Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.[NH2:23][CH2:24][C:25]([S:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH3:29])[CH2:26][CH2:27][OH:28].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:31]([S:30][C:25]([CH3:29])([CH2:26][CH2:27][OH:28])[CH2:24][NH:23][C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[N:2]([CH3:1])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:17])=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CC(CN)(CCO)SCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(C(=O)NCC(C)(CCO)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (2.00 g), 4-amino-3-(benzylthio)-3-methylbutan-1-ol (1.61 g), 1H-1,2,3-benzotriazol-1-ol (0.96 g) and N,N-dimethylformamide (20 ml) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.37 g) at room temperature, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (2.10 g, yield 65%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 132-133° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>CS(C)=O.CCOC(C)=O>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][CH:21]([N:20]([CH3:19])[C:2]2[CH:3]=[C:4]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:26][CH2:25]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(C(F)(F)F)c1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(c1cc(C(=O)OC(C)(C)C)cc(C(F)(F)F)n1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
A mixture of tert-butyl 2-chloro-6-(trifluoromethyl)isonicotinate (0.47 g, 1.7 mmol, from Example 21, Step 1), tert-butyl 4-(methylamino)piperidine-1-carboxylate (0.54 g, 2.5 mmol, from Step 1) and N,N-diisopropylethylamine (0.58 mL, 3.4 mmol) in dimethyl sulfoxide (1.4 mL) was heated in an oil bath held at 100° C. for 26 hours. The mixture was cooled to room temperature and diluted with EtOAc. The organic solution was washed with three portions of water, one portion of brine, was dried over sodium sulfate, filtered and concentrated. Flash chromatography using a 40 g silica gel cartridge and eluting with a gradient from 0-20% EtOAc in hexanes afforded product as a white solid (0.30 g, 39%).
Reaction SMILES: Br[C:2]1[C:3]([N:16]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17](=[O:20])[CH:18]=[CH2:19])=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8].C1COCC1>[Cl-].[Na+].O>[CH3:15][C:10]1[N:9]([C:5]2[N:6]=[C:7]([CH3:8])[C:2]3[CH:19]=[CH:18][C:17](=[O:20])[N:16]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[C:3]=3[N:4]=2)[C:13]([CH3:14])=[CH:12][CH:11]=1
Reactant: C=CC(=O)N(c1nc(-n2c(C)ccc2C)nc(C)c1Br)N1CCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-n2c(C)ccc2C)nc2c1ccc(=O)n2N1CCCC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a microwave vial was added N-(5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-yl)-N-(pyrrolidin-1-yl)acrylamide (2.0 g, 4.95 mmol) silver carbonate (2.73 g, 9.89 mmol) and anhydrous THF (100 ml). The reaction suspension was bubbled in nitrogen for 2 mins and then added the palladium tetrakis tert-(triphenylphosphine) (286 mg, 0.25 mmol). After stirring at 70° C. oil bath for 3 h, the reaction mixture was cooled to R.T. and diluted with 20 ml of brine. After stirring at R.T. for 5 mins, the reaction mixture was filtered through a celite pad. The cake was washed with ethyl acetate. The layers were separated. The organic layer was washed with brine 20 ml, dried with potassium carbonate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluted with 40% etoac:hex to give the titled compound weighted 480 mg 30%
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[CH3:11][N:12]1[C:16]([CH3:17])=[C:15]([C:18](O)=[O:19])[C:14](=[O:21])[N:13]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O.O>[Cl:8][C:7]1[CH:6]=[C:5]([OH:9])[C:4]([F:10])=[CH:3][C:2]=1[NH:1][C:18]([C:15]1[C:14](=[O:21])[N:13]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:12]([CH3:11])[C:16]=1[CH3:17])=[O:19]
