Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[C:6]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Br:22])[CH:18]=2)[N:13]=1)([CH3:11])[C:7]([F:10])([F:9])[F:8])(=O)=O.[CH3:23][Al](C)C>C1CCCCC1>[Br:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:6]([CH3:23])([CH3:11])[C:7]([F:10])([F:9])[F:8])[CH:21]=[CH:20]2
Reactant: C[Al](C)C
Reactant: CC(OS(C)(=O)=O)(c1ccc2cc(Br)ccc2n1)C(F)(F)F
Solvent: C1CCCCC1
Product: CC(C)(c1ccc2cc(Br)ccc2n1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A suspension of 6-bromoquinolin-2-yl-2,2,2-trifluoro-1-methylethyl methanesulfonate (11.97 g, 30 mmol) in cyclohexane (120 ml) was added trimethylaluminum (120 ml, 123 mmol, 1.03M in hexane solution) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction was carefully quenched with saturated sodium bicarbonate aqueous solution (30 ml), brine (10 ml) and diluted with ethyl acetate and heptane (200 ml). After the mixture was stirred for 30 minutes, formed precipitate was removed by celite and washed with ethyl acetate. The filtrate was concentrated and purified through silica gel column chromatography eluting with hexane only to furnish the title compound (9.56 g, 80% yield) as colorless oil. 1H NMR (300 MHz, CDCl3) ppm 1.72 (6H, s), 7.66 (1H, d, J=8.8 Hz), 7.75-7.80 (1H, m), 7.96-8.00 (2H, m), 8.06 (1H, d, J=8.8 Hz). MS (ESI): m/z 318, 320 (M+H)+.
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]1=[O:21])=O)C.[ClH:23].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:23].[NH2:7][C@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]1=[O:21]
Reactant: CCOC(=O)CN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCCC[C@H](N)C1=O
Reaction time: 0.75 h

Procedure:
A mixture of (S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-oxo-hexahydro-1H-azepine-1-acetic acid, ethyl ester (1.6 g., 5.0 mmole) and ethyl acetate (5 ml.) at 0° (ice bath) is treated with cold saturated hydrochloric acid/ethyl acetate (40 ml.). After stirring for 45 minutes at 0°, nitrogen is passed through the solution to remove excess hydrochloric acid. The ethyl acetate is evaporated and the resulting oil is triturated with ether (3 times) to give 1.1 g. of (S)-3-amino-2-oxo-hexahydro-1H-azepine-1-acetic acid, ethyl ester, monohydrochloride as a very hygroscopic white crystalline solid after drying in vacuo over phosphorus pentoxide. TLC (methylene chloride/acetic acid/methanol; 8:1:1) major spot at Rf =0.32.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:32])[NH:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:33])C.[OH-].[Na+].Cl>>[CH3:33][C:8]1[CH:9]=[C:10]([C:13](=[O:32])[NH:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)CCc1ccc(C(=O)NCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(=O)NCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)ccc1CCC(=O)O
Temperature: 50 °C
Yield: 106.3 %

Procedure:
To a solution of 3-(2-methyl-4-{[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-carbamoyl}-phenyl)-propionic acid ethyl ester (70 mg) in enthanol (1 mL) is added NaOH (5.0 N, 1.0 mL), the mixture is heated at 50° C. for 2 hrs, acidified with 5 N HCl, extracted with ethyl acetate, dried over sodium sulfate. Concentration gave the title compound (70 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@@H:8]2[CH2:9][C@H:3]1[CH2:4][CH2:5][C:6]2=[CH2:7].CSC.[OH-:14].[Na+].OO>C1COCC1.O.C(O)C>[CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:7][OH:14]
Reactant: [OH-]
Reactant: C=C1CC[C@@H]2C[C@H]1C2(C)C
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: CSC
Solvent: O
Product: CC1(C)C2CCC(CO)C1C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
(+)-β-pinene (113) (36.6 g; 0.27 mol) was dissolved in THF (100 ml) and cooled down to 0° C. BH3.DMS in THF (2 M; 47.3 ml) was added drop wise. The reaction mixture was stirred for 0.5 h. Ethanol (90 ml) was added. 1 M NaOH (aq) (95 ml) was added. The reaction mixture was cooled to 0° C. 33 ml 30% H2O2 was added drop wise while the temperature was not allowed to rise above 35° C. The reaction mixture was refluxed for 1 h and poured into water (1 l). The solution was extracted with TBME. The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated to dryness. Remaining α-pinene was distilled off using Kugelrohr distillation (8-12 mbar; 50-60° C.), giving 38.6 g (0.25 mol, yield=93%) of (+)-cis-myrtanol (14) as a colourless oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:8]=2)[NH:3]1.[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([CH:24]=O)=[CH:21][CH:22]=2)[CH:17]=[N:16]1>>[NH:15]1[C:23]2[C:18](=[CH:19][C:20](/[CH:24]=[C:10]3/[C:2](=[O:1])[NH:3][C:4]4[C:9]/3=[CH:8][CH:7]=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=4)=[CH:21][CH:22]=2)[CH:17]=[N:16]1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Product: CC(=O)Nc1ccc2c(c1)NC(=O)/C2=C/c1ccc2[nH]ncc2c1

