Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:16])[CH:7]=[C:8]([N+:13]([O-])=O)[C:9]=1[C:10]([OH:12])=[O:11])([O-])=O.[H][H]>CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH3:16])[CH:7]=[C:8]([NH2:13])[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])c(C(=O)O)c([N+](=O)[O-])c1
Solvent: CO
Product: Cc1cc(N)c(C(=O)O)c(N)c1
Yield: 81 %

Procedure:
3,5-dinitro-p-toluic acid (10.0 gm.) is dissolved in methanol (300 ml.) and 5% palledium on charcoal (1.0 gm.) added. Reduction is carried out in a Parr apparatus for one hour at 40 psi of hydrogen. The product precipitates and the reaction mixture warmed until solution is complete. The catalyst is removed by filtration, washed with a few cc of methanol and the filtrate cooled to 0°. The product precipitates in fine needles and is collected by filtration, washed with a few ml. of methanol and dried (5.95 gm., 81% yield, m.p. 218°-220° dec.). The thin layer chromatogram (Silica gel, 5% methanol in chloroform) shows the material to be homogeneous.
Reaction SMILES: [CH3:1][C@@H:2]([NH:6][CH2:7][C:8]1[S:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH:3]([CH3:5])[CH3:4].Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C@@H:2]([NH:6][CH2:7][C:8]1[S:12][C:11]([C:17]2[CH:18]=[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=2)[NH:22][CH:21]=[C:20]3[CH:29]2[CH2:30][CH2:31][N:32]([S:35]([CH2:38][CH3:39])(=[O:36])=[O:37])[CH2:33][CH2:34]2)=[CH:10][CH:9]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@@H](C)NCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN[C@H](C)C(C)C)s4)cc23)CC1
Yield: 30 %

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [(1R)-1,2-dimethylpropyl]amine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 20.5 mg of the title compound (30%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[C:22]2[O:23][CH2:24][O:25][C:21]=2[C:20]([C:26]#[C:27][CH2:28][NH:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[CH:19][C:18]=1[Cl:35].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:35][C:18]1[CH:19]=[C:20]([C:26]#[C:27][CH2:28][NH:29][C:30](=[O:34])[N:31]([CH3:32])[CH3:33])[C:21]2[O:25][CH2:24][O:23][C:22]=2[C:17]=1[NH:16][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CN(C)C(=O)NCC#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3c(Cl)cc(C#CCNC(=O)N(C)C)c4c3OCO4)c2cc1OC
Yield: 77.1 %

Procedure:
This was prepared using the method described in example 4 using 4-chloro-6,7-dimethoxyquinazoline (160 mg, 0.71 mmol), N′-[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]-N,N-dimethylurea (232 mg, 0.78 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 1.5 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (265 mg, 77%) as a pale brown solid; NMR Spectrum:DMSOd6) 2.81 (s, 6H), 3.91 (s, 3H), 3.92 (s, 3H), 4.09 (d, 2H), 6.14 (s, 2H), 6.82 (t, 1H), 7.07 (s, 1H), 7.18 (s, 1H), 7.82 (s, 1H), 8.33 (s, 1H), 9.47 (s, 1H); Mass Spectrum: M+H+ 484/486.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16]I)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:25]1[NH:26][C:27](=[O:31])[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16][N:26]3[C:27](=[O:31])[CH:28]=[CH:29][CH:30]=[N:25]3)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CI)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: O=c1cccn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2ncccc2=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 60 °C
Yield: 795.3 %

Procedure:
To a solution of tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-(iodomethyl)-1,4-oxazepane-4-carboxylate (335 mg) in DMF (7.0 mL) were added 3(2H)-pyridazinone (79 mg) and potassium carbonate (143 mg), and the mixture was heated at 60° C. for 4 hr. The reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (2.49 g).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH3:17])[CH:8]=1)=O.Cl.[N+:20]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH2:32])=[NH:31])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21]>>[CH2:16]([N:9]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]([C:5]2[CH:4]=[CH:3][N:32]=[C:30]([NH:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=3)[N:31]=2)=[CH:8]1)[CH3:17]
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Reactant: CCn1cc(C(=O)/C=C/N(C)C)c2cccnc21
Agent: Cl
Product: CCn1cc(-c2ccnc(Nc3cccc([N+](=O)[O-])c3)n2)c2cccnc21

