Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1[CH:5]=[C:6]([F:11])[C:7]([Cl:10])=[N:8][CH:9]=1)C=C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:33]C)C=C4)N(CC2)C1.[C:70]([OH:74])(C)([CH3:72])[CH3:71]>O>[Cl:10][C:7]1[N:8]=[CH:9][C:4]([CH2:71][C@@H:70]([OH:74])[CH2:72][OH:33])=[CH:5][C:6]=1[F:11]
Reactant: CC(C)(C)O
Reactant: C=CCc1cnc(Cl)c(F)c1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Solvent: O
Product: OC[C@H](O)Cc1cnc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of 2 (2.7 g, 16.2 mmol) in t-butanol (80 mL) and H2O (80 mL), AD-mix-beta (27.8 g) was added portion wise at 5° C. The reaction was slowly warmed to room temperature and further stirred at this temperature for 16 hrs. The reaction mixture was cooled down to 5° C. and then quenched by adding excess sodium sulfite and stirred for 20 min. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×2). The organic layers were combined which was washed with brine, dried over Na2SO4, and concentrated. The obtained residue was chromatographed on silica gel eluted with hexane/ethyl acetate (20%-100%) to afford 3.2 g (98%) of 3 as a colorless oil which was slowly solidified.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:33][O:34][CH2:35][C:36]#[N:37])[C:27]([O:29]CC#N)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:33][O:34][CH2:35][C:36]#[N:37])[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCON=C(C(=O)OCC#N)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#CCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.33 h

Procedure:
A mixture of 8.69 g of the product of Step A in 52 ml of dioxane was cooled on an ice bath and 17.1 ml of N sodium hydroxide solution were added thereto dropwise over 20 minutes. Spontaneous heating occured and then 10.5 ml of 2N hydrochloric acid were added thereto. The dioxane was distilled and only water remained as solvent. 20 ml of water and 30 ml of ether were added thereto and the mixture was stirred for 15 minutes and was vacuum filtered. The crystals were rinsed with water and ether and dried to obtain 4.32 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-cyanomethoxyimino-acetic acid melting at about 180° C. with decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:40]([F:43])([F:42])[F:41])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:34])(=[O:33])[NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:17][C:16]=3[F:35])[C:10]([CH2:36][CH2:37][CH2:38][CH3:39])=[N:9]2)[CH:7]=1.[C:44](Br)(=[O:47])[CH2:45][CH3:46].C(Cl)Cl>CN(C1C=CN=CC=1)C.CO>[CH2:36]([C:10]1[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:33])(=[O:34])[NH:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:17][C:16]=2[F:35])[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:44](=[O:47])[CH2:45][CH3:46])[CH:3]=[CH:4][C:5]=2[C:40]([F:42])([F:41])[F:43])[N:9]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Reactant: CCC(=O)Br
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F

Procedure:
The title compound was prepared by reaction of 2-[5-amino-2-(trifluoromethyl)phenyl]-5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step A) with propionyl bromide (3 equivalents) in the presence of DMAP (1.1 equiv) following the method of Example 69. Chromatographic purification of the crude product on silica gel (elution with 0.8% MeOH in CH2Cl2) afforded a nearly quantitative yield of off-white, stiff foam; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 682 (M+Li)+.
