Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[O:10])=[CH:4][CH:3]=2)=[CH:30][CH:29]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(Br)nc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
A mixture of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)amino]carbonyl}-1-piperidinecarboxylate (1.75 g, 4.55 mmol), [4-(methylsulfonyl)phenyl]boronic acid (911 mg, 4.55 mmol), 2M Na2CO3 (5 mL) and Pd(PPh3)2Cl2 (400 mg, 0.57 mmol) in DME (10 mL) was stirred at 80° C. overnight. The mixture was cooled to ambient temperature, and the organic phase was separated and concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 5% MeOH/CH2Cl2 to give 1.41 g (68%) of 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}amino)carbonyl]-1-piperidinecarboxylate as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.74 (bs, 1H), 8.57-8.46 (m, 1H), 8.16 (d, 2H, J=8.5 Hz), 8.03 (d, 2H, J=8.4 Hz), 7.81 (d, 1H, J=8.7 Hz), 4.28-4.11 (m, 2H), 3.07 (s, 3H), 2.85-2.74 (m, 2H), 2.55-2.44 (m, 1H), 2.00-1.80 (m, 2H), 1.82-1.69 (m, 2H), 1.45 (s, 9H); LRMS (ESI), m/z 460 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[S:5][C:6]=1[CH2:7]O.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:20][CH2:7][C:6]1[S:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[N:3][C:2]=1[CH3:1]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of {4-methyl-2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol (90.2 g, 0.732 mmol) in dichloromethane (10 mL) was added carbon tetrabromide (0.485 g, 1.464 mmol) and triphenylphosphine (0.384 g, 1.464 mmol). The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the residue was chromatographed on silica gel eluting with 10-20% ethyl acetate/hexane to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.18 (s, 1H), 8.06 (d, J=7.54 Hz, 1H), 7.67 (d, 1H), 7.56 (t, J=7.73 Hz, 1H), 4.72 (m, 2H), 2.48 (m, 3H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:4]1=[O:14])[CH3:2].ClC1C=CC=C(C(OO)=[O:23])C=1>C(OCC)(=O)C>[CH2:1]([N+:3]1([O-:23])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:4]1=[O:14])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN1CCN(c2ccncc2)C1=O
Solvent: CCOC(C)=O
Product: CC[N+]1([O-])CCN(c2ccncc2)C1=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 74.3 %

Procedure:
1-Ethyl-3-(4-pyridyl)-2-imidazolidinone (0.71 g, 3.7 mmol) and 3-chloroperbenzoic acid (77%, 1.67 g, 7.4 mmol) were dissolved in ethyl acetate (20 ml), and the mixture was stirred at room temperature for 40 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with methanol-ethyl acetate (2:3, v/v) were collected and concentrated to give the titled compound (0.57 g, 73%) as white crystals.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[C:14]([CH3:41])[CH:13]=1>>[N:2]1([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:39]=[CH:40][C:12]([F:11])=[CH:13][C:14]=3[CH3:41])=[CH:18][CH:19]=2)=[O:25])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: Cc1cc(F)ccc1Oc1ccc(NC(=O)[C@@H]2C[C@@H](Cc3ccc(F)cc3)CN2)cc1
Agent: Cl
Product: Cc1cc(F)ccc1Oc1ccc(NC(=O)[C@@H]2C[C@@H](Cc3ccc(F)cc3)CN2C(=O)Cn2cncn2)cc1
Yield: 42 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluoro-2-methylphenoxy)phenyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide, gave Compound 74, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluoro-2-methylphenoxy)phenyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide (189 mg, 42%). 1H-NMR (400 MHz, CDCl3): σ 8.96 (s, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.37 (d, 2H), 7.17-7.14 (m, 2H), 7.01 (t, 2H), 6.96-6.93 (m, 1H), 6.83-6.76 (m, 4H), 5.02 (d, 1H), 4.95 (d, 1H), 4.80 (d, 1H), 3.63 (t, 1H), 3.23 (t, 1H), 3.03-2.86 (m, 2H), 2.69-2.60 (m, 2H), 2.18 (s, 3H), 1.72-1.57 (m, 1H). MS (EI) for C29H27F2N5O3. found 532.2 (MH+).
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:18]O>>[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:4]=1[C:5]([O:7][CH3:18])=[O:6]
Reactant: CO
Reactant: Cc1cc(O)c(N)c(C(=O)O)c1
Agent: Br
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)cc(O)c1N
Temperature: 25 °C
Yield: 72 %

