Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl[S:13]([C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH:26][C:27](=[O:29])[CH3:28])=[CH:23]2)=[CH:18][CH:17]=1)(=[O:15])=[O:14]>C1COCC1.N1C=CC=CC=1>[C:27]([NH:26][C:22]1[CH:23]=[C:24]2[C:19]([CH:18]=[CH:17][C:16]([S:13]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=3)[C:7]([OH:9])=[O:8])(=[O:15])=[O:14])=[CH:25]2)=[CH:20][CH:21]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Nc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2ccc(S(=O)(=O)Nc3ccc(Cl)c(C(=O)O)c3)cc2c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To 15 g (0.087 mol) of 5-amino-2-chlorobenzoic acid was dissolved in 450 mL of THF and 15 mL of pyridine. The solution was cooled to 5° C. in an ice-water bath. Then, a solution of 20.8 g (0.074 mol) of compound 131 dissolved in 200 mL of THF was added over a 10 min period. The reaction was kept at 5° C. for 30 min, and then allowed to warm to room temperature. The reaction was allowed to stir for an additional 4 hours. Then, the reaction was filtered to remove some insoluble material and the resulting clear filtrate was reduced to a solid by the removal of the volatiles by rotary evaporation. This solid was extracted with ethyl acetate and 1 N HCl. The ethyl acetate layer was further extracted with 0.5 M NaOH (once) and 0.33 M NaOH (three times). The aqueous layers were combined, acidified with HCl, and back extracted into ethyl acetate. After drying (MgSO4), filtration, and removal of the ethyl acetate by rotary evaporation, the solid residue was dissolved in 2.8 L of 50/50 methanol/water with heating. The solution was allowed to cool to room temperature and a small amount of solid was removed by vacuum filtration and discarded. The clear filtrate was allowed to sit for 48 hours and then was reduced in volume to about 500 mL by rotary evaporation. The solid was collected by vacuum filtration. After drying in vacuo, this provided 17.6 g of compound 132.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1.[CH:23]([O:26][C:27]([NH:29][CH:30]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][NH2:32])=[O:28])([CH3:25])[CH3:24]>O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:32][CH2:31][CH:30]([NH:29][C:27]([O:26][CH:23]([CH3:25])[CH3:24])=[O:28])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:20])=[CH:21][CH:22]=1
Reactant: CC(C)OC(=O)NC(CN)Cc1ccccc1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)NC(CNC(=O)c1ccc(Cl)cc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
0.21 g of 1,1′-carbonylbis-1H-imidazole was added to a solution of 0.19 g of 4-chlorobenzoic acid in tetrahydrofuran and stirred for 1 hour at room temperature. Then 5 ml of a solution of 0.25 g of 2-(i-propoxycarbonylamino)-3-phenylpropylamine in tetrahydrofuran was added to the above solution and stirred at room temperature for 4 hours. The reaction mixture was rinsed with water, the organic layer was dried over magnesium sulfate anhydrous, and the residual oily material obtained under a reduced pressure was purified by column chromatography on silica gel (2:1 hexane/ethyl acetate) to obtain 0.26 g of the title compound as colorless crystals.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1.[C:15](=O)(O)[O-].[Na+]>CO>[NH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]1
Reactant: NC1CCC(C(=O)O)CC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCC(N)CC1
Reaction time: 14 h

Procedure:
Thionyl chloride (4.15 g, 34.92) was added to a cold (0° C.) stirred solution of 4-aminocyclohexane carboxylic acid (1 g, 6.98 mmol) in MeOH (10 mL). The reaction mixture was stirred under reflux conditions for 12-16 h. The reaction mixture was then concentrated under reduced pressure. The residue obtained was diluted with ice cold water, basified with aqueous sodium bicarbonate solution and extracted with DCM. The DCM layer was washed with water followed by brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 650 mg of the title compound as a brown liquid. MS (ESI): m/z 158 (M+H)
