Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[N:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+]([O-])=O)[CH:14]=2)[C:7]([NH2:10])=[N:8][N:9]=1)[CH2:2][CH:3]=[CH2:4].[N+:22]([C:25]1C=C(C=[CH:30][CH:31]=1)N)([O-])=O.C(CC(=O)CCC=C)#N.CC([O-])=O.[Na+]>>[CH2:1]([C:5]1[C:6](=[N:11][NH:12][C:13]2[CH:14]=[C:15]3[C:16](=[CH:17][CH:18]=2)[N:22]=[CH:25][CH:31]=[CH:30]3)[C:7]([NH2:10])=[N:8][N:9]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: C=CCCC1=NN=C(N)C1=NNc1cccc([N+](=O)[O-])c1
Agent: C=CCCC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [Na+]
Product: C=CCCC1=NN=C(N)C1=NNc1ccc2ncccc2c1
Yield: 61 %

Procedure:
In a similar manner, 5-but-3-enyl-4-[(3-nitrophenyl)hydrazono]4H-pyrazol-3-ylamine was prepared from 3-nitroaniline (166 mg, 1.2 mmole) and 1-cyano-5-hexen-2-one (123 mg, 1 mmole) with NaOAc (979 mg, 7.2 mmole) according to a procedure similar to Example 2. The crude material was purified by a prepreparative TLC (CH2Cl2:MeOH=21:1) to yield 175 mg (61%) of the title compound as an orange powder. MS (m/z, ES+): 287 (M+1, 100%); 1H NMR (ppm, 300 MHz, DMSO-d6-CDCl3) δ 11.60 (br s, 1H), 8.38 (s, 1H), 7.99 (m, 1H), 7.57 (t, 1H), 6.64 (br s, 2H), 5.84 (m, 1H), 5.03 (d, 1H), 4.92 (d, 1H), 2.88 (m, 2H), 2.48 (m, 2H).
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[O:24])=[CH:18][CH:17]=2)[CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C>O1CCCC1>[CH:1]1([C:5]([NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:24])=[CH:18][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCC1
Reactant: Nc1cc(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ccnc(NC(=O)C3CCC3)c2)cc1
Temperature: 25 °C

Procedure:
After adding 70 mg of cyclobutanecarbonyl chloride to a solution of 100 mg of N-[4-(2-aminopyridin-4-yl)oxyphenyl-]-N′-(4-fluorophenyl)urea, 0.12 ml of triethylamine and 10 ml of tetrahydrofuran stirred at room temperature, the mixture was further stirred for 15 minutes. NH type silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (chloroform:methanol=40:1). The obtained residue was solidified from ethyl acetate-methanol-hexane to obtain 64 mg of the target substance as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH2:11][CH:10](NC)[O:9][N:8]=2)=[CH:4][CH:3]=1.[CH2:14]([N:16]([CH2:19]C)CC)[CH3:15].ClCCl.C(Cl)(=[O:26])C>C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH2:11][CH:10]([CH2:19][NH:16][C:14](=[O:26])[CH3:15])[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(=O)Cl
Reactant: CNC1CC(c2ccc(Br)s2)=NO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)NCC1CC(c2ccc(Br)s2)=NO1
Temperature: 0 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
[3-(5-Bromo-thien-2-yl)-4,5-dihydro-isoxazol-5-yl]-methylamine (2.1 g, 8 mmol) and triethylamine (1.7 ml, 12 mmol) were added to anhydrous dichloromethane (50 ml) and cooled to 0° C. Acetyl chloride (0.670 ml, 9.6 mmol) was then added dropwise and the reaction was stirred for 3 hours followed by addition of ethyl acetate (100 ml). The precipitate was collected and washed with water (2×25 ml) to give the desired product (1.2 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1.Cl[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[CH2:26][O:25][CH:13]1[CH:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)=[CH:7][CH:8]=2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14]1
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccn3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 57(c)] with 2-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[3-(pyridin-2-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate as a colourless resin; MS: 583 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C1C(=O)N([I:20])C(=O)C1>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]2[N:6]([C:8]([I:20])=[CH:9][N:10]=2)[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CSc1nc(Br)cn2ccnc12
Solvent: CN(C)C=O
Product: CSc1nc(Br)cn2c(I)cnc12
Temperature: 60 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
To a stirred solution of 6-bromo-8-methylsulfanyl-imidazo[1,2-a]pyrazine (210.0 g, 860.3 mmol) in DMF (4200 mL) was added NIS (212.9 g, 946.3 mmol, 1.1 eq) in one portion at rt. After 18 h stirring at 60° C. the dark solution was evaporated and the brown residue was dissolved in DCM (7 L), washed with water (2×5 L) and sole (2×5 L) and dried over sodium sulphate. Crystallization by careful removal of solvent yielded 255 g (80.1%) 6-bromo-3-iodo-8-methylsulfanyl-imidazo[1,2-a]pyrazine: 1H-NMR (300 MHz, d6-DMSO): δ=8.24 (1H, s), 7.79 (1H, s), 2.46 (3H, s) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Reaction time: 4 h
Yield: 2121.9 %

