Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)CNC(=O)[C@H](NS(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)CC2C=CC=CC=2)C=CC=CC=1.C(N1C=C(CCO)N=C1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:85]([C:94]([O:96][C:97]([CH3:100])([CH3:99])[CH3:98])=[O:95])=[N:86][C:87]([O:89][C:90]([CH3:93])([CH3:92])[CH3:91])=[O:88]>C(Cl)Cl>[NH:85]([C:94]([O:96][C:97]([CH3:100])([CH3:99])[CH3:98])=[O:95])[NH:86][C:87]([O:89][C:90]([CH3:91])([CH3:92])[CH3:93])=[O:88]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: O=C(NCC(c1ccccc1)c1ccccc1)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C

Procedure:
To a stirred solution of the product of step 2 (3.40 g, 6.42 mmol) and 2-(1-trityl-1H-imidazol-4-yl)-ethanol (2.73 g, 7.70 mmol) in methylene chloride (40 mL) was added triphenylphosphine (2.19 g, 8.35 mmol) followed by di-tert-butyl azodicarboxylate (1.77 g, 7.69 mmol). After 3 hours the reaction was concentrated and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and concentrated to yield an amber gum. Flash chromatography over silica (methylene chloride/methanol) afforded 5.42 g (97%) of partially purified product (contaminated with di-tert-butyl hydrazodiformate) as a pale yellow foam: 1H NMR (CDCl3) δ 7.81-7.74 (m, 1H), 7.64-7.55 (m, 1H), 7.53-7.44 (m, 2H), 7.41-7.03 (m, 31H), 6.69 (t, J=5.6, 1H), 6.53 (s, 1H), 4.48 (t, J=8.1, 1H), 4.08 (t, J=8.1, 1H), 3.84-3.58 (m, 4H), 3.44-3.34 (m, 1H), 2.91-3.80 (m, 1H), 2.78-2.68 (m, 1H), 2.63-2.51 (m, 1H) ppm.
Reaction SMILES: [CH2:1]([C:8]1[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([Br:17])[C:11]=2[O:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN([CH:29]=[O:30])C>>[CH2:1]([C:8]1[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([Br:17])[C:11]=2[O:10][C:9]=1[CH:29]=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)c2occ(Cc3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Br)c2oc(C=O)c(Cc3ccccc3)c2c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
3-Benzyl-7-bromo-5-methyl-benzofuran (3.93 g, 13.05 mmol) was mixed with 10 ml DMF. Phosphorus oxychloride (1.8 ml, 19.3 mmol) was added and the reaction mixture was heated to 50° C. for 16 hours. Additional phosphorus oxychloride (3.6 ml, 38.6 mmol) was added and the reaction mixture was heated to 90° C. for an hour, then to 100° C. for five hours. The mixture was cooled to room temperature, poured onto ice and aqueous sodium hydroxide was added until the mixture reached pH=3. The mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered, and absorbed onto 20 gm silica gel. The silica gel was layered over 100 gm silica gel in a fritted funnel and eluted with five portions of 400 ml hexanes (to give 0.33 g recovered starting material) and two portions of 400 ml of 10/90 ethyl acetate/hexane to give 3-benzyl-7-bromo-5-methyl-benzofuran-2-carbaldehyde (2.61 g, 61% yield). MS: (M+H)+ 330.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([C:11]([OH:13])=O)[C:4]=1[C:14]([OH:16])=[O:15].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]2[C:14]([O:16][C:11](=[O:13])[C:5]=12)=[O:15]
Reactant: COc1ccc(OC)c(C(=O)O)c1C(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(OC)c2c1C(=O)OC2=O
Temperature: 12 °C
Reaction time: 1.5 h

