Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:23]=[CH:22][C:18]3=[N:19][O:20][N:21]=[C:17]3[CH:16]=2)O1.[NH2:25][C:26]1[C:31]([F:32])=[C:30](Cl)[N:29]=[C:28]([C:34]([O:36][CH3:37])=[O:35])[C:27]=1[Cl:38].C(#N)C>O.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>[NH2:25][C:26]1[C:31]([F:32])=[C:30]([C:15]2[CH:23]=[CH:22][C:18]3=[N:19][O:20][N:21]=[C:17]3[CH:16]=2)[N:29]=[C:28]([C:34]([O:36][CH3:37])=[O:35])[C:27]=1[Cl:38]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Reactant: CC1(C)OB(c2ccc3nonc3c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc3nonc3c2)c(F)c(N)c1Cl
Temperature: 85 °C
Reaction time: 4 h
Yield: 57.3 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (110 mg, 0.16 mmol) and sodium carbonate (210 mg, 2.0 mmol) were sequentially added to a stirred mixture of ˜60% 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole (900 mg, 2.2 mmol) and methyl 4-amino-3,6-dichloro-5-fluoropicolinate (480 mg, 2.0 mmol, 1.0 equiv) in a 1:1 mixture of water:acetonitrile (6.8 mL) at 23° C. The resulting brown mixture was heated to 85° C. and stirred for 4 h. The cooled reaction mixture was diluted with water (150 mL) and extracted with dichloromethane (3×80 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to afford the title compound as a tan powder (370 mg, 57% yield).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([C@@H:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](O)(=[O:33])[CH2:31][OH:32].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:31](=[O:32])[CH2:30][OH:33])[CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@@H]1CCCNC1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@@H]1CCCN(C(=O)CO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6) (38.62 g), glycolic acid (9.13 g) and triethylamine (27.90 mL) in THF (500 mL) stirring in an ice bath, was added HATU (45.63 g) in one portion. The reaction was allowed to warm up to room temperature and stirred overnight (16 hrs). Solvent was removed by rotoevaporation. The residue was diluted with dichloromethane (500 mL), washed with aqueous NaOH solution (10%, 300 mL). The solid was filtered off and the bi-layer system was separated. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was triturated with acetonitrile (300 mL) with some heating and cooled to room temperature. The mixture was filtered after sitting at room temperature overnight (16 hrs) and filtered. The solid collected was washed with small amount of acetonitrile and dried under high vacuo to provide the title compound a white powder with slight pink color (34.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=2)[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[OH:52][C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[C:56](O)=[O:57].C(N(CC)CC)C>CN(C=O)C.O>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH:14]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:56](=[O:57])[C:55]3[CH:59]=[CH:60][CH:61]=[C:53]([OH:52])[CH:54]=3)=[CH:3][CH:4]=2)[C:9](=[O:10])[N:11]([CH3:13])[CH3:12])[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=1
Reactant: COc1cc(C=C(C(=O)N(C)C)c2ccc(N)cc2)cc(OC)c1
Reactant: O=C(O)c1cccc(O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C=C(C(=O)N(C)C)c2ccc(NC(=O)c3cccc(O)c3)cc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-aminophenyl)-3-(3,5-dimethoxyphenyl)-N,N-dimethylacrylamide, 43, (0.59 g, 1.5 mmol), benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP,0.88 g, 2.0 mmol), 3-hydroxybenzoic acid (0.28 g, 2.0 mmol), triethylamine (0.2 g, 2.0 mmol) in DMF (8.0 mL) was stirred for 3 h at room temperature. The reaction mixture was poured in water (50 mL) and solid separated was filtered, dried and purity was checked by HPLC (97.6%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](=O)[CH3:4].C(N)(=O)C1C=CC=CC=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N)(=O)C>C1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[C:3](=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:4]
Reactant: Nc1ccccc1
Reactant: CC(=O)N(C)C
Agent: CC(N)=O
Agent: NC(=O)c1ccccc1
Solvent: c1ccccc1
Product: CC(=Nc1ccccc1)N(C)C
Yield: 53 %

