Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5].C(N(CC)CC)C.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>CN(C=O)C>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([NH:1][CH2:2][CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5])=[O:37]
Reactant: CCNC(=O)Nc1nc2ccc(C(=O)CCN)cc2s1
Reactant: O=C=Nc1ccccc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(C(=O)CCNC(=O)Nc3ccccc3F)cc2s1
Yield: 26 %

Procedure:
Similar to the synthesis of Example 249, a mixture of 1-(6-(3-aminopropanoyl)-2-benzothiazolyl)-3-ethylurea, triethylamine and 2-fluorophenyl isocyanate in DMF was reacted to give the desired compound 0.022 g (26%). LC/MS 430.01 (M+1); LC retention time 2.89 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:37]([S:40](Cl)(=[O:42])=[O:41])([CH3:39])[CH3:38].N1C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][S:40]([CH:37]([CH3:39])[CH3:38])(=[O:42])=[O:41])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(NS(=O)(=O)C(C)C)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reaction time: 76 h
Yield: 11.2 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in tetrahydrofuran (5 mL) was added at 0° C. potassium bis(trimethylsilyl)amide (0.91 M in tetrahydrofuran, 1.51 mL, 1.38 mmol). After stirring for 15 min at this temperature isopropylsulfonyl chloride (319 mg, 2.24 mmol) was added and stirring was continued at ambient temperature for 76 h. Further isopropylsulfonyl chloride (107 mg, 0.75 mmol) and pyridine (454 mg, 5.74) were added and stirring was continued for 24 h. The resulting suspension was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with aqueous sodium carbonate (saturated). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane 50:30:20 to 20:60:20) afforded the title compound (29 mg, 11%) as a yellow solid. MS: m/e 455.2 [M+H]+.
Reaction SMILES: C([BH3-])#N.[Na+].[OH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[CH2:15][CH:16]([OH:18])[CH3:17].N>C(O)(=O)C>[OH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][N:10]2[CH2:15][CH:16]([OH:18])[CH3:17]
Reactant: CC(O)Cn1ccc2c(O)cccc21
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(O)CN1CCc2c(O)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
1.4 g of sodium cyanoborohydride were added to a solution of 7 g of 4-hydroxy-1-N-(β-hydroxypropyl)indole, obtained in the preceding stage, in 40 cm3 of acetic acid, the temperature being maintained below 30° C. After stirring for 30 minutes, the reaction mixture was poured onto 200 g of ice-cold water and the pH was neutralized to 7.5 by addition of 30% aqueous ammonia. The precipitate obtained was filtered off and dried. 4 g of the expected product were obtained, the melting point of which was between 130 and 131° C. and the elemental analysis of which, calculated for C11H15NO2, was as follows:
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[OH:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH:20]=1)[C:17](O)=O.N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:17]([C:16]3[CH:20]=[C:12]([OH:11])[CH:13]=[N:14][CH:15]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: O=C(O)c1cncc(O)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Oc1cncc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 5-hydroxynicotinic acid (Matrix Scientific). 1H NMR (300 MHz, DMSO-d6) δ 7.66 (ddd, J=8.0, 4.9, 1.0 Hz, 1 H), 7.86 (dd, J=2.7, 2.0 Hz, 1 H), 8.31-8.55 (m, 2 H), 8.83 (s, 2 H), 9.26 (s, 1 H) ppm; MS (DCI/NH3) m/z 241 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1.[C:28]1(=[O:34])[NH:32][C:31](=[O:33])[CH2:30][CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1>[O:34]=[C:28]1[CH2:29][CH2:30][C:31](=[O:33])[N:32]1[CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1
Reactant: CN(c1cccc2cc(C3=NCC(CCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=C1CCC(=O)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(CCN4C(=O)CCC4=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.2 %

