Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][C:14]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:15]=1[CH2:16][N:17]1[C@@H:21]([C:22]#[CH:23])[CH2:20][CH2:19][C:18]1=[O:24].O>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:23]#[C:22][C@@H:21]2[N:17]([CH2:16][C:15]3[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:14]=3[O:13][CH3:12])[C:18](=[O:24])[CH2:19][CH2:20]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[C@H]1CCC(=O)N1Cc1ccc(OC)cc1OC
Reactant: CC(C)(C)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CN2C(=O)CC[C@@H]2C#Cc2ccc(C(C)(C)C)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
Copper iodide (74 mg) and bis(triphenylphosphine)palladium(II) dichloride (135 mg) were added to a solution of 4-tert-butyliodobenzene (3.0 g) in triethylamine (10 mL), and the mixture was stirred at room temperature for 15 minutes. (5R)-1-(2,4-Dimethoxybenzyl)-5-ethynylpyrrolidin-2-one (1.0 g) was added thereto over one hour, and the mixture was stirred at room temperature for three hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0→1:1) to give (5R)-5-[(4-tert-butylphenyl)ethynyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless powder (1.25 g, 84%).
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18](Br)[CH2:19][CH2:20][CH:11]([C:12]=23)[CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.O>C(Cl)Cl>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH2:19][CH2:20][CH:11]([C:12]=23)[CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1c2cccc3c2C(CCC3Br)C1c1ccccc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccccc1)N1c2cccc3c2C(CCC3N2CCOCC2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A portion (600 mg) of the compound obtained in Example 132 was dissolved in anhydrous methylene chloride (10 ml) and to the solution was added morpholine (0.25 ml). The mixture was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:19-1:3) to yield 560 mg (92%) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:5]([C:11]#[N:12])=[C:6]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Reactant: OCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1-c1ccccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 304 (M+, 100), 275 (33), 197 (50), 92 (30), 65 (34).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cccc(Cl)c3)CC2)nc[nH]1

Procedure:
6-[4-(3-Chloro-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-chlorobenzaldehyde. Mass spectrum (ES) MH+=305.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH:11][CH2:12][CH2:13][O:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[O:11][CH2:12][CH2:13][O:14][CH:15]1[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH2:20]1
Reactant: CC1(C)CC(OCCO)CC(C)(C)N1
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1(C)CC(OCCOc2nc3ccccc3o2)CC(C)(C)N1

Procedure:
A mixture of 2-chlorobenzoxazole, 4-(2-hydroxyethoxy)-2,2,6,6-tetramethylpiperidine and K2CO3 in 2-butanone was refluxed for ten hours. The hot mixture was filtered to remove K2CO3. After removal of solvent, the product I was obtained by washing the residue with heptane.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5]([N:11]=1)=[N:6][CH:7]=[CH:8][C:9]=2[CH3:10].ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]2[C:5]([N:11]=1)=[N+:6]([O-:20])[CH:7]=[CH:8][C:9]=2[CH3:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc2nccc(C)c2[nH]1
Solvent: ClC(Cl)Cl
Product: Cc1nc2c([nH]1)c(C)cc[n+]2[O-]
Temperature: 25 °C
Yield: 96.9 %

Procedure:
To a solution of 2,7-dimethyl-1H-imidazo[4,5-b]pyridine (4.29 g) in chloroform (43 ml) was added m-chloroperbenzoic acid (80%, 7.55 g) at room temperature and the mixture was refluxed under heating for 1 hr. After allowing to cool to room temperature, the reaction mixture was directly purified by silica gel column chromatography (chloroform/methanol=9/1) and powdered with ethyl acetate to give 2,7-dimethyl-1H-imidazo[4,5-b]pyridine-4-oxide as a brown powder (4.61 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:7]([CH2:13][CH2:14][CH2:15][CH3:16])[C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[O:5][CH:6]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[OH:25][C:6]1[O:5][C:4]([N:7]([CH2:13][CH2:14][CH2:15][CH3:16])[C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[N:3][C:2]=1[CH3:1]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCN(C(=O)C(C)C)c1nc(C)co1
Solvent: ClCCl
Product: CCCCN(C(=O)C(C)C)c1nc(C)c(O)o1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
4-methyl-2(N-butylisobutyramido)oxazole (15 g., 0.067 m.) in dry methylene chloride (100 c.c.) was cooled to 0° C. during the addition of m-chloroperbenzoic acid (16 g., 0.023 m.) over 1 hour. The mixture was then stirred at room temperature for 40 hours. The precipitated m-chlorobenzoic acid was then filtered off and the filtrate evaporated to dryness. The residue was taken in ether (100 c.c.) and stirred with 5% aqueous sodium sulphite solution for1 hour. The organic phase was then separated and washed successively with aqueous sodium carbonate (×2) and water, and then dried and evaporated to give a brown oil, 13.9 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].C(O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([Sn](=O)CCCC)CCC>>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH2:1][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:4])=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCCC[Sn](=O)CCCC
Product: O=C(OCc1ccccc1)c1ccc(O)cc1
Yield: 97.1 %

