Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH2:23]OS(C)(=O)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[N:29]([CH2:23][C@H:10]1[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](COS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN=[N+]=[N-])C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of tert-butyl (6S,7R)-7-(3,4-dichlorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (1.43 g) in DMF (15 mL) was added sodium azide (322 mg), and the mixture was stirred at 70° C. overnight. The solvent was evaporated under reduced pressure, distilled water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.23 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].O.Cl>CO>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)c(C=O)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1cc(F)c(CO)cc1F
Reaction time: 0.75 h

Procedure:
2,5-Difluoro-4-formylbenzonitrile (3.60 g, 0.0215 mol; see step (ii) above) was dissolved in 50 mL of methanol and cooled on an ice bath. Sodium borohydride (0.815 g, 0.0215 mol) was added in portions with stirring and the reaction was left for 45 min. Water (300 mL) was added and thereafter carefully 2M HCl was added until an acidic pH was attained. The mixture was extracted three times with diethyl ether, and the combined ethereal phase was washed with water, dried (Na2SO4) and evaporated. The crude product crystallised soon and could be used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[C:10]([S:21][CH3:22])=[CH:9]2)=[N:6][CH:7]=1.Cl[C:24]1[CH:29]=[C:28]([CH:30]2[CH2:32][CH2:31]2)[CH:27]=[CH:26][N:25]=1>>[CH:30]1([C:28]2[CH:27]=[CH:26][N:25]=[C:24]([C:2]3[CH:3]=[N:4][C:5]([N:8]4[C:16]5[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=5)[C:10]([S:21][CH3:22])=[CH:9]4)=[N:6][CH:7]=3)[CH:29]=2)[CH2:32][CH2:31]1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1
Reactant: Clc1cc(C2CC2)ccn1
Product: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C5CC5)ccn4)cn3)c2c1

Procedure:
Synthesized from methyl 1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indole-6-carboxylate (1.7 g, 4.49 mmol) and 2-chloro-4-cyclopropylpyridine (1.03 g, 6.73 mmol) in analogy to the procedures 141a) and b). White solid. Yield: 1.2 g (64% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[CH:18][C:13]=2[CH:12]=1)=[O:10].C(N(C(C)C)CC)(C)C.Cl.[NH2:41][CH:42]([CH3:47])[C:43]([CH3:46])([OH:45])[CH3:44]>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]2[N:15]=[C:16]([NH:41][CH:42]([CH3:47])[C:43]([OH:45])([CH3:46])[CH3:44])[N:17]=[CH:18][C:13]=2[CH:12]=1)=[O:10]
Reactant: CS(=O)(=O)c1ncc2cc(C(=O)Nc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1
Reactant: CC(N)C(C)(C)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(Nc1ncc2cc(C(=O)Nc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1)C(C)(C)O
Temperature: 140 °C