Procedure:
A solution (10 mL) of N-{2-[5-(2-hydroxyethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (100 mg), succinimide (29 mg) and triphenylphosphine (93 mg) in tetrahydrofuran was added a 40% toluene solution (0.155 mL) of diethyl azodicarboxylate, and the mixture was stirred at room temperature for 18 hr. A 40% toluene solution (0.155 mL) of diethyl azodicarboxylate was added again to the reaction solution, and the mixture was further stirred at room temperature for 5 days. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:8-10:0), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (36 mg, yield: 30%) as colorless prism crystals. MS: 503 (MH+). melting point 189-191° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][O:6][C@@H:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C@@H:3]1[OH:21].[OH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH:8]([C@H:5]1[CH2:4][C@H:3]([OH:21])[C@@H:2]([NH:1][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([OH:22])=[CH:24][CH:25]=2)[CH2:7][O:6]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: N[C@H]1CO[C@@H](C(c2ccccc2)c2ccccc2)C[C@@H]1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Oc1ccc(CN[C@H]2CO[C@@H](C(c3ccccc3)c3ccccc3)C[C@@H]2O)cc1

Procedure:
(2R,4S,5S)-5-amino-2-benzhydryl-tetrahydropyran-4-ol 31b (0.02 g, 0.07 mmol) was reacted with 4-hydroxybenzaldehyde (0.009 g, 0.071 mmol), glacial acetic acid (0.004 g, 0.071 mmol) and NaCNBH3 (0.005 g, 0.085 mmol) (Procedure H) to give (2R,4S,5S)-2-benzhydryl-5-(4-hydroxy-benzylamino)-tetrahydropyran-4-ol, (+)-32a, 0.023 g (85%, [α]D=(+)72.4, c=1, MeOH).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=[CH:20][C:15]=2[NH:14][C:13]1=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:32]1[C:33]2[CH:60]=[C:59]([Cl:61])[CH:58]=[CH:57][C:34]=2[N:35]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:36](=[O:47])[C@H:37]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])[N:38]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[C:18]([C:32]3[C:33]4[CH:60]=[C:59]([Cl:61])[CH:58]=[CH:57][C:34]=4[N:35]([CH2:48][C:49]4[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=4)[C:36](=[O:47])[C@H:37]([CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[Cl:46])[N:38]=3)[CH:19]=[CH:20][C:15]=2[NH:14][C:13]1=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2C(=O)[C@H](Cc3ccccc3Cl)N=C(Cl)c3cc(Cl)ccc32)cc1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(CN2C(=O)[C@H](Cc3ccccc3Cl)N=C(c3ccc4[nH]c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c4c3)c3cc(Cl)ccc32)cc1
Temperature: 90 °C
Yield: 12.6 %

Procedure:
1-(3-((Tert-Butyldimethylsilyl)oxy)propyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (0.46 g, 1.06 mmol) and (S)-5,7-dichloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.5 g, 1.06 mmol) were combined in toluene (4 mL) and saturated aqueous sodium bicarbonate (2 mL) and purged with nitrogen. Tetrakis(triphenylphosphine)palladium (122 mg, 0.106 mmol) was added and the mixture was heated at 90° C. for 7.5 h. After cooling, the mixture was diluted with ethyl acetate and washed twice with water then once with brine then dried (MgSO4). Chromatography, eluting with 10-50% ethyl acetate in hexanes gave the title compound as an orange brown solid (100 mg, 0.134 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1>>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:33]4[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(C)c3)cc3c2cnn3C2CCCC2)c(=O)[nH]1

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.226 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (70 mg, 0.338 mmol). The product was collected as a white solid (82 mg, 81%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (br. s., 1H) 8.48 (t, J=4.93 Hz, 1H) 8.30 (s, 1H) 8.26 (s, 1H) 8.04 (s, 2H) 7.81 (s, 1H) 5.90 (s, 1H) 5.22 (quin, J=7.14 Hz, 1H) 4.39 (s, 1H) 4.38 (s, 1H) 3.87-3.92 (m, 3H) 2.23 (s, 3H) 2.14-2.19 (m, 1H) 2.13 (s, 4H) 1.96-2.05 (m, 2H) 1.84-1.94 (m, 2H) 1.66-1.76 (m, 2H). LC-MS (ES) m/z=445.2 [M+H]+
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[S:15]1[C:19]2[C:20](C(Cl)=O)=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.Cl>C(#N)C.C(N(CC)CC)C>[S:15]1[C:19]2[C:20]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:12][CH2:13][CH3:14])=[O:11])=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1
Reactant: O=C(Cl)c1cccc2nnsc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)c1cccc2nnsc12
Temperature: 0 °C
Yield: 83.2 %

