Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([OH:15])=O)=O)(C)(C)C.C1C=CC(/C(/C2C=CC([N+]([O-])=O)=CC=2)=N/O)=CC=1.[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.[CH3:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH2:57][NH2:58]>>[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40]([N:8]2[CH2:12][CH2:11][S:10][CH:9]2[C:13]([NH:58][CH2:57][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=2[CH3:50])=[O:15])(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)O
Reactant: Cc1ccccc1CN
Agent: O=[N+]([O-])c1ccc(/C(=N\O)c2ccccc2)cc1
Product: Cc1ccccc1CNC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-biphenyl-4-sulfonyl chloride and (2-methylphenyl)methanamine, the title compound was obtained in 99% purity by HPLC.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][C:14]([CH3:17])([O-:16])[CH3:15].[K+]>C1(C)C=CC=CC=1>[C:14]([O:16][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1)([CH3:17])([CH3:15])[CH3:13]
Reactant: Clc1cc2ccccc2c(Cl)n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1nc(Cl)cc2ccccc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
1.0 g (5.05 mmol) of 1,3-dichloroisoquinoline from example 16.2 was dissolved in 20 ml of dry toluene, admixed with 0.68 g (6.06 mmol) of potassium tert-butoxide and stirred at 80° C. for 3 h. After the mixture had been cooled, it was filtered together with 50 ml of dichloromethane through a short silica gel column (1×5 cm) and the solvent was removed under reduced pressure. 1.06 g (4.50 mmol, 89.1%) of 1-t-butoxy-3-chloroisoquinoline were obtained.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[O:10].[CH2:14]([O:16][CH2:17][CH2:18]O)[CH3:15]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:8]([O:13][CH2:15][CH2:14][O:16][CH2:17][CH3:18])(=[O:12])[C:9]([CH3:11])=[O:10]
Reactant: CCOCCO
Reactant: CC(=O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOCCOC(=O)C(C)=O
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A toluene solution (1 L) contaning pyruvic acid (440 g, 5.0 mol), 2-ethoxyethanol (450 g, 5.0 mol) and p-toluenesulfonic acid monohydrate (2.5 g) was heated and refluxed for 16 hours under nitrogen flow. The reaction led to generation of water in the system. However, the water was removed using Dean-Stark trap. The resultant reaction solution was cooled down to room temperature, followed by removal of toluene using an evaporator under a reduced pressure. The residual was then purified using reduced pressure distillation (40 mmHg, 100 to 105° C.) to give 2-ethoxyethyl pyruvate (544 g, yield: 68%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[C:17]([O-:20])(O)=[O:18].[Na+]>C(Cl)Cl.O.CCOC(C)=O>[CH2:2]([O:4][C:5](=[O:16])[C@H:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[NH:7][C:17]([O:20][C:9]([CH3:14])([CH3:10])[CH3:8])=[O:18])[CH3:3]
Reactant: O=C([O-])O
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 180.9 %

Procedure:
To a mixture of L-tyrosine ethyl ester hydrochloride (55.08 g) and NaHCO3 (22.52 g) in CH2Cl2/H2O (280 ml/280 ml) was added di-tert-butyl bicarbonate (56.82 g) portionwise. The mixture was stirred for 2 hours at room temperature and diluted with AcOEt. The organic layer was washed with H2O, dried (Na2SO4) and evaporated. The residue was recrystallized from a mixture of diethyl ether and hexane to yield N-(tert-butoxycarbonyl)-L-tyrosine ethyl ester (62.71 g). mp. 87-88° C.; MS(APCI) m/z 327(M+NH4), 310(M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(OC)cc1[N+](=O)[O-]