Procedure:
3,6-Dimethoxybenzene-1,2-dicarboxylic acid (20 g) was dissolved in pyridine (100 ml) at room temperature. The solution was then cooled in a cold water bath and acetic anhydride (27 g, 25 ml) added dropwise over 10 minutes (temperature rose from 23° to 25° C.) The reaction mixture was then stirred for 90 minutes at 12° C., filtered, washed with ether (100 ml) and pulled dry to give a pale cream solid. Dried at 50° C. in a vacuum oven, m.p. 268°-269° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[C:8]1([C:14]2([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:28]([N:36]1[CH2:41][CH2:40][O:39][C:38]([C:54]2[CH:59]=[CH:58][C:57]([F:60])=[C:56]([F:61])[CH:55]=2)([CH2:42][CH2:43]OS(C2C=CC=CC=2)(=O)=O)[CH2:37]1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O.C(#N)C>[C:28]([N:36]1[CH2:41][CH2:40][O:39][C:38]([CH2:42][CH2:43][N:17]2[CH2:18][CH2:19][C:14]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:15][CH2:16]2)([C:54]2[CH:59]=[CH:58][C:57]([F:60])=[C:56]([F:61])[CH:55]=2)[CH2:37]1)(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(c1ccccc1)N1CCOC(CCOS(=O)(=O)c2ccccc2)(c2ccc(F)c(F)c2)C1
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccccc2)CCN(CCC2(c3ccc(F)c(F)c3)CN(C(=O)c3ccccc3)CCO2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of 18 g of potassium carbonate in 18 ml of water is added to a mixture of 22.6 g of tert-butyl (4-phenylpiperid-4-yl)carbamate hydrochloride (compound (IV)) and 30 g of compound of formula (III) obtained in Example 1 in 300 ml of acetonitrile, and the mixture is then heated at 70° C. for 12 hours and left overnight at room temperature. The acetonitrile is concentrated under vacuum, the residue is taken up in 300 ml of dichloromethane, the organic phase is washed successively with 150 ml of a 0.3 M solution of sodium hydroxide in water, with 150 ml of water, twice with 150 ml of pH 2 sulfate buffer, with 150 ml of water and with 150 ml of a 10% by weight solution of potassium carbonate in water, dried over magnesium sulfate and filtered, and the solvent is evaporated off under vacuum at room temperature. The expected product is obtained, which is used in Example 3.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:5]=[C:6]([CH:12]2[CH2:14][O:13]2)[CH:7]=[C:8]([F:11])[C:9]=1[F:10]>ClCCl>[CH3:1][NH:2][CH2:14][CH:12]([C:6]1[CH:5]=[C:4]([F:3])[C:9]([F:10])=[C:8]([F:11])[CH:7]=1)[OH:13]
Reactant: CN
Reactant: Fc1cc(C2CO2)cc(F)c1F
Solvent: ClCCl
Product: CNCC(O)c1cc(F)c(F)c(F)c1
Reaction time: 24 h
Yield: 69.6 %

Procedure:
To a solution of methylamine (20 mL, 2.0 M in methanol, 40 mmol) was added 2-(3,4,5-trifluorophenyl)oxirane (0.17 g, 0.98 mmol) at room temperature. The reaction mixture was stirred at that temperature for 24 hours. Solvent and excessive methylamine were evaporated, leaving a solid. The solid was dissolved in dichloromethane (5 mL). To the resulting clear solution was added hexanes (15 mL), standing overnight. The solid precipitant was collected by filtration to yield the title compound (0.14 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][NH:4][C:5]([N:7]1[CH2:11][CH:10]([CH2:12][CH3:13])[CH:9]=[N:8]1)=[S:6].I[CH3:17]>CO>[CH3:17][S:6][C:5]([N:7]1[CH2:11][CH:10]([CH2:12][CH3:13])[CH:9]=[N:8]1)=[N:4][CH2:3][C:2]([F:1])([F:14])[F:15]
Reactant: CCC1C=NN(C(=S)NCC(F)(F)F)C1
Reactant: CI
Solvent: CO
Product: CCC1C=NN(C(=NCC(F)(F)F)SC)C1
Temperature: 50 °C
Yield: 0.2 %

Procedure:
2.80 g (1 mol equiv.) 4-Ethyl-4,5-dihydro-pyrazole-1-carbothioic acid (2,2,2-trifluoro-ethyl)-amide was dissolved in 56 mL methanol; 7.3 mL (10 mol equiv.) iodomethane was added and the reaction mixture was heated at 50° C. for 4 hours. Volatiles were removed under reduced pressure, and the residue was taken up in DCM and extracted with 5% aqueous NaHCO3. The organic layer was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O:PA=1:1) afforded 0.57 g (19%) 4-ethyl-N-(2,2,2-trifluoro-ethyl)-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 0.99 (t, J=7.5 Hz, 3H), 1.46-1.70 (m, 2H), 2.48 (s, 3H), 3.01-3.11 (m, 1H), 3.50 (dd, J=11.5, 7.8 Hz, 1H), 3.90 (t, J=11.5 Hz, 1H), 3.99-4.11 (m, 2H), 6.85 (d, J=1.5 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH:12]=[C:13]([CH3:15])[CH3:14])C.[OH-].[Na+]>CO>[CH3:11][C:7]1[C:6]([CH:12]=[C:13]([CH3:15])[CH3:14])=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:16])=[O:3]
Reactant: CCOC(=O)c1cccc(C)c1C=C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=Cc1c(C)cccc1C(=O)O
Yield: 75 %

