Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[CH3:2].[CH3:8][CH2:9][S:10]([OH:13])(=[O:12])=[O:11]>C1(C)C=CC=CC=1>[CH3:9][S:10]([O-:13])(=[O:12])=[O:11].[CH2:1]([N+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]=1)[CH3:2]
Reactant: CCS(=O)(=O)O
Reactant: CCn1ccnc1
Solvent: Cc1ccccc1
Product: CC[n+]1ccn(C)c1
Product: CS(=O)(=O)[O-]
Temperature: 25 °C
Yield: 98 %

Procedure:
To a 200 ml four necked flask equipped with a stirrer, a dropping funnel, a cooling tube and a thermometer, 48.07 g (0.5 mol) of 1-ethyl imidazole and 50 ml of toluene were charged and heated to 100° C., to which 55.07 g (0.50 mol) of methylmethane sulfonic acid was dropped slowly taking one hour or more and reacted for 25 hours. After reaction, they were cooled to room temperature and 101.07 g of 1-ethyl-3-methyl imidazolium methyl sulfonate was obtained by drying under a reduced pressure. Then, 101.07 g of the obtained diethyl hexyl methyl ammonium phosphate was dissolved in 50 ml of water, and a solution in which 189.68 g of lithium bis(pentafluoroethyl sulfonyl)imide was dissolved in 50 ml of water was added thereto at a room temperature and stirred. From separated two layers, the lower layer was fractionated and by-products were removed by adding 40 wt % of purified water and water washing five times, and vacuum drying was applied to obtain 228.71 g of 1-ethyl-3-methyl imidazolium bis(pentafluoromethane sulfonyl)imide. As a result of ICP analysis, the total alkali metals was 1.7 ppm, chloride ion was 0.6 ppm, and each of iodide and bromide ions was 0.1 ppm or less (lower than ICP detection limit).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:6].[CH3:13][N:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]3[CH:24]4[CH2:29][NH:28][CH2:27][CH2:26][CH:25]4[N:17]([C:18]=23)[CH2:16][CH2:15]1.N>>[ClH:1].[CH3:13][N:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]3[C@@H:24]4[CH2:29][N:28]([CH2:2][CH2:3][CH2:4][C:5]([C:7]5[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=5)=[O:6])[CH2:27][CH2:26][C@@H:25]4[N:17]([C:18]=23)[CH2:16][CH2:15]1
Reactant: O=C(CCCCl)c1ccncc1
Reactant: CN1CCN2c3c(cccc31)C1CNCCC12
Agent: N
Product: CN1CCN2c3c(cccc31)[C@@H]1CN(CCCC(=O)c3ccncc3)CC[C@@H]12
Product: Cl

Procedure:
The title compound was prepared from addition of the of 4-chloro-1-(4-pyridyl)butan-1-one to 3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline following General procedure A of Example 197. 1H NMR (300 MHz, CDCl3) δ 8.79 (dd, J=4.4 Hz, 1.8 Hz, 2H), 7.74 (dd, J=4.4 Hz, 1.4 Hz, 2H), 6.64 (dd, J=7.4 Hz, 7.6 Hz, 1H),6.49 (d, J=6.9 Hz, 1H), 6.39 (d, J=7.7 Hz, 1H), 3.54-3.62 (m, 1H), 3.23-3.31 (m, 2H), 3.13-3.17 (m, 1H), 2.95-3.03 (m, 2H), 2.85 (s, 3H), 2.76-2.84 (m, 2H), 2.57-2.60 (m, 1H), 2.31-2.41 (m, 1H), 2.22 (td, J=11.7 Hz, 2.9 Hz, 1H), 1.92-2.02 (m, 3H),1.83-1.88 (m, 1H), 1.66-1.76 (m, 2H) ppm. MS (CI, NH3) m/e 376 (base, M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][C@@H:9]([NH2:11])[CH2:8][CH2:7][C:5]=2[N:6]=1.[S:12]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)([O:15][CH2:16][CH2:17][CH3:18])(=[O:14])=[O:13]>CN(C)C=O>[CH2:16]([NH:11][C@H:9]1[CH2:8][CH2:7][C:5]2[N:6]=[C:2]([NH2:1])[S:3][C:4]=2[CH2:10]1)[CH2:17][CH3:18].[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:20][CH:21]=1
Reactant: CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1nc2c(s1)C[C@@H](N)CC2
Solvent: CN(C)C=O
Product: CCCN[C@H]1CCc2nc(N)sc2C1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 75 °C

