Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:3]=1>CN(C=O)C.[Pd]>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[N:3]=[CH:2][C:7]([C:8]#[N:9])=[CH:6][CH:5]=2)=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2)nc1Cl
Agent: [Pd]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(Cl)cc2)nc1

Procedure:
2-Chloro-6-(4-chlorophenyl)-3-pyridinecarbonitrile (2.49 grams) and 5% Pd/C (0.3 gram) were reacted on a Parr shaker in 100 ml DMF. Next the reaction mixture was filtered and the filtrate poured into ice water. A solid formed which was collected and recrystallized from ethanol, yield 0.85 gram.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[N:15]1[NH:16][CH:17]=[C:18]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20][C:19]=12>ClCCl.CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:16]2[CH:17]=[C:18]3[C:19]([CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]3)=[N:15]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c[nH]nc2CC1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(NS(C)(=O)=O)cc3)nc2CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To {4-[(methylsulfonyl)amino]phenyl}boronic acid (commercially available from e.g. Combi-Blocks) (127 mg, 0.29 mmol) in dichloromethane (3 ml) was added copper(II) acetate (107 mg, 0.59 mmol) and 4 Å molecular sieves (190 mg), and the reaction stirred at room temperature, open to air, for 10 minutes. 1,1-Dimethylethyl 4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 9) (70 mg, 0.29 mmol) was added and the reaction stirred at room temperature, open to air, overnight. The reaction mixture was diluted with methanol and filtered through a celite pad, washing with methanol. Solvent was evaporated in vacuo. Ethyl acetate and water were added, and the product was extracted into ethyl acetate (×3), washed with water (×1), then saturated sodium bicarbonate solution (×1), and then dried over magnesium sulfate. Solvent was evaporated in vacuo. The resulting crude product was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate in hexane (0-50%). Relevant fractions were combined and solvent evaporated in vacuo. The resulting crude product was purified further by Mass Directed Autopreparation to afford the title compound (D39). MS (ES+) m/e 407 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7](O)=[O:8].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([Cl:15])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Solvent: c1ccccc1
Product: O=C(Cl)C=Cc1cccc(Cl)c1

Procedure:
100 ml of benzene was added to 18.3 grams of m-chlorocinnamic acid. 12 ml of thionyl chloride was added dropwise slowly thereto at ambient temperature. The temperature was elevated to 80° C. and the heating was continued until foaming ceased. Benzene and thionyl chloride were distilled off and the residue was dried thoroughly under reduced pressure.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1>CC(O)C>[CH:8]([O:12][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1)([CH3:9])[CH3:7]
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Solvent: CC(C)O
Product: COc1ccc2c(OC(C)C)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and propan-2-ol to give (1-isopropoxy-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 299(MH+).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]=[C:21]([CH2:23][C:24]([O:26]C)=[O:25])[N:22]=2)=[CH:14][CH:13]=1>C(O)C>[CH3:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:19][CH:20]=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[N:22]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)Cc1coc(-c2ccc(OCCN3CCCC3C)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1CCCN1CCOc1ccc(-c2nc(CC(=O)O)co2)cc1
Yield: 278.3 %

Procedure:
A 2 N aqueous sodium hydroxide solution (2.6 ml, 5.23 mmol, 6 eq) is added to a solution of methyl (2-{4-[2-(2-methylpyrrolidin-1-yl)ethoxy]phenyl}-1,3-oxazol-4-yl)acetate 152 (0.3 g, 0.87 mmol, 1 eq) in ethanol (15 ml). The mixture is stirred at reflux for 3 h and the solvent is then evaporated. The residue is taken up in water, acidified with 2 N hydrochloric acid and the solvent is evaporated under reduced pressure to give 0.8 g of (2-{4-[2-(2-methylpyrrolidin-1-yl)ethoxy]phenyl}-1,3-oxazol-4-yl)acetic acid i53 together with remaining sodium chloride. The compound is used in the next step without any other treatment.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C@H:9]1[C:20](O)=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][C@H:9]1[CH2:20][OH:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1C(=O)O
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1CO
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 124.3 %

