Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([C:14]#[N:15])=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:22]1[N:26]2[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[N:30][C:25]2=[N:24][CH:23]=1)CCC>>[F:16][C:5]1[CH:4]=[CH:3][C:2]([C:22]2[N:26]3[CH:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[N:30][C:25]3=[N:24][CH:23]=2)=[CH:7][C:6]=1[C:8]1[C:9]([C:14]#[N:15])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1ncccc1-c1cc(Br)ccc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: N#Cc1ncccc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-(5-Bromo-2-fluorophenyl)pyridine-2-carbonitrile was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane containing 4% methanol, then crystallisation from hot toluene, gave 3-[2-fluoro-5-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)phenyl]pyridine-2-carbonitrile: δH (400 MHz, DMSO) 9.39 (1H, d, J 7), 8.87 (1H, dd, J 5 and 1.5), 8.33 (1H, s), 8.30 (1H, dd, J 8 and 1), 8.09 (1H, dd, J 7 and 2), 8.00-8.03 (1H, m), 7.94 (1H, dd, J 8 and 5), 7.72 (1H, dd, J 10 and 9), 7.54 (1H, d, J 7); m/z (ES+) 384.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][NH2:16].C(=O)([O-])[O-].[K+].[K+].C(N(CCOCCOC)CCOCCOC)COCCOC>>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][NH:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)CCCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)CCCNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a stirred solution of 4-fluoronitrobenzene (7 g, 50 mmol), 3-dimethylaminopropylamine (6.1 g, 60 mmol) and potassium carbonate (7 g, 50 mmol) in 25 ml of dimethylsulfoixde was added 0.2 g of tris(3,6-dioxaheptyl)amine (TDA-1). The heterogenous mixture was heated at 90° for 2 h. After cooling to room temperature, 110 g of crushed ice was added to precipitate out the yellow product in 85% yield (9.5 g, 43 mmol).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.OC1C=CC(CC(=O)C)=CC=1.[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH:60](O)[CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>O1CCCC1>[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(=O)Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A solution of triphenylphosphine (18.5 g, 70.6 mmol) and 40% DEAD in toluene (12.3 g, 70.6 mmol) in 125.0 mL of tetrahydrofuran was cooled to 0° C. under N2 as a solution of 1-(4-hydroxy-phenyl)-propan-2-one (6.54 g, 43.6 mmol) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10.7 g, 53.2 mmol) in 125.0 mL of tetrahydrofuran was added dropwise via addition funnel. After stirred at rt overnight, the solvent was evaporated. The residue was stirred in hexane/EtOAc, the solid formed was filtered. The hexane/EtOAC solution was concentrated and purified by ISCO graduate chromatography (hexane-20% EtOAc in hexane) to give 4-[4-2-oxo-propyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (8.52 g, 59%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:6]([Se:19][C:20]2[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=2)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.[I-:31].[Na+].O.C(OCC)C>CCC(C)=O>[I:31][CH2:2][CH2:3][O:4][C:5]1[C:6]([Se:19][C:20]2[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=2)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCCCl)C(C)(C)CCC3(C)C)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCCI)C(C)(C)CCC3(C)C)cc1
Yield: 67.9 %

