Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C1(OC(=O)[C@H](CCCCN)N[C:16](=[O:38])[C@H:17]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH:18][C:19](=[O:33])[C@H:20]([CH:30]([CH3:32])[CH3:31])[NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)C2C(=CC=CC=2)C=CC=1.[OH-:45].[Na+]>CO>[C:22]([NH:21][C@H:20]([C:19]([NH:18][C@H:17]([C:16]([OH:38])=[O:45])[CH2:34][CH:35]([CH3:36])[CH3:37])=[O:33])[CH:30]([CH3:31])[CH3:32])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: [OH-]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C)C(=O)N[C@@H](CCCCN)C(=O)Oc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
In 150 ml of methanol was dissolved 5.0 g of the above ester, and 20 ml of 1N sodium hydroxide solution was added to the solution. The mixture was stirred at room temperature for 8 hrs. The reaction mixture was concentrated at a low temperature, after which ethyl acetate and distilled water were added to the residue. The resulting mixture was shaken, and the aqueous layer was separated and made weakly acidic with 10% hydrochloric acid solution. The oily substance thus precipitated was extracted with ethyl acetate, and the extract was washed with water and dried over anhydrous magnesium sulfate, and thereafter evaporated under reduced pressure to remove the solvent, thereby obtaining 3.0 g (yield 65%) of a colorless oily substance of N-benzoyl-L-valyl-L-leucine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:32][CH:29]1[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (1.0 g, 3.77 mmol) was treated with 4-amino-piperidine-1-carboxylic acid tert-butyl ester following general procedure B to afford 4-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (1.48 g). Thus obtained amino-ester (500 mg, 1.17 mmol) was subjected to reaction with 1-chloro-3-isocyanato-benzene according to general procedure C to furnish 4-[3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg). LCMS: m/z 537 [M+1]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[CH2:16][N:15]([CH3:17])[CH2:14][CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:20][C:21]1([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:23][O:22]1>CN(C=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[CH2:16][N:15]([CH3:17])[CH2:14][CH2:13][C:9]=3[N:10]([CH2:20][C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)([OH:22])[CH3:23])[C:11]=2[CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC1(c2ccncc2)CO1
Reactant: CC(C)c1ccc2c3c([nH]c2c1)CCN(C)C3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc2c3c(n(CC(C)(O)c4ccncc4)c2c1)CCN(C)C3
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.1 mmol) in DMF (10 mL) was added sodium hydride (252 mg, 6.3 mmol). After stirring for 10 min at RT, 4-(2-methyl-oxiranyl)-pyridine (444 mg, 3.2 mmol) was added and stirring continued for another 16 h. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and concentrated to afford crude product which was re-crystallized in ether and hexane to yield 1-(7-isopropyl-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol. 1H NMR (CD3OD, TFA salt) d (ppm): 8.60 (d, 2H), 8.05 (d, 2H), 7.25 (d, 1H), 6.90 (d, 1H), 6.78 (s, 1H), 4.65 (m, 1H), 4.42 (s, 2H), 4.30 (m, 1H), 3.90 (m, 1H), 3.60 (m, 2H), 3.30 (m, 1H), 3.10 (s, 3H), 2.85 (m, 1H), 1.80 (s, 3H), 1.18 (m, 6H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][CH2:29][CH2:30]O)[CH:24]=[C:25]([Cl:27])[CH:26]=1.[Br:32]Br.O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]([Br:32])[CH2:29][CH3:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: OCCCc1cc(Cl)cc(Cl)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCC(Br)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
Triphenylphosphine (315 mg, 1.20 mmol) was added to a solution of 3-(3,5-dichlorophenyl)-propanol (200 mg, 0.98 mmol) in CH2Cl2 (20 mL). The reaction mixture was cooled to 0° C. and bromine (207 mg, 1.30 mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h and was warmed to room temperature. The reaction was poured into water and the aqueous solution was extracted with CH2Cl2. The organic solution was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (hexanes) to afford the title compound (134 mg). 1H NMR (400 MHz, CDCl3) δ 7.21 (m, 1H), 7.08 (m, 2H), 3.37 (t, 2H), 2.74 (t, 2H), 2.13 (m, 2H).
