Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[C:3](=[O:28])[CH2:4][O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(N(CC=C)C(=O)C[O:36]CCN1CCN(C(C2C=CC=CC=2)C2C=CC([Cl:52])=CC=2)CC1)C=C>O1CCOCC1>[ClH:21].[ClH:52].[C:22]1([CH:14]([N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][O:5][CH2:4][C:3]([OH:28])=[O:36])[CH2:9][CH2:10]2)[C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=CCN(CC=C)C(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: CN(C)C(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Solvent: C1COCCO1
Product: Cl
Product: O=C(O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reaction time: 10 h
Yield: 69.3 %

Procedure:
The procedure described in Example 14 is followed with the difference that, instead of the (RS)-N,N-dimethyl-{2-[4-(α-phenyl-p-chloro-benzyl)piperazin-1-yl]ethoxy}-acetamide, 110.0 g (0.2 moles) of (RS)-N,N-diallyl-{2-[4-(α-phenyl-p-chloro-benzyl)piperazin-1-yl]ethoxy}-acetamide are used, 100 ml of dioxane are employed as cosolvent, and, during the alkaline hydrolysis, the reaction mixture is boiled for 10 hours Thus, 64.0 g (69.3%) of the title compound are obtained, m.p.: 225-228° C. The purity of the product corresponds to the quality requirements given in Eur. Pharm., 3, 1997, 1084.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:32]([C@@H:34]([O:36]C(=O)C)[CH3:35])=[O:33]>>[OH:36][C@@H:34]([CH3:35])[C:32]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:33]
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A171) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:14]([NH2:20])[C:15]1[O:19][CH:18]=[CH:17][CH:16]=1.S(Cl)(Cl)(=O)=O>CC(C)=O>[O:19]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:14][NH:20][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccco1
Solvent: O=S(=O)(Cl)Cl
Solvent: CC(C)=O
Product: O=C(O)c1ccc(S(=O)(=O)NCc2ccco2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
4-(Chlorosulfonyl)benzoic acid (5.0 g, 22.7 mmol) was added in three portions over a 10 minute period to a stirring solution of furfuryl amine (6.6 g, 68 mmol) in acetone (200 mL) cooled to 0° C. via an ice water bath. After addition of the sulfonyl chloride was complete the ice bath was removed and the solution was stirred for 1 hour at ambient temperature. The mixture was concentrated and subjected to silica gel chromatography (90% ethyl acetate, 8% hexanes and 2% acetic acid) to afford 4.4 of 4-(N-(furan-2-ylmethyl)sulfamoyl)benzoic acid (4.4 g, 68%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 4.04 (d, 2H, J=6 Hz), 6.13 (d, 1H, J=3.2 Hz), 6.25 (m, 1H), 7.43 (m, 1H), 7.83 (d, 2H, J=8.4 Hz), 8.05 (d, 2H, J=8.4 Hz), 8.36 (t, 1H, J=6 Hz), 13.4 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1CN(C)C(Cl)=O.[C:15]([Cl:18])(=[O:17])[NH2:16]>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:16]([CH2:4][CH2:3][CH2:2][CH2:7][CH3:6])[C:15]([Cl:18])=[O:17]
Reactant: NC(=O)Cl
Reactant: Cc1cccc(C)c1CN(C)C(=O)Cl
Product: CCCCCN(C(=O)Cl)c1c(C)cccc1C

Procedure:
When 2,6-dimethylphenyl-N-methyl-N-methylcarbamoyl chloride in Example 70 is replaced with the above carbamoyl chloride then the products prepared are
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[C:8]([O:15]C)[CH:7]=2)([CH3:3])[CH3:2].Br[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.Br.[F:26][C:27]1[CH:28]=[C:29]([CH2:33][NH2:34])[CH:30]=[N:31][CH:32]=1>>[F:26][C:27]1[CH:28]=[C:29]([CH2:33][NH:34][C:13]([C:12]2[C:11]3[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=3)[N:5]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:4]=2[CH:1]([CH3:2])[CH3:3])=[O:14])[CH:30]=[N:31][CH:32]=1
Reactant: BrCc1cccnc1
Reactant: NCc1cncc(F)c1
Reactant: COc1ccc2c(C=O)c(C(C)C)[nH]c2c1
Agent: Br
Product: CC(C)c1c(C(=O)NCc2cncc(F)c2)c2ccc(O)cc2n1Cc1cccnc1

