Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([N:18]3[C:23](=[O:24])[C:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:21][C:20]4[CH:32]=[CH:33][CH:34]=[N:35][C:19]3=4)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO.O1CCOCC1.O>[CH2:25]([C:22]1[C:23](=[O:24])[N:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:36]=[CH:37][C:5]([OH:4])=[CH:6][CH:7]=3)[CH:13]=2)[C:19]2[N:35]=[CH:34][CH:33]=[CH:32][C:20]=2[N:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)Oc1ccc(C(=O)Nc2cccc(-n3c(=O)c(Cc4ccccc4)nc4cccnc43)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.4 %

Procedure:
To a mixture of 4-[3-(4-acetoxybenzoylamino)phenyl]-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (147 mg) in methanol (3 ml) and 1,4-dioxane (3 ml) was added a solution of potassium carbonate (83 mg) in water (0.5 ml). The mixture was stirred at room temperature for 1.5 hours, then poured into a mixture of ethyl acetate and water. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated. The residue was crystallized from ethanol to give 2-benzyl-4-[3-(4-hydroxybenzoylamino)phenyl]-3-oxo-3,4-dihydropyrido [2,3-b]pyrazine (53 mg).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[NH2:35][CH2:36][CH2:37][S:38]([NH2:41])(=[O:40])=[O:39].Cl>C(N(CC)CC)C.O>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH2:32][NH:35][CH2:36][CH2:37][S:38]([NH2:41])(=[O:40])=[O:39])=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Reactant: NCCS(N)(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: NS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Yield: 36.7 %

Procedure:
In an analogous manner to Example 10, 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride (0.200 g, 0.436 mmol) was reacted with 2-aminoethylsulphonamide hydrochloride (0.200 g, 1.245 mmol) and triethylamine (10 drops). On completion of the reaction, the mixture was acidified with dilute HCl and diluted with water, to give the crude product as a precipitate collected by filtration. Treatment with triethylamine followed by purification by silica gel chromatography, eluting with 3-10% MeOH/CHCl3 gave the title compound as a yellow solid (0.085 g, 0.160 mmol, 37%); δH [2H6]DMSO 9.61 (2H, brs), 9.25 (1H,s), 8.58 (1H,s), 8.23 (1H,d), 7.77-7.88 (3H,m), 7.30-7.52 (5H,m), 7.26 (2H,s), 7.20 (1H,d), 7.08 (2H,d), 6.81 (1H,d), 5.14 (2H,s), 4.44 (2H,s), 3.34-3.60 (2H, m), 3.25-3.45 (2H, obscured by water); m/z (M+1+) 530.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:21])/[C:13](/I)=[CH:14]\[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:42]1[CH:43]=[CH:44][C:45]([S:54]([CH3:57])(=[O:56])=[O:55])=[C:46]([N:48]2[C:52]([CH3:53])=[N:51][N:50]=[N:49]2)[CH:47]=1.[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][O:11][C:12](=[O:21])/[C:13](/[C:42]1[CH:43]=[CH:44][C:45]([S:54]([CH3:57])(=[O:56])=[O:55])=[C:46]([N:48]2[C:52]([CH3:53])=[N:51][N:50]=[N:49]2)[CH:47]=1)=[CH:14]/[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)/C(I)=C\C1CCCC1
Reactant: Cc1nnnn1-c1cc(Br)ccc1S(C)(=O)=O
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C1CCCC1)c1ccc(S(C)(=O)=O)c(-n2nnnc2C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
A mixture of zinc dust (330 mg, 5 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane (93 mg, 0.5 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (54 mg, 0.5 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (prepared in Example 7, 420 mg, 1.5 mmol) in dry tetrahydrofuran (1 mL). The resulting reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (3 mL), and the stirring was stopped to allow the excess zinc dust to settle down (2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (27 mg, 0.05 mmol) and triphenylphosphine (52 mg, 0.2 mmol) in dry tetrahydrofuran (3 mL) was stirred at 25° C. under argon for 10 min and then treated with 1-(5-bromo-2-methanesulfonyl-phenyl)-5-methyl-1H-tetrazole (237 mg, 0.75 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 40-45° C. over the weekend. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (30 mL), and the organic compound was extracted into ethyl acetate (3×30 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1 to 1/1 hexanes/ethyl acetate) afforded (E)-3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid methyl ester (266 mg, 91%) as a white solid: mp 164-166° C.; EI-HRMS m/e calcd for C18H22N4O4S (M+) 390.1362, found 390.1368.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH:6]=[O:7].[Li+].[OH-].Cl>C1COCC1>[C:18]([O:17][C:15](=[O:16])[NH:14][C:4]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:6]([OH:7])[O:2][C:3]1=[O:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)C(CC=O)(NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccccc2)CC(O)OC1=O
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of compound 13 (6.14 g, 20 mmol) in THF (50 mL), 3N LiOH solution (20 mL, 60 mmol) was added. After stirring for 1 h, the resulting mixture was adjusted to pH=5-6 using 1N HCl, and extracted with ethyl acetate. The combined organic phases were concentrated to afford compound 14 (5.6 g, 95.6%). 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9 H), 2.85-2.87 (m, 1 H), 3.17-3.19 (m, 1 H), 5.74-6.11 (bs, 2 H), 7.34-7.46 (m, 5 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:3]=1
Reactant: OCc1ccncc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccncc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 293 (M+, 100), 92 (40), 65 (39).
Reaction SMILES: BrBr.[CH3:3][C:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[C:5]=1[CH:12]=[O:13].[Cl-].[NH4+].O1C[CH2:19][CH2:18][CH2:17]1>>[CH3:3][C:4]1[CH:5]([CH:12]([OH:13])/[CH:17]=[CH:18]\[CH3:19])[C:6]([CH3:10])([CH3:11])[CH2:7][CH2:8][CH:9]=1
Reactant: CC1=C(C=O)C(C)(C)CCC1
Reactant: C1CCOC1
Agent: BrBr
Agent: [Cl-]
Agent: [NH4+]
Product: C/C=C\C(O)C1C(C)=CCCC1(C)C
Reaction time: 1 h

Procedure:
When the addition of the bromine derivative was completed, the mixture was refluxed for 45 minutes; then cooled to -10°, at which temperature 110 g. of β-cyclocitral dissolved in 410 ml. of tetrahydrofuran were introduced dropwise within 45 minutes. Stirring was continued for 1 hour at -5°, then overnight at room temperature under nitrogen. The reaction mixture was poured into a suspension of 0.5 kg. of crushed ice in 1.5 l. of a saturated ammonium chloride solution. It was extracted 3 times with ether, the extracts were combined and washed 3 times with water and then with a concentrated NaCl solution. After drying over anhydrous Na2SO4 the volatile portions were evaporated and the residue distilled. There were thus obtained 91 g. (65.2%) of cis-2,6,6-trimethyl-1-[1-hydroxy-2-butonyl]-1-cyclohexene. B.p. 64°-68°/0.01 Torr. By replacing in the above procedure the β-cyclocitral by its analogue α, cis-2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]2-cyclohexene was obtained. 1700 ml. of absolute pyridine were cooled to 0°-5° and 154 g. of CrO3 were added portionwise within 30 minutes while stirring vigorously. Stirring was continued for 10 minutes at 5° and then 95 g. of cis-2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene dissolved in 300 ml. of pyridine were added dropwise within 20 minutes, while maintaining the temperature below 10°. When the addition was completed stirring was continued for 20 minutes, then the mixture was allowed to stand for 15 hours at room temperature. The reaction mixture was diluted with 5 l. of water and extracted with 6 portions of 800 ml. of ether each. The extracts were combined and successively washed