Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1.[CH2:16]([O:23][C:24](=[O:30])[NH:25][CH2:26][CH2:27][C:28]#[CH:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([O:23][C:24](=[O:30])[NH:25][CH2:26][CH2:27][C:28]#[C:29][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#CCCNC(=O)OCc1ccccc1
Reactant: Ic1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCC#Cc1ccc(I)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.5 %

Procedure:
To a mixture of anhydrous THF and triethylamine (24 mL, 2/1, v/v) were sequentially added 1,4-diiodobenzene (2.03 g, 6.15 mmol) and copper (1) iodide (0.094 g, 0.246 mmol). The mixture was stirred at room temperature for 15 min. The flask was then evacuated and re-filled with Argon. The procedure was repeated three more times to ensure no oxygen remained. The catalyst, dichlorobis(triphenylphosphine)palladium(II) (0.173 g, 0.246 mmol) was added into the mixture under Argon protection. The other starting material, but-3-ynylcarbamic acid benzyl ester (0.50 g, 2.46 mmol), dissolved in THF (8 mL) was added dropwise over 6 hours. The newly formed reaction mixture was further stirred at room temperature overnight. The solid in the reaction mixture was vacuum filtered. The filtrate was concentrated. The residue was re-dissolved in dichloromethane and purified by column chromatography, eluting with a mixture of ethyl acetate (0-12%) and hexanes (100-88%) to afford the product 22 (0.852 g, 86%) as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 2.61 (t, J=6.4 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 5.07 (br s, 1H), 5.12 (s, 2H), 7.10 (d, J=8.3 Hz, 2H), 7.35 (m, 5H), 7.63 (d, J=8.3 Hz, 2H). m/z (APCI) 405 [C18H16NO2+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][C:16]2[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:17]=2[O:25][CH3:26])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=2[O:25][CH3:26])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc([N+](=O)[O-])cc1C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1CCc1cccc(NC(=O)OC(C)(C)C)c1
Yield: 94.5 %

Procedure:
tert-Butyl{3-[(2-methoxy-5-nitrophenyl)ethynyl]phenyl}carbamate (63 mg, 0.17 mmol) and 10% palladium on carbon (122 mg, 0.10 mmol) were stirred in N,N-dimethylformamide (3.0 mL) under an atmosphere of hydrogen for 16 hours. The mixture was diluted with ethyl acetate (9.0 mL) and filtered through celite. Evaporation of the filtrate gave the desired compound (55 mg, 94%). LCMS for C20H27N2O3 (M+H)+: m/z=343.2.
Reaction SMILES: [F:1][CH2:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.CO.C1C(=O)N(Br)C(=[O:16])C1>O>[F:1][CH2:2][S:3]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:16]
Reactant: Cc1ccc(SCF)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)CF)cc1
Yield: 87.7 %

