Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCC1>CCCCCC>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CCCCCC
Solvent: C1CCNC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (5.0 g 0.018 moles) and 5-Fluoro-1,3-dihydro-indol-2-one (2.705 g; 0.018 moles) in n-hexane were reacted in presence of catalytic amount of pyrrolidine (0.08 mL) as base at reflux temperature for 2-8 hours. The resultant Sunitinib base was triturated in n-hexane at reflux temperature for 1-2 hours and isolated at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:22][CH:23]=4)[N:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7](O)=[O:8].[CH3:33][C:34]1[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([NH2:41])[CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH3:33][C:34]1[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([NH:41][C:7]([C:6]2[C:5]3[CH:10]=[CH:11][C:12]([O:14][C:15]4[C:24]5[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][N:28]6[CH2:32][CH2:31][CH2:30][CH2:29]6)=[CH:22][CH:23]=5)[N:18]=[CH:17][CH:16]=4)=[CH:13][C:4]=3[O:3][C:2]=2[CH3:1])=[O:8])[CH:35]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: Cc1oc2cc(Oc3ccnc4cc(OCCN5CCCC5)ccc34)ccc2c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(NC(=O)c2c(C)oc3cc(Oc4ccnc5cc(OCCN6CCCC6)ccc45)ccc23)c1
Reaction time: 48 h

Procedure:
A solution of 121-G (43 mg), 4,6-dimethylpyridin-2-amine (25 mg), HATU (132 mg) and Et3N (47 mg) in DMF (2 ml) was heated to 70° C. for 4 hours. A small amount of product was seen by TLC. The reaction was allowed to stay for another 48 hours at room temperature. The reaction mixture was purified by HPLC (20-60% CH3CN/H2O, 0.1% AcOH over 30 min.) to give N-(4,6-dimethylpyridin-2-yl)-2-methyl-6-{[7-(2-pyrrolidin-1-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide 121.
Reaction SMILES: C([O-])(=O)/C=C\[C:4]([O-:6])=[O:5].C[O:10][C:11](=[O:39])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:38])[C@H:18]([CH3:37])[NH:19][C@H:20](OCC)[C:21](=C=O)[S:22][CH:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1>>[C:4]([C@@H:20]([NH:19][C@H:18]([C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[C:11]([OH:10])=[O:39])=[O:38])[CH3:37])[CH2:21][S:22][CH:23]1[CH2:24][C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:31]1)([OH:6])=[O:5]
Reactant: CCO[C@@H](N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC)C(=C=O)SC1Cc2ccccc2C1
Reactant: O=C([O-])/C=C\C(=O)[O-]
Product: C[C@H](N[C@@H](CSC1Cc2ccccc2C1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Following the general procedure of Example 59, the title compound was prepared as white crystals from 300 mg of the maleate of β-isomer of N-[(R)-1-ethoxy-carbonyl-2(2-indanyl)thioethyl]-alanyl-(S)-proline methyl ester prepared in Example 58. Yield 165 mg.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:13]([NH2:15])=O>>[Br:11][C:10]1[CH:9]=[C:8]([Cl:12])[CH:7]=[C:3]2[C:2]=1[N:1]=[CH:13][NH:15][C:4]2=[O:5]
Reactant: Nc1c(Br)cc(Cl)cc1C(=O)O
Reactant: NC=O
Product: O=c1[nH]cnc2c(Br)cc(Cl)cc12

Procedure:
8-Bromo-6-chloro-4(3H)quinazolinone was prepared from 2-amino-3-bromo-5-chlorobenzoic acid (10 g, 40 mmol). The acid was heated in excess formamide (50 mL) at reflux overnight. The mixture was cooled and quenched with water. The solid that formed was washed with acetonitrile, 6.7 g crude (65%); MS: 260.8 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]12[CH2:13][CH:12]1[CH2:11][N:10]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:9]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:33]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:30])[N:7]([CH3:33])[C:8]12[CH2:13][CH:12]1[CH2:11][N:10]([S:14]([C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)(=[O:16])=[O:15])[CH:9]2[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: Cc1ccc(S(=O)(=O)N2CC3CC3(NC(=O)OC(C)(C)C)C2c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CC3CC3(N(C)C(=O)OC(C)(C)C)C2c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 105.6 %

