Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[CH3:26][O:27][C:28]([CH:30]1[CH2:33][NH:32][CH2:31]1)=[O:29].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:32]3[CH2:33][CH:30]([C:28]([O:27][CH3:26])=[O:29])[CH2:31]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: COC(=O)C1CNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 23.5 %

Procedure:
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.5 g, 1.0 eq.) was dissolved in DCM (20 mL). The reaction mixture was cooled to −60° C. where methylazetidine-3-carboxylate hydrochloride (0.25 g, 1.2 eq.), T3P (50% in EtOAc) (1.0 mL, 1.2 eq.) followed by DIPEA (0.48 mL, 2 eq.) were added. The clear reaction mixture was stirred at −60° C. for 45 min. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography (2-3% Methanol in DCM) to give (Z)-methyl 1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)azetidine-3-carboxylate (0.15 g, 24% yield).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12])#[CH:10].C(NCC)C>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.[Cu]I>[N:6]1[CH:7]=[CH:8][C:3]([C:10]#[C:9][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])=[CH:4][CH:5]=1
Reactant: C#CC(O)c1ccccc1
Reactant: Brc1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: OC(C#Cc1ccncc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8 %

Procedure:
Place 4-bromopyridine hydrochloride (2.33 g, 12 mmol), α-(ethynyl)-benzenemethanol (1.95 g, 14.8 mmol) and diethylamine (25 mL) under nitrogen atmosphere. Add bis(triphenylphosphine)palladium(II) chloride (105 mg) then copper(I) iodide (59 mg). Stir at room temperature for 3 hours. Evaporate the solvent in vacuo, stir the residue in ethyl acetate (50 mL) and filter the solids. Evaporate the solvent in vacuo and purify by silica gel chromatography (4:3 ethyl acetate/hexane) to yield 0.4 g. Recrystallize (hexane/chloroform) to yield 0.2 g of the title compound; mp 93°-96° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][NH:29]3)=[N:23][C:22]=2[CH:35]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:9])=[N:23][C:22]=2[CH:35]=1
Reactant: Cc1ccc(-c2cccnc2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-c2cccnc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(pyridin-3-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 475 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][CH:6]([CH:17]([CH3:19])[CH3:18])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21].[Br:22]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C.Br>[CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][C:6]([Br:22])([CH:17]([CH3:18])[CH3:19])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21]
Reactant: BrBr
Reactant: Cc1c2c(c3cc(C(=O)O)oc3c1C)CC(C(C)C)C2=O
Agent: Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c2c(c3cc(C(=O)O)oc3c1C)CC(Br)(C(C)C)C2=O
Temperature: 0 °C

Procedure:
A solution of 4,5-dimethyl-6-oxo-7,8-dihydro-7-isopropyl-6H-indeno[5,4-b]furan-2-carboxylic acid (0.01 mole) in acetic acid (60 ml.) is treated with 48% hydrobromic acid (1 drop) then with bromine (0.01 mole) in acetic acid (10 ml.) during a ten minute period. The solution is poured into ice water (300 ml.) containing sodium bisulfite (1 g.) to afford 4,5-dimethyl-6-oxo-7,8-dihydro-7-bromo-7-isopropyl-6-H-indeno[5,4-b]furan-2-carboxylic acid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([CH3:27])=[C:22]([CH:24]4[CH2:26][CH2:25]4)[N:23]=3)[CH:20]=2)[C:11](=[O:28])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH:24]1([C:22]2[N:23]=[C:18]3[CH:17]=[CH:16][C:15]([N:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]4=[O:28])=[CH:20][N:19]3[C:21]=2[CH3:27])[CH2:26][CH2:25]1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccccc4)cc3=O)cn12
Agent: [Pd]
Solvent: CO
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.2 %

Procedure:
To a stirred solution of 4-(benzyloxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (127 mg) in MeOH (8 ml) was added Pd/C (10%, 25 mg), and the mixture was stirred under H2 atmosphere at room temperature for 4 h. The insoluble materials were then filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (56 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:20]=[C:19]([C:21]([O:30][CH2:31][O:32][CH3:33])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:15]=[CH2:16])=[C:11]([CH:14]=1)[C:12]#[N:13])[CH2:2][CH3:3].C(=O)([O-])[OH:35].[Na+].ClC1C=C(C=CC=1)C(OO)=O.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[O:35]1[CH2:16][CH:15]1[C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:17]=[CH:18][C:19]([C:21]([O:30][CH2:31][O:32][CH3:33])([C:22]([F:23])([F:24])[F:25])[C:26]([F:28])([F:27])[F:29])=[CH:20][C:4]=2[CH2:1][CH2:2][CH3:3])=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: O=C([O-])O
Reactant: C=Cc1ccc(Oc2ccc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc2CCC)cc1C#N
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(C2CO2)c(C#N)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.5 %

