Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[C:2]([F:13])([F:14])[F:1])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reaction time: 10 h
Yield: 94.2 %

Procedure:
A mixture of 2-trifluoromethyl-4-nitrophenol (73.4 g, 0.354 mol), ethyl bromoacetate (65.2 g, 0.39 mol), potassium carbonate (58.7 g, 0.425 mol) and 2-butanone (400 mL) was refluxed under stirring for 10 h. The solid was filtered off, the filtrate was evaporated and the residue was fractionated yielding 97.8 g (95%) of 2-trifluromethyl-4-nitrophenoxyacetic acid ethyl ester, b.p. 126° C./40 Pa.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)C>CN(C=O)C>[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:2]=[CH:3]2)#[N:11]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)CCn1ccc2cc(C#N)ccc21
Temperature: 80 °C
Yield: 99.1 %

Procedure:
A mixture of 1H-indole-5-carbonitrile (1.42 g, 10 mmol), ethyl 3-bromopropanoate (1.92 ml, 15 mmol) and cesium carbonate (6.5 g, 20 mmol) in DMF (50 ml) was heated at 80° C. for 4 hours. Cooled the solution, added diethyl ether (300 ml) and washed with water (3×300 ml). Dried over MgSO4 and evaporated off the solvent to yield 2.4 g of pale orange oil. This crude product was used in the next stage (preparation of D52).
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[C:7]1[S:11][C:10]([CH:12]=[CH:13][CH2:14][CH:15]2[NH:21][C:20](=N)[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][CH:8]=1.BrC1SC(C2OCC[O:30]2)=CC=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[C:7]1[S:11][C:10]([CH:12]=[CH:13][CH2:14][CH:15]2[NH:21][C:20](=[O:30])[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][CH:8]=1
Reactant: N=C1CCCCC(CC=Cc2ccc(C3OCCO3)s2)N1
Reactant: Brc1ccc(C2OCCO2)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCCCC(CC=Cc2ccc(C3OCCO3)s2)N1

Procedure:
7-[3-[5-(1,3-dioxolan-2-yl)thien-2-yl)-2-propenyl]hexahydro-1H-azepin-2-imine, monohydrochloride ##STR199## 198 A) The Isomer B title material of Example 18 in acetonitrile is coupled to 2-(5-bromo-2-thienyl)dioxolane in the presence palladium acetate, tri-o-tolylphosphine, and triethylamine by the method of Example 32 to provide 7-[3-[5-(1,3-dioxolan-2-yl)thien-2-yl]-2-propenyl]hexahydro-1H-azepin-2-one as primarily the E isomer.
Reaction SMILES: N(C1C=C(NC(=O)NCC)N=CC=1C(O)=O)C1C=CC=CC=1.ClC1N=CC(N)=CN=1.[Cl:31][C:32]1[N:37]=[CH:36][C:35]([NH:38][C:39]([C:41]2[CH:42]=[N:43][C:44]([NH:54][C:55](=[O:59])[NH:56][CH2:57][CH3:58])=[CH:45][C:46]=2[NH:47][C:48]2[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=2)=[O:40])=[CH:34][N:33]=1.Cl.[CH3:61][C:62]1([C:68]([O:70][CH2:71][CH3:72])=[O:69])[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1.C(N(C(C)C)C(C)C)C>CS(C)=O>[Cl:31][C:32]1[N:33]=[CH:34][C:35]([NH:38][C:39]([C:41]2[CH:42]=[N:43][C:44]([NH:54][C:55](=[O:59])[NH:56][CH2:57][CH3:58])=[CH:45][C:46]=2[NH:47][C:48]2[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=2)=[O:40])=[CH:36][N:37]=1.[CH2:57]([NH:56][C:55]([NH:54][C:44]1[N:43]=[CH:42][C:41]([C:39]([NH:38][C:35]2[CH:34]=[N:33][C:32]([N:65]3[CH2:66][CH2:67][C:62]([CH3:61])([C:68]([O:70][CH2:71][CH3:72])=[O:69])[CH2:63][CH2:64]3)=[N:37][CH:36]=2)=[O:40])=[C:46]([NH:47][C:48]2[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=2)[CH:45]=1)=[O:59])[CH3:58]
