Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[C:23]([F:26])([F:25])[F:24])[C:14]([CH3:27])=[C:13]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[O:29])[CH:12]=1)C1C=CC=CC=1>CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:15]2[C:11]([CH2:10][CH2:9][OH:8])=[CH:12][C:13]([C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=3)=[O:29])=[C:14]2[CH3:27])=[C:17]([C:23]([F:24])([F:26])[F:25])[CH:18]=1
Reactant: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cc(CCOCc2ccccc2)n1-c1ccc(F)cc1C(F)(F)F
Solvent: CO
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cc(CCO)n1-c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a solution of 5-[2-(benzyloxy)ethyl]-1-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-N-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-carboxamide (220 mg, 0.38 mmol) in MeOH (3 mL), Pd(OH)2—C (20 mg) was added and stirred overnight under H2 atmosphere at room temperature. After the reaction, Pd(OH)2—C was filtered off and the solvent was evaporated. The residue was purified over silica gel (AcOEt/n-hexane, 9:1 v/v) to give the atropisomeric mixture of the title compound (170 mg, 92%) as a foam.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9](=[O:12])[CH2:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl/[C:21](=[N:27]\[OH:28])/[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[O:28][N:27]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:8]=2[C:9](=[O:12])[CH2:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=O)C#Cc1ccccc1
Reactant: CCOC(=O)/C(Cl)=N/O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1noc(-c2ccccc2)c1C(=O)CC
Temperature: 120 °C
Reaction time: 16 h
Yield: 23.2 %

Procedure:
To a solution of 1-phenylpent-1-yn-3-one (36.7 mg, 0.232 mmol) and triethylamine (0.113 mL, 0.812 mmol) in toluene (1 mL) at 120° C. was added (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (105 mg, 0.696 mmol) in toluene (1 mL) dropwise. The reaction mixture was stirred at 120° C. for 16 h. To the reaction mixture was added additional (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (105 mg, 0.696 mmol) and triethylamine (0.113 mL, 0.812 mmol), and the reaction mixture was stirred at 140° C. for 3 days. The reaction mixture was concentrated, diluted with ethyl acetate (5 mL), washed with water (1 mL), washed with a saturated aqueous solution of sodium bicarbonate (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by silica gel chromatography with hexanes/ethyl acetate (10/1) afforded ethyl 5-phenyl-4-propionylisoxazole-3-carboxylate (14.7 mg). The compound had an HPLC ret. time=3.15 min.−Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: 274+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:50])[C:22]([C:25]4[N:26]=[C:27]([NH:30]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[S:28][CH:29]=4)=[N:23][OH:24])[C:18](=[O:51])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1.C(O)=O.O>C(Cl)Cl.C(O)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:50])[C:22]([C:25]4[N:26]=[C:27]([NH2:30])[S:28][CH:29]=4)=[N:23][OH:24])[C:18](=[O:51])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.17 h

Procedure:
A mixture of the product of Step B and 4 ml formic acid containing 1/3 volume of water was stirred for 10 minutes and was then evaporated to dryness. The residue was triturated with 10 ml of water and was then vacuum filtered. The solid was washed with water and empasted with ether to remove triphenyl carbinol. The raw product was dissolved in 15 ml of acetone containing 20% water and the mixture was vacuum filtered. The product was triturated with 10 ml of ethanol to obtain 1 g of raw product which was empasted with 5 ml of a 1-1 methylene chloride-ethanol mixture to obtain 0.6 g of the syn isomer of 3-[(1-methyl-5-tetrazolyl)-thiomethyl]-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][C@H:9]([C:11]2[CH:12]=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:24][CH:23]=2)[C:3]=1[C:32]#[N:33].C(Cl)CCl.C1C=CC2N(O)N=[N:44]C=2C=1.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH:9]([C:11]2[CH:12]=[C:13]([C:17]([NH2:44])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:26][CH:27]=2)[C:3]=1[C:32]#[N:33]
