Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:14]([F:17])([F:16])[F:15])([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8]2)[OH:4].[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1>O1CCCC1>[F:16][C:14]([F:17])([F:15])[C:3]([C:2]([F:1])([F:18])[F:19])([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:23](=[O:24])[CH2:22][C:21](=[O:25])[CH3:20])[CH2:9][CH2:8]2)[OH:4]
Reactant: C=C1CC(=O)O1
Reactant: OC(c1ccc2c(c1)CCN2)(C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Temperature: 25 °C
Yield: 100.3 %

Procedure:
To a stirred solution of 343 g (1.25 mole) of α,α-bis(trifluoromethyl)-2,3-dihydro-1H-indole-5-methanol in 1880 ml of dry tetrahydrofuran cooled in an ice bath is added dropwise 106 g (1.26 mole) of diketene. The solution is allowed to warm to room temperature for 16 hours and then is refluxed for 30 minutes. The solvent is evaporated to give 463 g (100%) of crude α,α-bis(trifluoromethyl)-1-(1,3-dioxobutyl)-2,3-dihydro-1H-indole-5-methanol, m.p. 150°-151°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].Cl.Cl[CH2:14][CH2:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17]>ClC1C=CC=CC=1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:19][CH2:18][N:16]([CH3:17])[CH2:15][CH2:14]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: Cl
Solvent: CO
Solvent: Clc1ccccc1
Product: CN1CCN(c2cc([N+](=O)[O-])ccc2F)CC1
Temperature: 25 °C
Yield: 5.8 %

Procedure:
A mixture of 2-fluoro-5-nitrobenzenamine (4.06 g) and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (5.01 g) in chlorobenzene (20 ml) was heated at reflux under nitrogen for 21/2 days before cooling to room temperature- The dark tar-like material was dissolved in methanol (150 ml), the solution then concentrated in vacuo with silica and the product purified twice by FCC eluting with System A (400:8:1) followed by System A (300:8:1) to give the title compound as a crystalline brown solid (360 mg).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20].[CH2:21]([Mg]Br)[CH3:22]>O1CCCC1>[CH2:21]([C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20])[CH3:22]
Reactant: CC[Mg]Br
Reactant: CCCN1CC(C)=C(Cl)C2=C1N1CN(OC)C=C1C=N2
Solvent: C1CCOC1
Product: CCCN1CC(C)=C(CC)C2=C1N1CN(OC)C=C1C=N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7 g of intermediate A1 are suspended in 150 ml tetrahydrofurane. 30 ml of a solution of ethyl magnesium bromide in tetrahydrofurane (3 M) are added. The mixture is stirred for 4 hours at room temperature. After filtration the solvent is removed. The crude product is purified by preparative HPLC.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].O=O>>[N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[CH2:14][CH:13]=[CH:12][CH2:11][C:10]=3[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=O
Product: O=C1C2=C(CC=CC2)C(=O)c2c1cccc2[N+](=O)[O-]

Procedure:
A process for the preparation of 1-nitroanthraquinone by (1) reacting 5-nitro-1,4-naphthoquinone with butadiene, (2) oxidising the 1-nitro-5,8,11,12-tetrahydroanthraquinone so obtained to 1-nitroanthraquinone, and (3) isolating the 1-nitroanthraquinone, which process comprises reacting in step (2) 1-nitro-5,8,11,12-tetrahydroanthraquinone (a) with oxygen, as inorganic peroxide compound or a metal oxide as oxidising agent and isolating 1-nitro-5,8-dihydroanthraquinone, and then (b) oxidising this intermediate to 1-nitroanthraquinone with one of the above oxidising agents.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:10]1([NH:13][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=2)[CH2:12][CH2:11]1
Reactant: COc1cccc(Br)c1
Reactant: NC1CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cccc(NC2CC2)c1
Temperature: 80 °C

