Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N=C=N)C.[NH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1.N1C=CC=CC=1.[CH2:32]1C[O:35][CH2:34][CH2:33]1.CN(C=O)C>>[ClH:25].[Cl:25][C:21]1[CH:20]=[C:19]([NH:18][C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([NH:7][C:34](=[O:35])[CH:33]=[CH2:32])[CH:9]=3)[N:14]=[CH:13][N:12]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: C1CCOC1
Reactant: Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Agent: CCN=C=N
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Temperature: 0 °C
Yield: 48 %

Procedure:
1-3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1902 mg, 1 mmol) was added to a solution of 6-amino-4[(3-chlorophenyl)amino]quinazoline (136 mg, 0.5 mmol) acrylic acid (74 mg, 1.0 mmol) and pyridine (201 mg, 2.5 mmol) in THF/DMF (4:1, 2.5 mL), stirred under nitrogen at 0° C. After 20 minutes the reaction mixture was stirred at 25° C. for 3 hours, and then poured onto water (12.5 mL), and extracted with EtOAc (2×10 mL). The combined extracts were treated with dilute hydrochloric acid (0.5 M, 10 mL), and the precipitate was collected by Buchner filtration, rinsed with water (10 mL), ether (2×10 mL), and air dried to give N-[4-[(3-chlorophenyl)amino]quinazolin-6-yl] acrylamide hydrochloride (93 mg, 48%) as a dull yellow solid, mp 223-227° C.
Reaction SMILES: Br[C:2]1[C:3]2[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C([Li])CCC.CON(C)[C:20](=[O:23])[CH2:21][CH3:22]>O1CCCC1.CCOCC>[F:11][C:10]1[C:3]2[CH:2]=[C:6]([C:20](=[O:23])[CH2:21][CH3:22])[S:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCC(=O)N(C)OC
Reactant: Fc1cccc2scc(Br)c12
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(=O)c1cc2c(F)cccc2s1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
A solution of 3-bromo-4-fluorobenzo[b]thiophene (3.0 g) in tetrahydrofuran (10 ml) was added dropwise under nitrogen at −60-−70° C. over 10 minutes to a stirred solution of n-butyllithium (2.5M solution in hexanes; 6.75 ml) in ether (30 ml), then the mixture was stirred at −70° C. for 30 minutes. A solution of N-methoxy-N-methylpropionamide (1.31 g) in tetrahydrofuran (10 ml) was added dropwise at −70° C. over 10 minutes, then the mixture was stirred at −70° C. for 5 hours and allowed to stand at ambient temperature for 12 hours. The mixture was quenched by the addition of saturated aqueous ammonium chloride solution (40 ml), then the organic layer was separated, washed with saturated aqueous sodium chloride solution (40 ml), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 10:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(4-fluorobenzo[b]thiophen-2-yl)propan-1-one (0.54 g) as a colourless solid which was used without further purification.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C=O)C>[NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][O:4][CH2:19][CH:18]=[CH2:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.4 %

Procedure:
To a mixture of Boc-Ser-OH (21.5 g, 0.105 mol) in DMF at 0° C. was added sodium hydride (8.4 g, 0.21 mol). The reaction mixture was stirred at 0° C. for 15 mins, and then allyl bromide (13.3 g, 0.105 mol) was added. The mixture was stirred at 40° C. overnight. After TLC showed the reaction was completed, the mixture was quenched with aqueous NH4Cl solution and concentrated in vacuum. The residue was diluted with water, and sequentially washed with hexane and ether. The organic layers were discarded, and the aqueous layer was carefully adjusted to pH=3 with 1 N HCl. The acidic aqueous solution was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, and concentrated in vacuum to give Boc-Ser(O-allyl)-OH (14.0 g, 54.4%).
Reaction SMILES: N#N.[Br:3][C:4]([F:11])([F:10])[C:5]([O:7]CC)=O.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:3][C:4]([F:10])([F:11])[C:5]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:7]
Reactant: C1CCNC1
Reactant: CCOC(=O)C(F)(F)Br
Agent: N#N
Product: O=C(N1CCCC1)C(F)(F)Br
Temperature: 50 °C
Reaction time: 18 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), ethyl bromodifluoroacetate (0.88 mL, 6.89 mmol) was added dropwise to pyrrolidine (0.58 mL, 6.89 mmol) at rt. The reaction mixture was stirred at 50° C. for 2 h and at rt for 18 h. The mixture was then filtered through silica and the title compound obtained as a colorless oil. LC-MS-conditions 08: tR=0.70 min; [M+H]+=228.01.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:11][NH2:12]>>[CH3:11][NH:12][CH2:2][CH:3]=[CH:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CN
Reactant: CC(C)(C)C#CC=CCBr
Product: CNCC=CC#CC(C)(C)C