Procedure:
5-[2-Propyl-4-(2,2,2-trifluoro-1-methoxymethoxy-1-trifluoromethyl-ethyl)-phen oxy]-2-vinyl-benzonitrile (14 mg, 0.030 mmol) was dissolved in dichloromethane (300 μL). The resultant mixture was added with sodium hydrogen carbonate (7.5 mg, 0.089 mmol) and 3-chloroperoxybenzoic acid (8.5 mg, 0.030 mmol) under ice-cold conditions and stirred at room temperature for 1.5 hours. Subsequently, the resultant mixture was further added with sodium hydrogen carbonate (7.5 mg, 0.089 mmol) and 3-chloroperoxybenzoic acid (8.5 mg, 0.030 mmol) under ice-cold conditions and stirred at room temperature overnight. The reaction solution was added with a saturated aqueous solution of sodium sulfite and a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and 2-oxiranyl-5-[2-propyl-4-(2,2,2-trifluoro-1-methoxymethoxy-1-trifluoromethyl-ethyl)-phenoxy]-benzonitrile (5.5 mg, yield 38%) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33]Cl)[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33][N:40]5[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]5)[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(C3CCN(C(=O)CCl)C3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN1CCNCC1
Product: CN1CCN(CC(=O)N2CCC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)C2)CC1
Yield: 45.9 %

Procedure:
5-(2-benzyl-2H-indazol-6-yl)-7-[1-(chloroacetyl)pyrrolidin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.206 mmol) was reacted with 4-methylpiperazine (46 uL, 0.412 mmol) using the procedure of Example 132 to yield 52 mg (46%) of title compound. 1H NMR (300 MHz, methanol-d4) δ 8.04 (s, 1 H), 7.92 (s, 1 H), 7.78 (m, 3 H), 7.41 (m, 4 H), 7.22 (d, 1 H), 6.63 (d, 1 H), 5.46 (s, 2 H), 4.15-3.95 (m, 2 H), 3.90-3.40 (m, 4 H), 3.12 (m, 2 H), 2.60-2.10 (d, 13 H); ES-MS m/z 550.2 [M+H]+, HPLC RT (min) 2.10.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:34]3[CH:33]=[N:32][C:31]([N:28]4[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]4)=[CH:36][CH:35]=3)=[CH:14][C:6]1=2
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: FC(F)(F)c1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(Cc3cc(C(F)(F)F)ccc3Cl)CCN4)cn2)CC1
Yield: 13 %

Procedure:
1-(2-Chloro-5-trifluoromethylbenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (40 mg) was reacted with 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4A to give the title compound as a yellow film (13% yield). M.p. (film), LCMS: m/z=502.98 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.34 (s, 3H), 2.51 (t, J=5.3 Hz, 4H), 3.28 (t, J=5.3 Hz, 2H), 3.54 (t, J=5.0 Hz, 4H), 3.66-3.72 (m, 2H), 4.53 (s, 2H), 4.89 (bs, 1H), 6.53 (s, 1H), 6.64 (d, J=8.8 Hz, 1H), 7.46-7.54 (m, 4H), 7.63 (d, J=1.8 Hz, 1H), 8.18 (d, J=2.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]2[NH:11][C:10](=[O:12])[C@H:9]([CH3:13])[NH:8][C:7](=[O:14])[C:6]=2[CH:15]=1.O>[Pd].C(O)(=O)C>[NH2:16][C:4]1[C:5]2[NH:11][C:10](=[O:12])[C@H:9]([CH3:13])[NH:8][C:7](=[O:14])[C:6]=2[CH:15]=[CH:2][CH:3]=1
Reactant: C[C@@H]1NC(=O)c2cc(Cl)cc([N+](=O)[O-])c2NC1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: C[C@@H]1NC(=O)c2cccc(N)c2NC1=O
Reaction time: 0.25 h
Yield: 88.6 %