Procedure:
A mixture of 200 mg (0.4 mmol) of ethyl 4-[3-(2-chloroethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl]benzoate with 607 mg (4 mmol) of sodium iodide in MEK (4 ml) is refluxed for 12 h. The reaction medium is treated with water and ethyl ether. The organic phase is washed with water, dried over magnesium sulphate and concentrated on a rotary evaporator. The oil obtained is reacted under the same conditions. 159 mg (68%) of a yellow solid are obtained. m.p.=87° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:14])OCCCl)=[C:6]([NH2:15])[N:5]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:3]=1.O.[O:34]1CC[CH2:36][CH2:35]1>>[NH2:1][C:2]1[N:3]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:5]=[C:6]2[C:7]=1[N:8]([CH2:36][CH2:35][OH:34])[C:9](=[O:14])[NH:15]2
Reactant: C1CCOC1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1NC(=O)OCCCl
Solvent: O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)n(CCO)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
350 mg (0.833 mmol) of the compound obtained in example 6A were initially charged in 12 ml of tetrahydrofuran at 0° C. Then 1.665 ml of a 1M solution of bis(trimethylsilyl)sodium amide in tetrahydrofuran were added dropwise and the mixture was stirred at 0° C. for a further 10 min. The mixture was then stirred at RT overnight. Subsequently, 2 ml of water were added to the mixture, which was concentrated to dryness. The residue was purified by means of preparative HPLC (acetonitrile/water (+0.05% formic acid) gradient). 188 mg of the title compound were obtained (53% of theory).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:15]=[C:14]([CH2:25][OH:26])[CH:13]=1.C(N(CC)CC)C>ClCCl.O>[CH3:11][C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:15]=[C:14]([CH:25]=[O:26])[CH:13]=1
Reactant: Cc1ccc(Cn2nc(CO)cc2C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cn2nc(C=O)cc2C)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
To a stirred solution of oxalyl chloride (1.69 mL, 19.4 mmol) in dichloromethane (10 mL) at −78° C. was added DMSO (3.45 mL, 18.6 mmol) as a solution in dichloromethane (5 mL) dropwise over a period of 10 min. To this reaction mixture was added [5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]methanol (Step 1, 4.2 g, 19.42 mmol) as a solution in dichloromethane (50 mL) dropwise over a period of 30 min. The mixture was stirred at −78° C. for 1.5 h. and triethylamine (13.5 mL, 97.1 mmol) in dichloromethane (5 mL) was then added dropwise. The resultant mixture was warmed to 0° C. and stirred for 20 min. To this mixture was added water (25 mL) dropwise, followed by dichloromethane (100 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (1×100 mL). The combined organic extracts were washed with HCl (0.5 M aq., 1×50 mL), dried (Na2SO4), and filtered. The organic layer was passed through a small plug of silica gel using ethyl acetate as eluent, and was concentrated under reduced pressure to afford the title compound as a yellow oil (3.7 g, 89%): 1H NMR (300 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.12 (d, 2H), 7.03 (d, 2H), 6.57 (s, 1H), 5.36 (s, 2H), 2.25 (s, 3H), 2.23 (s, 3H): ES-MS m/z 214.98, HPLC RT (Method A) 3.33 min.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([Cl:24])=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C(=O)O)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCc1ccc(C#Cc2ccc(C(=O)Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a solution of 4-(4-butylphenylethynyl)benzoic acid (300 mg; 1.08 mmol) in anhydrous toluene (10 mL) was added thionyl chloride (0.39 ml; 5.39 mmol). The reaction mixture was stirred overnight at 60° C. under N2 atmosphere. The solvent and thionyl chloride were removed under reduced pressure to give 296 mg of the title compound as a green solid. 1H NMR (CDCl3) δ: 8.09 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 7.47 (d, J=8.3 Hz, 2H), 7.19 (d, J=8.3 Hz, 2H), 2.64 (t, J=8.7 Hz, 2H), 1.61 (q, J=7.6 Hz, 2H), 1.37 (q, J=7.8 Hz, 2H), 0.93 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[CH:3][C:4]([O:10]C(=O)C)(OC(=O)C)[CH3:5].[CH3:15][C:16]([CH3:20])=[CH:17][CH2:18]O.C(O)(=O)CC>>[CH3:14][C:2]([CH2:1][CH2:18][CH:17]=[C:16]([CH3:20])[CH3:15])=[CH:3][C:4](=[O:10])[CH3:5]
Reactant: CC(=O)OC(C)(C=C(C)C)OC(C)=O
Reactant: CC(C)=CCO
Solvent: CCC(=O)O
Product: CC(=O)C=C(C)CCC=C(C)C
Temperature: 200 °C
Yield: 81 %

Procedure:
A mixture of 25 parts of 4-methyl-2,2-diacetoxy-3-pentene, 10 parts of 3-methyl-2-buten-1-ol (prenol) and 0.3 part of propionic acid is heated for 3 hours at about 200°C in a vibratory autoclave at a pressure 30 atmospheres. After cooling, the reaction product is distilled off to give 9.4 parts of 4,8-dimethyl-3,7-nonadien-2-one having a boiling point of 60°-62°C/0.2 mm. The yield is 81% of theory at a conversion of 60% based on the prenol introduced.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:63]1([CH2:69][CH2:70][NH2:71])[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1>CN(C=O)C.O>[N:63]1([CH2:69][CH2:70][NH:71][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([C:18]3[N:17]=[C:16]4[N:12]([CH2:11][C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[N:13]=[N:14][C:15]4=[CH:20][CH:19]=3)=[CH:29][CH:28]=2)[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1
Reactant: NCCN1CCCCC1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCN1CCCCC1)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 12 h
Yield: 51.8 %