Procedure:
The starting material, racemic [2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acid tert-butyl ester (Intermediate 8) (0.6 g, 1.4 mmol) was slurried in DMF (5 mL) and the mixture was cooled to 0° C. Sodium hydride (oil free, 0.05 g, 2.1 mmol) was added in portions and the reaction was then stirred for 0.75 hours at room temperature. Methyl iodide (0.13 mL, 2.1 mmol) was added and the reaction stirred an additional hour at room temperature. The mixture was partitioned between 1N lithium chloride solution and EtOAc. The organics were washed with brine and dried over calcium sulfate, filtered and concentrated to give methyl-[2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acid tert-butyl ester as a yellow crystalline solid (0.654 g, 105%) which contained approximately 0.33 mol % of DMF by 1HNMR.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([CH3:15])[C:9]2=[O:16])=[N:6][CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#[CH:18].C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][N:10]1[C:11]([CH3:14])([CH3:13])[CH2:12][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:18]#[C:17][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:7][N:6]=2)[C:9]1=[O:16]
Reactant: C#Cc1ccccc1
Reactant: CN1C(=O)C(c2ccc(I)cn2)CC1(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1C(=O)C(c2ccc(C#Cc3ccccc3)cn2)CC1(C)C
Temperature: 60 °C
Yield: 80.6 %

Procedure:
A solution of (RS)-3-(5-iodopyridin-2-yl)-1,5,5-trimethylpyrrolidin-2-one (140 mg, 0.42 mmol), ethynylbenzene (65.0 mg, 69.9 μl, 0.64 mmol), triethylamine (129 mg, 177 μl, 1.27 mmol), bis(triphenylphosphine)palladium (II) chloride (17.9 mg, 25.4 μmol) and triphenylphosphine (3.34 mg, 12.7 μmol) in 4 ml of THF was purged with argon. Then copper (I) iodide (2.42 mg, 12.7 μmol) was added and the reaction was heated for 3 h at 60° C. After extraction with ethyl acetate/water, drying over sodium sulfate and concentration; the residue was taken up in ethyl acetate, adsorbed onto 3 g of silicagel which was loaded onto a 20 g prepacked flash chromato-graphy column. After elution with a 0% to 65% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 103 mg (72%) of the title compound as an amorphous yellow solid, MS: m/e=305.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:39])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C@@H:23]([N:31]3[CH2:36][C@@H:35]([CH3:37])[NH:34][CH2:33][C@@H:32]3[CH3:38])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=3)[CH:18]=2)[CH2:12][CH2:11]1)[CH3:2].[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH:45]=O>>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:39])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C@@H:23]([N:31]3[CH2:36][C@@H:35]([CH3:37])[N:34]([CH2:45][C:44]4[CH:47]=[CH:48][CH:49]=[C:42]([F:41])[CH:43]=4)[CH2:33][C@@H:32]3[CH3:38])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=3)[CH:18]=2)[CH2:14][CH2:15]1)[CH3:2]
Reactant: O=Cc1cccc(F)c1
Reactant: CCOC(=O)CCCCCN1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Product: CCOC(=O)CCCCCN1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4cccc(F)c4)C[C@@H]3C)c2)CC1
Yield: 54.1 %

Procedure:
The title compound was made by a procedure identical to that of Example 96 with 1.50 g of 6-(4-{3-[(R)-((2S,5R)-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperazin-1-yl)-hexanoic acid ethyl ester (2.72 mmol) and 0.68 g of 3-fluorobenzaldehyde (5.5 mmol) to give 0.97 g of desired compound as a light yellow solid. 1H NMR (300 MHz, d6-DMSO): □ 1.01-1.03 (d, J=5.8 Hz, 6H); 1.12-1.17 (t, 3H), 1.22-1.29 (m, 2H); 1.35-1.56 (m, 4H); 1.90-2.02 (m, 2H); 2.23-2.33 (m, 7H); 2.48-2.66 (m, 6H); 3.25-3.33 (m, 3H); 3.54-3.56 (m, 1H); 3.72-3.76 (dd, 1H); 3.98-4.05 (q, 2H); 4.95 (s, 1H); 6.62-6.71 (m, 3H); 6.97-7.43 (m, 9); 9.34 (s, 1H). MS: 659.0 (M+1, 80%), 437.2(85%), 221.2(100%), 209.1(70%). Calculated for C39H51FN4O4 0.11 CH2Cl2: C, 70.30; H, 7.73; N, 8.38; F, 2.84. Found: C, 70.32; H, 7.78; N, 8.41; F, 3.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>C(O)(=O)C>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1)[NH:6][CH2:14][CH2:13][C:12]([O:16][CH3:17])=[O:15]
Reactant: COc1cc(N)cc(OC)c1
Reactant: C=CC(=O)OC
Solvent: CC(=O)O
Product: COC(=O)CCNc1cc(OC)cc(OC)c1
Yield: 73.9 %

