Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1CCCCC1)(=O)N.Cl.S(=O)(=O)(O)O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2([C:31](=[O:33])[NH2:32])[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.BrBr.Br.[NH+]1C=CC=CC=1.BrC1CC(C2C=CC=C(OC)C=2)(C(=O)N)CCC1=O>C(COC)OC.C(O)C.CO.O1CCCC1.C(O)(=O)C>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:24]23[CH2:25][CH:26]([NH:32][C:31]2=[O:33])[C:27](=[O:30])[CH2:28][CH2:29]3)[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc(C2(C(N)=O)CCC(=O)CC2)c1
Agent: Br
Agent: BrBr
Agent: COc1cccc(C2(C(N)=O)CCC(=O)C(Br)C2)c1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cccc(C23CCC(=O)C(C2)NC3=O)c1

Procedure:
First of all, 1-(3-methoxyphenyl)-6-azabicyclo[3,2,1]-octane-7-one (VIII) is prepared by the six steps of (I) hydrolyzing 4-(3-methoxyphenyl)-4-cyano-1,1,-ethylenedioxy-cyclohexane (VII) with an alkali metal hydroxide(e.g., sodium hydroxide, potassium hydroxide) under heating in a solvent (e.g., methanol, ethanol, ethyleneglycol, a mixture of one of these solvents and water) to give 4-(3-methoxyphenyl)-4-carbamoyl-1,1-ethylenedioxy-cyclohexane, (2) reacting said carbamoyl-cyclohexane with an acid(e.g., hydrochloric acid, sulfuric acid, acetic acid) under heating, (3) brominating the resultant 4-(3-methoxyphenyl)-4-carbamoyl-cyclohexanone with bromine or pyridinium hydrobromide perbromide (C5H5N+HBr-) at room temperature in a solvent (e.g., acetic acid, tetrahydrofuran), (4) reacting the resultant 2-bromo-4-(3-methoxyphenyl)-4-carbamoyl-cyclohexanone with an alkali metal hydride (e.g., sodium hydride) or an alkali metal alkoxide (e.g., sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide) at room temperature in a solvent(e.g., methanol, ethanol, dimethoxyethane) to give 1-(3-methoxyphenyl)-6-azabicyclo[3,2,1]octane-4,7-dione, (5) refluxing a mixture of said product and hydrazine hydrate under heating in a solvent (e.g., ethanol, ethyleneglycol), and then (6) heating the resultant 1-(3-methoxyphenyl)-6-azabicyclo[3,2,1]octane-4,7-dione-4-hydrazone in the presence of an alkali agent(e.g., potassium hydroxide, potassium tert.-butoxide) in a solvent (e.g., toluene).
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-])=O>C(O)(=O)C.O.[Fe]>[C:14]1([NH:13][C:5]2[C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[S:8][C:4]=2[NH2:1])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1sc2ccccc2c1Nc1ccccc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1sc2ccccc2c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Into a solution of 2-nitro-N-phenylbenzo[b]thiophen-3-amine (13 g, 48 mmol) in acetic acid (200 ml) and water (20 ml) was added portionwise iron powder (14 g, 250 mmol). After stirring at room temperature for 2 h, it was filtered through a short plug of Celite and washed with DCM. The combined filtrate was washed with water and aqueous sodium carbonate solution. Upon evaporation off the solvent, the residue was purified by column chromatography on silica gel with hexane/DCM (4/1, v/v) as eluent to yield N3-phenylbenzo[b]thiophene-2,3-diamine (7.5 g, 65%) as a white solid.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][N:32]([CH3:38])[CH2:33][CH2:34][CH2:35][CH2:36][NH2:37]>>[CH3:31][N:32]([CH3:38])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: CN(C)CCCCN
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN(C)C)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N,N-dimethyl-butane-1,4-diamine by the procedure analogous to Example 1. MS (APCI, m/z): 460 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16]CC)=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(-c2ccc(C)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2cccc(C(=O)O)c2)cc1
Yield: 67.9 %

