Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][O:16][C:15]3[CH:18]=[C:19]4[C:23](=[CH:24][C:14]2=3)[CH2:22][CH2:21][O:20]4)[C:6]1=[O:25].C(N(CC)CC)C.[F:33][C:34]([F:46])([F:45])[O:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>ClCCl>[O:25]=[C:6]1[C:7]2([CH2:17][O:16][C:15]3[CH:18]=[C:19]4[C:23](=[CH:24][C:14]2=3)[CH2:22][CH2:21][O:20]4)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]1[CH2:4][CH2:3][CH2:2][NH:1][C:38](=[O:39])[C:37]1[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=1[O:35][C:34]([F:33])([F:45])[F:46]
Reactant: NCCCN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21)c1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
To a solution of 1′-(3-aminopropyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.20 g, 0.59 mmol) in anhydrous dichloromethane (10 mL) was added triethylamine (0.10 mL, 0.71 mmol) followed by 2-(trifluoromethoxy)benzoyl chloride. The reaction mixture was stirred at ambient temperature for 20 h and concentrated in vacuo. The residue was purified by column chromatography to afford N-[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propyl]-2-(trifluoromethoxy)benzamide (0.21 g, 67%) as a colorless foam: mp 65-70° C.; 1H NMR (300 MHz, CDCl3) δ 7.81 (dd, J=7.6, 1.7 Hz, 1H), 7.47 (ddd, J=9.4, 7.6, 1.5 Hz, 1H), 7.39-7.30 (m, 3H), 7.20 (d, J=6.9 Hz, 1H), 7.09 (dd, J=7.5, 7.5 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 6.47 (s, 1H), 6.41 (s, 1H), 4.90 (d, J=9.0 Hz, 1H), 4.67 (d, J=9.0 Hz, 1H), 4.53 (t, J=8.6 Hz, 1H), 4.02-3.83 (m, 2H), 3.58-3.33 (m, 2H), 2.99 (t, J=8.6 Hz, 2H), 2.05-2.01 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 179.0, 164.9, 161.9, 161.3, 145.7, 141.8, 132.8, 131.8, 130.7, 129.3, 128.9, 127.3, 124.1, 123.7, 121.5, 120.3 (d, JC-F=259.2 Hz), 120.0, 119.8, 118.7, 108.4, 93.3, 80.5, 72.4, 57.8, 37.1, 36.1, 29.0, 27.0; MS (ES+) m/z 524.5 (M+1).
Reaction SMILES: [OH:1][C:2]([C:7]1[O:11][N:10]=[C:9]([CH3:12])[N:8]=1)([CH3:6])[C:3](=[O:5])[CH3:4].C(O[CH:18](N(C)C)[N:19]([CH3:21])[CH3:20])(C)(C)C>>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:4][C:3](=[O:5])[C:2]([OH:1])([C:7]1[O:11][N:10]=[C:9]([CH3:12])[N:8]=1)[CH3:6]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)C(C)(O)c1nc(C)no1
Product: Cc1noc(C(C)(O)C(=O)C=CN(C)C)n1

