Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)=[CH:17][N:16]=1)=[CH:9][CH:8]=2)=[O:4].[OH-].[Na+].O.Cl>C1COCC1.[Cl-].[Na+].O>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13]3)=[N:16][CH:17]=1)=[O:31]
Reactant: COC(=O)c1cc2cc(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cn3)ccc2[nH]1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Oc2ccc3[nH]c(C(=O)O)cc3c2)nc1)c1ccc(Cl)c(Cl)c1
Yield: 90.3 %

Procedure:
5-[5-(3,4-Dichlorobenzoylamino)pyridin-2-yloxy]-1H-indole-2-carboxylic acid methyl ester (1.00 g, 2.19 mmol) was dissolved in THF (30 mL). To the solution were added 1 M sodium hydroxide (3.50 mL, 3.50 mmol) and water (15 ml), and the resulting solution was refluxed for 3 hours. After cooling with ice, 1 M hydrochloric acid (3.50 mL, 3.50 mmol) and brine (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 ml). After the organic layer was washed with brine, then dried over anhydrous sodium sulfate, the solvent was evaporated. The obtained residue was crystallized from n-hexane to yield 0.875 g of the title compound as a pale yellow powder.
Reaction SMILES: [CH:1](=O)[C:2]#[CH:3].[NH2:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH:7]=1>CN(C)C=O>[N:5]1[C:6]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[C:7]=2[CH:3]=[CH:2][CH:1]=1
Reactant: C#CC=O
Reactant: NC1=CC(=O)CCC1
Solvent: CN(C)C=O
Product: O=C1CCCc2ncccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
The procedure of Rimek and Zymalkowski (Arch. Pharm. 1961, 294, 759-765) was followed. Over a period of 1 hour, 40.9 g (0.757 mol) of freshly-distilled propiolaldehyde was added dropwise to a solution of 42.1 g (0.379 mol) of 3-amino-2-cyclohexenone in 1.5 1 of N,N-dimethylformamide (DMF). The solution was stirred at room temperature for 12 hours. The DMF was evaporated at reduced pressure. Vacuum distillation (bp 60°-65° C. at 0.025-0.050 mmHg) of the resultant black tars gave 30.2 g (54.2%) of 7,8-dihydro-5(6H)-quinolinone as a colorless liquid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][OH:6])[CH3:2].Cl[C:8]([CH3:12])([CH3:11])[C:9]#[CH:10]>C1COCC1.Cl[Cu]>[CH3:11][C:8]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][OH:6])([CH3:12])[C:9]#[CH:10]
Reactant: CCNCCO
Reactant: C#CC(C)(C)Cl
Agent: Cl[Cu]
Solvent: C1CCOC1
Product: C#CC(C)(C)N(CC)CCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In anaolgy to Geri, Roberto; Polizzi, Carmela; Lardicci, Luciano; Caporusso, Anna Maria; Gazz.Chim.Ital.; 124; 6; 1994; 241-248: To 14.3 ml (146.3 mmol) 2-Ethylaminoethanol in 60 ml THF were added 362 mg (3.7 mmol) CuCl, followed by 7.5 g (73.1 mmol) 3-Chloro-3-methyl-1-butyne. The solution was stirred at RT for 2 h, the solvent was removed and the residue dissolved in ether/2M HCl. The phases were separated and after addition of Na2CO3 to the aqueous phase (pH9), it was extracted with ether. The ether phase was dried over Na2SO4 and concentrated. Destillation by Kugelrohr yielded 2-[(1,1-Dimethyl-prop-2-ynyl)-ethyl-amino]-ethanol as colorless oil, MS: 155 (M).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.O.Cl[C:11]([CH3:15])([CH3:14])[C:12]#[CH:13]>[Cu].[Cu]Cl.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:11]([CH3:15])([C:12]#[CH:13])[CH3:14])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)Cl
Reactant: Nc1ccc(Br)cc1
Agent: Cl[Cu]
Agent: [Cu]
Solvent: O
Solvent: CCOCC
Product: C#CC(C)(C)Nc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-bromobenzenamine (4.0 g, 23 mmol), TEA (4.3 ml, 31 mmol), 2.0 ml of water, copper (0.058 g, 0.91 mmol) and copper(I) chloride (0.058 g, 0.59 mmol) in diethyl ether (9.8 ml, 20 mmol) was added 3-chloro-3-methylbut-1-yne (2.0 g, 20 mmol), dropwise. After stirring overnight, the reaction mixture was transferred to a seperatory funnel containing water and diethyl ether. The aqueous layer was washed 3× with EtOAc. The organic layers were combined, dried with MgSO4, filtered and concentrated. The crude oil was purified with by MPLC (100% DCM to 10% (91/10/1 DCM:MeOH:NH4OH)) to provide the product as an oil. MS m/z: 240 (M+2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:20]O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:20])=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 4-(4-methoxyphenyl)-butyric acid (25.1 g, 0.129 mol) in methanol (130 mL), was added sulfuric acid (concentrated, 1.0 mL) dropwise and it was stirred at room temperature overnight under nitrogen. The reaction mixture was concentrated on a rota-vapor, the residue was then partitioned between ethyl acetate (200 mL) and saturated sodium bicarbonate aqueous solution (200 mL). The organic phase was separated, washed with brine (3×200 mL), then dried over Na2SO4 and filtered. Evaporation of solvent gave the titled compound as an oil (26.8 g, 99%). Mass (MH+)=209.
Reaction SMILES: O.CC(C)([O-])C.[K+].C[O:9][C:10]([CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[CH:19]=2)[CH2:14][N:13]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:11]>C(OCC)C>[CH3:32][C:29]([O:28][C:26]([N:13]1[CH:12]([C:10]([OH:11])=[O:9])[CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[CH:19]=2)[CH2:14]1)=[O:27])([CH3:30])[CH3:31]
Reactant: COC(=O)C1Cc2cc(OC)c(OC)cc2CN1C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: COc1cc2c(cc1OC)CN(C(=O)OC(C)(C)C)C(C(=O)O)C2
Temperature: 8 °C
Reaction time: 0.08 h
Yield: 101.4 %

