Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:8]([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5].[C:11](=[O:14])(O)[O-:12].[Na+]>C1COCC1.CO>[C:8]([O:12][C:11]([NH:2][C@H:3]([CH:8]([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])=[O:14])([CH3:10])([CH3:9])[CH3:3]
Reactant: COC(=O)[C@H](N)C(C)C
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 190.8 %

Procedure:
(R)-methyl 2-amino-3-methylbutanoate hydrochloride (4.0 g, 23.86 mmol) was dissolved in THF (60 mL) and methanol (15 mL). The colorless solution was chilled to 0° C., followed by the addition of sodium bicarbonate (6.01 g, 71.6 mmol) in one portion, immediately followed by addition of solid BOC-anhydride (7.81 g, 35.8 mmol). The reaction mixture was allowed to warm to ambient temperature and left stirring overnight, quenched with 200 mL water, and extracted twice with 200 mL MTBE. The organic phase was washed with 200 mL saturated NaHCO3 solution and 200 mL brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on a Grace Reveleris 120 g column, eluted with 0-30% EtOAc in Hexanes (35 mL/min) to obtain the title compound (5.265 g, 22.76 mmol, 95% yield) as a colorless oil. MS (DCI+) m/z 249.2 (M+NH4); 1H NMR (300 MHz, DMSO-d6) δ 7.15 (d, J=8.1, 1H), 3.83 (dd, J=8.0, 6.8, 1H), 3.62 (s, 3H), 2.06-1.91 (m, 1H), 1.38 (s, 9H), 0.86 (dd, J=6.8, 3.2, 6H).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][CH2:13][CH2:14]Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([Cl:16])[CH:8]=2)[N:3]=1.[SH-:18].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:17])[N:3]=[C:2]1[C:11]([CH2:12][CH2:13][CH2:14][S:18]1)=[N:10]2
Reactant: ClCCCc1nc2cc(Cl)c(Cl)cc2nc1Cl
Reactant: [SH-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc2nc3c(nc2cc1Cl)SCCC3
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
To a solution of 2,6,7-trichloro-3-(3-chloropropyl)quinoxaline (0.15 g, 0.48 mmol) in dry DMF (50 ml) were added sodium hydrosulfide (0.11 g, 1.44 mmol) and potassium carbonate (0.20 g, 1.45 mmol). The reaction mixture was stirred for 4 days at room temperature. The solvent was evaporated in vacuo, followed by the addition of water. The resulting mixture was extracted with dichloromethane (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield 6,7-dichloro-3,4-dihydro-2H-1-thia-9,10-diaza-anthracene (>100%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[S:10][C:3]=12.Br[C:25]1[CH:26]=[N:27][C:28](=[O:39])[N:29]([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:30]=1>C1(C)C=CC=CC=1.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>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:25]3[CH:26]=[N:27][C:28](=[O:39])[N:29]([CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)[CH:30]=3)[S:10][C:3]=12
Reactant: O=c1ncc(Br)cn1CCN1CCOCC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=c1ncc(-c2cc3nccc(Cl)c3s2)cn1CCN1CCOCC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 15.3 %

Procedure:
To a solution of the tributyltin derivative 6 (1.88 g, 4.1 mmol) (scheme 2) in toluene (39 mL) was added 5-bromo-1-(2-morpholinoethyl)pyrimidin-2(1H)-one (413, 1.29 g, 4.5 mmol) and Pd(PPh3)4 (474 mg, 0.41 mmol). The reaction mixture was stirred at 100° C. for 16 h. The mixture was filtered and the solvent was evaporated. The residue was triturated in hexanes, then triturated in EtOAc to produce title compound 414 (236 mg, 15% yield). MS (m/z): 377.0 (M+H). 1H NMR (DMSO-d6) δ (ppm): 9.18 (d, J=3.5 Hz, 1H), 8.76 (d, J=3.3 Hz, 1H), 8.64 (d, J=5.1 Hz, 1H), 8.05 (s, 1H), 7.57 (d, J=5.1 Hz, 1H), 4.06 (t, J=5.9 Hz, 2H), 3.54 (t, J=4.5 Hz, 4H), 2.64 (t, J=5.9 Hz, 2H), 2.49-2.43 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[Br:18].Cl[CH2:20][CH:21](OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Br:18][C:3]1[C:2]2[N:7]([CH:20]=[CH:21][N:1]=2)[N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:4]=1
Reactant: CCOC(CCl)OCC
Reactant: COC(=O)c1cccc(-c2cc(Br)c(N)nn2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: COC(=O)c1cccc(-c2cc(Br)c3nccn3n2)c1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
A solution of methyl 3-(6-amino-5-bromopyridazin-3-yl)benzoate (1 g, 3.25 mmol), 2-chloro-1,1-diethoxyethane (0.6 g, 3.9 mmol), PTSA (0.62 g, 3.9 mmol) in isopropanol (10 mL) was heated to 80° C. for 40 h. After cooling to room temperature, the solution was concentrated in vacuo. The resulting mixture was treated with a saturated NaHCO3 solution (50 mL), extracted with dichloromethane (50 mL×3), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give methyl 3-(8-bromoimidazo[1,2-b]pyridazin-6-yl)benzoate (0.6 g, 56%) as a white solid. LC-MS: [M+H]+, 332.0, 333.9, tR=1.520 min.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:7][S:8]([C:11]1[CH:12]=[N:13][C:14](Cl)=[C:15]([Br:17])[CH:16]=1)(=[O:10])=[O:9])([CH2:5][OH:6])[CH3:4].[CH3:19][O-:20].[Na+].Cl>CO>[OH:1][CH2:2][C:3]([NH:7][S:8]([C:11]1[CH:12]=[N:13][C:14]([O:20][CH3:19])=[C:15]([Br:17])[CH:16]=1)(=[O:10])=[O:9])([CH2:5][OH:6])[CH3:4]
Reactant: CC(CO)(CO)NS(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ncc(S(=O)(=O)NC(C)(CO)CO)cc1Br
Yield: 39.4 %

