Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[C:18](=[O:19])[CH:17]=[CH:16][N:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:26]([Si:28]([CH3:31])([CH3:30])[CH3:29])#[CH:27].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CNC>C(O)C.CN(C=O)C.[Cu]I.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>[C:20]1([N:15]2[CH:16]=[CH:17][C:18](=[O:19])[C:13]([C:12]3[N:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:27]#[C:26][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:3]=4)[N:9]=[CH:10][CH:11]=3)=[N:14]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CNC
Solvent: CCO
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cccc(-n2nccc2-c2nn(-c3ccccc3)ccc2=O)c1
Temperature: 120 °C
Yield: 55.4 %

Procedure:
A mixture of 3-[2-(3-bromo-phenyl)-2H-pyrazol-3-yl]-1-phenyl-1H-pyridazin-4-one (example 23, 87 mg, 0.22 mmol), ethynyltrimethylsilane (47 ul, 0.33 mmol), CuI (3 mg, 0.01 mmol), (PPh3)2PdCl2 (10 mg, 0.01 mmol), PPh3 (122 mg, 0.44 mmol) and dimethylamine (596 ul, 3.3 mmol of a solution in ethanol) in DMF (0.9 ml) is heated at 120° C. for 20 minutes under microwave irradiation. After purification of the crude product by preparative HPLC 50 mg (55% yield) of the product is obtained as solid material.
Reaction SMILES: I.CS[C:4](=NC)[NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[OH:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][NH2:27].C(O)C.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>CO>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[OH:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][NH:27][C:4]1=[N:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[OH:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][NH:27][C:4]1=[N:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CN=C(Nc1cc(C)ccc1N1CCOCC1)SC
Reactant: NCCNCCO
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Product: Cc1ccc(N2CCOCC2)c(N=C2NCCN2CCO)c1

Procedure:
A mixture of 2-methyl-1-(5-methyl-2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (8.4 g prepared as described in Example 227), N-(2-hydroxyethyl)ethylenediamine (6.8 ml) and ethanol (80 ml)) was heated under reflux for 30 hours to give an oil which was treated with fumaric acid in methanol to give 4-{2-[1-(2-hydroxyethyl)-2-imidazolidinylideneamino]-4-methylphenyl}morpholine sesquifumarate (m.p. 135°-136° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([S:30][CH2:31][CH3:32])=[C:18]([CH:29]=2)[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:12])=[CH:4][CH:3]=1.[C:33](OC(=O)N(CC1C=C(N)C=CC=1SC(C)C)C)(C)(C)C.BrC1C=CC(C(CC)C(O)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([S:30][CH:31]([CH3:33])[CH3:32])=[C:18]([CH:29]=2)[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:12])=[CH:6][CH:7]=1
Reactant: CCSc1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1CN(C)C(=O)OC(C)(C)C
Reactant: CC(C)Sc1ccc(N)cc1CN(C)C(=O)OC(C)(C)C
Agent: CCC(C(=O)O)c1ccc(Br)cc1
Product: CC(C)Sc1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1CN(C)C(=O)OC(C)(C)C
Yield: 89 %

Procedure:
Using a procedure analogous to that used for preparation of 17B, 16E (0.418 g, 1.35 mmol) was reacted with 4-bromophenylbutanoic acid (0.340 g, 1.40 mmol) to give 18A (0.642 g, 89%) as a white solid. MS (ESI) m/z 537.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][CH:5]=1.I[C:14]1[C:22]2[C:17](=[CH:18][C:19]([CH:23]=[O:24])=[CH:20][CH:21]=2)[N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:15]=1>>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:14]2[C:22]3[C:17](=[CH:18][C:19]([CH:23]=[O:24])=[CH:20][CH:21]=3)[N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:15]=2)=[CH:6][CH:5]=1)[CH3:12]
Reactant: C=Cc1ccc(CN(C)C)cc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Product: CN(C)Cc1ccc(/C=C/c2nn(COCC[Si](C)(C)C)c3cc(C=O)ccc23)cc1
Temperature: 90 °C