Procedure:
To a solution of 2-amino-3-hydroxy-5-methylbenzoic acid hydrobromide (2.65 g, 10.7 mmol) in anhydrous CH3OH (50 mL) was added thionyl chloride (3.9 mL, 53.4 mmol) at −78° C. The resulting reaction mixture was allowed to warm to room temperature and then heated to reflux for 17 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with a saturated aqueous NaHCO3 solution to adjust pH to 7 and then extracted with EtOAc (4×100 mL). The combined organic phase was washed with H2O, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford methyl 2-amino-3-hydroxy-5-methylbenzoate (1.40 g, 72%): 1H NMR consistent.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1(O)C=CC=CC=1.[CH3:28][O:29][C:30](=[O:34])[CH:31](Br)[CH3:32]>>[N:1]1([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:31]([CH3:32])[C:30]([O:29][CH3:28])=[O:34])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cc(Cn2ncc3ccccc32)ccc1O
Reactant: COC(=O)C(C)Br
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1ccc(Cn2ncc3ccccc32)cc1[N+](=O)[O-]

Procedure:
Using 4-((1H-indazol-1-yl)methyl)-2-nitrophenol 345A as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives the title compound as a light yellow solid: ESI-MS: m/z 356.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][O:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C1COCC1.CCOC(C)=O>[CH3:34][O:35][CH:36]1[CH2:41][CH2:40][N:39]([S:20]([C:16]2[CH:15]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:21])=[O:22])[CH2:38][CH2:37]1
Reactant: COC1CCNCC1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC1CCN(S(=O)(=O)c2cccc(-c3cccc(-c4cc(-c5ccc(C(F)(F)F)cc5)cc(C)n4)n3)c2)CC1
Yield: 38.8 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 4-methoxypiperidine [CAS-no. 4045-24-3] (0.236 g, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.090 g, 39%) as a white foam. MS (ISP) 568.3 [(M+H)+]; mp 107° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:14]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCn1cc(Br)cn1
Reactant: CCOC(=O)c1cc(C)cc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)c1cc(C)cc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-5-methyl-benzoic acid ethyl ester and 4-bromo-1-ethylpyrazole.
Reaction SMILES: N.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1C=CC2N(O)N=[N:24]C=2C=1.CCN=C=NCCCN(C)C.Cl>O1CCCC1>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH2:24])=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.2 %

Procedure:
Into a 50-mL round-bottom flask was placed tetrahydrofuran saturated with NH3 (gas) (20 mL), 4′-hydroxybiphenyl-4-carboxylic acid (1 g, 4.67 mmol, 1 equiv), HOBt (900 mg, 6.67 mmol, 1.4 equiv), EDCl (1.34 g, 7.0 mmol, 1.5 equiv). The resulting solution was stirred for 4 hrs at room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in 50 mL of ethyl acetate, washed with 2×40 mL of H2O, 1×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The reside was purified by column chromatography on silica gel (eluting with 1:1 ethyl acetate/petroleum ether) to give 500 mg (50%) of 4′-hydroxybiphenyl-4-carboxamide as a white solid.
Reaction SMILES: C[O:2][C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[S:25][C:21]=3[CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([O:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:18]3)=[CH:9][CH:8]=1)=[O:4].[OH-]>O1CCCC1.CO>[C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[S:25][C:21]=3[CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:18]3)=[CH:9][CH:8]=1)([OH:4])=[O:2]
Reactant: COC(=O)COc1ccc(-c2c3ccc(OCC(=O)OC)cc3cc3sc4ccccc4c23)cc1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1ccc(-c2c3ccc(OCC(=O)O)cc3cc3sc4ccccc4c23)cc1
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a solution of [11-(4-methoxycarbonylmethoxy-phenyl)-benzo [b]naphtho[2,3-d]thiophen-8-yloxy]-acetic acid, methyl ester (0.268 g, 0.551 mmol) in tetrahydrofuran (8 mL) and methanol (5 mL) was added an aqueous solution of potassuim hydroxide (1 N, 2.2 mL, 2.2 mmol) dropwise at room temperature. After stirring 2 hours an addition of potassuim hydroxide (1 N, 1 mL, 1 mmol) was introduced. After stirring another 14 hours the solvents were removed and the residue was disolved in water (50 mL) and was acidified with 10% aqueous hydrochloric acid, and the organics were extracted with diethyl ether. The solvent was removed and chased with benzene and petroleum ether and dried at 53° C. to give the title compound as a white solid (0.18 g, 43%): mp 245-246° C.; NMR (DMSO-d6); δ13.08 (broad s, 2 H), 8.44 (s, 1 H), 7.93 (d, J=8 Hz, 1 H), 7.45 - 7.35 (m, 3 H), 7.31 (d, J=9 Hz, 2 H), 7.22 (d, J=9 Hz, 2 H), 7.17 (dd, J=3,9 Hz, 1 H), 7.10 (ddd, J=9, 9, 1 Hz, 1 H), 6.67 (d, J=8 Hz, 1 H), 4.84 (d, J=7 Hz, 4 H); MS (EI): [M+] 458; Anal. Calc. for C26 H18O6S: C, 68.11, H, 3.96, N, 0.00. Found: C, 66.41, H, 3.95, N, 0.05.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: C=Cc1ccccc1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C=Cc2ccccc2)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 34.7 %

