Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N(CC)CC)=CN=C3CC2)=O)=CC=1)=N)(C)(C)C.[F:71][C:72]1[CH:77]=[CH:76]C(S(Cl)(=O)=O)=[CH:74][CH:73]=1>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([C:32]4[CH:76]=[CH:77][C:72]([F:71])=[CH:73][CH:74]=4)(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)=[NH:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(C)(=O)=O)c(=O)n32)cc1
Agent: CCN(CC)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(=O)(=O)c4ccc(F)cc4)c(=O)n32)cc1
Yield: 41 %

Procedure:
Following a procedure similar to that for the preparation of 16a, intermediate 3a (50 mg, 0.117 mmol) and 4-fluorobenzene sulfonyl chloride (29.6 mg, 0.158 mmol) yielded 28.2 mg (41.0%) of 32a. MS (ESI) 585.0 (M+H+).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH2:22]([Br:26])[CH2:23][CH2:24][CH3:25]>C(#N)C>[Br-:26].[CH2:22]([N+:15]1([CH2:14][CH2:13][CH2:12][C:9]2[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCBr
Reactant: CS(=O)(=O)Nc1ccc(CCCN2CCCCCC2)cc1
Solvent: CC#N
Product: CCCC[N+]1(CCCc2ccc(NS(C)(=O)=O)cc2)CCCCCC1
Product: [Br-]

Procedure:
A mixture of 1.35 g (4.35 mmol) of hexahydro-1-[3-[4-(methylsulfonylamino)phenyl]propyl]-1H-azepine, (Table 5, Entry 7) and 4.7 ml of n-butyl bromide in 10 ml of acetonitrile is heated at 80°-90° C. (oil bath temperature) for 20 hrs. The reaction is concentrated and the residue is partitioned between water and methylene chloride. The aqueous layer (50 ml) is extracted with methylene chloride and then basified with sodium hydroxide to at least pH 12. The solution is saturated with potassium bromide and then reextracted with methylene chloride. The aqueous layer is acidified with hydrobromic acid and lyophilized. Solids are extracted with 5% methanol-methylene chloride, concentrated, and the residue extracted into methylene chloride (filtered through cotton) and concentrated to yield the title compound.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][N:33]4C(=O)C5=CC=CC=C5C4=O)[CH:27]=3)[C:15](=[O:25])[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:33][CH2:32][C:28]1[CH:27]=[C:26]([N:14]2[C:12]3=[N:13][C:8]([NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][CH:10]=[C:11]3[CH2:17][N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[C:15]2=[O:25])[CH:31]=[CH:30][CH:29]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1
Yield: 2.7 %

Procedure:
A solution of 230 mg of 7-anilino-3-(2-bromophenyl)-3,4-dihydro-1-[3-(phthalimidomethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 10 ml of ethanol was treated with 0.5 ml of hydrazine hydrate. After 18 hours the mixture was evaporated and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 50 ml of dichloromethane, washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 5 mg (2.8%) of 1-[3-(aminomethyl)phenyl]-7-anilino-3-(2-bromophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 121° C.
Reaction SMILES: CN1C2C(C(O)=O)=CCC1CC2.[CH3:13][N:14]1[C@H:18]2[C@@H:19]([C:31]([O:33]C)=[O:32])[C@@H:20]([O:22]C(C3C=CC=CC=3)=O)[CH2:21][C@@H:15]1[CH2:16][CH2:17]2.P(Cl)(Cl)(Cl)=O>Cl>[CH3:13][N:14]1[C@H:18]2[C@@H:19]([C:31]([OH:33])=[O:32])[C@@H:20]([OH:22])[CH2:21][C@@H:15]1[CH2:16][CH2:17]2
Reactant: COC(=O)[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2C
Agent: CN1C2CC=C(C(=O)O)C1CC2
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CN1[C@H]2CC[C@@H]1[C@@H](C(=O)O)[C@@H](O)C2

