Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:30])=[CH:11][C:12]([F:29])=[C:13]([CH:28]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][CH2:33][OH:34].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[C:10]([CH3:30])=[CH:11][C:12]([F:29])=[C:13]([CH:28]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:32][CH2:33][OH:34])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(Nc3cc(OCc4ccccc4)c(C)cc3F)ncnc2cc1O
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3cc(OCc4ccccc4)c(C)cc3F)ncnc2cc1OCCO
Temperature: 50 °C
Yield: 44.5 %

Procedure:
A mixture of 4-(5-benzyloxy-2-fluoro4-methylanilino)-7-hydroxy-6-methoxyquinazoline (440 mg, 1 mmol), 2-bromoethanol (77 ml, 1 mmol) and potassium carbonate (150 mg, 1.1 mmol) in DMF (5 ml) was heated at 50° C. for 1 hour, further 2-bromoethanol (42 ml, 0.6 mmol) and potassium carbonate (150 mg, 1.1 mmol) was added and the mixture was maintained at 50° C. for 2 hours. The reaction mixture was diluted with water, neutralised with 2M hydrochloric acid and extracted with ethyl acetate. The extracts were dried (MgSO4), the solvent removed by evaporation and the residue triturated with ether and hexane to give 4-(5-benzyloxy-2-fluoro-4-methylanilino)-7-(2-hydroxyethoxy)-6-methoxyquinazoline (200 mg, 41%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[CH:26]=[CH:25][C:14]2[O:15][C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18](=[O:20])[NH:19][C:13]=2[CH:12]=1)=O>C1COCC1>[OH:8][CH2:9][C:11]1[CH:26]=[CH:25][C:14]2[O:15][C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18](=[O:20])[NH:19][C:13]=2[CH:12]=1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)c1ccccc1O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2cc(CO)ccc2Oc2ccccc21
Reaction time: 0.75 h
Yield: 46 %

Procedure:
Lithium aluminum hydride (11 mL, 11 mmole) was slowly added to the solution of 11-Oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepine-8-carboxylic acid methyl ester (1.346 g, 5 mmole) in THF under N2 at room temperature. The reaction mixture was stirred for 1 hour and 45 minutes then quenched with 2N of HCl until the pH value reaches 2-3. Removed all the THF by rotary evaporation, and extracted the reaction mixture with ethyl acetate for five times, dried the organic layer with sodium sulfate and filtered and concentrated. Obtained the desired compound (white solid) in 46% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][NH:8][C:9](=[O:38])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:37])[CH2:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:2]1.[CH3:39][CH:40]([CH2:43][CH3:44])[CH:41]=O>>[CH3:39][CH:40]([CH2:43][CH3:44])[CH2:41][N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][NH:8][C:9](=[O:38])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:37])[CH2:17][C:18]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:2]1
Reactant: O=C(CCCCCNC(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1)NC[C@H]1CCCNC1
Reactant: CCC(C)C=O
Product: CCC(C)CN1CCC[C@H](CNC(=O)CCCCCNC(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Step 3 of Example 17, using N-{6-{((3S)-3-piperidyl)methyl}amino-6-oxohexyl}-3,3,3-triphenylpropanamide and 2-methylbutanal. The compound was obtained as a white foamy substance.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.Cl.[CH3:16][O:17][NH2:18]>>[Cl:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2]([NH:18][O:17][CH3:16])=[N:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:11]=1
Reactant: CON
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Cl)cc21
Agent: Cl
Product: CONC1=NS(=O)(=O)c2cc(Cl)ccc2N1
Yield: 53.5 %

Procedure:
Starting from 3,7-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (502 mg; 2 mmol) and O-methylhydroxylamine hydrochloride (300 mg) and with the use of the same procedure as in example 21, 280 mg (57%) of the title compound was prepared; m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 11.35 (s, 1H, NH), 11.28 (s, 1H, NH), 7.78 (d, 1H, H-8), 7.63 (dd, 2H, H-6 and H-5), 3.80 (s, 3H, CH3); 13C-NMR (DMSO-d6) ppm; 151.19, 132.79, 131.26, 127.10, 123.00, 120.83, 118.78, 63.25.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Br[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=1>C(Cl)Cl>[N+:19]([C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=1)[CH2:8][N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cc(CBr)cc(C(F)(F)F)c1
Reactant: O[C@H]1CCNC1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CN2CC[C@H](O)C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.7 %

