Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(C)C=CC=CC=1.O.[BH4-].[Na+]>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(CNc2ccccc2)c(OC)c1

Procedure:
Trifluoroaceticacid (10 drops) was added to a solution of 2,4-dimethoxybenzaldehyde (16.62 g, 100 mmol) and aniline (9.31 g, 100 mmol) in toluene (100 mL). The reaction mixture was stirred at reflux temperature and toluene/water was distilled off during 1.5 h. After cooling the reaction mixture was concentrated at reduced pressure and the residue was dissolved in MeOH (200 mL). NaBH4 (2.0 g, 54 mmol) was added in portions during 20 min and the reaction mixture was then stirred for 1 h. The product (22.16 g, 91%) crystallized from the reaction mixture and was isolated by filtration.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]([O-:32])(=[O:31])[CH:28]([CH3:30])[OH:29].[Na+].C(OCC)(=O)C.O>CN(C=O)C>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:32][C:27](=[O:31])[CH:28]([CH3:30])[OH:29])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC(O)C(=O)[O-]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)C(C)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 30 ml of DMF is dissolved 3.4 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one, and 2.5 ml of 70% aqueous sodium lactate is added. The mixture is stirred at room temperature (15°-25° C.) for 3 hours and poured into a mixture of 350 ml of ethyl acetate and 30 ml of water. The organic layer is separated, washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 100 ml of dichloromethane and 700 ml of diisopropyl ether in that order, elution is carried out with 1200 ml of diisopropyl ether-ethyl acetate (10:1). The eluate is evaporated under reduced pressure to remove the solvent, giving 3.0 g of the above-identified compound as a light yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[NH:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]3[CH2:27][CH2:26][C@H:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[N:12]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[NH:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]3[CH2:23][CH2:24][C@H:25]([CH2:28][C:29]([N:6]4[CH2:7][CH2:8][CH2:9][C@H:5]4[C:4]([O:3][CH3:2])=[O:10])=[O:30])[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)=[N:12]1
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc[nH]n3)cc2)CC1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1CCCN1C(=O)C[C@H]1CC[C@H](c2ccc(-c3cc[nH]n3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
L-Proline methyl ester hydrochloride (0.03 g, 0.18 mmol) was added to a stirred solution of the product from Example 37C (0.05 g, 0.17 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.042 g, 0.22 mmol), 1-hydroxybenzotriazole hydrate (0.03 g, 0.22 mmol) and N-methyl morpholine (0.1 mL, 0.87 mmol) in N,N-dimethylformamide (4 mL) at room temperature. The reaction was stirred at room temperature for 12 h and then quenched by addition of water. It was then extracted with ethyl acetate (3×25 mL), the organic extracts washed with water, brine, dried (MgSO4) and concentrated to afford the titled compound as a clear oil. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.09-1.18 (m, 2 H), 1.40-1.51 (m, 2 H), 1.75-1.86 (m, 6 H), 1.88-1.94 (m, 2 H), 2.13-2.27 (m, 3 H), 2.40-2.49 (m, 1 H), 3.51-3.58 (m, 2 H), 3.61 (s, 3 H), 4.30 (dd, J=10, 5 Hz, 1 H), 6.64 (d, J=3 Hz, 1 H), 7.27 (d, J=10 Hz, 2 H), 7.66-7.72 (m, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)=[O:4].[N+:10]([O-])([OH:12])=[O:11].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[S:7][CH:6]=1)=[O:4]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccsc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1csc([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 3-thiophene carboxylic acid methyl ester (1.8 g, 12.68 mmol) in acetic acid (7.5 ml) was added a mixture of nitric acid (0.67 ml), acetic acid (7.5 ml) and acetic anhydride (4.3 ml) at 0-10° C. The reaction mixture was stirred at 40° C. for 1 hr and then poured into crushed ice. The solid was filtered, washed with cold water and dried. The compound was recrystallised using ether/hexane to give 5-nitro-thiophene-3-carboxylic acid methyl ester (1.0 g, 42%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH2:25][CH2:26][NH:27][CH2:28]2)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:27]2[CH2:26][CH2:25][C:24]3[C:29](=[CH:30][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH2:28]2)[N:3]=1
Reactant: COc1ccc2c(c1)CNCC2
Reactant: COc1cc2c(N)nc(Cl)nc2c(OC)c1OC
Product: COc1ccc2c(c1)CN(c1nc(N)c3cc(OC)c(OC)c(OC)c3n1)CC2

