Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH2:20][CH3:21])[C:6]1=[O:22])=[O:4].[NH2:23][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:28]>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH2:20][CH3:21])[C:6]3=[O:22])=[O:4])[CH:39]=[CH:38][CH:37]=2)=[O:28])=[CH:31][CH:32]=1
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C3(C)OCCO3)ccc21
Reactant: Nc1cccc(C(=O)Nc2ccc(Cl)cc2)c1
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)Nc3ccc(Cl)cc3)c2)c2cc(C(C)=O)ccc21

Procedure:
Prepared as in Example 1 from 1-ethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-(4-chloro-phenyl)-benzamide. Recrystallized from ethyl acetate-hexanes. mp 119-121° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([C:36](O)=[O:37])[CH:27]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:36]([C:28]3[CH:27]=[C:26]([O:25][CH3:24])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[O:37])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: COc1cc(C(=O)O)nc2ccccc12
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: COc1cc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)nc2ccccc12

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 4-methoxy-quinoline-2-carboxylic acid. LC-MS (basic): tR=0.88 min; [M+H]+=518.1.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:13]=[CH:12][C:9]([NH:10][CH3:11])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.CO.[CH3:21][N:22](C=O)[CH3:23]>CNC>[OH:18][CH:16]([CH2:17][N:22]([CH3:23])[CH3:21])[CH2:14][N:10]([C:9]1[CH:12]=[CH:13][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1)[CH3:11]
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=O
Reactant: BrCC1CO1
Agent: CNC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: CN(C)CC(O)CN(C)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 86 %

Procedure:
Sodium hydride (60% dispersion in oil; 290 mg, 7.2 mmol) was added portionwise over 30 minutes to a solution of 4-nitro-N-methylaniline (1.0 g, 6.6 mmol) in DMF (30 ml) at 0° C. Epibromohydrin (0.62 ml, 7.2 mmol) was added dropwise to the solution at 0° C. and the mixture was left to stand overnight. Volatile material was removed by evaporation and the residue was dissolved in a solution of dimethylamine in methanol (5.6M, 132 mmol). The solution was left to stand for 12 hours and then concentrated. The residue was dissolved in DCM (200 ml) and the solution was washed with water (3×20 ml) and saturated sodium chloride (20 ml) and dried. Evaporation gave the product as an orange solid (1.44 g, 86%). MS (MH+): 254.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][NH:30][NH2:31])=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[I:1][C:2]1[C:7]([C:8]([NH:31][NH:30][CH2:29][C:28]2[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[O:10])=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1
Reactant: COc1nccc(I)c1C(=O)O
Reactant: COc1ccc(CNN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNNC(=O)c2c(I)ccnc2OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
To a solution of 4-iodo-2-methoxynicotinic acid (3.00 g) obtained in Step C of Example 6 in DMF (100 mL) were added DIEA (1.88 mL), (4-methoxybenzyl)hydrazine hydrochloride (2.06 g), EDCI hydrochloride (2.03 g) and HOBt (1.45 g) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was washed with ethyl acetate/diisopropyl ether to give the title compound (1.52 g).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].C(=O)([O-])[O-:11].[Ag+2:14]>>[S:4]([CH2:3][C:2]([F:9])([F:8])[F:1])([O-:11])(=[O:6])=[O:5].[Ag+:14]
Reactant: [Ag+2]
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Product: O=S(=O)([O-])CC(F)(F)F
Product: [Ag+]
Yield: 99 %

Procedure:
The procedure of Example 2 was used except that the starting material was 4.30 mL of 2,2,2-trifluoroethanesulfonyl chloride. The crude acid was reacted with 10 g of silver carbonate giving after workup 10.63 g (99% yield) of silver tresylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N(Br)C(=[O:34])C1.C([O-])(O)=O.[Na+]>O.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]=[O:34])[N:8]=[C:7]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:6]=[CH:5]2
Reactant: Cc1cc2nc(-c3ccccc3)ccc2cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1cc2nc(-c3ccccc3)ccc2cc1Cl
Temperature: 90 °C
Reaction time: 3 h