Procedure:
To a high-pressure tube was added 3-bromoanisole(0.250 mL, 2 mmol), cyclopropylamine (0.225 mL, 3.2 mmol), sodium t-butoxide (0.29 g, 3.0 mmol), (+/−) BINAP (0.04 g, 0.06 mmol), and Pd2(dba)3 (0.010 g, 0.01 mmol). This mixture was suspended in 4 mL anhydrous toluene. The tube was flushed with dry nitrogen gas, then capped and wrapped in aluminum foil. The reaction mixture was stirred and heated to 80° C. overnight, then allowed to cool, and the reaction vessel was opened. The mixture was diluted with diethyl ether, filtered through Celite, and the filtrate was concentrated to a yellow oil. LC/MS analysis showed one peak with the correct mass, and due to the limited stability of the material, it was carried through without further purification. FIA MS 164 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH:5]([OH:13])[CH2:6][N:7]2[CH3:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][C:16]=1[C:24]([F:27])([F:26])[F:25]>O1CCCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH:5]([OH:13])[CH2:6][N:7]3[CH3:12])=[O:23])=[CH:17][C:16]=1[C:24]([F:25])([F:26])[F:27]
Reactant: CN1CC(O)Cc2c(N)cccc21
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CN1CC(O)Cc2c(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cccc21
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 5-amino-1-methyl-1,2,3,4-tetrahydroquinolin-3-ol and 4-chloro-3-trifluoromethyl-phenyl isocyanate in tetrahydrofuran is stirred at 50° C. for 5 hours. After removing the solvent, the resulting residue is purified by silica gel column chromatography to provide N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(3-hydroxy-1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)urea.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)[CH:29]=[C:30](I)[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[N:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1>>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)[CH:29]=[C:30]([C:43]3[CH:44]=[CH:45][N:40]=[CH:41][CH:42]=3)[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: O=C(O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3cccc(F)c3)c2)c1CCC(=O)O
Reactant: OB(O)c1ccncc1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3ccncc3)cc(-c3cccc(F)c3)c2)c1CCC(=O)O
Yield: 25.9 %

Procedure:
A similar procedure as described in Example 5, step 2 was used, starting from 4-{2-(2-carboxy-ethyl)-3-[6-(3′-fluoro-5-iodo-bi phenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid (116 mg, 0.18 mmol) and pyridin-4-ylboronic acid (66 mg, 0.54 mmol) to obtain 4-{2-(2-carboxy-ethyl)-3-[6-(3′-fluoro-5-pyridin-4-yl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid (28 mg, 26%) as an amorphous white solid: ES(+)-HRMS m/e calculated for C36H38FNO6 (M+H)+ 600.2756, found 600.2754.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](/[C:9](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)/[C:10]([O:12][CH3:13])=[O:11])=[O:8])=[CH:4][CH:3]=1.ClCCCl.[Cl-].[Cl-].[Cl-].[Al+3]>>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:8])[C@@H:9]([C:10]([O:12][CH3:13])=[O:11])[C@H:14]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[C:4]=2[CH:3]=1
Reactant: COC(=O)/C(=C\c1ccc(Cl)cc1)C(=O)c1ccc(Br)s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)[C@@H]1C(=O)c2sc(Br)cc2[C@H]1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 63.4 %

Procedure:
To a 500 mL round bottom flask was added a solution of methyl (2Z)-2-[(5-bromo-2-thienyl)carbonyl]-3-(4-chlorophenyl)acrylate (6.26 g, 16.2 mmol), in 1,2-dichloroethane (210.0 mL, 2665.4 mmol). Aluminum trichloride (2.164 g, 16.23 mmol) was added and the reaction mixture was heated to 80° C. and allowed to stir for 18 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The crude material was dry loaded onto silica gel and then purified using a ISCO (40 g cartridge, gradient hexanes to 30% EtOAc over 30 min) to afford the title compound (3.96 g, 60%) as a brown oil. LC/MS (AA) ES− 385, 387, 389. 1H NMR (dmso-d6, 400 MHz): δ 7.43-7.29 (m, 5H), 4.91 (d, 1H), 4.04 (d, 1H), 3.71 (s, 3H).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:40][CH:41]([CH3:43])[CH3:42])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=4[F:39])[CH2:27][CH2:26]3)[N:21]=2)[CH:16]1[CH3:44])C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[O:31][CH:28]1[CH2:27][CH2:26][N:25]([C:20]2[N:21]=[C:22]3[CH2:23][CH2:24][NH:15][CH:16]([CH3:44])[C:17]3=[N:18][C:19]=2[NH:40][CH:41]([CH3:43])[CH3:42])[CH2:30][CH2:29]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(Cc1ccccc1)C2C
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2C
Reaction time: 3 h

