Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[F-].[Cs+].O>COCCOC.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>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 85 °C

Procedure:
A stirred mixture of 4-bromobenzoic acid, ethyl ester (23.6 g, 103 mmol), 4-methoxyphenylboronic acid (15.6 g, 103 mmol), tetrakis(triphenylphosphine)palladium (0) (2.0 g, 1.73 mmol) and powdered caesium fluoride (30.0 g, 200 mmol) in 1,2-dimethoxyethane (300 mL) is heated at 85° C. for 3 h. The mixture is then treated with water (500 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts are washed (saturated NaCl), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 5% ethyl acetate/95% cyclohexane) to 4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid, ethyl ester as a colourless crystalline solid. m.p. 103-104° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(=O)(O)O.[NH2:11][C:12]([NH2:14])=[NH:13].C(=O)=O>O>[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[NH2:13][C:12]([NH2:14])=[NH2+:11].[NH2:13][C:12]([NH2:14])=[NH2+:11]
Reactant: N=C(N)N
Reactant: O=C(O)C(=O)O
Agent: O=C(O)O
Agent: O=C=O
Solvent: O
Product: NC(N)=[NH2+]
Product: O=C([O-])C(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalic acid (2.0 g, 22.20 mmol) was dissolved in 40 ml of distilled water. Guanidine carbonate (4.0 g, 22.20 mmol) was added at room temperature (carbon dioxide gas was evolved) and the reaction was stirred at room temperature for one hour. The water was removed in vacuo with heating to approximately 90° C. for 4 hours. The product was isolated as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([CH2:21][NH:20][C:19](=[O:22])[CH:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:17]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[CH3:31])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:35][CH3:36]>C1COCC1>[CH2:35]([N:20]1[C:19](=[O:22])[CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:17][C:14]2([CH2:15][CH2:16][N:11]([C:9](=[O:10])[C:8]3[CH:29]=[CH:30][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH3:31])[CH:7]=3)[CH2:12][CH2:13]2)[CH2:21]1)[CH3:36]
Reactant: CCBr
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CNC(=O)C(c2ccccc2)O3)ccc1OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)OC(c2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-isopropoxy-3-methyl-benzoyl)-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-9-one (65 mg, 0.15 mmol) in THF (1 mL) at 0° C. was added NaH (6 mg, 0.15 mmol) and the reaction mixture was stirred for 30 minutes. Bromoethane (34 mg, 23 μL, 0.31 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography using 0-100% EtOAc/DCM as eluent to give 2-ethyl-9-(4-isopropoxy-3-methyl-benzoyl)-4-phenyl-5-oxa-2,9-diazaspiro[5.5]undecan-3-one as a viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.48-7.43 (m, 2H), 7.39-7.29 (m, 3H), 7.23-7.17 (m, 2H), 6.81 (d, J=8.2 Hz, 1H), 5.11 (s, 1H), 4.56 (dt, J=12.1, 6.0 Hz, 1H), 3.63 (d, J=12.4 Hz, 1H), 3.59-3.19 (m, 5H), 3.09 (d, J=12.4 Hz, 1H), 2.92 (d, J=28.7 Hz, 1H), 2.22 (s, 1H), 2.23-2.16 (m, 3H), 1.59 (s, 3H), 1.35 (d, J=6.0 Hz, 6H), 1.14 (t, J=7.2 Hz, 3H). ESI-MS m/z calc. 450.3. found 451.1 (M+1)+; Retention time: 1.76 minutes (3 min run).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].OS([O-])(=O)=O.[Na+]>C(Cl)Cl.O>[CH3:10][C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][C:5]=1[CH2:6][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cc(O)ccc1C=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)ccc1CN1CCCC1
Yield: 94.8 %

Procedure:
4-Hydroxy-2-methylbenzaldehyde (1.1 g, 8 mmol) was added in portions for 30 min to a mixture of pyrrolidine (0.84 mL, 10 mmol) and NaB(OAc)3H (2.14 g, 10 mmol) in CH2Cl2 (10 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 12 h and cooled with an ice bath. Water (20 mL) and 5N NaHSO4 (to pH 1) were added. The organic layer was separated and discarded. The aqueous one was alkalized with saturated K2CO3 to pH 6 and extracted with chloroform (2×25 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (1.45 g, 94%) was obtained as dark-yellow crystals. LCMS-data: (M+H)+ 193.1 and 192.1 (calculated for C12H17NO 191.3). 1H NMR data (DMSO-d6): 9.08 (br. s, 1H ArOH), 6.97 (d, 1H, J=8.1 Hz, Ar—H), 6.54 (d, 1H, J=2.4 Hz, Ar—H); 6.49 (dd, 1H, J1=2.4 Hz, J2=8.1 Hz, Ar—H), 3.40 (s, 2H, ArCH2), 2.33-2.45 (m, 4H, pyrrolidine (CH2)2N),), 2.21 (s, 3H, OCH3), 1.60-1.68 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [F-].[K+].I[CH3:4].[Si]([O:12][C:13]1[C:14]([F:22])=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH:16]=[O:17])(C(C)(C)C)(C)C.O>CN(C=O)C>[F:22][C:14]1[C:13]([O:12][CH3:4])=[CH:20][C:19]([F:21])=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(C=O)c1F
Reactant: CI
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(F)cc(C=O)c1F
Reaction time: 5 h
Yield: 74.4 %

