Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1](Cl)([O:8][CH2:9][CH2:10][CH2:11][CH3:12])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2].ClCCl.[CH2:17]([OH:21])[CH:18]([CH3:20])[CH3:19]>N1C=CC=CC=1>[P:1]([O:21][CH2:17][CH:18]([CH3:20])[CH3:19])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2]
Reactant: CCCCOP(=O)(Cl)OCCCC
Reactant: CC(C)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOP(=O)(OCCCC)OCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of di-n-butyl chlorophosphate (130.3 g, 0.57 mole) in 600 mL of dichloromethane containing 55.37 g (0.70 mole) of pyridine was cooled to 0° C. Isobutanol (42.25 g, 0.57 mole) was added dropwise over 1 hour. The formation of a white precipitate was immediately observed. The reaction mixture was then stirred for 24 hours at room temperature. The pyridinium hydrochloride was filtered off, and the solution was washed with water (2×250 mL), aqueous 0.5 N HCl (2×250 mL) and water (25×250 mL). The organic phase was dried over anhydrous magnesium sulfate for 12 hours. Filtration of the drying agent, followed by the removal of the solvent using a Roto-vap, yielded di-n-butyl isobutyl phosphate as a clear colorless liquid. Distillation of the crude product (68° C. at 0.02 torr) gave 125 g of 94.8% di-n-butyl isobutyl phosphate (DBIBP).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.Br[CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].CC(N1CCCC(C(C)=[O:29])=C1)C>>[CH3:1][C:2]1([CH3:12])[CH2:11][C:10]2[N:9]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:29])[CH2:3]1
Reactant: CC(C)CCBr
Reactant: CC(=O)C1=CN(C(C)C)CCC1
Reactant: CC1(C)C=CC2=C(C1)NCCC2
Product: CC(C)CCN1CCCC2=C1CC(C)(C)CC2=O

Procedure:
7,7-Dimethyl-1,2,3,4,7,8-hexahydro-quinolin- (5(6H)-one was reacted with 1-bromo-3-methylbutane according to the procedures of Part (b) of Example 1 to give 7,7-dimethyl-1,2,3,4,7, 8-hexahydro-1-(3-methylbutyl)-quinolin-5(6H)one (18) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C(S)CCCCCCCCCCC.C[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: COc1cccc(N)c1C(=O)NCc1ccccc1
Agent: CCCCCCCCCCCCS
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cccc(O)c1C(=O)NCc1ccccc1
Temperature: 150 °C
Yield: 81.6 %

Procedure:
To a solution of 2-amino-N-benzyl-6-methoxybenzamide (0.228 g, 0.89 mmol, 1.0 equiv) in 3 mL of anhydrous DMF was added 1-dodecanethiol (0.360 g, 1.78 mmol, 2.0 equiv), followed by adding NaOMe (0.385 g of 25% solution in MeOH, 1.78, 2.0 equiv). The mixture was heated in a microwave at 150° C. for 10 min. The mixture passed through a silica gel plug, which was washed with an ethyl acetate-methanol mixture (1:1). The crude product was purified by PL-SO3H MP SPE (Varian) to give 2-Amino-N-benzyl-6-hydroxybenzamide (0.176 g, 82%) as thick oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.55-4.20 (vb.s., 2H), 4.60 (s, 1H), 4.61 (s, 1H), 6.25 (d, J=7.8 Hz, 1H), 6.50 (d, J=8.2 Hz, 1H), 7.09 (t, J=8.0 Hz, 1H), 7.16-7.52 (m, 5H), 8.58 (br. s., 1H), 12.05 (br. s., 1H); HPLC: tR=3.97 min, UV254=98%; HRMS (ESI): m/z calcd for C14H14N2O2 [M+1]+ 243.1140. Found 243.1134.