Procedure:
To a solution of 5-Bromo-6-chloro-pyridine-3-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (550 mg, 2 mmol) in MeOH (5 mL) was added a solution of sodium methoxide (c=5.4 mol/L in MeOH, 10 mmol) at rt for 48 h. The reaction mixture was poured into a 1N solution of HCl and was extracted with 2 portions of EtOAc, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (heptane/EtOAc, 1:1) to give the title compound (0.28 g, 51%) as a white solid. MS (ISN) 353.1 [(M−H)−], 355.1 [(M+2−H)−].
Reaction SMILES: OC[N:3]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[C:5]([C:18]2[N:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][CH:19]=2)=[CH:4]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:12]1([C:11]2[C:6]3[C:5]([C:18]4[N:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][CH:19]=4)=[CH:4][NH:3][C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: N#Cc1cccc(-c2cn(CO)c3ncnc(N4CCOCC4)c23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1cccc(-c2c[nH]c3ncnc(N4CCOCC4)c23)n1
Reaction time: 0.5 h

Procedure:
A solution of 6-[7-(hydroxymethyl)-4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]pyridine-2-carbonitrile (C11) (from the previous step, 85 mg, ≦0.25 mmol) in acetonitrile (3 mL) was brought to a pH of >12 via addition of solid potassium carbonate. After 30 minutes at room temperature, the reaction mixture was filtered and concentrated in vacuo. Purification via preparative HPLC (Column: Phenomenex Gemini C18, 8 μm; Mobile phase A: ammonia in water, pH 10; Mobile phase B: acetonitrile; Gradient: 10% to 50% B) afforded the product as a white solid. Yield: 15.2 mg, 49.6 μmol, 20% over two steps. LCMS m/z 307.2 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.13 (dd, J=8.1, 7.7 Hz, 1H), 7.96 (br d, J=8 Hz, 1H), 7.89 (br d, J=8 Hz, 1H), 7.86 (s, 1H), 3.50-3.55 (m, 4H), 3.19-3.24 (m, 4H).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)(=[O:22])[CH3:21].O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: CC(=O)c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)c1ccccc1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Yield: 85.5 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-acetylphenylboronic acid (150 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (190 mg, 85.6%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(=O)C.CCO>[CH:12](=[N:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(NN=Cc1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.5 g, 0.0033 mol) in abs. EtOH (10 mL) and benzaldehyde (0.35 g, 0.0033 mol) was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.68 g, in 86% yield, mp: 226.4° C. 1H NMR (CD3OD) δ 8.30 (s, 1H), 7.83 (d, 4H), 7.42 (d, 3H), 6.88 (d, 2H). 13C NMR (CDCl3) δ 167.5, 162.9, 149.8, 135.7, 131.4, 130.9, 129.8, 128.7, 124.9, 116.3. Anal. Calcd for C14H12N2O2: C, 69.99; H, 5.03; N, 11.66. Found: C, 69.82; H, 5.34; N, 11.60.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][C:4]#[CH:5].Br[C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([Cl:17])[CH:16]=1)[C:13](=[O:18])[N:12]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:11]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)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>[Cl:17][C:15]1[CH:16]=[C:8]([C:5]#[C:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH:9]=[C:10]2[C:14]=1[C:13](=[O:18])[N:12]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:11]2
Reactant: C#CCN(C)C
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C)CC#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
A mixture of dimethyl-prop-2-ynyl-amine (0.036 mL, 0.32 mmol), 5-bromo-7-chloro-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.120 g, 0.28 mmol), PdCl2(PPh3)2 (0.011 g, 0.015 mmol), and CuI (0.0028 g, 0.015 mmol) in diisopropyl amine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-chloro-5-(3-dimethylamino-prop-1-ynyl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.122 g, 79%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.36 (s, 6H), 3.44 (s, 2H), 4.21 (s, 2H), 4.77 (s, 2H), 7.14-7.36 (m, 5H), 7.43 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:25])[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O.C(Br)(Br)(Br)[Br:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:27][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:25]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCN(CCCCCO)C(=O)Nc1ccc(F)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCN(CCCCCBr)C(=O)Nc1ccc(F)cc1F
Reaction time: 3 h
Yield: 100 %

