Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C([NH:6][C:7]1[N:16]=[C:15](C2N=CNN=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:22])[CH:13]=2)[N:8]=1)(=O)C.[CH3:23][O:24][CH2:25][CH2:26][OH:27]>>[NH2:6][C:7]1[N:16]=[C:15]([O:27][CH2:26][CH2:25][O:24][CH3:23])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:22])[CH:13]=2)[N:8]=1
Reactant: COCCO
Reactant: CC(=O)Nc1nc(-c2nc[nH]n2)c2cc(Br)ccc2n1
Agent: [H-]
Agent: [Na+]
Product: COCCOc1nc(N)nc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To 2-methoxyethanol (10 ml) was added NaH (80 mg of a 60% dispersion in mineral oil, 2.0 mmol). The mixture was stirred at room temperature for 10 minutes. Then, 2-acetamido-6-bromo-4-(1,2,4-triazolyl)-quinazoline (167 mg, 0.5 mmol) was added to this solution. The resulting mixture was stirred at room temperature for 30 minutes and then heated at 80° C. for 2 hours. The solvents were evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1:80), yielding the title compound as a white solid (140 mg, yield: 94%) which was characterized by its mass spectrum as follows: MS (m/z): 298 ([M+H]+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[N:35]1([CH2:41][CH2:42][CH2:43][NH2:44])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[S:23]([NH:22][C:20]1[CH:21]=[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:44][CH2:43][CH2:42][CH2:41][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:7]=2)[CH:17]=[CH:18][C:19]=1[F:34])(=[O:25])=[O:24]
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: NCCCN1CCOCC1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(NCCCN3CCOCC3)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (80 mg, 0.15 mmol) and 3-(4-morpholinyl)-1-propanamine (0.10 mL, approx. 6.9 mmol) the title compound was obtained as a white solid (85 mg, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (d, J=5.1 Hz, 1H), 7.52-7.67 (m, 1H), 7.36 (dd, J=7.6, 1.6 Hz, 1H), 7.21-7.32 (m, 2H), 7.07-7.21 (m, 3H), 6.14 (br. s., 1H), 3.57 (br. s., 4H), 3.20-3.36 (m, 8H), 2.36-2.41 (m, 1H), 1.65 (br. s., 2H), 1.31 (d, J=6.8 Hz, 6H). MS (ESI): 633.5 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.C(O)(=O)[CH2:26][C:27]([OH:29])=[O:28].P([O-])(O)(O)=O.[Na+]>C1(C)C=CC=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]/[CH2:26][C:27]([OH:29])=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCCCCOCCCCCCCC=O
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCOCCCCCC/C=C/CC(=O)O
Temperature: 90 °C
Reaction time: 16 h
Yield: 100.4 %

Procedure:
Under a nitrogen atmosphere, 8-heptyloxy-octanal (178.0 mg, 0.734 mmol) obtained in Step D-2 was dissolved in toluene (3.56 mL), and triethylamine (184 μL, 1.32 mmol) and a solution of malonic acid (137.6 mg, 1.32 mmol) in DMF (0.178 mL) were added in order at 75° C. The mixture was stirred at 90° C. for 16 hours. After cooling to room temperature, an aqueous solution (2.6 mL) of 30% sodium dihydrogen phosphate and ethyl acetate (5.2 mL) were added, and the mixture was stirred at room temperature for 5 minutes. After extraction, the organic layer was washed with water. The aqueous layer was washed with ethyl acetate. The combined organic layer was then washed again with water and a saturated brine, dried over anhydrous sodium sulfate, and then filtered. The solvent was distilled off to obtain 209.7 mg (quant.) of (E)-10-heptyloxy-dec-3-enoic acid (ESI (LC/MS positive mode) m/z 285 (M+H); Rt 2.23 min.)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=3)=[N:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31]>>[N:32]1([C:30]([C:25]2[CH:24]=[CH:29][CH:28]=[CH:27][C:26]=2[C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[N:19][C:18]([NH2:21])=[N:17][CH:16]=3)=[N:13][CH:14]=2)=[O:31])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: O=C(c1ccccc1Br)N1CCOCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3C(=O)N3CCOCC3)cn2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine and (2-bromophenyl)(morpholino)methanone. MS (ESI): mass calcd. for C20H19N5O2, 361.15; m/z found, 362.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.96 (s, 2H), 8.69-8.64 (m, 1H), 7.95-7.87 (m, 2H), 7.64-7.59 (m, 1H), 7.58-7.51 (m, 2H), 7.49-7.42 (m, 1H), 3.69-3.54 (m, 3H), 3.48-3.33 (m, 2H), 3.20-3.07 (m, 1H), 2.97-2.80 (m, 2H).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:33])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH2:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:36][C@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42]1[N:46]2[CH:47]=[C:48]([O:51][C@H:52]3[C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[C@@H:55]([NH2:62])[CH2:54][CH2:53]3)[CH:49]=[CH:50][C:45]2=[N:44][N:43]=1.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:62][C@@H:55]2[C:56]3[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=3)[C@H:52]([O:51][C:48]3[CH:49]=[CH:50][C:45]4[N:46]([C:42]([N:38]5[CH2:39][CH2:40][CH2:41][C@@H:37]5[CH3:36])=[N:43][N:44]=4)[CH:47]=3)[CH2:53][CH2:54]2)=[O:33])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH2:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[CH:17]=2)[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(Cl)c(OCCOC3CCCCO3)c2)n1
Reactant: C[C@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(Cl)c(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Yield: 19.3 %

Procedure:
A solution of Intermediate 53b (238 mg, 0.41 mmol), Intermediate 78b (220 mg, 0.61 mmol) and DIPEA (158 μL, 0.91 mmol) in dioxane (2.5 mL) was heated at 60° C. for 18 h. The reaction mixture was cooled and diluted with DCM (5 mL). The organic layer was washed with water (2×5 mL), passed through a phase separator and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to afford the title compound (62 mg, 19%). LCMS (Method 3): Rt: 4.00 min, m/z 783/785 [MH+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH3:31][O:32][C:33](=[O:62])[C@H:34]([CH2:58][CH2:59][S:60][CH3:61])[NH:35][C:36](=[O:57])[CH2:37][N:38]([CH2:50][C@@H:51]([NH2:56])[CH:52]([CH3:55])[CH2:53][CH3:54])[CH2:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1.CCN(CC)CC>CN(C=O)C>[CH3:31][O:32][C:33](=[O:62])[C@H:34]([CH2:58][CH2:59][S:60][CH3:61])[NH:35][C:36](=[O:57])[CH2:37][N:38]([CH2:50][C@@H:51]([NH:56][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C@@H:52]([CH3:55])[CH2:53][CH3:54])[CH2:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1
Reactant: CCC(C)[C@H](N)CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12)NC(=O)CCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(4-Nitrophenyl)butyric acid (73 mg, 350 μmol), dissolved in DMF (5 ml) was treated with HOBT (60 mg, 350 μmol), EDC (76 mg, 350 μmol) and N-[2(S)-amino-3-methylpentyl)-N-(1-naphthylmethyl)-glycyl-methionine methyl ester hydrochloride (160 mg, 300 μmol). The pH was adjusted to ~7.5 with Et3N (170 μl, 385 μmol) and the mixture was stirred at ambient temperature for 16 h. The mixture was concentrated and the residue was partitioned between EtOAc (100 ml) and H2O (100 ml). The organic layer was washed with H2O (2×50 ml), dried (MgSO4), filtered and concentrated to give a crude product which was purified by chromatography (silica gel, eluting with 1:1 to 1:2 hexane: EtOAc) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:9]([CH3:25])=[N:10][N:11]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=4[CH3:23])=[C:14]([CH3:24])[O:13][C:12]=23)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:33]([F:39])([F:38])C(OC)=O>CN(C=O)C>[F:38][CH:33]([F:39])[O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[N:11]3[N:10]=[C:9]([CH3:25])[C:8]([N:4]4[C:5]([CH3:7])=[N:6][C:2]([CH3:1])=[N:3]4)=[C:12]3[O:13][C:14]=2[CH3:24])=[C:17]([CH3:23])[CH:18]=1
Reactant: COC(=O)C(F)(F)Cl
Reactant: Cc1nc(C)n(-c2c(C)nn3c(-c4ccc(O)cc4C)c(C)oc23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C)n(-c2c(C)nn3c(-c4ccc(OC(F)F)cc4C)c(C)oc23)n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2,6-dimethylpyrazolo[5,1-b]oxazol-3-yl)-3-methylphenol (Step 1) (100 mg, 0.296 mmol) in dry DMF (4 ml) was treated with potassium carbonate (205 mg, 1.482 mmol) and stirred under N2 for 30 mins at 50° C. Methyl 2-chloro-2,2-difluoroacetate (428 mg, 2.96 mmol) was added and the reaction was heated to 90° C. for 1.5 hrs. After cooling to RT, the mixture was partitioned between EtOAc and water. The organic portion was washed with brine, dried (MgSO4) and concentrated in vacuo to give a brown oil. Purification of the crude product by reverse phase chromatography [prep-HPLC (Waters system)] yielded the title compound (TFA salt) as a colourless oil. The salt was taken up in DCM (2 ml) and MP-carbonate resin (macroporous polystyrene anion-exchange resin) (500 mg, 2.8 mmol/g, Argonaut) was added and the contents stirred at RT for 30 mins. The resin was filtered, washed with DCM and the filtrate was concentrated in vacuo to give the title compound as the free base. LC-MS Rt 4.86 mins; MS m/z 388.2 [M+H]+; Method=10minLC_v002. 1H NMR (400 MHz, CDCl3) δ 7.4 (1H, d), 7.15 (1H, s), 7.10 (1H, d), 6.6 (1H, t), 2.40 (6H, m), 2.35 (6H, m), 2.20 (3H, s).
Reaction SMILES: [NH2:1][C@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.CN1C2C(=CC=CC=2)C(C(OCC)=O)=C1C.[C:26]1([C:39](OC)=[O:40])[C:27]2[CH:28]=[C:29]3[CH2:38][CH2:37][CH2:36][CH2:35][N:30]3[C:31]=2[CH:32]=[CH:33][CH:34]=1>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@H:2]([NH:1][C:39]([C:26]1[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=1[CH:28]=[C:29]1[CH2:38][CH2:37][CH2:36][CH2:35][N:30]13)=[O:40])[CH2:3]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: COC(=O)c1cccc2c1cc1n2CCCC1
Agent: CCOC(=O)c1c(C)n(C)c2ccccc12
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2c1cc1n2CCCC1
Yield: 82 %

Procedure:
Proceeding as in Example 2, Method B, but replacing (RS)-3-amino-1-azabicyclo[2.2.2]octane with (S)-3-amino-1-azabicyclo[2.2.2]octane and ethyl 1,2-dimethylindole-3-carboxylate with methyl 6,7,8,9-tetrahydropyrido[1,2-a]indole-1-carboxylate, from Example 1, there was prepared (S)-1-[(1-azabicyclo[2.2.2]oct-3-yl)aminocarbonyl]-6,7,8,9-tetrahydropyrido[1,2-a]indole (82% yield), m.p. 163°-164° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.Br[C:12]1[CH:24]=[C:23]([F:25])[C:15]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[C:14]([F:26])[CH:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([C:12]3[CH:13]=[C:14]([F:26])[C:15]([CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[C:23]([F:25])[CH:24]=3)[C:6]=2[N:7]=1
Reactant: Clc1ncc2cc[nH]c2n1
Reactant: Fc1cc(Br)cc(F)c1CN1CCOCC1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Fc1cc(-n2ccc3cnc(Cl)nc32)cc(F)c1CN1CCOCC1
Temperature: 110 °C

Procedure:
In a sealed tube, 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 1.24 mmol), 4-(4-bromo-2,6-difluoro-benzyl)-morpholine (418 mg, 1.36 mmol), CuI (72.1 mg, 0.371 mmol), and K3PO4 (804 mg, 3.71 mmol) are suspended in 1,4-dioxane (8 mL). Then, trans-1,2-diaminocyclohexane (45.0 μL, 0.371 mmol) is added at rt. The reaction vial is flushed with Ar and the mixture is heated to 110° C. for 5 h. After cooling to rt, the reaction mixture is diluted with EtOAc and the organic layer is washed with saturated aqueous Na2CO3 solution (2×). The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (SiO2, gradient elution, hexane/EtOAc 100:0→30:70) to yield the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:22]>CN(C=O)C>[CH3:22][N:14]([CH:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)NC1CCCc2ccc([N+](=O)[O-])cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C1CCCc2ccc([N+](=O)[O-])cc21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A solution of 1.2 g (4.4 mmol) of N-(7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl)methanesulfonamide in 16 ml of DMF was added dropwise to a suspension of 0.15 g (5.1 nmol) 80 percent sodium hydride in 10 ml of DMF. After stirring at room temperature for 1 hr., 0.62 g (4.4 mmol) of iodomethane were added and the mixture was allowed to stand at room temperature overnight. The reaction mixture was completely concentrated in vacuo and the residue was then taken up in EA and water. After washing the organic phase with dil. hydrochloric acid and sodium bicarbonate solution and concentrating, the residue was purified by chromatography on silica gel using cyclohexane/EA 3:1 and 0.3 g of N-methyl-N-(7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl)methanesulfonamide was obtained; m.p. 138-140° C.
Reaction SMILES: BrC1C=C(C(Cl)=O)C=CC=1.[Cl:11][C:12]1[CH:18]=[C:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:13]=1[NH2:14].[Br:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1>C1(C)C=CC=CC=1.C(O)C>[Br:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1.[Br:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[C:41]([NH:43][C:44]([NH:14][C:13]1[CH:15]=[CH:16][C:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:18][C:12]=1[Cl:11])=[S:45])=[O:42]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: O=C(Cl)c1cccc(Br)c1
Agent: O=C(N=C=S)c1cccc(Br)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Br)c4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
3-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (56 mg, yield 58%).
Reaction SMILES: Br[CH:2](Br)[C:3]([C:5]1[N:6]=[N:7][C:8]([O:15][CH2:16][CH3:17])=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])=O.Cl.Cl.[N:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH2:28])[C:22]=1[NH2:29].C([O-])([O-])=O.[K+].[K+]>O.O1CCOCC1.[Cl-].[Na+].O>[CH2:16]([O:15][C:8]1[N:7]=[N:6][C:5]([C:3]2[N:29]=[C:22]3[N:21]=[CH:26][CH:25]=[C:24]([NH2:27])[C:23]3=[N:28][CH:2]=2)=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=1)[CH3:17]
Reactant: CCOc1cc(C(F)(F)F)c(C(=O)C(Br)Br)nn1
Reactant: Nc1ccnc(N)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(C(F)(F)F)c(-c2cnc3c(N)ccnc3n2)nn1
Temperature: 100 °C

Procedure:
Dissolve 2,2-dibromo-1-[6-ethoxy-4-(trifluoromethyl)pyridazin-3-yl]ethanone (5.45 g, 13.9 mmol), pyridine-2,3,4-triamine dihydrochloride (3.42 g, 17.4 mmol; prepared essentially as described by Kogl et al. (1948) Recueil des Travaux Chimiques des Pays-Bas et de la Belgique 67:29-44) and K2CO3 (19.2 g, 139 mmol) in H2O (80 mL) and dioxane (40 mL). Heat the mixture at 100° C. for 3 hours. Cool and add brine (50 mL). Extract with EtOAc (3×50 mL). Combine, dry and evaporate the organic extracts. Purify by silica gel column chromatography eluting with CH2Cl2/MeOH (97/3) to yield two different regioisomers as a (2:1) mixture with the title compound being the major more polar isomer. LC/MS (MH+) 337.04.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10](Cl)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[F:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=1.N1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:20][N:19]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: Nc1ccc(F)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1F

Procedure:
3-Cyano-4-fluorobenzenesulfonyl chloride (5 g, 20 mmol), 5-fluoropyridin-2-amine (3.37 g, 30 mmol) and pyridine (4.87 mL, 60 mmol) in dichloromethane (100 mL) were stirred at room temperature for 2 hours before concentrating in vacuo. The residue was triturated in hydrochloric acid (2 N aqueous solution, 100 mL) for 16 hours. The precipitate was filtered to afford the title compound as a pale pink solid, 6.1 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-])=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:22][C:16]1[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=1[O:14][CH2:13][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: Cc1ccc([N+](=O)[O-])c(OC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N)c(OC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c1
Yield: 56 %

Procedure:
(S)-2-(tert-butoxycarbonylamino)-3-(5-methyl-2-nitrophenoxy)propanoic acid (7.50 g, 22.0 mmol, Eq: 1.00) and 10% Pd/C (0.75 g, Eq: 0.03) in MeOH (300 mL) were hydrogenated at ambient pressure for 4 h at RT. The mixture was filtered through a pad of silica gel and the filtrate was concentrated to give (S)-3-(2-amino-5-methylphenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (3.85, 56%) as a yellow solid which was used without purification.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:20][CH2:21][CH3:22])[C:8]3[O:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][C:12](=[O:19])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:23]([OH:25])=[O:24])[CH:3]=1.C(=O)(O)[O-].[Na+:30]>O>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:20][CH2:21][CH3:22])[C:8]3[O:15][C:14]([C:16]([O-:18])=[O:17])=[CH:13][C:12](=[O:19])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:23]([O-:25])=[O:24])[CH:3]=1.[Na+:30].[Na+:30]
Reactant: CCCc1c2nc(C(=O)O)cc(Br)c2cc2c(=O)cc(C(=O)O)oc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCc1c2nc(C(=O)[O-])cc(Br)c2cc2c(=O)cc(C(=O)[O-])oc12
Yield: 94.9 %

Procedure:
The product of step (c), (2.166 g, 5.22 mmole), was added slowly to a solution of sodium bicarbonate, (0.876 g, 10.44 mmole), in water (35 ml). The resulting solution was filtered and the filtrate was freeze-dried to give the required salt as a brown solid, (2.23 g) 93%. The NMR spectrum was consistent with the required structure.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C(Cl)Cl>[C:14]([O:13][C:12]([NH:11][C@@H:3]([CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1)[CH2:2][NH:1][C:20](=[O:21])[O:22][C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@H](CN)C[C@H]1CCCOC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CNC(=O)Oc1ccc([N+](=O)[O-])cc1)C[C@H]1CCCOC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl (S)-1-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate (20.8 mg, 0.081 mmol) in anhydrous DCM (9 mL) was added 4-nitrophenyl chloroformate (17.1 mg, 0.085 mmol), followed by TEA (12.2 mg, 17 μL, 0.12 mmol). The resulting solution was stirred at rt for 5 min (monitored by LC-MS) and diluted to 12 mL. An aliquot of the carbamate mixture solution (2 mL) was used for the next step without purification.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]=[C:11]=[S:12])C.[CH2:13]([NH:15][CH2:16][C:17](O)=[O:18])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:13]([N:15]1[CH2:16][C:17](=[O:18])[N:10]([C:4]2[CH:3]=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:9])[C:11]1=[S:12])[CH3:14]
Reactant: CCNCC(=O)O
Reactant: CCc1cccc(C)c1N=C=S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2ccccc2C)C1=S

Procedure:
The title compound was prepared by the procedure described in Example 28 using 17.7 g of 2-ethyl-6-methylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. The residue was further purified by flash chromatography on silica gel (20% ethyl acetate in hexane).The title compound was obtained (8.6 g) as a light peach solid, m.p. 82°-84° C. Anal. Calcd. for. C14H18N2O S: C, 64.09; H, 6.92; N, 10.68. Found: C, 64.27; H, 7.04; N, 10.60. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: [Cl:1][C:2]1[C:26]2[O:25][C:9]3[C:10](=[O:24])[N:11]([C@@H:13]([CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[C:14](O)=[O:15])[CH2:12][C:8]=3[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[Cl:1][C:2]1[C:26]2[O:25][C:9]3[C:10](=[O:24])[N:11]([C@@H:13]([CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[C:14]([NH:27][C:28]4[S:29][CH:30]=[CH:31][N:32]=4)=[O:15])[CH2:12][C:8]=3[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Reactant: Nc1nccs1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Yield: 84.1 %

Procedure:
A solution of (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (100 mg, 0.27 mmol) (Example 20, Step 2c), commercially available 2-aminothiazole (32 mg, 0.32 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (40 mg, 0.29 mmol), and N-hydroxybenzotriazole (HOBt) (56 mg, 0.29 mmol) in methylene chloride (5 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, afforded (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-N-thiazol-2-yl-propionamide (104 mg, 85.2%), as a white solid. 1H NMR (DMSO-d6) δ: 12.55 (s, 1H), 7.50 (d, J=2.9 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.20-7.28 (m, 2H), 7.07-7.17 (m, 1H), 5.07 (dd, J=10.5, 4.2 Hz, 1H), 4.39 (d, J=19.1 Hz, 1H), 4.08 (d, J=18.6 Hz, 1H), 3.84 (br. s., 2H), 1.52-1.90 (m, 7H), 0.76-1.29 (m, 6H).