Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:25]([O:29][C:30](=[O:40])[C:31]([CH2:38][NH2:39])([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][CH3:34])([CH3:28])([CH3:27])[CH3:26]>CO>[C:25]([O:29][C:30](=[O:40])[C:31]([CH2:38][NH:39][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:9]=2)=[O:4])([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][CH3:34])([CH3:26])([CH3:28])[CH3:27]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CCCC(CN)(CCC)C(=O)OC(C)(C)C
Solvent: CO
Product: CCCC(CCC)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C
Yield: 82.5 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (135 mg) and 2-aminomethyl-2-propyl-pentanoic acid tert-butyl ester (193 mg) in MeOH (2 mL) was microwaved at 120° C. for 2 h. The mixture was cooled, concentrated with HOAc (0.02 mL), the residue was directly column purified to give the desired product (180 mg). LC MS ESI+: 518 (M+1)+.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][C:6]1([CH3:47])[C:10](=[O:11])[N:9]([C@@H:12]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[C:13]([NH:15][C@H:16]([CH3:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[C:8](=[O:26])[N:7]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:44])=[O:36])=[C:30]([O:45]C)[CH:29]=1.O>ClCCl>[CH3:47][C:6]1([CH3:5])[C:10](=[O:11])[N:9]([C@@H:12]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[C:13]([NH:15][C@H:16]([CH3:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[C:8](=[O:26])[N:7]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:44])=[O:36])=[C:30]([OH:45])[CH:29]=1
Reactant: COc1cc(CN2C(=O)N([C@@H](CC3CC3)C(=O)N[C@H](C)CC(=O)O)C(=O)C2(C)C)ccc1NC(=O)Nc1ccccc1C
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)Nc1ccc(CN2C(=O)N([C@@H](CC3CC3)C(=O)N[C@H](C)CC(=O)O)C(=O)C2(C)C)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
211 μL of boron tribromide were added under argon to a solution of 100 mg (0.169 mmol) of the compound of Example 1 in 20 mL of absolute dichloromethane at −78° C. and the reaction mixture was allowed to warm to 0° C. with ice cooling. After 30 minutes at 0° C., water was cautiously added. The phases were separated and the organic phase was dried over sodium sulfate. After filtration, removal of the solvent in vacuo, chromatographic purification by preparative HPLC and freeze drying of the product fractions, 35 mg (36%) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([C:15]#[N:16])=[C:4]([NH:27][CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[N:3]=1
Reactant: NCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccc(F)cc2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccn2)nc(N)nc1-c1ccc(F)cc1

Procedure:
From 2-amino-4-(4-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-picolylamine in DME. ES-MS m/e (%): 321 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C([Li])CCC.Cl[C:16]([O:18][CH3:19])=[O:17].O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: C#Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C#Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 66.3 %

Procedure:
A solution of 4-fluorophenylacetylene (2.86 mL, 3.00 g, 24.97 mmol) in tetrahydrofuran at −78° C. was treated with a solution of n-butyllithium in hexanes (2.29 M, 12.0 mL, 27.5 mmol) followed by stirring at −78° C. for 45 minutes. The solution was then treated rapidly with methyl chloroformate (2.12 mL, 2.60 g, 27.5 mmol) followed by stirring at −78° C. for 30 minutes and warming to room temperature for 18 hours. The mixture was treated with water and concentrated in vacuo to remove tetrahydrofuran. The residue was dissolved in ethyl acetate and washed with water and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded a yellow solid, which was chromatographed over a 340 g silica gel cartridge, eluting with 15-50% dichloromethane in hexanes. These procedures afforded the product (2.95 g, 66%) as an off-white fluffy solid.
Reaction SMILES: C[N:2]([CH:4]=[O:5])C.[C:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)C(O)=O)(=[O:8])[CH3:7].C(N(CC)CC)C.ClC(OCC)=O.[OH-].[NH4+]>>[C:6]([C:9]1[CH:17]=[C:16]([CH:15]=[CH:11][CH:10]=1)[C:4]([NH2:2])=[O:5])(=[O:8])[CH3:7]
Reactant: CC(=O)c1cccc(C(=O)O)c1
Reactant: CN(C)C=O
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(C(N)=O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
General Procedure FF: Into DMF (11 ml, 140 mmol) solution of 3-acetylbenzoic acid (706 mg, 4.30 mmol) which was cooled in ice/water bath was added triethylamine (602 μl, 4.30 mmol) followed by addition of ethyl chloroformate (424 μl, 4.30 mmol) dropwise in 5 min under an atmosphere of nitrogen. The mixture was stirred at 0° C. for 30 min and then at rt for 30 min. Ammonium hydroxide (28% aq. solution; 1.15 ml) was added, and the mixture was stirred at rt for 3 h. After that time, the mixture was poured into ice/water, extracted with EtOAc (3×50 ml). The extracts were washed with water (2×30 ml), brine (30 ml), dried over MgSO4, filtered and concentrated in vacuo, giving the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ=2.66 (s, 3H), 7.58 (dt, J=0.4 & 8.0 Hz, 1H), 8.05 (md, J=8.0 Hz, 1H), 8.12 (md, J=8.0 Hz, 1H), 8.38-8.41 (m, 1H). MS (ES+): m/z 164.10 [MH+]. HPLC: tR=1.89 min (polar—5 min, ZQ3).
Reaction SMILES: [CH:1]([CH:4](Cl)[C:5]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[C:7]([O:8][CH3:9])[CH:6]=1)([CH3:3])[CH3:2].[C-:16]#[N:17].[Na+].[OH-].[Na+]>O.C(N(CC)CC)C>[CH:1]([CH:4]([C:16]#[N:17])[C:5]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[C:7]([O:8][CH3:9])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(Cl)C(C)C)cc1OC
Reactant: [C-]#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(C#N)C(C)C)cc1OC