Procedure:
In later references Anhydroecgonine and esters thereof have been prepared by hydrolysis of cocaine in aqueous hydrochloric acid followed by dehydration with phosphorus oxychloride (J. Amer. Chem. Soc., 82 (1960), page 4643 and EP-A1-604 355 ). Although both the hydrolysis of cocaine and the dehydration of ecgonine produces high yields, it is a serious drawback to this method that the reaction mixture becomes syrupy during the dehydration step which makes stirring almost impossible. Using SOCl2 as dehydrating agent causes similar problems.
Reaction SMILES: [NH2:1][C@H:2]([C:35]([O:37][CH3:38])=[O:36])[CH2:3][S:4][CH2:5][C:6]1[C:24]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:23][C:22]([O:33][CH3:34])=[CH:21][C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:9].[CH3:39]I>C(#N)C.C(OCC)(=O)C>[CH3:38][O:37][C:35]([C@@H:2]([NH:1][CH3:39])[CH2:3][S:4][CH2:5][C:6]1[C:24]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])=[CH:23][C:22]([O:33][CH3:34])=[CH:21][C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)=[O:9])=[O:36]
Reactant: COC(=O)[C@@H](N)CSCc1c(O[Si](C)(C)C(C)(C)C)cc(OC)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CI
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN[C@@H](CSCc1c(O[Si](C)(C)C(C)(C)C)cc(OC)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OC
Yield: 26.7 %

Procedure:
A solution of 1.90 g of p-nitrobenzyl (R)-2-[[[2-amino-2-methoxycarbonyl-ethyl]thio]methyl]-3-(tert-butyldimethylsilyloxy)-5-methoxybenzoate and 0.91 g of methyl iodide in 5 ml of acetonitrile was stirred at room temperature for 3 hours. The solution was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution and with brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. The residual oil was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent to yield 0.52 g of p-nitrobenzyl (R)-2-[[[2-methoxycarbonyl-2-(methylamino)ethyl]thio]methyl]-3-(tert-butyldimethylsilyloxy)-5-methoxybenzoate as an oil.
Reaction SMILES: [C:1]([CH:4]([C:12](=O)[CH3:13])[CH:5]([C:9](=O)[CH3:10])[C:6](=O)[CH3:7])(=O)[CH3:2].[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([F:25])[CH:19]=1)[CH3:16].[NH2:26][NH2:27]>>[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:1]([CH3:2])=[C:4]3[C:5]([C:9]([CH3:10])=[N:26][N:27]=[C:12]3[CH3:13])=[C:6]2[CH3:7])=[C:20]([F:25])[CH:19]=1)[CH3:16]
Reactant: NN
Reactant: CC(=O)C(C(C)=O)C(C(C)=O)C(C)=O
Reactant: CCOc1ccc(N)c(F)c1
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)c(F)c1

Procedure:
Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (200 mg, 1.0 mol), 4-ethoxy-2-fluoro-phenyl amine (155 mg, 1.0 mmol) and hydrazine (50 μL) reacted to give 6-(4-ethoxy-2-fluoro-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.13 (t, 1H), 6.88 (m, 2H), 4.16 (q, 2H), 2.82 (s, 6H), 2.46 (s, 6H), 1.53 (t, 3H); MS (ESI) 314 (M+H)+.
Reaction SMILES: O.[NH2:2][C:3]1[NH:4][C:5]2[CH:11]=[C:10]([CH3:12])[C:9]([CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH3:14][N:15]=[C:16]=[O:17].[CH3:18][C:19]([CH3:21])=O>>[CH3:18][C:19]1([CH3:21])[N:15]([CH3:14])[C:16](=[O:17])[N:4]2[C:3](=[N:7][C:6]3[CH:8]=[C:9]([CH3:13])[C:10]([CH3:12])=[CH:11][C:5]=32)[NH:2]1
Reactant: Cc1cc2nc(N)[nH]c2cc1C
Reactant: CN=C=O
Reactant: CC(C)=O
Solvent: O
Product: Cc1cc2nc3n(c2cc1C)C(=O)N(C)C(C)(C)N3

