Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]2[O:35][C:36]([C:39](Cl)=[O:40])=[CH:37][CH:38]=2)=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]2[O:35][C:36]([C:39](=[O:40])[NH:7][C:6]3[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=3)=[CH:37][CH:38]=2)=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.29 g (1.8 mmol) of 4-trifluoromethylaniline were initially charged in 20 ml of THF1 0.14 g (1.8 mmol) of pyridine were added and a solution of 0.5 g (1.5 mmol) of 1-benzyl-3-(5-chlorocarbonyl-2-furyl)indazole in 10 ml of THF was added dropwise at RT. After 0.5 h, the mixture was poured into ice-water and the precipitate was filtered off with suction and recrystallized from isopropanol. This gave 0.47 g (69%) of the title compound. m.p.: 205-206° C.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:17])[CH2:12][C:13]([CH2:15]Br)=O)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[CH3:21][NH:22][C:23]([NH2:25])=[S:24].C(=O)(O)[O-].[Na+]>O>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([CH2:12][C:13]2[N:25]=[C:23]([NH:22][CH3:21])[S:24][CH:15]=2)=[O:17])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nnc(NC(=O)CC(=O)CBr)s1
Reactant: CNC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CNc1nc(CC(=O)Nc2nnc(C(C)(C)C)s2)cs1
Yield: 87.2 %

Procedure:
A reaction mixture containing 11.4 g (0.035 mole) of N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-4-bromoacetoacetamide, 150 ml of ethanol and 3.3 g (0.036 mole) of N-methylthiourea was refluxed for four hours. The reaction solution was poured into 300 ml of water and treated with excess aqueous sodium bicarbonate. The product was isolated and dried. There was obtained 9.5 g (87.2%) of white solid, m.p. 198°-200° (dec.). N.M.R. (CDCl3) ∂ 1.4 [C(CH3)3 ], 3.0 (CH3), 3.8 (CH2), 6.4 (hetero-aromatic).
Reaction SMILES: C1(O)C=CC=CC=1.FC(F)(F)S(OC[P:15]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[PH:15](=[O:24])([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=P(COS(=O)(=O)C(F)(F)F)(OCc1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Oc1ccccc1
Solvent: CC#N
Product: O=[PH](OCc1ccccc1)OCc1ccccc1
Reaction time: 3 h
Yield: 88 %

Procedure:
A solution of phenol 17 (123 mg, 0.19 mmol) and dibenzyl trifluoromethansulfonyloxymethanphosphonate YY (120 mg, 0.28 mmol) in CH3CN (1.5 mL) at room temperature was treated Cs2CO3 (124 mg, 0.38 mmol). The mixture was stirred for 3 h and partitioned in CH2Cl2 and saturated NaHCO3. The organic layer was washed with 0.1N HCl, saturated NaCl, dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (10% MeOH/CH2Cl2) affording phosphonate 18 (154 mg, 88%). 1H NMR (CDCl3) δ 7.96 (s, 1H), 7.68 (d, 2H), 7.35 (m, 10H), 7.10 (d, 2H), 6.97 (d, 2H), 6.80 (d, 2H), 5.63 (d, 1H), 4.96-5.24 (m, 6H), 4.37 (m, 1H), 4.20 (d, 2H), 3.84 (s, 3H), 3.52-3.95 (m, 7H), 2.55-3.20 (m, 8H), 1.48-2.00 (m, 7H), 1.02 (m, 2H). 31P NMR (CDCl3) δ 20.3.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([NH:12][CH2:13][CH2:14][C:15]([NH:17][CH3:18])=[O:16])[CH3:11].C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:3]([N:12]([CH2:10][CH3:11])[CH2:13][CH2:14][C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCNCCC(=O)NC
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CCC(=O)NC)c1nc(Cl)ncc1Br
Temperature: 100 °C
Yield: 66 %

