Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.BrN1[C:32](=[O:33])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C[O-].[Na+]>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH2:18][O:33][CH3:32])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COCc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(F)cc2OC)o1
Temperature: 70 °C
Reaction time: 4 h
Yield: 1.2 %

Procedure:
To a solution of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (1.95 g, 5.56 mmol) in carbon tetrachloride (20 ml) was added N-bromo succinimide (990 mg, 5.56 mmol) and 2,2′-azobis(2-methylpropionitrile) (46 mg, 0.28 mmol) and the reaction mixture was stirred for 4 h at 70° C. Further 2,2′-azobis(2-methylpropionitrile) (46 mg, 0.28 mmol) was added and stirring was continued for another 14 h at 70° C. N-Bromo succinimide (378 mg, 2.12 mmol) was added and the mixture stirred for another 4 h at 90° C. After the reaction mixture was cooled to 0° C. the suspension was filtered off and was washed with dichloromethane (30 mL) and aqueous sodium hydrogencarbonate (1 N). It was extracted with dichloroemthane and dried over sodium sulfate resulting in crude material (1.66 g). A part of this light brown solid (200 mg) was dissolved in tetrahydropyran (2 mL), sodium methoxide (30% in methanol, 0.43 ml, 2.32 mmol) was added and the resulting mixture was stirred for 1 h at ambient temperature. It was diluted with ethyl acetate (20 mL) and washed aqueous ammonium chloride (saturated). The aqueous layers were extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20) afforded the title compound (25 mg, 14%) as a white solid. MS: m/e=382.3 [M+H]+.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][Si:7]([CH3:24])([CH3:23])[O:8][CH:9]1[CH2:17][CH2:16][CH2:15][C@@:14]2([CH3:18])[CH:10]1[CH2:11][CH2:12][C@@H:13]2[C@@H:19]([CH3:22])[CH2:20]I.[Si]([O:32][C@H:33]1[CH2:37][C:36](=O)[CH:35]=[CH:34]1)(C(C)(C)C)(C)C.[Cl-].[NH4+].N12CCCNC1CCCC=C2>CCOCC.O1CCCC1.ClCCl.[Cu](I)I.CCCCCC>[CH3:6][Si:7]([CH3:24])([CH3:23])[O:8][CH:9]1[CH2:17][CH2:16][CH2:15][C@@:14]2([CH3:18])[CH:10]1[CH2:11][CH2:12][C@@H:13]2[C@H:19]([CH3:22])[CH2:20][C@H:36]1[CH2:37][C:33](=[O:32])[CH:34]=[CH:35]1
Reactant: C[C@@H](CI)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C=CC(=O)C1
Agent: I[Cu]I
Agent: C1=CN2CCCNC2CCC1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H](C[C@@H]1C=CC(=O)C1)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Temperature: -78 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A 10 ml amount of ether was placed into a 100 ml eggplant-shaped flask and cooled to -78° C., followed by adding 14.3 ml of a hexane solution of t-butyllithium (1.54 mol/liter). A 3.94 g amount of the compound (1-9), (2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1yl]-iodopropane was dissolved in 10 ml of ether and then added to the above solution which was then stirred at -78° C. for 1 hour. A 2.1 g amount of copper iodide and 5.5 ml of tri(N-butyl)phosphine were dissolved in 10 ml of tetrahydrofuran, the solution was then added to the above reaction solution, then this was stirred at -78° C. for 1 hour. Thereto 2.54 g of (4S)-4-(t-butyldimethylsilyloxy)-2-cyclopenten-1-one dissolved in 10 ml of tetrahydrofuran was added. The solution was then stirred at -40° C. for 2 hours. This was poured into 30 ml of a saturated aqueous solution of ammonium chloride, then extraction was performed by 50 ml, 30 ml of ether. The organic layer was washed 2 times with saturated saline, then was dried over anhydrous sodium sulfate, the desiccant was filtered out, and the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 11.7 g. This was dissolved in 150 ml of dichloromethane, 2 ml of 1,8-diazabicyclo[5.4.0]undecene was added, then the solution was stirred at room temperature over night. Thereto 400 ml of ether was added. This was then washed by a saturated aqueous solution of potassium hydrogensulfate, a