Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[N:26]3[C@@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>CN(C=O)C>[CH2:20]1[C@H:21]2[N:26]([CH2:25][CH2:24][CH2:23][CH2:22]2)[C@H:18]([C:15]2[CH:14]=[CH:13][C:12]([S:8][C:4]3[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=3)=[CH:17][CH:16]=2)[CH2:19]1
Reactant: Brc1ccc([C@@H]2CC[C@@H]3CCCCN32)cc1
Reactant: Nc1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cccc(Sc2ccc([C@@H]3CC[C@@H]4CCCCN43)cc2)c1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
A solution of 2 g (0.016 mole) of 3-aminothiophenol in 25 mL of dry DMF was added to 0.016 mole of sodium hydride (from 0.77 g of 50% sodium hydride washed with hexane to remove the oil). After all the sodium hydride has reacted, a solution of 2.8 g (0.01 mole) of trans-3-(4-bromophenyl)octahydroindolizine in 20 ml of dry DMF and 0.72 g (0.005 mole) of cuprous oxide were added. The mixture was refluxed overnight. Then an additional 0.35 g (0.002 mole) of cuprous oxide was added to the reaction mixture, and the mixture was refluxed for two days. The reaction was the cooled to room temperature, filtered and the DMF evaporated in vacuo to give a brown oil. The oil was flash chromatographed in SiO2 using 75% hexane, 25% EtOAc as the eluant. The product bearing fractions were pooled and the solvent evacuated in vacuo to give 1.5 g (46% yield) of the title compound as a red oil.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:16][C:17]([C:19]2[NH:20][N:21]=[N:22][CH:23]=2)=[O:18])[CH2:9][C@@H:10]([CH2:14][OH:15])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.Cl.[CH3:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37]O>O1CCOCC1>[CH3:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:12][C:11](=[O:13])[C@H:10]([CH2:14][OH:15])[CH2:9][C@H:8]([NH:16][C:17]([C:19]1[NH:20][N:21]=[N:22][CH:23]=1)=[O:18])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:2][CH:3]=1
Reactant: COCCOCCO
Reactant: O=C(N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](CO)C(=O)O)c1cnn[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: COCCOCCOC(=O)[C@H](CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 60 °C

Procedure:
(2S,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid (20 mg, 39 μmol, 1.0 eq.) was dissolved in 2-(2-methoxyethoxy)-ethanol, (3 mL) followed by the addition of 4 M of HCl in dioxane (295.0 μL). The mixture was heated and maintained at 60° C. for 4 hours. The mixture was concentrated and purified by preparative HPLC to yield the title compound (13 mg; purity 95%). MS m/z [M+H]+ calc'd for C26H32N4O6, 497.23. found 497.6.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[C:14]([O:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][C:25](Br)=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:25]2[CH:24]=[C:23]3[C:28]([CH2:29][CH2:30][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22]3)=[CH:27][CH:26]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Br)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2C1
Yield: 92.7 %

Procedure:
A mixture 4-(trifluoromethyl)phenylboronic acid (987 mgs, 5.2 mmol), 7-Bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.2 g, 4.0 mmol), potassium carbonate (1.1 g, 8.0 mmol), PdCl2(dppf) (146 mgs, 0.2 mmol) in toluene/ethanol/water (3 mL/1.5 mL/1.5 mL) was heated in pressure vessel at 120° C. for 2 h. The mixture was then concentrated and chromatographed (40 grams of SiO2, 30% EtOAc/hexanes) to provide the title compound (1.4 g, 92% yield over two steps).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:11][CH2:10]1)(C)(C)C.C1(C)C=CC=CC=1>O1CCOCC1>[ClH:1].[CH3:17][N:16]([CH3:18])[C:15]([CH:12]1[CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10][CH2:11]1)=[O:19]
Reactant: CN(C)C(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CN(C)C(=O)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
HCl (concentrated, 7 mL) was added to a solution of (4-dimethylcarbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (1.5 g) in 1,4-dioxane (20 mL), and the resulting mixture was stirred at RT for 5 h. Toluene was added and the reaction mixture was evaporated under reduced pressure. The oily residue was triturated with EtOAc to give 4-amino-cyclohexanecarboxylic acid dimethylamide hydrochloride salt (0.9 g).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([NH2:14])[N:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.[N+:17]([C:20]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:21]=1[C:22](O)=[O:23])([O-:19])=[O:18].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[N+:17]([C:20]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:21]=1[C:22]([NH:14][C:12]1[N:11]=[CH:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH:13]=1)=[O:23])([O-:19])=[O:18]
Reactant: Nc1cn(-c2cccc(C(F)(F)F)c2)cn1