Procedure:
To a solution of (S)-3-hydroxypyrrolidine (1.84 g, 21 mmol) in DCM (10 mL) at 0° C. was added a solution of 1-(bromomethyl)-3-nitro-5-(trifluoromethyl)benzene (2.00 g, 7 mmol) in DCM (10 mL) dropwise. After the addition, the reaction mixture was allowed to stir at rt for 2 h and then diluted with DCM and washed with brine. Removal of solvent gave (3S)-1-[3-nitro-5-(trifluoromethyl)benzyl]pyrrolidin-3-ol (2.25 g, 100% yield) as yellow oil. LCMS: (FA) ES+ 291.3.Step 2: 3-[((3S)-3-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidin-1-yl)methyl]-5-(trifluoromethyl)aniline
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13](=[O:15])[CH3:14])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13](=[O:15])[CH3:14])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S(=O)(=O)NC(C)=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)NS(=O)(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-[(3-methoxyphenyl)sulfonyl]acetamide (0.4 g, 1.75 mmol) in DCM at 0° C. was added BBr3 and the reaction was stirred at rt for 2 h. The reaction was quenched with pH=4 buffer and extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated to afford the title compound. LC-MS: mile 216 (M+H)+ (0.5 min).
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:6][CH2:5]1)#[N:2]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CC#N)CC1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCN(CCN)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a hydrogenation flask charged with a solution of tert-butyl (1-(cyanomethyl)piperidin-4-yl)methylcarbamate (5.4 g, 21.3 mmol) in CH3OH (20 mL) was added Raney nickel (˜1 g, rinsed with CH3OH). The flask was shaken at room temperature under hydrogen (40 psi) overnight. The reaction mixture was then filtered through a celite cake, and the filtrate was concentrated to give sticky foam which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14])=O.S(Cl)([Cl:22])=O>>[Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([Cl:22])=[N:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccnc(Cl)c1F)c1c(Cl)cccc1Br
Product: Fc1c(N=C(Cl)c2c(Cl)cccc2Br)ccnc1Cl
Temperature: 25 °C
Yield: 83 %

Procedure:
A stirred solution of 2-bromo-6-chloro-N-(2-chloro-3-fluoropyridin-4-yl)-benzamide (4.8 g, 13.2 mmol) in thionyl chloride (100 mL) was heated at 100° C. for 18 hours under a nitrogen atmosphere. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was purified by column chromatography on silica gel eluting with 30% diethyl ether in pentane to afford the title compound as a pale yellow solid (4.2 g, 83% yield). LCMS (Method D): RT=4.47 min, m/z: 383 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][CH2:12][CH2:11][CH2:10][S:9]2)=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][CH2:30][N:31]([CH2:33][CH:34]([CH3:37])[CH2:35]Cl)[CH3:32])=[CH:27][CH:26]=1>CCCCCC.O>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH2:30][N:31]([CH3:32])[CH2:33][CH:34]([CH3:37])[CH2:35][C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[S:9][CH2:10][CH2:11][CH2:12][S:13]2)=[CH:38][CH:39]=1
Reactant: CC(CCl)CN(C)CCc1ccc(Cl)cc1
Reactant: Clc1ccc(C2SCCCS2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(CN(C)CCc1ccc(Cl)cc1)CC1(c2ccc(Cl)cc2)SCCCS1
Reaction time: 2 h

