Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Yield: 58 %

Procedure:
4-Hydroxy-3-nitrobenzoic acid (10.0 g, 54.6 mmol) was suspended in methanol (60 mL). After addition of conc. sulfuric acid (0.1 mL), the suspension was heated overnight under reflux. The methanol was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (40 mL), washed successively with aqueous sodium hydrogen carbonate (20 mL×2) and saturated aqueous brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, to give 6.27 g (yield 58%) of the desired compound in the form of a pale brown crystalline product.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Pd]>[CH2:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[C:1]([C:11]([OH:13])=[O:12])[C:10]=2[CH2:9][CH2:8][CH2:7]1
Reactant: O=C(O)c1cccc2ccccc12
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)c1cccc2c1CCCC2
Reaction time: 96 h
Yield: 8.6 %

Procedure:
10% w/w Palladium-on-carbon (10 g) was added to a solution of 1-naphthoic acid (33.4 g) in glacial acetic acid (150 ml) and the mixture hydrogenated at 345 kPa (50 psi) and 85° C. for 4 days. The warm mixture was filtered through a short column of Arbacel (trade mark) filter aid and the pad washed with glacial acetic acid (150 ml). Water (1.5 L) was added to the filtrate and the resulting precipitate filtered off and washed with water. The precipitate was dissolved in dichloromethane, the solution dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give an oil which was crystallised from ethyl acetate to give 1,2,3,4-tetrahydro-5-naphthoic acid (2.94 g) as a white solid (m.p. 148-150° C.).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:12]=[C:11]([Cl:22])[C:10]=1[F:23])(C)(C)C.Cl>O1CCOCC1>[Cl:22][C:11]1[C:10]([F:23])=[C:9]([CH:14]=[C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[CH:12]=1)[CH2:8][NH2:7]
Reactant: CN1CCN(c2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(c2cc(Cl)c(F)c(CN)c2)CC1

Procedure:
was prepared according to Scheme C1 (step B) from [3-chloro-2-fluoro-5-(4-methyl-piperazin-1-yl)-benzyl]-carbamic acid tert-butyl ester and 4N HCl in dioxane. MS (LC-MS): 258.0 [M]+; tR (HPLC conditions f): 0.74 min.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:18])[CH:24]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Product: Cc1cccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)c1
Yield: 82 %

Procedure:
N-(3-methyl-5-isoxazolyl)-4-(3-methylphenyl)benzenesulfonamide was prepared in the same manner as described in Example 14b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide (Example 14a) and 3-methylbenzeneboronic acid resulting in an 82% yield.
Reaction SMILES: ClCCl.[OH:4][CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl.CCOCC>[CH3:24][S:25]([O:4][CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(O)Cc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1ccccc1)OS(C)(=O)=O
Yield: 93 %

Procedure:
To a stirred solution of phenylalanine (16.5 g, 0.1 mole) in 2N sulfuric acid at 0° C., was added sodium nitrite (10.5 g, 1.5 equiv) in small portions over a period of 0.5 hours and the mixture stirred overnight. Aqueous phase was extracted with ether (5×250 mL) and the ethereal extracts were washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give phenyllactic acid (1 equiv) in methanol (15 equiv) at 0° C. and the mixture stirred at room temperature overnight. Removal of volatiles in vacuo and chromatographic purification of the oil (20-25% ethyl acetate in hexane) gives methyl 2-hydroxy-3-phenylpropionate. 1H NMR (300 MHz, CDCl3): δ7.33-7.196 (m, 5H), 4.451 (dd, 1H), 3.764 (s, 3H), 3.1225 (dd, 4.45 Hz, 13.95 Hz, 1H), 2.9575 (dd, 7 Hz, 14 Hz, 1H), 2.787 (br s, 1H). A dichloromethane solution of methyl 2-hydroxy-3-phenylpropionate is treated with triethylamine (1.1 equiv) and methanesulfonyl chloride (1.1 equiv) at 0° C. Upon completion of reaction, the mixture is dissolved in dichloromethane/ether and washed with saturated aqueous solution of sodium chloride, dried and concentrated. Purification of crude material by flash column chromatography (40% ethyl acetate in hexane) gives methyl 2-methanesulfonyloxy-3-phenyl-propionate (1.6 g, 93%).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C>ClCCl>[O:6]=[C:5]([NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: NCc1ccccc1
Reactant: O=C1CCCC(=O)O1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)CCCC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.9 %

