Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18].C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[S:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: Nc1ccccc1S
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cc(Br)cc(-c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.03 g (19.1 mmol) of 3,5-dibromobenzaldehyde and 3.1 mL (28.6 mmol) of 2-aminothiophenol were dissolved in 60 mL of acetic acid. The solution was agitated at room temperature for 30 minutes. 9.78 g (21.0 mmol) of lead (IV) acetate was added thereto. The resulting mixture was agitated at 50° C. for 1 hour. Then, water was poured into the reactant. It was extracted with ethyl acetate. The extract was separated through a column and dried, obtaining 4.74 g (Y=67%) of a white solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:24][CH2:25][CH3:26])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])=[S:13])[CH:6]=1)[CH2:2][CH3:3].BrBr>C(O)(=O)C>[C:20]1([CH3:21])[CH:19]=[C:18]([CH3:22])[CH:17]=[C:16]([CH3:23])[C:15]=1[NH:14][C:12]1[S:13][C:6]2[C:7]([N:11]=1)=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:1][CH2:2][CH3:3])[CH2:24][CH2:25][CH3:26]
Reactant: CCCN(CCC)c1ccnc(NC(=S)Nc2c(C)cc(C)cc2C)c1
Agent: BrBr
Solvent: CC(=O)O
Product: CCCN(CCC)c1ccnc2nc(Nc3c(C)cc(C)cc3C)sc12
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
To 0.040 g (0.11 mmol) of 1-[4-(Dipropylamino)pyridin-2-yl]-3-mesitylthiourea in 2 mL of glacial acetic acid was added 6.1 μL (0.12 mmol) of bromine. After 30 min at room temperature, an additional 2 μL of bromine was added. The reaction mixture was concentrated after 2 h and washed with ethyl acetate/hexanes. The organics were concentrated and the resulting oil was purified by flash chromatography eluting with a 4% methanol/dichloromethane mixture to give 0.020 g (50%) of the title compound as a light yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1B(O)O.Br[C:17]1[C:18]([N+:28]([O-:30])=[O:29])=[N:19][N:20]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:21]=1.BrC1C=NN(C2CCCCO2)C=1[N+]([O-])=O.O>COCCOC.C(=O)([O-])[O-].[K+].[K+].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>[N+:28]([C:18]1[C:17]([C:3]2[CH:4]=[C:5]([O:8][C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:7][C:2]=2[OH:1])=[CH:21][N:20]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[N:19]=1)([O-:30])=[O:29]
Reactant: OB(O)c1cc(OC(F)(F)F)ccc1O
Reactant: O=[N+]([O-])c1nn(C2CCCCO2)cc1Br
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: O=[N+]([O-])c1c(Br)cnn1C1CCCCO1
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1nn(C2CCCCO2)cc1-c1cc(OC(F)(F)F)ccc1O
Temperature: 80 °C

Procedure:
To a solution of 2-hydroxy-5-(trifluoromethoxy)phenylboronic acid (Preparation 23, 20.5 g, 92.4 mmol) and 4-bromo-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole or 4-bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Preparation 22, 22.7 g, 82.2 mmol) in 1,2-dimethoxyethane (300 mL) and 2 M potassium carbonate in water (117 mL, 212 mmol) was added tetrakis(triphenylphosphine)palladium(0) (5.0 g, 4.3 mmol). The solution was sparged with argon (×3) and heated at 80° C. for 8 hours. The reaction mixture was cooled to ambient temperature and the layers separated. The aqueous phase was washed with ethyl acetate (×2). The combined organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate in hexanes gradient elution) and concentrated in vacuo. Excess hexanes was added to the residue and the resulting solid was collected by filtration and dried in vacuo to afford the title compound as off white crystals (19.5 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[Li]CCCC.[C:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C1COCC1>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:26])([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
Amine preparation: To a solution of 2-picoline (333 mg) in dry THF (5 mL) at −78° C. was added nBuLi (2.5M solution in hexanes, 1.50 mL). The reaction mixture was warmed to room temperature over 30 min and then cooled to −78° C. 1-BOC-4-piperidone (713 mg) was then added, and the reaction mixture was raised to 0° C. over 20 min. The reaction mixture was stirred overnight and then quenched with water. The organics were extracted into ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo to give crude product. The residue was purified using flash chromatography to yield 4-hydroxy-4-pyridin-2-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester (290 mg). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[CH2:11][N:10]=[C:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])[C:8]2[CH:7]=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=[CH:4][C:3]1=2.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1)[O:29][CH2:30][C:31]([OH:33])=[O:32]>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1)[O:29][C@@H:30]([C@:9]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])[NH:10][CH2:11][C:12](=[O:13])[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N+:21]([O-:23])=[O:22])=[CH:7][C:8]1=2)[C:31]([OH:33])=[O:32]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Reactant: COc1cc(OC)cc(OCC(=O)O)c1
Product: COc1cc(OC)cc(O[C@H](C(=O)O)[C@]2(c3ccccc3F)NCC(=O)N(C)c3ccc([N+](=O)[O-])cc32)c1

