Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH:30]1[CH:31]=[CH:32][C:33]([CH2:36][CH2:37]O)=[CH:34][CH:35]=1.C([C@@H](O)C1C=CC=C(OC2C=CC=CC=2)C=1)#N>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:9])[O:8][CH2:37][CH2:36][C:33]2[CH:34]=[CH:35][CH:30]=[CH:31][CH:32]=2)[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: OCCc1ccccc1
Agent: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCCc1ccccc1

Procedure:
Using the procedure of Step F of Example 9, the ester of Step A of Example 31 after reaction with phenethanol and (S)α-cyano-3-phenoxy-benzyl alcohol was reacted to obtain (S) -cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3[(Z) 3-oxo-3-phenethoxy-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+46 °±2.5° (c=0.5% in benzene).
Reaction SMILES: [C:1]([O:20][N:21]=[C:22]([C:60]1[N:61]=[C:62]([NH:65][C:66]([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[S:63][CH:64]=1)[C:23]([NH:25][CH:26]1[C:58](=[O:59])[N:28]2[C:29]([C:42]([O:44][CH:45]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])=[C:30]([CH:33]=[CH:34][S:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH2:31][S:32][C@H:27]12)=[O:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:85][I:86]>C(#N)C.C(Cl)Cl>[I-:86].[C:1]([O:20][N:21]=[C:22]([C:60]1[N:61]=[C:62]([NH:65][C:66]([C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)([C:79]2[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=2)[C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)[S:63][CH:64]=1)[C:23]([NH:25][CH:26]1[C:58](=[O:59])[N:28]2[C:29]([C:42]([O:44][CH:45]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)=[O:43])=[C:30]([CH:33]=[CH:34][S:35][CH2+:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]3[CH3:85])[CH2:31][S:32][C@H:27]12)=[O:24])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3ccccn3)CS[C@H]12)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CI
Solvent: ClCCl
Solvent: CC#N
Product: CN1C=CC=C[CH2+]1SC=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Product: [I-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of benzhydryl 7-[2-trityloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[2-(2-pyridyl)thiovinyl]-3-cephem-4-carboxylate (2.4 g) in a mixture of acetonitrile (12 ml) and methylene chloride (4.8 ml) was added methyl iodide (18.7 ml) and the mixture was stirred at room temperature for 3 days. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform (38 ml) and dripped into diisopropyl ether (120 ml). The resultant precipitate was recovered to provide benzhydryl 7-[2-trityloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[2-(1-methyl-2-pyridinio)thiovinyl]-3-cephem-4-carboxylate iodide (3.5 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:39]>>[ClH:39].[NH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:13])[O:14][CH2:15][CH3:16])[C:4]=23)[CH2:18]1
Reactant: ClCCl
Reactant: CCOC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](N)C3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(ethoxycarbonylamino)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.120 g, 0.249 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse phase chromatography (Biotage SP4, C-18 12M+, 0-50% CH3CN/water). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirred solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)-ethyl 4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamate hydrochloride (0.090 g, 79% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.23 (s, 1H), 7.28 (s, 1H), 4.11-4.06 (q, 2H), 3.78-3.75 (m, 1H), 3.53-3.49 (m, 1H), 3.40-3.43 (m, 1H), 3.27-3.18 (m, 2H), 2.09-2.06 (m, 1H), 1.81-1.69 (m, 2H), 1.60-1.54 (m, 1H), 1.19-1.16 (t, 3H). LCMS (APCI+) m/z 382, 384 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:22])[C@H:4]([CH2:12][C:13]1[CH:18]=[C:17](I)[C:16]([OH:20])=[C:15](I)[CH:14]=1)[NH:5]C(=O)C(F)(F)F.[IH2+].N12[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[CH2:29]CCCN2.C[OH:36]>>[NH2:5][C@H:4]([C:3]([OH:2])=[O:22])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:20][C:33]2[CH:34]=[CH:29][C:30]([OH:36])=[CH:31][CH:32]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)[C@H](Cc1cc(I)c(O)c(I)c1)NC(=O)C(F)(F)F
Reactant: CO
Reactant: C1CCC2CCCCN2NC1
Agent: [IH2+]
Product: N[C@@H](Cc1ccc(Oc2ccc(O)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
N-Trifluoroacetyl-3,5-diiodotyrosine methyl ester (552 mg, 1.0 mmol) prepared according to the procedure of N. Lewis and P. Wallbank, Synthesis 1103 (1987) (incorporated by reference) and all of the crude iodonium salt (3) from above is dissolved in 5 mL of anhydrous methanol. Diazabicyclo[5.4.0]undecane (DBU) (183 mg, 1.2 mmol) and a spatula tip of copper-bronze are added and the resulting mixture is stirred at room temperature overnight. The next day, the reaction mixture is filtered, and the filtrate is concentrated in vacuo. The crude residue is purified by flash chromatography (silica gel, 10% ethyl acetate/hexane) to provide 30 mg (4%) of the protected thyronine adduct (4).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[S:16]([NH:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25]CC)=[O:24])(=[O:18])=[O:17].[Li+].[OH-].C(O)(=O)C>C1COCC1.O>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[S:16]([NH:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([OH:25])=[O:24])(=[O:17])=[O:18]
Reactant: CCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(N4CCCC4)cc3c2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(N3CCCC3)cc12