Procedure:
6 g (0.022 mol) of (S)-7-chloro-3-methyl-9-nitro-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione, 200 ml of water, 200 ml of acetic acid and 0.5 g of 5% palladium-on-charcoal are placed in a Parr bottle. The catalytic hydrogenation is carried out under 40 psi at 50° C. The catalyst is filtered, is washed with an acetic acid/water (50/50) mixture and the filtrate is concentrated to dryness. It is taken up in water and the pH adjusted to alkaline with a sodium carbonate solution. The mixture is left stirring for 15 minutes, filtration is carried out, drying is carried out and the solvent evaporated to dryness. 4 g of product are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[N:11]=[C:12](SC)[NH:13][CH:14]=2)=[CH:4][N:3]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=2)=[C:25]([CH:28]=1)[C:26]#[N:27]>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:24]2[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][NH:18][C:12]3[NH:13][CH:14]=[C:9]([CH2:8][C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=4)[C:10](=[O:17])[N:11]=3)=[CH:28][C:25]=2[C:26]#[N:27])=[CH:31][C:32]=1[C:37]([F:38])([F:39])[F:40]
Reactant: CSc1nc(=O)c(Cc2cnc(C)nc2)c[nH]1
Reactant: N#Cc1cc(CCN)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Product: Cc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)cn1
Yield: 33.1 %

Procedure:
5-(2-Methyl-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (50 mg, 0.201 mmol, 1 eq) and 5-(2-Amino-ethyl)-2-(4-chloro-3-trifluoromethyl-phenoxy)-benzonitrile (110 mg, 1.6 eq) were heated in a sealed vial at 130° C. for 20 hours. Solvent was then evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 10 g normal phase silica SNAP column and DCM/20% MEOH in DCM solvent system (gradient 5-50% of 20% MeOH in DCM in 25 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and the resulting oil was triturated with cyclohexane and diethyl ether to obtain 2-(4-chloro-3-trifluoromethyl-phenoxy)-5-{2-[5-(2-methyl-pyrimidin-5-ylmethyl)-4-oxo-1,4-dihydro-pyrimidin-2-ylamino]-ethyl}-benzonitrile (36 mg, yield=29.7%, purity=90%) in form of tain coloured powder. MS: [M+H]+=541.34. 1H NMR (300 MHz; CDCl3) δ/ppm 2.65 (s, 3H), 2.94 (t, J=7.02 Hz, 2H), 3.57 (s, 2H), 3.59-3.68 (m, 2H), 5.49 (br.s., 1H), 6.89 (d, J=8.61 Hz, 1H), 7.15 (dd, J=8.30 Hz, J=2.98 Hz, 1H), 7.38 (d, J=2.76 Hz, 1H), 7.44 (dd, J=8.82 Hz, J=1.91 Hz, 1H), 7.51 (d, J=8.51 Hz, 1H), 7.60 (d, J=2.02 Hz, 1H), 7.71 (s, 1H), 8.53 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([F:16])([F:15])[F:14])=[N:10][C:9]=2[C:17]([O:19]CC)=[O:18])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([F:16])([F:14])[F:15])=[N:10][C:9]=2[C:17]([OH:19])=[O:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(C(F)(F)F)oc1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(C(F)(F)F)oc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
Compound ethyl 5-(4-fluorophenyl)-2-(trifluoromethyl)oxazole-4-carboxylate (150 mg, 0.49 mmol) was dissolved in THF (4.6 mL) and cooled on ice. To this solution is added LiOH (13 mg, 0.31 mmol) in water (1.5 mL) and the mixture was stirred for 1 hr then warmed to room temperature and stirred overnight. The THF was evaporated, and H2O (10 mL) was added and the solution then acidified with 1 N HCl and extracted in EtOAc (3×15 mL). The organic fractions were dried over Na2SO4 and concentrated. The crude material was fractionated by SiO2 chromatography (DCM to 90% DCM/10% MeOH gradient, the desired product elutes in 7% MeOH) to afford a white solid (17 mg, 11% yield). 1HNMR (400 MHz, MeOD, CDCl3): d 8.17 (m, 2H), 7.14 (t, 2H, J=8 Hz).
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)[C:4]([NH2:6])=[O:5])[CH3:2].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[CH:26]=O>>[CH2:1]([N:3]1[C:7]2[C:12](=[CH:11][C:10]3[O:13][CH2:14][O:15][C:9]=3[CH:8]=2)[CH:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)[NH:6][C:4]1=[O:5])[CH3:2]
Reactant: CCN(C(N)=O)c1ccc2c(c1)OCO2
Reactant: O=Cc1ccc2ccccc2c1
Product: CCN1C(=O)NC(c2ccc3ccccc3c2)c2cc3c(cc21)OCO3
Yield: 46 %