Procedure:
To a stirred solution of (2S, 4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylcarboxylic acid (2.39 g, 7.76 mmol) in THF (50 ml) was added BH3.DMS (1.55 ml, 15.5 mmol) at 0° C. After 10 min. stirring at the same temperature, the mixture was allowed to room temperature and then heated at 50° C. for 2 h. After cooling to room temperature, the mixture was concentrated in vacuo and quenched by the addition of water at 0° C. The mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was chromatographed on silica gel [60 g, CHCl3/MeOH (50/1)] to give (2S, 4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylmethanol (2.83 g, 100%) as a colorless oil. 1H-NMR (CDCl3) δ 1.47 (s, 9H), 1.95 (br, 1H), 2.36 (m, 1H), 3.56–3.74 (m, 3H), 3.89–4.52 (m, 3H), 4.85 (br, 1H), 6.84 (dd, J=8.8, 1.2 Hz, 2H), 6.97 (t, J=7.2 Hz, 1H), 7.29 (t, 2H, J=7.8 Hz).
Reaction SMILES: Br[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:27][C:28]1([CH3:35])[C:32]([CH3:34])([CH3:33])[O:31][BH:30][O:29]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[Cl-].[NH4+]>O1CCOCC1>[CH:14]1([C:3]2[C:4]3[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:5]=3[NH:6][C:2]=2[B:30]2[O:31][C:32]([CH3:34])([CH3:33])[C:28]([CH3:35])([CH3:27])[O:29]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC1(C)OBOC1(C)C
Reactant: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2[nH]c(B3OC(C)(C)C(C)(C)O3)c(C3CCCCC3)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of methyl 5-bromo-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (2.00 g, 5.84 mmol) in 1,4-dioxane (20 ml) was added triethylamine (3.20 ml, 22.9 mmol). 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (2.50 ml, 17.2 mmol) was added dropwise under an argon stream and the mixture was stirred at room temperature for 30 min. To the mixture were added 2-(dicyclohexylphosphino)biphenyl (245 mg, 0.699 mmol) and palladium acetate(II) (39.0 mg, 0.173 mmol) under an argon stream, and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. A mixed solvent of hexane-ethyl acetate (10:1) was added to the obtained residue and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to give methyl 6-cyclohexyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.66 g, yield 74%).
Reaction SMILES: [F:1][C:2]([F:18])([C@@H:7]([OH:17])[C@@H:8]([NH2:16])[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[C:3]([NH:5][CH3:6])=[O:4].C(NC(=O)C(F)(F)[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC1CCCCC1)C>>[F:1][C:2]([F:18])([C@@H:7]([OH:17])[C@H:8]([NH2:16])[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[C:3]([NH:5][CH3:6])=[O:4]
Reactant: CNC(=O)C(F)(F)[C@@H](O)[C@@H](N)CC1CCCCC1
Agent: CCNC(=O)C(F)(F)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Product: CNC(=O)C(F)(F)[C@@H](O)[C@H](N)CC1CCCCC1

Procedure:
An approximately 1:1 mixture (270 mg) of 2,2-difluoro-(R)-3-hydroxy-(S)-4-amino-5-cyclohexyl-N-methylvaleramide and 2,2-difluoro-(S)-3-hydroxy-(S)-4-amino-5-cyclohexyl-N-methylvaleramide obtained from 2,2-difluoro-(R,S)-3-hydroxy-4-t-butoxycarbonylamino-5-cyclohexyl-valeramide ethyl ester was treated according to the procedure of Example 1 with triethylamine, Mor-Phe-Nle, HBT and DCC to give, after identical workup and chromatography, the title substance (266 mg, 47%) which was well separated from the slightly less polar isomer (product of Example 1 (160 mg, 28%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:17]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:17]=2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cccc(CCN(C)C)c1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1cccc(CCN(C)C)c1
Yield: 77.5 %

Procedure:
Following general procedure F, 1-{6-bromo-4-[3-(2-(dimethylamino)ethyl)phenylamino]quinolin-3-yl}ethanone (50 mg, 0.120 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (52 mg, 0.180 mmol) to afford the desired product (46 mg, 77%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.31 (s, 1H), 8.20 (dd, J=8.8, 2.0 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.72 (s, 1H), 7.70-7.56 (m, 2H), 7.51 (s, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.10 (s, 2H), 3.40-3.30 (m, 2H), 3.21-3.11 (m, 2H), 2.94 (s, 6H), 2.82 (s, 3H); ESI MS m/z 494 [C27H25Cl2N3O2+H]+; HPLC 96.8% (AUC), tR=8.94 min.
Reaction SMILES: C([O:8][C:9](=[O:46])[CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][N:25]([C:29](=[N:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]3)=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1>O1CCCC1.CO.[C].[Pd]>[C:42]([O:41][C:39]([NH:38][C:29]([N:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][C:19]([O:18][CH2:17][CH:14]3[CH2:13][CH2:12][N:11]([CH2:10][C:9]([OH:46])=[O:8])[CH2:16][CH2:15]3)=[CH:20][CH:21]=2)[CH2:26]1)=[N:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])=[O:40])([CH3:43])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(CC(=O)OCc4ccccc4)CC3)cc2C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(CC(=O)O)CC3)cc2C1
Yield: 95.1 %

