Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:16]([NH:18][C@H:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH3:20])=[O:17])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:44][S:45]([CH2:48][CH2:49][CH2:50][O:51][C:52](=[O:54])[CH3:53])(=[O:47])=[O:46].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:16]([NH:18][C@H:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25](=[O:26])[NH:44][S:45]([CH2:48][CH2:49][CH2:50][O:51][C:52](=[O:54])[CH3:53])(=[O:46])=[O:47])=[CH:23][CH:22]=3)[CH3:20])=[O:17])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OCCCS(N)(=O)=O
Reactant: C[C@H](NC(=O)c1cccc2ccn(Cc3ccc(Cl)cc3)c12)c1ccc(C(=O)O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc([C@H](C)NC(=O)c2cccc3ccn(Cc4ccc(Cl)cc4)c23)cc1
Reaction time: 0.08 h
Yield: 61 %

Procedure:
To a mixture of 4-[(1S)-1-({[1-(4-chlorobenzyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid (250 mg) and DMF (5 mL) was added 1,1′-carbonyldiimidazole (187 mgl) at room temperature, followed by stirring for 5 minutes, and then 3-(aminosulfonyl)propylacetate (209 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (173 μL) were added in this order, followed by stirring for 3 days. The reaction mixture was ice-cooled, and 10% aqueous citric acid (30 mL) was added thereto, followed by stirring for 30 minutes. The precipitated solid was collected by filtration and washed with cold ethanol (4 mL) to obtain 1-(4-chlorobenzyl)-N-[(1S)-1-(4-{[(3-acetoxypropyl)sulfonyl]carbamoyl}phenyl)ethyl]-1H-indole-7-carboxamide (210 mg) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14].C(N(CC)CC)C>C(O)CCC>[NH2:14][CH2:13][CH2:12][NH:15][C:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1
Reactant: NCCN
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: NCCNc1nc(Cl)nc2[nH]ccc12
Yield: 39.5 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (160 mg, 0.85 mmol), ethylenediamine (0.170 mL, 2.55 mmol) and triethylamine (0.100 mL, 0.72 mmol) in nBuOH (4 mL) was stirred at 70° C. for 4 h. It was then purified by HPLC to give N-(2-aminoethyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a solid (71 mg).
Reaction SMILES: O[N:2]=[C:3]([C:5]1[C:6]([CH3:16])=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])[NH2:4].[ClH:17].[C:18]([C:21]1C(C)=CC(C)=C([CH:30]=1)C(OC)=O)(=N)N.C(C1C(C2CCC2)=CC(C)=C(C=1)C(OC)=O)#N.C(C1C(C)=CC(C)=C(C=1)C(OC)=O)#N>>[ClH:17].[C:3]([C:5]1[C:6]([CH:16]2[CH2:30][CH2:21][CH2:18]2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[NH:2])[NH2:4]
Reactant: COC(=O)c1cc(C(N)=NO)c(C)cc1C
Reactant: COC(=O)c1cc(C(=N)N)c(C)cc1C
Agent: COC(=O)c1cc(C#N)c(C)cc1C
Agent: COC(=O)c1cc(C#N)c(C2CCC2)cc1C
Agent: Cl
Product: COC(=O)c1cc(C(=N)N)c(C2CCC2)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for preparation of methyl 5-(N′-hydroxycarbamimidoyl)-2,4-dimethylbenzoate (compound 2.4) and methyl 5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5) using methyl 5-cyano-4-cyclobutyl-2-methylbenzoate (compound 152.4) instead of methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[OH-:11].[Cs+]>C(OCC)(=O)C.CCCCCCC>[N+:8]([C:4]1[CH:3]=[C:2]([OH:11])[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: [OH-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=[N+]([O-])c1cccc(O)c1
Yield: 78 %

