Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].[C:17](OC(=O)C)(=[O:19])[CH3:18]>S(=O)(=O)(O)O>[C:17]([NH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])(=[O:19])[CH3:18]
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1N
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: COc1ccc(C(=O)CCC(=O)O)cc1NC(C)=O

Procedure:
A mixture of 3-(3-amino-4-methoxybenzoyl) propionic acid (15.61 g.) with acetic anhydride (7.14 g.) was treated with concentrated sulphuric acid (2 drops) and heated on the steam bath for 3 hours. It was then cooled and decomposed by the addition of ice. The resultant solid was collected and crystallised from methanol to yield the product, (10.5 g.), m.p. 184°-185°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[C:23](Br)[CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C(O)CC.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[C:23]([C:32]2[CH:31]=[N:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=2)[CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc3c(Br)cccc3[nH]2)CC1
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCO
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc23)cn1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
An argon stream is bubbled through a solution of 182 from above (500 mg, 1.2 mmol) and 2-methoxy-5-pyridine boronic acid (181 mg, 1.2 mmol) in 4 ml of 1-propanol for 15 min. Then 2M aqueous sodium carbonate solution (1.2 ml, 2.4 mmol) and bis(triphenylphosphine)palladium-(II)-chloride (50 mg, 0.07 mmol) are added and the reaction mixture is stirred at 85° C. for 3 h. Then the mixture is cooled to 0° C. and ethyl acetate and concentrated sodium hydroxide solution is added until a pH of 11 is reached. The solution is washed with brine and the organic layers are dried over sodium sulfate and evaporated. The crude product is purified by flash-chromatography (silica gel, cyclohexane/ethyl acetate 7:3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2].[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1[NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2ccc(C)nc2n(CC)c1=O
Reactant: CN(C)CCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(NCCCN(C)C)c2ccc(C)nc2n(CC)c1=O

Procedure:
A stirred mixture of 8.7 g. (0.03 mole) of 1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, (Example 30) 3.06 g. (0.03 mole) of 3-dimethylaminopropylamine and 3.18 g. of sodium carbonate in 100 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was triturated with 150 ml. of water and was extracted with 150 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and the ether was evaporated. The residue was passed through a neutral aluminum oxide column using ethyl acetate as the eluent. The ethyl acetate was evaporated and the residue was dissolved in anhydrous diethyl ether and the solution was acidified with an ethereal hydrochloric acid solution. The precipitate which formed was collected and was dried to give 1.9 g. of product as the hydrochloride, monohydrate, m.p. 75° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:15][N:14]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[CH3:19][C:17]1[C:16]([O:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:15][N:14]=[C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH:18]=1
Reactant: O=COc1ccccc1
Reactant: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ncc1OCCC(F)(F)F
Product: Cc1cc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)ncc1OCCC(F)(F)F
Yield: 41 %

Procedure:
The title compound is prepared in 41% yield (30 mg, white solid) from 4-chloro-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (60 mg, 0.16 mmol, Intermediate-75) and phenyl formate (38 mg, 0.31 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]([CH:9]([CH3:11])[CH3:10])[C:5]1=[O:12].Cl.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]1.C(N(CC)CC)C>CN(C=O)C>[OH:21][CH2:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][N:6]([CH:9]([CH3:11])[CH3:10])[C:5]2=[O:12])[CH2:15][CH2:16]1
Reactant: CC(C)n1ccn(CCCl)c1=O
Reactant: OCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)n1ccn(CCN2CCC(CO)CC2)c1=O
Temperature: 70 °C
Reaction time: 20 h
Yield: 43 %