Procedure:
A solution of 0.4 g (0.112 mmol) of 1-t-butoxycarbonyl-4-(4-trifluoromethyl phenyl)-1,2,3,6-tetrahydropyridine in 1 mL of TFA and 3 mL of CH2Cl2 was stirred at rt for 1 h. The reaction mixture was then concentrated. A mixture of the residue and 0.1 g of 10% Pd/C in 20 mL of MeOH was hydrogenated at 45 psi for 4 h. The reaction mixture was flitered though a plug of celite and concentrated to give 0.54 g of the title compound. 1H NMR (CDCl3) δ1.94 (m,2H), 2.06 (m, 2H), 3.00 (m, 1H), 3.11 (m, 2H), 3.49 (m, 2H), 7.45 (d, 2H, J=8 Hz), 7.62 (d, 2H, J=8 Hz)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][N:26]4C(OC(C)(C)C)=O)=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]4)=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2[nH]c(C3CCCCN3)cc2c1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
tert-Butyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclo-propanecarboxamido)-1H-indol-2-yl)piperidine-1-carboxylate (55 mg, 0.11 mmol) was dissolved in dichloromethane (2.5 mL) containing trifluoroacetic acid (1 mL). The reaction mixture was stirred for 6 h at room temperature. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(piperidin-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 403.2, found 404.4 (M+1)+. Retention time of 0.95 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH2:12]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CC(CC)=O>C(OCC)(=O)C>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[C:3]=2[CH3:11])=[CH:22][CH:23]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: Cc1c(O)ccc(C=O)c1C
Reactant: CC(C)Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: Cc1c(C=O)ccc(OCc2ccc(CC(C)C)cc2)c1C
Yield: 88.2 %

Procedure:
A mixture of 4-hydroxy-2,3-dimethyl-benzaldehyde (220 mg), 4-isobutylbenzyl bromide (341 mg), potassium carbonate (1.38 g) and ethyl methyl ketone (10 ml) was refluxed for 6 hrs. After cooling, the reaction mixture was diluted with ethyl acetate, the solution was washed with dil hydrochloric acid, water, successively, dried and evaporated. The residue was purified by column chromatography on silica gel (hexane:EtOAc=10:1) to give the title compound (383 mg) having the following physical data:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:16])=[C:11]([CH:15]=2)[C:12]([NH2:14])=[O:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:17]1([CH:27]=O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[O:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:15]=[C:11]3[C:10](=[CH:9][CH:8]=2)[N:16]=[C:27]([C:17]2[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=2)[NH:14][C:12]3=[O:13])[CH2:2][CH2:3]1
Reactant: NC(=O)c1cc(N2CCOCC2)ccc1N
Reactant: O=Cc1cccc2ccccc12
Product: O=c1[nH]c(-c2cccc3ccccc23)nc2ccc(N3CCOCC3)cc12

Procedure:
Compound 29 was synthesized from 5-morpholinyl-2-aminobenzamide (13) (1.6 g, 7.3 mmol) and 1-naphthaldehyde (14) (1.1 g, 7.3 mmol): yield 1.7 g (64%); yellow crystals; mp 291 to 293° C.; 1H NMR (DMSO-d6) δ 3.22 (4H, t, J=4.7 Hz, CH2NCH2), 3.77 (4H, t, J=4.7 Hz, CH2OCH2), 7.51-7.66 (6H, m, 6×ArH), 7.73-7.76 (1H, m, 1×ArH), 8.00-8.11 (3H, m, 3×ArH), 12.48 (1H, br s, NH) ppm; MS (ESI) m/z 357; Anal. (C22H19N3O2): C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10](C=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:30][N:27]1[CH2:26][CH2:25][CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=2)[CH2:29][CH2:28]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Fc1ccc(CC2CCNCC2)cc1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCC1CN1CCC(Cc2ccc(F)cc2)CC1
Reaction time: 4 h
Yield: 91.1 %