Procedure:
This compound was synthesized from N-ethyl-N-[3,4-(methylenedioxy)phenyl]urea (247 mg) and 2-naphthaldehyde (182 mg) by the procedure described in example 10 in 46% yield, mp: 193-195° C. 1H NMR (CDCl3): 7.86-7.82 (m, 2H), 7.74 (s, 1H), 7.52-7.42 (m, 4H), 6.57 (s, 1H), 6.30 (s, 1H), 5.90 (s, 1H), 5.87 (s, 1H), 5.61 (s, 1H), 5.18 (s, 1H), 3.97 (q, J=6.6, 2H), 1.32 (t, J=6.6, 3H). Anal. calcd. for C21H18N2O3: C, 72.82; H, 5.24; N, 8.09. Found: C, 72.53; H, 4.95; N, 7.54.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[S:25][C:26]([Br:29])=[CH:27][CH:28]=3)=[O:23])=[CH:17][C:16]=2[N+:30]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>[Fe]>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[S:25][C:26]([Br:29])=[CH:27][CH:28]=3)=[O:23])=[CH:17][C:16]=2[NH2:30])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)c3ccc(Br)s3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)c3ccc(Br)s3)cc2N)cc1
Yield: 50 %

Procedure:
The product from Example 257a was reduced with Fe and NH4Cl following the procedure from Example 9E to provide the title compound (922 mg, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[NH2:9][NH2:10]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:9][NH2:10])[CH:3]=1
Reactant: NN
Reactant: Fc1cc(Br)ccn1
Solvent: c1ccncc1
Product: NNc1cc(Br)ccn1
Temperature: 70 °C
Yield: 82.6 %

Procedure:
To a solution of 4-bromo-2-fluoropyridine (2.0 g, 11.4 mmol) in pyridine (10 mL) was added hydrazine (5 mL, 159 mmol). The mixture was heated at 70° C. for 2 hours, then cooled to room temperature. The volatile organics were removed under reduced pressure, then water (60 mL) was added to the residue and an off-white solid precipitated. The solid was filtered, washed with water, and dried under reduced pressure at 50° C. to give 1.77 g (84%) of the title compound as an off-white solid. m/z (ES+) 188, 190 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:13]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:4])=[O:3].CN(C)C=O.S(Cl)([Cl:28])=O>>[CH3:1][S:2]([C:5]1[C:13]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([Cl:28])=[O:8])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1c(Sc2ccccc2)cccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1c(Sc2ccccc2)cccc1C(=O)Cl

Procedure:
A mixture of 2-methylsulphonyl-3-phenylsulphenylbenzoic acid and N,N-dimethylformamide (0.25 ml) in thionyl chloride was heated at reflux for 1.25 hours. The solution was evaporated to give 9.9 g of 2-methylsulphonyl-3-phenylsulphenylbenzoyl chloride as a pale yellow oil which was used directly in the next step without further purification.
Reaction SMILES: CCOCC.[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]#[N:15])[CH2:10][CH2:9]1.[OH:16][NH:17][C:18](=N)[CH:19]([CH3:21])[CH3:20]>CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[CH3:20][CH:19]([C:18]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][OH:6])[CH2:9][CH2:10]2)[O:16][N:17]=1)[CH3:21]
Reactant: N#CN1CCC(CO)CC1
Reactant: CC(C)C(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)c1noc(N2CCC(CO)CC2)n1
Reaction time: 0.5 h
Yield: 438 %

