Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C@@H:13]2[CH2:15][C@H:14]2[C:16](O)=[O:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.Cl>O1CCCC1>[OH:17][CH2:16][C@@H:14]1[CH2:15][C@H:13]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OC[C@@H]1C[C@H]1c1ccccc1
Reaction time: 0.5 h
Yield: 103.7 %

Procedure:
152 mg of lithium aluminium hydride suspended in 10 ml of tetrahydrofuran was mixed with 324 mg of trans-2-phenylcyclopropane-1-carboxylic acid under cooling with ice and stirred at the same temperature for 30 minutes and then at room temperature for 2 hours. Water was gradually added to the reaction solution and then 1N hydrochloric acid was gradually added. The reaction solution was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=3/1→2/1] to give 307 mg of trans-l-(hydroxymethyl)-2-phenylcyclopropane as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH:9]1([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Brc1ccccc1OC1CCCCC1
Reactant: C1CNCCN1
Product: c1ccc(N2CCNCC2)c(OC2CCCCC2)c1

Procedure:
NaH (8.4 g, 210 mmol, 60% in mineral oil) was slurred in DMF (40 mL) and heated to about 65° C. To the slurry was added cyclohexanol (7 g, 69.9 mmol) dissolved in DMF (50 mL). The mixture was stirred at 65° C. for about 1 hour. Ortho-fluoro bromobenzene (9.2 mL, 83.9 mmol) was added dropwise in DMF (10 mL) and the mixture was stirred at 65° C. for about 16 hours, and quenched with water and diluted with DCM. The mixture was concentrated to an oily solid and extracted between water and 1/1 EtOAc/hex. The organic layer was dried, filtered and concentrated. Chromatography on silica gel (EtOAc/hexanes) gave 1-bromo-2-cyclohydroxy-benzene (6.13 g, 34%) as a yellow oil. 1-Bromo-2-cyclohexyloxy-benzene was coupled to piperazine using the Buchwald chemistry described in preparation 1A. LRMS (ESI+): 261.1 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:29])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C:53]([N:55]=[C:56]=[S:57])=[O:54])=[CH:48][CH:47]=1.C(OCC)C>C(O)C.C1(C)C=CC=CC=1.CCCCCC>[F:29][C:4]1[CH:3]=[C:2]([NH:1][C:56]([NH:55][C:53](=[O:54])[CH2:52][C:49]2[CH:50]=[CH:51][C:46]([F:45])=[CH:47][CH:48]=2)=[S:57])[CH:28]=[CH:27][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][N:23]3[CH2:26][CH2:25][CH2:24]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCC(CN4CCC4)CC3)ncn2)c(F)c1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCC(CN4CCC4)CC3)ncn2)c(F)c1
Reaction time: 0.08 h

