Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.Br[C:26]1[S:27][C:28]([Cl:31])=[CH:29][CH:30]=1.N>>[Cl:31][C:28]1[S:27][C:26]([N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(Cl)cc2)cc1
Reactant: Clc1ccc(Br)s1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(Cl)s3)c(=O)c2-c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, substituting 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 2-bromo-5-chlorothiophene in place of 4-bromothioanisole (yield: 150 mg, 45%). mp 249-251° C. 1H NMR (300 MHz, CDCl3) δ 3.05 (s, 3H), 6.92 (d, J=9 Hz, 1H), 7.18 (d, J=9 Hz, 2H), 7.31 (d, J=9 Hz, 2H), 7.39 (d, J=9 Hz, 2H), 7.58 (d, J=6 Hz, 1H), 7.94 (d, J=9 Hz, 2 Hz, 2H), 8.04 (s, 1H). MS (DCI/NH3) m/z 477 (M+H)+, 494 (M+NH4)+. Anal. calc. for C21H14Cl2N2O3S2.H2O: C, 50.9; H, 3.03; N, 5.60. Found: C, 50.5; H, 2.79; N, 5.26.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].IC.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(C=O)c1

Procedure:
In this scheme 5-hydroxy-2-nitrobenzaldehyde 1 is reacted in DMF with iodomethane and potassium carbonate to yield 5-methoxy-2-nitrobenzaldehyde 2. The methoxybenzaldehyde is heated with p-toluene sulfonic acid monohydrate (catalytic amount) in toluene to obtain the dioxane derivative 3, which is hydrogenated to give 2-(1,3-dioxolan-2yl)-4-methoxyphenylamine 4. Following conversion to the ethoxycarboxamide 5 and then to the formyl carboxamide 6,6-methoxyquinazolin-2-ol 7 is obtained by ring closure with ammonia. Reaction with phosphorus oxychloride then yields the desired 2-chloro-6-methoxyquinazoline intermediate 8.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=1.[Cl:13][C:14]1[C:15]([C:31]#[N:32])=[C:16]([CH:28]=[CH:29][CH:30]=1)[O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[Cl:13][C:14]1[C:15]([C:31]#[N:32])=[C:16]([CH:28]=[CH:29][CH:30]=1)[O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:1][C:2]2[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=2)(=[O:25])=[O:26])=[CH:22][CH:23]=1
Reactant: N#Cc1c(Cl)cccc1Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)Cc1nc(N)sc1C
Product: COC(=O)Cc1nc(NS(=O)(=O)c2ccc(Oc3cccc(Cl)c3C#N)cc2)sc1C

Procedure:
The title compound was prepared from methyl 2-(2-amino-5-methyl-1,3-thiazol-4-yl)acetate and 4-(3-chloro-2-cyanophenoxy)benzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (28.3 mg) with purity >90%. LCMS (pos) m/z 478.2.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[CH3:4].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:44][CH2:45][C:46]1[C:47]([OH:54])=[N:48][C:49]([CH3:53])=[CH:50][C:51]=1[CH3:52]>ClCCl>[OH:54][C:47]1[C:46]([CH2:45][NH:44][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([CH:3]([CH:2]([CH3:1])[CH3:14])[CH3:4])=[CH:13][CH:12]=2)=[C:51]([CH3:52])[CH:50]=[C:49]([CH3:53])[N:48]=1
Reactant: CC(C)C(C)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)C(C)C)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
To a solution of 4-(3-methylbutan-2-yl)benzoic acid (0.10 g, 0.50 mmol), 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14 g, 0.7 mmol) and 1-hydroxybenzotriazole (0.10 g, 0.70 mmol) in dichloromethane (20 mL) was added triethylamine (0.2 g, 2.0 mmol). The reaction mixture was stirred at room temperature for 15 minutes, and followed by 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.08 g, 0.5 mmol). The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water, dried by anhydrous sodium sulfate, then the solvent removed in vacuo to give the crude product, which was purified by Prep-TLC (dichloromethane:methanol=20:1) to give the pure product N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(3-methylbutan-2-yl)benzamide (0.08 g, 44%) as a white solid. LR MS (M+H+): calcd for 326.2. found 326. HPLC Purity (214 nm) 99.6%. 1H NMR (CH3OH-d4, 300 MHz): δ 7.71 (d, J=8.1 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 6.10 (s, 1H), 4.49 (s, 2H), 2.49-2.44 (m, 1H), 2.37 (s, 3H), 2.24 (s, 3H), 1.82-1.75 (m, 1H), 3.14-3.06 (m, 1H), 1.24 (d, J=7.2 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), 0.76 (d, J=7.2 Hz, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[CH2:7][C:8]#[N:9].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:10][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][C:8]#[N:9])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CCC(=O)c1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC(=CC#N)c2ccco2)cc1
Yield: 92.5 %

