Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:22])NCOC)=[CH:14][CH:15]=2)[C:10]([CH2:23][CH2:24][N:25]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[C:9]1[C:43]1[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[CH:44]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:51][Li]>CCOCC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:22])[CH3:51])=[CH:14][CH:15]=2)[C:10]([CH2:23][CH2:24][N:25]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[C:9]1[C:43]1[CH:44]=[C:45]([CH3:50])[CH:46]=[C:47]([CH3:49])[CH:48]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COCNC(=O)c1ccc2c(c1)c(CCN(CCCCc1ccncc1)C(=O)OC(C)(C)C)c(-c1cc(C)cc(C)c1)n2C(=O)OC(C)(C)C
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)c1ccc2c(c1)c(CCN(CCCCc1ccncc1)C(=O)OC(C)(C)C)c(-c1cc(C)cc(C)c1)n2C(=O)OC(C)(C)C
Reaction time: 0.75 h

Procedure:
To a solution of 3-{2-[tert-butoxycarbonyl-(4-pyridin-4-yl-butyl)amino]ethyl}-2-(3,5 -dimethylphenyl)-5-(methoxymethylcarbamoyl) indole-1-carboxylic acid tert-butyl ester (0.069 g in 3 mL dry tetrahydrofuran) at -10° C. was added 0.20 mL of a 1.5M solution of methyllithium in ether and the mixture stirred at low temperature. After 45 minutes, the reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with ethyl acatate. The organic portion was washed with brine, dried over sodium sulfate and the concentrate purified by preparative TLC on silica gel (hexane:ethyl acetate, 2:3) to give the title compound (58 mg).
Reaction SMILES: [C:1]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15]OC(=O)C)[CH2:13][S:14][C@H:9]12)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(=O)([O-])O.[Na+].[CH3:30][C:31]1[N+:36]([O-:37])=[N:35][C:34]([SH:38])=[CH:33][CH:32]=1.P([O-])([O-])([O-])=O>>[C:1]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][S:38][C:34]3[N:35]=[N+:36]([O-:37])[C:31]([CH3:30])=[CH:32][CH:33]=3)[CH2:13][S:14][C@H:9]12)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Reactant: Cc1ccc(S)n[n+]1[O-]
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3ccc(C)[n+]([O-])n3)CS[C@H]12

Procedure:
A mixture of 0.356 g. of 7-acetoacetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid, 0.84 g. of sodium hydrogen carbonate, 0.156 g. of 6-methyl-1-oxidopyridazine-3-thiol and 20 ml. of a phosphate buffer of pH 6.4 is heated at 60° C for 7.5 hours. After cooling, the reaction mixture is washed with ethyl acetate, brought to pH 2 with 50 % phosphoric acid, saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate layer is dried over magnesium sulfate and concentrated under reduced pressure. The concentrate is allowed to stand under cooling with ice. The resultant crystals are loosened with the addition of ethyl ether, recovered by suction-filtration, washed with hexane and dried. The procedure gives 7-acetoacetamido-3-(6-methyl-1-oxidopyridazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid as crystals melting at 85°-87° C (decomp.). Yield 0.18 g. (41 %).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:5][C:4]=1[NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[N:26]=1)#[N:2].CS(C)=[O:35].[OH-].[Na+].OO>O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:5][C:4]=1[NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[N:26]=1)(=[O:35])[NH2:2]
Reactant: CS(C)=O
Reactant: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C(N)=O)c1
Reaction time: 0.33 h

