Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].O[N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][N:15]1[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]2[C:19]1=[O:20])=[O:12]
Reactant: O=C(O)CCCCCCCCCO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CCCCCCCCCO)ON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51 %

Procedure:
To a solution of 10-hydroxydecanoic acid (1.880 g, 10 mmol) in dichloromethane (25 mL) at room temperature was added N-hydroxyphthalimide (NHP) (1.63 g, 10 mmol) followed by N, N′-dicyclohexylcarbodimide (DCC) (2.1 g, 10 mmol). Quantitative conversion to product was achieved after stirring at room temperature for 45 minutes as determined by tlc using silica gel (ethyl acetate/heptane 4:1; Rf=0.28). The precipitate was removed by filtration and the filtrate was evaporated to dryness. The residue was chromatographed on silica gel column (2.5×30 cm) using chloroform/methanol (98:2) to give 1.7 g product (yield 52%) as a colorless syrup.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25]C(=O)C)[CH:23]=3)[CH:18]=[CH:17][C:15]2=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH2:25])[CH:23]=3)[CH:18]=[CH:17][C:15]2=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccc2ccc(=O)n(C3CCN(Cc4ccccc4)CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc2ccc(=O)n(C3CCN(Cc4ccccc4)CC3)c2c1
Yield: 90.1 %

Procedure:
To 1-(1-benzyl-4-piperidinyl)-7-acetylaminocarbostyril (3.0 g) are added ethanol (32 ml) and an aqueous 10% sodium hydroxide solution (32 ml) and the mixture is refluxed for 1 hour. After the reaction mixture is concentrated by distilling off the solvent, water is added to the residue and the resulting solution is extracted with dichloromethane. The extract is concentrated by distilling off the solvent and recrystallized from ethanol/chloroform to give 1-(1-benzyl-4-piperidinyl)-7-aminocarbostyril (2.4 g) as white powders, m.p. 238°-241° C.
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>CN(C)C=O>[F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:11][C:5]2[N:6]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3c(cc2F)OCC(=O)N3)c1=O
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3c(cc2F)OCC(=O)N3Cc2ccccn2)c1=O
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
0.20 g of 3-(7-fluoro-3-oxo-2H-1,4-benzoxazin-6-yl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)pyrimidinedione was added at room temperature to an N,N -dimethylformamide solution (5 ml) having suspended therein 0.05 g of sodium hydride (purity: 55%). After standing for 20 minutes, the solution was added with 0.09 g of 2-chloromethylpyridine hydrochloride and stirred for 4 hours. Then N,N-dimethylformamide was distilled off and the residue was extracted with ethyl acetate by adding water. The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off to obtain a crude product. This product was purified by preparative thin-layer chromatography using hexane/ethyl acetate (2:3) as developing solvent to obtain 0.09 g of the objective compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][S:6][C:7]1[NH:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[N:8]=1)[CH3:2].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:31](O)=[O:32]>O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][S:6][C:7]1[NH:11][C:10]2[C:12]([CH:31]=[O:32])=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[N:8]=1)[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)CSc1nc2ccc(OC)cc2[nH]1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CCOC(=O)CSc1nc2ccc(OC)c(C=O)c2[nH]1
Temperature: 120 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
A mixture of (6-methoxy-1H-benzoimidazol-2-ylsulfanyl)-acetic acid ethyl ester (14.70 g, 55.26 mmol), hexamethylenetetramine (15.47 g, 100.53 mmol) and trifluoroacetic acid (61 mL) was stirred under argon atmosphere at 120° C. for 1 h. The solution was cooled to room temperature and water (950 mL) was added. This aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na2SO4 and evaporated. The title compound (1.432 g, 4.87 mmol, 9%) was obtained by column chromatography in 2 consecutive steps followed by trituration with diethyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]#[N:24])=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22](=[CH:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:23]#[N:24])=[CH:14]1
Reactant: COc1ccc(C=O)cc1OC
Reactant: N#CCc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C=C(C#N)c2c[nH]c3ccccc23)cc1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 2.0 g (12.0 mmole) 3,4 dimethoxybenzaldehyde in 75 ml absolute ethanol are added 2.07 g (13.3 mmole) 3-indolylacetonitrile and 1.83 g (13.3 mmole) anhydrous potassium carbonate. The reaction flask is equipped with a condenser and a drying tube (using anhydrous CaSO4), and the reaction was stirred and heated. After refluxing for 24 hours, the reaction is allowed to cool to room temperature. The reaction mixture is filtered to remove the salts, and the solvent is removed by rotary evaporation. The residue is purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate, 3:1. The yellow solid is recrystallized from acetone-hexane to give 2-(3-indolyl)-3-(3,4-dimethoxy-phenyl)-2-propenenitrile, m.p. 139°-141° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH:9]1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[CH:24]2.C1CCN2C(=NCCC2)CC1>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][CH:25]=[CH:24]4)=[N:13][CH:12]=[N:11][C:10]=2[CH:9]1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CC1c2ncnc(Cl)c2CCN1C(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1c2ncnc(Oc3ccc4[nH]ccc4c3)c2CCN1C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a solution of 4-chloro-8-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (228 mg, 0.80 mmol), 5-hydroxyindole (139 mg, 1.05 mmol) and MeCN (5 mL) is added DBU (0.15 mL, 1.05 mmol). The resulting misture is heated at 80° C. for 4 h. The reaction is then concentrated in vacuo and the residue separated via FCC (5-60% EtOAc/heptane). MS (ESI) m/z 381.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29](Cl)[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33].[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][CH2:40][NH2:41]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([NH:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:42])[CH3:36])[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33]
Reactant: CN(C)CCCN
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cc(NCCCN(C)C)ccc1[N+](=O)[O-]