Procedure:
A 1000 ml, three necked flask was equipped with an overhead stirrer, a temperature probe, a heating mantle, a claisen joint, a condenser, and a 250 ml addition funnel. The flask was charged with 25 grams of (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole, followed by 200 ml of dimethyl formamide (DMF). Under continuous stirring, the mixture was heated to a temperature of 75° C. The addition funnel was charged with a solution of 39.5 grams propyl tosylate and 32.5 ml diisopropylethyleamine in 50 ml DMF. This solution was added to the 1000 ml flask dropwise over a period of 2.0 hours. The reaction was monitored by analysis on HPLC.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>O1CCCC1>[O:12]=[C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10][N:9]1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: O=C1NCCC1(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 21A (1.0 g, 4.21 mmol) in tetrahydrofuran (20 mL) was added potassium tert-butoxide (1.0 M in tetrahydrofuran, 6.3 mL, 6.3 mmol) via syringe under nitrogen followed by ethyl 2-bromoacetate (0.47 mL, 4.21 mmol). The reaction mixture was heated to 80° C. and stirred overnight. The reaction mixture was cooled to room temperature, concentrated, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (20:80) gave the title compound. MS (DCI+) m/z 324.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[CH:12](OC)(OC)OC>CO>[O:11]1[C:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]=2[N:1]=[CH:12]1
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: COC(OC)OC
Solvent: CO
Product: O=C(O)c1ccc2ncoc2c1
Temperature: 100 °C
Yield: 89.1 %

Procedure:
A mixture of 4-amino-3-hydroxybenzoic acid (250 mg, 1.63 mmol) and trimethyl orthoformate (500 μL, 4.57 mmol) are heated in an oil bath at 100° C. for 2 h. The mixture is cooled to rt and diluted with MeOH. The resulting solution is filtered through a pad of Celite, and the filtrate is concentrated in vacuo to give 1,3-benzoxazole-6-carboxylic acid as a brown solid (237 mg, 89%): 1H NMR (DMSO-d6) δ 13.2, 8.9, 8.3, 8.0, 7.9.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4](C)[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([F:28])[C:23]([C:26]#[CH:27])=[N:24][CH:25]=2)=[CH:16][CH:15]=1.C(N(CC)CC)C.CCOC(C)=O>C1COCC1.[Cu]I>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([F:28])[C:23]([C:26]#[C:27][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:10][CH:11]=3)=[N:24][CH:25]=2)=[CH:16][CH:15]=1
Reactant: Cc1cc(I)ccc1OCCO
Reactant: C#Cc1ncc(-c2ccc(Cl)cc2)cc1F
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCOc1ccc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under an argon atmosphere 14.8 mg (0.078 mmol) of CuI was added to a solution of 0.82 g (3.11 mmol) of 2-(4-iodo-2-methylphenoxy)ethanol, 0.72 g (2.11 mmol) of 5-(4-chlorophenyl)-2-ethynyl-3-fluoropyridine, 57 mg (0.078 mmol) of [1,1′-bis(diphenylphosphine)ferrocene]palladium (II) chloride, and 0.86 mL (6.22 mmol) of triethylamine in 20 mL of THF and the mixture was stirred for 16 hours at RT. The reaction mixture was combined with EtOAc, and the precipitate was filtered off and washed with EtOAc. The filtrate and the organic washing solutions were washed with 5% aqueous ammonia and water, dried over magnesium sulfate and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, PE/EtOAc 1:1). Yield: 0.20 g (18% of theoretical); C21H15ClFNO2 (M=367.800); calc.: molpeak (M+H)+: 368/370 (Cl); found: molpeak (M+H)+: 368/370 (Cl); HPLC-MS: 5.94 minutes (method B).
Reaction SMILES: C(O)C.O.O1CCOCC1.[C:11]([N:15]1[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O:26]CC)=[O:25])[CH:17]=[N:16]1)([CH3:14])([CH3:13])[CH3:12].O.[OH-].[Li+]>O.Cl>[C:11]([N:15]1[C:19]([C:20]([F:22])([F:23])[F:21])=[C:18]([C:24]([OH:26])=[O:25])[CH:17]=[N:16]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)n1ncc(C(=O)O)c1C(F)(F)F
Temperature: 40 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
In a solution of ethanol:water:dioxane (1:1:1, 9 mL) was placed ethyl 1-tert-butyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (750 mg, 2.84 mmol) and lithium hydroxide hydrate (357 mg, 8.51 mmol). The mixture was stirred at 40° C. for 3 hrs and then at RT overnight. The mixture was diluted with water (25 mL) and 1N HCl (10 mL) and extracted with ethyl acetate (2×25 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SO4) and evaporated at reduced pressure to afford 1-tert-butyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (646 mg, 94% yield) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.63 (s, 9H), 7.92 (s, 1H); MS (ESI) m/z: 259.0 (M+Na+).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[CH:27]=[CH:26][C:19]2[S:20][C:21]([C:23](O)=[O:24])=[CH:22][C:18]=2[CH:17]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:23]([C:21]2[S:20][C:19]3[CH:26]=[CH:27][C:16]([Cl:15])=[CH:17][C:18]=3[CH:22]=2)=[O:24])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1cc2cc(Cl)ccc2s1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2cc3cc(Cl)ccc3s2)C1