Procedure:
5-Bromo-2,4-dichloropyrimidine (Aldrich; 1.14 g, 5.00 mmol), 3-ethylamino-N-methyl-propanamide (Intermediate 83; 0.642 g, 5.00 mmol) and triethylamine (0.71 mL, 5.10 mmol) were combined in acetonitrile (25 mL) and heated to 100° C. for 4 hrs. The solvent was removed under reduced pressure and the residue taken up in Ethyl Acetate, washed with water and purified by flash silica chromatography (companion, 40 g, 0-10% Methanol/DCM) to give the title compound as a white solid (1.06 g, 3.3 mmol, 66%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[N:5]=[C:4]([NH:23][C:24]2[CH:29]=[C:28]([CH3:30])[C:27]([CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[CH:26][C:25]=2[O:38][CH:39]([CH3:41])[CH3:40])[N:3]=1.[NH2:42][NH2:43]>C(O)(C)C>[CH:39]([O:38][C:25]1[CH:26]=[C:27]([CH:31]2[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]2)[C:28]([CH3:30])=[CH:29][C:24]=1[NH:23][C:4]1[N:3]=[C:2]2[NH:42][N:43]=[C:8]([NH2:9])[C:7]2=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[N:5]=1)([CH3:41])[CH3:40]
Reactant: NN
Reactant: Cc1cc(Nc2nc(Cl)c(C#N)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C1CCN(C)CC1
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(N)n[nH]c3n2)c(OC(C)C)cc1C1CCN(C)CC1
Temperature: 120 °C

Procedure:
To a solution of 4-chloro-2-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenylamino)-6-(2-(isopropylsulfonyl)phenylamino)pyrimidine-5-carbonitrile (0.1 mmol) in 5 mL of isopropanol, was added hydrazine anhydrous (0.3 mmol). The solution was heated at 120° C. for 3 hours. Product was obtained after work-up and prep-HPLC. MS (ES+): 593.29 (M+1)+. 1H NMR (MeOD, 400 MHz) δ 8.01-8.03 (d, 1H), 7.83-7.86 (m, 1H), 7.31-7.43 (m, 3H), 6.91(s, 1H), 4.56-4.59 (m. 1H), 3.64-3.68 (m, 2H), 3.19-3.24 (m, 3H), 2.93(s, 3H), 2.25 (s, 3H), 2.02-2.07 (m, 4H), 1.17-1.32 (m, 12H); MS (ES+): 593.18 (M+1)+.
Reaction SMILES: [CH3:1][CH:2]([NH:5][S:6]([C:9]1[CH:20]=[C:13]2[C:14]([O:16]C(=O)[NH:18][C:12]2=[CH:11][CH:10]=1)=O)(=[O:8])=[O:7])[CH2:3][CH3:4].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)C.C(OCC)C>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:14](=[O:16])[C:13]2[C:12](=[CH:11][CH:10]=[C:9]([S:6](=[O:7])(=[O:8])[NH:5][CH:2]([CH2:3][CH3:4])[CH3:1])[CH:20]=2)[NH2:18])[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: CCC(C)NS(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Solvent: CCOCC
Solvent: CCO
Product: CCC(C)NS(=O)(=O)c1ccc(N)c(C(=O)N2CCN(C)CC2)c1

Procedure:
In a manner analogous to that described in Example 1, the reaction of 5-[N-(2-butyl)-sulfamoyl]-isatoic anhydride with 1-methylpiperazine yields 5-[N-(2-butyl)-sulfamoyl]-anthranilic acid (4-methyl)-piperazide with a melting point of 130°-132° (from an ethanol/diethyl ether mixture). The hydrochloride melts at 246°-248°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[C:18]([F:27])=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([CH3:26])=[CH:20]3)[N:13]=[CH:12][N:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C1([O:37][C:38](=O)[NH:39][C:40]2[CH:44]=[C:43]([C:45]([CH3:48])([CH3:47])[CH3:46])[O:42][N:41]=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:28])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[C:18]([F:27])=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:38](=[O:37])[NH:39][C:40]2[CH:44]=[C:43]([C:45]([CH3:47])([CH3:46])[CH3:48])[O:42][N:41]=2)[C:21]([CH3:26])=[CH:20]3)[N:13]=[CH:12][N:11]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: Cc1cc2c(F)c(Oc3cc(CN(C)C(=O)OC(C)(C)C)ncn3)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2c(F)c(Oc3cc(CN(C)C(=O)OC(C)(C)C)ncn3)ccc2n1C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [6-(4-fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-ylmethyl]-methyl-carbamic acid tert-butyl ester (275 mg, 0.712 mmol) in THF (7 mL), NaH (85 mg, 2.13 mmol) is added under nitrogen at 0° C. The resulting mixture is stirred for 2 h. Then (5-tert-butyl-isoxazol-3-yl)-carbamic acid phenyl ester (370 mg, 1.42 mmol) is added to this mixture. The resulting mixture is allowed to warm to rt and stir for 18 h. The mixture is then quenched with saturated aqueous ammonium chloride. The aqueous phase is extracted with EtOAc (2×). The combined organic layers are washed with brine, dried over anhydrous sodium sulphate, concentrated and purified by FCC (0-70% EtOAc/heptane) to provide the title compound. MS (ESI) m/z 553.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])[C:9]2=[O:12])=[CH:5][CH:4]=1>O1CCCC1>[CH2:7]([C:9]1([OH:12])[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH2:7][CH:8]1[NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])[C:6]1[CH:10]=[CH:11][CH:3]=[CH:4][CH:5]=1
Reactant: CCOC(=O)NC1Cc2ccc(OC)cc2C1=O
Solvent: C1CCOC1
Product: CCOC(=O)NC1Cc2ccc(OC)cc2C1(O)Cc1ccccc1
Temperature: 25 °C

