Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([O:11]C)([O:9][CH3:10])[CH2:4][CH2:5][CH2:6][C:7]#[CH:8].C([Li])CCC.[CH2:18]([O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[CH:36]=[O:37])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>O1CCCC1.CCOCC>[CH2:18]([O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[CH:36]([OH:37])[C:8]#[C:7][CH2:6][CH2:5][CH2:4][C:3]([O:9][CH3:10])=[O:11])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1ccc2ccccc2c1OCc1ccccc1
Reactant: C#CCCCC(OC)(OC)OC
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CCCC#CC(O)c1ccc2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
A solution of 1,1,1-trimethoxy-5-hexyne (3.90 g, 0.023 mo)e) in dry tetrahydrofuran (50 mL) was stirred at -78° and treated with n-butyllithium (1.6M in hexane; 15 mL, 0.024 mole). The solution was stirred for 30 minutes, then treated with a solution of 1-benzyloxy-2-naphthaldehyde (4.25 g. 0.016 mole) in dry tetrahydrofuran (12 mL). The reaction mixture was allowed to warm to room temperature, stirred for 4 hours, and poured into water. The crude product was isolated by extraction with ether and chromatographed with 3:1 ether/hexane. This afforded the title compound (6.15 g. 97%) as an oil.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:7][O:6][CH:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:4]1[CH2:14][CH2:15][CH2:16][OH:17].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C)C=O>[Si:18]([O:17][CH2:16][CH2:15][CH2:14][CH:4]1[CH:3]([OH:2])[CH2:7][O:6][CH:5]1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCC1C(O)COC1c1cccnc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCC1C(O)COC1c1cccnc1

Procedure:
A solution of 10 g (0.0448 mole) of 4-hydroxy-3-(3-hydroxyprop-1-yl)-2-(3-pyridyl)tetrahydrofuran hydrochloride, 7.68 g (0.048 mole) of t-butyldimethylsilyl chloride and 6.86 g (0.0977 mole) of imidazole in 105.8 ml of dimethylformamide is stirred at room temperature for 15 h and evaporated. The residue is triturated with ethyl acetate and washed with water and brine, dried (MgSO4) and evaporated. The residue is purified by flash chromatography using methylene chloride-ethyl acetate-methanol (20:4:1) to give 3-(3-t-butyldimethylsilyloxyprop-1-yl)-4-hydroxy-2-(3-pyridyl)tetrahydrofuran as an oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:28]=[CH:27][C:10]2[C:11]3[N:12]([CH:16]=[C:17]([C:19]4[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[CH:21][N:20]=4)[N:18]=3)[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=O)=O.[NH:31]1[CH2:35][CH:34]=[CH:33][C@@H:32]1[C:36]([NH2:38])=[O:37].C(N(CC)C(C)C)(C)C.CN(C)C(=O)C>>[CH:24]([N:23]1[C:19]([C:17]2[N:18]=[C:11]3[C:10]4[CH:27]=[N:28][C:7]([N:31]5[CH2:35][CH:34]=[CH:33][C@@H:32]5[C:36]([NH2:38])=[O:37])=[CH:8][C:9]=4[O:15][CH2:14][CH2:13][N:12]3[CH:16]=2)=[N:20][CH:21]=[N:22]1)([CH3:25])[CH3:26]
Reactant: NC(=O)[C@H]1C=CCN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OS(=O)(=O)C(F)(F)F)cc1OCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CC=C[C@@H]3C(N)=O)cc1OCC2
Temperature: 80 °C

Procedure:
A mixture of 134 mg (0.30 mmol) of 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl trifluoromethanesulfonate, (R)-2,5-dihydro-1H-pyrrole-2-carboxamide (84.1 mg, 0.750 mmol) and N,N-diisopropylethylamine (61.0 uL, 0.350 mmol) in N,N-Dimethylacetamide (3.0 mL, 32 mmol) was heated for 18 hours at 80° C. The mixture was concentrated in high vacuum, the residue triturated with 5% aqueous citric acid. The precipitate was filtered out, washed with aq. citric acid, water, dried in vacuum and purified by RP HPLC (acetonitrile gradient) to give 388. Yield 28 mg. M/z 407.2, calc. 406.19. 1H NMR (400 MHz, DMSO) δ 9.08 (s, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.38 (s, 1H), 6.98 (s, 1H), 6.13 (dd, J=6.2, 1.9, 1H), 6.02-5.88 (m, 3H), 4.97 (s, 1H), 4.52 (dd, J=9.3, 7.1, 4H), 4.39-4.18 (m, 2H), 1.48 (dd, J=6.6, 2.5, 6H)
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12](#[N:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15]>C(OCC)(=O)C>[C:12]([C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:4](=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]([OH:6])=[O:11])#[N:20]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: N#Cc1ccccc1N
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1NC(=O)c1ccccc1C(=O)O

Procedure:
A solution of sublimed phthalic anhydride in ethyl acetate is reacted with a solution of anthranilonitrile in ethyl acetate to form 2'-cyanophthalanilic acid. The 2'-cyanophthalanilic acid is then boiled with acetic anhydride to convert the acid to 2'-cyanophthalanil. The 2'-cyanophthalanil is thereafter boiled in a mixture containing 2% potassium hydroxide and 2.4% hydrogen peroxide, cooled and neutralized with hydrochloric acid to cyclicize it and form isoindolo [2,1-a]quinazoline-5,11-dione. A similar procedure is set forth by Bogert and Hand, 24 J. Am. Chem. Soc., 1031 (1902) for preparing 2-methyl-4-ketodihydroquinazoline from N-acetylanthranilonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][CH:7]2[CH2:10][NH:9][CH2:8]2)=[CH:4][CH:3]=1.[C:13]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH2:21][CH2:22]Br)([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:13]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH2:21][CH2:22][N:9]1[CH2:8][CH:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=2)[CH2:10]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Clc1ccc(CC2CNC2)cc1
Reactant: CC(C)(C)OC(=O)NCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCN1CC(Cc2ccc(Cl)cc2)C1

Procedure:
A solution of 3-(4-chloro-benzyl)-azetidine (1.0 g, 5.50 mmol), (3-bromo-propyl)-carbamic acid tert-butyl ester (1.31 g, 5.50 mmol) and diisopropylethylamine (1.91 ml, 11.0 mmol) in dry dimethylformamide (20 ml) is stirred at ambient temperature for 18 hours. The reaction mixture is partitioned between ethylacetate and water. The organic phase is washed with water and brine, dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography using 5% methanol in dichloromethane as eluent to afford {3-[3-(4-Chloro-benzyl)-azetidin-1-yl]-propyl]-carbamic acid tert-butyl ester. [M+H] 339.15
Reaction SMILES: [Br:1][C:2]1[C:15]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:21])=[CH:9][CH:10]=3)[C:5](=[O:22])[C:4]=2[CH:3]=1.[CH3:23][Mg]Cl.BrC1C=CC2OC3C(=NC(Cl)=CC=3F)C(=C)C=2C=1>C1COCC1>[Br:1][C:2]1[C:15]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:21])=[CH:9][CH:10]=3)[C:5]([CH3:23])([OH:22])[C:4]=2[CH:3]=1
Reactant: O=c1c2cc(I)ccc2oc2cc(OC(F)(F)F)c(Br)cc12
Reactant: C[Mg]Cl
Agent: C=C1c2cc(Br)ccc2Oc2c(F)cc(Cl)nc21
Solvent: C1CCOC1
Product: CC1(O)c2cc(I)ccc2Oc2cc(OC(F)(F)F)c(Br)cc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
A RBF was charged with 2-bromo-7-iodo-3-(trifluoromethoxy)-9H-xanthen-9-one (2.94 g, 6.06 mmol) and THF (33.7 mL). The black suspension was cooled to −78° C. using an i-PrOH/dry ice bath. Methylmagnesium chloride (3.0 M in THF, 4.45 mL, 13.34 mmol) was added dropwise. After 2 h, LCMS showed olefin product. The whole was quenched with satd' aq NH4Cl (20 mL) at 0° C., water (50 mL) and diluted with EtOAc (100 mL). The product was extracted with EtOAc (3×50 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated to afford yellow oil. 1H NMR confirmed the tertiary alcohol, 2-bromo-7-iodo-9-methyl-3-(trifluoromethoxy)-9H-xanthen-9-ol (3.04 g, 6.07 mmol, 100% yield). LCMS (ESI) calcd for C15H9BrF3IO3: [M]+=500. Found [M−H2O+H]+=483. Dehydration took place on LCMS to give the olefin, 2-bromo-7-iodo-9-methylene-3-(trifluoromethoxy)-9H-xanthene). This material was carried on to the next step.
Reaction SMILES: [Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[Cl:13][C:14]1[C:19]([NH:20][C:21]2[N:26]=[C:25]([N:27]([CH:37]3[CH2:39][CH2:38]3)[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:24]3=[N:40][CH:41]=[C:42]([C:43]#[N:44])[N:23]3[N:22]=2)=[CH:18][C:17]([C:45]#[N:46])=[CH:16][C:15]=1[N:47]1[CH2:52][CH2:51][CH:50]2[N:53](C(OC(C)(C)C)=O)[CH2:54][CH2:55][CH:49]2[CH2:48]1.N1C(C)=CC=CC=1C>ClCCl>[Cl:13][C:14]1[C:15]([N:47]2[CH2:52][CH2:51][CH:50]3[NH:53][CH2:54][CH2:55][CH:49]3[CH2:48]2)=[CH:16][C:17]([C:45]#[N:46])=[CH:18][C:19]=1[NH:20][C:21]1[N:26]=[C:25]([N:27]([CH:37]2[CH2:39][CH2:38]2)[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[C:24]2=[N:40][CH:41]=[C:42]([C:43]#[N:44])[N:23]2[N:22]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC5C(CCN5C(=O)OC(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC5NCCC5C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
TMS-OTf (0.281 ml, 1.553 mmol) was added to a solution of tert-butyl 5-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (360 mg, 0.518 mmol) and 2,6-lutidine (0.181 ml, 1.553 mmol) in dichloromethane (3 ml) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, The crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 5-40% ethyl acetate/hexanes). 2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (288 mg) was obtained as an off-white solid.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[CH3:21])=[C:10]([CH3:12])[CH:11]=2)[N:5]=[C:6]([CH3:8])[CH:7]=1.[C@@H:22]([NH2:26])([CH2:24][CH3:25])[CH3:23].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[N:4]3[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([NH:26][C@@H:22]([CH3:23])[CH2:24][CH3:25])[C:3]3=[CH:11][C:10]=2[CH3:12])=[C:14]([CH3:21])[CH:15]=1
Reactant: COc1ccc(-c2c(C)cc3c(Br)cc(C)nn23)c(C)c1
Reactant: CC[C@H](C)N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC[C@H](C)Nc1cc(C)nn2c(-c3ccc(OC)cc3C)c(C)cc12
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-7-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrrolo[1,2-b]pyridazine (0.137 g, 0.397 mmol), (S)-(+)-sec-butylamine (0.08 mL, 0.794 mmol), xantphos (0.025 g, 0.04 mmol), Cs2CO3 (0.18 g, 0.55 mmol) and Pd2(dba)3 (0.018 g, 0.02 mmol) in dioxane (4.0 mL) was refluxed for 17 h. Extra (S)-(+)-sec-butylamine (0.08 mL, 0.794 mmol), xantphos (0.025 g, 0.04 mmol) and Pd2(dba)3 (0.018 g, 0.02 mmol) were added to the reaction mixture and refluxed for additional 4 h. After cooling to room temperature, the mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo to dryness, the residue was subjected to column chromatography (silica gel, 1/10 EtOAc/heptane) to give 0.024 g (18%) of light yellow oil as the title compound. 1H NMR (300 MHz, CDCl3) δ 7.23 (d, J=11 Hz, 1H), 6.89 (d, J=4 Hz, 1H), 6.83 (dd, J=4, 11 Hz, 1H), 6.29 (br s, 1H), 5.54 (s, 1H), 3.87 (s, 3H), 3.64–3.56 (m, 1H), 2.32 (s, 3H), 2.16 (s, 3H), 2.11 (s, 3H), 1.77–1.57 (m, 2H), 1.32–1.28 (m, 3H), 1.06–0.99 (m, 3H); MS m/z 338.4 (M++H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-])=O.[H][H]>CO.[Ni]>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH2:9]
Reactant: CNc1ccncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CNc1ccncc1N
Yield: 83.8 %

Procedure:
2.3 g methyl-(3-nitropyridin-4-yl)-amine are hydrogenated in 50 ml of methanol with 0.8 g Raney nickel for 2.5 h at 50° C. under 50 psi hydrogen pressure. The catalyst is filtered off and the filtrate is evaporated to dryness. The product is purified by chromatography (Alox, dichloromethane/methanol of 99/1 to 19/1). 1.55 g product are obtained in the form of a solid. m.p: 163-165° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][C:8]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:9]=1[O:10][CH2:11][CH2:12][C:13]([OH:15])=O.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:7][C:8]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]2[C:9]=1[O:10][CH2:11][CH2:12][C:13]2=[O:15]
Reactant: COc1ccc(OCCC(=O)O)c(Cl)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: COc1cc(Cl)c2c(c1)C(=O)CCO2
Temperature: 0 °C
Yield: 92.8 %

Procedure:
Phosphorous pentachloride (1.3 g; 6.2 mmol) was added to a suspension of 3-(2-chloro-4-methoxyphenoxy)propionic acid (0.85 g; 3.7 mmol; from step (ii) above) in benzene (10 mL). The resultant clear solution was heated quickly to boiling and then cooled on an ice bath. Aluminium chloride (1.5 g; 11 mmol) was added in portions and, after complete addition, ice water was added. Extraction with ether, washing of the organic layer with NaHCO3/aq. and NaOH (2M; aq.), drying (Na2SO4) and concentration yielded 0.73 g (93%) of the sub-title compound.
Reaction SMILES: COCCN(S(F)(F)F)CCOC.B(F)(F)F.CCOCC.[C:23]([O:31][CH2:32][C@@:33]1([CH3:40])[CH2:38][C:37](=O)[CH2:36][CH2:35][O:34]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[FH:41].[FH:42].F.C(N(CC)CC)C.C[N+]1([O-])CCOCC1>C(Cl)Cl.CC(C)=O.CCOC(C)=O.[Os](=O)(=O)(=O)=O.O.C1COCC1>[C:23]([O:31][CH2:32][C@@:33]1([CH3:40])[CH2:38][C:37]([F:42])([F:41])[CH2:36][CH2:35][O:34]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@]1(COC(=O)c2ccccc2)CC(=O)CCO1
Reactant: F
Agent: O=[Os](=O)(=O)=O
Agent: COCCN(CCOC)S(F)(F)F
Agent: C[N+]1([O-])CCOCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@]1(COC(=O)c2ccccc2)CC(F)(F)CCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 289.2 %

Procedure:
To a solution of Deoxo-Fluor® (1.5 mL, 8.14 mmol) in DCM (5 mL) was added boron trifluoride etherate (1 mL, 7.89 mmol) dropwise at 0° C. The mixture was stirred at rt for 1 h. A solution of (R)-(2-methyl-4-oxotetrahydro-2H-pyran-2-yl)methyl benzoate (0.7 g, 2.82 mmol) in DCM (5 mL) and triethylamine trihydrofluoride (0.1 mL, 0.614 mmol) were added dropwise in a 0° C. The reaction mixture was stirred at rt for 18 h and was recooled the reaction mixture in ice bath, added another portion of Deoxo-Fluor® (1 mL, 5.42 mmol) dropwise. The reaction mixture was stirred at rt for another 2 h. The reaction mixture was cautionly poured into a stirred ice cold aq. NaHCO3 solution and extracted with EtOAc (2×). The combined organic extraction was washed with NaHCO3, brine, dried (MgSO4), removed the solvent and purified on a 25 g silica gel cartridge (EtOAc/hex: 0 to 20%) to afford the product contaminated with vinyl by-product. The product was dissolved in acetone (4 mL), THF (16 mL), and added water (4 mL), NMO (0.330 g, 2.82 mmol) and osmium tetroxide (0.4 mL, 0.032 mmol) in ice bath. The reaction mixture was stirred at rt for 3 days and was diluted with EtOAc, washed with water, NH4Cl, brine, dried (MgSO4) and purified by silica gel flash chromatography to afford (R)-(4,4-difluoro-2-methyltetrahydro-2H-pyran-2-yl)methyl benzoate (0.48 g, 63%). 1H NMR (400 MHz, CHLOROFORM-d) ppm 8.13-8.04 (m, 2H), 7.60 (tt, J=7.4, 1.3 Hz, 1H), 7.52-7.39 (m, 2H), 4.42-4.34 (m, 1H), 4.24 (d, J=11.5 Hz, 1H), 4.00-3.84 (m, 2H), 2.21-1.93 (m, 4H), 1.46-1.36 (m, 3H).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:18][O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[O:19][CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccccc1N
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1ccccc1OC
Yield: 33.6 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (4.95 g, 20mmol), 2-methoxyaniline (4.51 ml, 40mmol) and tetrahydrofuran (20 ml) were stirred at room temperature overnight. The hydrochloride salt was filtered off, converted to free base and recrystallised from ethyl acetate/petroleum ether to give 3-butyryl-4-(2-methoxyphenylamino)-8-methylquinoline (2.25 g), m.p. 135°-137°.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[C:25]([Br:26])=[CH:24][C:23]([C:27](=[O:29])[CH3:28])=[C:22]([OH:30])[C:21]=2[CH2:31][CH2:32][CH3:33])[C:7]=1[CH2:34][CH2:35][CH3:36].[OH-].[Na+]>CO.C(OCC)(=O)C>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:37])=[O:2])=[C:7]([CH2:34][CH2:35][CH3:36])[C:8]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:25]([Br:26])=[CH:24][C:23]([C:27](=[O:29])[CH3:28])=[C:22]([OH:30])[C:21]=1[CH2:31][CH2:32][CH3:33])(=[O:14])[CH3:13]
Reactant: CCCc1c(O)c(C(C)=O)cc(Br)c1OCCCOc1c(C(C)=O)ccc(OCC(=O)OC)c1CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(O)c(C(C)=O)cc(Br)c1OCCCOc1c(C(C)=O)ccc(OCC(=O)O)c1CCC
Reaction time: 16 h
Yield: 47.8 %

Procedure:
To a solution of 2.1 g (0.0037 mol) of [4-acetyl-3-[3-(4-acetyl-6-bromo-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid methyl ester in 50 ml of methanol was added 50 ml (0.05 mol) of 1N sodium hydroxide. The mixture was stirred at 25° for 16 hours and acidified to pH 4. The gummy precipitate was dissolved in ethyl acetate and washed with sodium choloride solution. The gummy solid obtained on concentration of the ethyl acetate was purified by C18 reverse phase column chromatography, eluting with 60% to 75% of methanol in water to yield 1.0 g, melting point 129°-130° (48% yield) of [4-acetyl-3-[3-(4-acetyl-6-bromo-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:20])[CH2:16][C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[F:31][C:32]1[CH:33]=[C:34]([NH2:54])[CH:35]=[CH:36][C:37]=1[O:38][C:39]1[CH:44]=[CH:43][N:42]=[C:41]2[CH:45]=[C:46]([C:48]3[N:49]([CH3:53])[CH:50]=[CH:51][N:52]=3)[S:47][C:40]=12.C(Cl)CCl>>[F:31][C:32]1[CH:33]=[C:34]([NH:54][C:17](=[O:19])[CH2:16][C:15]([NH:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:20])[CH:35]=[CH:36][C:37]=1[O:38][C:39]1[CH:44]=[CH:43][N:42]=[C:41]2[CH:45]=[C:46]([C:48]3[N:49]([CH3:53])[CH:50]=[CH:51][N:52]=3)[S:47][C:40]=12
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)CC(=O)O)CC1
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.4 %

Procedure:
To a solution of acid 42 (76 mg, 0.266 mmol) and HOBt (40 mg, 0.30 mmol) was added amine 9 (100 mg, 0.29 mmol) and the mixture was stirred at room temperature for 5 min. EDC (62 mg, 0.32 mmol) was added and combined mixture was stirred for additional 48 hours. Additional 42 (38 mg, 0.133 mmol) and EDC (31 mg, 0.16 mmol) were added and the reaction mixture was stirred for a further 24 hours. Again additional 42 (38 mg, 0.133 mmol) and EDC (31 mg, 0.16 mmol) were added and the reaction mixture was stirred for 24 hours more then partitioned between EtOAc and NaHCO3 solution. The organic phase was washed with brine, dried over anhydrous Na2SO4 then filtered and concentrated. The residue was purified by preparative HPLC to afford tert-butyl 4-(3-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylamino)-3-oxopropanamido)piperidine-1-carboxylate 42a (20 mg, 13% yield) as a white solid. This material was dissolved in a solution of TFA/DCM (1 mL/2 mL), stirred for 20 min and concentrated. The residue was purified by preparative HPLC (column Aquasil C-18, gradient, MeOH 60% to MeOH 95% in water) to afford the title compound 43 as a tris-trifluoroacetate salt (31 mg, 99%), white solid. 1H NMR (DMSO-d6) δ (ppm): 10.49 (s, 1H), 8.55 (d, 1H), 8.49 (bs, 1H), 8.27 (d, 1H), 8.00 (s, 1H), 7.86 (dd, 1H), 7.55 (s, 1H), 7.49 (t, 1H), 7.39 (dd, 2H), 7.26 (s, 1H), 6.74 (d, 2H), 4.00 (s, 2H), 3.83 (m, 1H), 3.24 (m, 2H), 3.00 (m, 2H), 1.92 (m, 2H), 1.56 (m, 2H). MS (m/z): 509.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([S:22]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: FC(F)(F)c1ccc(C2CCCN2)cc1
Product: O=S(=O)(c1ccccc1)N1CCCC1c1ccc(C(F)(F)F)cc1

Procedure:
The title compound, white solid, m.p. 95° C. and MS: m/e=355 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-trifluoromethyl-phenyl)-pyrrolidine and benzenesulfonyl chloride.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8]([CH:10]=[O:11])C.C(OC(N[C@H](CCCCNC(OC(C)(C)C)=O)C(NCCC(O[C:29]1[CH:30]=[CH:31][C:32]2[C:38]3[C:39]([O:47][CH3:48])=[C:40]([O:45][CH3:46])[C:41]([O:43][CH3:44])=[CH:42][C:37]=3[CH2:36][CH2:35][C@H:34]([NH:49][C:50](=[O:52])[CH3:51])[C:33]=2[CH:53]=1)=O)=O)=O)(C)(C)C>ClCCl>[C:10]([C:29]1[CH:30]=[CH:31][C:32]2[C:38]3[C:39]([O:47][CH3:48])=[C:40]([O:45][CH3:46])[C:41]([O:43][CH3:44])=[CH:42][C:37]=3[CH2:36][CH2:35][C@H:34]([NH:49][C:50](=[O:52])[CH3:51])[C:33]=2[CH:53]=1)(=[O:11])[NH2:8]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc1[C@@H](NC(C)=O)CC2
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1ccc(C(N)=O)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
Oxalyl chloride (0.44 g; 3.4 mmol) and DMF (50 μl) were added to a suspension of N-[(5S)-3-carboxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide (1) under argon atmosphere (1.15 g; 3 mmol) in dichloromethane (10 ml). The mixture was stirred at ambient temperature for 2 hours, evaporated to dryness and redissolved in dichloromethane (20 ml). The solution was cooled at −78° C. and ammonia gas was allowed to bubble through the solution for 5 minutes. The mixture was allowed to warm up and further stirred at ambient temperature for 15 minutes. After evaporation to dryness, the residue was taken up in aqueous sodium hydrogen carbonate/ethyl acetate. The organic phase was separated, evaporated and purified by flash chromatography eluting with ethyl acetate/methanol (95/5) to give N-[(5S)-3-carbamoyl-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15]C)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].B(Br)(Br)Br>ClCCl>[OH:15][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:14][CH2:13]2
Reactant: COC(=O)C1CCc2cccc(OC)c2C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)C1CCc2cccc(O)c2C1
Reaction time: 3 h
Yield: 76.7 %

Procedure:
To 8-Methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid methyl ester (660 mg, 3.0 mmol) in dichloromethane (3.0 mL) was added BBr3 (1 M, 3.0 mL, 3.0 mmol) at −78° C. The mixture was stirred for 3 hour and then worked up to give 8-hydroxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (470 mg, 2.3 mmol, 77%).