Procedure:
To a solution of 7-(4-fluoro-phenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (2-chloro-phenyl)-amide, 27, (0.11 g, 0.25 mmol) in N-methyl-pyrrolidinone (3 mL) is added diisopropylethylamine (0.22 mL, 1.28 mmol) and 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.11 g, 0.77 mmol). The mixture is heated to 140° C. for 4 hours and the resulting solution purified by preparative HPLC to afford the desired product as a yellowish solid: 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.33 (d, J=8.1 Hz, 1H), 8.23 (s, 1H), 7.45-7.40 (m, 3H), 7.32-7.22 (m, 3H), 7.13 (t, J=8.1 Hz, 2H), 3.92-3.82 (m, 1H), 1.26 (d, J=9.1 Hz, 6H), 1.20 (d, J=6.8 Hz, 3H); ESI+ MS: m/z (rel intensity) 468.0.0 (100, M++H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][CH2:11][C:12]1[N:16]([CH2:17][C:18]([O:20]CC)=[O:19])[N:15]=[N:14][N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C.O1CCCC1>[CH2:3]([O:10][CH2:11][C:12]1[N:16]([CH2:17][C:18]([OH:20])=[O:19])[N:15]=[N:14][N:13]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cn1nnnc1COCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cn1nnnc1COCc1ccccc1
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A 2.5N sodium hydroxide solution (100 ml, 0.25 mol) was added dropwise over fifteen minutes to ethyl 5-(1-benzyloxymethyl)tetrazolyl acetate 2 (36.21 gm, 0.131 mol) in 800 ml ethanol and 200 ml tetrahydrofuran at room temperature, causing a white precipitate. After one hour, the mixture was concentrated in vacuo. On liter of water was added and the aqueous phase was washed with two 400 ml portions of dichloromethane. The aqueous phase was acidified with 150 ml 2.5N hydrochloric acid and extracted with three 500 ml portions of ethyl acetate. The combined ethyl acetate extracts were dried over magnesium sulfate. Concentration in vacuo and trituration of the white solid from diethyl ether yielded 27.24 gm (84%) 5-(1-benzyloxymethyl)tetrazolylacetic acid 3 as a white solid: mp 125°-126°; 1H NMR (CDCl3 :DMSO d6, 10:1) δ 7.40 (5H, m), 5.87 (2H, S), 4.55 (2H, S), 4.09 (2H, S) mass spectrum FD 249 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[NH:16]([C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=1)[NH2:17].CC(O)=O>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[N:16]([C:18]3[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=3)[N:17]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1ccnc(-n2nc(-c3ccc(Cl)cc3)cc2O)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a mixture of ethyl 3-(4-chlorophenyl)-3-oxopropanoate (500 mg, 2.2 mmol) and 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2, 296 mg, 2.2 mmol) in EtOH (15 mL) was added AcOH (2 mL) at r.t. The reaction mixture was stirred at 90° C. overnight. After the reaction was completed, the mixture was concentrated, washed with PE/EA (10 mL, V/V=1/1) to give the title compound (500 mg, 76%) as a brown solid and used as crude for next step.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([N:30]=[C:31]=[O:32])=[O:29])[CH3:26]>O1CCCC1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:31]([NH:30][C:28](=[O:29])[O:27][CH2:25][CH3:26])=[O:32])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)N=C=O
Solvent: C1CCOC1
Product: CCOC(=O)NC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a solution of 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine (540 mg, 1.57 mmol) in 30 ml of freshly distilled tetrahydrofuran at 0° C. is added dropwise 194 μl (1.88 mmol) of ethoxycarbonyl isocyanate. The reaction mixture is stirred for 10 minutes at 0° C. and concentrated in vacuo. The residue is purified by column chromatography on silica using an ethyl acetate:methylene chloride gradient (15:85 to 1:1). Recrystallization from methylene chloride:hexane gives pure [[[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]carbonyl]carbamic acid, ethyl ester (68%); mp 147.5°-148° C.
Reaction SMILES: [C:1]1([N:7]2[C:10](=[O:11])[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][NH2:20]>C(#N)C>[CH3:19][NH:20][C:10]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([NH:9][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:18])=[O:11]
Reactant: O=C1N(c2ccccc2)C(=O)N1c1ccccc1
Reactant: CN
Solvent: CC#N
Product: CNC(=O)N(C(=O)Nc1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
In 30 ml of acetonitrile, 6.0 g (0.025 mol) of 1,3-diphenyl-1,3-diazetidine-2,4-dione was added. Then 3.9 ml (0.05 mol) of aqueous solution (40%) of methylamine was added dropwise thereinto with stirring. The reaction was continued at 50° C. for 0.5 hours, then the solvent was removed by distillation under a reduced pressure. The residue thus obtained was recrystallized from ethanol to obtain 5.1 g (yield 76%) of 1-methyl-3,5-diphenylbiuret having a melting point of 145°-147° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(#N)C.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)#[N:11].Br[CH:20]([CH2:26][CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:20]([CH2:26][CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:13]=1)#[N:11]
Reactant: CCOC(=O)C(Br)CC
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(CC)Oc1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Potassium carbonate (14.5 g, 105 mmol) was added to an acetonitrile (80.0 mL) solution of 4-cyanophenol (5.00 g, 42.0 mmol) and ethyl 2-bromobutyrate (9.83 g, 50.4 mmol) at room temperature, and the mixture was stirred for 3 hours at 80° C. After the mixture was cooled to room temperature, water was added to the reaction mixture, and the mixture was subjected to extraction two times with ethyl acetate. The organic layer thus obtained was washed with saturated brine, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1, v/v). Thus, the title compound (9.79 g, yield: 100%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH2:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH2:15])=[S:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc(CCC(N)=O)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(CCC(N)=S)cc1OC
Yield: 68.1 %

