Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14]1[N:18](COC)[C:17]([CH:22]=[O:23])=[CH:16][N:15]=1)[CH3:2].Cl>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14]1[NH:18][C:17]([CH:22]=[O:23])=[CH:16][N:15]=1)[CH3:2]
Reactant: CCOc1ccc2ccccc2c1-c1ncc(C=O)n1COC
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1ccc2ccccc2c1-c1ncc(C=O)[nH]1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-ethoxy-naphthalen-1-yl)-3-methoxymethyl-3H-imidazole-4-carbaldehyde (prepared as described for 1-ethyl-2-naphthalen-1-yl-1H-imidazole-4-carbaldehyde illustrated in example 2.F) (2.4 g, 7.4 mmol) in dioxane (30 ml) is added 6.0 N hydrochloric acid (10 ml). The resulting mixture is stirred at 80° C. for 3 hr, and then cooled to rt. Dioxane is evaporated, and the residue is basified with 2.0N sodium hydroxide solution. The solid precipitate is collected, washed with water, dried under vacuum to give the title compound. LCMS 267 (M+1).
Reaction SMILES: [K+].[NH:2]1[CH2:6][CH2:5][C@@H:4]([S:7][C:8]2[C@H:9]([CH3:22])[C@@H:10]3[C@@H:17]([C@H:18]([OH:20])[CH3:19])[C:16](=[O:21])[N:11]3[C:12]=2[C:13]([O-:15])=[O:14])[C:3]1=[S:23].[C:24]([O:29][CH2:30]I)(=[O:28])[CH:25]([CH3:27])[CH3:26].C(OCC)(=O)C>CN(C)C=O>[C:24]([O:29][CH2:30][O:14][C:13]([C:12]1[N:11]2[C:16](=[O:21])[C@H:17]([C@H:18]([OH:20])[CH3:19])[C@H:10]2[C@@H:9]([CH3:22])[C:8]=1[S:7][C@@H:4]1[CH2:5][CH2:6][NH:2][C:3]1=[S:23])=[O:15])(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@@H]3CCNC3=S)[C@H](C)[C@H]12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C(=O)OCOC(=O)C1=C(S[C@@H]2CCNC2=S)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 0.5 h
Yield: 24.1 %

Procedure:
(1R, 5S, 6S)-2-[(3R)-Pyrrolidine-2-thion-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid potassium salt (0.5 g) is suspended in N,N-dimethylformamide (5 ml). To the suspension is added isobutyryloxymethyl iodide (338 mg) under ice cooling, and the mixture is stirred at the same temperature for 30 minutes. To the reaction mixture is added ethyl acetate, and the mixture is washed with water, dried and concentrated to dryness under reduced pressure. The residue is purified by silica gel flash column chromatography (eluent, chloroform:methanol=20:1) to give (1R, 5S, 6S)-2-[(3R)-pyrrolidine-2-thion-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid isobutyryloxymethyl ester (0.14 g) as an amorphous powder.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:29][CH2:28]1>C(O)C>[O:27]1[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][N:38]([CH2:2][C:3]([N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[C:9](=[O:16])[NH:8][C:7]4[CH:17]=[CH:18][CH:19]=[N:20][C:6]3=4)=[O:4])[CH2:39][CH2:40]2)[CH2:31][CH2:32]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: C1CN(CCN2CCOCC2)CCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2cccnc2N(C(=O)CN2CCN(CCN3CCOCC3)CC2)c2ccccc21

Procedure:
5,11-Dihydro-11-{[4-(2-morpholino-ethyl)-1-piperazinyl]acetyl}-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one was prepared from 8.62 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one, 3.5 gm of sodium carbonate and 6.1 gm of 1-(2-morpholino-ethyl)piperazine in 100 ml of absolute ethanol in analogy to Example 1.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:6](=O)[CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10]>CCOCC.C(Cl)(Cl)Cl>[Br:1][C:9]1[NH:10][C:6]([C:5]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:3]([Cl:2])[CH:4]=2)=[CH:7][C:8]=1[C:11]#[N:12]
Reactant: Br
Reactant: N#CC(C#N)CC(=O)c1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)[nH]c1Br
Temperature: 0 °C
Yield: 24 %