Reaction SMILES: B(F)(F)F.CCOCC.[CH:10]1([CH2:13][C@@H:14]2[O:22][CH2:21][C:17]3=[N:18][O:19][CH2:20][C@@H:16]3[CH2:15]2)[CH2:12][CH2:11]1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1I.C([Li])CCC>C1(C)C=CC=CC=1>[CH:10]1([CH2:13][C@@H:14]2[O:22][CH2:21][C@:17]3([C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:29][C:28]=4[F:30])[NH:18][O:19][CH2:20][C@@H:16]3[CH2:15]2)[CH2:11][CH2:12]1
Reactant: Fc1ccc(I)c(F)c1
Reactant: C1O[C@@H](CC2CC2)C[C@H]2CON=C12
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1ccc([C@]23CO[C@@H](CC4CC4)C[C@H]2CON3)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boron trifluoride diethyl etherate (5.4 g, 17.9 mmol) was added drop-wise to a solution of rel-(3aR,5S)-5-(cyclopropylmethyl)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C69) (2.7 g, 14.9 mmol) in toluene (100 mL) at an internal temperature of −72.5° C. The reaction mixture was stirred at −73° C. to −76° C. for 30 minutes, then treated with 2,4-difluoro-1-iodobenzene (98%, 4.3 g, 17.9 mmol) in one portion. While the reaction temperature was maintained below −73° C., n-butyllithium (2.5 M in hexanes, 6.0 mL, 14.9 mmol) was added in a drop-wise manner over 15 minutes. The reaction mixture was stirred at −73° C. to −75° C. for 1.5 hours, then was quenched with saturated aqueous ammonium chloride solution (10 mL) at −74° C. and allowed to warm to room temperature. The resulting mixture was extracted with ethyl acetate (300 mL), and the aqueous layer was extracted with additional ethyl acetate (250 mL and 100 mL); the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 10% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 1.85 g, 6.25 mmol, 42%. LCMS m/z 296 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.92 (q, J=8.3 Hz, 1H), 6.88 (dt, J=8.2, 2.4 Hz, 1H), 6.80 (dt, J=10.4, 2.4 Hz, 1H), 6.31 (br s, 1H), 4.11 (dd, J=12.8, 1.6 Hz, 1H), 3.80 (d, J=12.8 Hz, 1H), 3.70 (d, J=7.2 Hz, 1H), 3.61-3.67 (m, 1H), 3.52-3.55 (m, 1H), 3.04-3.09 (m, 1H), 1.94 (dd, J=14.0, 6.8 Hz, 1H), 1.59-1.67 (m, 2H), 1.45 (q, J=15.1 Hz, 1H), 1.25 (quintet, J=6.9 Hz, 1H), 0.74-0.85 (m, 1H), 0.45-0.53 (m, 2H), 0.08-0.13 (m, 2H).
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:16])([F:15])[C:5]1[CH:6]=[N:7][C:8]2[CH2:9][CH2:10][NH:11][CH2:12][C:13]=2[CH:14]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH:33]([CH3:35])[CH3:34])([C:30](O)=[O:31])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:33]([C@:27]1([C:30]([N:11]2[CH2:10][CH2:9][C:8]3[N:7]=[CH:6][C:5]([C:4]([F:15])([F:3])[F:16])=[CH:14][C:13]=3[CH2:12]2)=[O:31])[CH2:28][CH2:29][C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:26]1)([CH3:35])[CH3:34]
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@]1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.7 %

Procedure:
To a solution of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine dihydrochloride (159 mg, 0.574 mmol) of Step A-1, (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (0.21 g, 0.79 mmol) of Step A-4 in Example 1 in dichloromethane (10 mL) were added 4-dimethylaminopyridine (38 mg, 0.32 mmol) and diisopropylethylamine (180 mg, 1.4 mmol) followed by bromotris(pyrrolydino)phophonium hexafluorophosphate (270 mg, 0.57 mmol). After being stirred overnight at room temperature, the solution was diluted with dichloromethane, washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography on silica eluting with 30% ethyl acetate in hexanes to give 300 mg of desired product. MS calculated for C23H32F3N3O3: (M+H)+456; found 356.2 (M−Boc+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)=[C:13](\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[CH2:14][CH3:15])=[CH:8][CH:7]=1)=[O:4].[Na+].[I-].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.Cl>C1COCC1.CCOC(C)=O>[N:35]1([CH2:2][C:3]([O:5][C:6]2[CH:11]=[CH:10][C:9](/[C:12](/[C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:24][CH:23]=3)=[C:13](\[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)/[CH2:14][CH3:15])=[CH:8][CH:7]=2)=[O:4])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: C1COCCN1