Procedure:
To a mixture of 3-(2-furyl)-3-oxopropanenitrile (5.29 g), p-toluenesulfonyl chloride (9.00 g) and dichloromethane (60 mL) was added dropwise triethylamine (5.99 g) under ice-cooling. After stirring under ice-cooling for 1.5 hrs, the mixture was diluted with dichloromethane (100 mL). The mixture was washed with water (150 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:methyl acetate=9:1→3:1) to give the title compound (10.48 g) as a mixture of (E)-form and (Z)-form (3:1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([NH2:8])=[O:7].[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32](Cl)[N:31]=4)=[CH:26][CH:25]=3)[CH:18]=2)[NH:13][CH:12]=1)#[N:10]>>[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][C:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([N:1]5[CH2:5][CH2:4][CH2:3][CH:2]5[C:6]([NH2:8])=[O:7])[N:31]=4)=[CH:26][CH:25]=3)=[O:37])[CH:18]=2)[NH:13][CH:12]=1)#[N:10]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: NC(=O)C1CCCN1
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(N5CCCC5C(N)=O)n4)cc3)cc12

Procedure:
Using pyrrolidine-2-carboxylic acid amide. and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 480 (M+H)+.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][C:12]([O:14]C)=[O:13])=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[O:1]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)Cc1ccc2c(n1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccc2c(n1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To methyl 2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)acetate (5.50 g, 25.1 mmol) in methanol (100 mL) was added aqueous 1N NaOH (50.2 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated and water (200 mL) was added. The aqueous solution was washed with 2-methyl-THF (2×200 mL). The aqueous layer was adjusted to pH˜5 and was concentrated. The resulting solids were suspended in chloroform (200 mL) and the mixture was heated to reflux with stirring. The mixture was heated at reflux for 10 minutes and was filtered while hot. The resulting filtrate was concentrated in vacuo to afford 2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)acetic acid (SM-1aj, 2.5 g, 57%). MS (ES+) 196.2 (M+H)+. 1H NMR (CDCl3) δ 3.23 (s, 2H), 4.14 (s, 2H), 4.30 (s, 2H), 6.77 (d, 1H), 7.08 (d, 1H).
Reaction SMILES: [O:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[Li+].[Cl-].C([Li])(C)(C)C.CCCCC.[CH:20]([C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([C:37]#[N:38])=[CH:29][CH:28]=2)=[C:24]([O:41][CH3:42])[CH:23]=1)=O.Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C1COCC1>[O:7]=[C:2]1[NH:3][C:4](=[O:6])[C:5](=[CH:20][C:22]2[CH:40]=[CH:39][C:25]([O:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]([C:37]#[N:38])=[CH:29][CH:28]=3)=[C:24]([O:41][CH3:42])[CH:23]=2)[O:1]1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C#N)c2ccccc12
Reactant: O=C1COC(=O)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCC
Product: COc1cc(C=C2OC(=O)NC2=O)ccc1Oc1ccc(C#N)c2ccccc12
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a mixture of oxazolidine-2,4-dione (50.5 mg, 0.50 mmol), LiCl (128 mg, 3.0 mmol) and anhydrous THF (5.0 mL) cooled to −78° C. was added dropwise 1.7 M tert-butyllithium solution in pentane (0.616 mL, 1.05 mmol). After stirring at −78° C. for 20 minutes, the reaction mixture was warmed to 0° C. for 5 minutes. The mixture was recooled to −78° C. and a solution of 4-(4-formyl-2-methoxy-phenoxy)-naphthalene-1-carbonitrile (Example 19a) was added dropwise. After stirring at −78° C. for 15 minutes, 1 N HCl (1.05 mL, 1.05 mol) was added dropwise. The reaction mixture was allowed to warm up to room temperature. After evaporation of most of the solvent, p-toluenesulfonic acid monohydrate (85 mg, 0.5 mmol) and toluene (25 mL) were added. The mixture was heated to reflux with a Dean-Stark trap for 5 hours. After removal of solvent, the residue was taken up with a mixture of DMF and methanol and purified on a preparative HPLC [Waters XTerra® Prep MS O8 OBD™ Column (5 μm, 30×50 mm) using a gradient mixture of 0.1% aqueous TFA and acetonitrile]. 1H NMR (400 Hz, DMSO-d6) δ 12.45 (s, 1H), 8.43 (d, 1H), 8.16 (s, 1H), 8.11 (d, 1H), 8.00 (d, 1H), 7.88 (t, 1H), 7.77 (t, 1H), 7.65 (d, 1H), 7.32 (d, 1H), 7.09 (s, 1H), 6.63 (d, 1H), 3.73 (s, 3H); LC/MS (m/z) [M+1]+ 386.9 (calculated for C22H14N2O6, 386.1).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:32][C:33]1[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:24])(=[O:22])=[O:23])(=[O:13])=[O:14])[CH:9]=3)[NH:4][N:3]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: OB(O)/C=C/c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(/C=C/c3ccc(F)cc3)c2c1
Yield: 29.4 %

