Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3](=[N:8][O:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5])#[N:2].C[O-].[Na+].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)O[C:21](=[O:22])C=2C=1.C(O)(=O)C>CO>[NH:2]=[C:1]([O:22][CH3:21])[C:3](=[N:8][O:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Reactant: CCON=C(C#N)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCON=C(C(=N)OC)C(=O)OC
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2-cyano-2-ethoxyiminoacetate (syn isomer) (4.7 g) in methanol (50 ml) was added 1 N methanolic solution (5 ml) of sodium methoxide under cooling in an ice-bath and stirring, which was continued for 20 minutes in an ice-bath and 15 minutes at room temperature. The mixture was neutralized to the end point of phenolphthalein with 1 N methanolic solution of acetic acid and evaporated. The residue was dissolved in methylene chloride (80 ml), washed with water, dried over magnesium sulfate and evaporated to give methyl 3-imino-3-methoxy-2-ethoxyiminopropionate (syn isomer) (4.8 g) as an oil.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.S([O-])([O-])(=O)=O.O[NH3+:23].O[NH3+]>>[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:23])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: [NH3+]O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
With stirring (20 rpm), a turbine dryer is charged at room temperature with 8000 parts by weight of anhydrous sodium sulfate, 1602 parts by weight of 4-methylbenzaldehyde and 1149 parts by weight of hydroxylammonium sulfate. Following evacuation to 35 mbar, the mixture is heated to 80° C. and stirred at this temperature for 21/2 hours. It is subsequently heated at 125° C. at a pressure of 80 mbar and held for 10 minutes; the pressure is then reduced to 60 mbar and held for a further 20 minutes, during which a total of about 480 parts by weight of water are removed by distillation. The distillation of the nitrile is initiated and controlled by successive reduction of the pressure to 10 mbar and subsequent raising of the jacket temperature to 170° C. 1265 parts by weight of 4-methylbenzonitrile are obtained with a purity of over 98% (HPLC), and also 37 parts by weight of a mixed fraction essentially consisting of 4-methylbenzonitrile and 4-methylbenzaldehyde.
Reaction SMILES: Cl.[CH:2]12[O:10][CH:6]([CH2:7][NH:8][CH2:9]1)[CH2:5][N:4]([CH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[CH2:3]2.Br[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:27]([O:26][C:25](=[O:31])[NH:24][CH2:23][CH2:22][CH2:21][N:8]1[CH2:9][CH:2]2[O:10][CH:6]([CH2:5][N:4]([CH2:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH2:3]2)[CH2:7]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: N#Cc1ccc(CN2CC3CNCC(C2)O3)cc1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 110.2 %

Procedure:
A suspension of 4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl-methyl)benzonitrile hydrochloride (6.8 g, 0.021 mol; see Preparation J above), tert-butyl (3-bromopropyl)carbamate (3.93 g, 0.017 mol; see Preparation I above) and dry K2CO3 (8.24 g, 0.059 mol) in 27 mL of dry acetonitrile was stirred at 60° C. overnight under a N2 atmosphere. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give 7.5 g of the sub-title compound as pale a liquid.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10](=[O:19])[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][C:13]1=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OC([NH:27][C@H:28]([C:36](O)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O)(C)(C)C>>[ClH:1].[CH2:2]([O:9][C:10](=[O:19])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:36](=[O:37])[C@H:28]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH2:27])[CH2:14][C:13]1=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CN1CCNCC1=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCN(CC(=O)OCc2ccccc2)C(=O)C1
Yield: 49.4 %

Procedure:
2-Oxopiperazine-1-acetic acid benzyl ester hydrochloride (2 g) and N-t-butoxycarbonyl-L-phenylalanine (5.6 g) were subjected to substantially the same procedure as in Working Example 21 to afford 1.5 g of the title compound as amorphous powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[Na].[NH3:15].[Cl-].[NH4+]>C(OCC)C>[NH2:15][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1
Reactant: Clc1ccc(-c2ccccc2)cn1
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCOCC
Product: Nc1ccc(-c2ccccc2)cn1
Yield: 36 %