Procedure:
Water (64 mg, 0.07 mL. 3.56 mmol) was added to a slurry of potassium t-butoxide (1.44 g, 12.8 mmol) in diethyl ether (25 mL) at 0° C. with stirring. After 5 minutes, the title B compound, 3,4-dihydro-6,7-dimethoxy-2,3(1H)-isoquinolinedicarboxylic acid 2-(1,1-dimethylethyl) 3-methyl ester (570 mg, 1.62 mmol) was added as a solution in 8 mL of ether. Stirring was continued for 45 minutes with warming to 8° C. after which the cooling bath was removed and stirring was continued at room temperature for 45 minutes. The reaction was quenched with 10 mL of saturated aqueous ammonium chloride, diluted with water, and extracted with ether. The aqueous solution was then acidified to pH 5 with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was dried (sodium sulfate) and concentrated to give 554 mg of the title compound as a viscous yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N+:11]([O-])=O)=[CH:5][N:4]=1)#[N:2]>CCOC(C)=O.CC(O)=O.[Fe]>[NH2:11][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: COc1cc([N+](=O)[O-])cnc1C#N
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(N)cnc1C#N
Temperature: 65 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
2-Cyano-3-methoxy-5-nitropyridine (1.0 g, 5.6 mmol) was dissolved in 1:1 EtOAc/AcOH (10 mL) and heated to 65° C. Iron powder (1.61 g, 28 mmol, 325 mesh) was added and the mixture stirred for two h. The mixture was filtered though Celite and the filtrate concentrated in vacuo. The residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by SiO2 Prep-TLC using CH2Cl2 as the eluent to give the compound 762D (0.805 g, 97%) as an off-white solid. HPLC: 100% at 1.31 min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 149.90 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[SH2:7].[F:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.C(N(CC)CC)C>O>[F:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]([NH2:14])=[S:7])=[CH:11][CH:10]=1
Reactant: S
Reactant: N#Cc1ccc(F)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1ccc(F)cc1
Reaction time: 4 h