Procedure:
The title compound was prepared from 2-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 137), 3-(bromomethyl)pyridine.HBr, and (5-fluoropyridin-3-yl)methanamine (Compound 145) by, in order, General Procedure J, General Procedure K, General Procedure C, and General Procedure L.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:5][CH:4]=1.O.NN>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[CH2:13][CH2:14][CH2:15][NH2:16])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(CCCN1C(=O)c3ccccc3C1=O)=CCC2
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)C(CCCN)=CCC2
Yield: 77.1 %

Procedure:
A solution of 2-[3-(7-methoxy-3,4-dihydronaphthalen-1-yl)propyl]isoindole-1,3-dione (11.8 g, 34.0 mmol) and hydrazine monohydrate (5.1 g, 0.1 mol) in ethanol (150 ml) was refluxed for 1 hour and then cooled in an ice bath. The resulting insoluble material was removed by filtration and the solvent was removed in vacuo to afford the titled compound (5.7 g, yield 77%, oil). This compound was provided for the next reaction without further purification.
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:8])=[O:7])(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.[Au]>[NH2:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:8])=[O:7]
Reactant: COC(=O)c1c(S(=O)(=O)NC(C)(C)C)ccn1C
Agent: [Au]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(S(N)(=O)=O)ccn1C

Procedure:
To a solution of 3.53 g of methyl 3-[[(1,1-dimethylethyl)amino]sulfonyl]-1-methyl-1H-pyrrole-2-carboxylate in 40 mL of methylene chloride under an nitrogen atmosphere was added 80 ml, of trifluoroacetic acid (TFA). The gold solution was stirred at room temperature overnight ca. 16 hours. The gold solution was concentrated to an oily residue. Diethyl ether was added to the residue and removed by evaporation to remove residual TFA. The resulting solid was suspended in diethyl ether and filtered affording the title compound as a tan solid, m.p. 105°-107° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:49]([CH2:51][NH2:52])[OH:50]>CN(C=O)C.CC(=O)OCC>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH:52][CH2:51][CH2:49][OH:50])=[O:22])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(C(=O)O)cc3)no2)cc1C
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(C(=O)NCCO)cc3)no2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
4-[5-(5-Diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid ethyl ester (1.42 g) is prepared starting from 4-(N-hydroxycarbamimidoyl)-benzoic acid ethyl ester (1.01 g, 4.84 mmol) and 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (1.00 g, 4.40 mmol) according to Method A; LC-MS: tR=0.63 min; [M+1]+=400.12; 1H NMR (CDCl3): δ 1.11 (t, J=7.0 Hz, 6H), 1.45 (t, J=7.0 Hz, 3H), 2.26 (s, 3H), 2.64 (q, J=7.0 Hz, 4H), 3.73 (s, 2H), 4.44 (q, J=7.3 Hz, 2H), 7.69 (s, 1H), 8.16-8.20 (m, 2H), 8.22-8.25 (m, 2H). This material (1.42 g, 3.58 mmol) is dissolved in 2 M LiOH in methanol (50 mL) and the mixture is stirred at rt for 20 h before it is acidified by adding aq. HCl. The mixture is extracted twice with EA. The combined organic extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid (710 mg) as a white solid; LC-MS: tR=0.52 min; [M+1]+=372.14. b) To a solution of 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid (400 mg, 1.08 mmol) in DMF (5 mL), HOBt (160 mg, 1.19 mmol) followed by EDC HCl (227 mg, 1.19 mmol) is added. The mixture is stirred at rt for 5 min before ethanolamine (72 mg, 1.19 mmol) is added. The reaction mixture is stirred at rt for 1 h. The mixture is diluted with EA and washed with sat. aq. NaHCO3. The washing is extracted back twice with EA. The combined organic extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with DCM containing 4% of methanol to give the title compound (290 mg) as a white solid; LC-MS: tR=0.47 min; [M+1]+=415.14; 1H NMR (CDCl3): δ1.11 (t, J=7.0 Hz, 6H), 2.26 (s, 3H), 2.64 (q, J=7.0 Hz, 4H), 3.67-3.72 (m, 2H), 3.73 (s, 2H), 3.90 (t, J=4.8 Hz, 2H), 6.69 (t br, J=5.3 Hz, 1H), 7.68 (s, 1H), 7.91-7.95 (m, 2H), 8.22-8.26 (m, 2H).
Reaction SMILES: C(Cl)CCl.[CH3:5][C:6]1[O:7][C:8]([CH3:14])=[C:9]([C:11]([OH:13])=O)[N:10]=1.C[O:16][C:17](=[O:67])[C@@H:18]([NH:34][C:35]([C@@H:37]1[CH2:46][C:45]2[CH:44]=[C:43]3[O:47][CH2:48][C@H:49]([C:51]4[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]5[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=5)=[CH:53][CH:52]=4)[O:50][C:42]3=[CH:41][C:40]=2[CH2:39][NH:38]1)=[O:36])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>C(Cl)Cl>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C@H:18]([NH:34][C:35]([C@@H:37]3[CH2:46][C:45]4[CH:44]=[C:43]5[O:47][CH2:48][C@H:49]([C:51]6[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]7[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=7)=[CH:53][CH:52]=6)[O:50][C:42]5=[CH:41][C:40]=4[CH2:39][N:38]3[C:11]([C:9]3[N:10]=[C:6]([CH3:5])[O:7][C:8]=3[CH3:14])=[O:13])=[O:36])[C:17]([OH:67])=[O:16])=[CH:25][CH:24]=2)=[CH:27][CH:28]=1)#[N:33]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: Cc1nc(C(=O)O)c(C)o1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)c(C)o1
Reaction time: 0.67 h