Procedure:
To a solution of ethyl 4'-methylbiphenyl-3-carboxylate (4.0 g) in ethanol (50 ml) was added a solution of 10 ml of 10% aqueous sodium hydroxide, and the mixture refluxed for 2 hours. Solvent was removed under reduced pressure, water added to the residue, and the solution filtered. The filtrate was acidified with dilute hydrochloric acid, and the white solid filtered off and dried under vacuum, yielding 2.4 g of 4'-methylbiphenyl-3-carboxylic acid m.p. 192° C.
Reaction SMILES: [C:1]([C:4]1O[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)(=O)[CH3:2].[CH2:15]([NH2:18])[CH2:16][NH2:17].O.[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>C(O)C>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[CH3:2][C:1]1[C:4]2[N:17]([CH:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:8]=2)[CH2:16][CH2:15][N:18]=1
Reactant: NCCN
Reactant: CC(=O)c1cc(-c2ccccc2)co1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: O
Product: CC1=NCCn2cc(-c3ccccc3)cc21
Yield: 31 %

Procedure:
2-Acetyl-4-phenylfuran (0.7 g) was heated at 100° C. for 1 hour under argon with 0.8 ml of 1,2-ethanediamine and 0.1 ml of water. After cooling 50 ml of water were added and the mixture was extracted three times with 50 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 0.7 g of brown oil, was chromatographed on 60 g of silica gel with methylene chloride/methanol (19:1) as the eluent. The crude product, 0.4 g of brown solid, was dissolved in a 50-fold amount of hot ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.4 g (31%) of 3,4-dihydro-1-methyl-7-phenylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 181° C. (dec.)
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH2:11][C:12]([OH:14])=O.[NH2:15][C@@H:16]([CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18]>>[CH2:36]([O:35][CH2:34][C@H:16]([NH:15][C:12](=[O:14])[CH2:11][N:3]1[CH2:2][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1Cc2ccccc2C1
Agent: Cl
Product: O=C(CN1Cc2ccccc2C1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 27.1 %

Procedure:
Proceeding as in Example 1, but substituting 2-(isoindolin-2-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 240, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(isoindolin-2-yl)acetamido)propanamide (11.7 g, 27.1%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.23 (s, 1H), 8.08 (d, 1H), 7.60 (d, 2H), 7.26 (m, 5H), 7.22 (m, 6H), 7.04-6.98 (m, 4H), 4.75 (m, 1H), 4.52 (s, 2H), 4.00 (s, 4H), 3.73 (m, 2H), 3.42 (s, 2H). MS (EI) for C32H30FN3O4. found 540.6 (MH+).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:5]([OH:12])=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8]>>[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH2:7][OH:8])[C:5]=1[OH:12]
Reactant: O=Cc1cccc(F)c1O
Agent: [BH4-]
Agent: [Na+]
Product: OCc1cccc(F)c1O

Procedure:
In an analogous manner to that described in (β) 3-fluoro-2-hydroxy-benzaldehyde was reduced by sodium borohydride to yield 2-fluoro-6-hydroxymethyl-phenol as a white solid; MS: 142 (M)+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[N:3]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([N:14]3[CH2:19][CH2:18][CH2:17][C@@H:16]4[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=5[CH2:26][C@H:15]34)=[O:13])=[CH:10][C:4]=2[N:3]=1
Reactant: Nc1nc2cc(C(=O)O)ccc2[nH]1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1nc2cc(C(=O)N3CCC[C@@H]4c5ccccc5C[C@@H]43)ccc2[nH]1
Yield: 71 %

Procedure:
The title compound is prepared from 2-amino-1H-benzoimidazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 71% of theory; LC (method 4): tR=1.64 min; Mass spectrum (ESI+): m/z=333 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[N:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][CH:16]=[C:4]2[CH2:3]1.[Cl:17]N1C(=O)CCC1=O>CN(C)C=O>[Cl:17][C:16]1[N:15]=[CH:14][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[N:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1Cc2cncn2-c2cccnc2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)ncn2-c2cccnc2C1=O
Reaction time: 0.5 h

Procedure:
0.56 g (2.6 mmol) of 4,5-dihydro-5-methyl-6H-imidazo[1,5-a]pyrido[2,3-f][1,4]diazepin-6-one and 0.35 g (2.6 mmol) of N-chlorosuccinimide are treated with 10 ml of dimethylformamide and the mixture is stirred at 90°-100° for 30 minutes. After evaporation to dryness, the residue is chromatographed on silica gel using chloroform containing 4% methanol for the elution. After recrystallization from ethyl acetate, there is obtained 3-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a]pyrido[2,3-f][1,4]diazepin-6-one of melting point 247°-248°.
Reaction SMILES: [C:1](=[S:4])([S-:3])[NH2:2].[NH4+].Br.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=O>C(O)C>[N:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:2]=[C:1]([SH:3])[S:4][CH:8]=2)=[CH:12][CH:13]=1
Reactant: O=C(CBr)c1ccncc1
Reactant: NC(=S)[S-]
Agent: Br
Agent: [NH4+]
Solvent: CCO
Product: Sc1nc(-c2ccncc2)cs1
Reaction time: 18 h

