Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:16][N:15]4[C:24]([C:27]#[N:28])=[CH:25][N:26]=[C:14]4[N:13]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[OH:29]O>CS(C)=O.CC(=O)OCC>[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:16][N:15]4[C:24]([C:27]([NH2:28])=[O:29])=[CH:25][N:26]=[C:14]4[N:13]=3)=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: OO
Reactant: N#Cc1cnc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cn12
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: NC(=O)c1cnc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cn12
Temperature: 60 °C

Procedure:
To a suspension of compound 4-10 (40 mg 0.11 mmol.) and K2 CO3 (30 mg, 0.22 mmol) in DMSO (1.0 mL) was added 0.1 mL of H2O2(30% aq.) and the mixture was heated at 60° C. for 3 h. After cooling, the mixture was diluted with 20 mL of EA, the combined organic phase was washed with sat.NaHSO3 (aq) and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.HPLC to give 19 mg of 4-11.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18](O)=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:21]([N:23]([CH2:24][CH3:25])[C:18]([C:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:19])[CH3:22]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc2ccccc2c(-c2ccc(Cl)cc2)n1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cc2ccccc2c(-c2ccc(Cl)cc2)n1
Yield: 45.9 %

Procedure:
Operations are carried out as for Example 7, starting from 2.83 g of 1-(4-chloro phenyl) isoquinoline 3-carboxylic acid, 1.15 g of triethylamine, 1.24 g of ethyl chloroformate and 0.95 of diethylamine in 100 ml of chloroform. 1.55 g of N,N-diethyl 1-(4-chloro phenyl) isoquinoline 3-carboxamide, melting at 122° C., is obtained.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16](O)=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.S(Cl)([Cl:26])=O>>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16]([Cl:26])=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Reaction time: 3 h

Procedure:
13.1 g (0.04 mol) of 2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionic acid (prepared according to example 3 a)) are reacted with 31.4 g (0.25 mol, about 20 ml) of thionyl chloride by boiling under reflux while continuously introducing nitrogen and constantly stirring for 3 hours. After distilling off the excess thionyl chloride with exclusion of moisture under reduced pressure, a distillation residue is obtained which can be directly used for further transformation.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([OH:14])=O)[CH2:9][NH:8][C:7]=2[CH:15]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>C(O)C>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([NH:19][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:9][NH:8][C:7]=2[CH:15]=1
Reactant: Cc1ccc2c(c1)NCC(C(=O)O)O2
Reactant: C=CCN
Agent: Cl
Solvent: CCO
Product: C=CCNC(=O)C1CNc2cc(C)ccc2O1
Temperature: 25 °C
Reaction time: 90 h

Procedure:
42.4 g of 4A and 38 g of 2-propenamine were mixed in 165 ml of ethanol and the mixture was stirred at room temperature for 90 hours. The solvent was removed under reduced pressure. The residue was partitioned between ether and water. The ether solution was dried (MgSO4), about half the solvent was evaporated, and solid which formed was filtered, then dried under reduced pressure to give 4, mp: 113°-115° C.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[CH2:5].[F-].[Cs+].[F:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])=[O:26])[CH:19]=[CH:20][C:21]=1[F:22]>CS(C)=O>[F:15][C:16]1[CH:17]=[C:18]([CH:23]([CH2:3][C:4]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)=[O:5])[CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])=[O:26])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: O=C(C=Cc1ccc(F)c(F)c1)c1ccccc1O
Reactant: C=C(O[Si](C)(C)C)c1ccco1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1ccccc1O)c1ccc(F)c(F)c1)c1ccco1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(furan-2-yl)ethylene (7.0 mmol; prepared according to J. Chem. Soc.,Perkin Trans. I 1989, 1585) and CsF (0.27 g, 1.76 mmol) were added to a suspension of 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one on Wang resin (2.0 g, 1.76 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% AcOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 3-(3,4-difluorophenyl)-5-(furan-2-yl)-1-(2-hydroxyphenyl)-1,5-pentanedione on Wang resin.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]2[N:9]=[C:10]([CH3:19])[N:11]([CH2:12][CH2:13][CH2:14][NH:15]C(=O)C)[C:7]=2[C:6]([CH3:20])=[C:5]([CH3:21])[N:4]=1>C(O)C>[NH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:7]2[C:6]([CH3:20])=[C:5]([CH3:21])[N:4]=[C:3]([NH2:2])[C:8]=2[N:9]=[C:10]1[CH3:19]
Reactant: CC(=O)NCCCn1c(C)nc2c(N)nc(C)c(C)c21
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.3 %