Procedure:
To a flask were added tert-butyl [(1S,2R)-2-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)cyclohexyl]carbamate (18.9 g, 43.3 mmol) and DMSO (380 mL). The resulting mixture was cooled in an ice bath. To the reaction mixture was added sodium hydroxide (6.0 M in water, 21.7 mL, 130 mmol) followed by the slow addition of hydrogen peroxide (35% solution in water, 7.96 mL, 91 mmol). The addition was performed at such a rate to maintain the internal reaction temperature between 25° C. and 30° C. After 20 minutes, the reaction mixture was slowly diluted with water (500 mL). After 30 minutes, the mixture was filtered, and the collected solids were washed with water and then dried overnight under a nitrogen bag. The collected solids were suspended in ethyl acetate (500 mL) and the resulting slurry was seeded with a previously processed batch of tert-butyl [(1S,2R)-2-({6-carbamoyl-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)cyclohexyl]carbamate. After 1 hour, the mixture was diluted with hexanes (150 mL), filtered, washed with hexanes, and dried in a nitrogen bag to afford tert-butyl [(1S,2R)-2-({6-carbamoyl-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)cyclohexyl]carbamate. MS ESI calc'd. for C24H35N6O3 [M+H]+ 455. found 455. 1H NMR (600 MHz, DMSO-d6) δ 11.68 (s, 1H), 8.51 (d, J=1.8 Hz, 1H), 7.81 (d, J=3.0 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.21 (s, 1H), 6.54-6.50 (m, 2H), 6.40 (s, 1H), 6.05 (d, J=6.0 Hz, 1H), 3.81 (s, 1H), 3.54 (s, 1H), 2.34 (s, 3H), 2.17 (s, 3H), 1.82-1.76 (m, 1H), 1.72-1.64 (m, 1H), 1.60-1.42 (m, 4H), 1.36-1.28 (m, 1H), 1.27 (s, 9), 1.10-1.06 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8](OC)[O:9]C)[C:3]=1[CH3:13].C([Li])CCC.C[O:20][B:21](OC)[O:22]C>CC(C)=O.Cl>[CH:8]([CH:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]1([B:21]([OH:22])[OH:20])[CH3:13])=[O:9]
Reactant: COB(OC)OC
Reactant: COC(OC)c1cccc(Br)c1C
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)=O
Product: CC1(B(O)O)C=CC=CC1C=O
Reaction time: 18 h
Yield: 38 %

Procedure:
The 1-bromo-3-dimethoxymethyl-2-methyl-benzene ((Example 6: step c) 500 mg, 2 mmol), butyllithium (2.5 M, 1 mL, 2.5 mmol), and trimethylborate (2.3 mL, 20 mmol) were reacted as in Example 5: step b. After aqueous workup, the residue was dissolved in acetone (18 mL) and HCl (1N, 2 mL). After standing for 18 h at rt, the volatile components were removed in vacuo and the residue was purified by SiO2 flash chromatography (25–40% EtOAc in hexanes) to give the title compound (126 mg, 38%). The title compound exists as a mixture of boronic acids and anhydrides in CDCl3, therefore the reported NMR signals represent pairs or groups of related signals. 1H-NMR (CDCl3): δ 10.44 (s, 1H), 8.38 (dd, 1H, J=1.4, 7.4 Hz), 7.49 (t, 1H, J=7.5 Hz), 3.12 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30]C)[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27]CC)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:33]1N=C(C)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1C1CC1>>[CH:15]1([C:14]2[N:13]=[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[OH:27])[C:11]([CH3:30])=[N:10][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:16][CH2:33]1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: Cc1nc(Br)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: Cc1nc(-c2ccc(Cl)cc2Cl)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-[(5-bromo-6-cyclopropyl-3-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.87-1.03, 1.60-1.69, 2.42, 2.71, 3.03, 3.25, 4.73, 4.99, 5.53, 7.12-7.66; MS (ESI+) for C23H21Cl2N3O m/z 426 (M+H)+.
Reaction SMILES: B(Br)(Br)[Br:2].S(O[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[C:23]2[C:18](=[CH:19][C:20]([O:24]C)=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1([C:27]1[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=1)[CH3:26])(C)(=O)=O.O>C(Cl)Cl>[Br:2][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[C:23]2[C:18](=[CH:19][C:20]([OH:24])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH3:26]
Reactant: BrB(Br)Br
Reactant: COc1ccc(C2(C)CCc3cc(OC)ccc3C2CCCCOS(C)(=O)=O)cc1
Solvent: O
Solvent: ClCCl
Product: CC1(c2ccc(O)cc2)CCc2cc(O)ccc2C1CCCCBr
Temperature: -60 °C

