Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C@@H:6]([C@@H:8]1[CH2:12][O:11][C:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[S:34][CH:35]=[CH:36][N:37]=3)=[C:27]([Cl:38])[CH:26]=2)=[N:9]1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:38][C:27]1[CH:26]=[C:25]([NH:24][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:10]4[O:11][CH2:12][C@@H:8]([C@H:6]([OH:5])[CH3:7])[N:9]=4)[CH:15]=3)[N:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1
Reactant: C[C@@H](OC(C)(C)C)[C@@H]1COC(Nc2ccc3ncnc(Nc4ccc(OCc5nccs5)c(Cl)c4)c3c2)=N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](O)[C@@H]1COC(Nc2ccc3ncnc(Nc4ccc(OCc5nccs5)c(Cl)c4)c3c2)=N1

Procedure:
(R)-1-((S)-2-(4-(3-chloro-4-(thiazol-2-ylmethoxy)phenylamino)quinazolin-6-ylamino)-4,5-dihydrooxazol-4-yl)ethanol is prepared from (1R,4S)—N6-[4-(1-tert-butoxyethyl)-4,5-dihydrooxazol-2-yl]-N4-[3-chloro-4-(thiazol-2-ylmethoxy)-phenyl]-quinazoline-4,6-diamine by standard deprotection methods using TFA in methylene chloride. MS ESI (+) m/z 497, 499 (M+1, Cl pattern) detected; 1H NMR (400 mHz, DMSO-D6) δ 9.53 (s, 1H), 8.47 (s, 1H), 8.08 (d, 1H), 7.87 (d, 1H), 7.80 (d, 1H), 7.76 (dd, 1H), 7.66 (m, 2H), 7.33 (d, 1H), 5.55 (s, 2H), 4.81 (m, 1H), 4.37 (m, 1H), 4.20 (m, 1H), 3.83 (m, 1H), 3.63 (m, 1H), 1.06 (d, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[S:13][CH:14]=[CH:15][C:8]=2[C:7]=1O)=[O:5])[CH3:2].[O-]CC.[Na+].C(OC(C1C(Cl)=C2C=CSC2=NC=1[Cl:32])=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[S:13][CH:14]=[CH:15][C:8]=2[C:7]=1[Cl:32])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2ccsc2[nH]c1=O
Reactant: CCOC(=O)c1c(Cl)nc2sccc2c1Cl
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)c1c(Cl)c2ccsc2[nH]c1=O

Procedure:
A preferred intermediate in the preparation of compounds of structure (III) is 4-chloro-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester, depicted by formula (42) below. To prepare this intermediate, methyl-2-amino-thiophene-3-carboxylate was reacted with ethylmalonyl chloride to yield intermediate 2-(2-ethoxycarbonyl-acetylamino)-thiophene-3-carboxylic acid methyl ester, depicted by formula (39). This intermediate was converted to 4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester, depicted by formula (40), by reacting it with sodium ethoxide, and then converting it into 4,6-dichloro-thieno[2,3-b]pyrdine-5-carboxylic acid ethyl ester, depicted by formula (41). Hydrolysis of 4,6-dichloro-thieno[2,3-b]pyrdine-5-carboxylic acid ethyl ester, depicted by formula (41), yielded 4-chloro-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester, depicted by formula (42), as shown in Scheme 20.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:19]([Si](C)(C)C)=[N+:20]=[N-:21].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([C:8]([C:9]2[N:19]=[N:20][NH:21][N:10]=2)([CH3:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C#N)c1ccc(-c2ccccc2)c(F)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(c1ccc(-c2ccccc2)c(F)c1)c1nn[nH]n1
Temperature: 150 °C

Procedure:
A mixture of 2-(2-fluoro-biphenyl-4-yl)-2-methyl-propionitrile (100 mg, 0.418 mmol), azidotrimethylsilane (222 μL, 1.672 mmol) and dibutyltin oxide (20 mg) in dry toluene (2.5 mL) was heated under microwave irradiation in a sealed vessel at 150° C. for 1000 seconds. The solution was then diluted with EtOAc, washed with water, the organics separated, dried (MgSO4), filtered and evaporated to dryness. The residue was purified by column chromatography (EtOAc) to afford the title compound, 5-[1-(2-Fluoro-biphenyl-4-yl)-1-methyl-ethyl]-2H-tetrazole as a colorless powder. 1H NMR (500 MHz, CD3OD) δ 7.50 (2H, m), 7.40-7.46 (3H, m), 7.35 (1H, m), 7.05-7.12 (2H, m), 1.87 (6H, s). LCMS(EI) 283.1 (M+H)+, 324.2 (M+Na+H3O)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].F[C:16](F)(F)C(OC(=O)C(F)(F)F)=O>>[CH3:16][NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(C(=O)O)cc1C(F)(F)F
Product: CNc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 45 °C
Reaction time: 8 h

