Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[NH:12][N:11]3[C:15](=[O:19])[N:16]([CH3:18])[N:17]=[C:10]3[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[N:12]([CH2:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)[N:11]3[C:15](=[O:19])[N:16]([CH3:18])[N:17]=[C:10]3[C:9]=2[C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)c(=O)[nH]n2c1=O
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)c(=O)n(Cc3ccc(C#N)cc3)n2c1=O
Temperature: 25 °C
Yield: 49.5 %

Procedure:
The solution of 7-(4-chlorophenyl)-2-methyl-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione (10 mg, 0.028 mmol), 4-(bromomethyl)benzonitrile (7 mg, 0.036 mmol), K2CO3(12 mg, 0.084 mmol) in DMF (0.5 ml), was heated at 80° C. for 20 min. After this time, the reaction mixture was cooled to RT and diluted with ethyl acetate. The resulting solution was then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound, 4-((7-(4-chlorophenyl)-2-methyl-3,6-dioxo-8-(pyridin-4-yl)-2,3-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-5(6H)-yl)methyl)benzonitrile (6.5 mg, 40%) as the mono trifluoro acetate salt as a yellow solid. Rt=2.78, M+H=469; 1H NMR (CD3OD) δ 8.81(2H), 7.71-7.60(6H), 7.32(2H), 7.07(2H), 5.96(2H), 3.57(3H).
Reaction SMILES: [CH2:1](B(O)O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+].Br[C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([C:25]([N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])=[O:26])[CH:24]=1)[C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:28]([N:27]([CH2:31][CH2:32][CH3:33])[C:25]([C:23]1[CH:22]=[C:17]([CH:16]=[C:15]([CH2:1][CH3:2])[CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:26])[CH2:29][CH3:30]
Reactant: CCB(O)O
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)OC)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Ethylboronic acid (0.800 g, 10.8 mmol), dichlorobis(triphenylphosphine)-palladium(II) (0.252 g, 0.360 mmol), potassium carbonate (2.50 g, 18.0 mmol) and lithium chloride (0.151 g, 3.60 mmol) are added to a mixture of methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (1.23 g, 3.60 mmol) in dry DMF (20 mL). The mixture is heated at 100 degrees C. for 18 hours. The mixture is then partitioned between ethyl acetate and water. The phases are separated and the ethyl acetate phase is washed with saline, dried over sodium sulfate and concentrated. The concentrate is column chromatographed (silica gel; ethyl acetate/hexanes, 15/85) to give the title compound, MS (ESI+) for C17H25NO3 m/z (M+H)+=292.2.
Reaction SMILES: [CH2:1](N(CC)CC)C.[CH2:8]([N:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:16]([C:18]([OH:20])=O)[CH3:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)=O.C(Cl)(Cl)(Cl)Cl.CC(C)(C)C(Cl)=O.C[Mg]Cl>O1CCCC1>[CH3:1][C:18]([CH:16]([N:15]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:17])=[O:20]
Reactant: CCN(CC)CC
Reactant: C[C@@H](C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: C[Mg]Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)C(C)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.75 h
Yield: 65 %