Procedure:
The CCl4 (45 ml) solution of 6-chloro-7-methyl-2-phenylquinoline (753.3 mg, 2.969 mmol), AIBN (48.8 mg, 0.1 eq.) and NBS (898.4 mg, 1.7 eq.) was heated at 80° C. under N2 for 8 h. After that time, the reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (60 ml), washed successively with H2O (30 mL), saturated NaS2O3 (30 mL), H2O (30 mL), and brine (30 mL). The organic extract was then dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in DMSO (105 mL), and then NaHCO3 (2495 mg, 10 eq.) was added. The reaction mixture was stirred at 90° C. for 3 h. Water (140 mL) was added and the mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were washed with H2O (4×60 mL) and brine (60 mL), and dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized from CHCl3/hexane (20:80, 10 mL) to give 6-chloro-2-phenylquinoline-7-carbaldehyde as pale-yellow solid; 1H NMR (CDCl3, 400 MHz) δ 7.51-7.58 (m, 3H), 7.93 (s, 1H), 8.03 (d, 1H, J=8.8 Hz), 8.18-8.20 (m, 3H), 8.75 (s, 1H), 10.63 (s, 1H); MS (ES+): 268.1/270.0 (M/M+2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11].N1C=CC=CC=1CCNC(C1C(C2C=CC=CC=2)=CC=CC=1CN[C:45]([O:47][CH:48]([CH3:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][C:45]([O:47][C@H:48]([CH3:55])[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1
Reactant: CC(OC(=O)NCc1cccc(-c2ccccc2)c1C(=O)NCCc1ccccn1)c1ccccc1
Product: C[C@@H](OC(=O)NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1)c1ccccc1

Procedure:
From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)-ethylamide (precursor 5d) and (R)-α-methylbenzyl N-succinimido-carbonate (precursor 4i), according to the general working procedure 60 mg of (R)-2′-(α-methylbenzyloxycarbonylaminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained. MS (ES+): m/e=480 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[Cl-:19].[NH4+]>O1CCCC1.C([Mg]Cl)CC1C=CC=CC=1>[CH3:18][N:2]([CH3:1])[C:3]1([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH2:8][CH2:7][C:6]([CH2:11][CH2:10][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)([OH:9])[CH2:5][CH2:4]1.[ClH:19].[CH3:18][N:2]([CH3:1])[C:3]1([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH2:8][CH2:7][C:6]([CH2:11][CH2:10][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)([OH:9])[CH2:5][CH2:4]1
Reactant: CN(C)C1(Cc2ccccc2F)CCC(=O)CC1
Reactant: [Cl-]
Agent: Cl[Mg]CCc1ccccc1
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(Cc2ccccc2F)CCC(O)(CCc2ccccc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.79 g 4-dimethylamino-4-(2-fluorobenzyl)cyclohexanone were dissolved in 35 ml analytical grade tetrahydrofuran, 42 ml 1.0 molar phenethylmagnesium chloride solution in THF were added under a nitrogen atmosphere, while cooling in an ice-bath, and the mixture was stirred overnight at room temperature. For working up, 42 ml ammonium chloride solution (20 per cent by weight) were added, while cooling with ice, the phases were separated, the aqueous phase was extracted three times with 50 ml diethyl ether each time, the combined organic phases were washed with 30 ml water and extracted three times with 50 ml dilute hydrochloric acid (5 per cent by weight) each time, the combined aqueous extracts were washed with 50 ml diethyl ether, adjusted to pH 9 with ammonia solution (25 per cent by weight) and extracted three times with 50 ml methylene chloride each time, the combined methylene chloride extracts were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. The crude product obtained (7.76 g) was chromatographed over silica gel with diethyl ether/hexane (v/v=1:1). 1.33 g of the nonpolar diastereoisomer of 4-dimethylamino-4-(2-fluorobenzyl)-1-phenethylcyclohexanol were obtained, from which 536 mg of the corresponding hydrochloride were prepared as described for example 4.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH2:8]([OH:10])[CH3:9].[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15].C(N(CC)CC)C.Cl>ClCCl>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH:15][S:2]([NH:5][C:6](=[O:7])[O:10][CH2:8][CH3:9])(=[O:4])=[O:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(CN)OC
Reactant: CCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NS(=O)(=O)NCC(OC)OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 54.6 %