Procedure:
The conventional procedure of Example 1 was repeated except that 32.7 g (0.375 mole) of N,N-dimethylacetamide was substituted for the benzamide and a solution of 11.6 g aniline in 50 ml of benzene was utilized. Workup as in Example 1 yielded N,N-dimethyl-N-phenylacetamidine in form of a colorless oil, b.p. 73° C. at 0.12 mm of mercury in only 53% yield based on aniline or 49% yield based on POCl3 and a meager 19.5% yield based on the acetamide.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH3:19][O:20][CH:21]([O:30][CH3:31])[CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[CH3:32][N:33]1[N:37]=[N:36][C:35]([C:38]2[CH:39]=[C:40]([CH:49]=[CH:50][CH:51]=2)[CH2:41][CH2:42][O:43][CH2:44][CH2:45][C:46](O)=[O:47])=[N:34]1.C(N(CC)CC)C>C1COCC1.C(#N)C.C(OCC)(=O)C>[CH:24]1([N:23]([CH2:22][CH:21]([O:30][CH3:31])[O:20][CH3:19])[C:46](=[O:47])[CH2:45][CH2:44][O:43][CH2:42][CH2:41][C:40]2[CH:49]=[CH:50][CH:51]=[C:38]([C:35]3[N:36]=[N:37][N:33]([CH3:32])[N:34]=3)[CH:39]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(CNC1CCCCC1)OC
Reactant: Cn1nnc(-c2cccc(CCOCCC(=O)O)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(CN(C(=O)CCOCCc1cccc(-c2nnn(C)n2)c1)C1CCCCC1)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of T3P (1.91 mL) dissolved in THF (1.57M) was added in one portion to a stirred solution of N-(2,2-dimethoxyethyl)cyclohexanamine (0.33 mL), 3-(3-(2-methyl-2H-tetrazol-5-yl)phenethoxy)propanoic acid [Example 7, Step iii)] (0.41 g) and triethylamine (2.51 mL) in acetonitrile (5 mL) at 25° C. The resulting solution was stirred at 25° C. for 15 min. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with saturated sodium hydrogen carbonate (20 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20-100% ethyl acetate in isohexane, then elution gradient 0-10% methanol in ethyl acetate to afford the subtitled compound (0.66 g). 1H NMR (400 MHz, CD3OD) δ 7.97-7.93 (m, 1H), 7.92-7.89 (m, 1H), 7.43-7.33 (m, 2H), 4.52 and 4.36 (2×t, J=5.3 Hz, 1H), 4.40 and 4.39 (2×s, 3H), 4.04-3.95 and 3.69-3.60 (2×m, 1H), 3.75-3.66 (m, 4H), 3.33 (s, 6H), 3.25 (d, J=4.9 Hz, 2H), 2.94-2.88 (m, 2H), 2.67-2.61 (m, 2H), 1.79-1.00 (m, 10H), a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26](O)=[O:27])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl:31]CCl>CN(C)C=O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([Cl:31])=[O:27])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)/C=C/c1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Temperature: 42 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a suspension of (E)-3-[4-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoic acid (9a) (0.30 g, 0.69 mmol) in dichloromethane (7 mL) oxalyl chloride (0.2 mL, 2.4 mmol) and a drop of dimethylformamide were added. The reaction mixture was stirred at ambient temperature for 0.5 hours and at 42° C. for 1 hour. The reaction mixture was evaporated and the residue was dried in vacuum to give (E)-3-[4-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (10a) (0.31 g) in a form of a crude product.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=1)=[O:16]>>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[CH2:12][CH2:11][N:10]([CH2:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:21][CH:22]=2)=[O:16])[CH2:9][CH2:8]1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Reactant: Cn1ccnc1N1CCNCC1
Product: Cn1ccnc1N1CCN(CC(=O)c2ccc(NS(C)(=O)=O)cc2)CC1
Yield: 43.5 %

Procedure:
Treatment of 1-(1-methyl-2-imidazolyl)piperazine (0.37 g) with N-[4-bromoacetylphenyl]methanesulphonamide (0.64 g) according to the method of Example 1 gave the title compound, (0.36 g), m.p. 196°-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]([F:42])([F:41])[F:40])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[C:15]([NH:17][C:18]3[CH:30]=[CH:29][C:21]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:20][CH:19]=3)=[O:16])[C:10](=[O:38])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]([F:42])([F:40])[F:41])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:29][CH:30]=3)=[O:16])[C:10](=[O:38])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)C(Cc2cccnc2)n2ccc(-c3cc(Cl)ccc3C(F)(F)F)cc2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(NC(=O)C(Cc2cccnc2)n2ccc(-c3cc(Cl)ccc3C(F)(F)F)cc2=O)cc1