Procedure:
A mixture of 4-bromo-2-nitrotoluene (0.432 g, 2.0 mmol), styrene (0.250 g, 2.40 mmol, 1.2 eq), palladium(II) acetate (4.5 mg, 0.020 mmol, 0.01 eq), tri-o-tolylphosphine (12.2 mg, 0.04 mmol, 0.02 eq), and triethylamine (0.405 g, 4.0 mmol, 2.0 eq) in dimethylformamide (2 mL) was heated in a 120° C. oil bath for 4 hours. The mixture was then cooled to room temperature and the solvent evaporated under a stream of nitrogen gas. The residue was partitioned between ethyl acetate and water and the aqueous layer further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a hexane/ethyl acetate gradient to provide the title compound as a yellow solid (166 mg, 35% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][C@H:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)[CH2:18][OH:19])[CH:13]=[CH:12][C:11]=2[N+:27]([O-])=O)[CH:5]=1)[CH3:2].[CH2:30](O)C.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([N:9]2[C:10]3=[N:15][C:14]([NH:16][C@H:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=4)[CH2:18][OH:19])=[CH:13][CH:12]=[C:11]3[N:27]=[CH:30]2)[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Reactant: CCO
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1cc(-n2cnc3ccc(N[C@@H](CO)c4ccc(F)cn4)nc32)n[nH]1
Temperature: 25 °C

Procedure:
(2R)-2-({6-[(5-ethoxy-1H-pyrazol-3-yl)amino]-5-nitropyridin-2-yl}amino)-2-(5-fluoropyridin-2-yl)ethanol (Intermediate 27, 0.2 g) was dissolved into ethanol (20 mL) with Pd—C (50 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formylamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 85° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.06 g of the title compound MS (electrospray): 384 (M+1) for C18H18FN7O2. 1H NMR (300 MHz, CD3OD) δ ppm 8.20 (d, 1H) 8.15 (s, 1H) 7.50 (d, 1H) 7.30 (dd, 1H) 6.40 (d, 1H) 5.85 (s, 1H) 5.00 (m, 1H) 4.00 (d, 2H) 3.80 (m, 2H) 1.00 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C(N(CC)CC)C.[CH2:18]([OH:22])[CH2:19][C:20]#[CH:21]>C(#N)C.[Pd](Cl)Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:22][CH2:18][CH2:19][C:20]#[C:21][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: C#CCCO
Reactant: COC(=O)c1cc(Br)cs1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#CCCO)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.7 %

Procedure:
A 50 mL round bottom flask, equipped with a magnetic stirrer and gas inlet, was charged with 0.8 mg (0.005 eq) of palladium chloride, 2.3 mg (0.01 eq) of triphenylphosphine, 1.6 mg of copper (1) iodide, 0.19 g of methyl 4-bromothien-2-ylcarboxylate (obtained by oxidation of 4-bromothien-2-ylaldehyde followed by esterification), 0.43 g of triethylamine, and 0.06 g of 3-but-yn-1-ol in 20 mL of acetonitrile under a nitrogen atmosphere. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 18 hours. After cooling to room temperature, volatiles were removed under reduced pressure and the residue was partitioned between chloroform and water. The organic extract was washed with water (2×), brine, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with 2:1 hexane/ethyl acetate. Fractions homogeneous by thin layer chromatography for the major component were combined and concentrated under reduced pressure to give 0.12 g (66.7%) of methyl 4-(4-hydroxybut-yn-1-yl)thien-2-ylcarboxylate as a yellow oil; IR (KBr, cm-1): 3025 3021, 3015, 1713, 1446, 1293, 1261, 1231, 1228, 1225, 1222, 1214, 1192, 1080, 1053; UV (Ethanol):λmax =294 nm (epsilon=3680), 228 nm (epsilon=26,900); 1H NMR (CDCl3, 300 MHz) delta 7.72 (s, 1H), 7.53 (s, 1H), 3.87 (s, 3H), 3.79 (t, J=6.2 Hz, 2H), 2.65 (t, J=6.3 Hz, 2H), 1.87 (bs, 1H); MASS: M+ =210 (EICEC).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([NH:7][CH2:8][C:9]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]2[C:10]=1[N:11]=[C:12]([O:22]C)[C:13]([O:20]C)=[N:14]2)=[O:6])[CH3:2]>Br.C(O)(=O)C.C(OCC)C>[CH2:1]([O:3][C:4](=[O:24])[C:5]([NH:7][CH2:8][C:9]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]2[C:10]=1[NH:11][C:12](=[O:22])[C:13](=[O:20])[NH:14]2)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)NCc1cc(Br)cc2nc(OC)c(OC)nc12
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)NCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
254 mg (0.79 mmol) of N-(7-bromo-2,3-dimethoxy-quinoxalin-5-ylmethyl)-oxalamic acid ethyl ester are dissolved in 6 ml of an approximately 25% solution of hydrogen bromide in acetic acid, and the solution is stirred at room temperature for 16 hours. The mixture is diluted with diethyl ether, and the solid is filtered off and washed with diethyl ether. After drying under a high vacuum, the title compound is obtained in the form of a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)O.C([O-])(O)=O.[Na+].[C:22](OCC)(=O)[CH3:23]>C(O)C>[CH2:22]([O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Br:1])[CH:7]=1)[CH3:23]
Reactant: O=C(O)Cc1ccnc(Br)c1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1ccnc(Br)c1
Temperature: 90 °C

