Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.N[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([O:9][CH3:10])=[O:8].[O-]S([O-])=O.[Na+].[Na+]>CC#N.O>[I:1][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([O:9][CH3:10])=[O:8]
Reactant: II
Reactant: COC(=O)c1ccc(C)c(N)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(C)c(I)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.1 %

Procedure:
To a stirring mixture of 23.0 g (90.6 mmol) of I2 and 5.4 mL (45.5 mmol) of tert-butylnitrile in 40 mL of CH3CN at 35° C. was added 5.0 g (30.3 mmol) of methyl 3-amino-4-methylbenzoate in 4 portions. Stirring was continued with cooling to r.t. in the dark (light off only). After 2.5 h, 400 mL of Na2SO3 in H2O was added gradually. The layers were separated, and the organic layer was washed with 80 mL of brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (5% EtOAc/hexanes) provided 5.7 g of methyl 3-iodo-4-methylbenzoate as a red liquid with some impurity in approximately 68% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[CH:10]=1)[C:5]([OH:7])=O.FC(F)(F)C(O)=O.[NH2:24][C@@H:25]([CH2:39][C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([F:47])[CH:41]=1)[C@H:26]([OH:38])[CH2:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[F:46][C:44]1[CH:45]=[C:40]([CH:41]=[C:42]([F:47])[CH:43]=1)[CH2:39][C@@H:25]([NH:24][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[CH:10]=[C:2]([CH3:1])[CH:3]=1)[C@H:26]([OH:38])[CH2:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1
Reactant: CCCCC(=O)c1cc(C)cc(C(=O)O)c1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCCCC(=O)c1cc(C)cc(C(=O)N[C@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(OC)c2)c1
Reaction time: 8 h

Procedure:
To a mixture of 3-methyl-5-pentanoylbenzoic acid (IX–LXXVII, 112 mg, 0.589 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanol dihydrochloride (VIII, 239 mg, 0.589 mmol), HOBt (80 mg, 0.589 mmol), and N-methylmorpholine (250 mg, 2.47 mmol) in methylene chloride (3 mL) is added EDC (203 mg, 1.06 mmol). The reaction mixture is stirred overnight and then partitioned between ethyl acetate and water. The organic phase is washed with hydrochloric acid (1 N), saturated sodium bicarbonate, saline, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica; methylene chloride/methanol, 12/1) gives the title compound, IR (ATR): 3297,2957, 1687 and 1628 cm−1; APCI-MS (m/z) [M+H]+=539.
Reaction SMILES: CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.[CH2:51]([C:58]1[CH2:62][CH2:61][C:60](=[O:63])[CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CCCCC>C(OCC)C>[CH2:51]([CH:58]1[CH2:62][CH2:61][C:60](=[O:63])[CH2:59]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=C1C=C(Cc2ccccc2)CC1
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Solvent: CCCCC
Solvent: CCOCC
Product: O=C1CCC(Cc2ccccc2)C1
Yield: 795.3 %

Procedure:
General procedure B using (S)-p-tol-BINAP and 3-benzylcyclopentenone (0.11 g, 0.7 mmol) gave, after 24 h at 0° C. and flash chromatography (6:1 pentane:diethyl ether), the title compound as a clear liquid (0.97 g, 85% yield). Spectroscopic data were consistent with previously reported data for this compound.12 [α]D25° C.−96° (c 1.3, CHCl3). Chiral HPLC analysis (Chiracel OD column) indicated that the title compound was obtained in 96% ee.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]3[CH:14]=[N:13][CH:12]=[CH:11][N:10]3[C:15]=2[NH:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:4][CH:3]=1.[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CC(=O)OCC.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.[Cu]I>[C:19]1([CH:17]([NH:16][C:15]2[N:10]3[CH:11]=[CH:12][N:13]=[CH:14][C:9]3=[N:8][C:7]=2[C:5]2[S:6][C:2]([C:32]#[C:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:3][CH:4]=2)[CH3:18])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(Nc1c(-c2ccc(Br)s2)nc2cnccn12)c1ccccc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(Nc1c(-c2ccc(C#Cc3ccccc3)s2)nc2cnccn12)c1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 30.4 %

