Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20](OCC)=[O:21])[N:19]=2)[CH:16]=1>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([F:9])=[C:2]([Cl:1])[CH:3]=3)=[O:21])[N:19]=2)[CH:16]=1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(Nc1ccc(F)c(Cl)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using 3-chloro-4-fluoroaniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: Cl[N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.[CH3:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH2:21].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH3:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH:21][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(Cl)S1
Reactant: CN(C)CCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CN(C)CCCNN1NC=C(c2ncc([N+](=O)[O-])n2C)S1
Temperature: 25 °C

Procedure:
A mixture consisting of 3.8 gm., 0.0155 mole of 2-(2-chloro-5-thiadiazolyl)-1-methyl-5-nitroimidazole, prepared as in Example 16 2.5 gm., 0.029 mole of 3-dimethylaminopropylamine, 2.1 gm. 0.025 mole, of sodium bicarbonate and 100 ml. of benzene is refluxed for 22 hours. The reaction mixture is cooled to room temperature, washed with aqueous sodium bicarbonate and sodium chloride solutions. Cooling to 5° C. gives a crystalline precipitate which is collected and recrystallized from benzene to give the pure compound melting at 153°-154° C. More product is obtained from the mother liquors to give an overall yield of 3.0 gm.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[O:4][CH:5]=[C:6]([CH:8]=O)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31](Br)(Br)([Br:33])[Br:32]>ClCCl>[Br:32][C:31]([Br:33])=[CH:8][C:6]1[CH:7]=[C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])[O:4][CH:5]=1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)c1cc(C=C(Br)Br)co1
Reaction time: 1 h

Procedure:
A solution of 2-trimethylsilyl-4-furaldehyde (Compound 4, 1.0 g, 5.95 mmol) in dichloromethane (2 ml) was added to a solution of triphenylphosphine (3.9 g, 14.9 mmol) and carbon tetrabromide 2.46 g, 7.44 mmol) in dichloromethane (15 ml) at 0° under argon. After 1 hour, the mixture was extracted thoroughly with pentane. Evaporation of the pentane extracts gave an oil, which was flash chromatographed on silica using hexane. Fractions with Rf of about 0.52 on evaporation gave the title silylfuran as a yellow oil.
Reaction SMILES: C(O[C@H:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]=[N+:25]=[N-:26])(=O)C.[BrH:27]>C(Cl)Cl.[Br-].C([N+](CC)(CC)CC)C>[C:9]([O:8][C@H:7]1[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:18][C@H:5]([Br:27])[C@@H:6]1[N:24]=[N+:25]=[N-:26])(=[O:11])[CH3:10]
Reactant: Br
Reactant: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 2 h

Procedure:
1 ,3,4,6- Tetra-O-acetyl-2-azido-2-deoxy-alpha-D-galactopyranose (14) (500 mg) was dissolved in 50 mL CH2Cl2 (anhydrous), treated with 50 mL of CH2Cl2 saturated with HBr at 0° C., and stirred for two hours. Then 2 g of tetraethyl ammonium bromide was added and stirred overnight. Next, the solution was washed with 100 mL ice-cold water and concentrated. The residue was crystallized from ethyl ether and pentane to give 400 mg of 3,4,6-tri-O-acetyl-2-azido-2-deoxy-alpha-D-galactopyranosyl bromide (18).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.C([O:19][CH2:20][C@@H:21]([OH:26])[C:22]([F:25])([F:24])[F:23])C1C=CC=CC=1>>[NH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[O:26][C@@H:21]([C:22]([F:25])([F:24])[F:23])[CH2:20][OH:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: O[C@H](COCc1ccccc1)C(F)(F)F
Product: Nc1ccc(F)cc1O[C@H](CO)C(F)(F)F