Procedure:
2-Amino-5,6-dimethylbenzimidazole monohydrate, acetone and methyl isocyanate were reacted, conducting the initial condensation and subsequent base hydrolysis of the intermediate 10-N-methylcarbamoyl precursor as described in Example 1. The title compound was recovered and purified by liquid chromatography to give a solid, mp 211° C. (dec.). The confirmatory elemental analysis is shown in Table III.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][N:8]([CH3:30])[CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=O)[C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[N:33]=1.O>O1CCCC1>[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)/[CH:10]=[CH:9]\[N:8]([CH3:30])[CH3:7])[N:33]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(Br)n1
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)/C=C\C(c1ccc(Cl)cc1)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of n-butyllithium (60 mL, 1.55M in hexane) was added dropwise during 45 min to a stirred suspension of (2-dimethylaminoethyl)triphenylphosphonium bromide (38.1 g) in dry tetrahydrofuran (500 mL) under nitrogen. After an additional hour at room temperature, a solution of 2-bromo-6-(4-chlorobenzoyl)pyridine (27.3 g) in dry tetrahydrofuran (200 mL) was added dropwise. The mixture was stirred at room temperature for 20 min, then refluxed for 80 min, cooled to room temperature, and poured into water (500 mL). The ether layer was separated and the aqueous phase extracted with three additional portions of ether. The ether layers were combined, washed once with water, dried (MgSO4) and evaporated to give an oil which was triturated with hexane (500 mL). The hexane layer was decanted and concentrated to give a crude mixture of isomeric Z and E alkenes which were separated by chromatography (Waters Prep 500) on silica gel with 95:5/methylene chloride: methanol (E, 7.53 g; Z, 15.19 g). The individual isomers were then rechromatographed on silica gel with ethyl acetate to yield (Z)-2-bromo-6-(1-(4-chlorophenyl)-3-dimethylaminoallyl)pyridine, m.p. 56°-62°, and (E)-2-bromo-6-(1-(4-chlorophenyl-3-diomethylaminoallyl)pyridine, 69°-70°.
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[H-].[Na+].C[N:18]([CH3:21])C=O.[N+]([C:25]1[CH:26]=[C:27]([C:33]#[N:34])[C:28](=[CH:31][CH:32]=1)[C:29]#[N:30])([O-])=O>O>[C:29]([C:28]1[CH:27]=[C:26]([CH:25]=[CH:32][C:31]=1[C:21]#[N:18])[O:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]#[N:34])[CH:26]=1)#[N:30]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: OCCCCCCCCCCCCO
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(OCCCCCCCCCCCCOc2ccc(C#N)c(C#N)c2)cc1C#N
Reaction time: 12 h
Yield: 40 %

