Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCCC1>[OH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:15][CH2:14]1
Reactant: OC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of benzyl chloroformate (35 ml, 247 mmol) in tetrahydrofuran (70 ml) was added to an ice-cold solution of 4-hydroxypiperidine (25 g, 247 mmol) and triethylamine (45 ml, 321 mmol) in tetrahydrofuran (350 ml). The mixture was stirred overnight at room temperature and the solvent removed under reduced pressure. The residue was partitioned between 5% hydrochloric acid and ethyl acetate, and the organic layer washed with brine, dried over magnesium sulfate, and the solvent removed under reduced pressure to give 4-hydroxy-N-CBZ-piperidine as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]2)=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:36]([C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=3)(=[O:38])=[O:37])[C@H:10]([CH3:14])[CH2:9]2)=[C:4]([C:15]([F:17])([F:16])[F:18])[CH:3]=1
Reactant: CC1CN(c2ccc(F)cc2C(F)(F)F)CCN1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCN(c3ccc(F)cc3C(F)(F)F)C[C@H]2C)cc1
Reaction time: 14 h

Procedure:
To solution of 1-(4-Fluoro-2-trifluoromethyl-phenyl)-3-methyl-piperazine (200 mg, 0.76 mmol) and DIPEA (0.33 mL, 1.90 mmol) in DCM (8.0 mL) was added 4-Methoxybenzenesulfonyl chloride. The reaction was allowed to stir over a 12-16 hr period, after which it was judged complete by TLC. The reaction mixture was concentrated in-vacuo, and the resultant crude oil was purified via normal phase SiO2 column chromatography using a 2%-10% EtOAc/Hex solvent gradient. The desired product, was isolated in >95% purity. HRMS: calcd for C19H20F4N2O3S+H+, 433.12035. found ([M+H]1+), 433.12037.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:5](=[O:11])[NH:6][C:7](=[S:10])[NH:8][CH:9]=1.[CH3:12]I>CCO>[CH3:3][C:4]1[C:5](=[O:11])[NH:6][C:7]([S:10][CH3:12])=[N:8][CH:9]=1
Reactant: Cc1c[nH]c(=S)[nH]c1=O
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc(C)c(=O)[nH]1
Yield: 86.6 %

Procedure:
A solution of 85% KOH (3.3 g, 50.7 mmol) and 5-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (7.2 g, 50.7 mmol) in absolute EtOH (100 ml) was stirred for 1 hour and then MeI (7.2 g, 50.7 mmol) was added dropwise. After refluxing the mixture for 2 hours, the solvent was removed under vacuum. The residue was triturated with water and the solid was filtered and dried in an oven to give 6.86 g of the title compound as a white powder (87% yield).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.CO>[C].[Pd].C(O)(=O)C>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][NH:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccccn2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCCCN2)ccc1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To an acetic acid (5 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-(pyridin-2-yl)benzamido)-4-phenylbenzoate (0.12 g), 10% palladium-carbon (0.060 g) was added, followed by stirring under hydrogen pressure (5 kg/cm2) at 80° C. for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and methanol and acetic acid were added thereto. The insoluble substance was removed by filtration, and the solvent was removed under reduced pressure. Chloroform and a saturated aqueous solution of sodium bicarbonate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.062 g of tert-butyl 2-(2-hydroxy-5-(piperidin-2-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]2[C:8]=1[NH:9][C:10](=[O:26])[N:11]2[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])[CH2:4][CH3:5])[CH3:2].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]2[C:8]=1[N:9]([CH3:27])[C:10](=[O:26])[N:11]2[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1nc(C)nc2c1[nH]c(=O)n2-c1c(C)cc(C)cc1C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1nc(C)nc2c1n(C)c(=O)n2-c1c(C)cc(C)cc1C