Procedure:
The title compound was synthesized according to the method described for Example A11B except substituting N-(2-oxoindolin-6-yl)acetamide (40 mg, 0.210 mmol) and 1H-indazole-5-carbaldehyde (34 mg, 0.231 mmol) to obtain 41 mg, 61%. 1H NMR (400 MHz, d6-DMSO) δ 13.31 (s, 1H), 10.55 (s, 1H), 10.07 (s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.71-7.64 (m, 2H), 7.61 (s, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.48 (s, 1H), 6.89 (d, J=8.3 Hz, 1H), 2.04 (s, 3H); MS ESI 319.1 [M+H]+, calcd for [C18H14N4O2+H]+ 319.12.
Reaction SMILES: [C:1]([O-])(C)(C)[CH3:2].[K+].[CH3:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=O)[C:17]([O:19][CH3:20])=[O:18].O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1>[CH3:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[CH:1][CH3:2])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COCc1ccccc1C(=O)C(=O)OC
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC=C(C(=O)OC)c1ccccc1COC
Temperature: 5 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
37.1 g (100 mmol) of ethyltriphenylphosphonium bromide are introduced under nitrogen into 300 ml of absolute tetrahydrofuran. At 5° C., 11.2 g (0.1 mol) of potassium t-butanolate are added. After stirring at 5° C. for one hour, 20.8 g (100 mmol) of methyl 2-methoxymethylphenylglyoxylate in 100 ml of tetrahydrofuran are added dropwise. The mixture is stirred at 5° C. for one hour and at 25° C. for one hour, 200 ml of water are added, the mixture is extracted with methylene chloride and the organic phases are washed with water. After drying over sodium sulfate, the solvent is removed under reduced pressure. The residue is purified by chromatography on a silica gel column (methyl tert-butyl ether/n-hexane=1/2). 17.2 g (78%) of the abovementioned ester are obtained as an oil (Z/E isomer=1/9).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9])(=[O:3])[CH3:2].[H-].[Na+].Cl[CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[N:26][C:27]([Cl:33])=[CH:28][CH:29]=2)[N:24]=1>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[N:26][C:27]([Cl:33])=[CH:28][CH:29]=2)[N:24]=1)(=[O:3])[CH3:2]
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC(=O)NCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NCCCCOC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 6.2 %

Procedure:
The procedure is as in Example 7, but starting with 4-acetylaminobutanol (6 g) in anhydrous tetrahydrofuran (250 cc), an oily suspension (50% by weight; 2.3 g) of sodium hydride and 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (10 g). The product obtained is purified by chromatography on neutral alumina (40 g) contained in a column 1.5 cm in diameter, and eluting with methylene chloride and collecting 10-cc fractions. Fractions 3 to 50 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C., and the residue obtained is crystallized by stirring into 2-propanol. 3-(4-Acetylaminobutoxy)-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (0.8 g), m.p. 120° C., is thereby obtained.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B.C1C[O:31]CC1>C1COCC1>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@@:4]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)([CH2:1][CH2:2][CH2:3][OH:31])[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: C1CCOC1
Agent: B