Procedure:
To a 25 ml eggplant-shaped bottle were added 0.15 g (0.717 mmol) 3-(3,4-dimethoxy-phenyl)-propanamide prepared in step 2, 0.16 g (0.717 mmol) P2S5 and 10 ml THF. A reflux condensing tube carrying a calcium chloride drying tube was mounted. The mixture was refluxed for 1 hour under magnetic agitation, concentrated under a reduced pressure, partitioned between ethyl acetate and saturated NaHCO3 solution each of 15 ml. The aqueous layer was extracted with ethyl acetate twice ×10 ml. The organic phase was combined, washed with saturated brine twice ×15 ml, dried over Na2SO4, filtered and concentrated to obtain a solid crude product which was purified under a reduced pressure by silica gel column chromatography eluted with petroleum ether and ethyl acetate at a ratio of 10:1 (V:V) to obtain a 0.11 g product as a white solid in a yield of 68.8%, mp: 140-141 └. 1H-NMR (CDCl3, 600 MHz) δ: 2.93 (2H, t, J=7.20 Hz, CH2), 3.07 (2H, t, J=7.84 Hz, CH2), 3.86 (3H, s, CH3O), 3.87 (3H, s, CH3O), 6.62 (1H, br), 6.75˜6.82 (3H, m, ArH), 7.35 (1H, br); ESI-MS (m/e, %): 248.3 (M+Na, 100), 226.3 (M+H, 64).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl.[F:25][C:26]1[CH:39]=[CH:38][C:29]([C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.O>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([N:35]4[CH2:34][CH2:33][N:32]([C:30](=[O:31])[C:29]5[CH:28]=[CH:27][C:26]([F:25])=[CH:39][CH:38]=5)[CH2:37][CH2:36]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Reactant: O=C(c1ccc(F)cc1)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1ccc(F)cc1)N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1
Temperature: 25 °C
Yield: 5 %

Procedure:
4-(7-Chloro-4-quinolinylamino)benzenesulphonyl chloride hydrochloride (7.8 g, 0.02 mol) was added portionwise with stirring to a cold mixture of 1-(4-fluorobenzoyl)piperazine hydrochloride (4.9 g, 0.02 mol) in chloroform (250 ml) and sodium carbonate (24.4 g) in water (250 ml). The cooling bath was removed and the mixture was allowed to warm to room temperature. After 1 hour the chloroform layer was separated and dried (MgSO4). The solvent was removed by evaporation to give a brown gum. Crystallisation from ethanol gave the pure title compound (0.53 g), m.p. 235°-237° C.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[C:26]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([N:30]1[CH2:35][CH2:34][N:33]([C:22]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:25])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)=[O:24])[CH2:32][CH2:31]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC(C)(C)N1CCNCC1
Product: CC1(C)c2cc(C(=O)N3CCN(C(C)(C)C)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 1-tert-butylpiperazine.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[Na+].Cl[C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(P(N(C)C)(N(C)C)=O)C>[F:1][C:2]([F:7])([F:6])[CH:3]([CH3:4])[O:5][C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=1
Reactant: CC(O)C(F)(F)F
Reactant: N#Cc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(Oc1ccc(C#N)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.1 %

Procedure:
Add 1,1,1-trifluoro-2-propanol (971 mg, 8.5 mmol) slowly to a slurry of sodium hydride (205 mg, 60% mineral oil, washed with hexane) in HMPA (8 mL) under nitrogen at 0° C. Allow the slurry to warm to ambient temperature and stir for 5 min. Add 5-chloro-pyridine-2-carbonitrile (590 mg, 4.2 mmol), then heat the mixture at 90° C. for 4 h. Adjust the mixture to pH 9 with sodium carbonate then extract with diethyl ether (2×50 mL). Dry the combined organic extracts over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (95/5 to 80/20) to obtain the desired intermediate (818 mg, 89%). GC-MS m/z: 216 (M+).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)[CH2:9][N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7]1)=[O:5])C>Cl>[CH2:18]([N:8]1[CH2:9][CH:10]([C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1c1cccc(C)c1
Agent: Cl
Product: Cc1cccc(C2CN(Cc3ccccc3)CC2C(=O)O)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-Benzyl-4-m-tolyl-pyrrolidine-3-carboxylic acid ethyl ester (4.6 g, 14.5 mmol) was suspended in aqueous HCl (73 mL, 18.0 M), and stirred overnight at 80° C. The reaction mixture was concentrated via rotary evaporation and placed on the vacuum line. MS calculated for C19H21NO2+H: 296, observed: 296.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:12]([C:14]([C:20]#[N:21])=[C:15](C#N)[C:16]#[N:17])#[N:13].CCCCCC>CN(C=O)C.C(=O)([O-])O.[Na+]>[CH2:10]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([C:15]([C:16]#[N:17])=[C:14]([C:20]#[N:21])[C:12]#[N:13])=[CH:6][CH:5]=1)[CH3:11]
Reactant: CCN(CC)c1ccccc1
Reactant: N#CC(C#N)=C(C#N)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCN(CC)c1ccc(C(C#N)=C(C#N)C#N)cc1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 73.8 %

