Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:35]#[N:36])[CH:19]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH:18][CH:17]([C:25](O)=[O:26])[CH:16]2[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[C:11]([O:37][CH3:38])[CH:10]=1.CC1(C)[O:44][C@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:44][C@@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:25]([CH:17]1[CH:16]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=2[O:37][CH3:38])([C:35]#[N:36])[CH:19]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH:18]1)=[O:26]
Reactant: CC1(C)OC[C@@H](CCN)O1
Reactant: COc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)O)C1c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)NCC[C@@H](O)CO)C1c1cccc(Cl)c1
Yield: 52.1 %

Procedure:
In a manner similar to the method described in Example 72a, rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid (0.2 g, 0.35 mmol) was reacted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.15 g, 1.0 mmol), HATU (0.24 g, 0.63 mmol) and iPr2NEt (0.3 mL, 1.7 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 57%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[F:36])[CH2:9][C:10]([N:12]1[CH2:21][C:20]2[N:16]([CH:17]=[N:18][N:19]=2)[C:15]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:14]=2[CH2:13]1)=[O:11])(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].CO>C(Cl)Cl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:7][C@H:8]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[F:36])[CH2:9][C:10]([N:12]1[CH2:21][C:20]2[N:16]([CH:17]=[N:18][N:19]=2)[C:15]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:14]=2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)N1Cc2ccc(F)cc2-n2cnnc2C1)Cc1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N[C@@H](CC(=O)N1Cc2ccc(F)cc2-n2cnnc2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of [3-(9-fluoro-4H,6H-2,3,5,10b tetraaza-benzo[e]-azulen-5-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid-tert-butyl ester, (2.04 g, 3.93 mmol); in dry DCM (12 mL) was added trifluoroacetic acid (11.79 mL, 3 mL/mmol) at 0° C. The reaction mixture was stirred at r.t. for 2 h under argon. After completion of the reaction as confirmed by TLC, methanol (2×5 mL) was added and the reaction mixture was evaporated under vacuo to remove excess of solvent and trifluoroacetic acid. The remaining solvents were removed under vacuo to obtain trifluoroacetic acid salt of (R)-3-amino-1-(9-fluoro-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl)-4-(2,4,5-trifluoro-phenyl)-butan-1-one as a white solid (1.82 g, 3.42 mmol, 87%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)C>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C:11]2=1
Reactant: O=C1CCCCC1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Product: Brc1ccc2[nH]c3c(c2c1)CCCC3

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 3. Thus, 4-bromophenylhydrazine, hydrochloride (5.398 g, 24.15 mmol) was reacted with cyclohexanone (2.257 g, 23 mmol) in ethanol (60 ml) to give the product (4.871 g, 19.473 mmol, 85%) as a white solid, mp 148-151° C. 1H NMR (DMSO-d6) δ 1.74-1.83 (m, 4H), 2.57 (t, J=6.0 Hz, 2H), 2.68 (t, J=5.7 Hz, 2H), 7.06 (dd, J=1.8, 8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.46 (s, 1H), 10.84 (s, 1H); [ESI(−)], m/z 248/250 (M−H)−.
Reaction SMILES: Cl.[Cl:2][C:3]1[S:7][C:6]([NH2:8])=[N:5][CH:4]=1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=1)[C:15](O)=[O:16].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=1)[C:15]([NH:8][C:6]1[S:7][C:3]([Cl:2])=[CH:4][N:5]=1)=[O:16]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: Nc1ncc(Cl)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)Nc1ncc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-chlorothiazol-2-amine hydrochloride (513 mg, 3 mmol), 5-chloro-2-methoxybenzoic acid (670 mg, 3.6 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (1.15 g, 6 mmol), 1-hydroxybenzotriazole hydrate (810 mg, 6 mmol) and 4-(dimethylamino)pyridine (73 mg, 0.6 mmol) in pyridine was stirred at room temperature for 2 hours. The volatiles were removed under vacuum, and the resulting mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried (Na2SO4), filtered and concentrated. The residue was washed with a small amount of ethyl acetate, and filtered to afford the title compound. MS (ESI) m/z 303 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59]>O1CCCC1.C(OCC)(=O)C.O>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)OC(=O)CBr
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](OCC(=O)OC(C)(C)C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 72 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (55.5 mg, 0.0993 mmol), sodium hydride (95%, 15 mg, 0.594 mmol) and 15-crown-5 (15 mg, 0.0681 mmol) in tetrahydrofuran (1 ml) was stirred at an external temperature of 72° C. for 1 hour, to which t-butyl bromoacetate (0.05 ml, 0.336 mmol) was then added at room temperature and further stirred at an external temperature of 72° C. for 5 hours and 15 minutes. After the reaction mixture was diluted with ethyl acetate, water was added dropwise under ice cooling. After washing with saturated aqueous sodium chloride, the organic layer was dried over anhydrous magnesium sulfate. After evaporation under reduced pressure to remove the solvent, the resulting residue was purified by preparative thin layer chromatography (0.5 mm×1 plate, hexane:ethyl acetate=10:1, developed once) to give the titled compound (55.1 mg, 82%) as a colorless oil.
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16](Cl)[CH:15]=[C:14]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:15]=[C:14]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Clc1cc(N2CCCC2)nc(NC23CC4CC(CC(C4)C2)C3)n1
Reactant: C1CNCCN1
Product: c1c(N2CCCC2)nc(NC23CC4CC(CC(C4)C2)C3)nc1N1CCNCC1
Yield: 69.7 %

