Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Yield: 97.4 %

Procedure:
1,1-Dimethylethyl 4-[3-(methyloxy)-4-nitrophenyl]-1-piperazinecarboxylate (combined batches) (5.16 g, 15.3 mmol) in DCM was cooled with an ice/H2O bath and TFA (30.0 mL, 398 mmol) was added dropwise via an addition funnel. Upon completion by TLC, the reaction was quenched slowly with 1N NaOH until the aqueous layer was basic as determined by pH paper. The mixture was extracted with DCM, dried (MgSO4) and concentrated to provide the title compound of step B (3.52 g, 14.9 mmol, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (br. s., 1H), 2.73-2.77 (m, 4H), 3.26-3.33 (m, 4H), 3.85 (s, 3H), 6.45 (d, J=2.4 Hz, 1H), 6.52 (dd, J=9.4, 2.5 Hz, 1H), 7.83 (d, J=9.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.Br[C:38]1[CH:39]=[N:40][CH:41]=[C:42]([CH:48]=1)[C:43]([N:45]([CH3:47])[CH3:46])=[O:44].C([O-])(O)=O.[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:38]3[CH:39]=[N:40][CH:41]=[C:42]([CH:48]=3)[C:43]([N:45]([CH3:46])[CH3:47])=[O:44])[CH:16]=2)[NH:11][CH:10]=1
Reactant: CN(C)C(=O)c1cncc(Br)c1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cncc(C(=O)N(C)C)c3)cc12
Yield: 56.7 %

Procedure:
Into a 5 mL Personal Chemistry microwave reaction vial were added 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.136 g, 0.270 mmol), 5-Bromo-N,N-dimethyl-nicotinamide (0.0756 g, 0.332 mmol; preparation described below), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (16.2 mg, 0.01 mmol), acetonitrile (2 mL) and saturated aqueous NaHCO3 (2 mL). The vial was sealed, purged with N2, and irradiated in a Personal Chemistry Optimizer at 90° C. for 15 min. The layers were separated, and the aqueous phase was extracted 3× with EtOAc. The combined organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in 3:1 MeOH/acetone (4 mL total) and treated with 500 μL of 50% w/w KOH(aq) for 1 h. Glacial Acetic acid was added to obtain pH 7, then the reaction mixture was concentrated. The residue was partitioned between EtOAc and water, then the layers were separated, and the organic phase was washed 2× with water. The organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. Purification by flash silica gel chromatography using a gradient of ethyl acetate (containing 10% MeOH) and hexanes afforded the title compound as a tan powder (57 mg, 57%). 1H-NMR (500 MHz, d6-DMSO) δ=11.96 (br. s, 1H), 8.95 (d, J=2.5 Hz, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.13 (t, J=2.0 Hz, 1H), 7.72 (d, J=3.0 Hz, 1H), 7.59 (dd, J=2.0, 5.5 Hz, 1H), 7.25 (dd, J=1, 7.5 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.99 (t, J=7.5 Hz, 1H), 3.76 (s, 3H), 2.97 (s, 3H), 2.92 (s, 3H); MS: m/z 373.1 [MH+].
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][O:56][C:57]1[CH:61]=[C:60]([C:62](O)=[O:63])[O:59][N:58]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:62]([C:60]2[O:59][N:58]=[C:57]([O:56][CH3:55])[CH:61]=2)=[O:63])[CH2:49][CH2:48]1
Reactant: COc1cc(C(=O)O)on1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)on1
Yield: 24 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3-methoxyisoxazole-5-carboxylic acid as starting materials in 24% yield. LCMS for C29H30ClN8O4 (M+H)+: m/z=589.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[NH2:21][C:22]1[CH:34]=[CH:33][C:25]2[N:26]([CH3:32])[C:27](=[O:31])[CH2:28][CH2:29][CH2:30][C:24]=2[CH:23]=1.Cl>CC(O)C.O1CCOCC1>[Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:21][C:22]3[CH:34]=[CH:33][C:25]4[N:26]([CH3:32])[C:27](=[O:31])[CH2:28][CH2:29][CH2:30][C:24]=4[CH:23]=3)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6]
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Cl
Yield: 70.1 %

