Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7](O)[CH:8]=[CH:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CC[O:15]CC.C(=O)(O)[O-].[Na+]>O1CCOCC1>[C:1]1([CH:7]=[CH:8][CH:9]([OH:15])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC=CC(O)c1ccccc1
Reactant: CCOCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(O)C=Cc1ccccc1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
1-Phenyl-2-buten-1-ol (135.88 g) was dissolved in 2300 mL of dioxane and treated with 2750 mL of dilute hydrochloric acid (2.3 mL of concentrated hydrochloric acid in 2750 mL of water) at room temperature. The mixture was stirred overnight and then poured into 4333 mL of ether and neutralized with 2265 mL of saturated sodium bicarbonate. The aqueous phase was extracted with 1970 mL of ether. The combined extract was dried over anhydrous potassium carbonate. Evaporation of the solvent followed by Kugelrohr distillation at 30° C. for 30 minutes afforded 131.73 g (96.8%) of the desired 4-phenyl-3-buten-2-ol as an oil which was used in the next step without further purification.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28](=[O:39])[NH:29][C:30]3[C:31]4[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=4[S:33][CH:34]=3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:33]1[CH:34]=[C:30]([NH:29][C:28]([O:27][C:24]2[CH:25]=[CH:26][C:21]([C:18]3[CH:17]=[CH:16][C:15]([S:12]([NH:11][CH:7]([CH:8]([CH3:9])[CH3:10])[C:6]([OH:40])=[O:5])(=[O:14])=[O:13])=[CH:20][CH:19]=3)=[CH:22][CH:23]=2)=[O:39])[C:31]2[CH:38]=[CH:37][CH:36]=[CH:35][C:32]1=2
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)Nc3csc4ccccc34)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)Nc3csc4ccccc34)cc2)cc1)C(=O)O
Reaction time: 4 h
Yield: 66 %

Procedure:
2-[4′-(Benzo[b]thiophen-3-ylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (180 mg, 0.31 mmol) was dissolved in methylene chloride under N2 atmosphere, added with TFA (2 mL) at 0° C. and stirred for 4 hrs. Solvent was evaporated and the product dried under high vacuum to give 2-[4′-(Benzo [b]thiophen-3-ylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid in 66% yield (108 mg).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: Cc1ccc(C(=O)CCCCCBr)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(C)cc2)CC1
Yield: 44.2 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound, potassium carbonate (2.5 g) and 6-bromo-1-(4-methylphenyl)-1-hexanone (1.3 g) were reacted and treated in the same manner as in Example 172 to give 0.87 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(4-methylphenyl)-6-oxohexyl)piperidin-4-yl)-methyl)benzamide.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:26][C:27]1[CH:28]=[C:29]([CH:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)O)[CH:30]=[CH:31][CH:32]=1.C(N(CC)CC)C>C1COCC1>[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[O:10])[CH2:5][CH2:4]1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: OC(c1cccc(F)c1)c1cccc(F)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN1CCC(C(=O)OC(c2cccc(F)c2)c2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
1-Methylpiperidine-4-carboxylic acid hydrochloride (250 mg, 1.39 mmol), EDC (400 mg, 2.09 mmol), and HOBT (320 mg, 2.09 mmol) were dissolved in dry THF (10 ml). Bis(3-fluorophenyl)methanol (337 mg, 1.53 mmol) was dissolved in dry THF (4 ml) and then added to the reaction mixture. Triethylamine (6790, 4.87 mmol) was finally added, and the resulting reaction was stirred at room temperature overnight. The reaction was evaporated, and the residue was taken up with EtOAc and washed with water and sat.NaHCO3. The organic phase was dried over sodium sulfate, filtered, and evaporated under vacuum. The crude was purified by flash chromatography (DCM/MeOH=9/1) to afford bis(3-fluorophenyl)methyl 1-methylpiperidine-4-carboxylate (150 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[Br:10]Br>C(Cl)(Cl)Cl>[Br-:10].[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH2:2][N+:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]=1
Reactant: BrBr
Reactant: CC(=O)c1ccccn1
Solvent: ClC(Cl)Cl
Product: O=C(C[n+]1ccccc1)c1ccccn1
Product: [Br-]
Temperature: 25 °C

