Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[N:7]([C@@H:10]1[C@@H:14]([CH2:15][OH:16])[O:13][C@@H:12]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:11]1)=[N+:8]=[N-:9].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)(Cl)Cl>[C:26]([O:16][CH2:15][C@H:14]1[O:13][C@@H:12]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:11][C@@H:10]1[N:7]=[N+:8]=[N-:9])(=[O:28])[CH3:27]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Reaction time: 8 h

Procedure:
To a pyridine (50 ml) solution of 3'-azido-3'-deoxythymidine (5.0 g, 18.7 mmole) 1 was added acetic anhydride dropwise in an ice-water bath. The mixture was allowed to stand overnight in the refrigerator. The solution was then poured into CHCl3 (20 ml), washed with H2O (200 ml×2), with a saturated solution of sodium bicarbonate and then H2O (200 ml×2). The organic layer was then dried (MgSO4). After removing the solvent, a syrup (6.5 g) was obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH:13]=[CH2:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: C=CCBr
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(NC(C)=O)cc1

Procedure:
Commercially available 4-acetamido phenol (1 molar equivalent), allyl bromide (1 molar equivalent) and potassium carbonate (1 molar equivalent) in butan-2-one were heated at reflux for 18 hours with stirring. The mixture was cooled, filtered and the solid residue washed with ether. The combined filtrates were evaporated and the solid residue was further purified by crystallisation from ethyl acetate-hexane to give 4-acetamido-1-allyloxy benzene as a colourless solid, m.p. 85°-86° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH:34][C:35]1[CH:42]=[CH:41][C:38](C=O)=[CH:37][CH:36]=1.[BH4-].C(OC(=O)C)(=O)C>C(O)C>[OH:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:27][N:24]2[CH2:23][CH2:22][CH:21]([N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:10](=[O:20])[CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[CH2:26][CH2:25]2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: [BH4-]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(Cc3ccc(O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 4-Hydroxybenzaldehyde (139 mg, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 19 mg; HRMS (FAB+, NBA) (M+H)+ 459.2655, C29H35N2O3 requires 459.2648; LC-MS: (M+H)+ 459.1, tr 2.84 min.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][CH2:16][CH2:17][C:18]1([CH3:23])[O:22][CH2:21][CH2:20][O:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].[CH2:37](Br)[CH:38]=[CH2:39]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@H:15]([CH2:16][CH2:17][C:18]1([CH3:23])[O:19][CH2:20][CH2:21][O:22]1)[CH2:39][CH:38]=[CH2:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: CC1(CCCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)OCCO1
Agent: C[Si](C)(C)[NH-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@@H](CCC1(C)OCCO1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1-9 (19.3 g, 57.9 mmol) in tetrahydrofuran (400 mL) at −78° C. under argon was added a solution of lithium bis(trimethylsilylamide) (75.2 mL of a 1.0 M solution in tetrahydrofuran) over 20 min. After an additional 20 min., allyl bromide (14.0 g, 116 mmol) was added in one portion. After 20 min., the reaction mixture was allowed to warm to 0° C. After 3.5 h, the reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography (silica gel, 25 to 35% ethyl acetate/hexanes) to give 1-10 as an oil.
Reaction SMILES: [Li][CH2:2]CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[N:8]=1.IC>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([CH3:2])[CH:10]=[C:9]([Cl:13])[N:8]=1
Reactant: Clc1cccc(Cl)n1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(Cl)nc(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