Procedure:
Reacting 1-bromo-6,6-dimethylhept-2-en-4-yne with excess methylamine to form N-methyl-N-(6,6-dimethylhept-2-en-4-ynyl)amine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][NH:11][C:3]=12.[CH2:18]([NH2:21])[CH:19]=[CH2:20]>C1(C)C(C)=CC=CC=1>[CH2:18]([NH:21][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][NH:11][C:3]=12)[CH:19]=[CH2:20]
Reactant: C=CCN
Reactant: Cc1cc(Cl)c2[nH]nc(-c3ccccc3)c2n1
Solvent: Cc1ccccc1C
Product: C=CCNc1cc(C)nc2c(-c3ccccc3)n[nH]c12
Reaction time: 48 h

Procedure:
A mixture of 7-chloro-5-methyl-3-phenyl-1H-pyrazolo[4,3-b]pyridine (D9) (1 g), xylene (80 ml) and allylamine (20 ml) was placed in a Parr pressure vessel and heated at 142° rising to 162° for 2 days during which time the internal pressure rose to 75 psi. The vessel was then allowed to cool, the pressure released and the contents evaporated to dryness. The residue was chromotographed on basic alumina eluting with ether and then a rising percentage of methanol (to 25%). Approximately 90% of the starting material was recovered. The fractions containing the required product were combined, evaporated to dryness and recrystallised from ether/pentane with charcoal decolourisation to give the title compound as an off-white crystalline solid, m.p. 92°-105° followed by resolidification and melting 171°-177°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([F:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:22][C:23]2[CH:24]=[C:25]([F:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(C)c(C)c1C(O)c1ccc(Cl)cc1
Reactant: Cn1cc(N)cc(F)c1=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(C)c(C)c1C(Nc1cc(F)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.4 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (Step 28.2) and 5-amino-3-fluoro-1-methylpyridin-2(1H)-one (Step 14.2). tR: 4.17 min (HPLC 1); tR: 0.93 min (LC-MS 2); ESI-MS: 433 [M+H]+ (LC-MS 2); Rf=0.77 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH:13]=O)=[CH:11][C:10]2[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6][C:5]=2[N:4]=1.[C:17]1([C@H:23]2[C@@H:28]([NH2:29])[CH2:27][CH2:26][CH2:25][NH:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:29][C@H:28]1[CH2:27][CH2:26][CH2:25][NH:24][C@H:23]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6]2
Reactant: COc1nc2c(cc1C=O)N(C)C(=O)CC2
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COc1nc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)N(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
The 2-methoxy-5-methyl-6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridine-3-carbaldehyde prepared in step 5 (0.35 g; 1.4 mmol) was dissolved in 20 ml of dichloroethane. To this was added 250 mg (1.1 mmol) of 2-(S)-phenyl-piperidin-3(S)-ylamine and 0.4 ml (2.8 mmol) of triethylamine, and the mixture was stirred for 60 minutes at room temperature. To this mixture was added 0.7 g (3.3 mmol) of sodium triacetoxyborohydride, and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water and stirred at room temperature for 30 minutes. The pH of the mixture was adjusted to 8.5 with Na2CO3. The organic layer was separated from the water layer. An additional 20 ml of water was added to the organic layer. The pH of the mixture was adjusted to 2 with 1N HCl and extracted with ethyl acetate. The pH of the water layer was adjusted to 7.5 with sodium bicarbonate and extracted with ethyl acetate. The pH=7.5 ethyl acetate extracts were combined, dried (Na2SO4), and evaporated to yield 300 mg of 6-methoxy-1-methyl-7-[(2(S)-phenyl-piperidin-3(S)-ylamino)-methyl]-3,4-dihydro-1H-[1,5]naphthyridin-2-one. 1H NMR (CDCl3) δ 7.2–7.4 (m, 5H), 6.85 (s, 1H), 3.90 (s, 1H), 3.85 (s, 3H), 3.60,3.38 (d,d 2H), 3.30 (d, 1H), 3.10 (s, 3H), 3.0 (s, 1H), 2.90 (m, 2H), 2.80 (m, 2H), 2.66 (m, 2H), 2.0–2.2 (m, 3H), 1.9 (m, 1H), 1.6 (m, 1H), 1.45 (m, 1H). Mass spectrum: m/e=381.1 (p+1). TLC: Rf=0.5; (5:1 chloroform/methanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:15]#[CH:16])=[CH:4][CH:3]=1.[CH2:22]([N:29]=[N+:30]=[N-:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]1[CH:16]=[C:15]([CH:14]([C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[N:31]=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C#CC(NS(C)(=O)=O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: [N-]=[N+]=NCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(NS(C)(=O)=O)c1cn(Cc2ccccc2)nn1