Procedure:
Is prepared in a similar manner as intermediate III.1 from 2,4-difluoro-1-nitro-benzene and (2R)-3-benzyloxy-1,1,1-trifluoro-propan-2-ol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH:24][O:25][CH3:26].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1>[CH3:26][O:25][N:24]([CH3:23])[C:18]([C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[CH:22][CH:21]=1)=[O:19]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid (0.7 g, 2.3 mmol), N,O-dimethylhydroxylamine (0.27 g, 2.8 mmol), 1-hydroxybenzotriazole (0.37 g, 2.7 mmol) and 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (1.1 g, 5.8 mmol) in tetrahydrofuran (15 mL) was stirred at ambient temperature for 48 hours. Additional N,O-dimethylhydroxylamine (0.14 g, 1 mmol) was added and the mixture stirred an additional 4 hours and concentrated. The residue was dissolved in ethyl acetate, washed with water and filtered through silica gel. The solution was concentrated and used without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]=[C:10]=[O:11])(=[O:8])=[O:7].[NH2:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([CH3:21])[N:14]=1.C(#N)C>C(Cl)Cl>[CH3:20][O:19][C:17]1[CH:16]=[C:15]([CH3:21])[N:14]=[C:13]([NH:12][C:10]([NH:9][S:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)(=[O:7])=[O:8])=[O:11])[N:18]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccco1
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccco2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.10 g of 2-furansulfonyl isocyanate in 40 ml of methylene chloride was added 1.60 g 2-amino-4-methoxy-6-methylpyrimidine. The resulting mixture was stirred for 1 hour at room temperature, then refluxed for 15 minutes, and the solvent was removed under vacuum. The solid obtained was allowed to stand under ethyl ether containing a trace of acetonitrile for one day, and was then filtered and dried to give the desired product melting at 185°-188° (dec).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[O:11]=[C:5]1[C:6]([C:7]([OH:9])=[O:8])=[CH:10][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][NH:4]1
Reactant: O=C(O)c1cc(Br)cnc1O
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(-c2ccccc2)c[nH]c1=O
Temperature: 110 °C
Yield: 18.1 %

Procedure:
A mixture of 5-bromo-2-hydroxynicotinic acid (436 mg, 2.00 mmol, Syn. Comm., 19 (3&4), 553–559 (1989)), phenylboronic acid (248 mg, 2.03 mmol), Cs2CO3 (1.20 g) and PdCl2 [(t-Bu)2P(OH)]2 (170 mg, CombiPhos Catalysts, Inc. Princeton, N.J.) in DMF (10 mL) and water (1.0 mL) was purged with Ar gas and heated at 110° C. for 6 h. Additional phenylboronic acid (75 mg) was added and the mixture was heated at 110° C. for 5 h. To the reaction was added TFA (3 mL), and the mixture was concentrated in vacuo to a volume of ˜12 mL. The mixture was purified by preparative HPLC to afford the desired product (78 mg, 18%). 1H NMR (DMF-d7) δ 14.8 (br s, 1H), 13.8 (br s, 1H), 8.73 (s, 1H), 8.46 (s, 1H), 7.74 (d, 1H, J=7.2 Hz), 7.53–7.42 (m, 3H), 5.81 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]>>[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: C1COCCN1
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(N5CCOCC5)n4)cc3)cc12

Procedure:
Using morpholine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 2.98 (bt, 2H, J=7 Hz); 3.56 (m, 2H); 3.70 (bs, 4H); 3.79 (bs, 4H); 7.18 (d, 1H, J=9 Hz); 7.32 (d, 1H, J=5 Hz); 7.49 (m, 2H); 7.94 (d, 2H, J=8 Hz); 8.22 (m, 3H); 8.50 (d, 1H, J=5 Hz); 8.74 (bt, 1H); 12.20 (bs, 1H). MS (ion spray) m/z 453 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:28]5[C@H:27]([CH3:26])[CH2:31][O:30][C:29]5=[O:32])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)nc2)CC1
Yield: 71.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (525 mg) described in Preparation Example 106 and (R)-4-methyloxazolidin-2-one (212 mg) described in Preparation Example 25, the title compound (394 mg) was obtained.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Si:7]([O:14][CH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)=O)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1>[Si:7]([O:14][CH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)=[CH2:1])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)[Si](C)(C)OCCC(=O)c1ccc(Cl)c(Cl)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: C=C(CCO[Si](C)(C)C(C)(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 59.1 %

