Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[C:10]3[CH:30]=[CH:31][N:32]=[C:33]([O:34]C)[C:9]2=3)[CH2:4][CH2:3]1.Cl.N1C=CC=CC=1>C(#N)C.O>[CH3:1][C:2]1([CH3:36])[CH2:3][CH2:4][CH:5]([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]5)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[C:10]3[CH:30]=[CH:31][N:32]=[C:33]([OH:34])[C:9]2=3)[CH2:6][CH2:7]1
Reactant: COc1nccc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCC(C)(C)CC3)c12
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: CC1(C)CCC(n2c3nc(Nc4ccc(N5CCNCC5)cn4)ncc3c3ccnc(O)c32)CC1
Temperature: 170 °C
Yield: 207.5 %

Procedure:
A mixture of compound 331 (90 mg, 153 μmol) and pyridine hydrochloride (177 mg, 1.53 mmol) was heated at 170° C. (oil bath) for 4 h. After cooling to room temperature, the mixture was subjected to reverse phase preparative HPLC (acetonitrile/water containing 0.1% TFA each, 40 min from 10 to 50%). Lyophilization provided compound 334 (150 mg) as a yellow solid (TFA salt). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.66 (1 H, br. s.), 9.30 (1 H, s), 8.80 (2 H, br. s.), 8.05 (1 H, d, J=2.7 Hz), 7.92 (1 H, d, J=8.6 Hz), 7.75 (1 H, br. s.), 7.28 (1 H, t, J=5.7 Hz), 7.06 (1 H, d, J=6.3 Hz), 3.33-3.43 (4 H, m), 3.29 (5 H, d, J=1.6 Hz), 2.71-2.94 (2 H, m), 1.47-1.70 (4 H, m), 1.31-1.45 (2 H, m), 1.16 (3 H, s), 0.99 (3 H, s). LCMS-ESI (POS), M/Z, M+1: Found 473.2.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24]>>[Cl:17][C:18]1[CH:19]=[C:20]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=3[CH:5]=[N:4][CH:3]=2)[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: CCC(=O)NC1CCCc2c(Br)cncc21
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: CCC(=O)NC1CCCc2c(-c3ccc(F)c(Cl)c3)cncc21
Yield: 74 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (intermediate A-1) was reacted with 3-chloro-4-fluorophenylboronic acid to give the title compound as light grey foam in 74% yield. MS: 333.1 (M+H+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 73.8 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (36.2 mg, 0.0881 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with piperidine (0.035 mL, 0.35 mmol), acetic acid (0.101 mL, 1.76 mmol) and sodium triacetoxyborohydride (93 mg, 0.44 mmol), followed by purification by preparative thin-layer chromatography (hexane/ethyl acetate=1/2) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (31.2 mg, yield 74%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[N+:18]([O-])=O.CN(C=O)C.[F:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[F:34])[NH2:30]>>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH3:7])[C:13]([NH:30][C:29]1[CH:31]=[CH:32][C:33]([F:34])=[C:27]([F:26])[CH:28]=1)=[O:15]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccc(F)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Yield: 87.4 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), DMF (1.0 mL, 12.92 mmol), and 3,4-difluoroaniline (5.0 mL, 50.42 mmol) to afford the product (6.17 g), m.p. 171-172° C.
Reaction SMILES: C(O[CH:5]1[O:11][C@H:10]([CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@:8](CC2C=CC=CC=2)([OH:9])[C@:6]1([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:7])(=O)C.CO.[CH3:37][C:38]([OH:40])=[O:39]>[Pd].N1C=CC=CC=1>[C:38]([O:40][C@H:5]1[O:11][C@H:10]([CH2:8][OH:9])[C@@H:12]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@:6]1([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[OH:7])(=[O:39])[CH3:37]
Reactant: CC(=O)O
Reactant: CC(=O)OC1O[C@H](COCc2ccccc2)[C@](O)(Cc2ccccc2)[C@@]1(O)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@]1(O)Cc1ccccc1
Yield: 39 %