Procedure:
To a solution of 25 gm (220 mMol) glutaric anhydride in dichloromethane (250 ml) was added a solution of 26.4 ml (242 mMol) benzylamine in dichloromethane (50 ml) dropwise. The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was then poured into diethyl ether (500 ml) and the resulting solid was filtered The filter cake was washed with diethyl ether, dried under vacuum and then recrystallized from ethyl acetate to give 24.8 gm (51%) 5-oxo-5-(phenylmethylamino)pentanoic acid as a crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=O)=[C:5]([CH3:7])[N:6]=1.C([O:16][C:17](=[O:37])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][NH:28]1)C.Cl.CN(C)CCCN=C=NCC.[OH-].[Na+]>CN(C=O)C.CN(C1C=CN=CC=1)C.C(O)=O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][C:17]([OH:37])=[O:16])=[C:21]([CH:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29][N:28]2[C:11]([CH:9]2[CH2:10][CH:8]2[C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])=[O:13])[CH:22]=1
Reactant: Cc1nc(C)c([C@@H]2C[C@H]2C(=O)O)s1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1NCCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=CO
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C2CC2C(=O)N2CCc3ccccc3C2c2cc(Cl)ccc2OCC(=O)O)s1
Temperature: 25 °C
Reaction time: 62 h

Procedure:
To a solution of (±)-trans-2-(2,4-dimethyl-thiazol-5-yl)cyclopropanecarboxylic acid (42 mg, 0.20 mmol, 1.0 eq.) and (±)-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester (73 mg, 0.20 mmol, 1.0 eq.) in DMF (2.4 mL), DMAP (37 mg, 0.30 mmol, 1.5 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol, 1.5 eq.) were added. The resulting solution was stirred at r.t. for 62 hours. 1M aq. NaOH soln. (1.2 mL) was added and the solution was stirred at r.t. for 3.5 hours. Formic acid (0.2 mL) was added. The crude mixture was purified by prep. HPLC (column: Waters XBridge, 19×50 mm, 5 um, UV/MS, acidic conditions). The two racemic diastereoisomers were separated (LC-MS 3: tR (±)-dial=0.81 and tR (±)-dia2=0.82). The title compound showed: tR=0.82.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:34]=[CH:33][C:14]3[CH2:15][CH2:16][C:17]4[C:18]([C:30]([NH2:32])=[O:31])=[N:19][N:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]#[CH:29])=[CH:24][CH:23]=5)[C:21]=4[C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[OH:36]S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([N:20]2[C:21]3[C:13]4[CH:12]=[C:11]([NH:10][C:8]([C:7]5[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=5)=[O:9])[CH:34]=[CH:33][C:14]=4[CH2:15][CH2:16][C:17]=3[C:18]([C:30]([NH2:32])=[O:31])=[N:19]2)=[CH:23][CH:24]=1)(=[O:36])[CH3:29]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: C#Cc1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4cccnc4Cl)ccc2CC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4cccnc4Cl)ccc2CC3)cc1
Temperature: 100 °C

