Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([OH:18])=O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].ON1C2C=CC=CC=2N=N1.[NH2:30][CH:31]([CH2:48][C:49]1[N:50]=[CH:51][N:52]([C:54]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:53]=1)[C:32]([NH:34][CH:35]([CH2:44][CH:45]([CH3:47])[CH3:46])[CH:36]([OH:43])[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])=[O:33].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:19][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([C:16]([NH:30][C@H:31]([C:32]([NH:34][CH:35]([CH:36]([OH:43])[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[CH2:44][CH:45]([CH3:47])[CH3:46])=[O:33])[CH2:48][C:49]1[N:50]=[CH:51][N:52]([C:54]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:53]=1)=[O:18])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:6])[CH3:3]
Reactant: CC(C)CC(NC(=O)C(N)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(O)C(=O)OC(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)CC(NC(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(O)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.3 %

Procedure:
To a mixture of 1.1 g (4 mmol) of N-[(1,1dimethylethoxy)carbonyl]-L-phenylalanine and 0.568 g (4.2 mmol) of 1-hydroxybenzotriazole in 5 ml of dimethylformamide at 0° C. is added 2.4 g (4.1 mmol) of 3-[[2-amino-1-oxo-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propyl]amino]-2-hydroxy-5-methylhexanoic acid, 1-methylethyl ester (mixture of [2R-[2R*,3S*(S*)]] and [2S-[2R*,3R*(R*)]]-isomers) in 15 ml of dimethylformamide. The solution is stirred for five minutes, treated with 0.867 g (4.2 mmol) of dicyclohexylcarbodiimide, stirred at 0° C. for one hour, warmed to room temperature, stirred overnight, filtered and the dimethylformamide evaporated in vacuo. The resulting oil is dissolved in ethyl acetate and washed successively with 30 ml of 1N citric acid solution, 30 ml of saturated solution of sodium bicarbonate and 30 ml of saturated solution of sodium chloride. The organic layer is separated, dried (magnesium sulfate) and evaporated in vacuo to a foam. The foam is chromatographed over 250 g of silica gel (230-400 mesh), eluted with 5% methanol 95% chloroform, the combined fractions evaporated in vacuo and the residue dried under high vacuum overnight to afford 2.3 g of the title compound as a white foam.
Reaction SMILES: N#N.[NH2:3][C:4]1[C:13]([C:14]2[CH2:15][CH2:16][O:17][CH2:18][CH:19]=2)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=3[C:27]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])[CH:10]=2)[N:5]=1>CCO.[Pd]>[NH2:3][C:4]1[C:13]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=3[C:27]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])[CH:10]=2)[N:5]=1
Reactant: Cc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(N)c(C3=CCOCC3)cc2c1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: Cc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(N)c(C3CCOCC3)cc2c1
Reaction time: 12 h

Procedure:
Pd/C (10%) (0.051 g, 0.048 mmol) was added to a degassed (N2) solution of (2-(2-amino-3-(3,6-dihydro-2H-pyran-4-yl)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone (0.020 g, 0.048 mmol) in EtOH (1.00 mL). The solution was degassed with H2 gas and then stirred under a balloon of H2 gas for 12 h. The reaction was degassed with N2 and then filtered through a pad of celite with EtOAc and concentrated. The crude material was purified by silica gel chromatography by eluting with 20:1 2M NH3 in MeOH/DCM to provide (2-(2-amino-3-(tetrahydro-2H-pyran-4-yl)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 416 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:11]N(P(N(C)C)(N(C)C)=O)C.CI>O.[Cl-].[Na+].O>[CH2:2]([O:9][NH:10][CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CNOCc1ccccc1

Procedure:
To a stirred solution of O-benzylhydroxyl amine hydrochloride (1.59 g, 10 mmole) in 15 ml of dry HMPA containing dry sodium bicarbonate (3.36 g, 40 mmole) was added methyl iodide (1.5 g, 11 mmole). After 5 hours the resulting mixture was diluted with 30 ml of water and 20 ml of brine and extracted three times with ethyl ether. The extracts were combined, washed, dried and evaporated to produce the crude product as an oil. The oil was chromatographed to afford 800 mg of title C compound, with consistent spectral data.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@H:37]([CH:42]=NNC(N)=O)[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([OH:52])CCC.C(O)(=O)C>O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@H:37]([CH:42]=[O:52])[CH2:38][CH:39]([CH3:40])[CH3:41])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCO
Reactant: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C[C@@H](C=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1