Procedure:
Triethylamine (8.85 mmol, 1.24 mL) was added under an argon atmosphere to a stirred solution of N,N-dibenzylalanine (8.85 mmol, 2.38 g) in tetrahydrofuran (THF) (53.0 mL) at -30° C. (dry ice/CCl4 bath). Trimethyl acetyl chloride (8.85 mmol, 1.42 mL) was then added dropwise via syringe and the turbid solution was allowed to stir at -30° C. for 30 minutes before dropwise addition of a solution of methylmagnesium chloride in THF (3.0M, 1.07 eq., 9.5 mmol, 3.23 mL) over 10 minutes. The solution was stirred for 45 minutes and then quenched with saturated solution of NH4Cl (5.0 mL). The solution was extracted with Et2O, the organic extracts washed with brine, dried over MgSO4, and filtered. The solvent was evaporated in vacuo and the residue was subjected to flash column chromatography on silica gel with 8:1 hexanes/ethyl acetate to isolate a pure product in 65% yield. Colorless oil; Rf =0.43 (7:1 hexanes/ethyl acetate) 1H NMR (300.15 MHz) δ1.19 (d, J=5.4 Hz, 3H), 2.25 (5, 3H), 3.39 (q, J=6.9 Hz, 1H), 2.57 (AB quartet, δA =3.33, δB =3. JAS=13.8 Hz, 4H), 7.19-7.43 (m, 10H); 13C NMR (75.5 MHz 7.1, 27.7, 54.6, 62.9, 27.2, 128.5, 128.8, 139.3, 210.8; IR (Neat) 1710 cm-1 ; MS (low resolution) m/e 268 M+H 22%), 224 (MeCHNBn2, 100%); HRMS for C18H22NO: 268-1709 (calc'd 268-1676); Anal: calc'd for C18H21NO: C 80.68, H 7.92, N 5.24; Found: C 80.79, H 7.95, N 5.17.
Reaction SMILES: O.[NH2:2][NH2:3].C1([O:10][C:11](=O)[NH:12][C:13]2[O:17][N:16]=[C:15]([CH3:18])[CH:14]=2)C=CC=CC=1>C(O)C>[CH3:18][C:15]1[CH:14]=[C:13]([NH:12][C:11]([NH:2][NH2:3])=[O:10])[O:17][N:16]=1
Reactant: NN
Reactant: Cc1cc(NC(=O)Oc2ccccc2)on1
Solvent: O
Solvent: CCO
Product: Cc1cc(NC(=O)NN)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrazine hydrate (95 μl) was added to a mixture of (3-methyl-isoxazol-5-yl)-carbamic acid phenyl ester (CA 81479-55-2) (417 mg) and ethanol (5 ml), and the resulting mixture was stirred overnight at room temperature. The precipitate was collected by filtration to obtain the title compound (100 mg).
Reaction SMILES: [C:1](O)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1>[Ti]>[CH:2]1([CH2:1][OH:11])[CH2:10][CH2:9][CH:5]([CH2:6][OH:7])[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: [Ti]
Product: OCC1CCC(CO)CC1
Yield: 59.2 %

Procedure:
A copolyester of terephthalic acid was produced by charging 35.0 grams of terephthalic acid (TPA), 50.0 grams of the PCI-oligomer produced in Example 1, 18.0 grams of 1,4-cyclo-hexanedimethanol, and approximately 50–70 parts per million (ppm) titanium catalyst (as acetyltriisopropyltitanate) based on final polymer weight to a 0.5 liter reaction vessel at room temperature. Total diol-to-diacid feed mole ratio in this case was 1.091:1. The reactor vessel was equipped with a mechanical agitator, a side arm for condensate removal, a nitrogen inlet port, and a heat source (generally an oil or metal bath). The reaction vessel was then immersed in the heat source and brought rapidly up to the starting temperature indicated in Table 1. Esterification and polymerization were carried out using the reaction profile shown in Table 1. For Example 2, the resulting polymer had an IV of 0.778 dl/g, an acid content of 38 meq/kg, and a titanium content of 48 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:34]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:9][C:10]2[N:11]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1.O.NN>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:34])[CH2:9][C:10]2[N:11]([C:15]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1C(Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Agent: NN
Solvent: O
Solvent: CO
Product: NC(Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
2-(1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethyl)isoindoline-1,3-dione (Intermediate 87) (1.78 g, 3.00 mmol) and hydrazine hydrate (0.204 mL, 4.19 mmol) in methanol (30 mL) were refluxed for 3 hours. The resulting clear solution was left to cool to room temperature overnight then filtered. The filtrate was applied to a 20 g SCX cartridge and eluted with methanol followed by 2N NH3(MeOH). Product-containing fractions were combined and concentrated by evaporation then purified by flash silica chromatography, elution gradient 2 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethanamine (0.942 g, 67.8%) as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([NH:7][CH3:8])=O.[N-:15]=[N+:16]=[N-:17].[Na+].S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:7]([CH3:8])[N:17]=[N:16][N:15]=2)[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CNC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cn1nnnc1-c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 41.1 %