Procedure:
A solution of the 3-methyl-2-(2-methyl-1-propenyl)benzoic acid ethyl ester (290) (3 g-0.014 mol) in MeOH (50 mL) is treated with 2N NaOH (10 mL) and refluxed for 6 h. The solvent is removed in vacuo and the residue diluted with water (75 mL). The aqueous phase is extracted with EtOAc (30 mL) and then separated and acidified to pH 2-3 with concentrated HCl. The solid precipitated is extracted into EtOAc (3×50 mL). The extracts are washed with water (2×30 mL) and brine (2×30 mL), and dried over MgSO4 and concentrated in vacuo to give the product as white solid (2.0 g, 75%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[C:2]=[O:3].[CH3:16][N:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:26])[C:20]=2[CH:19]=[N:18]1.N1C2C=CC=C(N)C=2C=N1>>[CH3:16][N:17]1[C:25]2[C:20](=[C:21]([NH:26][C:2]([NH:1][CH2:4][C:5]3[CH:10]=[CH:9][C:8]([N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:7][CH:6]=3)=[O:3])[CH:22]=[CH:23][CH:24]=2)[CH:19]=[N:18]1
Reactant: O=C=NCc1ccc(N2CCCC2)cc1
Reactant: Cn1ncc2c(N)cccc21
Agent: Nc1cccc2[nH]ncc12
Product: Cn1ncc2c(NC(=O)NCc3ccc(N4CCCC4)cc3)cccc21

Procedure:
The title compound was prepared using the procedure described in Example 89B using 1-[4-(isocyanatomethyl)phenyl]pyrrolidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) δ 8.98 (s, 1H), 8.16 (s, 1H), 7.63 (d, 1H), 7.13 (m, 3H), 7.12 (d, 1H), 6.94 (m, 1H), 6.73 (bs, 2H), 4.23 (s, 2H), 3.99 (s, 3H), 3.24 (m, 4H), 1.98 (m, 4H); MS (ESI) (M+H)+350.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([Cl:26])[CH:18]=1)([OH:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>COCCOCCO.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:26][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1)[C:14]([OH:16])=[O:15]
Reactant: COc1ccc2nc(Cl)ccc2c1
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOCCO
Product: COc1ccc2nc(-c3ccc(C(=O)O)cc3Cl)ccc2c1
Temperature: 110 °C
Yield: 46 %

Procedure:
A mixture of 2-chloro-6-methoxyquinoline (Intermediate 1) (200 mg, 1.04 mmol), 4-carboxy-2-chlorophenylboronic acid (247 mg, 1.24 mmol) and K2CO3 (369 mg, 2.70 mmol) in DEGME/H2O (7.0 mL/2.0 mL) was degassed three times under N2 atmosphere. Then PdCl2(dppf) (75 mg, 0.104 mmol) was added and the mixture was heated to 110° C. for 3 hours under N2 atmosphere. The reaction mixture was diluted with EtOAc (100 mL) and filtered. The filtrate was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give 3-chloro-4-(6-methoxyquinolin-2-yl)benzoic acid (150 mg, yield 46%) as a yellow solid, which was used for the next step without further purification.
Reaction SMILES: CC(C)([O-])C.[Na+].O1CCCC1.Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])[CH2:20][CH3:21]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC([B-](C2C=CC(C)=CC=2)(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.O>[C:23]1([C:19](=[O:22])[CH:20]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCC(=O)c1ccccc1
Reactant: Clc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)c1ccccc1)c1ccccc1
Yield: 77 %