Procedure:
A solution of 200 mg. of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl-L-leucinal semicarbazone in 2 ml. of the upper layer of a 4:1:5 by volume mixture of 1-butanol, glacial acetic acid and water was subjected to partition chromatography on a Sephadex (trade mark) G-25 column (column size: 2.5 cm. inner diameter×100.5 cm. length) and eluted with the same solvent as above. Fractions coloured with Pauli's reagent and 2,4-dinitrophenylhydrazine were collected and the solvent was removed under reduced pressure from the collected fractions. When diethyl ether was added to the residue, there were obtained 96 mg. of the desired compound as a white powdery solid, melting at 106°-108° C.; [α]22 -49.0° (C=0.5, methanol).
Reaction SMILES: [CH:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[CH:15][C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:30]([F:33])([F:32])[F:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:34]N1C(=O)CCC1=O>>[CH:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[C:15]([I:34])[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:30]([F:33])([F:31])[F:32])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Reactant: O=C1CCC(=O)N1I
Product: O=C(O)CC1CCn2c1c(I)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12

Procedure:
From 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid and 1-iodopyrrolidine-2,5-dione, in a similar manner to the one described in Example 1.4, the title compound was obtained as a brown solid. LCMS m/z=584.5 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.55-1.73 (m, 4H), 1.78-1.89 (m, 2H), 1.94-2.06 (m, 2H), 2.25-2.37 (m, 1H), 2.45-2.58 (m, 1H), 2.77-2.90 (m, 1H), 3.00 (dd, J=16.36, 3.35 Hz, 1H), 3.20-3.29 (m, 1H), 3.52-3.61 (m, 1H), 4.00-4.10 (m, 1H), 4.13-4.23 (m, 1H), 5.18 (s, 2H), 6.80 (d, J=2.40 Hz, 1H), 6.87 (dd, J=8.78, 2.34 Hz, 1H), 7.26 (d, J=8.72 Hz, 1H), 7.63 (d, J=8.08 Hz, 1H), 7.70-7.78 (m, 2H), 12.30 (bs, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[O:8]1[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+].CN(C)C=O>O.CCOCC>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[N:15]1[CH2:16][CH2:17][C:12]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:13][CH2:14]1
Reactant: Clc1ncccn1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: c1cnc(N2CCC3(CC2)OCCO3)nc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 47.9 %