Procedure:
A mixture of 8-{[(2-chloropyridin-3-yl)carbonyl]amino}-1-(4-ethynylphenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (442 mg, 1.2 mmol), water (65 mg, 3.6 mmol), and triflic acid (270 mg, 1.8 mmol) in dioxane (10 mL) was heated to 100° C. for 18 h. The mixture was cooled to RT, aqueous NaHCO3 was added, and filtered. The product was washed with water and ether, and dried. This gave product (293 mg, 67%). 1H NMR was consistent with its structure.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:19]3[C:10]([C:11]4[CH:12]=[C:13]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:14]([C:20]5[CH:25]=[CH:24][C:23]([C:26]6([NH2:34])[CH2:29][C:28]7(OCC[O:30]7)[CH2:27]6)=[CH:22][CH:21]=5)=[N:15][C:16]=4[CH:17]=[CH:18]3)=[N:9][N:8]=2)[N:4]=[CH:3]1.[O:41]=[C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44](=[O:51])N1C(OCC)=O.CCN(C(C)C)C(C)C.Cl>C(Cl)(Cl)Cl.CO.CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:19]3[C:10]([C:11]4[CH:12]=[C:13]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[C:14]([C:20]5[CH:21]=[CH:22][C:23]([C:26]6([N:34]7[C:42](=[O:41])[C:50]8[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=8)[C:44]7=[O:51])[CH2:29][C:28](=[O:30])[CH2:27]6)=[CH:24][CH:25]=5)=[N:15][C:16]=4[CH:17]=[CH:18]3)=[N:9][N:8]=2)[N:4]=[CH:3]1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C6(N)CC7(C6)OCCO7)cc5)nc4ccn23)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C6(N7C(=O)c8ccccc8C7=O)CC(=O)C6)cc5)nc4ccn23)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 2-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}-5,8-dioxaspiro[3.4]octan-2-amine (142) (1.3 g, 2.49 mmol) and ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate (0.37 g, 2.49 mmol) in CHCl3 (5 mL) was stirred at 70° C. for overnight. The mixture and DMF (5 mL) and DIPEA (0.44 mL, 2.49 mmol) were heated under microwave irradiation at 150° C. for 1 hour. The solvent was removed under reduced pressure, and to the residue was added MeOH. The resulting solid was collected by filtration. The solid (100 mg, 0.152 mmol) and 6N HCl in MeOH (1 mL) was stirred at room temperature for 1 hour. The mixture was quenched by aq. NaHCO3, extracted with CHCl3, dried (MgSO4), filtered, and concentrated under reduced pressure to yield (2-(1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}-3-oxocyclobutyl)-1H-isoindole-1,3(2H)-dione (1-13). MS (M+H)+: observed 616, calculated=616.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]([CH3:14])[CH3:13])[CH:7]=1)=[O:4].[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[CH:16]1>>[N:15]1([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N:12]([CH3:14])[CH3:13])[CH:7]=2)=[O:4])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[CH:16]1
Reactant: CN(C)c1cccc(NC(=O)CBr)c1
Reactant: c1ccc2[nH]cnc2c1
Product: CN(C)c1cccc(NC(=O)Cn2cnc3ccccc32)c1

Procedure:
Part B: The title compound was synthesised according to the procedure described in Example 94, from 2-bromo-N-(3-dimethylamino-phenyl)-acetamide and 1H-benzoimidazole. Calculated for C17H18N4O m/z: 294.3, found 295.3 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][CH:10]2[CH:5]3[CH2:6][CH:7]4[CH:9]2[CH:8]4[CH:4]13.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[S:21])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[S:21])[NH:2][CH:3]2[CH2:11][CH:10]3[CH:5]4[CH2:6][CH:7]5[CH:9]3[CH:8]5[CH:4]24)=[CH:15][CH:14]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: NC1CC2C3CC4C2C4C13
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: S=C(Nc1ccc(Cl)cc1)NC1CC2C3CC4C2C4C13