Procedure:
457.4 g (2 mol) of α-isopropyl-veratryl chloride, 108 g (2.2 mol) of sodium cyanide, 10 mol-% of phase transfer catalyst, 100 ml of water and 800 ml of triethylamine are stirred together for 5 hours at 60° C. After the addition of 60 ml of 30% sodium hydroxide solution and 300 ml of water, the organic phase is separated off. After removal of the triethylamine by distillation, the residue is distilled in a fine vacuum. The distillate obtained is recrystallised from methanol/water.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:15])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.[BH4-].[Na+]>CO.Cl[Ni]Cl>[NH2:29][C:27]1[CH:26]=[CH:25][C:3]([O:4][C:5]2[C:6]3[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:15])=[CH:11][C:7]=3[N:8]=[CH:9][N:10]=2)=[C:2]([F:1])[CH:28]=1
Reactant: O=C(NCCN1CCOCC1)c1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(Oc2ncnc3cc(C(=O)NCCN4CCOCC4)sc23)c(F)c1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 39.6 %

Procedure:
To a stirred solution of 24 (1.30 g, 2.72 mmol) in anhydrous MeOH (15 mL) at room temperature under nitrogen were added NiCl2×6H2O (605 mg, 2.54 mmol) and NaBH4 (192 mg, 5.08 mmol), respectively. The reaction mixture was stirred for 50 min, concentrated, cooled to 0° C., treated with HCl (10 mL, 1M) followed by addition of NH4OH (29%) (pH 9-10), and finally extracted with AcOEt. The organic extract was successively washed with water and brine, dried over Na2SO4, filtered, and concentrated to afford the title compound 25 (450 mg, 85% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ(ppm): 9.04 (t, J=5.6 Hz, 1H), 8.73 (s, 1H), 8.23 (s, 1H), 7.07 (t, J=8.8 Hz, 1H), 6.48 (dd, J=2.4 and 13.2 Hz, 1H), 6.40 (dd, J=2.4 and 8.8 Hz, 1H), 5.47 (s, 2H), 3.62-3.52 (m, 4H), 3.44 (q, J=6.8 Hz, 2H), 2.56-2.48 (m, 2H), 2.46-2.40 (m, 4H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:17]3[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@H:20]([OH:21])[C@H:18]3[OH:19])=[N:12][NH:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)[CH3:2].I[CH2:29][CH3:30]>>[CH2:29]([N:13]1[C:14]([CH3:15])=[C:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:11]([O:16][C@@H:17]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@H:20]([OH:21])[C@H:18]2[OH:19])=[N:12]1)[CH3:30]
Reactant: CCc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Reactant: CCI
Product: CCc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(CC)c2C)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 61 using 4-[(4-ethylphenyl)-methyl]-5-methyl-3-(β-D-glucopyranosyloxy)-1H-pyrazole instead of 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole and using iodoethane instead of iodopropane.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH3:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][C:7]=12)#[CH:2].[OH:23][CH2:24][CH2:25][NH:26][S:27]([C:30]1[S:31][C:32](Br)=[CH:33][CH:34]=1)(=[O:29])=[O:28]>>[OH:23][CH2:24][CH2:25][NH:26][S:27]([C:30]1[S:31][C:32]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([CH3:12])=[CH:10][C:9]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=4)=[N:8][C:7]=23)=[CH:33][CH:34]=1)(=[O:29])=[O:28]
Reactant: C#Cc1cnn2c(C)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(NCCO)c1ccc(Br)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C#Cc3ccc(S(=O)(=O)NCCO)s3)cnn12