Procedure:
4-(Azetidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (111 mg) was dissolved in ethanol (3 ml) under a nitrogen atmosphere, and then (S)-(+)-10-camphorsulfonic acid (65 mg) was added thereto, followed by stirring for 5 min. A 0.25 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (1.66 ml) was added thereto, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:8, then ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure to give a residue, to which diethyl ether (4 ml) and hexane (4 ml) were then added to suspend. The solid was filtered off, and dried under aeration to provide the titled compound (81.5 mg) as white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:19][C:20]([CH:22]2[CH2:25][CH2:24][CH2:23]2)=[O:21])C(O)=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:32]([O:34][C:35](=[O:39])[C:36](Cl)=[O:37])[CH3:33].[O-]CC.[Na+]>CN(C1C=CN=CC=1)C.C1COCC1.CCO>[CH2:32]([O:34][C:35](=[O:39])[C:36](=[O:37])[CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[NH:19][C:20]([CH:22]1[CH2:25][CH2:24][CH2:23]1)=[O:21])[CH3:33]
Reactant: O=C(NC(C(=O)O)c1cccc(OCc2ccccc2)c1)C1CCC1
Reactant: CCOC(=O)C(=O)Cl
Agent: CC[O-]
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(NC(=O)C1CCC1)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
A slurry of (3-benzyloxy-phenyl)-(cyclobutanecarbonyl-amino)-acetic acid (4.77 g, 14.1 mmol), pyridine (3.4 mL, 42.2 mmol) and DMAP (cat.) in anhydrous THF (26 mL) was charged dropwise with chloro-oxo-acetic acid ethyl ester (3.13 mL, 28.1 mmol) and heated to reflux for 1.5 h. The white precipitate was filtered through a fritted glass Buchner funnel into a flask containing H2O and EtOAc and the aqueous phase was separated from the organic phase. The aqueous was washed with EtOAc (3×) and the combined EtOAc layers were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo resulting in a yellow/orange oil. The oil was dissolved in anhydrous EtOH (28 mL) and a solution of 21 wt % of sodium ethoxide (NaOEt) in EtOH (2.0 mnL) was added at 0° C. and warmed to rt. The reaction mixture was concentrated in vacuo and the crude material was chromatographed on silica gel [eluting with 2% EtOAc in CHCl3], yielding the title compound as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 1.26 (t, J=7.2 Hz, 3H), 1.80-2.04 (m, 2H), 2.09 (m, 4H), 3.06 (quint, J=8.4 Hz, 1H) 4.17-4.30 (m, 2H), 5.04 (s, 2H), 6.18-6.32 (m, 2H), 6.86-7.00 (m, 3H), 7.22-7.48 (m, 5H); MS (ES+): m/z 396.03 (100) [MH+]; HPLC: tR=3.09 min (MicromassZQ, nonpolar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=[C:9]([N:18]2[CH2:24][CH2:23][C:20]3([CH2:22][CH2:21]3)[CH2:19]2)[N:8]=1.ClC1C=C(C=CC=1OC)CNC1C(C(OCC)=O)=CN=C(SC)N=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([N:18]2[CH2:24][CH2:23][C:20]3([CH2:21][CH2:22]3)[CH2:19]2)[N:8]=1
Reactant: CCOC(=O)c1cnc(N2CCC3(CC3)C2)nc1NCc1ccc(OC)c(Cl)c1
Agent: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(Cl)c1
Product: COc1ccc(CNc2nc(N3CCC4(CC4)C3)ncc2C(=O)O)cc1Cl
Yield: 54 %

Procedure:
The procedures were analogous to Example 1(2). Ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-(5-azaspiro[2.4]heptan-5-yl)pyrimidine-5-carboxylate (3.4 g, 8.17 mmol) was used in step 2 instead of ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate. Yield: 54%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28].O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:19])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([NH:17][S:29]([CH2:26][CH2:27][CH3:28])(=[O:31])=[O:30])[C:11]=1[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(F)c(C(=O)OCc2ccccc2)c1F
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-amino-2,6-difluoro-benzoic acid benzyl ester (43, 6.00 g, 22.8 mmol) in methylene chloride (150 mL) was added pyridine (2.76 mL, 34.2 mmol) and propane-1-sulfonyl chloride (3.80 mL, 33.8 mmol). The reaction was stirred at room temperature overnight. Then the reaction was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated with silica gel column chromatography to give a colorless oil (44, 7.0 g, 83.1%). MS(ESI) [M+H+]+=370.1.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH:12][C:13]([C:15]3[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=3[NH:17][C:18](=[O:22])[C:19]([O-:21])=[O:20])=[O:14])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+]>O>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH:12][C:13]([C:15]3[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=3[NH:17][C:18](=[O:22])[C:19]([OH:21])=[O:20])=[O:14])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])C(=O)Nc1ccccc1C(=O)NC1CCN(C2CCCCC2)C1
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=O)Nc1ccccc1C(=O)NC1CCN(C2CCCCC2)C1

Procedure:
The amorphous sodium salt from Example 5 was suspended in distilled water; the pH of the solution was 9.0. The stirred solution was cooled and acidified with dilute hydrochloric acid to pH 4 at which point maximum precipitation occurred. The precipitate was collected and air-dried to give 2.76 g. of product which melted at 268°-270° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:21]=[CH:20][C:7]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:9]([N+:11]([O-:13])=[O:12])[O:10][C:6]=2[CH:5]=1.[CH2:22](I)[CH3:23].O>C(COC)OC>[CH2:22]([O:3][C:4]1[CH:21]=[CH:20][C:7]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:9]([N+:11]([O-:13])=[O:12])[O:10][C:6]=2[CH:5]=1)[CH3:23]
Reactant: CCI
Reactant: O=[N+]([O-])c1oc2cc(O)ccc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOc1ccc2c(-c3ccccc3)c([N+](=O)[O-])oc2c1

