Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]([C@@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[CH3:23])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:26]([N:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:30][CH2:31][CH:32]([C:35]([N:13]2[CH2:14][CH2:15][C@@H:10]([N:8]([CH3:9])[C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:25][CH:24]=3)[C@H:11]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[CH3:23])[CH2:12]2)=[O:36])[CH2:33][CH2:34]1)(=[O:28])[CH3:27]
Reactant: Cc1cc(F)ccc1[C@@H]1CNCC[C@H]1N(C)C(=O)c1ccc(Br)cc1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(Br)cc3)[C@H](c3ccc(F)cc3C)C2)CC1

Procedure:
Using the compound obtained in Example 41 and 1-acetylpiperidine-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][C@H:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[Cl:29][C:30]1[CH:37]=[C:36](F)[CH:35]=[CH:34][C:31]=1[C:32]#[N:33].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C(OCC)C.O.O1CCCC1>[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][C@H:17]([N:20]([C:36]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:29])[CH:37]=2)[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(F)c(Cl)c2)C1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccc(F)c(Cl)c2)c2ccc(C#N)c(Cl)c2)C1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
To an anhydrous toluene solution containing 3(S)-[(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.6 mmol) and 2-chloro-4-fluorobenzonitrile (0.30 g, 1.9 mmol) was added a 1.45 ml tetrahydrofuran solution containing sodium bis(trimethylsilyl)amide (1.1 M) using a syringe. The mixture was heated under reflux under a nitrogen atmosphere for 8 hours and cooled to room temperature. Water was added to the reaction solution, and extraction with diethyl ether was conducted. After drying over sodium sulfate and concentration under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 0.56 g of white amorphous solid 3(S)-[(3-chloro-4-cyanophenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:10].Cl[C:25]1[N:30]=[C:29]([CH3:31])[N:28]=[C:27]([N:32]([CH3:34])[CH3:33])[CH:26]=1>>[CH3:33][N:32]([CH3:34])[C:27]1[N:28]=[C:29]([CH3:31])[N:30]=[C:25]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=4[N:19]4[N:20]=[CH:21][CH:22]=[N:23]4)=[O:10])[CH2:3][CH:4]3[CH2:8]2)[CH:26]=1
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(-n2nccn2)c1
Reactant: Cc1nc(Cl)cc(N(C)C)n1
Product: COc1ccc(C(=O)N2CC3CN(c4cc(N(C)C)nc(C)n4)CC3C2)c(-n2nccn2)c1

