Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O)C=CC=CC=1.C1(O)C=CC=CC=1.CC(C)=O.[C:19]1([CH:25]([CH3:27])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O-]O.C1(C(C)C)C=CC=CC=1.CC(C)(C1C=CC=CC=1)O>>[CH3:27][C:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH2:26]
Reactant: CC(C)c1ccccc1
Agent: CC(C)(O)c1ccccc1
Agent: [O-]O
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: C=C(C)c1ccccc1

Procedure:
The current process of choice for commercial phenol production utilizes the autocatalytic cumene/air oxidation to cumene hydroperoxide (CHP) route for over 50% of the world's production of phenol. A key step in this process is the decomposition (cleavage) of CHP produced in the oxidation section of the plant to phenol and acetone using dilute mineral acid (H2SO4) as an acid catalyst. Use of the liquid acid requires subsequent neutralization and purification of the phenol at substantial cost, and a waste stream generation that could be avoided if an effective solid acid catalyst could be used. CHP decomposition is a very exothermic reaction which is normally carried out on a commercial scale in continuous stirred or back-mixed reactors. In such reactors only a small fraction of CHP is unreacted at any given time and the reaction medium consists essentially of the products of decomposition of CHP, i.e., phenol and acetone, plus any solvent (e.g., cumene and/or recycle acetone) and other materials added with CHP to the reactor. During cumene oxidation small amounts of dimethylphenylcarbinol (DMPC) and acetophenone are also formed. In the presence of acid catalyst, DMPC dehydrates to alpha-methylstyrene (AMS), a useful by-product. Very high yields of AMS can be obtained from pure DMPC, e.g., 98% yield upon dehydration over acidic silica at 300° C. In the presence of phenol, however, and more specifically in a phenol/acetone/cumene mixture which is a solvent in the decomposition of CHP/DMPC mixtures, the ultimate AMS yield is normally about 50-60 mol % of the DMPC. Main by-products are AMS dimers and cumylphenol which have no commercial value. Formation of cumylphenol also reduces the phenol yield.
Reaction SMILES: [CH3:1][OH:2].[Na].[CH:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:5]=1.[F:21][C:22]([F:38])([F:37])[C:23]1[CH:24]=[C:25]([CH:34]=[CH:35][CH:36]=1)[O:26][C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1>C(Cl)Cl.N1C=CC=CC=1>[F:21][C:22]([F:38])([F:37])[C:23]1[CH:24]=[C:25]([CH:34]=[CH:35][CH:36]=1)[O:26][C:27]1[CH:32]=[CH:31][C:30]([O:20][C:17]2[CH:18]=[CH:19][C:14]([S:11]([C:6]3[CH:5]=[CH:4][C:9]([O:10][C:27]4[CH:28]=[CH:29][C:1]([O:2][C:25]5[CH:34]=[CH:35][CH:36]=[C:23]([C:22]([F:21])([F:37])[F:38])[CH:24]=5)=[CH:31][CH:32]=4)=[CH:8][CH:7]=3)(=[O:13])=[O:12])=[CH:15][CH:16]=2)=[CH:29][CH:28]=1
Reactant: FC(F)(F)c1cccc(Oc2ccc(Br)cc2)c1
Reactant: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CO
Agent: [Na]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Oc2ccc(Oc3cccc(C(F)(F)F)c3)cc2)cc1)c1ccc(Oc2ccc(Oc3cccc(C(F)(F)F)c3)cc2)cc1

