Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[NH:8][C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)#[N:2].C(Cl)Cl.C(N(CC)CC)C.Cl.[NH2:31][OH:32]>C(O)C.C(=O)(O)[O-].[Na+]>[OH:32][N:31]=[C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[NH:8][C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[NH2:2]
Reactant: COc1ccc(CC(=O)Nc2sccc2C#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2sccc2C(N)=NO)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-(3-cyanothiophen-2-yl)-2-(4-methoxyphenyl)acetamide (234 mg, 0.859 mmol) in a mixture of ethanol (5 mL), methylene chloride (0.5 mL) and triethylamine (202 μL, 1.46 mmol) was added hydroxylamine hydrochloride (90 mg, 1.29 mmol). The resulting solution was stirred at room temperature for 18 h and was subsequently diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phases were combined, dried (Na2SO4), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/ethyl acetate, 7/3 to 2/8) to give N-(3-(N′-hydroxycarbamimidoyl)thiophen-2-yl)-2-(4-methoxyphenyl)acetamide. Retention time (min)=1.161, method [1], MS(ESI) 306.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[CH2:11][CH2:12][CH3:13].Br[CH2:15][C:16](=O)[CH2:17][CH3:18].C1(C)C=CC=CC=1>O1CCOCC1>[CH2:17]([C:16]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([CH2:11][CH2:12][CH3:13])[CH:4]=2)[O:7][CH:15]=1)[CH3:18]
Reactant: CCCc1cc(C(N)=O)ccc1O
Reactant: CCC(=O)CBr
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCCc1cc(-c2nc(CC)co2)ccc1O
Yield: 48.8 %

Procedure:
A mixture of 4-hydroxy-3-propylbenzamide (200.0 mg, 1.1 mmol) (Example 43), 1-bromo-2-butanone (0.19 mL, 1.7 mmol), toluene (1.5 mL), and 1,4-dioxane (1.5 mL) was heated at reflux for 8 h with a Dean-Stark trap. The solvents were evaporated. The crude product was purified on HPLC to yield a solid (124.2 mg, 48%). LC/MS m/z 232 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.56-7.76 (m, 3H), 6.85 (d, J=8.4 Hz, 1H), 2.46-2.56 (m, 4H), 1.52-1.61 (m, 2H), 1.18 (t, J=7.6 Hz, 3H), 0.91 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:18])[O:4][CH:5]1[CH2:10][C:9]([CH2:12][CH3:13])([CH3:11])[NH:8][C:7]([CH2:15][CH3:16])([CH3:14])[CH:6]1[CH3:17].[CH2:19]1[O:21][CH2:20]1>CO.Cl>[CH3:1][NH:2][C:3](=[O:18])[O:4][CH:5]1[CH2:10][C:9]([CH2:12][CH3:13])([CH3:11])[N:8]([CH2:19][CH2:20][OH:21])[C:7]([CH2:15][CH3:16])([CH3:14])[CH:6]1[CH3:17]
Reactant: CCC1(C)CC(OC(=O)NC)C(C)C(C)(CC)N1
Reactant: C1CO1
Agent: Cl
Solvent: CO
Product: CCC1(C)CC(OC(=O)NC)C(C)C(C)(CC)N1CCO
Temperature: 100 °C
Yield: 50.2 %