Reaction SMILES: C([O-])(O)=O.[Na+].[NH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7]1.[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(C)=O>O>[N:6]1([C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[CH2:11][CH2:10][CH2:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 250-mL round-bottomed flask was charged with a solution of NaHCO3 (10.7 g, 127.38 mmol, 2.00 equiv) in H2O (80 mL), ethyl piperidine-3-carboxylate (10 g, 63.69 mmol, 1.00 equiv) and benzyl carbonochloridate (11.9 g, 70.00 mmol, 1.10 equiv). The resulting solution was stirred for 16 hours at room temperature. The progress was monitored by TLC (EtOAc: PE=1:5). Upon completion, the resulting solution was extracted with ethyl acetate (3×50 mL). Combined organic layers were dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:100) afford 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate as pale yellow oil (11.4 g, (62%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[OH-].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(O)(=O)C>O>[CH2:18]([O:17][C:15]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)ccc1NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A mixture of 4-amino-3-methylbenzoic acid (35.1 g, 232 mmol) in water (400 mL) was treated with 2.5N NaOH (200 mL, 500 mmol) and benzyl chloroformate (37.0 mL, 259 mmol). After 1 h, 150 mL water was added, the resulting mixture was treated with glacial acetic acid (15 mL) and the solids collected by filtration. The filter cake was rinsed with water and the resulting solid taken up in ethyl acetate/2-methyl tetrahydrofuran. The organic was washed with brine, dried over MgSO4, filtered and concentrated. The resulting solid was dried under vacuum to give 45.1 g of the title compound. LCMS m/z=307.9 MH+, Rt=2.508 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:19](=O)[CH2:18][CH2:17][C@@:16]2([CH3:21])[CH:3]1[C@@H:4]([CH2:24][OH:25])[C@@H:5]([OH:23])[C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:22].[ClH:27].Cl.[NH:29]1[CH2:34][CH2:33][CH:32]([O:35][NH2:36])[CH2:31][CH2:30]1>N1C=CC=CC=1>[ClH:27].[NH:29]1[CH2:34][CH2:33][CH:32]([O:35]/[N:36]=[C:19]2/[C:2]([CH3:26])([CH3:1])[CH:3]3[C@:16]([CH3:21])([CH2:17][CH2:18]/2)[C@@H:15]2[C@H:6]([C@H:7]4[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C@@H:10]([OH:22])[CH2:9][CH2:8]4)[C@H:5]([OH:23])[C@@H:4]3[CH2:24][OH:25])[CH2:31][CH2:30]1
Reactant: NOC1CCNCC1
Reactant: CC1(C)C(=O)CC[C@@]2(C)C1[C@@H](CO)[C@@H](O)[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C)/C(=N/OC2CCNCC2)CC[C@@]2(C)C1[C@@H](CO)[C@@H](O)[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
4,4-Dimethyl-6α-hydroxymethyl-7α,17β-dihydroxyandrostan-3-one (Preparation 10, 40 mg) and 4-piperidyloxyamine dihydrochloride (Preparation 16, 52 mg) were dissolved in pyridine (1.0 ml) and stirred at RT for 4 days. After evaporation of the solvent, the resulting solid was triturated with DCM/AcOEt 1/1 to give, after filtration, the title compound (40 mg, 86%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[C:17]([Mg]Br)([CH3:19])=[CH2:18]>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[N:6]=[CH:7][CH:8]=[C:9]3[CH:18]=[C:17]([CH3:19])[NH:1][C:4]=23)=[CH:11][CH:12]=1
Reactant: C=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1cccnc1-c1ccc(F)cc1
Product: Cc1cc2ccnc(-c3ccc(F)cc3)c2[nH]1
Yield: 37 %

Procedure:
In accordance with the same procedures as in Example 242, except for using 3-nitro-2-(4-fluorophenyl)pyridine prepared in Preparation 13 and isopropenyl magnesium bromide, the titled compound was obtained as a white solid. (Yield: 37%)
Reaction SMILES: [C:1]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].[SiH:21]([Cl:24])([Cl:23])[Cl:22]>>[Cl:22][Si:21]([Cl:24])([Cl:23])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:15][CH2:16][C:17]([F:18])([F:19])[F:20])=[O:14]