Procedure:
To a solution of acetate (V) (20.6 g, 4.46 mmol) in a 1:1 solution of MeOH/HOAc (100 ml) was added 2.0 g of 10% Pd/C and 82 μl of pyridine (0.4%). The solution was shaken on a Parr apparatus under 50 psig of H2. After 24 h the solution was filtered and concentrated, and the residue was purified on a Waters Prep-500 HPLC (EtOAc/hexane, 22/78) to yield 6.4 g of a light yellow oil (39%), homogeneous by TLC. This reaction routinely gave yields of 35-40%. The point at which the reaction is removed from the hydrogenator is determined by when the selectively reduced compound appears greatest by TLC analysis. 1H NMR (CDCl3)δ: 7.3 (s, 10H), 6.2 (br s, 1H), 3.6-4.7 (m, 9H), 2.10 (s, 3H). 13C NMR (CDCl3) δ: 169.9, 137.5, 137.1, 128.5 (4C), 128.0 (4C), 127.7 (2C), 100.4 (αC-1), 86.8, 84.6, 82.8, 72.4, 72.1, 62.1, 21.2 Elemental Analysis: Calculated for C21H24O6 : C, 67.73; H, 6.50. Found: C, 67.49; H, 6.50.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[N+:11]([O-])=O)=[CH:4][CH:3]=1>C(O)C.[Pd]>[NH2:11][CH:9]1[CH2:10][CH:8]1[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])C1CC1c1ccc(Br)cc1
Agent: [Pd]
Solvent: CCO
Product: NC1CC1c1ccccc1

Procedure:
3.5 g of 4-bromo-2-nitro-cyclopropylbenzene are dissolved in 30 ml of ethanol and, after addition of 0.5 g of palladium-on-charcoal (10%), are hydrogenated in a Parr apparatus at room temperature under a hydrogen pressure of 5 bar for 2.5 hours. After cooling, the solvent is distilled off in a rotary evaporator and the residue is rendered alkaline with 1N sodium hydroxide solution and extracted three times with 50 ml of ether each time. The combined organic phases are dried over sodium sulphate, the solvent is distilled off in a rotary evaporator and the residue is purified by column chromatography.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]2[CH:12]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(O)CO>[F:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][N:23]([CH2:2][C:3]3[N:4]=[C:5]4[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]4[CH:12]=3)[CH2:22][CH2:21]2)=[CH:18][CH:19]=1
Reactant: Cc1ccc2nc(CCl)cn2c1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: OCCO
Product: Cc1ccc2nc(CN3CCN(c4ccc(F)cc4)CC3)cn2c1
Temperature: 82.5 °C
Reaction time: 2.25 h
Yield: 55.3 %

Procedure:
A mixture of 2-(chloromethyl)-6-methylimidazo[1,2-a]pyridine (0.302 g), 1-(4-fluorophenyl) piperazine (Aldrich; 0.319 g), triethylamine (Aldrich; 0.26 mL), and ethylene glycol (2 mL) is stirred for 2.25 h at 80-85° C. The cooled mixture is then poured into saturated aq. sodium bicarbonate and extracted several times with dichloromethane. The combined organic layers are washed with brine, dried with MgSO4, and concentrated under reduced pressure. The crude material is chromatographed on silica gel using methanol/dichloromethane/ammonium hydroxide (4/96/0.25) and crystallized from ethyl acetate/hexane to give 0.300 g of the title compound; mp 112-112.5° C.; ms m/z 324; IR (mineral oil) 1511, 804, 1234, 1246, 1345 cm-1 ; 1H NMR (CDCl3) δ2.31, 2.74, 3.15, 3.76, 6.90, 7.46, 7.86.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[O:13][N:12]=2)=[CH:7][CH:6]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:21]([NH:28][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[O:13][N:12]=2)=[CH:7][CH:6]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: Fc1ccc2c(-c3ccc(OCCBr)cc3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(-c3ccc(OCCNCc4ccccc4)cc3)noc2c1