Reactant: On1nnc2ccccc21
Reactant: C[C@H](Sc1nc(N)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N)c1cccc(C(=O)O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(Sc1nc(N)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N)c1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
33 mg (0.072 mmol) of rac-3-[(1S)-1-({6-amino-3,5-dicyano-4-[4-(2-hydroxyethoxy)phenyl]-pyridin-2yl}sulfanyl)ethyl]benzenecarboxylic acid Example 16 were initially charged in 1.6 ml of DMF. After addition of 20.6 mg (0.107 mmol) of EDC and 14.5 mg (0.107 mmol) of HOBT, the mixture was stirred at RT for 10 min. 19.2 mg (0.358 mmol) of ammonium chloride and 64.8 mg (0.502 mmol) of N,N-diisopropylethylamine were then added, and the reaction solution was stirred at RT overnight. The reaction solution was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: ClN1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[C:12]([SH:16])[CH:13]=[CH:14][CH:15]=1.[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH3:18]>C(Cl)Cl>[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([C:30]=1[S:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Br:9])[CH:11]=1)=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Reactant: Sc1cccc(Br)c1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1Sc1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
N-Chlorosuccinimide (1.59 g, 12 mmol) was dissolved in DCM (100 mL) and the solution was cooled to −78° C. 3-Bromothiophenol (1.24 mL, 12 mmol) was added dropwise and the reaction stirred for 30 minutes. Then, 6-chloro-1H-indole-2-carboxylic acid ethyl ester (2.2 g, 10 mmol) as a solution in DCM was added in 3 portions and the reaction was allowed to slowly warm to room temperature and continued stirring overnight. The reaction mixture was concentrated then purified by silica gel chromatography (0-30% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: Br[C:2]1([CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)[CH:3]=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18](B(O)O)[CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[CH:3]=[O:4])[CH:17]=1
Reactant: OB(O)c1cccnc1
Reactant: O=CC1(Br)C=CC=CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccccc1-c1cccnc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a suspension of 1-bromobenzaldehyde (250 μL, 2.14 mmol), sodium carbonate (270 mg, 2.55 mmol), and 3-pyridineboronic acid (289 mg, 2.35 mmol) in 4.2 mL of N,N-dimethylformamide/water (2:1) were added palladium acetate (24 mg, 0.11 mmol) and triphenylphosphine (115 mg, 0.44 mmol) under nitrogen. After being stirred at 110° C. overnight, the reaction mixture was filtered. The filtrate was diluted with chloroform, and the solution was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (chloroform/methanol=99/1 to 95/5) to obtain the title compound as a white powder (250 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16](=O)[C:17]([NH:19][C:20]3[S:24][N:23]=[C:22]([CH3:25])[CH:21]=3)=[O:18])=[CH:8]2)=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].C([O-])(=O)C.[Na+]>CCO.C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16](=[N:30][OH:31])[C:17]([NH:19][C:20]3[S:24][N:23]=[C:22]([CH3:25])[CH:21]=3)=[O:18])=[CH:8]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(NC(=O)C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)sn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(NC(=O)C(=NO)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)sn1
Temperature: 25 °C

Procedure:
A stirred mixture of 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-N-(3-methyl-isothiazol-5-yl)-2-oxo-acetamide (0.102 g, 0.25 mmol), hydroxylamine hydrochloride (17 mg, 0.25 mmol), and sodium acetate (0.1 g, 1.2 mmol) in EtOH (3 mL) and THF (3 mL) was heated to reflux for 3 days. After being cooled to rt, the reaction mixture was poured into ice-H2O (20 mL). The precipitated product 2-[1-(4-Chloro-benzyl)-1H-indol-3-yl]-2-hydroxyimino-N-(3-methyl-isothiazol-5-yl)-acetamide was collected by filtration, washed with H2O, and dried in vacuo (95 mg, 90%). 1H NMR (DMSO-d6) δ 2.3 (s, 3H), 5.6 (s, 2H), 6.9 (s, 1H), 7.0-7.5 (m, 7H), 8.1 (d, 1H, J=7), 8.65 (s, 1H). ESMS calcd for (C21H17ClN4O2S): 424.1; found 425.1 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:21])[C:4]([NH:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([CH3:19])[CH:11]=1)([CH2:6][CH3:7])[CH3:5].C>[Pd].C(O)C>[Cl:1][CH2:2][C:3](=[O:21])[C:4]([NH:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([CH3:19])[CH:11]=1)([CH2:6][CH3:7])[CH3:5]