Procedure:
8-Aminotetracyclo[4,3,0,02,4,03,7 ]nonane hydrochloride (0.5 g.) (prepared as described in U.K. Patent Specification No. 1,180,749) was dissolved in a mixture of chloroform (25 ml.) and triethylamine (0.33 g.). To this solution was added p-chlorophenylisothiocyanate (0.5 g.) and the mixture refluxed for 16 hours. The chloroform solution, after cooling, was washed successively with 10 ml. portions of 2N HCl, water and saturated brine, and then dried over anhydrous MgSO4. After filtration, the solvent was evaporated in vacuo and the residue crystallised from toluene/cyclohexane (1:2 v/v) to give 8-[3-(p-chlorophenyl)thioureido]tetracyclo[4,3,0,02,4,03,7 ]-nonane, m.p. 168°-170°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:26][NH:27][O:28][CH3:29].C(N(CC)CC)C>C(Cl)Cl>[CH3:29][O:28][N:27]([CH3:26])[C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
A suspension of 10.00 g (59.46 mmol) of 3-(4-fluorophenyl)propionic acid, 12.54 g (65.41 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 6.381 g (65.41 mmol) of N,O-dimethylhydroxylamine hydrochloride in 300 mL of CH2Cl2 was cooled to 0° C. and treated with 18.23 mL (13.23 grams, 130.8 mmol) of triethylamine. The mixture was stirred for 16 h with slow warming to rt. The mixture was concentrated, and the residue was partitioned between 300 mL of EtOAc and 200 mL of aqueous 1 N hydrochloric acid solution. The separated organic layer was washed with aqueous 1 N hydrochloric acid solution (1×100 mL), saturated aqueous sodium hydrogencarbonate solution (2×200 mL), brine (1×100 mL), dried (Na2SO4), and evaporated to give 9.56 g (76% yield) of the title compound as an oil. 1H NMR (CDCl3) d 2.70(2H, t, J=8 Hz), 2.91 (2H, t, J=8 Hz), 3.15 (3H, s), 3.59 (3H, s), 6.92-6.97 (2H, m), 7.15-7.19 (2H, m). APCI MS (m/e) 212 (M++1).
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31][C:32]1[N:37]=[C:36](Cl)[C:35]([Cl:39])=[CH:34][N:33]=1.[Cl:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][C:46]=1[Cl:47].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOCC.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.CCO>[Cl:31][C:32]1[N:37]=[C:36]([C:44]2[CH:43]=[CH:42][C:41]([Cl:40])=[C:46]([Cl:47])[CH:45]=2)[C:35]([Cl:39])=[CH:34][N:33]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: N#Cc1ccccc1
Solvent: Cc1ccccc1
Product: Clc1ncc(Cl)c(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 0.19 g (0.5 mmol) of bis(benzonitril)dichloro-palladium (II) and 0.2 g 1,4-bis(diphenylphosphino)butane in 10 mL of toluene was heated at reflux with stirring for 1 h under nitrogen. The suspension was cooled to room temperature. One gram (6.6 mmol) of 3A, 1.57 g of 3,4-dichlorobenzene boronic acid (8.2 mmol), 2.5 mL EtOH and 5 mL of 1 M Na2CO3 were added and the mixture heated to reflux for 20 h. The reaction mixture was cooled and diluted with 100 mL Et2O. The suspension was filtered through a plug of silica gel and the cake washed with an additional 100 mL of Et2O. The ether was evaporated and the residue chromatographed over silica gel (10% EtOAc/hexane). A fraction containing 0.72 g (32%) of 2,5-dichloro-4-(3,4-dichlorophenyl)pyrimidine was isolated as a white solid. (m.p. 125-126° C.)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:5]=[C:4]([CH3:12])[N:3]=1.[C:13]1([O:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[O:19]([C:20]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:5]=[C:4]([CH3:12])[N:3]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(OC(F)F)nc(N)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(OC(F)F)nc(NC(=O)Oc2ccccc2)n1
Reaction time: 24 h
Yield: 54.4 %

Procedure:
To a solution of 9.0 g of 2-amino-4-difluoromethoxy-6-methyl-pyrimidine in 30 ml of absolute tetrahydrofuran are added successively 3.9 g of chloroformic acid-phenyl ester and 0.05 g of 4-dimethylamino-pyridine. After the solution has been stirred at 20° to 25° C. for 24 hours, the reaction mixture is diluted with 250 ml of ethyl acetate, and the occurring precipitate is separated. There are thus obtained 3.1 g of 2-amino-4-difluoromethoxy-6-methyl-pyrimidine hydrochloride, m.p. 204° to 205° C. (decomposition). In order to remove the residual starting material, the filtrate is eluted through an acid with ion-exchanger I®(MERCK), dried over sodium sulfate and concentrated by evaporation to thus obtain as crude product, in the form of a viscous oil, 4.0 g of 2-phenoxycarbonylamino-4-difluoromethoxy-6-methyl-pyrimidine (compound No. 2.28), which melts at 56° to 58° C. after crystallisation;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][CH3:12])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH2:13](N)[CH2:14][NH2:15]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]2[NH:15][CH2:14][CH2:13][N:10]=2)[CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(C#N)c1cccc(F)c1
Reactant: NCCN
Product: CCC(C1=NCCN1)c1cccc(F)c1

Procedure:
rac-2-[1-(3-Fluoro-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(3-fluoro-phenyl)-butyronitrile and ethylene diamine in analogy to Example 19 b): colourless powder; MS (ISP): 207.1 ((M+H)+.).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:13])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[OH:14]C1(C)COC2C=CC=CC=2OC1.[OH-].[Na+].[Mn]([O-])(=O)(=O)=O.[K+]>O>[CH3:13][C:3]1([C:2]([OH:14])=[O:1])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1
Reactant: CC1(CO)COc2ccccc2O1
Reactant: CC1(O)COc2ccccc2OC1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC1(C(=O)O)COc2ccccc2O1