A solution of n-BuLi (21.1 mL, 33.8 mmol, 1.6 M) in THF is cooled to −78° C. before a solution of 2,6-dichloropyridine (5.0 g, 33.8 mmol) in THF (36 mL) is added dropwise over a period of 20 min. The reaction mixture is stirred at −78° C. for 30 min, and then iodomethane (4.79 g, 33.8 mmol) is added. The mixture is stirred for 30 min before it is quenched with sat. aq. NH4Cl solution at −78° C. The mixture is extracted with diethyl ether, the org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 19:1 to give 2,6-dichloro-4-methyl-pyridine (2.34 g) as a colourless oil containing the regio isomer 2,6-dichloro-3-methyl-pyridine; LC-MS: tR=0.89 min, [M+1]+=161.97.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.CC1C=CC(S(O[CH:28]2[CH2:33][CH2:32][S:31][CH2:30][CH2:29]2)(=O)=O)=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=O>[CH3:13][CH:11]([CH3:12])[C:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)=[CH:16][C:6]=2[C:7]=1[CH3:15])=[O:14]
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(O)cc12
Reactant: Cc1ccc(S(=O)(=O)OC2CCSCC2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)C(C)C)oc2ccc(OC3CCSCC3)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
A solution of 1-(5-hydroxy-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (1.0 g) synthesized above, tetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (2.99 g) and tripotassium phosphate (1.26 g) in N,N-dimethylformamide (10 mL) was stirred at 80° C. for 3 hr then at 100° C. for 14 hr. Tetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (2.99 g) was added to the mixture, and the mixture was stirred at 100° C. for 20 min. Tripotassium phosphate (600 mg) was added to the mixture, and the mixture was stirred at 100° C. for 2 hr then at 120° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-90:10, v/v) to give the title compound (886 mg, 61%) as an orange oil.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:32]([CH3:33])=[CH:31][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][NH:27][C@@H:26]([CH3:30])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:59][C:60]([CH3:62])=O>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:11]1[C:32]([CH3:33])=[CH:31][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][N:27]([CH:60]([CH3:62])[CH3:59])[C@@H:26]([CH3:30])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN[C@@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(C)C)[C@@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
To crude (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-((S)-3-methylpiperazin-1-yl)pyrimidin-4-yl)benzo[d]thiazol-6-yl)acetate (43.8 mg, 0.075 mmol) and sodium triacetoxyborohydride (80.1 mg, 0.377 mmol) in DMF (1 mL) was added acetic acid (22.7 mg, 21.6 μL, 0.377 mmol) and acetone (17.6 mg, 22.2 μL, 0.302 mmol). The reaction mixture was heated at 60° C. for 6.5 h. Upon completion of the reaction, the reaction mixture was filtered through Celite (ethyl acetate eluent) and concentrated. Purification by flash column chromatography on silica gel using 100:5:1 EtOAc/MeOH/NH4OH (0 to 100%) in EtOAc provided the product. LCMS-ESI+ calc'd for C33H41ClN5O3S (M+H1): 622.3; Found: 622.2 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reactant: OB(O)c1cccc(F)c1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3cccc(F)c3)nc2c1
Yield: 58.1 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (90 mg, 0.30 mmol, 1.00 equiv) and 3-fluorophenylboronic acid (63.4 mg, 0.45 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) yielded 60 mg (55%) of 3-(3-fluorophenyl)-2-phenylquinoxaline-6-carboxylic acid as a light yellow solid.
Reaction SMILES: [Na].[C:2]([O:11]C)(=O)[C:3]1[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[SH:5].Cl.Cl[CH2:15][C:16](=[NH:20])[O:17][CH2:18]C>CO>[OH:11][C:2]1[C:3]2[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=2[S:5][C:15]=1[C:16](=[NH:20])[O:17][CH3:18]
Reactant: CCOC(=N)CCl
Reactant: COC(=O)c1ccccc1S
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=N)c1sc2ccccc2c1O