Procedure:
To a suspension of 0.34 g (0.008 mole) of sodium hydride in 45 ml of glyme is added dropwise a solution of 2.0 g (0.008 mole) of 6-hydroxy-2-nitro-3-phenylbenzofuran in 20 ml of glyme. To this suspension is added 16 g (0.010 mole) of ethyl iodide and the mixture is heated to its reflux temperature and maintained at reflux for 5 hours. After cooling to 25° C. an additional 0.1 g of sodium hydride and 5 ml of ethyl iodide are added and the mixture is refluxed for about three hours. The mixture is poured into water and extracted with diethyl ether. The extracts are washed with water and saturated sodium chloride solution and dried. Concentration of the extracts provides a residue which is recrystallized from aqueous ethanol to provide yellow needles of 6-ethoxy-2-nitro-3-phenylbenzofuran, m.p. 109°-111° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25].CO>CCOCC>[ClH:25].[CH3:24][O:23][C:22]1[C:17]2[O:16][N:15]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc2c(C3CCN(C(=O)OC(C)(C)C)CC3)noc12
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COc1cccc2c(C3CCNCC3)noc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A mixture of 4-(7-Methoxy-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.00 g, 9.03 mmol), HCl (35 mL of a 1 M ether solution, 35.0 mmol), and methanol (25 mL) was stirred at room temperature under nitrogen for 18 h. Ether (75 mL) was added, the mixture stirred at room temperature for 15 min, and the product collected by filtration to afford 2.37 g (98%) of the desired product as a white powder, mp: >250° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[CH2:16]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH2:31][CH3:32])=[CH:24][C:25]([CH3:30])([CH3:29])[O:26]2)=[CH:21][C:20]=1[C:33](=O)[CH3:34])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH2:31][CH3:32])=[CH:24][C:25]([CH3:29])([CH3:30])[O:26]2)=[CH:21][C:20]=1/[C:33](/[CH3:34])=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH3:17]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCOc1cc2c(cc1C(C)=O)C(CC)=CC(C)(C)O2
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OCC)OC(C)(C)C=C2CC

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (173 mg, 7.15 mmol) and 1-(7-ethoxy-4-ethyl-2,2-dimethyl-2H-chromen-6-yl)-ethanone (Compound 56, 394 mg, 1.43 mmol) were reacted to give the title compound as a yellow oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.C([N-]C(C)C)(C)C.[Li+].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][CH2:13][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[CH:3]=3)[N:8]=2)=[CH:34][CH:35]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc2cc(F)c(F)cc2n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1cc2ccc(CCc3ccc(OCc4ccccc4)cc3)nc2cc1F
Temperature: -10 °C