Reactant: C=CCCCCCCCCCCC(=O)OCC(F)(F)F
Reactant: Cl[SiH](Cl)Cl
Product: O=C(CCCCCCCCCCCC[Si](Cl)(Cl)Cl)OCC(F)(F)F
Temperature: 80 °C
Reaction time: 22 h

Procedure:
In a heavy-walled tube equipped with a magnetic stir bar, ester (5) (1.18 g, 4.00 mmol, 1.0 equiv.) and H2PtCl6.6H2O (21 mg, 0.14 mmol, 1.0 mol. %) were loaded. The tube was transferred into a glovebox and HSiCl3 (0.82 mL, 8.04 mmol, 2.0 equiv.) was added to the solution. The tube was tightly fastened then removed from the glovebox. The resulting solution was stirred at 80° C. for 22 h behind a protecting shield. Purification was achieved by Kugelrohr distillation under high vacuum and provided 1.16 g (67%) of TTTA (6) as a colorless oil; bp=170-180° C. (0.15 Torr); 1H NMR (400 MHz, CDCl3) δ 4.45 (q, J=8.5 Hz, 2H), 2.41 (t, J=7.4 Hz, 2H), 1.72-1.55 (m, 4H), 1.45-1.22 (m, 18H); 13C NMR (100 MHz, CDCl3) δ 172.4, 123.3 (q, J=275.8 Hz), 60.3 (q, J=36.4 Hz), 33.9, 32.0, 29.8, 29.7, 29.6, 29.5, 29.4, 29.2, 29.1, 24.9, 24.5, 22.5.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[C:8]([C:11]#[N:12])[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C([OH:22])C.[OH-].[K+].OO>O>[C:1]([N:5]1[C:9]([NH2:10])=[C:8]([C:11]([NH2:12])=[O:22])[C:7]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)n1nc(Nc2ccccc2)c(C#N)c1N
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)n1nc(Nc2ccccc2)c(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
1-tert-Butyl-3-phenylamino-5-amino-1H-pyrazole-4-carbonitrile (1.0 g, 0.004 mol), 50% aqueous ethanol (30 ml), potassium hydroxide (1.8 g, 0.03 mol) and 30% hydrogen peroxide (2.5 ml, 0.02 mol) were combined and stirred at room temperature for 24 hours, then refluxed on a steam bath for 1 hour. The reaction mixture was added to water, and the obtained solid was filtered and washed with water to afford 0.68 g (64%) of 1-tert-butyl-3-phenylamino-5-amino-1H-pyrazole-4-carboxamide as a gray solid, m.p. 225°-227° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[C:24]([Cl:25])[CH:23]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: Cc1c2n(c3c(-c4ccc(Cl)c(Cl)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (77 mg, 81%), MS (ISP) m/z=379.6 [(M+H)+], mp 240° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 3,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]=12.CC(O[CH:16](N(C)C)[N:17]([CH3:19])[CH3:18])(C)C>C1COCC1>[CH3:16][N:17]([CH:19]=[C:8]1[C:9](=[O:10])[C:4]2=[N:3][O:2][N:1]=[C:5]2[CH2:6][CH2:7]1)[CH3:18]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCc2nonc21
Solvent: C1CCOC1
Product: CN(C)C=C1CCc2nonc2C1=O
Yield: 57.1 %

Procedure:
A THF solution of 4,5,6,7-tetrahydro-2,1,3-benzoxadiazole-4-one 1 g (0.00725 mol) and Bredereck's reagent 1.89 g (0.0109 mol) was stirred at room temperature for 2 days. The crystalline precipitate was filtered, washed with THF and dried, 0.8 g desired product was obtained, the yield is 57%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[S:29][CH:30]=[C:31]([C:33](O)=[O:34])[N:32]=2)[CH:23]=1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:33]([C:31]4[N:32]=[C:28]([C:24]5[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=5)[S:29][CH:30]=4)=[O:34])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2csc(-c3cccnc3)n2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(pyrid-3-yl)thiazole-4-carboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and 2-(pyrid-3-yl)thiazole-4-carboxylic acid using method D. NMR; δH CDCl3 9.26,(1H, b), 9.24,(1H, d), 8.73,(1H, d), 8.28,(2H, m), 7.85,(2H, d), 7.72,(1H, dd), 7.60,(1H, d), 7.47-7.44,(3H, m), 7.32,(1H, d), 6.29,(1H, t), 3.36,(2H, m), 2.26,(3H, s), 1.10,(1H, m), 0.59,(2H, m), 0.31,(2H, m). LCMS: retention time 3.36 min, MH+469.