Procedure:
Potassium fluoride (7.79 g, 134 mmol) and iodomethane (4.98 ml, 80 mmol) were added to a stirred solution of 3-tert-butyldimethylsilyloxy-2,5-difluorobenzaldehyde (19.45 g, 67 mmol) in DMF (100 ml) at room temperature. After 5 hr, the mixture was poured into water (100 ml) and extracted with ethyl acetate (200 ml). The extract was washed with water (100 ml), brine (100 ml), dried (magnesium sulfate) and evaporated. The residue was purified by column chromatography (silica gel) eluting with ethyl acetate/n-hexane (1/10) to give 8.58 g (74%) of the titled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:29][CH2:30][NH2:31])[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.[C:41]([C:45]1[CH:50]=[CH:49][C:48]([N:51]=[C:52]=[O:53])=[CH:47][CH:46]=1)([CH3:44])([CH3:43])[CH3:42]>C(Cl)Cl>[C:41]([C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:52]([NH:31][CH2:30][CH2:29][CH2:28][N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[O:17]2)[CH:32]([CH3:34])[CH3:33])=[O:53])=[CH:47][CH:46]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCN)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: ClCCl
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCNC(=O)Nc3ccc(C(C)(C)C)cc3)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
A suspension of N1-(((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-N1-isopropylpropane-1,3-diamine (1.11 g, 2.00 mmol, crude from step 6) in methylene chloride (40 mL) was treated dropwise with a solution of 1-tert-butyl-4-isocyanatobenzene (0.36 mL, 2.0 mmol) in methylene chloride (3.5 mL) and allowed to stir at room temperature. After 1 h, reaction was complete by HPLC. The reaction mixture was concentrated to yield a glass. The crude material was purified by flash chromatography (100 g silica gel, 2-4% 7N NH3 in CH3OH/CH2Cl2 to yield the title compound (1.07 g, 73%) as a foam: MS (ESI+) for C10H55N7O6 m/z 730.4 (M+H)+; (ESI−) for C40H55N7O6 m/z 728.5 (M−H)−; HPLC purity, 89% (ret. time, 3.78 min).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Si](C)(C)O[Si](C)(C)C.[N+:22]([O-])([OH:24])=[O:23].O>S(=O)(=O)(O)O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([N+:22]([O-:24])=[O:23])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 78.9 %

Procedure:
To a stirred solution of 2,3,4-Trifluorobenzoic acid (70 Kg, 398 Mol) in sulphuric acid (96 wt %; 194 L) and hexamethyldisiloxane (6.5 Kg, 40 Mol), at 23° C., was added a 1:1 mixture of sulphuric acid (96 wt %) and nitric acid (98 wt %) (total 70.1 Kg), over 75 min. The temperature of the reaction mixture was maintained between 15 and 25° C. during the addition. The mixture was stirred for a further 5 hours and then run onto ice (700 Kg), keeping the temperature of the ice mixture below 0° C. Water (35 L) was used to rinse the nitration reactor into the quench reactor and the obtained mixture was stirred for 2 hours at 0° C., then isolated on a centrifuge. The resultant wet cake was washed with cold water (350 L), and the solid was then suspended in water (280 L) and stirred for 2 hours at 0° C. This suspension was then centrifuged and the cake was washed with cold water (210 L), then dried in a vacuum oven at 45° C. for 2 days, to provide 2,3,4-Trifluoro-5-nitro benzoic acid (69.4 Kg, 74.3% yield). 1H NMR (400 MHz, d6 DMSO) δ 8.44 (1H, apparent dt, J 2, 7, Ar—H). 19F NMR (376 MHz, d6 DMSO) δ−153.9, −131.5, −120.9. 13C NMR (100 MHz, d6 DMSO) δ 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C—F, dt, J 251, 10), 148 (C—F, dd, J 265, 13), 154 (C—F, dd, J 265, 10), 163 (COOH). IR vmax/cm−1 3108 (br), 1712, 1555, 1345, 1082. MS APCI (−) m/z 220 (M−1) detected.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH:8]([S:11]([CH2:14][S:15]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:19]2)(=[O:17])=[O:16])(=[O:13])=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1.O.Cl>ClCCl>[CH2:1]([CH:5]1[CH2:6][CH2:7][CH:8]([S:11]([C:14]([S:15]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[N+:37]=[N-:38])(=[O:13])=[O:12])[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCCCC1CCC(S(=O)(=O)CS(=O)(=O)C2CCC(CCCC)CC2)CC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCC1CCC(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C2CCC(CCCC)CC2)CC1
Reaction time: 0.25 h
Yield: 20.6 %