Procedure:
The title compound was prepared utilizing (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Example 288, product from Step B) and 6-chloro-N,N,2-trimethylpyrimidin-4-amine. MS (ESI) mass calcd. C23H28N8O2, 448.52; m/z found 449.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](=O)[CH2:4][CH3:5].P(Cl)(Cl)(Cl)=O.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)[C:18]([N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)=[N:17]2.C>C(#N)C.O>[CH3:30][N:27]1[CH2:28][CH2:29][N:24]([C:19]2[C:18]([N:31]3[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]3)=[N:17][C:16]3[C:21](=[CH:22][CH:23]=[C:14]([N:13]=[C:3]([N:2]([CH3:7])[CH3:1])[CH2:4][CH3:5])[CH:15]=3)[N:20]=2)[CH2:25][CH2:26]1
Reactant: CN1CCN(c2nc3ccc(N)cc3nc2N2CCN(C)CC2)CC1
Reactant: CCC(=O)N(C)C
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCC(=Nc1ccc2nc(N3CCN(C)CC3)c(N3CCN(C)CC3)nc2c1)N(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 11.33 g. (0.112 mole) of N,N-dimethylpropionamide in 110 ml. of acetonitrile (dried over molecular sieves) is added 8.3 ml. of phosphorous oxychloride at 5°-10° C. The mixture is stirred at room temperature for 90 minutes. To the resulting yellow solution is added 13.7 g. (0.040 mole) of 6-amino-2,3-bis(4-methyl-1-piperazinyl)quinoxaline (prepared as in Example 1) in several portions with stirring. The mixture is placed in an oil bath at 65° C. and stirred for 16 hours. The reaction mixture is cooled and is poured into 400 ml. of ice plus water, stirred for 10 minutes and filtered. The filtrate is made alkaline to a pH greater than 13 with 5 N sodium hydroxide and extracted with five 100 ml. portions of chloroform. The combined extract is washed with two 100 ml. portions of water, dried over anhydrous potassium carbonate and anhydrous calcium sulfate and stripped of solvent by water pump evacuation to yield a residual oil which is crystallized on standing. The residue formed is recrystallized from 350 ml. of acetonitrile and is filtered and the solid collected is dried in vacuo at 78° C. over phosphorous pentoxide. The yellow solid obtained is dissolved in 160 ml. of hot acetonitrile, treated with activated charcoal, recrystallized by cooling at -10° C. and is filtered and dried as above to give 4.0 g. of yellow solid, m.p. 173°-175° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:12]([NH:13][C:14]2[C:15](=[O:20])[C:16](=[O:19])[C:17]=2[CH3:18])=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:7][NH:8]2)[CH3:2].CCN(CC)CC.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1.C(Cl)Cl.C(Cl)Cl>[CH2:1]([S:3][C:4]1[C:12]([NH:13][C:14]2[C:15](=[O:20])[C:16](=[O:19])[C:17]=2[CH3:18])=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH2:21][CH2:22][CH2:23][O:24][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:7][NH:8]2)[CH3:2]
Reactant: CCSc1c(Nc2c(C)c(=O)c2=O)ccc2[nH]cc(CCCO)c12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSc1c(Nc2c(C)c(=O)c2=O)ccc2[nH]cc(CCCOS(C)(=O)=O)c12
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
A cold (5° C.) mixture of 3-(4-ethylthio-5-(4-methyl-1,2-dioxocyclobut-3-en-3-yl) amino-3-indolyl)1-propanol (0.708 g, 2.1 mmol) and Et3N (0.697 ml, 5.0 mmol) in THF:CH2Cl2 (1:2, 45 ml) mixture kept under argon atm. was treated dropwise with MsCl (0.387 ml, 5.0 mmol) and stirred at 23° C. for 1.5 h. The reaction mixture was diluted with CH2Cl2 (40ml) and washed with H2O (10ml) and saturated NaHCO3 solution. The organic phase was dried (MgSO4) and concentrated in vacuo. The crude material was purified on silica gel dry column using a mixture of CH2Cl2 :EtOAc (7.3) as eluting solvent. Appropriate fractions were concentrated in vacuo giving a yellow oil, 0.70 g, 79%. 1H NMR (DMSO-d6) δ (ppm): 11.26, 11.20, 10.81 and 10.53 (4 br s, 2H, indolic NH and 5-NH), 7.42 (br s, 1H), 7.32 (s, 1H), 7.09 (d, J=8.2 Hz, 1H), 4.27 (t, J=6.4 Hz, 2H, CH2OSO2), 3.17 (s, 3H, CH3SO2), 3.11 (t, J=7 Hz, 2H, CH2CH2CH2O), 2.67 (br s, 2H, CH3CH2S), 2.28 (br, s, 1H, CH3 of dioxocyclobutene), 2.0-2.15 (m, 2H, CH2CH2CH2O), 1.59 (br s, 2H CH3 of dioxocyclobutene), 0.9-1.1 (m, 3H, CH3CH2S). IR (film) n:3710, 3180, 1783, 1728, 1590, 1340 and 1170 cm-1.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([O:16]C)=O)[CH2:3]1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34].N12CCCN=C1CCCCC2>O1CCCC1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH:4]([C:14]([NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])=[O:16])[CH2:3]1
Reactant: NCC(F)(F)F
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCC(F)(F)F)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
A mixture of 21.9 g (0.10 mole) methyl 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate in 150 ml tetrahydrofuran, was cooled to 0° C. in an ice bath under nitrogen and 24.3 g (0.15 mole) carbonyl diimidazole was added. The reaction was stirred at 0° C. for 30 minutes, then at room temperature for 30 minutes. A solution of 13.6 g (0.10 mole) of 2,2,2-trifluoroethylamine hydrochloride, 15.2 g (0.10 mole) 1,8-diazabicyclo[5.4.0]undec-7-ene and 100 ml tetrahydrofuran was added. The reaction was stirred at room temperature overnight. The solvent was removed at reduced pressure. The residue was taken up in dichloromethane and washed 3×150 ml saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure. The product was purified by column chromatography on silica with ethyl acetate to give 8.50 g of 5-oxo-1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinecarboxamide, mp 110-112° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([NH:37][CH2:38][CH2:39][OH:40])=O)=[CH:29][CH:28]=2)=[CH:4][CH:3]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[O:40]1[CH2:39][CH2:38][N:37]=[C:35]1/[CH:34]=[CH:33]/[C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH:9]2[C:10]3[C:15](=[CH:14][C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:12][CH:11]=3)[CH2:16][CH2:17][N:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:32][CH:31]=1
Reactant: O=C(/C=C/c1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(/C=C/C3=NCCO3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a solution of (2E)-3-(4-{[2-(4-fluorophenyl)-6-(phenylmethoxy)(1,2,3,4-tetrahydroisoquinolyl)]methyl}phenyl)-N-(2-hydroxyethyl)prop-2-enamide (0.32 g, 0.6 mmol) and diethyl azodicarboxylate (0.136 g, 0.78 mmol) in tetrahydrofuran (10 mL) was added dropwise a solution of triphenylphosphine (0.205 g, 0.78 mmol) in tetrahydrofuran (2 mL). After it was stirred at room temperature for 2 hours, the solvent was evaporated. The residue was then purified by chromatography (SiO2, 50% ethyl acetate/hexane) to provide the title compound (0.267 g, 86% yield): 1H NMR (CDCl3) 7.29-7.44 (m, 9H), 7.01 (d, 2H), 6.92 (m, 2H), 6.69-6.76 (m, 5H), 6.60 (d, 1H), 5.03 (s, 2H), 4.75 (t, 1H), 4.35 (t, 2H), 3.99 (t, 2H), 3.56 (m, 1H), 3.50 (m, 1H), 3.16 (dd, 1H), 2.95 (m, 2H), 2.67 (dt, 1H); ES-MS m/z 519 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7].Cl.Cl[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[OH-].[NH4+]>O.COCCOCCOC>[F:1][C:2]([F:12])([F:13])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[N:7]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: Nc1ccccc1OCC(F)(F)F
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: COCCOCCOC
Solvent: O
Product: FC(F)(F)COc1ccccc1N1CCNCC1
Yield: 75.2 %