saturated aqueous solution of sodium hydrogencarbonate, and saturated saline and was dried over anhydrous magnesium sulfate. The desiccant was filtered out, then the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 10.9 g. This was purified by a silica gel column (IR-60, 400 g, hexane/ethyl acetate=40/1, 19/1, 9/1) to obtain the desired product (1-10), (4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-propyl}-2-cyclopenten-1-one in an amount of 1.76 g (yield 50%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:12][CH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=2)[CH2:15]1>C(OCC)(=O)C>[CH3:25][O:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([CH2:13][NH:12][C:1](=[O:3])[CH3:2])[CH2:23][CH2:22]2
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)CCC(CN)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CCC(CNC(C)=O)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
Acetyl chloride (0.67 g) was added to a pyridine solution (15 ml) of 2-aminomethyl-6-methoxytetralin hydrochloride (1.5 g; obtained in Reference Example 11), and the reaction mixture was stirred at room temperature for 16 hours, to which was added ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and a saturated aqueous sodium bicarbonate solution, then dried, and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-diusopropyl ether to obtain the entitled compound (960 mg).
Reaction SMILES: Br[C:2]12[CH2:9][CH2:8][C:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[F:15][C:16]1[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][CH:17]=1.Cl>[N+](C1C=CC=CC=1)([O-])=O.ClCCl.[Fe](Cl)(Cl)Cl>[F:22][C:21]1[C:16]([F:15])=[C:17]([C:2]23[CH2:9][CH2:8][C:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH2:6][CH2:7]2)[CH2:4][CH2:3]3)[CH:18]=[CH:19][C:20]=1[O:23][CH3:24]
Reactant: CCCCCC12CCC(Br)(CC1)CC2
Reactant: COc1cccc(F)c1F
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCC12CCC(c3ccc(OC)c(F)c3F)(CC1)CC2
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
A solution of 1-bromo-4-pentylbicyclo[2.2.2]octane (6 g, 23 mmol) in sieve-dried nitrobenzene (100 cm3) is added dropwise to a stirred solution of 2, 3-difluoro-4-methoxybenzene (6 g, 23 mmol) and anhydrous iron(III)chloride (1.2 g, 9 mmol) in sieve-dried nitrobenzene (100 cm3) maintained at 80° C. throughout the addition and overnight. The cooled solution is added to a small volume of hydrochloric acid and stirred for 20 min. The organic layer is separated off and steam-distilled to yield a solid residue. This is taken up in dichloromethane and dried (MgSO4). The raw product is crystallised from ethanol to yield the desired 2, 3-difluoro-1-methoxy-4-(4-pentylbicyclo[2.2.2]octyl)benzene (3.2 g, 44%)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][CH3:21])=[O:19])[CH:13]=3)[CH:8]=[C:7]([Cl:22])[C:5]=2[N:6]=1.Br[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[Cl:22][C:7]1[C:5]2[N:6]=[C:2]([NH:1][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[S:3][C:4]=2[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][CH3:21])=[O:19])[CH:13]=2)[CH:8]=1
Reactant: CNC(=O)c1cc(Oc2cc(Cl)c3nc(N)sc3c2)ccn1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2cc(Cl)c3nc(NCC4CCCCC4)sc3c2)ccn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To the solution of 4-(2-amino-4-chlorobenzo[d]thiazol-6-yloxy)-N-methylpicolinamide (30 mg, 0.089 mmol, 1.0 eq) in 2 mL of NMP was added bromomethyl cyclohexane (18 μL, 0.134 mmol, 1.5 eq) and potassium carbonate (36 mg, 0.267 mmol, 3.0 eq) at room temperature. The reaction mixture was stirred at 80° C. for 2 hours and thereafter purified via reverse phase HPLC. LC/MS (m/z) [431.0] (MH+)
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=O.Cl>[OH-].[K+].O>[CH:4]1[CH:2]=[C:2]2[CH:4]=[C:6]3[C:11](=[N:1][C:8]2=[CH:7][CH:6]=1)[CH:10]=[CH:9][CH:8]=[CH:7]3
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc2nc3ccccc3cc2c1
Temperature: 0 °C