Procedure:
2.77 g (0.012 mol) of 2-(4-chlorophenyl)-m-dithiane and 10 ml of abs. tetrahydrofuran were cooled to -70° in a sulphonation flask while gassing with argon and treated with 7.50 ml (0.012 mol) of butyllithium in hexane. Thereupon, the mixture was stirred at -20° for 2 hours. A solution of 2.50 g (0.0096 mol) of rac-4-chloro-N-(3-chloro-2-methylpropyl)-N-methylphenethylamine in abs. tetrahydrofuran was added dropwise thereto at -70° within 15 minutes, whereupon the mixture was left to stand at -20° for 18 hours and at room temperature for 3 hours. The reaction solution was then poured into water and extracted three times with ether. The ethereal extracts were dried over magnesium sulphate and evaporated. The residual oil was chromatographed on silica gel with toluene-hexane (1:1). After evaporating the solvent and warming the residue at 50° for 18 hours under reduced pressure there was obtained rac-N-(4-chlorophenethyl)-2-(4-chlorophenyl)-β,N-dimethyl-m-dithiane-2-propanamine as a viscous oil.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:22]/[N:23]=[C:24](/[C:55]2[N:56]=[C:57]([NH:60][C:61]([C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[S:58][CH:59]=2)\[C:25]([NH:27][CH:28]2[C:53](=[O:54])[N:30]3[C:31]([C:37]([O:39][CH:40]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])=[C:32]([CH2:35][Cl:36])[CH2:33][S:34][C@H:29]23)=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:88])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([O:14][C:15]([C:17]1([O:22]/[N:23]=[C:24](/[C:55]2[N:56]=[C:57]([NH:60][C:61]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)([C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)[S:58][CH:59]=2)\[C:25]([NH:27][CH:28]2[C:53](=[O:54])[N:30]3[C:31]([C:37]([O:39][CH:40]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)=[O:38])=[C:32]([CH2:35][Cl:36])[CH2:33][S:34](=[O:88])[C@H:29]23)=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1)=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS[C@@H]2C(NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CCCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS(=O)[C@@H]2C(NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CCCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Reaction time: 0.33 h

Procedure:
The residue obtained in (A) was dissolved in 50 ml of methylene chloride, and 710 mg (3.3 mmol) of m-chloroperbenzoic acid (purity: 80%) was added under cooling with ice. The mixture was stirred for 20 minutes. Then, 30 ml of methylene chloride and 40 ml of a 5% sodium bicarbonate aqueous solution were added to the reaction solution. The organic layer was separated and washed with water and with a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and then concentrated to obtain the residue of the above identified compound, which was used for the subsequent reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:16][C:17]([C:19]3[NH:23][C:22](=[O:24])[N:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.[C:38]([O:43][CH2:44]Cl)(=[O:42])[CH2:39][CH2:40][CH3:41].[Na+].[I-].CC1C=CC=C(C)N=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([OH:36])[C:33]([O:35][CH2:44][O:43][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[O:34])[NH:16][C:17]([C:19]3[NH:23][C:22](=[O:24])[N:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:20]=3)=[O:18])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: CCCC(=O)OCCl
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1nn(-c2ccccc2)c(=O)[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CCCC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1nn(-c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a solution of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)hydrazino]-2-hydroxypropionic acid (200 mg, 335 μmol) in dry DMF (6 mL) was added chloromethyl butyrate (68 mg, 503 mmol), NaI (101 mg, 670 mmol), and 2,6-dimethylpyridine (143 mg, 1.3 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 8 hours. Water (12 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=3:1) to yield the title compound as a white solid (21 mg). LC-MS: 625.9 [M+H]+. 1H NMR (DMSO-d6, 400 MHz) δ 0.84 (t, J=7.4 Hz, 3H), 1.45-1.56 (m, 2H), 2.29 (t, J=7.3 Hz, 2H), 3.31-3.17 (m, 2H), 4.18-4.35 (m, 2H), 4.35 (t, J=5.3 Hz, 1H), 5.68-5.79 (m, 2H), 7.28 (t, J=7.4 Hz, 1H), 7.34-7.40 (m, 1H), 7.43-7.55 (m, 7H), 7.58 (dd, J=6.8, 2.6 Hz, 1H), 7.90 (d, J=7.6 Hz, 2H), 9.98 (s, 1H), 12.76 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:54][S:55]([C:58]1[CH:63]=[C:62]([C@@H:64]([NH2:66])[CH3:65])[CH:61]=[CH:60][N:59]=1)(=[O:57])=[O:56].C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[CH3:54][S:55]([C:58]1[CH:63]=[C:62]([C@@H:64]([NH:66][C:17]([C:16]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[O:19])[CH3:65])[CH:61]=[CH:60][N:59]=1)(=[O:57])=[O:56]
Reactant: C[C@H](N)c1ccnc(S(C)(=O)=O)c1
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(C)(=O)=O)c1
Reaction time: 0.08 h