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1cc(F)c(O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2cc(F)c(O)cc2Cl)c(=O)n(-c2ccccc2)n1C
Temperature: 80 °C
Reaction time: 24 h
Yield: 53.2 %

Procedure:
To a suspension of 4-amino-5-chloro-2-fluorophenol (0.97 g, 6 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carb oxylic acid (1.42 g, 6.12 mmol) in DMF (20 mL) was added EDCI (0.38 mg, 7.2 mmol) and HOAT (0.16 g, 1.2 mmol). The mixture was allowed to warm up to 80° C. and stirred for 24 hours. Then H2O (200 mL) and EtOAc (2 mL) was added. The resulted mixture was stirred at 0° C. for 2 hours, then filtered to give the title compound as a light brown solid (1.2 g, 53.2%).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[C:18]([OH:26])[CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].[Cl:28]CCl.Cl>C(O)(C)C.C(N(CC)CC)C>[CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[CH:20]=[CH:19][C:18]([OH:26])=[C:17]([CH2:10][N:12]([CH3:24])[CH3:13])[C:16]2=[CH:15][C:14]=1[CH2:13]3)=[O:11].[ClH:28]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(O)ccc3nc2-1
Reactant: ClCCl
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(CN(C)C)c(O)ccc3nc2-1
Temperature: 27.5 °C
Yield: 238.7 %

Procedure:
10-hydroxy-camptothecin (1.0 kg), dichloromethane (about 13 kg) and isopropanol (about 8 kg) were charged into a suitable reactor. N,N-dimethylmethyleneiminium chloride (0.3-0.5 kg) was added into the reactor. Triethylamine (0.04-0.2 kg) was then added into the resulting mixture at 20-35° C. and stirred at 20-35° C. for at least 12 hours. When the reaction was complete, a mixture of hydrochloric acid (32%, 0.06-0.3 kg) and isopropanol (about 5 kg) was added into the resulting mixture. After the addition was completed, the resulting mixture was stirred, filtered, and then washed with dichloromethane (about 3 kg). The wet solids were dried to give about 1.5 kg of crude topotecan HCl.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].I[CH2:21][CH2:22][CH:23]1[CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][CH2:22][CH:23]1[CH2:25][CH2:24]1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: ICCC1CC1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(CCC2CC2)c2cc([N+](=O)[O-])c(N)cc21
Yield: 85.3 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (4 g) is alkylated using (2-iodo-ethyl)-cyclopropane (5.36 g; 27.3 mmol) and K2CO3 (6.30 g; 45.6 mmol) at 55° C. for 12 h. After aqueous work-up the crude material (4.21 g) is de-acetylated in hydrochloric acid (6 N, 30 ml) at reflux. After aqueous work-up 5-amino-1-(2-cyclopropyl-ethyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (3.75 g) is obtained and used without further purification.
Reaction SMILES: [OH:1][C:2]([C@H:5]1[CH2:9][CH2:8][NH:7][C@H:6]1[CH3:10])([CH3:4])[CH3:3].[Cl:11][C:12]1[C:19]([F:20])=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[Li+].[Li+]>CS(C)=O>[Cl:11][C:12]1[C:19]([F:20])=[C:18]([N:7]2[CH2:8][CH2:9][C@H:5]([C:2]([OH:1])([CH3:4])[CH3:3])[C@@H:6]2[CH3:10])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1ccc(F)c(F)c1Cl
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CS(C)=O
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)c(Cl)c1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
A mixture of (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (639 mg), 2-chloro-3,4-difluorobenzonitrile (491 mg), lithium carbonate (669 mg) and dimethyl sulfoxide (13 mL) was stirred at 90° C. for 1 hr. The reaction mixture was cooled and partitioned between water and ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane). The obtained solid was recrystallized from ethyl acetate to give the title compound as crystals (yield: 538 mg).
