Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=O)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH:40]([CH2:43][OH:44])[CH2:41][OH:42]>>[OH:42][CH2:41][CH:40]([NH:39][C:32](=[O:34])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[S:27]([CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:28])=[O:29])[CH2:43][OH:44]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: NC(CO)CO
Product: O=C(NC(CO)CO)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 38.1 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl] sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and serinol (46 mg, 0.50 mmol, 1.0M in DMF) were combined (reaction time 3 days at room temperature) to give 23 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 604 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:7])=[O:6].[OH:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:23]([C:22]1[CH:21]=[C:20]([O:19][CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:7])=[O:6])[CH:27]=[CH:26][CH:25]=1)#[N:24]
Reactant: N#Cc1cccc(O)c1
Reactant: CCOC(=O)C1CCCCN1S(=O)(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCCN1S(=O)(=O)CCCOc1cccc(C#N)c1
Temperature: 100 °C
Reaction time: 51 h
Yield: 52 %

Procedure:
A suspension of ethyl 1-[(3-chloropropyl)sulfonyl]piperidine-2-carboxylate obtained in Reference Example 97 (2.00 g, 6.72 mmol), 3-hydroxybenzonitrile (0.800 g, 6.72 mmol), potassium carbonate (0.928 g, 6.72 mmol) and sodium iodide (0.101 g, 0.672 mmol) in DMF (20 mL) was stirred at 100° C. for 51 hr. The reaction mixture was diluted with ethyl acetate, washed with water, 0.5N aqueous sodium hydroxide solution, 0.1N aqueous sodium hydroxide solution and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from methanol to give the title compound as a pale-yellow powder (1.34 g, 52%).
Reaction SMILES: [Cl-].C[NH3+].[C:4]([NH:6][C:7]([NH2:9])=[NH:8])#N.C[O-].[Na+].[C:13](OCC)(=[O:20])[CH2:14][C:15](OCC)=[O:16]>CO.O>[CH3:4][NH:6][C:7]1[N:9]=[C:15]([OH:16])[CH:14]=[C:13]([OH:20])[N:8]=1
Reactant: N#CNC(=N)N
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[NH3+]
Agent: C[O-]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CNc1nc(O)cc(O)n1
Temperature: 175 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
67.5 g (1 mole) of methylammonium chloride and 42 g (0.5 mole) of cyanoguanidine are heated to 175° C. to give a clear colourless melt. After onset of reaction, the heat of reaction causes the temperature of the reaction mixture to rise to 206° C. The batch is then stirred for 31/2 hours at 175° C., cooled to 80° C., diluted with 320 ml of methanol and then 172.3 g (0.97 mole) of a 30% solution of sodium methylate in methanol are added over 5 minutes. The resultant suspension is refluxed for 30 minutes and then 173 g (1.08 mole) of diethyl malonate are added over 5 minutes. This suspension is refluxed for another 6 hours and then diluted with 1.25 liters of water. The product is precipitated by acidifying the clear orange solution with glacial acetic acid to pH 4.5. The precipitate is isolated, washed with water and dried in vacuo over phosphorus pentoxide, affording 35.3 g (25% of theory) of 2-methylamino-4,6-dihydroxypyrimidine with a melting point of 290° C.
