Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:30])([F:29])[CH2:5][N:6]=[C:7]([NH2:28])[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([S:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:26][CH3:27])=[N:21][S:22]([CH3:25])(=[O:24])=[O:23])[N:10]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:14]1[C:9]([NH:8][C:7]([NH2:28])=[N:6][CH2:5][C:4]([F:29])([F:3])[F:30])=[N:10][C:11]([S:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:26][CH3:27])=[N:21][S:22]([CH3:25])(=[O:23])=[O:24])=[N:12][CH:13]=1
Reactant: BrBr
Reactant: CNC(=NS(C)(=O)=O)NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNC(=NS(C)(=O)=O)NCCCSc1ncc(Br)c(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
A solution of bromine (0.064 g.) in methylene chloride (2 ml.) was added dropwise over 15 minutes to a stirred solution of 4-[2-(2,2,2-trifluoroethyl)-guanidino]-2-[3-(2-methylsulphonyl-3-methylguanidino)-propylthio]pyrimidine (0.176 g.) and pyridine (0.2 ml.) in methylene chloride (10 ml.), and the mixture stirred at room temperature for one hour. The solution was evaporated to dryness, and the residue purified by preparative thin layer chromatography using ethyl acetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent to give 5-bromo-4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-methylsulphonyl-3-methylguanidino)propylthio]-pyrimidine (0.12 g.), m.p. 166°-167° after recrystallisation from ethanol.
Reaction SMILES: F[C:2](F)(F)OC1C=C(C=CC=1)CBr.C(O[N:19]1[CH2:24][CH2:23][C:22]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=2)([CH2:25][OH:26])[CH2:21][C:20]1=C=O)(C)(C)C.Cl.[C:42]([C:44]1[CH:58]=[CH:57][C:47]([CH2:48][N:49]2[C:53]([CH2:54][Cl:55])=[CH:52][N:51]=[C:50]2[CH3:56])=[CH:46][CH:45]=1)#[N:43]>>[ClH:55].[CH3:2][O:26][CH2:25][C:22]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:36])([F:38])[F:37])[CH:29]=2)[CH2:23][CH2:24][N:19]([CH2:54][C:53]2[N:49]([CH2:48][C:47]3[CH:57]=[CH:58][C:44]([C:42]#[N:43])=[CH:45][CH:46]=3)[C:50]([CH3:56])=[N:51][CH:52]=2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)ON1CCC(CO)(Cc2cccc(OC(F)(F)F)c2)CC1=C=O
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: Cc1ncc(CCl)n1Cc1ccc(C#N)cc1
Agent: Cl
Product: COCC1(Cc2cccc(OC(F)(F)F)c2)CCN(Cc2cnc(C)n2Cc2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using the protocol described in Example 30, Step A-C using 3-(trifluoromethoxy)benzyl bromide in Step B, and in Example 52, Step B-E substituting N-tert-butoxycarbonyl-4-(3-methylbenzyl)-4-hydroxymethylpiperidine with N-tert-butoxy-carbonyl-4-(3-trifluoromethoxybenzyl)-4-hydroxymethylpiperidine in Step B, and substituting 1-(4-cyanobenzyl)-5-chloromethyl-imidazole hydro-chloride salt with 1-(4-cyanobenzyl)-5-chloromethyl-2-methylimidazole hydrochloride salt in Step E.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH:9]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:10][C:11]#[N:12])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[F:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[C:46](Cl)=[O:47].C(#N)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[C:46]([N:5]1[CH2:4][CH2:3][N:2]([CH2:8][CH:9]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:10][C:11]#[N:12])[CH2:7][CH2:6]1)=[O:47]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Reactant: COc1ccc(C(=O)Cl)cc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(C(=O)N2CCN(CC(CC#N)n3cc(-c4ncnc5[nH]ccc45)cn3)CC2)cc1F
Reaction time: 16 h

Procedure:
To a solution of 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (125 mg, 0.211 mmol; from Example 12, Step 2) in DCM (2 mL) was added triethylamine (177 uL, 1.27 mmol) followed by 3-fluoro-4-methoxybenzoyl chloride (80 mg, 0.4 mmol). The reaction was stirred at for 16 hours. 4-Dimethylaminopyridine (5 mg, 0.04 mmol) was added. Acetonitrile (0.30 mL) was added to aid in solubility and additional 3-fluoro-4-methoxybenzoyl chloride (80 mg, 0.4 mmol) was added. When reaction was complete as evidenced by LCMS, solvent was removed in vacuo. The residue was stirred in a mixture of 1:1 DCM:TFA for 1 hour, concentrated, then stirred in MeOH (3 mL) containing ethylenediamine (0.5 mL). Preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH, was used to purify the product (50 mg, 48%). 1H NMR (400 MHz, d6-dmso): δ 12.12 (br s, 1H), 8.81 (s, 1H), 8.68 (s, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 7.27-7.15 (m, 3H), 6.98 (d, 1H), 4.99 (tt, 1H), 3.86 (s, 3H), 3.57-3.17 (m, 6H), 2.89-2.77 (m, 2H), 2.60-2.32 (m, 4H); LCMS (M+H)+: 489.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Cl[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22]
Reactant: Oc1ccccc1Br
Reactant: O=C1CCCCC1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCCC1Oc1ccccc1Br
Temperature: 60 °C
Reaction time: 4 h
Yield: 56.1 %

Procedure:
A mixture of 2-bromophenol (5 g), potassium carbonate (5.99 g) and 2-chlorocyclohexanone (4.22 g) in N,N-dimethylformamide was stirred at 60° C. for 4 hours. The reaction mixture was poured into cold water and the separated oil was extracted with diethyl ether. The extract was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from n-hexane to give 2-(2-bromophenoxy)cyclohexanone (4.36 g).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:21]=[C:20]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Nc1nc2c(Br)cccn2n1
Product: CS(=O)(=O)c1cccc(-c2cccn3nc(N)nc23)c1

Procedure:
8-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.0 g, 4.7 mmol) and 3-(methanesulfonyl)phenyl boronic acid (1.0 g, 5.0 mmol) in a manner analogous to Step 2c. The reaction product was isolated as an off-white solid (0.99 g, 73%). MP=173-183° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.64-8.60 (m, 1H), 8.59 (t, J=1.6 Hz, 1H), 8.50-8.46 (m, 1H), 7.98-7.94 (m, 1H), 7.86-7.83 (m, 1H), 7.78 (dd, J=7.8, 7.8 Hz, 1H), 7.02 (dd, J=7.1, 7.1 Hz, 1H), 6.18 (s, 1H), 3.29 (S, 3H). MS=289 (MH)+. 13b) [8-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine and [8-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-phenyl-amine were prepared from 8-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.3468 mmol) and 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (90.0 L, 0.434 mmol) in a manner analogous to Step 2d. The title compound 8-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine was isolated as a yellow foam (0.047 g, 28%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.66 (t, J=1.7 Hz, 1H), 8.47-8.44 (m, 1H), 8.39-8.35 (m, 1H), 8.01-7.97 (m, 1H), 7.26 (dd, J=7.8, 7.8 Hz, 1H), 7.68-7.65 (m, 1H), 7.54-7.48 (m, 2H), 6.99 (dd, J=7.0, 7.0 Hz, 1H), 6.96-6.92 (m, 2H), 6.91 (s, 1H), 4.11 (t, J=6.1 Hz, 2H), 3.13 (s, 3H), 2.91 (t, J=6.1 Hz, 2H), 2.68-2.58 (m, 4H), 1.85-1.78 (m, 4H). MS=478 (MH)+.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][OH:13])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:14](Cl)(=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[C:3]([NH2:2])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:1][N:2]([CH2:11][CH2:12][O:13][C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CN(CCO)C(=O)c1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(C)C(=O)c1ccccc1
Product: NC(=O)c1ccccc1

Procedure:
N-methyl-N-2-oleoyloxyethyl)benzamide was prepared by the procedure of example 1 from 18 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)benzamide and 30 gms. (0.1 mole) of oleoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][C:7]=1[C:14]([NH2:16])=[O:15]>C(Cl)Cl>[F:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[C:14]([NH2:16])=[O:15]
Reactant: COc1ccc(F)c(C(N)=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(=O)c1cc(O)ccc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.9 %

Procedure:
(Method H) Boron tribromide solution (1.0 M in CH2Cl2, 23.6 ml, 23.6 mmol, 2 equiv.) was added slowly, dropwise to stirred solution of 2-fluoro-5-methoxybenzenecarboxamide (2.0 g, 11.8 mmol, 1 equiv.) in CH2Cl2 (60 ml), at r.t., under N2. The reaction mixture was stirred at r.t. for 48 h. The solvent was removed under reduced pressure, the residue was dissolved in water (120 ml) and extracted with EtOAc (4×100 ml). The combined organic extracts were washed with water (2×100 ml), dried (Na2SO4) and filtered through a pad of silica gel. The filtrate was evaporated to dryness under reduced pressure, to give the desired compound as a grey solid (1.50 g, 82%).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4](=[O:7])(O)[O-:5].[Na+].C(Cl)Cl.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O>[OH:3][NH:2][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:16]([O:15][C:13]([O:3][NH:2][C:4](=[O:7])[O:5][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C([O-])O
Reactant: NO
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(NO)OCc1ccccc1
Product: O=C(NOC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 2 °C
Yield: 13 %
Yield: 70 %

Procedure:
Hydroxylamine hydrochloride (8.31 g, 120 mmol) is dissolved in water (200 mL) followed by the introduction of sodium bicarbonate (17.7 g, 211 mmol). Then CH2Cl2 (200 mL) is added to the solution and resulting the mixture is cooled in an ice bath to 0-4° C. Benzyl chloroformate (16.7 mL, 117 mmol) is added with vigorous stirring while maintaining the temperature below 4° C. After addition is complete the reaction mixture is left to stir for 2 h. The biphasic reaction mixture is transferred into a separating funnel and CH2Cl2 is added until the organic phase clarified. The aqueous phase is extracted with CH2Cl2 (3×100 mL) and then washed with brine, dried over MgSO4 and concentrated to give a colourless solid. Flash column chromatography (silica gel, CH2Cl2 then ethyl acetate/petroleum spirits 3:7 then 1:0) affords 13.7 g (70%) of 51 as a colourless solid along with 4.60 g (13%) of 52 as a colourless oil. Spectroscopic data are identical to those reported above.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C@@H:17]1[CH2:22][CH2:21][CH2:20][O:19][CH2:18]1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])C1C=CC=CC=1.C(OC(OC)=O)(OC)=O>CO.[Pd]>[CH3:1][O:8][C:9]([NH:11][C@@H:12]([C@@H:17]1[CH2:22][CH2:21][CH2:20][O:19][CH2:18]1)[C:13]([O:15][CH3:16])=[O:14])=[O:10]
Reactant: COC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H]1CCCOC1
Agent: [Pd]
Agent: COC(=O)OC(=O)OC
Solvent: CO
Product: COC(=O)N[C@H](C(=O)OC)[C@@H]1CCCOC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.7 %

Procedure:
10% Pd/C (69.3 mg, 0.065 mmol) was added to a solution of (S)-methyl 2-(benzyloxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetate (200 mg, 0.651 mmol) and dimethyl dicarbonate [4525-33-1] (0.104 mL, 0.976 mmol) in MeOH (10 mL). The reaction mixture was vacuum flushed with N2, followed by H2, and then the reaction was stirred under H2 (55 psi) at rt for 5 h. The reaction mixture was filtered through CELITE®/silica pad and the filtrate was concentrated to a colorless oil. The crude oil was purified by flash silica chromatography (loading solvent: DCM, eluted with 30% EtOAc in hexanes) to yield product (S)-methyl 2-(methoxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetate (132 mg) as colorless oil. LC-MS retention time 0.92 min; m/z 231.97 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 5.24 (d, J=8.5 Hz, 1H), 4.34 (dd, J=8.9, 5.6 Hz, 1H), 3.84-3.97 (m, 2H), 3.77 (s, 3H), 3.70 (s, 3H), 3.29-3.38 (m, 1H), 3.23 (dd, J=11.2, 10.4 Hz, 1H), 2.03-2.14 (m, 1H), 1.56-1.75 (m, 3H), 1.32-1.43 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:13]=[C:14]([OH:22])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:22][C:14]1[CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=[C:12]([F:11])[CH:13]=1)[CH:5]=[O:6]
Reactant: Oc1cc(F)cc(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2cc(F)cc(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D30 starting from 3,4-difluorobenzaldehyde and 3-fluoro-5-(trifluoromethyl)phenol.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH:7]1([CH2:12]CC(O)=O)[CH2:11][CH2:10][CH2:9][CH2:8]1>C(Cl)Cl>[CH:7]1([CH2:12][CH2:1][C:2]([Cl:4])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCC1CCCC1
Solvent: ClCCl
Product: O=C(Cl)CCC1CCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 1.0 g of oxalyl chloride in 15 ml of methylene chloride is added dropwise to a 0° C. solution of 0.65 g of 3-cyclopentylpropionic acid in 15 ml of methylene chloride. The solution is allowed to warm to room temperature and is stirred for 6 hours. The solution is concentrated at reduced pressure, rediluted with 25 ml of methylene chloride and reconcentrated to give 3-cyclopentylpropionyl chloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:15][C:16]1[CH:32]=[CH:31][C:19]([O:20][CH2:21][CH:22]2[CH2:30][N:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH:24]3[CH2:23]2)=[CH:18][CH:17]=1>C(O)CC(C)C>[F:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][CH:22]2[CH2:30][N:25]3[CH2:26][CH2:27][N:28]([C:2]4[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=4)[CH2:29][CH:24]3[CH2:23]2)=[CH:31][CH:32]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: Fc1ccc(OCC2CC3CNCCN3C2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: Fc1ccc(OCC2CC3CN(c4ccc(Cl)cn4)CCN3C2)cc1
Yield: 1.9 %

Procedure:
A mixture of 3.8 g (26 mmol) of 2,5-dichloropyridine, 1.3 g (12 mmol) of sodium carbonate, 1.3 g (5.2 mmol) of (7RS,8aSR)-7-(4-fluorophenoxy)methyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 2), and 20 mL of isoamyl alcohol was heated at reflux for 18 hours. The solvent was evaporated, the residue taken up in water and ethyl acetate, and the pH adjusted to 11 with sodium carbonate. The layers were separated and the organic phase was dried (magnesium sulfate), filtered, and evaporated. Purification by medium pressure silica gel chromatography with ethyl acetate gave 35 mg (2%) of the title compound. Mp (.HCl) 202-206° C. HRMS calc'd for C19H21ClFN3O (MH+): 362.1435, found: 362.1451.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.C[O-].[Na+].Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C=O)C>[N:22]1([CH2:21][CH2:20][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]3)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(OCCN3CCOCC3)ccc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
6.4 g of methyl 6-hydroxy-2-naphthoate and 2.56 g of sodium methoxide are stirred under N2 at 40° C. for 30 min in 100 ml of DMF. 8.04 g of N-(2-chloroethyl)morpholine are then added and the mixture is stirred at 80° C. for 2 h. The reaction mixture is poured onto water, and the precipitate which is deposited is filtered off with suction. 9.2 g of methyl 6-[2-(4-morpholinyl)ethoxy]-2-naphthoate are obtained.
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]([F:23])([F:22])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:17]([OH:18])=[C:16]([C:19]([CH3:21])=[O:20])[CH2:15][S:14]2)=[CH:9][CH:8]=1.S(Cl)(Cl)(=O)=O>O>[F:22][C:6]([F:5])([F:23])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][CH:15]=[C:16]([C:19]([CH3:21])=[O:20])[C:17]=2[OH:18])=[CH:11][CH:12]=1
Reactant: CC(=O)C1=C(O)C(c2ccc(C(F)(F)F)cc2)SC1
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1csc(-c2ccc(C(F)(F)F)cc2)c1O
Temperature: -4 °C
Reaction time: 0.17 h
Yield: 74.3 %

Procedure:
A chloroform (223 mL) solution of 2-(4-trifluoromethylphenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (22.25 g, 69.46 mmol, purity: 90%) was cooled to −46° C., and to this solution, a chloroform (334 mL) solution of sulfuryl chloride (6.70 mL, 1.2 equivalent amounts) was dropwise added over a period of 10 minutes, followed by stirring at −4° C. for 10 minutes. The temperature of the solution was raised to 0° C., and water (45 mL) was dropwise added thereto over a period of 15 minutes, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a saturated sodium hydrogencarbonate aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to obtain a crude product. The obtained crude product was isolated and purified by silica gel column chromatography (eluent: hexane/chloroform=1/1 (v/v)) to give the desired product as a yellow solid (14.78 g, yield: 69%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Br:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27](O)=[O:28])[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1cccc(Br)c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(3-bromophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.60 (t, J=1.8 Hz, 1H), 7.49 (dt, J=7.8, 1.5 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.34 (t, J=7.7 Hz, 1H), 3.83 (d, J=4.2 Hz, 4H), 3.69 (s, 2H), 3.09-3.11 (m, 4H); MS (ESI−) M/Z 441 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])[N:10]=2)[CH2:4]1.Cl[C:28]([O:30][C@H:31]1[CH2:35][CH2:34][O:33][CH2:32]1)=[O:29].C(N(CC)CC)C>CN(C=O)C>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:11]1[N:10]=[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([CH2:2][NH:1][C:28](=[O:29])[O:30][C@H:31]3[CH2:35][CH2:34][O:33][CH2:32]3)[CH2:4]2)[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[N:12]=1
Reactant: Cc1ccc2c(N3CCC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Reactant: O=C(Cl)O[C@H]1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC[C@@H](CNC(=O)O[C@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(4-((S)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (126.8 mg, 0.364 mmol) was dissolved in 5 mL anhydrous DMF and cooled to 0° C., and a solution of (S)-tetrahydrofuran-3-yl chloroformate (65.4 mg, 0.436 mmol) in 200 □1 of DMF was added dropwise followed by the addition of triethylamine (74 mg, 0.102 mL, 0.728 mmol). The reaction was allowed to warm to room temperature and was complete after two hours. The mixture was partitioned between H2O and CH2Cl2, separated, and the aqueous layer was extracted twice with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, and concentrated to a yellow solid. Purification via silica gel chromatography using 98% CH2Cl2/2% MeOH gave (S)-tetrahydrofuran-3-yl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate as an off white solid (116 mg, 69%). LC/MS: m/z 463.5 (M+H)+ at 2.37 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:19](OC)[O:20]C)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>O1CCCC1.O>[CH2:1]([S:8][CH:9]([CH:19]=[O:20])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(CNC(=O)OC(C)(C)C)SCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCC(C=O)SCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
tert-Butyl [2-(benzylthio)-3,3-dimethoxypropyl]carbamate (9.4 g) was dissolved in tetrahydrofuran (50 mL) and water (50 mL), and acetic acid (100 mL) was added. The reaction mixture was stirred overnight at 50° C., and concentrated, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give the title compound (5.35 g, yield 66%) as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (1:19).
Reaction SMILES: [Na].[CH3:2][OH:3].[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][S:14]([C:17]1[N:27]=[C:20]2[N:21]=[C:22](Cl)[CH:23]=[C:24](Cl)[N:19]2[N:18]=1)(=[O:16])=[O:15].[C:28]([OH:31])(=O)C>>[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][S:14]([C:17]1[N:27]=[C:20]2[N:21]=[C:22]([O:31][CH3:28])[CH:23]=[C:24]([O:3][CH3:2])[N:19]2[N:18]=1)(=[O:16])=[O:15]
Reactant: CC(=O)O
Reactant: Cc1ccc(Cl)c(NS(=O)(=O)c2nc3nc(Cl)cc(Cl)n3n2)c1Cl
Reactant: CO
Agent: [Na]
Product: COc1cc(OC)n2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nc2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium (469 mg, 20.4 mmol) was added to 25 ml of methanol under nitrogen and allowed to react. The resulting solution was allowed to cool and then 2.14 g (5.0 mmol) of N-(2,6-dichloro-3-methylphenyl)-5,7-dichloro-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide were added with stirring. After about one hour, 1 ml of acetic acid was added and the mixture was poured into about 150 ml of ice water. The solid present was collected by filtration and dried to obtain 1.76 g (84.2 percent of theory) of the title compound as a white powder, m.p. 218°-221° C.