Procedure:
2-Acetylpyridine (100 mmol) is treated with bromine (6.2 mL, 0.12 mol) at reflux in 200 mL of CHCl3 for 45 min. The solution is cooled to room temperature then washed with dilute aqueous NaHCO3/Na2S2O3. The organic phase is dried over Na2SO4, filtered, and evaporated. The residue is dissolved in 200 mL of tetrahydrofuran (THF) and 30 mL of pyridine is added. The resulting solution is refluxed for 30 min. The mixture is cooled and filtered to give the desired product. The nuclear magnetic resonance (NMR) and infrared (IR) spectra are consistent with the assigned structure and the product is homogeneous by TLC.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH2:11]([O:18][C:19]([C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:26]([O-])(=[O:28])C.[Na+]>C(Cl)Cl.O>[CH2:11]([O:18][C:19]([C:21]1[NH:22][C:23]([CH:4]=[O:5])=[CH:24][CH:25]=1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1.[CH2:11]([O:18][C:19]([C:21]1[NH:22][CH:23]=[C:24]([CH:26]=[O:28])[CH:25]=1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OCc1ccccc1)c1ccc[nH]1
Reactant: CN(C)C=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c(C(=O)OCc2ccccc2)c1
Product: O=Cc1ccc(C(=O)OCc2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To DMF (5.93 g) was added POCl3 (12.45 g) dropwise at 0° C. The mixture was warmed to RT, diluted with DCM (40 mL) and cooled again to 0° C. A solution of 1H-pyrrole-2-carboxylic acid benzyl ester (15.00 g, prepared by adopting a procedure from J. Barry, G. Bram and A. Petit, Heterocycles 1985, 23, 875-880) in DCM (40 mL) was added dropwise at such a rate that the temperature of the reaction mixture did not rise above 0° C. The reaction was the heated to reflux for 30 min whereupon it was cooled to 10° C. A solution of sodium acetate (28g) in water (90 mL) was added carefully. After stirring for 15 min the two resulting phases were separated and the aqueous phase was washed with DCM (3×75 mL). The combined organic phases were washed with saturated Na2CO3 solution and brine, dried over MgSO4 and concentrated. The residue was purified by flash column chromatography on silica (ethyl acetate/heptanes 1:2) to provide 5-formyl-1H-pyrrole-2-carboxylic acid benzyl ester (8.0 g) and 4-formyl-1H-pyrrole-2-carboxylic acid benzyl ester (4.0 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:10][C:11]([C:15](=[O:17])[CH3:16])=[C:12]([CH3:14])[N:13]=1.[OH-:18].[K+].[C:20](O)(=[O:22])C.[C:24](O)(=O)C.IC1C=CC=CC=1>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:10][C:11]([C:15]([O:22][CH3:20])([O:17][CH3:24])[CH2:16][OH:18])=[C:12]([CH3:14])[N:13]=1
Reactant: CC(=O)c1sc(-c2ccc(C)cc2C)nc1C
Reactant: [OH-]
Reactant: CC(=O)O
Agent: [K+]
Solvent: CO
Solvent: Ic1ccccc1
Product: COC(CO)(OC)c1sc(-c2ccc(C)cc2C)nc1C
Yield: 26.7 %