Procedure:
497 mg (1.25 mmol) of [2-(5-bromothiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-(1-phenyl-ethyl)-amine were dissolved together with 0.34 ml (3.13 mmol) of phenylacetylene, 43 mg (0.06 mmol) of bis(triphenylphosphine)-palladium(II) chloride and 24 mg (0.13 mmol) of copper(I) iodide in DMF (10 ml) After addition of 1.7 ml (12.5 mmol) of triethylamine, the mixture was stirred at 50° C. for 16 h. The reaction solution was then diluted with EA and combined with a sat. aq. sodium carbonate solution. The phases were separated and the aqueous phase extracted with EA. The combined organic phases were washed 2× with a sat. aq. sodium carbonate solution and 2× with a sat. aq. common salt solution and dried over magnesium sulfate. After filtration and removal of the solvents under a vacuum, column chromatography (EA/DCM 1:3) was carried out with the group, after which 158 mg (0.38 mmol, 30% of theoretical) of (1-phenyl-ethyl)-[2-(5-phenylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-amine were obtained.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[CH3:37][O:38][CH:39]([O:51][CH3:52])[C:40]1[N:45]=[C:44]([O:46][CH3:47])[C:43]([C:48](O)=[O:49])=[CH:42][CH:41]=1.[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1>[CH3:52][O:51][CH:39]([O:38][CH3:37])[C:40]1[N:45]=[C:44]([O:46][CH3:47])[C:43]([CH2:48][OH:49])=[CH:42][CH:41]=1
Reactant: COc1nc(C(OC)OC)ccc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [BH4-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1nc(C(OC)OC)ccc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
Diisopropylethylamine (4.56 mL) and Bop reagent (registered trademark) (10 g) were added to a solution of 6-(dimethoxymethyl)-2-methoxypyridine-3-carboxylic acid (4.1 g) in tetrahydrofuran (40 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0° C. and sodium borohydride (2.72 g) was added, followed by stirring at room temperature overnight. The reaction solution was poured into a saturated ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→1:1) to give [6-(dimethoxymethyl)-2-methoxypyridin-3-yl]methanol (2.3 g, 60%) as a colorless oil.
Reaction SMILES: N1C=CC=C(C[NH:8][CH2:9][CH2:10][NH2:11])C=1.[N+:12]([CH:15]=[C:16](SC)SC)([O-:14])=[O:13]>C1C=CC=CC=1>[N+:12]([CH:15]=[C:16]1[NH:11][CH2:10][CH2:9][NH:8]1)([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCNCc1cccnc1
Solvent: c1ccccc1
Product: O=[N+]([O-])C=C1NCCN1
Temperature: 25 °C
Yield: 131.8 %

Procedure:
A mixture of N-(3-pyridylmethyl)ethylenediamine (15.1 g), 1-nitro-2,2-bis(methylthio)ethylene (18.2 g) and benzene (150 ml) was refluxed for 4 hours with stirring. The generated gas was collected by an alkali trap. The reaction mixture was cooled to room temperature, and filtered to collect crystals. Recrystallization from methanol gave 1-(3-pyridylmethyl)-2-(nitromethylene imidazolidine (17 g) of the following formula as pale yellow crystals. mp. 169°-171° C. ##STR15##
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)(=O)C(C)(C)C.[CH3:46][O:47][C:48]1[CH:49]=[N:50][CH:51]=[C:52](B2OC(C)(C)C(C)(C)O2)[CH:53]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[C:42]([O:41][C@@H:9]([C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:52]4[CH:51]=[N:50][CH:49]=[C:48]([O:47][CH3:46])[CH:53]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[CH2:8][OH:7])([CH3:43])([CH3:44])[CH3:45]
Reactant: Cc1cc2nc(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cncc(-c2cccc(-c3nc4cc(C)c([C@@H](CO)OC(C)(C)C)c(-c5ccc(Cl)cc5)c4s3)c2)c1
Temperature: 120 °C
Yield: 61.7 %