Reactant: CCOC(=O)C1(C)CCNCC1
Agent: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)O)cn1
Agent: CCNC(=O)Nc1cc(Nc2cccnc2)c(C(=O)Nc2cnc(Cl)nc2)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCNC(=O)Nc1cc(Nc2cccnc2)c(C(=O)Nc2cnc(N3CCC(C)(C(=O)OCC)CC3)nc2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
N-(2-chloropyrimidin-5-yl)-6-(ethylcarbamoylamino)-4-(3-pyridylamino)pyridine-3-carboxamide (i) was prepared by coupling 4-anilino-6-(ethylcarbamoylamino)pyridine-3-carboxylic acid and 2-chloropyrimidin-5-amine. Compound (i) (30 mg, 73 woe, ethyl 4-methylpiperidine-4-carboxylate hydrochloride (23 mg, 0.11 mmol), N-ethyl-N-isopropyl-propan-2-amine (50 mmol, 0.29 mmol) and DMSO (2 mL) were combined and heated for 2 hr at 80° C. followed by 2 hr at 90° C. The reaction mixture was partitioned between EtOAc (50 mL) and saturated NH4Cl solution (50 mL). The organic layer was separated and further washed with saturated aqueous sodium hydrogen carbonate (50 mL) and brine (50 mL). The organic layer was separated and concentrated to give a crude oil. Flash chromatography on silica, eluting with 0-100% EtOAc gradient in n-heptane, gave crude product. Further flash chromatography (C18 column), eluting with 20-60% acetonitrile gradient in water (containing 0.1% formic acid), afforded Compound 136 (35 mg, 88%). 1H NMR (400 MHz, Acetone) δ 10.24 (s, 1H), 9.56 (s, 1H), 8.74-8.68 (m, 3H), 8.62 (d, J=2.6 Hz, 1H), 8.57 (s, 1H), 8.44 (s, 1H), 8.41 (dd, J=4.7, 1.3 Hz, 1H), 7.79 (ddd, J=8.4, 2.5, 1.5 Hz, 1H), 7.45 (dd, J=8.2, 4.7 Hz, 1H), 7.07 (d, J=4.4 Hz, 1H), 4.36 (dt, J=13.9, 4.4 Hz, 2H), 4.21 (q, J=7.1 Hz, 2H), 3.34-3.26 (m, 4H), 2.16 (s, 2H), 1.51-1.43 (m, 2H), 1.29 (dd, J=9.4, 4.8 Hz, 3H), 1.25 (s, 3H), 1.17 (t, J=7.2 Hz, 3H), [M+H]+ m/z=548.29.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6]3[C:7](=[CH:12][CH:13]=[CH:14][C:5]=3[C:4](=[O:15])[N:3]1[CH2:16][C:17]([OH:19])=[O:18])[CH:8]=[CH:9][CH:10]=2.O.[C:21]1(C)C=CC(S(O)(=O)=O)=C[CH:22]=1.C(O)C>C1(C)C=CC=CC=1>[CH2:21]([O:18][C:17](=[O:19])[CH2:16][N:3]1[C:4](=[O:15])[C:5]2[CH:14]=[CH:13][CH:12]=[C:7]3[C:6]=2[C:11](=[CH:10][CH:9]=[CH:8]3)[C:2]1=[O:1])[CH3:22]
Reactant: O=C(O)CN1C(=O)c2cccc3cccc(c23)C1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CN1C(=O)c2cccc3cccc(c23)C1=O
Temperature: 25 °C

Procedure:
A mechanically-stirred mixture of 1,3-dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid (125.0 g, 0.49 mole), p-toluenesulfonic acid hydrate (9.3 g, 0.049 mole), anhydrous pure ethanol (226 g, 288 ml, 0.49 mole) and dry toluene (750 ml) was heated at reflux for 16 hr in a Soxhlet apparatus in which the thimble was filled with hydrated alkali-aluminium silicate (3 A Molecular Sieves). The title compound was crystallized from the reaction mixture after cooling to room temperature. The crystals were collected and a second crop of crystals were obtained from the mother liquors. Recrystallization of the two crops of crystals from ethyl acetate gave the title compound; mp 160°-162° C.; UV (MeOH) 232, 332 and 341 nm, ε=48,613, 13,470 and 12,920, respectively; IR (CHCl3) 1745, 1705 and 1665 cm-1 ; Anal. Calc'd.: C, 67.84%; H, 4.63%; N, 4.94%; Found: C, 67.89%; H, 4.60 %; N, 4.87%.