Reaction SMILES: [F:1][B-](F)(F)F.[CH2:6]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([N+]#N)=[CH:21][CH:20]=[C:19]([N:25]([C:29](=[O:31])[CH3:30])[CH:26]3[CH2:28][CH2:27]3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[CH3:7].B([O-])([O-])[O-]>C1(C)C=CC=CC=1>[C:29]([N:25]([CH:26]1[CH2:28][CH2:27]1)[C:19]1[N:18]=[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH2:12][CH2:13]2)[C:22]([F:1])=[CH:21][CH:20]=1)(=[O:31])[CH3:30]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2[N+]#N)CC1
Agent: [O-]B([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2F)CC1
Yield: 39.1 %

Procedure:
To 800 ml of refluxing toluene was added in portions, as a solid, 46.2 g (0.1 mole) of 2-[4-(ethoxycarbonyl)-1-piperazinyl]-6-(acetylcyclopropylamino)-3-pyridinediazonium tetrafluoroborate. borate. After the addition was complete, the reaction was refluxed for ten minutes and the toluene was decanted from the insoluble precipitate. The toluene was evaporated in vacuo and the residue was partitioned between chloroform and water. The chloroform layer was washed with 5% aqueous sodium bicarbonate, water, dried over magnesium sulfate and evaporated in vacuo to give 13.7 g of the title compound, as a viscous oil. An additional 10.2 g could be obtained by partitioning the original toluene insoluble material in chloroform and water. The organic layer was washed with 5% aqueous sodium bicarbonate, dried over magnesium sulfate, evaporated in vacuo and the residue was chromatographed on silica gel eluting with chloroform/ethyl acetate (6:4). This fraction was also a viscous oil which did not crystallize upon standing. Both fractions were of sufficient purity to be used as is in the ensuing steps.
Reaction SMILES: [CH:1]([Si:4]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[N:18]2[CH:19]=[C:20]([O:23][C@H:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C@@H:27]([NH2:34])[CH2:26][CH2:25]3)[CH:21]=[CH:22][C:17]2=[N:16][N:15]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C[O:53][C:54](=O)[NH:55][C:56]1[N:57]([C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)[N:58]=[C:59]([C:61]([CH3:64])([CH3:63])[CH3:62])[CH:60]=1>O1CCOCC1>[C:61]([C:59]1[CH:60]=[C:56]([NH:55][C:54]([NH:34][C@@H:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:24]([O:23][C:20]3[CH:21]=[CH:22][C:17]4[N:18]([C:14]([C@@H:10]5[CH2:11][CH2:12][CH2:13][N:9]5[CH2:8][CH2:7][CH2:6][O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:35]([CH3:37])[CH3:36])[CH:38]([CH3:40])[CH3:39])=[N:15][N:16]=4)[CH:19]=3)[CH2:25][CH2:26]2)=[O:53])[N:57]([C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)[N:58]=1)([CH3:64])([CH3:62])[CH3:63]
Reactant: CC(C)[Si](OCCCN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)(C(C)C)C(C)C
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCN5CCCO[Si](C(C)C)(C(C)C)C(C)C)n4c3)c3ccccc32)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of Intermediate 84g (140 mg, 0.25 mmol) in 1,4-dioxane (3.00 mL) was added DIPEA (86.0 μL, 0.50 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 100 mg, 0.25 mmol). The reaction was heated to 60° C. overnight then further (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (50.0 mg, 0.12 mmol) was added and heating at 60° C. continued overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (70.0 mg, 34%). LCMS (Method 1): Rt 3.46, m/z 820.4 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O=[C:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[C:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: N#Cc1ccccc1N
Product: CCOC(=O)Cc1nc2ccccc2c(N)c1C(=O)OCC

Procedure:
Prepared as in Example 2a from 2-aminobenzonitrile and diethyl 3-oxopentanedioate as a pale yellow solid (25%). 1H NR (400 MHz, DMSO-d6) δ 1.19 (t, J=8.0 Hz, 3H), 1.30 (t, J=8.0 Hz, 3H), 4.08 (m, 4H), 4.28 (q, J=8.0 Hz, 2H), 7.50 (m, 1H), 7.73 (m, 2H), 8.10 (bs, 2H), 8.53 (d, J=8.0 Hz, 1H). MS 303 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[C:40]([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:41]>ClCCl>[C:43]1([O:42][C:40]([N:1]2[CH2:2][CH2:3][CH:4]([CH2:7][N:8]3[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]([C:18]4[C:26]5[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=5[CH:21]=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:13]3)[CH2:5][CH2:6]2)=[O:41])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCNCC4)CC3)cccc2[nH]1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCN(C(=O)Oc5ccccc5)CC4)CC3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To a solution of 2-isopropyl-1H-benzoimidazole-4-carboxylic acid (1-piperidin-4-ylmethylpiperidin-4-ylmethyl)amide (0.22 g, 0.55 mmol) and N,N-diisopropylethylamine (0.19 mL) in dichloromethane (5.0 mL) was added phenyl chloroformate (70 μL). The mixture was stirred at room temperature for 10 min, then concentrated in vacuo and purified via preparative reverse phase HPLC to afford the bis trifluoroacetate salt of the title compound as a white solid (98.4 mg, 0.13 mmol, 24%). (m/z): [M+H]+ calcd for C30H39N5O3 518.32; found 518.6. 1H NMR (300 MHz, MeOD-d3): δ (ppm) 1.14-1.28 (m, 2H), 1.39-1.53 (m, 6H), 1.52-1.62 (m, 2H), 1.70-1.78 (m, 2H), 1.92-2.06 (m, 4H), 2.82-2.97 (m, 6H), 3.32-3.38 (m, 2H), 3.43-3.50 (m, 1H), 3.52-3.69 (m, 2H), 4.04-4.12 (m, 1H), 4.18-4.26 (m, 1H), 6.91-6.98 (m, 1H), 7.08-7.13 (m, 1H), 7.21-7.28 (m, 1H), 7.45-7.50 (m, 1H), 7.73-7.77 (m, 1H), 7.81-7.87 (m, 1H), 9.02-9.32 (brs, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.[OH-].[NH4+]>CN(C=O)C>[CH3:22][O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid (I, 5.0 g, 0.017 moles, 1.0 equivalent) and potassium carbonate (2.5 g, 0.018 moles, 1.1 equivalent) and DMF (100 mL) are mixed. To this heterogeneous mixture is then added dimethyl sulfate (1.6 mL, 2.1 g, 0.017 moles, 1.0 equivalent) and the contents are then stirred at 20-25° overnight. Once the reaction is complete as measured by HPLC, ammonium hydroxide (10%, 20 mL) is added and allowed to stir for 1 hr. The contents are stirred for 30 min then cooled to 0° and filtered. The solids are washed with cold water (20 mL) and dried under reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11]>OS(O)(=O)=O>[Cl:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1cc(Cl)nc(Cl)c1
Agent: O=S(=O)(O)O
Product: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,6-dichloro-4-aminopyridine (5.0 g, 30.6 mmol) in conc. H2SO4 (25 mL) at 0° C. in an ice-acetone bath was added 90% HNO3 (10 mL) dropwise. The reaction mixture was warmed to ambient temperature and stirred for 1 h then poured onto ice (100 g). The solid precipitate was isolated by filtration, washed with cold H2O and dried under high vacuum. The resulting solid was dissolved in conc. H2SO4 (50 mL) and heated at 100° C. for 20 min. The reaction mixture was poured onto ice (150 g) and neutralized with conc. NH4OH while maintaining the temperature below 20° C. The precipitate was isolated by filtration, washed with cold H2O, and dried to yield the title compound. MS: m/z=208(M+1).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][NH:28][C:29](=[O:33])[CH:30](Cl)[CH3:31])[CH2:10]1)(C(C)(C)C)(C)C.[O-:34][C:35]#[N:36].[K+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[OH:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([CH2:27][N:28]2[C:29](=[O:33])[CH:30]([CH3:31])[NH:36][C:35]2=[O:34])[CH2:10]1
Reactant: CC(Cl)C(=O)NC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: N#C[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1NC(=O)N(C[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
A solution of (2S,4R)-4-(t-butyldimethylsilyloxy)-2-(2-chloropropionyl)aminomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (18.4 g), potassium cyanate (14.9 g) and tetrabutylammonium iodide (13.6 g) in N,N-dimethylformamide (180 ml) was stirred at 100°-110° C. for 3 hours. The reaction mixture was poured into water (300 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was dissolved in a mixture of methanol (150 ml) and concentrated hydrochloric acid (6.1 ml). The solution was stirred at ambient temperature for 2 hours and evaporated in vacuo. The resulting residue was chromatographed on silica gel (250 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-hydroxy-2-(4-methyl-2,5-dioxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (8.16 g).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][Cl:23].[CH2:24]([N:26](CC)[CH2:27]C)C>O>[Cl:23][CH2:22][CH2:24][N:26]([CH3:27])[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCCl
Solvent: O
Product: CN(CCCl)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h

Procedure:
138.95 g (1.85 mol) of 2-(methylamino)ethanol and 500 ml of dichloromethane are introduced into a 2-1 round bottom flask and gaseous hydrochloric acid is bubbled through for two 5-min periods with an interval of 30 min. The solution is partially concentrated and 145 ml (1.98 mol) of thionyl chloride are then added slowly over 1 h 30 min. The mixture is stirred at room temperature for 10 h and is then heated to 50° C. for 2 h. It is allowed to cool, the solvent is evaporated off and the residue is taken up twice with toluene, which is evaporated off. The residue is rinsed with a mixture of diethyl ether and pentane and is dried under vacuum in the presence of phosphorus pentoxide. 230.18 g of 2-chloro-N-methylethanamine hydrochloride are obtained. 46.17 g (355.1 mmol) of this are placed in a 1--1 round bottom flask placed under nitrogen and fitted with a dropping funnel, 100 g (358.7 mmol) of triphenylchloromethane and 400 ml of dichloromethane are added, and 100 ml of triethylamine are introduced slowly. Stirring is continued for 2 days, then water is added, the organic phase is separated off, is washed with water and dried over sodium sulphate and the solvent is evaporated off. The residue is purified by chromatography on a column of silica gel by eluting with a mixture of dichloromethane and cyclohexane and, after recrystallisation from cyclohexane, 79 g of compound are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[S:17][CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:20]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.F[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][N:29]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:21]1([C:19]2[CH:20]=[C:16]([C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([CH:4]4[CH2:5][CH2:6][N:1]([C:28]5[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][N:29]=5)[CH2:2][CH2:3]4)=[CH:8][CH:9]=3)=[O:15])[S:17][CH:18]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccc(F)nc1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1cc(-c2ccccc2)cs1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2CCC(c3ccc(NC(=O)c4cc(-c5ccccc5)cs4)cc3)CC2)nc1
Temperature: 175 °C
Yield: 47.1 %

Procedure:
A mixture of 4-phenyl-thiophene-2-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (181 mg, 0.5 mmol) and 6-fluoronicotinic acid (141 mg, 1 mmol) in dioxane (3 mL) containing diisopropylethylamine (0.5 mL, 2.7 mmol) was heated in a microwave at 175° C. for 30 minutes. The mixture was evaporated and extracted with ethyl acetate (containing THF and methanol) and 0.2N hydrochloric acid. The organic layer was dried and evaporated. The residue was crystallized from methanol and ethyl acetate to give a pale yellow solid as 4-{4-[(4-phenyl-thiophene-2-carbonyl)-amino]-phenyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (114 mg). LC-MS for C28H25N3O3S (in/e) calcd 483, obsd 484 (M+H). 1H-NMR is consistent with the desired structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH2:12][CH3:13])[N:9]=[C:8]([S:14]([CH3:17])(=[O:16])=[O:15])[N:7]=1)=[O:5])[CH3:2].[CH2:18](OC(C1C=C(CCC)N=C(SC)N=1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH2:12][CH2:13][CH3:18])[N:9]=[C:8]([S:14]([CH3:17])(=[O:16])=[O:15])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(CC)nc(S(C)(=O)=O)n1
Reactant: CCCc1cc(C(=O)OCC)nc(SC)n1
Product: CCCc1cc(C(=O)OCC)nc(S(C)(=O)=O)n1

Procedure:
The title compound is obtained as a yellow solid (107 mg) in analogy to 6-ethyl-2-methanesulfonyl-pyrimidine-4-carboxylic acid ethyl ester starting from 2-methylsulfanyl-6-propyl-pyrimidine-4-carboxylic acid ethyl ester; LC-MS: tR=0.85 min, [M+H]+=272.96.