Procedure:
The title compound was prepared by methylation of 6-(1-Ethyl-propoxy)-2-methyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin-8-one with lithium bis(trimethylsilyl)amide in THF, followed by quenching with methyl iodide. 1H NMR(CDCl3) d7.00(s,2H), 5.31(m,1H), 3.66(s,3H), 2.479s,3H), 2.33(s,3H), 2.06(s,6H), 1.79(m,4H), 1.01(t,6H) ppm.
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].C[O:7][C:8]([C:10]1[C:14]([NH:15][C:16]([C:18]2[C:23]([NH:24][C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:22][CH:21]=[C:20]([CH:31]3[CH2:33][CH2:32]3)[N:19]=2)=[O:17])=[CH:13][N:12]([CH3:34])[N:11]=1)=O>>[OH:4][CH2:3][CH:2]([NH:1][C:8]([C:10]1[C:14]([NH:15][C:16]([C:18]2[C:23]([NH:24][C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:22][CH:21]=[C:20]([CH:31]3[CH2:33][CH2:32]3)[N:19]=2)=[O:17])=[CH:13][N:12]([CH3:34])[N:11]=1)=[O:7])[CH3:5]
Reactant: CC(N)CO
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: CC(CO)NC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 14 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 2-amino-propan-1-ol with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (14%) as sticky yellow solid.
Reaction SMILES: C(N(CC)CC)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.C(NC1SC=C(C(=NOC)C(O)=O)N=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(OC[C:56]1[CH2:65][S:64][C@@H:59]2[C@H:60](N)[C:61](=[O:62])[N:58]2[C:57]=1[C:66]([OH:68])=[O:67])=O>CC(N(C)C)=O.C(Cl)Cl>[S:64]1[C@@H:59]2[CH2:60][C:61](=[O:62])[N:58]2[C:57]([C:66]([OH:68])=[O:67])=[CH:56][CH2:65]1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(O)C1=CCS[C@@H]2CC(=O)N12

Procedure:
The process of claim 1 comprising reacting at low temperature in dimethylacetamide, in the presence of triethylamine, tosyl chloride and the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetic acid and reacting the resulting product with 7-amino-cephalosporanic acid in methylene chloride in the presence of triethylamine to obtain the syn isomer of 3-acetoxymethyl-7-[2-tritylamino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH2:30])[CH:21]=[CH:22][C:23]=1[C:24]1[S:28][C:27]([CH3:29])=[N:26][CH:25]=1>CCCCCCC.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:30][C:20]2[CH:21]=[CH:22][C:23]([C:24]3[S:28][C:27]([CH3:29])=[N:26][CH:25]=3)=[C:18]([O:17][CH3:16])[CH:19]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(N)ccc1-c1cnc(C)s1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1cc(Nc2nc(C)cc(Cc3ccccc3)n2)ccc1-c1cnc(C)s1
Yield: 69.5 %

Procedure:
The title compound was prepared from 4-benzyl-2-chloro-6-methyl-pyrimidine (130 mg, 0.59 mmol) and 3-methoxy-4-(2-methyl-thiazol-5-yl)-phenylamine (131 mg, 0.59 mmol) using in analogous manner the procedure described in example 206c). Column chroma-tography (20 g silica, heptane/ethyl acetate 1:1 v/v) afforded the title compound as an off-white solid (165 mg, 69%). MS ISP (m/e): 403.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.90 (s, 1H), 7.82 (s, 1H), 7.45 (d, 1H), 7.29 (m, 5H), 7.14 (s, 1H), 6.98 (dd, 1H), 6.48 (s, 1H), 3.97 (s, 2H), 3.87 (s, 3H), 2.71 (s, 3H), 2.37 (s, 3H). Mp 138-141° C.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][O:11][C:10]2=[O:14])=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl.[OH-].[Na+].C(Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][O:11][C:10]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1OCCN1Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: Nc1ccc(CN2CCOC2=O)cc1

