Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[C:11]([CH:13]=[CH:14]C3C=CC=CC=3)[NH:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.CC[O:23]C(C)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:9]=[N:10][C:11]([C:13](=[O:23])[CH3:14])=[N:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: Clc1cccc(N2N=C(C=Cc3ccccc3)NN2)c1
Solvent: ClCCl
Product: CC(=O)c1nnn(-c2cccc(Cl)c2)n1
Yield: 79.4 %

Procedure:
The title compound of Example 10.1 (1.50 g, 5.06 mmol) was dissolved in dichloromethane (79 mL) and ozone was bubbled through the solution for a period of 15 minutes. The solution turned from orange to a darker orange colour. The reaction completeness was checked using a 10% EtOAc:hexanes TLC solvent system. Oxygen was bubbled through the solution for an additional 5 minutes to remove any excess ozone remaining. Dimethyl sulfide (5 mL) was added to the solution and the mixture was allowed to equilibrate to room temperature. The solvent was removed under vacuum and an oily brown substance remained. A 3 cm flash column was prepared containing 15 cm silica and ˜3 cm sand. The column was run using a 5% EtOAc:hexanes solvent system. The eluted fractions containing the product were collected and concentrated under low pressure. Flash column chromatography (silica, 5% EtOAc:hexanes) yielded 893 mg (79.4% yield) of the title compound.
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:43][C:44]1[CH:54]=[CH:53][CH:52]=[CH:51][C:45]=1[C:46]([NH:48][O:49][CH3:50])=[O:47].[CH3:55][N:56]1[CH:60]=[C:59]([NH:61][C:62]2[CH:67]=[C:66](I)[C:65]([C:69]([F:72])([F:71])[F:70])=[CH:64][N:63]=2)[C:58]([CH3:73])=[N:57]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OC)(C)(C)C.O1CCOCC1>[CH3:55][N:56]1[CH:60]=[C:59]([NH:61][C:62]2[CH:67]=[C:66]([NH:43][C:44]3[CH:54]=[CH:53][CH:52]=[CH:51][C:45]=3[C:46]([NH:48][O:49][CH3:50])=[O:47])[C:65]([C:69]([F:71])([F:70])[F:72])=[CH:64][N:63]=2)[C:58]([CH3:73])=[N:57]1
Reactant: Cc1nn(C)cc1Nc1cc(I)c(C(F)(F)F)cn1
Reactant: CONC(=O)c1ccccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: CONC(=O)c1ccccc1Nc1cc(Nc2cn(C)nc2C)ncc1C(F)(F)F
Temperature: 100 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.303 g, 0.52 mmol), palladium(II) acetate (0.059 g, 0.26 mmol), 2-amino-N-methoxybenzamide (1.479 g, 8.90 mmol), N-(1,3-dimethylpyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (2 g, 5.23 mmol) and cesium carbonate (3.41 g, 10.47 mmol) were weighed out in a round bottom flask. Dioxane (60 mL) was added and argon was bubbled through the mixture for 10 minutes. The suspension was stirred at 100° C. overnight. The reaction mixture was allowed to cool to room temperature with stirring, diluted with DCM and MeOH. Silica gel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel (150 g) eluting with 0 to 5% MeOH in EtOAc/DCM (1:1). The solvent was evaporated to dryness, giving. 35 mL of tBuOMe was added and the resulting solution was stirred at room temperature for 3 hours. The resulting precipitate was collected by filtration, washed with tBuOMe and dried to a constant weight to afford the title compound (1.53 g, 3.64 mmol, 69.5%) as a white solid. This solid was taken up into a minimum of acetonitrile, heated to 100° C. and more acetonitrile was added until complete solubilisation was achieved. The solution was filtered and left to cool to room temperature overnight. The resulting crystals were collected by filtration and dried to constant weight under high vacuum (7.10−2 mbar) at 50° C. for 1 hour, to give the title compound (1.2 g, 2.63 mmol, 50.2%) as a crystalline white solid.
Reaction SMILES: [CH3:1][C@:2]1([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:9][CH2:8][CH2:7][C@:4]2([O:6][CH2:5]2)[CH2:3]1.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[CH:26][C:25]=1[NH2:32]>C(O)(C)C>[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[CH:26][C:25]=1[NH:32][CH2:5][C@:4]1([OH:6])[CH2:7][CH2:8][CH2:9][C@@:2]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)([CH3:1])[CH2:3]1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CO2)C1
Reactant: COc1cc(OC)c(N)cn1
Solvent: CC(C)O
Product: COc1cc(OC)c(NC[C@]2(O)CCC[C@](C)(Cn3cnc4ccc(C#N)cc43)C2)cn1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A mixture of 1-(((3S,5S)-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.355 mmol) and 4,6-bis(methyloxy)-3-pyridinamine (110 mg, 0.711 mmol) in isopropanol (10 mL) was heated to reflux overnight. The reaction mixture was cooled to RT, and solvent was removed. The residue was redissolved in DCM and hexane was added. The solvent was removed, and the residue was purified via silica gel chromatography (ISCO, 40 g Silica, 40 mL/min, 0%-10% MeOH/CH2Cl2). Fractions with product were collected and concentrated to afford 1-(((1S,3S)-3-(((4,6-dimethoxypyridin-3-yl)amino)methyl)-3-hydroxy-1-methylcyclohexaneyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 64.6% yield). MS (m/z) 436 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][Li])[CH2:5][CH2:4][CH2:3]1.[CH3:14][O:15][C:16]1[CH:27]=[CH:26][C:19]2[N:20]=[C:21]([S:23](Cl)=[O:24])[NH:22][C:18]=2[CH:17]=1>C1C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:27]=[CH:26][C:19]2[N:20]=[C:21]([S:23]([CH2:12][C:10]3[CH:9]=[CH:8][CH:7]=[C:6]4[C:11]=3[N:2]([CH3:1])[CH2:3][CH2:4][CH2:5]4)=[O:24])[NH:22][C:18]=2[CH:17]=1
Reactant: COc1ccc2nc(S(=O)Cl)[nH]c2c1
Reactant: [Li]Cc1cccc2c1N(C)CCC2
Solvent: c1ccccc1
Product: COc1ccc2nc(S(=O)Cc3cccc4c3N(C)CCC4)[nH]c2c1
Yield: 3.6 %

