Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:11](=[O:15])[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C(=O)Cl
Reactant: COc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)C(C)C)c(Cl)c1Cl
Temperature: 5 °C

Procedure:
A stirred mixture of 2,3-dichloroanisole (100 g., 0.565 mole) and isobutyryl chloride (66 g., 0.62 mole) in methylene chloride (400 ml.) is cooled to 5°C. and treated with aluminum cloride (83 g., 0.62 mole) during a one-hour period. The reaction mixture is allowed to warm to 25°C. and after 24 hours is poured into ice water (400 ml.) and hydrochloric acid (30 ml.). The organic phase is washed with 5% sodium hydroxide, water, dried over magnesium sulfate and distilled at reduced pressure affording 68 g. of 2',3'-dichloro-4'-methoxyisobutyrophenone which distills at 120°C-130°C./0.5 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[O:11][CH2:10][CH2:9][CH2:8][C:7](=O)[C:6]=2[CH:13]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+].Cl>CO>[NH2:21][CH:7]1[C:6]2[CH:13]=[C:2]([Cl:1])[CH:3]=[C:4]([CH3:14])[C:5]=2[O:11][CH2:10][CH2:9][CH2:8]1
Reactant: Cc1cc(Cl)cc2c1OCCCC2=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(Cl)cc2c1OCCCC2N
Reaction time: 48 h
Yield: 61.3 %

Procedure:
3.0 g of 7-chloro-9-methyl-3,4-dihydro-2H-1-benzoxepin-5-one, 50 ml of anhydrous methanol, 10.9 g of ammonium acetate and 0.63 g of sodium cyanoborohydride were stirred for 5 h at 60° C. and then for 2 days at RT. The reaction mixture was then acidified with hydrochloric acid and then concentrated on a rotary evaporator. The residue was taken up in water, and the solution was rendered alkaline with ammonia solution and extracted with EA. After drying and concentrating, the product was purified by chromatography on silica gel using ethyl acetate/methanol 9:1 and 1.3 g of 5-amino-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine were obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][CH3:22])[C:17]([OH:23])=[C:16]([CH2:24][CH2:25][CH3:26])[CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:27])[CH:3]=1.Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36]([O:38][CH3:39])=[O:37].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:36]([CH:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:29]=1)[O:23][C:17]1[C:16]([CH2:24][CH2:25][CH3:26])=[CH:15][C:14]([CH2:13][N:8]2[C:6]3=[N:7][C:2]([CH3:1])=[CH:3][C:4]([CH3:27])=[C:5]3[N:10]=[C:9]2[CH2:11][CH3:12])=[CH:19][C:18]=1[CH2:20][CH2:21][CH3:22])([O:38][CH3:39])=[O:37]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1OC(C(=O)OC)c1ccccc1
Yield: 96 %

Procedure:
To a solution of (4.72 mmol) of the product of Step G and (5.19 mmol) of methyl 2-bromophenylacetate in 10 mL of acetone was added (9.44 mmol) of K2CO3 and the mixture was stirred and refluxed for 14 hours. The mixture was cooled, filtered and evaporated in vacuo and the residue was purified on a silica gel flash chromatography column to afford a 96% yield of the title compound.
Reaction SMILES: C[N:2]1CCN[CH2:4][CH2:3]1.[CH2:8]([O:10][C:11]([C:13]1[C:14]([CH3:35])=[N:15][C:16]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[C:17]([N+:20]([O-])=O)[C:18]=1Cl)=[O:12])[CH3:9]>>[CH2:8]([O:10][C:11]([C:13]1[C:18]2[C:17](=[N:20][CH:4]=[CH:3][N:2]=2)[C:16]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[N:15][C:14]=1[CH3:35])=[O:12])[CH3:9]
Reactant: CCOC(=O)c1c(C)nc(N2CCN(c3ccccc3)CC2)c([N+](=O)[O-])c1Cl
Reactant: CN1CCNCC1
Product: CCOC(=O)c1c(C)nc(N2CCN(c3ccccc3)CC2)c2nccnc12