Procedure:
The reaction mixture of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(trifluoromethylsulfonyloxy) phenyl)benzo[d]thiazol-6-yl)ethyl pivalate (20 mg, 0.029 mmol), 3-methoxypyridine-5-boronic acid pinacol ester (10 mg, 0.043 mmol), 2N K2CO3 (70 μL), Pd(PPh3)4 (3.3 mg, 0.0029 mmol) in dioxane (1 mL) was heated at 120° C. in sealed tube for 2 hours. After the reaction finished, the reaction was cooled down, to the reaction mixture was added MeOH (1 mL), 2N NaOH (500 μL) and heated at 45° C. for 3 hours. Then reaction mixture was washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product (10 mg, 62%). LCMS-ESI+: calc'd for C32H31ClN2O3S: 559.2 (M+H+); Found: 559.2 (M+H+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12](OC(C)(C)C)=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[C:19]1([C:25]2[N:30]=[N:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[C:19]1([C:25]2[CH:26]=[CH:27][C:28]3[N:29]([C:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[N:4]5)=[N:32][N:31]=3)[N:30]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: CC(C)(C)OC(=O)Cc1ccc2nccnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(-c2ccc3nnc(Cc4ccc5nccnc5c4)n3n2)cc1
Temperature: 150 °C

Procedure:
A mixture of tert-butyl 2-(quinoxalin-6-yl)acetate (0.15 g, 0.6 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.1 g, 0.7 mmol) and p-toluenesulfonic acid monohydrate (0.1 g, 0.6 mmol) in 3 mL of dioxane was heated with microwave at 150° C. for 1 hour in a microwave tube. The mixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO3 solution. The organic phase was separated and was washed with 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH/EtOAc) to give light yellow solid as desired product 6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoxaline.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:22][CH:21]=[CH2:20])[O:8][C:7](=[O:13])[CH:6]=[CH:5]2
Reactant: Cc1cc2ccc(=O)oc2cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc2oc(=O)ccc2cc1C

Procedure:
A mixture of 6-methyl-7-hydroxycoumarin (I) (14.5 g), anhydrous K2CO3 (5 g), allyl bromide (15 ml) and acetone (400 ml) was refluxed for 12 h under stirring. From the refluxed mixture the solid was filtered and washed several times with acetone. The acetonic solution and the pooled washings were concentrated to dryness and the residue crystallized from MeOH, yielding 6-methyl-7-allyloxycoumarin (IV) (11.4 g; m.p. 124°-5° C.). ##STR10##
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH:15]([OH:16])[C:14]([CH3:18])([CH3:17])[CH2:13][C:12](=[O:19])[C:11]([CH3:20])=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>O1CCCC1>[C:28]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]1[CH:15]([OH:16])[C:14]([CH3:17])([CH3:18])[CH2:13][C:12](=[O:19])[C:11]([CH3:20])=[CH:10]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=CC(NCc2ccccc2)C(O)C(C)(C)CC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N(Cc1ccccc1)C1C=C(C)C(=O)CC(C)(C)C1O
Temperature: 50 °C
Yield: 95 %

Procedure:
The 4-benzylamino-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one obtained in Example 1 (17.3 g, 63.4 millimoles) was dissolved in tetrahydrofuran (100 ml), triethylamine (19.2 g, 190 millimoles) was added, and acetic anhydride (12.9 g, 127 millimoles) was added dropwise while stirring on ice. After heating the reaction solution at 50° C. for 3 hours, it was poured into ice water (300 ml). After 30 minutes the aqueous solution was subjected to extraction with benzene, washed with water, and then dried over anhydrous magnesium sulfate. The benzene was distilled off, and the resulting residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 19.0 g (95%) of 4-(N-acetylbenzylamino)-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl.[C:23]([O:27][C:28](=[O:32])[CH2:29][NH:30][CH3:31])([CH3:26])([CH3:25])[CH3:24]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:30]([CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:32])[CH3:31])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Yield: 52.7 %