Procedure:
In an analogous procedure to that described in Example 15, N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-chloro-2-nitrobenzamide was reacted with 3-dimethylaminopropylamine to give the title compound; NMR Spectrum: (DMSOd6) 1.6-1.72 (m, 2H), 2.12 (s, 6H), 2.22-2.28 (m, 5H), 3.2-3.25 (m, 2H), 3.5-3.54 (m, 4H), 3.69-3.73 (m, 4H), 6.65-6.68 (m, 2H), 7.04 (d, 1H), 7.2 (d, 1H), 7.25 (d, 1H), 7.29 (t, 1H), 7.68 (d, 1H), 8.84 (s, 1H), 8.0 (d, 1H), 8.26 (d, 1H), 9.82 (s, 1H), 10.34 (s, 1H); Mass Spectrum: M+H+ 562.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]=2[CH:4]=1)#[CH:2].Br[C:33]1[CH:34]=[C:35]([C:47]2[O:48][C:49]([C:52]3[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])=[CH:54][CH:53]=3)=[N:50][N:51]=2)[CH:36]=[C:37]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=1>>[CH2:24]([C:6]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]2[CH:4]=[C:3]([C:1]#[C:2][C:33]3[CH:34]=[C:35]([C:47]4[O:48][C:49]([C:52]5[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])=[CH:54][CH:53]=5)=[N:50][N:51]=4)[CH:36]=[C:37]([C:39]#[C:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:38]=3)[CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Br)cc(C#Cc4ccccc4)c3)o2)cc1
Reactant: C#Cc1ccc2c(c1)C(CCCCCCCC)(CCCCCCCC)c1ccccc1-2
Product: CCCCCCCCOc1ccc(-c2nnc(-c3cc(C#Cc4ccccc4)cc(C#Cc4ccc5c(c4)C(CCCCCCCC)(CCCCCCCC)c4ccccc4-5)c3)o2)cc1