Procedure:
A solution of chlorosulfonylisocyanate (11.32 g, 80 mmol) in dichloromethane (120 mL) was cooled to 0° C. Ethanol (4.67 mL, 80.0 mmol, 1.0 equiv.) was added via addition funnel. The mixture was stirred at 0° C. for 1.5 h. To this mixture was added a solution of aminoacetaldehyde dimethyl acetal (8.76 mL, 80.0 mmol, 1.0 equiv.), triethylamine (TEA, 33.4 mL, 240 mmol, 3.0 equiv.) in dichloromethane (DCM, 120.0 mL) drop-wise via addition funnel 0° C. The reaction was warmed to room temperature and stirred overnight. The reaction was treated with 0.1 N hydrochloric acid and the collected organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuum to give the desired product (11.2 g, 55%) as a crude off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.13 (s, 1H), 7.81 (t, 1H, J=6.0 Hz), 4.37 (t, 1H, J=5.5 Hz), 4.09 (q, 2H, J=7.1 Hz), 3.23 (s, 6H), 2.97 (dd, 2H, J=5.8 Hz), 1.19 (t, 3H, J=7.1 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:13])=[O:12].[OH-:14].[Na+].O>C(O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:9][C:2](=[O:14])[CH:3]=[CH:4][C:5]2[CH:8]=[CH:13][C:11]([OH:12])=[CH:10][CH:6]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccc(O)cc1)C=Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
4-Hydroxybenzaldehyde (1f, 2.00 g, 16.4 mmol) and acetone (19, 0.61 ml, 8.3 mmol) were combined in ethanol (30 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (1.00 g, 25.0 mmol) and water (30 ml) was added and the mixture stirred for 4 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from ethyl acetate/hexane to give 0.85 g (39%) of a yellow solid: mp 235-237° C. [expected mp 238-239° C.]; 1H NMR: (DMSO) δ 6.82 (d, 4H, J=8.5 Hz), 7.08 (d, 2H, J=16.1 Hz), 7.61 (d, 4H, J=8.5 Hz), 7.64 (d, 2H, J=15.7 Hz), 10.08 (s, 2H); 13C NMR: (DMSO) δ 115.8, 122.6, 125.7, 130.3, 142.3, 159.7, 187.9.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([F:16])[CH:5]=1)(=O)[CH3:2].O.NN.[OH-].[K+].C(O)COCCO>C1(C)C(C)=CC=CC=1>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:6]([F:16])[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccccc2)c(F)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: OCCOCCO
Product: CCc1ccc(-c2ccccc2)c(F)c1
Yield: 67.8 %

Procedure:
4-Acetyl-2-fluorobiphenyl (150 gram), 99% hydrazine hydrate (150 ml), potassium hydroxide (105 gram), digol (900 ml) and xylene (150 ml) were heated at 125° C. for 16 hours with stirring, after which the xylene and excess hydrazine hydrate were distilled until the internal temperature reached 165° C. The mixture was heated under reflux for three hours, cooled to 40° and poured into 5 liters of water. The product was extracted with petroleum ether (bp 60°-80°, 2×2 liter), the extract washed with water, dried over anhydrous sodium sulphate and evaporated. 4-Ethyl-2-fluorobiphenyl (95 gram, 68% theory) formed a colourless oil bp 130°/0.8 mm. Other 4-Alkyl-2-fluorobiphenyls were prepared by reaction of 2-fluoro-4-biphenylyl magnesium bromides with n-alkyl bromides and were colourless oils with the following properties listed in Table 5.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11]>C(N)CC.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.[Cu]I>[OH:12][CH2:9][C:10]#[C:11][C:4]1[CH:3]=[C:2]([C:11]#[C:10][CH2:9][OH:12])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCO
Reactant: Brc1cccc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCN
Product: OCC#Cc1cccc(C#CCO)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.4 %