Procedure:
A mixture of 10 g (0.0873 mol) of 2-chloropyrimidine, 38 g (0.2654 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 18 g (0.130 mol) of K2CO3, and 100 ml of dimethylformamide is stirred at 100°-110° C. for 4 days. The reaction mixture is allowed to cool to ambient temperature, diluted with water and extracted with ethyl acetate. The combined organic extracts are washed copiously with water, then brine, dried over Na2SO4, and concentrated in vacuo to give a waxy solid. Trituration with ether furnishes 9.25 g (48%) of title compound: IR (KBr) 1670 and 1585 cm-1 ; NMR (CDCl3) δ8.30 (t, 1H), 6.46 (d, 2H), 4.02 (s, 4H), 3.98-3.88 (m, 4H), and 1.90-1.66 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:15])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:14])=[CH:11]/[CH:12]=[O:13].O>C1COCC1>[CH3:16][CH:2]([CH2:3][CH2:4][CH2:5]/[C:6](/[CH3:15])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:14])=[CH:11]/[CH:12]=[O:13])[CH3:1]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Solvent: C1CCOC1
Solvent: O
Product: C/C(=C\C=O)CC/C=C(\C)CCCC(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 0.53 g of 2 in 150 mL of dry THF in a round-bottom flask equipped with a water-cooled condenser was added a solid mixture of 31.04 g of NiCl2.6H2O and 4.27 g of Al powder (caution: exothermic). The reaction mixture was stirred at room temperature for 6 h. The solid mass was removed by filtration, and the solvent was dried over MgSO4 and removed by rotary evaporation, which afforded 0.50 g of racemic 3, predominantly the (E)-isomer. 1H NMR δ (ppm) 9.8 (t, CHO), 5.2 (t, CH3C(CH3)═CH and CH2C(CH3)═CH), 2.3 (m, CH2C(CH3)═CH), 2.2-2.4 (qd, CH2CHO), 2.0 (m, C═CHCH2CH2C(CH3)═CHCH2), 1.6-1.7 (all s, CH3C(CH3)═CHCH2CH2CCH3), 1.2-1.5 (m, CH2CH(CH3)CH2CO), 0.9 (d, CH2C(CH3)═CH).
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.O1CCCC1.[F:11][C:12]1[CH:26]=[CH:25][C:15]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=O)=[CH:14][CH:13]=1.[CH3:27][N:28]1[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:31][N:30]=[N:29]1>N1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl.O>[F:11][C:12]1[CH:26]=[CH:25][C:15]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:33]([C:32]2[N:28]([CH3:27])[N:29]=[N:30][N:31]=2)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:14][CH:13]=1
Reactant: CCOC(=O)Cc1nnnn1C
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of titanium tetrachloride (2 mL) and carbon tetrachloride (2 mL) was added to 15 mL of tetrahydrofuran at -78° C. under an argon atmosphere. The suspension was stirred at -78° C. for 30 minutes before 0.2 g of 4,4'-difluorobenzophenone was added. After stirring for an additional 30 minutes, a solution of 0.15 g of ethyl 1-methyl-5-tetrazolylacetate in 1 mL of dry pyridine was added dropwise. The dark brownish suspension was stirred at -78° C. for 15 minutes, then was allowed to warm to 0° C. forming a thick paste. The mixture was allowed to stand for 24 hours at ambient temperature before it was poured into water. The aqueous mixture was extracted with ethyl acetate to yield crude product. Analytical TLC eluted five times with 20% (v/v) ethyl acetate in hexanes showed the desired product at Rf =0.3. Purification by preparative chromatography on two 20×20 cm2 0.25 mm TLC plates eluted twice with 20% (v/v) ethyl acetate in hexanes to give the title compound which was identical to the compound of Example 3, Step A.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:39])(=[O:15])=[O:14])=[CH:9][C:8]=1[OH:40])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:48][C:49]1[CH:57]=[CH:56][C:52]([C:53](Cl)=[O:54])=[CH:51][CH:50]=1>>[C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:39])(=[O:14])=[O:15])=[CH:9][C:8]=1[O:40][C:53](=[O:54])[C:52]1[CH:56]=[CH:57][C:49]([Cl:48])=[CH:50][CH:51]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(OC(=O)c2ccc(Cl)cc2)c1

Procedure:
The title compound was prepared according to the procedure in Example 17, step 1, using 4-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.362 g, 0.615 mmol), pyridine (0.298 mL, 3.69 mmol) and 4-chlorobenzoyl chloride (0.156 mL, 1.23 mmol) to give the title compound. 1H NMR (DMSO-d6) δ 1.35 (s, 9 H), 1.57 (s, 3 H), 2.17 (s, 6 H), 2.33 (s, 3 H), 7.17 (s, 2 H), 7.35-7.40 (m, 2 H), 7.43 -7.48 (m, 1 H), 7.72 (d, 2 H), 7.98 (d, 1 H), 8.13-8.24 (m, 5 H), 8.50 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:32][CH2:31][C:19]3([CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:32][CH2:31][C:19]3([CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(C(=O)OC(C)(C)C)C4)n2)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CCNC4)CC3)n2)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.8 %