Procedure:
Following general mode A, 1-bromo-3-nitrobenzene (202 mg, 1.0 mmol) was reacted with cesium hydroxide to give the expected product in the form of a red solid with a yield of 78% (eluent: ethyl acetate/heptane 20:80).
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][O:18]S(C)(=O)=O)[C:14](=[O:23])[O:13][CH2:12][C@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:10](=[O:32])[O:9][C@H:8]1[CH3:33])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Na+].[I-].[C:36]([O-])(O)=[O:37].[Na+].CCOC(C)=O>CN(C=O)C>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][O:18][CH:36]=[O:37])[C:14](=[O:23])[O:13][CH2:12][C@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:10](=[O:32])[O:9][C@H:8]1[CH3:33])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCOS(C)(=O)=O
Reactant: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCOC=O
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution (3S,6S,7R,8R)-3-(tert-butoxycarbonylamino)-6-methyl-8-(2(methylsulfonyloxy)ethyl)-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (510 mg, 1.03 mmol) in DMF (3 mL) at room temperature (about 22° C.) was added NaI (1 g, 6.7 mmol). The resulting reaction mixture was heated to 80° C. and stirred for 48 h. After cooling to room temperature, saturated NaHCO3 solution (30 mL) and EtOAc (25 mL) were added. The phases were separated and the aqueous phase was extracted with EtOAc (2×25 mL). The combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated to dryness. The crude residue was purified via column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (228 mg, 50%) as a white solid (228 mg, 50%): mp 103-104; 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 5.43-5.15 (m, 2H), 5.06 (t, J=9.9 Hz, 1H), 4.93-4.77 (m, 2H), 4.19 (dt, J=11.1, 5.5 Hz, 1H), 4.05 (ddd, J=11.4, 8.9, 4.8 Hz, 1H), 3.60 (s, 1H), 2.71 (td, J=11.4, 2.8 Hz, 1H), 2.67-2.53 (m, 1H), 2.17-2.02 (m, 1H), 1.73 (dt, J=14.7, 7.4 Hz, 1H), 1.45 (s, J=15.6 Hz, 9H), 1.28 (d, J=6.3 Hz, 3H), 1.21 (dd, J=7.0, 0.5 Hz, 6H); ESIMS m/z 468 ([M+Na]+).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[N:14][CH:15]=2)[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:28]=[N+:29]=[N-:30].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:30][N:29]=[N:28][N:23]=3)=[N:14][CH:15]=2)[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C#N)nc1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Product: CCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Yield: 51.6 %

Procedure:
A mixture of 2-propyl-1-[[2-(2-cyanophenyl)-5-pyridinyl]methyl]-1H-benzimidazole (0.50 g, 1.42 mmol), NaN3 (0.18 g, 2.84 mmol), and tri-n-butyltin chloride (0.92 g, 2.84 mmol) in xylenes (10 mL) was heated under reflux for 48 h. The reaction mixture was concentrated and 2N HCl was added. The mixture was extracted with ether (discarded) and adjusted to pH 5 with 50% NaOH. The aqueous phase was extracted with CH2Cl2, and the extracts were washed with water, dried, and concentrated. Purification by flash chromatography (5% MeOH/CH2Cl2) and trituration with EtOH gave 0.29 g (51%) of product as a white solid, mp 240°-241° C.
Reaction SMILES: C(N1CCCC(C(OCC)=O)C1)(=O)C1C=CC=CC=1.[CH3:20][CH2:21][O:22][C:23]([CH:25]1[C:30](=[O:31])[CH2:29][CH2:28][NH:27][CH2:26]1)=[O:24].Cl.C(N(C(C)C)CC)(C)C.Cl[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>>[CH2:46]([O:45][C:43]([N:27]1[CH2:28][CH2:29][C:30](=[O:31])[CH:25]([C:23]([O:22][CH2:21][CH3:20])=[O:24])[CH2:26]1)=[O:44])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CNCCC1=O
Agent: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CCC1=O
Yield: 62 %

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with commercially available ethyl 4-piperidone-3-carboxylate hydrochloride (203.2 mg; 0.98 mmol), diisopropylethylamine (360 μl; 2.08 mmol), and benzyl chloroformate (141 μl; 0.99 mmol). The crude product was purified by chromatography on silica eluting with 15% ethyl acetate in hexane, giving ethyl 1-benzyloxycarbonyl-4-oxo-3-piperidinecarboxylate (185.5 mg) as a colorless oil. MS m/z (positive ion) 323 (M+NH4+; 75), 306 (MH+; 100), 262 (50).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[ClH:17].[N:18]1(C(=N)N)[CH:22]=[N:21]C=N1.CCOCC>CN(C)C=O>[ClH:17].[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:22](=[NH:18])[NH2:21])[CH2:3]1
Reactant: CC1CCCNC1
Reactant: N=C(N)n1cncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1CCCN(C(=N)N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of 3-methylpiperidine (2.347 ml, 20 mmol), diisopropylethylamine (3.49 ml, 20.00 mmol) and 1H-1,2,4-triazole-1-carboximidamide hydrochloride (2.444 g, 22.00 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature overnight. Ether (50 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 10 minutes. The ether layer was separated and DMF layer was stirred with ether (50 ml) at 5° C. (ice water bath) for 10 minutes and the ether layer was separated from the residue. Ether (20 ml) was added to the residue and the mixture was stirred at 5° C. The resulting solid was triturated with ether, collected, washed with ether and dried to give the title compound as a colourless solid (2.95 g, 83%). LC/MS [M+H]+=142.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]=[O:13])=[CH:10][N:11]=1
Reactant: COCCOc1ccc(CO)cn1
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: COCCOc1ccc(C=O)cn1
Yield: 82.8 %