Procedure:
To methanol (5 ml), 1-[2-(2,4-dimethylphenyl)-4-methylthiazol-5-yl]ethanone (981 mg) prepared in the Step 31-1-1 was added, and a solution of potassium hydroxide (673 mg) in methanol (10 ml) was added dropwise thereto under cooling by ice and stirring. Thereafter, iodobenzene diacetate (1.42 g) was added to the mixture, and then the resulting mixture was stirred at a room temperature for 22 hours. From the mixture methanol was distilled off under a reduced pressure, and water was added to the residue. The resulting mixture was subjected to extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate, and then dichloromethane was distilled off under a reduced pressure. Hexane was added to the residue, the precipitate was separated by filtration, washed with hexane, and then dried under a reduced pressure to give the title compound (328 mg, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:38]3[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCC1CCNCC1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(F)(F)F)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CO)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperidin-4-yl-methanol (Lancaster) to give the title compound. HR-MS (ES, m/z) calculated for C33H35N43O3F3Cl2 [(M+H)+] 648.2002, observed 648.2006.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:34]([F:35])=[CH:33][C:28]([O:29][CH2:30][CH2:31][OH:32])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].CCN(C(C)C)C(C)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(Cl)Cl>[CH3:48][S:49]([O:32][CH2:31][CH2:30][O:29][C:28]1[CH:27]=[C:26]([F:36])[C:25]([CH2:24][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:37][CH3:38])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[C:34]([F:35])[CH:33]=1)(=[O:51])=[O:50]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCOS(C)(=O)=O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a stirred solution of 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethanol (3.8 g, 6.75 mmol) and DIPEA (3.52 mL, 20.3 mmol) in DCM (100 mL) at 0° C. was added methanesulfonyl chloride (603 μL, 7.8 mmol). After the reaction was slowly warmed to ambient temperature over 30 min, it was partitioned in DCM (100 mL) and water (100 mL). Organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex/EtOAc=1:3) to give 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethyl methanesulfonate (4.1 g, 95% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J=8.25 Hz, 1H), 7.22 (s, 1H), 6.82-6.72 (m, 2H), 6.58-6.47 (m, 2H), 6.42-6.32 (m, 4H), 4.55 (dd, J=5.27, 3.62 Hz, 2H), 4.18 (dd, J=5.26, 3.64 Hz, 2H), 4.04 (s, 2H), 3.78 (s, 3H), 3.09 (s, 3H), 1.50 (d, J=10.49 Hz, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](B(O)O)[CH:29]=2)[NH:24][N:23]=1>>[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])[CH:29]=2)[NH:24][N:23]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: Cc1n[nH]c2ccc(B(O)O)cc12
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4[nH]nc(C)c4c3)ccn2c1=O
Yield: 91.1 %

Procedure:
Methyl 8-(3-methyl-1H-indazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A′ from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and (3-methyl-1H-indazol-5-yl)boronic acid (176.1 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (120 mg, 88%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH:17]=[O:18])[N:3]=1.[Mn]([O-])(=O)(=O)=[O:20].[K+]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([C:17]([OH:20])=[O:18])[N:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(C=O)n1
Agent: [K+]
Product: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(C(=O)O)n1

Procedure:
This compound was prepared from the compound of Example 46 reaction with potassium permanganate, mp. 227° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([NH:15][CH2:16][CH2:17][N:18]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:28])=[C:10]3[S:29][C:30]4[CH:35]=[C:34]([O:36]C)[CH:33]=[CH:32][C:31]=4[C:8]([C:9]=23)=[N:7]1)[CH3:2].B(Br)(Br)[Br:41].CO>ClCCl>[BrH:41].[BrH:41].[CH2:38]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([NH:15][CH2:16][CH2:17][N:18]3[C:19](=[O:28])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]3=[O:27])=[C:10]3[S:29][C:30]4[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:31]=4[C:8]([C:9]=23)=[N:7]1)[CH3:39]
Reactant: BrB(Br)Br
Reactant: CCN(CC)CCn1nc2c3c(c(NCCN4C(=O)c5ccccc5C4=O)ccc31)Sc1cc(OC)ccc1-2
Solvent: CO
Solvent: ClCCl
Product: Br
Product: CCN(CC)CCn1nc2c3c(c(NCCN4C(=O)c5ccccc5C4=O)ccc31)Sc1cc(O)ccc1-2
Reaction time: 3 h
Yield: 70.8 %