Procedure:
Prepared by treatment of (E)-3-(dimethylamino)-1-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one and 1-(3-nitrophenyl)guanidine hydrochloride. 1H-NMR (DMSO-d6) δ: 1.49 (t, 3H, J=7.2 Hz, CH3), 4.37 (q, 2H, J=7.6 Hz, CH2), 7.26 (m, 1H, Ar—H), 7.39 (d, 1H, J=5.2 Hz, Pyrimidin-H), 7.61 (t, 1H, J=8.0 Hz, Ph-H), 7.83 (m, 1H, Ar—H), 8.12 (d, 1H, J=8.0 Hz, Ph-H), 8.38 (m, 1H, Ar—H), 8.49 (d, 1H, J=5.2 Hz, Pyrimidin-H), 8.62 (s, 1H, Ph-H), 8.92 (d, 1H, J=8.0 Hz, Ph-H), 9.01 (s, 1H, Ar—H). MS (ESI+) m/z 361.1308 (M+H)+.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[OH:6][C:7]1[C:16]2[O:15][CH2:14][CH:13]([CH2:17][OH:18])[CH2:12][C:11]=2[CH:10]=[C:9]([O:19][CH3:20])[CH:8]=1>N1C=CC=CC=1>[OH:6][C:7]1[C:16]2[O:15][CH2:14][CH:13]([CH2:17][O:18][S:1]([CH3:4])(=[O:3])=[O:2])[CH2:12][C:11]=2[CH:10]=[C:9]([O:19][CH3:20])[CH:8]=1
Reactant: COc1cc(O)c2c(c1)CC(CO)CO2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(O)c2c(c1)CC(COS(C)(=O)=O)CO2
Reaction time: 1.5 h
Yield: 63.3 %

Procedure:
5.15 g of mesyl chloride was added to a solution of 6.30 g of 3,4-dihydro-8-hydroxy-3-hydroxymethyl-6-methoxy-2H-1-benzopyran in 90 ml of anhydrous pyridine, and the mixture was stirred for 1.5 hours. After the reaction, the solvent was distilled off. The residue was dissolved in 100 ml of ethyl acetate, and washed with water, 1 N hydrochloric acid and water in this order, and then dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give 5.47 g (yield 63.3%) of 3,4-dihydro-8-hydroxy-3-mesyloxymethyl-6-methoxy-2H-1-benzopyran as a pale brown viscous oil.
Reaction SMILES: N[C@H](C(O)=O)CC(=O)O.[NH:10](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:11]([C:20]([OH:22])=[O:21])[CH2:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]>ClCCl.N1CCCCC1>[NH2:10][C@H:11]([C:20]([OH:22])=[O:21])[CH2:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: N[C@@H](CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.1 %

Procedure:
Synthesis of Asp(OtBuj-OH. Fmoc-Asp(OtBu)-OH (500 mg, 1.2 mmole) was dissolved in a 9:1 mixture of dichloromethane-piperidine (5 mL) in a 25 mL round-bottomed flask. The reaction mixture was stirred overnight at room temperature. The next morning, TLC analysis indicated complete Fmoc deprotection. The reaction mixture was concentrated by rotoevaporation, coevaporated 2 times with toluene, and dried under vacuum to give a crude oil. This oil was purified by flash chromatography on silica gel (50 g) using a stepwise solvent gradient of 10%–50% methanol in dichloromethane to afford 250 mg (100%) of Asp(OtBu)-OH.
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1.CS(O[CH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1)(=O)=O.C(=O)([O-])O.[Na+]>CC(=O)C>[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:27][C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: CS(=O)(=O)OCc1cnccn1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(Cc2cnccn2)C[C@H]1OC

