Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:11]1[S:12][C@H:13]2[O:19][C@@H:18]3[CH2:20][O:21][CH:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:23][C@H:17]3[C@H:16]([OH:30])[C@H:14]2[N:15]=1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C.CCOC(C)=O>C(Cl)Cl>[CH3:31][S:32]([O:30][C@@H:16]1[C@H:14]2[N:15]=[C:11]([N:3]([C:4]([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:10])[CH2:1][CH3:2])[S:12][C@H:13]2[O:19][C@@H:18]2[CH2:20][O:21][CH:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:23][C@@H:17]12)(=[O:34])=[O:33]
Reactant: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@@H]3OC(c4ccccc4)OC[C@H]3O[C@@H]2S1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OS(C)(=O)=O)[C@@H]3OC(c4ccccc4)OC[C@H]3O[C@@H]2S1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl ethyl[(3aR,4aR,8aS,9R,9aR)-9-hydroxy-7-phenyl-3a,4a,5,8a,9,9a-hexahydro[1,3]dioxino[4′,5′:5,6]pyrano[3,2-d][1,3]thiazol-2-yl]carbamate (199.00 mg; 0.46 mmol; 1.00 eq.) in DCM (2.00 ml) was added methanesulfonyl chloride (0.05 ml; 0.68 mmol; 1.50 eq.) and N,N-diethylethanamine (0.09 ml; 0.68 mmol; 1.50 eq.). The reaction was stirred at room temperature for 2 h. The desired product was isolated by flash chromatography (KPNH, 20 to 75% EtOAc/Hex) to afford (3aR,4aR,8aR,9R,9aR)-2-[(tert-butoxycarbonyl)(ethyl)amino]-7-phenyl-3a,4a,5,8a,9,9a-hexahydro[1,3]dioxino[4′,5′:5,6]pyrano[3,2-d][1,3]thiazol-9-yl methanesulfonate (90 mg, 38%) as a white solid (once lyophilized).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[CH3:13][C:14]1[N:15]=[C:16]([NH2:25])[S:17][C:18]=1[CH2:19][CH2:20][O:21][N+:22]([O-:24])=[O:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:25][C:16]1[S:17][C:18]([CH2:19][CH2:20][O:21][N+:22]([O-:24])=[O:23])=[C:14]([CH3:13])[N:15]=1)=[O:12]
Reactant: Cc1nc(N)sc1CCO[N+](=O)[O-]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Product: Cc1nc(NC(=O)Cc2ccc(Cl)cc2Cl)sc1CCO[N+](=O)[O-]
Yield: 69 %

Procedure:
Pet-162 was prepared according to the general procedure described hereinabove and the procedure described above for the preparation of Pet-154, using (2,4-dichloro-phenyl)-acetic acid and 4-methyl-5-(2-nitrooxy-ethyl)-thiazol-2-ylamine (Pet-10) as the starting materials, in an overall yield of 69%.
Reaction SMILES: [CH2:1]1[O:8][C@@H:7]2[O:9][C@H:2]1[C@@H:3]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@@H:4]1[O:6][C@@H:5]12.[CH:18]([Mg]Br)=[CH2:19].[NH4+].[Cl-]>C1COCC1>[CH2:11]([O:10][C@@H:3]1[C@H:2]2[CH2:1][O:8][C@H:7]([O:9]2)[C@H:5]([CH:18]=[CH2:19])[C@H:4]1[OH:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(CO[C@H]2[C@@H]3O[C@@H]3[C@@H]3OC[C@H]2O3)cc1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C[C@H]1[C@@H]2OC[C@@H](O2)[C@@H](OCc2ccccc2)[C@@H]1O
Temperature: 60 °C

Procedure:
To a stirred solution of 1,6:2,3-dianhydro-4-O-benzyl-β-D-mannopyranose (7, 5.0 g, 21.3 mmol) in dry THF (25 ml), was added a solution of 1.77M vinylmagnesiumbromide 16 in THF (120.5 ml, 213 mmol). The mixture was gently refluxed for 3 h at 60° C. After cooling to room temperature a 2M NH4Cl aq. solution (650 ml, pH 8) was slowly added. The aqueous layer was extracted with ethyl acetate (2×250 ml). The combined organic layers were dried (MgSO4), filtered and concentrated. The crude product (4.87 g, 87%) was purified by flash chromatography using ethyl acetate/pentane 1:2 as eluent, to give 1,6-anhydro-4-O-benzyl-2-deoxy-2-C-vinyl-β-D-glucopyranose (8) as a white crystalline compound in 75.5% (4.23 g) yield. After recrystallization in ethanol: mp. 88°-91° C.; [α]D20 =-2.3° (c 4.1, CHCl3) (lit17 mp. 91°-93° C. [α]D20 =+1.2° (c 1.3, CHCl3)). 13C-NMR (50 MHz, CDCl3):δ135.5 (CH=), 137.7, 128.3), 127.6, 127.5 (Ph), 117.2 (CH2 =), 103.5 (C-1), 78.8 (C-4), 74.6 (C-3), 71.3, 70.4 (C-5, OCH2Ph), 65.4 (C-6), 51.8 ppm (C-2). 1H NMR (200 MHz, CDCl3): δ7.35 (d, 5H, Ph), 5.99 (m, 1H, CH=CH2), 5.25 and 5.17 (s, 1H og d, 1H, CH2 =), 4.63) (dd, 3H, OCH2Ph and H-5), 4.09 and 3.75 (d, 1H and m, 2H, H-3, H-6 and H-6'), 3.43 (s, 1H, H-4), 2.80 (broad s, 1H, OH), 2.45 (d, 1H, H-2). Anal. Calc. for C15H18O4 : C, 68.69; H, 6.92. Found: C, 68.58; H, 6.94.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C@@H:18]3[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]3[OH:24])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:38]([Si:41](OS(C(F)(F)F)(=O)=O)([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])([CH3:40])[CH3:39].O>C(Cl)Cl>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C@@H:18]3[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]3[O:24][Si:41]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:38]([CH3:40])[CH3:39])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCNC[C@H]2O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCNC[C@H]2O[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of N-(4-chloro-benzyl)-4-((+/−)trans-3-hydroxy-piperidin-4-yloxy)-N-isobutyl-benzenesulfonamide (202 mg, 447 μmol) in DCM (10 mL) was added triethylamine (187 μL, 1.34 mmol) followed by triisopropylsilyltrifluoromethanesulfonate (132 μL, 492 μmol) and the reaction was stirred at room temperature for 1 hour. To the reaction was added Et3N (187 μL, 1.34 mmol) followed by triisopropylsilyltrifluoromethanesulfonate (132 μL, 492 μmol) and reaction stirred for a further 30 minutes at room temperature. Water was added, and the mixture was extracted with DCM, filtered through a phase separator, concentrated then purified by silica gel column chromatography (0-10% MeOH in DCM) to give N-(4-chloro-benzyl)-N-isobutyl-4-((+/−)trans-3-triisopropylsilanyloxy-piperidin-4-yloxy)-benzenesulfonamide (189 mg, 70%). LCMS (m/z, Method A) ES+ 609 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.CN1CC[O:14][CH2:13]C1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:13]([O:9][CH2:8][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:14])[CH2:40][CH2:39]2)=[CH:36][CH:37]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CN1CCC(CO)CC1
Reactant: CN1CCOCC1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(C(=O)OCC3CCN(C)CC3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 10.3 %

Procedure:
(1-Methylpiperidin-4-yl)methanol (1.00 g, 7.74 mmol) was dissolved in DCM (20 mL) and cooled to 0° C. NMM (0.94 mL, 8.51 mmol) and 4-nitrophenyl chloroformate (1.56 g, 7.74 mmol) were added. The reaction mixture was stirred at 0° C. for 20 minutes and then added to a solution of 4-(4-methoxyphenyl)piperazine (1.64 g, 8.51 mmol) and DIPEA (2.02 mL, 11.01 mmol) in DMF (30 mL). The reaction mixture was stirred at room temperature for 4 h and then concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed sequentially with 1 M aq NaOH solution (5×100 mL), brine (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give (1-methylpiperidin-4-yl)methyl 4-(4-methoxyphenyl)piperazine-1-carboxylate (0.277 g, 10.3%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[S:22]([Cl:32])([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>C(Cl)(Cl)Cl>[ClH:32].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH:21][S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(N3CCN(CCN)CC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc2cccc(N3CCN(CCNS(=O)(=O)c4ccc(C)cc4)CC3)c2c1
Product: Cl

Procedure:
This compound was prepared according to the method described in Example 1, Stage E, from 1-(7-methoxy-1-naphthyl)-4-(2-aminoethyl)piperazine and tosyl chloride in solution in chloroform.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=O.[C-]#[N:14].[K+].C[CH:17]([OH:19])C>C(O)(=O)C>[Cl:12][C:7]1[CH:6]=[C:5]([C:3]2[NH:14][C:17](=[O:19])[O:1][CH:2]=2)[CH:10]=[CH:9][C:8]=1[Cl:11]
Reactant: CC(C)O
Reactant: O=C(CO)c1ccc(Cl)c(Cl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(Cl)c(Cl)c2)co1
Temperature: 50 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A mixture of 2-hydroxy-3′,4′-dichloroacetophenone (10.3 g), potassium cyanide (8.1 g) and 2-propanol (100 ml) was heated to 50° C., to which was added dropwise acetic acid (6.0 g) gradually and stirred at 50° C. for 2 hours. The reaction mixture was concentrated and poured into ice water (200 ml). The solid precipitates were filtered, washed with water, and air-dried to give crystals of 4-(3′,4′-dichlorophenyl)-2-oxazolone (6.0 g, 52%). Recrystallization from tetrahydrofuran-hexane gave pale yellow prisms. Melting point 262-263° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][CH:29]=[CH:28]3)=[C:5]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[N:7][CH:8]=1)#[N:2].F[P-](F)(F)(F)(F)F.[N:41]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:45]2C=CC=CC=2N=N1.CN.CO>CN(C=O)C.CS(C)=O>[C:1]([C:3]1[C:4]([NH:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][CH:29]=[CH:28]3)=[C:5]([C:9]2[CH:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([NH:41][CH3:45])=[O:23])=[CH:19][CH:20]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[N:7][CH:8]=1)#[N:2]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: N#Cc1cncc(-c2cccc(-c3ccc(C(=O)O)cc3)c2)c1Nc1ccc2[nH]ccc2c1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(-c2cccc(-c3cncc(C#N)c3Nc3ccc4[nH]ccc4c3)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.1 %

Procedure:
To a solution of 3′-[5-cyano-4-(1H-indol-5-ylamino)pyridin-3-yl]biphenyl-4-carboxylic acid 134 (40 mg, 0.09 mmol) and BOP (41 mg, 0.09 mmol) in DMF (1 mL) was added methylamine solution in MeOH (2M, 47 uL, 0.09 mmol) followed by TEA (19 uL, 0.14 mmol). The reaction mixture was stirred for 12 h at r.t. The crude reaction mixture was then dissolved in dimethylsulfoxide (DMSO, 1 mL) and purified by reversed phase HPLC to give 16 mg 3′-[5-cyano-4-(1H-indol-5-ylamino)pyridin-3-yl]-N-methyl biphenyl-4-carboxamide 196 (39%). MS: 44.2 (M+H); HPLC retention time: 2.10 min.(a).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[OH:12].[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[O:12][CH3:14]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(C#N)ccc1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(C#N)ccc1OC
Temperature: 65 °C
Yield: 42 %

Procedure:
To a mixture of methyl-2-hydroxy-5-cyano-benzoate (2.g, 5.6 mmol), K2CO3 (4.68 g, 16.8 mmol) in acetone (50 ml) was added methyl iodide (0.7 ml, 5.6 mmol). The reaction was then heated at 65° C. overnight resulting in formation of a solid which was filtered off whilst hot and washed with acetone to give 5-cyano-2-methoxy-benzoic acid methyl ester (0.45 g). The crude product was dissolved in THF (5 ml) and then treated with LiOH (0.108 g 0.26 mmol) in water (5 ml) and stirred at room temperature overnight. The reaction was acidified with 2M HCl and extracted EtOAc (×2). The organic portion dried (MgSO4) and reduced in vacuo to give 5-cyano-2-methoxy-benzoic acid (0.277 g). (LC/MS Acidic: Rt 2.92, [M+H]+ 178).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH2:29][CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:34][C@@H:31]([CH2:32][OH:33])[CH2:30][NH:29][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: NC[C@@H](O)CO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC[C@@H](O)CO)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with (R)-3-aminopropane-1,2-diol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=449.3 [M+H]+.
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[NH:3][CH:2]=1.C=O.[C:18]([BH3-])#N.[Na+].Cl>C(#N)C>[N:1]1[CH:5]=[C:4]([CH2:6][N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[CH3:18])[NH:3][CH:2]=1
Reactant: [BH3-]C#N
Reactant: COc1cccc(NCc2cnc[nH]2)c1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: COc1cccc(N(C)Cc2cnc[nH]2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.8 %

Procedure:
(3H-Imidazol-4-ylmethyl)-(3-methoxy-phenyl)-amine (0.070 g, 0.34 mmol) was dissolved in acetonitrile (10 ml). Then formaldehyde (0.0.06 ml, 0.86 mmol, 37% aqueous solution) and sodium cyanoborohydride (0.065 g, 1.03 mmol) were added and the reaction mixture was allowed to stir at room temperature for 10 minutes. The reaction mixture was then acidified to pH 2-3 by dropwise addition of concentrated hydrochloric acid whereupon precipitation occurred. The mixture was stirred for a further 1 h at room temperature before being concentrated in vacuo. The residue was taken up in ethyl acetate, washed with 1 M aqueous sodium hydroxide solution and the organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified using flash chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: methanol/dichloromethane gradient) to yield a white solid (0.056 g, 75%); MS (ISP): 218.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[S:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([S:12][C:11]([F:21])([F:10])[F:20])[CH:14]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1cccc(SC(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1cccc(SC(F)(F)F)c1

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-(trifluoromethylthio)aniline were reacted to provide 2-chloro-5-fluoro-N4-[3-(trifluoromethylthio)phenyl]-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.13 (bs, 1H), 7.92 (bs, 1H), 7.89–7.84 (m, 1H), 7.48–7.45 (m, 2H), 7.04 (bs, 1H); LCMS: purity: 97%; MS (m/e): 325(MH+).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:19](=O)[CH3:20])=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:8][CH2:7][C:6]=2[CH:18]=1.[N:22]1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>O>[CH3:20][C:19]1[C:3]2[C:2](=[CH:18][C:6]3[CH2:7][CH2:8][N:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:11][C:5]=3[CH:4]=2)[O:1][N:22]=1
Reactant: c1ccncc1
Reactant: CC(=O)c1cc2c(cc1O)CCN(C(=O)C(F)(F)F)CC2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: Cc1noc2cc3c(cc12)CCN(C(=O)C(F)(F)F)CC3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-[8-hydroxy-3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]ethanone (7.4 mmol) in pyridine (15 ml) hydroxylamine hydrochloride (8.9 mmol) was added at room temperature and the reaction mixture was stirred for 4 h. Solvent was removed under reduced pressure, the residue was partitioned between 10% aqueous Na2CO3 and EtOAc. The organic layer was collected and the aqueous phase extracted twice with EtOAc. The combined organic layers were concentrated and the resulting material was dissolved in THF (5 ml) and Ph3P (15 mmol) was added. The reaction mixture was stirred at 50° C. for 10 min while DEAD (15 mmol, 40% in toluene) was slowly added. The reaction mixture was stirred at 50° C. for 15 min then cooled to room temperature and water (0.4 ml) was added. Solvent was removed under reduced pressure and the residue was submitted to column chromatography to provide 3-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-isoxazolo[4,5-h][3]benzazepine (NMR 1H, CDCl3): δ 7.4-7.3 (m, 2H), 3.85-3.65 (m, 4H), 3.15-3.05 (m, 4H), 2.55 (s, 3H). MS (m/z): 299 [MH]+). Treatment with K2CO3 (4 eq) in MeOH:H2O (1:1) gave the title compound (1.3 mmol) as pale yellow oil, which was used without further characterisation.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][CH:10]([CH3:13])[CH:11]=O.[CH2:14]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[CH2:22]([N:21]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([CH:10]([CH3:13])[CH3:11])[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)C=O
Reactant: C#Cc1ccccc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)C(C#Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
In a dry, argon flushed 5 mL flask, equipped with a magnetic stirrer and a septum, CuBr (1.5 mg, 0.01 mmol, 5 mol %) and (R)(+)-FLiNAP (5.7 mg, 0.011 mmol, 5.5 mol %) were suspended in dry toluene (1 mL) and stirred for 30 min. Phenylacetylene (9) (21 mg, 0.2 mmol), 2-methylpropanal (7) (15 mg, 0.2 mmol) and dibenzylamine (8) (40 mg, 0.2 mmol) were then added. The reaction mixture was stirred at room temperature for 2 days. The crude product was concentrated under reduced pressure and purified by column chromatography on silica gel (95:5 pentane/ether) to yield the title compound 10 as an enantiomeric mixture. The enantiomers were subsequently separated using HPLC [(Chiralcel OD-H, 99% n-heptane/1% i-propanol, 0.2 mL/min): t, (min)=19.94 (−), 20.98 (+)]. The (−) isomer was isolated as an oil (60 mg, 85% yield, 87% ee).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:20]1[CH2:23][CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(OCC)C.C(N(CC)CC)C.CN(C)C=O>[N:20]1([C:16](=[O:18])[CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][CH2:13]2)[CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)CN1CCN(C(=O)c2ccccc2)CC1
Reactant: C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(C(=O)c2ccccc2)CC1)N1CCC1
Temperature: 25 °C
Reaction time: 66 h
Yield: 31.6 %

Procedure:
To (4-benzoylpiperazin-1-yl)acetic acid (2 g) was added N,N-dimethylformamide (80 ml) at room temperature, and then azetidine hydrochloride (1.51 g) and triethylamine (4.49 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.09 g) and 1-hydroxybenzotriazole (2.18 g) were added thereto in this order, and the mixture was stirred at room temperature for 66 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml), brine (50 ml) in this order and dried over anhydrous sodium sulfate The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then suspended in diethyl ether (10 ml). The solid was filtered off and dried under aeration to provide the titled compound (731.5 mg) as white powder.
Reaction SMILES: [C:1]([CH:4]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH2:8][CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5]1)#[C:2][CH3:3].C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O.C([O-])(O)=O.[Na+].C(N(CC)CC)C.[NH2:63][C:64]1[N:69]=[CH:68][C:67]([S:70](Cl)(=[O:72])=[O:71])=[CH:66][CH:65]=1>C(Cl)Cl>[NH2:63][C:64]1[N:69]=[CH:68][C:67]([S:70]([N:6]2[CH2:7][CH2:8][N:9]([C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:25])([C:17]([F:20])([F:18])[F:19])[C:21]([F:22])([F:23])[F:24])=[CH:14][CH:15]=3)[CH:4]([C:1]#[C:2][CH3:3])[CH2:5]2)(=[O:72])=[O:71])=[CH:66][CH:65]=1
Reactant: Nc1ccc(S(=O)(=O)Cl)cn1
Reactant: CC#CC1CN(C(=O)OCc2ccccc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CC1CN(S(=O)(=O)c2ccc(N)nc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 2-L round-bottomed flask was charged with benzyl 3-(1-propyn-1-yl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (21.8 g, 43.5 mmol, step 5) and TFA (130 mL). Trifluoromethanesulfonic acid (11.6 mL, 131 mmol, Acros/Fisher Scientific, Waltham, Mass.) was added slowly at rt resulting orange cloudy mixture. After stirring at rt for 10 min, the volume of the reaction mixture was reduced to half in vacuo. Solid NaHCO3 was added in potions until the mixture became sludge. Saturated aqueous NaHCO3 (800 mL) was added slowly until the pH was about 8. The aqueous phase was extracted with EtOAc (3×250 mL). The combined organic phases were washed with water (500 mL) and saturated aqueous NaCl (500 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. This material was dissolved into DCM (200 mL) and triethylamine (31.0 mL, 222 mmol) was added. Then 6-aminopyridine-3-sulfonyl chloride (9.40 g, 48.8 mmol, published PCT patent application no. WO 2009/140309) was added in potions over 10 min period. The brown mixture was stirred at room temperature for 10 min. The reaction mixture was washed with water (300 mL) and saturated aqueous NaCl (300 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (780 g of total silica, 30 to 90% EtOAc in hexanes) to afford 2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (19.4 g) as a mixture of two enantiomers.