Procedure:
According to the general procedure of Example 1, the reaction of 2-ethynyl-9,9-dioctyl-9H-fluorene (Example 8) with a molar equivalent of 2-(3-bromo-5-phenylethynylphenyl)-5-(4-octyloxy-phenyl)-[1,3,4]oxadiazole (Example 6) gives 2-[3-(9,9-dioctyl-9H-fluoren-2-ylethynyl)-5-phenylethynyl-phenyl]-5-(4-octyloxy-phenyl)-[1,3,4]oxadiazole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([SH:17])([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].Cl[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1>CC#N>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([S:17][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)S
Reactant: Fc1ccc(CCCCl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)SCCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
To a CH3CN (60 mL) solution containing methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-mercapto-3-methylbutanoate (as described above) (1.51 g, 5.73 mmol, 1.0 eq) was added sodium tert-butoxide (716 mg, 7.45 mmol, 1.3 eq). The resulting pale yellow mixture was allowed to stir at RT for 10 min at which time 1-(3-chloropropyl)-4-fluorobenzene (as described above) (1.09 g, 6.3 mmol, 1.1 eq) was added. The resulting solution was allowed to stir at RT for 18 hr. The reaction was then quenched with a sat NH4Cl solution, poured into H2O, and extracted (2×) with EtOAc. The combined extracts were dried over MgSO4 and concentrated in vacuo and then purified via flash chromatography using 5:1 hexanes/EtOAc as the mobile phase. Isolated 700 mg (1.75 mmol, 31% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:10])[C:5]([Cl:9])=[C:6]([F:8])[CH:7]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[F:18][C:19]([F:25])([F:24])[C:20](OC)=[O:21]>C1COCC1>[Cl:9][C:5]1[C:4]([F:10])=[CH:3][C:2]([C:20](=[O:21])[C:19]([F:25])([F:24])[F:18])=[CH:7][C:6]=1[F:8]
Reactant: Fc1cc(Br)cc(F)c1Cl
Reactant: COC(=O)C(F)(F)F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1cc(F)c(Cl)c(F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-bromo-2-chloro-1,3-difluorobenzene (2000 mg, 8.2 mmol) was stirred at room temperature in THF under N2 and the isopropylmagnesium chloride/LiCl reagent (1310 mg, 9.02 mmol, 6.94 mL) was added over about 1 minute—very slight exotherm noticed to ˜30° C. Reaction was stirred at room temperature for 30 minutes followed by the addition of methyl trifluoroacetate (1580 mg, 12.3 mmol, 1.24 mL) over about 1 minute—slight exotherm to ˜40° C. Solvents were evaporated under reduced pressure to provide the desired product. 1H NMR (CDCl3) δ ppm: 8.05 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[N+:12]([O-])([OH:14])=[O:13]>CC(O)=O>[N+:12]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][C:5]=1[OH:9])([O-:14])=[O:13]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(C(F)(F)F)cc1O
Temperature: 40 °C

Procedure:
A solution of 3-trifluoromethylphenol (3.0 mL, 25 mmol) in HOAc (10 mL) is added dropwise to a solution of 65% nitric acid (2.0 mL, 278 mmol) in HOAc (10 mL) at 0° C. The mixture is warmed to 40° C. and when the reaction is complete it is cooled to RT and partitioned between water and EtOAc. The organic layer is concentrated and the residue is chromatographed using 10% EtOAc/hexane as eluent to afford the title compound as a yellow oil: (M−1)−=206.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:15]#[N:16].[K+].Cl>C(OCC)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([C:15]#[N:16])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: N#CC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
A solution of 1-benzylpiperidin-4-one (7.00 g) in 1:1 diethyl ether-water (30 mL) was cooled to 0° C. and treated with potassium cyanide (6.02 g), followed by hydrochloric acid (7.71 mL). The ice bath was removed and the mixture was stirred at room temperature for 18 hours. The phases were separated, and the aqueous layer was extracted with diethyl ether, dried and evaporated in vacuo to provide the title compound (4.08 g) having the following physical data.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)[N:7]=[C:6]([OH:15])[CH:5]=2)[CH2:3][CH2:2]1.[S:16]([Cl:20])(=O)(=[O:18])[OH:17]>>[CH:1]1([C:4]2[CH:5]=[C:6]([OH:15])[N:7]=[C:8]([C:10]3[S:11][C:12]([S:16]([Cl:20])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[N:9]=2)[CH2:3][CH2:2]1
Reactant: Oc1cc(C2CC2)nc(-c2cccs2)n1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1ccc(-c2nc(O)cc(C3CC3)n2)s1
Temperature: 0 °C