Procedure:
2-(1-Adamantylamino)-4-chloro-6-pyrrolidinopyrimidine is reacted with piperazine as described in Example 5 to obtain the title compound in a yield of 69.7%, m.p.:160°-164° C.
Reaction SMILES: Cl.[CH3:2][Si:3]1([CH3:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]([F:27])[C:19]=1F.O>CCOC(C)=O>[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]([F:27])[C:19]=1[N:6]1[CH2:7][CH2:8][Si:3]([CH3:9])([CH3:2])[CH2:4][CH2:5]1
Reactant: C[Si]1(C)CCNCC1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si]1(C)CCN(c2c(F)cc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.7 %

Procedure:
To a solution of 4,4-dimethyl-1,4-azasilinane hydrochloride 4 (950 mg, 7.35 mmol) in EtOAc (15 mL), triethylamine (2.5 mL, 18.37 mmol) is added and stirred at 25° C. for 10 min. The reaction mixture is cooled to 0° C. and 1,2,3-trifluoro-5-nitrobenzene (1.29 g, 7.35 mmol) is added drop wise and allowed to stir at 25° C. for 6 h. Water is then added and the organic layer is separated. The aqueous layer is extracted with EtOAc (2×10 mL) and the solvent is removed under reduced pressure. The product obtained is purified by column chromatography using hexane-EtOAc mixtures to give the product as a crystalline yellow solid 9a (1.32 g) in 63% yield.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)[CH:2]=C.C(Cl)Cl.[BH4-].[Na+].C[OH:20]>>[N:9]1[C:10]2[C:5](=[C:4]([CH2:1][CH2:2][OH:20])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C=CCc1cccc2ncccc12
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: OCCc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
5-Allyl-quinoline (3.12 g, 18.4 mmol) was dissolved in 40 mL methanol and 40 mL methylene chloride and cooled to −78° C. Ozone was bubbled in until a green solution was seen. Sodium borohydride (1.4 g, 36.8 mmol) was added. The reaction was warmed to room temperature and stirred for 2 hours. The reaction was quenched with water. A saturated solution of KHPO4 was added and the mixture extracted with methylene chloride. The organic extracts were dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was chromatographed with ethyl acetate to yield 1.6 g (50%) of 2-quinolin-5-yl-ethanol as a yellow solid. MS (APCI) m/z 174.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[Cl:28][C:29]1[CH:38]=[C:37]2[C:32]([NH:33][CH2:34][CH2:35][N:36]2[CH:39]2[CH2:41][CH2:40]2)=[CH:31][C:30]=1[F:42]>CCCCCCC.C(OCC)(=O)C>[Cl:28][C:29]1[CH:38]=[C:37]2[C:32](=[CH:31][C:30]=1[F:42])[N:33]([C:11]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[O:4][C:3]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=1[Cl:1])=[O:12])[CH2:34][CH2:35][N:36]2[CH:39]1[CH2:41][CH2:40]1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: Fc1cc2c(cc1Cl)N(C1CC1)CCN2
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCN(C2CC2)c2cc(Cl)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 7-chloro-1-cyclopropyl-6-fluoro-1,2,3,4-tetrahydro-quinoxaline and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Light yellow solid (19%). MS (ESI): m/z=494.041 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:3][C:4]2=[O:18])=[CH:11][CH:12]=1
Reactant: BrCc1ccccn1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1cc(OCc2ccccn2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 500 mg (2.04 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 20 mL DMF is added 0.62 g (2.46 mmol) 2-bromomethyl-pyridine and 0.85 g (6.12 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT and is diluted with 60 mL of EtOAc. The organic phase is washed twice with water, separated, dried over MgSO4 and the solvent is evaporated to afford the product.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[CH2:27][CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:41]([O:48][C:49]1[CH:56]=[CH:55][C:52]([CH2:53]I)=[CH:51][CH:50]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(O)(=O)CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CN1CCCN(C)C1=O>[C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[C@H:27]([CH2:53][C:52]2[CH:55]=[CH:56][C:49]([O:48][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:50][CH:51]=2)[CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1CCC(=O)O1
