Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH-].[Na+].Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21].O>C1OCCOCCOCCOCCOC1.C1(C)C=CC=CC=1.CN(C=O)C.[I-].[Na+]>[Cl:8][C:4]1[N:3]=[C:2]([O:1][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc(Cl)n1
Reactant: COC(=O)Cc1ccccc1CBr
Agent: C1COCCOCCOCCOCCO1
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1COc1cccc(Cl)n1
Yield: 61.4 %

Procedure:
A mixture of 2-hydroxy6-chloropyridine (0.84 g, 6.5 mmol), sodium hydroxide (0.275 g, 6.9 mmol) and 15-crown-5 (1 drop) in dry toluene (15 ml) were stirred at reflux for 1.5 hours. The toluene was removed under reduced pressure and the white salt residue was dissolved in dry DMF (10 ml). Methyl 2-bromomethylphenylacetate (1.5 g, 6.2 mmol) in dry DMF (10 ml) was added dropwise along with sodium iodide (10 mg). The mixture was stirred at room temperature for 2 hours, poured into water and extracted with diethyl ether. The ether extracts were washed with water, dried and the ether removed in vacuo leaving a yellow oil which was purified by column chromatography (silica eluted with 10 % ethyl acetate in hexane) to give methyl 2-(6-chloropyrid-2-yloxymethyl)phenylacetate (1.11 g, 61%) (Compound No. 1 in Table 1) as a pale yellow oil; 1H NMR(270 MHz)δ:3.67(3H,s), 3.82(2H,s), 5.39(2H,s) 6.65(1H,d), 6.90(1H,d), 7.25-7.55(5H,m) ppm.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:5](=[O:7])[CH3:6])=[CH:12][CH:11]=1
Reactant: Cc1ccc(O)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C)cc1
Temperature: 0 °C
Yield: 76.1 %

Procedure:
Anhydrous aluminum chloride (88 g, 0.66 mol) was suspended in methylene chloride (1500 mL), and then acetyl chloride (51.5 g, 0.66 mol) was added while stirring and cooling on ice. The mixture was stirred for 20 minutes while cooling on ice and 4-methylphenol (50 g, 0.46 mol) was added. The reaction mixture was stirred at room temperature for 1 h, and then poured into ice water slowly to quench the reaction. After extraction with ethyl acetate, the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to yield acetic acid 4-methyl-phenyl ester (52.6 g, 76%). 1H-NMR (CDCl3): 2.25 (s, 3H), 2.36 (s, 3H), 6.96 (d, 2H), 7.18 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](Cl)=[N:15][N:14]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]=2[CH3:11])=[N:15][N:14]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1[nH]c2ccc(Cl)cc2c1-c1nnc(Cl)c2ccccc12
Temperature: 65 °C
Yield: 87.6 %