Procedure:
3-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (36.0 mg, 0.109 mmol) and 7-amino-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (22.8 mg, 0.120 mmol) were slurried in iPrOH (1.5 mL) prior to adding ˜0.2 mL of 4N HCl in dioxane. This mixture was heated in a microwave reactor (sealed vessel) at 120° C. for 40 min. The mixture was extracted into DCM, washed with saturated aqueous NaHCO3 solution and the organic layer was dried by passing through a plug of Na2SO4. The resulting filtrate was evaporated and the residue purified by chromatography (silica gel, DCM/5% NH4OH-MeOH gradient). The appropriate fractions were combined and evaporated to afford a solid that was triturated with ether (2×2 mL) and yielded product (37.1 mg, 70%) as a yellow foam that had the following properties: m.p.=145-160° C.; LC/MS (ESI+): 485 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 8.11 (s, 1H), 8.01 (s, 1H), 7.61 (d, 1H, J=8.1), 7.53 (d, 1H, J=8.1), 7.35-7.20 (m, 3H), 6.95 (m, 2H), 6.10 (br s, 1H), 3.38 (s, 3H), 2.83 (d, 3H, J=5.0), 2.55 (m, 2H), 2.24 (m, 2H), 2.09 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[S:10][C:9]2[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[C:7]=1[C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]([F:37])([F:36])[C:29]1[C:33]([CH:34]=[O:35])=[CH:32][NH:31][N:30]=1.Cl>CN(C=O)C.O>[CH:34]([C:33]1[C:29]([C:28]([F:37])([F:27])[F:36])=[N:30][N:31]([CH2:2][C:3]([NH:5][C:6]2[S:10][C:9]3[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=3[C:7]=2[C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])=[O:4])[CH:32]=1)=[O:35]
Reactant: O=Cc1c[nH]nc1C(F)(F)F
Reactant: O=C(CBr)Nc1sc2c(c1C(=O)NCCO)CCCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)nc1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.42 h
Yield: 49 %

Procedure:
2-(2-Bromoacetamido)-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (2.91 g, 8.06 mmol) was dissolved in DMF (25 mL) and potassium carbonate (2.23 g, 16.11 mmol), followed by 3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (1.39 g, 8.46 mmol), added. The mixture was stirred at 60° C. for 25 min after which time the reaction mixture was diluted with water (˜800 mL), then acidified with 5 N HCl until pH 1. During acidification a free flowing solid was obtained which was collected by filtration. NMR analysis indicated ˜60-70% purity of desired product. The solid was successfully triturated with a mixture of DCM/ether to give a light beige solid which was collected by filtration. The mother liquor was concentrated and a second batch obtained using a similar process. The batches were combined to yield the title product (1.76 g, 3.95 mmol, 49%).
Reaction SMILES: [F:1][C:2]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][N:19](C(OCCCC)=O)[CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][CH2:30][CH2:31][CH2:32][OH:33])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][CH2:30][CH2:31][CH2:32][OH:33])[N:7]=1
Reactant: CCCCOC(=O)N1CCN(S(=O)(=O)Nc2cc(OCCCO)nc(SCc3cccc(F)c3F)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(OCCCO)nc(SCc2cccc(F)c2F)n1)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tent-butyl 4-({[2-[(2,3-difluorobenzyl)thio]-6-(3-hydroxypropoxy)pyrimidin-4-yl]amino}sulfonyl)piperazine-1-carboxylate (the product from step ii), 0.83 g) in DCM (5 ml) was added TFA (5 ml) slowly. The reaction was then stirred at room temperature for 18 h. The reaction was reduced in vacuo and the residue purified by prep HPLC to give the title compound as a white solid. Yield 160 mg
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH:25][CH2:26][CH3:27].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH2:10]([O:28][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH:25][CH2:26][CH3:27]
Reactant: CCC=CCC=CCC=CCCCCCCCCO
Reactant: O=C(O)c1ccc(Br)o1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CCC=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)O)o1
Temperature: 110 °C