Procedure:
A solution of 8.9 g (49.6 mmol) of the product from Example 1, step 3 in 90 ml THF is cooled at −50° C. 28.6 ml (57.2 mmol) of a 2M solution of lithium diisopropylamide are added and the solution is allowed to heat to −10° C. After 15′ stirring at this temperature the deep colored solution is again cooled to −50° C. A solution of 11.6 g (49.8 mmol) of 1-benzyloxy-4-chloromethyl-benzene in 60 ml THF is dropped into the cooled solution. The system is allowed to heat to room temperature and stirred overnight. The solvent is evaporated and the residue that solidifies on cooling is stirred with ethyl ether and filtered. The residue is filtered through SiO2 eluting with dichloromethane. The yield is 3.75 g (20%).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([NH:13][CH2:14][C:15]([F:24])([F:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N+:17]=2[O-:22])[C:7]=1[F:25])C.[Li+].[OH-].Cl>CO>[Cl:12][C:11]1[C:6]([CH2:5][C:4]([OH:26])=[O:3])=[C:7]([F:25])[C:8]([NH:13][CH2:14][C:15]([F:23])([F:24])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N+:17]=2[O-:22])=[N:9][CH:10]=1
Reactant: CCOC(=O)Cc1c(Cl)cnc(NCC(F)(F)c2cccc[n+]2[O-])c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1c(Cl)cnc(NCC(F)(F)c2cccc[n+]2[O-])c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.58 g (1.49 mmol) ethyl(5-chloro-2-{[2,2-difluoro-2-(1-oxido-2-pyridinyl)ethyl]amino}-3-fluoro-4-pyridinyl)acetate 1-8 in 10 mL MeOH was added 1.64 mL (1.64 mmol, 1M aqueous solution) LiOH and the reaction mixture allowed to stir 16 hours at room temperature, then 0.16 mL (0.16 mmol) more LiOH was added and the mixture heated to 45° C. for 4 h, then cooled. To this was added 0.15 mL (1.79 mmol, 12M solution) HCl and the mixture concentrated to give (5-chloro-2-{[2,2-difluoro-2-(1-oxido-2-pyridinyl)ethyl]amino}-3-fluoro-4-pyridinyl)acetic acid 1-9 (mixed with LiCl). 1H NMR (400 mHz, CD3OD) δ8.36 (br d, 1H, J=6.23 Hz); 7.66 (dd, 1H, J=7.87 and 2.19 Hz); 7.56 (s, 1H); 7.51 (m, 2H,); 4.58 (t, 2H, J=13 Hz); 3.63 (d, 2H, J=1.65 Hz);
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[O:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][O:41][C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)[CH2:35][CH2:34]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>CN(C=O)C.[Cl-].[Na+].O>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:46][C:45]6[CH:47]=[CH:48][C:42]([O:41][CH2:40][CH2:39][N:36]7[CH2:35][CH2:34][O:33][CH2:38][CH2:37]7)=[CH:43][CH:44]=6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CNc5ccc(OCCN6CCOCC6)cc5)cn4)sc23)c(F)c1)NC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.1 %