Procedure:
To a solution of (2-bromo-pyridin-4-yl)-acetic acid (60.0 g, 277.7 mmol) in ethanol (600 ml), conc: sulfuric acid (5.0 ml) was added at rt and the reaction mixture was heated at 90° C. for 9 h. Reaction mixture was cooled to rt and concentrated under reduced pressure to remove solvent completely. The residue obtained was cooled to 0° C. and pH was adjusted to 8 using 10% aqueous NaHCO3 solution. The resultant contents were worked up with ethyl acetate by washing with water, brine and dried over anhy. Na2SO4. Organic layer was concentrated under reduced pressure to obtain crude compound. Column chromatography purification of the crude compound using 15% ethyl acetate in hexane as eluent furnished title compound as a brown oil. Yield: 65.0 g (88.5%). TLC (30% ethyl acetate in hexane) Rf=0.39; LCMS: RtH7=0.824 [M+1]+=243.8 and 245.8; HPLC RtH9=3.759 min (69%); 1H NMR (300 MHz, CDCl3): δ 8.32 (t, 1H), 7.43 (s, 1H), 7.21-7.15 (M, 1H), 4.18 (q, 2H), 1.27 (t, 3H).
Reaction SMILES: C(OC(=O)[O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([F:15])=[CH:8][C:7]=1[Cl:16])C.C(=O)(O)[O-].[Na+]>CO.O>[Cl:16][C:7]1[CH:8]=[C:9]([F:15])[C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=1[OH:5]
Reactant: CCOC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a solution of the product from Example 73B (0.87 g, 3.30 mmol) in methanol (20 mL) and water (1 mL) was added sodium bicarbonate (2.22 g, 26.4 mmol) and the mixture stirred at room temperature for 16 hours. The methanol was then removed under vacuum, dichloromethane (20 mL) was added to the mixture, the organic solution was washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title product (0.62 g, 98%).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH:13](=[N+:20]([CH3:22])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:21][N:20]([CH3:22])[CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(-n2cccc2)cc1
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1cccn1-c1ccccc1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-phenyl-1H-pyrrole and benzylidene-dimethyl-ammonium chloride.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[S:6][CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:9]=1)C.Cl>CC(C)=O>[CH:4]([C:5]1[S:6][CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:9]=1)=[O:3]
Reactant: CCOC(=O)c1csc(C(OCC)OCC)n1
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(C=O)n1
Yield: 87.5 %

Procedure:
A solution of ethyl 2-(diethoxymethyl)thiazole-4-carboxylate (1.6 g) and 1 M HCl (12.3 ml) in acetone (100 ml) was heated under reflux for 5 h. After the solvent was removed by evaporation, the residue was diluted with AcOEt, neutralized with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.0 g) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:25])[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].[CH3:28]I.O>CN(C=O)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([F:24])([F:22])[F:23])[CH:19]=[CH:20][C:15]=3[N:14]([CH3:28])[C:13]2=[O:25])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](Cn2c(=O)[nH]c3ccc(C(F)(F)F)cc32)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](Cn2c(=O)n(C)c3ccc(C(F)(F)F)cc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
trans-4-(2-Oxo-6-trifluoromethyl-2,3-dihydro-benzoimidazol-1-ylmethyl)-cyclohexanecarboxylic acid methyl ester (0.87 mg, 2.44 mmol) was dissolved in anhydrous DMF. NaH (1.95 g, 4.9 mmol, 60% in mineral oil) and MeI (0.30 ml, 4.9 mmol) were added and the mixture was stirred at room temperature for two days. H2O was added and the solvents were evaporated. The crude was dissolved in DCM (15 ml) and washed with H2O (10 ml). The organic layer was dried over Na2SO4, filtered and the solvent removed to give 0.93 g (yield quantitative) of the titled compound.