Procedure:
To a solution of 5.1 g of 2,6-diethyl-2,3,6-trimethyl-4-piperidyl methylcarbamate (Compound 66 - prepared as described in Preparation 4) in 8 ml of methanol were added 1.74 g of ethylene oxide and 1 drop of concentrated hydrochloric acid. The mixture was heated overnight at 100° C in a sealed tube. When the reaction was complete, the reaction mixture was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography on silica gel using a 1 : 1 by volume mixture of benzene and ethyl acetate as eluent, giving 3.0 g of Compound 84. The compound showed a single spot on thin layer chromatography on silica gel (developing solvent: benzene/ethyl acetate, 1 : 1 by volume), Rf value 0.51.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH:24]=[CH:25][C:26](=[O:28])[CH3:27]>C(O)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH:24]1[CH2:3][C:2](=[O:1])[CH2:27][C:26](=[O:28])[CH2:25]1
Reactant: CC[O-]
Reactant: CC(=O)C=Cc1cc(F)ccc1F
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: O=C1CC(=O)CC(c2cc(F)ccc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 20% solution of sodium ethoxide in ethanol (27.7 g) was combined at room temperature with diethyl malonate (13.0 g) and then with 4-(2,5-difluorophenyl)-3-buten-2-one (13.8 g) in portions. The reaction mixture was stirred at room temperature for 30 minutes and then heated with stirring for 2 hours. After allowing to stand to cool, the solvent was distilled off, and the residue was combined with water, and the aqueous layer was washed with ethyl acetate and concentrated. 2N Sodium hydroxide (42 ml) was added and the mixture was heated under reflux for 2 hours. After allowing to stand to cool, 2.5 M sulfuric acid (42 ml) was added over a period of 10 minutes, and then the mixture was heated under reflux for 3 hours. After allowing to stand to cool, the precipitated crystal was recovered by a filtration and washed successively with water and isopropyl ether to obtain 5-(2,5-difluorophenyl)cyclohexane-1,3-dione (11.6 g) as a colorless crystal.
Reaction SMILES: [CH:1]([C:4]1[N:5]([CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].[Li]CCCC.[CH3:20][Sn:21](Cl)([CH3:23])[CH3:22]>C1COCC1.CCOC(C)=O>[CH:1]([C:4]1[N:5]([CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[C:6]([Sn:21]([CH3:23])([CH3:22])[CH3:20])=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: C[Sn](C)(C)Cl
Reactant: COCCOCn1ccnc1C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCn1c([Sn](C)(C)C)cnc1C(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.4 %

Procedure:
A −78° C. solution of 2-isopropyl-1-((2-methoxyethoxy)methyl)-1H-imidazole (1.50 g, 7.57 mmol) in THF (30 mL) was treated drop-wise with n-BuLi (2.5N, 4.24 mL, 10.59 mmol), stirred for 10 min, then warmed to 0° C. for 45 min. The solution was re-cooled to −78° C., treated drop-wise, with trimethyltin chloride (1.0 N, 7.19 mL, 7.19 mmol), over 5 min, warmed to RT and stirred overnight. The mixture was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated to dryness to afford 2-isopropyl-1-((2-methoxyethoxy)methyl)-5-(trimethylstannyl)-1H-imidazole (2.45 g, 90%). MS (ESI) m/z: 363.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[CH:18][CH:19]=2)[CH:14]=[N:13]1)[CH3:11]>>[Cl:1][C:2]1[C:3]([N:22]([CH2:21][C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[N:12]([CH2:10][CH3:11])[N:13]=[CH:14]3)[S:23]([C:26]2[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=2)(=[O:25])=[O:24])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCn1ncc2cc(CNS(=O)(=O)c3ccc(C(=O)OC)cc3)ccc21
Reactant: Fc1ncc(Cl)cc1Cl
Product: CCn1ncc2cc(CN(c3ncc(Cl)cc3Cl)S(=O)(=O)c3ccc(C(=O)OC)cc3)ccc21

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and methyl 4-(N-((1-ethyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 15).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[C:21](F)=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31]C1C=CC=C(Cl)C=1C[Mg]Cl>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[C:21]([Cl:31])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(Cc1c(F)cccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: Cl[Mg]Cc1c(Cl)cccc1Cl
Product: OC(Cc1c(Cl)cccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 18a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol, using 2,6-dichlorobenzyl magnesium chloride as starting material (available from Rieke Metals) was followed making non-critical variations, to yield the title compound. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+=442 @ Rt 3.49 min. major peak.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:11]1[C:16](=O)[CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]1)=O.[CH3:25][C:26]1[N:27]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH2:40])=[NH:39])=[CH:33][CH:32]=2)[CH:28]=[CH:29][N:30]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CCO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[C:11]2[CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:15][C:16]=2[N:40]=[C:38]([NH:37][C:34]2[CH:35]=[CH:36][C:31]([N:27]3[CH:28]=[CH:29][N:30]=[C:26]3[CH3:25])=[CH:32][CH:33]=2)[N:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)Cc2ccccc2F)C1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 130 °C