Procedure:
33 mg (purity 94%, 0.05 mmol) of tert-butyl 4-{[2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-3-yl)propanoyl]amino}benzoate (racemate) (Example 9.1C) were hydrolysed with TFA according to General Method 2. Yield: 11 mg (40% of theory)
Reaction SMILES: C([O:5][C:6](=[O:46])[CH:7]([NH:30][C:31]([C:33]1[CH:34]=[C:35]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[CH:36]=[CH:37][CH:38]=1)=[O:32])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([C:20]([N:22]3[CH2:27][CH2:26][CH:25]([CH3:28])[CH2:24][CH2:23]3)=[O:21])[O:17][N:16]=2)=[C:11]([F:29])[CH:10]=1)(C)(C)C.COC(C1ON=C(C2C=CC(CC(C(OC(C)(C)C)=O)NC(C3C=C(C4C=CC(C)=CC=4)C=CC=3)=O)=CC=2F)N=1)=O.CC1CCNCC1>CO>[F:29][C:11]1[CH:10]=[C:9]([CH2:8][CH:7]([NH:30][C:31]([C:33]2[CH:34]=[C:35]([C:39]3[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=3)[CH:36]=[CH:37][CH:38]=2)=[O:32])[C:6]([OH:46])=[O:5])[CH:14]=[CH:13][C:12]=1[C:15]1[N:19]=[C:18]([C:20]([N:22]2[CH2:23][CH2:24][CH:25]([CH3:28])[CH2:26][CH2:27]2)=[O:21])[O:17][N:16]=1
Reactant: Cc1ccc(-c2cccc(C(=O)NC(Cc3ccc(-c4noc(C(=O)N5CCC(C)CC5)n4)c(F)c3)C(=O)OC(C)(C)C)c2)cc1
Agent: CC1CCNCC1
Agent: COC(=O)c1nc(-c2ccc(CC(NC(=O)c3cccc(-c4ccc(C)cc4)c3)C(=O)OC(C)(C)C)cc2F)no1
Solvent: CO
Product: Cc1ccc(-c2cccc(C(=O)NC(Cc3ccc(-c4noc(C(=O)N5CCC(C)CC5)n4)c(F)c3)C(=O)O)c2)cc1
Temperature: 55 °C
Yield: 71.4 %

Procedure:
3-{3-Fluoro-4-[5-(4-methyl-piperidine-1-carbonyl)-[1,2,4]oxadiazol-3-yl]-phenyl}-2-[(4′-methyl-biphenyl-3-carbonyl)-amino]-propionic acid tert-butyl ester. A mixture of 3-(4-{2-tert-butoxycarbonyl-2-[(4′-methyl-biphenyl-3-carbonyl)-amino]-ethyl}-2-fluoro-phenyl)-[1,2,4]oxadiazole-5-carboxylic acid methyl ester (50 mg) and 4-methyl-piperidine (13.5 mg) in MeOH (3 mL) was heated at 55° C. for 25 min in a microwave reactor. TLC showed the reaction was completed. The mixture was concentrated, 10 mL of 1N aq. HCl solution and 20 mL of ethyl acetate were added. The layers were separated and the aqueous portion was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (40 mg, 71.4% yield).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[C:19]([CH3:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[N:15]=2)[CH2:10][CH:9]1[C:34](=[O:46])[NH:35][C:36]1([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:38][CH:37]1[CH:39]=[CH2:40])=[O:7])(C)(C)C.O>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:44]([O:43][C:41]([C:36]1([NH:35][C:34]([CH:9]2[CH2:10][CH:11]([O:13][C:14]3[C:23]4[C:18](=[C:19]([CH3:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)[N:15]=3)[CH2:12][CH:8]2[C:6]([OH:7])=[O:5])=[O:46])[CH2:38][CH:37]1[CH:39]=[CH2:40])=[O:42])[CH3:45]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3cccc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3cccc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)O)C(=O)OCC
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
Compound 155 (0.896 g, 1.41 mmol) was dissolved in a mixture of DCM (30 mL), TFA (10 mL), a few drops of TES and a drop of H2O. The reaction was stirred for 30 minutes followed by removal of solvent by evaporation. The crude residue was partitioned between CHCl3 and saturated NaHCO3 (aq). The organic phase was dried (Na2SO4) and evaporated which gave the compound (0.81 g, 99%) as a white solid.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.[Cl:10][C:11]1[C:12]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1.CCN(C(C)C)C(C)C>FC(F)(F)CO>[Cl:10][C:11]1[C:12]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([N:7]3[CH2:8][CH:5]([N:4]([CH3:9])[CH3:3])[CH2:6]3)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1
Reactant: CN(C)C1CNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: OCC(F)(F)F
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Temperature: 140 °C
Yield: 93.7 %

