Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:41])[NH:6]2.Cl>O1CCOCC1>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:41])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCNCC1
Yield: 96 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 11, tert-butyl 4-[3-(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-yloxy)propyl]piperazine-1-carboxylate was reacted with hydrogen chloride in dioxane. The crude product was absorbed onto an Isolute SCX column, washing with methanol and eluting with 7N ammonia in methanol to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (96%) as a pale orange foam.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:77][CH:78]1[CH2:83][CH2:82][N:81]([CH2:84][CH3:85])[CH2:80][CH2:79]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:77][CH:78]5[CH2:83][CH2:82][N:81]([CH2:84][CH3:85])[CH2:80][CH2:79]5)=[O:27])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CCN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)NC2CCN(CC)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
To a mixture of 0.0644 g (0.141 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) and 4 mL of dimethylformamide was added 0.0309 g (0.229 mmole) of 1-hydroxybenzotriazole, 0.0825 g (0.229 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1113 g (0.862 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0273 g (0.211 mmole) of 4-amino-1-ethylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0596 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-N-(1-ethyl-piperidin-4-yl)-benzamide (I-216) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:29])=[C:4]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][C:14](=[O:16])[CH3:15])=[O:8].[C:30]([O:33][CH:34]([CH:38]([O:44][C:45](=[O:47])[CH3:46])[CH2:39][O:40][C:41](=[O:43])[CH3:42])[C:35](Br)=[O:36])(=[O:32])[CH3:31].C([O-])(O)=O.[Na+]>CN(C)C(=O)C>[C:30]([O:33][CH:34]([CH:38]([O:44][C:45](=[O:47])[CH3:46])[CH2:39][O:40][C:41](=[O:43])[CH3:42])[C:35]([NH:1][C:2]1[C:3]([I:29])=[C:4]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][C:14](=[O:16])[CH3:15])=[O:8])=[O:36])(=[O:32])[CH3:31]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OCc1c(I)c(NC(=O)C(OC(C)=O)C(COC(C)=O)OC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.7 %

Procedure:
5-Amino-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide (30.0 g, 40.3 mmol) was dissolved in dry N,N-dimethylacetamide (50 ml) and added dropwise to 2,3,4-triacetoxybutanoyl bromide (26.0 g, 0.93 mol) at 0° C. The mixture was stirred at ambient temperature for 5 h, and then added slowly to an aqueous solution of NaHCO3 (5%, 500 ml). A semi-crystalline precipitate was formed, filtered off and dissolved in ethyl acetate (200 ml). The organic phase was washed three times with diluted HCl (5%, 80 ml) and then twice with water (80 ml). After drying (Na2SO4) the solvent was evaporated to a semisolid residue. The residue was purified on a column of silica using methylene chloride/acetonitrile (4:1-3:2) as the eluent. The solvent was evaporated and the residue was further purified by preparative HPLC to give 13.8 g (35%) of the product.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:12])[CH:5]=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[N:7]=1.C(=O)([O-])[O-:14].[K+].[K+].C1COCC1>O>[OH:14][CH2:2][C:3]1[N:4]([CH3:12])[CH:5]=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[N:7]=1
Reactant: Cn1cc(S(N)(=O)=O)nc1CCl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(S(N)(=O)=O)nc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 2-(chloromethyl)-1-methyl-1H-imidazole-4-sulfonamide (300 mg; 1.4 mmol; 1 eq) in water (5 mL) is added potassium carbonate (300 mg; 2.2 mmol; 1.5 eq) in portions and the reaction mixture is stirred at room temperature for 2 h. THF (5 mL) is added and reaction mixture is heated up to 60° C. for 3 h. The reaction mixture is cooled down and the THF is removed under reduced pressure. The resulting suspension is freeze dried to give 320 mg (contaminated with potassium salts) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.58 (s, 1H), 7.10-6.40 (m, 2H), 4.18 (s, 2H), 3.68 (s, 3H). HPLC (max plot) 68%; Rt 0.96 min. LC/MS (ES+) 191.8; (ES−) 189.9.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][N:25]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCNC2)c2cnccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCN(S(C)(=O)=O)C2)c2cnccc12
Reaction time: 2 h

