Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.BrC1N=C(O[C@@H]([C@H]2CNC(=O)C2)C)C2N(C3CC3)C=NC=2C=1.[CH3:45][N:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52](B3OC(C)(C)C(C)(C)O3)[CH:53]=2)[C:48]2([CH2:66][N:65]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:64]2)[C:47]1=[O:74].C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.O>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@@H:11]4[CH2:12][C:13](=[O:16])[NH:14][CH2:15]4)[CH3:10])=[N:7][C:2]([C:52]4[CH:53]=[C:54]5[C:49]([C:48]6([CH2:64][N:65]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:66]6)[C:47](=[O:74])[N:46]5[CH3:45])=[CH:50][CH:51]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CN1C(=O)C2(CN(C(=O)OC(C)(C)C)C2)c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: C[C@@H](Oc1nc(-c2ccc3c(c2)N(C)C(=O)C32CN(C(=O)OC(C)(C)C)C2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C

Procedure:
In a 5 mL microwave vial, a mixture of (R)-4-((R)-1-((6-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one and (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 2.71 (50 mg, 0.14 mmol), tert-butyl 1′-methyl-2′-oxo-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[azetidine-3,3′-indoline]-1-carboxylate 7.59 (68 mg, 0.16 mmol), cesium carbonate (140 mg, 0.43 mmol), and PEPPSI-IPr catalyst (8.2 mg, 0.01 mmol) were taken up in dimethoxyethane (1.8 mL) and water (0.9 mL). After evacuating and backfilling with argon, mixture was heated at 100° C. for 90 minutes in a microwave reactor. After cooling to rt, reaction mixture was poured into water and extracted with ethyl acetate. Combined organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel column chromatography (0-10% methanol/dichloromethane) to yield tert-butyl 6′-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1′-methyl-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 3.84 (53 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H37N6O5: 573.27; found: 573.27.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:34]([NH:33][C:29]1[CH:28]=[C:27]([CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:14]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)=[O:16])[CH2:22][CH2:23]2)[CH:32]=[CH:31][CH:30]=1)(=[O:38])[CH2:35][CH2:36][CH3:37]
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCCC3)CC2)c1

Procedure:
Example 87 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.44 (s, 1H), 7.41–7.37 (m, 2H), 7.29–7.23 (m, 2H), 7.02–6.97 (m, 2H), 6.93 (d, 1H, J=6.8 Hz), 6.80 (br s, 1H), 3.29 (dd, 2H, J=5.6, 11.6 Hz), 2.92 (d, 2H, J=11.6 Hz), 2.46 (m, 1H), 2.36–2.30 (m, 6H), 1.96–1.30 (m, 18H), 1.01 (t, 3H, J=7.6 Hz), ESMS m/e: 508.3 (M+H)+.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[N:8]1([C:14]2([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][NH:16][CH2:15]2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(N(CC)CC)C.CN(C)CCN>ClCCl>[N:8]1([C:14]2([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:17][N:16]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[CH2:15]2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NCC1(N2CCOCC2)CNC1
Reactant: CCCS(=O)(=O)Cl
Agent: CN(C)CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N1CC(CNC(=O)OC(C)(C)C)(N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Propane-1-sulfonyl chloride (0.44 ml, 3.9 mmol) was added to tert-butyl [(3-morpholin-4-ylazetidin-3-yl)methyl]carbamate (0.71 g, 2.6 mmol) and triethylamine (0.91 g, 6.5 mmol) in dichloromethane (9 ml) at 0° C. The reaction was then stirred at room temperature for 30 mins before quenching with N,N-dimethylethylenediamine (0.5 eq). The resulting mixture was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness to give crude tert-butyl {[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}carbamate which was used without further purification m/z (M++H) 378.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].[F:6][C:7]([F:17])([F:16])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.C([O-])(=O)C.[NH4+].C(OC(=O)C)C>CCCCCC>[N+:1]([C:4]([CH3:5])=[CH:12][C:11]1[CH:14]=[CH:15][C:8]([C:7]([F:17])([F:16])[F:6])=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=Cc1ccc(C(F)(F)F)cc1)[N+](=O)[O-]
Temperature: 115 °C
Yield: 42.9 %

