Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:6](OC(C)(C)C)=[O:7].C(OC(=O)C)(=O)C>C(O)=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:6]=[O:7]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(OC)cc1
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: COC(=O)CN(C=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 250 ml of formic acid was dissolved 36.9 g of N-Boc-p-methoxyphenylglycine methyl ester, and the mixture was stirred at room temperature for 3 hours and subsequently at 40°-50° C. for 1 hour. After dropwise addition of 24.8 ml (2.1 eq.) of acetic anhydride, the mixture was stirred at room temperature overnight and 40°-50° C. for 2 hours. After the solvent was distilled off, the residue was neutralized with an aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off. The crystals were collected by filtration with hexane.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl.[CH:19]([N:32]1[CH2:35][CH:34]([CH2:36]Cl)[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH:19]([N:32]1[CH2:35][CH:34]([CH2:36][O:17][C:14]2[CH:15]=[CH:16][C:11]([C:5]3([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]3)=[CH:12][CH:13]=2)[CH2:33]1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: ClCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CC1(c2ccc(OCC3CN(C(c4ccccc4)c4ccccc4)C3)cc2)CCOCC1
Yield: 75.4 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (1.15 g, 5.65 mmol), 1-benzhydryl-3-chloromethyl-azetidine hydrochloride (1.58 g, 5.13 mmol), N,N-dimethylformamide (32 ml) and potassium carbonate (2.84 g, 20.52 mmol) were reacted together according to general procedure B. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with 2M sodium hydroxide (3×50 ml), brine (3×50 ml), dried over magnesium sulphate, filtered and concentrated in vacuo to provide 1-[4-(4-{[1-benzhydrylazetidin-3-yl]methoxy}phenyl)tetrahydro-2H-pyran-4-yl]-N,N-dimethylmethanamine (1.82 g, 81%) as an off-white solid.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[CH2:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([C:20]([O:22][CH3:23])=[O:21])[CH2:24][O:9]2)=[CH:17][CH:18]=1
Reactant: C=C(C(=O)OC)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(c2ccc(Cl)cc2)CO1
Temperature: 25 °C

Procedure:
MCPBA (35 g, 77%, 156 mmol) was added to a solution of methyl 2-(4-chlorophenyl)-acrylate (20 g, 102 mmol) in CHCl3 (200 mL). The mixture was refluxed for 24 hours. The reaction was cooled to room temperature, diluted with chloroform (200 mL) and washed with 10% Na2S2O3, 10% NaHCO3 and water. The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by hexane/ethyl acetate (9:1) to give methyl 2-(4-chlorophenyl)oxirane-2-carboxylate. Methyl 2-(4-chlorophenyl)oxirane-2-carboxylate (2 g, 9.4 mmol) and ethanol (10 mL) and isopropylamine (1 mL, 11.7 mmol) were added to a 50 mL high pressure bomb. The mixture was heated to 90° C. for 12 hours in the bomb. After cooling, the solvent was removed, and the residue was dissolved in DCM (20 mL) and TEA (2 mL). (Boc)2O (4 g, 23.0 mmol) was added to it. The mixture was stirred at room temperature for 48 hours. The solvent was removed, and the residue was dissolved in THF (20 mL). LiOH (3M, 14 mL) was added to the mixture. The mixture was stirred at room temperature for 16 hours and refluxed for 2 hours. After cooling, the mixture was quenched with 2N HCl (21 mL). The solvent was removed and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (1:1) to give 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)-2-hydroxypropanoic acid. LCMS (APCI+) [M−Boc+H]+ 258.1; Rf: 3.66 min.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.N1C=CN=C1.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C>[Si:30]([O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 18 h
Yield: 98.8 %

Procedure:
To a solution of estrone (18, 8.10 g, 30.0 mmol) in DMF (25 mL) were added imidazole (3.07 g, 45 mmol) and tert-butyldimethylchlorosilane (5.42 g, 36 mmol) at room temperature. The reaction mixture was stirred for 18 h and then quenched with H2O (100 mL). The precipitate was collected by filtration and washed with H2O to afford 11.4 g of 50 (99% yield), m.p. 171°-172° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)(=O)C>O1CCOCC1.C(OCC)C.[Pt](=O)=O>[N:25]1([C:16]2[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:15]=2[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH2:4][CH2:3][NH:2][CH2:1]3)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: OB(O)c1cccc2cnccc12
Reactant: FC(F)(F)c1ccc(Br)c(-n2ccnc2)c1
Agent: O=[Pt]=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(-c2cccc3c2CCNC3)c(-n2ccnc2)c1
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.049 g, 0.069 mmol), isoquinolin-5-ylboronic acid (Frontier Scientific, Logan, Utah, 0.297 g, 1.718 mmol), 1-(2-bromo-5-(trifluoromethyl)phenyl)-1H-imidazole (0.400 g, 1.374 mmol), and potassium phosphate (1.167 g, 5.50 mmol) in 6 mL dioxane 3 mL water was heated to 120° C. overnight. The reaction mixture was diluted with diethyl ether. The organics were separated and concentrated. The resulting residue was taken up in 6 mL MeOH, was treated with platinum(IV) oxide (0.031 g, 0.137 mmol) and acetic acid (0.236 ml, 4.12 mmol) and was placed under 45 psi (4559.6 kpa) H2 for 2 hours. The reaction mixture was filtered through a plug of diatomaceous earth eluting with EtOAc. The filtrate was washed with saturated NaHCO3 solution, the organics dried over MgSO4 and concentrated yielding 5-(2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.450 g, 1.311 mmol). [M+H]+=344.0
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C[CH2:33][N:34](C(C)C)[CH:35](C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CNC>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([N:34]([CH3:35])[CH3:33])=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.9 %

Procedure:
To a solution of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (80 mg, 0.16 mmol) in dry CH2Cl2:DMF (2.0:0.1 mL), added DIEA (29 μL, 0.16 mmol) and PyBOP® (46 mg, 0.088 mmol). After stirring the mixture at RT for 15 minutes, dimethylamine was bubbled through the solution for 15 minutes. Added another 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® after stirring the solution for 15 minutes, followed by dimethylamine bubbling for an additional 15 minutes. The solvent was removed in vacuo and the crude material was purified by prep HPLC (method 20-45—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N,N-dimethylacetamide (26 mg, 0.059 mmol, 37%).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[O:67]1[CH2:72][CH2:71][N:70]([CH2:73][CH2:74][O:75][C:76]2[CH:83]=[CH:82][C:79]([CH:80]=O)=[CH:78][CH:77]=2)[CH2:69][CH2:68]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:80]([C:79]3[CH:78]=[CH:77][C:76]([O:75][CH2:74][CH2:73][N:70]4[CH2:69][CH2:68][O:67][CH2:72][CH2:71]4)=[CH:83][CH:82]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(OCCN2CCOCC2)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Brc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Reaction time: 6 h
Yield: 18.2 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.076 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.23 mmol, 0.23 mL) and 4-(2-morpholinoethoxy)benzaldehyde (1.2 eq, 0.091 mmol, 22 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 85:15) gave the product (8 mg, 19%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.62 (t, J=4.0 Hz, 4H, piperazine N(CH2)2), 2.72 (t, J=5.7 Hz, 2H, PhOCH2CH2), 3.30 (hidden by DMSO water peak, 4H, morpholine N(CH2)2), 3.59 (t, J=4.6 Hz, 4H, morpholine O(CH2)2), 3.61 (s, 2H, NCH2), 3.65 (s, br, 4H, piperazine N(CH2)2), 4.17 (q, J=5.8 Hz, PhOCH2CH2), 7.10 (d, J=8.9 Hz, 2H, phenyl H-3 & H-5), 7.39 (ddd, J=7.6, 4.8, 0.4 Hz, 1H, pyridine H-5), 7.78 (dt, J=7.8, 1.8 Hz, pyridine H-4), 8.11 (d, J=8.8 Hz, 2H, phenyl H-2 & H-6), 8.20 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.8, 1.7 Hz, 1H, pyridine H-6), 8.56 (d, J=1.7 Hz, 1H, pyridine H-2), 13.39 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:27]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)c1