Procedure:
A solution of 23 g (1 mol) of sodium in 1 l of anhydrous methanol is mixed with 84 g (0.5 mol) of methyl thiosalicylate while stirring. This is then mixed with 79 g (0.5 mol) of ethyl chloro-acetimidate hydrochloride and heated under reflux for 10 hours. The sodium chloride precipitate is filtered off and the desired product isolated by evaporation (yield: 73 g. m.p. 201° C).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]=[C:10]=[O:11])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:19][N:20]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([NH2:29])[C:23]=2[CH:22]=[N:21]1.N1C2C=CC=C(N)C=2C=N1>>[N:12]1([C:3]2[CH:4]=[CH:5][C:6]([CH2:8][NH:9][C:10]([NH:29][C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:23]=3[CH:22]=[N:21][N:20]4[CH3:19])=[O:11])=[CH:7][C:2]=2[F:1])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cn1ncc2c(N)cccc21
Reactant: O=C=NCc1ccc(N2CCCCCC2)c(F)c1
Agent: Nc1cccc2[nH]ncc12
Product: Cn1ncc2c(NC(=O)NCc3ccc(N4CCCCCC4)c(F)c3)cccc21

Procedure:
The title compound was prepared using the procedure described in Example 89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]azepane and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) δ 9.03 (s, 1H), 8.19 (s, 1H), 7.67 (d, 1H), 7.24 (t, 1H), 7.12-6.95 (m, 5H), 4.22 (s, 2H), 3.99 (s, 3H), 3.35 (m, 4H), 1.78 (m, 4H), 1.55 (m, 4H); MS (ESI) (M+H)+ 396.
Reaction SMILES: C[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[CH:7][C:8]([C:12]([OH:14])=O)=[N:9]2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:37]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:48]([CH:50]([NH2:60])[CH2:51][CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:49])[CH2:44][CH2:43]1)=[O:41])[CH3:38]>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[CH2:37]([O:39][C:40]([N:42]1[CH2:43][CH2:44][N:45]([C:48]([CH:50]([NH:60][C:12]([C:8]2[CH:7]=[C:6]([OH:15])[C:5]3[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=3)[N:9]=2)=[O:14])[CH2:51][CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:49])[CH2:46][CH2:47]1)=[O:41])[CH3:38]
Reactant: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Reactant: CCOC(=O)N1CCN(C(=O)C(N)CCC(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccccc3n2)CC1
Reaction time: 0.17 h

Procedure:
To a suspension of 7-methyl-4-hydroxy-2-carboxyquinoline (0.81 g, 4 mmol) in methylene chloride: DMF (4:1, 25 mL) was added 1-hydoxybenzotriazole (HOBT) (0.64 g, 4.8 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.09 g, 4.8 mmol) and the reaction mixture was stirred for 10 minutes. A solution of 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (1.37 g, 4 mmol) in methylene chloride (10 mL) was added to the reaction mixture and the resulting mixture was stirred at ambient temperature for 6 hours. The solvent was evaporated in vacuo and the resulting residue was partitioned in ethyl acetate and water. The organic layers were combined and washed with water, brine and concentrated to afford an off-white foam, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-hydroxyquinoline; (1.44 g, 68%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]=[CH:16][C:17]1[C:30]2[C:31]3=[C:32]4[C:27](=[CH:28][CH:29]=2)[CH:26]=[CH:25][CH:24]=[C:23]4[CH:22]=[CH:21][C:20]3=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C1C=CC=CC=1>CO>[CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]1[C:30]2[C:31]3=[C:32]4[C:27](=[CH:28][CH:29]=2)[CH:26]=[CH:25][CH:24]=[C:23]4[CH:22]=[CH:21][C:20]3=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(=NCCCCCCNCc1ccccc1)c1ccc2ccc3cccc4ccc1c2c34
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: c1ccc(CNCCCCCCNCc2ccc3ccc4cccc5ccc2c3c45)cc1

