Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([OH:18])[CH2:10]2)=[CH:4][CH:3]=1.[Cl:19][C:20]([Cl:30])=[CH:21][C@@H:22]1[C@H:24]([C:25](Cl)=[O:26])[C:23]1([CH3:29])[CH3:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:19][C:20]([Cl:30])=[CH:21][C@@H:22]1[C@H:24]([C:25]([O:18][C@H:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:10]2)=[O:26])[C:23]1([CH3:28])[CH3:29]
Reactant: O[C@@H]1C[C@@H](Cc2ccc(F)cc2)c2ccccc21
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O[C@@H]1C[C@@H](Cc2ccc(F)cc2)c2ccccc21

Procedure:
In the manner of Example 4, the reaction of 1.00 g (0.004 mole) of trans-3-[(4-fluorophenyl)methyl]-1-indanol (96% trans, 4% cis) and 0.93 (0.004 mole) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride in the presence of 0.32 g (0.004 mole) of pyridine and 50 mL of toluene gave 1.42 g of trans-3-[(4-fluorophenyl)methyl]-1-indanyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate. The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:12]1([S:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Al+3].[Cl-].[Cl-].[Cl-]>S(Cl)(Cl)=O.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:15]2[CH:16]=[CH:17][C:12]([S:18][CH3:19])=[CH:13][CH:14]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CSc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
4-Bromophenylacetic acid (10.8 g, 0.050 mol) was disolved in thionyl chloride (50 mL) and stirred for 30 min at 90° C. The mixture was concentrated and the residual oil was disolved in carbon disulfide (100 mL) and thioanisole (12.5 g, 0.10 mol) was added and the mixture was cooled to 0° C. and AlCl3 (14.7 g, 0.11 mol) was added portionwise. The mixture was stirred at room temperature for 16 h. The resultant dark green suspension was poured into ice water (150 mL) and extracted with CH2Cl2 (150 mL×2), washed with aqueous saturated NaHCO3 (50 mL), dried over MgSO4, and concentarted in vacuo gave the solid. The solid was suspended in ether and collected by filtration to give the title compound (8.4 g, 46%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[N:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:11](I)[CH3:12].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:11]([N:6]1[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[CH3:12]
Reactant: CCI
Reactant: O=[N+]([O-])c1cn[nH]n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ncc([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
To a solution of 4-nitro-2H-1,2,3-triazole (2.02 g, 17.7 mmol) in N,N-dimethylformamide (40 ml), sodium hydride (1.06 g, 26.6 mmol) was added at 0° C., and the mixture was stirred at room temperature for 10 minutes. To the reaction solution was added ethyl iodide (4.15 g, 26.6 mmol), followed by stirring the mixture overnight at room temperature. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, the mixture was then extracted with ethyl acetate, and the combined organic layers were washed with water and a saturated saline solution, then dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Biotage, hexane:ethyl acetate=5:1 to 1:4) to give 2-ethyl-4-nitro-2H-1,2,3-triazole (1.35 g, yield: 53%) as a pale yellow oily substance. 2) To a solution of nitro intermediate (1.35 g, 9.46 mmol), obtained in the above reaction, in methanol (30 ml), was added palladium carbon (500 mg, 50% wet, 4.70 mmol), followed by overnight stirring the mixture under hydrogen atmosphere at room temperature under a pressure of one atmosphere. The reaction solution was filtered through Celite to remove palladium carbon, and the solvent was concentrated under reduced pressure to give 2-ethyl-2H-1,2,3-triazol-4-amine (979 mg, yield: 92%) as a red oily substance. 3) Using 2-ethyl-2H-1,2,3-triazol-4-amine (979 mg, 8.73 mmol) obtained in the above reaction and 4-chloroquinazolin-6-ylacetate (1.94 g, 8.73 mmol), 4-[(2-ethyl-2H-1,2,3-triazol-4-yl)amino]quinazolin-6-ol (1.52 g, yield: 68%) was obtained as a gray solid by the method as in Example 76.