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:42]2[N:43]=[C:44]([NH:47]C(OC(C)(C)C)=O)[S:45][CH:46]=2)\[C:23]([NH:25][C@H:26]2[C@@H:29]([CH2:30][N:31]3[CH2:35][CH2:34][O:33][C:32]3=[O:36])[N:28]([S:37]([OH:40])(=[O:39])=[O:38])[C:27]2=[O:41])=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:47][C:44]1[S:45][CH:46]=[C:42](/[C:22](=[N:21]/[O:20][C:17]2([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]2)/[C:23](=[O:24])[NH:25][C@H:26]2[C@@H:29]([CH2:30][N:31]3[CH2:35][CH2:34][O:33][C:32]3=[O:36])[N:28]([S:37]([OH:40])(=[O:39])=[O:38])[C:27]2=[O:41])[N:43]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCOC2=O)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(/C(=N/OC2(C(=O)O)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCOC2=O)cs1
Yield: 24.5 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (3S,4R)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)azetidine-1-sulfonic acid (1.10 g, 1.40 mmol), DCM (7.0 mL) and TFA (5.39 mL, 70.0 mmol). Additional TFA (3.24 mL, 42.0 mmol) was added after 1 h at rt and the solution was diluted with DCM and concentrated in vacuo after an additional 30 min. The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (178 mg, 23%) as a white powder. LCMS: Rt=0.30 min, m/z=518.9 (M+1) Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J=9.0 Hz, 1H) 6.92 (s, 1H) 5.23 (dd, J=9.1, 5.7 Hz, 1H) 4.12-4.23 (m, 3H) 3.72-3.62 (m, 2H assumed; obscured by water) 3.61-3.52 (m, 1H assumed; obscured by water) 3.26 (dd, J=14.5, 5.9 Hz, 1H) 1.36 (s, 4H). 1H NMR (400 MHz, D2O) δ 7.23 (s, 1H), 5.48 (d, J=5.8 Hz, 1H), 4.71-4.65 (m, 1H), 4.44 (t, J=8.2 Hz, 2H), 3.89-3.73 (m, 3H), 3.54 (dd, J=14.9, 4.9 Hz, 1H), 1.65-1.56 (m, 2H), 1.56-1.46 (m, 2H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:40])([F:39])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.[CH3:41][N:42]1[C:46]([CH2:47][CH2:48]O)=[CH:45][CH:44]=[N:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:41][N:42]1[C:46]([CH2:47][CH2:48][O:38][C:35]2[CH:36]=[CH:37][C:32]([N:29]3[CH2:28][CH2:27][N:26]([C:23]4[CH:24]=[CH:25][C:20]5[N:21]([C:17]([C:16]([F:15])([F:39])[F:40])=[N:18][N:19]=5)[N:22]=4)[CH2:31][CH2:30]3)=[CH:33][CH:34]=2)=[CH:45][CH:44]=[N:43]1
Reactant: Oc1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: Cn1nccc1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nccc1CCOc1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
DIAD (7.78 mL, 39.53 mmol) was added dropwise to 4-(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazin-1-yl)phenol (12 g, 32.94 mmol), 2-(1-methyl-1H-pyrazol-5-yl)ethanol (6.23 g, 49.41 mmol) and triphenylphosphine (12.96 g, 49.41 mmol) in THF (250 mL). The resulting solution was stirred at ambient temperature for 18 hours then split and added to a series of SCX columns (6). The crude product was eluted from the columns using 2M NH3/MeOH and the solvents evaporated. The crude product was diluted with DCM (200 mL) and washed with 2M NaOH (200 mL×2). The organic layer was dried over MgSO4, filtered and evaporated then purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness giving a yellow solid, which was triturated with ether then dried to afford 6-(4-(4-(2-(1-methyl-1H-pyrazol-5-yl)ethoxy)phenyl)piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine anhydrous Form A (9.18 g, 59.0%) as a cream solid.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[NH:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(N(CC)CC)C>CC(C)=O>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][S:10]([NH:25][C:23](=[NH:24])[C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N=C(N)c1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(C=CS(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: N=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