Procedure:
A 50 mL round-bottomed flask containing 6-benzyl-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (175 mg, 0.282 mmol) and Pd(OH)2 (20 wt %, 39.5 mg, 0.056 mmol) in THF (2.82 mL) was purged and placed under hydrogen (balloon) for 3 h. Filtration through Celite™ (washed with EtOAc) and concentration in vacuo gave the title compound as a TFA salt (150 mg) as a brown oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[NH2:14][CH:15]([CH2:18][CH3:19])[CH2:16]O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:18]([CH:15]1[N:14]2[N:4]=[C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]2=[N:3][CH2:16]1)[CH3:19]
Reactant: CCC(N)CO
Reactant: Clc1ccc(-c2cccnc2)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCC1CN=C2C=CC(c3cccnc3)=NN21
Temperature: 130 °C

Procedure:
A mixture of 5 g of 3-chloro-6-(3-pyridinyl)pyridazine and 30 ml of 2-amino-1-butanol is heated at 130° C. for 18 hours. Then the volatiles are removed by bulb to bulb distillation under high vacuum. As for Example 1, the product is reacted with thionyl chloride and the obtained product is ring closed with potassium carbonate in ethanol to give 2,3-dihydro-3-ethyl-6-(3-pyridinyl)imidazo[1,2-b]pyridazine which is dehydrogenated with lead tetraacetate in dichloromethane to give the desired product 3-ethyl-6-(3-pyridinyl)imidazo[1,2-b]pyridazine.
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[O:5][C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23].C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33].O>C1COCC1>[CH3:13][O:12][N:9]1[CH2:10][CH2:11][C:6]2([O:5][C:4](=[O:14])[C:3]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])=[C:2]2[O:1][C:32](=[O:33])[O:34][CH2:35][CH3:36])[CH2:7][CH2:8]1
Reactant: CON1CCC2(CC1)OC(=O)C(c1c(C)cc(C)cc1C)=C2O
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)OC12CCN(OC)CC2
Reaction time: 0.5 h

Procedure:
To a solution of crude (ca 50% purity) 4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1-oxa-8-aza-spiro[4.5]dec-3-en-2-one (1.0 g, 3.15 mmol), triethylamine (0.8 ml, 0.57 g, 5.67 mmol) in 6 ml THF at 0° C. under argon was added ethyl chloroformate (0.36 ml, 0.41 g, 3.78 mmol) dropwise. The suspension became immediately quite thick. It was diluted with additional 2 ml THF while stirring was continued at 0° C. for 30 minutes. The reaction mixture was poured into cold water (0° C.) and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The crude product (brown oil) was purified by column chromatography on silica gel (ethyl acetate/cyclohexane 1:1). Yield: 220 mg of carbonic acid ethyl ester 8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1-oxa-8-aza-spiro[4.5]dec-3-en-4-yl ester (title compound P1.5) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:35][CH2:36]O)[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([O:26]CC5C=CC=CC=5)[CH:14]=[CH:15][C:16]=4[O:18]CC4C=CC=CC=4)[C:11](=[O:34])[C:10]=1[C:9]=23.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:49]1[CH:54]=[CH:53]C=[CH:51][CH:50]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:35][CH2:36][N:49]([CH2:54][CH3:53])[CH2:50][CH3:51])[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([OH:26])[CH:14]=[CH:15][C:16]=4[OH:18])[C:11](=[O:34])[C:10]=1[C:9]=23
Reactant: O=C1c2c(OCc3ccccc3)ccc(OCc3ccccc3)c2-c2nn(CCO)c3ccc(Cl)c1c23
Reactant: c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCN(CC)CCn1nc2c3c(c(Cl)ccc31)C(=O)c1c(O)ccc(O)c1-2
Temperature: 0 °C
Reaction time: 50 h

Procedure:
An ice-cold mixture of 22 g (43 mmol) of 5-chloro-2-(2-hydroxyethyl)-7,10-bis(phenylmethoxy)anthra[1,9-cd]pyrazol-6(2H)-one, 12.3 g (65 mmol) of p-toluenesulfonyl chloride and 170 ml of pyridine is stirred for 50 hours. The solid is filtered, washed with methanol and diethyl ether, and dried to give 10.5 g of the product; mp 203°-206° C. (decomposition). Processing of the filtrate gives 9.3 g of additional product; mp 182°-188° C. (decomposition).
Reaction SMILES: [CH:1]1([C:4]2[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:17])([CH3:16])[C:8]=3[CH:7]=[C:6]([C:18]#[CH:19])[CH:5]=2)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=1[F:30].C(N(CC)CC)C.O1CCCC1>CCCCCC.[Cu]I.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(OCC)(=O)C>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([C:19]#[C:18][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:16])([CH3:17])[C:8]=3[CH:7]=2)=[CH:25][C:24]=1[F:30]
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC1(CC1)O2
Reactant: COC(=O)c1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1F