Procedure:
The procedure described in Example 1 was followed to prepare the above compound, starting from 4-amino-2-chloro-6,7,8-trimethoxyquinazoline and using 7-methoxy-1,2,3,4-tetrahydroisoquinoline as the reagent of choice on the same molar basis as before. In this particular case, the final product was isolated as the hydrochloride salt m.p. 236° C.
Reaction SMILES: N[C@H](C1C=NC=C(Br)C=1)[C@@H](C1C=C(F)C=CC=1F)O.[Cl:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]([C@@H:27]([NH:37]C(=O)OC(C)(C)C)[C@@H:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[OH:29])[CH:22]=1.O.C(O)(C(F)(F)F)=O>CC#N>[ClH:20].[ClH:20].[NH2:37][C@H:27]([C:23]1[CH:22]=[C:21]([Cl:20])[N:26]=[CH:25][N:24]=1)[C@@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)[OH:29]
Reactant: CC(C)(C)OC(=O)N[C@H](c1cc(Cl)ncn1)[C@H](O)c1cccc(F)c1
Agent: N[C@H](c1cncc(Br)c1)[C@H](O)c1cc(F)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: Cl
Product: N[C@H](c1cc(Cl)ncn1)[C@H](O)c1cccc(F)c1

Procedure:
Prepared according to the same procedure as (1R,2R)-2-amino-2-(5-bromopyridin-3-yl)-1-(2,5-difluorophenyl)ethanol, starting with tert-butyl(1R,2R)-1-(6-chloropyrimidin-4-yl)-2-(3-fluorophenyl)-2-hydroxyethylcarbamate. Analytical HPLC method: Phenomenex LUNA C18, 50×2 3μ, A=90% H2O/10% CH3CN, B=90% CH3CN/10% H2O, Modifier 0.1% TFA, 0.00 min=0% B, 4.0 min=100% B, 5.0 min=100% B, Flow rate=0.8 mL/min., TR=1.460 min, Mass spec.: 268.1 (MH)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][C@@H:16]([N:19]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[O:22])[CH3:20])[C@H:15]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH2:14]2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:38]C(C)([O-])C.[Na+].CI.O>CN(C=O)C>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([CH3:38])[C:11]([N:13]2[CH2:18][CH2:17][C@@H:16]([N:19]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[O:22])[CH3:20])[C@H:15]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH2:14]2)=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)N1CCC(NC(=O)N2CC[C@@H](N(C)C(=O)c3ccc(Cl)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CC(=O)N1CCC(N(C)C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(Cl)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Reaction time: 0.08 h
Yield: 53.7 %

Procedure:
To a solution of the compound obtained in Example 459 (100 mg) in DMF (3 mL) was added sodium tert-butoxide (25.3 mg) at 0° C., and the mixture was stirred for 5 min. Then, methyl iodide (16.5 μL) was added, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 0→12% methanol/ethyl acetate) to give the title compound (55 mg, 54%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:17])[C:3]=1[CH:18]([OH:23])[C:19]([O:21][CH3:22])=[O:20].C(Cl)Cl.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[C:3]([O:23][CH:18]([C:3]1[C:4]([CH3:17])=[N:5][C:6]2[N:7]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=2)[C:2]=1[Cl:1])[C:19]([O:21][CH3:22])=[O:20])([CH3:18])([CH3:4])[CH3:2]
Reactant: COC(=O)C(O)c1c(C)nc2cc(-c3ccccc3)nn2c1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2cc(-c3ccccc3)nn2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 121.6 %