Procedure:
Hydrogen bromide gas is bubbled through a mixture of (3,4-dichlorophenacyl)malononitrile (10.0 g, 0.0395 mol) in ether (150 mL) and chloroform (100 mL) at a moderate rate, keeping the reaction mixture temperature below 35°-40° C. After ten minutes, TLC shows the reaction is complete by UV analysis. The reaction mixture is poured into an ice-water mixture, the layers are separated and the aqueous layer is extracted with ether. The combined organic layer and ether extracts are dried and concentrated in vacuo to give a brown solid. The brown solid is washed with methylene chloride and filtered to obtain the title compound as an off-white solid (3.0 g, 24%, mp >200° C.) which is identified by IR and NMR spectral analyses.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH:9]=1)([O-])=O.[OH-].[Na+]>CO.O.CC(O)=O.[Fe]>[C:12]1([CH2:11][O:10][C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)nc1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(OCc2ccccc2)nc1
Reaction time: 0.33 h
Yield: 82.4 %

Procedure:
To a slurry of iron powder (5.32 g, 95 mmol) in MeOH/H2O/HOAc (7.5 mL/7.5 mL/0.30 mL) at 75° C. was added 5-nitro-2-[(phenylmethyl)oxy]pyridine (3.10 g, 13.4 mmol; step A above), portionwise over 20 min. After 2 h, the mixture was cooled, 1M NaOH (10 mL) was added. The mixture was filtered through Celite (MeOH wash×2) and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 2.21 g of the title compound as an orange syrup: MS (ESI) m/z 201 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH3:10].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C(OCC)C>[CH3:10][C:6]1[N:5]([CH2:4][CH2:3][OH:2])[CH:9]=[CH:8][N:7]=1
Reactant: COC(=O)Cn1ccnc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Cc1nccn1CCO
Reaction time: 1 h

Procedure:
A solution of (2-methyl-imidazol-1-yl)-acetic acid methyl ester (2,6 g) in diethyl ether (39 ml) is added drop wise to a suspension of LiAlH4 (1,3 g) in 130 ml diethyl ether (130 ml) at 0° C. After 1 hour 1.3 g water, 1.3 g 15% NaOH and 4 g water is added and the slurry stirred for 1 hour. After addition of MgSO,4;and filtration the filter cake is washed several times with hot ethyl acetate. After removal of the solvent, the crude product is used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[N:16]([CH3:17])[N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[N:30][CH:31]=1>CN(C)C=O>[CH3:17][N:16]1[C:12]([C:10]([NH:9][C:4]2[CH:3]=[C:2]([O:1][C:26]3[CH:31]=[N:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[O:11])=[CH:13][C:14]([CH3:18])=[N:15]1
Reactant: Cc1cc(O)cc(NC(=O)c2cc(C)nn2C)c1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc([N+](=O)[O-])nc2)c1
Yield: 64.9 %

Procedure:
In the same manner as in Reference Example 12 and using N-(3-hydroxy-5-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (8.30 g, 33.8 mmol), cesium carbonate (16.5 g, 50.8 mmol), 5-bromo-2-nitropyridine (6.54 g, 32.2 mmol) and N,N-dimethylformamide (40 mL) as starting materials, the title compound (7.68 g, 54%) was obtained as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([OH:12])[CH:3]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>>[CH:13]1([NH:16][C:6](=[O:8])[C:5]2[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=2[OH:12])[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(F)cc1O
Product: O=C(NC1CC1)c1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of methyl 4-fluoro-2-hydroxybenzoate (510 mg, 3.0 mmol) in cyclopropylamine (5 mL) was stirred at room temperature overnight when it became a clear solution. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-30% ethyl acetate in petroleum ether) to give the subtitled compound (493 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][C:10]=2[CH3:18])=[N:6][CH:7]=1.[CH3:19][N:20]([CH3:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:25][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[N:20]([CH3:19])[CH3:30])=[O:17])=[CH:11][C:10]=2[CH3:18])=[N:4][CH:3]=1
Reactant: CN(C)c1ccccc1C(N)=O
Reactant: Cc1cc(N=C=O)ccc1Oc1ncc(Cl)cn1
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NC(=O)c2ccccc2N(C)C)ccc1Oc1ncc(Cl)cn1