Procedure:
To a suspension of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (17.74 g, 68.98 mmol) in DMF (200 mL) was added DIPEA (30 mL, 170 mmol) followed by HATU (27.37 g, 71.98 mmol). After 5 minutes, a light brown precipitate formed and additional DMF (50 mL) was added to aid stifling. After 1.5 hours, (S)-1-(2-methanesulfonyl-pyridin-4-yl)-ethylamine hydrochloride (14.20 g, 59.99 mmol) was added, followed by additional DIPEA (10 mL, 55 mmol). After 18 hours, the mixture was poured into water (1.5 L) containing sodium bicarbonate (25 g). The solid was collected by filtration and washed with aqueous sodium carbonate (1 L), water (1 L) and dried by pulling vacuum through the filter cake. The crude product was passed through a pad of silica gel eluting with EtOAc in dichloromethane (1:9, then 2:8, then 5:5, then 100:0). The material from the pad was concentrated and triturated with diethylether to afford the title compound as an off-white solid.
Reaction SMILES: [CH:1]1([C:6]2[C:15]([CH:16](F)[C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[C:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:13]3[CH:12]([OH:36])[CH2:11][C:10]([CH3:38])([CH3:37])[CH2:9][C:8]=3[N:7]=2)CC[CH2:3][CH2:2]1.C1(C)C=CC=CC=1.C([Al]CC(C)C)C(C)C.[Cl-].[Na+]>CO>[CH:1]1([C:6]2[C:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[C:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:13]3[CH:12]([OH:36])[CH2:11][C:10]([CH3:37])([CH3:38])[CH2:9][C:8]=3[N:7]=2)[CH2:3][CH2:2]1
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O)C1
Agent: CC(C)C[Al]CC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1(C)Cc2nc(C3CC3)c(Cc3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O)C1
Temperature: -70 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
280 mg (0.52 mmol) of the compound from Example 4 are dissolved in 40 ml of abs. toluene and, at from −10° C. to −15° C., admixed dropwise with 3.5 ml of 25% strength diisobutylaluminium hyride solution. The mixture is stirred for 1 hour, cooled to −70° C. and admixed dropwise with 0.2 ml of methanol. At 20° C., the mixture is admixed with sodium chloride solution, the phases are separated and the organic phase is dried. The evaporation residue is purified over a silica gel column Crystallization from heptane gives 195 mg of colourless crystals of m.p. 126-127° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:10])[C:7]=1[CH2:8]O.ClC1C=C(OC)C=C(F)C=1C[N:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:18](=[O:26])(=[O:25])[N:17]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[C:16]1=[O:37]>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][N:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:18](=[O:26])(=[O:25])[N:17]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[C:16]1=[O:37]
Reactant: OCc1c(F)cncc1F
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3ccccc32)c(Cl)c1
Product: COc1ccc(N2C(=O)N(Cc3c(F)cncc3F)c3ccccc3S2(=O)=O)cc1OC

Procedure:
The title compound (47 mg, 0.10 mmol) was prepared from (IntA1) (167 mg, 0.50 mmol) and 3,5-difluoropyridine-4-methanol (109 mg, 0.75 mmol) using the methods of (113).
Reaction SMILES: [Cl:1][Si:2]([Cl:9])([Cl:8])[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].N1C=CC=CC=1.[Cl:16]Cl>C(Cl)(Cl)(Cl)Cl>[Cl:1][Si:2]([Cl:9])([Cl:8])[N:3]([Cl:16])[Si:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: C[Si](C)(C)N[Si](Cl)(Cl)Cl
Reactant: ClCl
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)N(Cl)[Si](Cl)(Cl)Cl
Reaction time: 4 h
Yield: 75 %