Reactant: CCC(C)(NC(=O)c1ccc([N+](=O)[O-])c(C)c1)C(=O)CCl
Agent: [Pd]
Solvent: CCO
Product: CCC(C)(NC(=O)c1ccc(N)c(C)c1)C(=O)CCl
Reaction time: 3 h
Yield: 2.8 %

Procedure:
The N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-3-methyl-4-nitrobenzamide (2 g) prepared in the previous step, 70 mL of ethanol and 150 mg of 5% palladium over charcoal were placed in a hydrogenation bottle and hydrogenated in a Parr apparatus (50 psia, room temperature) for 3 hours. The reaction mixture was then filtered through celite and the solvent eliminated under reduced pressure yield to the crude product. Separation of the crude product by chromatographic column (1:1 ethyl acetate:hexane) yielded 50 mg of the expected N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-amino-3-methylbenzamide.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.N1CCCCC1.[O:32]1[CH:36]=[CH:35][N:34]=[C:33]1[C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>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.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:40]#[C:39][C:37]([C:33]4[O:32][CH:36]=[CH:35][N:34]=4)([OH:41])[CH3:38])[CH:10]=3)[C:6]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: C#CC(C)(O)c1ncco1
Reactant: Nc1nccc(-n2nc(C(=O)N3CCOCC3)c3ccc(I)cc32)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(O)(C#Cc1ccc2c(C(=O)N3CCOCC3)nn(-c3ccnc(N)n3)c2c1)c1ncco1
Temperature: 35 °C
Reaction time: 2.5 h
Yield: 40.9 %

Procedure:
To a pressure tube was added 4-{6-iodo-3-[(morpholin-4-yl)carbonyl]-1H-indazol-1-yl}pyrimidin-2-amine (150 mg, 0.33 mmol) followed by piperidine (2.0 mL), tetrakis(triphenylphosphine)palladium(0) (38.5 mg, 0.03 mmol), copper(I) iodide (6.35 mg, 0.03 mmol) and 2-(1,3-oxazol-2-yl)but-3-yn-2-ol (68.53 mg, 0.5 mmol). The reaction was capped and stirred at 35° C. for 2.5 hr. The reaction mixture was concentrated in vacuo. DCM (5 mL×2) added and the mixture was concentrated in vacuo. Purification by column chromatography (1% to 10% MeOH in DCM), followed by trituration with a mixture of MeCN/diethyl ether mixture (3/1) gave the title compound as an off-white solid (62 mg): 1H NMR (500 MHz, DMSO) delta 3.67 (2H, d, J=4.26 Hz), 3.75 (4H, d, J=5.67 Hz), 3.94 (2H, d, J=3.94 Hz), 4.06 (3H, s), 6.72-6.89 (1H, m), 6.93-7.33 (4H, m), 7.45 (1H, d, J=7.57 Hz), 8.04 (1H, d, J=7.88 Hz), 8.11-8.23 (1H, m), 8.97 (1H, s); LC-MS: m/z=+460.15 (M+H)+.
Reaction SMILES: C(OC([C@@H:11]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:12]([C@H:21]1[CH2:25][C@@H:24]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH2:23][N:22]1C(OC(C)(C)C)=O)[O:13][Si](C(C)(C)C)(C)C)=O)C1C=CC=CC=1.[C:46]([NH:49][C@:50]1([C@@H:105]([CH2:107][CH3:108])[CH3:106])[CH2:54][CH2:53][N:52]([C@@H:55]([CH2:96][CH2:97][C:98]2[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=2)[C:56]([NH:58][C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2C[C@H](OC3C=CC=CN=3)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=[O:57])[C:51]1=[O:104])(=[O:48])[CH3:47].OOS([O-])=O.[K+]>CO.O>[C:46]([NH:49][C@:50]1([C@@H:105]([CH2:107][CH3:108])[CH3:106])[CH2:54][CH2:53][N:52]([C@@H:55]([CH2:96][CH2:97][C:98]2[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=2)[C:56]([NH:58][C@@H:11]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:12]([OH:13])[C@H:21]2[CH2:25][C@@H:24]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[CH2:23][NH:22]2)=[O:57])[C:51]1=[O:104])(=[O:48])[CH3:47]