Procedure:
Eighty-five ml of dry pyridine was saturated with hydrogen sulfide. To this was added 25 g of p-fluorobenzonitrile and 33 ml of triethylamine. Hydrogen sulfide was passed through the solution at room temperature, with good stirring. After 4 hours a sample on thin layer chromatography showed no nitrile. The solution was poured into water (600 ml) and ice. The solid product was filtered, washed with water and dried. Yield of 27.3 g, mp 143°--145° C.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:4]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:26]#[N:27].[CH3:28][O:29][CH2:30][CH2:31][OH:32]>>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:4]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:32][CH2:31][CH2:30][O:29][CH3:28])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:26]#[N:27]
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reactant: COCCO
Agent: [Na]
Product: COCCOc1cc2ncc(C#N)c(Nc3cc(OC)c(Cl)cc3Cl)c2cc1OC
Temperature: 125 °C

Procedure:
A mixture of sodium (118 mg, 5.11 mmol) and 2-methoxyethanol (5 mL) is heated at 120-130° C. for 3 hours. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (500 mg, 1.28 mmol) is added and the reaction mixture is heated at 120-125° C. for 1 hour. The temperature of the reaction mixture is increased to 140-150° C. and this temperature is maintained for 2.5 hours. The reaction mixture is cooled to room temperature and diluted with ice cold aqueous sodium bicarbonate. The solid is collected by filtration washing with water and hexane. Purification by flash column chromatography, eluting with 2% methanol in dichloromethane provides 550 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[2-methoxyethoxy]-3-quinolinecarbonitrile, mp 210-212° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[NH:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][N:37]=2)[CH2:32][CH2:31]1.C(=O)(O)[O-].[Na+].COCCOC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH2:25]([NH:24][C:23]1[CH:22]=[C:21]([CH3:27])[NH:20][C:19](=[O:28])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:39]2[CH:38]=[N:37][C:36]([N:33]3[CH2:32][CH2:31][N:30]([CH3:29])[CH2:35][CH2:34]3)=[CH:41][CH:40]=2)[CH:3]=1)=[O:15])[CH3:26]
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CCNc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1ccn2C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: CCNc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCN(C)CC3)nc2)cc2c1ccn2C(C)C
Temperature: 85 °C
Yield: 59.4 %

Procedure:
To a 20 mL microwave vial was added 6-bromo-N-{[4-(ethylamino)-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1-(1-methylethyl)-1H-indole-4-carboxamide (70 mg, 0.170 mmol), and 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (59.9 mg, 0.198 mmol). PdCl2(dppf)-CH2Cl2 adduct (14.67 mg, 0.018 mmol) and sodium bicarbonate (45.3 mg, 0.539 mmol) were added followed by 1,2-Dimethoxyethane (DME) (5 mL) and Water (2 mL). The vial was sealed and the reaction was heated to 85° C. for 1 hr. The reaction was cooled and evaporated. The material was taken into Methanol/DMSO and was filtered through an acrodisk and purified by reverse phase Gilson HPLC (5-80% acetonitrile/water+0.1% TFA, YMC ODS-A C18 Column 75×30 mm ID S-5 um, 12 nM Column, 6 minutes) the desired fractions were collected and evaporated from 0.1N NaOH which provided the desired product N-{[4-(ethylamino)-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1-(1-methylethyl)-6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide (57 mg, 0.101 mmol, 56.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.68 (s, 1H) 8.89 (t, J=5.94 Hz, 1H) 8.66 (d, J=2.02 Hz, 1H) 8.09 (dd, J=8.59, 2.02 Hz, 1H) 7.91 (s, 1H) 7.80 (s, 1H) 7.60 (d, J=3.03 Hz, 1H) 6.99 (d, J=8.84 Hz, 1H) 6.89-6.96 (m, 2H) 5.66 (s, 1H) 4.85-4.98 (m, 1H) 4.39 (d, J=5.81 Hz, 2H) 3.63 (br. s., 4H) 3.11-3.24 (m, 2H) 2.7 (bs, 4H) 2.08 (s, 3H) 1.47 (d, J=6.57 Hz, 6H) 1.20 (t, 3H). MS(ES) [M+H]+ 542.4.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:24][NH2:25])(=[O:23])[CH3:22].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:21]([NH:24][NH:25][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])(=[O:23])[CH3:22]
Reactant: CC(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.200 g, 0.720 mmol, US2005/20572 A1) in DCM (6.0 mL) were added acetohydrazide 173 (0.090 g, 1.085 mmol), 1-hydroxybenzotriazole (0.147 g. 1.085 mmol). 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.208 g, 1.085 mmol) and N,N-dimethylaminopyridine sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue, which was subjected to chromatography to give 174 (0.14 g, 60%) as a white foam.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][CH2:7][CH2:8][CH2:9][S:10](Cl)(=[O:12])=[O:11]>C1COCC1>[C:1]([NH:5][S:10]([CH2:9][CH2:8][CH2:7][Cl:6])(=[O:12])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)CCCCl
Temperature: -20 °C
Reaction time: 24 h
Yield: 98.6 %