Procedure:
A mixture of 2-(2,2,2-trifluoroethoxy)aniline (2.85 g, 14.9 mmol), bis(2-chloroethyl)amine hydrochloride (2.66 g, 14.9 mmol), potassium carbonate (2.06 g, 14.9 mmol), sodium iodide (0.45 g, 3 mmol) and bis(2-methoxyethyl) ether (7.3 mL) was heated 8 hours at reflux. The reaction mixture then was cooled, treated with concentrated ammonium hydroxide, poured into water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined extracts were washed with water (2×30 mL) and brine (1×30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (95:5) to give 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine (2.93 g, 11.2 mmol), m.p. 107°-108° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1.[CH2:13]([Li])CCC.CI.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH3:13])[CH:5]=[N:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: Clc1cncc(NC2CCC2)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(c1cncc(Cl)n1)C1CCC1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of 6-chloro-N-cyclobutylpyrazin-2-amine (535 mg) in THF (30 mL) was added dropwise n-butyllithium (1.6 M hexane solution, 2.4 mL) under an argon stream at −78° C., and the mixture was stirred for 30 min. To the reaction mixture was added dropwise a solution of methyl iodide (542 μL) in THF (1 mL), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added dropwise a saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 5→33% ethyl acetate/hexane) to give the title compound (492 mg, 85%).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][NH:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:33]([CH2:34][CH2:35][CH2:36][CH3:37])[CH3:32])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: CCCCNC
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: CCCCN(C)/C=C1/C(=O)O[C@H](COC)[C@@]2(C)C1=C(O)C(=O)C1=C2[C@H](OC(C)=O)C[C@@]2(C)C1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 20.9 mg (0.24 mmol) N-methylbutylamine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 38 mg (61.2%) product as an orange powder. MS (ESI) m/z 518.25 (M+1).
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)(CC(=O)C2C=CC=CN=2)C1=O)CCC.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[C:30](=[O:43])[C:29]2=[O:44].[CH3:45][O:46][C:47]1[N:52]=[C:51]([C:53](=[O:55])[CH3:54])[CH:50]=[CH:49][CH:48]=1>>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[C:30](=[O:43])[C:29]2([OH:44])[CH2:54][C:53]([C:51]1[CH:50]=[CH:49][CH:48]=[C:47]([O:46][CH3:45])[N:52]=1)=[O:55]
Reactant: COc1cccc(C(C)=O)n1
Reactant: O=C1C(=O)N(CCN2CCCCC2)c2ccc(Cl)cc21
Agent: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Product: COc1cccc(C(=O)CC2(O)C(=O)N(CCN3CCCCC3)c3ccc(Cl)cc32)n1