Procedure:
Prepared according to the procedure described in Example 40, Step 2, using N-{1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-ynyl}-methanesulfonamide and benzyl azide.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[OH:22].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[O:22][C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: Cc1cccc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1Oc1ccc(C#N)c(C#N)c1
Temperature: 60 °C
Yield: 87 %

Procedure:
A mixture of 4-nitro-phthalonitrile (1 eq), 2,6-dimethylphenol (1.2 eq), K2CO3 (2 eq), and DMF (1 mL/mmol 4-nitro-phthalonitrile) was heated under nitrogen at 60° C. for 3 h with stirring. After cooling to ambient temperature the mixture was poured into water (6 mL/mL DMF) with stirring. The mixture was extracted twice with EtOAc. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized from EtOH to give the title compound as a tan solid (yield: 87%); 1H NMR (CDCl3, 200 MHz): δ=7.70 (d, 1H), 7.05 to 7.16 (m, 5H), 2.08 (s, 6H).
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[H][H].[CH2:13]([O:15][C:16](=[O:22])[CH2:17][CH:18]([NH2:21])[C:19]#[CH:20])[CH3:14]>CCO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:13]([O:15][C:16](=[O:22])[CH2:17][CH:18]([NH2:21])[CH:19]=[CH2:20])[CH3:14]
Reactant: [H][H]
Reactant: C#CC(N)CC(=O)OCC
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: C=CC(N)CC(=O)OCC
Reaction time: 2.5 h

Procedure:
A mixture of 5% Pd/BaSO4 (0.025 g) and quinoline (0.30 mL) was stirred under a balloon of hydrogen for 30 minutes. 3-Amino-pent-4-ynoic acid ethyl ester (18-1) (for preparation, see J. A. Zablocki, et al., J. Med. Chem., 1995, 38, 2378-2394) (1.77 g, 10.0 mmol) in EtOH (15 mL) was added and the solution stirred for an additional 2.5 hours. The solution was filtered through a pad of celite and concentrated in vacuo to provide 2.65 g of crude product 18-2. 1H NMR (CDCl3, 300 MHz): δ 8.40-7.60 (br s, 2H), 6.11-5.96 (m, 1H), 5.58-5.53 (d, 1H), 5.44-5.41 (d, 1H), 4.31-4.16 (m, 3H), 3.12-2.86 (m, 2 H), 1.29-1.25 t, 3H). ##STR30##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH2:9].[C:10](OC(=O)C)(=[O:12])[CH3:11].O.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCc1ccccc1Cl
Reaction time: 0.5 h