Procedure:
5-Chloro-2-methylindole (0.74 g, 2.26 mmol) and 1,4-dichloro-phthalazine (0.45 g, 2.26 mmol) were treated with 30 mL of 1,2-dichloroethane and 3.2=mol of AlCl3 (427 mg). The resulting suspension was heated to 65° C. overnight. The reaction was cooled and quenched with 3 mL water. The resultant precipitate was filtered and dried under vacuum to give 0.65 g of the sub-title compound. MS: ESI (negative): 326, 328 (M−H).
Reaction SMILES: C[NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:41])/[CH:31]=[CH:32]/[C:33]3[CH:38]=CC(CCl)=[CH:35][CH:34]=3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:30](/[CH:31]=[CH:32]/[CH:33]([CH2:38][NH:2][CH:3]3[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]3)[C:34]3[CH:5]=[CH:4][CH:3]=[CH:8][CH:35]=3)=[O:41])=[CH:27][CH:28]=2)=[CH:19][CH:18]=1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(/C=C/c1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NCC(/C=C/C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
0.5 g (2.34 mmol) of tert-butyl 4-methylaminopiperidine-1-carboxylate is added to a suspension of 300 mg (0.79 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-chloromethylphenyl)acrylamide in 5 mL of DMF and the mixture is stirred for 18 hours at 80° C. Then the reaction mixture is poured onto water and the precipitate formed is suction filtered. Further purification is carried out by stirring out from a little methanol. Yield: 200 mg (45% of theory); C33H38ClN3O3 (M=560.13); melting point: 168° C.-169° C.; calc.: molecular ion peak (M+H)+: 560/562 (Cl); found: molecular ion peak (M+H)+: 560/562 (Cl).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([F:30])=[C:5]([C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][C:17]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[N:16]3)=[O:12])[C:6]([F:10])=[C:7]([F:9])[CH:8]=1.[CH2:31]([S:34](Cl)(=[O:36])=[O:35])[CH2:32][CH3:33]>C(Cl)Cl>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:17]2[CH:18]=[N:19][C:20]3[C:15]([N:16]=2)=[CH:14][C:13]([C:11]([C:5]2[C:4]([F:30])=[C:3]([N:2]([S:34]([CH2:31][CH2:32][CH3:33])(=[O:36])=[O:35])[S:34]([CH2:31][CH2:32][CH3:33])(=[O:36])=[O:35])[CH:8]=[C:7]([F:9])[C:6]=2[F:10])=[O:12])=[CH:22][CH:21]=3)=[CH:28][CH:27]=1
Reactant: Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(-c4ccc(Cl)cc4)nc3c2)c1F
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3ncc(-c4ccc(Cl)cc4)nc3c2)c1F)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
To a solution of (3-amino-2,5,6-trifluorophenyl)(3-(4-chlorophenyl)quinoxalin-6-yl)methanone hydrochloride (100 mg, 0.24 mmol, 1.0 eq.) in DCM (10 mL) were added TEA (242 mg, 2.4 mmol, 10.0 eq.) and propane-1-sulfonyl chloride (172 mg, 1.2 mmol, 5.0 eq.). The resulting mixture was stirred at rt for 1 h, then concentrated. The resulting residue was dissolved in EA (10 mL) and washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=4/1, v/v) to afford N-(3-(3-(4-chlorophenyl)quinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)-N- (propylsulfonyl)propane-1-sulfonamide (50 mg, 40.3%).
Reaction SMILES: [CH2:1]1[C:12]2[CH:4]([N:5]=[C:6]3[C:11]=2[CH:10]=[CH:9][CH:8]=[CH:7]3)[CH2:3][CH2:2]1.C[NH2:14]>>[NH2:14][CH:1]1[C:12]2[CH:4]([N:5]=[C:6]3[C:11]=2[CH:10]=[CH:9][CH:8]=[CH:7]3)[CH2:3][CH2:2]1
Reactant: CN
Reactant: c1ccc2c(c1)=NC1CCCC=21
Product: NC1CCC2N=c3ccccc3=C12

Procedure:
In Scheme 2, Step A, the phthalimide group of the tetrahydrocyclopenta[b]indole of formula (2) is cleaved with methylamine to provide an aminotetrahydrocyclopenta[b]indole of formula (3). Preferred conditions use a solvent such as ethanol at a temperature of about 0 to 35° C., for 3 to 24 hours. The resulting by-product is removed by making the pH alkaline and filtering the resultant precipitate. The product is isolated from the filtrate by precipitation with water and 10% NaOH.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]([F:24])([F:23])[CH2:20][CH2:21][OH:22]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH2:21][CH2:20][C:19]([F:24])([F:23])[F:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: OCCC(F)(F)F
Product: CC(C)(C)OC(=O)N1Cc2ccc(OCCC(F)(F)F)cc2C1

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 3,3,3-trifluoropropanol. Off-white solid. MS (m/e): 276.3 ([M+H-Me2C═CH2]+, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[F:21][C:22]1[CH:23]=[C:24]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:25][C:26]1[S:30][C:29]([NH2:31])=[N:28][N:27]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[F:35][C:33]1[CH:32]=[C:24]([CH:23]=[C:22]([F:21])[CH:34]=1)[CH2:25][C:26]1[S:30][C:29]([NH:31][C:16]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C@@H:8]3[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]3)=[CH:20][CH:19]=2)=[O:18])=[N:28][N:27]=1
Reactant: Nc1nnc(Cc2cc(F)cc(F)c2)s1
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)O)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)Nc3nnc(Cc4cc(F)cc(F)c4)s3)cc2)CC1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
2.2 g of cis-4-(4-methoxycarbonylcyclohexyloxy)benzoic acid (7.91 mmol, 1 eq.) are placed in 30 mL of dimethylformamide at room temperature. 1.98 g of 5-(3,5-difluorobenzyl)[1.3.4]thiadiazol-2-ylamine (8.70 mmol, 1.1 eq.), 4.42 g of bromotris-pyrrolidinophosphonium hexafluorophosphonate (9.49 mmol, 1.2 eq.) and 2.76 mL of diisopropylethylamine (15.81 mmol, 2 eq.) are successively added. The reaction mixture is stirred for 6 days at room temperature, poured into water and extracted with ethyl acetate. The organic phase is washed three times with water and once with brine. The organic phase is concentrated and the residue is chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane ranging from 7% to 30%. 1.5 g of methyl cis-4-{4-[5-(3,5-difluorobenzyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenoxy}cyclohexanecarboxylate are obtained.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.C(#N)C>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][NH:4][C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:34][CH2:33]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: BrCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Yield: 70.9 %