Procedure:
3-bromo-N-methyl-5-nitrobenzamide (23.20 g, 90 mmol, 1 equiv.) was suspended in 200 ml of acetonitrile at 25° C. under nitrogen then sodium azide (5.82 g, 90 mmol, 1 equiv.) was added. Cooled to 0° C. then very slowly added triflic anhydride (15.07 ml, 90 mmol, 1 equiv.) dropwise via an addition funnel. The reaction became an amber solution. Worked up after 4 hours by adding 200 ml of sat'd NaHCO3 and stirred 10 minutes. Then added ethyl acetate and separated the layers. The ethyl acetate was rinsed twice with sat'd NaHCO3 then once with brine. The ethyl acetate was dried over MgSO4 then stripped in vacuo to give a dark amber oil which was stirred in 25 ml of ethyl acetate. After stirring 5 minutes, solids which precipitated were filtered off, and pumped under high vacuum to give 10.5 g of tan solids. The filtrate was stripped then purified over silica gel in 100% methylene chloride to obtain an additional 9.0 g of solids. By NMR both solids were identical for product and were combined.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([CH3:22])([CH3:21])[CH2:16][CH:17]([C:18](O)=[O:19])[C:11]2=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.[CH2:30]([CH2:32][NH2:33])[OH:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([CH3:22])([CH3:21])[CH2:16][CH:17]([C:18]([NH:33][CH2:32][CH2:30][OH:31])=[O:19])[C:11]2=[CH:10][C:9]=1[C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1
Reactant: CC1(C)CC(C(=O)O)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2O1
Reactant: NCCO
Product: CC1(C)CC(C(=O)NCCO)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2O1

Procedure:
Using the product of Step B and ethanolamine, along with the procedure described in Example 88, the title compound was afforded. Further separation on an AS chiral column, eluting with 7% EtOH/heptane, afforded the enantiomers: (LC-2) HPLC/MS (fast isomer on AS): 471.3 (M+1), 473.3 (M+3); Rt=3.13 min. (LC-2) HPLC/MS (slow isomer on AS): 471.3 (M+1), 473.3 (M+3); Rt=3.13 min.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:7][CH:8]=[CH2:9].[CH2:17]([Si:20](Cl)([CH3:22])[CH3:21])[CH:18]=[CH2:19]>C1COCC1>[CH2:17]([Si:20]([CH3:22])([CH3:21])[C:9]#[C:8][CH2:7][CH2:6][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:18]=[CH2:19]
Reactant: C=CCCOC1CCCCO1
Reactant: C=CC[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC[Si](C)(C)C#CCCOC1CCCCO1
Temperature: -78 °C

Procedure:
A solution of n-butyllithium (12.0 ml, 30 mmol, 2.5 mol dm−3 in hexanes) was added dropwise to a stirred, cooled (−78° C.) solution of compound 2 (4.62 g, 30 mmol) in THF (60 ml) under an atmosphere of dry nitrogen. The reaction mixture was maintained at −78° C. for 1.5 h and a solution of allylchlorodimethylsilane (4.04 g, 30 mmol) in THF (20 ml) added dropwise. The reaction mixture was allowed to warm to room temperature, washed with water and the organic layer extracted into ethyl acetate/hexane (3 times). The combined extracts were washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield a clear oil. The crude product was purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1), Rf: 0.48]
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[C:13]([Cl:21])=[C:14]([O:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[Li+].[OH-]>CO.C1COCC1.O>[Cl:21][C:13]1[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:11][C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:32])=[O:3])=[CH:15][C:14]=1[O:16][CH2:17][CH:18]1[CH2:20][CH2:19]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OCC2CC2)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(C(=O)O)c1cc(OCC2CC2)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.2 %

Procedure:
The ethyl-2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (120 mg, 0.255 mmol) dissolved in 10 mL of MeOH/THF/H2O (10 mL/10 mL/5 mL) and LiOH (30 mg, 1.2 mmol) was added. The reaction mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (DCM:MeOH 9:1) gave 2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (89 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.68 (d, 2H), 7.55 (d, 2H), 6.92 (s, 1H), 6.85 (s, 1H), 3.96 (d, 2H), 3.64 (t, 1H), 1.98 (m, 1H), 1.68 (m, 1H), 1.55 (m, 1H), 1.32 (m, 1H), 0.91 (d, 6H), 0.64 (m, 2H), 0.42 (m, 2H);
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([N:7]([C:26]2[CH:31]=[CH:30][C:29](OC)=[CH:28][CH:27]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:3][CH:2]=1.Cl.N1C=CC=CC=1.N1C=CC=CC=1.[F:53][C:54]([F:67])([F:66])[S:55]([O:58]S(C(F)(F)F)(=O)=O)(=[O:57])=[O:56]>>[F:53][C:54]([F:67])([F:66])[S:55]([O:58][C:29]1[CH:28]=[CH:27][C:26]([N:7]([C:4]2[CH:3]=[CH:2][C:1]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:6][CH:5]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:31][CH:30]=1)(=[O:57])=[O:56]
Reactant: COc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccccc3)cc2-c2ccccc2)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccccc3)cc2-c2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 17 h
Yield: 94.4 %