Procedure:
(Fluoromethyl)(p-tolyl)sulfane (52.09 g, 320.06 mmol) was added to a mixture of methanol (250 mL) and water (50 mL). The resulting mixture was cooled to a temperature between 0° C. and 5°. NBS (68.36 g, 1.2 eq) was added in small portions, maintaining the same temperature range. The reaction mixture was stirred at the same temperature range until the reaction was complete. After that, the reaction mixture was quenched by the addition of Na2SO3 (10%, 150 mL). The pH of the reaction mixture was adjusted to a value between 7 and 8, with saturated NaHCO3 solution. The mixture was concentrated under vacuum at a temperature between 20° C. and 25° C. The residue was extracted with dichloromethane (200 mL, 150 mL). The combined organic layer was washed with water (2×300 ml) and concentrated to 1/3 of the volume. Heptane (50 mL) was added and then removed by distillation. The crude product was purified by flash chromatography (Ethyl Acetate/Hexane 30:70) to give 48.32 g (88%) of the desired product as a white solid.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@@H:9]([CH2:31][CH2:32][CH3:33])[CH:10]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:34][S:35]([O:8][C@@H:9]([CH2:31][CH2:32][CH3:33])[CH:10]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])(=[O:37])=[O:36]
Reactant: CCC[C@H](O)C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC[C@H](OS(C)(=O)=O)C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
500 ml of triethylamine are added to a solution of 236.9 g of 1 in 1.2 l of dichloromethane. With ice cooling, a solution of 83.6 ml of methanesulfonyl chloride in 200 ml of dichloromethane is added. The mixture is stirred at 5-100 for 30 minutes, the precipitated triethylamine hydrochloride is removed, and the product is subjected to conventional work-up, giving 2 as oil.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=[C:9]2[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=[O:21])[CH:18]=[CH:19][C:14]=3[CH2:13][CH2:12][C:11]3[CH:23]=[CH:24][CH:25]=[CH:26][C:10]2=3)[CH2:5][CH2:4]1.B(F)(F)F.[CH3:31][CH2:32]OCC>C(O)C>[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=[C:9]2[C:15]3[CH:16]=[C:17]([C:20]([O:22][CH2:31][CH3:32])=[O:21])[CH:18]=[CH:19][C:14]=3[CH2:13][CH2:12][C:11]3[CH:23]=[CH:24][CH:25]=[CH:26][C:10]2=3)[CH2:5][CH2:4]1
Reactant: CCOCC
Reactant: CN1CCC(=C2c3ccccc3CCc3ccc(C(=O)O)cc32)CC1
Agent: Cl
Agent: FB(F)F
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)C(=C1CCN(C)CC1)c1ccccc1CC2

Procedure:
A solution of 5.0 g 1-methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene) piperidine hydrochloride in 200 ml of absolute ethanol was treated with 5 ml of boron trifluoride etherate. After stirring and refluxing for 18 hours the ethanol was evaporated in vacuo and the residue was partitioned between saturated aqueous sodium carbonate solution and ether. The ether phase was separated, washed with 3×100 ml of water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue, 5.4 g of 1-methyl-4-(10,11-dihydro-3-ethoxycarbonyl-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, after recrystallization from acetonitrile had m.p. 85°-87° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[N:5]([CH2:8][C:9]#[CH:10])[C:6]=1[Cl:7].[OH-].[Na+].[I:23]I>CO.O>[Cl:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[N:5]([CH2:8][C:9]#[C:10][I:23])[C:6]=1[Cl:7]
Reactant: II
Reactant: C#CCn1c(Cl)c(Cl)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1c(Cl)c(Cl)n(CC#CI)c1-c1ccc(Cl)c(Cl)c1
Reaction time: 12 h

Procedure:
To a stirred mixture of 1.91 g (5.5 mmol) of 4,5-dichloro-2-(3,4-dichlorophenyl)-1-(2-propynyl)pyrrole-3-carbonitrile in 500 mL of methanol is added 69 mL of 10% aqueous sodium hydroxide and then 0.70 g (2.7 mmol) of iodine. The mixture is stirred for 12 hours and then acidified and diluted with 200 mL of water. The precipitated solids are collected and recrystallized from methanol to afford 0.51 g while crystals, m.p. 115°-116° C.
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]3[CH:41]=[CH:42][CH:43]=[C:44]4[C:49]=3[N:48]=[CH:47][CH:46]=[CH:45]4)[CH:35]=2)=[C:28]([C:51]#[N:52])[CH:27]=1>C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]3[CH:41]=[CH:42][CH:43]=[C:44]4[C:49]=3[N:48]=[CH:47][CH:46]=[CH:45]4)[CH:35]=2)=[C:28]([C:51]2[NH:52][N:7]=[N:6][N:5]=2)[CH:27]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1cc(Cl)ccc1NC(=O)c1cccc(-c2cccc3cccnc23)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)cc1-c1nnn[nH]1)c1cccc(-c2cccc3cccnc23)c1
Temperature: 100 °C
Reaction time: 66 h
Yield: 54 %

