Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2[NH:17][CH:18]=[C:19]([C:24]([O:26]C)=O)[C:20]([O:22][CH3:23])=[O:21])=[O:5].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[O:26]=[C:24]1[N:11]2[CH:12]=[N:13][C:14]3[CH:15]=[CH:16][C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:28])([CH3:1])[CH3:29])=[CH:8][C:9]=3[C:10]2=[N:17][CH:18]=[C:19]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(=CNc1ncnc2ccc(NC(=O)CC(C)(C)C)cc12)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COC(=O)c1cnc2c3cc(NC(=O)CC(C)(C)C)ccc3ncn2c1=O
Temperature: 260 °C
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
A mixture of dimethyl [{6-(3,3-dimethylbutyramido)-4-quinazolinylamino}methylene]propanedioate (7.30 g) and diphenylether (44 ml) was stirred at 260° C. for 10 minutes and then cooled to ambient temperature. To the mixture was added hexane to give crystals, which were filtered off and washed with hexane to give crystalline methyl 4-oxo-10-(3,3-dimethylbutyramido)-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (6.28 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[NH2:27][CH2:28][CH:29]([OH:34])[C:30]([F:33])([F:32])[F:31].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][CH:29]([OH:34])[C:30]([F:33])([F:32])[F:31])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: NCC(O)C(F)(F)F
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCC(O)C(F)(F)F)c(Cl)c32)c(F)cc1F
Temperature: 60 °C
Reaction time: 6 h
Yield: 79.6 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg), 1-amino-3,3,3-trifluoro-2-propanol (120 mg) and triethylamine (120 mg) were added to pyridine (400 mg), and the mixture was stirred for 20 hours at room temperature and for 6 hours at 60° C. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (3 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Concentrated hydrochloric acid (150 mg) was added to the residue, and the mixture was concentrated under reduced pressure. Ethanol (2 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (153 mg) as a colorless powder.
Reaction SMILES: [Mg].[CH2:2]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19]Cl)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:21][O:22][Si:23](OC)([O:26][CH3:27])[O:24][CH3:25]>C1COCC1>[CH2:2]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][Si:23]([O:26][CH3:27])([O:24][CH3:25])[O:22][CH3:21])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCl)CC2)CC1
Reactant: CO[Si](OC)(OC)OC
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C[Si](OC)(OC)OC)CC2)CC1
Reaction time: 2 h

Procedure:
A Grignard reagent was prepared from 100 ml of THF, magnesium (120 mmole) and trans-1-pentyl-4-(trans-4-chloromethylcyclohexyl)cyclohexane (100 mmole) under nitrogen atmosphere. A THF 100 ml solution of tetramethoxysilane (150 mmole) was heated to 65° C., and the Grignard reagent was added dropwise thereto. Further, the solution was stirred at the same temperature for 2 hours, and after left standing for cooling, the reaction mixture was filtered. The solvent was distilled off, and then trans-1-pentyl-4-(trans-4-trimethoxysilylmethyl-cyclohexyl)cyclohexane (65 mmole) was obtained by distillation under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[C:6]([O:17][CH2:18][CH2:19][CH3:20])[CH:5]=[C:4]([CH3:21])[N:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[C:6]([O:17][CH2:18][CH2:19][CH3:20])[CH:5]=[C:4]([CH3:21])[N+:3]=1[O-:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCOc1cc(C)nc(C)c1C(=O)Nc1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCOc1cc(C)[n+]([O-])c(C)c1C(=O)Nc1ccccc1
Yield: 91.2 %