Procedure:
The title compound is prepared from a mixture of 3-[4-(2-bromo-ethoxy)-phenyl]-6-fluoro-benzo[d]isoxazole, benzylamine, potassium carbonate, potassium iodide and 4% aqueous acetonitrile essentially as described above in Example 20B, except that the reaction mixtures were poured directly onto a column and eluted with a step gradient consisting of dichloromethane and 5% methanol in dichloromethane. Purity by LC/MS=77%, [M+H]+=363.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2S[C:10]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:5])[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[S:30](S([O-])=O)([O-:33])(=O)=[O:31].[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[CH2:1]([NH:3][C:4]([C:6]1[C:7]2[CH:8]=[CH:15][CH:16]=[CH:17][C:18]=2[S:30](=[O:33])(=[O:31])[C:10]=1[Si:11]([CH3:13])([CH3:12])[CH3:14])=[O:5])[CH3:2]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CCNC(=O)c1c([Si](C)(C)C)sc2ccccc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCNC(=O)C1=C([Si](C)(C)C)S(=O)(=O)c2ccccc21
Yield: 74.5 %

Procedure:
A mixture of the product of Example 8 (0.6 g, 2.2 mmol) and 1 g of 80-85% 3-chloroperoxybenzoic acid in 16 mL methylene chloride was refluxed for 2 h, then cooled and diluted with additional methylene chloride. The solution was treated sequentially with sat sodium metabisulfite, 1.25N NaOH, and brine; then dried and concentrated in vacuo. Flash chromatography of the residue with 35% ethyl acetate-hexane gave 0.5 g of the desired product as a white solid, a yield of 74.5%. m.p. 135-148° C.
Reaction SMILES: [C-]#N.[K+].CC(C)(O)[C:6]#[N:7].[Cl:10][C:11]1[CH:12]=[C:13](/[C:18](/[C:37]([F:40])([F:39])[F:38])=[CH:19]\[C:20]([C:22]2[CH:35]=[CH:34][C:25]([C:26]([NH:28][C:29]3([CH3:33])[CH2:32][S:31][CH2:30]3)=[O:27])=[C:24]([CH3:36])[CH:23]=2)=[O:21])[CH:14]=[C:15]([Cl:17])[CH:16]=1.O>C1(C)C=CC=CC=1>[C:6]([C@@:18]([C:13]1[CH:14]=[C:15]([Cl:17])[CH:16]=[C:11]([Cl:10])[CH:12]=1)([C:37]([F:40])([F:39])[F:38])[CH2:19][C:20]([C:22]1[CH:35]=[CH:34][C:25]([C:26]([NH:28][C:29]2([CH3:33])[CH2:32][S:31][CH2:30]2)=[O:27])=[C:24]([CH3:36])[CH:23]=1)=[O:21])#[N:7]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NC1(C)CSC1
Reactant: CC(C)(O)C#N
Agent: [C-]#N
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C(=O)C[C@](C#N)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NC1(C)CSC1
Temperature: 90 °C
Reaction time: 144 h
Yield: 23.7 %

Procedure:
Potassium cyanide (0.0090 g, 0.139 mmol) and acetone cyanohydrin (0.034 ml, 0.372 mmol) were added to a solution of 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-N-(3-methyl-thietan-3-yl)-benzamide (0.0600 g, 0.123 mmol) in toluene (3.0 ml). To this vigorously stirred suspension was added 2,3,4,5,6-pentafluorophenyl-methyl quininium chloride (0.0180 g, 0.031 mmol). The reaction mixture was stirred at 90° C. for 6 days. After this time water was added and the reaction mixture was extracted with dichloromethane (3×). The crude product was purified by flash chromatography (0% to 25% ethyl acetate in cyclohexane) to afford 4-[(R)-3-Cyano-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-N-(3-methyl-thietan-3-yl)-benzamide (0.015 g, 24%) as a light yellow solid. Chiral HPLC analysis (Chiralpack IB, Heptane:2-propanol=70:30, 1 ml/min, retention time 5.91 minutes (major enantiomer), 5.31 minutes (minor enantiomer) indicated that the reaction proceeded with 69% enantioselectivity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[C:5]([O:7]C)=[O:6].O.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(OC)c(I)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(Cl)cc(C(=O)O)cc1I
Temperature: 25 °C
Reaction time: 19 h
Yield: 96.7 %

Procedure:
Methyl 3-chloro-5-iodo-4-methoxybenzoate (2.96 g) was dissolved in tetrahydrofuran (23 mL) and water (7 mL), and lithium hydroxide monohydrate (1.52 g) was added to the solution, and then the mixture was stirred at room temperature for 19 hours. After the organic solvent was distilled off, the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.74 g) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:34][CH3:35])[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:36][CH3:37])[CH:6]=1.[C:38](=O)=O>CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:34][CH2:35][CH3:38])[C:17]4[CH2:22][CH2:21][C@H:20]([C:23]5[CH:24]=[CH:25][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[CH:27][CH:28]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:36][CH3:37])[CH:6]=1
Reactant: O=C=O
Reactant: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(OC(F)(F)F)cc1
Solvent: CO
Product: CCNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CC[C@@H]2c1ccc(OC(F)(F)F)cc1