Procedure:
A solution of 0.57 g (1.67 mmol) of 4-[3-(4-chloro-phenyl)-prop-2-ynyloxy]-benzenesulfonyl chloride and 0.61 g (3.34 mmol, 2 eq) of sarcosine t-butyl ester hydrochloride in 0.51 mL of pyridine and 15 mL of chloroform was allowed to react overnight at room temperature. The reaction was concentrated in vacuo, diluted with water/ethyl acetate, neutralized with NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to afford a yellow oil which was purified via flash chormatography using 6:1 hexane:ethyl acetate to afford 0.396 g (53%) of tert-butyl [[(4-{[3-(4-chlorophenyl)-2-propynyl]oxy}phenyl)sulfonyl](methyl)amino]acetate as a white solid. Electrospray Mass Spec 450.4 (M+H)+
Reaction SMILES: [Cl-].[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C1CCN2C(=NCCC2)CC1.N1C=CC=CC=1.[NH2:24][C:25]1[CH:26]=[C:27]([N:33]2[C:42]3[C:37](=[CH:38][C:39]([F:45])=[C:40](F)[C:41]=3[CH3:43])[C:36](=[O:46])[C:35]([C:47]([OH:49])=[O:48])=[CH:34]2)[C:28]([CH3:32])=[CH:29][C:30]=1[F:31]>C(OCC)C>[NH2:24][C:25]1[CH:26]=[C:27]([N:33]2[C:42]3[C:37](=[CH:38][C:39]([F:45])=[C:40]([N:5]4[CH2:6][CH:3]([OH:2])[CH2:4]4)[C:41]=3[CH3:43])[C:36](=[O:46])[C:35]([C:47]([OH:49])=[O:48])=[CH:34]2)[C:28]([CH3:32])=[CH:29][C:30]=1[F:31]
Reactant: Cc1cc(F)c(N)cc1-n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(C)c21
Reactant: OC1CNC1
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: Cc1cc(F)c(N)cc1-n1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(O)C3)c(C)c21
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 40.7 %

Procedure:
70 mg of 3-hydroxyazetidine monochloride, 200 mg of 1,8-diazabicyclo[5.4.0]-7-undecene, and 200 mg of pyridine were stirred at 80° C., and to this mixture was added 150 mg of 1-(3-amino-4-fluoro-6-methylphenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. The mixture was stirred at 90° C. for 20 minutes. Diethylether was added to the reaction solution, and the solution was decanted. 1 ml of ethanol was added to the residue and the solid precipitate was collected by filtration and dried to obtain 70 mg of the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH:14]([CH2:16][O:17][CH3:18])[NH:13][CH:12]([CH2:19][O:20][CH3:21])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:23]([BH3-])#N.[Na+]>C(#N)C.C=O.C(O)(=O)C>[C:1]1([S:7]([N:10]2[CH2:15][CH:14]([CH2:16][O:17][CH3:18])[N:13]([CH3:23])[CH:12]([CH2:19][O:20][CH3:21])[CH2:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [BH3-]C#N
Reactant: COCC1CN(S(=O)(=O)c2ccccc2)CC(COC)N1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: COCC1CN(S(=O)(=O)c2ccccc2)CC(COC)N1C
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 59.8 %