Procedure:
[6-(2-methoxyethoxy)pyridine-3-yl]methanol (1.83 g 10.0 mmol) was dissolved in toluene (50 ml) and heated to reflux under an air condenser. Finely powdered MnO2 (4.0 g) was added portion wise over 2 hours. After a further 2 and a half hours of heating the mixture was taken off the boil allowed to cool slightly then filtered through celite and washed with toluene. The filtrate was concentrated in-vacuo to yield a pale yellow oil which crystallized under high vacuum to yield the crude product (1.50 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:41][CH3:42])[C:4](=[O:40])[NH:5][C:6]1[C:7]([C:17]2[NH:18][C:19]3[CH:25]=[C:24]([N:26]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28])[C:23]([F:39])=[CH:22][C:20]=3[N:21]=2)=[N:8][N:9](C2CCCCO2)[CH:10]=1)[CH3:2].FC(F)(F)C([O-])=O>>[CH2:41]([N:3]([CH2:1][CH3:2])[C:4](=[O:40])[NH:5][C:6]1[C:7]([C:17]2[NH:18][C:19]3[CH:25]=[C:24]([N:26]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[C:27]([N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])=[O:28])[C:23]([F:39])=[CH:22][C:20]=3[N:21]=2)=[N:8][NH:9][CH:10]=1)[CH3:42]
Reactant: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N(CCN(C)C)C(=O)N(CC)CC)cc2[nH]1
Agent: O=C([O-])C(F)(F)F
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(N(CCN(C)C)C(=O)N(CC)CC)cc2[nH]1
Yield: 63.1 %

Procedure:
In the same manner as for step V1 of example 15 (see below), 100 mg of 1-{2-[4-(3,3-diethylureido)-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-6-fluoro-3H-benzimidazol-5-yl}-1-(2-dimethylaminoethyl)-3,3-diethylurea (stage 5, example 15) are deprotected, and 54 mg of 1-{2-[4-(3,3-diethylureido)-1H-pyrazol-3-yl]-6-fluoro-3H-benzimidazol-5-yl}-1-(2-dimethylaminoethyl)-3,3-diethylurea are isolated in the form of a trifluoroacetate salt. 1H NMR (300 MHz, DMSO-d6, δ in ppm), for this batch, we observe a 60%-40% resolution of tautomers with: 0.75 (m, 6H); 1.22 (m, 6H); from 2.30 to 2.86 (broad m partially masked, 8H); 3.02 (q, J=7.0 Hz, 4H); 3.42 (q, J=7.0 Hz, 4H); 3.64 (broad m, 2H); 7.36 (m, 1H); 7.52 (m, 1H); 8.02 (s, 1H); 9.35 (broad m, 1H); 9.71 (s, 0.4H); 9.74 (s, 0.6H); 13.1 (broad s, 1H); 13.15 (broad s, 0.4H); 13.2 (broad s, 0.6H). ES mass spectrum: 502(+)=(M+H)(+)
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH2:4][O:5][CH2:6][C:7]#[CH:8].C([Li])CCC.[CH2:15]1[O:25][C:24]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][C:17]=2[O:16]1.[Cl-].[NH4+]>O1CCCC1>[OH:21][CH:20]([C:19]1[CH:22]=[CH:23][C:24]2[O:25][CH2:15][O:16][C:17]=2[CH:18]=1)[C:8]#[C:7][CH2:6][O:5][CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1]
Reactant: C#CCOCC=C(C)C
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)=CCOCC#CC(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 g (161 mmol) of 1-[(3-methyl-2-butenyl)oxy)-2-propyne in 200 ml of tetrahydrofuran was treated at -78° under argon with 111 ml of n-butyllithium (1.6M in hexane). The mixture was left to stir at -40° for 30 minutes, again cooled to -78° and a solution of 26.6 g (177 mmol) of 3,4-methylenedioxybenzaldehyde in 150 ml of tetrahydrofuran was then added within 40 minutes. The reaction mixture was stirred at -78° for a further 1 hour, then warmed to room temperature and subsequently treated with 150 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained 1-hydroxy-4-[(3-methyl-2-butenyl)oxy]-1-[3,4-(methylenedioxy)phenyl]-2-butyne as a yellow oil.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][C:21]=1[CH2:31][NH2:32])(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:32]([CH2:31][C:21]2[CH:22]=[C:23]([O:26][C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:25][C:20]=2[S:17]([CH3:16])(=[O:19])=[O:18])[CH:10]=1
Reactant: CS(=O)(=O)c1ccc(OC(F)(F)F)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(OC(F)(F)F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 86.8 %

