Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[OH:12][C:13]1[N:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:20]2=[O:26])=[CH:15][CH:14]=1.N12CCN(CC1)CC2>O1CCCC1>[O:26]=[C:20]1[CH2:21][CH2:22][CH2:23][C:24](=[O:25])[N:19]1[C:16]1[CH:17]=[N:18][C:13]([O:12][C:3](=[O:4])[N:2]([CH3:1])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:14][CH:15]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C1CCCC(=O)N1c1ccc(O)nc1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: CN(C(=O)Oc1ccc(N2C(=O)CCCC2=O)cn1)c1ccccc1
Yield: 76.6 %

Procedure:
A solution of N-methyl-N-phenyl carbamoyl chloride (170 mg, 1.00 mmol), 6′-hydroxy-4,5-dihydro-3H-[1,3]bipyridinyl-2,6-dione (206 mg, 1.00 mmol) and 1,4-diazabicyclo[2,2,2]octane (112 mg, 1.00 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, first ethyl acetate:heptane 75:25 followed by pure ethyl acetate). Evaporation of the solvent yielded the title compound (260 mg, 77% yield) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[CH3:28][NH:29][CH3:30].C(C1C=CC(S(N)(=O)=O)=CC=1)(=O)C>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:29]([CH3:30])[CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: CC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: [Na+]
Product: CC(=O)c1ccc(S(=O)(=O)N(C)C)cc1

Procedure:
From the damp 4-acetylbenzenesulfonyl chloride from 200 g. of sodium 4-acetylbenzenesulfonate, and 1 l. of 20% aqueous dimethylamine, following the procedure of (c) above, there is obtained 4-acetyl-N,N-dimethylbenzenesulfonamide; m.p. 97°-99° C. after crystallization from aqueous ethanol.
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7](=[O:35])[N:8]([C:32](=[O:34])[CH3:33])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:24]=[N:23][C:22]3[C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:20][C:19](Cl)=[N:18][C:17]=3[CH:16]=2)[CH:10]=1)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:44]2[CH:45]=[N:46][C:47]([NH2:50])=[N:48][CH:49]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(Cl)(Cl)Cl.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.O>[C:1]([O:4][CH2:5][O:6][C:7](=[O:35])[N:8]([C:32](=[O:34])[CH3:33])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:24]=[N:23][C:22]3[C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:20][C:19]([C:44]4[CH:45]=[N:46][C:47]([NH2:50])=[N:48][CH:49]=4)=[N:18][C:17]=3[CH:16]=2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCOC(=O)N(C(C)=O)c1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(=O)OCOC(=O)N(C(C)=O)c1cccc(-c2cnc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3c2)c1
Temperature: 82 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a 50 mL sealed tube, ((acetyl(3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)phenyl)carbamoyl)oxy)methyl acetate (0.96 g, 0.0019 mol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.852 g, 0.0038 mol), potassium phosphate tribasic (0.81 g, 0.0038 mol), 1,4-dioxane (45 mL), and water (4 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)4 (0.11 g, 0.000096 mol) was added and the mixture was degassed with N2 for 5-10 min. The reaction mixture was stirred at 82° C. for 30 minutes. The volatiles were evaporated to provide a residue. The residue was dissolved in chloroform. The chloroform layer was washed with water, brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to provide a crude solid. The crude solid was purified by flash column chromatography (0-2% methanol in chloroform) to provide a solid. The solid was washed with methanol to provide the title compound as a light yellow solid (0.4 g, 40%). 1H NMR (400 MHz, DMSO-d6): δ 9.18 (s, 2H), 9.08 (s, 1H), 8.35 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.91 (br s, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.35 (d, J=7.6 Hz, 1H), 7.20 (br s, 2H), 5.68 (s, 2H), 4.52 (br s, 4H), 3.84 (t, J=4.0 Hz, 4H), 2.57 (s, 3H), 2.06 (s, 3H). LC-MS (ESI): Calculated mass: 558.20; Observed mass [M+H]+: 558.8 (RT: 0.40 min).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][CH:11]=1.[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15].[Cl-].[NH4+]>O1CCCC1>[CH3:6][C:7]1[N:8]=[C:9]([C:14](=[O:15])[C:13]([F:20])([F:19])[F:12])[S:10][CH:11]=1
Reactant: Cc1cscn1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1csc(C(=O)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexanes, 40.4 ml) was added dropwise to a stirred solution of 4-methylthiazole (l10 g) in anhydrous tetrahydrofuran at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, ethyl trifluoroacetate (12 ml) was added dropwise. After a further 2 hours the mixture was allowed to warm to room temperature and was, then left stirring overnight. Saturated aqueous ammonium chloride solution was added and the organic phase was separated, dried and evaporated to dryness. The residue was purified by flash chromatography to give the hydrate corresponding to the title compound as a white solid. M.p. 77°-81° C. 13C Nmr (d6 -DMSO) 16.4, 91.1 (q J 32 Hz), 116.3, 122.2 (q, J 287 Hz), 152.0 and 166.6 ppm.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:15]=2)=[N:13]1
Reactant: COC(=O)c1ccccc1S
Reactant: COC(=O)c1ccc(C#N)nc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2nc(=O)c3ccccc3s2)nc1
Yield: 57.2 %