Procedure:
A mixture of 1-(2-chloroethyl)-1,3-dihydro-3-(1-methylethyl)-2H-imidazol-2-one (12 g), 4-piperidinemethanol hydrochloride (9.1 g), N,N-diethylethanamine (21 ml) and KI (catalytic amount) in DMF (200 ml) was stirred for 20 hours at 70° C. The reaction mixture was cooled and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3)95/5). The pure fractions were collected and the solvent was evaporated, yielding 6.9 g (43%) 1,3-dihydro-1-[2-[4-(hydroxymethyl)-1-piperidinyl]ethyl]-3-(1-methylethyl)-2H-imidazol-2-one (intermediate 3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH:22]2[CH2:23][C:24](=O)[CH2:25][C:20]3[C:21]2=[C:16]([CH:17]=[CH:18][CH:19]=3)[NH:15]1>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].[Ti](Cl)(Cl)(Cl)Cl>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH:22]2[CH2:23][CH:24]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH2:25][C:20]3[C:21]2=[C:16]([CH:17]=[CH:18][CH:19]=3)[NH:15]1
Reactant: O=C1Cc2cccc3c2C(C1)C(c1ccccc1F)N3
Reactant: C1COCCN1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Fc1ccccc1C1Nc2cccc3c2C1CC(N1CCOCC1)C3

Procedure:
Morpholine (0.51 ml) was dissolved in an anhydrous chloroform (5 ml) and to the solution was added dropwise a solution of titanium tetrachloride (98 μl) in anhydrous chloroform (2 ml) under cooling with ice, followed by addition of the compound (0.34 g) obtained in Example 252. The mixture was heated to reflux for 30 minutes and allowed to cool. The reaction mixture was diluted with saturated aqueous solution of sodium hydrogencarbonate and extracted twice with methylene chloride. The organic layers were combined, washed twice with water and once with saturated aqueous solution of sodium chloride successively and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to yield 0.42 g of the titled compound as a crude brown oil. The compound was used in the subsequent reaction without further purification.
Reaction SMILES: [Cl-:1].[CH3:2][N+:3]([CH3:13])([CH3:12])[CH2:4][C:5]1([CH3:11])[CH2:9][O:8][C:7](=[O:10])[NH:6]1.C(O[Cl:19])(C)(C)C>CO>[Cl-:19].[Cl:1][N:6]1[C:5]([CH2:4][N+:3]([CH3:13])([CH3:12])[CH3:2])([CH3:11])[CH2:9][O:8][C:7]1=[O:10]
Reactant: CC1(C[N+](C)(C)C)COC(=O)N1
Reactant: CC(C)(C)OCl
Agent: [Cl-]
Solvent: CO
Product: CC1(C[N+](C)(C)C)COC(=O)N1Cl
Reaction time: 3 h
Yield: 31.3 %

Procedure:
To a solution of N,N,N-trimethyl-1-(4-methyl-2-oxooxazolidin-4-yl)methanaminium chloride (1.52 mmol) in MeOH (1 ml) was added, dropwise, tert-butylhypochlorite (250 uL, 2.10 mmol). The solution was stirred for 3 h, evaporated, and purified by preparatory HPLC (H2O/CH3CN) to afford the title compound as a yellow foam (115.6 mg, 0.475 mmol, 31% over two steps). 1H NMR (D2O, 400 MHz) δ 1.64 (s, 3H), 3.31 (s, 9H), 3.80 (d, J=15.2 Hz, 1H), 3.88 (d, J=14.8 Hz, 1H), 4.61 (d, J=9.6 Hz, 1H), 4.93 (d, J=10.0 Hz, 1H). ESI/APCI expected for C8H16ClN2O2+: 207.09. Found: 207 (M+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](Cl)=[O:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:28]([C:24]4[O:23][CH:27]=[CH:26][CH:25]=4)=[O:29])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4ccco4)cc3C2=O)C(=O)N1
Reaction time: 18 h
Yield: 75.2 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and furan-2-carbonyl chloride (0.39 g, 3.00 mmol) in CH2Cl2 (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 18 h, the product was isolated by filtration, washed with CH2Cl2 (10 mL) and dried in vacuo to give furan-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.86 g, 75% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.11 min (96.16%); mp: 180-182° C.; 1H NMR (DMSO-d6) δ 1.94-2.17 (m, 1H, CHH), 2.53-2.70 (m, 2H, CHH, CHH), 2.77-3.02 (m, 1H, CHH), 4.59 (d, J=6.0 Hz, 2H, CH2), 5.15 (dd, J=5.4, 12.7 Hz, 1H, CH), 6.65 (dd, J=1.8, 3.5 Hz, 1H, Ar), 7.15 (d, J=3.6 Hz, 1H, Ar), 7.74-7.85 (m, 2H, Ar), 7.85-7.97 (m, 2H, Ar), 9.12 (t, J=6.1 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 41.87, 48.99, 111.93, 113.86, 121.97, 123.54, 129.81, 131.59, 133.44, 145.28, 147.39, 147.52, 157.93, 166.97, 167.10, 169.80, 172.72; LCMS: MH=382; Anal Calcd for C19H15N3O6+0.1H2O: C, 59.56; H, 4.00; N, 10.97. Found: C, 59.26; H, 3.45; N, 10.80.
Reaction SMILES: I[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][CH:3]=1.[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:7]1([N:6]2[C:2]([C:14]#[C:13][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:3][CH:4]=[N:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccnn1-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccnn1-c1ccccc1
Temperature: 70 °C
Reaction time: 10 h
Yield: 86.5 %