Procedure:
240 mg (2.08 mmol) of trimethylsilyl azide and 25.9 mg (0.10 mmol) of dibutyl tin oxide were added to a toluene (50 mL) solution comprising 400 mg (1.04 mmol) of N-(4-chloro-2-cyanophenyl)-3-(quinolin-8-yl)benzamide, and the mixture was stirred at 100° C. for 66 hours. The reaction mixture was condensed, and ethyl acetate was added thereto. Solids were collected by filtration. The obtained solids were recrystallized using DMF/IPE. The resulting solids were suspended in H2O, and stirred at 80° C. for 6 hours. Thereafter, diluted hydrochloric acid was added, and solids were collected by filtration and dried, thereby giving 242 mg of the target N-[4-chloro-2-(1H-tetrazol-5-yl)phenyl]-3-(quinolin-8-yl)benzamide (yield: 54%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:43])[C@H:10]([N:14]([CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32](C(OC(C)(C)C)=O)[CH:31]=[CH:30]2)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:11]([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:43])[C@H:10]([N:14]([CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:11]([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccc3c(ccn3C(=O)OC(C)(C)C)c2)[C@@H](C(=O)OCc2ccccc2)C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccc3[nH]ccc3c2)[C@@H](C(=O)OCc2ccccc2)C(C)C)cc1
Yield: 75.4 %

Procedure:
A solution of 2(R)-[(N-tert-butoxycarbonylindol-5-ylmethyl)-(4-methoxybenzene-sulfonyl)amino]-3-methylbutyric acid benzyl ester (2.7 g. 4.45 mmol) and trifluoroacetic acid (5 mL) in methylene chloride (15 mL) was stirred for 2 h at room temperature. The organics were removed under vacuum and the residue was dissolved in ethyl acetate (80 mL) and the ethyl acetate layer was washed with 5% sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated to give a white foamy solid which was chromatographed on a silica gel column eluting with (5-100%) ethyl acetate/hexanes. This procedure gave 2(R)-[(1H-indol-5-yl-methyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (1.7 g) as a white foamy semi-solid, which was converted to 2(R)-[(1H-indol-5-ylmethyl)-(4-methoxy-benzenesulfonyl)amino]-3-methylbutyric acid by following the procedure described in Example 1, Step 6 above.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([I:14])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:6]=[N:7][C:8]=2[C:13]=1[I:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2c(nnn2CC2CC2)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1c(OCc2ccccc2)ccc2c1nnn2CC1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(Cyclopropylmethyl)-4-iodo-1H-benzotriazol-5-ol (9.01 g, 28.6 mmol) was suspended in degassed N,N-dimethylformamide (75 mL) and treated with benzylbromide (3.74 mL, 31.5 mmol, 1.1 equiv) and potassium carbonate (19.8 g, 143 mmol, 5 equiv). The mixture was placed into a preheated oil bath at 50° C. for 30 minutes, cooled to ambient temperature, and diluted with water (500 mL). The mixture was extracted with dichloromethane (2×500 mL) and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+:42]>C(O)C.O>[OH:37]/[N:36]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][C@H:11]([C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]([O-:33])=[O:32])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[Na+:42]
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(N2CCC(C(=O)O)CC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(N2CCC(C(=O)[O-])CC2)cc1
Temperature: 120 °C
Yield: 61.1 %

Procedure:
To a microwave vial was added (R)-1-(4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)phenyl)piperidine-4-carboxylic acid (100 mg, 218 μmol), hydroxylamine hydrochloride (45.5 mg, 654 μmol) and sodium hydrogencarbonate (91.6 mg, 1.09 mmol) in ethanol (2 mL) and water (0.2 mL). The vial was capped and heated at 120° C. for 15 min, then hydroxylamine hydrochloride (45.5 mg, 654 μmol) and sodium hydrogencarbonate (91.6 mg, 1.09 mmol) were added again. The vial was capped and heated at 120° C. for 10 min, then the reaction mixture was evaporated. The residue was washed with dichloromethane, then suspended in dichloromethane/methanol 9:1 and filtered. The filtrate was concentrated and purified by chromatography (SiO2; gradient dichloromethane/methanol 19:1 to dichloro-methane/methanol 4:1) to afford the title compound (66 mg, 61%). Light brown solid, MS (ESI−): m/z=472.4 (M−H)−.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]([N:12]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)(=[O:18])=[O:17])COC)=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].I[C:32]1[C:33]2[CH:40]=[CH:39][N:38](COCC[Si](C)(C)C)[C:34]=2[N:35]=[CH:36][N:37]=1.CO.Cl>C1COCC1.C([Mg]Cl)(C)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:12][C:11]2[C:6]([C:4]([C:32]3[C:33]4[CH:40]=[CH:39][NH:38][C:34]=4[N:35]=[CH:36][N:37]=3)=[O:5])=[N:7][CH:8]=[CH:9][CH:10]=2)(=[O:18])=[O:17])=[CH:20][C:21]=1[C:26]([F:28])([F:27])[F:29]
Reactant: C[Si](C)(C)CCOCn1ccc2c(I)ncnc21
Reactant: COCN(c1cccnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1ncccc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ncnc2[nH]ccc12