Procedure:
A mixture of methyl thiosalicylate (2.1 g, 12.3 mmol), methyl 6-cyanonicotinate (2.0 g, 12.3 mmol), triethylamine (3.0 ml, 21.5 mmol) and toluene (6 ml) was refluxed for 12 hrs as described in Example 1. The precipitated crystals were collected by filtration and recrystallized from diisopropylether-chlorobenzene to give the titled compound (2.1 g, 58%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12]O.O=S(Cl)Cl>C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(O)cc1

Procedure:
A mixture of 4-hydroxyphenylacetic acid (9.12 g, 0.06 mol), methanol (50 ml) and SOCl2 (2 mL, 0.028 mol) was refluxed for 3 hours. The residue was cooled, diluted with ethyl acetate (20 mL), washed first with aqueous 5% Na2CO3 solution and then twice with water (100 mL), then dried over anhydrous MgSO4, filtered and evaporated in vacuo to give methyl 4-hydroxyphenylacetate as an oil.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[O:8]([C:11]1[CH2:12][CH2:13][CH2:14][C:9](=[O:15])[CH:10]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C1C=C(Cl)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1C=C(Oc2ccccc2)CCC1

Procedure:
To a stirred solution of 3-chloro-cyclohex-2-enone (3.00 g, 23.0 mmol) and phenol (2.16 g, 23.0 mmol) in 25 mL of acetone was added powdered, anhydrous K2CO3 (3.81 g, 27.6 mmol). After refluxing for 18 h, the mixture was cooled and filtered. The filtrate was concentrated under reduced pressure and chromatographed on silica gel eluting with hexanes/EtOAc (4:1) to give 3-phenoxy-cyclohex-2-enone as a white solid: 1H NMR (CDCl3) δ 2.10 (quint, 2H, J=6.3 Hz), 2.40 (t, 2H, J=6.2 Hz), 2.68 (t, 2H, J=6.3 Hz), 5.14 (s, 1H), 7.05 (d, 2H, J=7.5 Hz), 7.26 (t, 1H, J=7.3 Hz), 7.41 (t, 2H, J=7.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH2:35]([N:38]1[CH2:42][CH2:41][CH2:40][C:39]1=[O:43])[C:36]#[CH:37].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:37]#[C:36][CH2:35][N:38]2[CH2:42][CH2:41][CH2:40][C:39]2=[O:43])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: C#CCN1CCCC1=O
Reactant: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCN4CCCC4=O)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 46 h
Yield: 39.3 %