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[CH2:24]([NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:25]([CH3:27])[CH3:26]>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH:3]=1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Reactant: CC(C)CNCC(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)CN(CC(C)C)c1cc(N)c([N+](=O)[O-])cc1C(=O)Nc1ccc2cn[nH]c2c1
Temperature: 25 °C

Procedure:
A solution 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol; see Example 48) in NMP (2 mL) was added with diisobutylamine (0.5 mL), and the resulting mixture was subjected to microwave irradiation at 140° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL). The solid formed was collected by filtration, washed with water, and dried in vacuo to provide 4-amino-2-diisobutylamino-N-(1H-indazol-6-yl)-5-nitrobenzamide.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:15]=[CH:14][C:13](I)=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[K+].[K+].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]1[C:48]2[C:43](=[N:44][CH:45]=[C:46](B3OC(C)(C)C(C)(C)O3)[CH:47]=2)[N:42]([S:58]([C:61]2[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][CH:62]=2)(=[O:60])=[O:59])[CH:41]=1>ClCCl>[CH3:5][O:4][C:2]([NH:6][C:7]1[CH:15]=[CH:14][C:13]([C:46]2[CH:47]=[C:48]3[C:40]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[O:33][CH3:32])=[CH:41][N:42]([S:58]([C:61]4[CH:62]=[CH:63][C:64]([CH3:67])=[CH:65][CH:66]=4)(=[O:60])=[O:59])[C:43]3=[N:44][CH:45]=2)=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:3]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Nc1ccc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl chloroformate (0.88 ml, 11.4 mmol) was added to a solution of 2-amino-5-iodo-benzoic acid (2.50 g, 9.5 mmol) and di-iso-propyl ethyl amine (5.96 ml, 34.4 mmol) in dichloromethane (50 ml) and the resulting mixture stirred at room temperature for 4 hours. The solvent was evaporated and the residue used without further purification. MS: m/z 322.1 (M+H+). To this crude was added tetrahydrofuran/acetonitrile/50% w/v potassium carbonate (80 ml), 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (4.80 g, 9.5 mmol). This mixture was degassed with nitrogen, split into 4 portions and irradiated in the microwave to 150° C. for 30 min. The reaction mixtures were then combined and extracted with ethyl acetate (3×), dried over magnesium sulfate, and purified by silica gel chromatography to produce 2-methoxycarbonylamino-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid as a white solid. (2.51 g, 46%). MS: m/z 572.6 (M+H+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[CH3:17])=[CH:7][C:6]=1[C:18]([F:21])([F:20])[F:19])(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:46][O:47][CH2:48][C:49](O)=[O:50].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([NH:16][C:49](=[O:50])[CH2:48][O:47][CH3:46])=[N:13][C:12]=2[CH3:17])=[CH:7][C:6]=1[C:18]([F:21])([F:20])[F:19])(=[O:3])=[O:4]
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Reactant: COCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamine (158a) (0.1 g, 0.3 mmol) is added to a solution of HATU (0.226 g, 0.6 mmol), methoxyacetic acid (0.046 ml, 0.6 mmol) and DIPEA (0.1 ml, 0.6 mmol) in DMF (7.5 ml). The reaction mixture was left to stir for 3 days at room temperature. The reaction mixture is filtered through basic alumina. The solvent is removed in vacuo and the product is purified by chromatography on silica eluting with ethyl acetate-hexane (3:1) to give the titled compound.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([CH:12]([CH3:14])C)S[C:10]=1N)=O)C.C(O[C:18]([C:20]1[N:21]=[C:22]([CH:32]([CH3:34])[CH3:33])[S:23][C:24]=1[NH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:19])C.C(C1SC(NC2C=NC=CC=2)=C(C(O)=O)[N:42]=1)(C)C>>[CH3:10][C:6]1[N:7]=[C:8]([NH:42][C:18]([C:20]2[N:21]=[C:22]([CH:32]([CH3:33])[CH3:34])[S:23][C:24]=2[NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:19])[CH:12]=[CH:14][CH:4]=1
Reactant: CCOC(=O)c1nc(C(C)C)sc1Nc1cccnc1
Reactant: CC(C)c1nc(C(=O)O)c(Nc2cccnc2)s1
Reactant: CCOC(=O)c1nc(C(C)C)sc1N
Product: Cc1cccc(NC(=O)c2nc(C(C)C)sc2Nc2cccnc2)n1

Procedure:
The title compound, MS (ISP): m/e=352.3 (M+H+), was prepared as for example 153, steps A to G. Step C was performed using isobutyryl chloride, and yielded cyano-isobutyrylamino-acetic acid ethyl ester, which was cyclized to 5-amino-2-isopropyl-thiazole-4-carboxylic acid ethyl ester in step D. This was used in step E to generate 2-isopropyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester, which was hydrolized to 2-isopropyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid in step F. Coupling as described in step G generated the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[N:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][C:11]=1[CH3:19].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[CH:15][N:10]=[C:11]([CH3:19])[CH:12]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Cc1cc(B(O)O)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2cc(C)nc(N)n2)ccn1
Reaction time: 8 h

Procedure:
A mixture of 2.00 g (13.9 mmol) 2-amino-4-chloro-6-methylpyrimidine, 2.48 g (18.1 mmol) 2-picoline-4-boronic acid, 0.43 g (2.8 mmol) tetrakis(triphenylphosphine)palladium(0) and 3.85 g (27.9 mmol) potassium carbonate in 40 mL 1,2-dimethoxyethane and 4 mL water is heated to reflux temperature and stirred overnight. The reaction mixture is concentrated under reduced pressure, water is added and the precipitated product is filtered off and dried in vacuo at 40° C. Yield: 1.94 g (69%).