Procedure:
The ethyl 3-{[(3-methyl-5-pyrrolidin-1-yl-1-benzothiophen-2-yl)sulfonyl]amino}benzoate (4.7 mg, 0.01 mmol) was hydrolyzed with LiOH (2.6 mg, 0.06 mmol) in THF/water (1:1, 2 mL) at 55° C. over night. The reaction mixture was neutralized with acetic acid (3.6 μL) and the mixture was concentrated. The crude product was purified by preparative HPLC (ACE C8, 5 μm 21×50 mm, flow 25 ml/min, 50 mM NH4OAc in water/CH3CN) to give 2.7 mg (6% over two steps) of the title compound. MS (ESI+) calcd for C20H20N2O4S2 416.086449, found 416.086649.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@@H:44]1[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])[C@H:46]([CH:62]2[CH2:67][CH2:66][N:65]([C:68]([O:70][CH2:71][C:72]3[CH:77]=[CH:76][C:75]([N+:78]([O-:80])=[O:79])=[CH:74][CH:73]=3)=[O:69])[CH2:64][CH2:63]2)[CH2:45]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:43][C@@H:44]3[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]4[CH:54]=[CH:55][C:56]([N+:59]([O-:61])=[O:60])=[CH:57][CH:58]=4)=[O:50])[C@H:46]([CH:62]4[CH2:67][CH2:66][N:65]([C:68]([O:70][CH2:71][C:72]5[CH:73]=[CH:74][C:75]([N+:78]([O-:80])=[O:79])=[CH:76][CH:77]=5)=[O:69])[CH2:64][CH2:63]4)[CH2:45]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 78.5 %

Procedure:
The same procedure as in Example 1-1 was carried by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (245 mg, 0.41 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)piperidin-4-yl]pyrrolidine (216 mg, 0.40 mmol, compound of Reference Example 32) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)piperidin-4-yl]pyrrolidin-4ylthio]-1-carbapen-2-em-3-carboxylate (279 mg, yield: 76.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[NH:11][C:12](=S)[CH2:13][N:14]=1.O.[NH2:22][NH2:23]>C(O)C>[NH:22]([C:12]1[CH2:13][N:14]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[N:11]=1)[NH2:23]
Reactant: CCc1cc2c(s1)NC(=S)CN=C2c1ccccc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCc1cc2c(s1)N=C(NN)CN=C2c1ccccc1Cl

Procedure:
[d] 32.1 g of 5-o-chlorophenyl-7-ethyl-1,2-dihydro-3H-thieno[2,3-e][1,4] diazepine-2-thione obtained in the above example [a] is suspended in 200 ml of ethanol, and to the suspension is added 8 g of hydrazine hydrate. Several minutes stirring turns the suspension into a homogeneous, red, transparent solution. Then crystals begin to precipitate. After stirring at room temperature for 2 hours and subsequent ice-cooling, the crystals are collected by suction filtration and washed well with methanol to give 28.6 g of almost pure 2-hydrazino-5-o-chlorophenyl-7-ethyl-3H-thieno[2,3-e][1,4]diazepine as yellowish crystals. The crystals, when recrystallized from a mixture of ethanol and diemethylformamide, show a melting point of 214° - 216°C (decomposition).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]([OH:11])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.C(Cl)(Cl)Cl>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:9](=[O:11])[CH2:8][CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][C:2]3=[O:1])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)CCN1CCCC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)CCN3CCCC3=O)nc12