Procedure:
Ammonium dithiocarbamate (0.444 g, 4.03 mmol) was added to 2-bromo-1-(4-pyridinyl)-1-ethanone hydrobromide (1.03 g, 3.67 mmol) in ethanol (10 ml and stirring continued at room temperature for 18 hr. The solid was filtered and re-crystallized from methanol to give 4-pyridin-4-yl-thiazole-2-thiol. This thiol (272 mg, 1.39 mmol) was then coupled with N1-3-chlorophenyl)-2-chloroacetamide (284 mg, 1.39 mmol) as described in earlier examples, in acetonitrile in the presence of triethylamine (0.580 ml, 4.2 mmol) to afford crude product. This was purified by reverse phase HPLC to afford N-(3-Chloro-phenyl)-2-(4-pyridin-4-yl-thiazol-2-ylsulfanyl)-acetamide. MS (ES) 363 (M+H)+
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Nc1ccc(Br)cc1
Product: Nc1ccc(-c2ccccc2Cl)cc1
Yield: 49.7 %

Procedure:
The title compound (176 mg) was prepared from 4-bromoaniline (300 mg, 1.74 mmol) and 2-chlorophenylboronic acid (354 mg, 2.26 mmol) as a yellow solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:17][C@H:18]([OH:30])[C:19]2[C:27]3[S:26][C:25](=[O:28])[NH:24][C:23]=3[C:22]([OH:29])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)(=O)=O.FC(F)(F)C(O)=O.[CH:45]([C:48]1[S:49][CH:50]=[C:51]([C:53]([N:55]2[CH2:60][C:59]3([CH2:65][CH2:64][NH:63][CH2:62][CH2:61]3)[O:58][CH2:57][CH2:56]2)=[O:54])[N:52]=1)([CH3:47])[CH3:46].C(N(CC)CC)C>CC#N>[OH:30][C@H:18]([C:19]1[C:27]2[S:26][C:25](=[O:28])[NH:24][C:23]=2[C:22]([OH:29])=[CH:21][CH:20]=1)[CH2:17][N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:63]2[CH2:62][CH2:61][C:59]3([O:58][CH2:57][CH2:56][N:55]([C:53]([C:51]4[N:52]=[C:48]([CH:45]([CH3:47])[CH3:46])[S:49][CH:50]=4)=[O:54])[CH2:60]3)[CH2:65][CH2:64]2)=[CH:14][CH:13]=1)[C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCOc4ccc(CN(C[C@H](O)c5ccc(O)c6[nH]c(=O)sc56)C(=O)OC(C)(C)C)cc4)CC3)C2)cs1
Temperature: 60 °C
Reaction time: 34 h