Procedure:
tert-Butyl 3-(2-(2-fluorophenyl)acetyl)-4-oxopiperidine-1-carboxylate, (0.88 mmol) together with 1 eq 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine and 2 eq of potassium carbonate were slurrified in 4 ml EtOH. The reactions were heated in the microwave oven to 130° C. for 3 h. DCM and water were added and the organic phases were separated, dried with MgSO4 and the solvent was removed under reduced pressure tert-butyl 4-(2-fluorobenzyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (292 mg, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of 3.85 g (7.00 mmol) of 2'-[(t-butoxycarbonylamino)methyl]-4-[(t-butyldiphenylsiloxy)methyl]-1,1'-biphenyl (Step E) in 25 mL of dry tetrahydrofuran under a nitrogen atmosphere was added by syringe 10.5 mL (0.530 mmol) of a 1.0M solution of tetra-n-butylammonium fluoride in tetrahydrofuran. The reaction mixture was stirred for two hours then diluted with 700 mL of diethyl ether. The mixture was washed with water (3×150 mL), saturated aqueous sodium bicarbonate (50 mL), saturated aqueous sodium chloride (50 mL), then dried over magnesium sulfate and filtered. The solvent was removed under vacuum to give an oil which was purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (55:45) to afford 2.02 g (92%) of the product as a white solid (mp 89-93° C.). 1H NMR (200 MHz, CDCl3): δ 1.40 (s, 9H), 2.50 (s, 2H), 4.20 (s, 2H), 4.70 (s, 2H), 7.18-7.45 (m, 8H). FAB-MS: calculated for C19H23NO3 313; found 314 (M+H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[N:33]=[C:16]2[C:17]([NH2:32])=[N:18][C:19]([C:21]#[C:22][CH2:23]CCC3C=CC=CC=3)=[CH:20][N:15]2[N:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[N:33]=[C:16]2[C:17]([NH2:32])=[N:18][C:19]([C:21]#[C:22][CH2:23][O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:20][N:15]2[N:14]=1
Reactant: Nc1nc(C#CCCCc2ccccc2)cn2nc(-c3ccco3)nc12
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(C#CCOc2ccccc2)cn2nc(-c3ccco3)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of phenol (9.4 mg, 0.1 mmol) and 3-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-prop-2-yn-1-ol (0.05 mmol, see Ex. 46 below which was prepared according to Example 3 above) in THF (1 mL) at 0° C. was treated with triphenyl phosphine (26 mg, 0.1 mmol) and diisopropyl azodicarboxylate (20 uL, 0.1 mmol). After 30 min at 0° C., the reaction was allowed to warm to room temperature and was stirred for an additional 14 hours. The reaction mixture was diluted with water and concentrated in vacuo. The aqueous phase was extracted with ethyl acetate, and the organic extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified using preparative HPLC (C18, H2O:MeCN gradient) to afford 2-furan-2-yl-6-(3-phenoxy-prop-1-ynyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.92 (d, 1H), 7.34 (br m, 2H), 7.34 (t, J=8.7 Hz, 2H) 7.14 (d, J=3 Hz, 1H), 7.0-7.1 (br m, 3H), 6.72 (dd, J=3.0, 1.8 Hz, 1H), 5.07 (s, 2H), MS: m/z 332 [M+1].
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[N:23]1[S:24][N:25]=[C:26]2[CH:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][C:27]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[Cl:53]CCl>CO.C(Cl)(Cl)Cl>[ClH:53].[N:23]1[S:24][N:25]=[C:26]2[CH:31]=[C:30]([CH2:32][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[N:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:4][CH2:3]3)[CH:29]=[CH:28][C:27]=12
Reactant: O=Cc1ccc2nsnc2c1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=c1ccc2ncc(=O)n3c2n1C[C@H]3CN1CCC(NCc2ccc3nsnc3c2)CC1