Procedure:
N-(5-chloro-7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4ylpropoxy)quinazolin-4-amine (250 mg, 0.42 mmol) and 1-prop-2-yn-1-ylpyrrolidin-2-one (103 mg, 0.84 mmol) in ethyl acetate (8 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, then treated with bis(triphenylphosphine) palladium(II) dichloride (30 mg, 10 mol %) followed by copper(I) iodide (8 mg, 10 mol %) and diisopropylamine (84 mg, 0.84 mmol). The reaction was allowed to warm to room temperature and stirred 46 hr. then filtered through Celite and evaporated. The residue was partitioned between dichloromethane and dilute aqueous ammonium chloride solution, the organic layer separated, dried over magnesium sulphate and evaporated then purified by chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent to give the title compound (98 mg, 40%) as a pale brown solid; NMR Spectrum:(CDCl3) 2.12 (m, 4H), 2.44 (t, 2H), 2.49 (m, 4H), 2.57 (t, 2H), 3.55 (t, 2H), 3.72 (m, 4H), 4.00 (s,3H), 4.25 (t,2H), 4.35 (s,2H), 6.08 (s,2H), 7.03 (s,1H), 7.10 (s, 1H), 7.17 (s, 1H), 7.30 (s, 1H), 8.60 (s, 1H); Mass Spectrum: M+H+ 594/596.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=2)[C:6]1=[O:19].C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>CN(C=O)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:2][CH2:3][CH2:4][N:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][C:9]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=3)[C:6]2=[O:19])=[CH:30][CH:29]=1
Reactant: COc1ccc(O)cc1
Reactant: COC(=O)c1ccc2ccn(CCCBr)c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(CCCOc3ccc(OC)cc3)c(=O)c2c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(3-bromopropyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (80 mg, 0.25 mmol) in DMF (2.5 mL) was added potassium carbonate (68 mg, 0.50 mmol) and 4-methoxyphenol (61 mg, 0.50 mmol). The reaction mixture was heated to 40° C. and stirred overnight. The mixture was then cooled to rt, filtered and concentrated to afford methyl 2-[3-(4-methoxyphenoxy)propyl]-1-oxo-1,2-dihydroisoquinoline-7-carboxylate. LC-MS: (FA) ES+ 368.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])(C)(C)[CH3:2].[NH2:12]C1C=CC=CC=1>>[O:11]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:1]=[CH:2][NH:12]1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)c1ccccc1O
Product: C1=Cc2ccccc2ON1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
1 mol of tertiary butylphenol, 2.2 mol of p-formaldehyde, and 1.1 mol of aniline were mixed and stirred without a solvent at 100° C. for 1 hour to produce a crude product. The crude product was washed twice with a 1N NaOH aqueous solution and once with distilled water. The washed crude product was then dried with magnesium sulfate. Then, the resultant was filtered. The resultant was dried in a vacuum to obtain the benzoxazine monomer represented by Formula 4. The benzoxazine monomer of Formula 4 was produced with a 95% yield. NMR spectrum of the benzoxazine monomer of Formula 4 is shown in FIG. 10.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].C(N(CC)CC)C>[Cu]I.C1COCC1>[CH3:16][Si:17]([C:20]#[C:21][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1)([CH3:19])[CH3:18]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1cncc(Br)c1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cncc(C#C[Si](C)(C)C)c1
Temperature: 50 °C
Yield: 62.6 %