Reactant: CC/C(=C(\c1ccc(/C=C/C(=O)O)cc1)c1ccc(OC(=O)CCl)cc1)c1ccccc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC/C(=C(\c1ccc(/C=C/C(=O)O)cc1)c1ccc(OC(=O)CN2CCOCC2)cc1)c1ccccc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of compound 32 (100 mg, 0.22 mmol) in THF (4 mL) was added NaI (100 mg, 0.67 mmol) and the mixture stirred for 1 h. The reaction was cooled to 5° C. and a solution of morpholine (0.029 mL, 0.33 mmol) in THF (2 mL) was added over 1 h. After stirring for 1 h, the reaction was diluted with EtOAc (40 mL) and poured into a mixture of ice water (30 mL) and 0.1 N HCl (10 mL). The layers were separated and the organic layer was washed with brine (40 mL), dried (MgSO4) and concentrated. Et2O (8 mL) was added and the mixture was stirred for 2 h. The resulting solid was filtered, rinsed with Et2O and dried to afford the title compound, 31, as a yellow solid (68 mg, 61%). 1HNMR (400 MHz, DMSO-d6): δ 0.85 (t, 3H), 2.39 (q, 2H), 2.52 (br, 4H), 3.43 (br, 2H), 3.55 (br, 4H), 6.50 (d, J=15.9 Hz, 1H), 6.80 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 7.09-7.19 (m, 5H), 7.24 (d, J=8.1 Hz, 2H), 7.58 (d, J=15.9 Hz, 1H), 769 (d, J=8.1 Hz, 2H), 12.33 (br s, 1H); MS m/z 498 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([N:29]2[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]2)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)C1CNC1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(C(=O)O)C2)no1
Temperature: 95 °C
Yield: 54.5 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (790 mg, 2.00 mmol) in dimethylsulphoxide (25 ml) was treated with 3-azetidine carboxylic acid (505 mg, 5.00 mmol) and potassium carbonate (690 mg, 5.00 mmol) and the resulting mixture was heated at 95° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled and the mixture treated with hydrochloric acid (1M, 25 ml) then diluted further with water (25 ml) and extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99:1) gradually changing to dichloromethane:methanol (90:10) to afford the title compound as a pale yellow oil (490 mg).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10](=[O:11])[N:9]([NH2:12])[C:8](SC)=[N:7][N:6]=1)([CH3:4])[CH3:3].[CH2:15]([NH2:17])[CH3:16]>>[NH2:12][N:9]1[C:10](=[O:11])[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[N:6][N:7]=[C:8]1[NH:17][CH2:15][CH3:16]
Reactant: CSc1nnc(C(C)(C)C)c(=O)n1N
Reactant: CCN
Product: CCNc1nnc(C(C)(C)C)c(=O)n1N
Temperature: 25 °C

Procedure:
A mixture of 150 g of technical metribuzin 200 g water and 100 g of 70% aqueous ethylamine was heated 90° for 7.0 hours in a stirred autoclave. The contents were cooled to room temperature, the solid filtered off and dried in a circulating air oven at 60°. The crude product was recrystallized from toluene to give 74 g of analytically pure product, m.p. 177°.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH2:23](Br)[C:24]#[CH:25].O>CN(C)C=O>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]([CH2:25][C:24]#[CH:23])[C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: C#CCBr
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN(C(C)=O)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
To 3.0 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide in 250 ml of dimethylformamide under argon was added 0.6 g of sodium hydride (50% in oil). The mixture was stirred for one hour, then 1.38 ml of propargyl bromide was added. This mixture was stirred for 12 hours then poured into 200 ml of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed on 300 g of silica gel with dichloromethane-methanol (97:3) as the eluent. Fractions containing the desired product were collected, evaporated in vacuo and recrystallized from dichloromethanhexane to give 2.5 g of orange crystals mp 195°-198° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:16]3[CH2:23][S:22][CH:21]4[N:18]([C:19](=[O:33])[CH:20]4[NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[C:17]=3[C:34]([O:36]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:35])=[CH:14][N:15]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1(OC)C=CC=CC=1>C(O)=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][C:13]([C:16]3[CH2:23][S:22][CH:21]4[N:18]([C:19](=[O:33])[CH:20]4[NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[C:17]=3[C:34]([OH:36])=[O:35])=[CH:14][N:15]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2ncc(C3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)C(NC(=O)Cc5cccs5)C4SC3)s2)cc1