Procedure:
4.8 g of magnesium chloride in 50 ml of acetonitrile are treated with 7.6 ml of diethyl malonate and 14 ml of triethylamine, with ice-cooling and stirring. The mixture is stirred for 20 minutes and then treated at 0°-5° C. with portions of a suspension of 9.6 g of benzo-1,2,3-thiadiazole-7-carboxylic acid chloride in 50 ml of acetonitrile, the temperature being maintained at between 5° C. and 15° C. The resulting beige suspension is stirred for a further hour in an ice-bath at 0° C. and subsequently overnight at room temperature. On the next day, it is cooled again to 0° C., brought to pH 4.5 using 15% hydrochloric acid, and extracted with ethyl acetate. The extracts are dried over sodium sulfate, filtered over silica gel and evaporated. This results in the title compound in a yield of 83.2% of theory and with a melting point of 72°-74° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:17])=[N:14][CH:15]=[CH:16][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.CN1CC[O:22][CH2:21][CH2:20]1.C(Cl)(=O)C>C1COCC1>[NH2:17][C:13]1[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:22])[CH3:20])=[CH:7][CH:6]=3)=[CH:9][S:10][C:11]=2[CH:16]=[CH:15][N:14]=1
Reactant: Nc1ccc(-c2csc3ccnc(N)c23)cc1
Reactant: CN1CCOCC1
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(-c2csc3ccnc(N)c23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A −30° C. solution of Example 17A (0.1 g, 0.41 mmol) and N-methylmorpholine (0.03 mL, 0.41 mmol) in THF (5 mL) was treated dropwise with acetyl chloride (0.03 mL, 0.41 mmol), stirred for 1 hour, warmed to 0° C. over 1 hour, quenched with water, and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide 111 mg of the desired product. Rf=0.24 (5% methanol/dichloromethane).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3][C:2]1=[S:11].Cl[CH2:13][C:14](O)=[O:15].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[S:11]1[C:2]2=[N:1][C:10]3[C:5]([CH2:4][N:3]2[C:14](=[O:15])[CH2:13]1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: S=C1NCc2ccccc2N1
Reactant: O=C(O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CSC2=Nc3ccccc3CN12
Temperature: 90 °C

Procedure:
A mixture of 1.0 g (0.006 mol) 3,4-dihydro-2(1H)-quinazolinethione (compound II), 0.57 g (0.006 mol) chloroacetic acid, and 0.54 g (0.0065 mol) sodium bicarbonate is mixed in 31.25 ml water, and heated overnight at 90° C. Then, 12.5 ml of dimethylformamide is added, and the reaction mixture is refluxed for 61/2 hours. After cooling, 5H-thiazolo[2,3-b]quinazolin-3(2H)-one, as the precipitated solid, is filtered off and recrystallized from anhydrous ethanol. Replacement of 3,4-dihydro-2(1H)-quinazolinethione by a derivative thereof in which a nuclear hydrogen of the benzene ring has been substituted with lower alkyl, alkoxy, halogen, trifluoromethyl, NO2 or NH2, results in the corresponding derivative of 5H-thiazolo[2,3-b]quinazolin-3(2H)-one.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Br[CH2:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:25])[CH2:20][CH2:21][O:22]2)=[CH:17][C:16]=1[Cl:26]>C(Cl)Cl>[C:1]([NH:5][CH2:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:25])[CH2:20][CH2:21][O:22]2)=[CH:17][C:16]=1[Cl:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCOc2cc(CBr)c(Cl)cc21
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NCc1cc2c(cc1Cl)C(=O)CCO2
Reaction time: 16 h