Procedure:
66.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 5-chloro-benzo[b]thiophene-2-carboxylic acid to give (R)-3-{[(5-chloro-benzo[b]thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. White solid. MS 392.9 ([M−H]−)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:16][CH3:15])[CH:22]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[CH2:12][CH2:13][CH3:14]
Reactant: COc1cccc(B(O)O)c1
Reactant: CCCCn1ccc2cc(Br)ccc21
Product: CCCCn1ccc2cc(-c3cccc(OC)c3)ccc21

Procedure:
The title compound was prepared from 5-bromo-1-butyl-1H-indole (Step 1 of Example 29) and 3-methoxyphenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (APCI, [M+H]+) m/z 280. 1HNMR (300 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.52 (d, 1H, J=8.30 Hz), 7.43-7.38 (m, 2H), 7.39 (dd, 1H, J=7.70 and 7.91 Hz), 7.22 (d, 1H, J=8.50 Hz), 7.17 (s, 1H), 6.85 (d, 1H, J=7.10 Hz), 6.46 (d, 1H, J=3.05 Hz), 4.18 (t, 2H, J=7.01 Hz), 3.81 (s, 3H), 1.73 (p, 2H, J=7.16 Hz), 1.25 (h, 2H, J=7.46 Hz), and 0.87 ppm (t, 3H, J=7.31 Hz).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)/[C:9]1=[O:26])=O)(C)(C)C.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([O:39][C:40]2[CH:45]=[CH:44][C:43]([I:46])=[CH:42][C:41]=2[CH:47]=[N:48][C:49]([O:51][Si](C)(C)C)=[CH2:50])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([O:39][C:40]2[CH:45]=[CH:44][C:43]([I:46])=[CH:42][C:41]=2[CH:47]2[C:10]3([C:11]4[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=4)[NH:8][C:9]3=[O:26])[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH2:50][C:49](=[O:51])[NH:48]2)[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: C=C(N=Cc1cc(I)ccc1OC1CCN(C(=O)OC(C)(C)C)C1)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)C1
Yield: 23.9 %

Procedure:
In a manner similar to the method described in example 1e, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 5b (1.1 g, 2.8 mmol) was reacted with (R/S)-1-[2-(1-tert-butoxycarbonyl-3-pyrrolidinyloxy)-5-iodo-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (5.3 g, 10 mmol) in toluene (30 mL) at 140° C. for 4 h to give racemic(2′R, 3R, 4′S)-2′-[2-(1-tert-butoxycarbonyl-3-pyrrolidinyloxy)-5-iodo-phenyl]-6-chloro-4′-(3-chlorophenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 0.5 g, 48%)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:13])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([C:7]([Cl:13])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromo-thiophene-2-carboxylic acid (2.00 g, 10.47 mmol) was dissolved in DCM (10 mL) to which was added oxalyl chloride (1.99 g, 15.71 mmol) and a catalytic amount of DMF (100 μL). This reaction mixture was stirred at room temperature for 1 hr at which time the solvent was removed under vacuum and taken forward immediately.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[C:7](N)[CH:6]=[CH:5][C:4]=1[C:10]1[CH:16]=[CH:15][C:13](N)=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:32].[Na+].[I:34]I>O.C(Cl)Cl>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[C:7]([I:32])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:16]=[CH:15][C:13]([I:34])=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18]
Reactant: Nc1ccc(-c2ccc(N)cc2C(F)(F)F)c(C(F)(F)F)c1
Reactant: [I-]
Reactant: II
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1cc(I)ccc1-c1ccc(I)cc1C(F)(F)F
Temperature: 0 °C
Yield: 78.7 %