Procedure:
Nitro ethane (30.94 mL, 430.73 mmol) was added to 4-trifluoromethyl-benzaldehyde (5 g, 28.71 mmol) and ammonium acetate (6.64 g, 86.15 mmol) and the resulting mixture was refluxed at 115° C. overnight. The reaction was monitored by TLC (10% ethylacetate in hexane). The reaction mass was cooled and partitioned between ethylacetate and water. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated. Purification by column chromatography on silica gel (2% ethylacetate in hexane) afforded 2.85 g of the product (42.93% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.C(N(CC)CC)C.[C:41](Cl)(=[O:45])[CH2:42][CH2:43][CH3:44]>O1CCCC1>[C:41]([O:29][C:26]1[CH:27]=[CH:28][C:23]([C:10]2[C:9]([CH2:8][O:7][C:6]3[CH:32]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:33])=[C:18]3[C:13]([NH:14][C:15]([CH3:22])([CH3:21])[C:16](=[O:20])[N:17]3[CH3:19])=[CH:12][CH:11]=2)=[C:24]([O:30][CH3:31])[CH:25]=1)(=[O:45])[CH2:42][CH2:43][CH3:44]
Reactant: CCCC(=O)Cl
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Oc1ccc(-c2ccc3c(c2COc2cc(F)ccc2C)N(C)C(=O)C(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
8-(5-Fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 11, 25 mg, 0.055 mmol) was dissolved in tetrahydrofuran (1 mL), and triethylamine (20 μL, 0.14 mmol) and butyryl chloride (7.6 μL, 0.073 mmol) were added successively. After the reaction mixture was stirred at room temperature for 1 hour, the mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (27 mg) as a colorless amorphous product. (Yield 92%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]=23)=[CH:4][CH:3]=1.[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O.O1CCOCC1.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:22]1[C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]([CH:18]4[CH2:21][CH2:20][CH2:19]4)[N:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]=34)=[CH:4][CH:3]=2)=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]1=2
Reactant: Nc1nccn2c(C3CCC3)nc(-c3ccc(Br)cc3)c12
Reactant: OB(O)c1cc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc(-c4cc5ccccc5s4)cc3)c12
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
A mixture of 1-(4-bromophenyl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine (30.0 mg, 0.0874 mmol), 1-benzothiophen-2-ylboronic acid (18.7 mg, 0.105 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol) in 1,4-dioxane (2 mL, 30 mmol) and H2O (0.2 mL, 9 mmol) was degassed and refilled with nitrogen (3×). The reaction was microwaved on 300 watts, PowerMAX enabled, 100° C. for 30 min. For the workup, the reaction was concentrated in vacuo to a solid and purified by 10 g Jones Chromatography column wetted with DCM, dried loaded the product, eluted with DCM to 5% MeOH in DCM], which afford 8.4 mg (24%) of the desired product as a yellow solid. 1H NMR (400 MHz, CDCl3); 6=2.03-2.14 (m, 1H), 2.16-2.27 (m, 1H), 2.48-2.59 (m, 2H), 2.61-2.74 (m, 2H); 3.78-3.89 (m, 1H), 6.93 (d, J=5.56 Hz, 1H), 7.14 (d, J=5.56 Hz, 1H), 7.33-7.43 (m, 2H), 7.66 (s, 1H), 7.74 (d, J=8.59 Hz, 2H), 7.80-7.92 (m, 4H). HPLC: tR=2.71 min. (Open Lynx polar—5 min.). MS (ES+): m/z 379.80/380.91 (100/60) [MH+].
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])[CH:16]=3)[CH:9]=2)[N:4]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:3]=1.[F:34][C:35]1[CH:36]=[C:37]([CH:55]=[CH:56][CH:57]=1)[CH2:38][N:39]1[C:43]([CH3:44])=[C:42](B2OC(C)(C)C(C)(C)O2)[C:41]([CH3:54])=[N:40]1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:36]=[C:37]([CH:55]=[CH:56][CH:57]=1)[CH2:38][N:39]1[C:43]([CH3:44])=[C:42]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])[CH:16]=4)[CH:9]=3)[N:4]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:3]=2)[C:41]([CH3:54])=[N:40]1
Reactant: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Yield: 50.7 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, 5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy-N-methylbenzenesulfonamide (intermediate 22) (140 mg, 0.234 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (154 mg, 0.469 mmol), Pd(PPh3)2Cl2 (3.22 mg, 0.011 mmol), sodium carbonate (75 mg, 0.702 mmol), Toluene/ethanol (3/5 ml) to afford 80 mg (51% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 8.63 (s, 1H), 8.14-8.12 (d, 2H), 8.04 (s, 1H), 7.73-7.64 (m, 3H), 7.49-7.46 (m, 1H), 7.33-7.30 (m, 3H), 7.15-7.12 (d, 1H), 7.01-6.95 (m, 2H), 6.86-6.83 (d, 1H), 5.31 (s, 2H), 4.84-4.83 (m, 1H), 4.03 (s, 3H), 2.63-2.61 (d, 3H), 2.39 (s, 3H), 2.20 (s, 3H), 2.13 (s, 3H). MS: m/z=674.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>C1COCC1>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([Cl:12])[CH:14]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(Cl)c1
Reaction time: 16 h