Procedure:
To a stirred mixture of tert-butylamine (7.3 g, 99.78 mmol) and Et3N (10.1 g, 99.78 mmol) in anhydrous CH2Cl2 (50 mL) was added a solution of 7-bromomethyl-6-chloro-chroman-4-one (25 g, 90.71 mmol) in CH2Cl2 (150 mL) dropwise. Stirring was continued for 16 h. The mixture was concentrated, taken up in H2O, acidified with 10% HCl until pH 1, and extracted with Et2O (discarded). The acidic aqueous layer was neutralized with 5 N NaOH, and extracted with CH2Cl2 (3×). The combined extracts were dried over MgSO4, concentrated to give a yellow solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:32])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=4[O:30][CH3:31])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:33][NH2:34]>>[Cl:32][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=2[O:30][CH3:31])[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH3:33])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: COc1cccc(-c2cc(Cl)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1OC
Product: CNCC1Cc2cc(Cl)cc(-c3cccc(OC)c3OC)c2O1

Procedure:
The title compound was prepared (0.046 g, 34%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.172 g, 0.36 mmol) and methylamine (0.112 g, 3.6 mmol). mp 105-107° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(Br)c1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(Br)cccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a mixture of 2-bromo-6-methoxybenzoic acid (40 g, 0.176 mol) in DMF (300 mL) was added K2CO3 (24.8 g, 0.176 mol) and CH3I (37 g, 0.264 mol). The mixture was stirred at RT overnight. The reaction was quenched with 1M HCl aq and the mixture was extracted with EtOAc (3×300 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound (41 g, 99%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([NH:26][C:27]4[C:32]([F:33])=[CH:31][C:30]([Cl:34])=[CH:29][C:28]=4[F:35])=[N:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:36][CH3:37])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:34][C:30]1[CH:31]=[C:32]([F:33])[C:27]([NH:26][C:20]2[C:19]3[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[C:17]([O:36][CH3:37])[CH:18]=3)[N:23]=[CH:22][N:21]=2)=[C:28]([F:35])[CH:29]=1
Reactant: COc1cc2c(Nc3c(F)cc(Cl)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3c(F)cc(Cl)cc3F)ncnc2cc1OCC1CCNCC1
Yield: 23 %

Procedure:
Using an analogous procedure to that described in Example 9, 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(4-chloro-2,6-difluoroanilino)-6-methoxyquinazoline (95 mg, 0.2 mmol) in methylene chloride (2 ml) was treated with TFA (800 μl) to give 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (20 mg, 26%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(Cl)Cl.[CH3:21][O:22][C:23]([O:27][Si](C)(C)C)=[C:24]([CH3:26])[CH3:25]>C1COCC1.Cl[Ti](Cl)(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:24]([CH3:26])([CH3:25])[C:23]([O:22][CH3:21])=[O:27])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: OC(c1ccccc1)c1ccc2[nH]ncc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2[nH]ncc2c1
Reaction time: 12 h
Yield: 66.7 %

