Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21].Cl>CC(OC)(C)C>[C:20]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH:9]=[C:10]([CH3:11])[CH3:12])(=[O:22])[CH3:21]
Reactant: CC(C)=CC(C)CCCCCO
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(=O)OCCCCCC(C)C=C(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 76 %

Procedure:
13 g (76 mmol) of 6,8-dimethylnon-7-enol (2), 10.8 g (107 mmol) of triethylamine and 200 ml of t-butyl methyl ether (MTBE) are placed in a 500 ml round-bottomed flask equipped with a thermometer and with a dropping funnel. Cooling is carried out to 5° C. and 8.4 g (107 mmol) of acetylchloride diluted in 20 ml of MTBE are added without exceeding a bulk temperature of 10° C. The mixture is stirred at ambient temperature for 14 hours. Cooling is carried out at 5° C. and neutralization is carried out with 100 ml of a 10% hydrochloric acid solution. The phases are separated and the organic phase is washed once with 100 ml of saturated aqueous NaHCO3 solution and then with aqueous saline solution to neutrality. The organic phase is dried and filtered, and the solvent is evaporated under reduced pressure. The acetate is purified by a distillation under reduced pressure (B.p.: 58° C./0.4 torr). The yield is 76%.
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH2:18].[C:19]([CH2:23][C:24](Cl)=[O:25])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH:18][C:24](=[O:25])[CH2:23][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)CC(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
A mixture of 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine (0.27 g, 1.1 mmol), t-butylacetyl chloride (0.18 mL, 1.3 mmol) and poly-(4-vinylpyridine) (700 mg) in dichloromethane (18 mL) was stirred at room temperature overnight. The resin was removed by filtration and washed with dichloromethane. The filtrate was concentrated and the product was purified by flash column chromatography (elution with 30% ethyl acetate-hexane) to provide 0.20 g of N-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-yl-3,3-dimethylbutanamide as a white solid. MS (ESI) m/z 339.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[C:26](Cl)(=[O:28])[CH3:27]>>[C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:26](=[O:28])[CH3:27])=[CH:22][CH:23]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(N)cc1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1ccc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cc1
Yield: 91 %

Procedure:
Following the general method as outlined in Intermediate 223, starting from tert-butyl{2-[(4-aminophenyl)ethynyl]-4-chlorophenoxy}acetate (Intermediate 222) and acetyl chloride, the title compound was obtained in 91% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]2[C:12](=[O:13])[CH:11]3[CH2:14][CH2:15][CH:16]=[CH:17][CH:10]3[C:9]2=[O:18])=[C:6]([F:19])[CH:5]=[C:4]([Cl:20])[C:3]=1[OH:21].[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2]1[C:3]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:4]([Cl:20])[CH:5]=[C:6]([F:19])[C:7]=1[N:8]1[C:12](=[O:13])[CH:11]2[CH2:14][CH2:15][CH:16]=[CH:17][CH:10]2[C:9]1=[O:18]
Reactant: BrC1CCCC1
Reactant: Nc1c(O)c(Cl)cc(F)c1N1C(=O)C2C=CCCC2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1c(OC2CCCC2)c(Cl)cc(F)c1N1C(=O)C2C=CCCC2C1=O

Procedure:
A mixture of 2-amino-6-chloro-4-fluoro-3-(tetrahydrophthalimido)phenol (0.31 g), cyclopentyl bromide (1.3 ml), potassium carbonate (0.14 g), and acetonitrile (5 ml) was heated under reflux for 2 hr. The solvent and excess reagent were removed under reduced pressure. The residue was purified by a silica gel column, eluted with ethyl acetate to give the title product (0.17 g).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[CH:6][C:7]([NH:13]N)=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10].O=[C:16]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17]1>C(O)(=O)C.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:7](=[C:8]([C:9]([OH:11])=[O:10])[CH:12]=1)[NH:13][C:16]1[CH2:17][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][CH2:20][C:21]2=1
Reactant: CCOC(=O)C1CCCC(=O)C1
Reactant: NNc1ccc(Br)cc1C(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(Br)cc23)C1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A cream colored suspension of 5-bromo-2-hydrazinylbenzoic acid dihydrochloride (6 g, 19.74 mmol) and ethyl 3-oxocyclohexanecarboxylate (3.70 g, 21.71 mmol) in glacial acetic acid, (˜0.4M) (45 mL) was heated at reflux for 4h. The reaction mixture turned in to dark yellow suspension. The reaction mixture was cooled to room temperature and it was concentrated to afford a dark yellow solid. The solid was then suspended in ethyl acetate (˜50 ml) and the solid was filtered, washed with water and ethyl acetate to give 4.14 g of 6-bromo-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid. MS (ESI) m/z 366.3 (M+H). 1H NMR (DMSO-d6) δ ppm 13.4-12.3 (b, 1H), 10.99 (s, 1H), 7.79 (d, 1H, J=1.9 Hz) 7.69 (d, 1H, J=1.8 Hz), 4.08-4.17 (m, 2H), 3.05 (dd, 1H, J=16.5, 5.0), 2.97-2.84 (m, 2H), 2.76-2.69 (m, 1H), 2.67-2.59 (m, 1H), 2.19-2.12 (m, 1H), 1.88-1.78 (m, 1H), 1.21 (t, 3H, J=7.2).
Reaction SMILES: [C:1]1([N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[S:9][CH:10]=[C:11]([CH:13]=O)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:21]1[CH2:27][C:25](=[O:26])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:22]1=[S:23].[Cl-].[NH4+].N>C(O)C>[C:1]1([N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[S:9][CH:10]=[C:11]([CH:13]=[C:27]3[S:21][C:22](=[S:23])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:25]3=[O:26])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1csc(N(c2ccccc2)c2ccccc2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(N(c3ccccc3)c3ccccc3)n2)SC1=S