Procedure:
Concentrated hydrochloric acid (5 mL) was slowly added to a solution of N-[3-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]acetamide (15.94 g, 57.9 mmol) in absolute ethanol (100 mL). A precipitate formed immediately and the mixture thickened. Ethanol (50 mL) was added followed by the addition of concentrated hydrochloric acid (119.5 mL). The reaction mixture was heated at reflux for 2 days. The solvents were removed under reduced pressure. Water (250 mL).was added to the residue, solid potassium carbonate was added until the pH reached 7 at which time chloroform (250 mL) was added. Sodium carbonate addition was resumed until the pH reached 10, then 50% sodium hydroxide was added until the pH reached 14. The mixture was diluted with additional chloroform (500 mL) and then stirred at ambient temperature for 2 days. The organic layer was separated, dried with magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from acetonitrile to provide 8.42 g of 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine as an off-white crystalline solid, m.p. 191.5-191.9° C. Analysis: Calculated for C12H19N5.0.25H2O: % C, 60.61; % H, 8.26; % N, 29.45; Found: % C, 60.50; % H, 8.28; % N, 29.57.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C-:18]#[N:19].[Na+].CS(C)=O>O>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][C:18]#[N:19])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: [C-]#N
Reactant: CCC[C@H]1CC[C@H](c2ccc(CCl)cc2)CC1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCC[C@H]1CC[C@H](c2ccc(CC#N)cc2)CC1
Temperature: 140 °C

Procedure:
114 g (0.45 mol) of 4-(trans-4'-propylcyclohexyl) benzyl chloride, 27 g (0.55 mol) of NaCN and 113 cm3 of DMSO were mixed and while stirring, the mixture was heated to a temperature of 140° C. by a mantle heater. The product of the reaction was cooled to room temperature. 400 cm3 of water was added and extracted three times with 100 cm3 of chloroform. The chloroform layers were combined and washed with 10% hydrochloric acid and water. The chloroform was distilled off under reduced pressure and the residue was distilled under reduced pressure (155° C./2.5 mmHg) to yield 106 g (0.44 mol) of 4-(trans-4'-propylcyclohexyl) benzyl cyanide.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])(C)(C)C.CN(C)[CH:29]=[O:30].[NH4+].[Cl-]>CCOCC.CCCCC>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17]([CH:29]=[O:30])=[CH:16][N:15]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2ccc(C#Cc3ccc(Br)cn3)cc21
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: CCOCC
Product: CC1(C)CCSc2ccc(C#Cc3ccc(C=O)cn3)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (-78° C.) solution of 358 mg (1.0 mmol) of 2-(4,4-dimethylthiochroman-6-yl)ethynyl-5-bromopyridine in 5 ml of anhydrous ether was added slowly under nitrogen 1.3 ml of 1.7M (2.21 mmol) tert-butyl lithium in pentane. The mixture was stirred at -78° C. for 1 h and then treated with 95 mg (1.3 mmol) of anhydrous dimethylformamide. The mixture was stirred at -78° C. for a further 0.5 hours, then warmed to 0° C. and treated with 5 ml of saturated NH4Cl solution followed by 5 ml of ether. The organic layer was separated and the aqueous layer was extracted with ether. The organic layers were combined, washed successively with water and saturated NaCl solution and then dried (MgSO4). The solvent was then removed in vacuo and the residue purified by flash chromatography (silica; 15% ethyl acetate in hexanes) followed by high pressure liquid chromatography (Whatman M-9 Partisil 10/50 column, 15% ethyl acetate in hexanes) to give the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10]([CH3:12])C)#[N:2].Cl.[Cl:24][C:25]1[CH:26]=C([CH:29]=[CH:30][CH:31]=1)N>C(O)C>[ClH:24].[Cl:24][C:25]1[CH:26]=[C:12]([N:10]2[C:1](=[NH:2])[C:3]3[C:4]([NH:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=4)=[N:5][NH:6][C:7]=3[N:8]=[CH:9]2)[CH:29]=[CH:30][CH:31]=1
Reactant: COc1cccc(CNc2n[nH]c(N=CN(C)C)c2C#N)c1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Product: COc1cccc(CNc2n[nH]c3ncn(-c4cccc(Cl)c4)c(=N)c23)c1
Temperature: 10 °C