Procedure:
4-amino-3-trifluoromethylbenzoic acid (3.6 g) was suspended in trifluoroacetic anhydride (90 ml) and the suspension was stirred overnight. The solvent was distilled off under vacuum and the resulting residue was dissolved in acetone (30 ml). Methyl iodide (9.9 g) was added to the solution and the mixture was heated to 45° C.; with vigorous stirring, a potassium hydroxide powder (6.8 g) was added slowly, followed by further stirring for 1 h at 45° C. Then, the solvent was distilled off under vacuum and the resulting residue was dissolved in water (50 ml). The solution was heated under reflux for 2 h. The reaction solution was then adjusted to pH of 3.5 with 1N HCl under cooling with ice. The white precipitate was recovered by filtration and washed with a small amount of water and vacuum-dried to yield the end product (2.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=[O:27])=[O:26])[CH2:23][CH2:22]1>C(N(CC)CC)C>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1
Reactant: O=S(=O)(CCCCCCBr)NC1CC1
Solvent: CCN(CC)CC
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2cccc(Cl)c2)CC1)NC1CC1
Yield: 94.1 %

Procedure:
1-[(3-Chlorophenyl)phenylmethyl]piperazine (458.6 mg, 1.60 mmol) and N-cyclopropyl-6-bromohexanesulfonamide (500 mg, 1.76 mmol) were refluxed in triethylamine (2 ml) for 4 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (737.8 mg) as an oil (yield based on 1-[(3-chlorophenyl)phenylmethyl]piperazine: 94.1%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=O)[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[C:9]2[C:8](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:5]2[N:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:3]=[C:2]([CH3:1])[C:6]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(Nc2ccccc2C(=O)O)n(-c2ccccn2)n1
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Temperature: 25 °C
Yield: 42.9 %

Procedure:
A solution of 2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (50.2 g, 0.17 mol) in phosphorous oxychloride (120 mL, 1.27 mol) was heated under reflux for 1 hour. After the solution was cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was poured into iced water. The solution was made basic by the addition of a sodium hydroxide solution, and organic matter was extracted with chloroform. The extract was washed with saturated brine and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Purification of the residue thus obtained by silica gel column chromatography (chloroform:methanol=98:2) gave the title compound (21.5 g, 43% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]2[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1.[Br:31]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:15][C:8]1[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 58.2 %

Procedure:
A mixture of ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-methylquinoline-3-carboxylate (411 mg), N-bromosuccinimide (NBS) (214 mg), 2,2'-azobis(isobutyronitrile) (10 mg) and carbon tetrachloride (10 ml) was stirred under reflux for 5 hours. The reaction mixture was washed with water and dried (MgSO4), and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with chloroform/ethyl acetate (10:1, v/v), ethyl 2-bromomethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (285 mg, 58%) was obtained and recrystallized from ethyl acetate/hexane.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:18]=[N:19][C:20]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:13]=[C:12]([CH3:34])[CH:11]=2)=[O:8])=[CH:5][C:4]([CH3:35])=[N:3]1.I[CH2:37][C:38]([NH2:40])=[O:39].C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:40][C:38](=[O:39])[CH2:37][N:19]1[C:20](=[N:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][C:17]([O:16][C:14]2[CH:15]=[C:10]([NH:9][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:35])[CH:5]=3)=[O:8])[CH:11]=[C:12]([CH3:34])[CH:13]=2)=[CH:18]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cc(C)cc(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cc(C)cc(NC(=O)c4cc(C)nn4C)c3)cn2CC(N)=O)cc1
Yield: 74.6 %

Procedure:
In the same manner as in Reference Example 5 and using 1,3-dimethyl-N-{3-methyl-5-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}-1H-pyrazole-5-carboxamide (3.88 g, 7.89 mmol), iodoacetamide (1.90 g, 10.27 mmol), N,N-diisopropylethylamine (1.80 mL, 10.3 mmol) and N,N-dimethylformamide (20 mL) as starting materials, the title compound (3.23 g, 75%) was obtained as a pale-yellow oil.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([NH:30][C@H:31]([C:44]([O:46]CC1C=CC=CC=1)=[O:45])[CH2:32][CH2:33][C:34]([O:36]CC1C=CC=CC=1)=[O:35])=[O:29])[C@@H:25]([CH3:27])[OH:26])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H][H]>[Pd]>[C:1]([O:18][CH:19]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([NH:30][C@H:31]([C:44]([OH:46])=[O:45])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:29])[C@@H:25]([CH3:27])[OH:26])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)[C@@H](C)O
Agent: [Pd]
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)[C@@H](C)O
Yield: 91.3 %