Procedure:
152.1 g (1 mole) of methyl p-hydroxybenzoate, 216.2 g (2 moles) of benzyl alcohol and 0.304 g (0.4% based on the weight of methyl p-hydroxybenzoate) of dibutyltin oxide were fed into a four-necked glass flask, and reacted at 200° C. for 6 hours with stirring. Methanol which distilled out during the reaction was recovered for re-use in methyl esterification. After the reaction, the excess of benzyl alcohol was recovered under reduced pressure to give 221.6 g (yield 97.1%) of crude benzyl p-hydroxybenzoate. The ratio of benzyl p-benzyloxybenzoate formed was 1.1%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:4][N:3]=1.[Br:13]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:6][N:7]=1
Reactant: Cc1ncc(-c2ccon2)cn1
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ncc(-c2ccon2)cn1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
A mixture of 2-methyl-5-isoxazol-3-yl-pyrimidine (30 gm), N-bromosuccinamide (49.8 gm), and 98% benzoyl peroxide (13.54 gm) in carbon tetrachloride (1200 ml) was heated to 75° C. temperature. The reaction mixture was stirred at 75° C. for 24 h. The reaction mixture was filtered under suction at 25° C. to 35° C. temperature. The solid was washed with carbon tetrachloride (400 ml). The filtrate was washed with saturated aqueous sodium bicarbonate solution (400 ml×2) and evaporated under vacuum to provide a crude material (52 gm) which upon silica gel column chromatography afforded desired compound in 14 gm quantity (40%), dibromo compound in 16.8 gm and starting material 6.5 gm quantities.
Reaction SMILES: [CH2:1]([C@:3]1([CH:21]([CH3:25])[C:22](O)=[O:23])[C@@H:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH3:20])[C:11]=32)[CH2:6][CH2:5][CH2:4]1)[CH3:2].CN1CCOCC1.ClC(OCC)=O.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[CH2:39]([NH:46][C:22](=[O:23])[CH:21]([C@@:3]1([CH2:4][CH3:5])[C@@H:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH3:20])[C:11]=32)[CH2:6][CH2:2][CH2:1]1)[CH3:25])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NCc1ccccc1
Reactant: CC[C@@]1(C(C)C(=O)O)CCCN2CCc3c(n(C)c4ccccc34)[C@@H]21
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC[C@@]1(C(C)C(=O)NCc2ccccc2)CCCN2CCc3c(n(C)c4ccccc34)[C@@H]21
Temperature: -5 °C
Yield: 78 %

Procedure:
3.40 g. (0.01 moles) of (-)-(1S,12bS)-1-ethyl-12-methyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-1-yl-propionic acid are added to a solution containing 2.04 g. (0.02 moles) of N-methylmorpholine (redistilled from sodium) in 20 ml. of dry tetrahydrofuran while stirring under nitrogen, then the solution is cooled to -5° C. and 1.10 g. (0.01 mole) of ethyl chloroformate are rapidly dropped in while stirring vigorously and keeping the inner temperature at or lower than 0° C. The mixture is stirred at 0° C. for 30 minutes, whereupon a solution containing 1.18 g. (0.011 moles) of benzylamine in 10 ml. of dry tetrahydrofuran is dropwise added at a temperature between -5° C. and 0° C. during 10 minutes. The mixture is stirred at 0° C. for 30 minutes, then during an additional stirring for 4 hours the mixture is allowed to warm to room temperature. The mixture is evaporated on a rotating evaporator and after shaking thoroughly the residue with 50 ml. of dichloromethane and 20 ml. of water, the phases are separated. The dichloromethane layer is washed at first with 20 ml. of 5% sodium carbonate solution, then three times with 20 ml. of water each, dried over anhydrous magnesium sulphate and evaporated. The residue which is the crude product, is purified by column chromatography on silica gel by using toluene containing 10% of diethylamine to give 3.36 g. (78% yield) of the title compound as an oily product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)=[CH:3][CH:2]=1.[CH3:16]I.[OH-].[Na+]>O.C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11]([S:14][CH3:16])=[N:12][CH:13]=2)=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1ccncc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ncc(Cc2ccncc2)c(=O)[nH]1