Procedure:
A solution of a mixture comprising 3.33 g of 4-(5-chloro-2-pyrimidinyloxy)-3-methylphenyl isocyanate, 2.1 g of 2-(dimethylamino)benzamide and 30 ml of toluene, was reacted at 100° C. for 4 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:16]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:15]3[C:10](=[N:11][CH:12]=[C:13](I)[CH:14]=3)[O:9][C:5]2=[CH:6][C:7]=1[F:8].[CH3:23][C:24]([OH:28])([C:26]#[CH:27])[CH3:25]>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.CN(C=O)C>[NH2:21][C:18]1[O:19][CH2:20][C:16]2([C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:27]#[C:26][C:24]([CH3:25])([OH:28])[CH3:23])[CH:14]=3)[O:9][C:5]3[C:4]2=[CH:3][C:2]([Br:1])=[C:7]([F:8])[CH:6]=3)[N:17]=1
Reactant: C#CC(C)(C)O
Reactant: NC1=NC2(CO1)c1cc(Br)c(F)cc1Oc1ncc(I)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1cnc2c(c1)C1(COC(N)=N1)c1cc(Br)c(F)cc1O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A vial charged with Pd(PPh3)4 (0.485 g, 0.420 mmol), copper(i) iodide (0.080 g, 0.420 mmol), 7-bromo-8-fluoro-3-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (2.000 g, 4.20 mmol), 2-methylbut-3-yn-2-ol (0.353 g, 4.20 mmol) and 9 mL DMF was degassed with argon and treated with DIPA (2.99 mL, 21.01 mmol). The resulting black mixture was allowed to stir at RT for 3 hours. The reaction mixture was then poured into water (25 mL) and extracted with EtOAc (3×30 mL). The organics were dried over MgSO4 and concentrated in vacuo. Purification of the crude residue by column chromatography [0-50% (9:1 CH2Cl2:MeOH)/CH2Cl2] provided 4-(2′-amino-7-bromo-8-fluoro-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yl)-2-methylbut-3-yn-2-ol.
Reaction SMILES: COC(CCC/C=[C:9]1/[C:10](=[O:17])[CH:11]2[CH:15]([CH2:16]/1)[CH2:14][CH2:13][CH2:12]2)=O.[OH-].[Li+].C(O)(=O)C>CO>[CH:11]12[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:9][C:10]2=[O:17]
Reactant: COC(=O)CCC/C=C1\CC2CCCC2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CCC2CCCC12
Temperature: 10 °C
Reaction time: 3.3 h
Yield: 148 %

Procedure:
A stirred solution of 6-[(E)-(mixture of 3β and 3β)-hydroxyoct-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (90 mg), prepared as described in Example 4 and predominantly in the 6β-configuration, otherwise known as (±)-methyl(5E,13E)-(9S),[mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-hydroxyprosta-5,13-dienoate, in methanol (2 ml) at 5° C. was treated with aqueous lithium hydroxide solution (1.5 ml; 1.0N). The resulting solution was stirred for 3.3 hours at 10° C. and was then treated with glacial acetic acid (0.1 ml). The methanol was removed in vacuo and the residue was diluted with ethyl acetate (10 ml), washed with hydrochloric acid (2N), then with water, and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated in vacuo, to give 3-[(E)-4-carboxybutylidene]-6-[(E)-(mixture of 3α and 3β)-hydroxyoct-1-enyl]bicyclo[3,3,0]octan-2-one (70.0 mg), thought to be in the 6β-configuration, otherwise known as (±)-(5E,13E)-(9S),[mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-hydroxyprosta-5,13-dienoic acid [NMR in deuterochloroform: multiplets at 6.6, 5.5, 4.8-3.7, 3.0-1.1, 1.1-0.7 p.p.m⟧
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=[CH:16][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:20]=1.C1C2CCC3C=CC=CC=3SC=2C=C(C(O)=O)C=1>>[OH:18][CH2:17][C:14]1[CH:15]=[CH:16][C:10]2[CH:9]=[CH:8][C:7]3[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[S:12][C:11]=2[CH:13]=1
Reactant: COc1ccc2c(c1)C=Cc1ccc(C(=O)O)cc1S2
Agent: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2
Product: COc1ccc2c(c1)C=Cc1ccc(CO)cc1S2