Procedure:
Example 60 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 480.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][C:40](O)=[O:41])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][C:40](=[O:41])[NH:1][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][S:12]([C:15]4[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=4)(=[O:13])=[O:14])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)CNc1ccc(S(=O)(=O)Oc2ccc3nc(N)sc3c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)CC4CCN(C(=O)OC(C)(C)C)CC4)sc3c2)cc1
Reaction time: 0.17 h

Procedure:
1st step: A solution of 4-isobutylaminobenzenesulfonic acid 2-aminobenzo-thiazol-6-yl ester (intermediate 27) (300 mg, 0.495 mmol), 4-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (361 mg, 1.485 mmol), HBTU (563 mg, 1.485 mmol) and N,N-diisopropylethylamine (432 μl, 2.475 mmol) in 4 ml of dimethylformamide is stirred at room temperature overnight. Water is added to the reaction medium, which is extracted with ethyl acetate. The organic phase is washed with water and then with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness. The residue obtained is purified by HPLC on a Dynamax C18, 60 Å, 21×300 mm column with a 95/5 mixture of water/acetonitrile, for 5 minutes, with a gradient of from 5% to 40% in water for 5 minutes, with a gradient of from 40% to 80% of acetonitrile in water for 30 minutes, with a gradient of from 80% to 95% of acetonitrile in water for 5 minutes, and then with a 5/95 mixture of water/acetonitrile for 5 minutes with a flow rate of 20 ml/minute. The solvents each contain 0.07% (v/v) of trifluoroacetic acid. The fractions are collected every 30 seconds and are monitored by analytical HPLC on a Hypersil C18, 4.6×50 mm column, with a gradient of from 0 to 100% of acetonitrile in water, over 10 minutes at a flow rate of 1 ml/minute. The solvents each contain 0.07% (v/v) of trifluoroacetic acid. The fractions containing the expected product are concentrated to dryness to give 4-{[6-(4-isobutylamino-benzenesulfonyloxy)benzothiazol-2-ylcarbamoyl]methyl}piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]2[O:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:9]=2[CH:8]=[C:7](N)[CH:6]=1)(=[O:3])[CH3:2].N(OC(C)(C)C)=O.[I:24]I.Cl>C(#N)C>[C:1]([O:4][C:5]1[C:10]2[O:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:9]=2[CH:8]=[C:7]([I:24])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(N)cc2c1OC(C)(C)C2
Reactant: II
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CC#N
Product: CC(=O)Oc1cc(I)cc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.2 %

Procedure:
A stirred solution of 1.0 gram (0.0045 mole) of 5-amino-2,2-dimethyl-2,3-dihydrobenzo[2,3-b]furan-7-yl acetate in 40 mL of acetonitrile was cooled in an ice-bath and 0.55 mL (0.0045 mole) of tert-butyl nitrite was added. Upon completion of addition, the reaction mixture was stirred for an additional 15 minutes with continued cooling. After this time 1.2 grams (0.0045 mole) of iodine was added in two portions during a five-minute period. Upon completion of addition, the reaction mixture was stirred for an additional one hour with continued cooling, allowed to warm to ambient temperature where it stirred for three hours, and then it was warmed to reflux where it stirred for 30 minutes. After