Procedure:
(±)-(S*)-(3,5-Dimethoxy-phenoxy)-[(5S*)-5-(2-fluoro-phenyl)-1-methyl-7-nitro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is prepared starting from flunitrazepam (5-(2-fluoro-phenyl)-1-methyl-7-nitro-1,3-dihydro-benzo[e][1,4]diazepin-2-one) and (3,5-dimethoxy-phenoxy)-acetic acid (Example 1) in analogy to Example 18. LC-MS1: tR=0.82 min, [M+1]+=526.02.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O.COCCOC>C(O)C>[Cl:9][CH2:10][C:11]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]2[CH:13]=1
Reactant: O=C(CCl)CCl
Reactant: Cc1ccc(N)nc1
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc2nc(CCl)cn2c1
Reaction time: 2.75 h
Yield: 17.9 %

Procedure:
A mixture of 2-amino-5-picoline (Aldrich; 5.028 g), 1,3-dichloroacetone (Aldrich; 5.893 g), and 1,2-dimethoxyethane (Aldrich; 43 mL) is stirred for 1 h at 55° C., at which time ethanol (47 mL) is added and the mixture is stirred for 2.75 h at reflux. The mixture is then concentrated under reduced pressure and partitioned between dichloromethane and saturated aq. sodium bicarbonate. The combined organic layers are washed with brine, dried with MgSO4, and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (1/99) and the appropriate fractions are combined and concentrated to give, after crystallization from ethyl acetate, 0.411 g of 2-(chloromethyl)-6-methylimidazo[1,2-a]pyridine. Methanol is added to the filtrate, which is then concentrated to a reduced volume. The addition of hexane gives an additional 1.50 g of 2-(chloromethyl)-6-methylimidazo[1,2-a]pyridine in two crops; mp 88-89.25° C.; ms m/z 180; IR (mineral oil) 796, 705, 699, 1343, 1510 cm-1 ; 1H NMR (CDCl3) δ 2.32, 4.76, 7.03, 7.47, 7.53, 7.86.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]2[CH:24]=[CH:23][C:15]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:14][CH:13]=2)=[N:6][CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]3[CH:24]=[CH:23][C:15]([CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:14][CH:13]=3)=[N:6][CH:7]=2)=[CH:28][CH:27]=1
Reactant: Brc1ccc(C#CCCc2ccc(CN3CCOCC3)cc2)nc1
Reactant: OB(O)Oc1ccc(Cl)cc1
Product: Clc1ccc(-c2ccc(C#CCCc3ccc(CN4CCOCC4)cc3)nc2)cc1

Procedure:
Prepared analogously to Example 2.20c from 90 mg (0.23 mmol) 4-{4-[4-(5-bromo-pyridin-2-yl)-but-3-ynyl]-benzyl}-morpholine and 73 mg (0.47 mmol) 4-chlorophenylboric acid.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C@H:10]([OH:13])[CH2:11][OH:12].[Cl:14][CH2:15][C:16](Cl)=[O:17]>CC#N.CO>[Cl:14][CH2:15][C:16]([NH:8][CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])=[O:17]
Reactant: NC[C@H](O)CO
Reactant: O=C(Cl)CCl
Solvent: CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CCl)NC[C@H](O)CO
Reaction time: 16 h
Yield: 89.9 %