Procedure:
(2R)-2-[(4-Amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (50 mg, 0.166 mmol) (for a preparation see Example 16(j)) and 2,1,3-benzothiadiazole-5-carbaldehyde (25 mg, 0.918 eq.) were stirred in 9:1 v:v chloroform:methanol (1 ml) for 2.5 hours. Sodium triacetoxyborohydride (105 mg, 3.000 eq.) was then added in one portion and the mixture was stirred vigorously at room temperature for 30 min. Saturated aqueous sodium hydrogen carbonate (0.5 ml) was then added, followed by dichloromethane (10 ml) and the mixture was stirred vigorously at room temperature for 10 min and the phases were separated (hydrophobic frit). The organic phase was evaporated under reduced pressure and the crude product was purified by column chromatography on silica (eluted with 0-12% (2M NH3 in MeOH) in DCM). Appropriate fractions were combined and evaporated under reduced pressure to give the free base of the title compound as a yellow solid (41 mg).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[OH:11].Cl[CH2:13][C:14](Cl)=[O:15].[N:17]1([C:22]2[N:27]=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:25]=[C:24]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[N:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(#N)C.C(N(CC)CC)C>[N:17]1([C:22]2[N:27]=[C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH2:13][C:14]([NH:9][C:7]4[CH:8]=[C:3]([CH3:2])[C:4]([OH:11])=[C:5]([CH3:10])[CH:6]=4)=[O:15])[CH2:30][CH2:29]3)[CH:25]=[C:24]([N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[N:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cc(N)cc(C)c1O
Reactant: O=C(Cl)CCl
Reactant: c1c(N2CCCC2)nc(N2CCCC2)nc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(NC(=O)CN2CCN(c3cc(N4CCCC4)nc(N4CCCC4)n3)CC2)cc(C)c1O
Reaction time: 0.5 h

Procedure:
To 2,6-dimethyl-4-aminophenol hydrogen chloride (5.0 g) in methylene chloride (20 ml) is added triethylamine (6.5 g) in methylene chloride (20 ml) dropwise at 0°. To the cold solution is added chloroacetylchloride (3.6 g) in methylene chloride (20 ml) dropwise over 5-10 m. The mixture is stirred at 0° for 30 min and then at 20°-25° for 1 hr. The mixture is washed with water (60 ml), dried over sodium sulfate and the solvent removed at reduced pressure to give a solid. MS (EI, m/e)=213, 215 (M+). Acetonitrile (40 ml), 2,6-bis(1-pyrrolidinyl)-4-(1-piperazinyl)pyrimidine (PREPARATION A-22, 1.42 g), potassium carbonate (0.65 g) are added to the solid and the mixture is heated at reflux for 10 hr. The solvent is removed at reduced pressure and residue is distributed between chloroform (100 ml) and water (100 ml). The phases are separated and the organic phase is dried over sodium sulfate and the solvent is removed at reduced pressure to give an oil. The oil is flash chromatographed on silica gel (175 g) eluting with ethyl acetate/hexane (2/1). The appropriate fractions were pooled and concentrated to give the title compound.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)[OH:8])[OH:4].[O:12]=[C:13]([N:27]1[CH2:32][CH2:31][N:30]2[C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=[C:29]2[CH2:28]1)[CH2:14][C@H:15]([NH2:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25]>C(O)(C)C.C(#N)C>[C:1]([O-:11])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)[OH:8])[OH:4].[O:12]=[C:13]([N:27]1[CH2:32][CH2:31][N:30]2[C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=[C:29]2[CH2:28]1)[CH2:14][C@H:15]([NH2:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25]
Reactant: O=C(O)c1cc(O)ccc1O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CC#N
Solvent: CC(C)O
Product: O=C([O-])c1cc(O)ccc1O

