Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH2:22]([C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:36][CH2:37]O)[CH3:23]>>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:37][CH2:36][C:25]2[N:26]=[C:27]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[O:28][C:24]=2[CH2:22][CH3:23])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CCc1oc(-c2ccc(F)cc2)nc1CCO
Product: CCc1oc(-c2ccc(F)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Yield: 88 %

Procedure:
Intermediate 58 was prepared as described above for the preparation of intermediate 52. From 230 mg of N-(Boc)-L-Tyrosine methyl ester and 200 mg of Intermediate 10B was prepared 350 mg of BOC-protected intermediate methyl ester (88% yield; 1H NMR (DMSO-d6, 300 MHz) δ8.07-8.01 (m, 2H), 7.15 (t, 2H, J=8.7), 7.04 (d, 2H, J=8.5), 6.84 (d, 2H, J=8.5), 4.50 (m, 1H), 4.24 (t, 2H, J=6.5), 3.72 (s, 3H), 3.04-2.99 (m, 2H), 2.77 (q, 2H, J=7.5), 1.44 (s, 9H), 1.33 (t, 3H, J=7.5); From 340 mg of BOC-protected ester intermediate was prepared 350 mg of intermediate 58 as a crude off-white colored solid. 1H NMR (DMSO-d6, 400 MHz) δ8.13 (br s, 2H), 7.91 (dd, 2H, J=8.8, 5.3), 7.3 (t, 2H, J=8.9), 7.10 (d, 2H, J=8.6), 6.85 (d, 2H, J=8.4), 4.13 (t, 2H, J=6.4), 4.08 (m, 1H), 2.98-2.95 (m, 2H), 2.88 (t, 2H, J=6.5), 2.70 (q, 2H, J=7.4), 1.19 (t, 3H, J=7.5); low resolution MS (ES+)m/e 399.13 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10](COCC[Si](C)(C)C)[C:9]([CH3:19])=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:20][C:21]1[N:30]=[C:29]([N:31]2[CH2:37][C:36]3[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][C:35]=3[O:34][CH2:33][CH2:32]2)[C:28]2[CH2:27][C:26]([CH3:46])([CH3:45])[CH2:25][CH2:24][C:23]=2[N:22]=1>>[CH3:19][C:9]1[NH:10][C:4]2[C:5]([N:8]=1)=[N:6][CH:7]=[C:2]([C:39]1[CH:40]=[CH:41][C:35]3[O:34][CH2:33][CH2:32][N:31]([C:29]4[C:28]5[CH2:27][C:26]([CH3:45])([CH3:46])[CH2:25][CH2:24][C:23]=5[N:22]=[C:21]([CH3:20])[N:30]=4)[CH2:37][C:36]=3[CH:38]=1)[CH:3]=2
Reactant: Cc1nc2ncc(Br)cc2n1COCC[Si](C)(C)C
Reactant: Cc1nc2c(c(N3CCOc4ccc(B(O)O)cc4C3)n1)CC(C)(C)CC2
Product: Cc1nc2c(c(N3CCOc4ccc(-c5cnc6nc(C)[nH]c6c5)cc4C3)n1)CC(C)(C)CC2

Procedure:
Prepared as acetate salt according to the method of example 5 by using 6-bromo-2-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazo[4,5-b]pyridine (reagent preparation 35) and [4-(2,6,6-trimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1 followed by SEM deprotection. 1H NMR (400 MHz, methanol-d4): 8.52 (d, 1H), 8.05 (d, 1H), 7.63 (d, 1H), 7.50 (dd, 1H), 7.09 (d, 1H), 4.73 (s, 2H), 4.33 (m, 2H), 4.00 (m, 2H), 2.75 (t, 2H), 2.64 (s, 3H), 2.47 (s, 2H), 2.41 (s, 3H), 1.96 (s, 3H), 1.66 (t, 2H), 0.91 (s, 6H); MS (EI) for C27H30N6O: 455 (MH+).