Procedure:
A solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (0.295 g) in MeCN (1.1 mL) was added dropwise to a solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.150 g) and triethylamine (0.11 mL) in MeCN (1.1 mL) at RT under argon. The resulting mixture was stirred at 60° C. under argon for 34 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM, washed with brine (×2), dried over sodium sulphate, filtered and evaporated in vacuo. The yellow solid was purified by silica gel chromatography eluting with 0-5% MeOH in DCM to give the subtitled compound as a green solid. Yield 0.135 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH:30]1[CH:31]=[CH:32][C:33]2[N:38](O)N=[N:36][C:34]=2[CH:35]=1.C1(N)C=CC=CC=1N>CN(C=O)C.CCOC(C)=O>[NH2:36][C:34]1[CH:35]=[CH:30][CH:31]=[CH:32][C:33]=1[NH:38][C:21]([C:20]1[CH:24]=[CH:25][C:17]([N:14]2[CH2:13][CH2:12][C:10]3([CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:11]3)[CH2:16][CH2:15]2)=[N:18][CH:19]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(c3ccc(C(=O)O)cn3)CC2)C1
Reactant: On1nnc2ccccc21
Agent: Nc1ccccc1N
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2(CCN(c3ccc(C(=O)Nc4ccccc4N)cn3)CC2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of tert-butyl 2,7-diazaspiro[3.5]nonane (660 mg, 2.91 mmol), methyl 6-chloronicotinate (500 mg, 2.91 mmol) and Et3N (0.487 mL, 3.50 mmol) in 2 mL of N-methylpyrrolidine was stirred under microwave irradiation for 20 min at a temperature of 180° C. The mixture was poured into EtOAc and washed with sat'd NaHCO3, dried (MgSO4), filtered and concentrated, giving tert-butyl 7-[5-(methoxycarbonyl)pyridine-2-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate. The methyl ester was dissolved in 2 mL of 1:1 THF/water, treated with LiOH.H2O (26 mg, 0.62 mmol) and stirred for 20 hours. The mixture was poured into EtOAc and washed with 1M HCl followed by brine, dried (MgSO4), filtered and concentrated, providing 6-[2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]non-7-yl]nicotinic acid. A mixture of the carboxylic acid in 2 mL of DMF was treated with EDC (132 mg, 0.69 mmol), HOBt (93 mg, 0.69 mmol) and phenylenediamine (125 mg, 1.15 mmol), stirred for 15 h at room temperature. The reaction mixture was then diluted with EtOAc and washed with sat.'d NaHCO3, dried (MgSO4), filtered and concentrated. The crude oil was purified by reverse phase flash chromatography (10-100% MeCN/H2O with 0.05% TFA) and formation of the desired product, tert-butyl 7-(5-{[(2-aminophenyl)amino]carbonyl}pyridine-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate, which was confirmed by MS (ESI+): cal'd [M+H]+ 438.2, obs'd 438.3.
Reaction SMILES: C(OC(=O)COC1C=CC(Cl)=CC=1C#C)(C)(C)C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])=[CH:22][C:21]=1[C:32]#[C:33][Si](C)(C)C>>[C:32]([C:21]1[CH:22]=[C:23]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=1[F:19])#[CH:33]
Reactant: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Agent: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: C#Cc1cc(S(=O)(=O)CCC)ccc1F

Procedure:
Following the general method as outlined in Intermediate 3, starting from {[2-Fluoro-5-(propylsulfonyl)phenyl]ethynyl}trimethyl silane (Intermediate 107), the title compound was obtained as a brown liquid after purification by column chromatography (silica) eluting with petroleum ether and ethyl acetate.
Reaction SMILES: [N+:1]([CH:4]([N+:21]([O-:23])=[O:22])[CH2:5][CH2:6][Si:7]([CH3:20])([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)([O-:3])=[O:2].[OH-].[K+].Cl([F:30])(=O)(=O)=O>CO>[F:30][C:4]([N+:1]([O-:3])=[O:2])([N+:21]([O-:23])=[O:22])[CH2:5][CH2:6][Si:7]([CH3:20])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Si](CCC([N+](=O)[O-])[N+](=O)[O-])(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[Si](CCC(F)([N+](=O)[O-])[N+](=O)[O-])(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
(3,3-Dinitropropyl)methyldiphenylsilane was dissolved in a solution of 0.217 mol of potassium hydroxide in 900 ml of methanol. The solution was placed in a 2 l flask equipped with a glass dip tube for introducing perchloryl fluoride, a thermometer, a magnetic stirrer and an ice bath. The flask was vented to the fume-hood atmosphere by means of a mineral oil bubbler, and another bubbler as well as an inverted vacuum trap (to prevent suck back) were placed between the dip tube and a perchloryl fluoride cylinder. Perchloryl fluoride was passed into the solution at 10° until it was no longer absorbed (2 hrs). Then, 1000 ml of water was added and the solution was allowed to stir 1 hr at room temperature. An additional 1500 ml of water was added and the mixture was made basic (pH 12) with potassium hydroxide. The product was extracted with four 400 ml portions of methylene chloride. The methylene chloride solution was washed with three 1000 ml portions of water, dried and stripped of solvent. The residue, 58.5 g, was chromatographed on a 750 g column of dry silica gel, using carbon tetrachloride (30 l) for elution, to give 44.5 g (79%) of (3-fluoro-3,3-dinitropropyl)methyldiphenylsilane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]1=[O:31]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][C:22]2=[O:31])=[CH:8][CH:7]=1)[CH3:2]
Reactant: O=c1ccc2ccccc2n1CCCBr
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(OCCCn2c(=O)ccc3ccccc32)cc1
Reaction time: 0.25 h