Procedure:
To a suspension of methyl 2-(7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (100 mg, 0.301 mmol) in tert-butyl acetate (2 mL) at room temperature was added CH2Cl2 (2 mL) followed by perchloric acid (0.027 mL, 0.452 mmol). The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with water and diluted with ethyl acetate. The organic phase was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (71 mg, 60.7%). 1H-NMR (500 MHz, CDCl3) δ1.27 (9 H, s), 2.66 (3 H, s), 3.73 (3 H, s), 5.66 (1 H, s), 6.93 (1 H, s), 7.34-7.52 (3 H, m), 8.01 (2 H, d, J=7.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]([N+:16]([O-:18])=[O:17])[C:4]=1[C:5]([OH:7])=O.[C:19](Cl)(=[O:23])[C:20](Cl)=O.[N:25]1(CO)C[CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[N+:16]([C:8]1[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([N:25]1[CH2:26][CH2:27][CH2:28][CH:20]1[CH2:19][OH:23])=[O:7])([O-:18])=[O:17]
Reactant: OCN1CCCC1
Reactant: COc1cc([N+](=O)[O-])c(C(=O)O)c(OC)c1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])c(C(=O)N2CCCC2CO)c(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A catalytic quantity of DMF (2 drops) was added to a stirred solution of 108 (10 g, 38.9 mmol) and oxalyl chloride (5.87 g, 46.2 mmol) in dry CHCl2 (100 mL) under a nitrogen atmosphere. The reaction mixture was allowed to stir overnight, and the product was used directly in the next stage of the reaction. The newly formed acid chloride was added dropwise to a stirred solution of pyrrolidinemethanol (3.92 g, 38.8 mmol) and anhydrous triethylamine (12.4 mL, 9.8 g, 97.0 mmol) in anhydrous DCM (50 mL) at 0° C. under nitrogen. Once the addition was complete, the reaction mixture was left to warm to room temperature and left to stir overnight. The reaction mixture was washed with 1N HCl (100 mL), water (100 mL), and brine (2×100 mL). The combined organic layers were dried (MgSO4) and the solvent was removed in vacuo to afford 109 (12.1 g, 91%) as a pale yellow oil: Rf=0.39 (silica, EtOAc); [α]21.9D+135° (c=0.1, DCM); IR (neat) 3400, 3105, 2947, 2878, 1652, 1568, 1538, 1455, 1348, 1250, 1195, 1115, 975, 922, 849, 822, 792, 758, 733, 646 cm−1; 1H NMR (270 MHz, CDCl3) δ 7.59 (1H, s), 4.46 (2H, d, J=2.93 Hz), 4.07 (3H, s), 4.03 (3H, s), 4.01 (3H, s), 3.89 (3%, t), 3.45-3.29 (2H, m), 2.24-2.17 (2H, m), 2.00-1.84 (2H, m); 13C NMR (67.8 MHz, CDCl3, rotamers) δ 165.7, 165.1, 153.3, 149.2, 148.1, 138.8, 122.5, 104.1, 66.4, 65.5, 62.4, 62.3, 61.3, 56.6, 49.2, 49.0, 28.7 24.3; MS (EI) m/z 341 (M+1), 324, 309, 293, 277, 264, 254.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][Br:6].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[Br-:6].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(OC)c(CBr)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1ccc(OC)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]

Procedure:
The 2,5-dimethoxybenzyl triphenylphosphonium bromide is prepared by refluxing a mixture of 2,5-dimethoxybenzyl bromide (12 g.) and triphenylphosphine (14.2.) in acetonitrile (200 ml.) for one hour and isolating the product by standard methods.
Reaction SMILES: O.NN.[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:36]=[CH:35][C:21]([CH2:22][O:23][N:24]2C(=O)C3=CC=CC=C3C2=O)=[CH:20][CH:19]=1.O1CCCC1>C(O)C.C(=O)([O-])[O-].[K+].[K+]>[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][O:23][NH2:24])=[CH:35][CH:36]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
Hydrazine monohydrate (1.15 ml) was added to a solution of N-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]phthalimide (5.22 g) in ethanol (40 ml)-tetrahydrofuran (40 ml) and heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, diluted with an aqueous solution of potassium carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (3.32 g, yield 90%) as colorless crystals. m.p. 68-69° C.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:20]=[CH:19][C:18]=2[O:30][CH3:31])[CH2:11][CH2:10]1)C)(C)(C)C.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[F:29][C:24]1[C:23]([C:21]2[CH:20]=[CH:19][C:18]([O:30][CH3:31])=[C:17]([CH:22]=2)[CH2:16][N:15]([CH:12]2[CH2:11][CH2:10][CH:9]([NH:7][CH3:6])[CH2:14][CH2:13]2)[C:39]([C:38]2[S:37][C:36]3[C:42]([F:47])=[CH:43][CH:44]=[C:45]([F:46])[C:35]=3[C:34]=2[Cl:33])=[O:40])=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2cccnc2F)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CNC1CCC(N(Cc2cc(-c3cccnc3F)ccc2OC)C(=O)c2sc3c(F)ccc(F)c3c2Cl)CC1