Procedure:
4.7 Parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide were dissolved in 160 parts of 2-propanone. Then there were added successively 3.2 parts of [(2-pyrazinyl)methyl] methanesulfonate (ester) and 1.7 parts of sodium hydrogen carbonate. The whole was stirred and refluxed for 18 hours while nitrogen gas was introduced. The precipitated product was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized twice from acetonitrile, yielding 1.16 parts of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-(2-pyrazinylmethyl)-4-piperidiny]benzamide; mp. 203.5° C. (compound 144).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=O)[C:7]2=[O:16])=[CH:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>CC(O)=O.CO>[CH3:24][C:21]1[CH:22]=[CH:23][C:18](/[N:17]=[C:8]2/[C:7](=[O:16])[N:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[C:14]3[C:9]/2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:19][CH:20]=1
Reactant: O=C1C(=O)N(c2ccsc2)c2ccccc21
Reactant: Cc1ccc(N)cc1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(/N=C2/C(=O)N(c3ccsc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.5 %

Procedure:
A solution of 1-(3-Thienyl)-1H-indole-2,3-dione (20 mg, 0.087 mmol) in 1% HOAc/MeOH (8 mL) was added to a solution of p-toluidine (19 mg, 0.18 mmol) in 1% HOAc/MeOH (8 mL). The reaction mixture was stirred for 12 h at room temperature, heated at 50° C. for 1 h, and concentrated in vacuo. The residue was purified by preparative TLC on silica using EtOAc/hexanes (3:7, 0.1% TEA) giving the desired product (14 mg, 50%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]1[OH:8].[C:9]([O:13][C:14]([NH:16][C:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:9]([O:13][C:14]([NH:16][C:17]1([C:20]([O:8][CH:3]2[CH:4]([CH3:7])[CH2:5][CH2:6][CH:2]2[CH3:1])=[O:21])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: CC1CCC(C)C1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1CCC(C)C1OC(=O)C1(NC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a solution of 2,5-dimethylcyclopentanol (0.55 g.), compound 1 (0.97 g), and 4-(dimethylamino)pyridine (0.06 g.) in methylene chloride (100 ml) was added dicyclohexylacarbodiimide (1.09 g.), and the resulting mixture was stirred overnight. The precipitated dicyclohexylurea was removed by filtration, and the filtrate was evaporated. Ethyl acetate was then added to the residue, and the mixture was filtered again. The filtrate was washed with 1M hydrochloric acid, saturated aqeuous sodium bicarbonate, and water, dried over magnesium sulfate, and the solvent was evaporated to a colorless oil (1.18 g. 83%). The product was purified by column chromotography on silica gel, 4:1 hexane:ethyl acetate, eluent.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:20])=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]=1[Br:7].[CH3:21][C:22](C)([O-])[CH3:23].[K+].BrC(C)C>>[Br:1][C:2]1[C:3]([O:20][CH:22]([CH3:23])[CH3:21])=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]=1[Br:7]
Reactant: CCOC(=O)c1c(O)c(Br)c(Br)n1Cc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)Br
Product: CCOC(=O)c1c(OC(C)C)c(Br)c(Br)n1Cc1ccccc1
Yield: 84.2 %