Procedure:
N-{3-[(E)-2-(4-Fluorophenyl)vinyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 1 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)-indazole-1-carboxylate, 575 mg trans-2-(4-fluorophenyl)vinylboronic acid, 28 ml of dimethylformamide, 3.25 ml of a saturated aqueous sodium hydrogencarbonate solution and 41 mg of tetrakis(triphenylphosphine)palladium[0]. 240 mg of N-{3-[(E)-2-(4-fluorophenyl)vinyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of an off-white solid melting at 248° C. (analysis C22H18FN3O4S2 % calculated C, 56.04; H, 3.85; F, 4.03; N, 8.91; O, 13.57; S, 13.60. % found C, 56.21; H, 4.09; F, 3.95; N, 8.64; S, 13.31).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:10]2[C:18]3[C:13](=[C:14]([CH2:19][S:20][CH3:21])[CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:48])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[C:10]2[C:18]3[C:13](=[C:14]([CH2:19][S:20]([CH3:21])=[O:48])[CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(F)c(Cl)c3)c[nH]c12
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(F)c(Cl)c3)c[nH]c12

Procedure:
The title compound was prepared starting from 100 mg (0.23 mmol) of the compound from Example 284 in analogy to the synthesis of the compound from Example 296. 102 mg (98% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=1)=[O:5])[CH3:2]>CCO.CC(O)=O.O=[Pt]=O>[C:4]([OH:5])(=[O:3])[CH3:6].[CH2:15]([O:14][C:12]([CH:10]1[CH2:11][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][NH:8][CH2:9]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cncc(C(=O)OCC)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1CNCC(C(=O)OCC)C1

Procedure:
Hydrogenate pyridine-3,5-dicarboxylic acid diethyl ester (13.4 g, 60.0 mmol) in EtOH (100 mL) and HOAc (35 mL) with PtO2 (2.7 g, cat.) overnight at room temperature and 60 psi. Filter through celite and concentrated to dryness. Partition between sat. aq NaHCO3 and CHCl3. Extract 3× with CHCl3. Wash with sat. aq NaHCO3, wash with brine, dry over Na2SO4, filter and concentrate to dryness. MS(IS) 231.1 (M+2); Carried on without further purification.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[C:9]1(C)[CH:14]=CC(S(O)(=O)=O)=C[CH:10]=1.COC(OC)(C)C>>[CH3:10][C:9]1([CH3:14])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: Oc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Product: CC1(C)Oc2ccccc2O1