Reaction SMILES: [C:1](=[O:7])([O:3][CH:4]([CH3:6])[CH3:5])[NH2:2].[C:8](Cl)(=[O:12])/[CH:9]=[CH:10]/[CH3:11].CC(C)([O-])C.[Li+].Cl>C(OCC)C.O1CCCC1>[C:8]([NH:2][C:1](=[O:7])[O:3][CH:4]([CH3:6])[CH3:5])(=[O:12])/[CH:9]=[CH:10]/[CH3:11]
Reactant: C/C=C/C(=O)Cl
Reactant: CC(C)OC(N)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C/C=C/C(=O)NC(=O)OC(C)C
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Isopropyl carbamate (30 g, 291 mmol, available from TCl) was charged to a 3 L Lara vessel and dry Tetrahydrofuran (THF) (150 ml) added. (2E)-2-butenoyl chloride (31.2 ml, 326 mmol, available from Aldrich) was added under Nitrogen and the jacket cooled to −30° C. When the solution temperature reached −17° C. 1M Lithium tert-butoxide (655 ml, 655 mmol) was added by peristaltic pump over 2 hours, keeping the reaction temperature between −10° C. and −18° C. Once the addition was complete the mixture was complete the mixture was stirred for 30 mins and brought to 0° C. Diethyl ether (450 ml) and 1M HCl (375 ml) were added and the mixture brought to 20° C. with vigourous stirring. The stirring was stopped, the layers allowed to separate and the aqueous layer run off. Brine (375 ml) was added and the mixture stirred vigourously. The stirring was stopped, the layers allowed to separate and the aqueous layer run off. The organic layer was dried (magnesium sulfate), filtered and evaporated to a brown oil (60 g). The mixture was loaded on to a 40+M Biotage silica column and eluted with DCM:ethyl acetate (1:1 to 0:1, 10 CV). The product containing fractions were evaporated to dryness and loaded on to a 1500 g Redisep Isco silica column and eluted with a gradient of 0 to 40% ethyl acetate in cyclohexane. The clean, product containing fractions were evaporated to an off white solid (15.41 g). LCMS (Method C): Rt=0.68, MH+=172
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([NH:20][C:21]3[CH2:29][C@H:28]4[C@H:23]([CH2:24][CH2:25][C:26]5[CH:33]=[C:32]([O:34]C)[CH:31]=[CH:30][C:27]=54)[N:22]=3)=[O:19])[CH2:14][CH2:13]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.Cl>ClCCl.CO>[C:1]1([S:7]([NH:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([NH:20][C:21]3[CH2:29][C@H:28]4[C@H:23]([CH2:24][CH2:25][C:26]5[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][C:27]=54)[N:22]=3)=[O:19])[CH2:14][CH2:13]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1N=C(NC(=O)[C@H]3CC[C@H](CNS(=O)(=O)c4ccccc4)CC3)C[C@H]21
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(NC1=N[C@H]2CCc3cc(O)ccc3[C@H]2C1)[C@H]1CC[C@H](CNS(=O)(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of trans-4-[[(phenylsulfonyl)amino]methyl]-N-(cis-3a,4,5,9b-tetrahydro-7-methoxy-1H-benz[e]indol-2-yl)cyclohexanecarboxamide (7) (0.200 g, 0.403 mmol) in dichloromethane (2 mL) was added dropwise with stirring, to a solution of boron tribromide (1.6 mmol) in dichloromethane (12 mL) at 0° C. The resultant suspension was stirred at 0° C. for 30 min. Methanol (˜1 mL) was added at which point the mixture became a clear yellow solution. The solution was stirred for 30 min at 0° C. The solvents were evaporated in vacuo, and the residue was purified by preparative HPLC on C18 reverse phase column, using water/acetonitrile/trifluoroacetic acid (50:50:0.1) as the eluent. The product obtained was dissolved in a minimum amount of methanol and converted to the hydrochloride salt by treatment with ethanolic hydrogen chloride. The solvents were evaporated in vacuo and the residue was triturated with diethyl ether to give trans-4-[[(phenylsulfonyl)amino]methyl]-N-(cis-3a,4,5,9b-tetrahydro-7-hydroxy-1H-benz[e]indol-2-yl)cyclohexanecarboxamide (9) as a beige solid (0.093 g, 45%). NMR (DMSO-d6): δ 0.77-0.95 (m, 2 H), 1.20-1.37 (m, 3 H), 1.64-1.80 (m, 2 H), 1.83-1.98 (m, 3 H), 2.43-2.64 (m, 5 H), 2.91 (d of d, 1 H), 3.48-3.74 (m, 4 H), 4.37-4.47 (m, 1 H), 6.54 (d, 1 H), 6.65 (d of d, 1 H), 7.03 (d, 1 H), 7.53-7.83 (m, 6 H), 9.37 (br s, 1 H), 11.56 (br s, 1 H), 13.22 (br s, 1 H); MS 482 (M+H)+ (FIG. 3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[OH:36][C:37]1([C:40](O)=[O:41])[CH2:39][CH2:38]1>>[OH:36][C:37]1([C:40]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[N:16][N:15]5[C:18]([C:21]6[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=6)=[CH:19][N:20]=[C:14]5[CH:13]=4)[CH:9]=[N:8]3)[CH2:3][CH2:2]2)=[O:41])[CH2:39][CH2:38]1
Reactant: O=C(O)C1(O)CC1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(C(=O)C6(O)CC6)CC5)c4)cnn23)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and 1-hydroxycyclopropanecarboxylic acid (Aldrich, Cat. No. 293881). LCMS (M+H)+: m/z=569.3.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][C:9]1[N:10]=[C:11]([O:35][CH2:36][CH2:37][CH3:38])[C:12]2[N:17]=[C:16]([C:18]3[CH:32]=[C:31]([CH3:33])[C:21]([O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[C:20]([CH3:34])[CH:19]=3)[O:15][C:13]=2[N:14]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][C:9]1[N:10]=[C:11]([O:35][CH2:36][CH2:37][CH3:38])[C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[C:20]([CH3:34])[C:21]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[C:31]([CH3:33])[CH:32]=3)[O:15][C:13]=2[N:14]=1
Reactant: CCCOc1nc(O[C@@H]2CCCC[C@H]2F)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOc1nc(O[C@@H]2CCCC[C@H]2F)nc2oc(-c3cc(C)c(OCC(=O)O)c(C)c3)nc12
Reaction time: 16 h

Procedure:
98 mg of tert-butyl {4-[5-(trans-2-fluorocyclohexyloxy)-7-propoxyoxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}acetate were dissolved in 3.5 ml of dichloromethane, and treated with 1.5 ml of trifluoroacetic acid. After 16 h, the mixture was concentrated and freeze-dried. This gave 96 mg of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=4)=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[Cl:32][C:28]1[CH:27]=[C:26]([NH:25][C:23]2[O:24][C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=4)=[CH:15][CH:16]=3)=[CH:21][N:22]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Clc1cccc(Nc2ncc(-c3ccc(C4=CCNCC4)cc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{4-[2-(3-chlorophenylamino)-oxazol-5-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.5 g, 5.5 mmol) in MeOH (1 mL) is added 4M HCl in dioxane (3 mL) and the mixture is stirred at RT for 2 h. It is concentrated and used in the next step as the bis HCl salt: (M+H)+352.1.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[CH:32](O)[CH3:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[F:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[CH:32]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH:10]=[C:9]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH3:24])[N:7]=4)[N:18]=3)[CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH3:33]
Reactant: CC(O)c1ccncc1F
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(O)cc2OCC3)n(C(C)C)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)c4ccncc4F)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol (300 mg, 0.92 mmol), 1-(3-fluoropyridin-4-yl)ethanol (195 mg, 1.38 mmol) and PPh3 (411 mg, 1.57 mmol) in dioxane (5 mL) was added DIAD (325 μL, 1.57 mmol) and the resulting yellow solution stirred at RT for 2 h. The reaction mixture was partitioned between EtOAc and 1M NaOH, the organic phase dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc) then triturated with TBME affording 167 (220 mg, 53%). LCMS: RT 4.36 min [M+H]+ 449.3. 1H NMR (DMSO, 400 MHz): δ 8.47 (1H, d, J=1.61 Hz), 8.39-8.36 (2H, m), 7.56 (1H, s), 7.39-7.34 (1H, m), 6.69 (1H, dd, J=8.99, 2.60 Hz), 6.46 (1H, d, J=2.57 Hz), 5.91-5.83 (1H, m), 5.66 (1H, q, J=6.47 Hz), 4.44-4.43 (2H, m), 4.39-4.35 (2H, m), 2.40 (3H, s), 1.68 (3H, d, J=6.45 Hz), 1.55 (6H, d, J=6.65 Hz)
Reaction SMILES: CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][C@H:7]([CH2:13][P:14]([C:18]#[C:19][C:20]1[C:21]([CH:39]([CH3:41])[CH3:40])=[N:22][C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:24][C:25]=1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)([O:16][CH3:17])=[O:15])[CH2:8][C:9]([O:11][CH3:12])=[O:10])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(O)=O.[N+](=C)=[N-]>C1COCC1.O.CCOCC>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]2[CH:24]=[C:23]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:22]=[C:21]([CH:39]([CH3:40])[CH3:41])[C:20]=2[C:19]#[C:18][P:14]([O:16][CH3:17])([CH2:13][C@@H:7]([OH:6])[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:15])=[CH:27][CH:28]=1
Reactant: COC(=O)C[C@@H](CP(=O)(C#Cc1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C)OC)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)C[C@H](O)CP(=O)(C#Cc1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C)OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.9 %

Procedure:
A mixture of (S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-[[[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]butanoic acid, methyl ester (800 mg, 1.07 mmol), tetra-n-butylammonium fluoride (1.0M in THF, 3.21 ml, 3.21 mmol), and HOAc (325 mg, 5.41 mmol) in THF (12 ml) was stirred at room temperature for 17 hours. The solution was cooled to 0° C., diluted with H2O, and extracted twice with EtOAc. The pooled EtOAc layers were washed with saturated NaHCO3 and brine. The organic layer was then washed twice 5% KHSO4, then with H2O and brine. Drying (Na2SO4), followed by filtration and removal of the solvent afforded a yellow oil. The oil was dissolved in Et2O (10 ml) and treated with excess diazomethane for 20 minutes. The excess diazomethane was destroyed by the addition of HOAc and the solvent was removed in vacuo. The residue was chromatographed (flash, Merck SiO2, 50×70 mm column 35% acetone in hexane (650 ml) followed by 1:1 acetone:hexane) to afford (S)-4-[[[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-ethynyl]methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester (463 mg, 85%) as a colorless foam.
Reaction SMILES: [CH3:1][CH:2]([C:8]([C:10]([F:13])([F:12])[F:11])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[NH4+:18]>C(O)C.O>[CH2:6]([O:5][C:3](=[O:4])[C:2]([CH3:1])=[C:8]([NH2:18])[C:10]([F:13])([F:12])[F:11])[CH3:7]
Reactant: [NH4+]
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)=C(N)C(F)(F)F
Temperature: 25 °C
Yield: 104.3 %

Procedure:
Ethyl α-methyl-4,4,4-trifluoroacetoacetate (24.5 g, 124 mmol) and ammonium acetate (28.6 g, 372 mmol) were dissolved in ethanol (50 ml) and water (2.5 ml). The solution was heated under reflux for 16 hours, allowed to cool to room temperature, diluted with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated to give the product as a pale brown liquid (25.5 g, 100% yield) which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][Cl:10])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[C:8]([CH2:9][Cl:10])=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:19])[CH3:2]
Reactant: CCc1ncccc1CCl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCc1c(CCl)ccc[n+]1[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The 2-ethyl-3-chloromethylpyridine (2.4 g, 15.4 mmol) was dissolved in CHCl3 (100 mL) and cooled under nitrogen to 0° C. and m-chloroperbenzoic acid (55%, 4.2 g) was added in small portions. The reaction was stirred for 2 hours. The reaction was extracted twice with saturated aqueous sodium bicarbonate (100 mL). The organic phase was dried with MgSO4, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel packed in 98:2 CH2Cl2 :MeOH and eluted with the same. The appropriate fractions were combined and the solvent removed under reduced pressure the give the desired 2-ethyl-3-chloromethylpyridine-N-oxide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:16]([CH3:23])([O:18][Si](C)(C)C)[CH3:17])[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([C:16]([OH:18])([CH3:23])[CH3:17])[CH:5]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[N:7]=1
Reactant: CC(C)(O[Si](C)(C)C)c1cc(Cc2ccc(Cl)cc2)nc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(Cc2ccc(Cl)cc2)nc(Cl)n1
Yield: 76.7 %

Procedure:
A solution of 2-chloro-4-(4-chloro-benzyl)-6-(1-methyl-1-trimethylsilanyloxy-ethyl)-pyrimidine (3.69 g, 10.0 mmol) and toluene-4-sulfonic acid monohydrate (0.19 g, 1.0 mmol) in 90% aqueous tetrahydrofuran (40 mL) was stirred at 20° C. for 2 h. The solution was diluted with ethyl acetate and washed successively with saturated sodium hydrogencarbonate solution and with brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residual oil was crystallized from cyclohexane to give the title compound (2.28 g, 77%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[C:7]=1[C:18]#[N:19])=[O:4].S(=O)(=O)(O)[OH:21].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[NH4+]>>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[C:7]=1[C:18](=[O:21])[NH2:19])=[O:4]
Reactant: CCCN(CCC)c1nsc(NC(=O)NC)c1C#N
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [NH4+]
Product: CCCN(CCC)c1nsc(NC(=O)NC)c1C(N)=O
Temperature: 0 °C

Procedure:
1-Methyl-3-(4-cyano-3-(dipropylamino)-5-isothiazolyl)urea (4.2 g) was slowly stirred into 10 ml of concentrated sulfuric acid and the resulting solution was warmed to 80° where it was maintained for about 16 hours. The solution was poured into 200 ml of ice-water and the solution was brought to pH 10 by adding a mixture of sodium bicarbonate, sodium carbonate, and ammonium hydroxide. The white precipitate was collected by filtration, but thin-layer chromatographic analysis showed the white solid to be a mixture of starting material and product. The solid was again placed in 10 ml of concentrated sulfuric acid. The solution was heated on a steam bath and then poured into 100 ml of water. This mixture was brought to pH 10 with aqueous ammonium hydroxide. The solid precipitate was collected by filtration and dried to give 4.2 g of 1-methyl-3-(4-carbamoyl-3-(dipropylamino)-5-isothiazolyl)urea, m.p. 168°-169°. The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: [CH:1]([N:4]1[CH2:17][CH2:16][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1)([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:35]=[C:36]([C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1)[CH3:37]>CN(C=O)C.[Cu]I>[CH:1]([N:4]1[CH2:17][CH2:16][C:7]2[N:8](/[CH:35]=[C:36](/[C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)\[CH3:37])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1)([CH3:3])[CH3:2]
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C(C)C)CC3
Reactant: CC(=CBr)c1ccncc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C(C)C)CC2)c1ccncc1
Temperature: 140 °C

Procedure:
2-Isopropyl-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (114 mg, 0.5 mmol), potassium phosphate (212 mg, 1 mmol), copper (I) iodide (9.5 mg, 0.05 mmol) and L-proline (11.5 mg, 0.1 mmol) were mixed in DMF and the contents were purged with nitrogen. 4-(1-Bromoprop-1-en-2-yl)pyridine (107.83 mg, 0.55 mmol) was added, the reaction mixture was purged with nitrogen and heated overnight at 140° C. The contents were purged with nitrogen and heated overnight at 140° C. The contents were cooled to RT and poured into water. The precipitate obtained was filtered, dried and purified by silica gel chromatography (100-200 mesh, neutralized with aqueous ammonia) eluting with 0-4% MeOH-DCM as eluent. The compound was further purified by HPLC. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 8.60 (d, 2H), 7.70 (d, 2H), 7.45 (s, 1H), 7.40 (s, 1H), 7.18 (d, 1H), 7.05 (d, 1H), 4.50 (m, 2H), 3.80 (m, 3H), 3.10 (m, 2H), 2.42 (s, 3H), 2.00 (s, 3H), 1.40 (d, 6H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][CH:9]([OH:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1B(O)O.CC(C)([O-])C.[K+]>COCCOC.C(O)(C)(C)C.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:15]1([CH3:14])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[C:2]1[N:7]=[C:6]([CH2:8][CH:9]([OH:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: CCCC(O)Cc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: CCCC(O)Cc1cccc(-c2c(C)cc(C)cc2C)n1
Temperature: 50 °C
Yield: 77.8 %

Procedure:
1-(6-Bromopyridin-2-yl)pentan-2-ol (3.23 g, 13.2 mmol) was dissolved in 30 mL of 1,2-dimethoxyethane. Tetrakis(triphenylphosphine)palladium(0) (0.76 g, 0.66 mmol) was added and the solution was heated to 50° C. for 15 min. After cooling the solution, 2,4,6-trimethylbenzeneboronic acid (2.60 g, 15.9 mmol) in 15 mL 1,2-dimethoxyethane was added to parent solution. Potassium t-butoxide (2.96 g, 26.5 mmol) in 15 mL t-butanol was added last. The reaction was heated at 90° C. for 0.5 h. After cooling, the solution was filtered and concentrated. Flash chromatography (20% ethyl acetate/hexanes) gave the title compound (2.91 g, 77% yield).