Procedure:
A solution of 5-(4-pyridylmethyl)-2-thiouracil (11.0 g), methyl iodide (7.2 g) and sodium hydroxide (2.1 g) in water (50 ml) and ethanol (100 ml) was stirred at 60° for 30 minutes, allowed to cool and filtered to give 5-(4-pyridylmethyl)-2-methylthio-4-pyrimidone m.p. 179°-182° (ethanol).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([NH:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: Nc1nccs1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1nccs1)c1ccc2c(Cl)nccc2c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask containing thiazol-2-amine (0.185 g, 1.843 mmol), perfluorophenyl 1-chloroisoquinoline-6-sulfonate (0.719 g, 1.755 mmol), and THF (0.163 mL) was cooled to 0° C. LHMDS (1.0 M in THF) (3.86 ml, 3.86 mmol) was added dropwise and the reaction was stirred for 5 minutes at 0° C. The reaction was quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was triturated in DCM and loaded onto a silica gel cartridge. The tan solid remaining at the top of the cartridge was scraped into a flask and put aside. The remaining material was purified by silica gel chromatography (40 g column, gradient elution 0 to 100% EtOAc:Heptane with a 10% MeOH:DCM flush). The product fractions were combined with the previously isolated material to afford 1-chloro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a tan solid. m/z (ESI) 326.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:29][CH:30]([O:36][CH2:37][CH3:38])[C:31]([O:33]CC)=[O:32])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:29][CH:30]([O:36][CH2:37][CH3:38])[C:31]([OH:33])=[O:32])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(NC(=O)OC(C)(C)C)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(NC(=O)OC(C)(C)C)c1)C(=O)O
Yield: 22.9 %

Procedure:
Ethyl 3-[3-[(tert-butoxycarbonyl)amino]-4-(2-{4-[(methylsulfonyl)oxy]phenyl}ethoxy)phenyl]-2-ethoxypropanoate (0.036 g; 0.100 mmole) was dissolved in THF and water (2:1), 0.1 M lithium hydroxide (1 ml) was added and the reaction mixture was stirred over night. Water was added and the THF evaporated. The remaining water was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate. Evaporation gave 0.012 g (52% yield) of the product.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH:2]([CH3:4])[CH3:3].CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[OH:35])O1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[OH:35])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC(=O)N1CCN(c2cncc(Cl)n2)CC1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)COC(=O)N1CCN(c2cncc(-c3ccccc3O)n2)CC1
Temperature: 120 °C

Procedure:
6′Chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid isobutyl ester (54 mg, 0.18 mmol), 47.9 mg (0.22 mmol) of 2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol, 3.2 mg (2.7 pmol) of Pd(PPh3)4, 49.2 mg (0.35 mmol) of K2CO3 were charged to a microwave reactor vial. The reaction mixture was heated by microwave irradiation at 120° C. for 15 minutes. The reaction was filtered and purified by reverse phase HPLC (10%-99% CH3CN/H2O), (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to give 33. LCMS: m/z 357.2 (M+H)+ at 3.53 minutes (10%-99% CH3CN/H2O), (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH:10]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH2:29]=O.O.[OH-].[Na+]>C(O)=O>[CH3:29][N:6]1[CH2:7][CH2:8][N:3]([CH2:9][CH:10]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH2:4][CH2:5]1
Reactant: OC1(C(CN2CCNCC2)c2cccc(OC(F)(F)F)c2)CCCCC1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CN1CCN(CC(c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)CC1
Temperature: 70 °C
Yield: 71.9 %

Procedure:
A solution of 1-{2-piperazin-1-yl-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol (590 mg, 1.59 mmol) (see Example 23), in formic acid (3.1 mL) at 50° C., was treated with an aqueous solution of formaldehyde (37% in water, 1.3 mL, 1.94 mmol). The reaction was heated at 70° C. for 1.5 h, after which time the reaction was poured into water (50 mL) and basified to pH=10 with the addition of a 2 N aqueous solution of sodium hydroxide. The product was then extracted with ethyl acetate (3×20 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated to yield 442 mg (72%) 1-{2-(4-methylpiperazin-1-yl)-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol as a colorless oil. The product was dissolved in methanol (0.5 mL) and the resulting solution was treated with a saturated methanolic solution of hydrochloric acid (0.5 mL) followed by diethyl ether (2 mL). The solution was stored in the refrigerator for 16 h. The resulting precipitate was filtered and washed with diethyl ether to yield 299 mg (57%) 1-{2-(4-methylpiperazin-1-yl)-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride as a white solid. HRMS: calcd for C20H29F3N2O2.2.00 HCl, 458.1715; found (ESI), 387.2263.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][CH2:9][CH2:10][N:11]([CH2:24][CH2:25][O:26][CH3:27])[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22].[F:28][C:29]1[CH:30]=[CH:31][C:32]([O:39][CH3:40])=[C:33]([C:35](=[N:37]O)[NH2:36])[CH:34]=1.CCN(C(C)C)C(C)C>>[F:28][C:29]1[CH:30]=[CH:31][C:32]([O:39][CH3:40])=[C:33]([C:35]2[N:36]=[C:16]([C:15]3[CH:19]=[CH:20][C:12]([N:11]([CH2:10][CH2:9][O:8][CH3:7])[CH2:24][CH2:25][O:26][CH3:27])=[C:13]([N+:21]([O-:23])=[O:22])[CH:14]=3)[O:18][N:37]=2)[CH:34]=1
Reactant: COc1ccc(F)cc1C(N)=NO
Reactant: COCCN(CCOC)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(CCOC)c1ccc(-c2nc(-c3cc(F)ccc3OC)no2)cc1[N+](=O)[O-]