Procedure:
(1-Methyl-1,2,3,4-tetrahydroquinolin-8-yl)methyl lithium (18.3 g) was dissolved in benzene (150 ml). After adding (5-methoxy-2-benzimidazolyl)sulfinyl chloride (20.1 g) thereto, the mixture was refluxed for 2 hours. The resulting lithium chloride was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate to give 8-(5-methoxy-2-benzimidazolyl)sulfinylmethyl-1-methyl-1,2,3,4-tetrahydroquinoline (1.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(/C=C/CO[Si](C)(C)C(C)(C)C)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(CCCO[Si](C)(C)C(C)(C)C)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 140 mg (0.23 mmol) di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-({5-[(E)-3-{[tert-butyl(dimethyl)silyl]oxy}prop-1-en-1-yl]pyridin-2-yl}methyl)-L-glutamate in 8 ml of methanol, palladium (10% on charcoal, 7 mg) was added and the suspension was stirred for 3 h at room temperature under a hydrogen atmosphere. The mixture was filtered over celite, and the solvent was evaporated. The crude material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1Cl.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.CC[O-].[Na+]>C(O)C.C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(Cl)c(C)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(-n2ccnc2)c(C)c1
Temperature: 110 °C
Yield: 48 %

Procedure:
30 mmol of 2,4-dimethylchlorobenzene (4.2 g), 40 mmol of imidazole (2.7 g), 35 mmol of NaOEt solution in ethanol (10% by weight) and 230 mg of trans-di-μ-chlorobis[2-[bis(1,1-dimethylethyl)phosphino]-2-methylpropyl-C,P]dipalladium(II) (1.0 mol %) are suspended in 50 ml of THF and heated at 110° C. in a pressure tube for 9 hours. After removal of the salts by filtration, the solvent is removed under reduced pressure. This gives crude 1-(2,4-dimethylphenyl)imidazole as a brown liquid which can be purified by distillation (boiling point: 122° C./12 torr); yield: 48%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19]>O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)C(C)Oc1ccc(C=O)cc1
Temperature: 60 °C
Yield: 71.4 %

Procedure:
A mixture consisting of 45 gm (0.37 mol) of 4-hydroxy-benzaldehyde, 111 gm (0.81 mol) of potassium carbonate, 89 ml (0.81 mol) of methyl 2-bromo-propionate and 300 ml of dimethylformanide was heated at 60° C. for 16 hours, while stirring. Thereafter, the reaction mixture was poured into 1 liter of water, and the aquous mixture was extracted with ether. The ethereal extract solution was washed with 1 N potassium hydroxide and then with water, dried and evaporated, leaving 55 gm of methyl 2-(4-formyl-phenoxy)-propionate as an oil, which was purified by passing it through a silicagel column with chloroform as the flow agent.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=[O:2].S(=O)(=O)([OH:20])N.Cl([O-])=O.[Na+]>CC(C)=O.O.O>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([O:7][C:6]2[CH:16]=[CH:17][C:3]([C:1]([OH:20])=[O:2])=[CH:4][CH:5]=2)=[N:9][CH:10]=1)#[N:13]
Reactant: NS(=O)(=O)O
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc(C(=O)O)cc2)nc1
Temperature: 0 °C
Yield: 86.9 %

Procedure:
6-(4-formyl-phenoxy)-nicotinonitrile (310 mg, 1.38 mmol) was dissolved in acetone-water mixture (3.5:3) (6.5 mL) and cooled to 0° C. Sulphamic acid (403 mg, 4.15 mmol) and sodium chlorite (499 mg, 5.52 mmol) dissolved in minimum amount of water were added and the resulting mixture was stirred at room temperature for half an hour. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulphate and concentrated to afford 288 mg 4-(5-cyano-pyridin-2-yloxy)-benzoic acid, (85.2% yield). LCMS Purity: 83.2%,
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[S:13]([C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([Cl:23])=[CH:18][C:17]=1[CH3:24])(=[O:15])=[O:14])C.[OH-].[Li+]>CO.O>[Cl:23][C:19]1[C:20]([CH3:22])=[CH:21][C:16]([S:13]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][CH2:5][C:4]([OH:25])=[O:3])(=[O:14])=[O:15])=[C:17]([CH3:24])[CH:18]=1
Reactant: CCOC(=O)CCC1CCCCN1S(=O)(=O)c1cc(C)c(Cl)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(S(=O)(=O)N2CCCCC2CCC(=O)O)c(C)cc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
Methanol/H2O (3:1, 90 ml) was added to 3-(1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)propionic acid ethyl ester (3.48 g, 9 mmol) at 25° C., the mixture was cooled to 0° C., lithium hydroxide (0.75 g, 18 mmol) was added, and the mixture was stirred for 16 h at 25° C. The solvent was removed under vacuum, the residue taken up in water and washed with dichloromethane. The aqueous phase was carefully acidified with hydrogen chloride solution (1 mol/l) and extracted with ethyl acetate. This organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated to small volume under vacuum. Yield: 89%
Reaction SMILES: CC1C=CC(S(O[C:12]2[CH:21]=[CH:20][C:19]3[C:18](=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=2)(=O)=O)=CC=1.[CH3:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][N:25]=1.C([O-])([O-])=O.[Na+].[Na+].[Li]Cl.O>CCO.O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][C:24]1[CH:29]=[C:28]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[CH2:17][CH2:16][CH2:15]3)[CH:27]=[CH:26][N:25]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c(c2)CCCC3=O)cc1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Li]Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2ccc3c(c2)CCCC3=O)ccn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a suspension of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl 4-methylbenzene-1-sulfonate (1.3 g, 4.4 mmol), 2-methylpyridine-4-boronic acid pinacol ester (800 mg, 3.7 mmol), Na2CO3 (773 mg, 7.3 mmol) and LiCl.H2O (442 mg, 7.3 mmol) in EtOH/H2O/toluene (4.4 mL/2.3 mL/20.0 mL) was added Pd(PPh3)4 (211 mg, 0.2 mmol) at rt under N2. The reaction was stirred at 100° C. overnight. The reaction was filtered and concentrated. Purification by silica gel chromatography (PE:EtOAc=1:1) gave 865 mg (quantitative) of the title compound as a yellow solid. [M+H] Calc'd for C16H15NO, 238. Found, 238.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].Cl.Cl.CC(O)=O>CO>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)NCCC[C@H](NC(=O)CN)C(=O)O
Yield: 189.9 %