Reactant: ICc1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2.47 g (6.0 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl]dihydrofuran-2-(3H)-one dissolved in 12 ml of THF and 1.2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone are treated, at -70° C. and under a protective gas, with 11.73 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and this mixture is stirred for 15 min; it is then alkylated with 1.946 g (6.0 mmol) of p-benzyloxybenzyl iodide (Example 1d)) in 3 ml of THF (60 min). For hydrolysing, 2.23 ml of propionic acid and 2.23 ml of water are added and the mixture is warmed to 0° C. The reaction mixture is poured onto 30 ml of 10% citric acid solution, and this mixture is extracted twice with ethyl acetate; the organic phases are washed twice with saturated NaHCO3 solution and, finally, with saline. Drying the organic phases with Na2SO4 and evaporating them, and column chromatography (SiO2, hexane/ethyl acetate 4:1) of the residue, and subsequent crystallization from ethyl acetate/hexane, affords the pure title compound: TLC Rf (D)=0.45; tRet (I)=19.9 min; FAB-MS (M+H)+ =608.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[O:13][CH2:12][CH:11]([S:14]C(=O)C)[CH2:10]1.C[O-].[Na+].CO.O1CCCC1.Cl.C(O)(C)C>C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[O:13][CH2:12][CH:11]([SH:14])[CH2:10]1
Reactant: CC(=O)SC1COC(c2ccc(F)cc2F)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: Fc1ccc(C2CC(S)CO2)c(F)c1
Yield: 86 %

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.250 g of product from Example 166, 243 μl of 25% sodium methoxide/methyl alcohol, 4.5 ml of tetrahydrofuran and 530 μl of 2N hydrochloric acid/isopropyl alcohol to give, after chromatography (silica gel: 5-10% ethyl acetate/hexane), 0.180 g of the desired product, as a mixture of isomers.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[C@:9]([CH3:29])([C:25]([F:28])([F:27])[F:26])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:16]=2[F:24])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(C)C.C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[C@:9]([CH3:29])([C:25]([F:28])([F:27])[F:26])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:24])([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)CO[C@@]1(C)C(F)(F)F
Agent: [Pd]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CO[C@@]1(C)C(F)(F)F

Procedure:
A solution of [(2R,5R)-5-(2-fluoro-5-nitro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (0.98 g, 2.25 mmol) in isopropanol-THF 2:1 (24 ml) was hydrogenated over 5% Pd—C for 4 h at 50° C. The catalyst was filtered off over Celite and the filtrate was concentrated to provide the title compound after crystallization from TBME-hexane as beige crystals: TLC (hexane-EtOAc 1:1): Rf=0.42; UPLC RtH5=0.955 min; ESIMS: 406 [(M+H)+]; 1H NMR (360 MHz, CDCl3): δ 6.82 (dd, 1H), 6.52 (m, 2H), 4.30 (dd, 1H), 3.97 (dd, 1H), 3.06 (br s, 2H), 1.58 (s, 3H), 1.48 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10][C@@H:11]([NH:20]C(OCC1C=CC=CC=1)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:52]1[S:53][CH:54]=[CH:55][N:56]=1)CCC>CN(C)C=O.C(Cl)(Cl)Cl.[Ag-]=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>[NH2:20][C@@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[CH:17][CH:18]=1)[CH2:10][C@H:9]([O:31][Si:32]([C:35]([CH3:37])([CH3:38])[CH3:36])([CH3:34])[CH3:33])[C@@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:44])[CH3:45])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: O=[Ag-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](N)Cc1ccc(-c2nccs2)cc1)O[Si](C)(C)C(C)(C)C
Yield: 130.1 %