Procedure:
(Step 3) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.6 g), 1-[2-(methylsulfonyl)-5-(trifluoromethoxy)phenyl]methanamine hydrochloride obtained in Step 2 (2.5 g) and potassium carbonate (2.83 g) were stirred in ethanol (30 ml) at 85° C. for 24 hr. The reaction mixture was treated with 1N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=4:1). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (4 ml) was added. The mixture was crystallized from methanol-ethyl acetate, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (1.36 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][N+:14]([O-:16])=[O:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(O)=[O:2].Cl>O1CCCC1>[OH:2][CH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][N+:14]([O-:16])=[O:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])CS(=O)(=O)c1ccc(CO)cc1
Reaction time: 2 h
Yield: 25.9 %

Procedure:
Borane-methyl sulphide complex (0.1 ml, 1 mmol) was added to a solution of (4-carboxyphenylsulphonyl)nitromethane (0.25 g, 1 mmol) in anhydrous tetrahydrofuran (5 ml) and the mixture was stirred for 2 hours. The mixture was acidified with 2M hydrochloric acid to pH 1 and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by MPLC eluting with methanol/dichloromethane (1:50 v/v) to give (4-hydroxymethylphenylsulphonyl)nitromethane (0.06 g) m.p. 73°-75° C.; microanalysis, found: C, 41.6; H, 3.9; N, 5.8%; C8H9NO5S requires: C, 41.6; H, 3.9; N, 6.1%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]Cl>CN(C)C=O>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a stirred soluton of 3-nitrophenol (5 g, 36 mmol) in dimethylformamide (100 ml) at 0° C. was added sodium hydride (1.029 g, 80% dispersion in mineral oil, 34.3 mmol). After the effervescence had subsided 2-dimethylaminoethyl chloride was added (5.746 g, 37.8 mmol). After 1 hour the reaction mixture was allowed to warm to room temperature. After a further 2 hours the reaction mixture was heated to 70° C. for 14 hours, then evaporated under reduced pressure. The residue was then partitioned between water and ethyl acetate and the organic phase washed twice with aqueous sodium hydroxide solution (SM) and then saturated aqueous sodium chloride solution. Drying and evaporation gave the product as a brown oil (4.64 g, 61%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[N:17]=[CH:16][C:15]([N:18]([CH3:27])[C:19](=[O:26])/[CH:20]=[CH:21]/[CH2:22][N:23]([CH3:25])[CH3:24])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[CH2:28]([Cl:30])Cl>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[N:17]=[CH:16][C:15]([N:18]([CH3:27])[C:19](=[O:26])/[CH:20]=[CH:21]/[CH2:22][N:23]([CH3:25])[CH3:24])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:14]3[CH:15]=[CH:16][C:28]([Cl:30])=[CH:12][CH:13]=3)[C:3]=12
Reactant: CN(C)C/C=C/C(=O)N(C)c1ccc(-n2nc(I)c3c(N)ncnc32)nc1
Reactant: ClCCl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: O
Product: CN(C)C/C=C/C(=O)N(C)c1ccc(-n2nc(-c3ccc(Cl)cc3)c3c(N)ncnc32)nc1
Yield: 291.6 %

Procedure:
To a suspension of (E)-N-(6-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl) pyridine-3-yl)-4-(dimethylamino)-N-methylbut-2-enamide (65) (100 mg, 0.21 mmol), arylboronic acid (0.27 mmol) and K3PO4.3H2O (168 mg, 0.63 mmol) in DME (8 mL) and water (2 mL) was added Pd(dppf)Cl2.DCM (9 mg, 0.02 mmol). The resulting mixture was purged with N2 (3×) before microwaved at 90° C. for 45 min. The solvents were evaporated and the residual was directly loaded to a silica gel column and pre-purified by column chromatography (0 to 10% MeOH in DCM) followed by preparative HPLC purification (RP C18, 10 to 95% acetonitrile in water (0.2% NH3)) to give (E)-N-(6-(4-amino-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)pyridin-3-yl)-4-(dimethylamino)-N-methylbut-2-enamide (66) (27 mg, 28%) as a white solid. 1H NMR (400 MHz, DMSO) δ 9.82 (br, 2H), 8.57 (d, J=2.5 Hz, 1H), 8.40 (s, 1H), 8.33 (d, J=8.7 Hz, 1H), 8.08 (dd, J=8.7, 2.6 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 6.73-6.65 (m, 1H), 6.34-6.19 (m, 1H), 3.80 (s, 2H), 3.34 (s, 3H), 2.69 (s, 6H). LC-MS (ESI): m/z (M/M+2) 463/465.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O.CN(C=O)C.O>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(NCc1nccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(c2ncc3c(Cl)nccn23)CC1
Temperature: 25 °C
Yield: 2537.3 %