Procedure:
A mixture of 1,12-dodecanediol (2,2 g, 0.011 mol), sodium hydride (0.91 g. 0.023 mol, 61%) and 25 ml of dry dimethylformamide were stirred under a nitrogen atmosphere at 90°-95° C. for 12 hours. After cooling, 4.0 g (0.23 mol) of 4-nitrophthalonitrile was added to the white salt mixture. The salt dissolved quickly and the mixture was heated at 100°-110° C. for 4 hours. Infrared analysis indicated that a large quantity of 4-nitrophthalonitrile was still present. The temperature was increased to 140°-145° C. and the mixture was stirred at this temperature for 15 hours. The cooled reaction mixture was poured into 200 ml of cold water and the product was extracted into three, 75 ml portions of methylene chloride. The combined extract was washed several times with water, charcoaled, dried over anhydrous sodium sulfate, and concentrated at reduced pressure. Recrystallization of the crude material from ethanol-water yielded 1.7 g (40%) of 1,12-bis(3,4-dicyanophenoxy) dodecane.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([N:11]=[N+:12]=[N-:13])[CH2:6]1)=[O:4].[CH2:14](I)[CH3:15]>C(#N)C.C1COCC1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([O:10][CH2:14][CH3:15])[C@@H:7]([N:11]=[N+:12]=[N-:13])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Reactant: CCI
Solvent: CC#N
Solvent: C1CCOC1
Product: CCO[C@H]1C[C@H](C(=O)OC)C[C@@H]1N=[N+]=[N-]
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (1R,3S,4S)-3-azido-4-hydroxy-cyclopentanecarboxylic acid methyl ester (500 mg) at r.t. in acetonitrile/THF 3:1 (8 ml) under an argon atmosphere were added Ag2O (1.88 g) and ethyl iodide (2.18 ml). The black suspension was stirred for 18 h at 60° C., then cooled to r.t. The black solid was filtered off and washed with ethyl acetate. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 7:3) to give (1R,3S,4S)-3-azido-4-ethoxy-cyclopentanecarboxylic acid methyl ester (474 mg) as light yellow oil. MS: 214.1 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[N:17]4)[N:11]([CH:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)[CH3:25])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[N:17]4)[N:11]([CH:24]([C:26]3[CH:27]=[CH:28][C:29]([C:30]([NH:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:31])=[CH:33][CH:34]=3)[CH3:25])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(c1ccc(C(=O)O)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1-c1ccc2nccnc2c1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)c1ccc(C(C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc3nccnc3c2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the intermediate from step G (39.7 mg, 0.08 mmol) in 3 mL of anhydrous DMF was added ethyl β-alaninate hydrochloride (19 mg, 0.12), 1-hydroxy-7-azabenzo-triazole (17 mg, 0.12 mmol), N,N-diisopropylethyl amine (0.04 mL, 0.24 mmol), and 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (24 mg, 0.12 mmol). The reaction was left stirring at room temperature for 12 hours then diluted with EtOAc and washed with 1N HCl (2×), saturated sodium bicarbonate (2×), and brine (1×). The organic layer was then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting solid was purified by flash chromatography (30% EtOAc/Hexanes) to afford a light yellow solid. Enantiomers were then separated using SFC-HPLC semi-prep methodology with the conditions as follows: column=ChiralCel OJ 10×250 mm 10 micron, flow rate=10.0 mL/min, mobile Phase=40% MeOH (0.1% TFA)/CO2, column temperature=40° C., UV wavelength=248 nm, outlet pressure=100 bar, concentration=50 mg/mL in MeOH. Retention time: Isomer A=4.03 min; Isomer B=5.01 min. LC-MS: 4.20 min. (M+H)=589.48.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:13]=O.Cl.[CH2:16]([NH:19][CH3:20])[CH:17]=[CH2:18]>C(O)(=O)C>[CH2:16]([N:19]([CH2:13][CH:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:11]1=[O:12])[CH3:20])[CH:17]=[CH2:18]
Reactant: C=CCNC
Reactant: C=O
Reactant: O=C1CCCCc2ccccc21
Agent: Cl
Solvent: CC(=O)O
Product: C=CCN(C)CC1CCCc2ccccc2C1=O
Yield: 86.1 %

Procedure:
5.2 g 6,7,8,9-tetrahydro-benzocyclohepten-5-one, 0.96 g paraformaldehyde and 10.0 g allyl-methylamine hydrochloride in 60 ml glacial acetic acid were reacted as in example 1, step 1. After analogous work-up, 6.7 g (84.8% of theoretical) 6-[(allyl-methyl-amino)-methyl]-6,7,8,9-tetrahydro-benzocyclohepten-5-one were obtained as a yellowish oil.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH3:15])=[C:9]2[CH2:16][C:17]#[N:18].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=1.C(OCC)C>C(O)C.ClCCl>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH3:15])=[C:9]2/[C:16](=[CH:25]/[C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)/[C:17]#[N:18]
Reactant: O=Cc1cccnc1
Reactant: COc1ccc2[nH]c(C)c(CC#N)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2[nH]c(C)c(/C(C#N)=C/c3cccnc3)c2c1
Temperature: 50 °C