Procedure:
5-Amino-2-chloro-benzoic acid (0.4 g, 2.33 mmol) was diluted with THF (12 mL), treated with 3-chloro-benzoyl chloride (0.330 mL, 2.56 mmol) and stirred for 16 h. Solvents were then removed and resulting solids were triturated with DCM. After filtration, the title compound was obtained as a white solid (0.5 g, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])=[C:7]([OH:13])[CH:6]=[CH:5]2.O[CH:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])=[C:7]([O:13][CH:15]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[CH:5]2
Reactant: CCOC(=O)C(O)Cc1ccccc1
Reactant: Cc1c(O)ccc2cc(Br)ccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccccc1)Oc1ccc2cc(Br)ccc2c1C
Yield: 43.7 %

Procedure:
Following the procedure described in Step 2 of Example 4, 6-bromo-1-methyl-2-naphthol (2.44 g 10.3 mmol) was coupled to ethyl 2-hydroxy-3-phenylpropanoate (3.0 g, 15 mmol) in presence of triphenylphosphine (4.17 g, 15.9 mmol) and diisopropyl azodicarboxylate (3.0 mL, 15 mmol) in benzene (65 mL). Purification by flash chromatography using 100% hexane and 1-4% ethyl acetate in hexane as eluants afforded ethyl 2-[(6-bromo-1-methyl-2-naphthyl)oxy]-3-phenylpropanoate as a transparent yellow gum (1.86 g). 1HNMR (400 MHz, DMSO-d6): δ8.1 (s, 1H), 7.9 (d, 1H, J=7.0 Hz), 7.7 (d, 1H, J=7.0 Hz), 7.6 (d, 1H, J=6.3 Hz), 7.3-7.4 (m, 4 H), 7.2-7.3 (m, 2H), 5.25 (t, 1H, J=6.3 Hz), 4.1 (q, 2H, J=7.0 Hz), 3.25-3.35 (m, 2H), 2.45 (s, 3H), and 1.1 ppm (t, 3H, J=7.0 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[C:7]([CH2:12][C:13]#[CH:14])[CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[OH:16][C:17]1[CH:26]=[C:25](I)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>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)I.C(N(CC)CC)C>[OH:16][C:17]1[CH:26]=[C:25]([C:14]#[C:13][CH2:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[O:5][CH2:4][CH2:3][C:2]3([CH3:15])[CH3:1])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: C#CCc1cccc2c1OCCC2(C)C
Reactant: COC(=O)c1ccc(I)cc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCc2cccc3c2OCCC3(C)C)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.18 g (5.9 mmol) of 3-(4,4-dimethylchroman-8-yl)-1-propyne, 1.60 g (5.9 mmol) of methyl 2-hydroxy-4-iodobenzoate and 60 ml of triethylamine are introduced into a three-necked flask under argon. The reaction mixture is degassed by sparging with nitrogen, 332 mg (0.46 mmol) of bis(triphenylphosphine)palladium(II) chloride and 134 mg of copper iodide are introduced and the mixture is stirred at room temperature for eight hours. The reaction mixture is evaporated to dryness, the residue is taken up in ethyl acetate and hydrochloric acid (1N), and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a silica column eluted with heptane. After evaporating the solvents, an oil, which slowly crystallizes, is obtained and is recrystallized from heptane. 1.00 g (50%) of methyl 2-hydroxy-4-[3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate is collected in the form of a white solid with a melting point of 92-93° C.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH2:18]([NH2:20])[CH3:19].CCN(C(C)C)C(C)C>C(#N)C>[CH2:18]([NH:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:19]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1F
Reactant: CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCNc1c([N+](=O)[O-])ccc(F)c1-c1ccccn1
Yield: 89.2 %