Procedure:
All apparatus is rigorously dried and flushed with nitrogen before use. The reaction is performed in a 100 mL 3-necked flask equipped with a mechanical stirrer, a reflux condenser topped with a nitrogen inlet tube, and a stopper. The flask is charged with methanol (20 mL) and sodium (0.735 g, 31.8 mmol). After all of the sodium has been consumed the methanol is distilled from the flask. The last traces of methanol are removed by azeotropic distillation with benzene. Pyridine (40 mL) and 4,4'-dihydroxydiphenyl sulfone (4 g, 15.9 mmol) are added, followed by 4-(3-trifluoromethylphenoxy)bromo-benzene (10.08 g, 31.8 mmol) and cuprous chloride (3.15 g, 31.8 mol), and the mixture is left to stir at reflux for 48 hours. The reaction mixture is analyzed by TLC, which shows three spots (Rf =0.00, 0.38, 0.95; CH2Cl2), with the upper spot being starting material and the middle spot being product. The mixture is cooled and filtered with the aid of ether (200 mL). The ethereal phase is washed successively with water (250 mL), 5% HCl (2×250 mL), saturated NaHCO3 (200 mL) and brine (200 mL), then is dried with MgSO4, and the solvents are removed on the rotary evaporator to leave 10.98 g of a yellow oil. Purification is accomplished by column chromatography on flash grade silica gel using a 1:1 mixture of hexane/CH2Cl2 as eluent. The product is obtained as a thick viscous oil (2.15 g, 18.7%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][C:7]([OH:9])=[O:8].C(OCCCCOC(=O)C)(=O)C.CC(CC(O)=O)=O.C(OC(OC(=O)C)CCC)(=O)C>O>[O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([OH:9])(=[O:8])[CH3:6]
Reactant: O=C(O)CC1CCCO1
Agent: CC(=O)CC(=O)O
Agent: CC(=O)OCCCCOC(C)=O
Agent: CCCC(OC(C)=O)OC(C)=O
Solvent: O
Product: C1CCOC1
Product: CC(=O)O
Yield: 89 %
Yield: 47 %

Procedure:
The tube reactor is charged with 88.1 grams of Linde 13X zeolite (150 pellets, pretreated at 200° C. with a tetrahydrofuran-acetic acid vapor mixture) and maintained at 190°-230° C. while 50.0 grams of 1,4-butanediol diacetate and 60 ml. of water are copassed, as in Examples 1-3, over a 1 hour period. The effluent is recycled three times until the diacetate is essentially converted. Quantitative glpc analysis of the final effluent shows the presence of 0.4 grams of butanediol diacetate (1% recovery), 9.5 grams of tetrahydrofuran (47% yield) and 30.4 grams of acetic acid (89% yield). A considerable amount of low boiling material is produced using this method.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:5][C:6](=[O:9])[C:7]=1[CH3:8])=O.[CH2:10]([CH2:12][NH2:13])[OH:11]>>[OH:11][CH2:10][CH2:12][N:13]1[C:6](=[O:9])[C:7]([CH3:8])=[C:2]([CH3:1])[C:3]1=[O:5]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: NCCO
Product: CC1=C(C)C(=O)N(CCO)C1=O
Temperature: 180 °C
Yield: 88.7 %

Procedure:
126 g (1 mol) of 2,3-dimethylmaleic anhydride and 61 g (1 mol) of ethanolamine are reacted by heating at 180° C. for 1 hour to give 150 g of N-(2-hydroxyethyl)-2,3-dimethylmaleimide (boiling point 110° C. under 13.33 Pa; yield 89% of theory). After drying, the N-(2-hydroxyethyl)-2,3-dimethylmaleimide is mixed with 181.5 g (1.78 mols) of acetic anhydride and 3 drops of concentrated sulfuric acid and the mixture is refluxed for one hour in an oil bath heated to 160° C. The acetic acid formed and the acetic anhydride are then distilled off in vacuo. Fractionation of the residue under a high vacuum yields 179 g of N-(2-acetoxyethyl)-2,3-dimethylmaleimide (boiling point 104° C./6.66 Pa; yield 95% of theory). The N-(2-acetoxyethyl)-2,3-dimethylmaleimide is introduced dropwise, under nitrogen, in the course of 75 minutes into a glass column which is filled with Raschig rings and is heated to 550° C. The pyrolysis products are collected at the lower end of the glass column in a cooled receiver. The yellow oil obtained is taken up in diethyl ether and treated with aqueous sodium bicarbonate solution in order to remove the acetic acid. After drying the organic phase over sodium sulfate, the solvent is removed in vacuo and the product is distilled under a high vacuum. In addition to 39.3 g of unconverted starting material, 84.7 g of (N-vinyl)-2,3-dimethylmaleimide are obtained in the form of a yellowish oil; boiling point 58°-60° C./53.33 Pa; yield: 85% of theory, based on converted starting material.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([OH:16])[CH:5]([N:11]1[CH2:14][CH2:13][C:12]1=[O:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[N-:17]=[N+:18]=[N-:19].[Na+]>CS(C)=O.ClCCl>[N:17]([CH2:2][CH2:3][CH:4]([OH:16])[CH:5]([N:11]1[CH2:14][CH2:13][C:12]1=[O:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:18]=[N-:19]
Reactant: CCOC(=O)C(C(O)CCCl)N1CCC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(C(O)CCN=[N+]=[N-])N1CCC1=O
Yield: 73 %

