C@@H:6]1[C@H:2]([OH:1])[CH2:3][NH:4][CH2:5]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CNC(=O)C(F)(F)F)[C@H](O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(NC[C@H]1CNC[C@H]1O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1,1-dimethylethyl(3S,4S)-3-hydroxy-4-{[(trifluoroacetyl)amino]methyl}-1-pyrrolidinecarboxylate (0.192 g, 0.615 mmol) was dissolved in methylene chloride (5 mL). HCl in dioxane (1.0 mL, 4.0 mmol) was added and the solution stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. (0.137 g, quant.) LCMS: m/z 213.2 (MH+).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@@H:12]([CH3:27])[C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C@H:16]1[C:24]([OH:26])=[O:25])=O.C1(NC2CCCCC2)CCCCC1.S(=O)(=O)(O)[O-:42].[K+].NN>CO>[NH2:3][C@H:12]([CH:27]=[O:42])[CH2:13][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C@H:16]1[C:24]([OH:26])=[O:25]
Reactant: C[C@@H](C(=O)N1c2ccccc2C[C@H]1C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: O=S(=O)([O-])O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: NN
Agent: [K+]
Solvent: CO
Product: N[C@H](C=O)CN1c2ccccc2C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(S)-2,3-Dihydro-1-[(S)-2-(1,3-dihydro-1,3-dioxo-2H-isoindol 2-yl)-1-oxopropyl]-1H-indole-2-carboxylic acid, dicyclohexylamine (20.4 g.) was treated with 5% aqueous potassium bisulfate solution (300 ml.), and the free acid that formed was extracted three times with methylene chloride (combined extracts 450 ml.). The combined extracts were washed with saline twice, then dried over anhydrous sodium sulfate. Evaporation of the methylene chloride on a rotary evaporator under reduced pressure, then in high vacuum gave an amorphous solid which was dissolved in methanol (200 ml.). Hydrazine (95%, 1.43 g.) was added to the methanol solution. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 24 hr., then chilled in an ice-salt mixture for 3 hr. A precipitate (phthalhydrazide, 4.06 g.) was collected on a filter, and washed with methanol. The combined filtrate and washings were evaporated on a rotary evaporator under reduced pressure, then in vacuo to give a solid residue. The residue was triturated with methylene chloride (ca. 250 ml.) and filtered. The filter residue was washed with methylene chloride several times and dried in vacuo. The crude product was dissolved in water (ca. 50 ml.) at room temperature, and filtered. The filter residue was washed with water. The combined filtrate and washings were evaporated carefully on a rotary evaporator under reduced pressure to give a solid residue which was dried over phosphorous pentoxide in vacuo to give the title product (6.31 g.), [α]D25 =-140.85 (c=1.44%, water). The analytical sample which was obtained by recrystallizations from methanol melted at 171°-172° (when the melting point was determined with rapid heating, the compound melted at 206.5°-209°), [α]D25 =-161.17° (c=1.065%, EtOH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH2:16]([Mg]Br)[CH:17]=[CH2:18]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:18][CH:17]=[CH2:16])=[CH:6][CH:7]=1
Reactant: C=CC[Mg]Br
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Solvent: C1CCOC1
Product: C=CCC(O)c1c(C)noc1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.375 g, 1.41 mmol) was dissolved in THF (3.75 mL) and cooled to 0° C. under N2 atmosphere. Allylmagnesium bromide (1 M in Et20, 1.55 mL, 1.55 mmol) was added and the reaction stirred at 0° C. for 1.5 hours. Additional allylmagnesium bromide (1 M in Et2O, 0.8 mL, 0.80 mmol) was added, and the reaction was stirred for 30 minutes at 0° C. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried and concentrated and the residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]([O:6][C@H:7]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C:9]3([O:34][C@H:10]3[CH2:11][C@@H:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8]1)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:35][CH2:36][CH2:37][C:38]1[N:42]=[CH:41][NH:40][CH:39]=1.C(O)CCC>COC(C)(C)C>[C:1]([O:6][C@H:7]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@:9]([OH:34])([C@H:10]([NH:35][CH2:36][CH2:37][C:38]3[N:42]=[CH:41][NH:40][CH:39]=3)[CH2:11][C@@H:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: NCCc1c[nH]cn1
Reactant: CCCC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]4[C@@H]3C[C@@H]3OC32C1
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: CCCC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]4[C@@H]3C[C@@H](NCCc3c[nH]cn3)[C@@]2(O)C1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
5,6α-epoxicholestan-3β-yl butyrate (10.4 g, 22.1 mmol, 1 eq) and histamine (4.9 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3β-yl butyrate as a white solid (7.8 g, 57%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 13% yield.
Reaction SMILES: [NH:1]([C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH3:12])=[C:5]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=1)[NH2:2].[CH3:20][C:21](=O)[CH2:22][C:23](=O)[CH3:24]>>[CH3:20][C:21]1[CH:22]=[C:23]([CH3:24])[N:1]([C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[CH3:12])=[C:5]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:4]=2)[N:2]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cn1cnc2c(Nc3ccccc3)nc(NN)nc21
Product: Cc1cc(C)n(-c2nc(Nc3ccccc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from (2-hydrazino-9-methyl-9H-purin-6-yl)-phenyl-amine and 2,4-pentanedione.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:24]>>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:24])=[O:2])=[CH:9][CH:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2ccccc2)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(OCc2ccccc2)cc1
Yield: 85 %