Procedure:
A mixture of 5.97 g (20 mmol) of 4-cyano-5-(dimethylamino-methyleneamino)-3-(3-methoxy-benzylamino)-pyrazole, 3.77 g (23 mmol) of 3-chloro-aniline hydrochloride and 100 ml of ethanol is heated under reflux for 36 hours. Cooling to approx. 10° C., filtering and washing the filter residue with ethanol yield title compound II; m.p. 251-253° C. (decomp.). The filtrate is concentrated by evaporation in vacuo, the oily residue is partitioned between ethyl acetate and water and the organic phase is washed with brine, dried over sodium sulfate and concentrated to a volume of approx. 25 ml using an RV, a crystalline precipitate being formed. Filtering and washing the filter residue with a small amount of ethyl acetate and diethyl ether yield title compound I (see Example 52); m.p. 194-195° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10]>CO>[CH3:13][O:12][C:8](=[O:11])[CH2:9][CH2:10][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCNC
Reactant: C=CC(=O)OC
Solvent: CO
Product: CCCCCN(C)CCC(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
106 g (1.05 mol) N-methyl-N-pentylamine was added to cooled methanol of a temperature of 0–5° C. 108 g (1.25 mol) methyl acrylate was added to the solution and the mixture was stirred at room temperature for 8 hours. Then methanol was distilled off in vacuo and the residue was purified by distillation to obtain 188.6 g N-methyl-N-pentyl-β-alanine methyl ester (96.1%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35]([CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:4][CH:3]=1)=[O:36])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1

Procedure:
(dd) In an analogous manner to that described in Example 44 (e), by alkylating tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 61 (c)] with ethyl bromoacetate there was obtained tert-butyl (3RS,4RS)-4-(4-ethoxycarbonylmethoxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 520 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([O:11][CH2:12][CH3:13])[C:7]=1[C:14]#[N:15])=[O:4].S(=O)(=O)(O)[OH:18]>>[CH3:16][N:2]([CH3:1])[C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([O:11][CH2:12][CH3:13])[C:7]=1[C:14](=[O:18])[NH2:15])=[O:4]
Reactant: O=S(=O)(O)O
Reactant: CCOc1nsc(NC(=O)N(C)C)c1C#N
Product: CCOc1nsc(NC(=O)N(C)C)c1C(N)=O

Procedure:
A mixture of 3.8 g of 1,1-dimethyl-3-(4-cyano-3-ethoxy-5-isothiazolyl)urea in 7 ml of concentrated sulfuric acid was treated as described in Example II to give 3.5 g of 1,1-dimethyl-3-(4-carbamoyl-3-ethoxy-5-isothiazolyl)urea, m.p. 172°-172°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:11][CH2:12][N:13]([C:30]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:31])[CH2:14][CH2:15]2)=[N:4][CH:3]=1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Reactant: O=C(Cl)N1CCOCC1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCN(C(=O)N3CCOCC3)CC2)CC1

Procedure:
Prepared in a similar manner to Example 554 using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and 4-morpholinecarbonyl chloride
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([Cl:15])=[C:7]([O:16][CH3:17])[N:6]=1.O>C(O)CC>[Cl:15][C:8]1[C:7]([O:16][CH3:17])=[N:6][C:5]([NH:2][NH2:3])=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=1
Reactant: COc1nc(Cl)c(C(F)(F)F)cc1Cl
Reactant: NN
Solvent: CCCO
Solvent: O
Product: COc1nc(NN)c(C(F)(F)F)cc1Cl
Temperature: 90 °C
Reaction time: 3 h

Procedure:
10.7 g (0.214 mol) of hydrazine hydrate were added in the course of 10 minutes with stirring at 50° C. to 25.0 g (0.102 mol) of 2,5-dichloro-6-methoxy-3-trifluoromethylpyridine in 100 ml of propanol and the mixture was stirred at 90° C. for 3 hours. After cooling, the resulting suspension was added to 1.2 liters of water, the precipitate was filtered off with suction and taken up in methylene chloride, and the solution was washed with water. The organic phase was dried and concentrated, and the residue was stirred with ether/pentane (1:1). After filtering off with suction and drying, 7.8 g (32% of theory) of the title compound of m.p. 140-142° C. were obtained.
Reaction SMILES: II.[Mg].[C:4]([O:7][C:8]1[C:13]([CH:14](Br)[CH2:15][CH2:16]Br)=[CH:12][CH:11]=[CH:10][C:9]=1[Br:19])(=[O:6])[CH3:5].Cl>C1COCC1>[C:4]([O:7][C:8]1[C:13]([CH:14]2[CH2:16][CH2:15]2)=[CH:12][CH:11]=[CH:10][C:9]=1[Br:19])(=[O:6])[CH3:5]
Reactant: CC(=O)Oc1c(Br)cccc1C(Br)CCBr
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)Oc1c(Br)cccc1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
Iodine (catalytic amount) was added to a mixture of magnesium (75.5 mg, 3.14 mmol) and anhydrous THF (1.5 ml) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. Subsequently, a solution of 2-bromo-6-(1,3-dibromopropyl)phenyl acetate (1.24 g, 2.99 mmol) in anhydrous THF (4.5 ml) was added to the mixture at 80° C. over 2 minutes. After the mixture was stirred at 80° C. for 1 hour and 30 minutes, the mixture was further stirred at room temperature for 2 hours. The reaction mixture was ice-cooled and 1M hydrochloric acid was added thereto to make pH to 2 or lower. The mixture was extracted with ethyl acetate. The organic layer was combined and successively washed with water and a saturated aqueous NaCl solution, followed by drying with anhydrous sodium sulfate. After the solid was removed by filtration, the filtrate was concentrated to obtain a residue. This residue was purified by silica gel column chromatography to obtain 316 mg of 2-bromo-6-cyclopropylphenyl acetate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.S(OC)(O[CH3:14])(=O)=O>C(O)(=O)C>[CH3:14][N:3]1[C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ncc([N+](=O)[O-])[nH]1
Solvent: CC(=O)O
Product: Cc1ncc([N+](=O)[O-])n1C
Yield: 75.5 %

