Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][NH:7][C:8]([C:10]1[C:11]2[CH:12]=[N:13][NH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1)=[O:9].C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1.CN[C@@H]1CCCC[C@H]1NC>O.C(OCC)(=O)C.[Cu]I>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][NH:7][C:8]([C:10]1[C:11]2[CH:12]=[N:13][N:14]([C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1)=[O:9]
Reactant: Fc1ccc(I)cc1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1cccc2[nH]ncc12
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1cccc2c1cnn2-c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 1H-indazole-4-carboxylic acid 3-trifluoromethyl-benzylamide (1.1 g, 3.4 mmol), copper(I) iodide (0.005 g, 0.02 mmol), potassium carbonate (0.04 g, 0.3 mmol) and 4-fluoroiodobenzene (0.04 g, 0.2 mmol) were charged in a sealed tube at room temperature. The tube was evacuated and back-filled with argon. The solids were dissolved in DMF (6 mL) and the resultant solution was treated with rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (0.005 g, 0.04 mmol). The solution was stirred at 120° C. for 3 hours and cooled to room temperature. The solution was diluted with water (15 mL) and ethyl acetate (30 mL). The organic layer was separated, washed with brine and dried over sodium sulfate. The solvent was removed in vacuo. The crude residue was purified by silica gel chromatography eluting with a gradient of 10-40% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [Si]([O:18][C:19]1[CH:64]=[CH:63][C:22]([O:23][CH2:24][C@@H:25]([OH:62])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:61]=[CH:60][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41](C4CCCCN4C(NCCCCCCCC)=O)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)(Cl)Cl.[CH3:69][OH:70]>>[CH2:28]([NH:27][C:69]([N:38]1[CH2:37][CH2:36][CH:35]([C:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:60]=[CH:61][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:62])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:64][CH:63]=4)=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)=[O:42])[CH2:40][CH2:39]1)=[O:70])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:60][CH3:61]
Reactant: CCCCCCCCNC(=O)N1CCCCC1C(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)CC1
Reactant: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)CC1

Procedure:
4-((4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinylcarbonyl)-N-octyl-1-piperidinecarboxamide (0.160 g, 0.180 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.02 g, 0.03 mmol).
Reaction SMILES: O[C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[C:5](=[O:6])[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)=[C:3]1[CH3:15].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][C:3]1[CH:2]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[C:5](=[O:6])[C:4]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: COc1cccc(C2=C(C)C(O)(c3cccc(OC)c3)C2=O)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C2=C(C)C(c3cccc(OC)c3)C2=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.7 %

Procedure:
A CH2Cl2 solution (15 mL) of 4-hydroxy-3-methyl-2,4-bis[3-(methyloxy)phenyl]-2-cyclobuten-1-one (246) (0.464 g, 1.50 mmol, 1 equiv) was cooled to ca. 0° C. Triethylsilane (3.02 mL, 1.0 M, 1.5 equiv) was added followed by TFA. After 5 min, the ice bath was removed and the reaction was allowed to warm to ambient temperature. After an additional 2 h, the reaction was quenched with 50% saturated aqueous NaHCO3. The organic portion was separated and pooled with those extracted using EtOAc (3×20 mL). The organic portions were dried (Na2SO4), filtered, and concentrated. Radial chromatography (SiO2, 2 mm plate, 80:20; hexanes/EtOAc) afforded the title compound as a yellow oil (0.374 g, 85%). 1H NMR (CDCl3, 300 MHz) δ 7.38-7.30 (m, 4H), 6.96-6.80 (m, 4H), 4.69 (s, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 2.49 (s, 3H). TLC (80:20; hexanes/EtOAc): Rf=0.46.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[CH2:10](O)[CH2:11][CH2:12][OH:13].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:13][CH2:12][CH2:11][CH2:10][O:7]2)=[CH:4][N:3]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: OCCCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCCO2)cn1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
To a solution of 6-bromopyridine-3-carbaldehyde (7) (25 g, 134 mmol) in toluene (130 mL) were added 1,3-propanediol (27) (20.45 g, 269 mmol) and 10-camphorsulfonic acid (3.12 g, 13.44 mmol). The reaction mixture was heated to reflux, with azeotropic removal of the evolved water, for 50 minutes, cooled down to r.t. and concentrated. The residue was partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 solution (100 mL). Organic phase was collected and the aqueous phase was extracted with EtOAc (2×150 mL). Combined organic fractions were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to yield a brown solid which was triturated with Et2O and hexane (10/200 mL), to afford intermediate 28 (27.7 g, 84% yield) as a beige solid. MS (m/z): 244.1, 246.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.40 (d, J=2.4 Hz, 1H), 7.35 (dd, J=8.0, 2.4 Hz, 1H), 7.66 (dd, J=8.0, 0.4 Hz, 1H), 5.61 (s, 1H), 4.15 (ddd, J=11.8, 5.0, 1.2 Hz, 2H), 3.98-3.91 (m, 2H), 2.028-1.95 (m, 1H), 1.46 (d quint, J=13.2, 1.2 Hz, 1H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([C@H:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12](O)=[O:13])[CH:5]=[CH:6][CH:7]=2)[O:2]1.S(Cl)([Cl:22])=O.CN(C)C=O>C(Cl)Cl>[CH2:1]1[O:9][C:8]2[C:3](=[C:4]([C@H:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12]([Cl:22])=[O:13])[CH:5]=[CH:6][CH:7]=2)[O:2]1
Reactant: O=S(Cl)Cl
Reactant: CCCCC[C@H](CC(=O)O)c1cccc2c1OCO2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCC[C@H](CC(=O)Cl)c1cccc2c1OCO2
Reaction time: 2 h