Procedure:
A 30-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.022 g (0.1 mmol) of palladium (II) acetate, 0.721 g (7.5 mmol) of sodium-tert-butoxide and 5 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.058 g (0.1 mmol) of tri-tert-butylphosphonium tetra-para-tolylborate obtained in Example B-3 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 22° C. for 30 minutes. 0.563 g (5 mmol) of chlorobenzene was added, followed by stirring at 22° C. for 30 minutes. 0.738 g (5.5 mmol) of propiophenone was added, followed by stirring at 70° C. for 6 hours. After the completion of the reaction, 2.5 ml of water was added, followed by separation. The organic phase was purified by column chromatography to afford 0.810 g of 1,2-diphenyl-1-propanone (yield: 77 mol % based on chlorobenzene). The identification of the product was made by mass spectroscopy, 1H-NMR and 13C-NMR.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[O:6][C@H:5]2[C@H:7]([NH:11][C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C@H:9]([OH:10])[C@H:4]2[O:3]1.[H-].[Na+].CC1C=CC(S(O[CH2:45][CH2:46][O:47][C:48]([CH3:51])([CH3:50])[CH3:49])(=O)=O)=CC=1>CN(C=O)C>[C:48]([O:47][CH2:46][CH2:45][O:10][C@@H:9]1[C@H:4]2[O:3][C:2]([CH3:31])([CH3:1])[O:6][C@H:5]2[C@H:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)([CH3:51])([CH3:50])[CH3:49]
Reactant: Cc1ccc(S(=O)(=O)OCCOC(C)(C)C)cc1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)C[C@H]2NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OCCO[C@H]1C[C@@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (3aR,4S,6R,6aS)-2,2-dimethyl-6-(tritylamino)tetrahydro-3aH-cyclopenta[d]-[1,3]dioxol-4-ol (10.0 g, 24.0 mmol) in dry DMF (100 mL) under nitrogen atmosphere was cooled at 0° C. followed by addition of NaH (60%, 1.2 g, 29.0 mmol). After stirring for 30 min at 0° C., 2-(tert-butoxy)ethyl 4-methylbenzenesulfonate (6.5 g, 24.0 mmol) was added and the reaction mixture was allowed to warm at room temperature. After stirring for 4 hours, the reaction mixture was quenched with water (100 mL). To the mixture was extracted 3×100 mL of EtOAc. The combined organic phases were dried over MgSO4, filtered and evaporated to the dryness. The pure IIIf was isolated from reaction mixture by chromatography on silica gel column (mobile phase: n-hexane/EtOAc).
Reaction SMILES: CN(C)CCO.C([Li])CCC.[N:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=1.[Br:20]C(Br)(Br)Br.BrC1C(C)=C(C)C=CN=1>CCCCCC.C1COCC1.O>[Br:20][C:17]1[CH:16]=[C:15]([CH3:18])[C:14]([CH3:19])=[CH:13][N:12]=1
Reactant: Cc1ccncc1C
Reactant: BrC(Br)(Br)Br
Agent: CN(C)CCO
Agent: Cc1ccnc(Br)c1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(Br)cc1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
71.3 g (0.8 mol) 2-(dimethylamino)-ethanol are initially introduced into 500 ml n-hexane and the mixture is cooled to 0° C. 1.0 liter (1.6 mol) n-butyllithium solution (1.6 M in n-hexane) is slowly added and the mixture is stirred at 0° C. for 15 min. A solution of 17.9 g (166.7 mmol) 3,4-lutidine in 500 ml n-hexane is then added dropwise and the mixture is stirred at 0° C. for 1 h. It is subsequently cooled to −78° C. and a solution of 331.7 g (1.0 mol) tetrabromomethane in 1.0 liter THF is added. The reaction mixture is subsequently stirred at −78° C. for 1 h and is thereafter allowed to warm to RT. It is cooled again to 0° C. and 1.5 liters water are slowly added dropwise. The phases are separated and the organic phase is washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue is first pre-purified over approx. 1 kg silica gel (mobile phase: cyclohexane/ethyl acetate 9:1, then 7:3). The product-containing fractions are combined and concentrated in vacuo. The residue is then purified again over silica gel (mobile phase: cyclohexane/ethyl acetate 9:1). The product obtained in this way contains approx. 10% of the regioisomeric 2-bromo-3,4-dimethylpyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]1=[O:15].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:14][CH2:13][C@@H:11]1[O:10][C:9](=[O:15])[N:8]([CH2:7][CH2:6][O:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=2[O:2][CH3:1])[CH2:12]1)(=[O:30])=[O:29]
Reactant: COc1ccccc1OCCN1C[C@H](CO)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1OCCN1C[C@H](COS(C)(=O)=O)OC1=O

Procedure:
Using dichloromethane solution of the compound of formula 2 prepared in Example 2 80.1 g (0.3 mol), triethylamine 45.5 g (0.45 mol) and methanesulfonyl chloride 37.8 g (0.33 mol), the procedures as described in Example 7 were carried out to obtain the targeted product.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[F:20][C:21]1[C:27]([F:28])=[C:26]([F:29])[CH:25]=[CH:24][C:22]=1[NH2:23].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C1(C)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)(C)(C)C>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:8]2[CH2:9][CH2:10][C:4]3[CH:3]=[C:2]([NH:23][C:22]4[CH:24]=[CH:25][C:26]([F:29])=[C:27]([F:28])[C:21]=4[F:20])[CH:19]=[CH:18][C:5]=3[C:6](=[O:17])[C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)C(=O)c1ccc(Cl)cc1CC2
Reactant: Nc1ccc(F)c(F)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(=O)c1ccc(Nc3ccc(F)c(F)c3F)cc1CC2
Yield: 72 %