Procedure:
Then a mixture of 1.42 g (5 m mol) of 2,6-dimethyl-N-phenyl-4-propoxy-3-pyridinecarboxamide obtained thus, 2.16 g (10 m mol) of a commercially available m-chloroperbenzoic acid (80% purity) and 40 ml of chloroform was stirred for 8 hours at room temperature. The reaction mixture was discharged to a separation funnel and after the addition of the 10% aqueous sodium hydrogen sulfite solution, was shaken. The separated oil phase was washed with aqueous saturated sodium hydrogen carbonate solution and then with aqueous saturated sodium chloride solution. It was then dehydrated over anhydrous magnesium sulfate and filtered. After the filtrate was concentrated, the residue was crystallized from a mixture of ethyl acetate and hexane to obtain 1.37 g of the title compound
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]([C:10]1[CH:25]=[C:24]2[C:13]([CH2:14][C:15]3[CH:19]=[CH:18][N:17]([CH2:20][CH:21](O)[CH3:22])[C:16]=32)=[CH:12][CH:11]=1)=[O:9].C(N(CC)CC)C.[N-:33]=[N+:34]=[N-:35].[Na+]>ClCCl.CN(C)C=O.O>[N:33]([CH:21]([CH3:22])[CH2:20][N:17]1[CH:18]=[CH:19][C:15]2[CH2:14][C:13]3[C:24]([C:16]1=2)=[CH:25][C:10]([C:8]([O:7][CH3:6])=[O:9])=[CH:11][CH:12]=3)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc2c(c1)-c1c(ccn1CC(C)O)C2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)-c1c(ccn1CC(C)N=[N+]=[N-])C2
Yield: 39.5 %

Procedure:
1.26 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 2.2 g of (RS)-1-(7-methoxycarbonyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 4.55 ml of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 1.05 g of sodium azide and the reaction mixture was heated to 60° for 15 hours while stirring. After cooling, the solution was poured into 100 ml of water and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 950 mg (40%) of (RS)-1-(2-azido-propyl)-7-methoxycarbonyl-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a light brown oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](O)([Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[C:1]([N:4]1[CH2:5][CH:6]=[C:7]([Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)C1(O)CCN(C(C)=O)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)C1=CCN(C(C)=O)CC1
Temperature: 0 °C
Reaction time: 60 h

Procedure:
1-Acetyl-4-hydroxy-4-tributylstannyl-piperidine, 20 (16.4 g, 38 mmol) and triethylamine (15.0 ml, 108 mmol) were dissolved in methylene chloride (250 ml) and the solution cooled to 0° C. Methanesulfonylchloride (6.0 ml, 50 mmol) in methylene chloride (50 ml) was added dropwise to the cooled solution and the mixture was allowed to warm to room temperature and stir for 60 hours. The reaction solution was washed with NaCl solution, dried (MgSO4), filtered, and evaporated to give a red oil which was purified by flash column chromatography on silica gel, eluting with 3% ethanol in CH2Cl2. After combining the appropriate fractions and evaporating the solvent, the title compound, 21, was obtained (7.5 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:12])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.C([Li])CCC.B(OC)(OC)[O:19]C.OO>O1CCCC1.C(OCC)(=O)C>[F:12][C:4]1[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=[C:2]([OH:19])[CH:3]=1
Reactant: Fc1cc(Br)cc2c1OCCO2
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Oc1cc(F)c2c(c1)OCCO2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
To a solution of 7-bromo-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxine (15.1 g, 64.8 mmol) in tetrahydrofuran (160 mL) at −78° C. was added a 1.6 M solution of n-butyllithium in hexanes (45 mL, 73 mmol). The reaction mixture was stirred at −78° C. for 15 min and trimethyl borate (8.5 g, 82 mmol) was added. The reaction mixture was allowed to warm to ambient temperature, stirred for 48 h and cooled to 5° C. 35% w/w aqueous hydrogen peroxide (12.6 mL, 129.6 mmol) was added, the reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. The reaction mixture was diluted with ethyl acetate (200 mL) and the organic phase was washed with 1 M hydrochloric acid (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography eluted with a 0% to 70% gradient of ethyl acetate in hexanes afforded 8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-ol (6.5 g, 59%) as a colorless solid: MS (ES+) m/z 153.0 (M−17).
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[C:51]=3[Cl:57])[N:48]=[CH:49][C:42]=12)[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[C:51]=3[Cl:57])[N:48]=[CH:49][C:42]=12)[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:27])([CH3:28])[CH3:29])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(Cl)c1Cl
Reactant: Nc1ccc(Cl)cn1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1cccc(Cl)c1Cl)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
Trimethylaluminium (2M in toluene) (0.638 mL, 1.28 mmol) was added to 5-chloropyridin-2-amine (164 mg, 1.28 mmol) in toluene (2 mL) under nitrogen. The resulting solution was stirred at room temperature for 15 minutes. (2S)-Methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AR1) (425 mg, 0.64 mmol) in toluene (8 mL) was added sealed into a 20 mL microwave tube. The reaction was heated to 120° C. for 4 hours in the microwave reactor and cooled to RT. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organics were dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane to afford (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-(1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (460 mg, 95%). m/z (ES+) (M+H)+=763; HPLC tR=3.94 min.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][C@H:40]([CH2:43][CH3:44])[CH2:41][OH:42]>>[OH:42][CH2:41][C@H:40]([NH:39][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[S:27]([CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:28])=[O:29])[CH2:43][CH3:44]
Reactant: CC[C@@H](N)CO
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: CC[C@H](CO)NC(=O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 53.2 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and (R)-2-amino-1-butanol (45 mg, 0.50 mmol, 1.0M in DMF) were combined to give 32 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 602 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12](=[N:14][OH:15])[NH2:13])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].[Na].[CH:19]1([C:25](OCC)=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[N:13]=[C:25]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[O:15][N:14]=3)[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17]
Reactant: CCOC(=O)C1CCCCC1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2CC(N)=NO
Agent: [Na]
Solvent: CCO
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1noc(C2CCCCC2)n1
Reaction time: 10 h
Yield: 76 %