Procedure:
After 125.7 g (0.25 mol) of BOC-Gly-Arg-CHA.HCl was dissolved in a small amount of MeOH, 500 ml (0.10 mol) of 2N HCl/AcOH was added to the solution. The mixture was reacted at room temperature for an hour with stirring. After completion of the reaction, the reaction mixture was reprecipitated in 4.5 liters of ether. The precipitated crystals were taken by filtration and dried to give 109.8 g (100%) of H-Gly-Arg-CHA.2HCl.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([Cl:33])[C:21]([S:23](=[O:32])(=[O:31])[NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][C:16]=3[N:15]=2)[CH:13]=1)=[O:8])C.C1COCC1>O>[Cl:33][C:20]1[C:21]([S:23](=[O:32])(=[O:31])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:22][C:16]2[N:15]=[C:14]([N:12]3[CH:13]=[C:9]([C:7]([OH:8])=[O:6])[CH:10]=[N:11]3)[NH:18][C:17]=2[CH:19]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(S(=O)(=O)Nc4ccccc4)c(Cl)cc3[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnn(-c2nc3cc(S(=O)(=O)Nc4ccccc4)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 78.5 %

Procedure:
Lithium hydroxide monohydrate (7.90 mg, 0.188 mmol), 1-(6-chloro-5-phenylsulfamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (28.0 mg, 62.8 μmol), THF (0.24 mL), and water (79 μL) were combined, briefly sonicated, and left to stir at 23° C. for 18 h. Solvent was evaporated and 2 mL water was added. This solution was brought to pH 1 with aqueous 1M HCl and the resulting precipitate was collected and dried to yield the titled compound (20.6 mg, 75% yield). MS (ESI/CI): mass calcd. for C17H12ClN5O4S, 417.0; m/z found, 418.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13.96 (s, 1H), 13.02 (s, 1H), 10.55 (s, 1H), 8.91 (s, 1H), 8.33 (s, 1H), 8.31-8.08 (m, 1H), 7.95-7.53 (m, 1H), 7.26-7.04 (m, 4H), 6.96 (t, J=7.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH3:10][O:11][P:12]([O:15]C)[O:13][CH3:14]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][P:12](=[O:15])([O:13][CH3:14])[O:11][CH3:10]
Reactant: Fc1cccc(CBr)c1
Reactant: COP(OC)OC
Product: COP(=O)(Cc1cccc(F)c1)OC

Procedure:
Following the procedure of Compound 11, 3-fluorobenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:8]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][C:9]=2[N:10]=[C:11]([CH2:13][CH2:14][C:15](O)=[O:16])[N:12]=1.S(Cl)([Cl:32])=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:8]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][C:9]=2[N:10]=[C:11]([CH2:13][CH2:14][C:15]([Cl:32])=[O:16])[N:12]=1
Reactant: COc1ccc(CNc2nc(CCC(=O)O)nc3sc4ccccc4c23)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CNc2nc(CCC(=O)Cl)nc3sc4ccccc4c23)cc1Cl