Procedure:
tert-Butylamine (3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooled to −20° C. and treated slowly with 3-chloropropanesulfonyl chloride (1.5 mol, 182.4 mL). The reaction mixture was warmed to room temperature and stirred for 24 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The concentrate was dissolved in dichloromethane (2.0 L), washed with 1N HCl (1.0 L), water (1.0 L), brine (1.0 L), dried over Na2SO4, filtered, and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to provide the desired product as a white solid (316.0 g, 99%). 1H NMR (CDCl3) δ 1.38 (s, 9H), 2.30-2.27 (m, 2H), 3.22 (t, J=7.35 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H), 4.35 (br, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.Br.[NH2:56][C:57]1[S:58][CH:59]=[C:60]([C:62](O)=[O:63])[N:61]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[NH2:56][C:57]1[S:58][CH:59]=[C:60]([C:62]([N:50]2[CH2:51][CH2:52][CH:47]([CH2:46][C:45]([NH:44][C:36]3[CH:37]=[CH:38][C:39]4[NH:40][C:41]5[N:42]=[C:26]([NH:27][C:28]6[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=6)[CH2:33][CH2:34][C:35]=3[CH:43]=4)[N:25]=[CH:24][C:23]=5[Cl:22])=[O:53])[CH2:48][CH2:49]2)=[O:63])[N:61]=1
Reactant: Nc1nc(C(=O)O)cs1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cs1
Yield: 36 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-amino-1,3-thiazole-4-carboxylic acid hydrobromide as starting materials in 36% yield. LCMS for C28H29ClN9O2S (M+H)+: m/z=590.2.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10]O)=O)(C)(C)C.[OH:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:8][CH2:9][CH2:10][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a cooled (0° C.) solution of 2-(N-tert-butoxycarbonylamino)ethanol (3.20 g, 19.9 mmol), methyl 4-hydroxybenzoate (3.02 g, 19.9 mmol) and Ph3P (6.25 g, 23.8 mmol) in THF (50 ml) was added dropwise DIAD (4.69 ml, 23.8 mmol) over for 5 min. The reaction mixture was heated under reflux for 3 hr. The mixture was evaporated and the residue was dissolved in CH2Cl2 (30 ml) and TFA (30 ml). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was dissolved in CHCl3 and H2O. The solution was made basic by sat. NaHCO3 and extracted with CHCl3. The extract was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3—MeOH (30:1, v/v) as eluent to give methyl 4-(2-aminoethoxy)benzoate (1.03 g, 34% for 2 steps) as a colorless oil. 1H-NMR (CDCl3) δ3.10-3.13 (m, 2 H), 3.89 (s, 3 H), 4.03-4.06 (m, 2 H), 6.92-6.94 (m, 2 H), 7.98-8.00 (m, 2 H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:37]=[CH:36][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:27]=[CH:26][N:25]=4)[CH:17]=3)=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:38]([OH:45])(=[O:44])[CH2:39][CH2:40][C:41]([OH:43])=[O:42].O>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:27]=[CH:26][N:25]=4)[CH:17]=3)=[O:14])=[CH:36][CH:37]=2)[CH2:4][CH2:3]1.[C:38]([O-:45])(=[O:44])[CH2:39][CH2:40][C:41]([O-:43])=[O:42]
Reactant: O=C(O)CCC(=O)O
Agent: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Solvent: O
Solvent: CCO
Product: O=C([O-])CCC(=O)[O-]
Temperature: 90 °C