Procedure:
To a solution of tert-butyl (5-bromopyridin-3-yl)carbamate (3.00 g, 11.0 mmol) and THF (30 mL) was added (trimethylsilyl)acetylene (1.60 g, 16.3 mmol), (triphenylphosphine)palladium(II) chloride (0.31 g, 0.44 mmol), copper(I) iodide (84 mg, 0.44 mmol) and triethylamine (1.7 mL, 12 mmol) under nitrogen atmosphere. The mixture was heated at 50° C. overnight. The solvent removed in vacuo. The residue was diluted with EtOAc and water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (2.0 g, 63%). LCMS calculated for C15H23N2O2Si(M+H)+: m/z=291.1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH2:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:22]([C:20]3[N:21]=[C:16]4[CH:15]=[CH:14][C:13]([Br:12])=[CH:18][N:17]4[CH:19]=3)=[O:23])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: NCc1ccc2c(c1)OCO2
Product: O=C(NCc1ccc2c(c1)OCO2)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using benzo[d][1,3]dioxol-5-ylmethanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [NH2:1][C@@:2]1([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([F:26])=[CH:21][C:20]=2[F:27])[CH2:7][O:6][C@@H:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][C@H:3]1[CH2:17][OH:18].[C:28]([N:36]=[C:37]=[S:38])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[CH2:10]([O:9][CH2:8][C@@H:5]1[O:6][CH2:7][C@@:2]([NH:1][C:37]([NH:36][C:28](=[O:35])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[S:38])([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([F:26])=[CH:21][C:20]=2[F:27])[C@H:3]([CH2:17][OH:18])[CH2:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@@]1(c2cc(Br)c(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2cc(Br)c(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To C7 (0.946 g, 2.14 mmol) in dichloromethane (22 mL) was added benzoyl isothiocyanate (0.273 mL, 2.04 mmol) and the resulting solution was allowed to stir at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, providing the product as an orange oily residue, which was carried forward into the next step without further purification. Yield: 964 mg, 1.59 mmol, 74%. LCMS m/z 607.6 [M+H+], Br isotopic pattern. 1H NMR (400 MHz, CD3OD), characteristic peaks: δ7.89-7.90 (m, 2H), 7.62-7.66 (m, 2H), 7.50-7.54 (m, 2H), 7.31 (d, J=6.6 Hz, 2H), 7.18-7.25 (m, 2H), 7.06 (dd, J=11.9, 8.8 Hz, 2H), 4.52-4.59 (m, 2H), 3.84-3.90 (m, 3H), 3.55-3.64 (m, 3H), 3.45-4.51 (m, 1H) 1.90-1.99 (m, 3H).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]2[NH:11][C:12](=[O:14])[S:13][C:9]=2[CH:8]=1)=[O:6])=[N+]=[N-].[ClH:17]>CO.[Pd]>[ClH:17].[NH2:1][CH2:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]2[NH:11][C:12](=[O:14])[S:13][C:9]=2[CH:8]=1)=[O:6]
Reactant: [N-]=[N+]=NCC(=O)c1ccc2[nH]c(=O)sc2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCC(=O)c1ccc2[nH]c(=O)sc2c1
Yield: 96 %

Procedure:
6-(2-Azidoethanoyl)-3H-benzothiazol-2-one (0.5 g, 2.14 mmol) and Pd—C (5%, 0.17 g) in methanol (40 mL) and concentrated HCl (0.5 mL) were subjected to hydrogenation at 20 psi and 25° C. for 1 hour. The catalyst was removed by filtration through a ‘filter aid’ and the solvent removed to give 6-(2-aminoethanoyl)-3H-benzothiazol-2-one hydrochloride as a light brown solid (0.5 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][O:12][CH2:13][CH:14]=2)=[CH:5][C:4]=1[N+:15]([O-])=O>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH2:15]
Reactant: COc1ccc(C2=CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2CCOCC2)cc1N
Yield: 71.9 %

Procedure:
1.3 g 4-(4-Methoxy-3-nitro-phenyl)-3,6-dihydro-2H-pyran (5.5 mmol) was dissolved in ethanol (100 ml) and treated with Pd/C 10% (0.065 g) under an atmosphere of hydrogen for 16 h. After filtration, evaporation and drying of the residue, 0.82 g of 2-methoxy-5-(tetrahydro-pyran-4-yl)-phenylamine (71%) were obtained as an off-white solid; M.p.: 102–103° C.
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].[NH:7]1[C:13](=[O:14])C[CH2:11][CH2:10][C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]1=2.BrCCC>C1COCC1.C([Li])CCCCC.O.Cl>[CH3:1][CH:2]([CH:4]1[C:13](=[O:14])[NH:7][C:8]2[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=2[CH2:10][CH2:11]1)[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCCc2ccccc2N1
Agent: Cl
Agent: [K+]
Agent: [Li]CCCCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCBr
Product: CC(C)C1CCc2ccccc2NC1=O
Temperature: 0 °C
Reaction time: 23 h
Yield: 46.2 %