Procedure:
EDC (3 eq.) and 2,5-dimethyl-oxazole-4-carboxylic acid (6 eq.) were dissolved in DCM and stirred 40 minutes. To this solution was added (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (20 mg) and stirred for 12 hours. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (22 mg). LCMS (m/z): 860.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O>[Ni].O1CCOCC1>[Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[NH2:17]
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)cc([N+](=O)[O-])c1Cl
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1cc(-c2ccccc2)cc(N)c1Cl

Procedure:
A solution of 2.79 g. (0.01 mole) of 4-chloro-3,5-dinitrobiphenyl [R. C. Hall and C. S. Giam, J. Agr. Food Chem. 20 (3) 546-52 (1972) ] in 200 ml. of dioxane is hydrogenated at 3 atmospheres using Raney Nickel Catalyst. The catalyst is removed by filtration and the residue concentrated under reduced pressure. The residue is recrystallized from ethanol-water. There is obtained 1.12 g. (51%) of material melting at 142°-144.5°. Additional recrystallization raises the melting point to 146°-7°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH3:25])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:26]([O:30][CH2:31]Cl)[CH:27]([CH3:29])[CH3:28].O>CN1CCCC1=O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:31][O:30][CH2:26][CH:27]([CH3:29])[CH3:28])[C:19](=[O:24])[N:18]([CH3:25])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)COCCl
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)COCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Reaction time: 1 h

Procedure:
1.9 g (14.08 mmol) of potassium carbonate were added at 60° C. to a suspension of 2.25 g (8.8 mmol) of 7-benzyl-3-methylxanthine (prepared according to Example 1 a) in 50 ml of N-methylpyrrolidone and the mixture was stirred at this temperature for one hour. 1.4 g (11.44 mmol) of isobutoxymethyl chloride were then added dropwise and the mixture was stirred at 80° C. for 3 hours. A further 0.5 g (4.4 mmol) of isobutoxymethyl chloride was then added and the mixture was stirred again for 2 hours. 50 ml of water were then added and the mixture was extracted three times using 60 ml of methyl tert-butyl ether each time. The combined organic phases were washed twice with 30 ml of water each time, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, dichloromethane/methanol (19/0.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([O:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: OCCN1CCOCC1
Solvent: C1CCOC1
Product: N#Cc1cnc2cnc(OCCN3CCOCC3)cc2c1Nc1ccc(F)c(Cl)c1
Yield: 8 %