Procedure:
To ice cold 2M benzylmagnesium chloride in tetrahydrofuran (6.14 ml, 12.28 mmol) was added dropwise a solution of ethyl 6-methoxy-1-oxo-2,3-dihydro-1H-inden-2-ylcarbamate (1.02 g. 4.09 mmol) in tetrahydrofuran (30 ml) and stirred over night, while the reaction mixture was allowed to warm up to room temperature. The reaction mixture was quenched with sat. ammonium chloride and the organic layer was evaporated. The residue was extracted twice with dichloromethane and the combined organic layers were washed subsequently with sodium bicarbonate and brine, dried, filtered and evaporated to obtain a dark gooey oil, that was purified by flash silica gel chromatography on 12 g SiO2-cartridge using 30% ethyl acetate in cyclohexane to afford the desired ethyl 1-benzyl-1-hydroxy-6-methoxy-2,3-dihydro-1H-inden-2-ylcarbamate as a brown grease. m=1.07 g (77%)
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.CN(C=O)C.[F:17][C:18]1[C:23]([OH:24])=[C:22]([CH:25]=[O:26])[CH:21]=[CH:20][C:19]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>O>[Br:1][C:20]1[C:19]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[C:18]([F:17])[C:23]([OH:24])=[C:22]([CH:25]=[O:26])[CH:21]=1
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Reactant: O=Cc1ccc(-c2ccc(F)cc2)c(F)c1O
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c(-c2ccc(F)cc2)c(F)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 181.8 %

Procedure:
Dibromoisocyanuric acid (8.87 g) was added at room temperature to a DMF (75 mL) solution of 2,4′-difluoro-3-hydroxybiphenyl-4-carbaldehyde (12.7 g), and the mixture was stirred at room temperature for 30 minutes. Water (50 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The resulting solid was collected by filtration, then washed with DMF-water, and dried to obtain the title compound (17.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30]CC)=[O:29])=[O:5])[CH3:2].[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:37]3[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([OH:30])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(OC(F)(F)F)cc2)c2ccc(Oc3ccc(Cl)cc3)cc12

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (150 mg, 0.39 mmol, see step (b) Example 9) and 4-chlorophenylboronic acid (110 mg, 0.68 mmol). Yield 140 mg (74%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][C:28](O)=[O:29]>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:28](=[O:29])[CH2:27][C:23]4[O:22][CH:26]=[CH:25][CH:24]=4)[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)Cc1ccco1
Product: Cc1ccc(NC(=O)Cc2ccco2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}6-methyl -1,1′-biphenyl-3-yl)-2-(fur-2-yl)acetamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4- carboxamide and fur-2-ylacetic acid using method D. NMR; δH [2H6]—DMSO 10.17,(1H, s), 8.61,(1H, t), 7.91,(2H, d), 7.55,(1H, m), 7.50-7.48,(2H, m), 7.40,(2H, d), 7.23,(1H, d), 6.38,(1H, m), 6.25,(1H, d), 3.70,(2H, s), 3.16,(2H, t), 2.16,(3H, s), 1.04,(2H, m), 0.42,(2H, m). LCMS: retention time 3.26 min, MH+389.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[N+:18]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.C(OCC)(=O)C.[Pd]>[NH2:18][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(NC2CCCCC2)c(N)c1

