Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH2:15][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cccc(CCBr)c1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CCc3cccc(Cl)c3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(2-bromoethyl)-3-chlorobenzene and isolated as light yellow gum. MS (m/e): 421.3 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:16])([CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(C)(C)c1ccc(N)cc1
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A mixture of ethyl (4-nitrophenyl)-2,2-dimethylacetate (3.30 g, 13.9 mmol) and 10% Pd/C in methanol (40 mL) was hydrogenated in a Parr apparatus at 50 psi for 2 hours. The catalyst was removed by filtration, and the solvent was evaporated to give ethyl (4-aminophenyl)-2,2-dimethylacetate (2.63 g, 91%) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].O.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][C:27](=O)[CH3:28])=[CH:18]1>C(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][C:27](=[N:2][OH:3])[CH3:28])=[CH:18]1
Reactant: NO
Reactant: CC(=O)Cc1cn(-c2ccccc2Cl)c2ccccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(Cc1cn(-c2ccccc2Cl)c2ccccc12)=NO
Reaction time: 8 h

Procedure:
2.1g (0.03 mole) of hydroxylamine hydrochloride and 2.1g of sodium acetate dissolved in 10 ml. of water are added to 5.8g (0.02 mole) of 1-(2-chlorophenyl)-3-(2-oxopropyl)indole dissolved in 50 ml of ethyl alcohol. Stirring is carried out overnight at room temperature, the oxime which has precipitated is filtered (without heat), washed with water and dried. It is recrystallised from 30 ml of di-isopropyl ether.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]=2[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3].C(N(CC)CC)C.[N+:33]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1)([O-:35])=[O:34]>CN(C)C=O>[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]3[CH2:16][CH2:17][N:18]([CH2:40][C:39]4[CH:42]=[CH:43][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=4)[CH2:19][CH2:20]3)[C:12]=2[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(Cc4ccc([N+](=O)[O-])cc4)CC3)c(F)c21
Temperature: 90 °C
Reaction time: 10.5 h
Yield: 81.5 %

Procedure:
A mixture of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid hydrochloride (6.7 g), triethylamine (5.45 g), p-nitrobenzylbromide (5.8 g) and dimethylformamide (200 ml) was stirred at 90° C. for 10.5 hrs. The solvent was evaporated off and the residue was treated with water. The solid was filtered, washed with water, dried, and recrystallized from a mixture of dimethylformamide and ethanol to give 6.9 g of 1-ethyl-6,8-difluoro-1,4-dihydro-7-[4-(p-nitrobenzyl)-1-piperazinyl]-4-oxoquinoline-3-carboxylic acid. mp: 241°-242° C.
Reaction SMILES: C(OC([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C.[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[CH:40]=O.[BH3-]C#N.[Na+]>CO>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]([CH2:40][C:36]2[S:35][CH:39]=[CH:38][CH:37]=2)[CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Reactant: O=Cc1cccs1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCc2ccc(CN(Cc3cccs3)C3CCCc4cccnc43)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
To a stirred solution of N-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.280 g, 0.610 mmol) in anhydrous methanol (6 mL), at room temperature, was added thiophene-2-carboxaldehyde (0.25 mL, 2.67 mmol) followed by NaBH3CN (0.081 g, 1.30 mmol) and the resultant solution was stirred at room temperature. After 1 day, an additional amount of NaBH3CN (0.083 g, 1.31 mmol) was added and the solution was stirred at room temperature for an additional 3 days. The solvent was removed under reduced pressure and CH2Cl2 (30 mL) and water (10 mL) were added to the residue. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic phases were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (2 mm plate, 40:1 CH2Cl2-MeOH) provided 0.173 g of the desired amine as a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]([NH2:32])([CH3:31])[CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[N:21]=1.Br>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:32][C:25]([C:22]3[N:21]=[C:20]([CH3:19])[O:24][N:23]=3)([CH3:31])[CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCC(F)F)c(C2CC2)cn1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Agent: Br
Agent: Cl
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)F)c(C3CC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(2,2-difluoroethoxy)pyridine-2-carboxylic acid;hydrochloride (example 145d) and 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-methylsulfonyl-propan-2-amine;hydrobromide (enantiomer B) (example 125b) as starting materials and isolated (25 mg, 31%); MS (ESI, m/z): 445.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[C:40]([F:41])=[CH:39][C:31]([C:32]([O:34]C(C)(C)C)=[O:33])=[CH:30][C:29]=3[F:42])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[C:29]([F:42])=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:39][C:40]=3[F:41])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(-n2c(C(C)(C)c3ccc(Cl)c(Cl)c3)cnc2SCc2c(F)cc(C(=O)OC(C)(C)C)cc2F)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-n2c(C(C)(C)c3ccc(Cl)c(Cl)c3)cnc2SCc2c(F)cc(C(=O)O)cc2F)ccc1F
Reaction time: 0.67 h

Procedure:
A solution of tert-butyl 4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzoate (540 mg, 0.85 mmol) in DCM (2 mL) was treated with TFA (2.0 mL) at ambient temperature. After 40 min, the reaction mixture was concentrated under reduced pressure to afford a colorless oil. This oil was taken up in DCM and toluene and again concentrated under reduced pressure to remove any residual TFA and to provide the title compound. MS (EI) m/z 581 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:17]#[N:18])[C:12](=[CH:15][CH:16]=2)[C:13]#[N:14])=[N:5]1.[C:19]([C:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[CH:26]=[C:25]([C:27]([NH:1][CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]#[N:18])[CH:10]=3)=[N:5]2)=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20]
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1C#N
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Product: CC(=O)c1cc(C(=O)NCCn2ccc(-c3ccc(C#N)c(C#N)c3)n2)[nH]n1

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-phthalonitrile (50 mg) and 3-acetyl-1H-pyrazole-5-carboxylic acid (34 mg) using the method of Example 34(d). Yield 43 mg. 1H-NMR (400 MHz; d6-DMSO): δ 2.49 (s, 3H), 3.70 (m, 2H), 4.37 (t, 2H), 7.00 (d, 1H), 7.27 (s, 1H), 7.86 (d, 1H), 8.13 (d, 1H), 8.28 (d, 1H), 8.45 (d, 1H), 8.63 (br s, 1H), 14.05 (br s, 1H).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Br:23])[CH:14]=1)=O)(=O)[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].ClC1C=C(C2[N:36]=C(CCC(OC)=O)OC=2)C=C(C(F)(F)F)C=1>>[Br:23][C:15]1[CH:14]=[C:13]([C:11]2[N:36]=[C:1]([CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])[O:9][CH:10]=2)[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: COC(=O)CCC(=O)OCC(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: COC(=O)CCc1nc(-c2cc(Cl)cc(C(F)(F)F)c2)co1
Product: COC(=O)CCc1nc(-c2cc(Br)cc(C(F)(F)F)c2)co1
Yield: 47 %

Procedure:
The title compound was prepared from 2-(3-bromo-5-(trifluoromethyl)phenyl)-2-oxoethyl methyl succinate (Reference Example 43) by a procedure similar to the one described for methyl 3-(4-(3-chloro-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 36) to provide methyl 3-(4-(3-bromo-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (3.62 g, 47%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.I[CH2:19][CH2:20][CH3:21].[BH4-].[Na+]>C(=O)([O-])[O-].[Na+].[Na+]>[Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH:17]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccncc2)c1Cl
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Product: CCCN1CC=C(c2cccc(S(C)(=O)=O)c2Cl)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To neat 4-[2-chloro-3-(methylsulfonyl)phenyl]-pyridine (1.0 g, 3.8 mmol) was added 1-iodopropane (5 ml) and the resulting mixture was heated at 100° C. for 2 h. Excess 1-iodopropane was evaporated under reduced pressure and ethanol (60 ml) was added. The mixture was cooled to −20° C. and sodium borohydride (1.3 g, 38 mmol) was added in portions. The resulting mixture was stirred for 1 h, after which aqueous sodium carbonate (10%, 50 ml) was added. The aqueous phase was extracted with ethylacetate (3×100 ml) and the combined organic phases was dried (MgSO4), filtered and evaporated to dryness. The residue was purified by flash column chromatography (ethylacetate/methanol, 1:1) to give the title compound (0.5 g). MS m/z (rel. intensity, 70 eV) 313 (M+, 18), 286 (39), 285 (17), 284 (bp), 128 (12).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:16]=[CH:15][C:7]2[C:8](=[O:14])[NH:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=1.[CH3:17]I>C1COCC1>[F:3][C:4]1[CH:16]=[CH:15][C:7]2[C:8](=[O:14])[N:9]([CH3:17])[C:10]([CH3:12])([CH3:13])[O:11][C:6]=2[CH:5]=1
Reactant: CC1(C)NC(=O)c2ccc(F)cc2O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)c2ccc(F)cc2OC1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
Sodium hydride (60% dispersion in oil) (112 mg, 2.82 mmol) was added to a solution of 7-fluoro-2,2-dimethyl-2,3-dihydro-4H-1,3-benzoxazin-4-one (0.5 g, 2.56 mmol) in THF (10 mL) at 0° C., under argon then the mixture allowed to warm to RT and methyl iodide (0.18 mL, 2.82 mmol) added. The reaction was stirred at RT for 24 hours, poured into ice/water (50 mL) and extracted into ethyl acetate (50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), and the solvent removed in vacuo to give a yellow oil which was chromatographed on silica, eluting with 30-60% ethyl acetate in isohexane, to give the desired compound as a colourless oil (0.36 g). 1H NMR δ (CDCl3): 1.65 (s, 6H), 3.08 (s, 3H), 6.61 (dd, 1H), 6.75-6.80 (m, 1H), 7.93-7.96 (m, 1H); m/z 210 (M+H)+
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[N:23]=[C:22]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:21]=3)=[CH:16][CH:15]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[CH:27]([O:26][C:24]1[N:23]=[C:22]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[N:21]=[C:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:3]([C:4]([N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)=[O:6])=[CH:2][CH:10]=3)=[O:36])=[CH:19][CH:18]=2)[N:25]=1)([CH3:28])[CH3:29]
Reactant: Cc1cc(NC(=O)Nc2ccc(-c3nc(OC(C)C)nc(N4CCOCC4)n3)cc2)ccc1C(=O)O
Reactant: CN1CCNCC1
Product: CC(C)Oc1nc(-c2ccc(NC(=O)Nc3ccc(C(=O)N4CCN(C)CC4)cc3)cc2)nc(N2CCOCC2)n1
Yield: 44 %

Procedure:
Starting from methyl 4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid (160 mg, 0.33 mmol) and 4-methylpiperazine following the procedure as outlined in Experimental 71, 80 mg (44% Yield) of the titled compound was isolated as white solid. MS (ESI) m/z 281.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH2:23])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N)c1
Reactant: CCOC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCNc1ccc(Cl)cc1Oc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 46.6 %

Procedure:
A mixture of tert-butyl[3-(2-amino-5-chlorophenoxy)benzyl]carbamate (3.5 g, 10 mmols), ethyl 6-bromohexanoate (3.6 ml, 21 mmols), potassium carbonate (4.2 g, 10 mmols) and N,N-dimethylformamide (30 ml) was stirred at 60° C. for 24 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 6-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]aminohexanoate (2.29 g, 46.6%).
Reaction SMILES: [O:1]=[S:2](Cl)Cl.[Br:5][C:6]1[CH:7]=[C:8]([C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:15])[CH2:13][OH:14])[CH:9]=[CH:10][CH:11]=1.N1C=CC=CC=1>CC#N>[C:19]([O:18][C:17]([N:16]1[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([Br:5])[CH:7]=2)([CH3:15])[CH2:13][O:14][S:2]1=[O:1])=[O:23])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC(C)(CO)c1cccc(Br)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1S(=O)OCC1(C)c1cccc(Br)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of SOCl2 (5.7 mL, 2.5 eq) in dry CH3CN (37 mL) under argon was cooled to −40° C. was added tert-butyl 2-(3-bromophenyl)-1-hydroxypropan-2-ylcarbamate (DC3; R4=Me) (10.3 g, 31 mmol) in dry CH3CN (27 mL) was added dropwise, followed by the addition of dry pyridine (12.4 mL, 160 mmol, 5 eq). The mixture was then allowed to warm to RT in 1 h. The mixture was concentrated to about 30 mL. EtOAc (30 mL) was added and the precipitate was filtered off. The filtrate was concentrated in vacuo to give 10.4 g (89%) of 3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2-oxide as a colorless oil. 1H NMR (CDCl3) 7.64 (t, J=2.0 Hz, 1H), 7.36-7.53 (m, 2H), 7.24 (m, 1H), 4.52 (q, J=9.5 Hz, 2H), 1.86 (s, 3H), 1.42 (br s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[OH-].[Na+].ClCCl.[CH3:16][C:17]([CH3:19])=[O:18]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:16]/[C:17](=[O:18])[CH3:19])=[C:4]([F:10])[CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)/C=C/c1ccc(Cl)cc1F
Yield: 76 %

Procedure:
To a mechanically stirred solution of 4-chloro-2-fluorobenzaldehyde (23.8 grams (g), 0.15 mole (mol)) in acetone (100 milliliters (mL)) at room temperature was added over 20 minutes (min) a solution of sodium hydroxide (NaOH, 6.6 g, 0.165 mol) in water (H2O, 400 mL). After stirring the reaction mixture overnight, dichloromethane (CH2Cl2, 100 mL) was added. The aqueous layer was separated and extracted with CH2Cl2 (100 mL), and the combined organic extracts were washed with brine and dried over magnesium sulfate (MgSO4). Solvent removal followed by Kugelrohr distillation gave 4-(4-chloro-2-fluorophenyl)-3-buten-2-one (1; 22.5 g, 76%) as a colorless liquid, which solidified upon standing: by 70-80° C., 0.1 mmHg (13.33 pascals (Pa)); 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=16.5 Hz, 1H), 7.50 (t, J=8.1 Hz, 1H), 7.22-7.12 (m, 2H), 6.76 (d, J=16.5 Hz, 1H), 2.39 (s, 3H); HRMS-ESI (m/z): calcd for C10H8ClFO, 198.024. found 198.025.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[C:7]([CH:12]([C:14]2[N:15]=[CH:16][N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:18]=2)O)=[C:6]([CH2:38][CH3:39])[CH:5]=1)[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[C:7]([CH2:12][C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)=[C:6]([CH2:38][CH3:39])[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(CC)c(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c(CC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(CC)c(Cc2c[nH]cn2)c(CC)c1

Procedure:
Prepared in analogy to Example 57(e) from rac-(4-ethoxy-2,6-diethyl-phenyl)-(1-trityl-1H-imidazol-4-yl)-methanol, triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 70° C. for 16 h. White crystalline solid. MS (ISP): 259.4 ([M+H]+).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[NH2:16].Cl.N1C=CC=CC=1>O>[NH2:16][C:7]1[N:6]([CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]=2[OH:2])[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: COc1ccccc1CN1Cc2ccccc2N=C1N
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: NC1=Nc2ccccc2CN1Cc1ccccc1O
Temperature: 140 °C

Procedure:
120 mg (0.45 mmol) 3-(2-methoxybenzyl)-3,4-dihydroquinazolin-2-amine and 5 g pyridine hydrochloride were combined and heated for 4 hours at approx. 140° C. After cooling the melt, the residue was dissolved in water, extracted three times with dichloromethane and the combined organic phases were dried, filtered and evaporated. The resulting crude product was purified over MPLC (silica gel: Bischoff Prontoprep 60-2540-C18E, 32 μm; mobile phase: CH3CN/H2O+0.1% acetic acid) and subsequent lyophilization yielded the target product as a beige white solid; 110 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([C:13]3[CH:14]=[C:15]([C:19]#[C:20][CH:21]([NH:23][OH:24])[CH3:22])[CH:16]=[CH:17][CH:18]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1.[Si]([N:29]=[C:30]=[O:31])(C)(C)C.CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([C:13]3[CH:14]=[C:15]([C:19]#[C:20][CH:21]([N:23]([OH:24])[C:30]([NH2:29])=[O:31])[CH3:22])[CH:16]=[CH:17][CH:18]=3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C#Cc1cccc(C2CC(c3ccc(F)cc3)=NO2)c1)NO
Solvent: CO
Solvent: C1CCOC1
Product: CC(C#Cc1cccc(C2CC(c3ccc(F)cc3)=NO2)c1)N(O)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of the product of Step 2, above (11, 1.9 g, 5.8 mmol), in THF (10 ml) was added TMS-NCO (1.1 ml, 8.8 mmol), and the reaction mixture was stirred at room temperature for 2 hours. To the mixture was added methanol (5 ml) and the reaction mixture was stirred for 10 minutes and then solvent was removed by evaporation. The residue was chromatographed on silica gel (5% methanol/ethyl acetate) to give the crude title compound. Recrystallization from methanol/n-hexane/ethyl acetate afforded the title compound (12, 1.5 g, 67% yield) as colorless solids.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:17]1[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=1)[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH:27][C:28]1C(C2C3C(=CC=CC=3)N(CCCCC)C2=O)=CC2OCOC=2C=1>>[OH:26][C:25]1[C:17]([C:4]2([CH2:28][OH:27])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])=[CH:18][C:19]2[O:23][CH2:22][O:21][C:20]=2[CH:24]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (67%): 1H NMR (300 MHz, CDCl3) δ 10.85-10.63 (br, 1H), 7.48-7.35 (m, 2H), 7.28-7.19 (m, 1H), 6.96 (d, 1H), 6.52 (d, 2H), 5.82 (dd, 2H), 4.63 (d, 1H), 4.11 (d, 1H), 3.70 (d, 2H), 2.04-1.74 (br, 1H), 1.65-162 (m, 2H), 1.31-1.24 (m, 4H), 0.84 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 180.3, 152.6, 148.1, 143.2, 141.3, 129.2, 129.1, 126.2, 123.3, 112.4, 109.6, 108.2, 101.9, 101.3, 64.6, 59.8, 40.6, 28.9, 26.9, 22.2, 13.9; MS (ES+) m/z 370.1 (M+1).
Reaction SMILES: Cl.C1(C(=[N:15][C:16]2[S:20][CH:19]=[N:18][C:17]=2[C:21]([O:23][CH3:24])=[O:22])C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:15][C:16]1[S:20][CH:19]=[N:18][C:17]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1ncsc1N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1ncsc1N
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Aqueous 3N HCl (1 mL) was added to a solution of methyl 5-(diphenylmethyleneamino)thiazole-4-carboxylate (1.22 g, 3.81 mmol) in THF (5 mL). The reaction mixture was stirred for 1 h and the white solid which had formed was isolated by filtration to give methyl 5-aminothiazole-4-carboxylate (0.527 g, 2.72 mmol, 71%). Retention time (min)=0.422, method [7], MS(ESI) 159.0 (M+H).