Procedure:
To a solution of 1-({5-chloro-1-[(3R)-(pyrrolidin-3-yl)]-1H-benzo[d]imidazol-2-yl}methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (200 mg, 0.46 mmol) and Et3N (0.2 mL) in 8 mL of DCM was added 80 mg of methanesulfonyl chloride. The mixture was stirred for 2 hours. The mixture was then purified by preparative-HPLC to give the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)=[N:2]1.ClCCl.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:17](=[O:18])[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8][CH:7]=2)=[N:2]1
Reactant: Nc1ccc(-c2ccon2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2ccon2)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
4-Isoxazol-3-ylphenylamine (Intermediate 5, 4 g, 24.69 mmol) was added to dichloromethane (20 ml) followed by pyridine (4.6 ml). The solution was cooled to 0° C. and benzyl chloroformate (5.27 ml, 37.02 mmol) was added drop wise. The solution was allowed to stir for 2 hours at room temperature and then concentrated under vacuum. The residue was added to 30 ml of 1:1 hexane:EtOAc mixture. The crystals were collected by filtration to yield the product (2.26 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:17]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:28]2[CH2:29][CH2:30][N:25]([C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:24])[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: NCc1ccccc1Oc1ccc(Cl)cc1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(c1ccccc1)N1CCC(NCc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and N-benzoyl-4-piperidone (87 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then, it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCN to DCM/MeOH 95:5 gradient as eluent gave {4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}phenylmethanone (152 mg, 84%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.19 min, m/z 423.35 (36), 421.34 (M++H, 100). HPLC tr=4.04 min (98.05%) 1H NMR (270 MHz, CDCl3) δ 1.24-1.44 (3H, m, CH2+NH), 1.76 (1H, m, ½CH2), 1.91 (1H, m, ½CH2), 2.72 (1H, hept, CHNH), 2.96 (1H, m, ½CH2), 3.80 (2H, m, CH2NH), 4.46 (1H, m, ½CH2), 6.84 (2H, AA′BB′, ArH), 6.86 (1H, m, ArH), 7.12 (1H, td, ArH), 7.23 (1H, m, ArH), 7.24 (2H, AA′BB′, ArH) and 7.33-7.41 (6H, m, ArH). 13C NMR (270 MHz, CDCl3) δ 32.26, 33.09, 40.78, 45.67, 46.29 (CH2), 53.81 (CH), 118.95, 119.63, 124.57, 126.86, 127.97, 128.54, 128.75, 129.58, 129.85, 130.58, 131.78, 136.33, 154.35, 156.38 (ArC), and 170.00 (C═O).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)(=[O:12])[CH3:11].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[C:10]([O:13][CH2:14][CH2:15][CH2:16][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)(=[O:12])[CH3:11]
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(=O)OCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OCCCn1cnc2ccccc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
In a nitrogen atmosphere, a mixture of 118 g of benzimidazole, 181 g of 3-bromopropyl acetate, 111 g of triethylamine, 2 g of sodium iodide, and 500 g of N,N-dimethylformamide was heated and stirred at 80° C. for 16 hours. The reaction mixture was subjected to conventional aqueous work-up and then purified by column chromatography, obtaining 3-(1H-benzimidazol-1-yl)propyl acetate (yield 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14]/[CH:15]=[C:16](\[CH3:22])/[CH2:17][CH2:18][CH2:19][CH2:20][OH:21].[CH3:23][C:24](OC(C)=O)=[O:25]>N1C=CC=CC=1>[C:24]([O:21][CH2:20][CH2:19][CH2:18][CH2:17]/[C:16](/[CH3:22])=[CH:15]/[CH2:14][C:4]1[C:5]([CH3:13])=[C:6]([O:11][CH3:12])[C:7]([CH3:10])=[C:8]([CH3:9])[C:3]=1[O:2][CH3:1])(=[O:25])[CH3:23]
Reactant: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCCO)c1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCCOC(C)=O)c1C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-en-1-ol in pyridine (2 mL) was treated with Ac2O (2 mL) at 0° C. and let stir overnight. The reaction was quenched with H2O (10 mL) followed by addition of EtOAc (10 mL) and separated. The aqueous phase was extracted with EtOAc (3×10 mL) and the combined organics washed with brine (15 mL), dried over anhydrous Na2SO4 and concentrated to a yellow oil. Flash chromatography on silica yielded 77.9 mg (62.3%) of (E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enyl acetate as a clear oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([CH:18]2[N:22](NC(C)(C)C)[CH2:21][CH:20](CO)[O:19]2)C=CC=CC=1>N1C=CC=CC=1>[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)([O-:19])(=[O:9])=[O:8].[OH:8][CH2:12][CH:18]1[NH:22][CH2:21][CH2:20][O:19]1
Reactant: CC(C)(C)NN1CC(CO)OC1c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: OCC1NCCO1