Reaction SMILES: [N:1]1[C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[C:11]([O:13][CH3:14])=[O:12].[OH-].[K+]>CO>[CH3:14][O:13][C:11]([C:2]1[N:1]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: COC(=O)c1cccc(C(=O)OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cccc(C(=O)O)n1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
Dimethyl 2,6-pyridinedicarboxylate (11.7 g, 59.9 mmol) was dissolved in methanol (300 mL). The solution was cooled in an ice bath while stirring under argon some starting material came back out of solution. Potassium hydroxide (3.52 g, 62.7 mmol) pellets were added and the mixture and it was stirred in an ice bath for 2 h. The mixture was then allowed to gradually warm to room temperature and stirred for 20 h. The solvent was removed under reduced pressure, and the pinkish residue was suspended in ethyl acetate (250 mL). The mixture stirred for 15 minutes and then the potassium salt was collected by filtration and washed with 2×25 mL of ethyl acetate. The solid was dissolved in water (200 mL). The solution was acidified to pH-3 with concentrated hydrochloric acid and extracted with chloroform (4×80 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, evaporated, and dried under vacuum to give the 6-[(methyloxy)carbonyl]-2-pyridinecarboxylic acid (6.71 g, 36.2 mmol, 60.4% yield) as a white solid. LC-MS m/z 182 (M+H)+, 0.75 min (ret time).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].C(N(CC)CC)C.[C:16](=S)=[S:17].ClC(OCC)=O.[OH-].[Na+]>ClCCCl.O>[N:8]([CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[C:16]=[S:17]
Reactant: S=C=S
Reactant: NCCc1cccs1
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: S=C=NCCc1cccs1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Thiopene ethylamine (4.60 mL, 39.31 mmol) and triethyl amine (5.00 mL, 39.31 mmol) were dissolved in 1,2-dichloroethane (25 mL), and the resulting mixture was cooled to 0° C. A solution of carbon disulfide (2.36 mL, 39.31 mmol) in 1,2-dichloroethane (50 mL) was added dropwise thereto over 15 min. The reaction mixture was allowed to warm to room temperature and re-cooled to 0° C., to which ethyl chloroformate (4.27 mL, 31.39 mmol) was added dropwise. The reaction mixture was stirred at room temperature for about 1-2 h, and water (150 mL) and aqueous 2N sodium hydroxide (75 mL) were sequentially added thereto. The resulting mixture was extracted with dichloromethane. The extract was washed with water and brine, dried over sodium sulfate, and concentrated, to obtain the yellow title compound in a liquid form (5.37 g, 80.75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][N:12]=[C:13]3[C:17]=2[NH:16][CH:15]=[C:14]3[C:18](=[O:22])[C:19]([O-])=[O:20])=[CH:5][CH:4]=1.[K+].[C:24]([N:32]1[CH2:37][CH2:36][NH:35][CH:34]([CH3:38])[CH2:33]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([N:32]1[CH2:37][CH2:36][N:35]([C:19](=[O:20])[C:18]([C:14]2[C:13]3[C:17](=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[CH:10]=[CH:11][N:12]=3)[NH:16][CH:15]=2)=[O:22])[C@H:34]([CH3:38])[CH2:33]1)(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(-c2ccnc3c(C(=O)C(=O)[O-])c[nH]c23)cc1
Reactant: CC1CN(C(=O)c2ccccc2)CCN1
Agent: [K+]
Product: COc1ccc(-c2ccnc3c(C(=O)C(=O)N4CCN(C(=O)c5ccccc5)C[C@H]4C)c[nH]c23)cc1

Procedure:
Example 67, 1-benzoyl-3-(R)-methyl-4-[(7-(4-methoxyphenyl)-4-azaindol-3-yl)oxoacetyl]piperazine was prepared from potassium 7-(4-methoxyphenyl)-4-azaindole-3-glyoxylate and the corresponding 1-benzoyl-3-methylpiperazine according to the above general procedure. MS m/z: (M+H)+ Calc'd for C28H27N4O4: 483.20; found 483.16. HPLC retention time: 1.28 minutes (column A).
