Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12].[CH2:15]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[Cl-].[Na+]>O1CCCC1>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]([S:11]([CH3:14])(=[O:13])=[O:12])[C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([O:29][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:38][CH:37]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CS(=O)(=O)NCc1ccccn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)S(C)(=O)=O)cc1
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a room temperature solution of 0.428 g of washed 50% sodium hydride in 15 ml of dry tetrahydrofuran is added, via cannula, 1.58 g of product from Example 121 dissolved in 20 ml of dry tetrahydrofuran. The mixture is stirred for 2 hours and 3.0 g of product from Example 3 dissolved in 20 ml of dry tetrahydrofuran is added, via cannula. After stirring at room temperature for 30 minutes, the reaction is heated at reflux temperature for 2 hours. The cooled mixture is poured into half saturated sodium chloride and extracted with chloroform. The organic layer is dried and concentrated in vacuo. The residue is purified by chromatography (silica gel: 15-40% ethyl acetate/hexane) to give 3.85 g of the desired product.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[Br:16][CH2:17][C:18](O)=[O:19].[CH3:21][O:22][C:23](=[O:41])[CH:24]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:25][NH:26][CH2:27][C:28]#[CH:29]>C(Cl)Cl.CCOCC>[CH3:21][O:22][C:23](=[O:41])[CH:24]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[CH2:25][N:26]([C:18](=[O:19])[CH2:17][Br:16])[CH2:27][C:28]#[CH:29]
Reactant: C#CCNCC(NC(=O)OCc1ccccc1)C(=O)OC
Reactant: O=C(O)CBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: C#CCN(CC(NC(=O)OCc1ccccc1)C(=O)OC)C(=O)CBr
Reaction time: 8 h
Yield: 47.9 %

Procedure:
DCC (2.27 g, 11.0 mmol) and bromoacetic acid (1.48 g, 10.7 mmol) is added to a solution of 2-benzyloxycarbonylamino-3-(prop-2-ynylamino)-propionic acid methyl ester (3.10 g, 10.7 mmol) in CH2Cl2 at RT. The mixture is stirred overnight then diluted with ether. The white solid which precipitates out is filtered and the filtrate is concentrated to give a yellow oil. The crude product is purified by chromatography eluting with a gradient of 40% EtOAc/hexanes to 50% EtOAc/hexanes to yield the title product (2.1 g, 5.12 mmol) as an oil. 1H NMR (CDCl3, 300 MHz) δ7.30 (m, 5H), 5.70 (d, 1H), 5.10 (s, 2H), 4.63 (m, 1H), 4.15 (d, 2H), 4.00 (m, 1H), 3.80 (s, 3H), 3.75 (s, 2H), 3.70 (dd, 1H), 2.27 (bs, 1H). Ion spray MS, [M+H]+=411, 413, Br pattern.
Reaction SMILES: [C@@H:1]12[O:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[CH2:2]2.[Cl:16][C:17]1[N:18]=[C:19](Cl)[C:20]2[N:25]=[CH:24][S:23][C:21]=2[N:22]=1.CCN(C(C)C)C(C)C>CS(C)=O.O>[C@@H:1]12[O:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:10]=[C:11]([NH:12][C:19]3[C:20]4[N:25]=[CH:24][S:23][C:21]=4[N:22]=[C:17]([Cl:16])[N:18]=3)[CH:13]=[CH:14][CH:15]=1)[CH2:2]2
Reactant: Clc1nc(Cl)c2ncsc2n1
Reactant: Nc1cccc(N2C[C@H]3CC[C@@H](C2)O3)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Clc1nc(Nc2cccc(N3C[C@H]4CC[C@@H](C3)O4)c2)c2ncsc2n1
Temperature: 30 °C
Yield: 84.7 %