Procedure:
The title compound was synthesized according to the method of Example A22A, utilizing N,N-dimethyl-1-(4-vinylphenyl)methanamine (42 mg, 0.26 mmol) and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (70 mg, 0.17 mmol) with heating in a sealed tube at 90° C. overnight instead of with microwave irradiation. Purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound to as a pale orange gum (33.4 mg, 44%). 1H NMR (400 MHz, CD3OD) δ ppm 10.13 (s, 1H), 8.27 (m, 2H), 7.81 (d, J=9.29 Hz, 1H), 7.69 (d, J=8.28 Hz, 2H), 7.61 (d, J=16.6 Hz, 1H), 7.50 (d, J=16.6 Hz, 1H), 7.43 (d, J=8.28 Hz, 2H), 5.86 (s, 2H), 3.82 (s, 2H), 3.62 (t, J=8.03 Hz, 1H), 2.50 (s, 6H), 0.87 (t, J=8.03 Hz, 2H), −0.09 (s, 9H); MS ESI 436.3 [M+H]+, calcd for [C25H33N3O2Si+H]+ 436.6.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].I[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(NCC)C.[Cu]I>[C:9]1([C:5]#[C:4][CH2:3][CH2:2][C:1]([OH:7])=[O:6])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#CCCC(=O)O
Reactant: Ic1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: O=C(O)CCC#Cc1ccccc1
Yield: 28.1 %

Procedure:
A solution of pent-4-ynoic acid (1.0 g, 10 mmol), iodobenzene (2.3 ml, 20 mmol), copper(I) iodide (75 mg, 0.40 mmol) and dichlorobis(triphenylphosphine)-platinum(II) (140 mg, 0.20 mmol) in 20 mL of diethylamine was stirred at rt for 3 days. The volatile material are evaporated by a rotary evaporator and the resulting residue was dissolved in 50 mL dichloromethane and washed with 1 M HCl (50 mL). The dichloromethane layer was dried over sodium sulfate and evaporated to dryness under vacuum. The residue was purified by column chromatography (ethyl acetate/dichloromethane) to afford 5-phenylpent-4-ynoic acid (0.49 g).
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:3][CH2:4][CH2:5]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[F:24][C:25]1[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[C:26]=1[CH2:27][N:28]1[C:33]([CH3:34])=[C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[C:31](=[O:41])[N:30]([CH2:42][C@H:43]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:29]1=[O:58].C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(#N)C>[C:53]([O:52][C:51](=[O:57])[NH:50][C@H:43]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:42][N:30]1[C:31](=[O:41])[C:32]([N:35]2[CH2:36][CH2:37][N:38]([CH2:5][CH2:4][CH2:3][C:2]([F:11])([F:1])[C:7]([F:10])([F:9])[F:8])[CH2:39][CH2:40]2)=[C:33]([CH3:34])[N:28]([CH2:27][C:26]2[C:59]([C:63]([F:65])([F:66])[F:64])=[CH:60][CH:61]=[CH:62][C:25]=2[F:24])[C:29]1=[O:58])([CH3:54])([CH3:55])[CH3:56]
Reactant: Cc1c(N2CCNCC2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: OCCCC(F)(F)C(F)(F)F
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(N2CCN(CCCC(F)(F)C(F)(F)F)CC2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.3 %

Procedure:
To a solution of 100 μl (0.416 mmol) of 4,4,5,5,5-pentafluoropentan-1-ol in 2 mL of dichloromethane were added 69 μl (1.2 eq) of triethylamine and 36 μl (1.1 eq) of methanesulfonyl chloride in the order, followed by stirring at room temperature for 30 min. The solution was washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate, filtrated and concentrated to produce a colorless oil. 60 μl of the oil, 30 mg of (R)-tert-butyl (2-(3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-5-(piperazin-1-yl)-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.049 mmol), and 21 mg (0.149 mmol) of potassium carbonate were dissolved at 80° C. for 7 hrs in 2 mL of acetonitrile, with stirring. The solution was concentrated, diluted with dichloromethane, and washed with an aqueous saturated sodium bicarbonate solution. After concentration of the organic layer thus formed, the residue was purified by prep-TLC (eluent: hexane/ethyl acetate, 1/1) and dried in a vacuum to afford 8 mg of the compound as a colorless oil (yield 21%). 1H NMR (300 MHz, CDCl3) δ 1.36 (9H, s), 1.77 (2H, m), 2.14 (4H, m), 2.36 (3H, s), 2.42 (2H, m), 2.53 (2H, m), 2.75 (2H, m), 3.61 (2H, m), 4.05 (1H, m), 4.28 (1H, m), 5.01 (1H, m), 5.33 (1H, m), 5.51 (1H, m), 5.82 (1H, d), 7.19-7.44 (7H, m), 7.55 (1H, m)
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:13](=[O:21])[C@H:14]([CH2:16][C:17]([O:19]C)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:30])[C:5]=2[NH:4][N:3]=1.O1CCCC1.CO.O.O.[OH-].[Li+]>>[Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[C:13](=[O:21])[C@H:14]([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:30])[C:5]=2[NH:4][N:3]=1
Reactant: COC(=O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CCN2CCCCC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CCN2CCCCC2)C1=O
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 50 %