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 31 (149 mg; 0.5 mmol; 1 eq.), Intermediate 23 (92 mg; 0.5 mmol, 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 50/50) followed by crystallisation from Et2O/n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.[P:6]([OH:9])([OH:8])[OH:7].P(Cl)(Cl)Cl>O>[CH3:1][N:2]([CH3:5])[CH:3]([P:6]([OH:9])(=[O:7])[OH:8])[P:6]([OH:9])(=[O:8])[OH:7]
Reactant: CN(C)C=O
Reactant: OP(O)O
Solvent: O
Solvent: ClP(Cl)Cl
Product: CN(C)C(P(=O)(O)O)P(=O)(O)O
Yield: 76 %

Procedure:
73.1 parts of dimethyl formamide were mixed with 41 parts by phosphorous acid and this mixture was reacted with 137.3 parts of phosphorus trichloride at about 70°C. A viscous mass was formed, which after about an hour was treated with 180 parts of water. The solution so obtained was filtered and treated with acetone. A precipitate was formed which was further treated as described in Example 1. N,N-dimethyl-1-aminomethane-1,1-diphosphonic acid was obtained in a yield of 76%, based on PCl3.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][N:16]([C:41]1[S:42][C:43]([C:46]2[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=2)=[N:44][N:45]=1)[C:17](=[O:40])[CH2:18][CH2:19][S:20]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl.C(=O)(O)[O-].[Na+]>[SH:20][CH2:19][CH2:18][C:17]([N:16]([CH3:15])[C:41]1[S:42][C:43]([C:46]2[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=2)=[N:44][N:45]=1)=[O:40]
Reactant: CN(C(=O)CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nnc(-c2cccnc2)s1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)CCS)c1nnc(-c2cccnc2)s1
Temperature: 23 °C
Yield: 85.5 %

Procedure:
Triethylsilane (76 μL, 0.48 mmol, 5.0 equiv) and trifluoroacetic acid (710 μL, 5.7 mmol, 100 equiv) were sequentially added to a stirred solution of N-methyl-N-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-(tritylthio)propanamide (50 mg, 0.096 mmol, 1.0 equiv) in dichloromethane (1.3 mL) at 23° C. The resulting solution was stirred at 23° C. for 30 m. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (40 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (Na2SO4), gravity-filtered, and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (ethyl acetate) to afford the title compound as a white powder (23 mg, 85%): mp 149-151° C.; 1H NMR (300 MHz, CDCl3) δ 9.17 (br s, 1H), 8.71 (m, 1H), 8.29 (m, 1H), 7.44 (dd, J=8, 5 Hz, 1H), 3.87 (s, 3H), 2.91-310 (m, 4H), 1.87 (t, J=8 Hz, 1H); ESIMS m/z 281 ([M+H]+).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[C:7](=[C:8]([CH2:13][C:14]([CH3:16])=[O:15])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>C1COCC1>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:7]=2[CH:6]=[CH:5][N:4]3[CH3:3])[C:14](=[O:15])[CH3:16])=[CH:20][CH:19]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(=O)Cc1cccc2c1ccn2C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)C(Cc1ccc(Cl)cc1)c1cccc2c1ccn2C
Reaction time: 1.5 h

Procedure:
To a suspension of 135 mg (3.38 mmol) of sodium hydride in 8 mL dry THF, a solution of 605 mg (3.23 mmol) 1-(1-methyl-1H-indol-4-yl)acetone in 2 mL THF was added. The mixture was stirred for 45 min during which time the sodium hydride dissolved and a yellow orange solution resulted. The reaction was cooled in ice bath and 660 mg (3.24 mmol) 4-chlorobenzyl bromide in 1 mL THF was added. The cold bath was removed and the solution was stirred for 1.5 h. The reaction was quenched with 1.2 N HCl and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was chromatographed using a gradient of 10-20% EtOAc/hexane to isolate the desired product. 1H NMR: (500 MHz, CDCl3): δ 2.03 (s, 3H), 3.07 (m, 1H), 3.58 (m, 1H), 3.84 (s, 3H), 4.23 (t, 1H), 6.52 (d, 1H), 6.9-7.3 (m, 8H).