Procedure:
The gentisic acid salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was formed by mixing gentisic acid (0.113 g), (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (0.300 g) in a mixture of isopropylalcohol (0.6 mL) and acetonitrile (1.5 mL), followed by stirring at reflux temperature for 2 h. The solvent was distilled out at reduced pressure to obtain solid gentisate salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine as an amorphous solid. [Wt.: 0.410 g, % purity: 98.9%, XRD=amorphous FIG. (2)].
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][NH:31][C:30](=[O:34])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][N:31]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=2)[C:30](=[O:34])[CH:29]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1cc(OCc2ccccc2)ccn1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
1-Bromomethyl-4-trifluoromethoxybenzene (3.32 g, 13.04 mmol) and potassium carbonate (3.51 g, 25.46 mmol) were added to a mixture of 4-benzyloxy-1H-pyridin-2-one (2.5 g, 12.42 mmol) in acetonitrile (10 ml). The reaction mixture was heated at reflux temperature for 24 hours. After cooling to room temperature, it was filtered through diatomaceous earth, the solid residues were washed with methanol and the combined organic extracts were evaporated in vacuo. The crude residue thus obtained was precipitated with DIPE to yield intermediate D14 (4.5 g, 96%) as a white solid.
Reaction SMILES: [Cl:1]Cl.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH2:11][C:12]([OH:14])=[O:13].O>C(O)(=O)C>[Cl:1][C:7]1[C:6]([CH3:10])=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[C:4]([CH3:3])=[CH:9][CH:8]=1
Reactant: ClCl
Reactant: Cc1cccc(C)c1CC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(Cl)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
At 10-15° C., 9.22 g [130 mmol] of chlorine gas are slowly introduced into a solution of 16.4 g [100 mmol] of 2,6-dimethylphenylacetic acid in 100 ml of glacial acetic acid. The reaction mixture is then stirred at room temperature for 16 hours and then poured into 500 ml of water. The precipitated solid is filtered off with suction, washed with water and dried. This gives 18.8 g of a white solid which, according to GC(sil.), has the following composition: 86.4% of 3-chloro-2,6-dimethylphenylacetic acid (corresponds to a yield of 81.8% of theory), 8.8% of dichloro-2,6-dimethylphenylacetic acid (isomer 1), 3.8% of dichloro-2,6-dimethylphenylacetic acid (isomer 2).
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([OH:9])=[O:8])[CH:2]=1.[P:10]([OH:13])([OH:12])[OH:11].P(Cl)(Cl)Cl>COCCOC>[CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:10]([OH:13])([OH:12])=[O:11])([P:10]([OH:13])([OH:12])=[O:11])[OH:9])[CH:2]=1.[OH2:8]
Reactant: O=C(O)Cn1ccnc1
Reactant: OP(O)O
Solvent: ClP(Cl)Cl
Solvent: COCCOC
Product: O
Product: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A suspension of 1-imidazolylacetic acid (20 g, 0.159 mol) and phosphorous acid (19.6 g, 0.239 mol) in 1,2-dimethoxyethane (72 ml) is heated to 75° C. for 30 minutes. The mixture is cooled to 35-40° C. and then gradually introduced phosphorous trichloride (48 ml, 0.543 mol) while maintaining the temperature between 35-45° C. The mixture is heated to 63-67° C. for 3 hrs, whereby white solid results. It is then cooled to 0-5° C. and quenched by slow addition of water (160 ml) at 0-5° C. over a period of 1 hr. The resulting clear solution is heated at 100° C. for 3 hrs, cooled to ambient temperature and charcoalized. To the charcoalized solution is added acetone (320 ml). The mixture is then stirred for 4 hours at 20-25° C., the crystallized product is filtered, washed sequentially with chilled water (80 ml), acetone (80 ml) and dried in air oven at 55-60° C. until water content is between 6.2-7.2% w/w. Appearance: white crystalline solid, purity >99.5%, meeting specification as per IHS.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=O)[CH:13]=[C:12]3[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:14]1[CH:13]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)[CH:10]=2)[N:15]=1
Reactant: O=c1cc(-c2ccccc2)c2cc(C(c3ccc(Cl)cc3)n3ccnc3)ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(C(c2ccc3nc(Cl)cc(-c4ccccc4)c3c2)n2ccnc2)cc1
Yield: 85 %

Procedure:
A mixture of (±)-6-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-4phenyl-2(1H)-quinolinone (0.022 mol) in phosphoryl chloride (100 ml) was stirred and refluxed for 2 hours. The mixture was evaporated in vacuo, the residue was taken up in CH2Cl2 and basified with K2CO3 (10%). The organic layer was dried (MgSO4), filtered off and evaporated. The product was used without further purification, yielding 8 g (85%) of (±)-2-chloro-6-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-4-phenylquinoline (interm. 5).