Procedure:
The isatin product was refluxed in 110 mL of 10% KOH solution in water over night. The dark green mixture was cooled and acidified with 400 mL of 1:1 ice/5 M HCl. The solid was washed with water and air-dried yielding the acridine acid. 1H NMR (DMSO-d6) δ 7.81-7.94 (m, 4H), 8.31-8.36 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:10][CH2:11][CH:12]([C:14]([OH:16])=[O:15])[N:13]=1>O=[Mn]=O.CN(C=O)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1
Reactant: O=C(O)C1CSC(c2ccc(O)cc2O)=N1
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Product: O=C(O)c1csc(-c2ccc(O)cc2O)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.5 %

Procedure:
In a DMF (5 mL) solvent, a suspension of Compound 101b (100 mg, 0.41 mmol) and MnO2 (640 mg, 6.26 mmol) was stirred at room temperature for 24 hours. After DMF was evaporated, 1 N a NaOH solution (0.5 mL) was added to the residual. The reaction mixture was filtered, washed with water, and the filtrate was acidified by using 1 N HCl to increase a pH to 2. The produced precipitate was filtered, and washed with cold water to obtain Compound 101 (46.2 mg, 43%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]([CH:17]1[CH2:22][CH2:21][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:30]([CH3:36])=[N:31][CH:32]=[N:33][C:34]=2[CH3:35])=[O:28])[CH2:19][CH2:18]1)[C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)#[N:2].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:13])=[CH:10][CH:9]=1)[CH:17]1[CH2:22][CH2:21][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:34]([CH3:35])=[N:33][CH:32]=[N:31][C:30]=2[CH3:36])=[O:28])[CH2:19][CH2:18]1)#[N:2]
Reactant: C1COCCN1
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)N3CCOCC3)cc2)CC1
Yield: 87.5 %

Procedure:
Using general procedure E, 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid (see EXAMPLE 129) (50 mg, 0.09 mmol) and morpholine (29 μL, 0.33 mmol) afforded COMPOUND 167 as a white solid (48 mg, 87%). 1H NMR (CDCl3) δ 0.84-1.18 (m, 2H), 1.03 (d, 3H, J=6.6 Hz), 1.50-1.60 (m, 1H), 1.70-1.84 (m, 3H), 2.14-2.26 (m, 1H), 2.51 (s, 6H), 2.53-2.65 (m, 1H), 2.71-2.92 (m, 3H), 3.27-3.39 (m, 1H), 3.57-3.92 (m, 10H), 3.96 (s, 2H), 6.52 (d, 2H, J=8.4 Hz), 7.25-7.30 (m, 2H), 7.43-7.59 (m, 4H), 8.54 (br s, 1H), 8.90 (s, 1H). 13C NMR (CDCl3) δ 13.84, 22.36, 29.54, 30.83, 31.12, 40.49, 43.87, 48.45, 52.39, 56.04, 60.76, 67.36, 77.61, 112.53, 113.14, 123.98, 129.89, 130.08, 131.17, 141.51, 149.88, 157.99, 163.53, 166.57, 171.00. ES-MS m/z 610 (M+H). Anal. Calcd. for C35H43N7O3.0.2CH2Cl2.0.1H2O: C, 67.26; H, 6.99; N, 15.60. Found. C, 67.44; H, 7.12; N, 15.30.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.O.C(Cl)Cl>[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
To methyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate (0.332 g, 0.914 mmol) in THF (6 mL) and water (3 mL) was added LiOH (0.066 g, 2.74 mmol). The solution immediately turned from yellow to orange-red. The reaction was stirred vigorously at RT for 16 h. The solution was acidified to pH 2 and diluted with water and CH2Cl2. The layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL) and the combined organic fractions were washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate (MgSO4), filtered and concentrated to give the title compound as a tan solid (0.29 g, 91%): mp 228-233° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.55-10.24 (m, 1H), 9.46 (s, 1H), 8.23 (d, J=8.0 Hz, 2H), 8.09 (d, J=7.9 Hz, 4H), 7.64 (d, J=8.5 Hz, 2H); ESIMS m/z 350 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24]([OH:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)([O-:29])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24]([O:26][C:33]1[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: O=C(Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Yield: 26 %