Procedure:
1 equivalent of 3-[4-(3-chloro-4-methoxybenzyl-amino)benzothieno[2,3-d]pyrimidin-2-yl]propionic acid and 1.2 equivalents of thionyl chloride are stirred in dichloromethane for 2 hours. The solvent is removed and 3-[4-(3-chloro-4-methoxybenzylamino)benzothieno[2,3-d]-pyrimidin-2-yl]propionyl chloride is obtained. The mixture is transferred to aqueous ammonia, stirred for one hour and, after customary working up, 3-[4-(3-chloro-4-methoxybenzylamino)benzothieno[2,3-d]pyrimidin-2-yl]propionamide is obtained.
Reaction SMILES: C([N:4]1[CH2:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[N:7]([CH3:14])[C:6]2[CH:15]=[N:16][C:17]([Cl:19])=[N:18][C:5]1=2)C=C.O>O1CCOCC1>[Cl:19][C:17]1[N:16]=[CH:15][C:6]2[N:7]([CH3:14])[C:8](=[O:13])[C:9]([CH3:11])([CH3:12])[CH2:10][NH:4][C:5]=2[N:18]=1
Reactant: C=CCN1CC(C)(C)C(=O)N(C)c2cnc(Cl)nc21
Solvent: O
Solvent: C1COCCO1
Product: CN1C(=O)C(C)(C)CNc2nc(Cl)ncc21

Procedure:
9-allyl-2-chloro-8,9-dihydro-5,7,7-trimethyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (1.21 g, 4.34 mmol, prepared by method C) and dichloro(2,7-dimethyl-octa-2,6-diene-1,8-yl) ruthenium (IV) (0.26 g, 0.43 mmol, prepared following Tetrahedron Letters, 1965, 47, 4187) were suspended in dioxane (10 mL) and water (30 mL) in a pressure tube. The resultant suspension was stirred at 100° C. over two nights.
Reaction SMILES: C([N:8]1[C@@H:16]2[C@@H:12]([CH2:13][NH:14][CH2:15]2)[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:17]>C(O)C.[Pd]>[ClH:17].[ClH:17].[C@@H:12]12[CH2:13][NH:14][CH2:15][C@@H:16]1[NH:8][CH2:9][CH2:10][O:11]2
Reactant: c1ccc(CN2CCO[C@@H]3CNC[C@@H]32)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: C1CO[C@@H]2CNC[C@@H]2N1

Procedure:
26 g (0.11 mol, 92% strength) of cis-5-benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane are hydrogenated on 3 g of palladium/active charcoal (10% Pd) at 100° C. and 100 bar H2 in 180 ml of ethanol and 19 ml of concentrated hydrochloric acid. The catalyst is filtered off with suction, the filtrate is concentrated and the crystals which have separated out are dried in a desiccator over phosphorus pentoxide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cc(C(=O)O)ccc1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c(N)c1
Temperature: 65 °C
Yield: 95 %