Procedure:
A solution of (+/−)-N-(t-butoxycarbonyl)-3-piperidinecarboxaldehyde (521 mg, 2.45 mmol) and 4-(4-flourophenylmethyl)piperidine (315 mg, 1.63 mmol) in dry CH2Cl2 (20 mL) was stirred for 15 min when sodium triacetoxyborohydride (691 mg, 3.26 mmol, Aldrich) was added. The reaction was stirred for 4 h and then quenched with 10% NaOH (10 mL) and CH2Cl2 (100 mL). The organic layer was separated, dried over MgSO4, and conc. in vacuo to a pale yellow oil. The oil was purified by radial chromatography (SiO2, CH2Cl2:MeOH, 98:2) to yield 580 mg the product as a colorless oil. MS (ESI) 391 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>[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(NC(C)C)(C)C>[CH3:29][Si:30]([CH3:32])([CH3:31])[C:33]#[C:34][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(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: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: Cc1cc(C)cc(C#C[Si](C)(C)C)c1
Temperature: 75 °C

Procedure:
A solution of 5-bromo-m-xylene (19.4 g, 105 mmol) and diisopropylamine (100 mL) was degassed with argon and kept under an argon atmosphere. CuI (2.07 g, 10.7 mmol), PPh3 (4.06 g, 15.3 mmol) and Pd(PPh3)2Cl2 (2.09 g, 2.92 mmol) were added followed by addition of trimethylsilylacetylene (12.3 g, 18 mL, 125 mmol). The reaction was heated to 75° C. for 2 h giving a dark brown viscous mixture. Additional trimethylsilylacetylene (6.15 g, 9 mL, 63 mmol), PPh3 (2.04 g, 7.78 mmol), CuI (1.05 g, 5.51 mmol) and Pd(PPh3)2Cl2 (1.62 g, 2.31 mmol) were added and then the reaction was heated to 80° C. for 4 h. After cooling the reaction to room temperature, hexanes (300 mL) was added and the solution was filtered through celite. The hexane layer was washed with 1N HCl (600 mL), brine (300 mL), dried (Na2SO4), and concentrated to give crude 1-trimethylsilyl-2-(3,5-dimethylphenyl)-acetylene which was used for the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([NH:8][C:9](=[O:15])[C:10]([O:12]CC)=O)[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1.[CH3:19][C:20]1([CH3:37])[CH2:25][CH:24]([NH:26][C:27](=[O:34])[CH2:28][CH2:29][C:30]([NH:32][NH2:33])=[O:31])[CH2:23][C:22]([CH3:36])([CH3:35])[NH:21]1>CO>[CH3:18][C:2]1([CH3:1])[CH2:7][CH:6]([NH:8][C:9](=[O:15])[C:10]([NH:33][NH:32][C:30](=[O:31])[CH2:29][CH2:28][C:27]([NH:26][CH:24]2[CH2:23][C:22]([CH3:35])([CH3:36])[NH:21][C:20]([CH3:37])([CH3:19])[CH2:25]2)=[O:34])=[O:12])[CH2:5][C:4]([CH3:16])([CH3:17])[NH:3]1
Reactant: CC1(C)CC(NC(=O)CCC(=O)NN)CC(C)(C)N1
Reactant: CCOC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Solvent: CO
Product: CC1(C)CC(NC(=O)CCC(=O)NNC(=O)C(=O)NC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1