Procedure:
A solution of 2.38 g of 2-(3-methyl-xanthine-7-yl)acetamidoxime in 25 ml of ethanol is admixed with a solution of 0.46 g of metallic sodium in 25 ml of ethanol and 3.02 g of ethyl cyclohexane carboxylate. The reaction mixture is heated to boiling under stirring for 10 hours, then evaporated. The residue is admixed with water and the pH is adjusted to 7. The precipitate is crystallized from aqueous ethanol. Thus 2.51 g of 3,7-dihydro-3-methyl-7-([5-cyclohexyl-1,2,4-oxadiazole-3-yl]methyl)-1H-purine-2,6-dione are obtained, m.p.: 245°-248° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]([O:15]C2C=CC=CC=2)=O)[CH:3]=1.[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24]1>>[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:13]([NH:12][C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[O:15])(=[O:30])=[O:29])=[CH:24]1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: Cn1ccc(S(N)(=O)=O)c1
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccn(C)c1

Procedure:
As the starting substances, methyl 4-chloro-2-phenoxycarbonylaminobenzoate and 1-methylpyrrole-3-sulfonamide were used and the same method was applied as in Example 36 to obtain N-(1-methylpyrrole-3-sulfonyl)-N'-(2-methoxycarbonyl-5-chlorophenyl)urea and further to obtain from 1.89 g (5.08 mmol) of N-(1-methylpyrrole-3-sulfonyl)-N'-(2-carboxy-5-chlorophenyl)urea 712 mg of the above-identified compound (yield 41.3%). Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6):3.71 (3H,s), 6.61 (1H,s), 6.90 (1H,s), 7.12 (1H,s), 7.23 (1H,d), 7.72 (1H,s), 7.86 (1H,d), 11.59 (1H,br).
Reaction SMILES: [Sn](Cl)Cl.[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[S:12]([N:15]1[CH2:20][CH:19]([NH:21][C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[C:18](=[O:29])[N:17]2[CH:30]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-])=O)=[CH:41][CH:40]=3)[C:31](=[O:37])[N:32]([CH:34]([CH3:36])[CH3:35])[CH2:33][CH:16]12)(=[O:14])=[O:13]>C(O)C>[NH2:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][CH:30]2[N:17]3[C:18](=[O:29])[CH:19]([NH:21][C:22]([CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])[CH2:20][N:15]([S:12]([C:6]4[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=4[Cl:4])(=[O:13])=[O:14])[CH:16]3[CH2:33][N:32]([CH:34]([CH3:35])[CH3:36])[C:31]2=[O:37])=[CH:40][CH:41]=1
Reactant: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCCC3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc([N+](=O)[O-])cc2)C1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCCC3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(N)cc2)C1=O
Temperature: 100 °C
Yield: 56.1 %