Procedure:
215 g (0.60 mole) of methyltriphenylphosphonium bromide and 54 g (0.48 mole) of potassium t-butoxide were added to 2 liters of dried benzene, and the mixture was stirred for 9 hours at room temperature. At the end of this time, 40 g (0.12 mole) of 3-(3,4-dichlorophenyl)-3-oxo-1-propanol t-butyldimethylsilyl ether [prepared as described in step (b) above] were dissolved in 800 ml of benzene and the resulting solution was slowly added dropwise to the mixture over a period of 2.5 hours. 1 liter of water was then added to the reaction mixture, and the mixture was stirred for 30 minutes, whilst ice-cooling. The organic layer was separated, and then washed with water and with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using hexane as the eluent, to give 23.5 g of the title compound. The physicochemical properties of this product were the same as those of the product produced as described in Example 1(b).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[C:9](F)[C:10]([F:17])=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[F:19][C:20]([F:24])([F:23])[CH2:21][OH:22].[H-].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[C:9]([O:22][CH2:21][C:20]([F:24])([F:23])[F:19])[C:10]([F:17])=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: O=c1c2cc(Br)ccc2oc2cc(F)c(F)cc12
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)ccc2oc2cc(OCC(F)(F)F)c(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of 7-bromo-2,3-difluoro-9H-xanthen-9-one (3.1 g, 9.97 mmol) and 2,2,2-trifluoroethanol (1.445 mL, 19.93 mmol) in DMF (33 mL) at 0° C. was added sodium hydride (0.598 g, 14.95 mmol) slowly in portions. After addition, the mixture was stirred at RT for overnight. Then, H2O (100 mL) was added slowly and the mixture was extracted with EtOAc (1×100 mL). The organic layer was collected, dried over MgSO4, and concentrated. The residue was then washed with hexane (1×100 mL) to give 2.76 g of 7-bromo-2-fluoro-3-(2,2,2-trifluoroethoxy)-9H-xanthen-9-one as a light yellow solid. MS (ESI, positive ion) m/z: 390.9, 392.9 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13]2[C:14]([NH2:41])=[N:15][CH:16]=[N:17][C:18]=2[N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[N:26]([CH2:38][CH2:39][OH:40])[CH:27]=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[CH:31]=4)[N:29]=3)[CH2:21][CH2:20]2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>C1COCC1>[NH2:41][C:14]1[C:13]([C:11]2[CH:10]=[N:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:12]=2)=[C:18]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[N:26]([CH2:38][CH2:39][O:40][S:52]([CH3:51])(=[O:54])=[O:53])[CH:27]=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[CH:31]=4)[N:29]=3)[CH2:21][CH2:20]2)[N:17]=[CH:16][N:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2cn(CCO)c(C3CCN(c4ncnc(N)c4-c4cnn(C(=O)OC(C)(C)C)c4)CC3)n2)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(-c2cn(CCOS(C)(=O)=O)c(C3CCN(c4ncnc(N)c4-c4cnn(C(=O)OC(C)(C)C)c4)CC3)n2)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 4-(4-amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-pyrazole-1-carboxylic acid tert-butyl ester (350.00 mg; 0.62 mmol; 1.00 eq.) in THF 5 ml added ethyl-diisopropyl-amine (0.28 ml; 1.56 mmol; 2.50 eq.), then added drop wised methanesulfonyl chloride (0.10 ml; 1.24 mmol; 2.00 eq.) at 0° C., the reaction mixture was stirred at RT for 1 hr, LC-MS showed desired as major, and starting material disappeared, removed off solvent, directly carried the crude product for next step reaction.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1>>[CH3:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[NH:15][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and m-toluidine (52 μl, 0.486 mmol) similar to Example 13 and isolated as a pale yellow oil (132 mg, 99%). 1H NMR (CDCl3): 8.76-8.74 (m, 1H), 8.43-8.40 (m, 1H), 7.78-7.72 (m, 1H), 7.55 (s, 1H), 7.31-7.08 (m, 4H), 6.92 (d, J=7.2 Hz, 1H), 6.55 (s, 1H), 2.41 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][N:21]([CH3:35])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][NH2:34])[CH2:27]1>>[CH3:35][N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][NH:34][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:27]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CN(C)CCCCC1CCCN(CCN)C1
Product: CN(C)CCCCC1CCCN(CCNC(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Yield: 53 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[4-(dimethylamino)butyl]-piperidin-l-yl]ethanamine in a yield of 53% of theory. Colourless crystals, m.p. 119°-120° C.
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:13]N1C(=O)CCC1=O.[CH2:21]([O:25][C:26]([N:28]([C:45]1[C:50]([O:51][CH3:52])=[N:49][C:48]([CH3:53])=[CH:47][N:46]=1)[S:29]([C:32]1[C:33]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])=[O:27])[CH:22]([CH3:24])[CH3:23]>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:44][C:41]1[CH:42]=[CH:43][C:38]([C:33]2[C:32]([S:29]([N:28]([C:26]([O:25][CH2:21][CH:22]([CH3:23])[CH3:24])=[O:27])[C:45]3[C:50]([O:51][CH3:52])=[N:49][C:48]([CH3:53])=[CH:47][N:46]=3)(=[O:31])=[O:30])=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:39][CH:40]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1-c1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Yield: 70.9 %