Procedure:
To a solution of sodium methanolate (162 mg, 3.0 mmol, 2.0 eq.) in anhydrous ethanol (20 mL) were added, under an argon atmosphere, (5-methoxy-2-methyl-1H-indol-3-yl)-acetonitrile (300 mg, 1.5 mmol, 1.0 eq.) and, after 30 minutes stirring, pyridine-3-carbaldehyde (352 μL, 3.8 mmol, 2.5 eq.). The reaction apparatus was protected from light and the mixture heated at 50° C. for 12 hours. The reaction was allowed to cool to room temperature and then, the solvent was removed under reduced pressure and the crude taken up in ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4 and then, evaporated. The residue was purified by silica gel flash-column chromatography (eluent: heptane/EtOAc, 40/60) to afford, after trituration with diethyl ether and dichloromethane, the compound (35) as a yellow solid (250 mg, 58%). IR □max (cm−1): 2212 (νCN); 1H NMR (DMSO, 300 MHz) δ (ppm): 2.54 (3H, s, 2′-methyl), 3.77 (3H, s, 5′-methoxy), 6.78 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.4 Hz, H6′), 7.18 (1H, d, J4′-6′=2.4 Hz, H4′), 7.27 (1H, d, J7′-6′=8.9 Hz, H7′), 7.50 (1H, s, H3), 7.55 (1H, dd, J5″-4″=8.1 Hz, J5″-6″=4.8 Hz, H5″), 7.74 (1H, s, H3), 8.35 (1H, d, J4″-5″=8.1 Hz, H4″), 8.61 (1H, d, J6″-5″=4.8 Hz, H6″), 8.97 (1H, s, H2″), 11.45 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz) δ (ppm): 12.6 (2′-methyl), 55.3 (5′-methoxy), 100.4 (C4′), 106.1 (C2), 106.9 (C3′), 110.9 (C6′), 111.9 (C7′), 118.0 (C1), 123.7 (C5″), 126.2 (C3a′), 129.9 (C2′), 130.5 (C3″), 134.6 (C3), 136.3 (C7a′), 137.6 (C4″), 149.8 (C6″), 150.0 (C2″), 154.1 (C5′); ESI-MS: m/z 290.1 ([M+H]+), 312.1 ([M+Na]+); HRESI-MS: m/z 290.1299 (calcd for C18H16N3O+, 290.1293).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2.CN1CCOCC1>CN(C)C=O>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([NH:18][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][CH2:7][CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:27][CH:26]=2)[CH:22]=[N:23]1
Reactant: O=C(O)c1ccccc1NCC1CCOCC1
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2[nH]ncc2c1)c1ccccc1NCC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.4 %

Procedure:
235 mg (1 mmol) of 2-(tetrahydropyran-4-yl)methylaminobenzoic acid is mixed in 10 ml of dimethylformamide with 266 mg (2 mmol) of 5-aminoindazole. 253 mg (2.5 mmol) of N-methylmorpholine and 456 mg (1.2 mmol) of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetamethyluronium hexafluorophosphate are added to this solution under argon and in a moisture-free environment. This mixture is stirred for 3 hours at room temperature. It is concentrated by evaporation in a vacuum, taken up in dilute sodium bicarbonate solution and extracted three times with 30 ml of ethyl acetate each. The combined organic phase is washed with water, dried, filtered and concentrated by evaporation. The residue is absorptively precipitated in ethyl acetate and suctioned off. The filtrate is concentrated by evaporation, and the residue is chromatographed on silica gel with methylene chloride:ethanol=10:1 as an eluant. 124 mg (35% of theory) of N-(indazol-5-yl)-2-(tetrahydropyran-4-yl)methylaminobenzoic acid amide with a melting point of 173.6° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[CH3:11][O:10][C:9]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[NH:6][CH:22]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]2=[O:14]
Reactant: COc1ccc(N)cc1OC
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c[nH]c2cc(OC)c(OC)cc2c1=O
Yield: 40.5 %