Procedure:
The title compound was prepared from 3-ethynyl-7-methyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.12) (75 mg, 0.25 mmol) and 5-bromo-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-amide (example B.59) according to general procedure II. Obtained as a yellow solid (87 mg, 68%). MS (ISP) 503.3 [(M+H)+]; mp 162-164° C.
Reaction SMILES: COC([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:17][CH:18]3[C:27]4[C:22](=[CH:23][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=4)[O:21][CH2:20][CH2:19]3)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=O.COC(N1C2C(=C(NC(NC3C4C(=CC(C(C)(C)C)=CC=4)OCC3)=O)C=CC=2)C=N1)=O>O>[NH:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:17][CH:18]3[C:27]4[C:22](=[CH:23][C:24]([C:28]([F:29])([F:31])[F:30])=[CH:25][CH:26]=4)[O:21][CH2:20][CH2:19]3)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCOc4cc(C(F)(F)F)ccc43)cccc21
Agent: COC(=O)n1ncc2c(NC(=O)NC3CCOc4cc(C(C)(C)C)ccc43)cccc21
Solvent: O
Product: O=C(Nc1cccc2[nH]ncc12)NC1CCOc2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared using the procedure as described in Example 1E, substituting the product of Example 4E for the product of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 13.00 (broad s, 1H), 8.67 (s, 1H), 8.04 (s, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.22 (m, 2H), 7.10 (m, 2H), 7.00 (d, J=7.5 Hz, 1H), 5.00 (m, 1H), 4.41-4.20 (m, 2H), 2.22-2.00 (m, 2H). S (ESI) m/e 377 (M+H)+. Calcd. For C18H15N4O2F3.0.7; H2O: C, 55.59; H, 4.25; N, 14.40. Found: C, 55.51; H, 3.98; N, 14.65.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)=[O:21])[CH:18]=1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)=[O:21])[CH:18]=1)=[O:6]
Reactant: Cc1ccc(N)cc1NC(=O)c1ccc2ncccc2c1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(Cl)c(Cl)c2)cc1NC(=O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
Using an analogous procedure to that described in Example 4, 3,4-dichlorobenzoyl chloride was reacted with N-(5-amino-2-methylphenyl)quinoline-6-carboxamide in the presence of triethylamine. The reaction mixture was stirred at ambient temperature for 16 hours and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound in 57% yield; Mass Spectrum: M+H+ 450.
Reaction SMILES: [CH3:1][C:2]([NH:6][CH2:7][CH:8]1[O:12][CH:11]([CH3:13])[CH:10]([CH3:14])[O:9]1)([CH3:5])[C:3]#[CH:4].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:27][CH:28]([CH3:32])[C:29](Cl)=[O:30]>O>[CH3:5][C:2]([N:6]([CH2:7][CH:8]1[O:9][CH:10]([CH3:14])[CH:11]([CH3:13])[O:12]1)[C:29](=[O:30])[CH:28]([Br:27])[CH3:32])([CH3:1])[C:3]#[CH:4]
Reactant: C#CC(C)(C)NCC1OC(C)C(C)O1
Reactant: CC(Br)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: C#CC(C)(C)N(CC1OC(C)C(C)O1)C(=O)C(C)Br

Procedure:
N-(1,1-Dimethylprop-2-ynyl)-N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)amine (10 grams), benzene (100 ml), water (100 ml) and sodium carbonate (8 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of 5° to 10° C. and α-bromopropionyl chloride (7 grams) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture reaches room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(1,1-dimethylprop-2-ynyl)-N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)-α-bromopropionamide.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC.[N+:17]([C:20]1[CH:38]=[CH:37][C:23]([CH2:24][NH:25][S:26]([C:29]2[N:30]=[CH:31][N:32]3[CH:36]=[CH:35][S:34][C:33]=23)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].[CH2:39]([Sn:43](Cl)([CH2:48][CH2:49][CH2:50][CH3:51])[CH2:44][CH2:45][CH2:46][CH3:47])[CH2:40][CH2:41][CH3:42].[Cl-].[NH4+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C.C(OCC)(=O)C>[N+:17]([C:20]1[CH:38]=[CH:37][C:23]([CH2:24][NH:25][S:26]([C:29]2[N:30]=[CH:31][N:32]3[CH:36]=[C:35]([Sn:43]([CH2:44][CH2:45][CH2:46][CH3:47])([CH2:48][CH2:49][CH2:50][CH3:51])[CH2:39][CH2:40][CH2:41][CH3:42])[S:34][C:33]=23)(=[O:27])=[O:28])=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(CNS(=O)(=O)c2ncn3ccsc23)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(S(=O)(=O)NCc3ccc([N+](=O)[O-])cc3)c2s1
Reaction time: 0.5 h