Procedure:
Prepared using the method described in Example 107 from ethyl 4,5-dibromo-3-hydroxy-1-(phenylmethyl)-1H-pyrrole-2-carboxylate (3.2 g, 0.008 moles), potassium tert-butoxide (1.0 g, 0.009 moles) and 2-bromopropane (2.0 g, 0.016 moles). The product crystallized upon aqueous workup and was filtered off, rinsed with water and dried to afford the pure product (3.0 g); mp 46°-48° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:31])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:30]=[CH:29][C:25]([C:26](N)=[O:27])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1.[OH-:32].[K+].Cl>C(O)C.O>[OH:1][CH2:2][C:3]1([CH3:31])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:30]=[CH:29][C:25]([C:26]([OH:27])=[O:32])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1
Reactant: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(N)=O)cn5)cc4)CC3)n2CCS1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(=O)O)cn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixed solution of the compound (200 mg, 0.458 mmol) obtained in Example 65 and potassium hydroxide (129 mg) in ethanol (5.00 mL) and water (1.50 mL) was stirred at 100° C. for 9 h. The reaction mixture was cooled to room temperature, poured into 0.05 N hydrochloric acid (50.0 mL) with ice cooling, extracted with dichloromethane/2-propanol (4/1), and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the white precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (166 mg, 83%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:34][CH2:33][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=[O:27])[C:12]2=[O:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.O[CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>CN(C)C1C=CN=CC=1.ClCCl>[O:56]1[CH2:57][CH2:58][N:53]([CH2:52][CH2:51][O:27][C:26]([C:25]2[CH:24]=[C:23]([CH:31]=[CH:30][CH:29]=2)[CH2:22][N:13]2[C:12](=[O:32])[C:11]3([CH2:33][CH2:34][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14]2)=[O:28])[CH2:54][CH2:55]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)O)c1)CN2c1ccccc1
Reactant: OCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)OCCN3CCOCC3)c1)CN2c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 118.8 %

Procedure:
To a solution of 3-((8-(tert-butoxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid (0.3 g, 0.65 mmol), dicyclohexylcarbodiimide (0.16 g, 0.78 mmol) and 4-(dimethylamino)pyridine (0.01 g, 0.078 mmol) in dichloromethane (10 mL), was added hydroxyethyl morpholine (0.037 g, 0.32 mmol, d=1.072). After stirring at room temperature for 18 hours, the reaction mixture was filtered, concentrated in vacuo and isolated by preparatory TLC (5% methanol/dichloromethane) to obtain the title compound (0.22 g, 59%); 1H NMR (DMSO-d6): δ 1.45 (s, 9H), 1.59-1.66 (m, 4H), 2.43-2.48 (m, 4H), 2.66 (t, 2H, J=5.6 Hz), 3.32-3.51 (m, 4H), 3.89 (br, 2H), 3.90 (br, 2H), 4.37 (t, 2H, J=5.6 Hz), 4.62-4.65 (m, 4H), 6.68 (d, 2H, J=8.4 Hz), 6.77 (t, 1H, J=7.2 Hz), 7.17 (t, 2H, J=8.8 Hz), 7.53-7.61 (m, 2H), 7.86-7.90 (m, 2H); MS for C32H42N4O6 m/z 579.09 (M+H)+.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Li]CCCC.[CH:23](N1CCOCC1)=[O:24].Cl>C1COCC1.O>[CH:23]([C:17]1[C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:24]
Reactant: CC(C)(C)C(=O)Nc1ccc2ccccc2n1
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)Nc1nc2ccccc2cc1C=O
Temperature: 25 °C
Yield: 52 %

Procedure:
To a solution of 2-pivaloylaminoquinoline (5.00 g, 21.92 mmol) in THF (75 mL) at −78° C. was added dropwise BuLi (5.48 mL, 10 M in hexane, 54.80 mmol). After 2 hours at −78° C. the dianion was quenched by the addition of N-formylmorpholine (3.79 g, 37.88 mmol). The reaction mixture was allowed to warm to room temperature and poured into 2M aqueous HCl (20 mL). The pH of the aqueous phase was adjusted to 7.0 by addition of 2M HCl and the aqueous phase was diluted with water (100 mL) and extracted with diethyl ether (2×100 mL). The organic phase was dried (MgSO4) and evaporated to dryness in vacuo. The crude product was recrystallized from petrol ether/ethyl acetate to give 2.92 g (52%) of the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12]([NH2:14])=[CH:11][CH:10]=[CH:9]2)=[N+:2]=[N-:3].N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>CCOCC>[C:21]([NH:14][C:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[N:1]=[N+:2]=[N-:3])[CH:9]=[CH:10][CH:11]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: [N-]=[N+]=Nc1cccc2cccc(N)c12
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc2cccc(N=[N+]=[N-])c12