Procedure:
To a suspension of tert-butyl 8-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-2-azaspiro[4.5]decane-2-carboxylate (13.2B: 0.13 g, 0.28 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 3.5 M). The mixture was stirred at room temperature for 1.5 h, then concentrated in vacuo. The residue was diluted with DCM (10 mL) and saturated Na2CO3 (10 mL) and then extracted with DCM/MeOH (v/v)=10/1 (30 mL×3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/2N NH3 in MeOH (v/v)=5/1) to afford 13.3B as a yellow solid (90 mg, 88%).
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:15]3[N:23]4[C:18]([CH:19]=[N:20][C:21](O)=[N:22]4)=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]2[N:37]([CH3:38])[CH2:36][CH2:35][N:34]([CH3:39])[C:33]2=[O:40])[CH:29]=[CH:30][CH:31]=1>>[CH3:39][N:34]1[CH2:35][CH2:36][N:37]([CH3:38])[CH:32]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([NH:25][C:21]3[N:20]=[CH:19][C:18]4=[CH:17][CH:16]=[C:15]([C:11]5[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([N:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)(=[O:8])=[O:7])[CH:10]=5)[N:23]4[N:22]=3)[CH:27]=2)[C:33]1=[O:40]
Reactant: O=S(=O)(c1cccc(-c2ccc3cnc(O)nn23)c1)N1CCCC1
Reactant: CN1CCN(C)C(c2cccc(N)c2)C1=O
Product: CN1CCN(C)C(c2cccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)N6CCCC6)c5)n4n3)c2)C1=O