Procedure:
Following the procedure described above in Example 36, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile was reacted with a 1 M solution of freshly prepared alkoxide of N-(2-hydroxyethyl)morpholine in THF. The product was collected by filtration to give a yellow solid (0.015 g, 8%). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.5 (m, 2 H) 2.7 (t, J=5.7 Hz, 2 H) 3.6 (m, 6 H) 4.3 (t, J=5.8 Hz, 2 H) 6.7 (ddd, J=8.7, 4.4, 2.5 Hz, 1 H) 6.8 (dd, J=6.8, 2.5 Hz, 1 H) 7.1 (dd, J=9.5, 8.7 Hz, 1 H) 7.4 (d, J=0.8 Hz, 1 H) 7.7 (s, 1 H) 8.4 (d, J=0.8 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][O:13][C:14]1[CH:30]=[CH:29][C:17]2[NH:18][C:19]([S:21][C:22]3[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=3)=[N:20][C:16]=2[CH:15]=1.[C:31]1(=O)[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH2:32]1>C(O)C>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:27]([C:25]3[O:26][C:22]([S:21][C:19]4[NH:18][C:17]5[CH:29]=[CH:30][C:14]([O:13][CH3:12])=[CH:15][C:16]=5[N:20]=4)=[CH:23][CH:24]=3)[C:32]3[C:33](=[O:37])[CH2:34][CH2:35][CH2:36][C:31]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: COc1ccc2[nH]c(Sc3ccc(C=O)o3)nc2c1
Reactant: O=C1CCCC(=O)C1
Reactant: CCOC(=O)c1[nH]ccc1N
Solvent: CCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3cc(OC)ccc3[nH]2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
A suspension of 462.5 mg (3.0 mmol) of 3-amino-2-ethoxycarbonylpyrrole and 822.9 mg (3.0 mmol) of 5-(5-methoxy-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (obtained from step 1) in 15 mL of ethanol under argon is stirred at room temperature for 1 hour. 1,3-Cyclohexanedione (336.4 mg, 3.0 mmol) is then added and the reaction mixture is heated at reflux temperature for 16 h. The mixture is then cooled to 0° C., filtered and the precipitate is washed with diisopropyl ether. The solid is then purified by chromatography on a prepacked 90 g 15-40 μm silica gel cartridge (eluting solvent: ethyl acetate/methanol/trifluoroacetic acid 98/1/1 v/v/v; rate: 40 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a prepacked 90 g 15-40 μm silica gel cartridge (eluting solvent: ethyl acetate/cyclohexane from 50/50 to 75/25 v/v; rate: 40 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. 330 mg of 9-[5-(5-methoxy-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester are obtained as a yellow powder. mp: 140° C. LCMS: m/z 505: [M+H]+ (base peak); m/z 503: [M−H]− (base peak).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[CH:14](OCC)(OCC)OCC.[N-:24]=[N+:25]=[N-:26].[Na+]>C(O)(=O)C.O>[CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH:14]=[N:26][N:25]=[N:24]2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N)ccc1SC
Reactant: CCOC(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(-n2cnnn2)ccc1SC
Temperature: 70 °C
Reaction time: 0.83 h

Procedure:
Combine methyl 2-methylthio-5-aminobenzoate (2.18 g, 11.1 mmol) and triethyl orthoformate (7.4 mL, 44.3 mmol) in glacial acetic acid (20 mL). After the formation of a yellow solid, add glacial acetic acid (40 mL). After 50 minutes, add sodium azide (2.9 g, 44.3 mmol). Heat to 70° C. After 2 hours, cool the reaction mixture to ambient temperature and stir. After 56 hours, cool in an ice bath and dilute with water (400 mL) to give a solid. After 1 hour, collect the solid by filtration, rinse with water, and dry to give methyl 2-methylthio-5-(1H-tetrazol-1-yl)benzoate: Rf=0.90 (silica gel, 10% methanol/ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.[H-].[Na+].[CH3:20][N:21]([CH3:26])[S:22](Cl)(=[O:24])=[O:23]>C1COCC1.CN(C=O)C>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([S:22]([N:21]([CH3:26])[CH3:20])(=[O:24])=[O:23])[C:6]=2[N:14]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1c2ccccc2c2cc(C(N)=O)c(N)nc21
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 138 mg, 0.610 mmol) in a 1:1 mixture of THF-DMF (4.5 mL) was added NaH (73.0 mg, 2.50 mmol). The mixture was stirred at RT. After 10-15 min, dimethylsulfamoyl chloride (212 mL, 1.10 mmol) was added and the reaction was stirred for another 2 h. The reaction was quenched with water (50 mL) and poured into a separatory funnel containing EtOAc (100 mL). The mixture was shaken and the layers were separated. The organic layer washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by HPLC (Phenomenex Luna 15 μm C18, aqueous HCOOH/CH3CN) to give 2-amino-9-[(dimethylamino)sulfonyl]-9H-pyrido[2,3-b]indole-3-carboxamide as a white powder (17, 24.9 mg, 12%). HCOOH standard conditions. DAD Retention time =3.68 min. M+H=334. 1H NMR (300 MHz, DMSO-d6): δ 8.78 (s, 1H), 8.06 (s, 1H), 8.00-7.97 (m, 1H), 7.84-7.81 (m, 1H), 7.72 (br s, 2H), 7.40-7.32 (m, 3H), 3.02 (s, 6H).
Reaction SMILES: [CH:1]1([C:7]2[CH:30]=[CH:29][C:10]([C:11]([N:13]([CH3:28])[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH:23]([NH:25][CH3:26])[CH2:22][C:21]4=[O:27])=[CH:16][CH:15]=3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([CH2:26][NH:25][CH:23]1[CH2:24][N:20]([C:17]2[CH:18]=[CH:19][C:14]([N:13]([CH3:28])[C:11](=[O:12])[C:10]3[CH:29]=[CH:30][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:8][CH:9]=3)=[CH:15][CH:16]=2)[C:21](=[O:27])[CH2:22]1)(=[O:33])[CH3:32]
Reactant: CNC1CC(=O)N(c2ccc(N(C)C(=O)c3ccc(C4CCCCC4)cc3)cc2)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)CNC1CC(=O)N(c2ccc(N(C)C(=O)c3ccc(C4CCCCC4)cc3)cc2)C1