Reaction SMILES: [NH2:1][C:2]1([C:10]([CH3:11])=[CH:9][C:8](Br)=[CH:7][CH:6]1[N+:13]([O-])=O)[C:3]([OH:5])=[O:4]>CO.[Pd]>[NH2:1][C:2]1([C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][CH:6]1[NH2:13])[C:3]([OH:5])=[O:4]
Reactant: CC1=CC(Br)=CC([N+](=O)[O-])C1(N)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC1=CC=CC(N)C1(N)C(=O)O
Reaction time: 48 h
Yield: 69 %

Procedure:
A suspension of 1-amino-4-bromo-6-methyl-2-nitrobenzoic acid (16 g) and Pd/C (3.2 g) in methanol (400 ml) was stirred under hydrogen (1 bar) for 48 h and filtered through Celite under nitrogen atmosphere. Evaporation of methanol and purification by chromatography (hexane/ethyl acetate 40:60) gave 1,2-diamino-6-methylbenzoic acid (6.7 g) as a brown solid (6.7 g). 1H-NMR (400 MHz, CDCl3): 12.09 (bs, 1H), 6.73 (d, 1H), 6.13 (d, 1H), 1.98 (s, 3H). LCMS: m/z=167.11 (M+H)
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][CH:5]([CH2:7][C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4](=[O:18])[O:3]1.C(B(CC)CC)C.[BH4-].[Na+].Cl>C1COCC1>[CH3:1][C:2]1([CH3:19])[O:6][CH:5]([CH2:7][CH:8]([OH:17])[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[C:4](=[O:18])[O:3]1
Reactant: CC(C)(C)OC(=O)CC(=O)CC1OC(C)(C)OC1=O
Agent: CCB(CC)CC
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(O)CC1OC(C)(C)OC1=O
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 55.4 %

Procedure:
To a solution of tert.-butyl 4-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)-3-oxobutanoate (10.88 g, 40.0 mmol) in THF (20 ml), a mixture of THF (96.0 ml) and triethylborane 1M in THF) (56.0 ml) was was added at -78° C. over 45 minutes, followed by stirring at -78° C. for 50 minutes. Thereafter, to the resulting mixture, sodium borohydride (1.51 g, 40.0 mmol) was added in one portion and stirred at -78° C. for 4 hours. After adding 1N hydrochloric acid at 0° C., the mixture was extracted with ethyl acetate and washed with saturated saline. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=2:1) to give pure tert.-butyl 4-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)-3-hydroxybutanoate (6.08 g, 22.16 mmol). Yield, 55%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[OH:13].Br[C:15]#[N:16].[OH-].[Na+]>O>[NH2:16][C:15]1[O:13][C:3]2[CH:4]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CC(C(=O)O)c1ccc(N)c(O)c1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc2nc(N)oc2c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a stirred solution of 2-(4-Amino-3-hydroxy-phenyl)-propionic acid (1.02 g) in H2O was added BrCN (648 mg) at room temperature. After stirred for 40 h at room temperature, the reaction mixture was neutralized with 30% aq. NaOH to pH 6˜7 and then stirred for 1 hour. The solid was filtered, washed with water and dried under reduced vacuum to afford the product as yellow solid. (760 mg, 65.5%)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[SH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][NH3+:38].N1C=CC=CC=1S[S:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][OH:67]>CO>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[OH:67][CH2:66][CH2:65][O:64][CH2:63][CH2:62][O:61][CH2:60][CH2:59][O:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][S:46][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][NH3+:38]
Reactant: OCCOCCOCCOCCCCCCCCCCCSSc1ccccn1
Reactant: [NH3+]CCOCCOCCOCCOCCOCCOCCCCCCCCCCCS
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Product: [NH3+]CCOCCOCCOCCOCCOCCOCCCCCCCCCCCSSCCCCCCCCCCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 33 h

Procedure:
To a solution of 7 (120 mg, 0.2 mmol) in 5 mL of MeOH was added 9 (101 mg, 0.22 mmol). The solution was stirred at room temperature for 33 hours. After concentration, the reaction mixture was purified by flash chromatography (gradient: CH2Cl2/MeOH, 20:1 to 10:1 to 5:1, v/v) to afford 137 mg of impure 8. 1H NMR 400 MHz (CD3OD) d 3.85 (t, J=4.8 Hz, 2 H), 3.76-3.52 (m, 32 H), 3.42 (m, 4 H), 3.14 (t, J=4.8 Hz, 2 H), 2.65 (t, J=7.4 Hz, 4 H), 1.67 (m, 2 H), 1.55 (m, 2 H), 1.40-1.18 (br m, 32 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Br:23][C:24]1[CH:29]=[CH:28][C:27](I)=[C:26]([O:31][CH3:32])[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:27]2[CH:28]=[CH:29][C:24]([Br:23])=[CH:25][C:26]=2[O:31][CH3:32])=[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Reactant: COc1cc(Br)ccc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1ccc(Br)cc1OC
Temperature: 120 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A RBF was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (2.39 g, 7.63 mmol, made via Method 42, Steps 1-2), 4-bromo-1-iodo-2-methoxybenzene (2.86 g, 9.15 mmol), Xantphos (0.221 g, 0.381 mmol), Pd2(dba)3 (0.175 g, 0.191 mmol), and cesium carbonate (4.97 g, 15.25 mmol) were added. A reflux condenser was attached and the flask was lowered into a 110° C. heating bath. After 2 h, an additional portion of cesium carbonate (1.4 g) was added, and the bath temperature was raised to 120° C. The mixture was heated for another 2 h then cooled to room temperature, diluted with EtOAc, and filtered through celite with the aid of EtOAc. The filtrate was concentrated. The oily residue was taken up in 2-PrOH. The mixture was concentrated to give a yellow solid with some oily solid present. The mixture was taken up in 2-PrOH to give a suspension, and the suspension was stirred for 16 hrs. The mixture was filtered, and the filtered solid was washed with 2-PrOH (3×). The collected solid was dried on the filter under a flow of N2 (g) for 15 min to give (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)phenyl)acrylate (3.136 g, 6.29 mmol, 83% yield) as a bright-yellow solid. 1 H NMR (400 MHz, DMSO-d6) □=7.72 (d, J=16.0 Hz, 1H), 7.68 (d, J=2.2 Hz, 1 H), 7.47 (s, 1 H), 7.37-7.19 (m, 6 H), 7.13 (d, J=2.2 Hz, 1 H), 6.94 (dd, J=2.2, 8.4 Hz, 1 H), 6.86 (d, J=8.5 Hz, 1 H), 6.55 (s, 1 H), 6.52 (d, J=7.7 Hz, 1H), 4.24 (s, 2 H), 4.15 (q, J=7.1 Hz, 2 H), 3.82 (s, 3 H), 1.23 (t, J=7.1 Hz, 3 H). m/z (ESI) 498.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=O)[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[NH:21]([C:23]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[S:24])[NH2:22].CN(C)C=O>Cl.O>[OH:1][C:2]1[C:3]([C:18](=[N:22][NH:21][C:23]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)=[S:24])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1
Reactant: CC(=O)c1nn(C)c(-c2cccc(C(F)(F)F)c2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2cccc(C(F)(F)F)c2)c1O
Yield: 68.3 %

Procedure:
1-[4-Hydroxy-1-methyl-5-(3-trifluoromethylphenyl)-1H-pyrazol-3-yl]ethanone (0.229 mmol, 65.0 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.229 mmol, 48.3 mg) were stirred with dimethylformamide (2.5 mL) and three drops of concentrated hydrochloric acid at room temperature for 24 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. Chloroform/n-hexane was added to the resulting solid, and is the precipitated solid was recovered by filtration and dried by means of a vacuum pump to give the desired product as a yellow solid (74.7 mg, yield 68%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10](O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10]([Cl:25])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccc(Cl)cc2)c(O)nn1Cc1ccccc1