Procedure:
The reaction described in Example 1 was repeated, but using 3 g of 2-diphenylaminothiazole-4-carbaldehyde, 1.7 g of rhodanine-3-acetic acid, 1.3 g of ammonium chloride, 1.3 ml of 28% v/v aqueous ammonia and 60 ml of ethanol, giving the title compound as orange needles.
Reaction SMILES: [CH:1]12[O:8][CH:7]1[CH2:6][O:5][CH:4]([C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[CH2:3][CH2:2]2.[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+]>CO.O>[N:20]([C@@H:1]1[CH2:2][CH2:3][C@@H:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[O:5][CH2:6][C@H:7]1[OH:8])=[N+:21]=[N-:22]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC2OC2CO1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](N=[N+]=[N-])[C@H](O)CO1
Temperature: 70 °C

Procedure:
To a solution of 5-(5,8-dioxabicyclo[5.1.0]octan-4-yl)-1-methyl-4-nitro-pyrazole (2.7 g, 11.3 mmol, intermediate 19) in MeOH/water (60 mL/15 mL) was added ammonium chloride (1.51 g, 28.3 mmol) and sodium azide (3.67 g, 56.5 mmol). The mixture was heated at 70° C. behind a blast shield for 4 hr. The MeOH was removed under reduced pressure and the aqueous residue extracted with EtOAc (100 mL). The organic layer was washed with aqueous NaHCO3 (3×20 mL), passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) followed by chiral SFC chromatography gave (3S,4R,7S)-4-azido-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-3-ol as the second eluting isomer as a clear gum (1.4 g, 41%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 5.43-5.37 (m, 1H), 4.18 (dd, J=13.9, 2.1 Hz, 1H), 4.06 (s, 3H), 3.97-3.77 (m, 3H), 2.45 (d, J=3.9 Hz, 1H), 2.32-2.09 (m, 2H), 2.10-1.85 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[Si:19]([O:18][CH2:17][CH2:16][N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][C:10]1=[O:14])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2N1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN1C(=O)CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
7-Nitro-3,4-dihydroquinolin-2(1H)-one, (2-bromoethoxy)(tert-butyl)dimethylsilane, potassium carbonate, potassium iodide and water were added to DMF, followed by stirring at room temperature for 2 days and then stirred at 40° C. for 3 days. By post-treating the reaction liquid, 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-7-nitro-3,4-dihydroquinolin-2(1H)-one was obtained.
Reaction SMILES: O1CCOCC1.Cl.C([O:10][C:11]([C:13]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:16]=2[O:15][CH:14]=1)=[O:12])C>O>[C:11]([C:13]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][C:16]=2[O:15][CH:14]=1)([OH:12])=[O:10]
Reactant: CCOC(=O)c1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc2occ(C(=O)O)c(=O)c2cc1Oc1ccccc1
Yield: 90.9 %

Procedure:
80 ml of dioxane and 40 ml of 6N hydrochloric acid were added to 4.03 g of 3-ethoxycarbonyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. The mixture was refluxed for 30 minutes. The reaction mixture was cooled. 200 ml of water was added thereto. The resulting crystal was collected by filtration, washed with water and recrystallized from acetic acid to obtain 3.41 g (yield: 91%) of 3-carboxy-7-methylsulfonylamino-6-phenoxy4H-1-benzopyran-4-one having a melting point of >250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1([S:17]([C:20]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:21]OCC)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([S:17]([C:20]([S:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])=[CH:21][NH:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)(=[O:18])=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC=C(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Product: O=[N+]([O-])c1ccc(NC=C(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)nc1
Yield: 73.8 %