Procedure:
Part D. To a solution of N'-(2,4-difluorophenyl)-N-heptyl-N-5-hydroxypentylurea (15.0 g, 0.042 mol) and carbon tetrabromide (16.75 g, 0.051 mol) in methylene chloride (350 mL) under a nitrogen atmosphere at ambient temperature, a solution of triphenylphosphine (13.24 g, 0.051 mol) in methylene chloride (100 mL) was added slowly. The reaction mixture was stirred for 3 hours and was concentrated in vacuo to give crude viscous oil. The product was purified by flash chromatography on silica gel (400 mL) eluting with hexane:ethyl acetate (90:10 v:v) to give N-(5-bromopentyl)-N'-(2,4-difluorophenyl)-N-heptylurea as a viscous colorless oil (17.5 g, 0.042 mol). 1H NMR (CDCl3) δ 8.14-8.00(m, 1H), 6.92-6.79(m, 2H), 6.35(bs, 1H), 3.49-3.25(m, 6H), 1.99-1.26 (m, 16H), 0. 915 (t, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)[CH:2]=1.[H][H]>C(O)C.[C].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)[CH:2]=1
Reactant: CCOC(=O)/C=C/c1ccc(Oc2cccnc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Oc2cccnc2)cc1
Yield: 99 %

Procedure:
In 20 ml of ethanol was dissolved 2.0 g of ethyl (E)-3-[4-(pyridin-3-yloxy)phenyl]acrylate, and to the resulting solution was added 1.0 g of 5% palladium-carbon, after which the resulting mixture was stirred in a hydrogen atmosphere at room temperature for 5 hours. The reaction mixture was filtered and the filtrate thus obtained was concentrated under reduced pressure to obtain 2.0 g (yield 99%) of colorless, oily ethyl 3-[4-(pyridin-3-yloxy)phenyl]propionate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[N+:23]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O)([O-:25])=[O:24].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19](=[N:22][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N+:23]([O-:25])=[O:24])[CH2:20][CH:21]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2nccc(OC3=CCC(=NCc4ccccc4[N+](=O)[O-])C=C3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenyloxy)quinoline (500 mg, 1.6873 mmol) was dissolved in tetrahydrofuran (64 ml), and after adding 2-nitrobenzaldehyde (320 mg, 2.1091 mmol) and acetic acid (0.58 ml), sodium triacetoxyborohydride (720 mg, 3.3746 mmol) was further added and the mixture was stirred at room temperature for 11 hours and 30 minutes. Water and saturated saline were added, the mixture was extracted with ethyl acetate, washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with hexane-diethyl ether, filtered out, washed with hexane and dried by aspiration at room temperature to obtain the title compound (453 mg) as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[N:4][C:5](O)=[N:6][C:7]=1[CH3:8].O=P(Cl)(Cl)[Cl:13].N(C1C=CC=CC=1)(CC)CC>>[Cl:13][C:5]1[N:4]=[C:3]([CH3:10])[C:2]([Cl:1])=[C:7]([CH3:8])[N:6]=1
Reactant: Cc1nc(O)nc(C)c1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Cc1nc(Cl)nc(C)c1Cl
Temperature: 125 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To 5-chloro-4,6-dimethylpyrimidin-2-ol (992 mg, 6.26 mmol) was added POCl3 (2.22 mL, 23.77 mmol) followed by Et2NPh (0.75 mL, 4.69 mmol) dropwise. The mixture was heated at 125° C. for 2 h. At approximately 2 h the reaction became homogeneous and was checked by HPLC and it showed all starting material had been consumed. The mixture was allowed to cool to room temperature and was then added dropwise to ice. After the ice had melted there was a white solid in a pink liquid. The aqueous layer was extracted with DCM and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (Hex to 10% EtOAc/Hex) afforded the desired product as a white solid (915 mg, 83%). 1H NMR (500 MHz, CDCl3): 2.57 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[O:10][CH:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:12]2[O:16][CH:15]([N:17]3[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]3=[O:24])[CH:14]([O:25][C:26](=[O:28])[CH3:27])[CH:13]2[OH:29])=[CH:5][CH:4]=1.N1C=CN=C1.[Si:49](Cl)([C:62]([CH3:65])([CH3:64])[CH3:63])([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:10][CH:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:12]2[O:16][CH:15]([N:17]3[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]3=[O:24])[CH:14]([O:25][C:26](=[O:28])[CH3:27])[CH:13]2[O:29][Si:49]([C:62]([CH3:65])([CH3:64])[CH3:63])([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:41][CH:40]=1
Reactant: COc1ccc(C(OC(c2ccccc2)C2OC(n3ccc(=O)[nH]c3=O)C(OC(C)=O)C2O)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(OC(c2ccccc2)C2OC(n3ccc(=O)[nH]c3=O)C(OC(C)=O)C2O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
The preparation of tert-butyldiphenylsilyl ethers is a common, routine procedure (Protective Groups in Organic Synthesis, 3rd edition, 1999, pp. 141-144 and references therein, Greene, T. W. and Wuts, P. G. M., eds, Wiley-Interscience, New York). In general, a solution of one eq. of 7 and imidazole (3.5 eq.) in anhydrous N,N-dimethylformamide (DMF) is treated with tert-butyldiphenylsilyl chloride (1.2 eq.). After stirring at room temperature for several hours, the reaction mixture is poured into ethyl acetate and washed extensively with water and saturated brine solution. The resulting organic solution is dried over anhydrous sodium sulfate, filtered, evaporated, and purified by silica gel chromatography to give Compound 8.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:9]=1[C:10]([N:12]=[S:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:11].[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:41])[F:40])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1>ClCCl>[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=3[Cl:22])=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:40])[F:41])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 2 h
Yield: 67.2 %