Procedure:
A solution of ethyl 5-chloro-3-hydroxy-2-(2-oxoazetidin-1-yl)valerate (3.45 g, 13.8 mmol) and sodium azide (1.1O g, 17 mmol) in dry dimethylsulphoxide (20 ml) was stirred between 55° and 65° C. for 5 hours. The reaction mixture was diluted with dichloromethane and the organic layer was washed three times with water before being dried (MgSO4) and evaporated. The residue was chromatographed on silica gel (Merck Art. 9385), eluting with ethyl acetate/hexane (2:1), to give ethyl 5-azido-3-hydroxy-2-(2-oxoazetidin-1-yl)valerate as a pale yellow oil in 73% yield (2.59 g). Bulb to bulb distillation at 0.2 mmHg between 185°-195° C. further purified the product to a colourless oil. νmax (KBr) 3405, 2102 and 1733 cm-1 ; δH (CHCl3, 250 MHz) 1.31 (3H,t,J 7 Hz), 1.81 (1H,m), 1.87 (1H,m), 3.03 (2H,t,J 3 Hz), 3.40 (2H,m), 3.53 (2H,m), 4.00 (1H,d,J 3.5 Hz), 4.25 (3H,m) and 4.53 (1H,d,J 4.5 Hz, exchangeable). (Found: C, 46.93; H, 6.46; N, 21.83%. C10H16N3O4 requires C, 46.87; H, 6.29; N, 21.86%).
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][C:5](=[O:13])[C:4]=2[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.CCOCC>C1COCC1>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:11])(=[O:12])[NH:7][CH2:6][C:5]([C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=3)([OH:13])[C:4]=2[CH:3]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=C1CNS(=O)(=O)c2sc(Cl)cc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=S1(=O)NCC(O)(c2ccc(Cl)cc2)c2cc(Cl)sc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
6-chloro-2,3-dihydro-4H-thieno[3,2-e][1,2]thiazin-4-one 1,1-dioxide (0.820 g, 3.45 mmol) was dissolved in THF (31 mL) and 1 M of 4-Chlorophenylmagnesium bromide in ether (8.2 mL, 8.2 mmol) was added. The solution was stirred at room temperature overnight. At that time, TLC indicated good conversion. Reaction was quenched by addition of satd NaHCO3 (20 mL) and extracted with EA (3×50 mL). The combined organic extracts were washed with brine (20 mL), dried with MgSO4, filtered and evaporated. The residue was purified using column chromatography on silica gel (80 g Analogix column, gradient 10% EA in hexane to 40% EA in hexane over 20 minutes) to give the product (0.34 g, 26%). LCMS: (FA) ES-348, 350, 352. 1H NMR (400 MHz, d6-DMSO) δ: 8.41 (dd, J=8.75, 5.76 Hz, 1H), 7.49-7.42 (m, 2H), 7.33-7.25 (m, 2H), 6.74 (s, 1H), 6.57 (s, 1H), 3.70-3.60 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:29])=[CH:26][CH:25]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cc1
Yield: 34.9 %