Procedure:
Repeat the process of Example 1, substituting an equivalent quantity of 8-methoxy-dibenzo[b,f]thiepin-3-carboxylic acid for the 10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid, to obtain the title product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[CH2:8][OH:9].[H-].[Na+].[N+](C1C=CC([O:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[CH2:26][CH2:25]2)=O)=CC=1)([O-])=O>C1COCC1>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[N:27]1[CH2:28][CH2:29][N:24]([C:22]([O:9][CH2:8][CH:3]2[CH2:4][O:5][CH2:6][CH2:7][N:2]2[CH3:1])=[O:21])[CH2:25][CH2:26]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2F)CC1
Reactant: CN1CCOCC1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCOCC1COC(=O)N1CCN(c2ccc(F)cc2F)CC1
Reaction time: 0.67 h
Yield: 18.8 %

Procedure:
(4-Methyl-morpholin-3-yl)-methanol (387 mg, 2.95 mmol) in THF (7.5 mL) was added dropwise to a suspension of NaH (60% dispersion in oil, prewashed with hexane; 354 mg, 8.85 mmol) in anhydrous THF (7.5 mL) at 0° C. and stirred under nitrogen for 40 minutes. 4-(2,4-Difluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 12; 1.28 g, 3.54 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with the addition of aqueous NaHCO3 (0.5 mL) at 0° C. The reaction mixture was stirred for 1 h and then the solvents were removed in vacuo. The residue was suspended between water and EtOAc. The aqueous phase was extracted with EtOAc (×3). The combined organic layers were washed with aqueous Na2CO3, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase, Apollo silica, 1% MeOH in DCM) and the solvents were removed in vacuo to give (4-methylmorpholin-3-yl)methyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate (197 mg, 19%) as a colourless oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([NH:13][C:14](=[O:22])OC3C=CC=CC=3)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:24][S:25]([N:28]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:30]2([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:29]1)(=[O:27])=[O:26].CCN(CC)CC>C(Cl)(Cl)Cl.CCOC(C)=O>[CH3:24][S:25]([N:28]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:30]2([CH2:31][CH2:32][N:33]([C:14]([NH:13][C:10]3[CH:9]=[N:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:12][N:11]=3)=[O:22])[CH2:34][CH2:35]2)[CH2:29]1)(=[O:26])=[O:27]
Reactant: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Reactant: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)N1CC2(CCN(C(=O)Nc3cnc(-c4ccccc4)cn3)CC2)c2ccccc21
Yield: 92.9 %

Procedure:
A mixture of phenyl N-(5-phenyl-2-pyrazinyl)carbamate 1-2 (7, 350 mg, 1.20 mmol), 1-methylsulfonylspiro[indoline-3,4′-piperidine] hydrochloride 1-3 (400 mg, 1.32 mmol) and Et3N (0.5 mL, 3.6 mmol) in CHCl3 (6 mL) was heated to reflux for 3 h. After cooling, the mixture was diluted with EtOAc, washed with 10% citric acid, sat. NaHCO3 and brine, dried over MgSO4, and concentrated under reduced pressure to start precipitation. The precipitate was collected by filtration and dried in vacuo to give 100 (517 mg, 93%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][N:14](C)[C:15](=O)C(F)(F)F)[CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][NH:14][CH3:15])[CH2:10][CH2:11]1
Reactant: CN(CCN1CCC(Oc2ccc(F)c(F)c2)CC1)C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNCCN1CCC(Oc2ccc(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.3 %

Procedure:
To a solution of the product of Step b (0.3 g) in ethanol (15 ml) was added a 2M solution of sodium hydroxide (5 ml). The mixture was stirred at RT for 72 hours. The resultant mixture was partitioned between EtOAc (20 ml) and water (20 ml). The organic layer was separated and dried with MgSO4. Removal of solvent under reduced pressure gave the title compound (0.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][CH:19]([CH:24]([CH3:26])[CH3:25])[C:18]=3[CH:27]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:28]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][CH:19]([CH:24]([CH3:25])[CH3:26])[C:18]=3[CH:27]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)C1OC(=O)Nc2ccc(OCCCSc3ccc(Cl)c(Cl)c3)cc21
Reactant: OO
Product: CC(C)C1OC(=O)Nc2ccc(OCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[3-(3,4-dichloro-phenylmercapto)-propoxy]-4-isopropyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][CH2:4]1
Reactant: NCC1CCC(C(=O)O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(Aminomethyl)cyclohexanecarboxylic acid (4.00 g, 25.44 mmol) was stirred in THF (100 mL) at 0° C. under a nitrogen atmosphere. LiAlH4 (2.90 g, 76.33 mmol) was then added and the reaction allowed to warm to RT and stir for 3 h. It was then cooled to 0° C. and quenched with H2O, Na2SO4 was then added and the mixture stirred for 10 minutes. It was then filtered through celite and the filtrate concentrated in vacuo to give the product as a colourless oil which solidified on standing to give the product as a white solid (3.72 g, 100%). 1H NMR (300 MHz, d6 DMSO) δ: 0.95 (4H, m), 1.22-1.47 (5H, m), 1.86 (4H, m), 2.55 (2H, d, J=6.6 Hz), 4.46 (2H, d, J=6.3 Hz).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13]CC3C=CC=CC=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=[O:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CC(C)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1ncc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: CC(=O)n1ncc2cc(O)ccc21
Yield: 42.7 %