Procedure:
4-[2-(N,N′-Di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidine-1-acetic acid benzyl ester (735 mg) was hydrogenated using 7.5% palladium carbon (220 mg) in a mixture of tetrahydrofuran (7 ml) and methanol (14 ml) at atmospheric pressure over 3 hours. After completion of the reaction, the reaction mixture was filtered through celite and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (600 mg).
Reaction SMILES: [CH2:1](B1OC(C)(C)C(C)(C)O1)[CH:2]=[CH2:3].[CH:13]([C:15]1[C@H:20]([C:21]([O:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[N:19]2[C:37](=[O:49])[C@@H:38]([NH:39][C:40](=[O:48])[CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@H:18]2[S:17][CH:16]=1)=[O:14]>C1(C)C=CC=CC=1>[OH:14][CH:13]([C:15]1[C@H:20]([C:21]([O:23][CH:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:22])[N:19]2[C:37](=[O:49])[C@@H:38]([NH:39][C:40](=[O:48])[CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C@H:18]2[S:17][CH:16]=1)[CH2:3][CH:2]=[CH2:1]
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Reactant: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=CCC(O)C1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
A mixture of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50 mg, 0.3 mmol), diphenylmethyl (4R, 6R, 7R)-3-formyl-7-phenylacetamidoceph-2-em-4-carboxylate (100 mg, 0.2 mmol), 0.4 nm molecular sieves (50 mg), and toluene (2 ml) was heated under reflux for 3 h and then cooled and purified by chromatography as in part a to give the title compound S-diastereomer, 20 mg (18%), and the R-diastereomer, 23 mg (20%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:50])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([NH:45][CH2:46][CH2:47][O:48][CH3:49])[N:39]=2)[CH:33]=1)=O)(C)(C)C>>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:28](=[O:50])[CH2:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([NH:45][CH2:46][CH2:47][O:48][CH3:49])[N:39]=4)[CH:33]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: COCCNc1nc(C)cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Product: COCCNc1nc(C)cc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (160 mg, 0.5 mmol) and 3-{3-[2-(2-methoxy-ethylamino)-6-methyl-pyrimidin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K51) (212 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (84 mg).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[OH:20])#[N:2].I[CH3:22].[H-].[Na+].Cl>O>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[O:20][CH3:22])#[N:2]
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 5-(4-cyano-3-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (100 mg, 0.375 mmol) and iodomethane (0.070 mL. 1.1 mmol) in 1V,N-dimethylformamide (10 mL) was added sodium hydride (60% oil dispersion, 45 mg, 1.1 mmol) at 0° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 2 h. Water and 1 M HCl were added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with hexane/diisopropyl ether to give 5-(4-cyano-3-methoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (92 mg, 87%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.C([O:15][C:16](F)(F)[CH:17]([F:19])[F:18])C>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:16](=[O:15])[CH:17]([F:18])[F:19])[CH3:2]
Reactant: CCOC(F)(F)C(F)F
Reactant: CCNCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)C(F)F
Reaction time: 0.33 h
Yield: 93.4 %

Procedure:
The crude reaction gas was bubbled at 10° C. in a 2 l plastic bottle charged with 219 g (3.0 mols) of diethylamine, 303 g (3.0 mols) of triethylamine and 300 g of methylene chloride. Then, 365 g (2.5 mols) of 1-ethoxy-1,1,2,2-tetrafluoroethane was fed over a period of about 75 minutes. Then, nitrogen was supplied to the gas phase reactor at a rate of 200 cc/min for 20 minutes. The crude reaction solution was washed with 2 l of water, and the aqueous phase was extracted with 300 g of methylene chloride. The organic layers were put together and distilled to obtain 353 g (yield: 93.5%) of N,N-diethyl difluoroacetic acid amide (boiling point: 64° C./11 torr) having a purity of at least 99.5%.
Reaction SMILES: Cl[CH:2]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C1COCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:10][CH:11]=1
Reactant: Clc1ccc(C(Cl)c2ccccc2)cc1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1