Procedure:
Ten grams of 2,2'-bis(trifluoromethyl)-benzidine (0.0312 mole) were dissolved in water (100 mls.) and concentrated sulfuric acid (60 mls.) and the solution was cooled to 0° C. A solution of sodium nitrite (4.5 grams; 0.0652 mole) in water (ten mls.) was added dropwise with stirring. The resulting cold tetrazonium salt solution was added slowly to a stirred solution of sodium iodide (20 grams) and iodine (20 grams) in water (20 mls.) maintained at a temperature of 0° C. During the addition, methylene dichloride was added to keep the product in solution. After stirring the mixture overnight at room temperature, excess iodine was destroyed by adding sodium bisulfite and the product was extracted with methylene dichloride. The organic phase was washed with aqueous sodium bisulfite, dried and evaporated to yield 13.3 grams (78%) of product, i.e., 2,2'-bis(trifluoromethyl)-4,4'-diiodobiphenyl, having a melting point of 119°-122° C. Recrystallization from methanol yielded white prisms having a melting point of 121°-123° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>C(#N)C>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH:2]2[CH2:3][O:4][C:5]3([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]3)[O:1]2)=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CCC2COC3(CCNCC3)O2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1,4-Dioxa-8-azaspiro[4.5]-decane (18.62 g, 130 mmoles) in 50 mL of acetonitrile was stirred under argon and treated with anhydrous potassium carbonate (27.60 g, 200 mmoles). The mixture was cooled to 0° C. and 2-(4-nitrophenyl)ethylbromide (23.01 g, 100 mmoles) was added in one portion. After 10 minutes, the ice bath was removed and the reaction was stirred for 14 hrs at room temperature. The mixture was diluted with 220 mL of ethyl acetate and 200 mL of water. The aqueous phase was separated, the organic phase washed with water (3×100 mL), and brine (2×50 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give 28.60 g (98%) of N(2-(4-nitrophenyl)ethyl-1,4-dioxa-8-azaspiro [4.5]-decane as a yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:17]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>CC(C)=O.O>[C:17]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:10][CH2:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)(=[O:29])=[O:28])=[CH:25][CH:26]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)NCCCN2CCOCC2)cc1
Temperature: 0 °C
Yield: 61.5 %

Procedure:
To the solution of 2.8 g (0.020 mol) of 3-morpholinopropylamine in 15 ml of acetone, the solution of 3.3 g (0.024 mol) of potassium carbonate in 3 ml of water was added under stirring. To this mixture, 5 g (0.021 mol) of 4-acetamidobenzenesulphonyl chloride XII was added portionwise at the room temperature for 15 min. The mixture was then stirred at the room temperature for another 2 hours. One half of the solvent volume was distilled off from the mixture, the mixture was cooled to 0° C., Obtained solid was separated, washed 3 times with 5 ml of ice water and dried. Afforded 4.2 g (62%) of 4-acetamido-N-(3-morpholinopropyl)benzenesulphonamide XIII, colourless solid, m.p. 97-98° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[C:7]=12.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[ClH:1].[F:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:8]1[C:7]2=[C:2]([NH:27][CH2:26][C:25]3[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=3)[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]1[CH3:12]
Reactant: NCc1ccc(F)cc1
Reactant: Cc1c(C)n(Cc2cccc(F)c2)c2c(Cl)nccc12
Product: Cc1c(C)n(Cc2cccc(F)c2)c2c(NCc3ccc(F)cc3)nccc12
Product: Cl
Yield: 70 %