Procedure:
The mixture of 3-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)aniline (0.061 g, 0.3 mmol), 5,7-dichlorothiazolo[5,4-d]pyrimidine (0.061 g, 0.3 mmol) and DIPEA (0.046 g, 0.36 mmol) in DMSO (10 mL) was heated to 30° C. for 2 h. Then it was diluted with water and extracted with ethyl acetate (3×10 mL), the organics were dried and concentrated. The residue was purified by column chromatography (silica gel, 200˜300 mesh, eluting with MeOH:DCM=1:80) to afford N-(3-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)-5-chlorothiazolo[5,4-d]pyrimidin-7-amine (0.095 g, 86%) as a yellow solid. LC-MS: 374 [M+H]+, tR=1.66 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH2:11][O:12][CH3:13])[CH:3]=1.CCO.O.[Cl-].[NH4+]>C(OCC)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH2:11][O:12][CH3:13])[CH:3]=1)[NH2:8]
Reactant: COCc1cc(Br)cc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COCc1cc(N)cc(Br)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 62.5 %

Procedure:
To a solution of the product of Step 1 (470 mg, 1.910 mmol) in (EtOH/water) (8.5 mL/4.2 mL) were added iron (533 mg, 9.55 mmol) and ammonium chloride (51 mg, 0.955 mmol). The reaction was stirred at 90° C. for about 4 hours. The reaction was then allowed to come to room temperature and diluted with ethyl acetate. The solution was then filtered through Celite and organic solvent was then removed in vacuo. Flash chromatography (hexane/ethyl acetate: 70/30) was used for purification to afford 3-bromo-5-(methoxymethyl)aniline (258 mg, 1.194 mmol, 62.5% yield). MS ESI: [M+H]+ m/z=216.0.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[C:18]2[N:17]=[C:16]([CH3:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.[H-].[Na+]>CN(C=O)C.CO>[CH2:1]([N:15]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:9])[C:18]=2[N:17]=[C:16]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: Cc1nc2c(Br)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1nc2c(Br)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl chloride (1.527 mL) was added to a solution of 4-bromo-2-methyl-1H-benzimidazole (1.40 g) and sodium hydride (0.531 g) in DMF (10 mL) at 0° C. The mixture was stirred at room temperature under a dry atmosphere for 1 h. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 5%-50% EtOAc in hexane) to give 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (1.88 g) as tan oil. The mixture of 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (496 mg), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (700 mg), Pd(Ph3P)4 (87 mg), sodium carbonate (476 mg) and THF (18 mL)-water (0.90 mL) was heated at 100° C. for 1 h under microwave irradiation. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10%-50% EtOAc in hexane) to give 3-[4-(1-benzyl-2-methyl-1H-benzimidazol-4-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (450 mg) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([Cl:12])[CH:3]=1.Cl.Cl[C:15]1[N:20]=[C:19]([NH:21][C@@H:22]2[CH2:30][C@H:29]3[N:25]([CH2:26][CH2:27][CH2:28]3)[C:24]([CH3:32])([CH3:31])[CH2:23]2)[C:18]([F:33])=[CH:17][N:16]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(O)C>[Cl:12][C:4]1[CH:3]=[C:2]([NH:1][C:15]2[N:20]=[C:19]([NH:21][C@@H:22]3[CH2:30][C@H:29]4[N:25]([CH2:26][CH2:27][CH2:28]4)[C:24]([CH3:31])([CH3:32])[CH2:23]3)[C:18]([F:33])=[CH:17][N:16]=2)[CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8][OH:9]
Reactant: Nc1ccc(OCCO)c(Cl)c1
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CC1(C)C[C@H](Nc2nc(Nc3ccc(OCCO)c(Cl)c3)ncc2F)C[C@@H]2CCCN21
Yield: 71.1 %