Reactant: CCCS(=O)(=O)[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@H](Oc3ccccn3)CN2C(c2ccccc2)c2ccccc2)C1=O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CCc2ccccc2)N2CC[C@](NC(C)=O)([C@H](C)CC)C2=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Step 22 (D): (2R,4R)-tert-butyl 2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-phenylpropyl)-4-(propylsulfonyl)pyrrolidine-1-carboxylate. A solution of 130 mg (0.2 mmol) of the compound of step 22 (C) dissolved in 2 mL of methanol was treated with a solution of 240 mg (0.4 mmol) of oxone dissolved in 0.4 mL of water. After stirring at rt for 30 min, the reaction solution was partitioned between ethyl acetate and water, the organic layer was concentrated, and the crude product was purified by chromatography eluting with a gradient of 20 to 80% ethyl acetate in hexanes to provide 86 mg (64%) of the desired sulfone and 37 mg (28%) of the sulfoxide intermediate as a lower-eluting compound. 1H NMR (500 MHz, CDCl3) δ 0.06 (s, 3 H) 0.11 (s, 3 H) 0.96 (s, 9 H) 1.07 (t, J=7.32 Hz, 3 H) 1.47 (s, 9 H) 1.87 (dd, J=13.43, 6.71 Hz, 3 H) 2.03 (s, 1 H) 2.26 (t, J=12.21 Hz, 1 H) 2.38 (s, 1 H) 2.68 (s, 1 H) 2.90 (s, 2 H) 3.46 (m, 2 H) 3.75 (s, 1 H) 4.09 (m, 2 H) 4.26 (d, J=7.02 Hz, 1 H) 4.77 (m, 1 H) 4.95 (m, 1 H) 7.18 (m, 10 H) MS (ESI) (M+H−Boc)+=575.25
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]4[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=4)[N:15]=[C:5]3[C:4]=2[CH:3]=1.[NH2:24][CH:25]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+].O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:21]([N:20]1[C:16]([C:14]2[N:15]=[C:5]3[C:4]4[CH:3]=[C:2]([NH:24][CH:25]5[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28]5)[N:12]=[CH:11][C:10]=4[O:9][CH2:8][CH2:7][N:6]3[CH:13]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(NC3CN(C(=O)OC(C)(C)C)C3)ncc1OCC2

Procedure:
A solution of 10-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (90.0 mg, 0.272 mmol), tert-butyl 3-aminoazetidine-1-carboxylate (46.9 mg, 0.272 mmol), Palladium Acetate (6.11 mg, 0.0272 mmol), XPhos (13.0 mg, 0.0272 mmol), and Sodium-tert-butoxide (52.3 mg, 0.544 mmol) in 1,4-Dioxane (1.50 mL, 19.2 mmol) was heated in microwave at 115 C for 20 min. The reaction was filtered thru celite then rinsed with EtOAc. The filtrate was washed with water and brine. The organic layer was dried Na2SO4, concentrated to give crude intermediate tert-butyl 3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepin-10-ylamino)azetidine-1-carboxylate which was dissolved in DCM (10.0 mL). Trifluoroacetic Acid (0.419 mL, 5.44 mmol) was added and the reaction was stirred 3 h. The reaction was concentrated and submitted rHPLC purification to give 261. MS: (ESI+)=367.2. 1H NMR (500 MHz, DMSO) δ 8.29 (s, 1H), 8.23 (s, 1H), 7.98 (s, 1H), 7.79 (s, 1H), 5.74 (dt, J=13.1, 6.5 Hz, 2H), 4.73-4.60 (m, 3H), 4.58-4.51 (m, 2H), 4.43 (dd, J=12.7, 6.9 Hz, 2H), 4.24 (dt, J=15.9, 5.6 Hz, 1H), 2.77 (m, J=34.8, 13.1, 5.3 Hz, 2H), 1.50 (d, J=6.6, 2.9 Hz, 6H)
Reaction SMILES: [N:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[NH:7][C:6]([CH3:16])([CH3:15])[CH2:5]1)=[N+]=[N-].O.C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOC(C)=O>[Br:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:15])([CH3:16])[CH2:5][CH:4]2[NH2:1]
Reactant: CC1(C)CC(N=[N+]=[N-])c2cc(Br)ccc2N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)CC(N)c2cc(Br)ccc2N1
Reaction time: 8 h

Procedure:
To a solution of 4-azido-6-bromo-2,2-dimethyl-1,2,3,4-tetrahydroquinoline (2.29 g, 8.15 mmol), water (6.50 ml, 361 mmol), and THF (20.4 ml, 8.15 mmol) was added triphenylphosphine (2.35 g, 8.96 mmol) in one portion. The resulting mixture was heated to 40 deg C. and stirred overnight. The crude mixture was dissolved with EtOAc and transferred to a sep. funnel containing 0.5 MHCl. The aqueous layer was washed 5×DCM. The aqueous layer was then neutralized with 6N NaOH and washed 3× with EtOAc. The organic layers were combined, dried with MgSO4, filtered and concentrated to provide the desired product. MS m/z: 239 (M−NH2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].O>CS(C)=O>[C:12]([NH:16][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)Nc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-chloro-2-fluoronitrobenzene (250 mg) and t-butylamine (0.40 mL) were dissolved in dimethyl sulfoxide (3.0 mL) and stirred at room temperature overnight. Then, the mixture was added with water and extracted with ethyl acetate. The thus obtained organic layer was washed with saturated brine, and the water was removed with sodium sulfate, and the solvent was removed by distillation under reduced pressure. The subsequent reaction was proceeded without further purification of the thus obtained compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[CH3:7].NCCCCN.C([Li])CCC.