Procedure:
Prepared from 248 mg (0.53 mmol) of 3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid methoxy-methyl-amide, 239 mg (0.58 mmol) of 90% 4-iodo-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine dissolved in 2 mL THF with 0.32 mL of 2 M isopropylmagnesium chloride solution in THF added. All of the resulting intermediate ketone was used in the second step with 4 mL methanol and 4 mL 6N hydrochloric acid mixture to give after purification 29 mg of the final product as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]#[C:11][C:12](=[O:17])[C:13]([Cl:16])([Cl:15])[Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20]([NH:25][NH2:26])=[N:21][CH:22]=[CH:23][CH:24]=1>C(OC)(C)(C)C>[CH2:1]([O:8][CH2:9][C:10]1[CH2:11][C:12]([C:13]([Cl:16])([Cl:15])[Cl:14])([OH:17])[N:25]([C:20]2[C:19]([Cl:18])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ncccc1Cl
Reactant: O=C(C#CCOCc1ccccc1)C(Cl)(Cl)Cl
Solvent: COC(C)(C)C
Product: OC1(C(Cl)(Cl)Cl)CC(COCc2ccccc2)=NN1c1ncccc1Cl
Temperature: 30 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
5-(Benzyloxy)-1,1,1-trichloropent-3-yn-2-one (2.9 g, 0.01 mol) and 3-chloro-2-hydrazinopyridine (1.43 g, 0.01 mol) were initially charged in 20 ml of methyl tert-butyl ether (exothermic), and the mixture was stirred at 30° C. for a further 1 h. The solvent was concentrated by rotary evaporation and the resulting mixture was analysed by means of LC/MS. Only one isomer at m/e 435 was identified. The yield was 94%, the purity 92% (area per cent).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[C:19]1([NH:18][C:15]([CH2:14][NH:13][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ncc2[nH]1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)c1cc2cc(Cl)ncc2[nH]1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of [(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino] acetic acid (EXAMPLE 40, 30 mg, 0.12 mmol) in DMF (2 mL) was added aniline (12 μL, 0.13 mmol), HOBt (16 mg, 0.12 mmol) and DIPEA (41 μL, 0.24 mmol). After 5 min, EDCI (29 mg, 0.15 mmol) was added, and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the solid partitioned between water (20 mL) and ethyl acetate (3×20 mL). The combined organic fractions were dried (MgSO4), concentrated in vacuo and the residue purified by chromatography on silica gel eluting with methanol/dichloromethane (1:19) to give the title compound as a yellow solid. m/z (ES+)=329 [M+H]+; RT=3.17 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:14]1[CH:19]=[CH:18][C:17]([C@H:20]([NH2:23])[CH2:21][OH:22])=[CH:16][CH:15]=1.Cl.[NH+]1C=CC=CC=1>COCCO.C(OCC)(=O)C>[OH:22][CH2:21][C@@H:20]([NH:23][C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)[C:17]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: N#Cc1cccc2c(Cl)ccnc12
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: COCCO
Product: N#Cc1cccc2c(N[C@H](CO)c3ccccc3)ccnc12
Reaction time: 2 h
Yield: 100.5 %