Procedure:
An intimate mixture of 2-amino-5-nitropyridine (19.0 g) and 1,1-bis(phenylsulphonyl)-2-ethoxyethene (30 g) was heated at 180°-190° C. for 1 hour. After cooling, the solid cake was pulverised and recrystallised from a mixture of methyl ethyl ketone and methanol, to give 1,1-bis(phenylsulphonyl)-2-(5-nitropyrid-2-ylamino)ethene (28 g) m.p. 229°-231° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[F:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([NH2:43])[CH:38]=1>C(Cl)Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][C:39]3=[N:43][C:9]=2[C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(F)ccn1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(C(=O)Nc2c(F)cccc2F)c1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3cc(F)ccn3c2-c2ccnc(Cl)n2)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a stirred solution of 3-[(2-chloro-4-pyrimidinyl)acetyl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1, step B) (0.6 g, 1.49 mmol) in DCM (15 mL) at rt under N2 was added NBS (0.278 g, 1.56 mmol). The reaction was stirred approximately 60 min, then concentrated under vacuum to a foam like solid. The solid was dissolved in dioxane (15 mL) and 4-fluoro-2-pyridinamine (0.5 g, 4.46 mmol) was added. The reaction was stirred under N2, heated to 75° C., and stirred for approximately 18 h, then cooled to rt. The reaction was diluted with EtOAc and half-saturated aqueous NaHCO3. The organic layer was separated and washed with brine. The combined aqueous layers were extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give the title compound of step B (0.391 g, 0.81 mmol, 55%) as a light yellow solid. MS (ESI): 480 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Br[C:34]1C=CC(C(OCC)=O)=C[CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.CN(C=O)C.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>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:19]=[C:20]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([O:32][CH2:34][CH3:35])=[O:31])=[CH:28][CH:29]=4)[CH:21]=[CH:22][CH:23]=3)[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: O=C(O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
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: [Na+]
Solvent: CCCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of NAPHTHYRIDINONE 3 (1 eq), ethyl 4-bromobenzoate (3 eq), Na2CO3 (3.5eq.; 2M in H2O), Pd(PPh3)4 (0.15eq.) in n-propanol-DMF (1:1, 0.1M) was stirred at 80° C. for 2 h. The mixture was cooled to rt, quenched with brine and diluted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was triturated in ether/EtOAc and then isolated by filtration to afford the title compound as a white solid.
Reaction SMILES: [Cl:1]Cl.[F:3][C:4]([F:14])([F:13])[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:8]1[CH:7]=[C:6]([O:5][C:4]([F:13])([F:14])[F:3])[CH:11]=[CH:10][C:9]=1[OH:12]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc(OC(F)(F)F)cc1Cl
Reaction time: 1 h

Procedure:
Gaseous chlorine was slowly introduced to a stirred solution of 35.6 g of 4-trifluoromethoxyphenol in 100 ml carbon tetrachloride. The reaction temperature was kept at 20° to 30° C. by outer cooling. After saturaring with chlorine, the reaction mixture was stirred at 20° to 30° C. for 1 hour, cooled, washed with water, dried over anhydrous sodium sulfate, and evaporated to give a pale yellow residue. The residue was distilled under reduced pressure to give 29.8 g of 2-chloro-4-trifluoromethoxyphenol which boiled at 67°-70° C./18 mmHg.
Reaction SMILES: [C:1]([NH:20][C@H:21]([C:25]([O:27][CH2:28][CH:29]([CH2:36][O:37][C:38](=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:26])[CH:22]([CH3:24])[CH3:23])([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.[F:57][C@@H:58]1[C@@H:62]([CH2:63]O)[O:61][C@@H:60]([N:65]2[C:75]3[N:74]=[C:72]([NH2:73])[NH:71][C:69](=[O:70])[C:68]=3[N:67]=[CH:66]2)[CH2:59]1.CN(C1C=CC=CN=1)C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[F:57][C@@H:58]1[C@@H:62]([CH2:63][O:34][C:33](=[O:35])[CH2:32][CH2:31][CH2:30][CH:29]([CH2:28][O:27][C:25](=[O:26])[C@H:21]([CH:22]([CH3:24])[CH3:23])[NH:20][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:36][O:37][C:38](=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[O:61][C@@H:60]([N:65]2[C:75]3[N:74]=[C:72]([NH2:73])[NH:71][C:69](=[O:70])[C:68]=3[N:67]=[CH:66]2)[CH2:59]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(CCCC(=O)O)COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(CCCC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F)COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Reaction time: 8 h