Procedure:
To a solution of 5-iodo-1-phenyl-1H-pyrazole (2.00 g) (J. Org. Chem. 2008, 73, 1, 177-183) in triethylamine (40.0 mL) were added ethynyl(trimethyl)silane (0.80 g), CuT (0.141 g) and PdCl2(PPh3)2 (0.260 g) under an argon atmosphere, and the mixture was stirred at 70° C. for 10 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane) to give the title compound (1.54 g).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.CCCCCC.[C:32]([C:34]1[CH:35]=[C:36](/[C:40](/[CH:46]([CH3:48])[CH3:47])=[CH:41]\[C:42](OC)=[O:43])[CH:37]=[CH:38][CH:39]=1)#[N:33]>ClCCl>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:42](=[O:43])/[CH:41]=[C:40](\[C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:32]#[N:33])[CH:35]=2)/[CH:46]([CH3:48])[CH3:47])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C(\c1cccc(C#N)c1)C(C)C
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)/C(=C/C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 2′-tert-butylaminosulfonyl-4-amino-[1,1′]-biphenyl (139 mg, 0.46 mmol) in 4 ml anhydrous dichloromethane was added a solution of 2M trimethylaluminum in hexane (0.69 ml, 1.38 mmol). Reaction was stirred at room temperature for 20 minutes to which a solution of crude methyl (2Z)-3-(3-cyanophenyl)-4-methylpent-2-enoate (105 mg, 0.46 mmol) in 2 ml anhydrous dichloromethane was added. Reaction was stirred at room temperature overnight. Reaction was quenched with 5 ml 1N HCl after which an additional 20 ml dichloromethane was added. Organic was washed with 2×20 ml water, dried over magnesium sulfate, filtered and concentrated to give (2Z)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-4-methylpent-2-enamide (190 mg, 82%) as an off-white foam which was sufficiently pure to be used without further purification. ES-MS (M+H): 501.2.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([NH:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:14])=[O:15])[C:6](=[CH2:11])[C:7]([O:9][CH3:10])=[O:8])(=[O:37])[CH3:36]
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC)N(Cc1ccccc1NC(C)=O)S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
A mixture of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate (8.0 g, 20.28 mmol) in methylene chloride (60 ml) was cooled to 0° C. and triethylamine (12.69 ml, 91.1 mmol) in methylene chloride (25 ml)was added, followed by the addition of acetyl chloride (4.34 ml, 60.84 mmol). The mixture was stirred at room temperature overnight and diluted with methylene chloride. The mixture was washed with water, 2N citric acid, saturated sodium chloride and then dried with anhydrous sodium sulfate. The solvent was removed in vacuo to give 8.6 g of a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7])=[CH2:2].[CH2:12]([O:19][C:20]1[CH:25]=[C:24](I)[CH:23]=[CH:22][C:21]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([CH:2]=[CH:1][C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=2)[C:6]([NH2:8])=[O:7])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][C:29](=[O:34])[NH:30][S:31]1(=[O:33])=[O:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=Cc1cccc(C(N)=O)c1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc(C=Cc2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)c1
Temperature: 120 °C