Procedure:
A solution of 2-chloro-5-phenylpyridine (4.0 g., 0.021 mole) in dry diethyl ether (160 ml.) was added dropwise to a solution of sodium (3.39 g., 0.15 g-atom) in liquid ammonia (160 ml.) containing ferrous nitrate hexahydrate (0.095 g.). The resulting suspension was allowed to reflux for 4 hours. Ammonium chloride was added and the ammonia allowed to evaporate. The residue was treated with 5% aqueous sodium hydroxide (5 ml.). The mixture was filtered. The aqueous layer was extracted with ether (2×100 ml.). The combined ethereal layers were washed with brine and dried over sodium sulfate. The solution was concentrated and the residue recrystallized from methylcyclohexane. The product was triturated with chloroform (100 ml.). The mixture was filtered and the filtrate evaporated to give 2-amino-5-phenylpyridine (1.3 g., 36%), m.p. 133°-135° (lit. m.p. 133° in Chem. Ber., 91, 247 (1958).
Reaction SMILES: [Na+].C(OC[C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:26])[CH:11]2[NH:15][C:16](=[O:25])[CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[CH:23]=[O:24])[C:8]=1[C:27]([O-:29])=[O:28])(=O)C.Cl[CH2:31][O:32][C:33](=[O:46])[C@H:34]([CH:43]([CH3:45])[CH3:44])[NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C)C=O.C(OCC)(=O)C>[C:39]([O:38][C:36]([NH:35][CH:34]([CH:43]([CH3:45])[CH3:44])[C:33]([O:32][CH2:31][O:29][C:27]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][CH:7]=1)[CH:11]([NH:15][C:16](=[O:25])[CH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=[O:24])[C:10]2=[O:26])=[O:28])=[O:46])=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)Cn3cccc3C=O)C2SC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCOC(=O)C1=CCSC2C(NC(=O)Cn3cccc3C=O)C(=O)N12
Reaction time: 72 h

Procedure:
A suspension of 5 grams of 3-[(acetyloxy)methyl]-7-[[(2-formyl-1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2ene-2-carboxylic acid sodium salt and 8.5 grams of N-tert-butoxycarbonyl-L-valine chloromethyl ester, prepared according to the general procedure described in W. German Offen. No. 2,236,620, are mixed in 100 ml of dimethylformamide (DMF) and stirred for 72 hours. The mixture is diluted with ethyl acetate, washed with water and aqueous sodium bicarbonate and again with water. The ethyl acetate portion is dried over magnesium sulfate, filtered and evaporated to dryness to give 3-](acetyloxy)methyl]-7-[[(2-formyl-1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid N-tert-butoxycarbonyl-2-amino-3-methylbutyryloxy-methyl ester from which the protecting group can be removed by standard procedures to give the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[NH:36]1[C:32]([C:31]2[CH:30]=[CH:29][C:28]([C:13]3[N:9]4[N:10]=[CH:11][CH:12]=[C:7]([N:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:8]4=[N:15][C:14]=3/[CH:16]=[CH:17]/[C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:35][CH:34]=2)=[N:33][N:38]=[N:37]1
Reactant: N#Cc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C(=C/c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(-c2nnn[nH]2)cc1)\c1ccc2ccccc2n1
Temperature: 130 °C