4-Nitrostyrylsulfonyl chloride (2.5 g., 0.01 mole) is added portion-wise to a solution of 4-nitrobenzamidine (1.65 g., 0.01 mole), prepared according to the procedure of L. Weintraub, et al., J. Org. Chem., 33, 1979 (1968), and triethylamine (1.01 g., 0.01 mole) in 50 ml. of acetone at 10° C. After stirring for a period of 1 hr. at 25° C., the mixture is concentrated under reduced pressure and the residual material stirred with water and collected. Triturating the filter cake with acetone provides N-(4-NITROSTYRYLSULFONYL)-4-NITROBENZAMIDINE, m.p. 173°-177° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]([NH2:37])[CH:28]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(#N)C>[C:10]([O:14][C:15](=[O:16])[NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22](=[O:24])[NH:37][C:29]2[CH:28]=[N:27][C:36]3[C:31]([CH:30]=2)=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:25][CH:26]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: Nc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)Nc2cnc3ccccc3c2)cc1
Temperature: 25 °C

Procedure:
N,N-diisopropylethyl amine (12.1 mL, 69.4 mmol) was added to a solution of 4-tert-butoxycarbonylamino-benzoic acid (9.05 g, 38.1 mmol), quinolin-3-ylamine (5.0 g, 34.7 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophospate (HBTU) (14.5 g, 38.1 mmol) in acetonitrile (200 mL) and was stirred at ambient temperature for ten minutes. The solution was heated at reflux for approximately 18 hours. Upon cooling to room temperature, the product crystallized and was collected by filtration, to give a colorless solid, 7.9 g (63%). MS: m/z 364 (MH+). 1H NMR (DMSO-d6): δ 1.51 (s, 9 H), 7.57-7.70 (m, 4 H), 7.75-8.00 (m, 4 H), 8.83 (d, J=2 Hz, 1 H), 9.15 (d, J=2 Hz, 1 H), 9.75 (br s, 1 H) and 10.54 (br s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1
Reactant: CCOC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COc1ccc(N)cc1

Procedure:
A solution of ethyl 4-nitrophenoxyacetate (15 g) in EtOH (400 mL) was hydrogenated at 40 PSI for 40 minutes in the presence of 10% Pd/C (1.5 g, 10% by weight). After the filtration through a celite the solvent was removed under a reduced pressure to obtain ethyl 4-aminophenoxyacetate. 1H NMR (CDCl3): δ 6.77 (d, 2H, 8.1 Hz), 6.60 (d, 2H, J=8.0 Hz), 4.50 (s, 2H), 4.24 (q, 2H), 1.24 (t, 3H); LCMS: ret. time: 12.00 min.; purity: 100%; MS (m/e): 196 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]1[C:29]([C:77]([NH:79][C@H:80]([CH2:91][OH:92])[C:81]([O:83]CC2C=CC=CC=2)=[O:82])=[O:78])=[N:30][C:31]([NH:50][CH2:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH3:76])=[C:32]([C:34]([NH:36][C@H:37]([CH2:48][OH:49])[C:38](=[O:47])[O:39]CC2C=CC=CC=2)=[O:35])[N:33]=1.C([O-])=O.[NH4+]>CO.O.[Pd]>[CH3:76][O:75][CH2:74][CH2:73][O:72][CH2:71][CH2:70][O:69][CH2:68][CH2:67][O:66][CH2:65][CH2:64][O:63][CH2:62][CH2:61][O:60][CH2:59][CH2:58][O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][CH2:51][NH:50][C:31]1[C:32]([C:34]([NH:36][C@@H:37]([C:38]([OH:47])=[O:39])[CH2:48][OH:49])=[O:35])=[N:33][C:28]([NH:27][CH2:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:29]([C:77]([NH:79][C@@H:80]([C:81]([OH:83])=[O:82])[CH2:91][OH:92])=[O:78])[N:30]=1
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCCNc1nc(C(=O)N[C@H](CO)C(=O)OCc2ccccc2)c(NCCCOCCOCCOCCOCCOCCOCCOCCOC)nc1C(=O)N[C@H](CO)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COCCOCCOCCOCCOCCOCCOCCOCCCNc1nc(C(=O)N[C@H](CO)C(=O)O)c(NCCCOCCOCCOCCOCCOCCOCCOCCOC)nc1C(=O)N[C@H](CO)C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A 250 mL round-bottom flask equipped with magnetic stir bar was charged with the above bis-benzyl ester 10 (0.390 g, 0.297 mmol) and ammonium formate (0.112 g, 1.78 mmol) in MeOH (10 mL) and water (10 mL). To this was added slurry of 10% Pd/C (0.095 g) in water (10 mL) and reaction mixture was stirred at 60° C. RP-LC/MS analysis after 1 h showed ˜60% mono-ester and the rest starting material. At this stage, additional ammonium formate (0.112 g, 1.78 mmol) and 10% Pd/C (0.095 g) were added and the reaction was completed in an hour. The catalyst was removed by filtration through Celite, washed with deionized water (˜100 mL), and the combined filtrates were concentrated in vacuo. The crude product was purified by preparative HPLC and the product was concentrated in vacuo and transferred into a 4 dram vial with acetonitrile, concentrated and vacuum dried to afford 8 (0.300 g, 76%) as red oil: HRMS (ESI) m/z calculated for C48H89N6O24 (M+H)+ 1133.5923, found 1133.5958.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:12])[CH3:11])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C(C)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