Procedure:
In an operation carried out in a manner similar to that described in Example 1, p-toluene-sulfonyl chloride is added portionwise to a cooled solution of 2-phenyl-3-(t-butylamino)-5-(hydroxymethyl)oxazolidine in pyridine while the temperature is maintained below 25° C. to obtain a tosylate of the 2-hydroxymethyloxazolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:15])[CH2:8]2.Br[CH2:17][C:18]([O:20]CC)=[O:19]>C1(C)C=CC=CC=1.C1C=CC=CC=1.[Zn]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([OH:15])([CH2:17][C:18]([OH:20])=[O:19])[CH2:8]2
Reactant: COc1ccc(OC)c2c1CCC(=O)C2
Reactant: CCOC(=O)CBr
Agent: [Zn]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c2c1CCC(O)(CC(=O)O)C2

Procedure:
A fifth of a solution of 20.6 g of 3,4-dihydro-5,8-dimethoxy-2(1H)-naphthalenone and 18.4 g of ethyl bromoacetate in 100 ml of toluene/benzene (1:1) was added to 7.4 g of activated zinc dust. An exothermic reaction set in after heating to reflux for a few minutes. The remainder of the solution was then added dropwise within 10 minutes. The reaction mixture was then heated to reflux for 11/2 hours, cooled and partitioned between 300 ml of benzene and 300 ml of 3N aqueous sulfuric acid. The organic phase was washed with water and saturated aqueous sodium bicarbonate solution and evaporated. The residue was dissolved in 200 ml of methanol, treated with a solution of 10 g of sodium hydroxide in 100 ml of water and the mixture was heated to reflux for 3 hours. The solution was concentrated to half of the volume, treated with 500 ml of water and the neutral constituents were extracted with 500 ml of chloroform. The aqueous phase was made acid with sulfuric acid and the product was extracted in 900 ml of ether. The extract was dried over magnesium sulfate and evaporated. Recrystallization of the residue yielded 5,8-dimethoxy-1,2,3,4-tetrahydro-2-hydroxy-2-naphthaleneacetic acid, m.p. 112°-114°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:25])[C:16]1[C:17](=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=1)[NH2:18])[CH3:13].[ClH:26]>N1C=CC=CC=1.C(OCC)C>[CH2:12]([O:14][C:15](=[O:25])[C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:17]=1[N:18]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:26])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH3:13]
Reactant: Cl
Reactant: CCOC(=O)c1cc(Cl)cc(Cl)c1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Cl)cc(Cl)c1N(S(=O)(=O)c1ccc(Cl)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 28 h