Procedure:
10 g (0.273 mol) of 2-bromo-N-(triphenylmethyl)ethanamine, 200 ml of acetonitrile, 5.15 g (0.0273 mol) of 1-(2-methoxyphenyl)piperazine, 5.6 g of anhydrous potassium carbonate, a few grains of sodium iodide and 1 ml of dimethylformamide are introduced into a 500 ml round-bottomed flask equipped with a reflux condenser and placed under nitrogen. The mixture is heated at reflux for 15 h, the solvents are evaporated, water and dichloromethane are added, the organic phase is separated, washed with water, dried over sodium sulphate and the solvent is evaporated under reduced pressure. A viscous oil is obtained which is purified by chromatography on a column of silica gel, the eluent being a mixture of ethyl acetate and dichloromethane. There are isolated 9.24 g of product which is used as is in the following stage.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:16][CH2:17]OS(C)(=O)=O)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].I.[CH2:30]([O:32][CH2:33][CH2:34][N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[N:44]1[CH2:50][CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[CH3:31].C(N(CC)C(C)C)(C)C.ClCCl>C(#N)C.CO.ClCCl.C(OCC)(=O)C>[C:1]([N:11]1[CH2:15][CH2:14][C:13]([CH2:16][CH2:17][N:47]2[CH2:48][CH2:49][CH2:50][N:44]([C:36]3[N:35]([CH2:34][CH2:33][O:32][CH2:30][CH3:31])[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)[CH2:45][CH2:46]2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CS(=O)(=O)OCCC1(c2ccccc2)CCN(C(=O)OCc2ccccc2)C1
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)OCc4ccccc4)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Alternately, combine 1-carbobenzyloxy-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (5.7 g, 14.1 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (7.52 g, 213.8 mmol), and N,N-diisopropylethylamine (9.6 mL, 55 mmol) in acetonitrile (200 mL). Heat to reflux. After 18 hours, evaporate in vacuo to give a residue. Combine the residue and dichloromethane. Extract twice with saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give residue. Chromatograph the residue on silica gel eluting sequentially with ethyl acetate and then 5% methanol/dichloromethane to give 1-carbobenzyloxy-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine: Rf=0.38 (silica gel, 5% methanol/dichloromethane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Br[CH2:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:26]=1[C:27]#[N:28].[H-].[Na+].ClCCl>O1CCCC1.CN(C)C=O.CO>[Cl:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:25]([CH2:24][N:17]2[CH2:18][CH2:19][CH:15]([N:12]3[CH2:13][CH2:14][CH:9]([C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=4)[CH2:10][CH2:11]3)[C:16]2=[O:20])[C:26]=1[C:27]#[N:28]
Reactant: COc1ccc(C(=O)C2CCN(C3CCNC3=O)CC2)cc1
Reactant: N#Cc1c(Cl)cccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C2CCN(C3CCN(Cc4cccc(Cl)c4C#N)C3=O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-(4-methoxybenzoyl)piperidin-1-yl)pyrrolidin-2-one (70 mg, 0.23 mmol) and 2-(bromomethyl)-6-chlorobenzonitrile (80 mg, 0.35 mmol) in tetrahydrofuran (1 mL) and dimethylformamide (0.1 mL) was added sodium hydride (46 mg, 1.2 mmol, 60% in mineral oil). The mixture was stirred at ambient temperature for 30 minutes. Dichloromethane and methanol were added slowly to quench the reaction. Then the mixture was filtered through a short pad of silical gel column, the solvent was removed in vacuo, and the residue was purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) first and then (methanol: dichloromethane, 1:99 to 10:90) to give brown oil which is further purified by HPLC to give a colorless product. 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 2H), 7.45 (t, J=8.0 Hz, 1H), 7.35-7.41 (m, 1H), 7.30 (d, J=7.5 Hz, 1H), 6.87 (m, J=9.0 Hz, 2H), 4.62 (q, J=15.6 Hz, 2H), 3.80 (s, 3H), 3.50 (t, J=9.0 Hz, 1H), 3.11-3.37 (m, 3H), 2.94-3.11 (m, 1H), 2.75-2.94 (m, 2H), 2.28-2.54 (m, 1H), 2.09-2.28 (m, 1H), 1.90-2.09 (m, 1H), 1.66-1.90 (m, 4H). HRMS calculated for C25H26ClN3O3 452.1741. found (ESI, [M+H]+), 452.1760.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:45](Cl)(=[O:47])[CH3:46]>ClCCl>[C:45]([N:36]1[CH2:37][CH2:38][N:33]([C:30]2[CH:31]=[CH:32][C:27]([C:19]3[N:20]4[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[C:17]([C:12]4[CH:13]=[CH:14][C:15]5[C:10]([CH:11]=4)=[N:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:16]=5)[CH:18]=3)=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)(=[O:47])[CH3:46]
Reactant: CC(=O)Cl
Reactant: Nc1ncnn2c(-c3ccc(N4CCNCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCN(c2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.8 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(4-piperazin-1-ylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.20 mmol) in dichloromethane (2 mL) was added pyridine (23 μL, 0.28 mmol) followed by acetyl chloride (17 μL, 0.24 mmol). The mixture was stirred (rt) overnight. The mixture was diluted with dichloromethane (25 mL) and was washed with H2O (20 mL), brine, and was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water to obtain 28 mg (26%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (s, 1 H), 7.97 (d, 2 H), 7.94 (s, 1 H), 7.81 (d, 1 H), 7.66-7.64 (m, 1 H), 7.36-7.26 (m, 5 H), 7.19 (dd, 1 H), 7.06-7.01 (m, 3 H), 5.66 (s, 2. H), 3.62-3.55 (m, 4 H), 3.26-3.21 (m, 2 H), 3.20-3.14 (m, 2 H), 2.05 (s, 3 H); ES-MS m/z 543.33 [M+H]+, HPLC RT (min) 2.65.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].[CH3:29][C:30]([OH:34])([CH:32]=[CH2:33])[CH3:31]>>[OH:34][C:30]([CH3:31])([CH3:29])[CH:32]=[CH:33][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26]
Reactant: C=CC(C)(C)O
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C=CC(C)(C)O)c(Cc3ccccc3C(F)(F)F)sc21

