Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH:3]=1.[Li][CH2:24]CCC.C[Si](C)(C)[O:30][C@@H:31]1[C@@H:36]([O:37][Si](C)(C)C)[C@H:35]([O:42][Si](C)(C)C)[C@@H:34]([CH2:47][O:48][Si](C)(C)C)[O:33][C:32]1=[O:53].CS(O)(=O)=O>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1.CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:32]2([O:53][CH3:24])[C@H:31]([OH:30])[C@@H:36]([OH:37])[C@H:35]([OH:42])[C@@H:34]([CH2:47][OH:48])[O:33]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][O:19][CH:20]2[CH2:22][CH2:21]2)=[CH:12][CH:11]=1
Reactant: Clc1ccc(Br)cc1Cc1ccc(CCCOC2CC2)cc1
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COC1(c2ccc(Cl)c(Cc3ccc(CCCOC4CC4)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-(3-cyclopropoxypropyl)benzyl)benzene (0.64 g, 1.69 mmol) in anhydrous toluene/THF (6 mL, v/v=2:1) was added dropwise n-BuLi (2.5 M in hexane, 0.81 mL) at −65° C., and the mixture was stirred for 30 min at −65 ° C. Then a −65° C. solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (0.86 g, 1.85 mmol) in toluene (6 mL) was added dropwise over 15 min. The mixture was stirred at −65° C. for 3.5 h until starting material was consumed. The reaction was quenched with methanesulfonic acid (0.23 mL, 3.58 mmol) in methanol (6 mL), and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated sodium bicarbonate, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated bicarbonate, then with water, and then with brine, and dried over sodium sulfate. Removal of the volatiles afforded a residue (0.73 g), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:16][C:15]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[N:14][C:13]=1[C:28]([NH2:30])=[O:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[S:16][C:15]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[N:14][C:13]=2[C:28]([NH2:30])=[O:29])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC(=O)c1nc(Nc2ccnc3ccccc23)sc1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: NC(=O)c1nc(Nc2ccnc3ccccc23)sc1NC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.9 %

Procedure:
To a mixture of 4-fluorobenzoylchloride (0.16 g, 1 mmol) and a catalytic amount of DMAP in pyridine (5 mL) was added dropwise a solution of 5-amino-2-(quinolin-4-ylamino)thiazole-4-carboxamide (0.25 g, 0.87 mmol) in pyridine (5 mL), and the mixture was stirred for 16 hrs at rt. The reaction mixture was quenched with ice-water. The resulting solids were collected by filteration and washed successively with water, ether, and MeOH to give 0.12 g (33% yield) of the titled compound. LCMS m/z [M+H]+408.2 .
Reaction SMILES: C1(N2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.NC1C(C2C=CC=CC=2[F:35])=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[Cl:50][C:51]1[CH:57]=[CH:56][C:54]([NH2:55])=[CH:53][CH:52]=1>C(O)(=O)C>[Cl:50][C:51]1[CH:57]=[CH:56][C:54]([N:55]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:35])[CH:18]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:53][CH:52]=1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: Nc1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3cccc(F)c3)c2ncn1-c1ccc(Cl)cc1
Yield: 73 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (50 mg, 0.2 mmol), triethyl orthoformate (0.45 ml), 4-chloroaniline (47.2 mg, 0.37 mmol), and acetic acid (0.05 ml) were used to give 52.1 mg (0.15 mmol, 73.0% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[C:4](=O)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[NH2:17][CH2:18][CH2:19][CH2:20][OH:21].C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[C:4](=[N:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: NCCCO
Reactant: O=C(Cn1ccnc1)c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: O
Product: OCCCN=C(Cn1ccnc1)c1ccc(Cl)cc1Cl
Yield: 95.6 %

Procedure:
153.2 g (0.60 mole) of N-(2,4-dichlorophenacyl)imidazole and 53.0 g (0.705 mole) of 3-amino-1-propanol are suspended or dissolved in 400 mol of toluene, and the mixture is heated under reflux with a water trap until no more water of reaction separates out. The reaction solution is then washed 3 times with water, the organic phase is dried with sodium sulfate and, after the solvent has been evaporated off, 179 g of 1-(2-(2,4-dichlorophenyl)-2-(3-hydroxypropylimino)ethyl)-1H-imidazole are obtained as a highly viscous oil. (Yield: 95.6%).
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:3]2([CH2:8][CH2:7][CH:6]([CH:9]=[C:10](Br)Br)[CH2:5][CH2:4]2)[O:2]1.C([Li])CCC>O1CCCC1.CCCCCC>[C:9]([CH:6]1[CH2:5][CH2:4][C:3]2([O:2][CH2:1][CH2:14][O:13]2)[CH2:8][CH2:7]1)#[CH:10]
Reactant: BrC(Br)=CC1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CC1CCC2(CC1)OCCO2
Temperature: 20 °C
Yield: 91.1 %

Procedure:
A solution of 14 g of 1,1-ethylenedioxy-4-(2,2-dibromovinyl)cyclohexane in 70 ml of tetrahydrofuran was cooled to -20° C. and treated slowly at this temperature with 76.62 ml of a 1.4M solution of butyl lithium in hexane (exothermic reaction). The cooling bath was removed and the mixture was left to warm to 20° C. within about 20 minutes. The reaction mixture was subsequently treated with 150 ml of water and extracted three times with diethyl ether. The organic phases were washed twice with water and the wash-water was back-extracted with diethyl ether. The organic phases were dried over magnesium sulphate, filtered and evaporated. Low-pressure chromatography of the residual, yellow liquid (8 g) on silica gel with ethyl acetate/petroleum ether (vol. 7:93) gave 6.5 g (91%) of 4-ethynyl-1,1-ethylenedioxycyclohexane as a clear liquid.
Reaction SMILES: C[Si]([C:5]1[NH:10][C:9](=[O:11])[N:8]([Si](C)(C)C)[C:7](=[O:16])[C:6]=1[F:17])(C)C.F[C:19]1[C:20](=[O:26])NC(=O)NC=1.[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]1[O:40][CH2:39][CH2:38][O:37]1)[CH3:28].C(OC1C=CC=CC=1C=O)C>ClCCl.C(O)CO>[C:20]([O:37][CH2:38][CH2:39][O:40][CH:36]([N:10]1[CH:5]=[C:6]([F:17])[C:7](=[O:16])[NH:8][C:9]1=[O:11])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[O:29][CH2:27][CH3:28])(=[O:26])[CH3:19]
Reactant: CCOc1ccccc1C1OCCO1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C[Si](C)(C)c1[nH]c(=O)n([Si](C)(C)C)c(=O)c1F
Agent: CCOc1ccccc1C=O
Solvent: ClCCl
Solvent: OCCO
Product: CCOc1ccccc1C(OCCOC(C)=O)n1cc(F)c(=O)[nH]c1=O

Procedure:
Bis(trimethylsilyl)5-fluorouracil prepared as in Example 1 from 5-fluorouracil (10 g), and 2-(2-ethoxyphenyl)-1,3-dioxolan (15 g) prepared from 2-ethoxybenzaldehyde and ethylene glycol were dissolved in dichloromethane (50 ml). The mixture was treated and acetylated as in Example 10 to give 6.2 g of crystalline 1-[α-(2-acetoxyethoxy)-2-ethoxybenzyl]-5-fluorouracil.
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1(S)C=CC=CC=1.[OH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>[OH-].[Na+]>[CH2:26]([O:25][C:23]([C:22]1[CH:28]=[CH:29][C:19]([O:18][CH2:2][CH2:3][S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:20][CH:21]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: BrCCSc1ccccc1
Agent: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1ccc(OCCSc2ccccc2)cc1

Procedure:
This compound was prepared by the condensation procedure 1A. The required intermediate 2-bromoethylphenyl sulphide may be prepared by condensing 1,2-bromoethane and thiophenol in sodium hydroxide solution, in a manner analogous to that used for preparation of the intermediates for compounds of Example Nos. 62-73, but in a method which gives better yields uses the scheme: ##STR25## Condensation with ethyl 4-hydroxybenzoate gave 1-(4-ethoxycarbonylphenoxy)-2-phenylthio ethane, m.p. 50°-51° C.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]/[CH2:7][C:8]1[C:13]([O:14]C(=O)C)=[C:12]([CH3:18])[C:11]([CH3:19])=[C:10]([O:20]C(=O)C)[C:9]=1[CH3:24])/[CH2:3][C:4]#[N:5].C=C(CCC1C(OC(=O)C)=C(C)C(C)=C(OC(=O)C)C=1C)CC#N.C[O-].[Na+].O>CO.CCOCC>[OH:20][C:10]1[C:11]([CH3:19])=[C:12]([CH3:18])[C:13]2[O:14][C:2]([CH3:1])([CH2:3][C:4]#[N:5])[CH2:6][CH2:7][C:8]=2[C:9]=1[CH3:24]
Reactant: CC(=O)Oc1c(C)c(C)c(OC(C)=O)c(C/C=C(/C)CC#N)c1C
Agent: C=C(CC#N)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC#N)O2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 93 %

Procedure:
A slurry of 500 mg (1.52 mmoles) of the mixture of E-and Z-3-methyl-5-(2,4,5-trimethyl-3,6-diacetyloxyphenyl)-3-pentenenitrile and 3-methylene-5-(2,4,5-trimethyl-3,6-diacetyloxy-phenyl)pentanenitrile in 5 ml of methanol was treated with 0.71 ml (3.34 mmoles) of a 4.7 M methanolic sodium methoxide solution. The resulting mixture was stirred at room temperature for 4.5 hr, then poured into 20 ml of water and worked-up with ether in the usual manner affording 345 mg (93%) of rac. 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetonitrile as a tan solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:31]=[CH:30][C:15]3[N:16]=[C:17]([NH:19][CH2:20][C:21]4([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[O:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].C[CH2:33][N:34](C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.CN.C1COCC1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:31]=[CH:30][C:15]3[N:16]=[C:17]([NH:19][CH2:20][C:21]4([C:27](=[O:28])[NH:34][CH3:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)[O:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: CNC(=O)c1cc(Oc2ccc3nc(NCC4(C(=O)O)CCCCC4)oc3c2)ccn1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(Oc2ccc3nc(NCC4(C(=O)NC)CCCCC4)oc3c2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-{[6-(2-methylcarbamoyl-pyridin-4-yloxy)-benzooxazol-2-ylamino]-methyl}-cyclohexanecarboxylic acid (1 eq) in DMF was added DIPEA (3 eq) and [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (1 eq). This was stirred at room temperature for 2 hours, then a 2 M solution of methylamine in THF (5 eq) was added and allowed to react overnight at 70° C. The mixture was diluted with ethyl acetate and washed twice with a saturated aqueous solution of ammonium chloride and once with brine, then dried with anhydrous sodium sulfate, filtered and concentrated, then purified by preparatory reverse phase HPLC. MH+=438.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][CH2:12][CH3:13])[C:4](=[O:14])[CH:3]=1.[N:15]([O-])=[O:16].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][CH2:12][CH3:13])[C:4](=[O:14])[C:3]=1[N:15]=[O:16]
Reactant: O=N[O-]
Reactant: CCCn1c(=O)cc(N)n(CC)c1=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCn1c(=O)c(N=O)c(N)n(CC)c1=O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 6-amino-1-ethyl-3-propyl-1,3-dihydropyrimidine-2,4-dione (1.4 g, 7.1 mmol) in a mixture of 50% acetic acid/water (35 ml) was added sodium nitrite (2 g, 28.4 mmol) in portions over a period of 10 minutes. The mixture was stirred at 70° C. for 1 hour, then the reaction mixture concentrated to a low volume under reduced pressure. The solid was filtered off, and washed with water, to provide 6-amino-1-ethyl-5-nitroso-3-propyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (1).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])=O.C(O)COCCOCCO.[N-:27]=[N+:28]=[N-]>CO.[Pd]>[N:5]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(NCCOCCOCCO)C(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: OCCOCCOCCO
Product: [N-]=[N+]=NCCOCCOCCO
Reaction time: 12 h

Procedure:
8-Trifluoroacetamido-3,6-dioxa-1-octanol (1f: 8-azido-3,6-dioxa-1-octanol (Amvamzollo, P. H.; Sinay, P. Carbohydr. Res. 1986, 150, 199-212) (0.7 g, 4.0 mmol) was synthesized from triethylene glycol following the reported procedure (Bertozzi, C. R.; Bednarski, M. D. J. Org. Chem. 1991, 56, 4326-4329). The azide was combined with Pd/C (150 mg) in MeOH (8.0 mL) and stirred 12 h under H2 (1 atm). The suspension was filtered over celite, and the filtrate was concentrated to afford the amine (0.590 g, 4.0 mmol) in quantitative yields (Sato, H.; Hayashi, E.; Yamada, N.; Yatagai, M.; Takahara, Y. Bioconjugate Chem. 2001, 12, 701-710.). Following general procedure 1, 2-[2-(2-aminoethoxy)ethoxy]ethanol (0.590 g, 3.95 mmol) was combined with triethylamine (1.378 mL, 9.89 mmol) and trifluoroacetic anhydride (0.782 mL, 5.54 mmol) in MeOH (5 mL). Purification by silica gel chromatography (EtOAc) yielded 0.576 g (60%) of if as a white solid. 1H (300 MHz, CD3OD): δ 7.87 (br s, 1H), 3.73 (m, 2H), 3.68-3.60 (m, 10H), 3.55 (t, 2H, J=4.5 Hz), 3.32 (br s, 1H); 13C (75 mHz, CD3OD): δ 157.6 (q, J=36.6 Hz), 116.1 (q, J=286.1 Hz), 72.68, 70.35, 70.24, 68.90, 61.52, 39.84; ESI-MS calcd for C8H14F3NO4 [M−H]−: 244.0797. found 244.0795.
Reaction SMILES: [SH:1][C:2]1[S:6][C:5]([S:7][CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:10]2(=[O:12])=[O:11])=[N:4][N:3]=1.Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[N:25]1([CH2:24][CH2:23][S:1][C:2]2[S:6][C:5]([S:7][CH2:8][N:9]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[S:10]3(=[O:12])=[O:11])=[N:4][N:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: ClCCN1CCCCC1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CSc1nnc(S)s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CSc1nnc(SCCN2CCCCC2)s1
Yield: 60.2 %

Procedure:
Following a procedure similar to that described above in Example 33A, 0.69 g (0.002 mol) of 2-(5-mercapto-1,3,4-thiadiazol-2-ylthiomethyl)saccharin was reacted with 0.74 g (0.004 mol) of 1-(2-chloroethyl)piperidine hydrochloride in 4 ml of DMF in the presence of 0.4 g of triethylamine to give 0.55 g (60%) of 2-(5-[2-(1-piperidinyl)ethylthio]-1,3,4-thiadiazol-2-ylthiomethyl)saccharin, mp 100.0°-101.0° C. (from ethyl acetate).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([C:13](=O)[CH3:14])=[CH:8][C:7]=1[F:16].O.[C:18]([OH:22])(=O)[CH:19]=O.O.[NH2:24][NH2:25]>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([C:13]2[CH:14]=[CH:19][C:18](=[O:22])[NH:24][N:25]=2)=[CH:8][C:7]=1[F:16]
Reactant: NN
Reactant: CC(=O)c1cc(F)c(OCCCCl)c(F)c1
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc(-c2cc(F)c(OCCCCl)c(F)c2)n[nH]1
Temperature: 100 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
A mixture of 1-(4-(3-chloropropoxy)-3,5-difluoro-phenyl]ethanone (11 g, 44.7 mmol) and glyoxalic acid monohydrate (4.2 g, 46.5 mmol) in acetic acid (16 mL) was stirred at 100° C. for 4 h. The acetic acid was evaporated at reduced pressure and diluted with water then cooled to 0° C. and neutralized with ammonium hydroxide to pH 8. To this mixture, hydrazine monohydrate (4.3 mL, 86 mmol) was added and heated at 100° C. for 1 h. The reaction was cooled to rt and the solid was filtered, then dried to give a crude product. The crude product was triturated sequentially with 5% aqueous sodium bicarbonate solution and with a mixture of methylene chloride, methanol, ether and hexane to provide relatively pure product. The product was purified by ISCO (120 g silica gel column) chromatography using 2 to 8% methanol in methylene chloride to furnish 6-[4-(3-chloropropoxy)-3,5-difluorophenyl]-2H-pyridazin-3-one (7.9 g, 59%), MS m/z 301 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]([CH:13]=[O:14])[CH:3]=1.[Cl:15]N1C(C)(C)C(=O)N(Cl)C1=O>CC#N>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]([CH:13]=[O:14])[C:3]=1[Cl:15]
Reactant: Nc1cc(C=O)nc(C2CCC2)c1F
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: CC#N
Product: Nc1c(F)c(C2CCC2)nc(C=O)c1Cl
Yield: 0.1 %

Procedure:
Using the procedure for Example 15, 4-amino-6-cyclobutyl-5-fluoropicolinaldehyde (0.5 g, 2.57 mol), 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.279 g, 1.416 mol) and CH3CN (26 mL) gave 4-amino-3-chloro-6-cyclobutyl-5-fluoropicolinaldehyde (289 mg, 45.7%) as a red foam: 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 4.77 (d, J=9.4 Hz, 2H), 3.87 (ttdd, J=9.3, 8.3, 2.3, 1.1 Hz, 2H), 2.49 (m, 2H), 2.30 (m, 2H), 2.10 (m, 1H), 1.95 (tddd, J=13.4, 7.1, 3.5, 2.1 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −140.24; 13C NMR (101 MHz, CDCl3) δ 191.04, 149.06, 147.71, 145.14, 142.84, 139.20, 115.84, 35.24, 26.86, 18.62; EIMS m/z 228.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:13][CH2:14][CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[CH2:6]([N:13]([CH2:14][CH3:15])[C:3](=[O:4])[CH2:2][N:29]([S:26]([C:23]1[CH:22]=[CH:21][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:25][CH:24]=1)(=[O:27])=[O:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Br)CBr
Reactant: CCNCc1ccccc1
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of 2-bromoacetyl bromide with N-benzyl-N-ethylamine and 4-tert-butyl-N-(2-methoxy-phenyl)-benzenesulfonamide
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br[CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36]>>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:39]=[CH:40][CH:41]=[C:32]([CH2:31][N:19]2[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)/[S:21][C:20]2=[O:22])[CH:33]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: COC(=O)c1cccc(CBr)c1
Product: COC(=O)c1cccc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)c1

Procedure:
3-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}benzoic acid methyl ester was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and methyl 3-bromomethylbenzoate following General Procedure S.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2.C[O:24][B:25](OC)[O:26]C>CCOCC>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[C:13]([B:25]([OH:26])[OH:24])[CH:14]=1
Reactant: COB(OC)OC
Reactant: Brc1cnc2ccccc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.5 %

Procedure:
A 2.5M solution of n-butyllithium in hexane (4.4 ml, 11 mmol) was slowly added to a stirred solution of 3-bromoquinoline (2.08 g, 10 mmol) in anhydrous ether (20 ml), under nitrogen, at −75° C. After a further 20 minutes at −75° C., trimethylborate (1.46 ml, 13 mmol) was added, whereupon the red colour changed to yellow. The reaction mixture was allowed to warm to room temperature and quenched with water, followed by 1M aqueous sodium hydroxide solution (10 ml). The resulting mixture was stirred for 30 minutes and then glacial acetic acid added until a pH ˜5-6 was attained, which generated a gummy precipitate. Diisopropyl ether was added to this mixture, stirring continued for 1 hour and then the clear aqueous and organic phases were decanted from the solid and discarded. The solid residue was dissolved in ethyl acetate and the solution washed with water, dried (MgSO4) and evaporated under reduced pressure to give the title compound as a pale yellow solid (580 mg, 34%). Found: C, 62.74; H, 4.11; N, 7.92. C9H8BNO2 requires C, 62.49; H, 4.66; N, 8.10%. δ(DMSOd6): 7.59 (t,1H), 7.76 (t,1H), 7.98 (m,2H), 8.42 (brs,2H,exchangeable), 8.70 (s,1H), 9.18 (s,1H).
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].[C:5](#N)C.Cl[CH:9]([C:15]([C:17]([F:20])([F:19])[F:18])=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(N(CC)CC)C>O>[CH2:2]([C:1]1[S:3][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([C:17]([F:20])([F:19])[F:18])[N:4]=1)[CH3:5]
Reactant: CC(N)=S
Reactant: CC#N
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1sc(CC)nc1C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a 250 mL, 3-necked flask fitted with a mechanical stirrer, thermometer, and a reflux condenser, was charged thioacetamide (9.02 g, 0.12 mol) and 60 mL acetonitrile. To this solution was added ethyl 2-chloro-4,4,4-trifluoroacetoacetate (21.86 g, 0.10 mol) dropwise over a period of 15 minutes. A slight exotherm occurred which raised the temperature to 50° C. The reaction mixture was stirred for two hours at room temperature during which time a yellow solid precipitated. Then triethylamine (35 mL, 0.25 mol) was added dropwise with the evolution of white fumes. The reaction temperature rose to about 50° C. The contents were gently refluxed for one hour during which the color changed from yellow to brown. After cooling, water (25 mL) was added. The mixture was extracted with ether (2 ×100 mL) and washed with 10% HCl (25 mL). After concentration and drying at 1 mm vacuum overnight, the desired compound was isolated as a brown solid, 22.15 g, a 90.6% yield with a 97.8 wt.% purity assay. m.p. 30°-32° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]3[C:25]([C:26]([O:28]C)=O)=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH3:31]>CO>[C:26]([C:25]1[C:19]2[O:18][C:17]([CH:14]3[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:16][CH2:15]3)=[N:21][C:20]=2[CH:22]=[CH:23][CH:24]=1)(=[O:28])[NH2:31]
Reactant: COC(=O)c1cccc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)oc12
Reactant: N
Solvent: O
Solvent: CO
Product: NC(=O)c1cccc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(1-(benzyloxycarbonyl)piperidin-4-yl)benzo[d]oxazole-7-carboxylate (102 mg, 0.26 mmol) was added to a mixture of methanol (5 mL) and ammonia water (10 mL) and the mixture was stirred at room temperature for overnight. Then the solid was filtered. 98 mg of solid of benzyl 4-(7-carbamoylbenzo[d]oxazol-2-yl)piperidine-1-carboxylate was obtained. LC-MS (ESI) m/z: 380 (M+1)+.