Procedure:
A racemic mixture of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (111 mg, 0.204 mmol from Example 98) was purified using chiral SFC to afford 29.5 mg of peak A (Example 98A) and 37.7 mg of peak B (Example 98B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 30% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 2.0 mL/min for 12 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=3.4 min, tR (peak B) 8.2 min. The absolute stereochemistry of individual enantiomers (Examples 98A and 98B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 98).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Br:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Br:37])[C:29]=1[C:30](=O)[C:31]([O:33]CC)=O.CC(O)=O>COCCO.CCOC(C)=O>[Br:37][C:28]1[CH:27]=[N:26][CH:25]=[C:24]([Br:23])[C:29]=1[C:30]1[C:31](=[O:33])[N:21]([CH3:22])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(=O)C(=O)c1c(Br)cncc1Br
Reactant: CNc1nc(Nc2ccc(N3CCOCC3)cc2)ncc1N
Solvent: CC(=O)O
Solvent: COCCO
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(-c2c(Br)cncc2Br)nc2cnc(Nc3ccc(N4CCOCC4)cc3)nc21
Yield: 26.2 %

Procedure:
A mixture of 0–30 g (1 mmol) of 5-amino-4-(methylamino)-2-[[4-(morpholin-4-yl)phenyl]amino]pyrimidine, 0.67 g (2 mmol) of ethyl 2-(3,5-dibromopyridin-4-yl)-2-oxoacetate (from preparation 17), and 0.5 mL of HOAc in 15 mL of 2-methoxyethanol is heated under reflux for 18 hours. Workup in EtOAc, followed by chromatography on silica, eluting with CH2Cl2/EtOAc (4:1), gives 0.15 g (26%) of the title compound (Compound 19): mp (EtOH) 204–206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[C:26](Cl)(=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(#N)C>[C:26]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])(=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.5 part of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazide and 19.6 parts of acetonitrile is added 0.298 part of sodium bicarbonate followed by 0.562 part of octanoyl chloride. The solution is stirred for 48 hours at room temperature, after which time the solvent is removed under reduced pressure and the resulting oil crystallized by trituration with cyclohexane. Recrystallization from cyclohexane yields 1-octanoyl-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl) hydrazine, melting at about 127°-129° and represented by the following structural formula ##SPC2##
Reaction SMILES: CS([O:5][CH:6]([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])(=O)=O.[C:13]1([C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([C:22](O)=[O:23])[C:20]=2[OH:28])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:8][CH:7]([CH:6]([O:5][C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[C:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]=1[OH:28])=[O:23])[CH:10]([CH3:12])[CH3:11])[CH3:9]
Reactant: CC(C)C(OS(C)(=O)=O)C(C)C
Reactant: O=C(O)c1cccc(-c2ccccc2)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(OC(=O)c1cccc(-c2ccccc2)c1O)C(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
In a four-neck flask having an inner volume of 100 ml, 4.86 g (25 m.mols) of (2,4-dimethyl-3-pentyl) methanesulfonate, 5.36 g (25 m.mols) of 3-phenylsalicylic acid, 2.65 g (25 m.mols) of sodium carbonate, and 50 ml of dimethyl formamide were placed and left reacting at 90° C. for three hours. After the reaction, the reaction mass was thrown into 100 ml of ice water and extracted twice with 150 ml of ethyl acetate. The organic layer obtained consequently was washed twice with 50 ml of water. Then, by distilling the organic layer thereby expelling the solvent by evaporation, 5.00 g (16 m.mols) of 2-(2,4-dimethyl-3-pentyloxy)carbonyl-6-phenylphenol was obtained as the product aimed at.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C:8]1([CH:15]=[O:16])[CH2:13][CH:12]2[CH2:14][CH:9]1[CH:10]=[CH:11]2)[CH2:6][CH3:7]>C1(C)C=CC=CC=1>[CH2:5]([CH:8]1[CH2:13][CH:12]2[CH2:11][CH:10]([CH:9]=[CH:14]2)[C:15]1=[O:16])[CH2:6][CH3:7]
Reactant: CCCC1(C=O)CC2C=CC1C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCCC1CC2C=CC(C2)C1=O
Temperature: -30 °C
Reaction time: 0.67 h
Yield: 67.6 %