Procedure:
To a solution of example 8 (0.120 g, 0.314 mmol) in DMF (0.7 ml), N-ethyldiisopropylamine (0.041 g, 0.314 mmol) and HATU (0.119 g, 0.314 mmol) were added and stirred for 5 min. (2-(piperidin-1-yl)ethanamine (0.040 g, 0.314 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as a yellow solid (0.080 g, 52%). M.P.: 104-107° C., 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.70 (d, J=8.7 Hz, 1H), 8.62 (bs, 1H), 8.38 (m, 3H), 8.21 (d, J=8.8 Hz, 1H), 8.03-7.98 (m, 4H), 7.84 (dd, J=8.7, 1.9 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s, 2H), 3.48 (bs, 2H), 2.48 (m, 6H), 1.54 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][N:15]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]2.[C:42](Cl)(=[O:51])[CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N(C(C)C)CC)(C)C>ClCCl>[O:51]=[C:42]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][N:15]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]2)[CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(N)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(NC(=O)CCc5ccccc5)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Reaction time: 1 h

Procedure:
40 mg of product obtained in stage 4 of example 41 are mixed with 11.97 mg of hydrocinnamoyl chloride, 25 μl of diisopropylethylamine and 2 ml of dichloromethane. Stirring is carried out for 1 hour at ambient temperature, followed by washing with brine, drying over magnesium sulfate and evaporation to dryness.
Reaction SMILES: [C:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=O)[O:6]C1=O)(=O)[CH3:2].[NH4+:18].[OH-]>>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:6])[NH:18][C:1]([CH3:2])=[CH:4]2
Reactant: COc1ccc2c(c1)C(C(C)=O)C(=O)OC2=O
Reactant: [NH4+]
Agent: [OH-]
Product: COc1ccc2c(=O)[nH]c(C)cc2c1
Temperature: 25 °C
Yield: 74 %

Procedure:
Cyclic anhydride 42 (405 mg; 1.73 mmol) was dissolved in aqueous NH4OH and heated at reflux for 1.5 h. The mixture was cooled to RT and the solid was filtered then dried overnight to give 270 mg (74%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][NH:15][CH2:16][CH2:17][C:18]=2[N:19]=1)=[O:10].[N:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[C:21]=[S:22].O>ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][N:15]([C:21]([NH:20][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[S:22])[CH2:16][CH2:17][C:18]=2[N:19]=1)=[O:10]
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Solvent: O
Solvent: ClCCl
Product: Nc1ccccc1NC(=O)c1nc2c(s1)CN(C(=S)Nc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide. obtained in step VIII of Example 1 (1 eq) in dichloromethane, a solution of isothiocynato benzene (1 eq) in dichloromethane was added and the reaction was stirred at room temperature for 3 h. Water was added and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH2:7][NH:8][CH:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:10][C:11]([F:14])([F:13])[F:12])C>C(#N)C>[CH3:18][O:17][C:15](=[O:16])[CH:9]([N:8]1[CH2:7][C:6]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[CH:5][C:4]1=[O:3])[CH2:10][C:11]([F:14])([F:13])[F:12]
Reactant: CCOC(=O)C=C(CNC(CC(F)(F)F)C(=O)OC)Oc1ccccc1Cl
Solvent: CC#N
Product: COC(=O)C(CC(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 150 °C
Yield: 42.1 %

Procedure:
A solution of 3-(2-chloro-phenoxy)-4-(3,3,3-trifluoro-1-methoxycarbonyl-propylamino)-but-2-enoic acid ethyl ester (410 mg, 1.00 mmol) in acetonitrile (4 mL) was placed in a sealed microwave reaction tube and heated in a microwave reactor at 150° C. for 3 h. The mixture was then cooled to room temperature and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 16% ethyl acetate/hexanes to 33% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4,4-trifluoro-butyric acid methyl ester (153 mg, 17% over two steps) as a yellow oil.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([C:26]#[N:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.S(=O)(=O)(O)O.[H][H]>[C].[Pd].C(O)C>[C:26]([C:13]([C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:27]
Reactant: [H][H]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixed solution obtained by mixing 3.9 g of 79% pure (S)-1-benzyl-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine with 3.1 ml of ethanol and adding dropwise 446 mg of 97% sulfuric acid thereto with cooling on an ice-water bath was charged, together with 158 mg of moist 5% palladium-carbon (water content 52% by weight), into an autoclave, hydrogen was introduced thereinto and the autoclave was heated to raise the temperature to 60 and the pressure to 203 kPa, and the reaction was allowed to proceed for 3.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and depressurized. The reaction mixture was taken out, the catalyst was filtered off, the filtrate obtained was concentrated under reduced pressure, toluene and water were added to the thus-obtained oily concentrate, and the pH was adjusted to 13 by adding dropwise 30% aqueous sodium hydroxide with stirring on an ice-water bath. The toluene layer was recovered, the aqueous layer was further extracted with toluene, and the toluene layers were combined, washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and, after filtration, concentrated under reduced pressure, to give an oil. This was purified by silica gel column chromatography using, as an eluant, dichloromethane containing methanol (0% to 10%). Main fractions containing the product were combined and concentrated under vacuum to give (S)-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine in a yield of 84 mole percent.
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(=CC=3)C(=O)N([C@@H](C(C)C)C(OC)=O)C4)=CC=2)=CC=1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:44]=[C:45]3[C:49](=[CH:50][CH:51]=2)[C:48](=[O:52])[N:47]([C@@H:53]([CH:58]([CH3:60])[CH3:59])[C:54]([O:56][CH3:57])=[O:55])[CH2:46]3)=[CH:39][CH:38]=1.[F:61][C:62]([F:73])([F:72])[C:63]1[CH:64]=[C:65]([N:69]=[C:70]=[O:71])[CH:66]=[CH:67][CH:68]=1>>[CH3:59][CH:58]([CH3:60])[C@H:53]([N:47]1[CH2:46][C:45]2[C:49](=[CH:50][CH:51]=[C:43]([C:40]3[CH:41]=[CH:42][C:37]([NH:36][C:70]([NH:69][C:65]4[CH:66]=[CH:67][CH:68]=[C:63]([C:62]([F:61])([F:72])[F:73])[CH:64]=4)=[O:71])=[CH:38][CH:39]=3)[CH:44]=2)[C:48]1=[O:52])[C:54]([O:56][CH3:57])=[O:55]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O

