Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24]C(C)(C)C)=O)[CH2:18][CH2:17]2)=[O:15])[NH:12][CH:13]=1.Cl.CO.[C:32](O)(=O)[CH:33]=C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:24])[CH:32]=[CH2:33])[CH2:20][CH2:21]2)=[O:15])[NH:12][CH:13]=1
Reactant: C=CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(Cl)cc3Cl)c[nH]2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N1CCN(C(=O)c2cc(-c3ccc(Cl)cc3Cl)c[nH]2)CC1
Reaction time: 1 h
Yield: 16.5 %

Procedure:
The mixture of tert-butyl 4-(4-(2,4-dichlorophenyl)-1H-pyrrole-2-carbonyl)piperazine-1-carboxylate (270 mg, 0.64 mmol) in HCl/MeOH (20 mL, 57.2 mmol) was stirred for 1 h. The mixture was concentrated in vacuo and the residue was dissolved in DMF (5 mL). To this mixture, acrylic acid (50 mg, 0.7 mmol), BOP (437 mg, 0.72 mmol) and DIEA (248 mg, 1.92 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=60:1) to afford the desired product (40 mg, 27% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 11.88 (s, 1H), 7.66-7.63 (m, 2H), 7.43 (m, 1H), 7.38 (s, 1H), 6.91 (s, 1H), 6.85-6.78 (m, 1H), 6.18-6.13 (dd, J=2.4, 12.4 Hz, 1H), 5.74-5.71 (dd, J=2.4, 10.4 Hz, 1H), 3.76 (s, 4H), 3.68-3.63 (m, 4H). ESI-MS m/z: 377.3 [M−H]−.
Reaction SMILES: [CH:1]([Si:4]1([CH:22]([CH3:24])[CH3:23])[O:11][C@H:10]2[C@@H:12]([OH:15])[CH:13]=[CH:14][C@@H:9]2[CH2:8][O:7][Si:6]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:5]1)([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:33])C=1>ClCCl>[CH:22]([Si:4]1([CH:1]([CH3:3])[CH3:2])[O:11][C@H:10]2[CH:12]([OH:15])[C@@H:13]3[O:33][C@@H:14]3[C@@H:9]2[CH2:8][O:7][Si:6]([CH:16]([CH3:18])[CH3:17])([CH:19]([CH3:21])[CH3:20])[O:5]1)([CH3:24])[CH3:23]
Reactant: CC(C)[Si]1(C(C)C)OC[C@H]2C=C[C@H](O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)[Si]1(C(C)C)OC[C@H]2[C@H]3O[C@H]3C(O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
To a stirred solution of compound 11 (13.7 g, 36.8 mmol) in dichloromethane (300 mL), m-CPBA (15.9 g, 92.0 mmol) was added portion wise at room temperature. The mixture was stirred at room temperature for 16 h, quenched with a saturated NaHCO3 solution and extracted with DCM (200 mL×2). The combined organic layer was washed with brine (100 mL×2) and dried over Na2SO4. The solvent was removed under reduced pressure and residue was purified by silica gel column chromatography (3% EtOAc/Hexane) to give epoxide 12 (12.2 g, 85%) as an oil. [α]24D +18.25° (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.00-1.11 (m, 28H), 2.30 (in, 1H,), 3.05 (s, 1H), 3.37 (s, 1H), 3.56 (d, J=2.5 Hz, 1H), 3.99-4.05 (m, 2H), 4.19 (d, J=5.0 Hz, 1H), 4.26 (dd, J=3.0, 11.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 12.6, 13.1, 13.3, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 48.2, 55.5, 58.4, 64.7, 70.7, 75.0; HR-MS Calcd. For (C18H36O5Si2+H)+ 389.2101. found 389.2171.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[CH3:14][NH:15][CH3:16]>CN(C1C=CN=CC=1)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=1[C:7]([N:15]([CH3:16])[CH3:14])=[O:8]
Reactant: CNC
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Agent: CN(C)c1ccncc1
Product: CN(C)C(=O)c1cc(Br)ccc1N
Reaction time: 8 h
Yield: 106.1 %