Procedure:
Triethylamine (4.0 ml, 28.9 mmol) was added to a solution of (S)-3-amino-1,2-propanediol (2.2 g, 24.1 mmol) in a mixture of CH3CN/MeOH (80 mL/13 mL) at −10° C. under nitrogen. Chloroacetyl chloride (2.1 mL, 26.5 mmol) was then added dropwise at −10° C. over 30 min. The reaction mixture was allowed to reach room temperature and stirred for 16 h. The mixture was concentrated under vacuum and purified by flash column chromatography on silica gel, eluting with methanol/ethyl acetate (8/92), to give the title compound as a white solid (3.63 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:29](=[O:30])[C:28]3[CH:27]=[C:26]([O:25][CH3:24])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (288 mg, 1.1 mmol) was dissolved in dichloromethane at -78° C. and treated with 4-methylmorpholine (0.25 mL, 2.27 mmol, 2 eq.) and 3,4,5-trimethoxy-benzoyl chloride (250 mg, 1.1 mmol, 1 eq) in dichloromethane (3 mL). The solution was allowed to warm to 0° C. and stir for 1 hour. The solution was washed with 1N HCl and 5% sodium bicarbonate and the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (30 g) with a gradient of 50% ethyl acetate in hexane to 6% methanol in dichloromethane to give 353 mg (71%) of the title compound.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[CH3:10]>>[C:1]1([NH:7][N:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)c1ccccc1
Product: CC(=NNc1ccccc1)c1ccccc1
Temperature: 15 °C