Procedure:
The general displacement procedure described herein was used with 2-(4-amino-2-chlorophenoxy)ethan-1-ol (9 mg, 0.05 mmol), (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (16 mg, 0.05 mmol) and pTsOH.H2O (18 mg, 0.1 mmol) in IPA (5 mL) at reflux to give the product (16 mg, 74% yield) as a solid after workup and purification by preparative thin-layer chromatography using DCM/2M NH3 in MeOH as eluent (9:1; 5 preparative TLC plates).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+].CO>C(Cl)Cl.CCN(CC)CC>[N:19]1([CH2:18][CH2:17][N:13]([CH2:14][CH2:15][CH3:16])[CH:9]2[CH2:10][C:11]3[CH:12]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]=3[CH2:7][CH2:8]2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: CCCN(CCN1CCNCC1)C1CCc2ccc(OC)cc2C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCN(CCN1CCNCC1)C1CCc2ccc(O)cc2C1
Temperature: -78 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
Compound 38a (3.21 g, 9.70 mmol) was dissolved in 120 ml of CH2Cl2 and cooled to −78° C. 1M boron tribromide (30 ml) was added dropwise and the mixture was allowed to warm to ambient temperature and was stirred overnight. Sat. NaHCO3 was added and the product extracted with dichloromethane, dried (Na2SO4), filtered, and concentrated to yield the crude product. Column chromatography (7:3:1 CH2Cl2:MeOH:Et3N) afforded 2.41 g (84%) of 39a. 1H NMR (400 MHz, CDCl3) 0.98-1.02 (t, 3H, 7.6 Hz), 1.27-1.31 (m, 2H), 1.70-1.82 (m, 3H), 2.25-2.28 (m, 1H), 2.58-2.06 (m, 1H), 2.73-2.78 (m, 4H), 2.97-3.09 (m, 5H), 3.16-3.20 (m, 9H), 6.45 (s, 1H), 6.53-6.55 (d, 1H, J=9.2 Hz), 6.84-6.85 (d, 1H, J=8.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH4+].[OH-]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[OH:24])[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: Nc1ccc(F)cc1O
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Temperature: 120 °C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (2.43 g), 2-amino-5-fluorophenol (2.43 g) and p-toluenesulfonic acid (190.0 mg) were dissolved in dioxane (50.0 ml) and heated at 120° C. for 4 h under nitrogen. The reaction mixture was allowed to cool and treated with 3M NH4OH. The resultant suspension was filtered, the solid was washed with ether and dried in vacuo at 60° C. over P2O5.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:13])[C:10](C)=[CH2:11].C(OCC)(=O)C(C)=C.C(O)(=O)C(C)=C>C1(C)C=CC=CC=1>[CH3:5][CH2:6][CH2:7][CH2:8][CH:3]([CH2:4][O:14][C:9]([CH:10]=[CH2:11])=[O:13])[CH2:2][CH3:1].[CH3:18][CH2:17][CH2:16][CH2:15][O:14][C:9]([CH:10]=[CH2:11])=[O:13]
Reactant: C=Cc1ccccc1
Reactant: C=C(C)C(=O)OCCCC
Agent: C=C(C)C(=O)O
Agent: C=C(C)C(=O)OCC
Solvent: Cc1ccccc1
Product: C=CC(=O)OCC(CC)CCCC
Product: C=CC(=O)OCCCC
Temperature: 110 °C
Reaction time: 2 h

Procedure:
An acrylic copolymer resin was prepared by feeding 150 parts of toluene into a 500-ml 4-necked flask equipped with a cooling tube, stirrer, and thermometer, heating it to 110° C., adding styrene 20 parts, n-butyl methacrylate 60 parts, ethyl methacrylate 120 parts, methacrylic acid 14 parts, azoisobutyronitrile 5 parts and toluene 70 parts spending 2 hours under an inert gas atmosphere, and heating for further 6 hours. The resulting toluene solution of copolymer was found to have 50.5% of nonvolatile matter and a polymer acid value of 18.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10]C(=O)C(F)(F)F)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18].[NH4+].[OH-]>OS(O)(=O)=O>[C:1]([C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][C:9]=1[N+:17]([O-:19])=[O:18])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1cccc(NC(=O)C(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CC(=O)c1cc(N)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
10 mmol of 3-acetyl-trifluoroacetylaminobenzene as a starting material was slowly added dropwise to 20 mL of concentrated H2SO4 at −20° C. and the reaction mixture was stirred 30 minutes. Then, nitric acid was slowly added dropwise thereto over 10 minutes. The reaction mixture was continuously stirred for 2 hours. When the reaction was completed, ice water was poured into the reaction mixture. The reaction mixture was extracted twice with 50 mL of ethyl acetate. The organic layer was washed with a solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The ethyl acetate was then distilled off under reduced pressure to give an impure product. The impure produce was added to concentrated NH4OH and stirred at 50° C. for 1 hour. The reaction mixture was evaporated on a rotary evaporator and extracted with EtOAc and water, and purified by silica gel column chromatography (hexane/EtOAc=3/1) to obtain the desired 3-acetyl-4-nitro-aminobenzene as a brown solid (54%).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11][C:12]#N)[C:8]([S:14][CH3:15])=[CH:7][C:5]=2[N:6]=1.[OH-:16].[Na+].[BH4-].[Na+].IC>C(O)C.O>[CH3:2][S:3][C:4]1[CH:10]=[C:9]([S:11][CH3:12])[C:8]([S:14][CH3:15])=[CH:7][C:5]=1[NH2:6].[CH2:10]([OH:16])[CH3:4]
Reactant: [OH-]
Reactant: CSc1cc2nc(N)sc2cc1SC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CI
Solvent: O
Product: CSc1cc(SC)c(SC)cc1N
Temperature: 25 °C