Procedure:
A solution of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.73 g) in dimethylformamide (10 mL) was treated with 55% sodium hydride (0.164 g), stirred for 15 minutes and then 1-(3-bromopropyl)-1,2-dihydro-2-oxoquinoline (1 g) was added and rinsed in with dimethylformamide (4 mL). The mixture was stirred at room temperature for 22 hours and worked up as in Example 20. The residual solid was purified by flash chromatography over silica gel (ethyl acetate-hexane; 1:4). Crystallization of the resulting solid furnished 1.0.g of 4-[3-(1,2-dihydro-2-oxo-1-quinolinyl)propoxy]-alpha-oxobenzeneacetic acid ethyl ester, mp 108°-109° C.
Reaction SMILES: [F:1][C:2]1([F:23])[C:10]2[C:5](=[CH:6][C:7]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:8](O)[CH:9]=2)[C:4]([F:22])([F:21])[O:3]1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O.C1(C)C=CC=CC=1>[F:21][C:4]1([F:22])[C:5]2[C:10](=[CH:9][C:8]3[O:20][C:13]([C:14]4[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=4)=[N:12][C:7]=3[CH:6]=2)[C:2]([F:23])([F:1])[O:3]1
Reactant: O=C(Nc1cc2c(cc1O)C(F)(F)OC2(F)F)c1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: FC1(F)OC(F)(F)c2cc3oc(-c4ccncc4)nc3cc21
Reaction time: 0.5 h
Yield: 11.1 %

Procedure:
To a mixture of 1.34 g of N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide, 10 ml of tetrahydrofuran and 1.07 g of triphenylphosphine, 2.67 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. After 30 minutes, 1.07 g of triphenylphosphine was added, 2.67 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise thereto and stirred for further two hours. Water was added thereto, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and the resultant solid was recrystallized to give 0.14 g of 5,5,7,7-tetrafluoro-2-pyridin-4-yl-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole (hereinafter, referred to as “active compound 16”).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:16][O:15][CH2:14][C@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C@@H:12]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C@H:11]([CH3:30])[O:10][C:9]1=[O:31])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:16][O:15][CH2:14][C@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C@@H:12]([O:25][CH2:26][CH:27]([CH3:28])[CH3:29])[C@H:11]([CH3:30])[O:10][C:9]1=[O:31]
Reactant: Cc1ccc(C[C@H]2COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@@H](C)[C@@H]2OCC(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(C[C@H]2COC[C@H](N)C(=O)O[C@@H](C)[C@@H]2OCC(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.8 %

Procedure:
To a solution of tert-butyl((3S,7S,8R,9S)-8-isobutoxy-9-methyl-7-(4-methylbenzyl)-2-oxo-1,5-dioxonan-3-yl)carbamate (0.03 g, 0.07 mmol) in CH2Cl2 (0.7 mL) was added a 4 M solution of HCl in dioxane (0.33 mL, 1.34 mmol), and the resulting colorless solution was stirred at room temperature for 1.5 h. The solvent was evaporated under a positive stream of N2 and the residue was dissolved in CH2Cl2, washed with saturated aqueous NaHCO3, dried by passing through a phase separator cartridge, and concentrated to give (3S,7S,8R,9S)-3-amino-8-isobutoxy-9-methyl-7-(4-methylbenzyl)-1,5-dioxonan-2-one (0.021 g, 90%) as a white solid: mp 81-84° C.; 1H NMR (400 MHz, CDCl3) δ 7.08 (t, J=2.7 Hz, 4H), 4.91 (dq, J=9.2, 6.4 Hz, 1H), 3.84 (dd, J=11.6, 7.5 Hz, 1H), 3.74 (m, 2H), 3.64 (m, 1H), 3.47 (dd, J=8.3, 6.4 Hz, 1H), 3.41 (dd, J=10.7, 6.1 Hz, 1H), 3.31 (m, 2H), 3.07 (m, 3H), 2.31 (s, 3H), 1.87 (m, 2H), 1.59 (m, 1H), 1.47 (d, J=6.4 Hz, 3H), 0.95 (dd, J=6.7, 1.6 Hz, 6H); ESIMS m/z 351 ([M+H]+).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10].[OH-].[Na+]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: COc1cc(C(=N)N)ccc1NCc1nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc2n1C
Yield: 78 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidino-2-methoxyphenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 78% of theory, C26H27N7O4 (501.6); Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=502.