Procedure:
(S)-Methyl 2-(1,4-dichloro-8-oxo-9-(2-(piperidin-1-yl)ethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate (260 mg, 0.573 mmol) was dissolved in a mixture of tetrahydrofuran (5.0 mL, 61.6 mmol) and methanol (5.0 mL, 123 mmol). Water (5.0 mL, 278 mmol) was added to the mixture followed by lithium hydroxide hydrate (65 mg, 1.549 mmol). Mixture was warmed to 50° C. and held with stirring for 4.5 hours. Mixture was cooled to room temperature. Organic solvents were removed from the mixture by roto-vap. Residue was neutralized with 1.6 mL 1N hydrochloric acid and treated with ethyl acetate. Mixture sat at room temperature for 20 minutes allowing solids to form. Solids were filtered off and washed with water. Solids were dried in vacuo. Title compound was obtained as white solid in 50% yield. MS (M−H)−=437.1, 439.2.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)=[O:25])[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6].C(OCC)(=O)C.[Na]>FC(F)(F)C(O)=O>[F:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([CH:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)=[O:25])[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc4c(ccn4C(=O)NCCF)c3)ccn2)CC1
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NCCF)c2)ccn1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
After dissolving 160 mg of N1-(2-fluoroethyl)-5-[(2-{[(1-tert-butyloxycarbonyl-4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide in 10 ml of trifluoroacetic acid, the solution was stirred at room temperature for 10 minutes. Ethyl acetate and sodium bicarnobate water were added to alkalinity for liquid separation. The ethyl acetate layer was washed once with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 86 mg of a colorless powder.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([O-])=O>O.C1COCC1.[Fe]>[N:12]1([C:9]2[CH:8]=[CH:7][C:6]([NH2:3])=[CH:11][CH:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(N2CCCCC2)cc1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
Ammonium chloride (228 mg, 4.2 mmol) in water (4 mL) was added to a solution of 1-(4-nitro-phenyl)-piperidine (220 mg, 1.0 mmol) in THF (6 mL) and the resulting mixture was stirred at 75° C. for 30 minutes. Iron powder (238 mg, 4.2 mmol) was then added portion wise and the mixture stirred for 5 hours at 75° C. The reaction mixture was filtered over celite, the filtrate was basified with sodium bicarbonate solution and the product extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 180 mg (96%) of 4-Piperidin-1-yl-phenylamine. LCMS: 177.13 (M+1)+, 80.6%, 1H NMR: (DMSO-d6): δ 6.67 (m, 2H), 6.47 (m, 2H), 4.51 (s, 2H), 2.57 (t, 4H), 1.6 (q, 4H), 1.49 (m, 2H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([CH3:15])[CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br-].[C:18]([CH2:21][CH2:22][CH2:23][CH2:24][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:20])=[O:19].[H-].[Na+].CC(O)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:7]([CH3:15])[CH:8]1[CH2:13][CH2:12][C:11](=[CH:24][CH2:23][CH2:22][CH2:21][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(=O)CC1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CN(C(=O)OC(C)(C)C)C1CCC(=CCCCC(=O)O)CC1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
5 g (21.99 mmol) Methyl-(4-oxo-cyclohexyl)-carbamic acid tert-butyl ester and 12.68 g (28.59 mmol) (4-Carboxy-butyl)-triphenyl-phosphonium bromide were dispended in 50 ml DMF. In small portions 2.49 g (57.2 mmol, 55%) NaH were added and the slurry was diluted by adding 50 ml DMF. The mixture was stirred at RT over night, 10 ml AcOH were added and the solvent was evaporated under reduced pressure. The residue was dissolved in ether and water, and the inorganic layer was extracted with ether. The combined organic phases were dried over and the crude materil was purified by column chromatography with ETOAc/hexane to give 5.86 g (83%) 5-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexylidene]-pentanoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[F:19][C:20]1[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=1>>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:24][CH2:25][C:20]([F:19])=[CH:21][CH2:22]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: FC1=CCNCC1
Product: FC1=CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)CC1