Procedure:
A 1.0 N lithiumbis(trimethylsilyl)amide/n-hexane solution (4.8 ml) was added to a solution of 0.68 g of 7-(4-nitrobenzylsulfamoyl)imidazo[5,1-b]thiazole in 20 ml of THF and 4 ml of HMPA in an argon atmosphere at −40° C. The mixture was stirred at the same temperature for 30 min. Tri-n-butylstannyl chloride (0.57 ml) was added thereto. The mixture was stirred at the same temperature for 30 min. A saturated aqueous ammonium chloride solution was added thereto. Ethyl acetate was then added thereto. The mixture was then washed with water and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 0.78 g of the tile compound.
Reaction SMILES: C(O[CH:5]1[O:13][CH2:12][CH:11]2[C:6]1([CH3:15])[CH:7]1[CH2:14][CH:10]2[CH2:9][CH2:8]1)(=O)C.[C:16]([OH:21])(=[O:20])[C:17]([CH3:19])=[CH2:18]>C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)C1C(O)=C(C(C)(C)C)C=C(C)C=1>[C:16]([O:21][CH:5]1[O:13][CH2:12][CH:11]2[C:6]1([CH3:15])[CH:7]1[CH2:14][CH:10]2[CH2:9][CH2:8]1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: CC(=O)OC1OCC2C3CCC(C3)C12C
Reactant: C=C(C)C(=O)O
Agent: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Product: C=C(C)C(=O)OC1OCC2C3CCC(C3)C12C
Temperature: 50 °C
Yield: 87.8 %

Procedure:
A mixture of 73 g of 2-methyl-4-oxatricyclo[5.2.1.02,6]decan-3-yl acetate, 150 g of methacrylic acid, and 40 mg of 2,2′-methylenebis(6-t-butyl-p-cresol) was heated at 50° C. under atmospheric pressure for 30 minutes, after which under a reduced pressure of 0.20 kPa, the reaction mixture was heated for 18 hours for distilling off the acetic acid formed. The reaction mixture was purified by distillation, obtaining 72 g (yield 91%) of the target compound.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[N:10][CH:9]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)=[O:27])[C:8]1=[O:36])=[O:5])C.[OH-].[Na+]>C(O)C.C1COCC1>[C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[N:10][CH:9]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)=[O:27])[C:8]1=[O:36])([OH:5])=[O:3]
Reactant: CCOC(=O)CN1C(=O)C(NC(=O)Nc2cccc(C)c2)N=C(c2ccccc2F)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(CC(=O)O)C2=O)c1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
To a suspension of N-[(3RS)-1-ethoxycarbonylmethyl-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl ]-N'-(3-methylphenyl)urea (5.71 g) in a mixture of ethanol (57 ml) and THF (43 ml) was added 1N aqueous sodium hydroxide solution (47 ml) under stirring at ambient temperature. The mixture was stirred under the same condition for 1 hour and the organic solvent was removed in vacuo. The residual aqueous solution was acidified with 6N aqueous hydrochloric acid and extracted with ethyl acetate twice. The combined extract was washed with water twice and dried over magnesium sulfate. Removal of the solvent gave an amorphous mass, which was triturated in a mixture of methanol and diisopropyl ether and collected by filtration to afford N-[(3RS)-1-carboxymethyl-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea (5.21 g) as a white crystalline powder, which was used in a following reaction step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:22][C:23]([C:25]1([CH3:28])[CH2:27][O:26]1)=[O:24]>>[OH:26][C:25]([CH3:28])([CH2:27][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=1)[C:23]([NH:22][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([N+:19]([O-:21])=[O:20])[C:13]=1[CH3:12])=[O:24]
Reactant: COCCc1ccc(O)cc1
Reactant: Cc1c(NC(=O)C2(C)CO2)cccc1[N+](=O)[O-]
Product: COCCc1ccc(OCC(C)(O)C(=O)Nc2cccc([N+](=O)[O-])c2C)cc1