Procedure:
42.8 kg (0.3 kmoles) of (2-chlorophenyl)methylamine was dissolved in 118.3 kg of dichloromethane and 32.2 kg (0.315 kmoles) of acetic anhydride was added dropwise at 20 to 40° C. over 1.5 hours, followed by aging at room temperature for 30 minutes. After the completion of the reaction, 60 kg of water was added 55.2 kg of an aqueous 25% sodium hydroxide solution was added dropwise at 20 to 40° C. over 20 minutes. The organic layer was partitioned to obtain 169.9 kg of a dichloromethane solution of N-[(2-chlorophenyl)methyl]acetamide.
Reaction SMILES: CC(OC([NH:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:11]=2[N:10]=1)=O)(C)C.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.O>N1C=CC=CC=1>[NH2:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]([NH:18][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(N)cc2s1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: c1ccncc1
Product: Nc1nc2ccc(NC(=O)c3ccc(OC(F)(F)F)cc3)cc2s1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 6-aminobenzothiazol-2-yl tert-butyl carbamate (Intermediate 4, 0.900 g, 3.39 mmol) in pyridine (8 mL), 4-trifluoromethoxybenzoyl chloride (0.535 mL, 3.39 mmol) was added. After stirring for 2 h at 60° C., the solution was poured into water (100 mL). The resulting precipitate was filtered off, washed with water and dried. The so obtained solid was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (20 mL) was added. After stirring for 3 h at r.t., the volatiles were removed in vacuo and dimethyl-formamide (100 mL) was added to the residue. The solution was neutralised by adding saturated sodium hydrogencarbonate solution. Water (400 mL) was added and the mixture was stirred overnight. The precipitated N-(2-aminobenzothiazol-6-yl)-4-trifluoromethoxy-benzamide was filtered off, washed with water and dried (grey solid, 1.16 g, 3.27 mmol, 84%). LC/ESI-MS: m/z=354 [M+H]+; m/z=352 [M−H]−; Rt=3.20 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=1.Cl.C(=O)([O-])[O-].[NH4+:47].[NH4+]>C(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[NH:47])[NH2:41])=[CH:36][CH:35]=1
Reactant: CCOC(=O)CCN(c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 1e from 1-methyl-2-[(4-cyanophenyl)-oxymethyl]-5-[N-(2-ethoxycarbonylethyl)-quinoline-8-sulphonylamino]-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.CC1C=CC(S(O[CH2:23][CH2:24][C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH3:30])(=O)=O)=CC=1>>[CH3:9][O:8][C:7]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH2:23][CH2:24][C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCC#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(C=O)cc1O
Product: CCCCC#CCCOc1cc(C=O)ccc1OC
Yield: 33.9 %

Procedure:
Isovanillin (0.90 g, 5.9 mmol) was alkylated with oct-3-ynyl 4-methylbenzenesulfonate (2.5 g, 8.9 mmol) according to Procedure 2. The crude product was recrystallised from purified by flash chromatography with 10% EtOAc/petrol as eluent to give 4-methoxy-3-(oct-3-ynyloxy)benzaldehyde (0.52 g, 34%) as a colourless crystalline solid; mp 42-43° C.; δH (400 MHz, CDCl3) 0.90 (t, J=7.2 Hz, 3H, CH3), 1.37-1.49 (m, 4H, CH3CH2CH2), 2.16 (tt, J=7.2, 2.4 Hz, 2H, CH2), 2.72 (tt, J=7.2, 2.4 Hz, 2H, CH2CH2O), 3.95 (s, 3H, OCH3), 4.17 (t, J=7.2 Hz, 2H, OCH2), 6.98 (d, J5,6=8.0 Hz, 1H, H5), 7.44 (d, J2,6=2.0 Hz, 1H, H2), 7.47 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 9.85 (s, 1H, CHO); δC (100 MHz, CDCl3) 13.6, 18.4, 19.7, 21.9, 30.9, 56.2, 67.6, 75.1, 82.5, 110.8, 111.0, 126.9, 130.1, 148.6, 154.9, 190.8; vmax 1019, 1132, 1262, 1508, 1585, 1684, 2932 cm−1.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:10][CH2:9][C:7]([C:3]2[O:2][CH:6]=[CH:5][CH:4]=2)=[O:8])=[O:23])=[CH:20][CH:19]=1
Reactant: NCC(=O)c1ccco1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(C(=O)NCC(=O)c2ccco2)cc1
Yield: 85.7 %

Procedure:
8.0 g of (2-furylcarbonyl)methylamine hydrochloride, 10.5 g of sodium bicarbonate and 10.1 g of 4-methoxybenzoyl chloride are treated in the same manner as described in Preparation 1-(1). 11.0 g of N-(4-methoxybenzoyl)-(2-furylcarbonyl)methylamine are thereby obtained. Yield: 85.3%
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18]
Reactant: O=S([O-])c1ccccc1
Reactant: COC(=O)C=CC=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C=CC=CCS(=O)(=O)c1ccccc1
Temperature: 20 °C
Yield: 73.2 %

Procedure:
A mixture of 6-bromohexa-2,4-dienoic acid methyl ester (0.41 g, 2.0 mmol), sodium benzene sulfinate (0.33 g, 2.0 mmol) and tetra-n-butylammonium iodide (37 mg, 0.1 mmol) was heated at reflux in dry THF (10 mL) under an atmosphere of nitrogen for 2 hours. The resulting slurry was allowed to cool to 20° C. and filtered. The filtrate was concentrated under reduced pressure to give an oil that was dissolved in ethyl acetate (20 mL). This solution was washed successively with saturated aqueous sodium hydrogen carbonate (10 mL), distilled water (10 mL), then with brine (10 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil that was purified by flash chromatography (7:3 to 1:1 to 1:1 60-80° C. petroleum ether:diethyl ether) to give a solid that was recrystallised to give the title compound (0.39 g, 73%) as white crystals, mp 105° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].C1(P(=[CH:30][CH:31]=[O:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH:30][CH:31]=[O:32])#[N:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1cccc(C=CC=O)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 57.3 %