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5-chloro-1-(2-(piperidin-1-yl)ethyl)indoline-2,3-dione and 1-(6-methoxypyridin-2-yl)ethanone (commercially available from Fisher Scientific). 1H-NMR δ 7.72 (t, 1H), 7.63 (d, 1H), 7.34 (d, 1H), 7.28 (d, 1H) 6.98 (d, 1H), 6.86 (d, 1H), 5.5 (bs, OH), 4.04 (d, 1H), 4.00 (s, 3H), 3.8 (m, 2H), 3.60 (d, 1H), 2.60 (m, 6H), 1.55 (m, 4H), 1.43 (m, 2H). calculated mass for C23H26ClN3O4, 443.16, observed, 444.1 (M+1).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C[O:12]S([O-])(=O)=O.CC1C=CC=C2C=1N=C1C(C=CC=C1)=[NH+]2.C(O)(=O)C.O.NN>O.[Ni]>[OH:4][C:3]1[C:5]([OH:12])=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: COS(=O)(=O)[O-]
Reactant: O=C(O)c1ccccc1O
Agent: [Ni]
Agent: Cc1cccc2[nH+]c3ccccc3nc12
Agent: NN
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cccc(O)c1O
Yield: 861.3 %

Procedure:
0.15 g of salicylic acid and 0.03 g of 9-methylphenazinium methylsulphate are placed into a reactor and dissolved in 100 ml of water acidified by acetic acid to the pH=3.0; then 3.0 ml of hydrazine hydrate and 0.5 g of Raney nickel are added thereto. Thereafter, the reaction mixture is maintained for 4 hours under vigorous stirring. Then nickel is filtered-off, the resulting mixture is evaporated to 10 ml and extracted with chloroform. After cooling the precipitated desired product is crystallized by a mixture of water and ethanol in the ratio of 1:1 to give 0.13 g of 2,3-dihydroxybenzoic acid (90% as calculated for the starting compound) having m.p. 203°-204° C. The composition, in %, is as follows:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(N)cc2)CC1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
11.3 g of ethyl 1-(4-nitrophenyl)cyclopropanecarboxylate are dissolved in 110 ml of tetrahydrofuran, 1 g of 5% Pd/C (52.3% of water) is added, and the mixture is stirred at 23° C. under a hydrogen atmosphere for 1 h. After aeration, the solid material is filtered off, and the filtrate is evaporated to dryness in vacuo. Yield: 9.8 g (100%) of ethyl 1-(4-aminophenyl)cyclopropanecarboxylate; LC-MS retention time: 1.18 min (“nonpolar” gradient).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[C:18]([O:20][C:21]4[C:22]([CH3:30])=[N:23][C:24]([N+:27]([O-])=O)=[CH:25][CH:26]=4)[CH:17]=[CH:16][N:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:30][C:22]1[N:23]=[C:24]([NH2:27])[CH:25]=[CH:26][C:21]=1[O:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:13][CH:12]=2)[CH:19]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2ccc(N3CCN(C)CC3)cc2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1nc(N)ccc1Oc1ccnc(-c2ccc(N3CCN(C)CC3)cc2)c1
Yield: 80.1 %