Procedure:
A 25° C. solution of 324.1 g (0.598 mol) of 2-[2-[[2-[2-(diethylamino)ethyl]-8-methoxy-2H-[1]benzothiopyrano[4,3,2-cd]indazol-5-yl]amino]ethyl]-1H-isoindole-1,3(2H)-dione (2) in 7.45 L of dichloromethane was treated dropwise over 2 hr with 2.1 L (2.1 mol) of a 1M solution of boron tribromide in dichloromethane. The mixture was heated at reflux for 6.75 hr, treated with an additional 300 mL (0.3 mol) of boron tribromide solution, then further heated overnight. The refluxing mixture was treated cautiously with 1.86 L of methanol, heated an additional 12 hr, then cooled and stirred for 3 hr in an ice bath. The solids were collected by filtration, washed successively with dichloromethane and hexane, then dried at 220 mm/45° C./20 hr to give 291.8 g (70.8%) of 3, mp 232.5°- 234° C., 98.9% pure by HPLC.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.Br[C@H:18]([CH3:22])[C:19]([OH:21])=[O:20]>C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C@@H:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH2:13][CH2:14]2)=[N:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: C[C@@H](Br)C(=O)O
Solvent: ClCCl
Product: C[C@@H](C(=O)O)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A solution of 1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (2.77 g, 11.99 mmoles) in DCM (42 mL) and TEA (4.2 mL) was treated with (2R)-2-bromo-propionic acid (1.19 mL, 13.2 mmoles) and stirred overnight at 35° C. The DCM was removed under reduced pressure to provide crude title compound as a yellowish solid that was used in the next step. MS(APCI+) m/z 304 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]2[C:12]([N:17]=1)=[N:13][CH:14]=[CH:15][CH:16]=2.CC(C)=[O:20].I([O-])(=O)(=O)=O.[Na+]>O>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]2[C:12]([N:17]=1)=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:20]
Reactant: CSc1ccccc1-c1nc2ncccc2o1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CS(=O)c1ccccc1-c1nc2ncccc2o1
Temperature: 25 °C

Procedure:
A solution of 0.5 g. of 2-(2-methylthiophenyl)oxazolo[4,5-b]pyridine in 50 ml. of acetone was treated with 3 g. of sodium metaperiodate. After stirring over the weekend at room temperature, the mixture was diluted with 30 ml. of water. The acetone was distilled out and the resulting precipitate was recrystallized to give 2-(2-methylsulfinylphenyl)oxazolo[4,5-b]pyridine, m.p. 153.5°-155.5° C.
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.[C-]#N.[Na+].Br[C:10]1[N:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=1>CN(C=O)C.CCOC(C)=O.O>[NH2:16][C:13]1[N:14]=[CH:15][C:10]([C:4]#[N:5])=[N:11][CH:12]=1
Reactant: N#C[Cu]C#N
Reactant: Nc1cnc(Br)cn1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cnc(N)cn1
Temperature: 135 °C
Yield: 49.9 %

Procedure:
Heat a suspension of 1.85 g (20.7 mmol) of copper cyanide and 1 g (20.7 mmol) of sodium cyanide in 20 ml of DMF to 135° C., while stirring. Add 3.6 g (20.7 mmol) of 5-bromopyrazin-2-amine to the solution obtained, and maintain the temperature of 135° C. for 18 h. Then add 2 equivalents of sodium cyanide and of copper cyanide and continue heating for a further 24 h. After cooling, add 100 mL of 0.3N aqueous solution of sodium cyanide, stir the mixture for 1 h at 40° C., then distribute it in 300 mL of EtOAc/water 1:1 mixture. After washing with 2×100 mL of water, dry the organic phase over Na2SO4 and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 100% of EtOAc. After concentration under reduced pressure, we obtain 1.24 g of 5-aminopyrazine-2-carbonitrile in the form of oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[NH:11][CH2:10][CH2:9][NH:8][C:7]1=[O:12].Cl[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[N:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9][NH:8][C:7]1=[O:12]
Reactant: COC(=O)CCl
Reactant: O=C1NCCNC1c1cccs1
Product: COC(=O)CN1CCNC(=O)C1c1cccs1

Procedure:
18.2 g (0.1 mol) of 3-(2-thienyl)-piperazin-2-one, prepared in accordance with Example 16, are reacted with methyl chloroacetate and worked up, as described in Example 6.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl[CH:35](Cl)[CH3:36]>O1CCCC1>[CH3:20][O:19][C:16]1[C:17]2[N:18]=[C:10]([NH:9][C:8]([N:28]3[CH2:33][CH2:32][C:31]4([C:8](=[O:27])[N:9]([CH3:10])[CH2:35][CH2:36]4)[CH2:30][CH2:29]3)=[O:27])[S:11][C:12]=2[C:13]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[N:14][CH:15]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: CC(Cl)Cl
Reactant: c1ccncc1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N3CCC4(CCN(C)C4=O)CC3)nc12