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:11][C:12]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[N:32]3[C:27]([CH:28]=[CH:29][CH:30]=[CH:31]3)=[C:26]([OH:33])[C:25]=2[CH3:34])=[O:23])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].[C:35]([O:39][C:40](=[O:51])[CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49]Br)[CH:44]=1)([CH3:38])([CH3:37])[CH3:36].S([O-])(O)(=O)=O.[K+]>O1CCCC1>[NH2:11][C:12]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[N:32]3[C:27]([CH:28]=[CH:29][CH:30]=[CH:31]3)=[C:26]([O:33][CH2:49][C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([O:42][CH2:41][C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:51])[CH:44]=3)[C:25]=2[CH3:34])=[O:23])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(O)c3ccccn23)ccc1N
Reactant: CC(C)(C)OC(=O)COc1cccc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)c2c(C)c(OCc3cccc(OCC(=O)OC(C)(C)C)c3)c3ccccn23)ccc1N
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
5.43 ml (2.71 mmol) of potassium bis(trimethylsilyl)amide at −20° C. are added to the solution of 0.80 g (2.47 mmol) of methyl 2-amino-5-[(1-hydroxy-2-methylindolizin-3-yl)carbonyl]benzoate in 12 ml of tetrahydrofuran. After 15 minutes, 1.49 g (4.93 mmol) of tert-butyl[3-(bromomethyl)phenoxy]acetate (CAS 176673-59-9 described in Patent Application WO2004014366) in solution in 2 ml of tetrahydrofuran are added and the mixture is then heated at 40° C. for 12 hours. The reaction medium is poured into a saturated aqueous solution of potassium hydrogen sulphate, and the mixture is extracted with ethyl acetate. The organic phase is washed with water and then with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (toluene/ethyl acetate gradient=100/00 to 60/40), 0.92 g (61%) of a yellow oil is obtained.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[N:23]=4)=[N:15][N:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:40]>O1CCCC1>[Cl:40][C:21]1[N:16]2[N:15]=[C:14]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[N:23]=3)[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:12]=3)=[C:17]2[CH:18]=[CH:19][CH:20]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: c1ccn2nc(-c3ccnc(NC4CCCC4)n3)c(-c3ccnc(NC4CCCC4)n3)c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccnc(NC4CCCC4)n3)nn12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
N-Cyclopentyl-N-(4-{2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)amine (140 mg, 0.32 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL). The resulting solution was cooled to −78° C., then n-butyllithium (0.99 mL, 1.6 mmol, 1.6 M in hexane) was added dropwise. The resulting dark solution was stirred at −78° C. for 20 minutes, then carbon tetrachloride (2 mL) was added. The reaction was stirred for additional 20 minutes and then quenched by the addition of water and allowed to warm to room temperature. The phases were separated and the aqueous phase extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (1:1 ethyl acetate:hexane) gave 80 mg (53%) of N-(4-{7-chloro-2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)-N-cyclopentylamine as a foam. 1H NMR (CDCl3): δ 8.37 (d, 1H), 8.27 (d, 1H), 8.16 (d, 1H), 7.26 (t, 1H), 7.06 (d, 1H), 7.04 (m, 1H), 6.62 (d, 1H), 5.21 (d, 1H), 5.15 (d, 1H), 4.32 (m, 1H), 4.10 (m, 1H), 1.4–2.1 (m, 16H); MS m/z 475 (M+1).
Reaction SMILES: O1CCOCC1.[O:7]=[C:8]1[NH:12][C:11](=[O:13])[C:10](=[CH:14][C:15]2[CH:34]=[CH:33][C:18]([O:19][CH2:20][CH2:21][C:22]3[NH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=4)=[CH:17][CH:16]=2)[S:9]1.II.[NH4+].[Cl-]>CO>[O:7]=[C:8]1[NH:12][C:11](=[O:13])[CH:10]([CH2:14][C:15]2[CH:34]=[CH:33][C:18]([O:19][CH2:20][CH2:21][C:22]3[NH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=4)=[CH:17][CH:16]=2)[S:9]1
Reactant: COc1ccc2[nH]c(CCOc3ccc(C=C4SC(=O)NC4=O)cc3)cc2c1
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2[nH]c(CCOc3ccc(CC4SC(=O)NC4=O)cc3)cc2c1
Temperature: 50 °C
Yield: 39.8 %