this time the reaction mixture was cooled and poured into 50 mL of aqueous 10% hydrochloric acid and the mixture was extracted with two 25 mL portions of methylene chloride. The combined extracts were washed with one 25 mL portion of an aqueous solution saturated with sodium chloride, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using methylene chloride as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.78 gram of the subject compound. The NMR spectrum was consistent with the proposed structure. The reaction was repeated to obtain additional intermediate.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:7]([NH:9][CH:10]([C:12]2[CH:13]=[N:14][C:15]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:16]([Cl:18])[CH:17]=2)[CH3:11])=[O:8])=[CH:5][N:6]=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>>[Cl:18][C:16]1[CH:17]=[C:12]([CH:10]([NH:9][C:7]([C:4]2[O:3][C:2]([NH:1][C:28]([CH:25]3[CH2:27][CH2:26]3)=[O:29])=[N:6][CH:5]=2)=[O:8])[CH3:11])[CH:13]=[N:14][C:15]=1[O:19][CH2:20][C:21]([F:23])([F:22])[F:24]
Reactant: CC(NC(=O)c1cnc(N)o1)c1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: O=C(Cl)C1CC1
Product: CC(NC(=O)c1cnc(NC(=O)C2CC2)o1)c1cnc(OCC(F)(F)F)c(Cl)c1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)oxazole-5-carboxamide (30 mg, 0.08 mmol, Step-1, single enantiomer) and cyclopropanecarbonyl chloride (13 mg, 0.12 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [CH3:1][C:2]1([OH:9])[CH2:4][CH:3]1[Si:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][C:2]1([O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:4][CH:3]1[Si:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC1(O)CC1[Si](C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(OS(C)(=O)=O)CC1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.2 g of a trans and cis mixture of 1-methyl-1-hydroxy-2-(trimethylsilyl)cyclopropane, prepared in Section 1, was dissolved in 15 mL of dichloromethane, and 1.7 g of triethylamine was added to the resulting solution. The reaction mixture was cooled to 0° C., 1.8 g of methanesulfonylchloride was gradually added thereto and the mixture was vigorously stirred for 1 hour. 5 mL of a saturated NaHCO3 solution was added to the reaction mixture, thereby terminating the reaction. An organic layer was separated, dried over anhydrous magnesium sulfate (MgSO4), and concentrated by low vacuum distillation at a low temperature of less than 30° C. Although it may be used directly without any further purification, the concentrate was finely purified by vacuum distillation (65-70° C./0.1 mmHg). As a result, 2.8 g of 1-methyl-1-(methanesulfonyloxy)-2-(trimethylsilyl)cyclopropane was obtained as a mixture of cis and trans isomers in a ratio of 3 to 4:1. Results of 1H-NMR and 13C-NMR for the major isomer (trans isomer) of the mixture are given below.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]([CH2:15][CH3:16])[C:8]=2[CH:9]=[C:10]2[O:14][CH2:13][O:12][C:11]=12.[ClH:21].[N:22]([O-])=O.[Na+]>O>[C:17]([C:5]1[C:4](=[O:20])[C:3]2[C:2]([N+:1]#[N:22])=[C:11]3[O:12][CH2:13][O:14][C:10]3=[CH:9][C:8]=2[N:7]([CH2:15][CH3:16])[CH:6]=1)([OH:19])=[O:18].[Cl-:21]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(N)c3c(cc21)OCO3
Reactant: O=N[O-]
Reactant: Cl
Agent: [Na+]
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2c([N+]#N)c3c(cc21)OCO3
Product: [Cl-]
Reaction time: 5 h
Yield: 38.8 %

Procedure:
To a pale brown suspension of 9-amino-5-ethyl-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5-g]quinoline-7-carboxylic acid (11 g, 39.8 mmol) in con. HCl (25 mL) stirred at r.t. was added dropwise sodium nitrite (3.57 g, 51.8 mmol) in water (9 mL) at such a rate that the temperature of the reaction mixture would not exceed 45° C. (Ice bath!Slow addition!). Stirring continued for 5 h. The solution was poured into 120 mL of water and allowed to stand overnight in the refrigerator. The precipitate was collected by filtration, washed with water and dried to afford 7-carboxy-5-ethyl-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5-g]quinoline-9-diazonium, Chloride (5 g, 15.45 mmol, 38.8% yield). LCMS: (M+H)+: 324.2.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[C@H:19]3[C:14]([C:15]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:16]=4[C@@H:17]([CH2:20][NH:21]5)[CH2:18]3)=[CH:13][C@@H:12]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:33].OO>CO.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[C:1]1([NH:7][C:8]([N:10]2[C@H:19]3[C:14]([C:15]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:16]=4[C:17](=[CH:20][N:21]5[OH:33])[CH2:18]3)=[CH:13][C@@H:12]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[CH2:11]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([C@@H]1C=C2c3cccc4c3[C@@H](CN4)C[C@H]2N(C(=O)Nc2ccccc2)C1)N1CCCC1
Reactant: O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: O=C([C@@H]1C=C2c3cccc4c3c(cn4O)C[C@H]2N(C(=O)Nc2ccccc2)C1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
212 mg (0.49 mmol) of the product of step 1 is dissolved in 12 ml methanol and 41 mg (0.12 mmol, 0.25 eq.) sodium wolframate dehydrate in some drops of water is added. Then 670 μl 30% H2O2 (10 eq.) is added at 0° C. and stirred at room temperature for 50 minutes. The reaction mixture is separated with dichloromethane and saturated aqueous bicarbonate solution, the organic layer is washed with brine, dried with Na2SO4 and evaporated and purified by chromatography on silica eluting with tert. butyl methyl ether:cyclohexane 9:1 to give (6aR,9R)-4-Hydroxy-9-(pyrrolidine-1-carbonyl)-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-7-carboxylic acid phenylamide. MS/ES: 441 (M+H)+
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:9]([OH:11])=O)[CH2:5][CH2:4]1.[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH2:18]([N:25]1[CH2:30][CH2:29][N:28]([C:9]([C:6]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)=[O:11])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CN1CCC(C(=O)O)(c2ccccc2)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC(C(=O)N2CCN(Cc3ccccc3)CC2)(c2ccccc2)CC1
Yield: 79.5 %

Procedure:
A solution of 1-methyl-4-phenylpiperidine-4-carboxylic acid hydrochloride (1.35 g, 5 mmol), benzyl piperazine 0.88 g (5 mmol), triethylamine 1 ml and EDC 1.91 g (10 mmol) and DMAP (catalytic) in 40 ml dichloromethane was stirred at room temperature overnight, concentrated, added water and extracted with ethyl acetate 2′50 ml. The combined organic solution was dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:10) as eluents to give 1.5 g of desired product.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].[C:4]([O-:7])(=O)[CH3:5].[Na+].O[CH2:10][C:11]([C:13]1C=C[CH:16]=[CH:15][CH:14]=1)=O.Cl>C(O)C.O>[OH:7][C:4]1[CH:5]=[CH:16][CH:15]=[CH:14][C:13]=1[C:11](=[N:3][OH:2])[CH3:10]
Reactant: CC(=O)[O-]
Reactant: O=C(CO)c1ccccc1
Reactant: [NH3+]O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1ccccc1O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Hydroxylammoniumchloride (6.96 g, 100 mmol) and sodium acetate.3H2O (13.6 g, 100 mmol) were dissolved in 150 mL ethanol:water (7:3) and added to a solution of 2-hydroxyacetophenone (6.81 g, 50 mmol) in 50 mL ethanol:water (7:3). The pH was adjusted to 4-5 with 4N HCl (˜10 mL) and the reaction mixture was then heated to reflux (100° C.) for 1 hour. The oil bath was removed and the mixture was left overnight with stirring. Ethanol was partly removed by evaporation and the aqueous phase was extracted with ethyl acetate two times. The combined organic phases were dried over magnesium sulphate and evaporated to dryness to produce 7.55 g of pure 24.