Procedure:
To a solution of 1.3 g (4.9 mmol) of (R)-3-(2, 3-methylenedioxyphenyl) octanoic acid in 20 ml of methylene chloride were added 1.1 ml of thionyl chloride and 0.1 ml of N, N-dimethylformamide, and the resultant mixture was refluxed under stirring for 2 hours. The reaction mixture was concentrated in vacuo to give (R)-3-(2, 3-methylenedioxyphenyl) octanoyl chloride as an oil. This oil was dissolved in methylene chloride to give a solution, which was dropwise added to a solution of 1.08 g (4.9 mmol) of 2, 6-diisopropyl-3-dimethylaniline and 1.0 ml of triethylamine in 20 ml of methylene chloride (5°-10° C.). The reaction mixture was allowed to react at room temperature overnight and chromatographed on a silica gel column, eluting with ethyl acetate/hexane to give 1.16 g of gelatinous material. This was dissolved in acetone and mixed with 22% solution of hydrogen chloride in 2 ml of ethyl acetate. The resultant mixture (hydrochloride) was concentrated and crystallized from hexane to give 1.23 g of (R)-N-(2, 6-diisopropyl-3-dimethylaminophenyl)-3-(2, 3-methylenedioxyphenyl) octanamide hydrochloride. Yield, 50%.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].Cl.[CH2:9]([O:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([NH:27][C:28]3C=C(O)[C:31]([Cl:35])=[CH:30][C:29]=3[F:36])=[CH:22][CH:23]=[N:24]2)=[CH:19][C:18]=1[O:37][CH3:38])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C1C=CN=CC=1>[C:5]([O:4][C:1]1[C:31]([Cl:35])=[CH:30][C:29]([F:36])=[C:28]([CH:2]=1)[NH:27][C:21]1[C:20]2[C:25](=[CH:26][C:17]([O:16][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:18]([O:37][CH3:38])[CH:19]=2)[N:24]=[CH:23][CH:22]=1)(=[O:7])[CH3:6]
Reactant: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ccnc2cc1OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Product: COc1cc2c(Nc3cc(OC(C)=O)c(Cl)cc3F)ccnc2cc1OCc1ccccc1
Yield: 102.8 %