Procedure:
Under an argon atmosphere, 70 ml of 1,4-dioxane were refluxed in a suitably equipped flask, 1 g of the product of step (b) was added, to give a clear solution after about 30 minutes, which was cooled to 50° C., followed by addition of 70 ml methanol, this flask being kept at 50° C. In a second flask, there was placed under an argon atmosphere, 1 g Mg turnings covered with methanol; two crystals of iodine were added, and after foaming began the mixture was stirred until the iodine color disappeared. The contents of the first flask were then poured into the second flask, and the temperature raised to 64° C. A further 1.4 g Mg turnings were added over 4 hours, and the reaction mixture was allowed to reflux for 5 days, until conversion as determined by UV was >95%. The mixture was cooled and poured into 500 ml of 20% NH4Cl solution extracted with 3×200 ml dichloromethane, washed with 5% aq. citric acid and water and rotoevaporated to give a solid which was dissolved in methanol and crystallized at −18° C. There were obtained 400 mg of the title compound as yellow crystals.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH2:6]([O:8][C:9]([C:11]1[C:12](=O)[NH:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:18][C:17]([Cl:27])=[CH:16][CH:15]=2)=[O:10])[CH3:7].N>O>[CH2:6]([O:8][C:9]([C:11]1[C:12]([Cl:3])=[N:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:18][C:17]([Cl:27])=[CH:16][CH:15]=2)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: O
Product: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Yield: 63 %

Procedure:
POCl3 (15 ml) was added to 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid ethyl ester (3 g, 9.15 mmol) and refluxed for 1 h. Then the reaction mixture was cooled to room temperature and diluted with cold water and the pH was adjusted to 7 with ammonia solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated in vacuo to afford a crude residue which was purified by flash column chromatography (100-200 mesh silica, eluting with 5-10% ethyl acetate in hexane) to afford pure 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (2 g, 63%) as pale yellow solid. LC-MS: 346 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH2:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2[nH]nc(C)c2N)cc1OC
Reactant: O=C(Cl)c1ccccc1
Product: COc1ccc(-c2[nH]nc(C)c2NC(=O)c2ccccc2)cc1OC

Procedure:
The preparation took place in analogy with Example 15a), starting with 500 mg of 5-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazol-4-ylamine (44) and 280 μl of benzoyl chloride. The following was obtained: 45
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:29][C:23]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4cc(Cl)ccc4Cl)c3O2)cc1
Product: CNCC1Cc2cc(F)cc(-c3cc(Cl)ccc3Cl)c2O1

Procedure:
The title compound was prepared (0.123 g, 80%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.2 g, 0.43 mmol) and methylamine (0.133 g, 4.3 mmol). mp 166-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.ClC1C=CC=C(C(OO)=O)C=1.[OH-:30].[Ca+2].[OH-:32]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:32])(=[O:30])[C:10]3[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: N#Cc1ccc2c(c1)Sc1ccc(Cl)cc1C=C2
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2c(c1)S(=O)(=O)c1ccc(Cl)cc1C=C2
Reaction time: 24 h

Procedure:
400 Mg. 8-chloro-3-cyanodibenzo[b,f]thiepin is dissolved in 30 cc. chloroform and 2 g. m-chloroperbenzoic acid added, and the solution stirred for 24 hours. 5 G. calcium hydroxide is added, the mixture stirred for five minutes and filtered through celite. The organic filtrate is evaporated to dryness and the residue chromatographed on silica gel and eluted with 5% ethyl acetate/benzene mixture to yield 339 mg. (76%) pure sulfone, m.p. 228°-230° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[N:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)=[N+:11]=[N-:12]>C([O-])(O)=O.[Na+].O>[N:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:21])=[O:20])=[CH:17][CH:18]=1)=[N+:11]=[N-:12]
Reactant: NCCCCCC(=O)O
Reactant: [N-]=[N+]=Nc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(S(=O)(=O)NCCCCCC(=O)O)cc1
Reaction time: 8 h
Yield: 41.9 %