Procedure:
A molar solution of boron tribromide in methylene chloride (27.6 ml.) was added to a stirred solution of (1RS,2RS)-1,2,3,4-tetrahydro-1-(4-mesyloxybutyl)-6-methoxy-2-p-methoxyphenyl-2-methylnaphthalene (Example 1; 2.3 g.) in methylene chloride (30 ml.) which was cooled to -60° C. under an atmosphere of argon, and the mixture was allowed to warm up to laboratory temperature and then poured into iced water. The mixture was extracted with ethyl acetate and the extract was dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 9:1 v/v mixture of toluene and ethyl acetate as eluent. There were thus separately obtained the (1RS, 2RS)- and (1RS,2SR)-isomers of 1-(4-bromobutyl)-2-p-hydroxyphenyl- 2-methyl-1,2,3,4-tetrahydronaphth-6-ol.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:14]([OH:42])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:15]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]C=O)[CH2:21][CH2:20]2)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl.[NH2:44][CH2:45][C@@H:46]([C:48]1[CH:57]=[CH:56][C:55]([OH:58])=[C:54]2[C:49]=1[CH:50]=[CH:51][C:52](=[O:59])[NH:53]2)[OH:47].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CO>[CH:36]1([C:14]([OH:42])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:15]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:44][CH2:45][C@H:46]([OH:47])[C:48]3[CH:57]=[CH:56][C:55]([OH:58])=[C:54]4[C:49]=3[CH:50]=[CH:51][C:52](=[O:59])[NH:53]4)[CH2:21][CH2:20]2)=[O:16])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: O=CCCCCCCCCCN1CCC(COC(=O)C(O)(c2ccccc2)C2CCCCC2)CC1
Reactant: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: O=C(OCC1CCN(CCCCCCCCCNC[C@H](O)c2ccc(O)c3[nH]c(=O)ccc23)CC1)C(O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (90 μL, 0.65 mmol) was added to a solution of (1-(10-oxodecyl)piperidin-4-yl)methyl 2-cyclohexyl-2-hydroxy-2-phenylacetate (182 mg, 0.39 mmol) and (R)-5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one hydrochloride (100 mg, 0.39 mmol) in methanol (4 mL). The reaction mixture was stirred at RT for 1 hour. Sodium triacetoxyborohydride (154 mg, 0.73 mmol) followed by acetic acid (74 μL, 1.29 mmol) were added, and the reaction mixture stirred at RT for 72 hours. The reaction was quenched with water (500 μL) and evaporated under reduced pressure. The residue was dissolved in dimethyl sulfoxide and submitted to reverse phase preparative HPLC for final purification. The title compound was isolated (42.3 mg, 16%).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C@@H:15]3[C@@H:11]([CH2:12][CH2:13][CH2:14]3)[C:10]([OH:16])=[C:9]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25](I)=[CH:26][C:20]=4[S:19](=[O:29])(=[O:28])[N:18]=3)[C:8]2=[O:30])=[CH:4][CH:3]=1.[C:33]1([CH2:39][S:40]([NH2:43])(=[O:42])=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N(CC(O)=O)C>CN(C)C=O>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C@@H:15]3[C@@H:11]([CH2:12][CH2:13][CH2:14]3)[C:10]([OH:16])=[C:9]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:43][S:40]([CH2:39][C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)(=[O:41])=[O:42])=[CH:26][C:20]=4[S:19](=[O:29])(=[O:28])[N:18]=3)[C:8]2=[O:30])=[CH:4][CH:3]=1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2CCC[C@@H]2N1Cc1ccc(F)cc1
Reactant: NS(=O)(=O)Cc1ccccc1
Agent: CNCC(=O)O
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)Cc4ccccc4)ccc3N2)=C(O)[C@@H]2CCC[C@@H]2N1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 20.5 h
Yield: 37.2 %