Procedure:
To a mixture of the above described (3SR,5SR)-1-benzenesulfonyl-3,5-bis-methoxymethyl-piperazine (1.68 g, 5.343 mmol) in acetonitrile (40 ml) and 36.5% formaldehyde solution in water (0.653 ml, 8.015 mmol) and 5-7 drops of acetic acid at 23° C. was added sodium cyanoborohydride (1.679 g, 26.71 mmol) and the mixture was stirred at 23° C. for 1.5 h. Poured onto water and extracted twice with ethyl acetate, dried the organic layer over sodium sulfate, filtered off, evaporated all volatiles totally and dried in high vacuum to give the title compound as a colorless oil (1.05 g, 60%), pure enough for further steps; MS (ISP) m/e=329.1 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]([C:18]([NH:20][NH2:21])=[O:19])=[C:5]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[S:29].C(N(CC)CC)C.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]([C:18]1[O:19][C:28](=[S:29])[NH:21][N:20]=1)=[C:5]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=c1[nH]nc(-c2c(N3CCCCC3)nc3ccc(Cl)cc3c2-c2ccccc2)o1
Temperature: 50 °C
Yield: 80.1 %

Procedure:
6-Chloro-4-phenyl-2-piperidin-1-yl-quinoline-3-carboxylic acid hydrazide (prepared as described in example 77 step E) (35 mg, 82.7 μmol, Eq: 1.00) and 1,1′-thiocarbonyldiimidazole (17.7 mg, 99.2 μmol, Eq: 1.2) were dissolved in THF (1.00 ml). Then triethylamine (11.7 mg, 16.1 μl, 116 μmol, Eq: 1.4) was added and the mixture was warmed to 50° C. for 72 h. Water was added and the mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, DCM/EtOAc 97:3) to afford the title compound as yellow solid (28 mg). MS (ESI): 423.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=1[O:43][CH3:44].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:42][O:41][C:38]1[CH:37]=[C:36]([O:43][CH3:44])[CH:35]=[CH:40][C:39]=1[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: COc1ccc(OB([O-])[O-])c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 m), 2,4-dimethoxyphenyl borate (116 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (6/0.6/0.6 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 7 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give colorless crystals of 7-(2,4-dimethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 48) (216 mg).
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]([C:7]2[O:11][C:10]([N:12]([CH3:14])[CH3:13])=[N:9][N:8]=2)=[N:5][N:6]=1.O1CCOCC1.CN(C)C=O.Br[CH2:27][CH2:28][C:29]([F:33])=[C:30]([F:32])[F:31]>O>[F:33][C:29](=[C:30]([F:32])[F:31])[CH2:28][CH2:27][S:1][C:2]1[O:3][C:4]([C:7]2[O:11][C:10]([N:12]([CH3:14])[CH3:13])=[N:9][N:8]=2)=[N:5][N:6]=1
Reactant: CN(C)c1nnc(-c2nnc(S)o2)o1
Reactant: FC(F)=C(F)CCBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: CN(C)c1nnc(-c2nnc(SCCC(F)=C(F)F)o2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.26 g of 2-mercapto-5-(2-dimethylamino-1,3,4-oxadiazol-5-yl)-1,3,4-oxadiazole according to Example H2 are initially introduced into 40 ml of dioxane and stirred with 2.24 g of potassium t-butylate. 4 ml of dimethylformamide and then 4.2 g of 4-bromo-1,1,2-trifluorobut-1-ene are added and the mixture is stirred overnight at room temperature. The mixture is poured into water and the crystals are filtered off with suction. After drying and stirring with ether, 4.6 g of the title compound of melting point 87°-90° C. are obtained.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[CH:3][NH:2]1.[C:11](N1CCNCC1)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>N1C=CC=CC=1>[C:11]([C:3]1[NH:2][O:1][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=1)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: C1=Cc2ccccc2ON1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)C1=Cc2ccccc2ON1
Temperature: 70 °C
Yield: 58.1 %

Procedure:
To a solution of 2.1 g of the benzoxazine (E) (R8 =CH3, R9 =C2H5, R10 =C6H5, X=F), in 30 ml pyridine is added 8 g of N-carbobenzoxypiperazine. The mixture is heated at 70° C. for 18 hours. The solvent is removed by evaporation under reduced pressure. The residue is washed with ether, water and ether. It is dried, yielding 2.45 g of the carbobenzoxy-benzoxazine (F) (R8 =CH3, R9 =C2H5, R10 =C6H5, Z=carbobenzoxy-piperazin-1-yl).