Procedure:
A solution of compound 45 (2.03 g, 7.29 mmol) in a mixture of methanol (25 mL) and ethyl acetate (25 mL) was hydrogenated over 10% palladium on carbon (0.20 g) at 25 psi for 15 h. The reaction mixture was filtered and concentrated to afford compound 46 as a crude grey-brown oil (1.99 g, 100%). ESI-MS m/e 249.3 (M+1).
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[CH3:13][O:14][C:15]1[CH:35]=[CH:34][CH:33]=[CH:32][C:16]=1[CH2:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:10][C:7]([N:18]([CH2:17][C:16]1[CH:32]=[CH:33][CH:34]=[CH:35][C:15]=1[O:14][CH3:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:6]
Reactant: COc1ccccc1CNc1ccccc1Oc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CN(C(=O)Cl)c1ccccc1Oc1ccccc1
Yield: 267.5 %

Procedure:
To a solution of 775 mg of triphosgene in 14 ml of methylene chloride was added gradually dropwise a solution of 2.16 g of N-(2-methoxybenzyl)-2-phenoxyaniline and 1.10 g of diisopropylethylamine in 25 ml of methylene chloride with stirring, followed by stirring at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure, poured into ethyl acetate, washed with 5% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:15) to give 2.57 g of N-chlorocarbonyl-N-(2-methoxybenzyl)-2-phenoxyaniline.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)#[N:9]>>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]#[N:9])=[CH:11][CH:12]=1
Reactant: OC(CCl)CCCl
Reactant: N#Cc1ccc(O)cc1
Product: N#Cc1ccc(OCC(O)CCCl)cc1
Yield: 13 %

Procedure:
Utilizing the procedure of Preparation 16, 1,4-dichloro-2-butanol was reacted with 4-cyanophenol to give white title compound, m.p. 78°-80° C. in 13% yield.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]([CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:15][C@@H:16]([OH:45])[C@@H:17]([NH:33][C:34](=[O:44])[O:35][C@@H:36]3[C@H:43]4[C@H:39]([O:40][CH2:41][CH2:42]4)[O:38][CH2:37]3)[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25]CC4C=CC=CC=4)=[CH:21][CH:20]=3)(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CO[C:52](OC)([CH3:54])[CH3:53].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]([CH2:15][C@H:16]3[O:45][C:52]([CH3:54])([CH3:53])[N:33]([C:34]([O:35][C@@H:36]4[C@H:43]5[C@H:39]([O:40][CH2:41][CH2:42]5)[O:38][CH2:37]4)=[O:44])[C@H:17]3[CH2:18][C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)[CH2:46][CH:47]([CH3:48])[CH3:49])(=[O:12])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COC(C)(C)OC
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(O)cc1)S(=O)(=O)c1ccc2c(c1)OCCO2

Procedure:
250 mg of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-benzyloxybenzyl)propylcarbamate, 2 mL of 2,2-dimethoxypropane, 0.5 g of p-toluenesulfonic acid in 50 mL of dichloromethane were refluxed for 3 h and then extracted with sodium bicarbonate solution. Chromatography on silica gel (1:1 ethylacetate/hexanes) gave 220 mg of the desired compound as an oil which was dissolved in methanol and hydrogenated (at 50 psi) over 5% palladium on carbon. Filtration and evaporation of the volatiles gave the desired title compound as an oil
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[NH4+:14]>CO>[NH2:14]/[C:2](/[CH2:8][CH3:9])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CC/C(N)=C/C(=O)OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.1 %

Procedure:
A mixture of methyl 3-oxovalerate (75.0 g, 576 mmol), ammonium acetate (222 g, 2.88 mol) and methanol (750 mL) was stirred at room temperature for 3 days. After concentration under reduced pressure, water (500 mL) was added to the residue and the mixture was extracted with ethyl acetate (200 mL). The extract was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and dried to give the title compound (68.5 g, 92%) as a pale-yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19]Br)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]>C(N(CC)CC)C.C(Cl)Cl.[OH-].[Na+]>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19][N:5]2[CH2:6][CH2:7][CH:3]([CH2:2][OH:1])[CH2:4]2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: OCC1CCNC1
Reactant: COc1ccc(CCBr)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCN2CCC(CO)C2)cc1OC