Procedure:
From 2-oxo-1-pyrrolidinepropionic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+21.5° (c=1.05, CHCl3), ES-MS m/e (%): 406 (M+H+, 100).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:13]([O-])([OH:15])=[O:14].O>C(O)(=O)C>[N+:13]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)=[CH:2][CH:3]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(C2CCOCC2)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(C2CCOCC2)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of 32.4 g of 4-(phenyl)-tetrahydropyran [Ber., Vol. 56 (1923), p. 2013] in 60 ml of acetic acid was added at -10 to -12° C over an hour to a solution of 120 ml of concentrated nitric acid and 50 ml of acetic acid and the mixture was stirred for 30 minutes at -10° C. 100 ml of ice and 100 ml of water were added to the mixture and the mixture was filtered. The recovered precipitate was washed with water and dried to obtain 35 g of 4-(p-nitrophenyl)-tetrahydropyran melting at 124° C.
Reaction SMILES: [C:1]1(=[O:11])[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][NH:2]1.[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([Cl:24])[C:18]([CH2:22]Br)=[C:19]([Cl:21])[CH:20]=1.Cl>CN(C=O)C.C(OCC)C>[Br:14][C:15]1[CH:16]=[C:17]([Cl:24])[C:18]([CH2:22][N:2]2[CH2:3][CH2:4][C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[C:1]2=[O:11])=[C:19]([Cl:21])[CH:20]=1
Reactant: Clc1cc(Br)cc(Cl)c1CBr
Reactant: O=C1NCCC12CCCCC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1N(Cc2c(Cl)cc(Br)cc2Cl)CCC12CCCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.2 %

Procedure:
Treat a solution of 2-aza-spiro[4.5]decan-1-one (0.138 g, 0.901 mmol) in DMF (5 mL) with 60% sodium hydride (0.054 g, 1.35 mmol) and stir at room temperature for 15 minutes under N2. Cool the reaction to 0° C., treat with 5-bromo-2-(bromomethyl)-1,3-dichlorobenzene (0.316 g, 0.991 mmol), and stir for 15 minutes at 0° C. Warm to room temperature and stir for 2 hours under N2. Acidify the reaction with 1 N HCl. Dilute with diethyl ether and wash with water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 100% ethyl acetate in hexanes gradient on silica gel to afford 0.258 g (73%) of the titled product. Rf=0.24 (3/1 ethyl acetate/hexanes). MS (m/z): 392 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[C:15]([OH:17])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[C:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cnoc1-c1ccc([N+](=O)[O-])cc1
Reactant: C1CCNC1
Product: O=C(c1cnoc1-c1ccc([N+](=O)[O-])cc1)N1CCCC1