Procedure:
Following general procedure F and using 8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 44, 0.03 g, 0.11 mmol), methyl-2-fluoro-4-iodo-benzoate (Reagent G, 0.025 g, 0.09 mmol), triethyl amine (3 mL), tetrahydrofuran(3 mL), copper(I)iodide(0.020 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.06 g, 0.085 mmol) followed by preparative normal phase HPLC using 10% ethyl acetate in hexane as the mobile phase, the title compound was obtained as a white solid (0.019 g, 40%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][C:19](=[O:21])[N:18]([CH3:22])[C:17]([NH:23]C(=O)OC(C)(C)C)=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:31])[N:11]=[C:10]([F:32])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:33][C:34]1[C:39](B(O)O)=[CH:38][CH:37]=[CH:36][N:35]=1>>[NH2:23][C:17]1[N:18]([CH3:22])[C:19](=[O:21])[CH2:20][C@:15]2([C:14]3[CH:13]=[C:12]([Cl:31])[N:11]=[C:10]([F:32])[C:9]=3[O:8][C:5]3[C:4]2=[CH:3][C:2]([C:39]2[C:34]([F:33])=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:7][CH:6]=3)[N:16]=1
Reactant: CN1C(=O)C[C@]2(N=C1NC(=O)OC(C)(C)C)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: OB(O)c1cccnc1F
Product: CN1C(=O)C[C@]2(N=C1N)c1cc(-c3cccnc3F)ccc1Oc1c2cc(Cl)nc1F

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Example 12 above, but using (S)-tert-butyl 7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate (Example 1-B) and 2-fluoropyridin-3-ylboronic acid.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:6]([CH3:12])[C:7]([Br:11])=[C:8]([Br:10])[CH:9]=1)=[O:4].[C:15](=O)([O-])[O-:16].[K+].[K+]>CO>[CH3:15][O:16][C:3]([C:5]1[N:6]([CH3:12])[C:7]([Br:11])=[C:8]([Br:10])[CH:9]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(C(=O)C(Cl)(Cl)Cl)cc(Br)c1Br
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(Br)n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
2,2,2-trichloro-1-(4,5-dibromo-1-methyl-1H-pyrrol-2-yl)-ethanone 14 (1.00 g, 2.60 mmol), anhydrous potassium carbonate (0.719 g, 5.20 mmol), and anhydrous methanol (20 mL) were charged into a reaction flask. The resulting suspension was stirred for 16 h at room temperature upon which the reaction was quenched with water (10 mL). The methanol was removed under reduced pressure and the residue partitioned between ethyl acetate (100 mL) and water (20 mL). The organic layer was subsequently washed with sat. NaHCO3 (2×30 mL), brine (2×20 mL), dried over anhydrous sodium sulfate, and filtered. Evaporation of the filtrate yielded the title compound (0.710 g, 92%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.05 (s, 1H), 3.90 (s, 3H), 3.76 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 159.38, 123.62, 118.51, 113.93, 98.06, 51.58, 35.78; HRMS (FAB) calcd for C7H7Br2NO2 (M+) 294.8844. found 294.8861.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:10][CH:9]=[C:8]([CH2:20][O:21]C(=O)C)[N:7]=1)=[O:5])[CH3:2].CC[O-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[CH:10][CH:9]=[C:8]([CH2:20][OH:21])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(COC(C)=O)ccc1NC(=O)OC(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc(CO)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of 0.99 g (2.92 mmol) of 6-Acetoxymethyl-3-tert-butoxycarbonylamino-pyridine-2-carboxylic acid ethyl ester in 15 ml of absolute ethanol was added 0.11 ml (0.3 mmol, 0.1 equiv.) of sodium ethylate 3N /Ethanol. After stirring for 1 h at room temperature, the mixture was extracted with methylene chloride/water. The aqueous phase was extracted three times with methylene chloride. The combined organic phases were dried over magnesium sulfate and concentrated to yield 0.81 g (2.7 mmol, 93%) of the title compound as an off-white solid, MS (ISP): m/e=297.3 (M+H+).
Reaction SMILES: [O:1]=[C:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[N:9]=[CH:8]1.[B-].[Na+]>C(O)C>[OH:1][CH:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[N:9]=[CH:8]1
Reactant: CC(=O)CCCCn1cnc2c1c(=O)n(C)c(=O)n2C
Agent: [B-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CCCCn1cnc2c1c(=O)n(C)c(=O)n2C