Procedure:
3 g (0.03 mol) of 3-hydroxymethyl-pyrrolidine and 7.5 g of 2-(3,4-dimethoxy-phenyl)-ethylbromide are heated in 20 ml of triethylamine for 7 hours at 100° C. The excess triethylamine is then distilled off in vacuo and the residue obtained is dissolved in methylene chloride and 6 molar sodium hydroxide solution. The organic phase is separated off, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue obtained is then purified over 400 g of alumium oxide (neutral, activity II) with methylene chloride and with increasing amounts of ethanol (up to 1%). Yield: 5.4 g (67.8% of theory), Rf value: 0.41 (aluminium oxide, neutral, eluant: 5% ethanol in methylene chloride).
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]([C@@H:10]([OH:16])[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CCCCC.CN(C=O)C>[CH2:18]([O:16][C@H:10]([C@@H:4]([O:3][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6])[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CN(C)C(=O)[C@H](O)[C@@H](O)C(=O)N(C)C
Reactant: CCCCCCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: CCCCCCCCCCCCO[C@@H](C(=O)N(C)C)[C@@H](OCCCCCCCCCCCC)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.4 %

Procedure:
Sodium hydride (3.60 g, 60%, 90.0 mmol) was washed with pentane (3×) before DMF (150 ml) and (+)-(2R,3R)-2,3-dihydroxy-N,N,N′,N′-tetramethylsuccinamide (9.2 g, 45.0 mmol, origin: Aldrich) were added. The reaction mixture was left stirring at room temperature for 90 min, then a solution of 1-iodododecane (28.0 g, 94.5 mmol) in DMF (50 ml) was added. The reaction was left stirring for another 2 h at room temperature and then heated at 80° C. overnight. After cooling to room temperature, the reaction mixture was extracted with ether (4×), washed with water (2×), dried (Na2SO4), and concentrated. Column chromatography (SiO2, dichloromethane/acetone 3:1) gave 5.93 g (28%) of a pale-yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:3]=1.[CH3:21][O-:22].[Na+]>CO.C(OCC)(=O)C>[CH3:21][O:22][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:3]=1
Reactant: Fc1ccc(-c2cc(Cl)nc(-c3ccccn3)n2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccc(F)cc2)nc(-c2ccccn2)n1
Yield: 77 %

Procedure:
5.5 g (0.02 mol) of 4-chloro-2-(2-pyridyl)-6-(4-fluorophenyl)-pyrimidine are dissolved in 50 ml of dry methanol, 8.6 g of a 22% strength solution of sodium methylate in methanol (corresponds to 0.04 mol) are added, and the mixture is refluxed for 40 hours. After the solvent has been removed, the residue obtained is taken up in ethyl acetate and the mixture is washed twice with water and dried over sodium sulphate. After the solvent has been removed, 4.3 g (77% of theory) of 4-methoxy-2-(2-pyridyl)-6-(4-fluorophenyl)-pyrimidine of melting point 97°-98° C. are obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH3:8].[S:9]1(=[O:20])(=[O:19])[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][CH2:11][NH:10]1>C(#N)C.O>[CH3:8][N:10]1[CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[S:9]1(=[O:20])=[O:19]
Reactant: CI
Reactant: O=S1(=O)NCNc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN1CNc2cccnc2S1(=O)=O
Temperature: 50 °C

Procedure:
0.52 g of potassium carbonate and 0.94 g of iodomethane are added to a solution of 0.25 g of 2,3- dihydro-4H-pyrido[3,2-e][1,2,4]thiadiazine 1,1-dioxide (Example 1) in 10 cm3 of acetonitrile. The suspension is heated at 50° C. for 3 hours. The acetonitrile is then removed by evaporation under partial vacuum and the residue obtained is taken up in 10 cm3 of water. The suspension is extracted with chloroform (5 times 100 cm3). The extraction solvent is dried over MgSO4 and then concentrated to dryness. The solid obtained is purified by chromatography on a silica column (elution solvent: 1/9 MeOH/CHCl3).