Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][C:9]1[O:13][C:12]([N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[CH3:19])=[N:11][C:10]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=O)=O.O[C:28]1[CH:37]=[CH:36][C:31]([C:32](OC)=[O:33])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[CH3:19])[O:13][C:9]=2[CH2:8][CH2:7][CH2:6][O:5][C:28]2[CH:37]=[CH:36][C:31]([CH2:32][OH:33])=[CH:30][CH:29]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOS(C)(=O)=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccc(CO)cc2)o1
Temperature: 90 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A mixture of 3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyl methanesulfonate (395 mg), methyl 4-hydroxybenzoate (225 mg), potassium carbonate (276 mg) and N,N-dimethylformamide (10 ml) was stirred at 90° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained yellow oily substance was dissolved in tetrahydrofuran (30 ml), lithium aluminum hydride (80 mg) was added little by little at 0° C., and stirring was carried out at 0° C. for 1 hour. To the reaction mixture, sodium sulfate decahydrate (1.0 g) was added, and stirring was carried out at room temperature for 30 minutes, after which filtration was carried out. The filtrate was concentrated and the residue was purified by silica gel column chromatography. From the fraction eluted with ethyl acetate, 4-({3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyl}oxy)benzyl alcohol (304 mg, yield 72%) was obtained as a colorless oily substance.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O[C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=1.P(CCCC)(CCCC)CCCC>C1COCC1>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([O:20][C:26]3[CH:25]=[CH:24][CH:36]=[CH:35][C:27]=3[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)COc1ccc(O)cc1
Reactant: CCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCCC(Oc1ccccc1OCC(=O)OCC)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 26.9 %

Procedure:
To a solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (99 mg, 0.32 mmol) in dry THF (6.4 mL) at 0° C. (ice/water bath) under nitrogen was added ethyl (4-hydroxyphenoxy)acetate (63 mg, 0.32 mmol) followed after 1 minute by ADDM (164 mg, 0.64 mmol) in one portion. The resulting orange slurry was stirred for 2 minutes and then treated with nBu3P (159 μL, 0.64 mmol) drop-wise over 1 minute. The resulting pale yellow/orange mixture was then allowed to warm slowly to rt over 69 hours. The cloudy mixture was then reduced under vacuum and the residue purified by SPE (silica) eluting with cyclohexane:EtOAc (gradient 100:1 to 1:1) to give the title compound (42 mg).
Reaction SMILES: [CH3:1][C:2]1(C)OC(=O)[CH:5]([CH:9]([C:20]2[C:28]3[C:23](=[C:24]([CH2:29][S:30][CH3:31])[CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[C:4](=[O:32])[O:3]1>N1C=CC=CC=1.C(O)C.[Cu]>[CH3:31][S:30][CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[NH:22][CH:21]=[C:20]2[CH: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)[CH2:5][C:4]([O:3][CH2:2][CH3:1])=[O:32]
Reactant: CSCc1cccc2c(C(c3ccc4ccccc4c3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(c1ccc2ccccc2c1)c1c[nH]c2c(CSC)cccc12

Procedure:
1.2 mg (0.02 mmol) of copper powder were added to 882 mg (1.92 mmol) of the compound from Example 20A in 15 ml of pyridine and 5 ml of ethanol. The reaction mixture was heated under reflux for 2 h. It was concentrated, and the crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) and preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to result in 635 mg (82% of theory) of the title compound.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[O:17][C:16]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C@H:27]4[CH2:32][CH2:31][C@H:30]([CH2:33][C:34]([O:36]C)=[O:35])[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)=[O:19])=[N:15][N:14]=2)=[CH:8][CH:7]=1)[CH3:5].Cl>O.C1COCC1.CO>[CH2:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[O:17][C:16]([C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C@H:27]4[CH2:32][CH2:31][C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)=[CH:25][CH:26]=3)=[O:19])=[N:15][N:14]=2)=[CH:8][CH:7]=1)[CH3:5]
Reactant: CCc1ccc(Nc2nnc(C(=O)Nc3ccc([C@H]4CC[C@H](CC(=O)OC)CC4)cc3)o2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1ccc(Nc2nnc(C(=O)Nc3ccc([C@H]4CC[C@H](CC(=O)O)CC4)cc3)o2)cc1
Reaction time: 24 h