Procedure:
By substituting N-phenylpiperazine for N-methylpiperazine in Example 1 b and the resulting 4-chloro-2-methyl-6-(4-phenyl-1-piperazinyl)-5-nitropyridine-3-carboxylic acid ethyl ester is processed as described in Example 1 c-e, 7-methyl-5-(4-phenyl-1piperazinyl)pyrido[3,4-b]pyrazine-8-carboxylic acid ethyl ester is formed, m.p. 85°-87° (ligroin).
Reaction SMILES: [BH4-].[Na+].[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]=[CH:15][S:16][C:17]=1/[CH:18]=[CH:19]/[C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([O:5][CH3:6])=[O:4]>O.C(O)(C)C>[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]=[CH:15][S:16][C:17]=1/[CH:18]=[CH:19]/[CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([O:5][CH3:6])=[O:4]
Reactant: CCCCCC(=O)/C=C/c1scnc1CCCCCCC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCCCCC(O)/C=C/c1scnc1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
The solution of 143 mg of sodium borohydride in 30 ml of water was added to the solution of 2.65 g of 4-(6-carbomethoxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole (Ia, R1 = H) in 30 ml of isopropanol. The obtained reaction mixture was stirred for 2 hours at room temperature, then poured onto 150 ml of water, and extracted with 3 × 75 ml of ethyl acetate. The ethyl acetate extract was washed with water to neutral and evaporated in vacuo. The obtained 2.5 g of evaporation residue was subjected to chromatography on a column prepared with 100 g of silicic acid, the elution was carried out with mixtures of n-heptane and ethyl acetate of gradually increasing ethyl acetate content. The desired 4-(6-carbomethoxyhexyl)-5-(3-hydroxy-1-trans-octenyl-thiazole, (Ic, R1 = H) was eluted from the column with a mixture consisting of 70 % n-heptane and 30 % ethyl acetate, affording 2.2 g of a product of chromatographic purity.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30](=[O:35])NCOC)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(O)(=O)C>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([CH:30]=[O:35])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCNC(=O)C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(C=O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
tert-Butyl 5-(tert-butyldiphenylsilanyloxy)-3-methoxymethylcarbamoylvalerate (4.61 g) and tetrahydrofuran (60 mL) were mixed. To the mixture was added dropwise diisobutylaluminum hydride (1.0 M in toluene) (13.1 mL) at −78° C. The mixture was stirred at −78° C. for 1.5 hr. To the mixture was added dropwise acetic acid (0.515 mL). After an addition of aqueous Rochelle salt at −20° C., the mixture was extracted with ethyl acetate. The organic layer washed with water, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/25) to give the title compound (2.60 g).
Reaction SMILES: C1C2SC3C(=CC=CC=3)SC=2C=CC=1S(Cl)(=O)=O.[CH:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[S:33](Cl)(=[O:35])=[O:34].C([O:41][C:42](=[O:48])[C@H:43]([CH:45]([CH3:47])[CH3:46])[NH2:44])(C)(C)C.C(OC(=O)[C@@H](C(C)C)N)(C)(C)C>>[CH3:46][CH:45]([CH3:47])[C@H:43]([NH:44][S:33]([C:20]1[CH:21]=[CH:22][C:23]2[O:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:31][C:32]=2[CH:19]=1)(=[O:35])=[O:34])[C:42]([OH:48])=[O:41]
Reactant: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1O2
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Agent: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1S2
Product: CC(C)[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2)C(=O)O

Procedure:
When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (D)-valine-t-butyl ester, (S)-3-methyl-2-(phenoxathiine-2-sulfonylamino)-butyric acid is obtained as an off-white solid; mp 171-175° C.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C:6]=2[CH:5]=[C:4]([Cl:14])[CH:3]=1.[CH3:15][C:16]1[N:20]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[N:18][C:17]=1[CH:40]=[O:41]>>[Cl:14][C:4]1[CH:3]=[C:2]([CH:40]([C:17]2[N:18]=[CH:19][N:20]([C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:16]=2[CH3:15])[OH:41])[C:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C:6]=2[CH:5]=1
Reactant: CC1(C)OCc2cc(Cl)cc(Br)c2O1
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1c(C(O)c2cc(Cl)cc3c2OC(C)(C)OC3)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 50 %