Reactant: O=C(O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cn(-c2cccc(C(F)(F)F)c2)cn1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 28 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 1-(3-(trifluoromethyl)phenyl)-1H-imidazol-4-amine (1.2 g, 4.49 mmol, 1.00 equiv, 85%) in dichloromethane (30 mL), 2-nitro-5-(piperidin-1-yl)benzoic acid (1.32 g, 5.07 mmol, 1.00 equiv, 96%), EDC.HCl (2 g, 10.42 mmol, 2.00 equiv), and 4-dimethylaminopyridine (1.29 g, 10.57 mmol, 2.00 equiv). The resulting solution was stirred overnight at 28° C. The resulting solution was diluted with 200 mL of dichloromethane. The resulting mixture was washed with 1×30 mL of 10% sodium bicarbonate and 1×30 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1) to give 600 mg (22%) of product as brown oil.
Reaction SMILES: C(OC([O:6][C@@H:7]1[C@@:37]2([CH3:38])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:32])[CH2:20][CH2:21][CH2:22][C:23]([O:26]C(OCC)C)([CH3:25])[CH3:24])[CH2:10][C@@H:9]([O:40]C(OCC)C)[CH2:8]1)C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[OH:6][C@@H:7]1[C@@:37]2([CH3:38])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:32])[CH2:20][CH2:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[CH2:10][C@@H:9]([OH:40])[CH2:8]1
Reactant: CCOC(C)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)(C)OC(C)OCC)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)OCC)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.2 %

Procedure:
A solution of 36.2 g of 1α,3β,25-tris(1-ethoxyethoxy)-cholest-5-ene in 0.75 liters of methanol was treated with 5.6 g (29 mmol) of p-toluenesulphonic acid monohydrate, and the mixture was stirred at room temperature for 45 minutes. 1.8 liters of water was dropped into the solution. The suspension was suction filtered, and the residue was washed neutral with water and dried. There was obtained 21.3 g of 1α,3β,25-trihydroxycholest-5-ene which melted at 172°-175° C. after recrystallization from acetone.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:28]([O:30]C)=[O:29])=[CH:4][N:3]=1.NC1C2C(C3C=CC(NC(NC4C=CC=C(F)C=4)=O)=CC=3)=CSC=2C(I)=CN=1.[C]=O.[OH-].[Li+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.C(N(CC)CC)C>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:15][CH:16]=3)=[CH:9][S:10][C:6]=2[C:5]([C:28]([OH:30])=[O:29])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(N)c2c(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)csc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Nc1ncc(I)c2scc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ncc(C(=O)O)c2scc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12

Procedure:
As shown in the Scheme above, 1-(4-(4-aminothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea ((1), prepared as described in WO2005/10009), in a mixture of pyridine and tetrahydrofuran can be treated with iodine at room temperature, followed by treatment with potassium hydroxide at elevated temperature to provide 1-(4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (2). Methyl 4-amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylate (3) can be prepared by reacting 1-(4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (2) with carbon monoxide gas in the presence of a catalyst such as but not limited to [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane, and a base such as but not limited to triethylamine. The reaction is typically performed under pressure and at an elevated temperature. Methyl 4-amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylate (3) can be reacted with aqueous lithium hydroxide to provide 4-amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylic acid (4). The reaction is typically performed at elevated temperature in a solvent such as but not limited to tetrahydrofuran and methanol. 4-Amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylic acid (4) can be reacted with N,N-diethyl-1,3-propanediamine in the presence of a coupling agent such as but not limited to 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, an auxiliary coupling reagent such as but not limited to 1-hydroxybenzotriazole hydrate, and a base such as but not limited to N-methylmorpholine to provide 4-amino-N-[3-(diethylamino)propyl]-3-(4-{[(3-fluorophenyl)carbamoyl]amino}phenyl)thieno[3,2-c]pyridine-7-carboxamide (5). The reaction is typically performed in a solvent such as but limited to N,N-dimethylformamide.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34]>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][N:27]4[C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CCCN1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CCCN1C(=O)C(C)C
Yield: 64.1 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 19, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-pyrrolidin-2-ylmethoxy]quinazoline (160 mg, 0.38 mmol), (prepared as described for the starting material in Example 13), was reacted with isobutyryl chloride (48 μl, 0.45 mmol). The product was purified by column chromatography, eluting with methanol/methylene chloride (2/98) to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]7-{[(2R)-1-isobutyrylpyrrolidin-2-yl]methoxy}-6-methoxyquinazoline (120 mg, 64%).
Reaction SMILES: [NH2:1][CH:2]([C:5]([N:7]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:9]([O:18][C@@H:19]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH3:20])[CH2:8]1)=[O:6])[CH2:3][OH:4].C(N(CC)CC)C.[C:42](Cl)(Cl)=[O:43]>C(Cl)Cl.C1(C)C=CC=CC=1>[F:33][C:31]([F:34])([F:32])[C:23]1[CH:22]=[C:21]([C@H:19]([O:18][C@@H:9]2[C@@H:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:11][N:7]([C:5]([CH:2]3[CH2:3][O:4][C:42](=[O:43])[NH:1]3)=[O:6])[CH2:8]2)[CH3:20])[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=1
Reactant: C[C@@H](O[C@H]1CN(C(=O)C(N)CO)C[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O[C@H]1CN(C(=O)C2COC(=O)N2)C[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 15 mg (0.03 mmol) 2-amino-3-[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-phenylpyrrolidin-1-yl]-3-oxopropan-1-ol (Example 5) in 3 mL methylene chloride was added 0.011 mL (0.08 mmol) triethylamine. The resulting mixture was cooled to 0° C. and 0.015 mL (0.03 mmol) of a 2M solution of phosgene in toluene was added by syringe. The reaction mixture was stirred at RT for 8 hr and the volatiles were removed under vacuum. The dark yellow residue was purified by prep TLC eluting with methylene chloride/methanol (95/5) to afford the title compound. 1H-NMR (CDCl3) rotamers: δ: 1.43 (d, 3H, 6.5 Hz), 3.30-4.13 (m, 7H), 4.40-4.70 (m, 3H), 7.00-7.10 (m, 2H), 7.20-7.30 (m, 3H), 7.55 (s, 2H), 7.60 (s, 1H), 7.75, 7.77 (2s, 1H)ppm. MS: 517.0 (MH+) observed.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH2:11][C:10](=[O:14])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[C:8]2=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:26]([CH:29](CCCC)[C:30]([O:32]CC)=[O:31])=[C:27]=[O:28].C1(N)CCCCC1.C(Cl)(=O)CC(Cl)=O>ClCCl>[C:30]([CH2:29][NH:26][C:27]([C:11]1[C:12](=[O:13])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8](=[O:25])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:10]=1[OH:14])=[O:28])([OH:32])=[O:31]
Reactant: CCCCC(N=C=O)C(=O)OCC
Reactant: CCOC(=O)CCCCCN1C(=O)CC(=O)N(C2CCCCC2)C1=O
Agent: O=C(Cl)CC(=O)Cl
Solvent: NC1CCCCC1
Solvent: ClCCl
Product: O=C(O)CCCCCn1c(O)c(C(=O)NCC(=O)O)c(=O)n(C2CCCCC2)c1=O
Yield: 71 %

Procedure:
Ethyl 6-(3-cyclohexyl-2,4,6-trioxotetrahydro-1(2H)-pyrimidinyl)hexanoate. Ethyl isocyanatohexanoate (790 mg, 4.26 mmoles) and cyclohexylamine (490 uL, 4.26 mmoles) were stirred together in dichloromethane (100 mL) for 2 hours. Malonyl dichloride (414 uL, 4.26 mmoles) was added and the mixture was heated under gentle reflux for 2 hours. The mixture was purified by flash chromatography (dichloromethane to 5% methanol in dichloromethane) to give the title compound (1.07 g, 71%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.56-4.67 (m, 1 H), 4.62 (tt, J=12.25, 3.79 Hz, 1 H), 4.13 (q, J=7.24 Hz, 2 H), 3.85 (t, 2 H), 2.31 (t, 2 H), 2.26 (dq, 2 H), 1.85 (d, J=13.39 Hz, 2 H), 1.57-1.73 (m, 7 H), 1.29-1.43 (m, 4 H), 1.26 (t, J=7.07 Hz, 3 H), 1.06-1.24 (m, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[F:21][CH:22]([F:32])[O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH:22]([F:21])[F:32])[CH:25]=1)[CH3:2]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: FC(F)Oc1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: [Br-]
Product: CCOC(=O)C(Cc1cccc(OC(F)F)c1)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
N-(Diphenylmethylene)Glycine ethyl ester (500 mg, 1.87 mmol), Tetrabuylammonium Bromide (63 mg, 0.187 mmol) and 3-(Difluoromethoxy)benzyl bromide (0.5 mL, 1.87 mmol) were placed in a flask. The flask was evacuated and backfilled with argon. Anhyd dichloromethane was added to the flask, and the reaction was cooled in dry-ice acetone bath to −78° C. 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (0.7 mL, 2.44 mmol) was added slowly under argon at −78° C. The reaction was allowed to stir at −78° C. for 30 minutes, and then warmed to room temperature over 16 h. The solvent was removed under vacuum. The residue was pre-adsorbed on to SiO2 and the product was isolated via SiO2 to yield 700 mg of light yellow oil. MS 424.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[O:15][C:14]3[C:13](SC)=[N:12][CH:11]=[N:10][C:9]=3[CH:8]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[CH:3]1.O.[NH3:25]>[Cl-].[NH4+].O1CCOCC1>[CH3:1][N:2]1[C:6]([C:7]2[O:15][C:14]3[C:13]([NH2:25])=[N:12][CH:11]=[N:10][C:9]=3[CH:8]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[CH:3]1
Reactant: N
Reactant: CSc1ncnc2cc(-c3c(-c4ccccc4)ncn3C)oc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cnc(-c2ccccc2)c1-c1cc2ncnc(N)c2o1
Temperature: 170 °C
Yield: 84 %

Procedure:
A mixture of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)furo[3,2-d]pyrimidine (Intermediate 87) (50 mg) and saturated aqueous ammonium chloride solution (2 drops) in concentrated aqueous NH3 (1 mL) and 1,4-dioxane (2 mL) was heated under microwave conditions (CEM explorer, 170° C., 150 minutes). Water (10 mL) was added, and the mixture extracted into EtOAc (2×20 mL). The combined organic phases were dried and concentrated in vacuo. Purification by flash chromatography on silica (0-5% MeOH in EtOAc) afforded the title compound as an off-white solid (38 mg, 84%);
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[N:11]2[CH:12]=[CH:13][C:14]([C:16]([CH3:26])([O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:17])=[N:15][C:10]2=[N:9][CH:8]=1.C([Sn](Cl)(CCCC)CCCC)CCC.Cl[C:42]1[CH:47]=[CH:46][N:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[N:43]=1>C1COCC1.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>[CH3:17][C:16]([C:14]1[CH:13]=[CH:12][N:11]2[C:7]([C:42]3[CH:47]=[CH:46][N:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[N:43]=3)=[CH:8][N:9]=[C:10]2[N:15]=1)([O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:26]
Reactant: FC(F)(F)c1nccc(Cl)n1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(Br)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(C(F)(F)F)n3)cnc2n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
A solution of isopropylmagnesium chloride (2.0M in THF, 525 μl, 1.05 mmol) was added dropwise to a stirred suspension of 3-bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (370 mg, 1.0 mmol) in THF (5 ml) at −78° C. under N2. The resulting solution was stirred at −78° C. for 15 min and then tributyltin chloride (298 μl, 1.1 mmol) was added. The reaction was warmed to 0° C. and stirred for 1 h. 4-Chloro-2-trifluoromethylpyrimidine (200 mg, 1.