Procedure:
A mixture of 4-methoxy-2-nitrophenol 6 (1.69 g, 0.01 mol), potassium carbonate (2.76 g, 0.02 mol) and ethyl bromoacetate 7 (1.1 mL, 0.01 mol) in 20 mL anhydrous acetone was refluxed for overnight (12 h). The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was evaporated, the residue was diluted with water and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated to give ethyl 2-(4-methoxy-2-nitrophenoxy)acetate 8 which was purified by silica gel column chromatography using 0-50% gradient of hexane and ethyl acetate. Yellow solid (2.18 g, 85%). 1H NMR (400 MHz, CDCl3): δ 1.28 (t, J=7.2 Hz, 3H); 3.82 (s, 3H); 4.25 (q, J=7.2 Hz, 2H); 4.70 (s, 2H); 7.01 (d, J=9.2 Hz, 1H); 7.08 (dd, J=3.2, 9.2 Hz, 1H); 7.40 (d, J=2.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][CH3:22])=[C:4]([NH:8][C:9]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])=S)[CH:5]=[CH:6][CH:7]=1>C(#N)C.C(OCC)(=O)C.[Hg](Cl)Cl>[C:13]1([CH3:20])[CH:14]=[C:15]([CH3:19])[CH:16]=[C:17]([CH3:18])[C:12]=1[NH:11][C:9]1[N:21]([CH3:22])[C:3]2[C:2]([NH2:1])=[CH:7][CH:6]=[CH:5][C:4]=2[N:8]=1
Reactant: CNc1c(N)cccc1NC(=S)Nc1c(C)cc(C)cc1C
Agent: Cl[Hg]Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(Nc2nc3cccc(N)c3n2C)c(C)c1
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a solution containing 0.25 g (0.79 mmol) of 1-(3-amino-2-methylaminophenyl)-3-mesitylthiourea in acetonitrile was added 0.52 g (1.6 mmol) of mercury (II) chloride, and the mixture stirred for 1 h. The reaction mixture was diluted with ethyl acetate (2 ml) and filtered through a prepacked celite column. The filtrate was concentrated under reduced pressure and the residue purified via Biotage chromatography eluting with 20% ethyl acetate/dichloromethane to afford 0.12 g (55%) of product.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[C@@:10]([OH:19])([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:3].CN(C[C@H]1[C@](O)(C2C=CC=C(OC)C=2)CCCC1)C>CCO>[CH3:3][N:2]([CH2:4][C@@H:5]1[C@@:10]([OH:19])([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:1]
Reactant: COc1cccc([C@@]2(O)CCCC[C@@H]2CN(C)C)c1
Agent: COc1cccc([C@]2(O)CCCC[C@H]2CN(C)C)c1
Solvent: CCO
Product: CN(C)C[C@H]1CCCC[C@]1(O)c1cccc(O)c1

Procedure:
To prepare the (+) enantiomer of the title compound, the reaction was run under the same conditions except that (+)-tramadol as the free base was used instead of the (-)-tramadol to yield 2.8 g of the (+) enantiomer of O-desmethyl tramadol (mp. 242°-3° C.) [α]D25 =+32.2 (C=1, EtOH).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Cl.Cl[CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:18]1([CH2:17][CH2:16][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccnc(-c2cn(CCN3CCCC3)cn2)c1
Temperature: 90 °C

Procedure:
A mixture of 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (20 mg, 0.12 mmol), 1-(2-chloroethyl)pyrrolidine hydrogen chloride (34 mg, 0.2 mmol) and cesium carbonate (130 mg, 0.4 mmol) in 2 mL DMF was heated at 90° C. for 2 hr. The reaction mixture was purified by ISCO flash column chromatography (MeOH/DCM=0-100%). [M+H] Calc'd for C15H17N5, 268. Found, 268.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])=[CH:8][CH:7]=1.[OH-:22].[K+].[BH4-].[Na+].[CH3:26]O>>[CH3:26][O:22][C:2]([CH3:1])([CH3:21])[CH2:3][CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])=[CH:8][CH:7]=1
Reactant: [OH-]
Reactant: CO
Reactant: CCOC(=O)NCCOc1ccc(OCC=C(C)C)cc1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Product: CCOC(=O)NCCOc1ccc(OCCC(C)(C)OC)cc1
Reaction time: 1 h

Procedure:
To ethyl N-{2-[4-(3-methyl-2-butenoxy)phenoxy]ethyl}-carbamate (0.60 g, 2.05 mmol) in methanol (7 ml) at ~40° is added mercuric acetate (0.67 g, 2.1 mmol) in methanol (8 ml) over 10 min. The mixture is stirred at 5° for 1 hour, then at 10°-15° for 30 min. Additional mercuric acetate (0.13 g, 0.41 mol) in methanol is added, and the mixture is allowed to stand at RT overnight. The mixture is then cooled to 3° and potassium hydroxide (0.57 g, 10.2 mmol) in methanol (4 ml) is added over 5 min., followed by addition of sodium borohydride (0.039 g, 1.02 mmol) in portions over 10 min. The resulting slurry is stirred at 3-5° for 45 min. Celite is added to the reaction mixture and the mercury is filtered off. Methanol is removed by rotoevaporation and ether and water are added to the residue. Following extraction with ether (3X), the ether extracts are combined and washed with water until neutral and with brine and dried over calcium sulfate. The crude product is filtered, rotoevaporated and purified by prep. TLC to yield ethyl N-{2-[4-(3-methoxy-3-methylbutoxy)phenoxy]ethyl }carbamate (compound 12, Table A).
Reaction SMILES: [N+:1]([CH:4]=[C:5]([S:11][CH3:12])[NH:6][CH2:7][CH2:8][CH2:9]Br)([O-:3])=[O:2].[H-].[Na+]>O1CCCC1>[CH3:12][S:11][C:5]1[NH:6][CH2:7][CH2:8][CH2:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC1=C([N+](=O)[O-])CCCN1
Yield: 28.7 %