Procedure:
Starting from 8-bromo-6-chloro-2,2-dimethyl-4H-1,3-benzodioxin and 5-methyl-1-triphenylmethyl-1H-imidazole-4-carboxaldehyde. The addition of the organomagnesium compound is carried out at 0° C. Yield: 50% of theory;
Reaction SMILES: [Cl-].[NH4+].C(O)C.[CH3:6][C:7]1[C:8]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:32][CH2:31][O:30][C:29]4=[O:33])=[CH:24][C:23]=3[N+:34]([O-])=O)=[O:21])[CH2:16][CH2:15]2)=[N:9][CH:10]=[C:11]([CH3:13])[CH:12]=1>O>[NH2:34][C:23]1[CH:24]=[C:25]([N:28]2[CH2:32][CH2:31][O:30][C:29]2=[O:33])[CH:26]=[CH:27][C:22]=1[C:20]([N:17]1[CH2:16][CH2:15][N:14]([C:8]2[C:7]([CH3:6])=[CH:12][C:11]([CH3:13])=[CH:10][N:9]=2)[CH2:19][CH2:18]1)=[O:21]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3[N+](=O)[O-])CC2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N)CC2)c(C)c1
Temperature: 65 °C
Yield: 17.2 %

Procedure:
A mixture of ammonium chloride (0.779 g), reduced iron (0.56 g), ethanol (16 mL) and water (4.3 mL) was stirred with heating at 60-70° C., and 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-nitrophenyl}oxazolidin-2-one (1.105 g) described in Example 129 was added. After completion of the reaction, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (0.177 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][NH2:31])=[CH:29][C:24]=2[O:23][CH2:22]1>>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][NH:31][C:14]([C:12]3[S:13][C:9]([S:8][C:7]4[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=4[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=3)=[O:15])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1ccc2c(c1)OCO2
Product: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and benzo[d][1,3]dioxol-5-ylmethylamine (58.0 mg, 0.39 mmol). The title compound was obtained as a solid (98 mg, 60% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.31 (1H, m), 8.99 (2H, s), 8.46 (1H, s), 6.84 (2H, m), 6.76 (1H, m), 5.97 (2H, s), 4.30 (2H, m). MS m/z: 482.11, 484.08 [M+H]+.
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.Cl[CH:14](Cl)[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:31][CH3:32])=[C:22]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:23]=2)[CH2:18][CH2:17][N:16]=1>CCO.C(Cl)Cl>[CH3:32][O:31][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][C:22]=1[O:25][CH2:26][C:27]([F:30])([F:28])[F:29])[C:15]([CH2:14][S:3][C:4]1[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=1)=[N:16][CH:17]=[CH:18]2
Reactant: COc1cc2c(cc1OCC(F)(F)F)C(C(Cl)Cl)=NCC2
Reactant: Sc1nc2ccccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: COc1cc2ccnc(CSc3nc4ccccc4[nH]3)c2cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a solution of 514.8 mg of 86% KOH (7.87 mmol) in 20 ml of 99% EtOH were added 434.1 mg of 2-mercaptobenzimidazole (II-1) (2.89 mmol) and 900.1 mg of 1-dichloromethyl-6-methoxy-7-(2,2,2-trifluoroethoxy)-3,4-dihydroisoquinoline (IV-1) (2.63 mmol) in order. After stirring for 30 min. at room temperature, the mixture was refluxed for 3 hr. and concentrated under reduced pressure. The residue was mixed with water and extracted with CHCl3. The objective compound existing as an insoluble material was filtered and combined with CHCl3 extract to give 722.5 mg of the crude product. It was dispersed in 15 ml of CH2Cl2, filtered and washed with CH2Cl2 to give 666.5 mg of the titled compound 2-{[6-methoxy-7-(2,2,2-trifluoroethoxy)isoquinolin-1-yl]methylthio}-benzimidazole (Ia-7) (Yield: 60.4%).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[O:25][CH2:26][CH3:27])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:28]1([CH2:31][NH2:32])[CH2:30][CH2:29]1>>[CH:28]1([CH2:31][NH:32][C:2]2[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:15][C:14]=4[O:25][CH2:26][CH3:27])[N:10]=[CH:11][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:30][CH2:29]1
Reactant: NCC1CC1
Reactant: CCOc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Product: CCOc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(NCC3CC3)c2n1
Yield: 5 %