Procedure:
In 91 g of dichloromethane were dissolved 10.5 g (0.025 mol) of the bis(4-n-butylcyclohexylsulfonyl)methane prepared above and 7.5 g (0.038 mol) of p-toluenesulfonylazide. The solution was cooled on an ice bath, to which 3.7 ml (0.0025 mol) of diazabicyclo[5.4.0]-7-undecene (DBU) was added dropwise at a temperature below 5° C. The solution was ripened at the temperature for 15 minutes, after which 38 g of water and 10 g of 12N conc. hydrochloric acid were added. The organic layer was separated and washed with 50 g of water. The solvent was distilled off in vacuum, leaving an oily matter. It was purified by silica gel column chromatography (using dichloromethane as a developing solvent), obtaining 2.3 g of the desired bis(4-n-butylcyclohexylsulfonyl)diazomethane. The yield was 20%.
Reaction SMILES: C([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][C:4]=1[C:14]([OH:16])=[O:15])C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH3:25].I[CH2:27][CH3:28]>C(#N)C.C(OCC)(=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:27][CH3:28])[C:4]([C:14]([O:16][CH2:24][CH3:25])=[O:15])=[CH:3]2)#[N:13]
Reactant: CCBr
Reactant: CCc1c(C(=O)O)[nH]c2ccc(C#N)cc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(C#N)ccc2n1CC
Temperature: 80 °C
Reaction time: 18 h

Procedure:
2 Ethylcarboxy-5-cyanoindole (497 mg) [Liebigs Ann Chem, (3), 438-55 (1986)] and potassium carbonate (960 mg) were mixed in acetonitrile (25 ml) and bromoethane (191 μl) added. The reaction mixture was stirred for 18 hrs at 80° C. under a atmosphere of nitrogen. Iodoethane (200 μl) was added and the reaction mixture heated to 60° C. for 18 hrs after which time the mixture was diluted with ethyl acetate (100 ml) and washed with water, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with Hexane/Isopropanol/ 0.88 ammonium hydroxide (95/5/0.25, v/v) to afford the title compound as a white solid (455 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:12].[C:13]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:13][O:12][C:2]1[CH:1]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([OH:11])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc2ccc(O)cc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc2ccc(O)cc2c1
Temperature: 0 °C
Yield: 36.8 %

Procedure:
To a mixture of naphthalene-2,7-diol (25 g, 156.08 mmol) and K2CO3 (32.3 g, 232.02 mmol) in acetone (300 ml) was added iodomethane (22.2 g, 156.41 mmol) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The solids were filtered off and the filtrate was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 1%-10% ethyl acetate in petroleum ether to afford 7-methoxynaphthalen-2-ol as a light yellow solid (10 g, 37%). (ES, m/z): [M+H]+ 175.1; 1H NMR (400 MHz, DMSO-d6): δ 9.65 (s, 1H), 7.65 (d, J=8.8 Hz, 2H), 6.79 (dd, J=13.6, 1.6 Hz, 2H), 6.92-6.89 (m, 2H), 3.84 (s, 3H).
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[CH2:8]([Li])[CH2:9][CH2:10]C.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])C(C)C.C(Br)C#C>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:19]([O:18][C:13](=[O:17])[C:5]([CH3:6])([CH3:7])[CH2:10][C:9]#[CH:8])[CH3:20]
Reactant: CC(C)NC(C)C
Reactant: [Li]CCCC
Reactant: CCOC(=O)C(C)C
Agent: C#CCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C#CCC(C)(C)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (45.9 mL, 0.33 mol) was dissolved in THF (300 mL) and cooled to 0° C. under N2. n-Butyllithium (2.5M in hexanes; 131.0 mL, 0.33 mol) was added dropwise over 30 minutes, and the mixture was stirred at 0° C. for an additional 30 minutes and then cooled to −78° C. Ethyl isobutyrate (40 mL, 0.30 mol) in THF (30 mL) was added dropwise, and the solution was stirred at −78° C. for 1 hour. Propargyl bromide (36.4 mL, 0.33 moml) in HMPA (60 mL) was added dropwise, and the reaction was stirred at −78° C. for 1 hour and then quenched with saturated aqueous NH4Cl and warmed to room temperature. THF was removed in vacuo, and the residue was dissolved in Et2O and washed four times with H2O. The organic layer was dried over MgSO4, filtered, and concentrated, and the crude material was distilled under reduced pressure (˜29 inHg, by 68-70° C.) to give the title compound.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:36])=[CH:31][CH:30]=2)=[CH:6][C:7]([N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20]C(=O)OC(C)(C)C)[CH2:15]2)=[N:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:7]2[CH:6]=[C:5]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[O:36])=[CH:31][CH:30]=3)[C:4]([C:1]([NH2:2])=[O:3])=[C:9]([O:10][CH2:11][CH2:12][CH3:13])[N:8]=2)[CH2:15]1
Reactant: CCCOc1nc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc(Nc2ccc(C(=O)N3CCOCC3)cc2)c1C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1nc(N2CCC[C@@H](N)C2)cc(Nc2ccc(C(=O)N3CCOCC3)cc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A solution of (R)-tert-butyl 1-(5-carbamoyl-4-(4-(morpholine-4-carbonyl)phenylamino)-6-propoxypyridin-2-yl)piperidin-3-ylcarbamate (530 mg, 0.910 mmol) in CH2Cl2 (5 mL) was treated with TFA (5 mL, 64.9 mmol) and stirred at rt for 1 hr. Solvent was removed by evaporation on a rotary evaporator. The residue was dissolved in CH2Cl2 and washed with NaHCO3 and concentrated to give 380 mg of (R)-6-(3-aminopiperidin-1-yl)-4-(4-(morpholine-4-carbonyl)phenylamino)-2-propoxynicotinamide as a white solid. LCMS: (M+H)+=483.36. 1H NMR (400 MHz, CDCl3) δ ppm 11.60 (1H, s), 7.94 (1H, br. s.), 7.41 (2H, d, J=8.35 Hz), 7.27 (2H, d, J=8.35 Hz), 6.03 (1H, s), 5.69 (1H, br. s.), 4.36 (2H, t, J=6.48 Hz), 4.06 (1 H, d, J=10.77 Hz), 3.86 (1H, d, J=12.96 Hz), 3.71 (8H, br. s.), 2.81-2.97 (2H, m), 2.75 (1H, dd, J=12.30, 9.23 Hz), 1.89-2.05 (1H, m), 1.80-1.88 (2H, m), 1.70-1.80 (1H, m), 1.53 (1H, ddd, J=10.44, 3.41, 3.30 Hz), 1.25-1.38 (1H, m), 1.05 (3H, t, J=7.36 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[C:18]([CH3:20])[C:5]([O:6][C:7]2[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([CH3:16])[N:10]=[C:9](Cl)[N:8]=2)=[C:4]([CH3:21])[CH:3]=1.[NH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.N1C=CC=CC=1>C1COCC1.CO>[Br:1][C:2]1[CH:19]=[C:18]([CH3:20])[C:5]([O:6][C:7]2[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([CH3:16])[N:10]=[C:9]([NH:22][C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[N:8]=2)=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1Oc1nc(Cl)nc(C)c1[N+](=O)[O-]
Reactant: N#Cc1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: c1ccncc1
Product: Cc1cc(Br)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(C)c1[N+](=O)[O-]
Temperature: 80 °C
Yield: 84.3 %