Procedure:
The title compound was prepared from 5-(4-nitrophenyl)isoxazole-4-carboxylic acid (11.7 mg, 0.050 mmol) and pyrrolidine (4.3 mg, 0.060 mmol) as described in synthetic method A and thereafter purified, first by preparative HPLC method A and then by method B, to give a solid (13.4 mg). MS (pos) m/z 288.2 (M+H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23]>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:22](=[O:23])[O:24][C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc(Oc2ccccc2)cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 4-phenoxyphenol (50 g, 0.27 mol) and pyridine (22 mL, 0.27 mol) in 500 mL of methylene chloride was added under nitrogen dropwise over 1.5 hours to a solution of 4-nitrophenyl chloroformate (54 g, 0.27 mol) at room temperature. After the addition the reaction was stirred overnight at room temperature. The reaction was extracted two times with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 94.86 g of a light yellow crystalline solid. Recrystallization from methylene chloride-diisopropyl ether gave 69.13 g (73%) of the title compound as a light tan crystalline solid, mp 113°-115° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:11].[C:12]1(B(O)O)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]1([C:2]2[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=2[NH2:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: OB(O)C1=CCCCC1
Reactant: CC(C)c1ccc(N)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)c1ccc(N)c(C2=CCCCC2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a mixture of 2-bromo-4-isopropyl-phenylamine (214 mg, 1.00 mmol), cyclohexane-1-enyl boronic acid (139 mg, 1.10 mmol) and Pd(PPh3)4 (116 mg, 0.100 mmol) in 5 mL of 1,4-dioxane was added 2.0 M aqueous Na2CO3 solution (4.0 mL, 8.0 mmol). The resulting mixture was stirred at 80° C. for 8 h under Ar, and then cooled to RT. The reaction was treated with EtOAc (20 mL) and washed with H2O (2×10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (DCM) to give 205 mg (95%) of the title compound as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C15H21N, 216.2 (M+H), found 216.1.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C.ClCCl>[CH:15]1([NH:18][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate 90.3 g, 1.5 mmol) in dichloroethane (10 mL) was add cyclopropylamine (0.13 mL, 1.95 mmol), sodium triacetoxyborohydride (0.48 g, 2.26 mmol) and a few drops of acetic acid. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with NaHCO3 solution. The organic phase was separated and then dried over MgSO4. Following concentration, the residue was chromatographed on silica gel eluting with 5% methanol/dichloromethane to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 4.03 (d, J=12.21 Hz, 2 H), 2.79 (m, 3 H), 2.14 (m, 1 H), 1.91 (d, J=12.55 Hz, 2 H), 1.69 (m, 2 H), 1.46 (m, 9 H), 1.27 (m, 2 H), 0.47 (m, 2 H), 0.36 (m, 2 H).
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:4]1=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CN(C)C=O>[CH2:37]([O:36][C:34]([CH2:33][O:23][C:20]1[CH:19]=[CH:18][C:17](/[CH:16]=[CH:15]/[C:9]2[N:10]([CH3:14])[C:11]3[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]([CH2:24][CH3:25])[C:7]=3[N:8]=2)=[CH:22][CH:21]=1)=[O:35])[CH3:38]
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(O)cc3)n2C)n(CC)c1=O
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(/C=C/c2nc3c(c(=O)n(CC)c(=O)n3CC)n2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
Compound 175 (300 mg, 0.88 mmol) obtained in Reference Example 114 was dissolved in 10 ml of dimethyl formamide. To the solution were added 731 mg (5.29 mmol) of potassium carbonate and 0.47 ml (4.41 mmol) of ethyl chloroacetate, and the mixture was stirred at room temperature for 2 hours. Water was added thereto to dissolve potassium carbonate and the deposited crystals were collected by filtration. The collected crude crystals were dissolved in chloroform, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give 341 mg (yield 91%) of Compound 180 as pale yellow needles.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[C:9]2[C:8](=[O:18])[N:7]([CH3:19])[CH:6]=[N:5][C:4]=2[CH:3]=1.C[N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].[CH3:48][CH:49](O)[CH3:50]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:49]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([C:2]3[N:11]=[C:10]([NH:12][C@@H:13]4[CH2:17][CH2:16][O:15][CH2:14]4)[C:9]4[C:8](=[O:18])[N:7]([CH3:19])[CH:6]=[N:5][C:4]=4[CH:3]=3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)([CH3:50])[CH3:48]
Reactant: Cn1cnc2cc(Cl)nc(N[C@@H]3CCOC3)c2c1=O
Reactant: CC(C)O
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)N1CCN(c2ccc(-c3cc4ncn(C)c(=O)c4c(N[C@@H]4CCOC4)n3)cc2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-7-chloro-3-methyl-5-(tetrahydrofuran-3-ylamino)pyrido[4,3-d]pyrimidin-4(3H)-one (15 mg, 0.053 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (19.4 mg, 0.059 mmol), Pd(PPh3)4 (6.1 mg, 0.0053 mmol), K2CO3 (22 mg, 0.16 mmol), 2-propanol (3 mL) and H2O (1 mL) was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature and worked-up. The residue was purified on slilica gel flash column chromatography (eluent: 0-10% methanol in dichloromethane) to afford (R)-7-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methyl-5-(tetrahydrofuran-3-ylamino)pyrido[4,3-d]pyrimidin-4(3H)-one as a slightly yellow solid. 1H NMR (CDCl3) δ (ppm) 8.80 (d, 1H), 8.04 (d, 2H), 8.00 (s, 1H), 7.10 (s, 1H), 6.98 (d, 2H), 4.92-4.84 (m, 1H), 4.22 (dd, 1H), 4.06-3.99 (m, 1H), 3.95-3.89 (m, 1H), 3.80 (dd, 1H), 3.51 (s, 3H), 3.34-3.31 (m, 4H), 3.77-3.68 (m, 5H), 2.46-2.36 (m, 1H), 2.06-1.96 (m, 1H), 1.10 (d, 6H); HPLC-MS calculated C25H32N6O2 (M+H+): 449.27, found: 449.20.