Procedure:
A mixture of compound 13a (95 mg, 0.21 mmol), sodium azide (20 mg, 0.31 mmol) and ammonium chloride (16 mg, 0.31 mmol) in DMF (3 mL) was heated at 130° C. overnight. The reaction mixture was cooled to rt and water (20 mL) was added. The mixture was extracted with DCM/MeOH (9:1 v/v, 2×100 mL). The combined organic layers were washed with brine, and dried over Na2SO4. The mixture was filtered and concentrated to obtain a residue, which was washed with MeOH (2×2 mL). The resulting solid was purified by flash column chromatography on silica gel (0-20% MeOH/DCM) to give compound 13b as an orange solid. 1H-NMR (400 MHz, CDCl3+CD3OD) δ (ppm): 8.27 (d, J=8.3 Hz, 2H), 8.09-8.14 (m, 1H), 8.02-8.07 (m, 1H), 8.00 (d, J=5.6 Hz, 1H), 7.84-7.92 (m, 3H), 7.73-7.80 (m, 2H), 7.65-7.72 (m, 2H), 7.46-7.53 (m, 1H), 6.12 (d, J=5.6 Hz, 1H), 4.04-4.11 (m, 4H), 3.96-4.02 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H23N9O: 502.2 (M+H). Found 502.5.
Reaction SMILES: [OH:1][C:2]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]2[C:21](=[O:24])[N:22]=[N:23][C:3]=12.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.C(Cl)Cl>[C:25]([O:1][C:2]1[C:8](=[O:9])[N:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]2[C:21](=[O:24])[N:22]=[N:23][C:3]=12)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1nnc2c(O)c(=O)n(-c3ccccc3)c3cc(Cl)ccc3n1-2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1c2nnc(=O)n-2c2ccc(Cl)cc2n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3.4 g of 4-hydroxy-8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione and 1.0 g of acetic anhydride in 10 ml of pyridine are warmed in a steam bath for 0.2 hour and stirred at room temperature for 10 hours. The reaction mixture is cooled, diluted with 100 ml of methylene chloride and washed with 100 ml water containing 0.84 g sodium bicarbonate. The organic phase is washed four times with water, dried and evaporated. The residue is triturated with a minimum amount of ether and the title compound filtered off, dried and recrystallized from methylene chloride and ether.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].O>C(Cl)Cl>[C:11]([NH:15][C:7](=[O:8])[C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)N
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
To a solution of p-toluoyl chloride (34.2 ml, 259 mmol) in DCM (250 ml), charged to a 500 mL round bottom, t-butylamine (57.3 ml, 543 mmol) was added slowly at 0° C. The reaction mixture was stirred at 0° C. for 45 min. The reaction mixture was then partioned between additional DCM and water. The organic layer was then washed with water 2 and brine. The organic layer was then dried over magnesium sulfate and concentrated under vacuum to give a white solid N-tert-butyl-4-methylbenzamide (47.07 g, 95.1% yield). MS (M+H)+ 192.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:12]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:4](N)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:28]>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].CS(C)=O>[CH2:14]([O:13][C@@H:12]1[C@H:19]([OH:20])[C@@H:21]([CH2:23][OH:24])[O:22][C@H:11]1[N:8]1[C:9]2[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:28])[C:5]=2[N:6]=[CH:7]1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21

Procedure:
2,6-diamino-9-(2'-O-pentyl-β-D-ribofuranosyl)purine (1.9 g) in 0.1M sodium phosphate buffer (50 ml, pH 6.0) and DMSO (25 ml) was treated with adenosine deaminase (added in two aliquots--first aliquot 50 mg, second aliquot 80 mg) at 35° C. as per the procedure of Example 3 to yield 1.4 g of product. 1H NMR (DMSO-d6) δ 0.8 (t, 3, CH3), 1.16 (m, 4, 2×CH2), 1.4 (m, 2, CH2), 3.38, 3.6 (m, 4, OCH2, H-5'), 3.93 (s, 1, H-4'), 4.28 (m, 2, H-2', H-3'), 5.17 (br, 2, 5', 3'-OH), 5.8 (d, 1, H-1'), 6.53 (br s, 2, NH2), 8.0 (s, 1, H-8) and 10.68 (br, 1, NH).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([C:18]1[S:19][C:20](Br)=[CH:21][C:22]=1[NH:23][S:24]([C:27]1[C:28]([CH3:33])=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25])=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(C)C=CC=CC=1.CO.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:11]([O:15][C:16]([C:18]1[S:19][C:20]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:21][C:22]=1[NH:23][S:24]([C:27]1[C:28]([CH3:33])=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1ccccc1S(=O)(=O)Nc1cc(Br)sc1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(NS(=O)(=O)c3ccccc3C)c(C(=O)OC(C)(C)C)s2)cc1
Temperature: 70 °C
Yield: 87.7 %