Procedure:
Prepared in analogy to example 3 from N-(4-benzyloxy-phenyl)-malonamic acid methyl ester and ammonium hydroxide. Yield=85%. Colorless solid. MS: m/e=285.1 (M++H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]1[NH:14][CH:15]=[C:16]([CH2:18][CH3:19])[N:17]=1)(=O)C.Cl>>[CH2:18]([C:16]1[N:17]=[C:13]([CH:5]2[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4]2)[NH:14][CH:15]=1)[CH3:19]
Reactant: CCc1c[nH]c(C2Cc3ccccc3N2C(C)=O)n1
Agent: Cl
Product: CCc1c[nH]c(C2Cc3ccccc3N2)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 105.8 %

Procedure:
1-acetyl-2-(4-ethyl-1H-imidazol-2-yl)-2,3-dihydro-1H-indole (0.0035 mol) and HCl, 6N (50 ml) were combined under nitrogen atmosphere. The reaction mixture was heated immediately and the heating was continued for 3.5 hours. The mixture was allowed to cool to room temperature, then extracted with diethylether (2×75 ml), cooled to 0° C., alkalized (with cooled 3 N NaOH), then extracted with chloroform (3×60 ml). The combined organic layers were dried, filtered and the solvent was evaporated, yielding 0.79 g of 2-(4-ethyl-1H-imidazol-2-yl)-2,3-dihydro-1H-indole (intermediate 15).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[NH2:14][CH:15]([CH2:18][CH3:19])[CH2:16][OH:17].[OH-].[NH4+]>C1(C)C=CC=CC=1>[CH3:12][N:11]1[C:3]2[C:2]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][OH:17])=[N:7][C:6]([CH3:8])=[N:5][C:4]=2[C:9]([CH3:13])=[N:10]1
Reactant: CCC(N)CO
Reactant: Cc1nc(Cl)c2c(n1)c(C)nn2C
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCC(CO)Nc1nc(C)nc2c(C)nn(C)c12
Yield: 30.1 %

Procedure:
A mixture of 8 g (0.04 mol) of 7-chloro-1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidine (Ex. 3) and 9 g (0.1 mol) of 2-amino-1-butanol in 75 ml of toluene is heated on the steam bath four hours. The warm solution is shaken with 100 ml of 4N ammonium hydroxide. The aqueous extract is concentrated in vacuo to give 3 g of 2-[1,3,5-trimethyl-1-H-pyrazolo[4,3-d]pyrimidin-7-yl]amino-1-butanol, mp 165°-168° C. Another 2.2 g of product is obtained by concentrating the toluene solution.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][CH:9]=[C:10]([CH2:11][C:12]([O:14]C)=[O:13])[C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[C:3]1=[O:18].OS(O)(=O)=O>O1CCOCC1.O>[CH3:1][N:2]1[C:7]2[S:8][CH:9]=[C:10]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[C:3]1=[O:18]
Reactant: COC(=O)Cc1csc2c1c(=O)n(C)c(=O)n2C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(=O)c2c(CC(=O)O)csc2n(C)c1=O

Procedure:
A mixture of Step 9 intermediate (1.3 g, 4.850 mmol) and 6 N H2SO4 (12 ml) in 1,4-dioxane (12 ml) was stirred at reflux temperature for 1 h to give a homogeneous pale yellow solution. This solution was cooled, diluted with water and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water, dried over Na2SO4 and concentrated. The residue obtained was triturated in diethyl ether, solid obtained was collected by filtration to give 450 mg of the product as a white solid; 1H NMR (DMSO-d6, 300 MHz) δ 3.21 (s, 3H), 3.45 (s, 3H), 3.79 (s, 2H), 7.01 (s, 1H), 12.22 (br s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)=[CH:10][C:2]1=2.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([Br:31])[C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24].C(N(CC)CC)C>ClCCl>[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([Br:31])[C:28]=1[O:29][CH3:30])[C:23]([N:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)=[CH:10][C:2]1=2)=[O:24]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: N#Cc1ccc(-c2cnc3c(c2)NCCO3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccc(C#N)cc4)cc32)cc1Br
Yield: 75.6 %

Procedure:
By the same method as in the step c) of Example 45, 4-(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-benzonitrile (71.4 mg, 0.30 mmol), 3,5-dibromo-4-methoxy-benzoyl chloride (148 mg, 0.45 mmol) and triethylamine (84 μl, 0.60 mmol) were dissolved in dichloromethane (3 ml) and reacted at room temperature for 3 hours to obtain 4-[1-(3,5-dibromo-4-methoxy-benzoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-benzonitrile as white solid (120 mg, 75.6%).