Procedure:
In an atmosphere of argon, 42.3 g (0.28 mol) of N,N-diethylaniline was dissolved in 570 ml of anhydrous DMF, and the solution obtained was cooled to 0° C., and then 46.3 g (1.25-fold equivalent weight) of tetracyanoethylene was added thereto. Then, the solution obtained was restored to room temperature, and stirred for 4.5 hours, which was thereafter poured in 1 liter of a saturated aqueous sodium hydrogencarbonate solution. The solid thus deposited was filtered to obtain a residue, and the residue was subjected to azeotropic distillation twice with 300 ml of toluene to remove the water content. Thereafter, 300 ml of ethyl acetate was added, and the atmosphere was replaced with argon, followed by heating at 80° C. for 1 hour to effect dissolution. To the mixture obtained, 800 ml of hexane was added with stirring, and the solution obtained was cooled to room temperature. The solid thus deposited was collected by filtration, and the residue obtained was vacuum-dried to obtain 51.7 g of N,N-diethyl-4-tricyanovinylaniline (yield: 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.O=[C:11]([CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:12].Br>C(O)(=O)C>[CH3:15][C:14]1([CH3:16])[CH:13]=[C:11]([CH3:12])[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:9]1
Reactant: CC(=O)C=C(C)C
Reactant: COc1cccc(N)c1
Agent: Br
Solvent: CC(=O)O
Product: COc1ccc2c(c1)NC(C)(C)C=C2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
273 g (2.2 mol) m-anisidine and subsequently 221 g (2.2 mol) mesityl oxide were added dropwise at 15-20° C. to 25 ml glacial acetic acid. Then the solution was stirred for ca. 18 hours at room temperature. Subsequently 500 ml hydrobromic acid was added dropwise at 20-30° C. After stirring for 1 h at room temperature the precipitate was filtered. The precipitate which was still wet, was suspended in ca. 1 l acetone, filtered and dried. 200 g 2,2,4-trimethyl-7-methoxy-1,2-dihydro-quinoline hydrobromide was resuspended in a mixture of 1 l water and 500 ml chloroform. The suspension was then neutralized with 10% sodium hydroxide solution. The organic phase was subsequently washed with water, dried over sodium sulfate and evaporated to dryness in a rotary evaporator. The green coloured oil solidified after a short time. The solid was recrystallized from hexane. Colourless crystals formed in a yield of 39% with a melting point of 67° C.-69° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[S:3]([O:6][C:7]1[CH:24]=[CH:23][C:10]2[C:11](=[O:22])[C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4].[H][H]>C(OCC)(=O)C.[Pd]>[F:26][C:2]([F:1])([F:25])[S:3]([O:6][C:7]1[CH:24]=[CH:23][C:10]2[C:11](=[O:22])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][O:14][C:9]=2[CH:8]=1)(=[O:4])=[O:5]
Reactant: O=C1C(=Cc2ccccc2)COc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=c1c(Cc2ccccc2)coc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reaction time: 3 h
Yield: 94.4 %

Procedure:
To a solution of the compound of step D (26.6 g, 69.2 mmole) in 250 mL of ethyl acetate in a 500 mL Parr shaker flask was added 10% palladium on carbon catalyst (1.3 g). The mixture was hydrogenated at 40 psi until hydrogen uptake ceased after about 3 hours. The mixture was filtered through celite (a tradename for diatamaceous earth) to remove the palladium catalyst, and chromatographed over silica gel (hexane-ether); 25.1 g (94% yield) of the title product was obtained
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][CH3:14])=[CH:7]2)([OH:3])=[O:2].Br[CH2:16][C:17](C)=[CH2:18]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][CH2:14][C:17]([CH3:18])=[CH2:16])=[CH:7]2)([OH:3])=[O:2]
Reactant: CCc1cc2cc(C(=O)O)ccc2[nH]1
Reactant: C=C(C)CBr
Product: C=C(C)CCc1cc2cc(C(=O)O)ccc2[nH]1