Procedure:
4-Dimethylaminopyridine (12 mg, 0.1 mmol) and acetic anhydride (122 mg, 1.2 mmol) were added to a suspension of 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxyquinoline hydrochloride (461 mg, 1 mmol), (prepared as described in Example 12). The mixture was heated at reflux for 1 hour and the volatiles were removed by evaporation. The residue was triturated with water and the resulting precipitate was collected by filtration and dried under vacuum to give 4-(5-acetoxy-4-chloro-2-fluoroanilino)-7-benzyloxy-6-methoxyquinoline (480 mg, 95%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31]([NH:33][S:34]([N:37]([CH2:39][CH:40](OC)[O:41]C)[CH3:38])(=[O:36])=[O:35])=[O:32])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16]([O:26][CH2:27][CH2:28][NH:29][CH3:30])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31]([NH:33][S:34]([N:37]([CH3:38])[CH2:39][CH:40]=[O:41])(=[O:35])=[O:36])=[O:32])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16]([O:26][CH2:27][CH2:28][NH:29][CH3:30])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNCCO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)CC(OC)OC)cc3n2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNCCO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)CC=O)cc3n2C1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A solution of (7S)-14-cyclohexyl-N-{[(2,2-dimethoxyethyl)(methyl)amino]sulfonyl}-7-[2-(methylamino)ethoxy]-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxamide (0.06 M) in DCM was treated with an excess of TFA and H2O (>50 eq). The mixture was stirred at 40° C. for 30 min. All the volatiles were concentrated in vacuo to give the title compound, which was taken on without further purification. (ES+) m/z 583 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[CH3:24])=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:25]1(B(O)O)[CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:25]1([C:2]2[C:3]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]3[CH3:24])=[CH:4][C:5]([F:15])=[C:6]([CH:14]=2)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:27][CH2:26]1
Reactant: CC1CCCCC1COc1cc(F)c(C(=O)OC(C)(C)C)cc1Cl
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CCCCC1COc1cc(F)c(C(=O)OC(C)(C)C)cc1C1CC1
Temperature: 130 °C
Yield: 100 %

Procedure:
To a solution of tert-butyl 5-chloro-2-fluoro-4-((2-methylcyclohexyl)-methoxy)benzoate (1.50 g, 4.30 mmol), cyclopropylboronic acid (0.55 g, 6.41 mmol), potassium phosphate (3.60 g, 17.2 mmol) and tricyclohexylphosphine tetrafluoroborate (0.31 g, 0.86 mmol) in toluene (15 mL) and water (1.5 mL) under a nitrogen atmosphere was added palladium acetate (0.09 g, 0.43 mmol). The reaction mixture was heated at 130° C. for 30 minutes in the microwave, and then cooled to ambient temperature. Water (20 mL) was added and the mixture extracted with ethyl acetate, the combined organics were washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (5% ethyl acetate in hexanes) afforded tert-butyl 5-cyclopropyl-2-fluoro-4-((2-methylcyclohexyl)-methoxy)benzoate (1.5 g, 4.3 mmol), which was used directly for the next step. To a solution of this compound (1.50 g, 4.30 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was stirred at 0° C. for 1 hour and then concentrated in vacuo. The residue was triturated in diethyl ether (10 mL), the solid was filtered, rinsed with diethyl ether (2×10 mL) and dried to give the title compound (0.63 g, 48%): 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J=8.4 Hz, 1H), 6.58 (d, J=12.9 Hz, 1H), 3.87 (dd, J=6.7, 2.3 Hz, 2H), 2.17-1.91 (m, 3H), 1.76-1.31 (m, 8H), 0.98-0.84 (m, 5H), 0.67-0.58 (m, 2H).
Reaction SMILES: [C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Mg:11].[OH:12][CH2:13][CH2:14][N+:15]([CH3:18])([CH3:17])[CH3:16].[C:19]([O:28]CC[N+](C)(C)C)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:22]>>[C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:19]([O-:28])(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:22].[C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Mg+2:11].[OH:12][CH2:13][CH2:14][N+:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: C[N+](C)(C)CCOC(=O)c1ccccc1O
Reactant: [Mg]
Agent: C[N+](C)(C)CCO
Agent: O=C([O-])c1ccccc1O
Product: [Mg+2]

Procedure:
This example illustrates the preparation of a non-stable, solid choline magnesium salicylate composition by a granulation technique employing liquid choline salicylate.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C1COCC1.C(N(CC)CC)C.[Br:21][C:22]1[C:23]([F:32])=[CH:24][C:25](F)=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1>CN(C=O)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:25]1[CH:24]=[C:23]([F:32])[C:22]([Br:21])=[CH:27][C:26]=1[N+:28]([O-:30])=[O:29])[CH3:3]
Reactant: O=[N+]([O-])c1cc(Br)c(F)cc1F
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNc1cc(F)c(Br)cc1[N+](=O)[O-]
Yield: 65.9 %