Reaction SMILES: [CH2:1]1[O:27][C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])([C:5]2[C:10]([CH2:11]SC3C=CC=CC=3)=[CH:9][CH:8]=[C:7]([Cl:19])[CH:6]=2)[O:3][CH2:2]1.C[I:29]>>[CH2:1]1[O:27][C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])([C:5]2[C:10]([CH2:11][I:29])=[CH:9][CH:8]=[C:7]([Cl:19])[CH:6]=2)[O:3][CH2:2]1
Reactant: CI
Reactant: Fc1ccccc1C1(c2cc(Cl)ccc2CSc2ccccc2)OCCO1
Product: Fc1ccccc1C1(c2cc(Cl)ccc2CI)OCCO1

Procedure:
The starting material is obtained as follows: The solution of 10 g of 3-chloro-2'-fluoro-6-phenylmercaptomethyl-benzophenone ethylene ketal (Example 2) in 50 ml of methyl iodide is refluxed under nitrogen for 5 days. It is evaporated and the formed methyl phenyl thioether distilled off at 60°/0.1 mm Hg, to yield the 3-chloro-2'-fluoro-6-iodomethyl-benzophenone ethylene ketal.
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[C:27](=[O:28])[C:26]([C:29]([NH2:31])=[O:30])=[C:25]([OH:32])[C@:24]2([OH:33])[C@H:5]1[CH2:6][C@H:7]1[C:21]([C:22]2=[O:23])=[C:20]([OH:34])[C:10]2[C:11]([OH:19])=[C:12]([NH2:18])[CH:13]=[C:14]([N:15]([CH3:17])[CH3:16])[C:9]=2[CH2:8]1)[CH3:3].[C:35]([N:39]([C:51]([O:53][CH3:54])=[O:52])[CH2:40][C:41](OC(OCC(C)C)=O)=[O:42])([CH3:38])([CH3:37])[CH3:36]>>[NH2:31][C:29]([C:26]1[C:25](=[O:32])[C@:24]2([OH:33])[C@@H:5]([CH2:6][C@H:7]3[C:21](=[C:22]2[OH:23])[C:20](=[O:34])[C:10]2[C:11]([OH:19])=[C:12]([NH:18][C:41](=[O:42])[CH2:40][N:39]([C:35]([CH3:37])([CH3:36])[CH3:38])[C:51](=[O:52])[O:53][CH3:54])[CH:13]=[C:14]([N:15]([CH3:16])[CH3:17])[C:9]=2[CH2:8]3)[C@H:4]([N:2]([CH3:1])[CH3:3])[C:27]=1[OH:28])=[O:30]
Reactant: COC(=O)N(CC(=O)OC(=O)OCC(C)C)C(C)(C)C
Reactant: CN(C)c1cc(N)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]3(O)C(=O)C1=C2O
Product: COC(=O)N(CC(=O)Nc1cc(N(C)C)c2c(c1O)C(=O)C1=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C[C@@H]1C2)C(C)(C)C

Procedure:
The title compound is prepared by the procedure of Example 42, using 1 equivalent of 9-amino-minocycline and 2 equivalents of isobutoxycarbonyl N-(tert-butyl)-N-(methoxycarbonyl)glycinate Reference Example 120 to give the product of the example.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[N:7]=[C:6]([N:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:17][CH2:18]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Clc1nccc(N2CCN(Cc3ccccc3)CC2)n1
Temperature: 40 °C

Procedure:
A mixture of 9.9 g (0.0664 mol) of 2,4-dichloropyrimidine, 200 ml of water and 11.7 ml (0.0673 mol) of 1-(phenylmethyl)piperazine was heated to 40° C. for 2 hours in an ultrasound bath. After cooling the mixture was made alkaline with potassium carbonate and extracted thoroughly with ethyl acetate. The crude product obtained after working up in the usual way was purified by column chromatography over silica gel (30-60 μm) using FM2 and FM4 (2/1 v/v) as eluant. Working up the appropriate fractions yielded 7.4 g (38.6% of theory) of a colourless oil, Rf=0.51 (FM4; Macherey-Nagel POLYGRAM® SIL G/UV254, ready-made films for TLC).