Procedure:
The title compound was prepared according to the method described for Example 99 using 8-chloro-N-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Preparation 114) and cyclopropanemethylamine for 5 hours. The residue was further purified by passage through a SCX-2 cartridge eluting with 100% MeOH—0.5 M NH3 in MeOH to give the title compound (2.6 mg, 5%).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH2:5].C(=O)([O-])[O-].[K+].[K+].O.[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:15]=1[C:16](Cl)=[O:17]>ClCCl>[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:15]=1[C:16]([NH:5][CH2:4][CH2:3][Cl:2])=[O:17]
Reactant: NCCCl
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(NCCCl)c1c(Cl)cccc1Cl
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a stirred (vigourously) mixture of 17.4 parts of 2-chloroethanamine hydrochloride, 20.7 parts of potassium carbonate and 225 parts of water was added dropwise a mixture of 31.3 parts of 2,6-dichlorobenzoyl chloride and 120 parts of dichloromethane at room temperature: slightly exothermic reaction. Upon completion, stirring at room temperature was continued for one hour. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, dried, filtered and evaporated. The residue was crystallized from methylbenzene. The product was filtered off and dried, yielding 25.8 parts (68.8%) of 2,6-dichloro-N-(2-chloroethyl)benzamide; mp. 113.8° C. (intermediate 30).
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][CH2:10][CH2:11]CCCC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:16]1OC1CCC.[OH-].[Na+].Cl>O>[C:3]([CH:2]1[CH2:16][CH:8]([CH2:9][CH2:10][CH3:11])[O:7][C:1]1=[O:6])(=[O:4])[CH3:5]
Reactant: CCCCCCCCOC(=O)CC(C)=O
Reactant: CCCC1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC1CC(C(C)=O)C(=O)O1
Temperature: 24 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
n-Octyl acetoacetate (313.3 g, 1.42 moles), 1,2-pentylene oxide 101.8 g, 1.18 moles) and 157.5 g distilled water were combined in a reactor. A solution of 59.6 g sodium hydroxide (1.49 moles) in 59.6 g distilled water was added over a one-hour period while maintaining the temperature in the range of 22 to 26° C. The reaction mixture was then allowed to stir for an additional 111/2 hours while maintaining the temperature between 28° C. and 36° C. The reaction mixture was then acidified to pH 5.8 by the addition of concentrated hydrochloric acid. After separation of the organic and aqueous phases, the organic layer was stripped under reduced pressure to remove the n-octanol and any unreacted n-octyl acetoactetate. 3-Acetyl-5-propyldihydro-2(3H)-furanone ##STR12## was recovered upon distillation in 62.4% yield.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][CH2:12][CH:11]([N:15]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:16][C@H:17]([O:26][Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][C:9]=2[CH:41]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.C(=O)(O)[O-].[Na+]>O1CCCC1.CCCCCC>[OH:2][CH2:3][C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][CH2:12][CH:11]([N:15]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:16][C@H:17]([O:26][Si:27]([CH2:28][CH3:29])([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][C:9]=2[CH:41]=1
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(C(=O)OC)cc2C1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])O
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(CO)cc2C1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a cold (−78° C.) solution of 8-[N-tert-butoxycarbonyl-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid methyl ester (5.90 g) in tetrahydrofuran (120 ml) was added dropwise a solution of diisobutylaluminum hydride in hexane (0.95M, 53.2 ml). The reaction mixture was warmed to room temperature over 4 hours, and then saturated sodium bicarbonate solution was added dropwise to the mixture. The resulting precipitate was filtered off and washed with ethyl acetate. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (5:1) to afford N-(3-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxy-carbonylamine (5.20 g).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=2[C:8](=[O:16])[NH:7][C:6]2[CH:17]=[CH:18][CH:19]=[N:20][C:5]1=2)=[O:3].[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH2:35])[CH2:24][CH3:25])[CH3:22]>C(#N)C>[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH:35][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=2[C:8](=[O:16])[NH:7][C:6]2[CH:17]=[CH:18][CH:19]=[N:20][C:5]1=2)=[O:3])[CH2:24][CH3:25])[CH3:22]
Reactant: Cc1ccc2c(c1)C(=O)Nc1cccnc1N2C(=O)Cl
Reactant: CCN(CC)CC1CCCCN1CCN
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2ccc(C)cc2C(=O)Nc2cccnc21
Yield: 55 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(diethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 55% of theory. Colourless crystals, m.p. 148°-150° C. (acetonitrile).
Reaction SMILES: [CH3:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[Br:11][CH2:12][CH2:13][CH2:14]Br.[OH-].[Na+]>>[CH3:6][O:5][C:3](=[O:4])[C:2]([CH2:14][CH2:13][CH2:12][Br:11])([CH3:1])[C:7]([O:9][CH3:10])=[O:8]
Reactant: BrCCCBr
Reactant: COC(=O)C(C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C(C)(CCCBr)C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
NaH at 60% in mineral oil (1.63 g, 40.8 mmol. 1.3 eq) was washed three times with hexane and subsequently dried. After addition of dried THF (30 mL) the suspension was cooled to 0° C. Dimethyl methylmalonate (4.7 g, 32.3 mmol, 1.0 eq) was slowly and carefully added and gas development was observed. The mixture was stirred for 15 minutes and subsequently 1,3-dibromopropane (24 g, 119.0 mmol, 3.7 eq) was added in one portion. The mixture was allowed to reach room temperature and was then stirred for further 16 hours. NaOH 1.0 M solution was added, the crude was extracted with ethyl acetate; the organic layers were collected and dried, the obtained oil was purified by SiO2 column (elution: cyclohexane followed by EtOAc). The title product (6.6 g, 76% yield) was obtained.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([CH2:27][CH3:28])=[C:14]2[CH2:29][C:30]([NH2:32])=[O:31])(=[O:6])[O:4]C.[OH-].[Na+]>CO.O>[CH3:1][O:2][P:3]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([CH2:27][CH3:28])=[C:14]2[CH2:29][C:30]([NH2:32])=[O:31])(=[O:4])[OH:6]
Reactant: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(OC)OC)ccc2n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(O)OC)ccc2n1Cc1ccccc1
Yield: 77.1 %