Procedure:
4-Cyclohexyl-N-methyl-N-[4-(4-methylamino-2-oxopyrrolidin-1-yl)phenyl]benzamide (101 mg) was mixed with pyridine (20 mg) and acetic anhydride (25 mg) and, after 3 hours, volatile fractions were removed in vacuo. This resulted in the product with the molecular weight of 447.58 (C27H33N3O3); MS (ESI): 448 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=3)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4]>O1CCCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[O:6][C:7]=3[CH3:26])=[CH:13][CH:14]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1cc(COc2ccc(-c3ccc(OC)cn3)cc2)c(C)o1
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)nc1
Reaction time: 2 h
Yield: 53.6 %

Procedure:
A solution of 4-[4-(5-methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carboxylic acid methyl ester (52) (118 mg, 0.33 mmoles) in dry tetrahydrofuran (10 ml) was treated with potassium trimethylsilanoate (260 mg, 2.0 mmoles) and the mixture stirred under an argon atmosphere for 2 hours. After evaporation of the solvent the residue was purified by HPLC (gradient: 18% acetonitrile/82% water containing 0.1% trifluoroacetic acid to 98% acetonitrile/2% water at a rate of 1%/min) to afford compound 53(60 mg) as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]12[CH2:13][CH:10]([CH:11]=[CH:12]1)[CH2:9][CH:8]2[CH:14]=[O:15].Cl[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].O>O1CCCC1.CCCCCC>[O:15]1[CH:14]([CH:8]2[CH2:9][CH:10]3[CH2:13][CH:7]2[CH:12]=[CH:11]3)[CH:17]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=CC1CC2C=CC1C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)OC(=O)C1OC1C1CC2C=CC1C2
Reaction time: 1 h
Yield: 94.9 %

Procedure:
In a nitrogen atmosphere, a solution of 112 g of potassium tert-butoxide in 400 g of dry tetrahydrofuran was added dropwise over 2 hours to a mixture of 122 g of 5-norbornene-2-carbaldehyde, 151 g of tert-butyl chloroacetate, and 500 g of dry tetrahydrofuran at 0-5° C. After one hour of stirring, 400 g of water was added to stop the reaction. The organic layer obtained by hexane extraction was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by vacuum distillation yielded 224 g (yield 95%) of tert-butyl 2,3-epoxy-3-(5-norbornen-2-yl)propionate as a fraction having a boiling point of 92-94° C./53 Pa.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.C(N(C(C)C)C(C)C)C>ClCCl>[OH:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:15]1
Reactant: OCC1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (7.88 ml) was added over ten minutes to an ice-cold solution of 3-hydroxymethyl piperidine (5.76 g) and ethyldiisopropylamine (9.58 ml) in dichloromethane (300 ml). The reaction mixture was allowed to warm to room temperature and stirred for 1 hr. The reaction was then diluted with dichloromethane (500 ml), washed with 1N aqueous hydrochloric acid (200 ml), dried over magnesium sulphate, and evaporated to afford benzyl 3-(hydroxymethyl)-1-piperidinecarboxylate as an oil (12.4 g).