Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=O)[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:35])[CH3:34].[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:14])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)[CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:35])[CH3:34]
Reactant: Cc1ccc(N2CCN(c3cccc(C4CC(C)(C)c5cc(F)cc(C(=O)O)c5N4)c3)CC2)cc1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(N2CCN(c3cccc(C4CC(C)(C)c5cc(F)cc(C(=O)NS(C)(=O)=O)c5N4)c3)CC2)cc1
Yield: 19.9 %

Procedure:
A mixture of 6-fluoro-4,4-dimethyl-2-[3-(4-p-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (150 mg, 0.32 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (91 mg, 0.48 mmol), 4-dimethylaminopyridine (59 mg, 0.48 mmol), methane sulfonamide (91.2 mg, 0.96 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-{6-fluoro-4,4-dimethyl-2-[3-(4-p-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carbonyl}-methanesulfonamide (35 mg, 20%) as a light yellow solid: MS (ESI) M+1=551.3.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[SH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>O>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[S:11][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Sc1ccc2ccccc2c1
Reactant: O=C(O)c1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1Sc1ccc2ccccc2c1

Procedure:
A well stirred mixture of 37.2 g. (0.15 mole) of o-iodobenzoic acid, 34.0 g. (0.15 mole) of 2-mercaptonaphthalene, 20.6 g. (0.15 mole) of potassium carbonate and 300 ml. of pyridine is heated at 50° C. for 1 hour, then 5 g. of cuprous chloride is added and the stirred mixture is heated at reflux for 18 hours. The mixture is poured into 1.2 liters of water and filtered. The filtrate is acidified and the resulting mixture is extracted into methylene chloride. The extracts are dried, concentrated, and the solid residue is recrystallized to give 2-(2-naphthylthio)benzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:14][CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:14][CH2:15][CH2:16][OH:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1CCCO
Temperature: 85 °C
Yield: 94.9 %

Procedure:
To a solution of (S)-pyrrolidine-2-carboxylic acid tert-butyl ester (350 mg, 2.04 mmol) in CH3CN (5 mL), 3-bromo-propan-1-ol (268 μL, 3.06 mmol) and K2CO3 (844 mg, 6.12 mmol) were added. The mixture was heated at 85° C. overnight, concentrated and purified by silica gel column chromatography (DCM/MeOH=95/5) to afford 444 mg (S)-1-(3-hydroxy-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester. MS: 230.2 (M+H)+, tR=0.99 min (method 1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[NH2:27][CH2:28][C@H:29]([OH:31])[CH3:30]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][C@H:29]([OH:31])[CH3:30])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: C[C@@H](O)CN
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: c1ccncc1
Product: C[C@@H](O)CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 95.7 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg) and (R)-1-amino-2-propanol (150 mg) were added to pyridine (450 mg), and the mixture was stirred at 55° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Concentrated hydrochloric acid (150 mg) was added to the resultant residue, and the mixture was concentrated under reduced pressure. Ethanol (1 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (164 mg) as a colorless powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].C([Li])CCC.CN(C)[C:16](=[O:18])[CH3:17].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:7][C:3]1[C:2]([CH2:8][C:16](=[O:18])[CH3:17])=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccnc1C
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)Cc1ncccc1C
Temperature: 0 °C

Procedure:
To a stirred solution of 2,3-lutidine (3.21 g) in tetrahydrofuran (20 ml) was added a solution of n-butyllithium in n-hexane (1.56M, 23.1 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (3.63 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×3). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, n-hexane:ethyl acetate=1:2) to give 1-(3-methylpyridin-2-yl)propan-2-one (3.70 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[CH:4][C:5]2[N:9]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:12][CH2:11]3)[NH:7][C:6]=2[CH:26]=1.C(N(CC)C(C)C)(C)C.[CH3:40][Si:41]([CH3:48])([CH3:47])[CH2:42][CH2:43][O:44][CH2:45]Cl>ClCCl>[Br:1][C:2]1[C:3]([C:27]([F:30])([F:28])[F:29])=[CH:4][C:5]2[N:9]([CH2:45][O:44][CH2:43][CH2:42][Si:41]([CH3:48])([CH3:47])[CH3:40])[C:8]([N:10]3[CH2:11][CH2:12][N:13]([C:16]4[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:26]=1
Reactant: FC(F)(F)c1cc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2cc1Br
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc2cc(Br)c(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-bromo-5-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-benzoimidazole (203 mg, 0.41 mmol, Example 89g) in dichloromethane (6 mL) was added N,N-diisopropylethylamine (148 mg, 1.15 mmol) followed by 2-(trimethylsilyl)ethoxymethyl chloride (94 mg,; 0.57 mmol, Aldrich). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with EtOAc/hexane (1:3) to afford the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 624 (M+1).
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].I[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH:19]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2)([CH3:21])[CH3:20]
Reactant: CC(C)I
Reactant: Oc1cccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc2ncccc12
Temperature: 80 °C
Yield: 91 %