Procedure:
3-Hydroxy-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-butan-2-one (see example 58a) (102 mg, 0.6 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 28a) to give crude title compound (138 mg) as a yellow oil which was used directly in the next step.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].[I:21][C:22]1[CH:23]=[C:24]2[C:40]([C:41]([NH:43][CH3:44])=[O:42])=[C:39]([C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=3)[O:38][C:25]2=[N:26][C:27]=1[N:28]([CH2:33][CH2:34][CH2:35][CH:36]=[O:37])[S:29]([CH3:32])(=[O:31])=[O:30]>C1COCC1>[OH:37][CH:36]([CH2:35][CH2:34][CH2:33][N:28]([C:27]1[N:26]=[C:25]2[O:38][C:39]([C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=3)=[C:40]([C:41](=[O:42])[NH:43][CH3:44])[C:24]2=[CH:23][C:22]=1[I:21])[S:29]([CH3:32])(=[O:31])=[O:30])[C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)C
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCC=O)S(C)(=O)=O)c(I)cc12
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C(O)CCCN(c1nc2oc(-c3ccc(C)cc3)c(C(=O)NC)c2cc1I)S(C)(=O)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of diisopropylamine (1.4 eq., 18 μl) in THF (0.5 ml) cooled at 0° C. was added n-BuLi (1.6 M in hexane, 1.2 eq., 68 μl). The resultant solution was stirred at 0° C. for 10 min and cooled to −78° C., and then a solution of ethyl isobutyrate (1 eq., 10.5 mg) in THF (0.5 ml) was added. After the reaction mixture was stirred at −78° C. for 1 h, a solution of 5-iodo-N-methyl-6-(N-(4-oxobutyl)methylsulfonamido)-2-p-tolylfuro[2,3-b]pyridine-3-carboxamide (1 eq., 50.0 mg) in THF (1 ml) was introduced. The reaction mixture was stirred at −78° C. for 1 h, quenched with saturated aqueous NH4Cl, and extracted with diethyl ether. The combined ethereal layers were washed with brine, dried over MgSO4, filtered, and concentrated to yield the crude title compound which was used in next step without purification.
Reaction SMILES: [CH2:1]1[CH:16]2[N:4]([CH2:5][CH2:6][C:7]3[NH:8][C:9]4[N:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=32)[CH2:3][CH2:2]1.[H-].[Na+].[O:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>CN(C=O)C>[N:25]1[CH:26]=[CH:27][C:22]([CH:20]([OH:19])[CH2:21][N:8]2[C:7]3[CH2:6][CH2:5][N:4]4[CH:16]([C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]2=3)[CH2:1][CH2:2][CH2:3]4)=[CH:23][CH:24]=1
Reactant: c1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(Cn1c2c(c3cccnc31)C1CCCN1CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluorene (1 g, 4.6 mmol) in DMF (20 mL) were portion wise added NaH (60%, 0.552 g, 13.8 mmol) and 4-(oxiran-2-yl)pyridine (0.709 g, 5.6 mmol). The reaction mass was stirred at RT overnight. The progress of reaction was monitored by LCMS. The reaction mixture was quenched with ice cold water (300 mL) and extracted with EtOAc (3×100 mL). The combined organic layer was washed with water (10×100 mL), followed by brine (2×100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography followed by reverse phase HPLC to yield the title compound;
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]([NH2:12])[CH:4]=1)[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([C:20]2[N:25]=[C:24]([CH3:26])[C:23]([C:27](O)=[O:28])=[CH:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]([NH:12][C:27]([C:23]2[C:24]([CH3:26])=[N:25][C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=3)=[N:21][CH:22]=2)=[O:28])[CH:4]=1)[CH3:2]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: CCc1cn(N)c2cnccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cn(NC(=O)c2cnc(-c3cccc(F)c3)nc2C)c2cnccc12
Reaction time: 1 h
Yield: 39.7 %

Procedure:
A mixture of 3-ethyl-pyrrolo[2,3-c]pyridin-1-ylamine (93 mg, 0.577 mmol), 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (134 mg, 0.757 mmol), HATU (263 mg, 0.692 mmol) and DIPEA (223 mg, 1.73 mmol) in DMF (3 mL) is heated at 1500 C. for 1 h. The reaction is quenched with water and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography eluting with 0-100% ethyl acetate in heptane to afford 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-ethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide (86 mg). MS: 376 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.15 (s, 1H), 8.69 (s, 1H), 8.37 (d, 1H), 8.15-8.26 (m, 2H), 7.70 (d, 1H), 7.55 (q, 1H), 7.49 (s, 1H), 7.29 (t, 1H), 2.80-2.90 (m, 5 H), 1.38 (t, 3H). IC50=7 nM.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:9]=2[N:8]=[CH:7]1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:37][CH:38]1[CH:45]2[CH2:46][C:41]3([OH:48])[CH2:42][CH:43]([CH2:47][CH:39]1[CH2:40]3)[CH2:44]2.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[OH:48][C:41]12[CH2:46][CH:45]3[CH2:44][CH:43]([CH2:47][CH:39]([CH:38]3[NH:37][C:15]([C:13]3[CH:12]=[CH:11][C:10]4[N:6]([CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[CH:7]=[N:8][C:9]=4[CH:14]=3)=[O:17])[CH2:40]1)[CH2:42]2
Reactant: [N-]=[N+]=NCCn1cnc2cc(C(=O)O)ccc21
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NCCn1cnc2cc(C(=O)NC3C4CC5CC3CC(O)(C5)C4)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.9 %