Procedure:
(4aR,7aS)-1-(4-Fluoro-benzyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1,4a,5,6,7,7a-hexahydro-[1]pyrindin-2-one (prepared as described in Example 39c, 301 mg, 0.53 mmol), α-toluenesulfonamide (272 mg, 1.59 mmol) copper(I) iodide (50.4 mg, 0.265 mmol) potassium phosphate (338 mg, 1.59 mmol), and sarcosine (N-methyl glycine) (37.4 mg, 0.42 mmol) were suspended in N,N-dimethylformamide (8 mL). The mixture was degassed and backfilled with nitrogen (3×). The resulting mixture was stirred at 100° C. for 20.5 h. The mixture was filtered through a plug of Celite. The Celite was washed with 10% methanol in dichloromethane and the combined filtrates were concentrated in vacuo to afford the crude product which was further purified by prep-HPLC [Column ODS-A 5μ 100 Å, 150×21.2 mm, 5 micron, 30%-100% in 13.5 min @ 22 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (4aR,7aS)-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-C-phenyl-methanesulfonamide 120.4 mg, 0.197 mmol, 37.2%, as a light purple solid. The estimated e.e. is 97% based on the chiral amino acid starting material used. 1H NMR (DMSO-d6, 400 MHz): δ 1.44-1.62 (m, 3H), 1.94-2.11 (m, 3H), 2.77 (t, 1H, J=7.4 Hz), 3.01 (t, 1H, J=7.4 Hz), 4.40-4.52 (m, 1H), 4.54 (s, 2H), 4.90 (d, 1H, J=15.6 Hz), 7.15 (t, 2H, J=8.8 Hz), 7.24-7.26 (m, 2H), 7.29-7.32 (m, 4H), 7.36-7.46 (m, 3H), 7.50-7.58 (m, 3H), 10.27-10.29 (m, 1H). LC-MS (ESI) calcd for C29H27FN4O6S2 610.14, found 611.5 [M+H+]. Anal. calcd for C29H27FN4O6S2H2O: C, 55.40; H, 4.65; N, 8.91; found: C, 55.41; H, 4.38; N, 9.11.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(OC([N:45]([C:53]1[N:58]=[CH:57][C:56](B2OC(C)(C)C(C)(C)O2)=[CH:55][N:54]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:30][C:26]1([C:23]2[CH:22]=[CH:21][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:56]3[CH:57]=[N:58][C:53]([NH2:45])=[N:54][CH:55]=3)=[CH:25][CH:24]=2)[CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cn1
Temperature: 160 °C
Yield: 56.4 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.09 mmol), di-tert-butyl[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]imidodicarbonate (75 mg, 0.18 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6.3 mg, 0.01 mmol) and K3PO4 (72 mg, 0.27 mmol) in DMF/water (0.9 mL, 6:1, v/v) was heated at 160° C. under microwave irradiation for 1 hour. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water (×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by HPLC. The fraction was evaporated and the residue was dissolved in methanol (10 mL) and 4M HCl in dioxane (10 mL). After overnight reaction, the mixture was evaporated and the residue was purified by HPLC to give the titled compound as a white solid (24 mg, 43%). 1HNMR (DMSO-d6) 400 MHz δ: 8.56 (s, 1H), 8.26 (d, J=15.5 Hz, 2H), 8.08 (dd, J=4.6, 1.7 Hz, 1H), 7.93 (dd, J=8.0, 1.7 Hz, 1H), 7.50 (d, J=8.6 Hz, 2H), 7.35 (td, J=7.6, 1.5 Hz, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.21 (d, J=8.6 Hz, 2H), 7.10 (t, J=7.4 Hz, 1H), 6.89 (dd, J=8.0, 1.7 Hz, 1H), 6.75 (dd, J=8.0, 4.6 Hz, 1H), 6.72 (s, 2H), 2.45-2.38 (m, 2H), 2.23-2.16 (m, 2H), 2.10-2.00 (m, 1H), 1.75-1.66 (m, 1H); LCMS: 473 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].CC(O)=O.[C:34]1([C:40]2[S:41][CH:42]=[C:43](C=O)[N:44]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:17][C:43]3[N:44]=[C:40]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[S:41][CH:42]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: O=Cc1csc(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3csc(-c4ccccc4)n3)CC1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester hydrochloride (600 mg, 1.78 mmol, Intermediate 1) in DCM (30 ml) was treated with TEA (0.25 ml, 1.77 mmol). The pH was adjusted to 5 with AcOH and then 2-phenylthiazole-4-carbaldehyde (404 mg, 2.13 mmol) and NaBH(OAc)3 (554 mg, 2.62 mmol) were added. The mixture was stirred for 2 h at RT and then partitioned between DCM and aqueous NaHCO3 solution. The organic layer was dried over Na2SO4 and evaporated. The crude residue was purified by column chromatography (eluent: DCM/MeOH 99:1) to give (E)-3-{1′-(2-phenyl-thiazol-4-yl-methyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (602 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[N:25]4[CH:26]=[CH:27][N:28]=[C:24]4[CH:23]=[C:22]([C:29]4[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=4)[N:21]=3)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].[ClH:35]>O1CCOCC1>[ClH:35].[CH3:34][N:32]1[CH:33]=[C:29]([C:22]2[N:21]=[C:20]([C:18]3[CH:17]=[N:16][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:7][NH:6][CH2:5]4)[CH:19]=3)[N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH:23]=2)[CH:30]=[N:31]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(C(=O)OC(C)(C)C)C4)c3)n2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Reaction time: 2 h
Yield: 103 %