with: 4 portions of water, 8 portions of 10% HCl at 0°, 3 portions of water, 2 portions of 5% Na2CO3, 2 portions of water. Moreover, each washing portion was extracted with ether before being discarded, and the extract was added to the main extract after washing. The ethereal solution was dried over anhydrous Na2SO4, concentrated in vacuo and the residue distilled. There were thus obtained 57 g. of a liquid fraction, b.p. 75°-85°/0.001 Torr, which fraction was redistilled by means of a spinning band column and yielded 24 g. (25.5%) of pure trans-2,6,6-trimethyl-1-crotonoyl-1-cyclohexene.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=2)=[CH:12][N:11]=1.[H-].[Na+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=2)=[CH:12][N:11]=1
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(O)c(F)c3F)nc2)cn1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCCCCCCCC)c(F)c3F)nc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A solution of 2.4 mmol of 2-(2,3-difluoro-4-hydroxyphenyl)-5-(6-octyloxypyridin-3-yl)pyrimidine in 10 ml of DMF is added dropwise at room temperature and under a protective gas to a suspension of 2.7 mmol of sodium hydride (80 percent in mineral oil) in 5 ml of dry DMF. The mixture is stirred for a further 30 minutes, and 2.7 mmol of 1-bromooctane, dissolved in 10 ml of DMF, are then added slowly. The reaction mixture is stirred at room temperature for 20 hours and introduced into 100 ml of ice/water, the mixture is extracted a number of times with dichloromethane, and the combined organic extracts are washed with sat. sodium chloride solution and dried using magnesium sulfate. After the solvent has been removed in vacuo, the crude product is chromatographed on silica gel 60 using dichloromethane/ethyl acetate 20:1 (v/v) as eluent and recrystallized from acetonitrile, giving 0.77 g (61%) of colorless crystals, X 89 S3 73.5 SC 164 SA 167 I.
Reaction SMILES: [N:1]1([S:7]([N:10]2[CH2:15][CH2:14][O:13][C:12]3[N:16]=[CH:17][C:18]([C:20](Cl)=[O:21])=[CH:19][C:11]2=3)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:23]([NH:27][C:20]([C:18]1[CH:17]=[N:16][C:12]2[O:13][CH2:14][CH2:15][N:10]([S:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)(=[O:9])=[O:8])[C:11]=2[CH:19]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(Cl)c1cnc2c(c1)N(S(=O)(=O)N1CCCCC1)CCO2
Reactant: CC(C)(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cnc2c(c1)N(S(=O)(=O)N1CCCCC1)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
To a biphasic mixture of 1-(piperidin-1-ylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonyl chloride (38 mg, 0.110 mmol) in DCM (2 mL) and saturated aqueous NaHCO3 (2 mL) was added tert-butylamine (50 μL, 0.472 mmol). The reaction was stirred at room temperature for 16 h. The biphasic mixture was extracted with DCM (3×2 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was purified by flash column chromatography using a gradient elution of hexanes with 10-70% EtOAc to provide N-tert-butyl-1-(piperidin-1-ylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide (27.7 mg, 0.072 mmol, 65.2% yield over 2 steps) as a white solid. LCMS (+ESI) m/z=383.1 [M+H]+; 1H-NMR (CDCl3) δ 8.27. (d, 1H), 8.17 (d, 1H), 5.86 (br s, 1H), 4.49 (dd, 2H), 3.78 (dd, 2H), 3.29 (dd, 4H), 1.67-1.53 (m, 6H), 1.46 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25]S(C)(=O)=O)=[CH:21][CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[OH-].[Na+].O.Cl>O1CCOCC1>[Cl:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CS(=O)(=O)Oc1ccc(-c2c3ccccc3c(Cl)c3sc4ccccc4c23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(-c2c3ccccc3c(Cl)c3sc4ccccc4c23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