Procedure:
A mixture of 57.0 g (0.300 mole) of 5-bromo-2-furoic acid, 119.0 g (0.450 mole) of 9,12,15-octadecatrienol, and 84.0 g (0.750 mole) of potassium tert-butoxide in dry toluene is stirred with heating. The tert-butanol formed in the reaction is allowed to distill off and the mixture is refluxed at 110° C with stirring for 48 hours. The mixture is allowed to cool, then is acidified with acetic acid and diluted with ice-water. The toluene organic layer is separated, washed with water, then extracted three times with 5% sodium bicarbonate solution. The combined aqueous extracts are cooled and acidified with 10% HCl solution to give 5-(9,12,15-octadecatrien-1-yloxy)-2-furoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1.Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[N:11]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[C:10]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(Br)c1
Product: Cc1c(Sc2cccc(Br)c2)c2ccc(Cl)cc2n1-c1cccnc1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(3-bromo-phenylsulfanyl)-6-chloro-2-methyl-1H-indole and 3-bromopyridine.
Reaction SMILES: [NH2:1][C:2](=[O:39])[CH:3]([C:5]1[CH:38]=[CH:37][CH:36]=[CH:35][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([Cl:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]2[CH:18]=[N:19][N:20]([CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH:21]=2)[N:10]=1)[CH3:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:14]1[C:9]([CH2:8][CH2:7][C:6]2[CH:35]=[CH:36][CH:37]=[CH:38][C:5]=2[CH:3]([CH3:4])[C:2]([NH2:1])=[O:39])=[N:10][C:11]([NH:16][C:17]2[CH:18]=[N:19][N:20]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:21]=2)=[N:12][CH:13]=1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCNCC3)c2)ncc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26 %

Procedure:
To a stirred solution of tert-butyl 4-(4-(4-(2-(1-amino-1-oxopropan-2-yl)phenethyl)-5-chloropyrimidin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate A32 (0.090 g, 0.162 mmol) in DCM (5 mL) was added TFA (2.0 mL) and the mixture was stirred at room temperature for 1.5 hours. The solvent was removed and the residue was suspended in EtOAc (5 mL) and washed with 1M HCl. The aqueous layer was basified with 1M NaOH and extracted with EtOAc (2×5 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a crude purple oil which was purified by flash chromatography (Combiflash Rf, 0-30% MeOH in DCM) to give the title compound 43 as a red oil (0.019 g, 26% yield). LCMS-C: rt 4.24 min; m/z 454 [M+H]+.
Reaction SMILES: [NH:1]([C:5]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][C:6]=1[CH2:7]Br)[C:2]([CH3:4])=[O:3].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>C(Cl)(Cl)Cl.C(O)C>[NH:1]([C:5]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][C:6]=1[CH2:7][N:20]([CH2:21][CH3:22])[CH2:18][CH3:19])[C:2]([CH3:4])=[O:3]
Reactant: CCOC(=O)c1ccc(NC(C)=O)c(CBr)c1
Reactant: CCNCC
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(NC(C)=O)c(CN(CC)CC)c1

Procedure:
30 gm of 2-acetamino-5-carbethoxy-benzyl bromide were dissolved in a mixture of 400 ml of chloroform and 100 ml of ethanol, and the solution was refluxed with 22 gm of diethylamine for 1 hour. Thereafter, the reaction solution was cooled, then evaporated in vacuo, the residue was distributed between a mixture of dilute ammonia and chloroform, and the chloroform phase was dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silicagel (elution agent: ethyl acetate) and recrystallized from ethanol, yielding 2-acetamino-5-carbethoxy-N,N-diethyl-benzylamine, m.p. 57-59° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9].O[NH:13][C:14](=[NH:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22]>N1C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][N:23]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:13]=1
Reactant: COC(=O)CCCCC(=O)Cl
Reactant: COc1ccccc1C(=N)NO
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CCCCc1nc(-c2ccccc2OC)no1
Yield: 62.1 %