Procedure:
N,N-dimethylazetidin-3-amine (Intermediate 26, 144 mg, 0.83 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 76, 312 mg, 0.75 mmol) and DIPEA (0.460 mL, 2.64 mmol) in 2,2,2-trifluoroethanol (5 mL). The mixture was heated in a microwave at 140° C. for 1 h. The cooled mixture was purified by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo onto silica. Further purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (347 mg, 93%) as an orange solid after trituration with diethyl ether; 1H NMR: 2.14 (6H, s), 3.09-3.18 (1H, m), 3.76 (2H, dd), 3.89 (3H, s), 4.01-4.11 (2H, m), 6.28 (1H, s), 6.98 (1H, t), 7.13-7.20 (1H, m), 7.46 (1H, d), 8.15 (1H, s), 8.23 (1H, d), 8.37 (1H, s), 8.47 (1H, s), 8.49 (1H, s), 11.84 (1H, s); m/z: ES+ MH+ 494.16.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:26])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[N+:23]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>O.C(O)C.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:26])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[NH2:23])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(N(C)c2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(N(C)c2ccc(OCc3ccccc3)cc2)c(N)c1
Temperature: 25 °C

Procedure:
A mixture of the product from Example 133B (129.4 mg, 0.3714 mmol), iron powder (128 mg, 2.284 mmol), ammonium chloride (130 mg, 2.433 mmol) in water (1 mL) and ethanol (2 mL) was heated at 70° under a nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature and vacuum filtered, washing the residue with methanol. The filtrate was concentrated under vacuum and azeotroped with toluene (50 mL). The residue was purified by silica gel flash chromatography using methylene chloride as eluent to provide the title compound as a waxy solid (85 mg, 72%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=O)[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([CH3:50])[C:28]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([CH3:29])[NH:27]C(C3C=CC(C(C)(C)C)=CC=3OCC)=[N:25]2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([CH3:50])[C:28]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)([CH3:29])[NH:27][C:6]([C:5]3[CH:9]=[CH:10][C:11]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:12][C:4]=3[O:3][CH2:1][CH3:2])=[N:25]2)=[CH:20][CH:19]=1
Reactant: CCOc1cc(S(C)(=O)=O)ccc1C(=O)Cl
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Product: CCOc1cc(S(C)(=O)=O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1

Procedure:
rac-(4S*,5R*)-4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methanesulfonyl-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was prepared from 2-ethoxy-4-methanesulfonyl-benzoyl chloride (prepared from ethyl 2-ethoxy-4-fluoro-benzoate and sodium thiomethoxide in 4 steps) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) in an analogous manner as described in example 2 (method 1).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>CC(N(C)C)=O.C(#N)C>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3[C:4](=[N:5][CH:6]=[CH:7][N:8]=3)[N:3]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Clc1nc(-c2ccccc2)c2nccnc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC#N
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(-c3ccccc3)c3nccnc3n2)CC1