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) was reacted as described in Preparation Hc with 4-fluoro-1,2,3,6-tetrahydropyridine to afford 2-chloro-4-(4-fluoro-5,6-dihydropyridin-1(2H)-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation Hs).
Reaction SMILES: BrCC(NCC(N(C1C(Cl)=C(C(Cl)=CC=1)CO[C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([CH3:26])[CH:22]=[CH:21]2)C)=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:26][C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:24]=1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CBr)c3Cl)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114.6 %

Procedure:
A mixture of 8-[3-[N-(bromoacetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (80 mg) 5-amino-1,3,4-thiadiazole-2-thiol (24 mg), potassium carbonate (42 mg) in dimethylformamide (2 ml) was stirred for 30 minutes at ambient temperature. To the mixture was added water, and the mixture was extracted with ethyl acetate twice. Combined organic layers were washed with water three times, dried over magnesium sulfate and concentrated. The residue was pulverized from diethyl ether to give 8-[3-[N-(5-amino-1,3,4-thiadiazol-2-ylthio)acetylglycol]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (25 mg) as a solid.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.C(I)(C)(C)C.II.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[Cl:26])[N:22]=[CH:21][CH:20]=C2C.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>CS(C)=O.O.O.O.O.[Fe](Cl)Cl.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[Cl:26])[N:22]=[CH:21][CH:20]=[C:2]2[CH:3]=[O:5]
Reactant: Cc1ccnc2cc(Cl)c(Cl)cc12
Reactant: O=C(O)C(F)(F)F
Agent: Cl[Fe]Cl
Agent: CC(C)(C)I
Agent: II
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccnc2cc(Cl)c(Cl)cc12
Yield: 99 %

Procedure:
Trifluoroacetic acid (360 μL, 4.7 mmol), tert-butyl iodide (450 μL, 3.8 mmol), iodine (990 mg, 3.9 mmol) and iron(II) chloride tetrahydrate (170 mg, 0.85 mmol) were added sequentially to a solution of 6,7-dichloro-4-methylquinoline (Reference compound No. 1-2, 790 mg, 3.7 mmol) in dimethylsulfoxide (18 mL) at room temperature, and the mixture was stirred at 80° C. for 7 hours. Then saturated sodium thiosulfate aqueous solution (100 mL) was added, and then ethyl acetate (300 mL) and saturated aqueous sodium hydrogencarbonate solution (200 mL) were added thereto. The mixture was separated into the organic layer and the aqueous layer, and the organic layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, The solvent was evaporated under reduced pressure to give 840 mg of the title reference compound as a brown solid (Yield: 99%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:8]2[NH:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:11][C:7]=2[CH2:6][CH2:5]1.[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19]>CN(C=O)C>[O:3]=[C:4]1[C:8]2[N:9]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:11][C:7]=2[CH2:6][CH2:5]1
Reactant: CCOC(=O)c1cc2c([nH]1)C(=O)CC2
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(n1COCC[Si](C)(C)C)C(=O)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To sodium hydride (60% dispersion in mineral oil) (0.46 g, 11.4 mmol, 1.1 equiv) in anhydrous DMF (10 mL) under a nitrogen atmosphere at 0° C. was added dropwise a solution ethyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (2.0 g, 10 mmol, 1 equiv) in anhydrous DMF (15 mL). After stirring for 30 min at 0° C., SEM-Cl (2.1 g, 12.4 mmol, 1.2 equiv) was then added dropwise over 5 min and the mixture warmed to rt overnight. The reaction was quenched by pouring the reaction contents into a beaker of ice water. It was extracted with EtOAc (4×50 mL) and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0-30% EtOAc/heptane) to afford 2.9 g of ethyl 6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (86% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.84 (s, 1H), 5.87 (s, 2H), 4.35 (q, J=7.13 Hz, 2H), 3.57 (dd, J=8.59, 7.71 Hz, 2H), 2.82-2.92 (m, 4H), 1.38 (t, J=7.14 Hz, 3H), 0.85-0.92 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23](O)=[O:24])=[CH:13][CH:12]=2)[C:8]2[C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[H-].[Li+].[Al+3].[H-].[H-].[H-].Cl>C(Cl)(Cl)Cl.O1CCCC1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][OH:24])=[CH:15][CH:16]=2)[C:8]2[C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2CO)cc1