Procedure:
Azobis(isobutyronitrile) (150 mg) and N-bromosuccinimide (1.68 g) were added to a solution of N-(isobutoxycarbonyl)- N-(3-methoxy-5-methylpyrazin-2-yl)-4'-methyl-2-biphenylsulphonamide (4.44 g) in carbon tetrachloride (150 ml). The mixture was heated under reflux for 4 hours and then allowed to cool and filtered. The filtrate was concentrated by evaporation and the residue was purified by flash chromatography on silica (150 g), eluting with 20% ethyl acetate in isohexane. Fractions containing the product were combined and evaporated to give 4'-bromomethyl- N-(isobutoxycarbonyl)- N-(3-methoxy-5-methylpyrazin-2-yl)-2-biphenylsulphonamide (3.67 g); 1H NMR (d6 -DMSO): 0.6 (s, 6H), 1.6-1.7 (m, 1H), 3.8 (d, 2H), 3.95 (s, 3H), 4.8 (s, 2H), 7.3-7.5 (m, 5H), 7.7-7.8 (m, 2H), 8.15 (s, 1H), 8.45-8.55 (m, 1H); mass spectrum (+ve FAB, methanolBA): 548 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([C:6]2[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([Cl:1])[C:7]=2[Cl:8])=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(F)cc2)c(Cl)c1Cl
Temperature: 25 °C
Yield: 53.5 %

Procedure:
A mixture of 2,3-dichloroanisole (35.4 g.; 0.20 mole), 4-fluorobenzoyl chloride (34.8 g.; 0.22 mole) and methylene chloride (300 ml.) at 5° C. was stirred vigorously and treated with finely powdered aluminum chloride (28.0 g.; 0.21 mole). The reaction mixture was slowly heated and refluxed for two hours. The reaction mixture was cooled to room temperature and decomposed with ice and hydrochloric acid (50 ml.). The aqueous solution was extracted twice with methylene chloride. The combined methylene chloride solution was washed with aqueous sodium bicarbonate solution and finally with water. The organic layer was dried (MgSO4) and filtered. The solvent was removed in vacuo, and the residue on triturating with pet. ether gave the product 32 g. (50%); m.p. 138°-140°. This product was used for Step B without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8](Br)[C:7]([O:11][CH3:12])=[N:6][CH:5]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)(O)[O-].[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.O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:15]([F:26])([F:25])[F:14])[CH:21]=2)[C:7]([O:11][CH3:12])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(OC)c(Br)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
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: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(OC)c(-c2cccc(C(F)(F)F)c2)c1
Yield: 107.6 %