Procedure:
4.57 g of ε-aminocaproic acid were dissolved in a solution of 8.8 g of NaHCO3 in 100 ml water. 7.6 g of p-azidobenzenesulfonic acid chloride were suspended therein and the mixture was stirred overnight. The product was precipitated from the resulting solution with HCl, filtered off and washed with water. 4.56 g of ε-(p-azidobenzenesulfonylamino)caproic acid were obtained after drying in a high vacuum at room temperature. The IR showed the expected bands at 2907 (azide), 1715 (acid carbonyl), 1585+1400 (aromatic), 1282 (COOH), 1319+1153 (aryl sulfonyl), 834 (p- disubst. benzene); TLC (silica gel: EtOAc)/EtOH=3) Rf=0.55; m.p.=126-127° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:15][C:16]1[CH:21]=[C:20]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:19]=[CH:18][CH:17]=1
Reactant: Oc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(F)c2)CC1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
To a solution of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (24 g, 112 mmol), 3-fluorophenol (5.6 g, 59 mmol) and triphenylphosphine (31.4 g, 118 mmol) in THF (100 ml) was added di-isopropylazodicarboxylate (23.3 ml, 118 mmol). The reaction was stirred at room temperature over-weekend and then the solvent was removed in vacuo. The residue was diluted with DCM, hexane was added and the resultant precipitate was filtered off. The filtrate was concentrated in vacuo and purified by column chromatography. Elution with DCM gave the title compound (16.4 g, 87% pure). δH (CDCl3, 250 MHz) 1.47 (9H, s), 1.76 (2H, m), 1.92 (2H, m), 3.35 (2H, ddd), 3.69 (2H, ddd), 4.44 (1H, m), 6.65 (3H, m), 7.20 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C=O>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(O)cc2C1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of N-tert-butoxycarbonyl-5-hydroxyindan-2-amine (0.42 g), potassium carbonate (0.34 g), ethyl bromoacetate (0.24 ml), and N,N-dimethylformamide (4.2 ml) was stirred at ambient temperature for 20 hours. An additional portion of ethyl bromoacetate (0.12 ml) and potassium carbonate (0.17 g) was added to the mixture, and stirring was continued for an additional 12 hours. The mixture was diluted with ethyl acetate and the precipitates were filtered off. The filtrate was concentrated in vacuo, and the residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification of the residue by column chromatography on silica gel (eluent; 5:1 n-hexane-ethyl acetate) to give N-tert-butoxycarbonyl-5-ethoxycarbonylmethoxyindan-2-amine (0.44 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C@H:20]1[CH2:37][C@@:35]2([CH3:36])[C@@H:31]([CH2:32][CH2:33][C@@H:34]2[OH:38])[C@@:30]2([CH:39]=[CH2:40])[C@H:21]1[C:22]1[CH:23]=[CH:24][C:25]([OH:41])=[CH:26][C:27]=1[CH2:28][CH2:29]2>>[O:4]1[CH2:5][CH2:6][N:1]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C@H:20]2[CH2:37][C@@:35]3([CH3:36])[C@@H:31]([CH2:32][CH2:33][C@@H:34]3[OH:38])[C@@:30]3([CH:39]=[CH2:40])[C@H:21]2[C:22]2[CH:23]=[CH:24][C:25]([OH:41])=[CH:26][C:27]=2[CH2:28][CH2:29]3)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCCl)C[C@@]1(C)[C@H]2CC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCN1CCOCC1)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with morpholine (10 equivalents) with the addition of sodium carbonate analogously to instructions 17.2, 32 mg of mixture 30b yields 32 mg of amine 35b as a colorless foam (GC-MS: m/z theor.: 467, pract.: 467).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=3)[CH:19]=2)[CH2:15][CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:31]1[C:39]2[C:34](=[CH:35][C:36]([CH2:40][CH2:41][NH2:42])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1>>[CH2:15]([N:14]([CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:42][CH2:41][CH2:40][C:36]3[CH:35]=[C:34]4[C:39](=[CH:38][CH:37]=3)[NH:31][CH:32]=[CH:33]4)[N:25]=2)[CH:21]=[CH:22][CH:23]=1)[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH3:16]
Reactant: NCCc1ccc2[nH]ccc2c1
Reactant: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CCN(C(=O)OC(C)(C)C)CC1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3ccc4[nH]ccc4c3)n2)c1)C1CCNCC1