Procedure:
To a solution of 3-cyanobenzaldehyde (4.5 g) in toluene (200 ml) was added (triphenylphosphoranylidene)acetaldehyde (13.6 g) and the mixture was stirred at 70° C. for 4 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane as an eluant and then the product was recrystallized from a mixture of toluene and hexane to give the desired compound (3.09 g, yield 57%) as pale yellow needle crystals.
Reaction SMILES: C([O:8][C:9](=[O:45])[CH2:10][C@@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42](=[O:44])[NH2:43])=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])C1C=CC=CC=1.C([C@H](NC(=O)[C@H](N1C=CC(C2C=CC(C3C=CC(C(=O)N)=CC=3)=CC=2)=C1)CC(O)=O)CO)C1C=CC=CC=1.[K+].[Br-]>C(Cl)(Cl)Cl>[CH2:18]([CH:15]([NH:14][C:12](=[O:13])[C@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42](=[O:44])[NH2:43])=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)[CH2:10][C:9]([OH:45])=[O:8])[CH2:16][OH:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)c1ccc(-c2ccc(-c3ccn([C@H](CC(=O)OCc4ccccc4)C(=O)N[C@H](CO)Cc4ccccc4)c3)cc2)cc1
Agent: NC(=O)c1ccc(-c2ccc(-c3ccn([C@H](CC(=O)O)C(=O)N[C@H](CO)Cc4ccccc4)c3)cc2)cc1
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccc(-c2ccc(-c3ccn([C@H](CC(=O)O)C(=O)NC(CO)Cc4ccccc4)c3)cc2)cc1
Yield: 95 %

Procedure:
According to the procedure described in Example 1(a), N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester was hydrogenolyzed to N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid in 95% yield, mp 218-20° C. 1H NMR (DMSO-d6): ∂ 8.12 (d, 1H, J=8.5 Hz), 7.97 (s, 1H), 7.88 (d, 2H, J=8.5 Hz), 7.72 (d, 2H, J=8.5 Hz), 7.57 (d, 2H, J=8.1 Hz), 7.33 (bs, 1H), 7.24 (s, 1H), 7.22-7.11 (m, 6H), 6.80 (bs, 1H), 6.42 (bs, 1H), 4.98-4.90 (bm, 1H), 4.80-4.72 (m, 1H), 3.82-3.76 (m, 1H), 2.82-2.70 (m, 2H), 2.62-2.50 (m, 1H). IR (KBr): 3402, 2925, 1658, 1601, 1400, 1202, 825, 782, 702, 633 cm−1. HRFABMS: Calculated for C30H29N3O5Cs (M+Cs+): 644.1162. Found: 644.1147. Anal. Calculated for C30H29N3O5•0.3 CHCl3: C, 66.49; H, 5.40; N, 7.68. Found: C, 66.30; H, 5.50; N, 7.50.
Reaction SMILES: [OH-].[K+].[CH2:3]([SH:6])[CH2:4][CH3:5].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15]>CN(C)C=O>[CH2:3]([S:6][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])[CH2:4][CH3:5]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: CCCS
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCSc1ccccc1S(N)(=O)=O
Yield: 82.1 %

Procedure:
To a solution of potassium hydroxide (85%, 12 gm, 0.2 mole) and n-propylmercaptan (18.1 ml, 0.2 mole) in 100 ml dimethylformamide at 90° C. was added a solution of 2-chlorobenzenesulfonamide (19.1 gm, 0.1 mole) in 100 ml dimethylformamide. The reaction mixture was heated to reflux for five hours, cooled, and the solvent was removed in vacuo. The residue was diluted with water, made acidic with concentrated hydrochloric acid and extracted with ether. The ether extracts were washed with water and brine, dried over MgSO4 and concentrated in vacuo to yield the crude product. Recrystallization from a suitable solvent such as toluene afforded 19 gm (82%) product: m.p. 58°-64°.