Procedure:
A 5 L 4-neck flask was equipped with an overhead stirrer and purged with N2. To this was added tert-butyl 3-(cyanomethyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (Example 61; 60.83 g, 132.4 mmol) and dioxane (661.9 mL, 132.4 mmol) and the flask was placed in a cool water bath. 4N HCl in dioxane (661.9 mL, 2648 mmol) was added in a fast stream. An additional 50 mL of dioxane was added to wash down the sides. The reaction stalled after 2 hours, so another 140 mL of HCl in dioxane was added. After 4 hours, another 50 mL of HCl in dioxane was added to drive to completion. The solids were filtered, washed with dioxane, and then washed with Et2O. The resultant solids were dried under high vacuum to afford 76 g (77% by weight, 103% yield) of the title compound as a powdery white solid. MS (apci) m/z=360.2 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[CH2:17]1[O:26][C:25]2[C:19](=[C:20]([CH:22]=[CH:23][CH:24]=2)[NH2:21])[O:18]1>C(O)CC>[C:15]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[C:25]3[O:26][CH2:17][O:18][C:19]=13)=[CH:10][C:9]([O:12][CH3:13])=[C:8]([OH:14])[CH:7]=2)#[N:16]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1O
Reactant: Nc1cccc2c1OCO2
Solvent: CCCO
Product: COc1cc2c(Nc3cccc4c3OCO4)c(C#N)cnc2cc1O
Temperature: 115 °C

Procedure:
A mixture of 4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline (5 g), 2,3-methylenedioxyaniline (3.07 g) and propanol (100 ml) was stirred and heated to 115° C. for 18 hours. The resultant precipitate was isolated, washed in turn with propanol and diethyl ether and dried under vacuum. There was thus obtained the title compound (5.51 g); NMR Spectrum: (DMSOd6) 3.99 (s, 3H), 6.06 (s, 2H), 6.93-7.0 (m, 3H), 7.48 (s, 1H), 8.16 (s, 1H), 8.94 (s, 1H); Mass Spectrum: M+H+ 336.
Reaction SMILES: S([O-])([O-])(=O)=O.[NH2:6][CH2:7][CH2:8][NH:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11].[CH3:18][CH:19]([CH3:36])[CH2:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH:30]2[O:33][CH:31]2[CH3:32])=[CH:27][CH:26]=1>>[OH:33][CH:31]([CH2:30][O:29][C:28]1[CH:34]=[CH:35][C:25]([O:24][CH2:23][CH2:22][O:21][CH2:20][CH:19]([CH3:36])[CH3:18])=[CH:26][CH:27]=1)[CH2:32][NH:6][CH2:7][CH2:8][NH:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)COCCOc1ccc(OC2OC2C)cc1
Reactant: NCCNC(=O)N1CCOCC1
Agent: O=S(=O)([O-])[O-]
Product: CC(C)COCCOc1ccc(OCC(O)CNCCNC(=O)N2CCOCC2)cc1

Procedure:
N-(2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)propyl)amino)ethyl)-4-morpholinecarboxamide was prepared in accordance with example 4 using 10.1 g of the neutral sulphate of N-2-aminoethyl-4-morpholinecarboxamide and 9.3 g of 3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy-1,2-epoxypropane as starting materials. Yield 3.9 g. Melting point 95°-96° C. (base). The structure was determined using NMR-analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>>[CH3:14][S:15]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(CCOCCO)cc1
Product: Cc1ccc(CCOCCOS(C)(=O)=O)cc1
Yield: 83 %

Procedure:
The 2-[2-(4-methylphenyl)ethoxy]ethanol obtained according to the preceding paragraph was sulfonylated with methanesulfonyl chloride in a manner analogous to that described in Example 1(c) to give 7.8 g (83%) of 2-[2-(4-methylphenyl)ethoxy]ethyl methanesulfonate in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)Cl>[CH3:1][C:2]1([CH3:12])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH+:3]1[O-:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CS(=O)(=O)CC(C)(C)N1
Solvent: ClCCl
Product: CC1(C)CS(=O)(=O)CC(C)(C)[NH+]1[O-]
Temperature: 25 °C

Procedure:
5.7 g (0.03 mole) of 2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide is dissolved in 100 ml of methylene chloride. To this solution there is then added dropwise at 20° C in ca. 90 minutes a solution of 11.2 g of m-chloroperoxybenzoic acid in 100 ml of methylene chloride. The reaction is slightly exothermic. Stirring is subsequently maintained for 15 hours at room temperature, and the precipitated m-chlorobenzoic acid filtered off. The reddish coloured methylene chloride solution is extracted twice with 50 ml of 2N sodium hydroxide solution each time, and then with 50 ml of 2N hydrochloric acid, and subsequently dried over sodium sulphate. After the solvent has been distilled off, the residue is crystallised from ethanol to obtain 2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-1,4,4-trioxide (8) of the formula ##STR19## M.P. 163° C.