Procedure:
The compound of example 246 was prepared analogous to compound of example 224 by reaction of compound of example 223 with 3-trifluoromethyl phenyl isocyanate. The compound of example 246 was used directly without isolation for the preparation of compound of example 247.
Reaction SMILES: [CH3:1][CH:2]([C:8]([C:10]([F:13])([F:12])[F:11])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H][H]>[Pt].C(N(CC)CC)C>[CH3:1][CH:2]([CH:8]([OH:9])[C:10]([F:13])([F:11])[F:12])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Agent: [Pt]
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)C(O)C(F)(F)F
Temperature: 40 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
Ethyl 2-methyl-4,4,4-trifluoroacetoacetate (50 g), under a blanket of nitrogen gas, is heated to 40° C. and treated with platinum (0.1 g of 5% Pt/C, 0.01% load) and triethylamine (0.2 g, 0.4 % load). Hydrogen is charged to a pressure of 5 bars, and the mixture agitated at 40° C. for 6h. After filtration to remove the catalyst, 48.5 g (96% yield) of ethyl 2-methyl-4,4,4-trifluoro-3-hydroxybutyrate is obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:38]=[CH:37][C:19]3[N:20]([CH3:36])[C:21]([C:23]4[N:33]([CH2:34][CH3:35])[C:26]5=[CH:27][N:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:38]=[CH:37][C:19]3[N:20]([CH3:36])[C:21]([C:23]4[N:33]([CH2:34][CH3:35])[C:26]5=[CH:27][N:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1
Reactant: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)ccc3n2C)cc2cc(OC)ncc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](N)C4)ccc3n2C)cc2cc(OC)ncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a stirred solution of (R)-tert-butyl(1-(2-(1-ethyl-5-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)piperidin-3-yl)carbamate (106 mg, 0.199 mmol) in dichloromethane (DCM) (3 mL) was added TFA (3 mL, 38.9 mmol) dropwise with continuous stirring. The reaction was stirred at room temperature under nitrogen for 1 hr. LCMS showed the reaction was complete with no starting material remaining. The reaction mixture was concentrated in vacuo before being dissolved in MeOH and purified by SPE on sulfonic acid (SCX) 5 g, first washing with MeOH and then eluting using a 10% NH3/MeOH solution to give the free base of the product. The appropriate fractions were combined and evaporated in vacuo before being azeotroped with cHex and dried on the high vacuum line to give the required product (69 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)=[C:11]([CH3:25])[N:10]=[C:9]2[CH2:26][N:27]([CH3:29])C)=[C:4]([C:30](=O)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[CH:3]=1.O.NN.[CH2:42](O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:9]([CH2:26][N:27]([CH3:42])[CH3:29])=[N:10][C:11]([CH3:25])=[C:12]3[CH2:13][N:14]=[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[C:4]=2[CH:3]=1
Reactant: Cc1nc(CN(C)C)n(-c2ccc(F)cc2C(=O)c2ccccc2Cl)c1CN1C(=O)c2ccccc2C1=O
Reactant: CCO
Agent: NN
Solvent: O
Product: Cc1nc(CN(C)C)n2c1CN=C(c1ccccc1Cl)c1cc(F)ccc1-2

Procedure:
In the manner given in Example 4, N-[[1-[4-fluoro-2-(o-chlorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide in ethanol is heated with hydrazine hydrate to give 8-fluoro-6-(o-chlorophenyl)-1-[(dimethylamino)methyl]-3-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine.