Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[N+:8]([C:11]1[C:16](C)=[CH:15][N+:14]([O-])=[C:13](C)[C:12]=1[CH3:20])([O-:10])=[O:9].C(O)(=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.CO>[OH:7][CH2:5][C:6]1[C:16]([CH3:15])=[C:11]([N+:8]([O-:10])=[O:9])[C:12]([CH3:20])=[CH:13][N:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cnc(CO)c(C)c1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 4 h

Procedure:
151.3 gms (1.4833 mole) of acetic anhydride was added at 45-50° C. to a mixture of 90.0 gm (o.4595 moles) of 4-nitro-2,3,5-trimethylpyridine-N-oxide of formula-IV and 45.0 gms of acetic acid and heated to 85° C. and maintained at the temperature at 85-90° C. for 4 hrs. 75 ml of methanol was added to the reaction mixture at room temperature and distilled off acetic acid and methanol at temperature of 60-65° C. under vacuum to get an oil. 40% Sodium hydroxide solution (240 g) was added to the cooled oil at 0-5°°C. and stirred for 4 hrs. The crude product was obtained by extraction of the reaction mass with methylene chloride and distillation of the solvent. Pure 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine of formula-II was obtained by re-crystallization of the crude material in toluene.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].CO[Na].[Br:8][C:9]1[CH:28]=[CH:27][C:12]2[O:13]C[CH:15](C3C=CC=CC=3)[CH2:16][C:17](=[N:18][C:19]#[N:20])[C:11]=2[CH:10]=1>CO>[Br:8][C:9]1[CH:10]=[C:11]2[C:17]3([O:4][N:3]([CH3:2])[C:19]([NH2:20])=[N:18]3)[CH2:16][CH2:15][O:13][C:12]2=[CH:27][CH:28]=1
Reactant: N#CN=C1CC(c2ccccc2)COc2ccc(Br)cc21
Reactant: CNO
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: CN1OC2(CCOc3ccc(Br)cc32)N=C1N
Reaction time: 0.17 h
Yield: 93.9 %

Procedure:
To a solution of N-methyl-hydroxylamine hydrochloride (42 mg, 0.5 mmol) in MeOH (10 mL) was added MeONa (0.1 mL, 25% (Wt.) in MeOH), followed by N-(7-bromo-3-phenyl-3,4-dihydrobenzo[b]oxepin-5(2H)-ylidene)cyanamide (170 mg, 0.5 mmol). After stirred for 10 minutes, the solvent was removed in vacuo. The residue was purified by preparative TLC to give 6-bromo-2′-methyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (140 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=O)[CH2:21][C:22]([O:24][CH3:25])=[O:23])(=[O:13])=[O:12].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-]>CO>[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:8][C:3]2[C:2](=[CH:7][CH:6]=[CH:5][N:4]=2)[N:1]=1)(=[O:13])=[O:12]
Reactant: COC(=O)CC(=O)c1ccccc1S(C)(=O)=O
Reactant: Nc1cccnc1C=O
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2ncccc2nc1-c1ccccc1S(C)(=O)=O
Temperature: 100 °C
Yield: 26 %

Procedure:
A mixture of 3-aminopicolinaldehyde (1.09 g, 8.97 mmol), methyl 3-(2-(methylsulfonyl)phenyl)-3-oxopropanoate (2.3 g, 8.97 mmol) and cerium chloride heptahydrate (587 mg, 1.79 mmol) was heated to 100° C. for 3 h. The residue was dissolved in MeOH and purified by column chromatography on neutral alumina using 0-50% EtOAc in hexane to give methyl 2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridine-3-carboxylate (800 mg, 26% yield): 1H NMR (400 MHz, DMSO-d6) δ 3.155 (s, 3H), 3.688 (s, 3H), 7.486-7.507 (m, 1H), 7.733-7.816 (m, 2H), 7.951-7.982 (m, 1H), 8.059-8.081 (m, 1H), 8.510 (d, J=8.4 Hz, 1H), 8.965 (s, 1H), 9.165-9.178 (m, 1H); LC-MS (ESI) m/z 342.9 [M+H]+.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][C:39]=1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:17][NH:18][C:19]1[N:23]([C@@H:24]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]2[OH:26])[C:22]2[CH:33]=[CH:34][CH:35]=[CH:36][C:21]=2[N:20]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][C:39]=1[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:17][NH:18][C:19]1[N:23]([C@@H:24]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]2[OH:26])[C:22]2[CH:33]=[CH:34][CH:35]=[CH:36][C:21]=2[N:20]=1
Reactant: OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4ccccc4)c(OCCCCOCc4ccccc4)c3)nc3ccccc32)[C@H](O)[C@@H]1O
Agent: [Pd]
Solvent: CCO
Product: OCCCCOc1cc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)ccc1-c1ccccc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 70.4 %