Procedure:
In accordance with the same procedures as in Step 3 of Example 198, except for using 7-chloro-2,3-dimethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and 4-fluorobenzylamine, the titled compound was obtained as a white solid. (Yield: 70%)
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[CH3:12]O>>[ClH:1].[ClH:1].[CH3:12][O:10][C:9](=[O:11])[C@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][NH2:8])[NH2:2]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H](N)CCCCN
Yield: 91.6 %

Procedure:
To a mixture of L-Lysine-Hydrochloride (100 g) in 1.75 L of methanol at 0° C. was bubbled dry HCl for 7 hours. The crude solid product was filtered, dried to get pure L-Lysine methyl ester dihydrochloride (117 g, 91.6%) as a white powder with a melting point of 204.5-206° C. The compound was characterized by 1H NMR (DMSO-d6) δ 1.48 (m, 2H, CH2), 1.68 (m, 2H, CH2), 1.90 (m, 2H, CH2), 2.80 (m, 2H, CH2), 3.78 (s, 3H, Ester), 4.00 (t, 1H, CH), 8.20 (bs, 2H, NH2), 8.70 (bs, 2H, NH2).
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].[CH3:13][S:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1.[Cl-].[Na+]>O.CO>[CH3:13][S:14]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:2]
Reactant: CSc1c[nH]c2ccccc12
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)c1c[nH]c2ccccc12

Procedure:
Potassium persulfate (KHSO5, 55 g, 179 mmol) in water (300 ml) was slowly added to a solution of 3-methylthioindole (29.3 g, 179 mmol) in methanol (300 ml) cooled in a ice bath. One half hour after the addition was completed, water was added, the solution was saturated with sodium chloride and the product was extracted into chloroform. The extract was dried, evaporated in vacuo and the residue was crystallized from chloroform-ethyl acetate to give the title product.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[F:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26]>>[F:22][C:23]1[CH:24]=[C:25]([NH:26][S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)(=[O:3])=[O:4])[CH:27]=[CH:28][C:29]=1[F:30].[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(S(=O)(=O)Nc3ccc(F)c(F)c3)cc2c2cc[nH]c12
Yield: 23.3 %

Procedure:
This compound is prepared according to synthesis 25, from 150 mg (0.46 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 55 μL (0.55 mmol) of 3,4-difluoro-aniline. After purification by chromatography on silica gel (dichloromethane/methanol 95/5) then trituration in diethyl ether, 24 mg (12%) of 8-(3,4-difluorophenylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)[N:7]=1.[CH3:28][CH2:29][N:30]([CH:34](C)C)C(C)C.C([S:39]N=C=O)C>CN(C=O)C>[Br:12][C:11]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([NH:30][CH2:29][CH3:28])=[S:39])=[N:7][C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)=[N:9][CH:10]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Reactant: CCSN=C=O
Solvent: CN(C)C=O
Product: CCNC(=S)NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A solution of N-(3-((4-((3-aminopropyl)amino)-5-bromo-2-pyrimidinyl)amino)phenyl)-1-pyrrolidinecarboxamide (100 mg, 0.20 mmol) and DMF (5 mL) was treated with DIEA (0.1 mL, 0.6 mmol, 3eq) and ethylthioisocyanate (15 mg, 0.17 mmol, 0.9 eq). The resulting mixture was stirred at RT for 2 hr. Then the crude mixture was purified by HPLC using acetonitrile/water to afford the title compound (82 mg).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][NH:35][CH2:36][CH3:37])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][N:35]([CH2:36][CH3:37])[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: O=C(O)CO
Reactant: CCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CCN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)CO
Yield: 70 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(ethylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 5, preparation of starting materials) to give the title compound in 70% yield; NMR spectrum (DMSO-d6) 1.10 (t, 3H), 3.29-3.45 (m, 2H), 3.80-3.95 (m, 2H), 4.10 (s, 2H), 4.30-4.55 (m, 2H), 4.42 (t, 1H), 5.30 (s, 2H), 7.18 (d, 1H), 7.22 (d, 1H), 7.30-7.40 (m, 2H), 7.60 (d, 2H), 7.70-7.78 (m, 1H), 7.82-7.92 (m, 1H), 7.95 (s, 1H), 8.43 (s, 1H), 8.60 (d, 1H), 9.80 (s, 1H); Mass spectrum MH+ 508.