Procedure:
To the mixture of 4-methylbenzeneboronic acid (38.0 mg, 0.279 mmol) and 5-Bromo-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (40 mg, 0.0925 mmol) in 5:1 mixture of toluene/MeOH (2.0 mL) was added a solution of Pd(PPh3)4 (12.0 mg, 0.01 mmol, 10 mol %) in toluene (1.0 mL) followed by aqueous 2M Na2CO3 solution (0.1 mL, 0.2 mmol). The resultant reaction mixture was heated at 70° C. for 16 h, cooled to room temperature, filtered off through MgSO4 and washed with EtOAc. Evaporation of the solvent and purification of the residue over preparative TLC (1 mm, 60 A°) using ethyl acetate/hexane (1:10) as an eluent furnished 3-(Toluene-2-sulfonylamino)-5-p-tolyl-thiophene-2-carboxylic acid tert-butyl ester (36.0 mg, 81% yield). 1H NMR (CDCl3, 300 MHz) 9.94 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.44-7.25 (m, 6H), 7.18 (d, J=8.1 Hz, 2H), 2.71 (s, 3H), 2.36 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].NC1C=[C:16]([O:18]C)[CH:15]=CC=1C(=O)C>>[NH2:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:8]([O:9][CH3:10])=[CH:7][C:6]=1[C:16](=[O:18])[CH3:15]
Reactant: COc1ccc(C(C)=O)c(N)c1
Reactant: COc1ccc(N)cc1Cl
Product: COc1cc(C(C)=O)c(N)cc1Cl
Yield: 50 %

Procedure:
40 g. Compound 40 g was synthesized from 3-chlor-4-methoxy-aniline 39 g as a brown solid in 50% yield, according to the procedure as described for compound 40a.
Reaction SMILES: O[CH2:2][CH:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[C:17]4[CH:30]=[CH:29][S:28][C:18]=4[C:19](=[O:27])[NH:20][C:21]=3[CH:22]=[CH:23][C:24]=2[O:25]C)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:4].[Br:31]B(Br)Br>>[Br:31][CH2:2][CH:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[C:17]4[CH:30]=[CH:29][S:28][C:18]=4[C:19](=[O:27])[NH:20][C:21]=3[CH:22]=[CH:23][C:24]=2[OH:25])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:4]
Reactant: BrB(Br)Br
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NC(C)CO)cc1
Product: CC(CBr)NS(=O)(=O)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 79 %

Procedure:
Following General Procedure F, N-(1-hydroxypropan-2-yl)-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzenesulfonamide (55 mg, 0.12 mmol) was reacted with tribromoborane (0.2 mL) to afford the desired product (48 mg, 79%) as an off-white solid: 1H NMR (500 MHz, CD3OD); ESI MS m/z 494 [C20H17BrN2O4S2+H]+; HPLC 99.0% (AUC), tR=11.39 min;
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C>C1COCC1>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
1-Benzyl-4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine was dissolved in THF (10 mL). The reaction was cooled to −20° C. and 1-chloroethylchloroformate (0.5 mL) in THF (2 ml) was added. The reaction was stirred at −10° C. for 3 h and then concentrated. MeOH (10 mL) was added to the crude mixture and refluxed for 2 h. The solvent was removed to provide 4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine (HCl) which was used without further purification. 1H NMR (400 MHz, DMSO-d6) 9.40 (s, 2H), 7.74 (m, 4H), 6.39 (m, 1H), 3.79 (m, 2H), 3.33 (m, 2H), 2.74 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.C([Li])CCC>CCCCCC.O1CCCC1>[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:17]([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:16]=2)=[O:19])[CH2:24]1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: CC1CCCNC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1CCCN(C(=O)c2nc(-c3ccccc3)nc3ccccc23)C1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), 3-methylpiperidine (3 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from isopropyl ether, 3-methyl-1-[(2-phenylquinazolin-4-yl)-carbonyl]-piperidine (1g), melting at 116° C., is obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([O:25]CC2C=CC=CC=2)=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)(C)(C)C>CO>[NH2:7][C@@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH:19]=[CH:18]3)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2ccc3c(OCc4ccccc4)nccc3c2)CC1
Solvent: CO
Product: N[C@H]1CC[C@@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1