Procedure:
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide (4.94 g, 10 mmol) is added to a solution of butanedioic acid (succinic acid; Fluka, Buchs, Switzerland; 1.18 g, 10 mmol) is added to a solution of in ethanol (25 mL). The mixture is heated to 90° C., treated with water (0.2 g) and filtered. Upon cooling, the product crystallizes and is filtered and dried to afford 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide, succinate as a pale-yellow crystalline solid, having the following analytical properties: Analysis found: C, 64.19; H, 6.11; N, 15.82%; H2O, 0.87%. Calculated for C33H37N7O5-0.30 H2O: C, 64.23; H, 6.14; N, 15.89%; H2O, 0.88%.
Reaction SMILES: Cl[C:2]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([F:22])[CH:14]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].FC1C=C(C(C(OCC)=O)C(OCC)=O)C=CC=1[N+]([O-])=O.C(OCC)(=O)C.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:14][C:15]=1[F:22]
Reactant: CCOC(=O)C(Cl)(C(=O)OCC)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Agent: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1ccc(N)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of diethyl chloro(3-fluoro-4-nitrophenyl)propanedioate and diethyl (3-fluoro-4-nitrophenyl)propanedioate (1.7 g, ˜5.7 mmol) suspended in ethanol was treated with 5-10 ml ethyl acetate until in solution. This was treated with 10% Pd/C (wet paste) (170 mg) under argon and then ammonium formate (1.8 g, 5 eq) added. Stirred for 1 hour at reflux under argon. Cooled to room temperature and Pd removed by filtration through celite, under argon. Evaporated to a brown oil ˜1.7 g. Purified by flash chromatography, 40+™M Si cartridge, eluting 5-40% ethyl acetate in hexane over 10 column volumes. Fraction evaporated to give the title compound as a yellow oil (722 mg).
Reaction SMILES: Cl[C:2]1(Cl)[CH2:7][O:6][CH2:5][CH2:4][O:3]1.[CH3:9][C:10]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=1[NH2:12]>C1COCC1>[N+:17]([C:15]1[CH:14]=[CH:13][C:11]([N:12]2[CH2:2][CH2:7][O:6][CH2:5][C:4]2=[O:3])=[C:10]([CH3:9])[CH:16]=1)([O-:19])=[O:18]
Reactant: ClC1(Cl)COCCO1
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1N1CCOCC1=O
Temperature: 80 °C

Procedure:
1.05 g of a mixture of 2-chlorodioxene and 2,2-dichlorodioxane (molar ratio 1:1) are added to a solution of 1.10 g (7.24 mmol) of 2-methyl-4-nitroaniline in 20 ml of THF, and the mixture is heated to the boil. The solvent is distilled off, and the residue, a brown viscous liquid, is heated at 80° C. for 18 hours. After cooling, the residue is recrystallised from toluene/tert-butyl methyl ether: 1.50 g of 2-(2-chloroethoxy)-N-(2-methyl-4-nitrophenyl)acetamide as yellowish crystals, m.p. 113-114° C. 1H-NMR (d6-DMSO): δ=2.35 (s; 3H), 3.82 (m; 4H), 4.23 (s; 2H), 8.05 (d, J=8 Hz, 1H) 8.09 (dd, J=9 Hz, J=1 Hz, 1H), 8.16 (d, J=1 Hz, 1H), 9.33 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:11][NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)=[O:14])[C:6]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)([OH:26])[CH2:5]2.C=O.O.[C:37]1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1=[N:11][N:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=3)=[O:14])[CH2:37][O:26][C:6]1([C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[CH2:5]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(NN=C1c2ccc(Cl)cc2CC1(O)c1ccc(Cl)cc1)Nc1ccc(C(F)(F)F)cc1
Agent: C=O
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1COC2(c3ccc(Cl)cc3)Cc3cc(Cl)ccc3C2=N1
Yield: 172.8 %

Procedure:
A mixture of 0.30 g (0.0006 moles) of the product obtained in Step D, 0.36 g (0.012 moles) of paraformaldehyde, 50 mg of p-toluene sulfonic acid monohydrate and 30 mL of acetonitrile was refluxed for 1 hour. The resulting mixture was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated to give an oil that was chromatographed on silica gel using 4:1 hexanes-ethyl acetate to give 0.23 g of an oil that solidified on standing, melting point, 213°-214° C.