Procedure:
N-([1,1′-biphenyl]-4-yl)-N-(4-methoxyphenyl)-[1,1′:3′,1″-terphenyl]-4′-amine (12.4 g, 24.7 mmol) and pyridine hydrochloride (28.8 g, 250.0 mmol) were purged with nitrogen for overnight. The mixture was refluxed for 2 h. After cooling, the precipitate was filtered and washed by excess water. The solid dissolved in DCM was filtered through a silica pad and washed with DCM. The solvent was removed in vacuo. The residue was dissolved in DCM (100 mL) and cooled down to 0° C. After that, pyridine (8.1 mL, 100.0 mmol) and trifluoromethanesulfonic anhydride (8.4 mL, 50.0 mmol) were added at 0° C. The mixture was stirred for 17 h from 0° C. to room temperature. The reaction mixture was quenched by the addition of saturated K2CO3 solution and extracted with DCM. The extracts were dried over MgSO4 and the solvent was removed in vacuo and the residue was purified by flash chromatography using 15% toluene/hexane (containing 0.5% triethylamine) to afford 4-([1,1′-biphenyl]-4-yl([1,1′:3′,1″-terphenyl]-4′-yl)amino)phenyl trifluoromethanesulfonate (14.5 g, 95% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][CH:19]([OH:21])[CH3:20]>>[OH:21][CH:19]([CH3:20])[CH2:18][N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: CC(O)CCl
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)O

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 1-chloro-2-propanol: 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=8.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 6.59 (s, 1H), 4.20 (m, 1H), 4.12 (m, 2H), 2.52 (s, 3H), 1.33 (d, J=6.1 Hz, 3H); MS (ES) m/z 283 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:9][C:10]1([CH3:13])[CH2:12][O:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:9][C:10]([OH:11])([CH3:13])[CH3:12])[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cc(Br)ccc1=O
Temperature: 100 °C
Yield: 76 %