Procedure:
1.41 g (0.00733 mol) of 1-benzyl-4-hydroxypiperidine and 1.8 ml (0.0129 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.79 ml (0.00586 mol) of 4-methoxy-benzoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:3→1:2). 0.666 g (35%) of 1-benzyl-piperidin-4-yl 4-methoxy-benzoate was obtained as yellowish crystals; m.p. 55°-56°.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH2:10][C:9](=[O:11])[C:8]([CH3:12])([CH3:13])[CH2:7][O:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CC(=O)C(C)(C)COc1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)(COc1ccc(Cl)cc1)C(=O)CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
36 g (0.159 mole) of 1-(4-chlorophenoxy)-2,2-dimethyl-butan-3-one (Example 2) were dissolved in 300 ml of chloroform, and 25.5 g (0.159 mole) of bromine were added dropwise at 20° C. in a manner such that continuous decolorization occurred. After the addition, the mixture was stirred at room temperature for 30 minutes and was then concentrated by distilling off the solvent in vacuo, 48.5 g (quantitative conversion) of crude 1-bromo-4-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one were obtained as an oil. ##STR41##
Reaction SMILES: Cl.[CH:2]1[C:13]2[N:12]([CH2:14]CCN3CCC(C(O)=O)CC3)C3C=CC=CC=3OC[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C[O-:31].[Na+].[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH2:41]Cl>C(O)C>[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH2:41][O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:13]=1[NH:12][CH:14]=[O:31]
Reactant: ClCOc1ccccc1Br
Reactant: C[O-]
Reactant: O=C(O)C1CCN(CCCN2c3ccccc3OCOc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=CNc1ccccc1OCOc1ccccc1Br
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
1-(3-(12H-Dibenzo[d,g][1,3,6]dioxazocin-12-yl)-1-propyl)-4-piperidinecarboxylic acid hydrochloride ##STR13## N-(2-Hydroxyphenyl)formamide (16.0 g, 130 mmol) was dissolved in 99.9% ethanol (65 ml). Sodium methoxide 7.0 g, 130 mmol) was suspended in 99.9% ethanol (70 ml) and added dropwise over 30 minutes. The resulting mixture was stirred for 30 minutes. 1-Bromo-2-chloromethoxybenzene (26.1 g, 118 mmol, synthesis described in J. Heterocycl. Chem., 11, 1974, 331-337) was added dropwise over 15 minutes. The reaction mixture was stirred for 2.5 h at room temperature, heated at reflux temperature for 2 h, and stirred at room temperature overnight. The mixture was filtered and evaporated. The residue was dissolved in toluene (500 ml) and washed with a saturated sodium carbonate solution (2×200 ml). The organic phase was dried (MgSO4) and evaporated. The residue was suspended in ethanol (40 ml), filtered and washed with ethanol (3×10 ml). After drying, this afforded the product, N-(2-(2-bromophenoxymethoxy)phenyl)formamide (14.1 g, 37%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[NH:5][C:4](=[O:16])[C:3]=1[NH:17][CH3:18].[H-].[Na+].[C:21]([O:24][C@H:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29]Cl)(=[O:23])[CH3:22]>CS(C)=O>[C:21]([O:24][C@H:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29][N:5]1[C:4](=[O:16])[C:3]([NH:17][CH3:18])=[C:2]([NH2:1])[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]1=[O:15])(=[O:23])[CH3:22]
Reactant: CC(=O)O[C@H](C)CCCCCl
Reactant: CNc1c(N)n(Cc2ccccc2)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNc1c(N)n(Cc2ccccc2)c(=O)n(CCCC[C@@H](C)OC(C)=O)c1=O
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
6-Amino-1-benzyl-5-methylaminouracil (11 g, 43 mmol) was added to a suspension of sodium hydride (1.032 mg, 43 mmol) in anhydrous dimethylsulfoxide (75 ml). After stirring for 30 minutes, (R)-5-acetoxy-1-chlorohexane (7.675 g, 43 mmol) was added. The mixture was heated at 70-80° C. for 12 hours. After cooling to room temperature, the reaction was quenched by the addition of water (150 ml) and extracted with ethyl acetate (3×125 ml). The combined extracts were washed with water (2×50 25 ml), with saturated aqueous sodium chloride solution (50 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to provide (R)-3-(5-acetoxyhexyl)-6-amino-1-benzyl-5-methylaminouracil (7.89 g).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[OH:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.[ClH:17]>CO>[ClH:17].[OH:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:2][CH2:1][OH:3])[CH2:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: Oc1cccc(C2CCCNC2)c1
Reactant: C1CO1
Agent: Cl
Solvent: CO
Product: OCCN1CCCC(c2cccc(O)c2)C1
Temperature: -30 °C
Yield: 41 %