Procedure:
By using 7.61 g (54.5 mmol) of glycine ethyl ester hydrochloride, 15 ml of THF, 7.64 ml of triethylamine, 10 ml of DMF and 11.8 g (49.6 mmol) of 5-bromo-2,4-difluoronitrobenzene, 10.5 g (60%) of N-(4-bromo-5-fluoro-2-nitrophenyl)glycine ethyl ester was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[O:3]1.C(N(CC)CC)C.[Br:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[Br:34][CH2:35][C:36]([N:12]([CH2:11][C:10]1[C:4]2[O:3][C:2]([CH3:26])([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:37]
Reactant: CC1(C)Cc2cccc(CNc3ccccc3Oc3ccccc3)c2O1
Reactant: O=C(Cl)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)Cc2cccc(CN(C(=O)CBr)c3ccccc3Oc3ccccc3)c2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a solution of N-(2,2,-Dimethyl-2,3-dihydrobenzofuran-7-ylmethyl)-N-(2-phenoxy phenyl)amine (0.20 g, 0.58 mmol) dissolved in DCM (2 mL) was added triethylamine (0.24 g, 2.32 mmol, 0.32 mL). The reaction was cooled to 0° C. and bromoacetyl chloride (0.18 g, 1.16 mmol, 0.10 mL) was added. The mixture was stirred at room temperature for 2 h. LC-MS indicated starting material and product (1:1). Further triethylamine (0.24 g, 2.32 mmol, 0.32 mL) and bromoacetyl chloride (0.18 g, 1.16 mmol, 0.10 mL) were added and stirred at room temperature for 2 h. The solvents were removed in vacuo, the residue quenched with water (10 mL), extracted with DCM (2×20 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with petroleum spirit (A) and EtOAc (B) (30% B, 80 g, 2.5 CV, 60 mL/min). The impure product was further purified by silica gel chromatography eluting with DCM (A) and EtOAc (B) (1-5% B, 80 g, 5 CV, 60 mL/min) to afford 170 mg (63%) of 2-Bromo-N-(2,2,-Dimethyl-2,3-dihydrobenzofuran-7-ylmethyl)-N-(2-phenoxy phenyl)acetamide as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:5][C:4]=1[N+:15]([O-])=O.[ClH:18]>C(O)C.[Pd]>[ClH:18].[NH2:15][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CCNC(C)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(CCNC(C)=O)cc1N
Yield: 94 %

Procedure:
N-[2-(4-methoxy-3-nitrophenyl)ethyl]acetamide (7.4 g) in 150 mL of ethanol was hydrogenated in the presence of 3.5 mL of concentrated HCl and 0.4 g of 10% Pd/C at 30-40 psi for 3 hours in a Parr shaker. After this time, the catalyst was filtered off, and the solvent was removed by rotary evaporation to yield 7.1 g of N-[-2-(3-amino-4-methoxyphenyl)ethyl]acetamide hydrochloride as an off-white solid (94.0% yield). 1HNMR (DMSO-d6) spectrum was consistent with the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[C:23]([CH2:25][OH:26])[N:22]([CH3:27])[N:21]=1)=[CH:16][CH:15]=3.[CH2:33]([O:35][CH2:36][CH2:37]Cl)[CH3:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[C:23]([CH2:25][O:26][CH2:34][CH2:33][O:35][CH2:36][CH3:37])[N:22]([CH3:27])[N:21]=1)=[CH:16][CH:15]=3
Reactant: CCOCCCl
Reactant: Cn1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cc1CO
Product: CCOCCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)nn1C