Procedure:
138.0 g of 4-chlorobenzenesulfonic acid chloride are added in portions, at room temperature, to a solution of 50.0 g of 3,5-dichloroanthranilic acid ethyl ester in 210 ml of dry pyridine. The reaction mixture is heated to 80°-90° C. and stirred for 28 hours at that temperature to complete the reaction. After cooling, the reaction mixture is poured onto ice/water and acidified with 2N hydrochloric acid. The sticky, oily precipitate is dissolved in diethyl ether, and the aqueous phase is removed. The organic phase is washed with water and saturated sodium chloride solution. After drying over magnesium sulfate, the ether is evaporated off and the crystals remaining are stirred in a mixture of diethyl ether/hexane 4:1. The crystals, which are filtered off, weigh 87.3 g after drying and correspond to the title compound (m.p. 148°-150° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:18]([OH:20])=[O:19])=[C:11]([CH2:13][O:14][CH2:15][O:16][CH3:17])[N:12]=2)=[CH:4][CH:3]=1.[CH3:21][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:18]([O:20][CH3:21])=[O:19])=[C:11]([CH2:13][O:14][CH2:15][O:16][CH3:17])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COCOCc1nc(-c2ccc(Cl)cc2)oc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: COCOCc1nc(-c2ccc(Cl)cc2)oc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
138 mg (0.52 mmol) of the compound from Example 42A are dissolved in 3 ml toluene and 2.5 ml of methanol. 0.4 ml (0.79 mmol) of a 2 M solution of trimethylsilyl-diazomethane in hexane is then added dropwise. The mixture is stirred at RT for 10 min and the solvent is then removed on a rotary evaporator. The residue is used without further purification in the subsequent reaction.
Reaction SMILES: OP([O-])([O-])=O.[K+:6].[K+].OC(CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=O.[CH3:24][C:25]1([CH3:46])[S:29][C@@H:28]2[C@H:30]([NH:33][C:34]([CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[O:35])[C:31](=[O:32])[N:27]2[C@H:26]1[C:43]([OH:45])=[O:44]>>[CH3:24][C:25]1([CH3:46])[S:29][C@@H:28]2[C@H:30]([NH:33][C:34]([CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[O:35])[C:31](=[O:32])[N:27]2[C@H:26]1[C:43]([O-:45])=[O:44].[K+:6]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: O=P([O-])([O-])O
Agent: [K+]
Product: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Temperature: 30 °C
Reaction time: 0.02 h

Procedure:
Culture treated as under A is incubated for about 72 seconds at 30° C. in the shaking machine until it attains a cell titre of >109 per ml of culture solution. 0.1 ml of this cell suspension is transferred into 10 ml of the following nutrient solution (nutrient solution B): 0.05% NaH2PO4, 0.20% K2HPO4, 0.05% MgSO4.7H2O, 0.02% CaCl2.2H2O, 0.005% MnSO4.4H2O, 0.005% (Fe)2SO4.7H2O, 0.10% (NH4)SO4, 0.0001% biotine, 0.10% Tween 80 and 0.10% BNC. After shaking for 18 hours at 30° C. diluted with fresh, preheated nutrient solution of the same composition to about 106 cells per ml, 1000 IU penicillin G are added and incubation for a further 7 hours is carried out. The antibioticum is then removed by centrifuging of the cells with washing with sterile, physiologic sodium chloride solution and the cells further incubated for 3 days in the above-mentioned medium with 0.2% sitosterol instead of BNC. The penicillin treatment is repeated once more and the cell suspension finally plated out on the same nutrient medium A plus 1.6% agar. After the propagation of the cells to visible colonies, the cells are transfered with the aid of the "replica stamp technique" on nutrient medium B plus 1.6% agar and those colonies are selected and used as strain cultures which are not able to continue to grow, or scarecly able, on this medium.
Reaction SMILES: [OH2:1].[CH2:2]([SH:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].S(=O)(=O)(O)O.[CH:20](O)([CH3:22])[CH3:21]>>[CH2:5]([CH2:4][CH2:3][C:2]([OH:1])=[S:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:21][CH2:20][CH3:22]
Reactant: CCCCCCCCCCCCS
Reactant: O
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCCCC(O)=S
Temperature: 60 °C
Yield: 98.2 %