Procedure:
To a solution of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (0.65 g, 0.0028 mol) in dry DMF (5.0 mL) was added with stirring HOBt (0.46 g, 0.0034 mol), DIPEA (2.5 mL, 0.014 mol), 4-aminoadamantan-1-ol (0.685 g, 0.0034 mol) at 0° C. To the resulting mixture was added EDCl (0.65 g, 0.0034 mol) and stirred for 15 h at ambient temperature. The reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water, dried (Na2SO4) and the solvent evaporated affording (1.0 g, 93.5%) of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (5-hydroxyadamantan-2-yl)-amide. MS-ESI m/z 381 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7](Cl)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O-:15].[Na+].[NH4+].[Cl-]>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:15][CH3:14])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C#N)c(Cl)n1
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(C)(C)C)ccc1C#N
Yield: 85 %

Procedure:
In a screw cap pressure tube, 6-tert-butyl-2-chloronicotinonitrile (410.0 mg, 2.1 mmol) was dissolved in anhydrous MeOH (3.0 ml) under N2. NaOMe (159.3 mg, 2.9 mmol) was added as a solution in anhydrous MeOH (3.0 ml). The tube was sealed and the mixture refluxed for 20 hours. The mixture was allowed to cool. NH4Cl (sat.) was added and the product extracted with EtOAc. The combined organic extracts were washed with water, dried (MgSO4), filtered and concentrated. Purification was done by flash chromatography (Pet. Ether/EtOAc 95:5) to give the title substance in 85% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:5]=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.O>C(#N)C>[Br:20][C:3]1[CH:4]=[CH:5][C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=2)=[N:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)c1ccc(CNc2cccc(Cl)n2)cn1
Solvent: CC#N
Solvent: O
Product: FC(F)(F)c1ccc(CNc2ccc(Br)c(Cl)n2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (567, 4.50 g, 0.0156 mol) in acetonitrile (120.0 mL) under an atmosphere of nitrogen, N-bromosuccinimide (3.03 g, 0.0170 mol) in acetonitrile (50 mL) was added slowly. The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified with silica gel column chromatography eluting with 25% to 100% ethyl acetate in hexane to give a white solid (568, 6.20 g, 80.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>>[CH2:30]([N:32]([CH2:33][CH3:34])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:31]
Reactant: CCNCC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Cl)c(-c3ccccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI): predicted mass calcd. for C23H22ClN5O2, 435.9
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>CN(C)C=O>[CH:24]([NH:27][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1)([CH3:26])[CH3:25]
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Reactant: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NCc1nc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)no1
Yield: 67.3 %

Procedure:
3.30 g (10 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature for 2.5 hours with 3 g (50 mmol) of isopropylamine and 20 ml of N,N-dimethylformamide. After evaporating the solvent the residue was dissolved in methylene chloride and the solution was washed twice with water. The organic solution was dried over magnesium sulfate and concentrated. By recrystallizing the residue from ethyl acetate there were obtained 2.37 g (67%) of 3-(5-isopropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 142°-144°, which was converted into the hydrochloride of m.p. 252°-254°.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH3:10][O:11][CH2:12]Cl.[Br:14][C:15]1[CH:16]=[C:17]([O:24][CH3:25])[C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=[O:21]>ClCCl>[Br:14][C:15]1[CH:16]=[C:17]([O:24][CH3:25])[C:18]([O:23][CH2:10][O:11][CH3:12])=[C:19]([CH:22]=1)[CH:20]=[O:21]
Reactant: COCCl
Reactant: COc1cc(Br)cc(C=O)c1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1c(C=O)cc(Br)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.8 %