Procedure:
A mixture of 1-nitro-2-methylthio-2-(3-bromopropylamino)ethylene (3.2 g, 0.012 mol) and sodium hydride (50% in oil, 0.9 g, 0.019 mol) in dry tetrahydrofuran (50 ml) was refluxed for 18 hours. The mixture was filtered, and the filtrate was evaporated to dryness. The residue was chromatograped on a silica gel column, the product being eluted with ethyl acetate. Recrystallisation of the product from methanol/propan-2-ol gave 2-methylthio-3-nitro-1,4,5,6-tetrahydropyridine (0.6 g, 29%) m.p. 230.5°-231.5°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@@:8]2([CH3:32])[N:17](CC3C=CC(OC)=CC=3OC)[C:16](=[O:29])[C:11]3([CH2:15][CH:14]=[CH:13][CH2:12]3)[S:10](=[O:31])(=[O:30])[CH2:9]2)[CH:7]=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@@:8]2([CH3:32])[NH:17][C:16](=[O:29])[C:11]3([CH2:12][CH:13]=[CH:14][CH2:15]3)[S:10](=[O:31])(=[O:30])[CH2:9]2)[CH:7]=1
Reactant: COc1ccc(CN2C(=O)C3(CC=CC3)S(=O)(=O)C[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CC=CC2)C(=O)N1
Temperature: 23 °C
Yield: 94.3 %

Procedure:
A mixture of (R)-8-(5-bromo-2-fluoro-phenyl)-9-(2,4-dimethoxy-benzyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-2-en-10-one (450 mg, 836 μmol, Eq: 1.00) and trifluoroacetic acid (9.53 g, 6.44 ml, 83.6 mmol, Eq: 100) was stirred at 23° C. After 1 hour trifluoromethanesulfonic acid (251 mg, 148 μl, 1.67 mmol, Eq: 2.0) was added and the dark red solution was stirred for 2 hours. Poured into 1 M Na2CO3-sol. and extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was chromatographed on 10 g silica gel with heptane/ethyl acetate 1:1 to give (R)-8-(5-bromo-2-fluoro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-2-en-10-one (340 mg, 788 μmol, 94.3% yield) as a white solid. MS (ISP): m/z=388.1 [M+H]+ and 390.2 [M+2+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[NH:9])=[CH:6][CH:5]=1.C(O)(=O)C.[CH:17]([NH2:19])=[NH:18].NN.ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(#N)C>[N:18]1[CH:17]=[N:19][N:10]=[C:8]([C:7]2[CH:11]=[CH:12][C:4]([NH2:3])=[CH:5][CH:6]=2)[N:9]=1
Reactant: N=CN
Reactant: N=C(N)c1ccc(N)cc1
Agent: Cl
Agent: NN
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC#N
Solvent: CC(=O)O
Product: Nc1ccc(-c2nncnn2)cc1
Yield: 19.1 %