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (2.0 g, 4.8 mmol) in THF (48 ml) was added BH3.THF (5.7 ml, 1 mol/L) at 0° C. under nitrogen atmosphere, and the resulting solution was stirred for 2 h at rt. The reaction was quenched with water. Then aqueous NaOH solution (2.0 ml, 3 mol/L) and H2O2 (2 mL, 30%) were added to the mixture. The resulting mixture was stirred for 2 h at rt. The mixture was diluted with EtOAc, and the pH was adjusted to 6-7 with 1M aq HCl. The aqueous phase was extracted with EtOAc, and the combined organic phase was washed with satd aq NaHCO3 and brine, dried over Na2SO4, concentrated to give the crude product, which was purified on silica gel to give (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (1.13 g, 54%). 1H NMR: (400 MHz, CDCl3): 1.32 (m, 1H), 1.43 (d, 3H), 1.63 (m, 1H), 1.90 (m, 2H), 2.21 (m, 3H), 2.84 (m, 1H), 3.51 (t, 2H), 5.54 (q, 1H), 6.72 (d, 2H), 6.98 (t, 2H), 7.18 (m, 4H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[N:21]=[C:20]3[NH:22][N:23]=[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=5)[N:26]=4)[C:19]3=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCO>[Cl:39][C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[CH2:32][NH:31][C:27]1[N:26]=[C:25]([C:24]2[C:19]3[C:20](=[N:21][C:16]([NH:15][CH2:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[N:17][CH:18]=3)[NH:22][N:23]=2)[CH:30]=[CH:29][N:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ncc3c(-c4ccnc(NCc5cccc(Cl)c5)n4)n[nH]c3n2)CC1
Agent: Cl
Solvent: CCO
Product: Clc1cccc(CNc2nccc(-c3n[nH]c4nc(NCC5CCNCC5)ncc34)n2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4-({3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.36 mmol) in EtOH (4 mL) was added conc. HCl (4 mL). The reaction mixture was stirred at room temperature for 15 hours. The solvent was then removed and the residue was purified by prep-HPLC to afford {3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-piperidin-4-ylmethyl-amine; hydrochloride. (Yield 60 mg, 30.0%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[N:14]([S:16]([C:19]2[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27]C)=O)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38][NH2:39]>CO>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:13]1[N:14]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]([NH:39][CH3:38])=[O:27])=[CH:29][CH:30]=2)(=[O:17])=[O:18])[CH:15]=[C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=1
Reactant: COC(=O)COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)cc1
Reactant: CN
Solvent: CO
Product: CNC(=O)COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Methyl 2-(4-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetate 4e (100 mg, 0.19 mmol) was dissolved in 5 mL of a solution of methylamine in methanol (33%), and the reaction solution was heated up to 40° C. and stirred for 2 h. The reaction solution was concentrated under reduced pressure to obtain the title product tert-butyl ((5-(2-fluorophenyl)-1-((4-(2-(methylamino)-2-oxoethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 4f (100 mg, a yellow oil), which was used directly in the next step.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:41])=[C:18]([CH2:20][N:21]3[C:29]4[C:24](=[CH:25][C:26]([C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[CH:27][CH:28]=4)[CH2:23][CH:22]3[CH3:40])[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CO>[Pd].O1CCCC1>[CH3:41][C:17]1[O:16][C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[N:19][C:18]=1[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([OH:39])([C:31]([F:34])([F:33])[F:32])[C:35]([F:36])([F:37])[F:38])=[CH:27][CH:28]=2)[CH2:23][CH:22]1[CH3:40]
Reactant: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CN1c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2CC1C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(O)cc2)nc1CN1c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2CC1C
Reaction time: 10 h
Yield: 38.2 %

Procedure:
A solution of 1.2 g (2.1 mmol) of 2-{1-[2-(4-benzyloxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-2-methyl-2,3-dihydro-1H-indol-5-yl}-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 79) in 15 ml of a 2:1-mixture of methanol and tetrahydrofuran was treated with 400 mg of Pd/C (10% Pd) and stirred vigorously under H2 at atmospheric pressure during 10 hrs. Filtration, evaporation of the solvent, and chromatography on silica gel with toluene/EtOAc (gradient from 9:1 to 1:1) gave 390 mg (39%) of 4-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-oxazol-2-yl}-phenol, light yellow foam, MS: 487 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](Cl)(Cl)=[O:10])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15](=[O:29])[C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:17][CH2:18][CH2:19][CH2:20][OH:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9]2(=[O:10])[N:17]([C@H:16]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:15]([O:14][CH3:13])=[O:29])[CH2:18][CH2:19][CH2:20][O:21]2)=[CH:5][CH:4]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NCCCO