Reaction SMILES: C1(C2(CCC3C=C(C(C)(C)CNC(C4C=CNN=4)=O)C=CC=3)CC(=O)CC(=O)O2)CCCC1.[Cl:34][CH2:35][C:36]#[N:37].[NH2:38][C:39]1[CH:43]=[CH:42][S:41][C:40]=1[C:44]([O:46]C)=O.Cl>O1CCOCC1>[Cl:34][CH2:35][C:36]1[NH:37][C:44](=[O:46])[C:40]2[S:41][CH:42]=[CH:43][C:39]=2[N:38]=1
Reactant: N#CCCl
Reactant: COC(=O)c1sccc1N
Agent: CC(C)(CNC(=O)c1cc[nH]n1)c1cccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c(CCl)nc2ccsc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.4 %

Procedure:
This compound was prepared by a modification of a method reported for related fused pyrimidine-4(3H)-ones: (1) Shishoo, C. J.; Devani, M. B.; Pathak, U.S.; Ananthan, S.; Bhadti, V. S.; Ullas, G. V.; Jain, K. S.; Rathod, I. S.; Talati, D. S.; Doshi, N. H. J. Heterocyclic Chem. 1984, 21, 375, and (2) Gerecke, M.; Kyburz, E.; Borer, R.; Gassner, W. Heterocycles 1994, 39, 693). An oven-dried 1-L round bottomed flask was charged with chloroacetonitrile (21.86 g, 0.29 mol, 1.3 equiv), methyl 3-aminothiophene-2-carboxylate (35 g, 0.223 mol), and 4 M HCl in 1,4-dioxane (350 mL). The reaction mixture was stirred at room temperature for 1 d. The mixture was evaporated to dryness. The residue was dissolved in water (600 mL) and treated with aqueous 10% sodium bicarbonate to a pH of 8. The resulting slurry was filtered, and the cake washed with water and dried, affording 38.2 g (85%) of the title product. 1H NMR (DMSO-d6) δ 4.58 (s, 2H), 7.42 (d, J=5.3 Hz, 1H), 8.22 (d, J=5.3 Hz, 1H), 12.84 (br s, 1H). LC-MS (APCI) calcd for C7H5ClN2OS: 200.0; Found (M+H+): 201.0 m/z.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[C:49]([F:51])[C:48]([F:52])=[CH:47][C:46]=1[Cl:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[C:49]([F:51])[C:48]([F:52])=[CH:47][C:46]=3[Cl:53])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Fc1cc(Cl)c(CBr)cc1F
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cc(F)c(F)cc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-4,5-difluorobenzene and isolated as colorless gum (8.3 mg, 45%). MS (m/e): 443.4 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11](/[CH:13]=[C:14](\[CH2:18][CH3:19])/[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C(Cl)(Cl)Cl>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]([CH2:13][CH:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC/C(=C\c1ccc(C(=O)OC(C)(C)C)s1)C(=O)O
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(Cc1ccc(C(=O)OC(C)(C)C)s1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
(E)-3-(5-tert-butoxycarbonylthiophen-2-yl)-2-ethylpropenoic acid (20.43 g, 72.4 mmol) was dissolved in ethyl acetate (300 mL), methanol (20 mL) and chloroform (10 mL), palladium hydroxide (2.0 g) was added, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. After completion of the reaction, palladium hydroxide was removed by celite filtration, and the solvent was evaporated under reduced pressure to give the title compound (20.6 g, quantitative).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH3:11])([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([NH2:49])[CH:47]=2)[N:42]([CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)[N:41]=1>CN(C=O)C>[NH:33]1[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N:31]=[C:32]1[C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([NH:49][C:8]([C:5]3([CH3:11])[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[O:10])[CH:47]=2)[N:42]([CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)[N:41]=1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Reactant: CN1CCC(C)(C(=O)O)CC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1CCC(C)(C(=O)Nc2ccc3c(c2)c(-c2nc4ccccc4[nH]2)nn3C2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
1,4-Dimethylpiperidine-4-carboxylic acid (3 mg, 0.019 mmol), HOBt (4 mg, 0.029 mmol), EDC (5.5 mg, 0.028 mmol) and sodium bicarbonate (1.6 mg, 0.019 mmol) were added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (6.4 mg, 0.019 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (3.5 mg) as a solid. 1H NMR (400 MHz, CD3OD): δ 8.54 (s, 1H), 7.77 (m, 1H), 7.71 (m, 2H), 7.38 (m, 2H), 7.29 (m, 2H), 5.94 (d, 1H, J=8.0 Hz) 4.00 (m, 1H), 3.85 (m, 1H), 3.46 (m, 2H), 2.89 (s, 3H), 2.69 (m, 2H), 2.56 (m, 1H), 2.15 (m, 3H), 1.86 (m, 3H), 1.72 (m, 3H), 1.46 (s, 3H).