Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][C@H:16]1[CH3:21].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]=[C:39]([CH3:41])[O:38][N:37]=2)=[CH:32][CH:31]=1>CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[N:15]1[CH2:20][CH2:19][N:18]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]3[N:40]=[C:39]([CH3:41])[O:38][N:37]=3)=[CH:34][CH:35]=2)[CH2:17][C@H:16]1[CH3:21]
Reactant: C[C@@H]1CNCCN1c1nc(-c2ccncn2)cc(=O)n1C
Reactant: Cc1nc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(CN3CCN(c4nc(-c5ccncn5)cc(=O)n4C)[C@H](C)C3)cc2)no1
Reaction time: 4 h
Yield: 62.9 %

Procedure:
To a solution of 1-methyl-2-((2R)-2-methyl-piperazin-1-yl)-1H-[4,4′]bipyrimidinyl-6-one (0.15 g, 0.52 mmol) and potassium carbonate (0.22 g, 1.59 mmol) in N,N-dimethylformamide (1.5 ml) was added 3-[4-(bromomethyl)phenyl]-5-methyl-1,2,4-oxadiazole (0.14 g, 0.55 mmol) at room temperature and the mixture was stirred for 4 hours. The mixture was partitioned between water and dichloromethane, and the organic layer was washed with water, brine, and dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate) to afford 1-methyl-2-{(2R)-2-methyl-4-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-piperazin-1-yl}-1H-[4,4′]bipyrimidinyl-6-one (0.15 g, 63%).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].N1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1)(=[O:28])=[O:27]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccccc1N
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.6 %

Procedure:
To a solution of 2.00 g (0.013 mol) of methyl anthranilate dissolved in 20 mL of chloroform was added 3.2 mL (0.039 mol) of pyridine followed by 2.733 g (0.013 mol) of p-methoxybenzenesulfonyl chloride. The reaction mixture was stirred at room temperature for 5 h and then washed with 3N HCl and water. The organics were then dried over Na2SO4, filtered and concentrated in vacuo. The resulting white solid was washed with ether and dried in vacuo to provide 3.7 g (87%) of the desired sulfonamide. CI Mass Spec: 322 (M+H).
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13](Cl)[N:12]=[C:11]([NH2:16])[N:10]=2)=[CH:5][CH:4]=1.[NH2:23][C:24]1[CH:37]=[CH:36][C:27]([O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([Cl:35])[CH:30]=2)=[CH:26][CH:25]=1>>[NH2:16][C:11]1[N:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([Cl:35])[CH:30]=3)=[CH:36][CH:37]=2)[N:12]=1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cc1
Reactant: CC(C)(C)OC(=O)Oc1ccc(-c2cc(Cl)nc(N)n2)cc1
Product: Nc1nc(Nc2ccc(Oc3ccnc(Cl)c3)cc2)cc(-c2ccc(O)cc2)n1

Procedure:
This material was prepared by a method analogous to that described for Example 1, starting from the product from 4-(2-amino-6-chloropyrimidin-4-yl)phenyl tert-butyl carbonate and Intermediate 2R. 1H NMR (DMSO-d6) δ 9.79 (s, 1H), 9.25 (s, 1H), 8.22 (d, 1H), 7.86 (m, 2H), 7.74 (m, 2H), 7.09 (m, 2H), 6.95 (m, 2H), 6.80 (m, 2H), 6.39 (s, 1H), 6.23 (s, 2H); MS ES 406 (M+H)+, calcd 406, RT=2.74 min.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1.[OH-:35].[Na+]>>[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:26][C:27]=1[O:35][CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1
Reactant: Oc1ccc(-c2cccc(Cl)c2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: [OH-]
Agent: [Na+]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2Cl)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from 0, Step A was treated with 3′-Chloro-biphenyl-4-ol from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C25H25ClO5 [M+NH4]+: 458, [M+Na]+: 463.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH:6]1[C:19]2[C:10](=[CH:11][C:12]3[C:17]([C:18]=2[CH:20]=O)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[CH:16]1[C:17]2[C:12](=[CH:11][C:10]3[C:19]([C:18]=2[CH2:20][NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1c2ccccc2cc2ccccc12
Reactant: NCCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OCCCNCc1c2ccccc2cc2ccccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a stirred solution of 3-amino -1-propanol, 15a (0.87 g, 11.65 mmol) in 25% MeOH/CH2Cl2 (20 mL), was added a solution of aldehyde 8 (2.00 g, 9.7 mmol) in 25% MeOH/CH2Cl2 (15 mL) under N2. The mixture was stirred at room temperature overnight until the imine formation was complete (monitored by NMR). The solvent was removed in vacuo, the solid residue dissolved in 50% MeOH/CH2Cl2 (40 mL) and the solution was cooled to 0° C. NaBH4 (29.1 mmol) was added in small portions to the solution and the mixture was stirred at rt overnight. The solvent was removed in vacuo, the solid residue dissolved in CH2Cl2 (40 mL) and washed with 10% aq. Na2CO3 solution (3×30 mL). The CH2Cl2 layer was separated, dried over anhydrous Na2SO4, filtered and removed in vacuo to give an oily residue. The oil was purified by flash column chromatography (6% MeOH/CHCl3) to yield the product 14a as a pale yellow thick oil (78%), Rf=0.3 (6% MeOH/CHCl3); 1H NMR (CDCl3) δ 8.39 (s, 1H), 8.27 (d, 2H), 7.99 (d, 2H), 7.52 (m, 2H), 7.45 (m, 2H), 4.71 (s, 2H), 3.79 (t, 2H), 3.09 (t, 2H), 1.74 (q, 2H).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1([CH2:19][NH2:20])[CH2:18][CH2:17]1.C([BH3-])#N.[Na+]>CO>[CH:16]1([CH2:19][NH:20][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:18][CH2:17]1
Reactant: NCC1CC1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(Oc2ccc(CNCC3CC3)cc2)cc1
Reaction time: 48 h
Yield: 78.4 %

Procedure:
4-Phenoxybenzaldehyde (3.0 g, 15.1 mmol) and cyclopropylmethylamine (1.1 g, 15.1 mmol) were dissolved in methanol (85 mL) under a nitrogen at room temperature. Sodium cyanoborohydride (0.95 g, 15.1 mmol) was added, and stirring was continued for 48 hours. The solvent was evaporated, and the residue was suspended in ether, washed with brine, and dried over Na2SO4. The ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol in methylene chloride to provide 3.0 g (78%) of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 0.08-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.93-1.05 (m, 1H), 1.45 (br s, 1H), 2.50 (d, J=7.5 Hz, 2H), 3.78 (s, 2H), 6.95-7.03 (m, 4H) 7.05-7.13 (m, 1H), 7.25-7.38 (m, 4H). MS (DCl/NH3) m/e 254 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[CH:13](N(CC)C(C)C)(C)[CH3:14].C[Si](C#C)(C)C>C1(C)C=CC=CC=1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:13]([C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)#[CH:14]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: Cc1ccccc1
Product: C#Cc1nc(C)c(C(=O)OCC)s1
Temperature: 40 °C
Yield: 79.4 %

Procedure:
To a solution of ethyl 2-bromo-4-methylthiazole-5-carboxylate (0.50 g, 2.00 mmol) in anhydrous toluene (5 mL) was added copper(I) iodide (0.008 g, 0.040 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.028 g, 0.040 mmol) and N,N-diisopropylethylamine (0.52 mL, 3.00 mmol). The reaction mixture was degassed and the reaction flask was flashed and filled with nitrogen followed by the addition of trimethylsilylacetylene (0.42 mL, 3.00 mmol). The reaction mixture was heated at 40° C. for 5 hours, cooled to ambient temperature, poured onto a silica gel pad and eluted with hexanes and hexanes/ethyl acetate (10/1). The collections were concentrated in vacuo and the obtained clear oil was dissolved in dichloromethane (5 mL) and treated with 10% aqueous sodium hydroxide (0.5 mL) at ambient temperature for 1 hour. The reaction mixture was diluted with dichloromethane (15 mL), washed with water (7 mL) and brine (7 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a yellowish solid (0.31 g, 77%): 1H NMR (300 MHz, CDCl3) δ 4.24 (q, J=7.1 Hz, 2H), 3.53 (s, 1H), 2.63 (s, 3H), 1.27 (t, J=7.1 Hz, 3H); MS (ES+) m/z 196.2 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[C:17]([CH3:25])=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20]>ClCCl.CCCCCC>[Cl:15][C:16]1[C:17]([CH3:25])=[C:18]([C:19]([N:6]2[CH2:5][CH2:4][NH:3][C:2](=[O:1])[CH2:7]2)=[O:20])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1c(Cl)cccc1C(=O)Cl
Reactant: O=C1CNCCN1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(Cl)cccc1C(=O)N1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Oxopiperazine (1.5 g, 14.98 mmol, commercially available from e.g. Sigma-Aldrich) was suspended in dry dichloromethane (DCM) (40 mL), cooled in an ice bath before adding triethylamine (3.13 mL, 22.47 mmol), followed by 3-chloro-2-methylbenzoyl chloride (I130) (2.97 g, 15.73 mmol) in Dichloromethane (DCM) (15 mL) dropwise over 15 mins. The reaction mixture was then stirred for 16 hours at RT, under argon. Solvent removed under reduced pressure. Residue partitioned between DCM (100 ml) and water (60 ml). Layers separated and aqueous layer extracted with DCM (2×50 ml). Combined extracts were washed with saturated sodium bicarbonate solution (70 ml), brine (70 ml), dried (Na2SO4), filtered and evaporated to afford an off-white solid. Solid was stirred in n-hexane (50 mL) at 55° C. for 30 mins, before filtering and drying in the vacuum oven at 40° C. for 18 hours to afford the desired product in 3.39 g as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]2[O:17][CH2:16][CH2:15][C:8]3([S:12][C:11](=[O:13])[NH:10][C:9]3=[O:14])[C:6]=2[CH:7]=1.[C:19](O)(=[O:21])[CH3:20]>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:21])[CH3:20])[C:5]2[O:17][CH2:16][CH2:15][C:8]3([S:12][C:11](=[O:13])[NH:10][C:9]3=[O:14])[C:6]=2[CH:7]=1
Reactant: CC(=O)O
Reactant: Nc1cc(F)cc2c1OCCC21SC(=O)NC1=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(F)cc2c1OCCC21SC(=O)NC1=O

Procedure:
61 mg of (±)-6-fluoro-8-amino-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione were heated to 50° C. for 90 minutes in a mixture of 1.2 ml of glacial acetic acid and 1.2 ml of acetic acid anhydride and the resulting mixture was subsequently concentrated to dryness in vacuo. After boiling up briefly with active carbon in methanolic solution, the residue was crystallized from methanol and yielded (±)-6-fluoro-8-acetamido-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione in the form of a light brownish material of melting point 278°-280° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:12]1([CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:24]2[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][N:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:26][CH2:25]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: C1CCN(CCCN2CCNCC2)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(CCCN2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,4-dichlorophenylisocyanate (0.3 g; 1.5 mmol) in a mixture of DMF (0.5 ml) and dichloromethane (5 ml) was added to 1-(3-piperidinopropyl)-piperazine (0.21 g; 1 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight.
Reaction SMILES: [CH:1]1([N:7]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[C@H:8]2[CH2:12]C[NH:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([NH:25][C@H:26]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:27]([NH:29]N1CC(NC2CCCCC2)C1)=[O:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(Cl)(=O)C(C)C>[C:18]([NH:25][C@H:26]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:27]([NH:29][N:10]1[CH2:9][CH:8]([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:13](=[O:17])[CH:14]([CH3:15])[CH3:16])[CH2:12]1)=[O:28])([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)NN1CC(NC2CCCCC2)C1
Reactant: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCNC1
Agent: CC(C)C(=O)Cl
Product: CC(C)C(=O)N(C1CCCCC1)C1CN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared following the procedure described in Step A of Intermediate 36 using (2R)-2-(BOC)amino-N-[3-(cyclohexylamino)azetidine-1-yl]-3-(4-chlorophenyl)propionamide prepared in Intermediate 202 and isobutyrylchloride.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C@H:5]([CH:46]([CH3:48])[CH3:47])[CH2:6][C@H:7]([OH:45])[C@@H:8]([NH:16][C:17]([C@@H:19]([NH:26][C:27]([C@@H:29]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)=[O:18])[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.[CH2:58]([N:62]=[C:63]=[O:64])[CH2:59][CH2:60][CH3:61]>C(O)C>[CH2:58]([NH:62][C:63](=[O:64])[NH:2][CH2:3][CH2:4][C@H:5]([CH:46]([CH3:48])[CH3:47])[CH2:6][C@H:7]([OH:45])[C@@H:8]([NH:16][C:17]([C@@H:19]([NH:26][C:27]([C@@H:29]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:41])[CH3:42])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)=[O:18])[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:59][CH2:60][CH3:61]
Reactant: CCCCN=C=O
Reactant: CC(C)[C@@H](CCN)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCCCNC(=O)NCC[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
0.100 g (0.145 mmol) of t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-6-amino-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate hydrochloride in 1 ml of ethanol is treated with 0.05 ml (0.25 mmol) of Hunig base, cooled to 0° and treated with 0.018 ml (0.16 mmol) of butyl isocyanate in 1 ml of ethanol. Then, the reaction mixture is stirred at room temperature for 2 hours and subsequently evaporated under reduced pressure. Chromatography of the residue on 5 g of silica gel with a mixture of methylene chloride and isopropanol as the eluting agent yields 0.063 g of t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-6-(3-butylureido)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate as an amorphous solid, MS: 754 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([F:26])([F:25])[F:24])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14]C)=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17].[Br-].[Li+].C(N(CC)CC)C>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([F:26])([F:24])[F:25])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(C(F)(F)F)c(F)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of dimethyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (7.17 g, 19.00 mmol) in acetonitrile (60 mL) and water (1.2 mL) was added lithium bromide (13.20 g, 152.02 mmol) and triethylamine (10.54 mL, 76.01 mmol). The resulting mixture was heated under reflux for 2 h, then cooled to room temperature. Water was added and acetonitrile removed by evaporation. The aqueous layer was further diluted with water, then washed with MTBE. The organic layer was extracted with water. The combined aqueous layers were acidified with 3.8 M HCl, a colorless precipitate formed. The solids were extracted with DCM 6 times. The aqueous layer was extracted twice again with DCM. The combined organic layers were dried over MgSO4 and evaporated. 2-(3-Fluoro-4-(trifluoromethyl)benzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (6.56 g, 95%) was isolated as an off-white solid. MS m/z 364 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-:32].[Na+].O>O1CCCC1>[ClH:1].[CH3:24][NH:23][CH2:22][C:13]1[CH:14]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:32])=[N:7][CH:6]=2)(=[O:10])=[O:9])[CH:12]=1
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(Cl)nc2)c1)C(=O)OC(C)(C)C
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(O)nc2)c1
Product: Cl
Temperature: 50 °C
Reaction time: 48 h

Procedure:
tert-Butyl {[1-(6-chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate (175 mg) was dissolved in tetrahydrofuran (10 mL), a 8 mol/L aqueous sodium hydroxide solution (3.8 mL) was added, and the mixture was stirred at 50° C. for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→0:1) to give a free salt of the title compound. To a solution (1 mL) of the obtained free salt in ethanol was added a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL). After stirring at room temperature for 4 hr, the solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-ethyl acetate to give the title compound (yield 40 mg, 27%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([S:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)=[CH:20]2.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([S:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:12]([C:9]3[CH:10]=[CH:11][C:5]4[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)=[O:14])[CH2:32][CH2:31]1)=[CH:20]2
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.5 %

Procedure:
3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (21 mg, 0.09 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-ylamine (30 mg, 0.09 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by 1-hydroxybenzotriazole (13 mg, 0.10 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (20 mg, 0.10 mmol, 1.15 eq) and N,N-diisopropylethylamine (35 μL, 0.20 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×5 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide as a white solid (30 mg, 59% yield).
Reaction SMILES: C(ON=O)(C)(C)C.[CH3:8][CH:9]([C:11]1[N:15]=[C:14](N)[S:13][N:12]=1)[CH3:10].[BrH:17].O>CC(C)=O.C(Cl)Cl>[Br:17][C:14]1[S:13][N:12]=[C:11]([CH:9]([CH3:10])[CH3:8])[N:15]=1
Reactant: CC(C)c1nsc(N)n1
Reactant: Br
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)c1nsc(Br)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 111.1 %

Procedure:
t-Butylnitrite (50%, 2.3 mL, 17.22 mmol) was added dropwise to a degassed solution of CuBr2 (1.64 g, 7.35 mmol) in acetone (30 mL) at 0° C. under N2. The mixture was stirred at ambient temperature for 90 min, then charged with a solution of 3-(1-methylethyl)-1,2,4-thiadiazol-5-amine (1 g, 7 mmol) in acetone (7 mL), and stirred at ambient temperature for 1 h. The mixture was cooled to 0° C., and was charged dropwise with 48% HBr (1.8 mL, 4.65 mmol). The mixture was stirred at 0° C. for 30 min, and then brought to ambient temperature. The mixture was charged with water (100 mL) and CH2Cl2 (75 mL), then stirred at ambient temperature for 10 min. The organics were separated, dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 15% EtOAc/hexane to give 1.07 g (74%) of 5-bromo-3-(1-methylethyl)-1,2,4-thiadiazole as a golden oil. 1H NMR (400 MHz, CDCl3): δ 3.29 (septet, 1H, J=6.9 Hz), 1.37 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 207/209 (M+H).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13]N=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[CH2:33]([S:36](Cl)(=[O:38])=[O:37])[CH2:34][CH3:35]>>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][CH:2]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][N:30]([S:36]([CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])[CH2:29][CH2:28]2)[N:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)N1CCC(Nc2ccc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The title compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt (Example 22) and 1-propanesulfonyl chloride (Aldrich 97%) using the procedure described in Example 24. HRMS, observed 451.1817, Calcd for (M+H)+: 451.1810.