Procedure:
Into an 15 mL high pressure glass vial (with Teflon screw cap) were added 5-bromoisatoic anhydride (0.401 g, 1.66 mmol), DMAP (20 mg, 0.16 mmol), and dimethyl amine (2 M in THF; 5.0 mL, 10.0 mmol). The vial was sealed and placed in an oil bath at 70° C. for 8 h after which it was concentrated under vacuum. The crude product was dissolved in EtOAc and washed 2× with water followed by brine. The organic phase was dried (Na2SO4), filtered and concentrated to afford 0.428 g of 2-Amino-5-bromo-N,N-dimethyl-benzamide as a pink solid, which was used directly for the next step. 1H-NMR (500 MHz, d6-DMSO) δ=7.19 (dd. J=2.0, 8.5 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.63 (d, J=8.5 Hz, 1H), 5.31 (br. s, 2H), 2.89 (br. s, 6H). MS: m/z 198/200 [C═O+].
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[C:5]([CH2:10][CH3:11])=[C:4]([Cl:12])[CH:3]=1.Cl[CH2:14][C:15](Cl)=[O:16].C([O-])([O-])=O.[K+].[K+]>>[Cl:12][C:4]1[C:5]([CH2:10][CH3:11])=[C:6]([Cl:9])[C:7]2[O:8][CH2:14][C:15](=[O:16])[NH:1][C:2]=2[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: CCc1c(Cl)cc(N)c(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1c(Cl)cc2c(c1Cl)OCC(=O)N2
Yield: 92.1 %

Procedure:
6-Amino-2.4-dichloro-3-etylphenol (95MF2226) (0.293 g, 1.5 mmol), 2-chloroacetyl chloride (0.19 g, 1.7 mmol) and K2CO3 (0.44 g, 3.2 mmol) were mixed according to GP1 to give the title compound as a crude (95MF46) (0.34 g).
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].Br[C:17](Br)([F:19])[F:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(N(C)C)=O.O.[Zn]>[F:18][C:17]([F:19])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCCCCCCCCC=O
Reactant: FC(F)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)CCCCCCCCCC=C(F)F
Temperature: 25 °C
Reaction time: 60 h
Yield: 49.5 %

Procedure:
A stirred mixture of 7.5 grams (0.035 mole) of methyl 11-oxoundecanoate and 14.7 grams (0.07 mole) of dibromodifluoromethane was cooled to 0°-10° C., and a solution of 18.4 grams (0.07 mole) of triphenylphosphine in 50 ml of dimethylacetamide was added dropwise. During the addition the temperature of the reaction mixture was maintained at 0°-10° C. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature, and 4.6 grams (0.07 mole) of zinc dust was added in two portions. The addition caused an exothermic reaction which raised the temperature of the reaction mixture to 90° C. The reaction mixture was allowed to cool to ambient temperature where it stood without stirring for 60 hours. The reaction mixture was diluted with water and was subjected to a steam distillation with pentane. The appropriate fractions were combined and concentrated under reduced pressure yielding 4.3 grams of methyl 12,12-difluoro-11-dodecenoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](Cl)=[O:8])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[CH2:20][NH:21][CH2:22][C:23]1[C:24]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:25][N:26]([C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][CH:29]=2)[CH:27]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([N:21]([CH2:20][C:13]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=2[O:11][CH3:10])[CH2:22][C:23]2[C:24]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[N:25][N:26]([C:28]3[CH:33]=[CH:32][C:31]([I:34])=[CH:30][CH:29]=3)[CH:27]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: COc1ccc(CNCc2cn(-c3ccc(I)cc3)nc2-c2ccccc2)c(OC)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(Cc2cn(-c3ccc(I)cc3)nc2-c2ccccc2)C(=O)c2ccc(Cl)s2)c(OC)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 651 mg (3.597 mmol) of 5-chlorothiophene-2-carbonyl chloride in 10 ml of anhydrous tetrahydrofuran is added to a solution of 1.89 g (3.597 mmol) of the product from Example 3A and 1.25 ml of diisopropylethylamine (Hünig-Base) in 40 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred at room temperature for 15 hours. The solvent is then removed on a rotary evaporator, and the residue is taken up in dichloromethane and washed successively with saturated sodium bicarbonate solution and water. After drying over anhydrous sodium sulphate, the mixture is filtered, evaporated and the residue is purified by preparative HPLC (Method 7). This gives 1.05 g (43% of theory) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][C@@H:10]2[CH2:15][O:14][CH2:13][CH2:12][N:11]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.Cl[C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35]>C1COCC1>[O:38]=[C:33]([N:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:9][C@@H:10]1[CH2:15][O:14][CH2:13][CH2:12][N:11]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:34]([O:36][CH3:37])=[O:35]
Reactant: c1ccc(CNC[C@@H]2COCCN2Cc2ccccc2)cc1
Reactant: COC(=O)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=O)N(Cc1ccccc1)C[C@@H]1COCCN1Cc1ccccc1
Reaction time: 3 h
Yield: 107.5 %