Procedure:
Into a 3-necked 50 ml flask was introduced a 60.9% solution of ethyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate in methanol (4.27 g, 0.01 mole), N-(2,2,6,6-tetramethyl-4-piperidinyl)-N'-aminosuccinamide (2.7 g, 0.01 mole) and 25 ml of anhydrous methanol. The flask was equipped with a thermometer, a magnetic stirrer and a Dean Stark trap with a reflux condenser. The reaction mixture was heated to reflux for 1/2 hour. Liquid chromatography of the reaction mixture indicated that the starting materials had essentially disappeared and there was one new peak corresponding to the product. The reaction mixture was filtered hot to remove some insoluble material. The filtrate was stripped to dryness on a rotatary evaporator under reduced pressure. The residue was scraped out of the flask and pulverized into a white powder with a mortar and pestle. The white powder was air dried on a watch glass overnight. The product weighed 1.0 grams and had a melting range of 130°-135° C. An infrared scan (nujol mull) of the product contained a strong carbonyl band at 1655 cm-1 and two moderate carbonyl bands at 1575 and 1495 cm-1.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([C:16]3[S:20]C=N[CH:17]=3)[C:13]([CH3:21])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[C:22](O)=[O:23])[CH2:2][CH2:3][CH3:4].[N:25]1[N:26]=[CH:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]=12.CN(C(ON1N=N[C:44]2C=CC=C[C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([C:16]3[S:20][CH:43]=[CH:44][CH:17]=3)[C:13]([CH3:21])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[C:22]([N:31]1[CH2:32][CH2:33][N:28]2[CH:27]=[N:26][N:25]=[C:29]2[CH2:30]1)=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: c1nnc2n1CCNC2
Reactant: CCCCc1c(C(=O)O)cnn1-c1ncc(C)c(-c2cncs2)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1c(C(=O)N2CCn3cnnc3C2)cnn1-c1ncc(C)c(-c2cccs2)n1
Yield: 3.2 %

Procedure:
To a solution of 5-butyl-1-(5-methyl-4-(thiazol-5-yl)pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid (72 mg, 0.21 mmol), 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (50 mg, 0.23 mmol), HBTU (119 mg, 0.32 mmol) and 4 mL of DMF was added DIEA (54 μL, 0.73 mmol). The reaction was stirred at room temperature for 2 hours at which time the crude mixture was purified directly by reverse phase preparative HPLC to provide 3.0 mg of 30 as a white solid. 1H NMR (400 MHz, MeOD-d3) δ 0.78 (t, J=7.2 Hz, 3H), 1.35 (m, 2H), 1.61 (m, 2 H), 2.69 (s, 3H), 3.4 (t, J=7.7 Hz, 2H), 4.18 (t, J=5.1 Hz, 2H), 4.31 (t, J=5.5 Hz, 2H), 5.10 (s, 2H), 7.32 (t, J=4.5 Hz, 1H), 7.82 (d, J=5.1 Hz, 1H), 7.96 (s, 1H), 7.99 (d, J=2.7 Hz, 1H), 8.54 (s, 1H), 8.76 (s, 1H). LCMS (ES+) m/z 449 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([OH:15])[CH2:10]2)[CH:5]=[CH:4][N:3]=1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[C:31](O)=[O:32]>>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[C:31]([O:15][C@H:11]1[CH2:12][CH2:13][CH2:14][N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)[CH2:10]1)=[O:32]
Reactant: O[C@@H]1CCCN(Cc2ccnc(F)c2)C1
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Product: O=C(O[C@H]1CCCN(Cc2ccnc(F)c2)C1)[C@@H]1CCCCN1c1nc2ccccc2o1

Procedure:
The title compound was prepared by a similar method to Example 36 from (3R)-1-[(2-fluoro-4-pyridinyl)methyl]-3-piperidinol [see Preparation 39] and (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3]. The crude product was partly purified by column chromatography on silica gel eluting with a solvent gradient of 3:1 changing to 1:1, by volume, ethyl acetate:hexane, the product was further purified by trituration with 95:5, by volume, hot hexane:ethyl acetate, followed by trituration with hot petroleum ether:diethyl ether, 95:5 to afford (3S)-1-[(2-fluoro-4-pyridinyl)methyl]-3-piperidinyl (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylate. The hydrochloride salt was prepared by addition of saturated hydrogen chloride gas in diethyl ether to a solution of product in ethyl acetate, and isolated as a white solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:18][N:19]([CH2:27][C@@H:28]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)[CH3:29])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:33]1[CH:32]=[CH:31][C:30]([C@@H:28]([CH3:29])[CH2:27][N:19]([CH3:18])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:35][CH:34]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@@H](CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CN(C)C(=O)OC(C)(C)C)cc1
Yield: 34.8 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (700 mg, 2.3 mmol) was reacted with (R)-tert-butyl methyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)carbamate (1.3 g, 3.4 mmol) to afford the desired product (383 mg, 38%) as a yellow solid: ESI MS m/z 479 [C27H30N2O4S+H]+.
Reaction SMILES: [N:1]1([C:7](=[NH:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([CH:14]([CH:20]([CH2:26][CH2:27][CH3:28])[C:21](OCC)=[O:22])[C:15]([O:17]CC)=[O:16])(=O)[CH2:11][CH3:12].C[O-].[Na+]>CO>[CH2:27]([C:26]1[N:9]=[C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[NH:8][C:21](=[O:22])[C:20]=1[CH:14]([CH2:10][CH2:11][CH3:12])[C:15]([OH:17])=[O:16])[CH3:28]
Reactant: N=C(N)N1CCCCC1
Reactant: CCCC(C(=O)OCC)C(C(=O)CC)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC(C(=O)O)c1c(CC)nc(N2CCCCC2)[nH]c1=O