Solvent: O=CO
Solvent: COc1ccccc1
Product: CC(=O)Nc1ccc(-c2ncc(C3=C(C(=O)O)N4C(=O)C(NC(=O)Cc5cccs5)C4SC3)s2)cc1
Yield: 86.3 %

Procedure:
Following the working method described in Example 4, 3-[2-(4-acetamido-phenyl)-thiazol-5-yl]-2-benzhydryloxycarbonyl-8-oxo-7-[(thien-2-yl)-acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.5 g) is treated with formic acid (25 cc) and anisole (5 cc) at 50° C. for 20 minutes. 3-[2-(4-acetamido-phenyl)-thiazol-5-yl]-2-carboxy-8-oxo-7-[(thien-2-yl)-acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.99 g) is obtained in the form of a yellow solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[NH:8][C:7](=O)[N:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:7]1[N:8]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)[nH]1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1

Procedure:
The title compound was prepared from 6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-1H-pyrimidin-2-one (8.72 g, 28.3 mmol) and phosphoryl chloride (80 mL) according to the general procedure I. Obtained as a light brown solid (9.13 g, 98%). MS (EI) 326.0 [(M)+]; mp 71.5° C.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2([CH2:24]S(C3C=CC=CC=3)(=O)=O)[CH2:23][O:22][CH2:21]2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].Cl>CO.C1COCC1>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2([CH3:24])[CH2:21][O:22][CH2:23]2)[CH2:16][CH2:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(CC1(N2CCN(C(c3ccccc3)c3ccccc3)CC2)COC1)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(N2CCN(C(c3ccccc3)c3ccccc3)CC2)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To a suspension of 1-benzhydryl-4-(3-((phenylsulfonyl)methyl)oxetan-3-yl)piperazine (2.49 g, 5.38 mmol) in MeOH (50 mL), THF (10 mL) was added MAGNESIUM (0.654 g, 26.9 mmol) which was pretreated with 1.0 N HCl and rinsed with MeOH, stirred at rt overnight. The Et2O was added and followed by Na2SO4.10H2O, stirred at room temperature for 1 hr, filtered, and filtrate was concentrated. The crude was purified by 40 g ISCO silica column, eluted with EA: HX-0-100%, the desired fractions were concentrated to yield 1-benzhydryl-4-(3-methyloxetan-3-yl)piperazine (1.08 g) as a white solid.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1(=O)[O:11][C:9](=[O:10])[CH2:8][O:7][CH2:6]1>N1C=CC=CC=1>[OH:2][CH2:1][CH2:3][N:4]1[C:9](=[O:10])[CH2:8][O:7][CH2:6][C:5]1=[O:11]
Reactant: NCCO
Reactant: O=C1COCC(=O)O1
Solvent: c1ccncc1
Product: O=C1COCC(=O)N1CCO
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.6 %

Procedure:
Ethanolamine (2.44 g, 40 mmol) was added dropwise to a solution of diglycolic anhydride (2.32 g, 20 mmol) in pyridine (10 ml). The mixture was stirred for 5 minutes at ambient temperature and then heated at reflux for 2 hours. The volatiles were removed by evaporation and the residue was heated at 180° C. for 2 hours. The reaction mixture was allowed to cool and was purified by column chromatography eluting with methylene chloride/methanol (9/1) to give 4-(2-hydroxyethyl)3,5dioxomorpholine (400 mg, 12.5%)
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9](Cl)=[O:10].[CH:12]1([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C>O1CCCC1>[CH:12]1([N:15]([C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:9]([C:3]2[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=2[F:1])=[O:10])[CH2:13][CH2:14]1
Reactant: c1ccc([C@H]2CCCC[C@H]2NC2CC2)cc1
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(C)c(F)c1C(=O)N(C1CC1)[C@@H]1CCCC[C@@H]1c1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