Procedure:
2-Hydroxy-3-[4-(2-methoxyethyl)phenoxy]-2-methyl-N-(2-methyl-3-nitrophenyl)propionamide was prepared as described in Example 1 starting from 4-methoxyethylphenol and 2-methyloxirane-2-carboxylic acid (2-methyl-3-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-2% methanol). 1H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.28 (3H, s), 2.72 (2H, t, J=6.8 Hz), 3.22 (3H, s), 3.47 (2H, t, J=6.8 Hz), 3.94 (1H, d, J=9.4 Hz), 4.15 (1H, d, J=9.4 Hz), 6.11 (1H, s), 6.84 (2H, d, J=7.9 Hz), 7.12 (2H, d, J=7.9 Hz), 7.41-7.45 (1H, m), 7.65-7.68 (1H, m), 7.72-7.75 (1H, m), 9.71 (1H, s).
Reaction SMILES: [CH2:1]([N:3]([CH2:17]C)[CH2:4][CH2:5][C@@H:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C@H:7]1[OH:16])C.N.CCO>CCOCC>[CH3:17][N:3]([CH3:1])[CH2:4][CH2:5][C@@H:6]1[CH2:15][C:14]2[CH2:13][CH:12]=[CH:11][CH2:10][C:9]=2[CH2:8][C@H:7]1[OH:16]
Reactant: CCN(CC)CC[C@@H]1Cc2ccccc2C[C@H]1O
Agent: N
Solvent: CCOCC
Solvent: CCO
Product: CN(C)CC[C@@H]1CC2=C(CC=CC2)C[C@H]1O
Reaction time: 0.17 h

Procedure:
A solution of 14.6 g (66.6 mmol) of trans-3-[2-(diethylamino)ethyl]-1,2,3,4-tetrahydro-2-naphthalenol (prepared as in Example 10) in 125 ml of ether is added to 1 liter of NH3 (liquid). To this stirred solution is added 10 l g of Li in pieces over 10 minutes. When the addition is complete, the reaction mixture is stirred for 30 minutes, after which time absolute EtOH (~ 150 ml) is added dropwise until the blue color is discharged. The NH3 is then allowed to evaporate, the residue is diluted with water, and this thoroughly extracted with ether. The combined ether extracts are washed with saturated aqueous NaCl, dried, and concentrated in vacuo to 13.4 g (92%) of the title compound as an oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].C(N(CC)CC)C.[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCCCCC>C(Cl)(Cl)Cl>[C:4]([CH2:3][NH:2][C:20](=[O:21])[CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:5]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#CCN
Agent: Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: N#CCNC(=O)Cc1ccccc1

Procedure:
To aminoacetonitrile hydrochloride and 40 g (0.4 moles) triethylamine in 300 ml chloroform which was then cooled in an ice bath, the acid chloride from step (a) in 50 ml chloroform was dropped in over 60 minutes. The reaction mixture was washed three times with 200 ml water, dried over magnesium sulfate and stripped to give an oil. The oil was rubbed with 50 ml hexane and immediately solidified to give 30.4 g of beige solids, melting point 87° C. to 91° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:32])([F:31])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)=[O:11]>C(Cl)Cl>[F:32][C:9]([F:8])([F:31])[C:10]([C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)=[CH:16][CH:17]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)C(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(N2CCNCC2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2.0 mL TFA were added to a solution of 267 mg (0.75 mmol) tert. butyl 4-[4-(2,2,2-trifluoro-acetyl)-phenyl]-piperazin-1-carboxylate in 30 mL DCM cooled to 0° C. and the reaction mixture was stirred for 24 h, while warming up to RT. It was evaporated down i.vac.; the crude product was further reacted without purification.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]([CH3:10])([C:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3]
Reactant: CCCCC(O)C(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCC(=O)C(C)(C)C
Yield: 89.2 %

Procedure:
2,2-Dimethyl-heptan-3-ol (0.23 mol) was dissolved in 350 mL of CH2Cl2 in a 500 mL round bottom flask with a magnetic stirbar. The flask was partially cooled with ice. 76.6 g (0.355 mol) of pyridinium chlorochromate was added, while vigorously stirring. The reaction turned black and warmed up slightly. The reaction mixture was stirred at room temperature for 24 hours. The solution was decanted away from the black sludge, which was rinsed with hexane. The organic extracts were combined and chromatographed directly on silica gel. (Note: only silica has been found to trap and remove the reduced non-reacted chromium compounds). The product, 2,2-dimethyl-heptan-3-one, eluted with CH2Cl2/hexane and in a subsequent 10% ethyl acetate/hexane fraction to yield 29.19 g of product at 88% yield. 1H NMR (CDCl3, 500 MHz) δ (ppm): 2.48 (t, 2H), 1.54 (m, 2H), 1.28 (m, 2H), 1.13 (s, 9H), 0.90 (m, 3H).