Procedure:
127 parts of 2-methyl-5-nitroimidazole, 350 parts of acetic acid and 126 parts of dimethyl sulfate are boiled under reflux for 4 hours. The acetic acid is distilled off in vacuo and the residue is dissolved in 500 parts of water and adjusted to pH 1.8 with aqueous ammonia solution. After cooling to from 0° to 5° C. the unreacted 2-methyl-5-nitroimidazole is suction filtered, the filtrate is adjusted to pH 10 and after cooling the 1,2-dimethyl-5-nitroimidazole is isolated. In addition to 30.4 parts of starting material (II) there is obtained 81 parts of 1,2-dimethyl-5-nitroimidazole (melting point 140° C.); this is equivalent to a yield of 75.5% of theory.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][OH:25])[CH2:19]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][OH:25])[CH2:19]2)[N:7]=1
Reactant: OCC1CCCNC1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N2CCCC(CO)C2)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 30.3 %

Procedure:
This compound was prepared according to the method described in Example 26 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (0.10 g, 0.41 mmol), 3-piperidinemethanol (Aldrich Chemical Company) (0.241 g, 2.09 mmol) and K2CO3 (0.34 g, 2.50 mmol) in H2O (2.5 mL) to obtain crude pink solids. Recrystallization from EtOH/MeOH gave 0.040 g (30%) of the title compound as an off-white solid. Mp: 255-256° C. 1H NMR (DMSO-d6; 500 MHz): δ 1.45 (m, 1), 1.59 (m, 1), 1.67 (m, 1), 1.83 (m, 2), 2.42 (s, 3), 3.47 (m, 2), 3.55 (m, 1), 3.68 (m, 2), 3.86 (m, 1), 5.44 (br s, 1), 6.77 (s, 1), 7.38 (m, 1), 7.47 (m, 2), 7.87 (d, 2, J=7.2), 11.24 (br s, 1). MS m/z: 321 (M−1).
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>C(O)COCCO.O>[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[N:20]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH3:16])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: COc1cccc2c1=NC(=O)C1CCOC=21
Reactant: Cc1ccccc1N
Solvent: OCCOCCO
Solvent: O
Product: COc1cccc2c3c(c(=O)[nH]c12)CCN3c1ccccc1C
Temperature: 250 °C
Yield: 76.7 %

Procedure:
4-Oxo-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline (217 mg, 1.0 mmol) was dissolved in 10 ml of diethylene glycol in a pressure tube and 2-methylaniline (267 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 250° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, amd concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 235 mg of desired compound as solid in 77% of yield.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](O)=[O:4].C([N:19](CC)CC)C.ClC(OCC(C)C)=O.N>C(OCC)(=O)C>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:19])=[O:4]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(N)=O
Temperature: -10 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
2.29 g (10 mmoles) of BOC-HPro-OH are dissolved in 30 ml of ethyl acetate, 1.4 ml (10 mmoles) of triethylamine are added to the solution, the mixture is cooled to -10° C., and then 1.3 ml (10 mmoles) of isobutyl chloroformate are added dropwise. After 15 minutes of stirring gaseous ammonia is introduced into the reaction mixture for 0.5 hours at -10° C., and then the mixture is allowed to stand at 0°-5° C. for 2 hours. The precipitate is filtered off, the filtrate is evaporated, and the oily residue is dissolved in 30 ml of chloroform. This solution is washed twice with 10 ml of n hydrochloric acid, each, twice with 10 ml of n sodium hydrocarbonate solution, each, and then with 10 ml of water, dried over anhydrous sodium sulfate, and evaporated. The oily residue is crystallized from n-hexane to obtain 1.95 g of a crude product. This crude product is recrystallized from a mixture of ethyl acetate and ether to obtain 1.78 g (78%) of BOC-HPro-NH2 ; m.p.: 138°-140° C., Rf2 =0.43, [α]D25 =-24.85° (c=1%, in acetic acid).