Procedure:
The preparation of the 2-substituted-1,3-benzodioxole starting compounds is known to the art. For example, catechol is subjected to dehydration and the resulting mixture is treated with para-toluenesulfonic acid. Thereafter, dimethoxypropane or another dialkoxyalkane within the ambit of this invention is added to this mixture and the final reaction mix is heated to distill off methanol and drive to reaction to completion. The resulting product is isolated as 2,2-dimethyl-1,3-benzodioxole. It is also possible to condense catechol with a ketone, using P2O5, directly, employing a dehydrating agent to drive off water and to thereby form the desired dioxole starting product.
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:4]=1[CH2:5]Cl.CC1C=C(C)C=C(C)C=1C[Mg]Cl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([C:36]2[CH:37]=[N:38][C:39]([CH3:42])=[N:40][CH:41]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1>CCOCC.C1COCC1>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([C:36]2[CH:41]([CH2:5][C:4]3[C:3]([CH3:2])=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=3[CH3:12])[NH:40][C:39]([CH3:42])=[N:38][CH:37]=2)(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: COc1ccc(S(=O)(=O)c2cnc(C)nc2)cc1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Agent: Cc1cc(C)c(C[Mg]Cl)c(C)c1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2=CN=C(C)NC2Cc2c(C)cc(C)cc2C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a mixture of magnesium (240 mg, 10 mmol) and ether (20 mL) was added 2,4,6-trimethylbenzyl chloride (1.69 g, 10 mmol) in ether (20 mL) dropwise at reflux under N2. The freshly prepared solution of 2,4,6-trimethylbenzylmagnesium chloride in ether was added to a solution of 5-(4-methoxy-benzenesulfonyl)-2-methylpyrimidine (264 mg, 1.0 mmol) in THF (10 mL) dropwise at 0° C. The mixture was stirred under N2 at 0° C. for 1 h and then quenched by addition of saturated aqueous NH4Cl. The organic layer was separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (EtOAc) to provide 5-(4-methoxy-benzenesulfonyl)-2-methyl-6-(2,4,6-trimethylbenzyl)-1,6-dihydro-pyrimidine (203 mg, 51%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J=9.0 Hz, 2H), 7.45 (s, 1H), 6.99 (d, J=9.0 Hz, 2H), 6.83 (s, 2H), 4.40 (dd, J=10.8, 3.2 Hz, 1H), 3.86 (s, 3H), 2.96 (dd, J=14.2, 10.8 Hz, 1H), 2.87 (dd, J=14.2, 3.2 Hz, 1H), 2.25 (s, 6H), 2.24 (s, 3H), 1.91 (s, 3H); ESI MS m/z 399 [(M+H)+, calcd for C22H27N2O3S, 399.2].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[Cl:9]
Reactant: ClCc1ccccc1
Reactant: Oc1ccc(Br)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(OCc2ccccc2)ccc1Br

Procedure:
2 g of 4-bromo-3-chlorophenol dissolved in 20 cm3 of dimethylformamide are added to 480 mg of sodium hydride at 60% in oil, in 10 cm3 of dimethylformamide, followed by addition of a solution of 1.38 cm3 of benzyl chloride dissolved in 5 cm3 of dimethylformamide. The reaction medium is concentrated under reduced pressure and taken up in 100 cm3 of ethyl acetate. The organic phase is washed successively with 2×50 cm3 of water and with 50 cm3 of saturated sodium chloride solution, separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 3 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). 2.63 g of 1-bromo-2-chloro-4-(phenylmethoxy)benzene are obtained in the form of an orange-coloured oil which crystallizes.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:12][CH2:11]2)=[O:9])[N:6]=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1>>[O:9]=[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][CH2:11]1)[CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:31]([C:28]2[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=2)=[O:32])[S:3][CH:4]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1
Product: O=C(Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1)c1ccc(Cl)cn1

Procedure:
In analogy to example 37.5, 2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone (example 37.4) was coupled with 5-chloro-pyridine-2-carboxylic acid, using general method D, to give 5-chloro-pyridine-2-carboxylic acid (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide. Yellow solid. MS 477.3 ([M+H]+)
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][NH:20][CH3:21].Cl>>[CH3:19][N:20]([CH3:21])[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNC
Reactant: ClCCOc1ccccc1C=Cc1ccccc1
Agent: Cl
Product: CN(C)CCOc1ccccc1C=Cc1ccccc1