Procedure:
To a solution containing the product from Example 92D (0.050 g, 0.070 mmol) in N,N-dimethylformamide (1.8 mL) were added silver(I) oxide (0.016 g, 0.070 mmol), tetrakis(triphenylphosphine)palladium (0.004 g, 0.003 mmol), and 2-tributylstannylthiazole (0.126 g, 0.337 mmol), and the mixture was irradiated at 60 W in a microwave (internal temperature reached 100° C.) for 2 minutes. The mixture was then irradiated at 200 W in a microwave (internal temperature reached 100° C.) for 4 minutes The reaction was cooled, diluted with chloroform and washed with dilute NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 30% methanol in chloroform containing 0.2% ammonium hydroxide to give the title compound (0.053 g).
Reaction SMILES: Cl.[O:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:18][CH2:19][C:20](Cl)=[O:21].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:18][CH2:19][C:20]([N:5]1[CH2:6][CH2:7][CH2:8][O:2][CH2:3][CH2:4]1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: C1CNCCOC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(CCl)N1CCCOCC1
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A suspension of 1,4-oxazepane hydrochloride (24.80 g, 180 mmol), sodium acetate (29.60 g, 360 mmol) and acetic acid (20.6 ml, 360 mmol) in tetrahydrofuran (400 ml) was stirred for 1 hr, a solution of chloroacetyl chloride (14.3 ml, 180 mmol) in tetrahydrofuran (100 ml) was added dropwise under ice-cooling, and the mixture was stirred overnight at room temperature. To the reaction mixture was added, sodium hydrogen carbonate (65.7 g, 792 μmmol), and the mixture was stirred for 1 hr. The insoluble material was filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:2) to give N-chloroacetyl-1,4-oxazepane (29.8 g, yield 93%).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.O1CCCC1>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6]
Reactant: C1=COCCC1
Reactant: OCCCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 100.0 g of 1,4-butanediol and 20 ml of 3,4-dihydro-2H-pyrane in 80 ml of dichloromethane and 140 ml of tetrahydrofuran, 1.8 g of pyridinium p-toluenesulfonate was added. After stirring at room temperature for 18 hours, the solvent was evaporated under reduced pressure. The residue was extracted three times with diethyl ether after adding saturated brine. After the extract was washed with a small amount of water and dried over anhydrous magnesium sulfate, the solvent was evaporated to obtain 35.98 g of the desired crude product as a colorless oily substance.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[C:17](Cl)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>CC(C)=O.O>[CH2:20]([O:19][C:17](=[O:18])[NH:11][C:7]1[N:6]=[C:5]2[O:4][CH2:3][CH2:2][O:1][C:10]2=[CH:9][CH:8]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc2c(n1)OCCO2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccc2c(n1)OCCO2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of 2,3-dihydro-1,4-dioxino[2,3-b]pyridin-6-amine (commercial; 2.70 g) in acetone/water 1:1 (40 mL) was treated at 0° C. with 1M. NaHCO3 (35 mL) and CbzCl (2.63 mL). The reaction mixture was stirred at rt for 3 h, the org. solvent was evaporated under reduced pressure and the residue was partitioned between water and ether/EA. The org layer was dried over MgSO4 and evaporated under reduced pressure, affording a beige solid (5.3 g; 100% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.C(O)(=O)C.[Br:37]Br.C(O)(=O)C>O>[Br:37][C:7]1[C:2]([OH:1])=[C:3]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:4]2=[N:5][CH:6]=1
Reactant: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(O)ccnc32)CC1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c2ncc(Br)c3O)CC1
Reaction time: 0.17 h
Yield: 71 %

Procedure:
To a solution of the title compound from Example 252 (0.19 grams) and glacial acetic acid (4 mL) was added a 0.7M bromine-acetic acid solution (0.7 mL) at 25° C. under N2. After 10 minutes, water was added and the resulting solid was filtered and washed with water several times and dried to give the title compound (0.18 grams, 71%, MH+ 526).