Procedure:
To a suspension of potassium carbonate (1.42 g, 10 mmol, 1.50 equiv) and 2-amino-3,5-dichloro-N-(diethyl-λ4-sulfanylidene)benzamide (2.00 g, 6.83 mmol) in dichloromethane (10 mL) was added a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (2.77 g, 7.59 mmol, 1.10 equiv.) in dichloromethane (5 mL) at room temperature. After 2 h at this temperature, the solids were filtered off and water was added to the filtrate. The mixture was extracted with dichloromethane and dried over Na2SO4. After filtration, the filtrate was concentrated in vacuum and the resulting solids were crystallized from diethyl ether to yield the title compound (2.6 g, 67%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:5][C:6](=[O:15])[C:7]=1[CH:8]([CH2:12][CH2:13][CH3:14])[C:9]([OH:11])=[O:10].S(Cl)(Cl)=O.[CH3:26]O>>[CH3:1][C:2]1[N:3]=[C:4]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:5][C:6](=[O:15])[C:7]=1[CH:8]([CH2:12][CH2:13][CH3:14])[C:9]([O:11][CH3:26])=[O:10]
Reactant: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)[nH]c1=O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)[nH]c1=O

Procedure:
The 2-(4-methyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)pentanoic acid (17.16 g) was suspended in dry methanol (150 mL) and thionyl chloride (87 mL; 120 mmol) was added dropwise. The stirred reaction mixture was heated at reflux for 18 h. After cooling, the white precipitate was filtered off, washed with methanol and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate (25 mL) and heptane (50 mL) was added. The white precipitate was filtered and dried under reduced pressure. The filtrate was concentrated and the residue was precipitate another time with the same procedure to furnish 12.1 g (80% overall yield) of the title compound as a white powder. ESI/APCI(+): 301 (M+H); ESI/APCI(−): 299 (M−H).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:5]=[C:6]2[N:13]([CH3:14])[CH2:12][CH2:11][N:7]2[C:8](=[O:10])[N:9]=1.[OH:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[C:21]([CH:24]=1)[C:22]#[N:23].Cl>CN(C=O)C>[CH3:14][N:13]1[C:6]2[N:7]([C:8](=[O:10])[N:9]=[C:4]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=4)=[C:21]([CH:24]=3)[C:22]#[N:23])[CH:5]=2)[CH2:11][CH2:12]1
Reactant: N#Cc1cc(CO)ccc1Oc1cccc(C(F)(F)F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3cccc(C(F)(F)F)c3)c(C#N)c1)nc2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
NaH (28.8 mg, 60%, 0.72 mmol) was added to a solution of 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (44 mg, 0.24 mmol) and 5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile (71 mg, 0.242 mmol) in DMF (1.8 mL). The reaction mixture was stirred at rt for 30 min. Aqueous HCl solution was added to adjust pH to ˜7. Purification by Mass Directed AutoPrep (MDAP) afforded the title compound as a white solid (60 mg, 56% yield).