Procedure:
A mixture of 162 mg (0.35 mmol) of [3-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester and 5 mL of 1N NaOH in 10 mL of MeOH was heated to maintain reflux for 5 hours, diluted with water and extracted with ethyl acetate. The aqueous layer was made acidic to pH 2-3 with 1N HCl and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4) and concentrated at reduced pressure to give 120 mg (77% yield) of [3-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid monomethyl ester.
Reaction SMILES: [NH2:1][N:2]=[CH:3][NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][N:14]=[CH:15]OCC)[N:9]=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>CO>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:29][CH:15]=[N:14][CH2:13][CH2:12][S:11][CH2:10][C:8]2[N:9]=[C:5]([NH:4][CH:3]=[N:2][NH2:1])[S:6][CH:7]=2)(=[O:27])=[O:28])=[CH:24][CH:25]=1
Reactant: CCOC=NCCSCc1csc(NC=NN)n1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Solvent: CO
Product: NN=CNc1nc(CSCCN=CNS(=O)(=O)c2ccc(Br)cc2)cs1
Temperature: 25 °C

Procedure:
To the crude product composed by ethyl N-[2-[[[2-[(aminoiminomethyl)amino]-4-thiazolyl]methyl]thio]ethyl]formimidate, 7.7 g of p-bromobenzenesulfonamide in 50 ml of methanol are dropwise added under stirring and at room temperature. The mixture is kept under stirring for 1 hour at room temperature, the solvent is removed by distillation under reduced pressure, and the obtained residue is purified by 60-silicagel column chromatography. 13.5 g of N-p-bromobenzene-sulphonyl-N'-[2-[[[2-[(aminoiminomethyl)amino]-4-thiazolyl]methyl]thio]ethyl]formamidine are obtained.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([CH3:12])[N:5]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1>CO>[NH2:22][C:21]1[C:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)=[CH:10][C:9]2[CH:8]=[N:7][C:6]([CH3:12])=[N:5][C:4]=2[N:3]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: Cc1ncc(C=O)c(N)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncc2cc(-c3ccc(F)cc3)c(N)nc2n1
Temperature: 20 °C
Yield: 78 %

Procedure:
60 ml of 40% strength by weight aqueous potassium hydroxide solution were added to a suspension of 90 g (0.66 mol) of 4-amino-5-formyl-2-methylpyrimidine and 88.7 g (0.66 mol) of p-fluorophenylacetonitrile in 900 ml of methanol at 40° C., a homogeneous solution being formed. After cooling to about 20° C., the precipitate formed was separated off. 1 l of water was added to the alcoholic phase, with the result that further product crystallized out. Yield: 78%; mp.: 252°-254° C.