Procedure:
In accordance with L. P. Filonenko and A. M. Pinchuk in J. Gen. Chem. USSR 49, 302 (1979), 13.8 g (0.063 mol) compound A1 and 5.1 ml (0.063 mol) pyridine are initially introduced into a reaction vessel in 180 ml carbon tetrachloride. 5 g (0.141 mol) chlorine are condensed at -40° C. and transferred to the reaction vessel. After stirring for 4 hours, the precipitate is filtered off and washed and the solvent is distilled off from the combined filtrates. Subsequent fractionation leads to 16.4 g of the yellowish liquid A2 in a yield of 75%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][CH:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][CH:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[N-:22][N:21]=1
Reactant: Cc1cc(C)[nH]n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(C)[n-]n1
Reaction time: 0.5 h

Procedure:
After 4.98 g of N-benzyloxycarbonyl-D,L-proline was dissolved in 100 ml of dichloromethane, 2.12 g of 3,5-dimethylpyrazole and 4.5 g of dicyclohexylcarbodiimide were added to the solution. The temperature was reverted to room temperature 30 minutes after the addition and stirring was continued for 20 hours. At the end of the reaction, 0.3 ml of acetic acid was added to the reaction mixture. Insoluble matters were filtered off and the solvent was removed by distillation. The residue was dissolved in a small volume of ethyl acetate. After insoluble matters were filtered off, the filtrate was evaporated to dryness under vacuum to give 6.0 g (yield, 91.7%) of N-benzyloxycarbonyl-D,L-proline-3,5-dimethylpyrazolide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Br[C:12]1[C:13]2[N:14]([C:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[F:31])=[O:23])=[CH:20][N:21]=2)[N:15]=[C:16]([Cl:18])[CH:17]=1.O>CN(C=O)C>[Cl:18][C:16]1[CH:17]=[C:12]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[C:13]2[N:14]([C:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[F:31])=[O:23])=[CH:20][N:21]=2)[N:15]=1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Reactant: Nc1ccc(F)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccncc1F)c1cnc2c(Nc3ccc(F)cn3)cc(Cl)nn12
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
To a solution of 5-fluoropyridin-2-amine (20.63 mg, 0.184 mmol) in DMF (1 mL) was added 60% NaH (7.36 mg, 0.184 mmol). The mixture was stirred for 10 min until cessation of H2 evolution. 8A (24 mg, 0.074 mmol) was added. The mixture was stirred at room temperature overnight. Water was added, and the yellow solid was collected by filtration and dried to give 16A (25.2 mg, 57%). [M+H]=4 01. HPLC Peak Rt=3.345 minutes (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm.).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.[CH3:16][C:17]1[O:18][CH:19]=[CH:20][C:21]=1[SH:22].C(=O)([O-])[O-].[K+].[K+]>>[F:15][C:10]1[C:9]([C:3]2[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=2[S:22][C:21]2[CH:20]=[CH:19][O:18][C:17]=2[CH3:16])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Cc1occc1S
Reactant: O=Cc1cc(-c2cccnc2F)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1occc1Sc1sc(C=O)cc1-c1cccnc1F
Yield: 97 %

Procedure:
With 5-bromo-4-(2-fluoropyridin-3-yl)thiophene-2-carbaldehyde (250 mg) as a starting material, and using 2-methyl-3-furanthiol (0.114 mL) and potassium carbonate (193 mg), an operation similar to that of Reference Example 1 was performed to give the title compound as a pale-yellow oil (yield 271 mg, yield 97%).
Reaction SMILES: O[C:2]([C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH3:31])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:17][CH:16]=1)([C:6]1[N:7]([CH2:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:9][CH:10]=1)[CH2:3][CH2:4][CH3:5].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>>[CH3:14][O:13][CH2:12][CH2:11][N:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[CH:2]([C:15]1[CH:16]=[CH:17][C:18]([N:21]([CH3:31])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:19][CH:20]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(O)(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)c1cccn1CCOC
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Product: CCCC(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)c1cccn1CCOC

Procedure:
The title compound was prepared from N-(4-{1-hydroxy-1-[1-(2-methoxyethyl)-1H-pyrrol-2-yl]-butyl}-phenyl)-N-methyl-benzenesulfonamide (Example 3) using triethylsilane and boron trifluoride diethyl etherate as described in Example 88 of co-pending application Ser. No. 10/354,922, entitled “Arylsulfonamidobenzylic Compounds” and provided below as Preparative Example B.