Procedure:
6-Cyclopropyl-2-(thiophen-2-yl)pyrimidin-4-ol (2.5 g, 11.46 mmol) in sulfurochloridic acid (30 mL) was stirred at rt for 7 days. The solution was poured into ice-water while stirring vigorously. The mixture was maintained below 25° C. during the quenching, the reaction mixture was extracted with EA (3) and the combined organic layers were washed (cold water), dried (Na2SO4) and concentrated to provide the crude product 5-(4-cyclopropyl-6-hydroxypyrimidin-2-yl)thiophene-2-sulfonyl chloride which is used for the subsequent step without further purification. LC-MS (m/z)=316.1 [M+H]+
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][C:29]=2[Cl:30])[NH:26][CH:25]=[C:24]3[C:31]([O:33][CH3:34])=[O:32])=[CH:17][C:16]=1[O:35][CH3:36])=O)(C)(C)C.Cl>ClCCl>[Cl:30][C:29]1[CH:28]=[C:27]2[C:23]([C:24]([C:31]([O:33][CH3:34])=[O:32])=[CH:25][NH:26]2)=[CH:22][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[C:16]([O:35][CH3:36])[CH:17]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OC[C@@H]4CCCN4C(=O)OC(C)(C)C)c(OC)c3)cc12
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OC[C@@H]4CCCN4)c(OC)c3)cc12
Reaction time: 2 h

Procedure:
To a solution of (S)-methyl 5-(4-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-3-methoxyphenyl)-6-chloro-1H-indole-3-carboxylate (25.8 mg, 0.050 mmol) in dichloromethane (0.5 mL) was added hydrogen chloride (4M solution in dioxane, 0.075 mL, 0.30 mmol). After 2 h, the solution was concentrated in vacuo to provide the title compound as the hydrochloride salt contaminated with neopentyl glycol. MS (ES+) 415.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 8.80 (br. s, 1H), 8.17 (d, 1H), 7.94 (s, 1H), 7.65 (s, 1H), 7.11 (d, 1H), 7.06 (d, 1H), 6.96 (dd, 1H), 4.34-4.26 (m, 2H), 4.15 (dd, 1H), 4.01-3.92 (m, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.29-3.19 (m, 2H), 2.21-2.10 (m, 1H), 2.08-1.86 (m, 2H), 1.83-1.72 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[CH2:12]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[Cl:23])[CH2:16][CH:11]1[CH2:10][CH:9]2[NH:8][CH:13]([CH2:14][CH2:15]2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(Cc1ccc(Cl)c(Cl)c1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(CC2CC3CCC(C2)N3)cc1Cl
Yield: 98.4 %

Procedure:
3-(3,4-Dichloro-benzyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.35 g, 0.94 mmol) was stirred in 2 mL of CH2Cl2 with 0.5 mL of TFA at rt for 3 h. After being quenched with 20% NaOH to basic medium, the mixture was extracted with EtOAc. The organic layer was washed with NaCl (sat.), dried over Na2SO4 and concentrated to give 0.25 g of 3-(3,4-Dichloro-benzyl)-8-aza-bicyclo[3.2.1]octane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:16])([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:9]=[CH2:10])[CH:5]=[C:4](F)[CH:3]=1.FC1C=C(C(O)(C(F)(F)F)C(F)(F)F)C=C([S:25]CC[Si](C)(C)C)C=1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:16])([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:9]=[CH2:10])[CH:5]=[C:4]([SH:25])[CH:3]=1
Reactant: C[Si](C)(C)CCSc1cc(F)cc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: C=CC(O)(c1cc(F)cc(F)c1)c1nccs1
Product: C=CC(O)(c1cc(F)cc(S)c1)c1nccs1