Procedure:
Add 5-chlorocarbonylpentanoic acid methyl ester (15.30 g, 86 mmol) to a solution of N-hydroxy-2-methoxybenzamidine (12.0 g, 71 mmol) in pyridine (40 mL) and under nitrogen at a rate to keep the mixture at a gentle reflux. Then, heat the mixture at reflux for 4 hours. Dilute the mixture with water (300 mL) and extract with methylene chloride (3×200 mL). Wash the combined organic extracts with brine (100 mL), dry over sodium sulfate and remove the solvent under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:19), to afford 5-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]pentanoic acid methyl ester (12.8 g, 55%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18]([CH:20]=[CH:21]N(C)C)=O)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:25][CH3:26])[CH:7]=1)=[O:5])C.Cl.[NH2:28][C:29]([NH2:31])=[NH:30].CC(C)([O-])C.[K+].C(O)(=O)C>C(O)(C)(C)C>[NH2:30][C:29]1[N:31]=[C:18]([C:11]2[CH:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]3[CH2:25][CH3:26])=[CH:13][C:12]=2[F:17])[CH:20]=[CH:21][N:28]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)C=CN(C)C)c(F)cc2c1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3ccnc(N)n3)cc21
Yield: 35.9 %

Procedure:
To 900 mg (2.5 mmol) of the 7-(2'-dimethylaminoethenyl)carbonyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester in 15 ml of t-butanol at 50° C. was added 580 mg (2.5 eq) of guanidine hydrochloride that had been previously treated with 1.35 g (5 eq) of potassium t-butoxide at 50° C. in t-butanol for 30 minutes. The final mixture was stirred for 24 hours at 60° C. It was poured into 8% aqueous acetic acid and extracted into chloroform. The chloroform was extracted three times with water. The chloroform was dried magnesium sulfate and concentrated. The residue was purified by column chromatography and gave 295 mg of 7-(2-amino-4-pyrimidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 245°-247° C.
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13]([CH2:15][NH2:16])[OH:14]>C(O)C>[OH:14][CH2:13][CH2:15][NH:16][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NCCO
Reactant: N#Cc1cccc([N+](=O)[O-])c1Cl
Solvent: CCO
Product: N#Cc1cccc([N+](=O)[O-])c1NCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
2-chloro-3-nitrobenzonitrile (74 g, 0.408 mol) is mixed with ethanol (370 ml) and ethanolamine (57 ml). The mixture is stirred for 16 hrs at room temperature. To complete the reaction, the mixture is refluxed for 2 hours. After cooling, the mixture is concentrated under vacuum; the product precipitates as a red solid. To eliminate the ethanolamine hydrochloride salt, the suspension is triturated with 500 ml of water and filtrated under vacuum. The solid is washed with ethanol and ether then dried to give the desired product (75 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C@@H:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13].C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C@@H:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: C[C@H]1COc2c(ccc(F)c2F)N1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN1c2ccc(F)c(F)c2OC[C@@H]1C)C(=O)OCC
Reaction time: 0.5 h

Procedure:
1.20 g (99.8% ee) of (3S)-7,8-difluoro-3-methyl-3,4-dihydro-2H-[1,4]benzoxazine was dissolved in toluene (0.5 ml). After adding diethyl ethoxymethylenemalonate (1.92 g), the mixture was stirred at 120 for 30 minutes and then at 140° C. under reduced pressure for 30 minutes. The residue was subjected to silica gel column chromatography. Thus, 2.19 g (99.8% ee) of the title compound was obtained as a yellow oily product. The physical constants of the obtained compounds was identical with those described in Japanese Patent No. 2,769,174.
Reaction SMILES: C([N:9]1[C:17]2[CH:16]=[CH:15][C:14](I)=[C:13]3[CH2:19][C@H:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][C@@H:11]([C:12]=23)[CH2:10]1)(=O)C1C=CC=CC=1.C[SiH](C)C.[CH:33]#[CH:34].C[Sn](C)C>C1(C)C=CC=CC=1>[C:33]([C:14]1[CH:15]=[CH:16][C:17]2[NH:9][CH2:10][C@H:11]3[CH2:21][C@@H:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:19][C:13]=1[C:12]=23)#[CH:34]
Reactant: C#C
Reactant: CCCN(CCC)[C@H]1Cc2c(I)ccc3c2[C@H](C1)CN3C(=O)c1ccccc1
Agent: C[SiH](C)C
Agent: C[Sn](C)C
Solvent: Cc1ccccc1
Product: C#Cc1ccc2c3c1C[C@H](N(CCC)CCC)C[C@@H]3CN2
Temperature: 25 °C
Reaction time: 4 h
Yield: 136.4 %