Procedure:
A mixture of 2-chloro-4-phenyl-pteridine (0.33 g, 1.36 mmol, 1.0 equiv; commercially available from Specs Research Laboratory, The Netherlands), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.41 g, 2.04 mmol, 1.5 equiv; commercially available) and triethylamine (0.28 mL, 0.21 g, 2.04 mmol, 1.5 equiv) in anhydrous DMAc (2 mL) and acetonitrile (9 mL) was heated by microwave irradiation to 120° C. for 20 min. The organic phase was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.5 g (91%) of the title compound. MS (ISP): 407.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH2:13][C@H:14]([O:16][CH3:17])[CH3:15])[CH:6]=2.[O:19]1CCOCC1>O>[F:1][C:2]1[C:3]([CH:18]=[O:19])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH2:13][C@H:14]([O:16][CH3:17])[CH3:15])[CH:6]=2
Reactant: CO[C@H](C)COc1ccc2cc(F)c(C)nc2c1
Reactant: C1COCCO1
Solvent: O
Product: CO[C@H](C)COc1ccc2cc(F)c(C=O)nc2c1
Yield: 76 %

Procedure:
A solution of (R)-3-fluoro-7-(2-methoxypropoxy)-2-methylquinoline (0.030 g, 0.120 mmol) and SeO2 (0.0160 g, 0.144 mmol) in dioxane (10 mL) and water (0.1 mL) was stirred at 102° C. (bath) for 5 hours. The solid was removed by filtration. The mother liquor was concentrated under reduced pressure. The residue obtained was purified by flash chromatography 2.5:1 hexane/ethyl acetate to give (R)-3-fluoro-7-(2-methoxypropoxy)quinoline-2-carbaldehyde (0.024 g, 0.091 mmol, 76% yield) as a solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[O:16]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:24][CH:25]=2)[CH:8]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: Cl
Product: COC(=O)CCc1cccc(CNCc2ccc(Oc3ccccc3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 4-phenoxy-benzaldehyde using the method described in Example 12z, Step A. 1H NMR (400 MHz, CDCl3) δ 7.37-6.95 (m, 13H), 3.82 (s, 2H), 3.79 (s, 2H), 3.64 (s, 3H), 2.93 (t, 2H), 2.63 (t, 2H); MS 376 (M+1).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[C:7]([NH:25][C@H:26]2[C@H:28]([C:29]3[CH:30]=[CH:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=3)[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([C@H:14]3[C@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([O:21][CH2:22][CH2:23][OH:24])[CH2:15]3)[C:9]=2[N:10]=1.[ClH:37]>C(OCC)(=O)C>[CH3:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[C:7]([NH:25][C@H:26]2[C@H:28]([C:29]3[CH:30]=[CH:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=3)[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([CH:14]3[C@H:18]([OH:19])[C@H:17]([OH:20])[CH:16]([O:21][CH2:22][CH2:23][OH:24])[CH2:15]3)[C:9]=2[N:10]=1.[ClH:37]
Reactant: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn(C3CC(OCCO)[C@@H](O)[C@H]3O)c2n1
Temperature: 27.5 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
Ticagrelor (0.5 g) and ethyl acetate (15 mL) were charged into a round bottom flask and the mixture was stirred at about 25-30° C. for about 15 minutes for clear solution. Then aqueous hydrochloric acid (0.12 mL, 35%) was added to the above reaction mixture at 25-35° C. and stirred for solid separation for about 2 hours. The solid was filtered, washed with ethyl acetate (5 mL) and dried to afford the title compound in about 75% yield having chiral HPLC purity of 99.55%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[C:16]([F:25])[CH:15]=1)#[CH:13].N>>[F:25][C:16]1[CH:15]=[C:14]([C:12]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:13]=2)[CH:19]=[CH:18][C:17]=1[O:20][C:21]([F:22])([F:23])[F:24]
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1ccc(OC(F)(F)F)c(F)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3ccc(OC(F)(F)F)c(F)c3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 4-ethynyl-2-fluoro-1-(trifluoromethoxy)benzene (Apollo, 102 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.51 (s, 1H), 7.59-7.69 (m, 1H), 7.85 (ddd, J=8.8, 2.0, 1.4 Hz, 1H), 7.93 (dd, J=10.9, 2.0 Hz, 1H), 8.17 (ddd, J=9.2, 2.7, 1.7 Hz, 1H), 8.62 (d, J=2.7 Hz, 1H), 8.97 (t, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 343 (M+H)+.