Procedure:
A solution of lithium hydroxide monohydrate (110 mg, 2.64 mmol.) in water (1.4 mL) was added to a suspension of methyl (trans-4-{4-[({5-[(4-ethylphenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}cyclohexyl)acetate (152 mg, 0.33 mmol) in THF (1.6 mL) and MeOH (2.6 mL). After 24 h, 1M aqueous HCl (5 mL) was added followed by water (10 mL). The solid was filtered off and washed with water (2×5 mL), Et2O (2×5 mL) then hexane (2×5 mL) to give the title compound as a solid (105 mg, 71%); 1H NMR δ 1.04-1.19 (5H, m), 1.37-1.51 (2H, m), 1.65-1.85 (5H, m), 2.11-2.15 (2H, m), 2.39-2.47 (1H, m), 2.57 (2H, q), 7.21 (4H, m), 7.49 (2H, d), 7.68 (2H, d), 10.84 (1H, s), 10.91 (1H, s), 11.99 (1H, s); MS m/e MH+ 449.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].[Br:5][C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([Cl:13])[CH:7]=1.O>CN(C)C=O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([S:3][CH2:1][CH3:2])=[C:8]([Cl:13])[CH:7]=1
Reactant: CC[S-]
Reactant: Fc1ccc(Br)cc1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1ccc(Br)cc1Cl
Temperature: 65 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
Sodium ethanethiolate (2.0 g) was added to a solution of 4-bromo-2-chloro-1-fluorobenzene (5.0 g) in N,N-dimethylformamide (20 mL), and the mixture was stirred at 65° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:1→0:100) to give the title compound as a colorless oil (4.8 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:10]([CH3:20])[C:9]2[C:8]([OH:21])=[CH:7][C:6]([CH3:22])=[CH:5][C:4]=2[N:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36](=[O:39])[CH2:37]Br>O>[CH3:34][O:35][C:36](=[O:39])[CH2:37][O:21][C:8]1[CH:7]=[C:6]([CH3:22])[CH:5]=[C:4]2[C:9]=1[C:10]([CH3:20])=[C:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:2]([Cl:1])=[N:3]2
Reactant: Cc1cc(O)c2c(C)c(Cc3ccc(Cl)cc3)c(Cl)nc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc(C)cc2nc(Cl)c(Cc3ccc(Cl)cc3)c(C)c12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-3-(4-chlorobenzyl)-4,7-dimethylquinolin-5-ol (1.7 g), N,N-dimethylformamide (25 mL), potassium carbonate (2.1 g) and bromoacetic acid methyl ester (1.1 g) was stirred at 60° C. overnight. The mixture was cooled to room temperature, diluted with water and the resulting precipitate collected by filtration, washed with water and then dried to afford title compound, 0.53 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH3:10])[CH:5]=[N:6][CH:7]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH3:10])[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNCc1cncc(Br)c1
Product: CN(Cc1cncc(Br)c1)C(=O)c1ccccc1
Yield: 87.4 %