Procedure:
The title compound was prepared by stirring cis-[4-(1-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (27) at room temperature in methanol/2 N HCl (1:1). After complete conversion, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC. The obtained trifluoroacetate was converted to the corresponding hydrochloride by dissolving the compound in 2 N HCl and evaporation of the solvent. After dissolving the residue in water and lyophilisation, the desired product (HCl-salt) was isolated as a colourless solid. Rt=0.75 min (Method B). Detected mass: 259, 2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][C:3]=1[OH:13].CCN=C=NCCCN(C)C.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>O>[Cl:12][C:5]1[C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]([NH:1][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[C:3]([OH:13])[CH:4]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)c(Cl)cc1O)c1ccncc1
Temperature: 80 °C
Yield: 58.6 %

Procedure:
A mixture of 1.2 g of 2-amino-5-chloro-4-trifluoromethylphenol, 1.35 g of WSC, 0.67 g of isonicotinic acid and 10 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.01 g of N-[4-chloro-2-hydroxy-5-trifluoromethylphenyl]isonicotinamide.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([NH:16][NH2:17])=[N:5][CH:6]=[C:7]([CH:15]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CO[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=N>CO>[Cl:2][C:3]1[C:4]2[N:5]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:17][N:16]=2)[CH:6]=[C:7]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH:15]=1
Reactant: CC(C)(C)OC(=O)c1cnc(NN)c(Cl)c1
Reactant: COC(=N)c1ccccn1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc(Cl)c2nnc(-c3ccccn3)n2c1
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 7.6 %

Procedure:
To a solution of tert-butyl 5-chloro-6-hydrazinonicotinate hydrochloride salt (5.5 g, 17.4 mmol) in methanol (80 mL) was added methylpyridine-2-carboximidoate (4.73 g, 34.7 mmol). The mixture was heated to 65° C. After 2.5 h, the mixture was cooled to ambient temperature. The solid crashed out was filtered off and the filtrate was concentrated. Purification by silica gel chromatography (100% hexanes→60% hexanes/ethyl acetate) gave 0.44 g of the title compound and 1.3 g of a side product. The side product (1.3 g) was dissolved in methanol (28 mL) and acetic acid (0.53 mL) was added. The mixture was heated to 65° C. After 7 h, the reaction was cooled to ambient temperature and saturated aqueous sodium bicarbonate was added. The mixture was extracted with ethyl acetate (3×). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give another 1.0 g of the title compound: LC-MS [M+1]=331.1.
Reaction SMILES: [NH2:1][C:2]1([C:5]([O:7][CH3:8])=[O:6])[CH2:4][CH2:3]1.C([O-])(O)=O.[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl.O>[C:19]1([CH2:18][O:17][C:15]([NH:1][C:2]2([C:5]([O:7][CH3:8])=[O:6])[CH2:4][CH2:3]2)=[O:16])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C1(N)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)OCc2ccccc2)CC1
Reaction time: 2 h
Yield: 46.1 %

Procedure:
Methyl 1-aminocyclopropanecarboxylate (15.83 g, 104.43 mmol) was dissolved in a mixture of CH2Cl2 (150 mL) and water (150 mL). To this mixture was added NaHCO3 (35.09 g, 417.72 mmol) followed by benzyl chloroformate (15.43 mL, 109.64 mmol). The mixture was stirred vigorously for 2 hours, and after separation of the two layers, the aqueous layer was extracted with 100 mL of CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide methyl 1-({[(phenylmethyl)oxy]carbonyl}amino)cyclopropanecarboxylate (12.0 g, 46%). LCMS: (M+H)+: 206.1.