Procedure:
The process is carried out as in Example 101 above, with the compound from Example 82, 3-(2,4-dichlorophenyl)-6-(5-hydroxymethyl-1-methyl-1H-pyrazol-3-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and 2-chloroethyl ethyl ether
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:4].S(C1C=CC(C)=CC=1)(O)(=O)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.O[CH2:46][C@H:47]1[CH2:51][CH2:50][C@@H:49]([CH2:52]O)[O:48]1>CN(C)C=O>[CH2:3]([O:5][C:6]([C:7]1([N:8]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:52][CH:49]2[O:48][CH:47]([CH2:51][CH2:50]2)[CH2:46]1)=[O:22])[CH3:4]
Reactant: OC[C@@H]1CC[C@H](CO)O1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(N=C(c2ccccc2)c2ccccc2)CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.41 grams, 17.1 mmole) in N,N-dimethylformamide (50 mL) at 0° C. was added dropwise a solution of N-diphenylmethylene glycine ethyl ester (2.07 grams, 7.8 mmol) in N,N-dimethylformamide (50 mL). After stirring for 30 minutes at room temperature, a solution of cis-2,5-bis(hydroxymethyl)-tetrahydrofuran ditosylate (4.1 grams, 9.3 mmole) in N,N-dimethylformamide (50 mL) was added dropwise. The reaction mixture was gradually heated to 100° C. in an oil bath and stirred at this temperature overnight. The solvent was evaporated under vacuum and the reside was taken up in water and extracted twice with diethyl ether. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to a brown oil, from which the title compound (1.42 grams, 51%, a 3:1 mixture of exo/endo diastereomers) was isolated by chromatography on silica gel (20% ethyl acetate in hexane as eluant).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:16]([CH3:28])[C:15]([CH:29]=[CH2:30])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:31]1CCOCC1>O.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])=[C:16]([CH3:28])[C:15]([CH:29]([OH:31])[CH3:30])=[CH:14][CH:13]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(NS(=O)(=O)c2ccc(F)cc2)c(C(=O)OCc2ccccc2)c1C
Reactant: C1COCCO1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1c(C(C)O)ccc(NS(=O)(=O)c2ccc(F)cc2)c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
A solution of Example 173B (150 mg, 0.35 mmol) in dioxane (6 mL) and water (2 mL) was added OSO4 (2.5% wt in t-butanol, 0.5 mL) was stirred for 8 minutes at ambient temperature, treated with NaIO4 (128 mg, 0.6 mmol), stirred for 30 minutes, treated with brine, and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in anhydrous THF (6 mL), cooled to 0° C., treated dropwise with methyl magnesium bromide (3.0M in diethyl ether, 0.37 mL), treated with water (20 mL) and 1N HCl (1.0 mL), and extracted with ethyl acetate (2×20 mL). The ethyl acetate solution was dried (MgSO4), filtered and concentrated. The residue was purified by flash column chromatography on silica gel with 40% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C.O>[Br:19][C:10]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1
Reactant: CC(C)(C)c1ccccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-tert-butylaniline (14.9 g, 100 mmol) was added a solution of NBS (17.8 g, 100 mmol) in DMF at rt. The reaction mixture was stirred for 1 h at rt, diluted with water (30 mL) and extracted with Et2O (3×250 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC to give compound P25a (19 g, 83%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[C:3]=1[F:17].O.[NH2:19][NH2:20]>CS(C)=O>[F:17][C:3]1[C:2](=[N:19][NH2:20])[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]=1[NH:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1
Reactant: NN
Reactant: CSc1nc(Cl)c(F)c(NCc2nccs2)n1
Solvent: CS(C)=O
Solvent: O
Product: CSc1nc(=NN)c(F)c(NCc2nccs2)[nH]1
Temperature: 80 °C
Yield: 29.3 %

Procedure:
6-Chloro-5-fluoro-2-(methylthio)-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine (0.6773 g, 2.336 mmol) was dissolved in DMSO (7 mL) and hydrazine monohydrate (0.91 mL, 18.72 mmol). The reaction vessel was pressure sealed and heated to 80° C. for 2 hours. The reaction mixture was purified by RP-HPLC to provide 5-fluoro-2-(methylthio)-6-[(1,3-thiazol-2-ylmethyl)amino]-4(1H)-pyrimidinone hydrazone as an orange solid (0.1958 g, 29%). LCMS: (M+H)+=287.1.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH3:9][C:10](=[CH2:12])[CH3:11]>C(Cl)Cl>[C:10]([O:4][C:3](=[O:5])[C@@H:2]1[CH2:6][CH2:7][CH2:8][NH:1]1)([CH3:12])([CH3:11])[CH3:9]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: C=C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1

Procedure:
It was found that reaction of proline and excess isobutylene in methylene chloride using anhydrous benzenesulfonic acid in situ to effect phase transfer and N-protection of free proline (solubilization via protonation) afforded an 80% assay yield of proline t-butyl ester. This equilibrium reaction required three days to complete at 0°-5° C. at an optimized charge ratio of proline:benzenesulfonic acid:isobutylene of 1:1.5:12. A strongly basic workup neutralized the benzenesulfonate salts and freed the t-butyl ester for extraction into a neutral organic solvent. The product was typically used as a solution in methylene chloride or alternatively isolated in pure form by concentration and vacuum distillation.