Reactant: COc1ccc(P(=O)(Cl)Cl)cc1
Product: COC(=O)[C@@H](Cc1ccccc1)N1CCCOP1(=O)c1ccc(OC)cc1

Procedure:
Starting materials: 4-Methoxyphenylphosphonic dichloride and N-(3-hydroxypropyl)-D-phenylalanine methyl ester.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[C:11]2[CH:12]=[C:13]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)C.O[Li].O>C1COCC1.O>[O:22]=[C:20]1[NH:19][C:18](=[O:23])[C:17](=[CH:16][C:13]2[CH:14]=[CH:15][C:10]3[O:9][CH:8]=[C:7]([CH:6]=[CH:5][C:4]([OH:24])=[O:3])[C:11]=3[CH:12]=2)[S:21]1
Reactant: CCOC(=O)C=Cc1coc2ccc(C=C3SC(=O)NC3=O)cc12
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C=Cc1coc2ccc(C=C3SC(=O)NC3=O)cc12
Reaction time: 15 h
Yield: 89.9 %

Procedure:
3-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-acrylic acid ethyl ester (205 mg, 0.6 mmol) (example 71) were dissolved in THF/water 4:2. To this solution was added under stirring 81 mg (4 eq.) of LiOH.H2O. The reaction was stirred for 15 h. The solvents were evaporated, and the residue was precipitated with ether. The solid was washed with 1NHCl and dried to afford 170 mg (90%) of pure 3-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-acrylic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[N:6]=1.Cl[C:25]1[N:30]=[C:29]([NH2:31])[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.C(N)CN>CN(C)C(=O)C>[NH2:31][C:29]1[N:30]=[C:25]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[NH:15][CH:14]=[CH:13][N:12]=3)=[C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[N:6]=2)[CH:26]=[CH:27][C:28]=1[N+:32]([O-:34])=[O:33]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCNc1ccc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: NCCN
Product: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Temperature: 87.5 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
A mixture of (2-aminoethyl)[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine (0.14 M), 6-chloro-3-nitro-2-pyridylamine (0.14 M), N,N-dimethylacetamide (40 ml), and Hünig's base (2.5 ml) was stirred for 12 hours at 85-90° C. under argon. Ethylene diamine (3.8 ml) was added to remove the unreacted chloropyridine, and the mixture was stirred for an additional 0.75-1 hour at 85-90° C. under argon. After cooling, the reaction was diluted with ethyl acetate (500-600 ml), extracted with saturated sodium bicarbonate (4×200 ml), distilled water (3×150 ml), saturated sodium chloride (150 ml). The organic layer was dried with sodium sulfate briefly (2-3 minutes) so as not to initiate precipitation of the product. The organic layer was filtered, concentrated, and dried in vacuo. To cause precipitation of the product, a minimal amount of methanol (3-5 ml) was added followed with the addition of an equal volume of ethyl acetate. The mixture was allowed to age for 2-3 hours. The solid was collected by filtration, washed with minimal 1:1 methanol/ethyl acetate (5 ml), and a finally 100% ethyl acetate (2×10 ml). The yellow solid was dried in vacuo to give {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine in 61% yield.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:11][C:9]1[C:8]([F:12])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([F:13])=[CH:15][CH:16]=2)[N:10]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)c(Cl)nc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 2,6-dichloro-5-fluoronicotinic acid (500 mg, 2.381 mmol) and 4-fluoroaniline (265 mg, 2.381 mmol) in THF (30 mL) was treated with 1 M lithium bis(trimethylsilyl)amide in THF (7.14 mL, 7.14 mmol) slowly and stirred at rt. Solvent was removed on rotary evaporator. The residue acidified with 1 N HCl, extracted into ethyl acetate, and concentrated to give a dark solid. LCMS: (M+H)+=285.12.