Procedure:
To solution of 2,4-dibenzyloxyphenylacetic acid (2.0 g) and para-nitrophenol (920 mg) in N,N-dimethylformamide anhydride (20 ml) is added drop by drop a solution of of dicyclohexylcarbodiimide (1.2 g) in N,N-dimethylformamide anhydride (10 ml) at 0 ° C. and the mixture is left to stand at room temperature (15 ° C.) for 22 hours. The resulting solution is concentrated under reduced pressure to dryness and thereto is added ethyl acetate (70 ml). The precipitate produced is removed by filtration. The filtrate is concentrated under reduced pressure and the residue is separated and purified by use of a silica gel column [silica gel: 350 ml ; developer : hexane-ethyl acetate mixture (4:1)] to yield para-nitrophenyl 2,4-dibenzyloxyphenylacetate (0.70 g; yield 26%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]#[N:10])=[N:6][CH:7]=1.Br[CH2:12][CH2:13]Br>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:9]#[N:10])[CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: N#CCc1ccc(Br)cn1
Reactant: BrCCBr
Product: N#CC1(c2ccc(Br)cn2)CC1
Yield: 88 %

Procedure:
Alternatively, the title compound was prepared from (5-bromo-pyridin-2-yl)-acetonitrile and 1,2-dibromoethane following a procedure analogous to that described in Step 3 for Intermediate 4. Yield: 88% of theory.
Reaction SMILES: NN1CCCC1.Cl[C:8]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:24][CH3:25])[CH:14]=2)[N:9]=1.Cl.[NH2:27][C@H:28]1[CH2:32][CH2:31][N:30]([C:33](=[O:46])[CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=2)[CH2:29]1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O.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].O1CCOCC1>[CH3:25][O:24][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:27][C@H:28]1[CH2:32][CH2:31][N:30]([C:33](=[O:46])[CH2:34][C:35]3[CH:36]=[CH:37][C:38]([O:41][C:42]([F:43])([F:44])[F:45])=[CH:39][CH:40]=3)[CH2:29]1)[CH:17]=[C:16]2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: COc1ccc2nc(Cl)cc(N3CCOCC3)c2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2nc(N[C@H]3CCN(C(=O)Cc4ccc(OC(F)(F)F)cc4)C3)cc(N3CCOCC3)c2c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 26.6 %

Procedure:
A mixture of 2,4-dichloro-6-methoxyquinoline (0.228 g), morpholine (262 μL), N,N-diisopropylethylamine (348 μL), and ethylene glycol (4 mL) was heated with microwave (145° C.) for 75 min with stirring. The reaction mixture was cooled to room temperature, followed by addition of water, the mixture was extracted with chloroform and washed with saturated brine, and the organic layer was dried with anhydrous sodium sulfate. The desiccant was removed by filtration, the residue concentrated under reduced pressure was purified by silica gel column chromatography (chloroform/hexane=1/1) to obtain 2-chloro-6-methoxy-4-morpholinoquinoline (0.182 g). (2) To a mixture of 2-chloro-6-methoxy-4-morpholinoquinoline (0.160 g), Pd2(dba)3 (0.026 g), (±)-BINAP (0.054 g), (S)-1-(3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.210 g), and 1,4-dioxane (3 mL) was added sodium t-butoxide (0.111 g) under nitrogen atmosphere, and the mixture was stirred at 70° C. for 1.5 h. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate and water, the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, ethyl acetate/hexane) to obtain light yellow amorphous (S)-1-(3-(6-methoxy-4-morpholinoquinolin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.081 g).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8](/[N:10]=[C:11](\N)/[C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]2[N:28]([CH3:29])[C:27]3[CH:26]=[CH:25][C:24]([C:30]([N:32]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][N:45]=4)[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:23][C:22]=3[N:21]=2)=[CH:16][CH:17]=1)=[O:9].CS(O)(=O)=[O:49].CS(O)(=O)=O>O>[CH2:6]([O:7][C:8]([NH:10][C:11]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]2[N:28]([CH3:29])[C:27]3[CH:26]=[CH:25][C:24]([C:30]([N:32]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][N:45]=4)[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:23][C:22]=3[N:21]=2)=[CH:16][CH:17]=1)=[O:49])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CS(=O)(=O)O
Reactant: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Solvent: O
Product: CCCCCCOC(=O)NC(=O)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)O)c4ccccn4)ccc3n2C)cc1
Temperature: 55 °C
Reaction time: 168 h
Yield: 28.4 %