Procedure:
Prepared using 5-bromo-3-methyl-1-(2-methylpropyl)-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione and 2-methyl-3-buten-2-ol. The crude product was purified by flash silica chromatography eluting with a gradient of 0-2% ethanol in dichloromethane to give the title compound as a cream foam (0.20 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=O)=O.[NH3:18]>CN(C)C=O>[NH2:18][CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: N
Reactant: CS(=O)(=O)OCCNC(=O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: NCCNC(=O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
The N-(2-methylsulfonyloxyethyl)-4-chlorobenzamide obtained is dissolved in 5 ml of dimethylformamide and added dropwise at room temperature to a solution of ammonia in dimethylformamide. After stirring for 2 hours, the mixture is worked-up and there is obtained N-(2-aminoethyl)-4-chlorobenzamide which is identical with the product obtained in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9](=[O:12])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1.[CH2:13](O)[CH2:14][CH2:15][OH:16].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.S(=O)(=O)(O)O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:10]([C:9]1([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[O:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH3:11]
Reactant: OCCCO
Reactant: CCC(=O)c1ccnc(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1(c2ccnc(OC)c2)OCCCO1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
To a stirred solution of 38.23 g of 1-(2-methoxy-pyridin-4-yl)-propan-1-one (231.4 mmol) as obtainable from Example 2 in 575 mL toluene were added 100 mL 1,3-propandiol (1.39 mol, 6.0 eq), 473 μL sulfuric acid (4.63 mmol, 0.02 eq) and 889 mg para-toluene sulfonic acid monohydrate (4.63 mmol, 0.02 eq). The reaction mixture was heated for 72 h (NMR control: <2% starting material 1-(2-methoxy-pyridin-4-yl)-propan-1-one) to reflux using a Dean-Stark trap (oil bath temperature 160° C.). After cooling down to room temperature, 500 mL saturated aqueous NaHCO3 were added and the phases were separated. The organic phase was washed twice with 250 mL, in total with 500 mL brine and was then dried over 50 g Na2SO4 (30 min) and filtered. The filter cake was washed with 100 mL toluene. After evaporation of solvent in a rotary evaporator (50° C./10 mbar), the crude product (40.31 g, 78% by weight) was obtained as a brown oil (HPLC purity 93.9% area). Purification was achieved using a high vacuum distillation (bp 95° C. at 0.056 mbar, oil bath temperature 125° C., 40 cm Vigreux column) furnishing the title compound (31.80 g, 142.4 mmol, 62% by weight) as colourless liquid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=3)[C:9]2=[O:21])[CH2:2]1.C1(S(O[CH2:32][CH2:33][CH2:34][C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:37][CH:36]=2)(=O)=O)C=CC=CC=1>CN(C)C=O.C(N(CC)CC)C>[NH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:35]([CH2:34][CH2:33][CH2:32][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]3[CH2:16][C:15]4[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=4)[C:9]3=[O:21])[CH2:2]2)=[CH:36]1
Reactant: COc1cc2c(cc1OC)C(=O)N(CC1CCCNC1)C2
Reactant: O=S(=O)(OCCCc1c[nH]c2ccccc12)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(=O)N(CC1CCCN(CCCc3c[nH]c4ccccc34)C1)C2