Procedure:
In a manner similar to that of Example 2(f), starting with 0.5 g (3 mmol) of (5-bromopyrid-3-ylmethyl)methylamine and 0.4 ml (3.6 mmol) of benzoyl chloride, 0.8 g (90%) of N-(5-bromopyrid-3-ylmethyl) -N-methylbenzamide is obtained.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:8]=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=N[CH:18]=2)[O:10][C:11]=1[CH3:12])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[CH:24][CH:23]=1.[C:39](=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:9]2[O:10][C:11]([CH3:12])=[C:7]([CH:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[CH:26][CH:27]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=2)=[CH:18][CH:39]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2cc(C(Cl)CC(C)C)c(C)o2)cn1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)cc3)oc2C)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[4-(1-chloro-3-methylbutyl)-5-methylfuran-2-yl]-2-methoxypyridine (382 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (400 mg), sodium carbonate (170 mg) and sodium iodide (240 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 65% ethyl acetate/hexane) to give ethyl 3-[{[4-({1-[5-(4-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate. Ethyl 3-[{[4-({1-[5-(4-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (210 mg, 34%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH3:16])[C:3]=1[C:4]#[N:5].[S:17](Cl)(=[O:20])(=[O:19])[NH2:18].C(O)C.[OH-].[Na+]>CC(N(C)C)=O.C(OCC)(=O)C>[NH2:5][C:4]1[C:3]2[C:6]([O:10][C@@H:11]3[CH2:15][CH2:14][CH2:13][C@H:12]3[CH3:16])=[CH:7][CH:8]=[CH:9][C:2]=2[NH:1][S:17](=[O:20])(=[O:19])[N:18]=1
Reactant: C[C@@H]1CCC[C@H]1Oc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CCC[C@H]1Oc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 2-amino-6-(trans-2-methylcyclopentyloxy)benzonitrile (Example 264a) (150 mg, 0.694 mmol) in dimethylacetamide (3 mL) under N2 was added sulfamoyl chloride (3 equiv.). The reaction mixture was stirred at room temperature under N2 for 2 hours, diluted with ethyl acetate (50 mL) and quenched with water (20 mL). The layers were separated. The organic extract was evaporated. Ethanol (3 mL) and aqueous NaOH (2N, 2.5 equiv.) were consecutively added to the residue. The resulting mixture was heated at 90° C. for 16 hours. The workup was performed as in Example 111 to provide the desired product (160 mg, 78%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 1.02 (d, J=6.4 Hz, 3H), 1.26 (m, 1H), 1.71 (br s, 3H), 1.89 (m, 1H), 2.12 (m, 1H), 2.24 (m, 1H), 4.55 (br s, 1H), 6.60 (d, J=8.0 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.73 (br s, 1H), 8.35 (br s, 1H), 10.96 (br s, 1H). MS 296 (MH+).
Reaction SMILES: O[C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:19].[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.CCN(CC)CC>O>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:19])[N:7]=3)=[CH:16][CH:15]=2)=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(-c2ccnc(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)c1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
The crude 4-(2-hydroxy-pyrimidin-4-yl)-benzoic acid is treated with POCl3 (4 mL) at 100° C. for 14 h and cooled down to room temperature. POCl3 is removed under vacuum and the residue is flushed once with toluene (3 mL). The residue is dissolved in anhydrous dichloromethane (4 mL) and put into ice bath. 4-Chloroaniline (790 mg, 6.28 mmol) is added followed by the addition of Et3N (1.2 g, 12 mmol). After stirring at 0° C. for 1 h, the mixture is poured into water (100 mL) and extracted with EtOAc (3×50 mL). The combined extracts is washed with brine, dried (MgSO4) and concentrated. The residue is purified by flash column chromatography (silica gel, 0-80% EtOAc/hexane) to provide the desired N-(4-chloro-phenyl)-4-(2-chloro-pyrimidin-4-yl)-benzamide as yellow solid (650 mg, 44%). HPLC-MS calculated C17H11Cl2N3O (M+1+): 344.0. Found: 344.0.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][C:7]=2[C:8]#[N:9])[CH2:3][CH2:2]1.Br[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([Cl:30])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:30][C:26]1[CH:25]=[C:24]([C:11]2[CH:12]=[CH:13][C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)=[C:7]([CH:10]=2)[C:8]#[N:9])[CH:29]=[CH:28][N:27]=1
Reactant: Clc1cc(Br)ccn1
Reactant: CC1(C)OB(c2ccc(OCC3CC3)c(C#N)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1cc(-c2ccnc(Cl)c2)ccc1OCC1CC1
Temperature: 90 °C
Reaction time: 6 h
Yield: 73.8 %