Procedure:
A mixture of methyl 2-butyl-1-[2'-carboxybiphenyl-4-yl]methylbenzimidazole-7-carboxylate (0.44 g) and thionyl chloride (0.15 ml) in chloroform (4 ml) was heated for 30 minutes under reflux with stirring. The reaction mixture was concentrated, and the resulting product was used for the subsequent reaction without purification. A stirred solution of the above product in tetrahydrofuran (6 ml) was added dropwise to a suspension of aluminium lithium hydride (40 mg) in tetrahydrofuran (6 ml) under ice-cooling. The reaction mixture was stirred for one minutes at the same temperature, and to the mixture were added 2N-HCl and, then water, followed by extraction with chloroform. The extract was washed with water and dried (MgSO4), and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel to give an oil. Crystallization of this product from isopropyl ether afforded colorless prisms (0.13 g, 31%), m.p.126°-127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]3[CH:22]=C[C:20]([N:23]4[CH2:27][CH2:26][C@H:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]4)=[CH:19][CH:18]=3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClC1C=CC([N+]([O-])=O)=C[N:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:27][CH2:26][C@H:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:24]4)=[N:39][CH:22]=3)=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ccc(NC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2)C1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ccc(NC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cn2)C1

Procedure:
The synthetic sequence for preparing tert-butyl (R)-[1-(4-{[4-(4-chlorophenyl)piperidin-1-carbonyl]amino}phenyl)pyrrolidin-3-yl]methylcarbamate was carried out starting from 2-chloro-5-nitropyridine instead of 4-fluoronitrobenzene. This resulted in the product with the molecular weight of 514.07 (C27H36ClN5O3); MS (ESI): 514 (M+H+).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[NH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH2:36])[N:31]=3)=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=1.Cl[C:40]1[S:41][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[N:43][N:44]=1>>[C:45]1([C:42]2[S:41][C:40]([NH:18][C:19]3[CH:38]=[CH:37][C:22]([O:23][C:24]4[C:29]([C:30]5[CH:35]=[CH:34][N:33]=[C:32]([NH2:36])[N:31]=5)=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:21][CH:20]=3)=[N:44][N:43]=2)[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: Clc1nnc(-c2ccccc2)s1
Reactant: Nc1ccc(Oc2ncccc2-c2ccnc(N)n2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: Nc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)s3)cc2)n1

Procedure:
A slurry of pyridinium p-toluenesulfonate (0.18 g, 0.72 mmol), 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine (0.100 g, 0.36 mmol), and 2-chloro-5-phenyl-1,3,4-thiadiazole (0.077 g, 0.39 mmol; prepared by method described in J. Med. Chem., 31:902 (1988)) was heated in 2 mL 2-BuOH in a sealed tube to 110° C. The reaction became dark brown and homogeneous. After 2 h the reaction was quenched with 1N NaOH and DCM. The aqueous layer was extracted 2×DCM, and the emulsified aqueous layer was filtered and rinsed with dichloromethane. The resulting solid was adsorbed onto silica gel from MeOH/DCM, dried, and purified by silica gel chromatography, 0-100% 90/10 DCM/MeOH in DCM to give 4-(2-(4-(5-phenyl-1,3,4-thiadiazol-2-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amine as a white solid. MS m/z=440 [M+H]+. Calc'd for C23H17N7OS: 439.5.