Procedure:
Ethylenoxide (0.36 ml, 7.0 mmol) was added to a stirred solution of 3-(3-hydroxyphenyl)piperidine (1.0 g, 5.6 mmol) in methanol (150 ml), maintaining the temperature at -30° C., whereafter the reaction mixture was allowed to reach room temperature. (The reaction was followed by TLC). More ethylenoxide (0.5 ml, 9.8 mmol) was added in portions until the reaction was complete (two weeks). An excess of ethereal hydrogen chloride was added and the solvent was evaporated. The oily residue was passed through a silica column with 10% methanol in chloroform. After evaporation the hydrochloride was recrystallized from ethanol/ether to yield 0.6 g (41%) of 2-[3-(3-hydroxyphenyl)-piperidino]ethanol hydrochloride, m.p. 116.5°-120° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[C:12]([OH:14])=O.CCN(CC)CC.ClC(OCC(C)C)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CC(C)=O.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[C:12]([N:30]=[N+:31]=[N-:32])=[O:14]
Reactant: O=C(O)/C=C/c1cc2ccccc2s1
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NC(=O)/C=C/c1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring mixture of (2E)-3-(1-benzothien-2-yl)acrylic acid and Et3N (1.3 equiv) in acetone (0.22 M) at 0° C. was added isobutyl chloroformate (1.3 equiv). The mixture was stirred at 0° C. for 1 h. A solution of NaN3 (1.3 equiv) in H2O was added, the mixture was stirred at 0° C. for 0.5 h and then at room temperature for 0.5 h. The mixture was poured into H2O, stirred and filtered to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[NH:27])[NH:25][OH:26])=[CH:20][CH:19]=2)=[O:16])(=[O:10])=[O:9])[CH:7]=1.N1C=CC=CC=1.C(C(CCCC)[CH2:42][O:43]C(Cl)=O)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[NH:27][C:42](=[O:43])[O:26][N:25]=3)=[CH:22][CH:23]=2)=[O:16])(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Nc1cccc(C(=O)Nc2ccc(C(=N)NO)cc2)c1
Reactant: CCCCC(CC)COC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cl)cc1S(=O)(=O)Nc1cccc(C(=O)Nc2ccc(-c3noc(=O)[nH]3)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A solution of 3-(5-chloro-2-methoxy-benzenesulfonylamino)-N-[4-(N-hydroxycarbamimidoyl)-phenyl]-benzamide (145 mg, 0.30 mmol) in dimethylformamide (2.0 ml) was treated with pyridine (26 mg, 1.08 equiv.) and cooled to 0° C. Chloroformic acid 2-ethylhexyl ester (59 mg, 0.30 mmol, 1 equiv.) in DMF (0.1 ml) was added dropwise. The mixture was stirred at 0° C. for 30 min, then diluted with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated. The residue was suspended in xylene and the mixture was stirred at 100° C. for 1 h and then at 145° C. for 1 h. After cooling to room temperature, the precipitated solid was filtered, washing with xylene, and dried under high vacuum to yield the title compound (115 mg, 75%) as a white solid, MS (ISP): m/e=499.0 (M−H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[CH:8]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:10]2[CH:11]=[CH:12][N:13]([CH:16]([CH2:18][CH3:19])[CH3:17])[C:14]=2[CH:15]=1.NCC1[C:27](=[O:36])NC(C)=CC=1CCC.[OH-].[Na+]>CN(C=O)C.O>[Br:6][C:7]1[CH:8]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:10]2[C:11]([CH:27]=[O:36])=[CH:12][N:13]([CH:16]([CH2:18][CH3:19])[CH3:17])[C:14]=2[CH:15]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: CCC(C)n1ccc2c(C(=O)OC)cc(Br)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(C)n1cc(C=O)c2c(C(=O)OC)cc(Br)cc21
Reaction time: 0.5 h