Procedure:
To a solution of 1-phenyl-N-{[(3R)-4-(phenylmethyl)-3-morpholinyl]methyl}methanamine (3.3777 g, 11.40 mmol) in THF (114 mL) was added N,N-diisopropylethylamine (3 mL, 17.22 mmol). To the solution was added methyl chloro(oxo)acetate (1.15 mL, 12.50 mmol) dropwise via syringe, and the mixture was stirred for 3 h. The solvent was removed in vacuo, and the residue was dissolved in EtOAc (200 mL) and washed with sat. aq. NaHCO3 followed by water. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford crude methyl oxo((phenylmethyl){[(3R)-4-(phenylmethyl)-3-morpholinyl]methyl}amino)acetate (4.6881 g, >100% crude yield) as a yellow oil. LCMS: (M+H)+: 383.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[O:37][CH3:38])[C:21]([Cl:39])=[CH:20][N:19]=1>>[Cl:39][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][C:26]=2[O:37][CH3:38])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)cc2CC1

Procedure:
5-Chloro-N*2*-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 308c. Product isolated as an off-white solid (137 mg, 75%). m.p.=144-146° C.; LCMS (m/e) 539 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.25 (d, 1H, J=8.8 Hz), 8.00 (s, 1H), 7.59 (s, 1H), 7.39 (s, 1H), 7.22-7.16 (m, 1H), 7.01 (d, 1H, J=8.0 Hz), 6.84 (s, 1H), 6.54 (bs, 1H), 6.52-6.46 (m, 1H), 3.92 (s, 3H), 3.92-3.86 (m, 4H), 3.54 (t, 2H, J=5.6 Hz), 3.36 (s, 3H), 3.19-3.13 (m, 4H), 2.94-2.87 (m, 4H), 2.78-2.68 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.C(N(CC)CC)C.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][NH2:24]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:24][CH2:23][CH2:22][CH2:21][O:20][CH3:19]
Reactant: COCCCN
Reactant: O=[N+]([O-])c1cccc(Cl)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCNc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
1-Chloro-2-fluoro-3-nitrobenzene (2.85 mmol, 0.500 g) was added to an oven dried 50 mL round-bottomed flask equipped for stifling under nitrogen. Dichlormethane (10 mL) and triethylamine (3.13 mmol, 0.437 mL) were added and the resultant solution was cooled to 0° C. with an ice-bath. 3-Methoxypropan-1-amine (2.85 mmol, 0.292 mL) was then added drop-wise via syringe and the resultant solution was stirred at 0° C. for 1 hr. The ice-bath was removed and the reaction was allowed to warm to room temperature and stirred for 16 hr. The reaction solution was poured into water and extracted twice with dichloromethane (50 mL). The organic layer was collected and water was subsequently removed with anhydrous Na2SO4 and the suspension was filtered. The filtrate was collected, concentrated, and dried in-vacuo affording an orange oil, which was then purified by chromatography on slica gel (10-70% ethyl aetate/hexanes) to afford 2-chloro-N-(3-methoxypropyl)-6-nitroaniline (30A) as a yellow solid (2.23 mmol, 0.542 g, 78% yield). ESI-MS: m/z 245.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[CH:20])[CH:14]=1.N>>[Cl:12][C:13]1[CH:14]=[C:15]([C:19]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[CH:11]=3)[CH:20]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Agent: N
Product: Clc1cncc(-c2cc(-c3cccc(Cl)c3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1-chloro-3-ethynylbenzene (Apollo, 41 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.61-7.68 (m, 2H), 7.85-7.89 (m, 1H), 7.90 (s, 1H), 7.96-8.00 (m, 1H), 8.43 (t, J=2.1 Hz, 1H), 8.81 (d, J=2.4 Hz, 1H), 9.08 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 291 (M+H)+, 293 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([O:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])C>O1CCCC1.C1(C)C=CC=CC=1.[Cl-].[NH4+]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:12](=[O:11])[C:13]([F:16])([F:15])[F:14])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cn1)C(F)(F)F
Reaction time: 0.29 h
Yield: 68.8 %