Procedure:
A mixture of 3,5-dimethoxyaniline (114.9 g., 0.75 mole), methyl acrylate (69.73 g., 0.81 mole) and glacial acetic acid (2 ml.) is refluxed for 20 hours. Reflux is discontinued and the reaction mixture is concentrated and then distilled in vacuo, to yield 106.8 g. (73.9%) of the title product, b.p. 174°-179° C. (0.7 mm.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12](=O)[NH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:12]1[CH:11]=[CH:10][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:14][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc(-c2ccc(=O)[nH]c2)c1
Product: COc1cccc(-c2ccc(Cl)nc2)c1

Procedure:
In the manner described in Example 26, a mixture of 5-(3-methoxyphenyl)-2(1H)-pyridinone and phosphorus oxychloride yields the product of the Example.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](O)(=[O:5])=[O:4].[NH2:9][C:10]1[S:11][C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]([F:8])([F:7])[S:3]([NH:9][C:10]1[S:11][C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[N:14]=1)(=[O:5])=[O:4]
Reactant: Nc1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)s1
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)s1)C(F)(F)F

Procedure:
2.68 ml of anhydrous trifluoromethanesulfonic acid was slowly dropped into a solution of 2.88 g of 2-amino-4,5-bis(4-fluorophenyl)thiazole and 1.8 ml of triethylamine in chloroform under stirring in a nitrogen atmosphere at -20° to -15° C., and the resulting mixture was stirred as such for 1 hour. Then the reaction mixture was successively washed with diluted hydrochloric acid, a 5% aqueous solution of sodium hydrogencarbonate and water in this order and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the reaction product was separated with a silica gel column by using isopropyl ether as a developer. The crystals thus obtained were recrystallized from petroleum ether/diethyl ether to give 0.47 g of 2-trifluoromethanesulfonylamino-4,5-bis(4-fluorophenyl)thiazole. The melting point of this product was from 193° to 195° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]1[CH2:10][NH:9][C:8]2[CH:11]=[C:12]([C:15]([O:17]C(C)(C)C)=[O:16])[CH:13]=[CH:14][C:7]=2[O:6]1.[C:23]1(C)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]1[CH2:10][N:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=[CH:14][C:7]=2[O:6]1
Reactant: Cc1ccccc1
Reactant: COC(=O)CC1CNc2cc(C(=O)OC(C)(C)C)ccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)CC1CN(c2ccccc2)c2cc(C(=O)O)ccc2O1
Yield: 51.2 %