Procedure:
(1H-Indazol-5-yl)(phenyl)methanol (12.1 g, 54 mmol) was dissolved in 200 mL of dry THF and 200 mL of DCM and cooled to 0 C. Added 1-methoxy-2-methyl-1-(trimethylsiloxy)propene (43.6, 250 mmol) followed by dropwise addition of TiCl4 (60 mL of 1.0 M DCM solution, 60 mmol). After 12 h, the reaction was quenched with MeOH, poured into brine and extracted 2×DCM. The organic layers were dried over MgSO4, filtered, concentrated, and then chromatographed using 1:2 EtOAc/hexane to give 11.1 g (66% yield) of methyl 3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate which was separated by chiral chromatography. MS found: (M+H)+=309.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]([NH:20][CH:21]1[C:50](=[O:51])[N:23]2[CH:24]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[C:25]([CH2:29][O:30][C:31](=[O:33])[CH3:32])=[C:26]([CH3:28])[S:27][C@H:22]12)=[O:19]>C(Cl)Cl>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]([NH:20][CH:21]1[C:50](=[O:51])[N:23]2[C:24]([C:34]([O:36][CH:37]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:35])=[C:25]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[CH:26]([CH3:28])[S:27](=[O:9])[C@H:22]12)=[O:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)OCC1=C(C)S[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S(=O)C1C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A solution of 13.7 g of m-chloroperbenzoic acid in 50 ml of CH2Cl2 was added to a solution of 37.3 g of diphenylmethyl 7-(2-thienylacetamido)-2-methyl-3-acetoxymethylceph-2-em-4-carboxylate in 300 ml of CH2Cl2 at -20° C., and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was washed with 5% aqueous NaHCO3 and saturated aqueous NaCl solutions, and dried over MgSO4, followed by distilling off the solvent under reduced pressure. AcOEt.Et2O (1:3) was added to the residue, thus yielding 32 g (84%) of crystals of diphenylmethyl 7-(2-thienylacetamido)-2-methyl-3-acetoxymethylceph-3-em-4-carboxylate 1-oxide.
Reaction SMILES: [Li]CCCC.[N:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]3[CH2:19][CH2:18][CH2:17][C:14]3=[N:15][N:16]=2)=[CH:8][CH:7]=1.Br[CH2:21][C:22]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[O:24][N:23]=1.[NH4+].[Cl-]>C1COCC1>[Cl:33][C:29]1[CH:28]=[C:27]([C:25]2[O:24][N:23]=[C:22]([CH2:21][CH:17]3[C:14]4=[N:15][N:16]=[C:12]([C:9]5[CH:8]=[CH:7][N:6]=[CH:11][CH:10]=5)[N:13]4[CH2:19][CH2:18]3)[N:26]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: c1cc(-c2nnc3n2CCC3)ccn1
Reactant: Clc1cccc(-c2nc(CBr)no2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1cccc(-c2nc(CC3CCn4c(-c5ccncc5)nnc43)no2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 1.3 %

Procedure:
nBuLi (2.5 M, hex., 600 μl) was added to a solution of 3-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (250 mg, 1.33 mmol) in THF (13 ml) at 0° C. After 10 min the reaction mixture was cooled to −78° C. and 3-(bromomethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (400 mg, 1.46 mmol) in THF (10 ml) was added. After stirring at −78° C. for 30 min stirring was continued at 0° C. reaching r.t. o.n. Aq. sat. NH4Cl was added and the mixture was extracted with EA. The organic phase was washed with water and brine, dried and concentrated. Flash chromatography (DCM/MeOH 40:1) followed by preparative HPLC afforded 6.5 mg (1%) of the title compound. 1H NMR: 2.72 (m, 1H), 3.13 (m, 2H), 3.62 (m, 1H), 3.93 (m, 1H), 4.31 (m, 2H), 7.47 (t, 1H), 7.56 (m, 1H), 7.74 (d, 2H), 7.98 (m, 1H), 8.08 (m, 1H), 8.74 (m, 2H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11](Cl)=[O:12].[CH3:14][O:15][C:16](=[O:29])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:14][O:15][C:16](=[O:29])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:11]([C@@H:2]3[O:1][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3]3)=[O:12])[CH2:24]2)[CH:18]=1
Reactant: COC(=O)c1cccc(C2CCCNC2)c1
Reactant: O=C(Cl)[C@H]1COc2ccccc2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc([C@H]2CCCN(C(=O)[C@H]3COc4ccccc4O3)C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (240 mg, 1.21 mmol) in DCM (5 ml) was added to an ice-cold mixture of 3-(piperidin-3-yl)benzoic acid methyl ester (267 mg, 1.21 mmol), triethylamine (59 mg, 0.58 mmol) and DCM (10 ml). After stirring for 2 h at RT, the mixture was washed with 1 M HCl (10 ml) and 1 M Na2CO3. The organic phase was dried over Na2SO4 and evaporated to dryness and the residue was purified by flash chromatography using heptane/EtOAc as eluent. The first eluting diastereomer was collected to afford 98 mg of the title compound.