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.[C:8]([O:12][C@@H:13]([C:17]1[C:38]([CH3:39])=[CH:37][C:20]2[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4C=NC(=O)[NH:34][CH:35]=4)[CH:25]=3)[S:23][C:19]=2[C:18]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:14]([OH:16])=[O:15])([CH3:11])([CH3:10])[CH3:9].C([O-])([O-])=O.[K+].[K+].CI.C[C:56]([N:58]([CH3:60])[CH3:59])=[O:57]>>[C:8]([O:12][C@@H:13]([C:17]1[C:38]([CH3:39])=[CH:37][C:20]2[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[N:34][C:56](=[O:57])[N:58]([CH3:60])[CH:59]=4)[CH:25]=3)[S:23][C:19]=2[C:18]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:14]([O:16][CH3:1])=[O:15])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc2nc(-c3cccc(-c4cnc(=O)[nH]c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(-c4cnc(=O)n(C)c4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To the TFA salt of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(2-oxo-1,2-dihydropyrimidin-5-yl)phenyl)benzo[d]thiazol-6-yl)acetic acid (94.8 mg, 0.141 mmol) in DMA (3.0 mL) was added K2CO3 (194.4 mg, 1.406 mmol) and methyl iodide (199.6 mg, 0.088 mL, 1.406 mmol). The reaction was stirred at room temperature for 45 minutes, filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+: calc'd for C32H31ClN3O4S (M+H1): 588.2; Found: 588.2 (M+H+).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C@H:14]1[O:19][C@@H:18]([CH3:20])[CH2:17][N:16]([CH2:21][CH2:22][O:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([N:30]3[C:35](=[O:36])[C:34]([CH2:37][C:38]4[CH:43]=[CH:42][C:41]([C:44]5[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=5)=[CH:40][CH:39]=4)=[C:33]([CH2:52][CH2:53][CH3:54])[N:32]4[N:55]=[CH:56][N:57]=[C:31]34)[CH2:26][CH2:25]2)[CH2:15]1>C(OCC)(=O)C>[CH3:13][C@H:14]1[O:19][C@@H:18]([CH3:20])[CH2:17][N:16]([CH2:21][CH2:22][O:23][C@H:24]2[CH2:25][CH2:26][C@H:27]([N:30]3[C:35](=[O:36])[C:34]([CH2:37][C:38]4[CH:39]=[CH:40][C:41]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=5[C:50]5[NH:3][C:4](=[O:7])[O:5][N:51]=5)=[CH:42][CH:43]=4)=[C:33]([CH2:52][CH2:53][CH3:54])[N:32]4[N:55]=[CH:56][N:57]=[C:31]34)[CH2:28][CH2:29]2)[CH2:15]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCN3C[C@@H](C)O[C@@H](C)C3)CC2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCCN3C[C@@H](C)O[C@@H](C)C3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.51 g), sodium hydrogen carbonate (0.82 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-(trans-4-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.095 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.081 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was adjusted to pH 7 with 1 N hydrochloric acid and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.19 g, 59%).