Procedure:
POCl3 (8.3 g, 54.3 mmol) was added at 0° C. to anhydrous DMF (230 mL) in a round bottom flask and stirred for 30 min. Then a solution of methyl 6-bromo-1-sec-butyl-1H-indole-4-carboxylate, 5 (14 g, 45.3 mmol) in DMF (60 mL) was added to the reaction mixture at 0° C. and stirred at room temperature for 2.5 h. The reaction mixture was diluted with cold water, adjusted pH˜8 using with 2N NaOH solution and extracted with ethyl acetate (4×200 mL). The combined organic layer was washed with cold water (2×100 mL), brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford desired product methyl 6-bromo-1-sec-butyl-3-formyl-1H-indole-4-carboxylate, 6 (15.2 g, 99%) as pale yellow solid. This was used as such in the next step without purification. 1H NMR (CDCl3, 400 MHz) δ (0.831-0.859 (m, 3H), 1.515-1.574 (d, J=6.8 Hz, 3H), 1.729-1.972 (m, 2H) 3.997 (s, 3H), 4.394-4.445 (m, 1H), 7.756 (d, J=1.2 Hz, 1H), 7.958 (d, J=2 Hz, 1H), 8.079 (s, 1H), 10.452 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:18][CH:19]([NH2:21])[CH3:20]>>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([NH:21][CH:19]([CH3:20])[CH3:18])=[O:17])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)N
Reactant: O=C(O)C1CCc2c(sc3ncnc(Cl)c23)C1
Product: CC(C)NC(=O)C1CCc2c(sc3ncnc(Cl)c23)C1

Procedure:
13.18 g (49.05 mmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using propan-2-amine to give after working up and purification 11.39 g (71%) of the title compound.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C1COCC1>[Pd].CO>[C:22]([O:21][C:19](=[O:20])[NH:18][CH2:17][CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCNCC1
Reaction time: 48 h

Procedure:
A mixture of 28 g of 4-(tert-butoxycarbonylamino-methyl)-piperidine-1-carboxylic acid benzyl ester, 1 g of 10% palladium on carbon, 100 mL of THF and 200 mL of methanol was stirred under an atmosphere of hydrogen for 2 days. The mixture was filtered concentrated under reduced pressure. Drying under reduced pressure gave a white solid:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](Br)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.S(Cl)([Cl:23])=O.[OH-].[Na+]>>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([Cl:23])[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(F)c(Br)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(F)c(Cl)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 1-cyclopropyl-6-fluoro-7-bromo-5-methyl-1,4- dihydro-4-oxoquinoline-3-carboxylic acid (0.2 g) is added thionyl chloride (2 ml) and the mixture is refluxed for 1 hour. After cooling, the reaction mixture is poured into ice-water and made alkaline with 10% aqueous sodium hydroxide solution. After stirring for 30 minutes, the resultant is extracted with dichloromethane. The aqueous layer is made acidic with 10% hydrochloric acid and then extracted with dichloroethane. The solvent is concentrated and the residue is recrystallized from acetic acid to give 1-cyclopropyl-6-fluoro-7-chloro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (80 mg), as white crystals, m.p. 258°-260° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Nc1cccc(Br)c1
Agent: [Na+]
Product: Cn1c(CC(=O)Nc2cccc(Br)c2)nc(N2CCOCC2)cc1=O
Yield: 17.2 %

Procedure:
The product is prepared according to the procedure described in Example 68, using 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 257 mg of 3-bromoaniline. 51 mg of N-(3-bromophenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following: