Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([N:13]([CH2:17][CH2:18]Cl)[CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[N:29]1[CH2:30][CH2:31][N:32]([CH2:18][CH2:17][N:13]([CH:14]([CH3:15])[CH3:16])[S:10]([C:3]2[CH:4]=[C:5]([Cl:9])[C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:12])[CH2:33][CH2:34]1
Reactant: CC(C)N(CCCl)S(=O)(=O)c1cc(Cl)c(Cl)cc1Cl
Reactant: c1ccc2[nH]c(N3CCNCC3)nc2c1
Product: CC(C)N(CCN1CCN(c2nc3ccccc3[nH]2)CC1)S(=O)(=O)c1cc(Cl)c(Cl)cc1Cl

Procedure:
The title compound was prepared using the procedure described in Example 1 using D7 and 1-(1H-benzimidazol-2-yl)piperazine. MH+ 530/532/534/536.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2].[CH2:27]([Mg]Br)[CH:28]=[CH2:29]>C(Cl)Cl.CCCCCC>[CH:1]([C:4]1[C:9]([CH:10]([OH:11])[CH:27]=[CH:28][CH3:29])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: C=CC[Mg]Br
Reactant: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC=CC(O)c1c(C(C)C)nc(C(C)C)c(CCCCC)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine (Example 1) and allylmagnesium bromide according to the procedures described in Example 114. 1H NMR (300 MHz, CDCl3): δ 7.09 (m, 4 H), 6.58 (m, 1 H), 5.06 (s, 1 H), 5.01 (m, 1 H), 4.47 (m, 1 H), 3.71 (septet, J=6.6 Hz, 1 H), 3.20 (septet, J=6.6 Hz, 1 H), 2.59 (m, 1 H), 2.35 (m, 1 H), 2.18 (t, J=4.8 Hz, 2 H), 1.72 (d, J=2.9 Hz, 1 H), 1.28 (m, 14 H), 1.11 (m, 4 H), 0.783 (t, J=6.6 Hz, 3 H). FAB-MS: calcd for (C26H36FNO) 397, found 398 (M+H). Anal. Calcd for C26H36FNO: C, 77.88; H, 9.41; N, 3.63; F, 4.93. Found: C, 78.10; H, 9.21; N, 3.43; F, 4.89. mp 70-72° C. Rf=0.2 (50% CH2Cl2/hexane).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][CH3:11])[CH2:4]1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH2:9]([N:5]1[CH2:6][CH2:7][O:8][CH:3]([CH2:2][O:1][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH2:4]1)[CH2:10][CH3:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCN1CCOC(CO)C1
Solvent: c1ccncc1
Product: CCCN1CCOC(COS(=O)(=O)c2ccc(C)cc2)C1
Reaction time: 3 h
Yield: 96 %

Procedure:
2-Hydroxymethyl-4-n-propylmorpholine (16.2 g.) is dissolved in dry pyridine (50 ml.) and a solution of toluene-p-sulphonylchloride (21.4 g.) in dry pyridine (50 ml.) is added dropwise with stirring. The mixture is stirred at 20°-≅°C. for 3 hours. The pyridine is removed under reduced pressure, water (100 ml.) is added to the residue and the product is extracted into ether (3 × 150 ml.). The ethereal solution is washed with water, dried (MgSO4), filtered and the ether evaporated to give 4-n-propyl-2-toluene-p-sulphonyloxymethylmorpholine (30.6 g.) as an oil which forms a hydrochloride, m.p. 172°-173°C. on recrystallisation from methanol/ether.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH2:34][CH3:35])[N:12]=[C:11]2[CH3:36])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:37][Mg]Br.C(OCC)(=O)C.O>O1CCCC1>[CH2:32]([C:13]1[N:12]=[C:11]([CH3:36])[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([OH:3])([CH3:37])[CH3:2])[CH:5]=2)[C:15](=[O:16])[C:14]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[CH2:33][CH2:34][CH3:35]
Reactant: C[Mg]Br
Reactant: CCCCc1nc(C)n(-c2cccc(C(C)=O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(-c2cccc(C(C)(C)O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4′-{[1-(3-acetylphenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) in tetrahydrofuran (10 mL) was added methylmagnesium bromide (1.0 M tetrahydrofuran solution, 2.5 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 12 hr while allowing to warm to room temperature. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.54 g, 52%).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[O:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:7][CH2:6]1.N1C=CC=CC=1>C(Cl)Cl>[O:16]=[C:12]1[N:11]([CH:8]2[CH2:9][CH2:10][O:5][CH2:6][CH2:7]2)[CH2:15][CH2:14][N:13]1[C:1]([Cl:4])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: O=C1NCCN1C1CCOCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A 0° C. solution of phosgene (20% in toluene, 0.267 mL, 0.506 mmol) in DCM (5 mL) was treated slowly drop-wise with a solution of Example B1 (0.086 g, 0.505 mmol) and pyridine (0.082 mL, 1.011 mmol) in DCM (3 mL). The mixture was warmed to RT, stirred for 1 hour, then concentrated to dryness to afford 2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carbonyl chloride as an off-white solid. The material was carried on to the next step assuming 100% yield (118 mg). MS (ESI) m/z: 304.1 (M+H+) (for material quenched into benzylamine).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)=[C:24]([C:26]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:27])[N:25]=1
Reactant: Nc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-Amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.21 min; [M+H]+=497.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([Cl:12])(=[O:11])=[O:10])[CH3:2].O(Cl)[Cl:14]>C(Cl)(Cl)(Cl)Cl>[Cl:14][CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([Cl:12])(=[O:11])=[O:10])[CH3:2]
Reactant: ClOCl
Reactant: CCc1ccccc1S(=O)(=O)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Cl)c1ccccc1S(=O)(=O)Cl
Yield: 83.9 %

Procedure:
A solution of 2-ethylbenzenesulfonyl chloride (obtained by chlorosulfonation of ethylbenzene) (7.78 g) in carbon tetrachloride (5.0 ml) was contacted with a solution of dichlorine monoxide (82 mmol) in carbon tetrachloride (100 ml) and the mixture was heated in a closed system at 50°-60° for 16 hrs. The mixture was dried (MgSO4) and volatiles were removed under vacuum. The residue was kugelrohr distilled to give 7.63 g of colorless oil, bp 75°-80° (0.15 mm). 1H nmr δCDCl3TMS 8.20-7.35 (m). 6.13 (g, J-7 Hz), 1.90 (d, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.CO[C:40](OC)([CH3:42])[CH3:41].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@@H:12]3[O:22][C:40]([CH3:42])([CH3:41])[O:21][C@@H:13]3[C@@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:15]2)=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:3]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound is prepared by dissolving N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate J) in a 2:1 mixture of acetone and 2,2-dimethoxypropane with a catalytic amount of toluene-4-sulfonic acid, and stirring at room temperature overnight. The volatile components are removed under reduced pressure to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[F:8])([OH:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Fc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a stirring solution of 1-bromo-2-fluorobenzene (2 g, 11.4 mmol) in tetrahydrofuran (30 mL) at −70° C. under nitrogen was added a solution of n-butyllithium (5.0 mL, 12.6 mmol, 2.5 M in hexane). After 30 minutes, 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.97 g, 14.9 mmol) was added in one portion. After 30 minutes, the reaction was quenched with water (2 mL) and was allowed to warm to ambient temperature. After one hour at ambient temperature, the reaction mixture was poured into water (75 mL) and the mixture was extracted with ethyl acetate (2×75 mL). The organic layers were combined, washed with saturated aqueous sodium chloride and concentrated at reduced pressure. The resulting crude product was triturated with hexane (35 mL) for 2 hours, filtered and dried to give the product as a white solid (2.22 g, 65%). 1H NMR (CDCl3) δ 7.45 (m, 1H,), 7.24 (m, 1H), 7.19-7.01 (m, 2H), 4.03 (br s, 2H), 3.23 (m, 2H), 18 (m, 3H), 1.81 (m, 2H), 1.45 (m, 9H). MS (ES+)=296 (MH)+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].Cl[C:25]([O:27][CH3:28])=[O:26]>N1C=CC=CC=1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:25](=[O:26])[O:27][CH3:28])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Solvent: c1ccncc1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)OC)cc2)n1
Reaction time: 3.5 h
Yield: 40 %

Procedure:
To a solution of 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline (0.18 mmol) in pyridine (1.5 mL) was added methyl chloroformate (0.18 mmol). After 3.5 h, the reaction mixture was quenched with methanol and concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC provided the title product as a pale yellow powder (40%). ESMS [M+H]+: 362.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:55][C:56]1[CH:63]=[CH:62][C:59]([CH2:60][NH2:61])=[C:58]([C:64]([F:67])([F:66])[F:65])[CH:57]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:61][CH2:60][C:59]3[CH:62]=[CH:63][C:56]([F:55])=[CH:57][C:58]=3[C:64]([F:67])([F:65])[F:66])=[O:21])=[CH:22][CH:23]=2)[N:10]=1
Reactant: NCc1ccc(F)cc1C(F)(F)F
Reactant: O=C(O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1C(F)(F)F)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 16.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoic acid (Intermediate-9, 0.100 g, 0.30 mmol), THF (5 mL), di-isopropyl ethyl amine (2.0 mL), TBTU (0.177 g, 0.540 mmol) and 4-fluoro-2-trifluoromethyl benzylamine (0.089 g, 0.600 mmol) to afford 0.025 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 4.63 (d, J=4.5 Hz, 2H), 7.48-7.50 (m, 6H), 8.05 (s, 4H), 9.16 (t, 1H), 12.67 (br, 1H); MS (m/z): 509.05 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][NH2:25].[CH3:26][O:27][CH2:28][CH:29]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][N:25]=[CH:29][CH2:28][O:27][CH3:26]
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Reactant: COCC=O
Product: COCC=NOCCC1=C(C)/C(=C/c2ccc(S(C)=O)cc2)c2ccc(F)cc21

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylsulfinylphenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with methoxyacetaldehyde by the method of Example 1.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[NH2:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[CH:17]1[C:18]2[CH:6]([CH2:5][O:4][C:2]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:2]([O:4][CH2:5][CH:6]3[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[C:13]4[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:3])=[O:3])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Product: O=C(NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 71 %

Procedure:
The reaction of 9-fluorenylmethyl chloroformate with L-lysine according to the conditions described in example 2 provided the title product in 71% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]2[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]2)[CH:5]=[CH:6][C:7]=1[N:8]=C(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO>CO>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH:22]2[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:23]2)=[CH:3][C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N=C(c3ccccc3)c3ccccc3)c(Cl)c2)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(3-chloro-4-(diphenylmethyleneamino)phenyl)morpholine-4-carboxylate (0.63 g) in methanol (8 ml) were added sodium acetate (325 mg) and hydroxylamine hydrochloride (202 mg). The reaction mixture was stirred at room temperature for 16 hours and then at 60° C. for 5 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 70% EtOAc in hexanes) to afford tert-butyl (RS)-2-(4-amino-3-chlorophenyl)morpholine-4-carboxylate (345 mg, 84%) as a white solid. MS (ISP): 337.2 ([{37Cl}M+Na]+), 335.1 ([{35Cl}M+Na]+), 314.9 ([{37Cl}M+H]+), 313.0 ([{35Cl}M+H]+), 259.1 ([{37Cl}M+H—C4H8]+), 257.1 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[C:16]([Cl:20])=[CH:17][C:18](Cl)=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[Cl:21])[C:6]1=[O:22])[CH:2]=[CH2:3].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C.C(#N)C>O>[CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[C:16]([Cl:20])=[CH:17][C:18]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[Cl:21])[C:6]1=[O:22])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)c2ccc(Cl)c3c(Cl)cc(Cl)c(c23)C1=O
Reactant: C1CCNC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCON1C(=O)c2ccc(Cl)c3c(N4CCCC4)cc(Cl)c(c23)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
A suspension of 2-allyloxy-4,6,7-trichlorobenzo[de]isoquinoline-1,3-dione (0.5 g, 1.5 mmol, from Example I4), pyrrolidine (0.14 g, 2.0 mmol), triethylamine (0.3 g, 3.0 mmol), and 25 mL of acetonitrile was stirred at room temperature for 4 hours. The reaction was diluted with 100 mL of water, and the precipitate was removed by filtration, washed with water, and dried in vacuo to give 0.53 g of the title compound.
Reaction SMILES: [C:1]([N:4]([C:12]1[N:13]=[C:14]([C:18]2[CH:19]=[N:20][C:21]([NH:28][C:29]3[CH:37]=[CH:36][C:32]4[N:33]=[CH:34][S:35][C:31]=4[CH:30]=3)=[CH:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[O:15][C:16]=1[CH3:17])C(=O)OC(C)(C)C)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:35]1[C:31]2[CH:30]=[C:29]([NH:28][C:21]3[N:20]=[CH:19][C:18]([C:14]4[O:15][C:16]([CH3:17])=[C:12]([NH:4][C:1](=[O:3])[CH3:2])[N:13]=4)=[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])[CH:22]=3)[CH:37]=[CH:36][C:32]=2[N:33]=[CH:34]1
Reactant: CC(=O)N(C(=O)OC(C)(C)C)c1nc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)oc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)oc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl acetyl(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-yl)carbamate (35) (30 mg, 0.057 mmol) in DCM (5 mL) was treated with TFA (0.230 mmol) and stirred at room temperature for 3 h. The reaction mixture was concentrated and azeotroped with chloroform three times to obtain gummy solid. The crude material obtained was purified by prep HPLC to furnish N-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-yl)acetamide. 1H NMR: 400 MHz, CD3OD: δ 1.33 (d, J=6.40 Hz, 6H), 2.16 (s, 3H), 2.35 (s, 3H), 3.73-3.79 (m, 1H), 6.14 (s, 1H), 7.52 (dd, J=2.40, 8.80 Hz, 1H), 7.97 (d, J=8.80 Hz, 1H), 8.38 (d, J=2.00 Hz, 1H), 8.49 (s, 1H), 9.07 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min; retention time: 1.823 min; LCMS (ES-API), m/z 423.2 (M+H). HPLC: XBridge Phenyl (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 6.484 min; Purity: 95.1%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:24]1[CH2:27][CH2:26][C@H:25]1[CH2:28][OH:29].CCN(C(C)C)C(C)C.CCOC(C)=O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13]([N:24]3[CH2:27][CH2:26][C@H:25]3[CH2:28][OH:29])[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Reactant: OC[C@@H]1CCN1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC[C@H]3CO)c2CC1
Temperature: 80 °C

Procedure:
To 50 mg (0.155 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester (route 1, from step a to d) and 22 mg (0.17 mmol) (S)-azetidin-2-yl-methanol hydrogen chloride in 2 mL ethanol was added 2 mL (0.31 mmol) DIPEA, and the reaction mixture was heated at 80° C. for 19 hours. The reaction was cooled to room temperature and 20 mL EtOAc was added. The organic layer was washed with 10 mL citric acid (1 M), H2O (2×10 mL), 10 mL saturated brine, and dried over MgSO4. After evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 1:5).
Reaction SMILES: Br.[NH2:2][C@H:3]([C:5]([N:7]1[CH2:20][CH2:19][CH2:18][C@H:8]1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])=[O:6])[CH3:4].C(N(CC)CC)C.[C:28]12([C:38](Cl)=[O:39])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2>O1CCCC1>[C:28]12([C:38]([NH:2][C@H:3]([C:5]([N:7]3[CH2:20][CH2:19][CH2:18][C@H:8]3[C:9]([NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:10])=[O:6])[CH3:4])=[O:39])[CH2:35][CH:34]3[CH2:33][CH:32]([CH2:31][CH:30]([CH2:36]3)[CH2:29]1)[CH2:37]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](NC(=O)C12CC3CC(CC(C3)C1)C2)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.42 g (0.01 mol) of L-alanyl-L-proline anilide hydrobromide were suspended in 100 ml of dry tetrahydrofuran and the suspension was cooled to 0° C. There were then added 2.8 ml (0.02 mol) of triethylamine followed by 1.72 g (0.001 mol) of 1-adamantoyl chloride. The mixture was stirred at 0° C. for 0.5 hour and at room temperature for 2 hours and then evaporated. The residue was extracted twice with 40 ml of ethyl acetate each time. The combined ethyl acetate extracts were washed successively with two 20 ml portions of 1-N hydrochloric acid, 20 ml of water, two 20 ml portions of 5% sodium bicarbonate solution and two 20 ml portions of water, dried over magnesium sulphate and evaporated. The residue was crystallised from ether/petroleum ether and further purified by chromatography on 100 g of silica gel using chloroform for the elution. Evaporation of the chloroform eluate and crystallisation of the residue from ether/petroleum ether yielded 1.09 g (24%) of pure N-(1-adamantylcarbonyl-L-alanyl-L-proline anilide of melting point 119°-121° C.; [α]D20 =-142.9° (c=1% in methanol).