Procedure:
To a mixture of quinolin-5-ol (2.00 g, 13.8 mmol) and K2CO3 (7.62 g, 55.1 mmol) in DMF (20 mL) was added 2-iodopropane (2.76 mL, 27.6 mmol). The reaction mixture was heated at 80° C. overnight before it was partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to dryness. The crude material was purified by column chromatography (10-20% EtOAc-Hex) to provide 5-isopropoxyquinoline (91%) as a light yellow oil. ESI-MS m/z calc 187.1, found 188.3 (M+1)+. Retention time: 1.06 minutes (3 min run).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[O:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][CH:25]=1)[O:18][CH2:19][CH2:20][CH2:21]2)=[O:6]
Reactant: c1ccc2c(c1)CCCO2
Reactant: O=C(O)c1cc(I)ccc1Br
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)CCCO2)c1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a stirred solution of 2-bromo-5-iodobenzoic acid (1.0 g, 3.06 mmol) in DCM (5 mL) was added DMF (0.2 mL) and oxalyl chloride (0.44 mL, 4.59 mmol) at 0° C. After complete addition, the reaction mixture was stirred at room temperature for 3 h. The volatiles were evaporated under reduced pressure, and the crude product was dissolved in DCM (4 mL) and added to chroman (488 mg, 3.67 mmol) which had been cooled to 0° C. To this mixture was added aluminum chloride (488 mg, 3.67 mmol) in portions. After stirring for 4 h, the reaction was quenched by pouring it into crushed ice. This was extracted with dichloromethane (50 mL×2): The dichloromethane layers were combined and washed with water (20 mL), saturated aqueous sodium bicarbonate solution (20 mL×2), and brine (20 mL), then dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography to furnish (2-bromo-5-iodo-phenyl)-chroman-6-yl-methanone (1.2 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[C:11](O)(=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCC(=O)O
Reactant: NCc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCC(=O)NCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 2,4-difluorbenzylamine (0.43 g, 3.0 mmol) in methylene chloride (30 mL) were added heptanoic acid (0.39 g, 3.0 mmol) and DMAP (0.37 g, 3.0 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.58 g, 3.0 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (100 mL), and the organic phase was washed with 5% HCl (3×75 mL), aqueous NaHCO3 (75 mL) and brine (75 mL), and dried over Na2SO4. Concentration in vacuo afforded 0.63 g (82%) of a yellow oil.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([C:18]#[C:19][C:20]3[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=3)=[C:16]([CH3:27])[N:15]=[C:14]([NH2:28])[N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1.O>[NH2:28][C:14]1[N:13]=[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)[C:17]([C:18]#[C:19][C:20]2[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=[C:16]([CH3:27])[N:15]=1
Reactant: CCOC(=O)C1CCN(c2nc(N)nc(C)c2C#Cc2ccc(N)nc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(N)nc(N2CCC(C(=O)O)CC2)c1C#Cc1ccc(N)nc1
Yield: 83.3 %

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 1.0 g (2.63 mmol) 1-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester and 126 mg (5.26 mmol) LiOH in 80 mL THF and 20 ml water. Yielding 772 mg (2.19 mmol) of the desired product.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@:10]1([CH:50]1[CH2:52][O:51]1)[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:53][NH2:54]>CO.O1CCCC1>[CH3:53][NH:54][CH2:52][CH:50]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@@H:9]2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:51]
Reactant: CN
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@@](C5CO5)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(O)CNC)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(oxiran-2-yl)-6,8-dioxabicyclo[3.2.1]octane 10a (50 mg, 0.56 mmol, obtained from the synthetic method described in step 1 of example 10) in a methanol/tetrahydrofuran mixture (v/v=2/1, 9 mL) was added methylamine solution (1 mL, 1.25 mmol). The mixture was heated to 55° C. and stirred for 16 h. The resulting mixture was extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with water (10 mL×2) and saturated brine (10 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with EtOAc to give the title compound 11a as a white solid (37.4 mg, 71.6%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.41 (m, 2H), 7.40 (m, 1H), 7.32 (m, 3H), 7.26 (m, 6H), 7.17 (m, 3H), 7.04 (d, 2H), 6.85 (m, 2H), 6.73 (m, 2H), 4.87 (m, 1H), 4.75 (m, 3H), 4.26 (m, 1H), 4.11 (m, 2H), 3.97 (m, 2H), 3.92 (m, 3H), 3.82 (m, 2H), 3.72 (m, 3H), 2.65 (m, 1H), 2.55 (m, 1H), 2.22 (s, 3H), 1.27 (t, 3H).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[C:23]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([O-:7])=[O:6].[F:24][C:25]1[C:30](O)=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[F:24][C:25]1[C:30]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][C:1]([O:9][CH2:10][C:11]2[C:23]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:8])=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C([O-])CCCC(=O)OCc1cccc2c1Cc1ccccc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(CCCC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1cccc2c1Cc1ccccc1-2
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Fluorenylmethyl glutarate (2.5 kg) and pentafluorophenol (1.63 kg) were dissolved in ethyl acetate (25 L). The solution was treated with a solution of dicyclohexylcarbodiimide (1.83 kg) in ethyl acetate (7.5 L) and the mixture was stirred at 20° C. overnight. The resulting slurry was filtered and the solids were washed through with ethyl acetate (10 L). The filtrate was evaporated at atmospheric pressure to a volume of 7.5 L and diluted with hexane (75 L). The slurry was filtered at 60–65° C. then allowed to cool to room temperature and stirred overnight. The slurry was cooled to 0° C. for 1 hour, the solid collected by filtration and washed with 10:1 hexane/ethyl acetate (15 L). The solid was dried in vacuo at 45° C. to afford the title compound as a white crystalline solid. Yield: 3.553 kg, 93%. HPLC; >99 A %.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:19][N:20]([CH3:36])[CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]3[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=3[N:30]=2)[CH2:22]1>CN(C=O)C.C(Cl)Cl>[CH3:19][N:20]([CH3:36])[CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]3[CH:34]=[C:33]([NH:35][C:8](=[O:10])[CH:7]=[CH:6][C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:12][CH:11]=4)[CH:32]=[CH:31][C:29]=3[N:30]=2)[CH2:22]1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Reactant: Cc1ccc(C=CC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C=CC(=O)Nc2ccc3nc(N4CCC(N(C)C)C4)sc3c2)cc1
Yield: 62 %

Procedure:
Combine 4-methylcinnamic acid (0.093 g, 0.572 mmol), CH2Cl2 (5.0 mL), and DMF (3 drops) with stirring. Add oxalyl chloride (0.17 mL, 1.91 mmol) and stir the mixture for 2.5 h at room temperature. Concentrate the mixture in vacuo, add hexane (approximately 10 mL), re-concentrate in vacuo, and add CH2Cl2 (4.0 mL). Transfer the mixture to a 40 mL reaction vial and add a solution of 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (0.100 g, 0.381 mmol) (example 1, step 3) in CH2Cl2 (5.0 mL). Shake the reaction vial for 1 h at room temperature. Dilute the reaction mixture with CH2Cl2 (25 mL), wash with aqueous 1.0 M NaOH (50 mL), concentrate in vacuo, and purify using silica gel chromatography (12 g column, 10-20% MeOH/CH2Cl2 for 16 min.) to afford the title compound as a yellow solid (96 mg, 62%). mass spectrum (m/e): 407.3 [M+1], 405.2 [M−1]. 1H NMR (400 MHz, CDCl3): δ 8.33 (s, 1H), 7.71 (d, 1H, J=15.6 Hz), 7.67 (s, 1H), 7.50 (d, 1H, J=9.2 Hz), 7.39 (d, 2H, J=7.2 Hz), 7.13-7.19 (m, 3H), 6.51 (d, 1H, J=15.6 Hz), 3.82 (t, 1H, J=8.0 Hz), 3.71 (t, 1H, J=9.2 Hz), 3.53 (m, 1H), 3.39 (t, 1H, J=8.0 Hz), 2.89 (m, 1H), 2.36 (s, 3H), 2.30 (s, 6H), 2.25 (m, 1H), 1.99 (m, 1H).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:34])([F:33])[C:22](B1OC(C)(C)C(C)(C)O1)=[CH2:23].C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[F:20][C:21]([F:34])([F:33])[C:22]([C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH2:23]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: C=C(B1OC(C)(C)C(C)(C)O1)C(F)(F)F
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: O
Solvent: COCCOC
Product: C=C(c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2)C(F)(F)F
Temperature: 85 °C
Reaction time: 12 h
Yield: 87.4 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (328 mg, 1.00 mmol), 1-(trifluoromethyl)vinylboronic acid pinacol ester (222 mg, 1.00 mmol), saturated aqueous sodium carbonate solution (6 ml) and tetrakis(triphenylphosphine)palladium(0) (32.6 mg, 0.0282 mmol) in dimethoxyethane (10 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the desired product (300 mg, 87.5%) as an oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:35])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)=[O:20])[CH2:15]1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([NH:22][CH2:21][C:19](=[O:20])[NH:18][CH:16]2[CH2:15][N:14]([CH:10]3[CH2:11][CH2:12][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8][CH2:9]3)[CH2:17]2)=[O:35])=[CH:25][C:26]=1[C:31]([F:34])([F:32])[F:33]
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: O=C(CNC(=O)c1ccc(F)c(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1ccc(F)c(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-phenyl-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-4-fluoro-3-trifluoromethyl-benzamide using the procedure described in Step C of Example 4.
Reaction SMILES: COP([CH2:7][C:8](=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=O)OC.[H-].[Na+].[CH3:23][Si:24]([CH3:33])([CH3:32])[C:25]1[O:29][CH:28]=[C:27]([CH:30]=O)[CH:26]=1>O1CCCC1>[O:20]=[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])/[CH:7]=[CH:30]/[C:27]1[CH:26]=[C:25]([Si:24]([CH3:33])([CH3:32])[CH3:23])[O:29][CH:28]=1
Reactant: CCCCCCCCCCCC(=O)CP(=O)(OC)OC
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)/C=C/c1coc([Si](C)(C)C)c1
Reaction time: 0.5 h

