Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+].[CH:46]1([NH2:51])[CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[CH:46]1([NH:51][CH2:27][CH2:28][S:29]([N:23]2[CH2:24][CH2:25][CH:20]([C:11]3[C:10]4[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)[CH:9]=4)[NH:13][N:12]=3)[CH2:21][CH2:22]2)(=[O:31])=[O:30])[CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: NC1CCCC1
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=S(=O)(Cl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCNC4CCCC4)CC3)n[nH]c12
Reaction time: 0.17 h
Yield: 5.7 %

Procedure:
The title compound was prepared according to the procedure described in Example 33. Thus, 5-(3-fluorophenyl)-3-(4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 15) (75 mg, 0.167 mmol) was reacted with 2-chloro-1-ethanesulfonyl chloride (17 uL, 0.167 mmol) in the presence of triethyl amine (93 uL, 0.665 mmol) in DMF (2 mL) at 0° C. After 10 mins., K2CO3 (46 mg, 0.334 mmol) and cyclopentyl amine (49 uL, 0.501 mmol) were added to afford the title compound (4.9 mg, 8.1% for 2 steps).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].[CH2:13](O)[CH3:14].Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCO
Reactant: O=C(O)C1Cc2ccccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 25.2 g of indoline-2-carboxylic acid, 50 ml of ethanol and 200 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 3 days. At the end of this time, the reaction mixture was poured into an aqueous solution of potassium carbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 28.1 g of the title compound having Rf=0.81 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:16])=[C:12]([NH2:15])[CH:13]=2)[C:8]([CH3:18])([CH3:17])[CH2:7]1)(=[O:5])[CH3:4].[CH:19](N)=O>>[C:3]([N:6]1[C:14]2=[CH:13][C:12]3[NH:15][CH:19]=[N:16][C:11]=3[CH:10]=[C:9]2[C:8]([CH3:18])([CH3:17])[CH2:7]1)(=[O:5])[CH3:4]
Reactant: NC=O
Reactant: CC(=O)N1CC(C)(C)c2cc(N)c(N)cc21
Agent: Cl
Product: CC(=O)N1CC(C)(C)c2cc3nc[nH]c3cc21
Reaction time: 0.67 h

Procedure:
A mixture of 3.0 g. (0.01 mole) 1-acetyl-5,6-diamino-3,3-dimethylindoline dihydrochloride (Example 2b) and 35 ml. formamide is heated to reflx for 40 minutes and then evaporated. The residue is mixed with water, extracted with dichloromethane and the extract evaporated to give 2.6 g. (85% of theory) of the title compound; m.p. 214°-216° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[OH:15][CH2:16][CH2:17][CH2:18][C:19](=O)[CH3:20]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:19]([CH3:20])[CH2:18][CH2:17][CH2:16][OH:15])=[CH:6][CH:7]=1
Reactant: CC(=O)CCCO
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCCO

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 5-hydroxy-pentan-2-one.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:16][C:15](=[O:17])[C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])=[O:16])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)c1ccc(-c2nc3ccccc3c(=O)o2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccccc2)cc1
Yield: 8.9 %

Procedure:
To a stirred solution of 2-(4-tert-butylphenyl)-4H-3,1-benzoxazin-4-one (1.0 g, 3.6 mmol) in toluene (15 mL) was added aniline (0.33 g, 3.6 mmol). After refluxing for 8 h, the solution was allowed to cool, diethyl ether was added, and the precipitate was filtered and dried In vacuo to give 120 mg (9%) of the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:13]=2)[C:7](=[O:29])[C:6]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[NH:47][C:46](=[O:48])[O:45][N:44]=2)=[CH:33][CH:32]=1)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>O1CCCC1>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][OH:21])[CH:13]=2)[C:7](=[O:29])[C:6]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[NH:47][C:46](=[O:48])[O:45][N:44]=2)=[CH:33][CH:32]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2cccc(OCCO[Si](C)(C)C(C)(C)C)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2cccc(OCCO)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 69.9 %

Procedure:
To a solution of 6-butyl-3-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (0.95 g) in tetrahydrofuran (7 mL) was added tetrabutylammonium fluoride (0.56 g), and the mixture was stirred at 50° C. for 12 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.55 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH2:9])[N:5]=[C:4]([OH:10])[N:3]=1.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[CH:16]=O>C(O)(=O)C.CCO>[F:11][C:12]([F:25])([F:26])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1)[CH:16]=[N:9][NH:8][C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([OH:10])[N:5]=1
Reactant: NNc1nc(O)nc(Cl)n1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: CCO
Product: Oc1nc(Cl)nc(NN=Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
To a solution of 4-chloro-6-hydrazino-[1,3,5]triazin-2-ol (0.13 g, 0.0008 mol) and 3,5-bis(trifluoromethyl)benz aldehyde (0.39 g, 0.0016 mol) in abs. EtOH (10 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give red solid 0.21 g, in 72% yield, mp: 258.3° C. 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 8.97 (s, 1H), 8.54 (s, 1H), 7.59 (s, 1H), 7.30 (s, 2H). 13C NMR (DMSO-d6) δ 179.0, 160.2, 149.8, 148.8, 128.3, 127.6, 125.4, 124.7.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11].[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11])=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ncoc1CSCCN
Reactant: O=C(N=C=S)c1ccccc1
Product: Cc1ncoc1CSCCNC(=S)NC(=O)c1ccccc1

Procedure:
5-[(2-Aminoethyl)thiomethyl]-4-methyloxazole is reacted with benzoyl isothiocyanate by the procedure of Example 18 to give N-benzoyl-N'-[2-((4-methyl-5-oxazolyl) methylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-((4-methyl-5- oxazolyl)methylthio)ethyl]thiourea.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[C:21]1([S:27][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Sc1ccccc1
Solvent: CO
Product: COC(=O)C(Sc1ccccc1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
Methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate (7.11 g) is reacted with 2.75 g of thiophenol in methanol, as in Example 16, to yield a yellow oil. After a brief distillation at 0.02 mm to remove volatile impurities, the residue is evaporatively distilled (173° C at 0.01 mm) to afford the product as a colorless oil which solidifies, mp 64°-68.5° C. A portion is recrystallized from hexane to give white plates, mp 71.5°-72.5° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.[F:21][C:22]([F:40])([F:39])[C:23]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([Cl:34])[CH:26]=[C:25]([C:35]([F:38])([F:37])[F:36])[N:24]=1.Cl[C:42]([O:44][CH2:45][CH3:46])=[O:43]>COCCOC>[F:40][C:22]([F:21])([F:39])[C:23]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([Cl:34])[C:26]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:25]([C:35]([F:36])([F:37])[F:38])[N:24]=1
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: COCCOC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1Cl
Reaction time: 0.08 h
Yield: 30 %

Procedure:
To a cold (-78° C. ) solution of LDA, from 0.0155 mol of n-BuLi, 0.0157 mol (2.2 ml) of diisopropylamine and 30 ml of dry DME was added a solution of 3.2 g (0.01 mol) of product of Example 9 in 5 ml of DME. The resulting purple solution was stirred for 5 minutes and treated with 4 ml of ethyl chloroformate. The mixture was stirred at -78° C. for minutes, the cooling bath was removed, and the reaction mixture was stirred for an additional 30 minutes, then poured into water. The mixture was extracted with ether. The ether extract was washed with 50 ml of 3N HCl, dried, and concentrated. The residue was kugelrohr distilled at 53 Pa. The low bp distillate (pot temperature 50°-60° C. ) was identified as ethyl N,N-diisopropylurethane. The higher bp distillate (pot temperature 100° C. ) was 1.64 g of a solid which was recrystallized from hexane at low temperature to give 1.2 g (30%) of product; mp 76°-77° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][CH:5]=[C:4]([F:15])[C:3]=1[CH2:16][NH:17][C:18]1[C:19]([F:26])=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[F:24].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][CH:5]=[C:4]([F:15])[C:3]=1[CH2:16][NH:17][C:18]1[C:19]([F:26])=[C:20]([CH:21]=[CH:22][C:23]=1[F:24])[O:25][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(F)c(NCc2c(F)ccc(-c3cccc(F)c3)c2F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2c(F)ccc(-c3cccc(F)c3)c2F)c1F
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of 3-[[2,6-difluoro-3-(3-fluorophenyl)phenyl]methylamino]-2,4-difluoro-phenol (300 mg, 0.82 mmol, 1.0 eq) in DMF (5 mL) was added Cs2CO3 (375 mg, 1.15 mmol, 1.4 eq) at room temperature. The reaction mixture was stirred for 1 h, then ethyl 2-bromoacetate (151 mg, 0.90 mmol, 1.1 eq) was added. The reaction mixture was stirred for a further 1 h and the resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered, evaporated in vacuo and purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (240 mg, 65%).
Reaction SMILES: [CH3:1][CH:2]([S:6]([C:8]1[S:12][CH:11]=[N:10][N:9]=1)=[O:7])[C:3]([OH:5])=O.[NH2:13][CH:14]1[C:28](=[O:29])[N:16]2[C:17]([C:25]([OH:27])=[O:26])=[C:18]([CH2:21][N:22]=[N+:23]=[N-:24])[CH2:19][S:20][C@H:15]12>>[CH3:1][CH:2]([S:6]([C:8]1[S:12][CH:11]=[N:10][N:9]=1)=[O:7])[C:3]([NH:13][CH:14]1[C:28](=[O:29])[N:16]2[C:17]([C:25]([OH:27])=[O:26])=[C:18]([CH2:21][N:22]=[N+:23]=[N-:24])[CH2:19][S:20][C@H:15]12)=[O:5]
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C(=O)O)S(=O)c1nncs1
Product: CC(C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)S(=O)c1nncs1

Procedure:
412 mg. of 2-methyl-1,3,4-thiadiazol-5-ylsulfinylacetic acid and 7-amino-3-azidomethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 124 mg. of 7-(2-methyl-1,3,4-thiadiazol-5-ylsulfinylacetamido)-3-azidomethyl-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:3]=1[C@H:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[C:28]=3[CH3:29])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14].[C:36](O)(=[O:38])[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.C(Cl)Cl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:3]=1[C@H:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([CH:30]4[CH2:31][CH2:32][N:33]([C:36](=[O:38])[CH3:37])[CH2:34][CH2:35]4)[C:28]=3[CH3:29])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14]
Reactant: Cc1c(-c2cnc3[nH]cc([C@H](C)c4c(OC(F)F)ccc(F)c4Cl)c3c2)cnn1C1CCNCC1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(n2ncc(-c3cnc4[nH]cc([C@H](C)c5c(OC(F)F)ccc(F)c5Cl)c4c3)c2C)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-5-[5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine (40.0 mg, 0.0794 mmol), acetic acid (23.8 mg, 0.397 mmol), TBTU (51.0 mg, 0.159 mmol), triethylamine (40.2 mg, 0.397 mmol) and DCM (4 mL, 60 mmol) was stirred at rt for 10 min. The solution was extracted with EtOAc, washed with 1 M HCl, and then sat. NaHCO3. The organic layer was concentrated in vacuo, loaded onto silica gel and purified via column chromatography. The product was eluted with 2-3% (7N NH3 in MeOH)/DCM, and the fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.84 (d, J=7.3 Hz, 3H), 1.93-2.04 (m, 3H), 2.12 (dd, J=15.4, 2.5 Hz, 1H), 2.16 (s, 3H), 2.26 (s, 3H), 2.76-2.88 (m, 1H), 3.32-3.35 (m, 1H), 4.08 (dd, J=14.0, 1.9 Hz, 1H), 4.43-4.54 (m, 1H), 4.64-4.73 (m, 1H), 5.11 (q, J=7.0 Hz, 1H), 6.43 (br. s., 1H), 7.12 (dd, J=8.8, 4.5 Hz, 1H), 7.19 (t, J=8.7 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.39 (d, J=1.3 Hz, 1H), 7.48 (s, 1H), 8.13 (d, J=2.0 Hz, 1H). MS (ES+): m/z=546.17/548.18 (100/50) [MH+]. HPLC: tR=1.43 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:8][C:6]1[CH:7]=[C:2]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(-n2ccnc2)ncn1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A mixture of 4,6-dichloropyrimidine (5 g, 33.56 mmol), imidazole (2.28 g, 33.56 mmol) and potassium carbonate (4.63 g, 33.56 mmol) in DMF (50 ml) is stirred at room temperature over night. The mixture is diluted with four volumes of water and extracted with dichloromethane. The organic extract is concentrated under reduced pressure and eluted through silica gel with a mixture of ethyl acetate and methanol (9:1). Evaporation of solvent and trituration of the residue with a mixture of diethyl ether and petroleum ether (1:1) leaves 15b (4.07 g, 67%). Mp 198-200° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C@@:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:41])([F:42])[F:43])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C@@:8]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(CCCCCCCC[C@H]1c2ccc(OC)cc2SC[C@@]1(C)c1ccc(OC)cc1)CCCC(F)(F)C(F)(F)F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(CCCCCCCC[C@H]1c2ccc(O)cc2SC[C@@]1(C)c1ccc(O)cc1)CCCC(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 67.3 %

Procedure:
A solution of ethyl 10-[(3R,4R)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoate (3.23 g, 4.902 mmol) in dichloromethane (60 ml) was cooled to −78° C. To this solution, a solution of boron tribromide in dichloromethane (1M, 39.22 ml, 39.22 mmol) was slowly added dropwise, and the resulting mixture was stirred for 1 hour. The reaction vessel was then transferred to an ice-bath and the reaction mixture was further stirred for 3 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/20) to give ethyl 10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoate (2.08 g, Yield 67%) as a foam.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([F:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][NH:30][CH3:31])=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][N:30]([CH3:31])[C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:8]([C:6]4[CH:7]=[C:2]([NH2:1])[C:3]([F:22])=[CH:4][C:5]=4[F:21])[C:9](=[O:20])[N:10]3[CH3:19])=[CH:15][N:14]=2)=[CH:27][CH:26]=1
Reactant: CNCc1ccc(OC)cc1
Reactant: Cn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(Cl)cc21
Product: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2F)c(=O)n3C)cc1
Temperature: 200 °C
Yield: 91 %

Procedure:
3-(5-Amino-2,4-difluorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (2.4 g, 7.5 mmol) and 4-methoxy-N-methylbenzylamine (10 mL) were combined in a sealed vessel and heated to 200° C. overnight. The volatiles were removed in vacuo and the residue was purified by column chromatography to give 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2,4-difluorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (3 g, 91% yield), which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:10].[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.[CH2:20]=[C:21]([CH3:23])[CH3:22].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]2[CH2:20][C:21]([CH3:23])([CH3:22])[C:9]3[C:2](=[C:3]([Cl:10])[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=3)[NH:1]2)[CH:17]=[CH:18][CH:19]=1
Reactant: C=C(C)C
Reactant: N#Cc1ccc(N)c(Cl)c1
Reactant: O=Cc1cccc(Br)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2cccc(Br)c2)Nc2c(Cl)cc(C#N)cc21
Temperature: 85 °C
Reaction time: 18 h
Yield: 39.6 %

Procedure:
To a stirred solution of 4-amino-3-chloro-benzonitrile (8.0 g, 52.4 mmol) and 3-bromobenzaldehyde (6.2 mL, 52.4 mmol) in acetonitrile (150 mL) were added isobutene (14.7 mL, 209.7 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (4.0 g, 6.3 mmol). The resulting mixture was stirred at 85° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)-8-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (7.8 g, 40.0%) as a light yellow solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 374.9 & 376.9.
Reaction SMILES: Br[CH2:2][C@H:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[N:25]([CH2:2][C@H:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCC(C)COc1ccc([C@H](CBr)NC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(C)COc1ccc([C@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of t-butyl (1R)-2-bromo-1-(4-(2-methylpentyloxy)phenyl)ethylcarbamate (17.8 g, 44.5 mmol) in dimethylformamide was added sodium azide (11.56 g, 178 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched by addition of water (25 mL) and the mixture was transferred to a separatory funnel and the aqueous layer was extracted with dichloromethane (3×40 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (30→40% ethyl acetate in hexanes) to afford t-butyl (1R)-2-azido-1-(4-(2-methylpentyloxy)phenyl)ethylcarbamate (14.2 g, 88% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.01 (d, J=7.8 Hz, 1H), 4.78 (br. s., 1H), 3.78 (dd, J=9.1, 5.8 Hz, 1H), 3.68 (dd, J=8.8, 6.5 Hz, 1H), 3.57 (d, J=4.8 Hz, 2H), 1.86-1.97 (m, 1H), 1.42 (s, 9H), 1.26-1.51 (m, 3H), 1.14-1.24 (m, 1H), 0.99 (d, J=6.5 Hz, 3H), 0.90 (t, J=7.2 Hz, 3 H); LRMS (ESI) m/e 363.3 [(M+H)+, calcd for C19H31N4O3Br 363.2].