Procedure:
2-(2,6-Difluoro-3-nitrophenyl)pyridine (1.00 g, 4.29 mmol), ethylamine (2.24 mL, 4.29 mmol) and then DIPEA (0.75 mL, 4.29 mmol) were added to acetonitrile (10 mL) and the resultant mixture stirred at 20° C. for 40 hours under a nitrogen atmosphere. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (Si—PPC, gradient 0-50% EtOAc/cyclohexane) to give the title compound as yellow oil (1.00 g, 90%). 1H NMR (CDCl3) δ: 8.73 (1H, ddd, J=6.6, 2.4, 1.3 Hz), 8.28 (1H, dd, J=12.6, 8.1 Hz), 7.80 (1H, td, J=10.3, 2.4 Hz), 7.45 (1H, dq, J=10.4, 1.6 Hz), 7.33 (1H, ddd, J=10.1, 6.5, 1.6 Hz), 6.51 (1H, dd, J=12.7, 10.9 Hz), 2.54-2.44 (2H, m), 1.03 (3H, t, J=9.6 Hz)
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CS(C)=O>[CH2:15]([N:14]([C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1)[CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1ccc2nc(Cl)cnc2c1
Reactant: CNCc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CN(Cc1ccccc1)c1cnc2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,6-Dichloroquinoxaline (0.500 g, 2.5 mmol) was dissolved in DMSO (10 mL) at RT and N-methyl-1-phenylmethanamine (1.53 g, 12.56 mmol) was added to the reaction mixture. The reaction mixture was stirred at RT for 16 hrs. After completion of reaction (checked by TLC), water (100 mL) was added to the reaction mixture and it was extracted with ethyl acetate (50 mL×3). The organic layer was washed with water (10 mL), brine (10 mL) and dried over Na2SO4. The organic layer was concentrated under vacuum to give the crude product.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[N:28]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37](=[O:38])[C:36]5[CH:40]=[CH:41][C:33]([N:28]6[CH:32]=[CH:31][CH:30]=[CH:29]6)=[CH:34][CH:35]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)c1ccc(-n2cccc2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(-n2cccc2)cc1

Procedure:
The title compound, white solid (90 mg, 72%), MS (ISP) m/z=500.4 [(M+H)+], mp 236.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-pyrrol-1-yl-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[CH3:13])=[CH:5][CH:4]=1.[N+:16]([O-])([O-:18])=[O:17].[K+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[CH3:13])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc2[nH]c(=O)c(=O)n(C)c2c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c(=O)n2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 0.5 g (2.4 mmol) 7-methoxy-1-methylquinoxaline-2,3(1H,4H)-dione in 20 ml concentrated sulfuric acid was added at 0° C. 0.25 g (2.48 mmol) potassium nitrate. Stirring was continued at 0° C. for 30 min, and then at 25° C. for 90 min. The reaction mixture was poured into 100 ml ice-water to give 0.51 g (84% of 7-methoxy-1-methyl-6-nitroquinoxaline-2,3(1H,4H)-dione as a precipitate. M.p. 343° C. NMR (DMSO-d6): 11.9 (1H, broad s), 7.67 (1H, s), 7.0 (1H, s), 3.97 (3H, s), 3.53 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]([CH3:10])=[N:3]1.C1COCC1.[C:16]([C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)#[CH:17]>CCN(CC)CC>[C:16]([C:18]1[CH:19]=[C:20]([NH:24][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=2)=[O:8])[CH:21]=[CH:22][CH:23]=1)#[CH:17]
Reactant: C#Cc1cccc(N)c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Temperature: 55 °C
Yield: 71.9 %