Procedure:
1-Acetyl-5-hydroxy-1H-indazole can be obtained in the following way: a suspension of 467 mg of 1-acetyl-5-benzyloxy-1H-indazole, 525 mg of ammonium formate, 1 g of 10% palladium-on-charcoal and 50 ml of acetone is brought to reflux for 3 hours. After returning to a temperature in the region of 20° C., the reaction medium is filtered through a bed of Celite 535. The filtrate is concentrated by evaporation under reduced pressure and the oil obtained is purified by chromatography on a silica column with a dichloromethane/methanol (98/2 by volume) mixture as eluent. 132 mg of 1-acetyl-5-hydroxy-1H-indazole are thus obtained in the form of a white solid (Rf=0.32, silica gel thin layer chromatography, eluent: methanol/dichloromethane (2/98 by volume)).
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][C:7](=[O:8])[N:4]2[C:3]([C:9]([O-:11])=[O:10])=[CH:2]1.[SH:12][C@@H:13]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C@H:15]([CH:31]2[N:34]([CH3:35])[C:33](=[O:36])[CH2:32]2)[CH2:14]1>>[OH:36][C@@H:33]([C@H:6]1[C:7](=[O:8])[N:4]2[C:3]([C:9]([O:11][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:10])=[C:2]([S:12][C@@H:13]3[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=4)=[O:19])[C@H:15]([CH:31]4[N:34]([CH3:35])[C:33](=[O:36])[CH2:32]4)[CH2:14]3)[CH2:1][C@H:5]12)[CH3:32]
Reactant: O=C([O-])C1=CC[C@@H]2CC(=O)N12
Reactant: CN1C(=O)CC1[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CC(=O)N4C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Yield: 185.8 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-8 (R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (235 mg, 0.40 mmol) and (2S,4S)-4-mercapto-2-(N-methyl-2-azetidinon-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (149 mg, 0.41 mmol, compound of Reference Example 7) to obtain p-nitrobenzyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2S,4S)-2-(N-methyl-2-azetidinon-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (265 mg, yield: 94.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:13]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[CH:8]([NH2:10])[CH3:9].CCN(C(C)C)C(C)C.Cl[C:34]1[N:39]=[C:38]([NH:40][C:41]2[CH:45]=[C:44]([CH:46]3[CH2:48][CH2:47]3)[NH:43][N:42]=2)[CH:37]=[CH:36][N:35]=1>CC(C(O)C(C)C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[N:13]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[CH:8]([NH:10][C:34]1[N:39]=[C:38]([NH:40][C:41]2[CH:45]=[C:44]([CH:46]3[CH2:48][CH2:47]3)[NH:43][N:42]=2)[CH:37]=[CH:36][N:35]=1)[CH3:9]
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C(C)N)c(Cl)cc32)cc1
Agent: CC(C)C(O)C(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(C)Nc4nccc(Nc5cc(C6CC6)[nH]n5)n4)c(Cl)cc32)cc1
Temperature: 140 °C
Yield: 142.2 %

Procedure:
A mixture of 1-(6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (180 mg, 0.51 mmol), DIPEA (133 mg, 1.03 mmol), and 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (97 mg, 0.41 mmol) in 2,4-dimethyl-3-pentanol (0.5 mL) was heated at 140° C. for 18 h. The reaction mixture was concentrated under reduced pressure to afford a crude 320 mg (41%) of N2-(1-(6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as brown solid, which was used in the next step without further purification. MS (ESI): m/z=549.2 [M+1]+.