A biphasic mixture of methanesulfonic acid 4-(6-chloro-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenyl ester (0.917 g, 2.09 mmol) in dioxane (13 mL) and a solution of sodium hydroxide (2.5 N, 6.7 mL, 16.7 mmol, 8 eq) was heated at reflux overnight. After cooling to room temperature the reaction mixture was combined with water (50 mL), acidified with concentrated hydrochloric acid, and stirred for 15 minutes. The crude white solid product was collected by filtration, redissolved in ether, combined with silica gel, and the solvent was removed. The adsorbate was flash chromatographed (gradient 85/15-80/20 petroleum ether/ethyl acetate) to give the title compound as a white solid (0.705 g, 94%); mp 193-195° C.; NMR (CDCl3); δ 8.37 (ddd, J=8, 1, Hz, 1H), 7.81 (ddd, J=8, 1, 1 Hz, 1H), 7.68-7.63 (m, 2H), 7.44 (ddd, J=8, 7, 1 Hz, 1H), 7.39 (ddd, J=8, 7, 1 Hz, 1H), 7.29-7.26 (m, 2H,), 7.14-7.09 (m, 3H), 6.81 (ddd, J=8, 1, 1 Hz, 1H), 5.01 (d, J=4 Hz, 1H); MS (+EI): [M+], 1 chlorine isotope pattern, 360 (100%), 362 (45%); Anal. calc. for C22H13ClOS: C, 73.23, H, 3.63, N, 0.00. Found: C, 72.86, H, 3.24, N, 0.04.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=1)=O.[C:16]1([CH3:26])[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([NH2:25])=[NH:24])[CH:17]=1.[OH-].[Na+]>COCCO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:16]1([CH3:26])[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]2[N:25]=[C:5]([C:7]3[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=3)[CH:4]=[CH:3][N:24]=2)[CH:17]=1
Reactant: Cc1cccc(NC(=N)N)c1
Reactant: CN(C)C=CC(=O)c1ccc(C(=O)O)s1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Cc1cccc(Nc2nccc(-c3ccc(C(=O)O)s3)n2)c1
Temperature: 100 °C
Yield: 53.9 %

Procedure:
5-(3-dimethylamino-acryloyl)thiophene-2-carboxylic acid (200 mg, 0.888 mmol), N-m-tolylguanidine (71.1 mg, 1.77 mmol) and NaOH (264 mg, 1.77 mmol) were dissolved in 2-methoxyethanol (2 mL) and heated at 100° C. for 48 hours. After cooling, the reaction was diluted with 10% Aqueous citric acid solution and the solids were collected by filtration. The solids were washed with water and Et2O and dried to afford 5-(2-m-tolylamino-pyrimidin-4-yl)thiophene-2-carboxylic acid (149 mg, 53.8%) as a yellow solid. MS: m/z 312 (M+H+).
Reaction SMILES: [CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][N:18]=1)=[O:16].[OH-].[Na+].Cl>C(O)C>[CH:3]1[C:4]2=[C:13]3[CH:8]([CH2:7][CH2:6][CH2:5]2)[CH2:9][CH2:10][CH2:11][C:12]3=[CH:1][C:2]=1[NH:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=1)=[O:16]
Reactant: COC(=O)c1ccc(C(=O)Nc2cc3c4c(c2)CCCC4CCC3)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C(=O)Nc2cc3c4c(c2)CCCC4CCC3)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A suspension of methyl 6-[(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)carbamoyl]nicotinate (0.194 g) in ethanol (10 ml) was added with 2 N aqueous sodium hydroxide (2 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethyl acetate-n-hexane to obtain the title compound (0.161 g, yield: 87%) as pale yellow needles (melting point: 252-253° C.).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)=[CH:33][CH:32]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC)cc2)c2ncnn12
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a suspension (20 mL) of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), (4-methoxyphenyl)boronic acid (0.41 g), triethylamine (0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethane was added copper(II) acetate (0.49 g), and the mixture was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.64 g, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](Br)[C:3]=1[Cl:10].C(=[NH:24])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl>C1(C)C=CC=CC=1.CCOCC.C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Pd]>[Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[NH2:24]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Br)c(Cl)c(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(N)c(Cl)c(Br)c1