Procedure:
To a stirred solution of 2,5-Dibromo-pyridine (4 g, 6.87 mmol) in dry tetrahydrofuran (30 mL) and dry toluene (40 mL) is added drop wise n-Butyl litihum (1.62 g, 25.31 mmol) at −78° C. After stirring for 15-20 minutes, added trifluoro-acetic acid ethyl ester (3.56 g, 25.31 mmol) at −78° C. then stirred at −78° C. for another 30 minutes. The reaction mixture is diluted with saturated ammonium chloride solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography eluting in 20% ethyl acetate in hexane to afford the title compound (1.2 g). 1HNMR (400 MHz, DMSO-d6) δ: 7.72 (d, J=8.32 Hz, 1H), 7.85-7.88 (dd, J1=8.32 Hz, J2=2.44 Hz 1H), 8.52 (d, J=2.36 Hz, 1H). LC-MS (m/z): [M+H]=255.8.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:40])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([O:35][CH2:36][CH2:37][CH2:38]Br)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:41]([O:48]CC)([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44]>>[CH2:43]([O:42][P:41]([CH2:38][CH2:37][CH2:36][O:35][C:12]1[CH:11]=[C:10]([C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:40])[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=1)(=[O:48])[O:45][CH2:46][CH3:47])[CH3:44]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCBr)cc(C(=O)OCc2ccccc2)c1
Reactant: CCOP(OCC)OCC
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCP(=O)(OCC)OCC)cc(C(=O)OCc2ccccc2)c1
Yield: 59.6 %

Procedure:
A mixture of 4.91 g (7.95 mmol) of 3-(3-bromopropoxy)-5-(octadecyloxy)benzoic acid phenylmethyl ester and 1.5ml (8.74 mmol) of triethyl phosphite was stirred and heated at 150° for 32 horns. Purification by chromatography on 250 g of silica gel gave 3.2 g (60% yield) of 3-[3-(octadecyloxy)-5-(phenylmethoxycarbonyl)phenoxy]propylphosphonic aciddiethyl ester as an oil. The structure was confirmed by the nmr spectrum.
Reaction SMILES: O=[C:2]([CH3:21])[C:3](=[CH:6][C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:20])[C:11]=2[CH:10]=[CH:9][CH:8]=1)[C:4]#[N:5].[CH:22]([O:25][C:26]1[N:31]=[C:30]([NH2:32])[N:29]=[C:28]([NH2:33])[CH:27]=1)([CH3:24])[CH3:23]>C(O)(C)C>[NH2:32][C:30]1[N:31]=[C:26]([O:25][CH:22]([CH3:24])[CH3:23])[C:27]2[CH:6]([C:7]3[C:19]4[C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[C:12](=[O:20])[C:11]=4[CH:10]=[CH:9][CH:8]=3)[C:3]([C:4]#[N:5])=[C:2]([CH3:21])[NH:33][C:28]=2[N:29]=1
Reactant: CC(C)Oc1cc(N)nc(N)n1
Reactant: CC(=O)C(C#N)=Cc1cccc2c1-c1ccccc1C2=O
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cccc3c2-c2ccccc2C3=O)c2c(nc(N)nc2OC(C)C)N1

Procedure:
81 mg (0.29 mmol) of 3-oxo-2-[(9-oxo-9H-fluoren-4-yl)methylene]butanenitrile are dissolved with 50 mg (0.29 mmol) of 6-isopropoxypyrimidine-2,4-diamine in 5 ml of isopropanol and heated under reflux under argon for 6 h. The suspension is cooled and then filtered with suction, and the remaining solid is washed with isopropanol. 74 mg (59% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[N:24][NH:25][CH:26]=4)[CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:34]O>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[N:24][N:25]([CH3:34])[CH:26]=4)[CH:19]=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: CO
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1
Product: Cc1ccc(-c2nn(C)cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1

Procedure:
The title compound is prepared as described in Example 55 starting from [4(4methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (Example 60) and methanol.
Reaction SMILES: C(O)C.Cl.[OH:5][C:6]1[C:7]([CH2:21][OH:22])=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH:11]([NH:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]2.[H][H]>[Pd].C(N(CC)CC)C>[OH:16][CH:12]1[C:13]2[C:8](=[C:7]([CH2:21][OH:22])[C:6]([OH:5])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH:11]1[NH:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)NC1CCc2c(ccc(O)c2CO)C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)NC1CCc2c(ccc(O)c2CO)C1O