[C:20](=[O:22])=[O:21]>CCCCCC.C(OCC)C.O.C1COCC1>[CH3:8][C:3]1[C:2]([Cl:1])=[C:6]([CH2:7][C:20]([OH:22])=[O:21])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cl
Reactant: O=C=O
Agent: NCCCCN
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1noc(CC(=O)O)c1Cl
Reaction time: 2 h

Procedure:
A mixture of 12 g of 4-chloro-3,5-dimethyl isoxazole (prepared by chlorination of 3,5-dimethyl-isoxazole in acetic acid at 50° C) in freshly distilled THF and 13.8 ml of tetramethylenediamine in a 3-necked vessel was reacted under a nitrogen atmosphere with 50 ml of a 20% n-butyl lithium solution in hexane at -70° C and the mixture was stirred for 2 hours. A stream of carbon dioxide was passed therethrough for an hour and then water and diethyl ether were added thereto. The aqueous layer was extracted with diethyl ether at a pH of 2 and the combined organic layers were dried over magnesium sulfate, treated with activated carbon and concentrated to dryness under reduced pressure. The 6.3 g of product was crystallized from a petroleum ether-acetone mixture to obtain 3-methyl-4-chloro-isoxazole-5-yl acetic acid melting at 128°-131° C (sublimation)
Reaction SMILES: [Br:1]Br.[CH3:3][S:4]([N:7]1[CH2:12][CH2:11][CH2:10][S:9][C:8]1=[CH:13][N+:14]([O-:16])=[O:15])(=[O:6])=[O:5].CCOCC>C(Cl)Cl>[CH3:3][S:4]([N:7]1[CH2:12][CH2:11][CH2:10][S:9][C:8]1=[C:13]([Br:1])[N+:14]([O-:16])=[O:15])(=[O:5])=[O:6]
Reactant: CS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Reactant: BrBr
Solvent: CCOCC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCSC1=C(Br)[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A solution of 1.6 g of bromine in 10 ml of methylene chloride was added drop-by-drop over a period of 10 minutes to a solution of 2.38 g of (1A) in 50 ml of methylene chloride at 0° C. and under a nitrogen blanket. The resulting mixture was stirred for a further 10 minutes, charcoaled, and stripped of solvent. The residue was dissolved in a minimum amount of methylene chloride, then ether was added to the solution, resulting in a gum. The gum was dissolved in methylene chloride, the solution was charged onto a flash chromatograph column (silica gel) and the product was eluted with methylene chloride, to give (1) on workup.
Reaction SMILES: [CH3:1][C@H:2]1[C:3](=[O:29])[NH:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:11]2[CH:12]=[CH:13][N:14]=[C:15]([CH:28]=2)[C@@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17][CH:18]=[CH:19]1>CCOC(C)=O.[Pt](=O)=O>[CH3:1][C@@H:2]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:15]2[CH:28]=[C:11]([CH:12]=[CH:13][N:14]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][C:3]1=[O:29]
Reactant: C[C@@H]1C=CC[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2ccccc2NC1=O
Agent: O=[Pt]=O
Agent: C[C@@H]1/C=C/C[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2ccccc2NC1=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
45F (974 mg, 2.475 mmol) in EtOAc (49.500 mL) was added platinum(IV) oxide (56.2 mg, 0.248 mmol). The reaction mixture was charged with H2 balloon and vacuum/H2 several times. The reaction was stirred at rt under H2 overnight. The reaction was filtered and concentrated to give the desired product (0.95 g, 97%) as a brownish solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.68 (d, J=5.0 Hz, 1H), 7.47-7.30 (m, 5H), 7.26-7.22 (m, 1H), 6.79 (br. s., 1H), 5.85 (d, J=7.7 Hz, 1H), 4.74 (br. s., 1H), 2.52-2.42 (m, 1H), 2.18-2.07 (m, 1H), 1.66-1.57 (m, 1H), 1.51-1.46 (m, 1H), 1.43 (s, 9H), 1.40-1.33 (m, 1H), 1.07 (br. s., 1H), 1.00 (d, J=6.9 Hz, 3H), 0.83 (d, J=9.9 Hz, 1H). MS (ESI) m/z: 396.2 (M+H)+.