Procedure:
A mixture of 3-vinylbenzamide (32 mg, 0.22 mmol), 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (80 mg, 0.18 mmol), Pd(OAc)2 (20 mg, 0.09 mmol) and triethylamine (0.256 mL, 1.84 mmol) in MeCN (2 mL) is heated in a microwave apparatus at 120° C. for 25 min. The mixture is filtered over Celite and washed with MeCN. The filtrate is evaporated to give the title compound which is used directly in the next step.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[H][H].[OH-].[Na+]>C(O)(=O)C.O>[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH2:9]2
Reactant: [H][H]
Reactant: Cc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)CCN2
Reaction time: 3 h
Yield: 75 %

Procedure:
28.74 g (457 mmol) of sodium cyanoborohydride are added in small portions at below 20° C. to a solution of 20.0 g (152 mmol) of 5-methylindole in 300 ml of glacial acetic acid. The addition, which is slightly exothermic, is made over 3 hours and is accompanied by slight evolution of hydrogen. The mixture is stirred for 12 hours at below 20° C., and then 300 ml of water are added and the pH of the reaction medium is adjusted to between 10 and 12 by addition of 500 ml of 30% sodium hydroxide solution. The mixture is extracted twice with dichloromethane and the organic phase is washed with 100 ml of water. It is evaporated and the residue is purified by flash chromatography on a silica column, the eluent used being a mixture of increasing polarity of methanol in methylene chloride. 15.3 g (yield=75%) are obtained of a colourless oil which develops a brown colour on storage (under a nitrogen atmosphere with the exclusion of light).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][C:13](=[O:15])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:16][Mg]Cl>C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:12][C:13]([CH3:16])([OH:15])[CH2:14]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: C[Mg]Cl
Reactant: O=C1CC(c2ncc3c(Cl)nccn23)C1
Solvent: C1CCOC1
Product: CC1(O)CC(c2ncc3c(Cl)nccn23)C1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
3-(8-Chloroimidazo[1,5-α]pyrazin-3-yl)cyclobutanone (1.95 g, 8.80 mmol) in anhydrous THF (77.78 mL) at −78° C. under an atmosphere of nitrogen was treated slowly with a 3.0 M solution of methylmagnesium chloride in THF (5.9 mL). The solution stirred for 3 hr at −78° C. then quenched with 40 mL of semi-saturated aqueous NH4Cl (NH4Cl dilution in 1:1 mixture with water) at −78° C. and allowed to warn up to rt. The mixture was then extracted with EtOAc (3×40 mL) and the combined extracts washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude solid was purified by chromatography over silica gel eluting with 1:1 EtOAc/DCM to 4% MeOH in (1:1) EtOAc/DCM to afford desired product. 1H-NMR (400 MHz, CDCl3) δ ppm 1.54 (s, 3 H), 2.74-2.60 (m, 4 H), 3.75-3.39 (m, 1 H), 7.35 (d, J=5.04 Hz, 1 H), 7.71 (d, J=5.00 Hz, 1 H) and 7.86 (s, 1 H). MS (ES+): m/z 238.15 and 240.17 [MH+].
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3]OS(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+].[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20]>CCOC(C)=O.O>[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:3][C:2]([F:13])([F:12])[F:1])[CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCCN(CC(F)(F)F)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (0.42 g, 1.8 mmol) was dissolved in a mixture of 1.5 mL of EtOAc and 1.5 mL of H2O containing 0.95 g of NaHCO3 (7.5 mmol). The resulting suspension was warmed to 50 C. A solution of racemic piperidin-3-yl-carbamic acid tert-butyl ester (0.30 g, 1.5 mmol) in 1 mL of EtOAc was added dropwise over a 30 minute period. The reaction mixture was left stirring at 50° C. for one hour before being cooled to RT. The organic phase was separated and the aqueous layer was back extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered and evaporated to give 0.38 g of racemic [1-(2,2,2-trifluoro-ethyl)-piperidin-3-yl]-carbamic acid tert-butyl ester as a colorless oil which was used in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]I.[H-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH3:17])[N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NN=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(N=Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 72 h
Yield: 92.7 %