Procedure:
To a solution of 3-amino-4-hydroxybenzoic acid (10 g, 0.65 mol) in methanol (1.5 L) was added thionylchloride (233 g, 1.96 mol) drop-wise at 5-10° C. with stirring and allowed to reflux at 65° C. for 16 h. Excess methanol and thionylchloride was distilled off and crude dissolved in ethylacetate (500 mL). The organic layer was washed with 5% aqueous NaHCO3 solution, water, brine and dried. The solvent was removed under vacuum to give methyl-3-amino-4-hydroxybenzoate (105 g, 95%).
Reaction SMILES: [Na].C1C2C(=CC=CC=2)C=CC=1.CC1C=CC(S([N:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:27][N:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][S:31][C:30]3[CH:39]=[CH:40][CH:41]=[CH:42][C:29]2=3)(=O)=O)=CC=1>COCCOC>[NH:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][N:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH2:32][S:31][C:30]2[CH:39]=[CH:40][CH:41]=[CH:42][C:29]1=2
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CN2c3ccccc3CSc3ccccc32)cc1
Agent: [Na]
Solvent: COCCOC
Solvent: c1ccc2ccccc2c1
Product: c1ccc2c(c1)CSc1ccccc1N2C[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
Sodium (55 mg) was added to a solution of naphthalene (340 mg) in DME (6 ml) and the mixture stirred at room temperature for one hour, treated with a solution of (S)-5,11-dihydro-5-(1-[4-methylphenylsulphonyl]-2-pyrrolidinylmethyl)dibenzo[b,e][1,4]thiazepine (see Preparations 15 and 16) (200 mg) in DME (4 ml), stirred with ice-cooling for one hour, quenched with water and extracted with ethyl acetate. The organic extract was worked-up and purified as described in Preparation 13 to give the title compound as a colourless oil, (16 mg, 12%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])[CH2:4][OH:5].[OH-].[K+].C1C[O:18][CH2:17]C1.C(=O)(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl>O.CCOC(C)=O>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C@H:3]1[CH2:4][O:5][C:17](=[O:18])[NH:2]1
Reactant: C1CCOC1
Reactant: N[C@H](CO)c1ccccc1Cl
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1N[C@@H](c2ccccc2Cl)CO1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.8 %

Procedure:
To a solution of (S)-2-amino-2-(2-chlorophenyl)ethanol hydrochloride (500 mg, 2.40 mmol) in water (12 mL) at 0° C. was added potassium hydroxide (809 mg, 14.4 mmol) followed by THF (12 mL) and the reaction was stirred at 0° C. for 20 minutes. Bis(trichloromethyl) carbonate (713 mg, 2.40 mmol) was added and the reaction was stirred at 0° C. for 2 hours. The reaction was poured into EtOAc and the organic phase washed with 1N HCl, 1N NaOH and brine. The organic layer was dried over MgSO4, filtered and concentrated to provide (S)-4-(2-chlorophenyl)oxazolidin-2-one (265 mg, 55.8% yield) as an oil which solidified upon standing.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][CH2:11][CH2:12][O:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[N+:24]([O-:26])=[O:25])=[CH:18][CH:17]=1.O>CS(C)=O>[CH3:9][O:10][CH2:11][CH2:12][O:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]2[CH2:2][C@H:23]2[N+:24]([O-:26])=[O:25])=[CH:18][CH:17]=1
Reactant: C[S+](C)(C)=O
Reactant: COCCOCOc1ccc(/C=C/[N+](=O)[O-])cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCCOCOc1ccc([C@@H]2C[C@H]2[N+](=O)[O-])cc1
Yield: 57.6 %

Procedure:
Trimethylsulfoxonium iodide (0.76 g, 3.44 mmol) was added in small portions to a suspension of NaH 0.14 g (60% in mineral oil), 3.44 mmol] in dry DMSO (5 mL). The mixture was stirred until gas evolution ceased and a clear solution was formed (45 min). Then, a solution of (E)-1-((2-methoxyethoxy)methoxy)-4-(2-nitrovinyl)benzene (Intermediate J, 0.73 g, 2.86 mmol) in DMSO (5 mL) was transferred via cannula and the reaction was stirred for additional 20 h. The mixture was poured into water (20 mL) and extracted with Et2O (3×15 mL). The organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered; after removal of the solvent, the residual orange oil was purified by column chromatography on silica gel (10-20% EtOAc/Hexanes) affording 0.44 g of 1-((2-methoxyethoxy)methoxy)-4-((trans)-2-nitrocyclopropyl)benzene [Rf=0.4 (50% AcOEt/Hexanes), colorless oil, 36% yield].