Procedure:
3-Amino-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-6-(4-nitrobenzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione was reacted in analogy to Example 31 to give the cyclopentane carboxamide. The latter was reacted further in the following way: 71 mg (0.3 mmol) of tin(II) chloride were added to a solution of 50 mg (0.07 mmol) of N-[1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-6-(4-nitrobenzyl)-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide (Example 200) in 3 ml of ethanol. The mixture was heated at 100° C. in a microwave oven for 5 minutes and concentrated in vacuo. The residue was diluted with ethyl acetate, filtered through kieselguhr and concentrated in vacuo. It was then chromatographed on 4 g of SiO2 (elution with ethyl acetate/heptane, gradient 0-100% ethyl acetate). 25 mg of the desired aniline were obtained as an oil. LC/MS MW (calculated, monoisotopic)=635.17 and measured value (M+H)=636.14.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH3:8])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: COCCOCCOCCOCCOCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCOCCOCCOCCOCCOC(=O)OC(C)Cl

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate was reacted with pentaethylene glycol monomethyl ether (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give 1-chloroethyl 2,5,8,11,14-pentaoxahexadecan-16-yl carbonate. This was then reacted with 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-[2-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxycarbonyloxy]-ethyl ester as a white solid. LCMS (ES+) m/z calcd. for C45H56Cl2F2N3O12 [(M+H)+]: 938, found: 938.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=2)[N:14]=[CH:13]1)[CH3:2].[NH4+].[Cl-].[N-:27]=[N+:28]=[N-:29].[Na+].Cl.[OH-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([C:23]3[N:27]=[N:28][NH:29][N:24]=3)[CH:20]=[CH:19][N:18]=2)[N:14]=[CH:13]1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOc1ccccc1CCn1cnc(-c2cc(C#N)ccn2)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOc1ccccc1CCn1cnc(-c2cc(-c3nn[nH]n3)ccn2)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a mixture of 2-[1-[2-(2-ethoxyphenyl)ethyl]imidazol-4-yl]pyridine-4-carbonitrile (1 eq) and NH4Cl (10 eq) in DMF was added NaN3 at rt, then stirred for 2 hr at 110° C. in a microwave oven, LC/MS showed the reaction was completed, acidified to PH=3-4 by conc. HCl, stirred for 1 hr, then adjusted to PH=7-8 by NaOH, concentrated and purified by HPLC to give the title compound (56%). 1H NMR (400 MHz, DMSO): δ 1.36 (3H, t, J=6.4 Hz), 3.06-3.09 (2H, m), 4.02-4.03 (2H, m), 4.25-4.29 (2H, m), 6.82-7.19 (4H, m), 7.69 (1H, s), 7.76-7.81 (2H, m), 8.47 (1H, s), 8.61 (1H, d, J=6.0 Hz). [M+H] Calc'd for C19H19N7O, 362. Found, 362.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47]1([CH2:53][C:54](Cl)=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:54](=[O:55])[CH2:53][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:43]=[CH:44][CH:45]=2)=[N:8]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.125 g, 0.207 mmol), in tetrahydrofuran (5 mL), were added, phenyl acetyl chloride (0.049 g, 0.315 mmol, 0.025 mL) and triethyl amine (0.107 g, 1.06 mmol, 0.147 mL). The reaction mixture was stirred at room temperature for 12 hours. After evaporation of the solvent, the residue was dissolved in 10 mL of ethyl acetate and was washed 3 times with water (5 mL). The crude was used without further purification (0.186 g, 99% yield): ES-MS (m/z) 721 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:7](Br)[CH2:8][CH2:9][CH3:10].[OH-].[Na+]>C(O)C>[CH2:7]([N:1]([CH2:2][CH2:3][CH2:4][CH3:5])[CH2:2][CH2:3][CH2:4][CH:5]=[O:6])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCBr
Reactant: NCCCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCN(CCCC)CCCC=O
Yield: 39 %

Procedure:
A! A solution of 4-aminobutyraldehyde diethylacetale (90 ml, 0.5 mole) and butyl bromide (121 ml, 1.1 mole) in ethanol (1.000 ml) was added with a 1N solution of sodium hydroxide (1.130 ml). The reaction mixture was refluxed for 8 hours. The reaction solvent was evaporated off and the aqueous solution was extracted with diethyl ether. The organic phases were combined and anhydrified over sodium sulfate, then evaporated under vacuum. The resulting crude was purified by fractionated distillation to yield 54 g of 4-dibutylaminobutyraldehyde diethylacetale (yield: 39%). B.p.: 95°-06° C. (0,05 mmHg).