Procedure:
Ethyldiisopropylamine (3.01 ml, 17.1 mmol) and methoxymethylchloride (1.5 ml, 15.7 mmol) were added to a dichloromethane solution (30 ml) of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (3.3 g, 14.3 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1→11:9). The purified product was concentrated to dryness under reduced pressure to obtain 5-bromo-3-methoxy-2-methoxymethoxybenzaldehyde (4.2 g) as light yellow solid.
Reaction SMILES: CN(C)C=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:25])[F:24])=[O:16].[CH2:27](I)[CH3:28].[H-].[Na+]>O>[CH2:27]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:24])[F:25])=[O:16])[CH3:28]
Reactant: CCI
Reactant: CC(CCCCOC(=O)c1cc2ccccc2[nH]1)=C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(C(=O)OCCCCC(C)=C(F)F)cc2ccccc21
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.32 g (1.1 mmol) of 6,6-difluoro-5-methyl-5-hexenyl 1H-indole-2-carboxylate and 0.34 g (2.2 mmol) of ethyl iodide, followed by the addition of 0.06 g (1.5 mmol) of sodium hydride at room temperature and stirring at the same temperature for 1 hour. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:5) to obtain 0.31 g (yield: 88%) of 6,6-difluoro-5-methyl-5-hexenyl 1-ethyl-1H-indole-2-carboxylate.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=4)=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=[C:7]([F:30])[C:3]=1[C:4]([NH2:6])=[O:5].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=4)=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=[C:7]([F:30])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1ccc(-c2ccc3sc(COc4ccc(F)c(C(N)=O)c4F)nc3c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(=O)c1c(F)ccc(OCc2nc3cc(-c4ccc(O)cc4)ccc3s2)c1F
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 2.7 %

Procedure:
Compound 2,6-difluoro-3-[5-(4-methoxy-phenyl)-benzothiazol-2-ylmethoxy]-benzamide (0.095 g, 0.223 mmol) was dissolved in 5 ml of DCM and cooled to −70° C. To this, BBr3 (0.1 ml 0.156 mmol) was added drop wise. After complete addition, reaction mixture was stirred at r.t. for 30 min. The reaction mixture was quenched with MeOH. Reaction mixture was concentrated and purified by column chromatography to obtain (0.0025 g, 3%) compound as white solid. 1H NMR (DMSO-d6, 400 MHz); δ 5.70 (s, 2H), 6.88 (d, 1H, J=8.4 Hz (o-coupling), 7.10 (m, 1H), 7.41 (m, 2H), 7.60 (d, 2H, J=8.8 Hz, (o-coupling), 7.71 (d, 2H), 7.89 (broad s, 1H), 8.13-8.17 (m, 2H), 9.62 (broad s, 1H); MS ES+ (413.0).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:6][C:7]1[CH:12]=[C:11](Cl)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:6][C:7]1[CH:12]=[C:11]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: c1c[nH]cn1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(-n2ccnc2)ccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 48 h

Procedure:
240 mmol of imidazole, 240 mmol of 2-amino4-chloronitrobenzene and 240 mmol of potassium carbonate in 450 ml of dimethylformamide (DMF) are stirred in a 1 litre round-bottomed flask. The mixture is maintained at 130° C. with stirring for 48 hours. After the DMF has been removed by evaporation, the residue is taken up in water. The precipitate that forms is filtered off and then washed with water. It is then dissolved in 550 ml of 1N hydrochloric acid. After insoluble material has been filtered off, the filtrate is rendered alkaline and the precipitate that forms is filtered off and washed with water. After drying, the expected product is obtained after purification by chromatography on silica gel using a dichloromethane/methanol mixture(95/5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:6].Br[C:29]([CH3:35])([CH3:34])[C:30]([O:32][CH3:33])=[O:31]>>[CH3:34][C:29]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][NH:7][C:5](=[O:6])[C:4]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:3]=3[O:2][CH3:1])=[CH:15][CH:14]=2)=[CH:17][CH:18]=1)([CH3:35])[C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)C(C)(C)Br
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Product: COC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3cc(Cl)ccc3OC)cc2)cc1
Yield: 19 %