Procedure:
To a solution of N'-benzylidenehydrazinecarboxylic acid tert-butylester (2.0 g, 9.07 mmol) in anhydrous tetrahydrofuran (20 ml) was added methyl iodide (4.54 ml, 72.6 mmol) and the solution was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 1.09 g, 27.2 mmol) was slowly added and the mixture was stirred at room temperature for 3 days. The tetrahydrofuran (50 ml) was added and the mixture was filtered. The filtrate was concentrated in vacuo and chromatographed on silica (100 g) with heptan:ethyl acetate (1:1) to give 1.97 g (93%) of N'-benzylidene-N-methylhydrazinecarboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [Mg].[CH3:2][CH:3]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:5](=[O:6])[CH2:4]1.Cl[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].II.Cl>CCOCC.C1C=CC=CC=1>[OH:6][C:5]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][CH:3]([CH3:2])[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7]1
Reactant: CCOC(=O)CCl
Reactant: CC1CC(=O)CC(C)(C)C1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)CC1(O)CC(C)CC(C)(C)C1
Temperature: 0 °C

Procedure:
300 ml of absolute ether, 150 ml of dry benzene and 170 g of magnesium shavings are added to a 6 liter flask which is fitted with a stirrer, thermometer, dropping funnel and reflux condenser. Now, there is introduced dropwise a mixture of 1.100 kg of dihydroisophorone and 960 g of ethyl chloroacetate dissolved in 1.200 l of ether and 600 ml of benzene. (If the reaction does not begin during the addition of the first 200 ml and warming at slight reflux does not begin spontaneously, then a few small crystals of iodine are added). The beginning of the reaction is recognizable by turbidity and heat-evolution. The addition of the reagents is continued in such a manner that the mixture boils only moderately, the addition being completed within 11/4 hours. Thereafter, the mixture is held at reflux temperature for a further 31/2 hours and, after cooling, added to 2.5 kg of ice and 1.2 l of concentrated hydrochloric acid. The organic phase is separated and washed with water (containing 1% concentrated hydrochloric acid), with water and several times more with 10% sodium carbonate solution. After evaporating the solvent in vacuo, there remain behind 1.69 kg of crude product which are distilled. The main fraction (1.250 kg) is washed with 10% sodium carbonate solution and again distilled (100° C./3 mm Hg). There are thus obtained 1.046 kg of ethyl 1-hydroxy-3,3,5-trimethyl-cyclohexylacetate.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([CH:13]=[C:14]([Br:17])[C:15]=1[CH3:16])[NH2:12].C(=O)([O-])[O-].[Li+].[Li+]>CN1CCCC1=O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][NH:12][C:11]1[CH:10]=[C:9]([Br:8])[C:15]([CH3:16])=[C:14]([Br:17])[CH:13]=1)[CH3:7]
Reactant: CCOC(=O)CCl
Reactant: Cc1c(Br)cc(N)cc1Br
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)CNc1cc(Br)c(C)c(Br)c1
Yield: 33 %

Procedure:
The DNA ligase inhibitor L67 (10) was synthesized by incubation of ethyl chloroacetate with 3,5-dibromo-4-methylaniline in the presence of lithium carbonate in N-methyl-2-pyrrolidinone as the solvent at 100° C. for 16 hours to produce N-(3,5-dibromo-4-methylphenyl)glycine ethyl ester in 33% yield after recrystallization from ethanol.