Procedure:
2-(β-Dimethylamino-ethoxy)-stilbene was prepared from 2-(β-chloro-ethoxy)-stilbene and dimethylamine, and the free base was converted into its hydrochloride, yielding 45% of theory of the compound of the formula ##STR14## which had a melting point of 199° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[O:5][C:6]=1Br.[OH-].[NH4+].Cl>[Zn].O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[O:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)c(Br)o1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(Br)co1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.5 %

Procedure:
A mixture of 4,5-dibromo-furan-2-carboxylic acid 22a (5.5 g, 20.3 mmol) and 18 mL of ammonium hydroxide was added to 63 mL of water followed by addition of zinc powder (1.46 g, 22.33 mmol). Upon completion of the addition, the reaction mixture was stirred at room temperature for 6 hours. The mixture was adjusted to pH 3 with 1 M hydrochloric acid to form a great quantity of precipitates. The mixture was filtered and the filter cake was washed with n-hexane (15 mL×4) and dried to obtain the title compound 4-bromo-furan-2-carboxylic acid 22b (3.2 g, yield 83.1%) as a white solid.
Reaction SMILES: [C@H:1]1(F)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[N-:13]=[N+:14]=[N-:15].[Na+]>C(#N)C>[C@H:1]1([N:13]=[N+:14]=[N-:15])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: OC[C@H]1O[C@H](F)[C@@H](O)[C@@H](O)[C@@H]1O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: [N-]=[N+]=N[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O

Procedure:
12 g of α-mannosyl fluoride were heated with 4.7 g of sodium azide in 100 ml of acetonitrile for 80 hours at the reflux temperature. After the mixture had been worked up as in Example 1, 10.3 g of a syrup containing 92% of α-azidomannose were obtained.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:10]1[C:14]2[C:15](=O)[NH:16][N:17]=[CH:18][C:13]=2[C:12]([CH3:20])=[C:11]1[CH3:21])[CH:7]=[CH:8][CH3:9].[OH-].[Na+]>O>[CH2:6]([N:10]1[C:14]2=[C:15]([Cl:3])[N:16]=[N:17][CH:18]=[C:13]2[C:12]([CH3:20])=[C:11]1[CH3:21])[CH:7]=[CH:8][CH3:9]
Reactant: CC=CCn1c(C)c(C)c2cn[nH]c(=O)c21
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Temperature: 97 °C
Reaction time: 2.5 h
Yield: 93.3 %

Procedure:
39 ml (0.43 mole) of phosphorus oxychloride were added to 3.53 g (0.0163 mole) of 1-(2-butenyl)-2,3-dimethyl-6,7-dihydropyrrolo[2,3-d]pyridazin-7-one (cis/trans=24/76) and the mixture was stirred at 97° C. for 2.5 hours. The reaction mixture was allowed to cool to room temperature and added dropwise to water with ice-cooling. The mixture was neutralized with a 40% aqueous solution of sodium hydroxide and extracted with dichloromethane. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by column chromatography through silica gel using a 1:1 mixture of toluene and ethyl acetate as an eluent to give 3.59 g (0.0152 mole) of 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=21/79) as pale brown crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br)([CH3:4])([CH3:3])[CH3:2].[N:19]([O-:21])=[O:20].[Na+].C1(C=C(O)C=C(O)C=1)O>CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCBr
Agent: Oc1cc(O)cc(O)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCCCCCCCC[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 24 h
Yield: 41.9 %

Procedure:
In a 100 ml two-neck round bottom flask 11-bromoundecanoic acid t-butyl ester (6.10 g, 19.0 mmol) was dropped into a stirred solution of NaNO2 (2.60 g, 38.0 mmol) and phloroglucinol (3.10 g, 19.0 mmol) in DMF (10 ml). The reaction mixture was warmed at 50° C. and stirred for 24 h, then poured into a mixture of 40 mL of ice/water and 40 mL of PET. After separation, the aqueous phase was further extracted with PET (3×30 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica-gel column chromatography (PET/diethyl ether 95/5) obtaining a light yellow solid (2.29 g, 42%). M.p. 39-42° C. ESI-MS: 288 (MH+); (Calc. for C15H29NO4: 287 u.m.a.).