Procedure:
A solution of 1N ZnCl2 in Et2O (182 mL, 182 mmol) was added to a solution of 4-(hydroxymethyl)-1-piperidinecarbonitrile (21.3 g, 152 mmol) and N-hydroxy-2-methylpropanimidamide (18.6 g, 182 mmol) in EtOAc (50 mL) at ambient temperature. The reaction mixture was left at ambient temperature for 30 min, decanted, and was treated with concentrated HCl (45 mL) and ethanol 20 mL). The mixture was heated at reflux for 2 h. The mixture was evaporated to dryness, and the resulting residue was charged with water and the pH was adjusted to basic with K2CO3. The mixture was extracted with EtOAc and the material obtained was combined with 9 other batches prepared similarly and purified by silica gel chromatography to give 150 g of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol.
Reaction SMILES: [NH2:1][C:2]1([C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[O:6])[CH2:4][CH2:3]1.IC.[CH2:27](N(CC)CC)C>C(Cl)Cl>[CH3:27][NH:1][C:2]1([C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[O:6])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccccc1-c1ccc(CNC(=O)C2(N)CC2)cc1
Reactant: CCN(CC)CC
Solvent: CI
Solvent: ClCCl
Product: CNC1(C(=O)NCc2ccc(-c3ccccc3C(=O)OC)cc2)CC1
Yield: 34.8 %

Procedure:
Methyl 4′-({[(1-aminocyclopropyl)carbonyl]amino}methyl)-1,1′-biphenyl-2-carboxylate (200 mg, 0.62 mmol), prepared according to Example 1, was dissolved in 5 mL of DCM along with iodomethane (130 mg, 0.93 mmol) and triethylamine (75 mg, 0.74 mmol). After no reaction was observed at ambient temperature, the reaction mixture was heated to reflux for about two days. After the first day, additional iodomethane was added (ca. 3–5 equiv.). After two days >50% of the starting material was consumed. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography eluting with 1–10% MeOH in DCM to afford 73 mg of methyl 4′-[({[1-(methylamino)cyclo-propyl]carbonyl}amino)methyl]-1,1′-biphenyl-2-carboxylate.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([CH2:25][CH:26]=[CH2:27])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:24])C.[CH3:29][NH2:30]>>[CH2:25]([C:6]12[C:15]3[CH:14]=[C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]1([OH:24])[N:30]([CH3:29])[C:4](=[O:3])[CH2:5]2)[CH:26]=[CH2:27]
Reactant: C=CCC1(CC(=O)OCC)C(=O)CCc2ccc(OCc3ccccc3)cc21
Reactant: CN
Product: C=CCC12CC(=O)N(C)C1(O)CCc1ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 6.30 g (167 mmol) ethyl-1-allyl-7-benzyloxy-2-oxo-1,2,3,4-tetrahydro-1-naphthaleneacetate (IXc), 31.0 g methylamine and 200 ml 1:1 ethanol-dioxane was stirred at room temperature for 3 days. The reaction mixture was concentrated by evaporation of the solvent (35°-40° C.) to half the volume and diluted with 200 ml ether to provide a crystalline product which was collected to give 51.0 g (86%) Xc, m.p. 188°-190°; IR (Nujol), 3250, (broad), 1665, 1615, 1505 cm-1.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@H:3]1[NH:8][CH2:7][C@@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:24][C:25]1[CH:30]=[C:29](Cl)[N:28]=[C:27]([S:32][CH3:33])[N:26]=1>C1COCC1>[Cl:24][C:25]1[N:26]=[C:27]([S:32][CH3:33])[N:28]=[C:29]([N:8]2[C@H:3]([C:2]([F:12])([F:1])[F:13])[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7]2)[CH:30]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: O=C(O)[C@H]1CC[C@@H](C(F)(F)F)NC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nc(Cl)cc(N2C[C@@H](C(=O)O)CC[C@H]2C(F)(F)F)n1
Reaction time: 0.08 h

Procedure:
To cis-6-(trifluoromethyl)-3-piperidinecarboxylic acid (3.393 g, 14.52 mmol) in THF (1.5 mL) were added molecular sieves, and the resulting mixture was stirred for 5 minutes into a 250 mL RB flask. The mixture was cooled in an ice bath, and then LiHMDS (43.6 mL, 43.6 mmol) was added slowly. After the addition was completed, 4,6-dichloro-2-(methylthio)pyrimidine (3.40 g, 17.43 mmol) was added. After 0.5 hours, the reaction was quenched with 30 mL of water and by the dropwise addition of 6N HCl until pH was acidic. The resulting mixture was extracted with EtOAc (3×30 mL). The organics were combined, washed with brine, dried (MgSO4), filtered and concentrated to afford the crude title compound as an oil. LC-MS (ES) m/z=356 [M+H]+.