Procedure:
To a suspension of benzyl 4-{[(3-chloropyrazin-2-yl)methyl]carbamoyl}piperidine-1-carboxylate (0.100 g, 0.220 mmol) in EtOAc (0.9 mL) and DMF (0.068 mL) at 0° C. was slowly added POCl3 (0.082 mL, 0.88 mmol). After stirring at rt for an hour the mixture was cooled to 0° C. then treated with solid NaHCO3. The mixture was stirred for 20 min at rt, diluted with water and extracted with EtOAc (3×20 mL). The combined extracts were washed with water (2×30 mL) and brine (30 mL), then dried over Na2SO4, and concentrated in vacuo to yield 2.07 g of desired product. 1H NMR (400 MHz, CDCl3): δ 1.98-2.04 (m, 4H), 3.03-3.20 (m, 3H), 4.30-4.33 (m, 2H), 5.16 (s, 2H), 7.33 (d, J=5.2 Hz, 1H), 7.35-7.38 (m, 5H), 7.26 (d, J=4.4 Hz, 1H), 7.79 (s, 1H). MS (ES+): m/z 371.22 [MH+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C@@H:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[B:19](OC)([O:22]C)[O:20]C.Cl>O1CCCC1>[CH3:18][C@@H:11]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:22])[OH:20])=[CH:3][CH:4]=1
Reactant: CC(C)=CCC[C@H](C)CCOc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)=CCC[C@H](C)CCOc1ccc(B(O)O)cc1
Temperature: -78 °C
Yield: 67 %

Procedure:
2.5 M n-Butylithium in hexanes (49.3 cm3, 0.12 mol) was added dropwise to a cooled (−78° C.) solution of 1-bromo-4-[(S)-3,7-dimethyloct-6-enyloxy]benzene (35 g, 0.11 mol) in tetrahydrofuran (350 cm3). The resultant solution was stirred at this temperature for 1 h and then trimethyl borate (23.8 g, 0.23 mol) was added dropwise to the mixture while maintaining the temperature at −78° C. 20% hydrochloric acid (250 cm3) was added and the resultant mixture was stirred for 1h and then extracted into diethyl ether (2×200 cm3). The combined organic layers were washed with water (2×100 cm3) and dried (MgSO4). After filtration the solvent was removed under reduce pressure to yield 20.35 g (65%) of the desired product.
Reaction SMILES: [N+](C1C=CC(COC([NH:12][S:13]([NH:16][CH2:17][CH2:18]O)(=[O:15])=[O:14])=O)=CC=1)([O-])=O.[OH:22][C@@H:23]([C@H:25]1[C:61](=[O:62])[N:27]2[C:28]([C:48]([O:50]CC3C=CC([N+]([O-])=O)=CC=3)=[O:49])=[C:29]([C:32]3[S:36][C:35]4=[C:37]([C:40]([C:42]5[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=5)=[O:41])[N:38]=[CH:39][N:34]4[CH:33]=3)[C@H:30]([CH3:31])[C@H:26]12)[CH3:24]>>[OH:22][C@@H:23]([C@H:25]1[C:61](=[O:62])[N:27]2[C:28]([C:48]([O-:50])=[O:49])=[C:29]([C:32]3[S:36][C:35]4=[C:37]([C:40]([C:42]5[CH:43]=[N+:44]([CH2:18][CH2:17][NH:16][S:13](=[O:15])(=[O:14])[NH2:12])[CH:45]=[CH:46][CH:47]=5)=[O:41])[N:38]=[CH:39][N:34]4[CH:33]=3)[C@H:30]([CH3:31])[C@H:26]12)[CH3:24]
Reactant: O=C(NS(=O)(=O)NCCO)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(C(=O)c5ccc[n+](CCNS(N)(=O)=O)c5)c4s3)[C@H](C)[C@H]12
Yield: 17.7 %

Procedure:
The title compound (101 mg) was prepared in the same manner as in steps a) and b) of Example 4, except that 572 mg of 2-(4-nitrobenzyloxycarbonylaminosulfonyl)aminoethanol was used instead of 3-azido-1-propanol in step a) of Example 4 and 585 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was used as the starting compound.