Procedure:
A solution of 2-cyclopropylmethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (3.0 g, 0.010 mol) in acetonitrile (60 ml) and water (20 ml) is degassed for 10 min. 4-Bromo-2-chloropyridine (1.92 g, 0.010 mol), potassium carbonate (2.76 g, 0.02 mol) and tetrakis(triphenyl phosphine)palladium(0) (0.11 g, 0.0001 mol) are added. The reaction mixture is stirred at 90° C. for 6 h. The mixture is cooled to room temperature, filtered and evaporated in a rotary evaporator. The residue is taken up in ethyl acetate (200 ml), washed with water (2×200 ml) and saturated sodium chloride solution (1×200 ml). The mixture is subsequently dried over sodium sulfate, evaporated in a rotary evaporator and chromatographed for purification, giving 2.1 g of a pale-yellow solid;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:19])[N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[S:11].[I:20][CH3:21]>CO>[I-:20].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH+:9]=[C:10]([NH:12][C:13](=[O:19])[N:14]([CH2:15][CH3:16])[CH2:17][CH3:18])[S:11][CH3:21]
Reactant: CCN(CC)C(=O)NC(=S)Nc1c(C)cccc1C
Reactant: CI
Solvent: CO
Product: CCN(CC)C(=O)NC(=[NH+]c1c(C)cccc1C)SC
Product: [I-]

Procedure:
(0.1 mole) of 1-(2,6-dimethylphenyl)-3-(N,N-diethylcarbamyl)thiourea is combined with 200 ml. of methanol and 14.1 g. (0.1 mole) of iodomethane and refluxed for 4 hours. This is then evaporated to dryness and 100 ml. of hexane is added. The mixture is filtered to obtain 1-(2,6-dimethylphenyl)-3-(N,N-diethylcarbamyl)-2-methylthiouronium iodide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([CH3:22])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:27]4[CH:28]=[CH:29][C:24]([NH2:23])=[N:25][CH:26]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)=[CH:15][C:16]=1[CH3:21]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-3-methylphenyl)-6-methyl-pyrimidine (example E.77) (0.37 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.24 g, 1.2 mmol) according to the general procedure VI. Obtained as a white solid (0.27 g, 70%). MS (ISP) 387.2 [(M+H)+]; mp 158° C. (dec.).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]2[N:8]=[C:9]([C:13]([OH:15])=O)[CH:10]=[C:11]([CH3:12])[C:6]2=[N:5][N:4]=1.F[B-](F)(F)F.C(OC([C:26](=NOC(N(C)C)=[N+](C)C)[C:27]#[N:28])=O)C.C(NCC)C>CN(C=O)C>[CH2:27]([NH:28][C:13]([C:9]1[CH:10]=[C:11]([CH3:12])[C:6]2[N:7]([C:3]([NH2:2])=[N:4][N:5]=2)[N:8]=1)=[O:15])[CH3:26]
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Reactant: Cc1cc(C(=O)O)nn2c(N)nnc12
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCNC(=O)c1cc(C)c2nnc(N)n2n1
Reaction time: 2 h
Yield: 38.9 %