Procedure:
A dry 25 mL flask was charged with 2,5-dimethyl-2H-pyrazole-3-carbonyl chloride (0.135 g, 0.854 mmol) and THF (5 mL) was added. 3-Ethynyl-phenylamine (0.100 g, 0.854 mmol) was added to the THF solution of the acid chloride followed by NEt3, and the mixture was allowed to stir at 55° C. The reaction mixture was then allowed to cool to room temperature. The reaction was extracted twice with EtOAc (˜5 mL) and water (˜10 mL) followed by saturated aqueous NaHCO3(˜10 mL). The combined organic layers were dried over anhydrous Na2SO4 (s) and then concentrated. The crude residue was purified by chromatography (silica gel, gradient elution EtOAc/Hexanes 0 to 60%). The product containing fractions were concentrated to give the title compound as a tan solid (147 mg. 72%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:16]([O-])=O)[CH:3]=1.C1COCC1>[Pt].CO>[Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([CH:3]=1)[NH2:16]
Reactant: CNc1cc(N2CCOCC2)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(N2CCOCC2)c(Cl)cc1N

Procedure:
The sub-title compound was prepared from (4-chloro-5-morpholin-4-yl-2-nitro-N-methyl-aniline (260 mg, 1.0 mmol), THF (6 mL), MeOH (6 mL) and Pt/C (50 mg) in analogy to example 1 step (f).
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH2:13][C:14]1[C:19]([CH2:20][NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]([Br:28])=[CH:16][N:15]=1>O1CCOCC1>[Br:28][C:17]1[CH:16]=[N:15][C:14]2[NH:13][C:6](=[O:7])[N:21]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][C:19]=2[CH:18]=1
Reactant: CCOC(=O)CNCc1cc(Br)cnc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: CCOC(=O)CN1Cc2cc(Br)cnc2NC1=O
Yield: 5.6 %

Procedure:
CDI (1.8 g, 114 mmol) was added to a solution of ethyl 2-((2-amino-5-bromopyridin-3-yl)methylamino)acetate (1.1 g, 38.17 mmol) in dioxane (36 mL). The reaction mixture was stirred at reflux for 5 hours and then concentrated to dryness. The residue was partitioned between dichloromethane (40 mL) and water (30 mL). The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic phases were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The isolated compound was finally precipitated from a mixture dichloromethane/pentane to give the title product as a yellow solid (670 mg, 56%).
Reaction SMILES: [C:1](=[O:12])([S:9][CH2:10][CH3:11])[O:2][O:3][CH:4](Cl)[CH2:5][CH2:6][CH3:7].[CH:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[C:1](=[O:12])([S:9][CH2:10][CH3:11])[O:2][O:3][CH:4]([O:20][C:18]([CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19])[CH2:5][CH2:6][CH3:7]
Reactant: CCCC(Cl)OOC(=O)SCC
Reactant: O=C(O)C1CCCC1
Product: CCCC(OOC(=O)SCC)OC(=O)C1CCCC1
Temperature: 75 °C
Reaction time: 120 h
Yield: 82.5 %

Procedure:
A mixture of (66) (1.33 g, 6.76 mmol) and cyclopentancarboxylic acid (1.30 g, 10.1 mmol) was stirred at 75° C. for five days. The reaction was then cooled to room temperature and partitioned between water and ether. The ether layer was washed with brine, dried over anhydrous Na2SO4. Filtration then removal of the solvent by rotary evaporation gave the title thiocarbonate (67) (1.62 g, 86%). 1H NMR (CDCl3, 400 MHz): δ 0.95 (t, 3H), 1.20–1.85 (m, 15H), 2.68 (m, 1H), 2.82 (m, 2H). 6.84 (t, 1H).