Procedure:
A solution of the compound obtained in Step A (0.244 mol) and SnCl2.2H2O (1.0 mol) in ethanol (300 ml) is stirred at reflux for 20 minutes. The solution is brought to 0° C. and made alkaline at pH=10-12 with aqueous sodium hydroxide solution; 500 ml of DCM are added and the emulsion obtained is filtered over Celite. The filtrate is then extracted with DCM (2×300 ml); the organic phases are combined. The organic phase obtained is washed with water and with saturated aqueous NaCl solution, dried over sodium sulphate and then filtered. The filtrate obtained is evaporated to dryness to yield the title product, which is used directly in the next Step.
Reaction SMILES: [CH2:1]([C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)([CH2:6]3)[CH2:4]1)[CH2:10]2)[CH3:2].[OH2:19]>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([C:3]12[CH2:4][C:5]3([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:11][CH:9]([CH2:8][C:7]([OH:19])([CH2:6]3)[CH2:12]1)[CH2:10]2)[CH3:2]
Reactant: O
Reactant: CCC12CC3CC(C1)CC(c1ccccc1)(C3)C2
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCC12CC3CC(O)(C1)CC(c1ccccc1)(C3)C2
Temperature: 4 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
To a solution of 0.03 mol of chromiumtrioxide, in 20 ml glacial acetic acid and 20 ml acetic anhydride, add 0.0095 mol of 1-ethyl-3-phenyl adamantane (II) at 0° C. and stir for 24 hours at 4° C. Pour the reaction mixture into water and extract with three portions of pentane. Wash the organic phase with saturated sodium chloride solution, dry over magnesium sulfate, filter and evaporate to dryness under vacuum. Hydrolize the residue with 20 ml of 2N NaOH and 50 ml of methanol. Remove the methanol under vacuum and dilute the residue with water. Then extract with three portions of ether. Dry the organic phase, filter and evaporate to dryness under vacuum. Recrystallize the residue from cyclohexane. (Yield: 50%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C(Cl)(=O)C(C)(C)C.[NH2:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][C:24](=[O:26])[NH2:25]>C(N(CC)CC)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][C:24](=[O:26])[NH2:25])=[O:13]
Reactant: NC(=O)C[C@H](N)C(=O)O
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O

Procedure:
Accordingly, the present invention also includes a process for the manufacture of these compounds. Such a process embraces in a first step the manufacture of a mixed anhydride and its conversion into quinargine as described above. The mixed anhydride, e.g. 2,2-dimethylpropionic acid-quinoline-2-carboxylic acid anhydride, can be obtained by adding an adjuvant base, e.g. triethylamine, to a mixture of quinoline-2-carboxylic acid and a reactive acid derivative, preferably pivaloyl chloride. The resulting mixed anhydride is subsequently reacted with asparagine in alkaline solution to give N-(2-quinolylcarbonyl)-L-asparagine. This substance is then converted in a subsequent step with 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)carboxamide into N-t-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]-amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide as described above or optionally into a corresponding salt, preferably the methanesulphonic acid salt, or into an ester.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH:13]([CH2:17][CH3:18])[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH:13]([CH2:17][CH3:18])[C:14]([OH:16])=[O:15])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CCC(N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCC(Nc1ccc(F)cc1[N+](=O)[O-])C(=O)O
Temperature: 80 °C
Reaction time: 23 h

Procedure:
A mixture of 2,5-difluoronitrobenzene (119 ml, 1.10 mol), 2-aminobutanoic acid (114 g, 1.10 mol), and potassium carbonate (152.2 g, 1.10 mol) in dimethyl sulfoxide (410 ml, 1.10 mol) was stirred at 80° C. for 23 h. ([Note 1]: The mixture had a deep orange red color. The internal temperature of the mixture went up to ˜110° C. for 1 h and then went down to 80° C.). After 23 h, the reaction was cooled to rt and carefully poured into water (2 L+1 L). The aqueous mixture was washed with diethyl ether (1 L×2) to remove organic impurities. The aqueous layer was then acidified to ˜pH 1.5 with concentrated HCl (300 mL) to generate a yellow solid. The yellow solid was collected by filtration, washed with water (3 L), and air-dried to give the desired product, a wet orange solid. The wet orange solid was recrystallized from 3 L toluene and stood at rt overnight to afford the desired product as an orange crystalline solid. The orange crystalline solid was filtered, washed with toluene (2 L), and dried under high vacuum at 80° C. for 4 h and then on lyophilizer overnight to afford 2-(4-fluoro-2-nitrophenylamino)-butanoic acid (203.6 g, 76.4% yield) as an orange crystalline solid. The orange crystalline solid was carried on without further purification to the next step.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CON=C(C(=O)OC)c1ccc(OC)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: CON=C(C(=O)O)c1ccc(OC)c(Cl)c1
Yield: 101.8 %