Procedure:
Phenylhydrazine (10.8 g, 0.10 mole) is added to 20 g (0.10 mole) of acetophenone with stirring at about 15° C. The reaction produces a slight exotherm and the solution solidifies. The title product is allowed to sit for about 12 hours at room temperature and is then used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[C:5]2[CH2:19][CH2:20][C:21](O)=[O:22].[C:24]1([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[C:5]2[CH2:19][CH2:20][C:21]([N:34]1[CH2:35][CH2:36][N:31]([CH2:30][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:32][CH2:33]1)=[O:22]
Reactant: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)O)c2cc(Cl)ccc21
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: C1CCOC1
Product: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)N2CCN(Cc3ccccc3)CC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
1,1-Carbonyl diimidazole (47 mg, 0.29 mmol) was added to a solution of 5-chloro-2-(4-chlorophenyl)-1-methyl-1H-indole-3-propanoic acid (Description 12, 100 mg, 0.29 mmol) in tetrahydrofuran (4 mL) and the mixture was heated under reflux for 2 h. The mixture was cooled and 1-(phenylmethyl)piperazine (48 mg, 0.27 mmol) was added. The mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. Water (4 mL) was added and the mixture was stirred at 80° C. for 2 h. The mixture was cooled, the water was decanted and the residue was dissolved in dichloromethane. Using a Bond Elut™ cartridge to separate the layers the solution was washed with hydrochloric acid (1M), and aqueous sodium hydroxide (2M). The organic fraction was evaporated under reduced pressure to a small volume and filtered through a plug of silica on a Bond Elut™ cartridge, eluting with hexane/EtOAc (85:15 increasing to 70:30), to give the title compound as a colorless solid (95 mg, 65%). 1H NMR (360 MHz, CDCl3) δ2.10-2.13 (2H, m), 2.25-2.28 (2H, m), 2.40-2.43 (2H, m), 2.89-2.93 (2H, m), 3.13-3.16 (2H, m), 3.78 (2H, s), 3.46 (3H, s), 3.48-3.51 (2H, m), 7.10-7.26 (9H, m), 7.40 (2H, d, J 8.3 Hz), and 7.50 (1H, s). m/z (ES+) 506, 508 (M+1).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C@@:5]1([C:31]([O:33]C)=O)[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16]CC3C=CC=CC=3)=[CH:12][CH:11]=2)[N:6]1C(OC(C)(C)C)=O)#[N:2].C(O)(C(F)(F)F)=O>CO.[Ni].ClCCl>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[CH2:8][CH2:9][C@:5]3([CH2:4][CH2:3][CH2:1][NH:2][C:31]3=[O:33])[NH:6]2)=[CH:11][CH:12]=1
Reactant: COC(=O)[C@]1(CCC#N)CC[C@H](c2ccc(OCc3ccccc3)cc2)N1C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C1NCCC[C@]12CCC(c1ccc(O)cc1)N2
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 19.4 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2R,5R)-2-(2-cyanoethyl)-5-{4-[(phenylmethyl)oxy]phenyl}-1,2-pyrrolidinedicarboxylate (D49, 215 mg, 0.46 mmol) in methanol (20 mL) was added Raney Nickel (slurry in water, 1 spatula) and the mixture was stirred under a hydrogen atmosphere (6 atm) for 4.5 hours. The catalyst was filtered off, the solvent removed under reduced pressure, and the residue treated with toluene (3×20 mL) and dried under vacuum. The crude oil obtained was dissolved in dichloromethane and the resulting solution cooled to 0° C. and TFA (0.2 mL) was added dropwise. After 1 h at room temperature the solvent was removed under vacuum and the residue purified by SCX column and by chromatography on silica gel using dichloromethane/methanol (95:5) to afford the title compound (22 mg, 19%) as a 66/33 mixture of epimers at the benzylic position. Rt (HPLC) 2.16 min; MS: (ES/+) m/z: 247 [MH+]; C14H18N2O2 requires 246.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[C:4]=1[OH:18])=[O:2].[OH-].[K+].S(OC)(O[CH3:25])(=O)=O.Cl>C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9]([CH3:14])([CH3:15])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[C:4]=1[O:18][CH3:25])=[O:2]
Reactant: Cc1cc(C=O)c(O)c2c1C(C)(C)CCC2(C)C
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1c(C=O)cc(C)c2c1C(C)(C)CCC2(C)C
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
Methylation. 2-Formyl-1-hydroxy-4,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (42 g, 0.17 mol) was stirred with toluene (656 mL), and potassium hydroxide 85% (16.8 g, 0.255 mol) was added in one portion. The mixture was heated to 40° C., dimethyl sulfate (32.13 g, 0.255 mol) added at 40°-45° C. during 0.5 h, and the heating continued at 50° C. for an additional 1.5 h. The mixture was cooled to 20° C., neutralized with 5% HCl solution, then washed with water (20 mL), and finally washed with brine (25 mL). The solvent was removed by distillation and the residue distilled to give 2-formyl-1-methoxy-4,5,5,8,8- pentamethyl-5,6,7,8-tetrahydronaphthalene (36 g), bp 140°-142° C./1.5 mm, GLC purity 95%. Crystallization from hexane gave 28 g material, GLC purity 99%. 1H-NMR (CDCl3) δ10.23 (2 H, s), 7.41 (1H, s), 3.89 (3H, s), 2.52 (3H, s), 1.63 (4H, s), 1.42 (6H, s), 1.40 (6H, s). 13C-NMR (CDCl3) δ189.9 (1C, d), 162.3 (1C, s), 153.1 (1C, s), 139.9 (1C, s), 132.7 (1C, s), 131.3 (1C, d), 126.5 (1C, s), 66.0 (1C, q), 39.4 (1C, t), 38.2 (1C, t), 36.4 (1C, s), 35.6 (1C, s), 30.0 (2C, q), 28.9 (2C, q), 23.7 (1C, q). IR (KBr) 1683, 1235 cm-1, MS (m/e) 260.3 (M+, 46.3), 245.2 (100.0), 175 (38.5), 128 (31.1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][N:11]([CH3:22])[CH2:12][CH2:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.[C:23](Cl)(Cl)=[S:24]>O1CCCC1>[CH3:10][N:11]([CH3:22])[CH2:12][CH2:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([N:19]=[C:23]=[S:24])=[CH:17][CH:16]=1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: S=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(N=C=S)cc1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
Diisopropylethylamine (344 mg, 2.66 mmol, 2.4 eq.) was added with stirring to a solution of 4-[2-(dimethylamino)ethoxy]aniline (200 mg, 1.11 mmol, 1 eq.) in tetrahydrofuran (2 mL) at 0° C., and then thiophosgene (153 mg, 1.33 mmol, 1.2 eq.) was added dropwise with stirring. The reaction mixture was allowed to warm to room temperature with stirring, and stirred at room temperature for 40 minutes, during which a precipitate formed. The tetrahydrofuran was removed under vacuum, and the residue was dissolved in ethyl acetate and washed with brine (3×10 mL), then the ethyl acetate layer dried over magnesium sulfate and the ethyl acetate evaporated to give 4-[2-(dimethylamino)ethoxy]phenyl isothiocyanate (0.20 g) as a dark brown oil, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[BH4-].[Na+].C(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: OC(c1ccc(Br)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To 4′-bromo-2,2,2-trifluoroacetophenone (5.0 g, 19.76 mmol) in THF (50 mls) at 0° C. was added NaBH4 (1.5 g, 39.52 mmol). The mixture was warmed to room temperature and stirred for 1 hour. The reaction was complete by TLC (CH2Cl2). The mixture was quenched with H2O, rotary evaporated to remove most of the THF, and extracted 2 times with CH2Cl2. The organics were combined, washed with brine, concentrated to a small volume and filtered through a plug of silica gel. The silica was washed with CH2Cl2 to elute the product, and the resulting solution was concentrated to give 4.65 g of 1-(4-bromophenyl)-2,2,2-trifluoroethanol. Yield 92%.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.[H-].[Na+].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>O1CCCC1>[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([N:3]1[C:4]2=[N:9][C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:7][C:6](=[O:16])[N:5]2[CH2:17][C@@:2]1([CH3:1])[C:18]([F:21])([F:19])[F:20])=[O:28]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1C(=O)c1ccccc1Cl