Procedure:
Following the procedure described for Thiophenol 1, Step 3, but substituting the 5-fluoro-3-[3-hydroxy-3-(thiazol-2-yl)propen-3-yl]-1-(2-trimethylsilylethylthio)benzene from Step 4 for 5-fluoro-3-(hexafluoro-2-hydroxyprop-2-yl)-1-(2-trimethylsilylethylthio)benzene as starting material, the title compound was obtained.
Reaction SMILES: Br[C:2]1[C:3]([O:15][CH3:16])=[C:4]([C:13]#[N:14])[C:5](=[O:12])[N:6]([CH:8]([CH2:10][CH3:11])[CH3:9])[CH:7]=1.[CH3:17][N:18]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[CH:8]([N:6]1[CH:7]=[C:2]([C:20]2[CH:21]=[CH:22][N:18]([CH3:17])[N:19]=2)[C:3]([O:15][CH3:16])=[C:4]([C:13]#[N:14])[C:5]1=[O:12])([CH2:10][CH3:11])[CH3:9]
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: CCC(C)n1cc(Br)c(OC)c(C#N)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCC(C)n1cc(-c2ccn(C)n2)c(OC)c(C#N)c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a mixture of 5-bromo-1-(sec-butyl)-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step B (130 mg), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (114 mg), 2M aqueous sodium carbonate solution (1.37 mL) and 1,2-dimethoxyethane (2.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (52.7 mg), and the mixture was stirred with microwave irradiation at 100° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted twice with ethyl acetate. The extracts were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane) to give the title compound (90 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[C:13]([C:14](=O)[CH3:15])=[C:12]([CH3:17])[N:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[C:10]=1[CH3:27])=O.[NH2:29][NH2:30]>C(O)C>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][C:7]1[C:9]2=[C:10]([CH3:27])[N:11]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=3)[C:12]([CH3:17])=[C:13]2[C:14]([CH3:15])=[N:30][N:29]=1
Reactant: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(=O)CCCC(=O)OC)c2C)cc1
Reactant: NN
Solvent: CCO
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(CCCC(=O)OC)c3c2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]-5-oxo-pentanoic acid methyl ester (250 mg, 0.65 mmol) in ethanol (1 mL) was added a 1.0M solution of hydrazine in ethanol (0.72 mL, 0.72 mmol). The solution was stirred overnight at rt and concentrated in vacuo to give 4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-butyric acid methyl ester as a white solid: 1H NMR (CDCl3, 500 MHz) δ 7.11-7.08 (m, 2H), 7.05-7.03 (in, 2H), 4.11 (q, 2H), 3.63 (s, 3H), 3.12 (t, 2H), 2.77 (s, 3H), 2.51 (t, 2H), 2.41 (s, 3H), 2.40 (s, 3H), 2.14 (quintet, 2H), 1.47 (t, 3H); MS (ESI) 382 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:31]1([C:37]2[NH:41][N:40]=[C:39]([C:42]([NH:44][CH2:45][C:46]([OH:48])=O)=[O:43])[CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.[F:50][C:51]1[CH:52]=[C:53]([CH:59]=[C:60]([C:62]([F:65])([F:64])[F:63])[CH:61]=1)[O:54][CH:55]1[CH2:58][NH:57][CH2:56]1>CN(C=O)C>[F:50][C:51]1[CH:52]=[C:53]([CH:59]=[C:60]([C:62]([F:64])([F:63])[F:65])[CH:61]=1)[O:54][CH:55]1[CH2:58][N:57]([C:46](=[O:48])[CH2:45][NH:44][C:42]([C:39]2[CH:38]=[C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:41][N:40]=2)=[O:43])[CH2:56]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Fc1cc(OC2CNC2)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CC(Oc2cc(F)cc(C(F)(F)F)c2)C1)c1cc(-c2ccccc2)[nH]n1
Yield: 24.4 %

Procedure:
DIPEA (143 mg, 1.1 mmol) followed by HOBt (39 mg, 0.29 mmol) and EDCI (56 mg, 0.29 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (68 mg, 0.27 mmol) in DMF (2 mL) After 2 minutes of stirring, 3-(3-fluoro-5-trifluoromethyl-phenoxy)-azetidine hydrochloride (prepared by the method used for the synthesis of Intermediate 71) (75 mg, 0.27 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between cold water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by preparative HPLC afforded 31 mg (24.4% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[3-(3-fluoro-5-trifluoromethyl-phenoxy)-azetidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 463, 81.67%. 1H NMR (300 MHz, DMSO-d6): δ 13.75 (s, 1H), 7.8 (d, 2H), 7.42 (t, 2H), 7.26 (m, 2H), 7.1 (d, 1H), 7.04 (s, 1H), 5.2 (m, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 4.2 (m, 2H), 3.7 (m, 2H).