Procedure:
Methyl 2-methoxyimino-2-(3-chloro-4-methoxyphenyl)acetate (syn isomer) (2.7 g.) and a 2N aqueous solution of sodium hydroxide (10.6 ml.) were treated according to a similar manner to that of Preparation 5-(3)(c) to give crystals of 2-methoxyimino-2-(3-chloro-4-methoxyphenyl)acetic acid (syn isomer) (2.6 g.), mp 133° to 135° C. (dec.).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([C:23]1[CH:27]=[C:26]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][C@@H:53]5[CH3:58])=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:25]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([O:65][CH2:66][CH2:67][O:68]C3CCCCO3)[CH:60]=2)[N:24]=1)([CH3:22])[CH3:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([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.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[Si:1]([O:18][CH2:19][C:20]([C:23]1[CH:27]=[C:26]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][C@@H:53]5[CH3:58])=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:25]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([O:65][CH2:66][CH2:67][OH:68])[CH:60]=2)[N:24]=1)([CH3:21])[CH3:22])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Temperature: 45 °C
Reaction time: 19 h
Yield: 75 %

Procedure:
A solution of Intermediate 153g (317 mg, 0.31 mmol) in MeOH (3.1 mL) was treated with pyridinium para-toluenesulfonate (235 mg, 0.93 mmol) and the mixture was stirred at 45° C. for 19 h. The cooled solution was concentrated in vacuo, and the residue was partitioned between DCM and a saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with water, a saturated aqueous sodium bicarbonate solution, and brine, dried (Na2SO4) and concentrated in vacuo to a cream coloured foam. The foam was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as a colourless glass (217 mg, 75%). LCMS (Method 3): Rt 5.06 min, m/z 933.7 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH:14]=1)[O:7][CH2:8][C:9](OCC)=[O:10].O>C(O)(=O)C.[Fe]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:15][C:9](=[O:10])[CH2:8][O:7][C:6]=2[CH:14]=1
Reactant: CCOC(=O)COc1cc(F)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: O=C1COc2cc(F)ccc2N1
Temperature: 60 °C
Yield: 74.8 %