Procedure:
To a solution of piperidine-1-carboximidamide (dimer complexated with H2SO4) (1 g; 7.86 mmol) and diethyl 2-propionyl-3-propylsuccinate (2.14 g; 7.86 mmol) in methanol (8 mL) was slowly added a solution of sodium methoxide in methanol (25% w:w) (3.60 mL; 15.72 mmol) and the reaction was heated under reflux for 18 h. The mixture was concentrated under reduced pressure and the curde residue was used as such in the next reaction.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:30]1COCC1.C[Mg]Br.CCOCC>C(#N)C.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])([CH3:30])[CH3:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])=[C:15]([N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)[CH:16]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: CC(C)(O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
A 4 mL vial was charged with 4-acetyl-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)benzenesulfonamide (synthesized according to general procedures F and G, 100 mg, 0.23 mmol) and 1.5 mL THF. The resultant slurry was cooled to −78° C. in a dry ice-acetone bath, 2.0 M methylmagnesium bromide in Et2O (350 μL, 0.70 mmol) was added dropwise, and the mixture was stirred for five hours. The reaction mixture was subsequently diluted with ˜2 mL of acetonitrile/H2O and purified by reversed phase HPLC to afford N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-(1-hydroxy-1-methyl-ethyl)-benzene-sulfonamide: MS (ES) M+Na expected 466.0, found 466.0.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:7]2([CH2:12][CH2:11][N:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19](C(=O)C)=[CH:18][CH:17]=3)=[O:14])[CH2:9][CH2:8]2)[CH2:6]1)(=[O:4])=[O:3].[BH4-].[Na+].Cl.[CH2:34]([OH:36])[CH3:35].ClCCl>>[CH3:1][S:2]([N:5]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:7]2([CH2:12][CH2:11][N:10]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:35][CH2:34][OH:36])=[CH:20][CH:21]=3)=[O:14])[CH2:9][CH2:8]2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: CC(=O)c1ccc(NC(=O)N2CCC3(CC2)CN(S(C)(=O)=O)c2ccccc23)cc1
Reactant: CCO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)N1CC2(CCN(C(=O)Nc3ccc(CCO)cc3)CC2)c2ccccc21
Reaction time: 1 h

Procedure:
To a stirred solution of 1-methylsufonyl-N-(4-acetylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (400 mg) in ethanol/dichloromethane (5/5 mL) at 0° C., was added sodium borohydride (100 mg). The mixture was stirred for 1 hour, then 3 N HCl (0.2 mL) was added to destroy the excess hydride. The mixture was then concentrated and partitioned between water and dichloromethane. The organic layer was dried over MgSO4 and evaporated to give the title compound, 1600 as white powder (386 mg). ESI-MS: 430 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10]OS(C)(=O)=O)[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl.[F:23][C:24]1([F:29])[CH2:28][CH2:27][NH:26][CH2:25]1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]#[C:9][CH2:10][N:26]2[CH2:27][CH2:28][C:24]([F:29])([F:23])[CH2:25]2)[CH:3]=1
Reactant: CS(=O)(=O)OCC#Cc1cncc(Br)c1
Reactant: FC1(F)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC1(F)CCN(CC#Cc2cncc(Br)c2)C1
Temperature: 80 °C

Procedure:
To a solution of methanesulfonic acid 3-(5-bromo-pyridin-3-yl)-prop-2-ynyl ester (Intermediate 223) (1 eq, 1.95 mmol, 566 mg) in DMF (6 ml) are added K2CO3 (2.5 eq, 4.88 mmol, 674 mg) and 3,3-difluoro-pyrrolidine hydrochloride (ABCR GmbH & Co. KG, Karlsruhe, Germany) (1.2 eq, 2.34 mmol, 336 mg). The resulting mixture is heated at 80° C. for 2 h. The reaction mixture is cooled to r.t. before adding water and extracting the mixture with EtOAc. The organic layer is dried with MgSO4, filtered, and the solvents are removed in vacuo. Purification by column chromatography yields the title compound; [M+H]+=301/303.