Procedure:
5-Bromo-6-methoxy-nicotinic acid methyl ester (1.03 g, 4.18 mmol), 3-trifluoromethylbenzeneboronic acid (0.795 g, 4.19 mmol), tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.021 mmol) and sodium bicarbonate (1.05 g, 12.5 mmol) were partitioned between toluene (10 ml) and water (10 ml) under argon and stirred in reflux for 1 h. The material was partitioned between ethyl acetate and water, the combined organic extracts were dried over sodium chloride, filtered over a small plug of silica and evaporated to dryness. The solid material was titured with methanol, filtered and dried in vacuo to yield the title compound (1.4 g) sufficiently pure for further synthesis.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[Na+].CCOCC>O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OCCCCc1ncccn1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: BrCCCCCCOCCCCc1ncccn1
Reaction time: 20 h

Procedure:
A mixture of 2-pyrimidinebutanol (1.31 g), 1,6-dibromohexane (5 ml), 50% aqueous sodium hydroxide solution (5 ml) and TAB (140 mg) was vigorously stirred under nitrogen at 23° for 20 h. Ether (25 ml) and water (20 ml) were added, the organic phase separated, washed with brine (20 ml), dried and evaporated in vacuo. The residue was purified by FCC. Elution with hexane and hexane-ether (9:1) followed by ether afforded the title compound as a colourless oil (1.67 g)
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:14])([F:13])[CH2:9][CH:10]1[CH2:12][CH2:11]1)(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[CH:10]1([CH2:9][C:8]([F:14])([F:13])[CH2:7][N:17]=[N+:18]=[N-:19])[CH2:12][CH2:11]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(OCC(F)(F)CC1CC1)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(F)(F)CC1CC1
Temperature: 25 °C

Procedure:
A solution of 1.68 g (6.3 mmol) of 3-cyclopropyl-2,2-difluoropropyl trifluoromethanesulfonate and 820 mg (12.6 mmol) of sodium azide in 6.0 mL of DMF was heated at 50° C. under Ar overnight. After cooling to rt, the mixture was diluted with 40 mL of water, and extracted with two 75 mL portions of ether. The combined organic layers were washed thrice with water, brine, and dried over MgSO4. The solvents were concentrated by distillation at atmospheric pressure to give a solution of the title compound in ether that was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([NH2:22])[CH3:21])=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][C:8](=[O:10])[CH:7]=[CH:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=2)[CH3:21])=[CH:16][C:15]=1[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: CC(N)c1ccc(F)c(N2CCOCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)C=Cc1ccc(F)cc1)c1ccc(F)c(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A mixture of 4-fluorocinnamic acid (3.16 g, 19.6 mmol), 1-(4-Fluoro-3-morpholin-4-yl-phenyl)-ethylamine (4.39 g, 19.1 mmol), EDC.HCl (7.53 g, 39.2 mmol), DMAP (2.39 g, 19.6 mmol) and Et3N (8.23 ml, 58.8 mmol) in CH2Cl2 (60 ml) was stirred at room temperature for 16 hours. Purification by flesh chromatography over silica gel (elution with 50% ethyl acetate in hexane) gave 6.9 g of the title compound. The enantiomer was separated by Chiralpak AD column (50×500 mm, 20um) eluted with 45% EtOH in hexane, RT=36.1 min.