Procedure:
2,4,5-Trimethylthioaniline was prepared by combining 2-amino-5-methylthio-6-thiocyanatobenzothiazole (220 g, 0.87 mol) with 1.2 L of water, 1.0 L of 50% sodium hydroxide solution, and sodium borohydride (40 g, 1.06 mol) in a 5 L, 3-necked flask. The mixture was stirred with a mechanical stirrer and refluxed under a nitrogen atmosphere for 15 hr. The mixture was cooled to room temperature and ethanol (800 mL) was added followed by addition of iodomethane (300 g, 2.11 mole). The solution was collected and dried. The product was recrystallized from ethanol (66 g, 33% yield).
Reaction SMILES: CP(C1C=CC(N)=C(S(C(C)C)(=O)=O)C=1)(C)=O.ClC1N=C(Cl)C(Cl)=CN=1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([P:41]([CH3:44])([CH3:43])=[O:42])=[CH:37][C:36]=2[S:45]([CH:48]([CH3:50])[CH3:49])(=[O:47])=[O:46])[C:31]([Cl:51])=[CH:30][N:29]=1.[N:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[N:58]1[CH2:63][CH2:62][N:61]([C:64]2[O:68][C:67]([NH2:69])=[N:66][N:65]=2)[CH2:60][CH2:59]1>>[Cl:51][C:31]1[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([P:41]([CH3:44])([CH3:43])=[O:42])=[CH:37][C:36]=2[S:45]([CH:48]([CH3:50])[CH3:49])(=[O:47])=[O:46])=[N:33][C:28]([NH:69][C:67]2[O:68][C:64]([N:61]3[CH2:60][CH2:59][N:58]([C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][N:52]=4)[CH2:63][CH2:62]3)=[N:65][N:66]=2)=[N:29][CH:30]=1
Reactant: Nc1nnc(N2CCN(c3ccccn3)CC2)o1
Reactant: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(Cl)ncc1Cl
Agent: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1N
Agent: Clc1ncc(Cl)c(Cl)n1
Product: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(Nc2nnc(N3CCN(c4ccccn4)CC3)o2)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline with 2,4,5-trichloropyrimidine to generate 2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine. 2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine is then reacted with 5-[4-(pyridin-2-yl)piperazin-1-yl]-1,3,4-oxadiazol-2-amine according to the procedure described in Example 32.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([N:11]3[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:20])[OH:19])[CH2:12]3)=[C:5]2[NH:4][C:3]1=[O:21].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]>>[C:24]([O:20][C:18](=[O:19])[NH:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:10]2[CH:9]=[CH:8][N:7]=[C:6]3[N:2]([CH3:1])[C:3](=[O:21])[N:4]([CH2:23][C:24]4[CH:31]=[CH:30][CH:29]=[C:26]([C:27]#[N:28])[CH:25]=4)[C:5]=23)[CH2:12]1)([CH3:25])([CH3:31])[CH3:23]
Reactant: Cn1c(=O)[nH]c2c(N3CCC[C@@H](NC(=O)O)C3)ccnc21
Reactant: N#Cc1cccc(CBr)c1
Product: Cn1c(=O)n(Cc2cccc(C#N)c2)c2c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccnc21
Yield: 105.2 %