Reaction SMILES: [F:1][C:2]([F:19])=[C:3]([F:18])[C:4]([F:17])([F:16])[O:5][C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[Br:9].[O:20]=O>>[F:10][C:8]([F:11])([Br:9])[C:7]([F:12])([F:13])[C:6]([F:14])([F:15])[O:5][C:4]([F:16])([F:17])[C:3]1([F:18])[O:20][C:2]1([F:19])[F:1]
Reactant: FC(F)=C(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)Br
Reactant: O=O
Product: FC(F)(Br)C(F)(F)C(F)(F)OC(F)(F)C1(F)OC1(F)F
Yield: 33 %

Procedure:
A 100-ml metal tube containing 20.0 g (0.053 mol) of perfluoro(7-bromo-4-oxa-1-heptene) from Part C and 60 ml of CF2ClCFCl2 was heated at 140° while O2 was injected incrementally over a 4 h period until absorption ceased. The mixture was cooled, gases vented, and the liquid product fractionated to give 6.9 g (33%) of perfluoro(1-bromo-6,7-epoxy-4-oxaheptane), bp 94°-95°. IR(CCl4): 6.50 (epoxide), 8-9μ (CF, C--O) with weak band indicating COF impurity near 5.3μ. NMR (CCl4): 19F -65.6 (t of m, JFF 9.8 Hz, 2F, CF2Br), -80.2 (AB multiplets 2F, CF2O), -80.4 (AB multiplets, 2F, CF2O), -121.9 (m, 2F, CF2), and -156.6 ppm (t of m, JFF 17.6 Hz, 1F, CF), with AB multiplets for ring CF at -10368 and -10409 Hz (d of d of m, JFF 18.5, 9.8 Hz, 1F) and -10596 and -10637 Hz (d, JFF 17.3 Hz, 1F).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1

Procedure:
11.28 g (33.04 mmol) benzyl 4-(4-nitro-phenyl)-piperazine-1-carboxylate are dissolved in 500 mL methanol and combined with 1 g Raney nickel. The mixture is hydrogenated for 18 h at 5 bar hydrogen pressure. Then the catalyst is filtered off and the residue is combined with 70 mL of aqueous 1 N hydrochloric acid and the solvent is eliminated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH:10][C@H:11]2[C@@H:16]([CH2:17][OH:18])[C@H:15]3[CH2:19][C@@H:12]2[CH2:13][CH2:14]3)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Cl[Si:30]([CH2:35][CH3:36])([CH2:33][CH3:34])[CH2:31][CH3:32]>C1COCC1>[NH2:1][C:2]1[CH:9]=[C:8]([NH:10][C@H:11]2[C@@H:16]([CH2:17][O:18][Si:30]([CH2:35][CH3:36])([CH2:33][CH3:34])[CH2:31][CH3:32])[C@H:15]3[CH2:19][C@@H:12]2[CH2:13][CH2:14]3)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1N[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1CO
Reactant: CC[Si](Cl)(CC)CC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)OC[C@H]1[C@@H]2CC[C@@H](C2)[C@H]1Nc1cc(N)ncc1C#N
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Racemic 6-amino-4-(((1S*,2R*,3S*,4R*)-3-(hydroxymethyl)bicyclo[2.2.1]heptan-2-yl)amino)nicotinonitrile (intermediate 57, 420 mg, 1.63 mmol) was dissolved in THF (8 ml), treated with DIPEA (1.99 ml, 11.4 mmol) and chlorotriethylsilane (1.36 ml, 8.13 mmol). The reaction mixture was then stirred at 70° C. for 2 h. The reaction mixture was quenched with water and diluted in EtOAc. The org layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 6.41 (s, 2H), 6.08 (d, 1H), 5.64 (s, 1H), 3.72 (d, 2H), 3.43 (t, 1H), 2.10-2.20 (m, 2H), 1.85-1.92 (m, 1H), 1.73 (d, 1H), 1.43-1.58 (m, 2H), 1.21 (t, 2H), 1.06 (d, 1H), 0.91 (t, 9H), 0.55-0.64 (m, 6H).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[O:5][C:4]([CH3:15])([CH3:14])[CH:3]1[OH:16].[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](OC)=[N:22][C:21]2=[O:30]>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([NH:1][CH:2]1[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=3)[O:5][C:4]([CH3:14])([CH3:15])[CH:3]1[OH:16])=[N:22][C:21]2=[O:30]
Reactant: CC1(C)Oc2ccc(C#N)cc2C(N)C1O
Reactant: COc1nc(=O)c2cc(Cl)ccc2[nH]1
Solvent: Cc1ccccc1
Product: CC1(C)Oc2ccc(C#N)cc2C(Nc2nc(=O)c3cc(Cl)ccc3[nH]2)C1O

Procedure:
4-Amino-3-hydroxy-2,2-dimethyl-chroman-6-carbonitrile (5 mmoL) and 6-chloro-2-methoxy-1H-quinazolin-4-one (5 mmoL) in toluene (15 mL) in a sealed tube were heated at 150° C. for 4 hrs. The solvent was removed and the residue was purified by silica gel chromatography with hexanes and ethyl acetate to yield the title compound as white solid.
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]3[CH2:33][CH2:34][C:35](=[O:38])[NH:36][N:37]=3)=[CH:31][C:26]=2[N:25]=[CH:24]1>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][N:23]3[C:27]4[CH:28]=[CH:29][C:30]([C:32]5[CH2:33][CH2:34][C:35](=[O:38])[NH:36][N:37]=5)=[CH:31][C:26]=4[N:25]=[CH:24]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Reactant: NCCn1cnc2cc(C3=NNC(=O)CC3)ccc21
Product: O=C1CCC(c2ccc3c(c2)ncn3CCNCC(O)COc2ccc(CCOCC3CCC3)cc2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)-phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[O:17][N:16]=[C:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:14]=1.CO>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[O:17][N:16]=[C:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:14]=1
Reactant: COC(=O)CCCCc1noc(-c2ccccc2OC)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCCCc1noc(-c2ccccc2O)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Add boron tribromide (4.9 mL, 51.7 mmol) dropwise to a stirred solution of methyl 5-[5-(2-methoxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (3.0 g, 10.3 mmol) in methylene chloride (70 mL) at 0° C. under nitrogen. Allow to warm to room temperature and stir for 5 hours. Cool the mixture to 0° C., add methanol (20 mL) dropwise and allow to warm to room temperature. Remove the solvents under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:9), to provide methyl 5-[5-(2-hydroxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate, which is used without further purification. Add a solution of sodium hydroxide (800 mg, 20 mmol) in water (15 mL) to a solution of methyl 5-[5-(2-hydroxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (2.6 g, 9.4 mmol) in methanol (30 mL) at room temperature and stir the mixture for 2 hours. Adjust the pH of the mixture to 2 with 1 N HCl and extract with ethyl acetate (2×150 mL). Wash the combined organic extracts with water (3×150 mL), dry over sodium sulfate and remove the solvent under reduced pressure. Triturate the residue with hexanes/ethyl acetate and collect the solids by vacuum filtration to afford the title compound (2.4 g, 89% over two steps). APCI MS m/z 261 [C13H14N2O4−H]−.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].[S:24]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)([O:27][CH2:28][CH:29]1[O:31][CH2:30]1)(=[O:26])=[O:25]>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:30][CH:29]([OH:31])[CH2:28][O:27][S:24]([C:32]4[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=4)(=[O:26])=[O:25])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCC2CO2)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(O)COS(=O)(=O)c4ccc(C)cc4)CC3)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32.4 %

Procedure:
39.4 mg of 1-ethyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxo-3-quinoline carboxylic acid were mixed with 50 ml of N,N-dimethylformamide in a round flask of 100 ml and slowly stirred at room temperature for 20 minutes. 14.4 mg of glycidyl tosylate were added thereto, it was stirred at room temperature, and then washed with 30.0 ml of N,N-dimethylformamide. The reactants were held at 80° C. for 5 hours and then stirred at 25° C. for 10 minutes. The reactants were crystalized through column chromatography (20 gm silica, 10% ethylacetate/hexane), filtered, and then dried to give 11.2 mg of 1-ethyl-6-fluoro-1,4-dihydro-7-{4-[2-hydroxy-3-(toluene-4-sulfonyloxy)-propyl]-1-piperazinyl}-4-oxo-3-quinoline carboxylic acid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][NH:3]1.[O:13]1[CH:17]=[CH:16][CH2:15][CH2:14]1>N1C=CC=CC=1>[O:13]1[CH2:14][CH2:15][CH2:16][CH:17]1[N:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:8])[N:7]([CH:14]2[CH2:15][CH2:16][CH2:17][O:13]2)[C:2]1=[O:1]
Reactant: COC(=O)c1c[nH]c(=O)[nH]c1=O
Reactant: C1=COCC1
Solvent: c1ccncc1
Product: COC(=O)c1cn(C2CCCO2)c(=O)n(C2CCCO2)c1=O
Yield: 12.9 %

Procedure:
In 14 ml. of pyridine are dissolved 3.4 g. (20.0 mmoles) of methyl 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate and 4.9 g. (70.0 mmoles) of 2,3-dihydrofuran and the solution is heated in a closed reaction vessel at 140° C. for 6 hours. The reaction mixture is then concentrated to dryness under reduced pressure and the residue is dissolved in 30 ml. of chloroform and applied to a column of 68 g. of silica gel. Elution is carried out with 250 ml. of chloroform and the eluate is concentrated to dryness under reduced pressure to give 0.8 g. (yield 12.9%) of methyl 1,3-bis(2-tetrahydrofuryl)-1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1([CH3:21])[CH2:20][CH2:19][CH2:18][NH:17]1)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42](O)=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42]([N:17]2[CH2:18][CH2:19][CH2:20][C:16]2([CH2:15][O:14][C:13]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH3:21])=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32]
Reactant: COC(=O)c1ccc(OCC2(C)CCCN2)c([N+](=O)[O-])c1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1ccc(OCC2(C)CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c([N+](=O)[O-])c1
Yield: 90 %

Procedure:
A mixture of methyl 3-nitro4-(2-methyl-2-pyrrolidinylmethoxy)benzoate (0.188 g, 0.920 mmol), 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (0.289 g, 0.920 mmol), HOBt (0.149 g, 1.10 mmol), DMAP. (11.2 mg, 0.0920 mmol) and EDC (0.211 g, 1.10 mmol) in DMF (5 mL) was stirred for 14 hr at room temp. EtOAC was added to the mixture and the solution was washed successively with 0.5 N HCl, sat. NaHCO3, and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo to afford 0.489 g (q.y.) methyl 4-[[1-[3-methoxy4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-methyl-2-pyrrolidinyl]methoxy]-3-nitrobenzoate as a yellow crystalline material. 1H-NMR (CDCl3) δ 1.26 (d, J=5.9 Hz), 1.85–4.50 (m, 10H), 2.30 (s, 3H), 3.67 (s, 2H), 3.92 (s, 3H), 6.36 (s, 2H), 6.75–7.52 (m, 7H), 8.02 (d, J=7.8 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 8.47 (s, 1H).
Reaction SMILES: [NH2:1][S:2]([CH2:5][CH2:6][CH2:7][C:8]([N:10]([CH3:44])[CH2:11][CH2:12][N:13]([CH3:43])[C@@H:14]1[CH2:21][N:20]2[C:22]3[CH:23]=[C:24]([C:35]([O:37][CH3:38])=[O:36])[CH:25]=[CH:26][C:27]=3[C:28]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:19]2[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=2[O:16][CH2:15]1)=O)(=[O:4])=[O:3].CSC>C1COCC1>[NH2:1][S:2]([CH2:5][CH2:6][CH2:7][CH2:8][N:10]([CH3:44])[CH2:11][CH2:12][N:13]([CH3:43])[C@@H:14]1[CH2:21][N:20]2[C:22]3[CH:23]=[C:24]([C:35]([O:37][CH3:38])=[O:36])[CH:25]=[CH:26][C:27]=3[C:28]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:19]2[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=2[O:16][CH2:15]1)(=[O:3])=[O:4]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN(C)C(=O)CCCS(N)(=O)=O)COc1ccccc1-3
Solvent: CSC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN(C)CCCCS(N)(=O)=O)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl(7R)-7-[{2-[[4-(aminosulfonyl)butanoyl](methyl)amino]ethyl}-(methyl)amino]-14-cyclohexyl-7,8-dihydro -6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.03 M) in THF was treated with BH3.DMS complex (2 M in THF; 15 eq.). The resulting solution was stirred at RT for 1 h. The reaction was quenched by the careful addition of HCl/MeOH (1.25 M) and the resulting solution heated at 80° C. until all volatiles had evaporated to afford the title compound. The product was used in the next step without further purification. (ES+) m/z 611 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[NH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>CS(C)=O>[F:9][C:8]([F:11])([F:10])[C:5]1[N:6]=[CH:7][C:2]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[N:3][CH:4]=1
Reactant: FC(F)(F)c1cnc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
A solution of 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 6.78 ml, 54.9 mmol), tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 10 g, 49.9 mmol) and DIPEA (26.2 ml, 150 mmol) in DMSO (160 ml) was heated at 140° C. for 18 hours. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (200 ml). The aqueous layer was extracted with ethyl acetate (2×100 ml). The combined organics were washed with brine (3×100 ml), filtered through a hydrophobic frit, further dried over magnesium sulphate and then concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-40% ethyl acetate/petrol). Impure fractions were further purified by column chromatography (silica, 10-40% ethyl acetate/petrol) and combined to afford the title compound.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1>FC(F)(F)C(O)=O>[Br:1][C:5]1[CH:6]=[C:7]([C:11]([F:14])([F:12])[F:13])[C:8]([NH2:10])=[N:9][C:4]=1[CH3:3]
Reactant: BrBr
Reactant: Cc1ccc(C(F)(F)F)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)c(C(F)(F)F)cc1Br
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Bromine (1.7 g, 548 μl, 10.6 mmol, Eq: 5) was added to 6-methyl-3-(trifluoromethyl)pyridin-2-amine (375 mg, 2.13 mmol, Eq: 1) in trifluoroacetic acid (7 ml). The mixture was stirred for 30 min and then concentrated to an oil. Water (30 ml) and dichloromethane (10 ml) were added. The mixture was alkalized by addition of sodium bicarbonate and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to an oil. The crude product was purified by chromatography (SiO2, ethyl acetate/n-heptane) to give the desired product (450 mg, 82.9%) as a yellow solid. MS: m/z=255.1 (M+H+)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([N:7]1[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])[CH3:6])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:20])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(C)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)C(C)N1C(=O)COc2cc(C)c(Br)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
To a solution of 2-(7-methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (21.0 g, 80 mmol) in DCM (250 mL) was added 1-bromopyrrolidine-2,5-dione (15.6 g, 88 mmol) and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was quenched by addition of a saturated solution of thiosulfate in water (50 mL). The organic phase was separated and the aqueous portion was extracted with DCM (3×20 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give -(6-bromo-7-methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as solid (23.1 g, 85%). LC/MS (Table 1, Method 3) Rt=1.259 min.; MS m/z: 342/344 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]([CH:19]([CH3:21])[CH3:20])[N:11]=2)=[C:4]([F:22])[CH:3]=1.[Cl:23]N1C(=O)CCC1=O>CN(C)C=O>[Cl:23][C:14]1[C:10]([C:5]2[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[CH:3][C:4]=2[F:22])=[N:11][N:12]([CH:19]([CH3:20])[CH3:21])[C:13]=1[C:15]([F:17])([F:18])[F:16]
Reactant: COc1cc(-c2cc(C(F)(F)F)n(C(C)C)n2)c(F)cc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COc1cc(-c2nn(C(C)C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Temperature: 80 °C
Yield: 87.3 %

Procedure:
To a solution of 1.6 g of 3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-(1-methylethyl)-5-(trifluoromethyl)-1H-pyrazole in 20 mL of dimethylformamide was added 2.0 g of N-chlorosuccinimide. The solution was heated to 80° C. for 2 hours, allowed to cool and poured into ice water. The aqueous mixture was extracted three times with methylene chloride, the combined organic extracts washed with water, dried with MgSO4 and concentrated to give a crude oil. The oil was purified by chromatography and distilled bulb-to-bulb to afford 1.54 g of 4-chloro-3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-(1-methylethyl)-5-(trifluoromethyl)-1H-pyrazole as a yellow oil, nD 1.5192 (24° C.).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[C:19](OC)=[N:18][S:17](=[O:22])[N:16]=2)=[CH:7][CH:6]=1)[CH3:3].[CH3:23][NH2:24]>>[CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[C:19]([NH:24][CH3:23])=[N:18][S:17](=[O:22])[N:16]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: COC1=NS(=O)N=C1NCCSCc1ccc(CN(C)C)o1
Reactant: CN
Product: CNC1=NS(=O)N=C1NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To the methanolic solution of the product of Step A that was cooled to 5° in an ice-water bath was added anhydrous methylamine for 8 minutes. The reaction mixture was stirred at ambient temperature for 17 hours, then evaporated under reduced pressure to give the product as a yellow oil that was placed on 55 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fraction was evaporated, dissolved in methanol and diluted with diethyl ether to yield the title compound (2.32 g) as a solid that was dried in vacuo at ambient temperature over P2O5 for 3 hours, mp 86°-92°.
Reaction SMILES: CC([C:5]1[N:6]=[C:7]([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[CH:41]=[N:40][CH:39]=[CH:38]3)[S:8][C:9]=1[N:10]([CH2:14][C@@H:15]([NH:27]C(OC(C)(C)C)=O)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)C(=O)[O-])(C)C.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[NH2:27][C@@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][CH:18]=1)[CH2:14][NH:10][C:9]1[S:8][C:7]([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[CH:41]=[N:40][CH:39]=[CH:38]3)=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)[O-])c1sc(-c2ccc3cnccc3c2)nc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CNc1cnc(-c2ccc3cnccc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a 250 mL round-bottomed flask containing 1,1-dimethylethyl((2S)-2-((((1,1-dimethylethyl)oxy)carbonyl)-amino)-3-(4-(trifluoromethyl)phenyl)propyl)(2-(6-isoquinolinyl)-1,3-thiazol-5-yl)carbamate (8.9 mg, 0.014 mmol) was added TFA (1 mL). The mixture was stirred at room temperature 1 hour and evaporated. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 5% to 100% over 15 minutes, to provide the product (4.9 mg, 64% yield) as a brown oil. 1H NMR (400 MHz, CD3OD) δ ppm 3.11-3.20 (m, 2H), 3.43-3.51 (m, 2H), 3.77-3.84 (m, 1H), 7.12 (s, 1H), 7.55 (d, J=8.02 Hz, 2H), 7.71 (d, J=8.22 Hz, 2H), 8.37 (d, J=6.65 Hz, 1H), 8.43 (s, 3H), 8.49 (d, J=6.65 Hz, 1H), 9.59 (s, 1H). HRMS Theoretical (M+H) 429.13553, found 429.13603.