Procedure:
A solution of N-benzyl-N′-pyren-1-ylmethylene-hexane-1,6-diamine (420 mg, 1.00 mmol) and sodium borohydride (190 mg, 5.00 mmol) in methanol (10.0 ml) was stirred at room temperature for 3 hours under a nitrogen atmosphere. The solvent was removed under vacuum, and the residue was dissolved in chloroform and washed with water, and dried over magnesium sulphate. The solvent was removed and the residue was dried under vacuum to give a yellow oil (386/mg, 92%). 1H NMR (CDCl3) δ/ppm 1.32 (4H, m, (CH2)2), 1.45 (2H, m, BnNCCH2), 1.55 (2H, m, PyCNCCH2), 2.55 (2H, t, BnNCH2), 2.75 (2H, t, PyCNCH2), 3.75 (2H, s, PhCH2), 4.50 (2H, s, PyCH2), 7.15-7.25 (5H, m, Ph-H), 7.95-8.10, 8.15-8.22, 8.37 (4H, 4H, 1H respectively, m, m, d, Py-H). 13C NMR (CDCl3) δ/ppm 27.35, 30.16, 49.46, 50.02, 51.94, 54.13, 54.13, 123.19, 124.72, 125.00, 125.09, 125.89, 126.89, 127.03, 127.50, 127.64, 128.14, 128.40, 129.06, 131.34, 134.15; m/z (EI) 420 ([M])+, 7%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:41]=[CH:40][C:8]2[NH:9][C:10]([C:12]3[N:13]=[C:14]([C:36]([F:39])([F:38])[F:37])[S:15][C:16]=3[N:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:34])[CH2:24][N:25]4[C:29]5=[N:30][CH:31]=[CH:32][CH:33]=[C:28]5[N:27]=[CH:26]4)[C@H:19]([CH3:35])[CH2:18]3)=[N:11][C:7]=2[CH:6]=1)=O.[CH2:42]([Mg]Br)[CH3:43]>C1COCC1.C(Cl)Cl.C([O-])(O)=O.[Na+].CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[OH:2][C:3]1([C:5]2[CH:41]=[CH:40][C:8]3[NH:9][C:10]([C:12]4[N:13]=[C:14]([C:36]([F:37])([F:38])[F:39])[S:15][C:16]=4[N:17]4[CH2:22][CH2:21][N:20]([C:23](=[O:34])[CH2:24][N:25]5[C:29]6=[N:30][CH:31]=[CH:32][CH:33]=[C:28]6[N:27]=[CH:26]5)[C@H:19]([CH3:35])[CH2:18]4)=[N:11][C:7]=3[CH:6]=2)[CH2:43][CH2:42]1
Reactant: COC(=O)c1ccc2[nH]c(-c3nc(C(F)(F)F)sc3N3CCN(C(=O)Cn4cnc5cccnc54)[C@H](C)C3)nc2c1
Reactant: CC[Mg]Br
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2sc(C(F)(F)F)nc2-c2nc3cc(C4(O)CC4)ccc3[nH]2)CCN1C(=O)Cn1cnc2cccnc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of Example 167 (25 mg) in THF (1.15 mL) was added Ti(OiPr)4 (0.0126 mL). Ethylmagnesium bromide (1M in THF, 0.513 mL) was added dropwise over 30 min at RT. The reaction mixture was stirred at RT for 20 h and diluted with DCM and 1M NaHCO3. The phases were separated. The org. phase was washed with water, dried (Na2SO4), filtered off and evaporated in vacuo. The residue was purified by preparative LC-MS (III) to afford 1 mg of pale yellow solid. LC-MS (B): tR=0.65 min; [M+H]+: 583.18.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([Br:23])=[CH:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([Br:23])=[CH:17][N:18]3[S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]cc(Br)c23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
To a solution of 0.35 g (0.92 mmole) 4-(3-bromo-1H-indol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 mL benzene was added 0.106 g (1.1 mmole) sodium t-butoxide and 0.19 g (1.1 mmole) benzenesulfonyl chloride. The reaction mixture was stirred at room temperature for 16 hrs. The mixture was washed with 2 mL water, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to provide 0.42 g of 4-(1-benzenesulfonyl-3-bromo-1H-indol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester, m.p. 188-189°.
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:16][CH3:17])=[CH:9][CH:8]=1.Cl[C:19]([O:21][CH3:22])=[O:20]>C1CCCCC1.C(OCC)C>[CH3:22][O:21][C:19]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:16][CH3:17])=[CH:9][CH:8]=1)=[O:20]
Reactant: CCn1ccc2ccc(Br)cc21
Reactant: COC(=O)Cl
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CCn1ccc2ccc(C(=O)OC)cc21
Temperature: 25 °C

Procedure:
Sec-butyl lithium (9.4 ml of a 1.3M solution in cyclohexane) was added to a stirred solution of 6-bromo-1-ethylindole [the compound of step (a), 2.5 g] in diethylether (20 ml) at −78° C. under a nitrogen atmosphere. After 30 minutes this solution was transferred by cannula to a stirred solution of methyl chloroformate (1.29 ml, 16.74 mmol) in diethyl ether (8 ml) at −78° C. under a nitrogen atmosphere. After 1 hour the cooling bath was removed and the mixture was allowed to warm to room temperature. After a further 1 hour the mixture was poured into brine and extracted with ethyl acetate. The organic layers were dried (MgSO4) and concentrated in vacuo to give a yellow oil. Flash column chromatography (elution with 90% hexane, 10% ethyl acetate) gave 1.76 g of the subtitle compound as a pale yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.Cl.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH2:21][CH2:20]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][C:13]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)[CH2:21][CH2:20]2)=[O:15])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC(=O)c1ccc(OCCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(OCCC(=O)NC2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1
Reaction time: 12 h
Yield: 60.2 %