Procedure:
To a stirred suspension of tert-butyl 2-(2-methoxy-2-oxoethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (5.3 g, 17.3 mmol) in toluene (50 mL) 1,4-cyclohexandione (2.8 g, 25 mmol) and p-toluenesulfonic acid (1 g) were added. The resulting solution was stirred at reflux for 4 hours, using a condenser equipped with a Dean-Stark apparatus. The reaction mixture was concentrated in vacuo. The remaining oil was purified by flash chromatography on silica gel column eluting with ethyl acetate to give 2-(2-methoxy-2-oxoethyl)-4-phenyl-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (2.9 g, 52%) as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH:10]([F:12])[F:11])=[C:6]([Cl:9])OC)C.[CH3:14][NH:15][NH2:16]>>[Cl:9][C:6]1[N:15]([CH3:14])[N:16]=[C:4]([OH:3])[C:5]=1[CH:10]([F:12])[F:11]
Reactant: CCOC(=O)C(=C(Cl)OC)C(F)F
Reactant: CNN
Product: Cn1nc(O)c(C(F)F)c1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
50.14 g (0.25 mol) of 3-chlorodifluoromethyl-3-methoxypropenoic acid ethyl ester was placed in a flask in ice water. 12.67 g (0.275 mol) of methylhydrazine was added while stirring until the reaction mixture boiled. Additional methylhydrazine was added and the mixture was left standing overnight. The solvent was evaporated off and the residue recrystallized from hot methylcyclohexane to give 17.4 g of off-white solid, m.p. 122°-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[O:33]([NH2:35])[CH3:34].O>C(Cl)Cl>[CH3:34][O:33][NH:35][C:17](=[O:19])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: CON
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CONC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A warm solution of 2-[(2,6-dichlorophenyl)amino]-benzeneacetic acid (2.03 g; 7 mmol) in CH2Cl2 (100 mL) is treated with 1,1'-carbonyl-diimidazole (1.75 g; 11 mmol) and the mixture is stirred at room temperature for 5.0 minutes when a clear solution is obtained. The solution is then treated with methoxylamine hydrochloride (1.50 g; 18 mmol) and the reaction mixture stirred at room temperature for 108 hours. It is then decomposed with water, extracted with CH2Cl2, dried over Na2SO4 and then evaporated to dryness to give a solid. Fractional recrystallization of the crude product from a mixture of toluene-CH2Cl2 gives off-white crystalline solid (1.27 g; 55.8%); mp 177°-178° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:15]1([NH:14][S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: O=C(O)c1cccc(S(=O)(=O)Nc2ccccc2)c1
Yield: 100.8 %

Procedure:
3-Chlorosulfonyl-benzoic acid (300 mg, 1.36 mmol), and aniline (0.30 mL, 3.29 mmol) were stirred at room temperature in anhydrous CH2Cl2 (10 mL) overnight under N2. The reaction mixture was concentrated in vacuo. Purification of the residue on IR-120 ion exchange resin column (eluted with methanol) afforded the title compound (380 mg, 100%) as a white solid.
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][N:9]=2)[CH2:4][CH2:3]1.[CH2:16]([NH:18][CH2:19][CH:20]=[O:21])[CH3:17]>C1C=CC=CC=1>[CH2:16]([N:18]([CH2:19][CH:20]=[O:21])[C:14]([NH:13][C:11]1[S:12][C:8]([CH:5]2[CH2:4][CH2:3][CH:2]([Cl:1])[CH2:7][CH2:6]2)=[N:9][N:10]=1)=[O:15])[CH3:17]
Reactant: O=C=Nc1nnc(C2CCC(Cl)CC2)s1
Reactant: CCNCC=O
Solvent: c1ccccc1
Product: CCN(CC=O)C(=O)Nc1nnc(C2CCC(Cl)CC2)s1

Procedure:
A mixture of 5-(4-chlorocyclohexyl)-1,3,4-thiadiazol-2-yl isocyanate dimer (13 grams), the dimethyl acetal of 2-ethylaminoacetaldehyde (6.9 grams) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-{1-ethyl-3-[5-(4-chlorocyclohexyl)-1,3,4-thiadiazol-2-yl]ureido}acetaldehyde.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:31]([C:34]3[CH:35]=[CH:36][C:37]([C:38]([OH:40])=[O:39])=[CH:41][CH:42]=3)(=[O:33])=[O:32])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-ol and 4-chlorosulfonyl-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a white solid, mp 186-188° C.; MS m/e 559 (M-H)+;
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[NH2:18][C:19]1[N:24]=[C:23]([C:25]2[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=2)[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22]([CH3:38])=[CH:21][N:20]=1>N1C=CC=CC=1>[F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:18][C:19]4[N:24]=[C:23]([C:25]5[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=5)[C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[C:22]([CH3:38])=[CH:21][N:20]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1cnc(N)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 90 °C