Procedure:
A solution of 4-Chloro-quinoline-8-carbonitrile (200 mg, 1.1 mmol), (S)-Phenylglycinol (160 mg, 1.2 mmol), pyridinium hydrochloride (138 mg, 1.2 mmol) in 2-methoxyethanol (3.5 mL) was placed in a microwave 150° C., 50 Watts for 2 h. The solution was diluted with ethyl acetate and washed with brine solution. Purification by silica gel (20-80% ethyl acetate/heptane) afforded 4-((S)-2-Hydroxy-1-phenyl ethylamino)-quinoline-8-carbonitrile (320 mg, 33%) as a white solid. LCMS (ESI) 290 (M+H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH2:14])[C:8]([OH:21])=[C:7]([CH3:22])[C:6]=1[CH3:23])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Ca+2].[I:29](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>O1CCCC1.CO>[C:1]([O:4][C:5]1[C:6]([CH3:23])=[C:7]([CH3:22])[C:8]2[O:21][CH:13]([CH2:14][I:29])[CH:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9]=2[C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: C=CC(c1ccccc1)c1c(C)c(OC(C)=O)c(C)c(C)c1O
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(c1ccccc1)C(CI)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a suspension of 4-hydroxy-2,3,6-trimethyl-5-(1-phenyl-2-propenyl)phenyl acetate (5.10 g, 16.4 mmol) and calcium carbonate (2.13 g, 21.3 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was added benzyltrimethylammonium dichloroiodate (6.28 g, 18.0 mmol) slowly. The mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with 10% aqueous sodium hydrogen sulfite, water, an aqueous saturated solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, treated with activated carbon, filtrated and the filtrate was concentrated in vacuo to provide 5.30 g of 2-iodomethyl-4,6,7-trimethyl-3-phenyl-2,3-dihydrobenzofuran-5-yl acetate. A mixture of this compound (5.30 g, 12.1 mmol) and 1,8-diazabicyclo[5,4,0]-7-undecene (9.0 m, 60.0 mmol) in toluene (20 mL) was stirred under an argon atmosphere at 100° C. for 3 hours. To that mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with 2N hydrochloric acid, and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain the title compound (4.0 g, yield 79%). This was oily.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CN(C)C=O>[Br:1][C:2]1[C:3]([O:21][CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: ClCCCN1CCOCC1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(Br)c(O)cc2N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN=C(c2ccccc2Cl)c2cc(Br)c(OCCCN3CCOCC3)cc2N1
Temperature: 50 °C
Reaction time: 73 h
Yield: 69.8 %

Procedure:
A mixture of 1.8281 g (0.005 mole) of 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-hydroxy-2H-1,4-benzodiazepin-2-one (Ipp) from the previous step, 0.636 g of sodium carbonate, 0.9818 g (0.006 mole) of 4-(3-chloropropyl)-morpholine and 50 mL of dimethylformamide was stirred at 50° C., under an argon atmosphere for 73 hours. The mixture was then cooled and partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was then reextracted with ethyl acetate. The ethyl acetate layers were washed successively with saturated sodium bicarbonate, water, brine and then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-(3-(4-morpholinyl)propoxy)-2H-1,4-benzodiazepin-2-one (Ij). Pure 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-(3-(4-morpholinyl)propoxy)-2H-1,4-benzodiazepin-2-one (Ij) (1.721 g) was obtained by silica gel chromatography eluting with ethyl acetate-methanol (90:10). MH+/Z=492.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:21])[NH:10][C:11](=S)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:21])[NH:10][C:11]([NH:23][NH2:24])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=c1[nH]c(=S)[nH]c(-c2ccncc2)c1-c1ccc(F)cc1
Solvent: O
Product: NNc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)[nH]1
Temperature: 120 °C

Procedure:
A mixture of 5-(4-fluorophenyl)-6-(4-pyridyl)-2-thiouracil (500 mg, 1.66 mmol) and hydrazine hydrate (800 ml, ˜14 mmol) was heated at 120° C. for 60 min. It was evaporated and the reaction product was recrystallized from hot methanol to provide the title compound. MS (m/z): 298.0 (M+H)+; C15H12FN5O requir. 297.3. 1H-NMR (DMSO-d6): d 8.41, 7.12 (2m, each 2H, Pyrid.), 7.05, 7.00 (2m, each 2H, PhF).