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[NH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:21][CH:22]1[C:28]2[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:27]=2[O:26][CH2:25][CH2:24][NH:23]1>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:21][CH:22]1[C:28]2[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:27]=2[O:26][CH2:25][CH2:24][N:23]1[CH2:2][C:3]([NH:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCOc3cc(OC)c(OC)cc32)cc1OC
Reactant: NC1CCc2ccccc21
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3OCCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-bromoacetyl bromide with rac-1-aminoindane and 5-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl 6-hydroxyhexanoate (5 g, 31.2 mmol) in anhydrous dichloromethane (115 mL) under nitrogen at −10° C. was added triethylamine (8.7 mL, 62.5 mmol) followed by methanesulfonyl chloride (4.8 mL, 62.5 mmol) dropwise over 1 hour. The resulting solution was stirred at room temperature for 6 hours and then diluted to 300 mL using dichloromethane. The solution was washed with twice saturated NaHCO3, and the aqueous layers backextracted with dichloromethane. The combined organics were dried over MgSO4, filtered, and concentrated. The resulting dark orange oil was purified by column chromatography (column 5″L×2″W; eluted with a gradient of 100% hexanes→10%→20% ethyl acetate in hexanes) to afford the product as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:7][CH2:6]C(=C)[CH2:4][CH2:3]1.C[N+]1([O-])[CH2:16][CH2:15][O:14]CC1.[O-:18]S([O-])(=S)=O.[Na+].[Na+].Cl>O=[Os](=O)(=O)=O.O>[F:1][C:2]1([F:9])[CH2:7][CH2:6][C:16]([CH2:15][OH:14])([OH:18])[CH2:4][CH2:3]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C1CCC(F)(F)CC1
Reactant: O=S([O-])([O-])=S
Agent: O=[Os](=O)(=O)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: OCC1(O)CCC(F)(F)CC1
Temperature: 50 °C
Reaction time: 96 h

Procedure:
To the solution from EXAMPLE 302D was added water (75 mL), then N-methylmorpholine-N-oxide (6.4 mL, 50% solution in water) and OsO4 (14.2 g, 2.5 wt % solution in tert-butanol) were added, and the reaction was stirred for 96 hours at 50° C. The solution was cooled to room temperature, treated with saturated aqueous Na2S2O3 solution (100 mL) for 30 minutes, and then acidified with concentrated aqueous HCl. The solution was then extracted three times with ethyl acetate, and the organic layers were combined, washed with 1M HCl, and brine, and concentrated. The crude mixture was chromatographed on silica gel using 10-100% ethyl acetate in hexanes, and then 5% methanol in ethyl acetate to give the product.