Procedure:
15 g of 7-(5-oxohexyl)-1,3-dimethylxanthine are dissolved in 100 ml of ethanol and mixed portionwise at room temperature with 3.8 g of sodium borohydrate (110% of theory) in solid form or in alcoholic suspension. At the end of addition stirring takes place for 30 minutes. Subsequently heating takes place to boiling temperature. At this time the reaction is completed. The course of the reaction is followed by thin layer chromatography. The solvent is evaporated on a rotary evaporator. The residue is boiled e.g. with 50 ml isopropanol or ethyl acetate. The insoluble substance is filtered off and discarded. The extract is crystallised by evaporation. 7-(5-hydroxyhexyl)-1,3-dimethylxanthine of m.p. 93° to 94° C. in a yield of 86% by weight is obtained. The substance after chromatography with silica gel F254 (Merck sheets) as the absorbent and with a mixture of benzene and acetone in a volume ratio of 60:40 as the eluting agent has a Rf -value of 0.15.
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14](C)=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1.[NH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH:29][CH3:30])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>>[NH2:16][C:11]1[NH:12][N:13]=[CH:14][C:10]=1[C:8]1[S:9][C:5]2[CH:4]=[C:3]([CH2:2][NH:19][C:20]3[CH:21]=[C:22]([S:26]([NH:29][CH3:30])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=3)[CH:18]=[CH:17][C:6]=2[N:7]=1
Reactant: CNS(=O)(=O)c1cccc(N)c1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Product: CNS(=O)(=O)c1cccc(NCc2ccc3nc(-c4cn[nH]c4N)sc3c2)c1

Procedure:
The title compound (9 mg) was prepared starting from 40 mg of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine and excess 3-amino-N-methylbenzenesulfonamide. MS (m/z, ES+): 429.2 (M+1, 100%).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]2[O:11][CH2:12][O:13][C:8]2=[CH:7][C:6]=1[C:14](=[O:17])[CH2:15][Cl:16])(=O)C>C(O)C>[NH2:4][C:5]1[CH:10]=[C:9]2[O:11][CH2:12][O:13][C:8]2=[CH:7][C:6]=1[C:14](=[O:17])[CH2:15][Cl:16]
Reactant: CC(=O)Nc1cc2c(cc1C(=O)CCl)OCO2
Solvent: CCO
Product: Nc1cc2c(cc1C(=O)CCl)OCO2
Yield: 51.7 %

Procedure:
To 2'-acetylamino-4',5'-methylenedioxy-2-chloroacetophenone (0.9 g, 3.53 mmol) or an equivalent amount of 2'-pivoylamino-4',5'-methylenedioxy-2-chloroacetophenone in ethanol (60 mL) at about 5° C. is added, dropwise, conc. HCI (12.5 mL, 149.7 mmol). The reaction mixture is then heated at reflux for about an hour, then poured over 2 N NaOH/ice (80 mL/60 g) and washed with ethyl acetate (3 ×70 mL). The organic portions are combined and washed with brine (50 mL), dried (anhydrous sodium sulfate) and concentrated in vacuo to yield a greenish-yellow solid. This solid is recrystallized from ethyl acetate/isopropanol/hexane, treated with activated charcoal, to yield 2'-amino-4',5'-methylenedioxy-2-chloroacetophenone (0.39 g, 52% of theory).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH3:46])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH3:46])[CH:42]=[CH:43][N:44]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-ethylimidazol-2-yl)methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (150 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (55.3 mg) in dichloromethane (10 ml) at −78° C. After finishing the dropping, an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-ethylimidazol-2-yl)methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (82 mg) (Compound 333) as yellow crystals.