Procedure:
From (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester with 4-spiro-[3-(N-methyl-2-pyrrolidone)]-piperidine hydrochloride and pyridine in dichloroethane and tetrahydrofuran. ES-MS m/e (%): 461 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].[I:24][C:25]1[CH:26]=[C:27]([C:31]2[O:36]C(C)(C)[O:34][C:33](=O)[CH:32]=2)[CH:28]=[CH:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:22][C:33](=[O:34])[CH2:32][C:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([I:24])[CH:26]=1)=[O:36])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(I)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1cccc(I)c1
Yield: 101 %

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) (1.0 g, 3.24 mmol) and 6-(3-iodo-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J7) (1.78 g, 3.57 mmol) according to the general procedure K. Obtained as a light yellow solid (1.9 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](Cl)(Cl)Cl.[OH2:16].[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16]
Reactant: c1ccccc1
Reactant: Clc1ccccc1C(Cl)(Cl)Cl
Reactant: O
Agent: [Al+3]
Agent: [Cl-]
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Reaction time: 2 h

Procedure:
Into a flask, benzene (380 ml) was charged, and aluminum chloride (88 g) was suspended therein. A solution of o-chlorobenzotrichloride (138 g, 0.6 mole) in benzene (145 ml) was dropwise added thereto over 2 hours while keeping the temperature at 60° C. After the addition was completed, the mixture was refluxed for 2 hours. The reaction mixture was poured into water (600 ml), and the flask was washed with benzene (240 ml) and water (120 ml). The combined mixture was refluxed for 4 hours. The organic layer was separated, washed with water (400 ml), treated with charcoal (6 g) and filtered. Evaporation of the benzene filtrate gave 172.6 g of o-chlorophenyldiphenylmethanol as a crystalline mass. Yield, 97.7%. M.P., 88.5°-91.5° C.
Reaction SMILES: [Na].[C:2]1([CH3:9])[C:3](C)=[CH:4][CH:5]=[CH:6][CH:7]=1.[P:10]([O-:17])([O:14]CC)[O:11]CC.C(Cl)(Cl)C1C=CC=CC=1>O1CCCC1>[C:2]1([CH:9]([P:10]([OH:17])(=[O:11])[OH:14])[P:10]([OH:17])(=[O:14])[OH:11])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP([O-])OCC
Reactant: Cc1ccccc1C
Agent: [Na]
Solvent: ClC(Cl)c1ccccc1
Solvent: C1CCOC1
Product: O=P(O)(O)C(c1ccccc1)P(=O)(O)O
Temperature: 62 °C

Procedure:
There were charged into the reaction vessel 23.0 grams (1.0 mole) of sodium metal along with 90 cc. of xylene and 80 cc. of tetrahydrofurane. The vessel was placed under a nitrogen blanket and 138.10 grams (1.0 mole) of diethyl phosphite added over a 35 minute period. An exothermic reaction ensued which was maintained at 62° C. by external cooling. After addition was complete the mixture was heated to 100° C. and held there until all of the sodium metal was gone. The mixture was cooled to 60° to 70° C. and 80.50 grams (0.5 mole) of benzal chloride were added gradually over a 25 minute period. An exothermic reaction ensued which was maintained at 60° to 70° C. by external cooling. The mixture was then heated for 4 hours at 70° to 75° C., cooled to 60° C. The liquid material was separated from the solid and the solid boiled 8 times with 100 cc. of benzene to extract the organic material. The eluate product was then distilled, terminal conditions being a pot temperature of 201° C., distillate temperature 125° C. and pressure 6 mm. The solid residue of 70 grams was tetraethyl phenyl methane diphosphonate. This product was hydrolyzed and the hydrolysis product purified as in Example 1 to obtain phenyl methane diphosphonic acid.