Procedure:
In accordance with general method AA, 0.50 g (1.8 mmol) of 2-chloro-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one (34), 0.27 g (1.8 mmol) of 2,3,4-trifluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)2, 0.10 g (0.21 mmol) of 2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.60 g (6.2 mmol) of Na—O-tert-butylate, 5 ml of toluene and 1 ml of tert-BuOH are used. Reaction time: 1 h. Purification is carried out via flash chromatography (SiO2, hexane/ethyl acetate 8+2). Yield: 72%; melting point: 128° C.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.O1CCCC1.[OH-].[Li+].O>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([OH:35])=[O:3])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)O)n3)cc2CC1
Reaction time: 48 h

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester (1.168 g, 2.355 mmol) was dissolved in tetrahydrofuran (117 mL, 1440 mmol). Lithium hydroxide (67.7 mg, 2.82 mmol) dissolved in water (23.4 mL, 1.30 mol) was added and the reaction was stirred for 48 hours. The reaction was concentrated under reduced pressure and azetroped twice with toluene. The reaction was then further dried under high vacuum to obtain 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid. 2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid (1.55 g, 3.31 mmol) was placed in toluene (40.0 mL, 376 mmol) and methanol (10.0 mL, 247 mmol). 2.00 M of Trimethylsilyldiazomethane in hexane (4.50 mL) was added and the reaction was stirred overnight. The reaction was quenched with acetic acid and then concentrated under reduced pressure. The residue was taken up in DCM (50 mL) and washed with sat. NaHCO3 (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by amine capped silica gel chromatography using a gradient of 0-60% EtOAc/hex as the eluting solvent to obtain 2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid methyl ester as a pale yellow solid (344 mg, 21%). m.p.=152-156° C.; LCMS (m/e) 482 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.13 (s, 1H), 8.86 (d, 1H, J=8.6 Hz), 8.14 (s, 1H), 8.09 (d, 1H, J=8.0 Hz), 7.55-7.46 (m, 1H), 7.35 (s, 1H), 7.30-7.22 (m, 1H), 7.14-7.02 (m, 2H), 6.92 (s, 1H), 3.99 (s, 3H), 3.56 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.98-2.89 (m, 4H), 2.80-2.71 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[C:29]([CH3:30])=[CH:28][C:22]([CH:23]=[CH:24][C:25](O)=O)=[C:21]([CH3:31])[CH:20]=1>>[CH3:17][O:18][C:19]1[C:29]([CH3:30])=[CH:28][C:22](/[CH:23]=[CH:24]/[C:25]2[NH:1][C:2]3[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)=[C:21]([CH3:31])[CH:20]=1
Reactant: COc1cc(C)c(C=CC(=O)O)cc1C
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cc(C)c(OC)cc3C)nc2n(CCC)c1=O
Yield: 45 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.5 g (11.1 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.51 g (12.17 mmol) of 4-methoxy-2,5-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from ethanol/water to give 1.98 g (yield 45%) of Compound 44 as white crystals.
Reaction SMILES: [C:1]([C:3]([S:6]([CH2:9][C:10]([NH:22]S(C(C)(C)C)=O)([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[F:21])[CH3:11])(=[O:8])=[O:7])([CH3:5])[CH3:4])#[N:2].Cl>CO.[Cu]Cl>[NH2:2][C:1]1[C:3]([CH3:5])([CH3:4])[S:6](=[O:8])(=[O:7])[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[F:21])([CH3:11])[N:22]=1
Reactant: CC(CS(=O)(=O)C(C)(C)C#N)(NS(=O)C(C)(C)C)c1cc([N+](=O)[O-])ccc1F
Agent: Cl[Cu]
Agent: Cl
Solvent: CO
Product: CC1(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C(C)(C)C(N)=N1
Yield: 98.7 %

Procedure:
A suspension of N-(1-((2-cyanopropan-2-yl)sulfonyl)-2-(2-fluoro-5-nitrophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide (560 mg, 1.292 mmol) in MeOH (10 ml) was treated with hydrogen chloride (4M in 1,4-dioxane) (3.23 ml, 12.92 mmol) for 1 h at RT. The mixture was concentrated in the stream of nitrogen, redissolved in 10 ml EtOH and copper (I) chloride (134 mg, 1.356 mmol) was added. The mixture was sonicated for 5 min, and heated at reflux for 2 h. After concentrating in vacuo, the residue was partitioned between 10 ml DCM and 10 ml 2N NaOH solution. The organic layer was separated, washed with brine and concentrated to afford crude 5-amino-3-(2-fluoro-5-nitrophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide (420 mg, 1.275 mmol, 99% yield), which was used without further purification.