Procedure:
To a mixture of 4-Aminobenzamidine dihydrochloride (1 mmol, 208 mg) and formamidine acetate (4 mmol, 416 mg) in acetonitrile (25 mL) was added anhydrous hydrazine (10 mmol, 315 uL). The solution was heated to reflux for 1 hour, cooled, and the solvent was removed by rotary evaporation. The residue was resuspended with water (25 mL) and was stirred with solid tetrachloro-1,4-benzoquinone (2 mmol, 492 mg) for 1 hour. After removal of the solids from the pink solution by filtration, the reaction was concentrated by rotary evaporation and purified by preparative HPLC using a gradient from 0-40% buffer B (buffer A is water with 0.1% TFA, and buffer B is acetonitrile with 10% water and 0.1% TFA) to afford pure 4-(1,2,4,5-tetrazin-3-yl)aniline (33 mg, 19%), as a pink solid. LRMS-ESI [M+H]+ calcd. for C8H8N5+: 174.08, found: 173.9.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([C:16]([OH:54])([CH3:53])[CH2:17][O:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][CH:52]=[C:26]34)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1>C(OCC)(=O)C>[CH:13]1([C:16]([OH:54])([CH3:53])[CH2:17][O:18][C@H:19]2[CH2:20][CH2:21][C@H:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:45]5[NH:3][C:4](=[O:7])[O:5][N:46]=5)=[CH:37][CH:38]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][CH:52]=[C:26]34)[CH2:23][CH2:24]2)[CH2:14][CH2:15]1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(O)C3CC3)CC2)c2ccnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(O)C3CC3)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.33 g), sodium hydrogen carbonate (0.49 g) and dimethyl sulfoxide (2 mL) was stirred at 50° C. for 30 min, 4′-({4-[trans-4-(2-cyclopropyl-2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.22 g) was added, and the mixture was stirred at 90° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.076 g) and then with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.070 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.13 g, 52%).
Reaction SMILES: B.[Cl:2][C:3]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:4]=1[O:5][CH:6]([CH3:10])[C:7](O)=[O:8].Cl>O1CCCC1.CO>[Cl:2][C:3]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:4]=1[O:5][CH:6]([CH3:10])[CH2:7][OH:8]
Reactant: CC(Oc1ccc(Cl)cc1Cl)C(=O)O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(CO)Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 100.1 %

Procedure:
43 ml of a 1M solution of borane in tetrahydrofuran (THF) were stirred under nitrogen and cooled in ice while a solution of 6.8 g of 2-(2,4-dichlorophenoxy)propionic acid in 40 ml of THF was added dropwise thereto. The mixture was heated to boiling under reflux for 1 hour and then cooled to room temperature. 22 ml of a saturated solution of hydrogen chloride in methanol were added dropwise and the solution was heated to boiling under reflux for 1 hour. The mixture was evaporated and the residue was treated with 22 ml of a saturated solution of hydrogen chloride in methanol. After heating under reflux for 1 hour the mixture was evaporated and the residue was partitioned between 100 ml of saturated sodium bicarbonate solution and 100 ml of methylene chloride. The layers were separated and the aqueous layer was extracted with 100 ml of methylene chloride. The combined organic extracts were dried over sodium sulphate and evaporated to gave 6.4 g of 2-(2,4-dichlorophenoxy)propanol as a yellow oil.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[NH:30]1[C:38]2[C:33](=[CH:34][C:35]([OH:39])=[CH:36][CH:37]=2)[CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:39][C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:30]([C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=1)=[O:29])[CH2:31][CH2:32]2
Reactant: Oc1ccc2c(c1)CCN2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2cc(O)ccc21

Procedure:
0.15 g (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 50 mg (0.37 mmol) 2,3-dihydro-1H-indol-5-ol, 150 μL (0.87 mmol) DI PEA and 0.13 g (0.41 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])/[CH:5]=[CH:6]/[CH:7]=[O:8])[CH3:2].[N+](C1C=CC=CC=1C(O)=O)([O-])=O.N1CCCC1.[OH:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([O:38][CH3:39])[C:29]=1[CH:30]=O>CS(C)=O>[CH2:1]([O:3][C:4]([CH:5]1[C:6]([CH:7]=[O:8])=[CH:30][C:29]2[C:28](=[C:35]([O:36][CH3:37])[CH:34]=[CH:33][C:32]=2[O:38][CH3:39])[O:27]1)=[O:9])[CH3:2]
Reactant: COc1ccc(OC)c(C=O)c1O
Reactant: CCOC(=O)/C=C/C=O
Agent: O=C(O)c1ccccc1[N+](=O)[O-]
Solvent: C1CCNC1
Solvent: CS(C)=O
Product: CCOC(=O)C1Oc2c(OC)ccc(OC)c2C=C1C=O
Temperature: 25 °C
Reaction time: 78 h
Yield: 21.8 %