Procedure:
2-[3-(4-Benzyloxybutoxy)-4-phenylbenzylamino]-1-(β-D-ribofuranosyl)-1H-benzimidazole (35 mg) was dissolved in ethanol (5 mL). To the solution was added a catalytic amount of 10% palladium-carbon powder, and the mixture was stirred at 60° C. under a hydrogen atmosphere for 24 hour. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (21 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([C:18]2([OH:23])[CH2:22][O:21][CH2:20][CH2:19]2)[CH:14]=[C:15]([F:17])[CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:24]I>O1CCCC1>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([C:18]2([O:23][CH3:24])[CH2:22][O:21][CH2:20][CH2:19]2)[CH:14]=[C:15]([F:17])[CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: OC1(c2cc(F)cc(OCc3ccccc3)c2)CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2cc(F)cc(OCc3ccccc3)c2)CCOC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% w/w dispersion in mineral oil, 1.3 g) was added to a solution of 4-(3-benzyloxy-5-fluorophenyl)-4-hydroxytetrahydrofuran (9.1 g) in tetrahydrofuran (30 ml). The mixture was stirred at room temperature for about 1 hour then cooled to about 0° C. with an ice-bath. Methyl iodide (4 ml) was added and the mixture stirred at room temperature for about 20 hours. The mixture was quenched with aqueous 10% hydrochloric acid (1 ml) and the tetrahydrofuran was evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was separated, dried over sodium sulfate and evaporated to give 5.9 g of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2([C:21]([O:23][CH3:24])=[O:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:2]2[C:3]([C:8]3([C:21]([O:23][CH3:24])=[O:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:37][CH:36]=1
Reactant: COC(=O)C1(c2nccnc2Cl)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C1(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Yield: 39.3 %

Procedure:
To a vial with 1-tert-butyl 4-methyl 4-(3-chloropyrazin-2-yl)piperidine-1,4-dicarboxylate (58 mg, 0.163 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (39.5 mg, 0.163 mmol), and cesium carbonate (106 mg, 0.326 mmol) under N2 is added DMSO (1.0 mL). The reaction is heated to 100° C. in an oil bath 3 h. The reaction was cooled to rt, added to H2O (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by RPHPLC to give 1-tert-butyl 4-methyl 4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidine-1,4-dicarboxylate (36 mg, 0.064 mmol, 39.3% yield) as a white solid. [M+1]=562.1. IC50 (uM) +++++.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[O:4][C:5]2[C:6](=[C:8]([C:13]([O-:15])=O)[CH:9]=[C:10]([Cl:12])[CH:11]=2)[N:7]=1.[Li+].Cl.Cl.[NH2:20][C@H:21]1[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1>>[N:23]12[CH2:22][C@@H:21]([NH:20][C:13]([C:8]3[CH:9]=[C:10]([Cl:12])[CH:11]=[C:5]4[O:4][C:3]([N:2]([CH3:1])[CH3:16])=[N:7][C:6]=34)=[O:15])[CH:26]([CH2:27][CH2:28]1)[CH2:25][CH2:24]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: CN(C)c1nc2c(C(=O)[O-])cc(Cl)cc2o1
Agent: Cl
Agent: [Li+]
Product: CN(C)c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cc(Cl)cc2o1