Procedure:
Methyl 2-Methyl-2-{4-[2-(2-methoxy-5-chloro-benzamido)-ethyl]biphenyl-4'-oxy}-propionate was prepared from 4-[2-(2-methoxy-5-chloro-benzamido)-ethyl]-4'-hydroxy-biphenyl and methyl 2-bromo-2-methyl-propionate analogous to Example 1. Yield: 19% of theory; m.p. <20° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:16]([CH:17]=[O:18])=[C:15]([C:19]#[N:20])[CH:14]=[N:13]2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:12]2[C:16]([CH:17]3[O:23][CH2:22][CH2:21][O:18]3)=[C:15]([C:19]#[N:20])[CH:14]=[N:13]2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9]
Reactant: OCCO
Reactant: Cn1nc(-n2ncc(C#N)c2C=O)c(Cl)c1OC(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1nc(-n2ncc(C#N)c2C2OCCO2)c(Cl)c1OC(F)F

Procedure:
0.6 g (2.0 mmol) 1-(4-chlor-5-difluormethoxy-1-methyl-3pyrazolyl)-5-formyl-4-pyrazol-carbonitrile is dissolved in 30 ml toluene and 0.14 g (2.2 mmol) ethylene glycol and a catalytic amount of p-toluene sulphonic acid are added. The mixture is heated for 2 hours on the water-separator, the cooled solution is washed with sodium chloride solution, and it is then dried and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[CH:22][NH:21][N:20]=2)[C:14]=1[F:30])(=[O:11])=[O:10].[H-].[Na+].Cl.[C:34]([O:37][CH2:38][CH3:39])(=O)C>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[CH:22][N:21]([CH:38]3[CH2:39][CH2:34][O:37]3)[N:20]=2)[C:14]=1[F:30])(=[O:10])=[O:11]
Reactant: CCOC(C)=O
Reactant: O=S(=O)(Nc1cccc(-c2n[nH]cc2-c2ccncc2)c1F)c1cc(F)ccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1cccc(-c2nn(C3CCO3)cc2-c2ccncc2)c1F)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of 2,5-Difluoro-N-[2-fluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide (200 mg, 0,465 mmol)(prepared as described in Example 15) in anhydrous DMF (4 mL) was added to sodium hydride (60% in mineral oil)(46 mg, 1.162 mmol, 2.5 eq) previously washed with n-hexane under argon atmosphere and cooled to 0° C. After stirring at 0° C. for 40 minutes, freshly prepared 3-oxetanol trifluoromethanesulfonyl ester (144 mg, 0.689 mmol, 1.5 eq) dissolved in dry DMF (1 mL) was added and the mixture was stirred at 0° C. for 1 h. A further addition of sodium hydride (40 mg) and 3-oxetanol trifluoro-methanesulfonyl ester (40 mg) was then made and the reaction mixture was then allowed to warm to room temperature during a night. The reaction mixture was then diluted with water and ethyl acetate. The aqueous phase was brought to pH 4-5 with HCl 2 N and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (ethyl acetate/n-hexane 7:3) affording 24 mg of the title product as a white solid. HPLC (254 nm): Rt: 6.99 min; 1H NMR (DMSO-d6) Shift: 10.68 (br. s., 1H), 8.52 (s, 1H), 8.36-8.40 (m, 2H), 7.51-7.59 (m, 1H), 7.31-7.49 (m, 4H), 721-7.29 (m, 1H), 7.02-7.08 (m, 2H), 5.64 (quip, J=6.9 Hz, 1H), 4.90-5.00 (m, 4H); HRMS (ESI) calcd for C23H18F3N4O3S [M+H]+ 487.1046. found 487.1043.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:11][C@H:12]([C:14]([C:16]1([NH2:37])[C:22](=[O:23])[N:21]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[N:18]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:17]1=[O:36])=[O:15])[CH3:13]>>[CH:1]1([CH2:6][C:7]([NH:11][C@H:12]([C:14]([C:16]2([NH2:37])[C:22](=[O:23])[N:21]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:17]2=[O:36])=[O:15])[CH3:13])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Reactant: O=C(O)CC1CCCC1
Agent: Cl
Product: C[C@H](NC(=O)CC1CCCC1)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O

Procedure:
Following General Procedure I above using cyclopentylacetic acid (Aldrich) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-U), the title compound was prepared as a white foam. Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1 gradient to 2:3). Rf=0.50 (CH2Cl2/EtOAc, 1:1).