Procedure:
1-benzoyl-(2aS,4R)-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (100 mg, 0.205 mmol) and trimethyltin acetylene trimethylsilane (272 mg, 1.0 mmol, 3 eq) was dissolved in anhydrous toluene (5 mL), to which was then added tetrakis-triphenylphosphine palladium (20 mg, 0.017 mmol, 0.05 eq). The resulting light yellow solution was brought to reflux under N2 atmosphere. After 4 hr, the reaction mixture was cooled to room temperature, filtered and concentrated to dryness. The residue was chromatographed over silica gel with hexanes:ethyl acetate (1:1) to afford the desired product (79 mg, 84%). This material was dissolved in a 1N solution (5 mL) of tetrabutylammonium fluoride in THF, and stirred at room temperature overnight (12 h). The solution was diluted with EtOAc (10 mL) and rinsed successively with H2O (3×10 mL), brine (10 mL) and dried over Na2SO4. The residue was chromatographed over silica gel with hexanes:ethyl acetate (1:1) to afford a mixture of the 1-benzoyl (61%) and the N-deprotected indoline (33%).
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[K+].Br[CH2:26][C:27]#[N:28].O>O1CCCC1>[C:27]([CH2:26][CH:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:16])#[N:28]
Reactant: N#CCBr
Reactant: O=C1CC(c2ccccc2)(c2ccccc2)c2ccccc21
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCC1C(=O)c2ccccc2C1(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
Spiro[3,3-diphenyl-2,3-dihydro(1H)indene-1,3,-2'-cyanooxirane] (Compound 5) and 2-cyanomethyl-3,3-diphenylindanone (Compound 9) were synthesized as follows: 3,3-diphenylindanone (Compound 2), 5.0 g (0.0176 mole) and 2.62 g (0.0229 mole) of potassium hydride were stirred at room temperature in 40 mL of tetrahydrofuran. After the gas evolution subsided (approx. 45 min), 1.5 mL (0.0215 mole) of bromoacetonitrile was added. The dark red mixture was stirred for 1 hour and then 50 mL of water was added. The mixture was extracted three times with 75 mL of ethyl acetate. The combined organic extracts were concentrated in vacuo, loaded onto a silica gel column and eluted with 10% ethyl acetate in hexane. Three fractions were collected. After evaporation of the solvent, the first fraction yielded unreacted starting material (3.5 g). The second fraction yielded 0.49 g (9% yield) of spiro[3,3-diphenyl-2,3-dihydro(1H)indene-1,3'-2'-cyanooxirane] (Compound 5) as a white solid. The third fraction yielded 1.05 g (18% yield) of 2-cyanomethyl-3,3-diphenylindanone (Compound 9) as a yellow oil.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.[CH:17](=O)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Na].C([BH3-])#N>CO.O>[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8]2
Reactant: O=CCCc1ccccc1
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CNCC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na]
Solvent: CO
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(Br)c2c1CN(CCCc1ccccc1)CC2
Reaction time: 6 h
Yield: 93.3 %

Procedure:
A solution of the product from Example 5 (1 g, 3.24 mmol) and hydrocinnamaldehyde (0.94 g, 7 mmol) in 2:1 MeOH/H2O (50 mL) was treated with sodium i 15 cyanoborohydride (0.56 g, 9 mmol) portionwise under nitrogen and stirred for six hours. The solvent was decanted and the semi-solid was dissolved in dichloromethane, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude compound was chromatographed on silica gel (eluted with 25% ethyl acetate in hexane) to give the title compound (1.18 g, 94% yield) as a brown oil.