Procedure:
Refer to 36a) using 3-bromo-2-methylpropene as the alkylating agent.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:11]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[N:12][CH:13]=[CH:14][CH:15]=2)[C:5]([C:22]([F:25])([F:24])[F:23])=[CH:4][N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([OH:35])[CH3:34])=[CH:29][CH:28]=1.OP([O-])([O-])=O.[K+].[K+]>CS(C)=O>[OH:35][CH:33]([C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:2]2[N:7]=[C:6]([NH:8][CH2:9][C:10]3[C:11]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[N:12][CH:13]=[CH:14][CH:15]=3)[C:5]([C:22]([F:25])([F:24])[F:23])=[CH:4][N:3]=2)=[CH:28][CH:29]=1)[CH3:34]
Reactant: CC(O)c1ccc(N)cc1
Reactant: CN(c1ncccc1CNc1nc(Cl)ncc1C(F)(F)F)S(C)(=O)=O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CS(C)=O
Product: CC(O)c1ccc(Nc2ncc(C(F)(F)F)c(NCc3cccnc3N(C)S(C)(=O)=O)n2)cc1
Temperature: 100 °C
Reaction time: 36 h

Procedure:
A solution of C9 (0.253 mmol) and anhydrous DMSO (0.5 ml) was treated with 1-(4-aminophenyl)ethanol (0.277 mmol) followed by potassium phosphate dibasic (0.746 mmol). The mixture was stirred at 100° C. for 1.5 days, and treated with additional 1-(4-aminophenyl)ethanol (0.583 mmol). The mixture was stirred at 100° C. for 15 hours and concentrated. The resultant residue was purified first by column chromatography (silica gel; 10% (NH4OH/MeOH)/CH2Cl2) followed by preparatory thin layer chromatography developed in 5% MeOH/CH2Cl2 to provide 12. Yield: 13.6 mg, 10.8%. 1H NMR (CD3OD) δ: 8.39 (d, 1H), 8.13 (s, 1H), 7.73 (d, 1H), 7.33 (m, 3H), 7.14 (d, 2H), 4.87 (s, 2H), 4.72 (q, 1H), 3.17 (s, 3H), 3.10 (s, 3H), 1.37 (d, 3H). MS: m/z 497 (MH+).
Reaction SMILES: [PH:1]([CH2:4][CH3:5])[CH2:2][CH3:3].N([C:13]([CH3:17])([CH3:16])C#N)=NC(C)(C)C#N>>[CH2:17]([P:1]([CH2:4][CH2:5][P:1]([CH2:4][CH3:5])[CH2:2][CH3:3])[CH2:2][CH2:3][P:1]([CH2:4][CH3:5])[CH2:2][CH3:3])[CH2:13][CH3:16]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: CCPCC
Product: CCCP(CCP(CC)CC)CCP(CC)CC
Yield: 5502.7 %

Procedure:
A mixture of n-PrP(CH=CH2)2 (1.29 g, 10.0 mmol), Et2PH (2.25 g, 25.0 mmol) and 2,2'-azobis(isobutyronitrile) (AIBN, 30 mg) in a closed flask under inert atmosphere was irradiated by a GE Sunlamp (275 W) one foot away for 24 hours. The resulting colorless liquid was stripped of volatiles under vacuum and vacuum distilled to give 3.1 g (97% yield) of product collected at 132-135° C./0.35 mm Hg. 31P-NMR (toluene): δ--18.5 (2P); δ--22.8 (1P).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH2:15]([C:17]1[O:21][C:20]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:19]=2[CH:18]=1)[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>CO>[CH2:15]([C:17]1[O:21][C:20]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:19]=2[C:18]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:4]=1)[CH3:16]
Reactant: CCc1cc2cc(C)ccc2o1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Product: CCc1oc2ccc(C)cc2c1C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
is obtained as described in Example 1 from 10 g 4-chloro-3-sulfamoylbenzoyl chloride and 6.2 g 2-ethyl-5-methylbenzo[b]furan in the presence of 11.4 g aluminum chloride. Colorless crystals, m.p. 147°-150° C. (from methanol).