Procedure:
To a solution of the aldehyde 47 (0.161 g, 0.359 mmol), 4-(2-morpholinoethoxy)aniline (0.120 g, 0.540 mmol), and dibutyltin dichloride (0.197 g, 0.648 mmol) in DMF (5 mL) was added a solution of phenylsilane (0.047 g, 0.434 mmol) in DMF (2 mL). The reaction mixture was stirred for 3 hours at RT and treated with a mixture of brine/sat. NAHCO3 solution. A precipitate was formed which was collected by filtration, washed with water and dried. Crude material was purified by flash column chromatography, eluent a 10 to 20% gradient of MeOH in AcOEt—to afford the title compound 331 (139 mg, 59.1% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.72 (s, 1H); 8.62 (d, J=1.6 Hz, 1H); 8.51 (dd, J=5.5 Hz, 1H); 8.30 (s, 1H); 8.22 (d, J=8.2 Hz, 1H); 7.88 (dd, J=8.2, 2.2 Hz, 1H); 7.73 (dd, J=13.5, 2.5 Hz, 1H); 7.38 (t, J=9.2 Hz, 1H); 7.20 (dd, J=8.8 1.2 Hz, 1H); 6.72-6.69 (m, 2H); 6.63 (dd, J=5.5, 0.8 Hz 1H); 6.58-6.54 (m, 3H); 5.95 (t, J=6.3 Hz, 1H); 4.30 (d, J=6.1 Hz, 2H); 3.82 (t, J=5.9 Hz, 2H); 3.55 (t, J=4.5 Hz, 4H); 2.60 (t, J=5.7 Hz, 2H); 2.57-2.62 (m, 1H); 2.42 (t, J=4.5 Hz, 4H); 0.68-0.63 (m, 2H); 0.47-0.41 (m, 2H). MS (m/z): 655.6 (M+1)+
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([C:13](OC)=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[OH:14][CH2:13][C:10]1[CH:11]=[CH:12][C:4]2[O:3][C:2]([CH3:17])([CH3:1])[C:7](=[O:8])[NH:6][C:5]=2[CH:9]=1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(C)(C)O2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(CO)cc2NC1=O
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A solution of 75.60 g of methyl 2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylate in 2700 ml of anhydrous tetrahydrofuran is cooled to −40° C. 858 ml of diisobutylaluminium hydride solution (1M in toluene) are added dropwise at −45-−40° C. The reaction mixture is subsequently stirred at −40° C. for a further 2 hours and finally warmed slowly to −20° C. The reaction mixture is poured onto 360 ml of 32% HCl. The phases are separated and the organic phase is washed with 1000 ml of 1M aqueous sodium potassium tartrate solution. The combined aqueous phases are re-extracted with 1000 ml of tetrahydrofuran and the combined organic phases are dried over sodium sulphate and concentrated by evaporation. The residue is taken up in 500 ml of tert-butyl methyl ether and the suspension is stirred at 45° C. over 1 hour. The title compound is obtained as a beige solid by filtration. Rt=2.69.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)C(=O)CN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 58.5 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (2 g) is alkylated using 1-bromo-3,3-dimethyl-butan-2-one (2.72 g; 15.2 mmol) and K2CO3 (2.1 g; 15.2 mmol) at 40° C. for 16 h. After aqueous work-up and purification by RP chromatography the pure material (1.65 g) is de-acetylated in hydrochloric acid (6 N, 10 ml) at reflux. After aqueous work-up 5-amino-1-(3,3-dimethyl-2-oxo-butyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (1.42 g) is obtained and used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[S:7][C:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:12])=[CH:9][N:10]=1.C(N(CC)CC)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.P([O-])([O-])([O-])=O>ClCCl>[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]2[S:7][C:8]([C:11](=[O:12])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[CH:9][N:10]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccccc1C(=O)c1cnc(NCCCN)s1
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCCCNc2ncc(C(=O)c3ccccc3C)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[2-(3-Amino-propylamino)-thiazol-5-yl]-o-tolyl-methanone was dissolved in dichloromethane and triethylamine and toluene-4-sulfonyl chloride added. The mixture was stirred overnight at room temperature, poured into 1 M pH4 phosphate buffer (5 ml) and extracted with dichloromethane (3×10 ml). The combined organic phases were dried over magnesium sulfate and evaporated. The oily residue was purified by column chromatography on silica gel (13:7 hexane/acetone eluant), using a small amount of dichloromethane to apply the mixture to the column. The title compound was isolated as an off-white solid. MS (m/e): 428.3 (M−H, 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:27][CH3:28]>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14]([O:16][CH2:27][CH3:28])=[O:15])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Benzyl-4-phenylamino-piperidine-4-carboxylic acid (40.1 g, 0.13 mol) and NaOH (5.12 g, 0.13 mol) was dissolved in methanol (1000 mL). The mixture was heated to reflux for 0.5 h. Then the solvent was removed under reduced pressure. The residue was dissolved in HMPT (300 mL). Bromo-ethane (17.44, 0.16 mol) was added at 20° C. The mixture was stirred overnight at 20° C. The reaction mixture was poured into ice-water and extracted with EtOAc (3×400 mL). The combined organics were washed with brine, dried over Na2SO4 and evaporated under vacuum. The residue was purified by silicagel column chromatography (Petroleum ether./EtOAc 2:1) to give ethyl 1-benzyl-4-(phenylamino)piperidine-4-carboxylate.
Reaction SMILES: C([O:5][C:6]([C@:8]12[CH2:15][CH:14]([F:16])[CH2:13][C@H:12]1[C:11](=[O:17])[N:10]([C@@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[CH2:9]2)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:16][CH:14]1[CH2:15][C@@:8]2([C:6]([OH:7])=[O:5])[C@H:12]([C:11](=[O:17])[N:10]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:9]2)[CH2:13]1
Reactant: C[C@H](c1ccccc1)N1C[C@@]2(C(=O)OC(C)(C)C)CC(F)C[C@H]2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccccc1)N1C[C@@]2(C(=O)O)CC(F)C[C@H]2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R,5R)-7-Fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octan-1-ylcarboxylic acid tert-butyl ester (705 mg, 2.03 mmol) was dissolved in methylene chloride (4 mL). Trifluoroacetic acid (4 mL) was added under ice-cooling, and then the mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated under reduced pressure again to give 595 mg (quantitative) of the title compound as a white solid.