Procedure:
A solution of the 49.0 grams (0.20 mole) of ethyl 2-(5-fluoro-2-nitrophenoxy)acetate in 100 ml of glacial acetic acid was added to a warm (60° C.), stirred mixture of iron powder (50.0 grams, 0.90 mole) in 300 ml of glacial acetic acid. The reaction temperature was allowed to reach 100° C., and the mixture was stirred for approximately three hours. This mixture was poured into water, forming a precipitate. The precipitate was collected by filtration and was recrystallized from ethanol to yield 25.0 grams of 7-fluoro-2H-1,4-benzoxazin-3(4H)-one; another sample of this compound prepared in a similar manner, and then purified further, had a melting point of 205°-206° C. and an nmr spectrum which was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:18][C@H:17]([OH:19])[C@H:16]([CH2:20][NH:21]C(=O)OCC3C=CC=CC=3)[CH2:15]1)=[N:9][C:8]([O:32][CH3:33])=[CH:7][CH:6]=2>CO.[OH-].[OH-].[Pd+2]>[NH2:21][CH2:20][C@H:16]1[CH2:15][N:14]([CH2:13][CH2:12][C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:32][CH3:33])[N:9]=3)[N:4]=[CH:3][C:2]=2[F:1])[CH2:18][C@H:17]1[OH:19]
Reactant: COc1ccc2ncc(F)c(CCN3C[C@@H](CNC(=O)OCc4ccccc4)[C@@H](O)C3)c2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2ncc(F)c(CCN3C[C@H](CN)[C@H](O)C3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of phenylmethyl(±)-[(cis-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]carbamate (1.57 g, 3.46 mmole) in MeOH (100 mL) in a round bottom flask was added Pd(OH)2 (˜100 mg). The reaction contents were stirred under a balloon of H2 overnight at RT. The reaction contents were filtered through Celite® (MeOH) and concentrated to give the title compound (1.11 g, quant.) as a light yellow foam: LC-MS (ES) m/e 321 (M+H)+.
Reaction SMILES: [O-]CC.[Na+].Cl.[CH:6]1([NH:11][C:12]([NH2:14])=[NH:13])[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:15][C:16]1[CH:21]=[CH:20][N:19]2[N:22]=[C:23]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:24]([C:25](=O)[C:26]#[CH:27])=[C:18]2[CH:17]=1>C(O)C>[Cl:15][C:16]1[CH:21]=[CH:20][N:19]2[N:22]=[C:23]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:24]([C:25]3[CH:26]=[CH:27][N:14]=[C:12]([NH:11][CH:6]4[CH2:10][CH2:9][CH2:8][CH2:7]4)[N:13]=3)=[C:18]2[CH:17]=1
Reactant: N=C(N)NC1CCCC1
Reactant: C#CC(=O)c1c(-c2ccc(OC)cc2)nn2ccc(Cl)cc12
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
Sodium ethoxide (0.7 mL (2.09 mmol), 21% in ethanol) and N-cyclopentyl guanidine hydrochloride (0.47 g, 2.88 mmol) were added sequentially to ethanol (30 mL). The resulting solution was stirred at room temperature for 30 minutes. 1-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (0.5 g, 1.61 mmol) was added, and the suspension was stirred at room temperature for 2 days. The reaction was quenched by the addition of water. The aqueous phase was extracted by ethyl acetate. The organics were combined, washed with brine and dried over magnesium sulfate. Filtration and concentration gave a solid. This solid was recrystallized from methanol to give 4-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (0.45 g, 66%) as a pale yellow solid. 1H NMR (CDCl3): δ 8.59 (broad s, 1H), 8.42 (d, 1H), 8.05 (d, 1H), 7.59 (d, 2H), 7.03 (d, 2H), 6.91 (dd, 1H), 6.39 (d, 1H), 5.34 (broad s, 1H), 4.42 (m, 1H), 3.92 (s, 3H), 2.17 (m, 2H), 1.86-1.60 (m, 6H); MS m/z 420 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[CH3:14].[NH2:15][C:16]1[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:19].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([N:20]2[C:18](=[O:19])[C:17]3[C:16](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:15]=[C:9]2[C:8]2[CH:11]=[C:12]([CH3:13])[C:5]([O:4][CH2:3][CH2:2][OH:1])=[C:6]([CH3:14])[CH:7]=2)=[CH:22][CH:23]=1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: Nc1ccccc1C(=O)Nc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(F)cc2)cc(C)c1OCCO
Temperature: 155 °C

Procedure:
To a mixture of 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.420 g, 2.17 mmol) and 2-amino-N-(4-fluoro-phenyl)-benzamide (0.500 g, 2.17 mmol) in N,N-dimethylacetamide (5 mL) was added sodium hydrogen sulfite (0.350 g, 3.26 mmol) and p-toluenesulfonic acid (0.21 g, 0.11 mmol). The reaction mixture was heated at 155° C. for 14 hours. The reaction mixture was cooled to room temperature and diluted with cold water (20 mL) to produce the precipitate. The yellow solid was filtered, washed with cold water (2×20 mL), methanol, and dried under vacuum to provide crude product, which was purified by column chromatography (silica gel 230-400 mesh; 10% EtOAc/hexane as eluent) to give the title compound as white solid. Yield: 0.10 g (11%). MP 95-97° C. 1H-NMR (400 MHz, CDCl3): δ 8.35 (d, 1H), 7.81-7.78 (d, 2H), 7.58-7.40 (m, 1H), 7.20-7.15 (m, 2H), 7.15-7.01 (m, 4H), 3.98-3.80 (m, 4H), 2.21 (s, 6H), 2.01 (t, 1H). MS (ES+) m/z: 405.01 (M+1).