Procedure:
In a mixture of 20 ml. ethanol and 2 ml. of triethylamine is dissolved 200 mg. of 6-hydroxy-5-hydroxymethyl-2-isopropylamino-3,4-dihydro-1(2H)-naphthalenone hydrochloride and, with the addition of 50 mg. of 5 % palladium-on-carbon, the solution is agitated in a current of hydrogen for 15 hours. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The resiude is dissolved in tetrahydrofuran. The insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue is recrystallized from ethanol-ethyl acetate. The procedure yields colorless crystals of 1,6-dihydroxy-5-hydroxymethyl-2-isopropylamino-1,2,3,4-tetrahydronaphthalene which is identical with the product according to the procedure of Example 71. Yield 108 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]#[C:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2(OCC[O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].Cl.O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]#[C:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])[CH:20]1[CH2:21][CH2:22][C:23](=[O:24])[CH2:28][CH2:29]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(=O)CC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (1 eq.) is dissolved in tetrahydrofuran and treated with 3.6 N HCl solution. The reaction is stirred at 40° C. for 5 h. Water is then added and the reaction mixture is cooled to room temperature. The reaction mixture is extracted with ethyl acetate (2×50 mL). The combined extracts are washed with 25 mL of aqueous saturated NaHCO3 and 2×50 mL of water. The organic layer is concentrated to a thick oil and 50 mL of heptane is added to the mixture to precipitate the desired compound which is filtered to give of 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[O:19]=[C:20]1[CH2:25][NH:24][CH2:23][CH2:22][NH:21]1.N1C=CC=CC=1.C(O)(=O)C>[OH-].[Na+]>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:24]3[CH2:23][CH2:22][NH:21][C:20](=[O:19])[CH2:25]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: O=C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(=O)C3)cc21
Yield: 32.4 %

Procedure:
A mixture of 1-ethyl-7-chloro-1,4-dihydro-6-fluoro-4-oxoquinoline-3-carboxylic acid (0.80 g), 2-oxopiperazine (3.0 g) and 4 ml pyridine was heated for 18 hours. The reaction mixture was evaporated under vacuum, an aqueous solution of caustic soda was added to adjust the pH to 10, ice cooled and the undissolved matter was collected and washed with a small amount of an aqueous solution of NaOH. The filtered product was suspended in water, acidified with acetic acid, filtered and washed. The product obtained was dissolved in an aqueous solution of NaOH and acidified with acetic acid. The precipitate was filtered, washed and dried to obtain 0.32 g (32%) of 1-ethyl-1,4-dihydro-6-fluoro-7-(3-oxo-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][C:18]#[C:19][CH2:20][CH2:21][CH3:22].C([CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=[O:28])(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:26]/[C:27]([NH:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=[O:33])=[O:28])=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: CCCC#COc1cc(C=O)ccc1OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: C#CCCCOc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 75.3 %

Procedure:
Piperidine (0.45 mL, 4.6 mmol) was added to a suspension of 4-methoxy-3-(pent-1-ynyloxy)benzaldehyde (1.0 g, 4.6 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.93 g, 4.2 mmol) in toluene (10 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(4-methoxy-3-(pent-4-ynyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (1.2 g, 77%) as a yellow crystalline solid; mp 154-156° C.; δH (400 MHz, DMSO-d6) 1.91 (p, 7.6 Hz, 2H, CH2), 2.34 (dt, J=7.6, 2.4 Hz, 2H, CH2CCH), 2.82 (t, J=2.4 Hz, 1H, CCH), 3.80 (s, 3H, OCH3), 4.10 (t, J=7.6 Hz, 2H, OCH2), 6.78 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.25 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.38 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.26 (s, 1H, NH), 13.56 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 14.5, 27.8, 55.6, 66.8, 71.6, 83.8, 111.7, 111.8, 116.6, 119.9, 120.3, 122.6, 122.8, 127.2, 131.1, 134.0, 141.1, 141.6, 148.1, 150.9, 164.1, 169.4; HRMS (ESI) calculated for C22H21NO5 [M+H]+ 380.1492. found 380.1490; vmax 754, 1257, 1510, 1584, 1659, 2944, 3250, 3512 cm−1.