Reaction SMILES: [C:1]([N:3]=[C:4]([N:7]1[CH2:12][CH2:11][C:10]([CH2:27][C:28]#[N:29])([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)SC)#[N:2].[NH3:30].CO>N.C(O)(C)C>[C:1]([N:3]=[C:4]([N:7]1[CH2:12][CH2:11][C:10]([CH2:27][C:28]#[N:29])([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)[NH2:30])#[N:2]
Reactant: CSC(=NC#N)N1CCC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Reactant: N
Solvent: CO
Solvent: CC(C)O
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CCN(C(N)=NC#N)CC1
Temperature: 100 °C
Reaction time: 0.1 h

Procedure:
Methyl N-cyano-4-(cyanomethyl)-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-piperidine-1-carbimidothioate (41.3 mg, 0.102 mmol) (53 mg TFA salt) was dissolved in 2.0 M ammonia in isopropyl alcohol (4.00 mL). The resulting mixture was heated to 100° C. for 1 h in a microwave reactor. Analysis by HPLC and LCMS showed 60% reaction to give the expected M+H 375 (50 area %). To this mixture was added 2 mL of 7 N NH3/MeOH. The resulting mixture was heated at 120° C. for one hour. HPLC and LCMS analyses showed no remaining starting material. The reaction mixture was concentrated on a rotory evaporator. The product was isolated by prep HPLCMS using a 30 mm×100 mm C18 column, eluting with a solvent gradient; 10% ACN—H2O (0.1% TFA), 1.5 min, to 30% at 6 min; 60 mL/min; detector set at m/z 375; retention time, 4.7 min. The eluate was freeze-dried to yield 11.7 mg of the product TFA salt as a white solid. 1H NMR (d6-DMSO) δ 12.69 (s, 1H, NH); 8.92 (s, 1H); 8.81 (s, 1H); 8.51 (s, 1H); 7.75 (m, 1H); 7.22 (m, 1H); 7.18 (s, 2H, NH2); 3.84 (m, 2H); 3.23 (s, 2H); 2.99 (m, 2H); 2.60 (m, 2H); 1.97 (m, 2H). MS(ES) 375 (M+H).
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][CH2:8][CH:9]1[CH2:12][CH:11]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:10]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][CH:11]1[CH2:10][CH:9]([CH2:8][CH2:7][OH:6])[CH2:12]1
Reactant: CC(C)(C)[Si](OCCC1CC(OC2CCCCO2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCC1CC(OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
Tert-butyl(diphenyl){2-[3-(tetrahydro-2H-pyran-2-yloxy)cyclobutyl]ethoxy}silane (4.66 g, 10.6 mmol) was dissolved in tetrahydrofuran (50 mL) and tetrabutylammonium fluoride (1.0 N in tetrahydrofuran, 1.66 mL, 10.6 mmol). The reaction was stirred at room temperature overnight. The reaction was evaporated in vacuo and purified on silica gel with a heptane-ethyl acetate gradient (10% ethyl acetate, then 50% ethyl acetate) to give 2-[3-(tetrahydro-2H-pyran-2-yloxy)cyclobutyl]ethanol (2.14 g, 100%) as a yellow oil. Partial 1H NMR indicated a ˜4:1 mix of unknown cis-trans isomers. (CDCl3, δ ppm, key peaks are 4.07 (m, 0.80H), 4.35 (m, 0.20H), 4.54 (m, 0.20H), 4.56 (m, 0.80H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[I:12]Cl.O.CO>C(O)(=O)C.C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[I:12]
Reactant: ClI
Reactant: COC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(O)c(I)c1
Temperature: 45 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a 500 mL 3-necked flask equipped with a magnetic stirrer, a thermometer, and a condenser were added 10.0 g of methyl 4-hydroxybenzoate (Aldrich) and 30 mL of glacial acetic acid. To this suspension was added a solution of 11.74 g of iodine monochloride in 30 mL of glacial acetic acid via addition funnel. The solution was heated at 80° C. for 1 h, 45° C. for 18 h, and 90° C. for an additional 4 h. Cooling to RT afforded a thick red-orange suspension which was transferred to a 1 L separatory funnel and dissolved in 500 mL of CHCl3 by shaking vigorously. The dark purple solution was washed with water (2×100 mL), saturated aqueous sodium thiosulfate (2×100 mL), and 5% aqueous NaHCO3 (2×100 mL). A light yellow solution resulted which was dried over MgSO4, and concentrated in vacuo to give a white solid. This material was recystallized from water-MeOH to afford 14.92 g (82%) of methyl 4-hydroxy-3-iodobenzoate as a white crystalline solid, m.p. 145-146° C.