Procedure:
The specific operation referred to the step (5) described in Example 1 for details. 347 mg (R)-1-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)piperidin-3-yl carbamic acid ter.-butyl ester (1 mmol) and 235 mg 3-(bromomethyl)benzonitrile (1.2 mmol) were charged. A column chromatography was performed to afford 292 mg titled product with a yield of 63.2%.
Reaction SMILES: [F:1][C:2](=[C:6]([F:8])[F:7])[CH2:3][CH2:4][OH:5].CC(C)=[O:11].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[F:1][C:2](=[C:6]([F:8])[F:7])[CH2:3][C:4]([OH:11])=[O:5]
Reactant: OCCC(F)=C(F)F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CC(F)=C(F)F

Procedure:
The first method involves hydrolysis of 4-bromo-1,1,2-trifluoro-1-butene (H) with water in the presence of N-methyl pyrrolidinone to give 3,4,4-trifluoro-3-buten-1-ol (III), followed by Jones oxidation under conditions not previously known. These conditions are at a temperature of about 51°-54° C. In addition, the 3,4,4-trifluoro-3-buten-1-ol in acetone solvent and the Jones reagent are added to the reaction vessel simultaneously to afford 3,4,4-trifluoro-3-butenoic (IV) add in 52% overall yield. ##STR4## Method 2, Scheme 1, Compound IV
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-])=O)[C:5]([F:12])=[C:4]([Cl:13])[C:3]=1[OH:14].[H][H]>CO.[Ni]>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH2:9])[C:5]([F:12])=[C:4]([Cl:13])[C:3]=1[OH:14]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1c(F)c(Cl)c(O)c(Cl)c1F
Agent: [Ni]
Solvent: CO
Product: Nc1c(F)c(Cl)c(O)c(Cl)c1F

Procedure:
18 g of 2,6-dichloro-3,5-difluoro-4-nitrophenol are hydrogenated in 100 ml of methanol in the presence of 1.5 g of Raney nickel at 25°-45° C. using 30-50 bar of hydrogen until the take-up of hydrogen is complete. After filtration, the solution is freed from solvent under recuced pressure. 13 g of aminophenol (GC purity 98.4%) remain; m.p. 151° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[CH3:16])[CH:5]=[CH:4][N:3]=1.[N:17]1[N:18]=[CH:19][CH2:20][CH:21]=1.[C:22]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.CCOC(C)=O.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>[CH3:16][C:10]1[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:20]2[CH:21]=[N:17][N:18]([CH3:22])[CH:19]=2)[CH:7]=1
Reactant: C1=NN=CC1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(N)ccc1Oc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(N)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 90 °C
Yield: 88.1 %

Procedure:
A solution of 4-(2-chloropyridin-4-yloxy)-3-methylbenzenamine (595 mg, 2.54 mmol), 1-methyl-4-(4,4,5,5-tetramethyl)-[1,3,2]dioxaborolan-2-yl)-4H-pyrazole (790 mg, 3.80 mmol) and Cs2CO3 (2.53 g, 7.77 mmol) in 10 mL of DMF (10 mL) and water (3 mL) was de-gassed under vacuum and blanketed with nitrogen. Pd(PPh3)4 (295 mg, 0.26 mmol) was added and the reaction mixture was heated to 90° C. overnight. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (2×10 mL) and brine (2×10 mL). The aqueous portion was extracted with EtOAc (2×15 mL) and the combined organics were washed with brine (10 mL), concentrated in vacuo and purified on silica gel to provide 3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine as a pale yellow colored foam (627 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.27 (d, J=6.0 Hz, 1H), 8.18 (s, 1H), 7.90 (d, J=0.7 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 6.49 (d, J=2.5 Hz, 1H), 6.46-6.40 (m, 2H), 5.02 (s, 2H), 3.84 (s, 3H), 1.94 (s, 3H); MS (ESI) m/z: 281.2 (M+H+).
Reaction SMILES: CO[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][C:6](=O)[CH2:7][O:8]2.Cl.NCCCCN1C(=[O:30])CC2(CCCC2)CC1=O>C(O)C>[CH:12]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][CH2:6][C:5](=[O:30])[C:4]=2[CH:3]=1
Reactant: NCCCCN1C(=O)CC2(CCCC2)CC1=O
Reactant: COc1cccc2c1CC(=O)CO2
Agent: Cl
Solvent: CCO
Product: O=C1CCOc2ccccc21