Procedure:
Prepared from 2-[(piperidin-3-yl)-methyl]-5,6-dimethoxy-1-oxo-1,3-dihydro-isoindole and 3-(3-benzenesulphonyloxy-propyl)-indole in dimethylformamide and triethylamine analogously to Example 1.
Reaction SMILES: [CH:1]1([C:9]([CH2:11]Br)=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:13]([C:16]1[CH:17]=[C:18](/[CH:22]=[CH:23]/[C:24](=[S:26])[NH2:25])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>C(O)C>[CH:1]1([C:9]2[N:25]=[C:24](/[CH:23]=[CH:22]/[C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=3)[S:26][CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CBr)C1CCCCCCC1
Reactant: NC(=S)/C=C/c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: O=[N+]([O-])c1cccc(/C=C/c2nc(C3CCCCCCC3)cs2)c1
Temperature: 0 °C
Yield: 49.4 %

Procedure:
A solution composed of 6.2 g of bromomethyl cyclooctyl ketone, 5.6 g of (E)-3-(3-nitrophenyl)-2-propenethioamide and 75 ml of ethyl alcohol was heated to reflux for 1 hr afterwhich it was diluted with 200 ml of ice water and extracted with methylene chloride. The combined extracts were washed with water, dried (MgSO4) and condensed in vacuo to give an oil which was further purified by chromatography over florisil using methylene chloride as the eluant to yield 4.5 g of (E)-4-cyclooctyl-2-[2-(3-nitrophenyl)ethenyl]thiazole; m.p. 64°-65° C. after crystallization from ethyl alcohol.
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:19])[NH:8][CH:9]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[O:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH:54]1[O:59][NH2:60]>CN(C=O)C>[CH:1]1([NH:6][C:7](=[O:19])[NH:8][CH:9]([C:11]2[S:15][C:14]([C:16]([NH:60][O:59][CH:54]3[CH2:55][CH2:56][CH2:57][CH2:58][O:53]3)=[O:18])=[CH:13][CH:12]=2)[CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NOC1CCCCO1
Reactant: CC(NC(=O)NC1CCCC1)c1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)NC1CCCC1)c1ccc(C(=O)NOC2CCCCO2)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(1-(3-cyclopentylureido)ethyl)thiophene-2-carboxylic acid obtained in step 2 in DMF (1 mL) was added HATU (62 mg, 0.165 mmol) and N,N-diisopropylethylamine (130 μL, 0.75 mmol) was added a solution of O-(tetrahydropyran-2-yl)hydroxylamine (19.3 mg, 0.165 mmol) in N,N-dimethylformamide (1.0 mL). The reaction was stirred at room temperature for 12 hours. The solution was evaporated to dryness and to the residue was added 1,2-dichloroethane (3 mL), sat. NaHCO3 solution (0.5 mL), and water (0.5 mL). After separation, the aqueous layer was extracted with 1,2-dichloroethane (2×3 mL). The combined organic phases were evaporated to dryness to give crude 5-(1-(3-cyclopentylureido)ethyl)-N-(tetrahydro-2H-pyran-2-yloxy)thiophene-2-carboxamide. LC-MS: (FA) ES+382.