Procedure:
A mixture of 5-bromopyridin-2(1H)-one (600 mg, 3.5 mmol), 2,2-dimethyloxirane (750 mg, 10 mmol) and K2CO3 (960 mg, 6.9 mmol) in DMF (3 mL) was heated at 100° C. for 2 hours. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate (80 mL), washed with water, brine, and dried over MgSO4. The organic layer was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 10 to 50% EtOAc/hexane) to give Compound B387a (650 mg, 76% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.50 (d, J=2.6 Hz, 1H), 7.40 (dd, J=9.6, 2.8 Hz, 1H), 6.54 (d, J=9.7 Hz, 1H), 3.99 (s, 2H), 3.57-3.39 (s, 1H), 1.27 (s, 6H).
Reaction SMILES: O.[CH3:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:6]([O:8][C:9](=[O:27])[C@@H:10]([C@H:12]([C:14]([O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)=[O:15])[OH:13])[OH:11])=[O:7]>C1(C)C=CC=CC=1>[OH2:7].[CH3:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:6]([O:8][C:9](=[O:27])[C@H:10]([C@@H:12]([C:14]([O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)=[O:15])[OH:13])[OH:11])=[O:7]
Reactant: Cc1ccc(C(=O)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(=O)c2ccc(C)c(C)c2)cc1C
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C(=O)OC(=O)[C@@H](O)[C@H](O)C(=O)OC(=O)c2ccc(C)c(C)c2)cc1C
Temperature: 63 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To the reaction vessel employed in Example 30, 50 g of O,O'-bis(3,4-dimethylbenzoyl)-L-tartaric anhydride and 150 g of water were supplied and the mixture was stirred at 90°-95° C. for 1 hour to carry out hydrolysis. After cooling the reaction mixture to 63° C., 5 g of toluene and 0.1 g of seed crystal of O,O'-bis(3,4-dimethylbenzoyl)-L-tartaric acid were added and the mixture was slowly cooled. Since oily product began to crystalize at 60° C., the mixture was stirred for 1 hour at this temperature. After completion of crystallization, the reaction slurry was cooled to room temperature and the crystals were collected by filtration. The thus obtained cake was dried to obtain 52.1 g of O,O'-bis(3,4-dimethylbenzoyl)-D-tartaric acid hydrate in the form of white crystals. The content of crystal water was measured by Karl Fischer method, which was 3.8% (yield: 95.9%). The crystals were sieved through a 20-mesh sieve and 96 wt % of the crystals passed through the sieve. The amount of the crystals which adhered to the wall or to the stirrer of the reaction apparatus so that which could not be removed from the reaction apparatus was 1.3 g which was 2.4 wt % of the total crystals produced.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:33][N:32]=[C:31]2[C:7]=1[CH2:8][CH:9]1[CH:22]3[CH:13]([C:14]4[CH:15]=[CH:16][C:17]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:18][C:19]=4[CH2:20][CH2:21]3)[CH2:12][CH2:11][C:10]12[CH3:34])=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH2:24]([O:23][C:17]1[CH:16]=[CH:15][C:14]2[CH:13]3[CH:22]([CH2:21][CH2:20][C:19]=2[CH:18]=1)[CH:9]1[CH2:8][C:7]2[C:31]([C:10]1([CH3:34])[CH2:11][CH2:12]3)=[N:32][NH:33][C:6]=2[CH2:4][OH:3])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1[nH]nc2c1CC1C3CCc4cc(OCc5ccccc5)ccc4C3CCC21C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC12CCC3c4ccc(OCc5ccccc5)cc4CCC3C1Cc1c2n[nH]c1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Benzyloxy-6a-methyl-4b,5,6,6a,8,10,10a,10b,11,12-decahydro-7,8diaza-pentaleno[2,1-a]phenanthrene-9-carboxylic acid ethyl ester (457 mg, 1.0 mmol, CAB03049) was added to a suspension of LiAlH4 (100 mg) in THF (20 mL). The mixture was stirred for 30 minutes at room temperature, then water (1 mL) was added (to destroy the excess of LiAlH4). Stirring was continued for 1 hour (light yellowgreen suspension), acetic acid (0.5 mL) was added, the inorganic solids were filtered of and washed carefully with THF (ca. 50 mL).The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was crystallised from ethyl acetate/diethyl ether. Yield: 215 mg (52%) colorless crystals. 1H-NMR (CDCl3, 400 MHz), δ: 1.01 (s, 3H, —CH3), 1.40-2.46 (m, 10 H), 2.60 (dd, J=13.7, 6.3 Hz, 1H), 2.82-3.00 (m, 2H), 4.69 (s, 2H, —CH2OH), 5.04 (s, 2H, —CH2Ph), 6.28 (bs, 2H, —OH and NH), 6.73 (d, J=2.3 Hz, 1H), 6.80 (dd, J=8.6, 2.3 Hz, 1H), 7.21 (d, J=8.6 Hz, 1H), 7.30-7.45, (m, 5H). LRMS (FAB+): 91.1 (100), 415.3 (60, [M+H]+). HRMS (FAB+): 415.238434 C27H31N2O2 requires 415.238554
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([Cl:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH2:18]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>O1CCOCC1.C(OCC)(=O)C>[CH2:18]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:17])[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1Nc1ccc(Cc2ccccc2)cc1
Temperature: 85 °C
Yield: 71.3 %

Procedure:
To a solution of Ethyl-4,6-dichloroquinoline-3-carboxylate (1.0 g, 3.7 mmol) in 1,4-dioxane (10 mL) was added a solution of 4-benzylbenzenamine (733 mg, 4.0 mmol) in 1,4-dioxane (10 mL) at room temperature. After stirred at 85° C. 1 hour, the reaction mixture was then cooled down to room temperature and then treated with 20 mL of water. The resulting suspension treated with 10 NNaOH solutions to reach the pH about 9. It was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 9:1 v/v hexane:ethyl acetate as solvent to afford title compound (1.1 g, 65% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].[F:7][C:8]([F:16])([F:15])[CH:9]([OH:14])[C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C>O>[F:1][C:2](=[CH2:6])[C:3]([O:14][CH:9]([C:10]([F:13])([F:12])[F:11])[C:8]([F:16])([F:15])[F:7])=[O:4]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: C=C(F)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(F)C(=O)OC(C(F)(F)F)C(F)(F)F
Reaction time: 3 h

Procedure:
12 g of 2-fluoroacryloyl chloride and 27 g of 1,1,1,3,3,3-hexafluoro-2-propanol were introduced into a round-bottomed flask placed in an ice bath. 16 g of triethylamine were added portionwise to the reaction mixture. After reacting for an additional 3 h, approximately 70 ml of water were added. The aqueous and organic phases were subsequently separated and the organic phase was analysed by GC. The conversion of the 1,1,1,3,3,3-hexafluoroisopropanol was 68%. The yield of ester, based on the amount of 2-fluoroacrylic acid employed in the first stage, was 66%.