Procedure:
Dibenzyl N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-threonyl]-L-glutamate (48 g) in demethylformamide (500 ml) was hydrogenated over palladium black (1 g) at room temperature at 1 atmospheric pressure. After the theoritical amount of hydrogen was adsorbed, dimethylformamide was removed under reduced pressure. The residual crude crystal was recrystallized from ethanol to give N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-threonyl]-L-glutamic acid (35.5 g).
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(OC)cn1
Reactant: NO
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(N(CCCCCCC(=O)NO)c2ccccn2)nc1
Reaction time: 28 h
Yield: 60 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (11.65 mg, 0.033 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 28 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×10 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 then 100:6) to furnish IV as a colourless oil (6.76 mg, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=O)[CH3:8].[C:10]1([C:16](=[N:23][NH2:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[C:7](=[N:24]/[N:23]=[C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)/[CH3:8]
Reactant: CC(=O)c1sccc1Br
Reactant: NN=C(c1ccccc1)c1ccccc1
Solvent: CCO
Product: C/C(=N\N=C(c1ccccc1)c1ccccc1)c1sccc1Br
Temperature: 80 °C
Yield: 83.6 %

Procedure:
1-(3-Bromothiophen-2-yl)ethanone (8.0 g, 39.0 mmol) and (diphenylmethylene)hydrazine (8.42 g, 42.9 mmol) were dissolved in ethanol (75 mL). The reaction mixture was heated in an oil bath at 80° C. for 16 hours. Following reaction, the volatiles were evaporated, and the condensed mixture was purified via silica gel column chromatography, eluting with a gradient of 0-100% hexane and EtOAc. The pure fractions were combined and evaporated to give the title compound as a yellow solid (12.5 g, 84%). ESI-MS m/z [M+H]+ calc'd for C19H15BrN2S, 384. found, 384.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[C:6](\[CH3:9])/[CH:7]=O)[C@H:3]1[C:10]([O:12][CH3:13])=[O:11].Cl.[CH:16]([O:19][NH2:20])([CH3:18])[CH3:17].N1C=CC=CC=1>C(OCC)(=O)C>[CH:16]([O:19][N:20]=[CH:7]/[C:6](/[CH3:9])=[CH:5]/[C@@H:4]1[C@@H:3]([C:10]([O:12][CH3:13])=[O:11])[C:2]1([CH3:14])[CH3:1])([CH3:18])[CH3:17]
Reactant: COC(=O)[C@@H]1[C@@H](/C=C(\C)C=O)C1(C)C
Reactant: CC(C)ON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1[C@@H](/C=C(\C)C=NOC(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.9 %

Procedure:
Under nitrogen atmosphere, a mixture of 0.30 g of methyl (1R)-trans-2,2-dimethyl-3-[(E)-2-methyl-3-oxo-1-propenyl]cyclopropanecarboxylate, 0.17 g of O-isopropylhydroxylamine hydrochloride and 2 ml of pyridine was stirred at room temperature for 6 hours. Then, ethyl acetate was added to the reaction mixture, and the mixture was washed with 1 mol/L hydrochloric acid and saturated brine respectively. The organic layer was dried over anhydrous magnesium sulfate, then, filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.27 g of methyl (1R)-trans-3-[(E)-3-isopropoxyimino-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate:
Reaction SMILES: [CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](C2C=CC=CC=2C([O-])=O)=[CH:12][C:11]=1[N+:25]([O-:27])=[O:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH2:28].O.[OH-].[Li+].Cl>CO>[CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:28])=[CH:12][C:11]=1[N+:25]([O-:27])=[O:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O
Reactant: CCCCCC[C@H](C)Oc1ccc(-c2ccccc2C(=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC[C@H](C)Oc1ccc(O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
Compound 32a (380 mg, 1.02 mmol) was dissolved in 10 ml methanol, and water (approximately 3 ml) was added until the solution remained milky yellow with vigorous stirring. Lithium hydroxide monohydrate (258 mg, 6.1 mmol) was added, the reaction mixture was stirred for six hours at 25° C., and then was acidified with concentrated HCl. The reaction mixture was extracted with dichloromethane (30 ml). The organic layer was separated, washed with saturated sodium bicarbonate, followed by brine, and dried over magnesium sulfate. The solvent was evaporated and the crude product was purified via flash chromatography over silica gel (50/50, v/v, Hex/EtOAc) to yield 269 mg (98%) of an orange oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)=[O:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COCCNCC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1
Solvent: C1CCOC1
Product: COCCN(CC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1)C(=O)Nc1ccc(Cl)cc1

Procedure:
A mixture of 3-(3-Chloro-2-methyl-phenyl)-1-[2-(2-methoxy-ethylamino)-acetyl]-imidazolidin-4-one (100 mg, 0.3 mmol, 1 eq), 1-Chloro-4-isocyanato-benzene (56 mg, 0.36 mmol, 1.2 eq), in THF (2 ml) was stirred at room temperature overnight. It was concentrated, dissolved in acetonitrile and purified with HPLC to give the desired product. LCMS observed for (M+H)+: 479.1
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH2:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH3:2]
Reactant: C=Cc1ccc2[nH]cc(CCN3CCCC3)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc2[nH]cc(CCN3CCCC3)c2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.3 %