Reaction SMILES: [CH3:1][N:2]([C@@H:12]1[C@H:17]([CH3:18])[CH2:16][CH2:15][NH:14][CH2:13]1)[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl.N1C=CC=CC=1>[CH3:18][C@@H:17]1[CH2:16][CH2:15][N:14]([C:19](=[O:21])[CH3:20])[CH2:13][C@@H:12]1[N:2]([CH3:1])[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC(=O)Cl
Reactant: C[C@@H]1CCNC[C@@H]1N(C)c1ncnc2[nH]ccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CC[C@@H](C)[C@@H](N(C)c2ncnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.3 %

Procedure:
To a stirred solution of the product from Method B (0.03 grams, 0.114 mmol) dissolved in 5 mL of 10:1 dichloromethane/pyridine was added (0.018 grams, 0.228 mmol) of acetylchloride and the resulting mixture stirred at room temperature for 18 hours. The reaction mixture was then partitioned between dichloromethane and saturated sodium bicarbonate (NaHCO3). The organic layer was washed again with saturated NaHCO3, dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by preparative thin layer chromatography (PTLC) (silica; 4% methanol in dichloromethane) affording 0.005 g (15%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH:2]=[CH2:3].I[CH2:22]I.[Cl-].[NH4+]>CCCCCC.C([Zn]CC)C>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][O:4][CH2:1][CH:2]2[CH2:22][CH2:3]2)=[CH:8][CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CCOCCc1ccc(OCc2ccccc2)cc1
Reactant: ICI
Agent: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Product: c1ccc(COc2ccc(CCOCC3CC3)cc2)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred solution of compound of formula (7), (12 g, 0.0447 mol) in dry hexane (50 ml), diethyl zinc (1.1 M solution in hexane, 185 ml) was added at 0° C. under nitrogen atmosphere followed by diiodomethane (18 ml, 0.224 mol). The reaction was stirred for 6 h at 0° C. and poured over cold aqueous solution of ammonium chloride. The organic layer was separated and the aqueous layer extracted repeatedly with diethyl ether. The combined organic layer was washed with aq. solution of sodium thiosulphate, dried over anhydrous sodium sulphate, filtered and concentrated. The crude product was purified over silica gel column using ethyl acetate and light petroleum ether (1:50) as an eluent to afford compound of formula (8), as a colorless liquid 11.365 g (90%).
Reaction SMILES: [N:1](OCCC(C)C)=O.[CH2:9]([O:11][C:12](=[O:34])[C@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([CH3:28])[C:22]=1[CH2:29][O:30][C:31](=[O:33])[CH3:32])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10]>C(O)(=O)C.C(Cl)(Cl)Cl.ClCCl>[CH2:9]([O:11][C:12](=[O:34])[C@H:13]([CH2:20][C:21]1[C:22]([CH2:29][O:30][C:31](=[O:33])[CH3:32])=[C:23]2[C:24](=[CH:25][CH:26]=1)[NH:27][N:1]=[CH:28]2)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10]
Reactant: CC(C)CCON=O
Reactant: CCOC(=O)C[C@@H](Cc1ccc(N)c(C)c1COC(C)=O)C(=O)OCC
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C[C@@H](Cc1ccc2[nH]ncc2c1COC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
Isoamyl nitrite (170 μL, 1.3 mmol) was added dropwise to a cooled (water ice bath) solution of 2-(R)-(2-acetoxymethyl-4-amino-3-methyl-benzyl)-succinic acid diethyl ester in 5% acetic acid—chloroform (5 mL). Mixture was stirred at 0° C. for 1.5 hours. Mixture was diluted with dichloromethane (20 mL) and then washed with saturated aqueous sodium bicarbonate (2×20 mL). Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as amber oil in 99% yield. MS m/e (M+H)+=377.1.
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][N:26]3[C:31]([C:32]=2[CH3:33])=[C:30]([CH:34]2[CH2:36][CH2:35]2)[CH:29]=[C:28]([C:37]([OH:39])=[O:38])[C:27]3=[O:40])=[CH:19][C:18]=1[F:41])=O)(C)(C)C>C(#N)C>[NH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][N:26]3[C:31]([C:32]=2[CH3:33])=[C:30]([CH:34]2[CH2:35][CH2:36]2)[CH:29]=[C:28]([C:37]([OH:39])=[O:38])[C:27]3=[O:40])=[CH:19][C:18]=1[F:41]
Reactant: Cc1c(-c2ccc(CNC(=O)OC(C)(C)C)c(F)c2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1c(-c2ccc(CN)c(F)c2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Reaction time: 4 h

Procedure:
A solution of 4M hydrochloric acid in dioxane (1 mL, 4 mmol) was added to a solution of 8-(4-((tert-butoxycarbonylamino)methyl)-3-fluorophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (24 mg, 0.051 mmol) in ACN (4 mL). The mixture was stirred for 4 h and a suspension was formed. The product compound 4 was collected by filtration (17.7 mg, 78%).