Procedure:
The product can be prepared as described in Example 21, but using 200 mg of (2S)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one, 31 mg of sodium hydride at 60% in oil and 115 mg of 2-chlorobenzoyl chloride in 4 ml of tetrahydrofuran. After purification by silica column chromatography (eluent: dichloromethane/methanol: gradient of 100/0 to 97/03), 74 mg of (2S)-1-[(2-chlorophenyl)carbonyl]-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained in the form of an ivory-coloured foam, the characteristics of which are the following:
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][C@H:14]1[CH2:28][C@@H:27]2[C@@H:17]([CH2:18][C:19]3[C:29]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]2=4)[NH:21][CH:20]=3)[N:16]([CH3:30])[CH2:15]1>C(#N)C>[CH3:30][N:16]1[C@H:17]2[C@H:27]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:29]=3[C:19]([CH2:18]2)=[CH:20][NH:21]4)[CH2:28][C@H:14]([CH2:13][NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])[CH2:15]1
Reactant: CN1C[C@@H](CN)C[C@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC#N
Product: CN1C[C@@H](CNC(=S)NC(=O)c2ccccc2)C[C@H]2c3cccc4[nH]cc(c34)C[C@H]21

Procedure:
1.05 ml of benzoyl isothiocyanate were added to a suspension of 2 g of 8α-aminomethyl-6-methyl-10β-ergoline in 22 ml of acetonitrile at 80° C. under shaking. The solution was refluxed for thirty minutes and then evaporated in vacuo to dryness. The residue was chromatographed on silica gel (eluant chloroform with 2% methanol) to give 2.2 g of the title compound, m.p. 153°-155° C., after crystallization from diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14](O)=[O:15])=[CH:10][C:9]=2[C:19]([N:21]2[C@H:30]([CH2:31][OH:32])[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:20])[C:6]=1[CH3:7].[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl>[CH2:35]([N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[C:33]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14](=[O:15])[NH:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:10][C:9]=2[C:19]([N:21]2[C@H:30]([CH2:31][OH:32])[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:20])[N:4]=1)=[O:43])[CH2:36][CH2:37][CH3:38]
Reactant: Nc1ccccc1
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OCC(=O)O)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OCC(=O)Nc3ccccc3)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.6 %

Procedure:
To a stirred solution of [4-(4-chloro-3-dibutylcarbamoyl-5-methyl-pyrazol-1-yl)-3-((S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-phenoxy]-acetic acid (15 mg, 0.025 mmol) and aniline (3.4 uL, 0.037 mmol) in dichloromethane (0.2 mL) under nitrogen atmosphere was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (7.1 mg, 0.037 mmol) and hydroxybenzotriazole (5.6 mg, 0.037 mmol). The mixture was stirred at ambient temperature for 5 minutes. Triethylamine (10 uL, 0.074 mmol) was added to the mixture. The reaction was stirred for 12 hours. After eluting through a short pad of silica gel column, the crude material was purified by HPLC to afford the title compound (8 mg, 50% yield). MS (ESI) [m/e, (M+H)+]=686.3. 1H NMR (400 MHz, chloroform-d) δ ppm 6.82-7.69 (m, 12H), 4.13-5.38 (m, 5H), 2.38-3.75 (m, 8H), 2.15-2.32 (m, 3H), 1.12-1.70 (m, 8H), 0.66-0.99 (m, 6H).