Procedure:
Aluminum chloride (AlCl3, 110 g) was suspended in toluene (1 L) and chilled to −30° C. using a dry ice/isopropanol bath. 2-Propylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde (136 g, synthesized as above) was fed in using an addition funnel over 1 hour while the temperature was maintained at −30° C. After the feed was completed the temperature was allowed to rise to 0° C. GC analysis showed the reaction was completed after 40 minutes. The reaction mixture was then poured onto H2SO4 (1 L, 20%) over ice. The resulting biphasic mixture was shaken to split the organic and aqueous layers. The aqueous layer was washed once with toluene (300 mL) and combined with the organic layers. The mixture was then washed with NaOH solution (750 mL, 10%), followed by water until the water was tested neutral. The resulting organic material was purified by distillation to yield 3-propylbicyclo[3.2.1]oct-6-en-2-one (92 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[N+:18]([C:21]1[O:25][C:24]([C:26](Cl)=[O:27])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[O:25][C:24]([C:26]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:27])=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc([N+](=O)[O-])o4)nc23)CC1
Yield: 61.5 %

Procedure:
Beginning with 0.10 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.0093 mL (0.053 mMol) 5-nitro-2-furoyl chloride, 0.010 gm (64%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: FC1C=CC(C(Cl)=O)=CC=1.NC1C=CC=CC=1O.[F:19][C:20]1[CH:44]=[CH:43][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33]C(=O)C2C=CC(F)=CC=2)=[O:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:44]=[CH:43][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Nc1ccccc1OC(=O)c1ccc(F)cc1)c1ccc(F)cc1
Agent: Nc1ccccc1O
Agent: O=C(Cl)c1ccc(F)cc1
Product: O=C(Nc1ccccc1O)c1ccc(F)cc1

Procedure:
The examples below serve to illustrate the process according to the invention in more detail. 4-fluorobenzoic chloride (B) was added drop wise to a mixture of 2-aminophenol (A) in the respective solvent. The concentration of the 4-fluorobenzoic chloride (B) in the solvent [g/ml] is given in table 1. Afterwards the reaction was stirred under nitrogen. The conditions and results are listed in table 1. The amount of base is given as mol-equivalents based on the amount of 4-fluorobenzoic chloride (B). The reaction mixtures were analyzed after the indicated time by HPLC (254 nm, area %) in particular for determining the amount of 4-fluoro-Benzoic acid 2-[(4-fluorobenzoyl)amino]phenyl ester (i.e. the diacylated product, DAP). Then, 4-Fluoro-N-(2-hydroxyphenyl)-benzamide (IVa) was isolated resulting in the yields as indicated in the table 1 (purity >98% (HPLC at 254 nm)).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](I)=[CH:5][N:4]=1.[Cl:12][C:13]1[C:18](B(O)O)=[CH:17][CH:16]=[C:15]([CH3:22])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:12][C:13]1[C:18]([C:6]2[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)=[CH:17][CH:16]=[C:15]([CH3:22])[N:14]=1
Reactant: COc1ncc(I)c(OC)n1
Reactant: Cc1ccc(B(O)O)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: COc1ncc(-c2ccc(C)nc2Cl)c(OC)n1

Procedure:
2,4-Dimethoxy-5-iodopyrimidine (957 mg, 3.59 mmol) was dissolved in degassed n-PrOH (18 ml) and then 2-chloro-6-methylpyridine-3-boronic acid (923 mg, 5.39 mmol), Na2CO3 (761 mg, 7.2 mmol), PPh3 (94 mg, 0.35 mmol) and Pd(OAc)2 (40 mg) were added. The suspension was stirred at reflux for 3 hours. The solvent was evaporated under vacuum and the crude was partitioned between water and DCM. The organic phase was dried (Na2SO4) and evaporated to give the title compound that was used without further purification in the next step (quantitative yield).