To a stirred solution of 4-Acetyl-benzoic acid methyl ester (5.0 g, 28.06 mmol) in MeOH (25 mL) at 0° C., was added sodium borohydride (NaBH4) (2.12 g, 56.12 mmol), the reaction mixture was stirred at rt for 3 h. The solvent was removed under reduced pressure, was diluted with H2O, the reaction mixture was extracted with ethyl acetate (150 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was dried under vacuum for 3 h to afford 4-(1-hydroxy-ethyl)-benzoic acid methyl ester (4.9 g, 99%): 1H NMR (300 MHz, CDCl3): δ 8.0 (d, J=7.8 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 5.20 (q, J=6.9 Hz, 1H), 3.91 (s, 3H), 2.02 (d, J=7.2, Hz, 3H). TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:2); Rf=0.5.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([Br:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[OH:36].C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([Br:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:32]1[CH:33]=[CH:34][C:35]([OH:36])=[C:30]([F:29])[CH:31]=1
Reactant: OB(O)c1ccc(O)c(F)c1
Reactant: C[C@H](Nc1ncnc(N)c1I)c1nn2ccc(Br)c2c(=O)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H](Nc1ncnc(N)c1-c1ccc(O)c(F)c1)c1nn2ccc(Br)c2c(=O)n1-c1ccccc1
Yield: 0.2 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-bromo-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (90 mg, 0.16 mol) was treated with (3-fluoro-4-hydroxyphenyl)boronic acid (38 mg, 0.24 mol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (22 mg, 0.02 mol) and a solution of sodium carbonate (2M, 317 μl, 0.73 mol) according to the method described in Example 3 to give 150 mg of the title compound that was used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][OH:16])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1.Cl[C:18]1[NH:19][C:20]2[C:26]([NH:27][C:28](=[O:38])[C:29]3[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=3)=[CH:25][C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][C:21]=2[N:22]=1>CCO>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:18]3[NH:19][C:20]4[C:26]([NH:27][C:28](=[O:38])[C:29]5[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=5)=[CH:25][C:24]([C:39]([F:42])([F:40])[F:41])=[CH:23][C:21]=4[N:22]=3)[C@H:10]([CH3:14])[CH2:9]2)=[N:6][CH:5]=[C:4]([CH2:15][OH:16])[CH:3]=1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1
Reactant: O=C(Nc1cc(C(F)(F)F)cc2nc(Cl)[nH]c12)c1cc(F)c(F)c(F)c1
Solvent: CCO
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(NC(=O)c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
A mixture of {5-chloro-6-[(3R)-3-methyl-piperazin-1-yl]-pyridin-3-yl}-methanol (530 mg, 2.2 mmol, Example 150a) and N-(2-chloro-6-trifluoromethyl-3H-benzoimidazol-4-yl)-3,4,5-trifluoro-benzamide from step (d) above (787 mg, 2.0 mmol) in EtOH (2 mL, Aldrich) reacted under the conditions of Example 3c to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 599 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Yield: 86.6 %

Procedure:
4-(4-Nitrophenoxy)piperidine-1-carboxylic acid tert-butyl ester (53.687 g) was hydrogenated using 7.5% palladium carbon (8.05 g) in a mixture of tetrahydrofuran (215 ml) and ethanol (215 ml) at 3 atm over 3 hours. After completion of the reaction, the reaction mixture was filtered through celite and the solvent was evaporated. Hexane was added to the obtained residue, and the obtained solid was collected by filtration and dried under reduced pressure to give the title compound (42.157 g).