Procedure:
A mixture of 4-(4-bromo-2,6-dimethylphenoxy)-2-chloro-6-methyl-5-nitropyrimidine (22.0 g, 59.3 mmol), 4-aminobenzonitrile (7.7 g. 65.2 mmol) and pyridine (4.8 ml, 59.3 mmol) in THF (300 ml) was heated to 80° C. for 10 hours. The reaction mixture was dissolved in methanol, washed with brine and extracted with ethyl acetate. The organic layer was washed twice with brine, dried over MgSO4 and concentrated to dryness. The solid was washed with a mixture of hexane:ethyl acetate (80:20) before filtration. After filtration, the solid was washed again with methanol. The filtrate was concentrated again until dryness. The second round of precipitation was collected following the same procedure. The operation was repeated until total product was recovered. The combined solids were recrystallized from acetone to obtain the title compound (22.72 g, 50 mmol, 84%). 1H NMR (CDCl3, 400 MHz) δ 2.14 (s, 6H), 2.60 (s, 3H), 7.22 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.9, 2H), 7.27 (s, 2H), 12.75 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=[O:6].O.[BH4-].[Na+].Cl>C(O)C.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH2:5][OH:6]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Solvent: O
Product: OCc1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
Then, 37.91 g of 3,4,5-trifluorobenzaldehyde and 10 mL of water were dissolved in 50 mL of ethanol and cooled with ice, and 2.69 g of sodium tetrahydroborate was slowly added to the resultant solution. The mixture was stirred at room temperature for 2 hours, and 10% hydrochloric acid was added until the system became acidic, followed by stirring for 1 hour. Then, hexane was added to the mixture to separate an organic layer, and an aqueous layer was subjected to extraction with hexane. The hexane extract was combined with the organic layer and washed with saturated brine. The resultant mixture was dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure. Then, reduced-pressure distillation (3.9 kPa, b. p.=116° C. to 118° C.) yielded 26.73 g of 3,4,5-trifluorobenzyl alcohol (A).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1.[NH2:31][CH2:32][CH2:33][OH:34].CO>O1CCCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[S:22][CH:23]=[C:19]([CH2:18][S:17][C:4]3[C:5]([C:15]#[N:16])=[C:6]([C:10]4[CH:14]=[CH:13][NH:12][N:11]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:31][CH2:32][CH2:33][OH:34])[N:3]=3)[N:20]=2)=[CH:25][CH:26]=1
Reactant: NCCO
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cc[nH]n1
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1c(NCCO)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cc[nH]n1
Reaction time: 0.5 h

Procedure:
58 mg (0.124 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(1H-pyrazol-3-yl)pyridine-3,5-dicarbonitrile were dissolved in 1 ml of tetrahydrofuran, and 15 mg (0.247 mmol) of 2-aminoethanol were added. After 30 minutes of stirring, methanol was added, the mixture was filtered and the filtrate was purified by preparative HPLC. This gave 63 mg (100% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][NH2:10])=[O:8])=[CH:4][CH:3]=1.[N:11]([CH2:14][CH2:15][O:16][CH3:17])=[C:12]=[O:13]>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][NH:10][C:12]([NH:11][CH2:14][CH2:15][O:16][CH3:17])=[O:13])=[O:8])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)s1
Reactant: COCCN=C=O
Solvent: C1CCOC1
Product: COCCNC(=O)NNC(=O)c1ccc(Cl)s1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A quantity of 3.1 g (17.55 mmol) of 5-chlorothiophene-2-carbohydrazide was suspended largely finely in 30 ml of dry THF at 50° C. Then 1.81 g (17.90 mmol) of 1-isocyanato-2-methoxyethane in solution in 30 ml of THF were added dropwise. The mixture was stirred at 50° C. for 2.5 h. After cooling to RT, the solvent was removed on a rotary evaporator and the residue was admixed with diethyl ether. The crystals were filtered off with suction, washed with diethyl ether and dried in an HV. This gave 4.87 g (100% of theory) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].Br[CH2:10][C:11]#[N:12].CCN(CC)CC>C1COCC1>[OH:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[CH2:10][C:11]#[N:12]
Reactant: N#CCBr
Reactant: OCC1CCCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CCN1CCCCC1CO

Procedure:
The method follows that of S3 using 2-piperidinemethanol (26.50 g, 0.230 mol), BrCH2CN (30.35 g, 0.253 mol), Et3N (35.27 mL, 0.253 mol) and dry THF (150 mL). The crude product was purified by flash chromatography using ether/CH3OH (19:1) as eluent. The title-compound was crystallised from ether yielding cream-coloured crystals (31.46 g, 89%). δH(250 MHz; CDCl3); 1.2-1.85 (m, 6H, NCH2CH2CH2, CH2CH2CH2CH and CH2CH2CH), 2.05 (s (broad), 6H, OH), 2.4 (m, 1H, NCH2CH2), 2.55 (3×d, 1H. 1×NCH2CH2), 2.95 (m, 1H, NCHCH2), 3.45 (d, 1H, J=17 Hz, 1×NCH2CN), 3.5 (2×d, 1H, J=3 Hz and 12 Hz, 1×CHCH2OH), 3.76 (2×d, 1H, J=3 Hz and 12 Hz, CHCH2OH) and 4.05 (d, 1H, J=17 Hz, 1×NCH2CN); δC (62.9 MHz; CDCl3); 23.71, 25.25, 28.69, 43.43, 54.04, 60.73, 64.46 and 115.05 (CN); FAB MS, m/z(M+H)+ 155; IR υmax/cm−1; 3400 (OH, m broad), 2350 and 2240 (CN) and 1650.