Procedure:
1,4-Dimethyl-3-(3-{7-[3-(pyrrolidine-1-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-phenyl)-piperazin-2-one was prepared from 7-[3-(pyrrolidine-1-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 3-(3-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1052a. Product isolated as an orange foam (82 mg, 49%). LCMS (m/e) 546 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.75 (s, 1H), 8.65 (d, 1H, J=8.2 Hz), 8.31 (s, 1H), 7.87-7.77 (m, 2H), 7.70-7.62 (m, 1H), 7.41-7.32 (m, 2H), 7.12-7.03 (m, 2H), 6.94 (s, 1H), 6.85 (d, 1H, J=4.7 Hz), 3.78-3.65 (m, 2H), 3.34-3.25 (m, 4H), 3.25-3.15 (m, 1H), 3.70-2.96 (m, 1H), 2.99 (s, 3H), 2.74-2.62 (m, 1H), 2.18 (s, 3H), 1.82-1.72 (m, 4H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:14][C:15]1[N:16]=[C:17]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][Cl:35])=[CH:27][CH:26]=2)[O:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(OCC)C>C(#N)C>[Cl:35][CH2:34][CH2:33][CH2:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:17]2[O:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]([CH2:14][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:16]=2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1CBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A suspension of piperidine (90 μl, 0.86 mmol, 1.1 eq) and potassium carbonate (0.43 g, 3 mmol, 4 eq) in acetonitrile (5 ml) is treated dropwise with a solution of ethyl 4-(bromomethyl)-2-[4-(3-chloropropoxy)phenyl]-1,3-oxazole-5-carboxylate i93 (0.30 g, 0.77 mmol, 1 eq) in acetonitrile (2 ml) and is stirred at room temperature overnight. Diethyl ether is then added and the solution is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 210 mg of crude ethyl 2-[4-(3-chloropropoxy)phenyl]-4-(piperidin-1-ylmethyl)-1,3-oxazole-5-carboxylate i95, used as such in the next step.
Reaction SMILES: C(O[C@H:5]1[C@@H:9]([NH:10][C:11](=[O:28])[C@H:12]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:8][CH2:7][O:6]1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:40]([O:44][CH2:45][CH3:46])(=[O:43])[CH2:41][OH:42]>O1CCCC1>[CH2:17]([O:16][C:14]([NH:13][C@H:12]([C:11]([NH:10][C@H:9]1[CH2:8][CH2:7][O:6][CH:5]1[O:42][CH2:41][C:40]([O:44][CH2:45][CH3:46])=[O:43])=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)O[C@@H]1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COC1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In tetrahydrofuran (10 ml) was suspended (2S,3S)-2-acetoxy-3-[[N-benzyloxycarbonyl-(L)-leucyl]amino]tetrahydrofuran (0.8 g) and following addition of p-toluenesulfonic acid (0.02 g) and ethyl glycolate (5 ml), the mixture was stirred at room temperature for 5 hours. The reaction mixture was then concentrated under reduced pressure and the residue was chromatographed on a silica gel column, elution being carried out with ethyl acetate-hexane (1:1, v/v). From the eluate was obtained ethyl [(3S)-3-[[N-benzyloxycarbonyl-(L)-leucyl]amino]tetrahydrofuran-2-yl]oxyacetate (0.6 g) as an oil. This oil was dissolved in methanol (5 ml) followed by addition of potassium carbonate (0.1 g)-water (5 ml) and the mixture was stirred at room temperature for 3 hours. This reaction mixture was neutralized with 1N--HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried ((MgSO4) and the solvent was distilled off. The residue was dissolved in ethanol (20 ml) and following addition of 1N--NaOH (0.6 ml), the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to provide sodium [(3S)-3-[[N-benzyloxycarbonyl-(L)-leucyl]amino]tetrahydrofuran-2-yl]oxyacetate (chemical formula below) (0.35 g, 41%). As recrystallized from methanol-ether, colorless powder, m.p. 125°-127° C., optical rotation [α]D +50.7° (c=0.33, dimethyl sulfoxide)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([CH:30]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[N:14][CH:15]=1)=[O:8].C(N(C(C)C)CC)(C)C.[C:41](Cl)(=[O:52])[O:42][C:43]1[C:48]([CH3:49])=[CH:47][C:46]([CH3:50])=[CH:45][C:44]=1[CH3:51]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:31][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:41](=[O:52])[O:42][C:43]2[C:48]([CH3:49])=[CH:47][C:46]([CH3:50])=[CH:45][C:44]=2[CH3:51])=[CH:30][C:6]=1[C:7](=[O:8])[NH:9][C:10]1[CH:11]=[N:12][C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]3)=[CH:19][CH:18]=2)=[N:14][CH:15]=1
Reactant: Cc1cc(C)c(OC(=O)Cl)c(C)c1
Reactant: Cc1ccc(N)cc1C(=O)Nc1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(OC(=O)Nc2ccc(C)c(C(=O)Nc3cnc(Nc4ccc(N5CCN(C)CC5)cc4)nc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 16×100 mm vial was charged with 5-amino-2-methyl-N-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)benzamide 30 (0.100 g, 0.24 mmol), 4-(dimethylamino)pyridine (0.0059 g, 0.048 mmol), dichloromethane (2 mL), and diisopropylethylamine (0.050 ml, 0.29 mmol). A solution of mesityl carbonochloridate (0.048 g, 0.24 mmol) in dichloromethane (1 mL) was added dropwise and the reaction mixture stirred at room temperature for 20 hours. The reaction mixture was purified via column chromatography on silica gel (gradient elution with 0 to 20% methanol in dichloromethane) to afford mesityl 4-methyl-3-((2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)carbamoyl)phenylcarbamate 47 as a bright yellow solid. MS m/z found 580 [MH+]; calc. for C33H37N7O3=579.69.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([C@@:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[CH:20]=[CH:19][C:7]([C@@:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1
Reactant: O=C(O)[C@@](O)(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: Nc1ccc([C@@](O)(C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
A solution of (R)-4-nitrobenzilic acid (2.0 g, 7.33 mmol) in ethanol (25 ml) was treated with hydrazine (1.0 ml) and Raney-Ni (0.8 g) and stirred at room temperature for 18 hours under a nitrogen atmosphere. The Raney-Ni powder was removed by filtration, washed with ethanol, the ethanol layer concentrated to a small volume and diluted with water (75 ml). The aqueous layer was extracted with ether (2×50 ml) and the aqueous layer was evaporated under vacuum to provide a light yellow solid of (R)-4-aminobenzilic acid in 82% yield (1.46 g); mp 139°-140° C. (decomp); TLC [silica gel, acetone] Rf 0.20; 1NMR (D2O) δ6.75 and 7.18 (2d, 4H, C6H4) and 7.31 (s, 5H, C6H5).