Procedure:
Following the synthetic protocol described in Method D′; 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carboxylic acid [5-(2-fluoro-pyridin-3-yl)-2-methoxy-benzyl]-(4-methylamino-cyclohexyl)-amide is prepared starting from {4-[5-(2-Fluoro-pyridin-3-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester and 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carbonyl chloride. The desired product is isolated in 45%.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7].[C:10]([N:17]1C=CN=C1)(N1C=CN=C1)=[O:11].CCN(C(C)C)C(C)C.Cl.[CH2:32]([O:39]N)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][C:10](=[O:11])[NH:17][O:39][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(CCCN)OC
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(CCCNC(=O)NOCc1ccccc1)OC
Temperature: 60 °C
Yield: 74.1 %

Procedure:
To a solution of 4-aminobutyraldehyde dimethyl acetal (2.73 g, 20.5 mmol) in THF (50 mL) was added 1,1′-carbonyldiimidazole (3.39 g, 20.9 mmol) and the resultant mixture was stirred at room temperature for 45 minutes. The mixture was concentrated under reduced pressure and the residue was dissolved in DMF (50 mL) and treated with DIPEA (18 mL, 103 mmol) and benzyloxyamine hydrochloride (10.2 g, 64.0 mmol). The mixture was heated at 60° C. overnight then concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and the solution was washed with brine (5×25 mL), dried (MgSO4), and concentrated. Purification of the crude material by column chromatography on silica gel (4:1 hexanes—EtOAc followed by 100% EtOAc) provided 4.29 g (73%) of 3-(4,4-dimethoxy-butyl)-1-(benzyloxy)-urea as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH:25]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)(=[O:15])[CH2:11][C:12]([CH3:14])=O.[NH2:40]/[C:41](/[CH3:48])=[CH:42]\[C:43]([O:45][CH2:46][CH3:47])=[O:44]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:41]([CH3:48])[NH:40][C:12]([CH3:14])=[C:11]2[C:10]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH:25]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=3)[CH2:21][CH2:20]2)=[O:15])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccc(C)cc2)c2ccc(C)cc2)CC1
Reactant: O=Cc1cccc(Cl)c1
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccc(C)cc3)c3ccc(C)cc3)CC2)C1c1cccc(Cl)c1
Yield: 48.4 %

Procedure:
A mixture of m-chlorobenzaldehyde, 2-[4-(4,4'-dimethylbenzhydryl)-1-piperazinyl]ethyl acetoacetate and ethyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-[4-(4,4'-dimethylbenzhydryl)-1-piperazinyl]ethyl ethyl 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as a colorless powder, m.p. 79°-81° C. (sintering). Yield 48.4%. IR(Nujol)cm-1 : 3330, 1680. NMR(CDCl3) δ: 1.16(3H,t,J=7,--CH2CH3), 2.22(6H,s, ##STR44## 2.28(6H,s, ##STR45## 4.05(2H,q,J=7,--CH2CH3), 4.08(1H,s,>N--CH<), 4.11(2H,t,J=6,--COOCH2CH2 --), 4.93(1H,s,C(4) --H), 5.64(1H, broad s, NH).
Reaction SMILES: [CH2:1]([N:5]1[C:12](=[O:13])[C:11]2[CH2:14][CH:15]3[CH2:17][CH:6]1[CH:7]=[CH:8][S:9][C:10]=2[S:16]3)[CH:2]([CH3:4])[CH3:3].COC1C=CC(C[NH2:25])=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl[S:35]([OH:38])(=O)=[O:36]>>[CH2:1]([N:5]1[C:12](=[O:13])[C:11]2[CH2:14][CH:15]3[CH2:17][CH:6]1[CH:7]=[C:8]([S:35]([NH2:25])(=[O:38])=[O:36])[S:9][C:10]=2[S:16]3)[CH:2]([CH3:4])[CH3:3]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)CN1C(=O)C2=C3SC=CC1CC(C2)S3
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CC(C)CN1C(=O)C2=C3SC(S(N)(=O)=O)=CC1CC(C2)S3
Reaction time: 0.5 h