Procedure:
Synthesized according to General Procedure A: chloro(4-chlorophenyl)phenylmethane (4{26}, 5 mL, 26.1 mmol, 1 equiv.), piperazine (13.5 g, 156.7 mmol, 6 equiv.), THF (57.0 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{26} (6.34 g, 85%) as a yellow liquid. 1H-NMR (500 MHz, CDCl3): δ 7.39-7.37 (m, 4H), 7.30-7.24 (m, 4H) 7.20 (t, 1H, J=7.5 Hz), 4.21 (s, 1H), 2.89 (t, 4H, J=5.0 Hz), 2.36 (br s, 4H), 1.82 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 142.0, 141.2, 132.4, 129.2, 128.5, 128.5, 127.8, 127.0, 75.9, 53.2, 46.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[Cl-].[Cl:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:16]=1[CH:17]=[N+:18]([CH3:20])[CH3:19].ClC1C=CC=C(F)C=1C=O.CNC>>[Cl:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:16]=1[CH:17]([N:18]([CH3:20])[CH3:19])[C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[NH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: C[N+](C)=Cc1c(F)cccc1Cl
Agent: CNC
Agent: O=Cc1c(F)cccc1Cl
Agent: [Cl-]
Product: CN(C)C(c1c(F)cccc1Cl)c1c[nH]c2cccc([N+](=O)[O-])c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-nitroindole and (2-chloro-6-fluoro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2-chloro-6-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:16]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:18])[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH:16]([CH3:18])[CH3:17])=[CH:21][CH:22]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Product: CCOC(=O)c1cc2cc(-c3ccc(OC(C)C)cc3)ccc2[nH]1

Procedure:
The sub-title compound was prepared in accordance with Example 1(a) form 5-bromoindole-2-carboxylic acid ethyl ester and 4-isopropoxyphenylboronic acid.
Reaction SMILES: [CH3:1][C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[CH2:24]C(O)=O>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[CH2:24][C:3]1[C:4](=[O:5])[CH:6]2[CH:11]([C:12](=[O:13])[C:2]=1[CH3:1])[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CC1=CC(=O)c2ccccc2C1=O
Reactant: COc1ccc(OC)c(CC(=O)O)c1
Product: COc1ccc(OC)c(CC2=C(C)C(=O)C3C=CC=CC3C2=O)c1
Yield: 80 %

Procedure:
As starting materials for the coupling reaction menadione and 2,5-dimethoxyphenylacetic acid were used. Synthesis is realized according to the general procedure described in general procedure of example 1. After chromatography on silica gel (petroleum ether:CH2Cl2=1:3, UV), 1.96 g (6.08 mmol, 80% yield) of P_TM60 were isolated as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](SC)[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:22][NH2:23])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 72 h

Procedure:
To a solution of 2 parts of 7-chloro-2-methylmercapto-5-phenyl-3H-1,4-benzodiazepine in 70 parts by volume of ethanol is added 5 parts by volume of 80% hydrazine hydrate and the mixture is allowed to stand at room temperature for 3 days. After evaporation of the solvent, a small amount of water is added to the residue, whereby 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine is obtained as crystals. Recrystallization from a mixture of methylene chloride and benzene gives crystals. Melting point; 175° C (browning), 205° C to 207° C (decomposition).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:25]>>[C:1]1([CH2:11][CH:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([Cl:25])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(Cc1ccccc1)Cc1cccc2ccccc12
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C(Cc1ccccc1)Cc1cccc2ccccc12
Yield: 100 %

Procedure:
A solution of 1.5 9 (5.2 mmol) of 2-(1-naphthylmethyl)-2-benzylacetic acid in 10 mL SOCl2 was stirred at room temperature overnight. The SOCl2 was removed under reduced pressure, the residue taken up in Et2O, and the solvent again removed under reduced pressure to give 1.6 g (100% yield) of the product as an oil.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][CH2:29][CH2:30][Cl:31]>CN(C)C=O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:28][CH2:29][CH2:30][Cl:31])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCCBr
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Solvent: CN(C)C=O
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCCl)cc12
Yield: 27 %

Procedure:
6-(3-Chloro-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime was prepared in 27% yield using the method described in example 85A, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) and 1-bromo-3-chloropropane in dimethylformamide. The title compound was isolated as a yellow solid.