Product: O=c1cc(-c2ccc(Cl)cc2)c(Cl)nn1Cc1ccccc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A suspension of 2-benzyl-5-(4-chlorophenyl)-6-hydroxypyridazin-3(2H)-one (8.5 g, 27.2 mmol) in phosphorus oxychloride (50 mL) was stirred at 95° C. for 1 h. Analysis by HPLC/MS indicated the starting material had been consumed. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with EtOAc. The resulting EtOAc solution was washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (330 g) eluting with a gradient of EtOAc (0-40%) in hexanes to afford 6.2 g (69%) of the title compound as a white solid. HPLC/MS (method A): retention time=3.80 min, (M+H)+=331.0. 1H NMR (CDCl3, 400 MHz): δ 7.27-7.80 (m, 9H), 6.88 (s, 1H), 5.36 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(OC(C)(C)C)=O)=[C:13]([F:25])[CH:12]=3)[C:3]=12.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)[N:9]=2)=[CH:12][C:13]=1[F:25]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2nn(C3CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Nc1ccc(-c2nn(C3CCNCC3)c3ncnc(N)c23)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
A mixture of tert-butyl 4-(4-amino-3-{4-[(tert-butoxycarbonyl)amino]-3-fluorophenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (6.26 g, 11.9 mmol), 5M HCl (95 mL) and acetone (390 mL) was stirred at ambient temperature for 16 h. The reaction was basified with sodium carbonate and concentrated under reduced pressure. The residues were partitioned between CH2Cl2 (200 mL) and water (200 mL) and the aqueous phase was extracted with additional CH2Cl2 (2×200 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness to afford 3-(4-amino-3-fluorophenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.427 g, 88%); 1H NMR (DMSO-d6, 400 MHz) δ 1.85 (2H, br t), 2.06 (2H, m), 2.65 (2H, m), 3.10 (2H, m), 4.72 (1H, m), 5.45 (2H, br s), 6.89 (1H, m), 7.22 (2H, m) and 8.19 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[N:10](S(=O)(=O)N(C)C)[CH:11]=[CH:12][N:13]=2)[N:3]=1.C([O-])(O)=O.[Na+]>Cl>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[NH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: CN(C)S(=O)(=O)n1ccnc1-c1cc(Cl)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1cc(-c2ncc[nH]2)nc(Cl)n1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
A solution of 2,4-Dichloro-6-(1-dimethylsulfamoylimidazole-2-yl)pyrimidine 83 (246 mg, 0.76 mmol) in 10 mL of 1.5 N HCl was refluxed for 1 h. After cooling to RT, the pH was adjusted to 8.5 with aq NaHCO3 and the product was extracted into CH2Cl2. After drying the CH2Cl2 layer was evaporated to give 110 mg of 2,4-dichloro-6-(imidazole-2-yl)pyrimidine. A mixture of 2,4-dichloro-6-(imidazole-2-yl)pyrimidine (121 mg, 0.56 mmol), K2CO3 (100 mg, 0.72 mmol) and CH3I (2.280 g, 1 mL, 16 mmol) in 15 mL of dry acetone was refluxed for 48 h. After cooling to RT, the solvent was evaporated and the residue was partitioned between water and CH2Cl2. The CH2Cl2 layer was washed successively with water and brine, and then the solvent was evaporated to give 75 mg of 2,4-dichloro-6-(1-methylimidazole-2-yl)pyrimidine 86.