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (110 mg, 10 mol %) were added and the reaction heated at reflux for 18 h. The mixture was concentrated under reduced pressure while dry loading onto silica and then purified by column chromatography on silica using 50-80% EtOAc/isohexanes as the eluent to afford 7-(1-methyl-1-triethylsilanyloxyethyl)-3-(2-trifluoromethylpyrimidin-4-yl)imidazo[1,2-α]pyrimidine (136 mg): 1H NMR (400 MHz, CDCl3) δ 10.10 (1H, d, J 7.4), 8.82 (1H, d, J 5.5), 8.57 (1H, s), 7.78 (1H, d, J 5.5), 7.67 (1H, d, J 7.4), 1.70 (6H, s), 1.00 (9H, t, J 8.0), 0.68 (6H, q, J 8.0); m/z (ES+) 438 (M+H+).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])([CH3:5])([CH3:4])[CH3:3].[CH3:17]O>>[CH3:17][O:12][C:11](=[O:13])[C:10]1[CH:14]=[C:6]([C:2]([CH3:5])([CH3:3])[CH3:4])[CH:7]=[CH:8][C:9]=1[O:15][CH3:16]
Reactant: COc1ccc(C(C)(C)C)cc1C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(C(C)(C)C)ccc1OC
Yield: 95 %

Procedure:
Hydrogen chloride gas was bubbled for 5 min into a stirred solution of 5-tert-butyl-2-methoxybenzoic acid (5.00 g, 24.0 mmol) in methanol (100 ml) at 0° C., after which time the solution was heated under reflux for 17.5 h. The reaction was cooled, evaporated to dryness under reduced pressure and purified by chromatography on silica using diethyl ether as eluent to afford 5-tert-butyl-2-methoxybenzoic acid methyl ester as a pale cream solid (5.06 g, 95%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[C@H:10]1([NH2:17])[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11]1.O>C(O)C>[Cl:9][C:4]1[N:3]=[C:2]([NH:16][C@H:13]2[CH2:14][CH2:15][C@H:10]([NH2:17])[CH2:11][CH2:12]2)[CH:7]=[C:6]([I:8])[CH:5]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Clc1cc(I)cc(Cl)n1
Solvent: O
Solvent: CCO
Product: N[C@H]1CC[C@H](Nc2cc(I)cc(Cl)n2)CC1
Temperature: 180 °C

Procedure:
A mixture of 2,6-dichloro-4-iodopyridine (1 g, 3.65 mmol) and trans-cyclohexane-1,4-diamine (2 g, 18 mmol) in ethanol (2 mL) was heated in a Biotage Initiator microwave reactor at 180° C. for 4 h. After cooling, the mixture was poured into water and the solid collected by filtration and washed with water to give the title compound. Yield: 1.02 g (79%). MS (DCI/NH3) m/z 352 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[Cl:20].N([O-])=O.[Na+].CCCCCC>C(O)C>[Cl:20][C:8]1[CH:9]=[C:10]([C:16]([F:17])([F:18])[F:19])[CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[CH:7]=1
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Product: O=[N+]([O-])c1cc(Cl)cc(C(F)(F)F)c1
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
(see also: EP 0 516 297 A1) 56.7 ml of 96% sulfuric acid are added dropwise over a period of 30 minutes to a brown solution of 90 g (374 mmol) of 4-amino-3-chloro-5-nitro-benzotrifluoride (Maybridge; Tintagel/England) in 500 ml of ethanol (exothermic). After heating to 75° C., 64.53 g (935 mmol) of sodium nitrite are added in portions over a period of one hour (evolution of gas). The mixture is stirred for 2.5 hours at 75° C. and then cooled to room temperature. The reaction mixture is poured onto 1.5 liters of ice-water and extracted four times with ether. Washing the organic phases with 0.1 N HCl, saturated NaHCO3solution and brine, drying (Na2SO4) and concentration by evaporation yield a brown oil. Column chromatography (SiO2; hexane) yields the title compound in the form of an oil: 1H-NMR (DMSO-d6) 8.62 (m, 1H), 8.46 (m, 2H), MS 225 (M)+, 179 (M—NO2)+.