Procedure:
A mixture (23.7 g) of 2-hydroxymethyl-2-methyl-1,4-benzodioxan and 3-hydroxy-3-methyl-2H-1,5-benzodioxepine (~3:1 ratio; prepared according to the method of A. Salimbeni, E. Manghisi, J. Heterocyclic Chem., 17, 489, 1980) was stirred with 1 N aqueous sodium hydroxide solution (135 ml) and cooled to 0°-10°. A solution of potassium permanganate (42 g) in water (165 ml) was added slowly so that the temperature was maintained below 10°. After 48 hours at room temperature the mixture was filtered and the filtrate acidified with 1 M aqueous sulphuric acid and extracted with methylene chloride. The extracts were washed with aqueous sodium bicarbonate solution and the aqueous layer was acidified with sulphuric acid. Extraction with methylene chloride followed by washing, drying and evaporation of the extracts gave the carboxylic acid (11.5 g); m.p. 125°-129.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[ClH:10].[Cl:11][CH2:12][CH2:13][NH2:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[ClH:11].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:12][CH2:13][NH2:14])=[CH:5][CH:4]=1.[ClH:10]
Reactant: NCCCl
Reactant: COc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(SCCN)cc1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of 4-methoxybenzenethiol (25 g), 2-chloroethylamine HCl (1.1 eq.) and Cs2CO3 (2.4 eq.) in DMF (200 mL) was stirred at 60° C. for 2 days. The solvents were removed by evaporation under reduced pressure and the crude product was dissolved in 300 mL of EtOAc. The organic phase was washed with H2O (2×50 mL) and concentrated under reduced pressure. The residue was dissolved in 200 mL 1N HCl and washed with EtOAc (2×50 ml). Evaporation of the aqueous phase gave the desired product as HCl salt and white solid. Yield: 34.8 g, 91%. (The free amine can be obtained by treatment of the salt with 1N NaOH).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1([O-])C=CC=CC=1.[K+].[F:22][C:23]1[C:28]([F:29])=[C:27](F)[N:26]=[CH:25][N:24]=1>C1COCC1>[F:29][C:28]1[C:27]([O:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:26][CH:25]=[N:24][C:23]=1[F:22]
Reactant: Oc1ccccc1
Reactant: Fc1ncnc(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [O-]c1ccccc1
Solvent: C1CCOC1
Product: Fc1ncnc(Oc2ccccc2)c1F
Temperature: 0 °C
Yield: 68.1 %

Procedure:
With stirring, 50.4 g (0.45 mol) of potassium tert-butoxide (M=112.22) are added to a solution of 42.4 g (0.45 mol) of phenol in 400 ml of THF. The resulting potassium phenolate solution is added dropwise to a solution of 80 g (0.6 mol) of 4,5,6-trifluoropyrimidine in 1 l of THF which had been cooled to 0° C., and the mixture is stirred for 30 minutes. The solution is concentrated under reduced pressure and the residue is mixed with water and extracted with ethyl acetate. The organic phase is separated off, dried over sodium sulphate and concentrated under reduced pressure. The crude product is stirred with petroleum ether and filtered off. 63.8 g (68.1% of theory) of 5,6-difluoro-4-phenoxypyrimidine of melting point 65-66° C. are obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:20](=[O:44])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C@H:26]([N:29]([S:34]([C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)(=[O:36])=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:27][OH:28])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.Cl>C(O)C>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C@H:26]([N:29]([S:34]([C:37]1[CH:38]=[CH:39][C:40]([NH2:43])=[CH:41][CH:42]=1)(=[O:36])=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:27][OH:28])=[O:44]
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CCO
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
(1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexylcarbamoyl}-2-naphthalen-2-yl-ethyl)-carbamic acid tert-butyl ester (698 mg, 1.089 mmol) was added to 6 mL of ethanol and 6 mL of HCl. The mixture was stirred at room temperature until completion by TLC. The ethanol was evaporated and the acidic mixture was poured into an extracting funnel containing 75 mL of ethyl acetate and 50 mL of HCl 1M and separated. The aqueous layer was washed with ethyl acetate. The aqueous phase was basified with pellets of NaOH and poured into an extracting funnel. The organic layer was washed with NaOH 1M and brine, dried over sodium sulfate, filtered, evaporated and dried under vacuum to give 544 mg (92%) of a yellow solid (Rf=0, 100% EtOAc, indicator: ninhydrin).