Procedure:
A solution of 1,3-dibromobenzene (0.6 ml, 5.0 mmol) in n-propylamine (15 ml) is admixed successively with Pd(Ph3P)4 (116 mg, 2%), CuI (28 mg, 3%) and propargyl alcohol (0.9 ml, 15 mmol) and stirred at RT for 20 h. More Pd(Ph3P)4 (58 mg, 1%), CuI (14 mg, 1.5%) and propargyl alcohol (0.45 ml, 7.5 mmol) are then added, and the mixture is stirred at reflux for a further 6.5 h. After cooling, the reaction mixture is filtered off with suction over kieselguhr, and the filter cake is washed with ethyl acetate (20 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [Tol/Ac (8:2)] over a silica gel column. This gives the title compound (0.6 g) as a colorless oil. TLC, silica gel (glass plates), [toluene/acetone (8:2)], Rf=0.22.
Reaction SMILES: [CH2:1]1COCC1.C([Li])CCC.[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([Cl:23])[N:16]=1)([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[C:11]([C:15]1[N:16]=[C:17]([Cl:23])[C:18]([CH:19]=[CH2:1])=[CH:21][CH:22]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C1CCOC1
Reactant: CC(C)(C)c1ccc(C=O)c(Cl)n1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C=Cc1ccc(C(C)(C)C)nc1Cl
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a diethyl ether (17 ml) solution of 6-ten-butyl-2-chloronicotinonitrile (Tetrahedron 1965, 21, 2453-2467, 1.0 g, 5.4 mmol) was added 0.94 M diisobutylaluminum hydride in toluene solution (8.6 ml, 8.0 mmol) at −78° C. and the reaction was allowed to warm to room temperature over 2 hours with stirring. Then the reaction was quenched with 10% potassium sodium tartrate tetrahydrate aqueous solution and the whole was extracted with EtOAc, and washed with 2M sodium hydroxide aqueous solution and brine. The organic layer was evaporated and purified by silica gel column chromatography, eluting with hexane/EtOAc (5:1), to give 6-tert-butyl-2-chloronicotinaldehyde (1.0 g, 95%). To a THF (24 ml) suspension of methyltriphenylphosphonium bromide (5.3 g, 14.8 mmol) was added 1.60 M n-butyllithium (9.3 ml, 14.8 mmol) in hexane solution at 0° C. and the reaction was stirred for 30 minutes. Then to this mixture was added a THF (5 ml) solution of the 6-tert-butyl-2-chloronicotinaldehyde (1.0 g, 5.2 mmol) at 0° C., and the reaction was stirred for 2 hours at room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution, and the whole was extracted with EtOAc, and dried over magnesium sulfate. The organic layer was evaporated and purified by silica gel column chromatography, eluting with hexane/EtOAc (10:1), to give the title compound (735 mg, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:11])=[N:5][C:6]([Cl:10])=[C:7]([Br:9])[N:8]=1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>>[Br:9][C:7]1[N:8]=[C:3]([O:2][CH3:1])[C:4]([NH:11][S:20]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=2[Cl:12])(=[O:22])=[O:21])=[N:5][C:6]=1[Cl:10]
Reactant: COc1nc(Br)c(Cl)nc1N
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Product: COc1nc(Br)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Procedure as for Example 1 (reaction performed at room temperature) using 3-methoxy-5-bromo-6-chloro-2-pyrazinamine (Example 125a) (0.5 g) and 2,3-dichlorobenzenesulphonyl chloride (2.21 g). Yield 3.2 g.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([OH:11])[C@H:3]1[O:8][C:6](=[O:7])[C@@H:5]([OH:9])[C@H:4]1[OH:10].C[C:14]([CH3:17])(C)[CH3:15].[CH3:18][C:19]([CH3:21])=O>>[CH3:18][C:19]1([CH3:21])[O:11][CH:2]([CH:3]2[O:8][C:6](=[O:7])[CH:5]3[O:9][C:14]([CH3:17])([CH3:15])[O:10][CH:4]23)[CH2:1][O:12]1
Reactant: CC(C)(C)C
Reactant: CC(C)=O
Reactant: O=C1O[C@H]([C@@H](O)CO)[C@H](O)[C@@H]1O
Product: CC1(C)OCC(C2OC(=O)C3OC(C)(C)OC32)O1