Procedure:
0.04 mole of 5-methoxychroman-3-one is dissolved in 10 ml of ethanol. At the same time, 1 g of N-(4-aminobutyl)-8-azaspiro[4.5]decane 7,9-dione hydrochloride is dissolved in 10 ml of ethanol, and the solution of chromanone obtained above is added to this solution. 0.16 g of sodium hydroxide in solution in 10 ml of ethanol is then added thereto. The mixture is stirred for one hour at ambient temperature, filtered and placed in a hydrogenating apparatus. 0.5 g of palladized carbon is added, the apparatus is purged with nitrogen and then with hydrogen, and the mixture is hydrogenated at ambient temperature and pressure. The mixture is filtered and the filtrate is evaporated to dryness. The residue is taken up in ethyl acetate and gaseous hydrochloric acid is added thereto. The mixture is allowed to precipitate and is drained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C@H:24]1[C@H:29]([CH2:30][CH:31]=[CH2:32])[CH2:28][CH2:27][C:26](=[O:33])[CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34](O)[CH2:35][OH:36].C1(C)C=CC(S(=O)=O)=CC=1.[OH-].[Na+]>CCCCC.CCOCC.C1C=CC=CC=1>[CH2:35]1[O:36][C:26]2([CH2:27][CH2:28][C@@H:29]([CH2:30][CH:31]=[CH2:32])[C@H:24]([C:10]3[CH:11]=[CH:12][C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:25]2)[O:33][CH2:34]1
Reactant: C=CC[C@@H]1CCC(=O)C[C@H]1c1ccc(C(C)(C)CCCCCC)cc1OCc1ccccc1
Reactant: OCCO
Agent: Cc1ccc([SH](=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CCCCC
Product: C=CC[C@@H]1CCC2(C[C@H]1c1ccc(C(C)(C)CCCCCC)cc1OCc1ccccc1)OCCO2

Procedure:
A mixture of 17.0 g. (38.1 mmoles) of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(2-propenyl)cyclohexanone, 47.2 g. (0.762 mole) ethylene glycol and 250 mg. of p-toluenesulfonic acid monohydride in 200 ml. of benzene was heated at reflux for 3 hours with a Dean-Stark trap. The reaction was cooled and added to 200 ml. 1 N sodium hydroxide, 100 ml. ether and 100 ml. pentane. The organic extract was washed twice with 200 ml. portions of water, twice with 200 ml. portions of saturated sodium chloride, dried over magnesium sulfate and evaporated (aspirator) giving a quantitative yield of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH2:14])[CH2:6][C:7]([F:13])([F:12])[CH2:8][CH:9]([CH3:11])[CH3:10].C(NC(C)C)(C)C.[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>ClCCl>[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH:14][C:29]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:30])[CH2:6][C:7]([F:13])([F:12])[CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(=O)[C@@H](N)CC(F)(F)CC(C)C
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COC(=O)[C@H](CC(F)(F)CC(C)C)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 65.9 %

Procedure:
To a mixture of (S)-2-amino-4,4-difluoro-6-methyl-heptanoic acid methyl ester hydrochloride (238 mg, 0.97 mmol) and diisopropyl amine (2.42 mmol, 313 mg) in dry dichloromethane (5 mL) under N2 is added drop wise morpholine carbonyl chloride (1.45 mmol, 218 mg). The mixture is stirred at room temperature for 23 h, then diluted with dichloromethane (25 mL) and washed with dilute HCl (30 mL), and saturated NaHCO3 (30 mL). The organic layers are dried over magnesium sulfate and concentrated in vacuum. Purification over 12 g silica gel, eluting with EtOAc:Heptane (1:1, then 2:1) affords (S)-4,4-Difluoro-6-methyl-2-[(morpholine-4-carbonyl)-amino]-heptanoic acid methyl ester (206 mg, 66%).