Procedure:
To a solution of 5-(N-trityl-L-valyloxymethyl)-6-stearoyloxyhexanoic acid (462 mg, 0.6 mmole) and 2′,3′-dideoxy-3′-fluoroguanosine (340 mg, 1.25 mmol) in DMF (3 ml) were added dimethylaminopyridine (7 mg, 0.06 mmole), and DCC (136 mg, 0.66 mmol). The reaction was kept at room temperature overnight, and then at 40° C. for two hours. The reaction mixture was filtered through Celite and poured into dichloromethane, and washed with aqueous sodium hydrogen carbonate solution. The product 2′,3′-dideoxy-3′-fluoro-5′-O-[5-(N-trityl-L-valyloxymethyl)-6-stearoyloxyhexanoyl]guanosine was isolated by silica gel column chromatography. (93 mg)
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[CH3:27][O:28][CH2:29][C:30]1[N:31]2[CH:37]=[N:36][CH:35]=[C:32]2[S:33][CH:34]=1>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:36]3[CH:35]=[C:32]4[S:33][CH:34]=[C:30]([CH2:29][O:28][CH3:27])[N+:31]4=[CH:37]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: COCc1csc2cncn12
Product: COCc1csc2cn(CC3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)c[n+]12
Yield: 10.3 %

Procedure:
The same procedure as in Example 1 was repeated except that 76 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 53 mg of 3-methoxymethylimidazo[5,1-b]thiazole were used, thereby obtaining 8.4 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[C:10]([I:11])[C:3]=12.[H-].[Na+].[CH:14](Br)([CH3:16])[CH3:15]>CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:14]([CH3:16])[CH3:15])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)Br
Reactant: Clc1nc[nH]c2ncc(I)c1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(I)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-5-iodopyrrolo[2,3-d]pyrimidine (10.0 g, see Example 17) was added in portions with stirring under nitrogen at 0° C. to a suspension of sodium hydride (1.6 g of a 60% dispersion in mineral oil) in N,N-dimethylformamide (250 ml). When the addition was complete the mixture was allowed to warm up to ambient temperature and when no more gas evolution was observed, a solution of isopropyl bromide (34.0 ml) in N,N-dimethylformamide (20 ml) was added dropwise. The mixture was stirred at ambient temperature overnight then quenched by the dropwise addition of water (300 ml) with external ice-cooling. The mixture was then washed with ethyl acetate (3×300 ml), the combined organic layers were washed with water, dried, filtered and evaporated to give 4-chloro-5-iodo-7-isopropylpyrrolo-[2,3-d]pyrimidine as a yellow solid, m.p. 116-118° C. The structure was confirmed by 1H nmr.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:64][N:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][N:65]5[CH2:70][CH2:69][O:68][CH2:67][CH2:66]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reactant: NN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)NN2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.3 %

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (50 mg, 0.11 mmol, 1 eq), DIPEA (38 μL, 0.23 mmol, 2 eq) and TBTU (40 mg, 0.12 mmol, 1.1 eq) were added to 5 mL DCM and the resulting solution stirred at rt for 15 min before the addition of 4-aminomorpholine (12 mg, 0.14 mmol, 1.2 eq). The RM was then stirred at rt for 16 hours before concentrating in vacuo and purifying by preparative RP-HPLC-MS (Preparative—1) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxy-N-morpholinobenzamide (26 mg, 44%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Clc1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1ccc(-c2cnccn2)cc1
Temperature: 80 °C
Yield: 71.7 %

Procedure:
A mixture of 2-chloropyrazine (0.230 ml, 2.62 mmol), 4-(hydroxymethyl)phenylboronic acid (517 mg, 3.41 mmol), tetrakis(triphenylphosphine)palladium (0) (303 mg, 0.262 mmol) and 2 M potassium phosphate aqueous solution (2.62 ml, 5.24 mmol) in dioxane (10 mL) was heated at 80° C. overnight under nitrogen. The mixture was cooled down, poured into water and extracted with ethyl acetate. The combined organic layers were dried and concentrated. The residue was purified by preparative HPLC to give the title compound (350 mg) as an off-white solid. LCMS m/z=187.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 4.79 (s, 2H), 7.52 (d, J=8.1 Hz, 2H), 8.02 (d, J=8.1 Hz, 2H), 8.51 (d, J=2.5 Hz, 1H), 8.63 (dd, J=2.4 and 1.6 Hz, 1H), 9.03 (d, J=1.6 Hz, 1H).