Procedure:
4-{[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-ethyl-amino}-piperidine-1-carboxylic acid tert-butyl ester (intermediate 84) was coupled with 2-(1H-indol-5-yl)-ethylamine (intermediate 124) following procedure F then deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 455. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.31 ppm) δ 8.7 (m, 1H) 8.4 (m, 3H) 7.9 (m, 1H) 7.6 (m, 4H) 7.4 (m, 1H) 7.2 (m, 1H) 4.4 (m, 1H) 3.9 (m, 2H) 3.7 (m, 7H) 3.2 (m, 3H) 2.5 (m, 2H) 2.3 (m, 2H) 1.3 (m, 3H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[C:21]2[N:20]=[C:19]([S:22][CH2:23][C:24]3[C:29]([CH3:30])=[C:28]([O:31][CH3:32])[C:27]([CH3:33])=[CH:26][N:25]=3)[NH:18][C:17]=2[CH:16]=[C:15]([CH3:34])[C:14]=1[O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].[OH-].[Na+]>C(Cl)Cl.O>[CH3:12][C:13]1[C:21]2[N:20]=[C:19]([S:22]([CH2:23][C:24]3[C:29]([CH3:30])=[C:28]([O:31][CH3:32])[C:27]([CH3:33])=[CH:26][N:25]=3)=[O:9])[NH:18][C:17]=2[CH:16]=[C:15]([CH3:34])[C:14]=1[O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCOc1c(C)cc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCOc1c(C)cc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1C
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
m-Chloroperbenzoic acid, 91% (1.13 g, 0.0059 mol) dissolved in CH2Cl2 (25 ml) and cooled to -10° C. was added under stirring to 4,6-dimethyl-5-heptyloxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (2.7 g, 0.0059 mol) dissolved in CH2Cl2 (50 ml) maintaining the temperature at -5° C. Stirring was continued at -5° C. for 10 min. The two phases were separated and then NaOH (0.26 g, 0.0066 mol) dissolved in water (50 ml) was added under vigorous stirring. The two phases were separated. The organic phase was dried (Na2SO4), filtered and the solvent evaporated off giving a residual oil, which according to NMR included 30% of unreacted starting material. The oil was chromatographed on a silica column using CH3OH--CH2Cl2 5:95 as eluant and then the product was recrystallized from CH3CN giving the desired product in crystalline form (0.85 g, 32%), m.p. 116° C.
Reaction SMILES: [C:1]([C:5]([CH2:7][C:8]#[N:9])=O)([CH3:4])([CH3:3])[CH3:2].[NH2:10][NH2:11]>C(O)C>[CH3:2][C:1]([C:5]1[CH:7]=[C:8]([NH2:9])[NH:11][N:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NN
Solvent: CCO
Product: CC(C)(C)c1cc(N)[nH]n1
Temperature: 25 °C

Procedure:
The ketone thus formed was dissolved in 150 ml of ethanol containing 32 g of hydrazine. The reaction mixture was heated at reflux for twelve hours, and then cooled to room temperature. Removal of the solvent by evaporation under reduced pressure provided a solid residue, which when triturated with 250 ml of petroleum ether, filtered and air dried, was identified as 12.5 g of 3-tert.-butyl-5-amino-1H-pyrazole.
Reaction SMILES: [I:1]I.[CH2:3]([O:5][C:6](=[O:22])[C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)[NH:8][CH:9]=[O:10])[CH3:4]>C(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[CH2:3]([O:5][C:6](=[O:22])[C@H:7]([CH2:11][C:12]1[C:17]([I:1])=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)[NH:8][CH:9]=[O:10])[CH3:4]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC)c(OC)c1)NC=O
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cc(OC)c(OC)cc1I)NC=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.3 %

Procedure:
Iodine (2.1 g, 8.3 mmol) was added to a solution of dimethoxy derivative 2 (2.1 g, 7.5 mmol) and silver trifluoroacetate (2.0 g, 9.1 mmol) in methylene chloride (110 mL) and the reaction mixture was stirred at room temperature for 48 h. The yellow precipitate that formed was filtered and washed with methylene chloride. The combined filtrates were washed with 1M Na2S2O5 (2×75 mL), water (2×75 mL), dried and concentrated under reduced pressure to give a solid residue. Recrystallization of this residue from ethyl acetate and petroleum ether gave a white solid 3 (2.3 g, 75%); m.p. 151°-152° C.