Procedure:
3-Amino-8-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylic acid hydrochloride (W1.141; 300 mg) was dissolved in DMF (6 ml) and admixed with O-[(ethoxycarbonyl)-cyanomethyleneamino]-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TOTU; 429 mg) and diethylamine (573 mg). After 2 h, the DMF was drawn off and the residue was purified using silica gel (24 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). The product was taken up with water and freeze-dried. In order to remove residual diethylamine, the mixture was chromatographed using a short column (dichloromethane/methanol 95:5). 112 mg of the title compound were obtained, which was still contaminated with diethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([NH:54][C:55]2[S:56][CH:57]=[CH:58][N:59]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1nccs1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
A solution of rac-(3,4-dichloro-phenyl)-[(tetrahydro-pyran-4-yl)oxy]-acetic acid (90 mg, 0.30 mmol) in dichloromethane (10 mL) was treated with BOP reagent (195 mg, 0.44 mmol), triethylamine (0.12 mL, 0.88 mmol), and 2-aminothiazole (44 mg, 0.44 mmol) at 25° C. After the resulting brownish-orange solution was stirred 16 h at 25° C., it was diluted with water (10 ml) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (1×10 mL), 1N sodium hydroxide solution (1×10 mL), 1N hydrochloric acid (1×10 mL) and brine (1×10 mL), then were dried over sodium sulfate and evaporated in vacuo. The residual material was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) to give rac-2-(3,4-dichloro-phenyl)-2-[(tetrahydro-pyran-4-yl)oxy]-N-thiazol-2-yl-acetamide (98 mg, 86% yield) as a white foam: EI-HRMS m/e calcd for C16H16Cl2O3N2S (M+) 386.0258, found 386.0261.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:26]C(C)C)=[C:22]([CH:25]=3)[C:23]#[N:24])=[N:14][C:12]=2[N:13]=1.[OH:37]S(O)(=O)=O.[OH-].[Na+]>O>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([OH:26])=[C:22]([CH:25]=3)[C:23]([NH2:24])=[O:37])=[N:14][C:12]=2[N:13]=1
Reactant: CC(C)Oc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1C#N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@H]1COCCN1c1nc(N2CCOC[C@@H]2C)c2ccc(-c3ccc(O)c(C(N)=O)c3)nc2n1
Temperature: 90 °C

Procedure:
5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-isopropoxy-benzonitrile (1 equiv) was added portionwise to concentrated H2SO4 (0.1 M substrate in acid). The reaction was heated to 90° C. and maintained at this temperature until all starting material had dissolved to give a bright red solution. The mixture was cooled and water (2 reaction volumes) added dropwise, then the solution was neutralized by careful addition of solid NaOH until pH 4-5 was attained. The mixture was cooled and neutralised by addition of 2N NaOH and then extracted using EtOAc (2×10 reaction volumes). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash chromatography (SiO2) using MeOH/DCM—0:100 going to 5:95 as eluent to give the desire product as a yellow powder.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].C(OC([NH:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)=O)(C)(C)C>>[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)(=[O:3])=[O:4])=[CH:32][CH:31]=1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Product: CCC(=O)[O-]
Product: Nc1ccc(NS(=O)(=O)c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cc1
Yield: 5.1 %

Procedure:
This compound is prepared according to synthesis 25, from 150 mg (0.46 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 115 mg (0.55 mmol) of N-tert-butoxycarbonyl-para-phenylenediamine. After purification by chromatography on silica gel (chloroform/methanol/ammonia 90/25/4) then trituration in diethyl ether, 5 mg (3%) of 8-(4-aminophenylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH:7]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([C:22]3[C:23](=[O:29])[NH:24][C:25](=[O:28])[NH:26][CH:27]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl[CH2:38][C:39]1[N:44]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:42]=[CH:41][CH:40]=1>CS(C)=O>[CH:7]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([C:22]3[C:23](=[O:29])[NH:24][C:25](=[O:28])[N:26]([CH2:38][C:39]4[N:44]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:42]=[CH:41][CH:40]=4)[CH:27]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cccc(CCl)n1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Cesium carbonate (1.63 g) was added to a stirred solution of the product of step (iv) (1.5 g) in dimethylsulphoxide (20 ml). After 15 minutes triethylamine (0.71 ml) was added followed by the product from step (ii) (1.11 g). The mixture was stirred at room temperature for 4 hours and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Purification was by chromatography eluting with 5% methanol in chloroform. Yield 1.86 g.