Procedure:
3,4-Dimethoxyaniline (3.0 g) and diethyl ethoxymethylenemalonate (5.1 g) were subjected to condensation and ring closure in the same manner as in Experimental Example 1 to give 6,7-dimethoxy-3-ethoxycarbonyl-4(1H)-quinolone (2.2 g).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15](=[N:17][OH:18])[NH2:16])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[CH3:19][CH2:20][O-:21].[Na+].[CH3:23]O>>[OH:21][CH2:20][CH2:19][C:23]1[O:18][N:17]=[C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[N:16]=1
Reactant: Cn1c(=O)c2c(ncn2CC(N)=NO)n(C)c1=O
Reactant: CO
Reactant: CC[O-]
Agent: [Na+]
Product: Cn1c(=O)c2c(ncn2Cc2noc(CCO)n2)n(C)c1=O
Yield: 87 %

Procedure:
5.04 g. of 2-(theophyllin-7-yl)-acetamidoxime, 4.8 g. hydracrylyc acid ethyl ester, 2.16 g. of sodium ethylate and 100 cm3 of methanol are heated under pressure at 100° C. for 12 hours. The solvent is distilled off and the residue is crystallized from water. 5.3 g. (87% yield) of 7-[{5-(2-hydroxy-ethyl)-1,2,4-oxadiazol-3-yl}-methyl]-theophylline are obtained, m.p.: 145° C. The raw hydroxy ethyl compound is heated with 20 cm3 thionyl chloride and 20 cm3 benzene for 2 hours. The solvent is distilled off and the obtained 7-[{5-(2-chloroethyl)-1,2,4-oxadiazol-3-yl}-methyl]-theophylline is stirred in 50 cm3 of dimethylformamide with 6 cm3 diethylamine and 5 g. of potassium carbonate vigorously for 10 hours at 100° C. 4.4 g. (61% yield) of 7-[{ 5-(2-diethylaminoethyl)-1,2,4-oxadiazol-3-yl}-methyl]-theophylline are obtained. M.p.: 65°-68° C. (cyclohexane).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:3]=1[O:23][CH2:24][CH3:25]>[Pt].CO.CC(=O)OCC>[Cl:1][C:2]1[C:3]([O:23][CH2:24][CH3:25])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[N:7]=1
Reactant: CCOc1c(Cl)nc(-c2ccc([N+](=O)[O-])cc2)nc1N1CCOCC1
Agent: [Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1c(Cl)nc(-c2ccc(N)cc2)nc1N1CCOCC1
Yield: 70.8 %

Procedure:
4-[6-chloro-5-ethoxy-2-(4-nitro-phenyl)-pyrimidin-4-yl]-morpholine (0.2 g, 1 eq) was stirred under hydrogen balloon with platinum on carbon (10 percent, 0.11 g, 0.1 eq) in a mixture of MeOH and EA (1:1, 8 mL) at room temperature overnight. The reaction mixture was then filtered through Celite, the volatiles in the mixture was removed in vacuo, and the residue was purified by flash chromatography to give a white solid (0.13 g, 83%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:11](=[O:23])[C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([Br:20])[C:13]=1[O:21]C)[CH2:2][CH3:3].[ClH:24].CC(C)=O>CCO>[ClH:24].[CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:11](=[O:23])[C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([Br:20])[C:13]=1[OH:21])[CH2:2][CH3:3]
Reactant: CCCN1CCCC1CNC(=O)c1c(OC)ccc(Br)c1OC
Agent: Cl
Solvent: CC(C)=O
Solvent: CCO
Product: CCCN1CCCC1CNC(=O)c1c(OC)ccc(Br)c1O
Yield: 48 %

Procedure:
The title compound was prepared from (-)-N-n-propyl-2-(3-bromo-2,6-dimethoxybenzamidomethyl)pyrrolidine by dealkylation in the same manner as described in Example 2. Yield 48%. M.p. (HCl) 140°-141° C. (acetone). [α]D25 =-78° C. (c=0.80, EtOH) base.