Procedure:
To a stirred solution of 8-azido-1-naphthylamine (1.84 g., 0.01 mole) in 70 ml. of pyridine was added a solution of acetyl chloride (0.784 g., 0.01 mole) in 10 ml. of ether. The mixture was warmed on a steam bath for 30 minutes. The solvents were removed in vacuo and the residue washed with water and dried. Recrystallization from hexane provided 1-acetamido-8-azidonaphthalene in the form of colorless, long needles having a yield of 2.1 g., 93 percent, m.p. 148°C.-149°C., Lit. m.p. 147°C.-148°C. and an analysis of: Calcd. for C12H10N4C: C, 63.70; H, 4.46; N, 24.77 Found: C, 63.90; H, 4.14; N, 24.66
Reaction SMILES: [CH2:1]([O:4][N:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]([CH3:15])([CH3:14])[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH2:3].C(N([C:26](C)(C)[C:27](NC(C)(C)C)=[O:28])O)(C)(C)C.ClC1CCCCO1>>[O:28]1[CH2:27][CH2:26][CH2:3][CH2:2][CH:1]1[O:4][N:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]([CH3:15])([CH3:14])[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)NC(=O)C(C)(C)N(O)C(C)(C)C
Reactant: C=CCON(C(C)(C)C)C(C)(C)C(=O)NC(C)(C)C
Agent: ClC1CCCCO1
Product: CC(C)(C)NC(=O)C(C)(C)N(OC1CCCCO1)C(C)(C)C
Yield: 33 %

Procedure:
The compound is prepared in analogy to compound (204) from tert-butyl-(dimethyl-tert-butylaminocarbonyl-methyl)-hydroxylamine and 2-chlor-tetrahydropyrane in 33% yield as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[CH3:23])=[O:4].C1C(=O)N([Br:31])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:16])[C:6]=1[CH2:23][Br:31])=[O:4]
Reactant: COC(=O)c1c(C)n(S(=O)(=O)c2ccccc2)c2ncccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncccc12
Temperature: 25 °C
Yield: 72.2 %

Procedure:
To 1-benzenesulfonyl-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (0.27 g, 0.88 mmol) in 1,2-dichloroethane (5.0 mL) was added NBS (0.178 g, 1.00 mmol) and AIBN (0.032 g, 0.20 mmol and the reaction mixture was heated under reflux for 1 h. After cooling to ambient temperature the solvent was removed by evaporation and the resultant residue was purified by flash chromatography (silica, 5 g column, ISCO, 0-65% DCM in pentane) to afford the title compound as a white solid (0.26 g, 72%). LCMS (Method B): RT=3.95 min, M+H+=409/411.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.O.Cl>O>[O:1]([CH2:8][CH2:9][NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCCOc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCOc2ccccc2)cc1

Procedure:
A mixture of 12 g of ethyl p-(2-phenoxyethylamino)-benzoate, 12 g of potassium hydroxide and 200 ml of ethanol-water (9:1) is refluxed for 3.5 hours. The solution is acidified while hot with concentrated hydrochloric acid, diluted with water, cooled, filtered and the solid washed with water to give crystals, mp 172°-175° C. Recrystallization from ethanol gives off-white crystals, mp 174°-176° C.
Reaction SMILES: [N:1]1[C:13]2[N:4]([C:5](=[O:14])[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[NH:3][C:2]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[H-].[Na+].[CH3:22]I>CN(C)C=O>[CH3:22][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2=[N:1][C:2]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:3][N:4]2[C:5]1=[O:14]
Reactant: CI
Reactant: CCOC(=O)c1nc2c3ccccc3nc(=O)n2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2c3ccccc3n(C)c(=O)n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.0 g (0.047 mole) of ethyl 1,2,4-triazolo[1,5-c]quinazolin-5-one-2-carboxylate in 100 ml of absolute dimethylformamide were added dropwise to a suspension of 0.053 mole of NaH in 100 ml of absolute dimethylformamide at room temperature. After 2 hours, 7.5 g (0.053 mole) of methyl iodide were added, and the mixture was stirred overnight at room temperature and then poured into 400 ml of ice water. The precipitate was filtered off under suction and dried. Yield: 6.6 g (52%), mp.: 258° C.