Procedure:
A solution of dimethyl-2-oxotridecylphosphonate (984 mg. 3.21 mmol) in tetrahydrofuran (25 ml) was added to a suspension of sodium hydride (78 mg, 3.21 mmol) in tetrahydrofuran (5 ml) at 0° C. (u.c.) under argon. After 30 min, a solution of 5-trimethylsilyl-3-furaldehyde (450 mg. 2.68 mmol) in tetrahydrofuran (15 ml) was added. Stirring was contained overnight while the cooling bath attained room temperature. The reaction mixture was quenched with saturated ammonium chloride and the organic layer separated. Evaporation of the dried (magnesium sulfate) organic layer gave a residue, which was purified by flash chromotography on a silica using 5% ethyl acetate/hexane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][N:5]=[C:4]([Cl:11])[CH:3]=1.C(Cl)(=O)C(Cl)=O.C[N:19](C=O)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([NH2:19])=[O:9])=[CH:6][N:5]=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1cnc(Cl)cc1Cl
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cnc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
4,6-Dichloro-nicotinic acid (10.3 g, 53.4 mmol) was suspended in CH2Cl2 (200 mL). Oxalyl chloride (14 mL, 158 mmol) was added and the reaction was placed in an ice bath. DMF (1.0 mL) was added and the reaction was fitted with an air cooled condenser. The reaction was stirred for 3 h and allowed to warm to 25° C. The volatiles were removed in vacuo and the crude residue was resuspended in THF (200 mL) and cooled to 0° C. To this stirred suspension was added concentrated aqueous ammonia (75 mL) dropwise and the reaction was allowed to stir for 1 h. The volatiles were removed and the crude was redissolved in EtOAc and poured into brine. The aqueous phase was separated and extracted twice with EtOAc. The organic layers were combined, dried (Na2SO4), decanted and concentrated to afford 4,6-dichloro-nicotinamide as a beige solid (7.27 g, 71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5]O.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5][Cl:16]
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(C(F)(F)F)c(F)c1
Solvent: ClC(Cl)Cl
Product: Fc1cc(CCl)ccc1C(F)(F)F
Yield: 86.1 %

Procedure:
To absolution of 3-fluoro-4-(trifluoromethyl)benzyl alcohol (10 g, 52 mmol) in chloroform (20 ml) was added thionyl chloride (18.5 ml, 257 mmol) and the mixture was heated under ref lux for 4 hrs. The reaction solution was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 3-fluoro-4-(trifluoromethyl)benzyl chloride (9.52 g, 87%).