Procedure:
5-Vinyl-3-(2-pyrrolidinylethyl)-1H-indole (Example 10c, 8.0 mg, 0.033 mmol) in ethyl acetate (3 mL) containing a spatula tip of Pd/C (10%) was stirred at room temperature under an atmosphere of hydrogen for 2.5 h. Filtration through celite using 10% 2M methanolic ammonia in dichloromethane and evaporation of the solvent in vacuo. A final filtration through silica gel using 10% 2M methanolic ammonia in dichloromethane yielded 5-ethyl-3-(2-pyrrolidinylethyl) -1H-indole (4.5 mg, 56%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:13])=O>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:13])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(I)c1
Product: O=C(Cl)c1cccc(I)c1
Yield: 67 %

Procedure:
2.21 g (0.00891 mol) of 3-iodobenzoic acid were dissolved in 25 ml of thionyl chloride under argon and boiled under reflux for 2 hrs. The excess thionyl chloride was distilled off and the residue was taken up twice with 50 ml of toluene and concentrated each time. 1.6 g (67%) of 3-iodobenzoyl chloride were obtained as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][NH2:20].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:20][CH2:19][CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCCc1ccccn1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCCc1ccccn1)c1ccc(Br)cc1
Reaction time: 12 h
Yield: 97.9 %

Procedure:
Add a solution of 4-bromo-benzenesulfonyl chloride (1.278 g, 5.0 mmol) in 10 mL dichloromethane at r.t. to a solution of 2-pyridin-2-yl-ethylamine (611 mg, 5.0 mmol) and triethylamine (708 μL, 5.0 mmol) in 5 mL dichloromethane over a period of 20 min via syringe pump and stir for 12 h. Add 20 mL saturated aqueous sodium bicarbonate solution and extract the aqueous phase with dichloromethane. Wash the combined organic extracts with brine, dry over sodium sulfate, filtrate and concentrate under reduced pressure to obtain 4-bromo-N-(2-pyridin-2-yl-ethyl)-benzenesulfonamide (1.67 g) as a pale yellow oil which slowly crystallizes upon storage at ambient temperature. Further purification is not necessary. MS (m/e): 342 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.CN1C(=O)CCC1.[F:28][C:29]([F:37])([F:36])[C:30]([F:35])([F:34])C([O-])=O.[Na+].C(=O)([O-])O.[Na+]>[Cu](I)I.C1(C)C(C)=CC=CC=1>[CH2:18]([S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=[C:2]([C:30]([F:35])([F:34])[C:29]([F:37])([F:36])[F:28])[CH:3]=[C:4]2[N:10]=1)[CH3:19]
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Agent: I[Cu]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CN1CCCC1=O
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)C(F)(F)F)cnc2n1C
Temperature: 170 °C
Yield: 7.7 %

Procedure:
A mixture of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (500 mg), NMP (24 ml), xylene (10 ml), copper iodide (1.1 g), and sodium pentafluoropropionate (1.1 g) was heated to 170° C., and stirred with heating for 3 days. Into the reaction mixture cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with tert-butyl methyl ether. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 43 mg of 2-(2-ethylsulfanylphenyl)-3-methyl-6-pentafluoroethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 55).
Reaction SMILES: [Si:1]([C:8]#[CH:9])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)S(O[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][C:17]=1[Cl:28])(=O)=O.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:4]([Si:1]([C:8]#[C:9][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][C:17]=1[Cl:28])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: C#C[Si](C)(C)C(C)(C)C
Reactant: O=S(=O)(Oc1ccc(-c2ccccc2)cc1Cl)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)C#Cc1ccc(-c2ccccc2)cc1Cl

Procedure:
0.84 g (1.2 mmol) of bis-(triphenylphosphine)palladium (II) chloride, 0.23 g (1.2 mmol) of copper (I) iodide, and 6.28 mL (33.6 mmol) of (tert-butyldimethylsilyl)acetylene is added under an argon atmosphere to a solution of 8.1 g (24 mmol) of 3-chlorobiphenyl-4-yl trifluoromethanesulfonate in 50 mL of absolute DMF and 13.31 mL (96 mmol) of triethylamine.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH2:34])[CH2:23][CH3:24])[CH3:21]>C(#N)C>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH:34][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH2:23][CH3:24])[CH3:21]
Reactant: CCN(CC)CC1CCCCN1CCN
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2ccccc2NC(=O)c2cccnc21
Yield: 52 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbony)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 2-[2-[(diethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 52% of theory. Colourless crystals, m.p. 146°-147.5° C. (acetonitrile).