At ambient temperature, a solution of 180 mg (1.02 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride in 1 ml of tetrahydrofurane is added dropwise to a solution of 200 mg (0.93 mmol) of cis-N-cyclopropyl-2-phenylcyclohexanamine and 100 mg (1.02 mmol) of triethylamine in 5 ml of tetrahydrofurane. The reaction mixture is stirred for 2 hrs at 70° C. The solvent is removed under vacuum and 100 ml of water are then added to the residue. The watery layer is extracted twice with ethyl acetate (2×50 ml) and the combined organic layers are successively washed by a 1 N solution of HCl, a saturated solution of potassium carbonate and brine and dried over a Chemelut™ cartridge to yield after concentration 380 mg of a yellow oil. Column chromatography on silica gel (gradient heptane/ethyl acetate) yields 160 mg (46% yield) of cis-N-cyclopropyl-5-fluoro-1,3-dimethyl-N-(2-phenylcyclohexyl)-1H-pyrazole-4-carboxamide as a colorless oil (M+H=356).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([NH:10][CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[O:20][CH3:21])[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=1>>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:11]([NH:10][C:7]1[O:8][CH2:9][C:4]3[CH:3]=[C:2]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[N:26]=4)[CH:23]=[CH:22][C:5]=3[N:6]=1)[CH2:12][CH2:13]2
Reactant: Nc1cccc(C(F)(F)F)n1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(Br)cc3CO1)CC2
Product: COc1cccc2c1C(NC1=Nc3ccc(Nc4cccc(C(F)(F)F)n4)cc3CO1)CC2
Yield: 63.4 %

Procedure:
The title compound (144 mg, 63%), light brown foam, MS (ISP): m/e=455.3 (M+H+), was prepared in accordance with the general method of Example 35 from rac-(6-bromo-4H- benzo[d][1,3]oxazin-2-yl)-(7-methoxy-indan-1-yl)-amine (Example 74) (187 mg, 0.5 mmol) an commercially available 2-amino-6-trifluoromethyl-pyridine (162 mg, 1.0 mmol).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]1[C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH:21]1[CH2:28]O.[Br:30]C(Br)(Br)Br>ClCCl>[Br:30][CH2:28][CH:21]1[CH2:22][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:20]1
Reactant: BrC(Br)(Br)Br
Reactant: OCC1CC2(C1)OCCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCC1CC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Triphenylphosphine (6.28 gm, 24 mmol) in dichloromethane was added drop wise to a solution of 5,8-dioxaspiro[3.4]oct-2-ylmethanol (2.3 gm, 16 mmol) (step d) and tetrabromomethane (6.62 gm, 20 mmol) in dichloromethane. The reaction mixture was stirred at room temperature for about 6 hours. The solvent was removed under reduced pressure and the residue was extracted with diethyl ether. The organic layer was concentrated under reduced pressure to get a crude product, which was purified by column chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)Oc1cc(Br)ccc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 85.4 %

Procedure:
To a pre-stirred solution of 4-bromo-2-trifluoromethoxybenzaldehyde (1.82 g, 9.0 mmol) and piperidine (0.97 mL, 9.9 mmol) in DCM (40 mL) at 0° C. was added sodium triacetoxyborohydride (2.85 g, 13.4 mmol) in portions. The reaction mixture was then allowed to warm to ambient temperature and stirred for an additional 14 h. The reaction was quenched by the addition of water (30 mL) and extracted into ethyl acetate (75 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a colourless oil (2.6 g, 84%) that was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz): 7.47 (d, J=8.2 Hz, 1H), 7.41 (d, J=1.9 Hz, 1H), 7.39-7.35 (m, 1H), 3.46 (s, 2H), 2.42-2.32 (m, 4H), 1.64-1.51 (m, 4H), 1.48-1.37 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[CH:8]=[C:9]([Br:17])[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:5][CH:4]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:17][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:16])[C:14]3[C:6]([C:7]=2[CH:8]=1)=[CH:5][CH:4]=[C:3]([CH2:2][O:20][C:18](=[O:21])[CH3:19])[CH:15]=3
Reactant: O=C1c2cc(CBr)ccc2-c2cc(Br)ccc21
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1ccc2c(c1)C(=O)c1ccc(Br)cc1-2
Temperature: 100 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
7-Bromomethyl-3-bromo-9-fluorenone (1.7 g) was suspended in DMF (25 ml). To this suspension was added potassium acetate (576 mg). The reaction mixture was stirred at 100° C. for one hour. It was then diluted with ethyl acetate, washed four times with water, twice with brine, dried and evaporated. The residue was chromatographed on silica gel using 2% ethyl acetate/methylene chloride and gave the desired product (1.18 g).