Procedure:
A solution of 1-methyl-4-(4-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)phenyl)piperazine (0.333 g, 0.821 mmol) in MeOH (20 mL) was treated with 10% Pd/C (50% wet, 0.089 g, 0.082 mmol) and hydrogenated (1 atm) overnight. The solids were removed via filtration through diatomaceous earth, washed with MeOH and the filtrate concentrated to dryness to afford 6-methyl-5-((2-(4-(4-methylpiperazin-1-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-amine (247 mg, 80%). 1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J=5.7 Hz, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.21-7.20 (m, 2H), 6.98 (d, J=8.8 Hz, 2H), 6.57 (dd, J=5.6, 2.4 Hz, 1H), 6.35 (d, J=8.7 Hz, 1H), 5.94 (s, 2H), 3.20 (t, J=4.7 Hz, 4H), 2.45 (s, 4H), 2.22 (s, 3H), 2.07 (s, 3H); MS (ESI) m/z: 376.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:18]=[O:19].O>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:18]=[O:19])=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: COc1nc(Br)ccc1I
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1nc(Br)ccc1C=O
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of 6-bromo-3-iodo-2-methoxypyridine (1.0 g) in diethyl ether (38 mL) was cooled to −80° C. in a nitrogen atmosphere, and n-butyllithium (2.6 M, 0.735 mL) were added dropwise. After stirring at the same temperature for one hour, N,N-dimethylformamide (0.62 mL) was added dropwise. The mixture was stirred at the same temperature for one hour and water was added to the reaction system, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=94:6→9:1) to give 6-bromo-2-methoxynicotinaldehyde as a colorless powder (618 mg, 90%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH3:8])=[CH:4][CH:3]=1.C(O)C>[OH-].[Na+]>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH2:13][CH2:14][CH:9]([N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:26][CH:25]=3)[CH3:8])[CH2:10][CH2:11]2)=[CH:20][CH:19]=1)([OH:23])=[O:22]
Reactant: COC(=O)c1ccc(N2CCC(N(C)Cc3ccc(F)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(Cc1ccc(F)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Yield: 75.1 %

Procedure:
2.5 g (7 mmol) of the product from Example 27 in 140 ml of 1M sodium hydroxide solution/ethanol (1:1) were refluxed for 5 hours. The mixture was then worked up in a similar manner to Example 16. 1.8 g of 1-(4-carboxyphenyl)-4-(N-(4-fluorobenzyl)-N-methylamino)piperidine were obtained. Melting point: 256°-258° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22]Br)=[C:14]([Br:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NC(N)=[S:27].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][SH:27])=[C:14]([Br:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(CBr)nc3N21
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(CS)nc3N21
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.1 %

Procedure:
To a suspension of 0.90 g (4R,9aR)-7-bromo-6-bromomethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 10 ml ethanol was added at room temperature 0.2 g thiourea and the mixture was stirred at ambient temperature for 5 h. To the resulting clear solution was added 1 ml of 2N aqueous sodium hydroxide and the mixture was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=9:1 to yield 0.51 g of the title compound as crystalline solid (MS: 414.1 and 416.2 (M+H+)).
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1)(C([O-])=O)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].[S:23]([O-:26])([O-:25])=[O:24].[Na+:27].[Na+].[OH-].[Na+].Cl>O.C(O)C>[C:1]([NH:4][C@H:5]([C:6]([OH:8])=[O:7])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][S:23]([O-:26])(=[O:25])=[O:24])=[CH:17][CH:16]=1)(=[O:3])[CH3:2].[Na+:27]
Reactant: O=S([O-])[O-]
Reactant: CCOC(=O)C(Cc1ccc(CCl)cc1)(NC(C)=O)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)N[C@@H](Cc1ccc(CS(=O)(=O)[O-])cc1)C(=O)O
Temperature: 120 °C
Yield: 39 %

Procedure:
1.1 g of ethyl 2-acetamido-2-(4-chloromethylbenzyl)malonate are added to a solution of 3.31 g of sodium sulfite in 20 cm3 of distilled water, and 8 cm3 of a 10% aqueous solution of caustic soda, and the reaction mixture is heated for 3 hours to a temperature of about 120° C. After cooling to a temperature of about 20° C., the reaction mixture is taken to pH=1 by means of a 1N aqueous solution of hydrochloric acid, and the mixture is again heated to 120° C. for 1 hour. The reaction mixture is cooled to a temperature of about 20° C., and taken up in 150 cm3 of ethanol; the inorganic salts are separated off by filtration and the filtrate is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 30° C. The residue obtained is passed through a 2.5 cm diameter chromatography column packed with 100 g of silica gel, eluting with a mixture of dichloromethane, methanol, water and acetic acid (respectively 70-30-6-3 by volume). 424 mg of monosodium N-acetyl-4-sulfonatomethylphenylalanine are thus obtained.