Procedure:
The same basic ingredients and quantities thereof were reacted as specified in Example 1, except the initial reaction composition included 75 ml. of isopropanol and 50 ml. of water. The resulting clear solution was cooled to 60° C., and the 1-dodecylmercaptan or laurylmercaptan was added during a 30-minute time period. No temperature change was noted, the composition was heated to reflux, and 25 ml. of water were added. Adding 25 ml. of isopropyl alcohol resulted in a clear solution, which was refluxed for 3 hours, moderate foaming being observed. After cooling, 58.3 grams of 50% aqueous sulfuric acid were added, and the composition was poured into a separatory funnel and washed with three 100 milliliter aliquots of hot water with sodium sulfate. Vacuum stripping yielded 134.5 grams of 3-dodecylthiopropionic acid product having a melting point of 60°-62.5° C., an acid value of 202.5 (204.4 theoretical), a laurylmercaptan percentage of 0.02%, and a yield of 98.2% by GLC.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([CH3:18])=[C:15]([CH3:17])[S:16][C:10]=3[NH:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([CH3:18])=[C:15]([CH3:17])[S:16][C:10]=3[N:9]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:8]2=[O:19])=[CH:20][CH:21]=1
Reactant: Cc1sc2[nH]c(=O)n(Cc3ccc(Cl)cc3)c(=O)c2c1C
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)cc2)c(=O)c2c(C)c(C)sc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 92 %

Procedure:
A 0.6 g quantity of 3-(4-chlorobenzyl)-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (Compound III-1) was dissolved in 20 ml of anhydrous N,N-dimethylformamide. To the solution were added at room temperature 0.1 g of 50% sodium hydride and then 0.4 g of ethyl bromoacetate. The mixture was stirred at room temperature for 17 hours, concentrated and acidified by adding diluted hydrochloric acid with ice-cooling. The crystals precipitated were collected by filtration and recrystallized from ethanol, giving 0.7 g of 3-(4-chlorobenzyl)-1-ethoxycarbonylmethyl-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione having a melting point of 151° to 152° C. in a yield of 92%.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[NH:6][C:5](=O)[CH:4]=1.P(Br)(Br)([Br:24])=O>>[Br:24][C:5]1[CH:4]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1cc(C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)[nH]1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Br)n2)cc1

Procedure:
The title compound was prepared from 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (example A.17 step 2) (15 g, 49 mmol) and phosphoryl bromide (42 g, 146 mmol) according to the general procedure Ia to d preparation of bromides. Obtained as a brown solid (18 g, quant.). MS (EI) 368.9 [(M)+] and 370.8 [(M+2)+]; mp 35-37° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.O1CCOCC1.Cl[CH2:27][CH2:28][S:29]([F:32])(=[O:31])=[O:30]>O>[F:32][S:29]([CH2:28][CH2:27][NH:4][C:3]1[CH:5]=[C:6]([NH:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][C:2]=1[CH3:1])(=[O:31])=[O:30]
Reactant: CC(=O)Nc1ccc(C)c(N)c1
Reactant: O=S(=O)(F)CCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1ccc(C)c(NCCS(=O)(=O)F)c1

Procedure:
2-Methyl-5-acetamido aniline (49.2 g, 0.3 m), triethyl amine (32.7 g, 0.3 m) and p-dioxane (350 ml) are stirred together at room temperature. 2-Chloroethane sulfonylfluoride (43.0 g, 0.3 m) is added dropwise allowing temperature to rise to 45° C. The reaction mixture is then heated at reflux for 3 hrs. When thin-layer chromatography shows reaction to be complete, the reaction is allowed to cool and then drowned into water (2000 ml). The product is collected by filtration, washed with water and melts at 154°-155° C.