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:5].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][C:21]=1[F:28].O>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:4]([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]2)=[O:5])=[CH:22][C:21]=1[F:28]
Reactant: CON(C)C(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cc([Mg]Br)ccc1Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)c2ccc(Cl)c(F)c2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 65.5 %

Procedure:
(R)-tert-Butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (1.107 g, 4.285 mmol) was dissolved in THF (21.4 mL, 0.2M), cooled to 0° C., and degassed with N2. 4-Chloro-3-fluorophenylmagnesium bromide (0.5M in THF; 17.14 mL, 8.571 mmol) was added drop wise by syringe, and the reaction was then stirred at 0° C. for 1.5 hours. Water (10 mL) was then added to quench the reaction. The mixture was concentrated by rotovap to remove the bulk of the THF. The remaining mixture was diluted to 50 mL with water and extracted with 4/1 dichloromethane/isopropyl alcohol (2×50 mL). The combined organics were washed with water (100 mL), were isolated, dried over sodium sulfate, filtered and concentrated. The crude product was loaded onto an SP1 samplet and purified by silica gel chromatography using a gradient from 2% to 50% ethyl acetate in hexanes. Product containing fractions were pooled and concentrated to afford (R)-tert-butyl 3-(4-chloro-3-fluorobenzoyl)pyrrolidine-1-carboxylate as an oil (920 mg, 65% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>COCCOC.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:15])[CH:9]([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)nc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of ethyl 3-(6-chloro-3-pyridyl)-3-oxopropionate (9.0 g, 39.5 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.58 g, 39.5 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (9.45 g, 39.5 mmol) in 1,2-dimethoxyethane (50 ml), and the mixture was stirred overnight at room temperature. The reaction solution was poured into water (200 ml), saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:ethyl acetate=1:1) to give ethyl 3-(6-chloro-3-pyridyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (14.2 g, 93%) as a colorless oil.
Reaction SMILES: Cl[CH2:2][Si:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[C:15]([O-:18])(=[O:17])[CH3:16].[Na+].C(Cl)(Cl)(Cl)Cl>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[C:15]([O:18][CH2:2][Si:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)([CH3:5])[CH3:4])(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: CCOc1ccc([Si](C)(C)CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1ccc([Si](C)(C)COC(C)=O)cc1
Temperature: 25 °C
Yield: 105.4 %

Procedure:
In a flask under nitrogen were placed 10.1 g (0.044 mole) of (chloromethyl)(4-ethoxyphenyl)dimethylsilane, 4.0 g (0.049 mole) of sodium acetate, 1.2 g (0.0043 mole) of tetrabutylammonium chloride, and 75 ml of carbon tetrachloride. This mixture was refluxed for four days. After cooling to room temperature, 2.0 g (0.024 mole) of sodium acetate and 0.60 g (0.0022 mole) of tetrabutylammonium chloride was added, and the reaction mixture was refluxed for five more days. This mixture was then diluted with diethyl ether, filtered through silica gel, and the solvent was evaporated under reduced pressure, leaving 11.7 g of 2-(4-ethoxyphenyl)-2-methyl-2-silapropyl acetate as a clear, light brown oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)Cl>[Br:9][C:3]1[N:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cncc(Cl)n1
Solvent: ClCCl
Product: Nc1cnc(Br)c(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
6-Chloropyrazin-2-amine (2.50 g, 19.3 mmol) was stirred in CH2Cl2 (60 mL) at 0° C. N-Bromosuccinimide (2.92 g, 16.4 mmol) was added slowly and the reaction mixture was stirred at 0° C. for 60 minutes. The reaction mixture was filtered through celite and concentrated to give a brown oil. Purification by flash chromatography, eluting with 0-25% EtOAc-hexanes, gave 5-bromo-6-chloropyrazin-2-amine as a yellow solid (1.69 g, 8.16 mmol, 42% yield).