Procedure:
L-Gulonolactone is treated with acetone and dimethylpropane to give the lactone, 2,3:5,6-di-O-isopropylidene-L-gulonolactone.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:11]=2[O:10][CH2:9][C:8]1=[O:24])=[N+]=[N-].[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[C:35](O)=[O:36].Cl.CN(C)CCCN=C=NCC>C(O)C.CN(C=O)C.C(OCC)(=O)C.[C].[Pd]>[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[C:35]([NH:1][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:11]=2[O:10][CH2:9][C:8]1=[O:24])=[O:36]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: [N-]=[N+]=NCCCN1C(=O)COc2c(OC3CCCCO3)cccc21
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(NCCCN1C(=O)COc2c(OC3CCCCO3)cccc21)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 51.7 %

Procedure:
A solution of 4-(3-azidopropyl)-3-oxo-8-(tetrahydropyran-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine (1.0 g) in ethanol (10 ml) was added to a suspension of 10% palladium carbon (containing 50% water) (100 mg) in ethanol (20 ml), and the mixture was stirred at room temperature for 22 hours under a hydrogen atmosphere. The reaction solution was filtered with Celite, and the solvent was distilled off under reduced pressure to obtain a crude amine. The thus-obtained crude amine was dissolved in DMF (10 ml), and 2-naphthalenecarboxylic acid (780 mg) and 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (865 mg) were added to the resultant solution, and the mixture was stirred at room temperature for 19 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by column chromatography (silica gel:ethyl acetate/n-hexane=3:2) to obtain the object compound (717 mg, yield 55%).
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[C:9]2[CH2:10][N:11]([CH3:27])[CH2:12][C:13]3[N:14]([C:15](=O)[NH:16][C:17]=3[C:18]#[C:19][C:20]3([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:28]I>CS(C)=O>[Cl:3][C:4]1[C:9]2[C:10](=[O:1])[N:11]([CH3:27])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[C:18]#[C:19][C:20]3([O:25][CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: [OH-]
Reactant: CN1Cc2c(Cl)cccc2-n2c(c(C#CC3(O)CCCC3)[nH]c2=O)C1
Agent: [K+]
Solvent: CS(C)=O
Product: COC1(C#Cc2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)CCCC1

Procedure:
2.35 g (42 mmol) of freshly powdered potassium hydroxide was stirred in 30 ml of dimethyl sulfoxide for 5 minutes. There were then added in succession 4.0 g (11.25 mmol) of 7-chloro-4,5-dihydro-3-[(1-hydroxycyclopentyl)ethynyl]-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine-one and 3.12 g (22.5 mmol) of methyl iodide and the mixture was stirred for a further 1 hour before the dimethyl sulfoxide was removed by evaporation. The residue was taken up in water and extracted three times with methylene chloride. The combined organic extracts were dried over magnesium sulphate, evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate/hexane (1:1). After recrystallization from ethyl acetate there was obtained 7-chloro-4,5-dihydro-3-[(1-methoxycyclopentyl)ethynyl]-5-methyl-6H-imidazo[1,5-a][1,4]-benzodiazepin-6-one of melting point 174°-175°.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:35])[CH3:34]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c1
Reactant: CC(=O)Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c[nH]c23)c1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A154) and acetyl chloride the title compound is obtained as colorless solid.