Procedure:
(E)-4-oxo-but-2-enoic acid ethyl ester (7.30 mL, 60.37 mmol), 2-nitro benzoic acid (1.852 g, 10.98 mmol), and pyrrolidine (0.91 mL, 10.98 mmol) were added simultaneously to a solution of commercially available 2-hydroxy-3,6-dimethoxy-benzaldehyde (10.0 g, 54.89 mmol) in dimethysulfoxide (50 mL) at 25° C. and the solution was stirred for 78 hours at 25° C. The reaction was quenched by the addition of water. The reaction mixture was then partitioned between water and ethyl acetate. The combined organics were washed with a saturated brine solution, dried over anhydrous sodium sulfate, filtered, rinsed and concentrated in vacuo. The residue obtained was purified on a silica gel flash column chromatography using ethyl acetate-hexanes (1:1.2) as eluents, yielding 3-formyl-5,8-dimethoxy-2H-chromene-2-carboxylic acid ethyl ester (3.5 g, 62.3%).
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[N:8]([CH2:9][CH3:10])[N:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:5]=1[CH:15]=[O:16].O.C(OCC)(=O)C>CS(C)=O>[CH2:9]([N:8]1[C:4]([F:1])=[C:5]([CH:15]=[O:16])[C:6]([C:11]([F:14])([F:13])[F:12])=[N:7]1)[CH3:10]
Reactant: CCn1nc(C(F)(F)F)c(C=O)c1Cl
Reactant: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCn1nc(C(F)(F)F)c(C=O)c1F
Temperature: 100 °C
Reaction time: 72 h
Yield: 26.8 %

Procedure:
34.3 g (591.3 mmoles) of potassium fluoride (a spray-dried product) was added, at room temperature, into a solution of a crude product of 5-chloro-1-ethyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde (equivalent to 197.1 mmoles) dissolved in 100 ml of dimethyl sulfoxide. The mixture was stirred at 100° C. for 3 days to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 11.1 g (yield: 26.8%) of 1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:11]([CH3:12])[CH2:10][C:9](=[O:13])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:14][C:15]([F:35])([F:34])[C:16]1[N:17]=[C:18]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[N:19]([CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:20]=1.C(N(CC)CC)C>CN1CCCC1=O>[CH3:12][C@H:11]1[C:3]2[C:2]([N:31]3[CH2:30][CH2:29][CH:28]([C:18]4[N:19]([CH2:21][CH2:22][N:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[CH:20]=[C:16]([C:15]([F:34])([F:35])[F:14])[N:17]=4)[CH2:33][CH2:32]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9](=[O:13])[CH2:10]1
Reactant: C[C@@H]1CC(=O)Nc2ncnc(Cl)c21
Reactant: FC(F)(F)c1cn(CCN2CCCC2)c(C2CCNCC2)n1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CC(=O)Nc2ncnc(N3CCC(c4nc(C(F)(F)F)cn4CCN4CCCC4)CC3)c21
Temperature: 130 °C
Yield: 70.2 %

Procedure:
Add (R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (28.30 g, 143.20 mmol), 4-(4-trifluoromethyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine (49.83 g, 1.10 eq) and triethylamine (43.47 g, 3.0 eq) in N-methylpyrrolidinone (86 mL). Heat the reaction mixture to 130° C. Cool the reaction mixture to room temperature after 2 hours. Pour the reaction mixture over ice/water (500 mL) with stirring. Extract with ethyl acetate (4×200 mL). Wash the organics with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate and concentrate in vacuo. Suspend the solid in hexanes and stir for 30 minutes. Filter and dry under vacuum. Add 75% methyl tert-butyl ether in hexanes (800 mL) and heat to reflux. Cool the mixture to room temperature. Filter, wash with 75% methyl tert-butyl ether in hexanes (200 mL), and dry under vacuum at 40° C. to give the title compound (48.00 g, 70%). MS (ES) m/z=478 [M]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]([CH3:25])=[CH:16][CH:17]=[CH:18][C:19]([CH3:24])=[CH:20][C:21]([OH:23])=[O:22])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([C:5]1[CH:6]=[C:7]([CH:15]([CH3:25])[CH2:16]/[CH:17]=[CH:18]/[C:19](/[CH3:24])=[CH:20]/[C:21]([OH:23])=[O:22])[CH:8]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C=CC=C(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1)=CC(=O)O
Solvent: CO
Product: CC(/C=C/CC(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1)=C\C(=O)O

Procedure:
Compound 14 was prepared from 13 in a similar manner as described for compound 9: TLC (10% MeOH-90% CHCl3) Rf 0.5; mp 127°-128° C.; 1H-NMR (CDCl3) δ1.28 (d, J=8 Hz, 3H, CH3), 1.32 (s, 18H, 6(CH3)), 2.23, (s, 3H, CH3), 2.46 (m, 2H, CH2), 2.86 (m, 1H, CH), 5.69 (s, 1H, =CH), 6.10 (m, 2H, =CH), 7.01 (d, J=1 Hz, 2H, Ar-H), 7.26 (t, J=I Hz, 1H, Ar-H).