Procedure:
29,01 g (0,253 mol) potassium tert-butylate is suspended in 227 ml of THF and 40 g (0,249 mol) 1,3,4,5-tetrahydro-benzo[b]azepin-2-one is added in portions at a temperature of −16°. At the same temperature 140,22 g (0,50 mol) of n-hexyllithium (33% in hexane) are added over the course of 30 min. Then a solution of 34,28 g (0,276 mol) 3-bromo propane in 21,8 ml THF is added at a temperature of −16°. After the solution has been stirred for 23 hours and meanwhile was allowed to reach room temperature, 150 g of water is added dropwise while stirring and cooling with ice water. The resulting mixture is acidified with 62 g hydrochloric acid (37%), the phases are separated and the organic phase is evaporated. 150 ml dichloromethane is added to the residue, the suspension is filtered and the filter is washed with additional 60 ml dichloromethane. The solution is concentrated and the crystals which precipitated on cooling to 0° over night are filtered off. The solid is recrystallized from 94,9 g 2-propanol. 23,3 g (0,115 mol) of 4,5-dihydro-3-(2-propyl)-1H-benzo[b]azepine-2-one is obtained [46,1%, HPLC 98,4 area %].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([F:21])([F:20])[CH2:18]I.O>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:18][C:17]([F:21])([F:20])[F:16]
Reactant: FC(F)(F)CI
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccccc1OCC(F)(F)F
Temperature: 120 °C
Reaction time: 10 h
Yield: 87.3 %

Procedure:
To a solution of 2-Methoxy phenol (IX) (5 g, 0.04 moles) in N-methylpyrrolidone (50 ml) were added, potassium carbonate (7.8 g, 0.06 mole) and 2,2,2-trifluoroethyl iodide (33.8 g, 0.16 mole) under stirring. The reaction mixture was stirred vigorously at 120° C. for 10 hours. Water (150 ml) was added to the reaction mixture and the mixture was extracted in Toluene (250 ml). Organic layer was washed with 1 N Sodium hydroxide solution (150 ml), followed by brine wash. The extract was dried over sodium sulphate. The solvent was evaporated under reduced pressure to give 7.2 g of (X) as oil. Purity (by GC)=94%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#N)=[CH:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S([O-])([O-])(=O)=[O:18].[Na+].[Na+]>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]=[O:18])=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(N)nc1
Reactant: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-5-cyanopyridine (1.02 g) was dissolved in THF (40 ml) and added with Lithium aluminum hydride (637 mg) and the whole was stirred at room temperature for 2 hours. Water was added thereto to stop the reaction, and the whole was added with a saturated sodium sulfate aqueous solution and subjected to filtration through Celite. The residue obtained by concentration of the filtrate was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (1.04 g) as a yellow solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.[CH3:14][N:15]([CH2:17][CH:18]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:19]1)[CH3:16].[C:32]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1>O>[C:32]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:33]=[CH:34][C:35]([CH2:38][CH2:31][S:28]([N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:27][CH:18]([CH2:17][N:15]([CH3:14])[CH3:16])[CH2:19]2)(=[O:29])=[O:30])=[CH:36][CH:37]=1
Reactant: CN(C)CC1Cc2ccccc2N(S(C)(=O)=O)C1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CC1Cc2ccccc2N(S(=O)(=O)CCc2ccc(-c3ccccc3)cc2)C1
Yield: 10.7 %

Procedure:
LDA (1.9 M/THF, 1.2 ml) was added dropwise to a THF solution of 3-(N,N-dimethylamino)methyl-1-methylsufonyl-1,2,3,4-tetrahydroquinoline (0.24 g). The reaction mixture was stirred under ice-cooling for 30 minutes. A THF (1 ml) solution of 4-biphenylylmethyl bromide (0.16 g) was added to the reaction mixture, which was stirred at room temperature for 3 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water, Lil then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate), which was further recrystallized from hexane-ethyl acetate to give the entitled compound (30 mg).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:4]([C:6]2[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]3[C:15]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:5])[CH2:29][CH2:28]1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C)nn1
Reactant: NC1CC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2CC2)nn1
Yield: 80 %

Procedure:
As described for example 59, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) was converted, using cyclopropylamine instead of aminomethylcyclopropane, to the title compound (118 mg, 80%) which was obtained as a white solid. MS: m/e=369.1 [M+H]+.