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (91 mg, 0.35 mmol) and tert-butyl 3-(2-amino-5-methylpyrimidin-4-yl)benzoate (50 mg, 0.175 mmol), pyridine (2 mL) was added. The reaction was heated at 90° C. for twenty four hours. The pyridine was evaporated under reduced pressure. The resulting mixture was dissolved in ethyl acetate and filtered. The filtrate was washed with saturated aqueous NaHCO3 (×3). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield tert-butyl 3-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-5-methylpyrimidin-4-yl)benzoate. ESI-MS m/z calc. 509.18, found 510.5 (M+1)+. Retention time 2.22 minutes
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([OH:15])[CH:10]([N+:12]([O-])=O)[CH3:11])=[CH:5][CH:4]=1.[H][H]>CO.[Pd]>[NH2:12][CH:10]([CH3:11])[CH:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[OH:15]
Reactant: [H][H]
Reactant: COc1ccc(C(O)C(C)[N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C(O)C(C)N)cn1
Yield: 23.7 %

Procedure:
1-(6-methoxypyridin-3-yl)-2-nitro-propan-1-ol (2.20 g, 10.37 mmol) was dissolved in methanol (410 mL) and hydrogenated using a H-Cube™ hydrogenation reactor (THALES nanotechnology) equipped with a cartridge of 10% Pd/C. The flow rate was set to 0.8 mL/min, temperature 80° C. and full the hydrogen production at full mode. After evaporation of the solution diastereomers can be separated on preparative HPLC (XTerrra C18, 19×50 mm) using a gradient of 5-30% acetonitrile in water (+1% NH3) gave the pure subtitle compound (448 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[CH2:5][CH2:6][OH:7].C(O[CH:17](OCC)[CH2:18][Cl:19])C.Cl>O>[Cl:19][CH2:18][CH:17]1[C:8]2[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=2[O:12][CH3:13])[CH2:5][CH2:6][O:7]1
Reactant: CCOC(CCl)OCC
Reactant: COc1ccc(OC)c(CCO)c1
Agent: Cl
Solvent: O
Product: COc1ccc(OC)c2c1CCOC2CCl
Reaction time: 1 h
Yield: 105.1 %

Procedure:
To a mixture of 10 g of 2,5-dimethoxyphenethyl alcohol and 10 g of chloroacetaldehyde diethyl acetal was added 14 ml of 10% hydrochloric acid and, after stirring at 80°-90° C for 1 hour, the reaction mixture was diluted with 100 ml of water and extracted with benzene. The extract was rinsed with water, dried and concentrated under reduced pressure. The residue was recrystallized from a solvent mixture of ether and petroleum ether. By the above procedure was obtained 14 g of 1-chloromethyl-5,8-dimethoxyisochroman as colorless needles, melting point: 101°-102° C.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[OH:5][C:6]1[C:7]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:7]1[C:6]([O:5][CH2:2][CH2:3][CH3:4])=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: CCCI
Reactant: COCCOc1c(O)cccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cccc(C=O)c1OCCOC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-Iodopropane (3.09 mL, 31.60 mmol) was added to a solution of 3-hydroxy-2-(2-methoxyethoxy)benzaldehyde (3.1 g, 15.8 mmol) and potassium carbonate (4.37 g, 31.60 mmol) in DMF (80 mL) and the mixture was stirred at 100° C. overnight under a nitrogen atmosphere. The reaction mixture was partitioned between saturated ammonium chloride (aq.) and CH2Cl2. The organic phase was washed with brine, dried (Na2SO4) and concentrated to give the title compound in quantitative yield (3.8 g) as an oil. This material was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][CH2:16][C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[F:15][CH2:16][C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([CH:6]3[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:7]3)=[CH:13][CH:12]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Reactant: C[C@@H](CF)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc([C@@H](C)CF)cc3)cc2)C1
Yield: 4.9 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (150 mg, 0.78 mmol) in CH2Cl2/pyridine 1:1 (12 ml) was treated with 4-((R)-2-fluoro-1-methyl-ethyl)-benzenesulfonyl chloride (242 mg, 1.02 mmol). Purification of the crude product by chromatography on reversed phase silica gel (H2O+0.1% acetic acid:CH3CN+0.1% acetic acid, 75:25) provided the title compound (15 mg, 5%) as a colourless gum.