Procedure:
5-Isobutyl-4-oxo-3,4,5,6-tetrahydro-2H-2,6-methanothieno[3,2-g]-l,5-thiazocine, prepared as described in Example 1, steps A, B and C but substituting isobutylamine for 4-methoxybenzylamine (4 g, 15 mmol), was added to a mixture of phosphorous pentachloride (6.23 g, 30 mmol) and chlorosulfonic acid (7 ml) at 0° C. After 0.5 hour at this temperature and 0.5 hour at 50° C., the reaction mixture was poured over crushed ice. The resulting sulfonyl chloride was separated and treated with concentrated aqueous ammonia (100 ml) in ethyl acetate (100 ml) at 0° C. The ethyl acetate layer was separated and evaporated under reduced pressure. The resulting solid was chromatographed over silica gel (ethyl acetate: hexane; 1:1) to give 2.0 g of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=3)=[CH:23][N:24]=[N:25]2)=[CH:20][CH:19]=1>C(Cl)(Cl)Cl.O>[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([NH:1][CH:2]4[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]4)(=[O:36])=[O:37])=[CH:33][CH:34]=3)=[CH:23][N:24]=[N:25]2)=[CH:20][CH:19]=1
Reactant: CCN1CCCC(N)C1
Reactant: O=S(=O)(Cl)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN1CCCC(NS(=O)(=O)c2ccc(Nc3cnnc4cc(Cl)ccc34)cc2)C1
Temperature: 3 °C
Reaction time: 0.75 h

Procedure:
3-Amino-1-ethylpiperidine (0.4 ml) in chloroform (15 ml) was treated with anhydrous sodium carbonate (2.94 g) in water (15 ml) and cooled to 3° C. The mixture was vigorously stirred and treated with 4-(7-chloro-4-cinnolinylamino)benzenesulphonylchloride hydrochloride (1.0 g). The dark orange mixture was stirred at 3° C. for 15 minutes, then at room temperature for 45 minutes. During this period the colour lightened considerably. The chloroform layer was separated and dried over magnesium sulphate. The residue on evaporation solidified when triturated with methanol, to give the title compound (0.5 g), m.p. 213°-15° C. (with decomposition).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:5][S:6][C:7]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:10])#[N:2].S(=O)(=O)(O)[OH:28]>>[NH2:2][C:1]([C:3]1[C:4]([C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[N:5][S:6][C:7]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:10])=[O:28]
Reactant: COC(=O)CCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C#N
Reactant: O=S(=O)(O)O
Product: COC(=O)CCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
Methyl 3-[({[4-cyano-3-(4-nitrophenyl)isothiazol-5-yl]amino}carbonyl)amino]propanoate (36.0 g) was added portion wise to concentrated sulfuric acid (150.0 mL) at ambient temperature over 20 min. The resulting suspension was heated to 45° C. over 90 min. The reaction mixture was cooled to ambient temperature. The reaction mixture was poured into ice water (600 ml), stirred for 30 min. The solid which formed was collected by filtration and washed with water then dried in vacuo to give the title compound as an off white solid (28.0 g, 75%).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:9]=1)=[O:7])(C)(C)C.O.[OH-].[Li+]>O1CCCC1.O>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Yield: 68.1 %

Procedure:
To a stirred solution of 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (6-01) (5 g, 10.68 mmol) in a mixture of tetrahydrofuran and water (2:1, 90 mL) was added lithium hydroxide, monohydrate (2.2 g, 53.4 mml). The mixture was refluxed for 18 h. After completion of the reaction, the volume was reduced by evaporation as much as possible, water was added and the mixture was washed with ethyl acetate to remove non-acidic impurities. The separated aqueous part was acidified with 1N HCl to bring the pH to about 5 to 6. The acidified aqueous part was extracted with dichloromethane to get 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid (7-01) (3 g, 68%) as a white solid.