Procedure:
25 g of dabigatran etexilate mesylate were suspended in 180 mL of deionized water. 1.32 g of methanesulfonic acid were added. The reaction mixture was heated to 55° C. and stirred at this temperature for 7 days. The resulting mixture was filtered, and the solid was dried under vacuum. The solid was purified by column chromatography, eluting with dichloromethane:methanol (10:1 v/v) mixture. After solvent evaporation of the selected fractions containing the desired compound, 5.9 g of 3-{[(2-{[(4-{[({hexyloxy}carbonyl)amino]carbonyl}phenyl)-amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoic acid were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([O:7][CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24][C:25](=[O:38])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:28][CH:27]=3)=[CH:17][CH:16]=2)[C:9]([O:11]CC)=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([O:7][CH:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][NH:24][C:25](=[O:38])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:28][CH:27]=3)=[CH:19][CH:20]=2)[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Oc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(OC(Cc2ccc(OCCNC(=O)c3ccc(-c4ccccn4)cc3)cc2)C(=O)O)cc1
Yield: 51 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(4-methoxyphenoxy)-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (310 mg), which is the product of Example 124, was reacted with aqueous sodium hydroxide solution (1N, 2.00 ml) and the reaction mixture was treated to give the title compound (150 mg) as a white powder.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[N+:14]([O-:16])=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:24](=[O:26])[CH3:25])=[CH:9][C:8]=2[N+:14]([O-:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of 4-cyclohexyl-3-nitro-aniline (1.54 g, 6.99 mmol) in DCM (15 mL) was added Et3N (1.9 mL, 13.63 mmol), followed by the addition of acetic anhydride (3.3 mL, 34.98 mmol). The reaction mixture was stirred at room temperature for 2 h, quenched with water, the layers separated and the organic layer was washed with 0.1N HCl, followed by washing with H2O. The organic layer was dried over MgSO4, filtered and concentrated to obtain N-(4-cyclohexyl-3-nitrophenyl)acetamide (1.7 g, 93%). 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=2.2 Hz, 1H), 7.69 (dd, J=8.6, 2.2 Hz, 1H), 7.52 (s, 1H), 7.40 (d, J=8.6 Hz, 1H), 3.01-2.87 (m, 1H), 2.22 (s, 3H), 1.95-1.78 (m, 5H), 1.42 (t, J=10.4 Hz, 4H), 1.32-1.21 (m, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([Cl:17])=[N:12][C:13](Cl)=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br-].[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22][Zn+]>C1COCC1.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>[Si:1]([O:8][CH2:9][C:10]1[C:11]([Cl:17])=[N:12][C:13]([CH2:22][C:21]2[C:20]([F:19])=[CH:27][CH:26]=[CH:25][C:24]=2[F:28])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)nc1Cl
Reactant: Fc1cccc(F)c1C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Cc2c(F)cccc2F)nc1Cl
Temperature: 25 °C

Procedure:
To a solution of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,6-dichloropyridine (from Step B above, 8.5 g) in THF was added 2,6-difluorobenzylzinc bromide (90 mL, 0.5M in THF) and tetrakis(triphenylphosphine)palladium (2 g), and heated to reflux for a couple of hours until reaction completed. The mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with ethyl acetate, washed with 1N NaOH, brine, dried over MgSO4 and concentrated to give title compound.