Reaction time: 1.5 h
Yield: 43.8 %

Procedure:
To an Argon sparged solution of 1,3-dibromo-2-chloro-5-methylbenzene (5 g, 17.6 mmol), benzophenone imine (3.1 mL, 18.5 mmol), sodium tert-butoxide (2.53 g, 26.4 mmol) in toluene, (S)-BINAP (1.6 g, 2.6 mmol) and Pd2(dba)3 (0.81 g, 0.88 mmol) were added and the reaction was heated in an oil bath. When the temperature reached 60° C. an exotherm was noted, with reflux of the solvent. Heating was maintained and the reaction was complete after 1.5 hours. The reaction mixture was cooled, diluted with Et2O and stirred with Siliabond DMT (Pd scavenger), and was then filtered through Celite. The filtrate was washed with water, brine, dried (MgSO4), and concentrated to afford a sticky brown residue. The residue was dissolved in THF (60 mL) and aqueous 6.0 M HCl solution was added. The reaction mixture was stirred for 30 minutes, partitioned with Et2O and 1M NaOH was added until the aqueous layer was pH 9. The layers were separated and the organic layer was washed with water, brine, dried (MgSO4), and concentrated. Purification by flash chromatography (SiO2, 0-20% EtOAc in heptane) furnished 3-bromo-2-chloro-5-methylaniline (1.7 g) with a small amount of benzophenone as a contaminant: 1H NMR (300 MHz, CDCl3) δ 2.21 (s, 3H) 4.11 (br s, 2H) 6.52 (s, 1H) 6.85 (s, 1H).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:5][CH:4]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=O)[CH2:3]1.CO.C(O)(=O)C.C(=O)([O-])O.[Na+]>C(O)C.[Pd].C(OCC)(=O)C>[F:1][C:2]1([F:18])[CH2:5][CH:4]([C:6]2[NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)[CH2:3]1
Reactant: O=C(Nc1ccccc1[N+](=O)[O-])C1CC(F)(F)C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: CC(=O)O
Product: FC1(F)CC(c2nc3ccccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.6 %

Procedure:
[step 2] 3,3-Difluoro-N-(2-nitrophenyl)cyclobutanecarboxamide (400 mg, 1.56 mmol) obtained in step 1 was dissolved in ethanol (10 mL), methanol (40 mL), and ethyl acetate (40 mL), and 10% Pd—C (120 mg) was added. The reaction system was purged with hydrogen gas, and the mixture was stirred at room temperature for 3 hr. After completion of the reaction, the reaction mixture was filtered through celite, and the solution was concentrated under reduced pressure. To the obtained residue was added acetic acid (2.2 mL, 38.4 mmol), and the mixture was stirred at 80° C. for 1 hr. Under ice-cooling, saturated aqueous sodium hydrogen carbonate was added to the mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-30/70 v/v) to give 2-(3,3-difluorocyclobutyl)-1H-benzo[d]imidazole (135 mg, 42%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[N:6][CH:5]=1.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].O>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH:10][C:20](=[O:21])[C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=2)[C:7]([NH2:11])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(N)c(N)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cnc(N)c(NC(=O)c2ccc([N+](=O)[O-])cc2)c1
Reaction time: 18 h
Yield: 68.4 %

Procedure:
To a solution of 5,6-Diamino-nicotinic acid methyl ester (4) (3.22 g, 19 mmol) in dry pyridine (100 ml) was added 4-nitrobenzoyl chloride (3.5 g, 19 mmol) and the mixture stirred for 18 h. The mixture was poured into H2O and the resulting solid collected by filtration, dried in vacuo to give the product as a yellow solid (4.05 g, 13 mmol, 66%). 1H NMR (500 MHz, DMSO-d6) δ9.98 (s, 1H), 8.47 (s, 1H), 8.36 (d, J=8.7 Hz, 2H), 8.23 (d, J=8.7 Hz, 2H), 8.0 (s, 1H), 6.92 (s, 2H), 3.79 (s, 3H), EIMS m/z M−1 315.4.