Procedure:
3-(4-Acetylphenyloxy)propionic acid (1.0 g) and 4-amino-1-(3,4-dichlorobenzyl)piperidine dihydrochloride (1.6 g) were suspended in DMF (50 mL), and triethylamine (1.3 mL), EDC hydrochloride (1.1 g) and HOBt (0.9 g) were added to the suspension. The suspension was stirred for 12 hrs. The reaction mixture was washed with water and then saturated brine and dried, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to crystallize to give the title compound (1.3 g) as a white solid.
Reaction SMILES: C[N@+]1(CCC[O:32][C:33](/[C:35](/[Cl:70])=[CH:36]/[C:37]([O:39]CCC[N@+]2(C)[C@@H](C3C=C(OC)C(OC)=C(OC)C=3)C3C=C(OC)C(OC)=CC=3CC2)=[O:38])=[O:34])[C@H](CC2C=C(OC)C(OC)=C(OC)C=2)C2C(=CC(OC)=C(OC)C=2)CC1.Cl/C(=C\C([O-])=O)/C([O-])=O.C(N(CC)CC)C>C(#N)C>[Cl:70]/[C:35](=[CH:36]\[C:37]([OH:39])=[O:38])/[C:33]([OH:34])=[O:32]
Reactant: COc1cc2c(cc1OC)[C@H](c1cc(OC)c(OC)c(OC)c1)[N@@+](C)(CCCOC(=O)/C=C(\Cl)C(=O)OCCC[N@+]1(C)CCc3cc(OC)c(OC)cc3[C@H]1Cc1cc(OC)c(OC)c(OC)c1)CC2
Agent: O=C([O-])/C=C(\Cl)C(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)/C=C(\Cl)C(=O)O

Procedure:
Gantacurium, an asymmetrical chlorofumarate, was prepared in four chemical transformations from compound (XIIIB) using minor modifications of previously reported chemistry, see WO2005/041960. Isoquinolylalkanol compound (XIIIB) was condensed with trans-2,3-dichlorosuccinic anhydride and triethylamine in acetonitrile solvent to provide a monoester of chlorofumaric acid, which was then condensed with isoquinolylalkanol compound (XIIIC):
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][C:6]1[S:7](=[O:21])(=[O:20])[O:8][C:9]2[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][CH:13]=[CH:12][C:10]=2[CH:11]=1.N12CCCN=C1CCCCC2.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:5][C:6]1[S:7](=[O:21])(=[O:20])[O:8][C:9]2[C:15]([S:16]([NH:17][C:3]([NH:2][CH3:1])=[O:4])(=[O:19])=[O:18])=[CH:14][CH:13]=[CH:12][C:10]=2[CH:11]=1
Reactant: CN=C=O
Reactant: CC1=Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)NS(=O)(=O)c1cccc2c1OS(=O)(=O)C(C)=C2
Reaction time: 2 h

Procedure:
1.15 g of methyl isocyanate are added dropwise at 0° C. to a solution of 5.5 g of 3-methyl-8-sulfamoyl-2,2-dioxo-1,2-benzoxathiine and 3.2 g of 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction mixture is stirred for 2 hours at 20°-25° C., then diluted with water, neutralised with 5% sodium carbonate solution and filtered. The filtrate is acidified and 5.4 g of N-(3-methyl-2,2-dioxo-1,2-benzoxathiin-8-yl-sulfonyl)-N'-methylurea precipitate. This precipitate is isolated and dried.
Reaction SMILES: C(O)C.[CH2:4]=[C:5]1[CH2:13][CH2:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]1=O.O.[NH2:16][NH2:17]>O>[N:16]1[NH:17][CH2:4][CH:5]2[C:6]=1[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[CH2:12][CH2:13]2
Reactant: C=C1CCc2sccc2C1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: c1cc2c(s1)CCC1CNN=C21

Procedure:
To 20 mL of anhydrous ethanol was added 1.2 g of the product from Step A and 0.40 g of hydrazine hydrate. The reaction mixture was heated at reflux for 2 h, cooled, poured into cold water and extracted with ether. The ether extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and utilized without concentration or purification in Step C.