Procedure:
Following general procedure GP-C1, lithium 2-(dimethylamino)-6-chlorobenzoxazole-4-carboxylate and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-6-chloro-2-(dimethylamino)benzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][NH:15][CH3:16].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:15]([CH3:16])[CH3:14])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Reactant: CNC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CN(C)C(=O)C1(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Bromophenyl)cyclopropanecarboxylic acid (247, 1.00 g, 4.15 mmol) was dissolved in 10 mL DMF and 90 mL dioxane. To it were added dimethylamine (2M in THF, 10.4 mL, 20.7 mmol) and then PyBOP (4.32 g, 8.30 mmol). The mixture was stirred at RT for 2 hours, concentrated in vacuo, diluted with 100 mL EtOAc, washed with water ×3, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 3% MeOH in DCM to isolate 1-(4-bromophenyl)-N,N-dimethylcyclopropanecarboxamide (248) in quantitative yield. It was dissolved in 100 mL dioxane. To the solution were added tert-butyl carbamate (2.91 g, 24.9 mmol), Pd2(dba)3 (760 mg, 0.83 mmol), XantPhos (1.44 g, 2.49 mmol), fine-powder cesium carbonate (8.12 g, 24.9 mmol). The mixture was degassed using N2 stream for 5 min, and stirred under N2 atmosphere at 115° C. for 2 days. It was cooled to RT, concentrated in vacuo, diluted with 200 mL EtOAc, washed with water ×3, dried, concentrated, and subjected to silica flash column to isolate tert-butyl 4-(1-(dimethylcarbamoyl)cyclopropyl)phenylcarbamate (249, 600 mg). It was treated with 20 mL commercial 4N HCl in dioxane at RT for 1.5 hour. The mixture was concentrated in vacuo to dryness to give 1-(4-aminophenyl)-N,N-dimethylcyclopropanecarboxamide (250) as HCl salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH:12]=[CH2:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[C:18]([CH2:22]Cl)=[CH:17][N:16]=1.C(N1C2C=CC=CC=2C=CC2N=C(Cl)C(F)=CC=2C1)(=O)C>>[C:9]([N:8]1[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH:12]=[CH:13][C:19]2[CH:20]=[C:15]([Cl:14])[N:16]=[CH:17][C:18]=2[CH2:22]1)(=[O:11])[CH3:10]
Reactant: ClCc1cnc(Cl)cc1Cl
Reactant: C=Cc1cc(Cl)ccc1NC(C)=O
Agent: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2cnc(Cl)cc2C=Cc2cc(Cl)ccc21
Yield: 51.7 %

Procedure:
The title compound (67.6 mg, 52%) was prepared from 9B (80 mg, 0.41 mmol) and 41B (80 mg, 0.41 mmol) in two steps by a route analogous to that used for the preparation of 1D. HPLC Rt=2.886 min; LCMS Found: (M+H)+=319.
Reaction SMILES: [ClH:1].C([O:6][C:7](=[O:35])[CH2:8][N:9]([S:17]([C:20]1[CH:29]=[C:28]2[C:23]([C:24]([Cl:34])=[CH:25][N:26]=[C:27]2[NH:30][C:31]([NH2:33])=[NH:32])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)(C)(C)C>O1CCOCC1>[ClH:34].[ClH:1].[Cl:34][C:24]1[C:23]2[C:28](=[CH:29][C:20]([S:17]([N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:8][C:7]([OH:35])=[O:6])(=[O:18])=[O:19])=[CH:21][CH:22]=2)[C:27]([NH:30][C:31]([NH2:33])=[NH:32])=[N:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)CN(Cc1ccccn1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)Cc3ccccn3)cc12
Temperature: 60 °C
Yield: 145.2 %

Procedure:
A solution of HCl (3 mL, 2 M, 6 mmol) was added to a solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(2-pyridylmethyl)glycine t-butyl ester (115 mg, 0.23 mmol) in dioxane (5.0 mL) and the mixture was heated at 60° C. for 18 h. The solvents were evaporated in vacuo and the residue triturated with hot EtOAc to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(2-pyridylmethyl)glycine dihydrochloride (95 mg, 0.167 mmol) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[O:10]1[CH2:15][CH:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C@H:25]([CH2:27]OS(C)(=O)=O)[O:24][C:23]3=[O:33])=[CH:18][C:17]=2[F:34])[CH2:12][CH2:11]1>CN(C)C=O>[O:10]1[CH2:11][CH:12]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C@H:25]([CH2:27][N:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]4=[O:1])[O:24][C:23]3=[O:33])=[CH:18][C:17]=2[F:34])[CH2:14][CH2:15]1
Reactant: Oc1ccccn1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCOCC3)c(F)c2)C(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1O[C@@H](Cn2ccccc2=O)CN1c1ccc(C2=CCOCC2)c(F)c1
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
2-Hydroxypyridine (108 mg, 1.14 mM) was added at room temperature, under an atmosphere of nitrogen, to a stirred suspension of sodium hydride (60% dispersion in oil, 48 mg, 1.2 mM) in N,N-dimethylformamide (5 ml). The reaction was stirred for 30 minutes then (5R)-3-(4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl)-5-methanesulfonyloxymethyloxazolidin-2-one (400 mg, 1.08 mM; WO 97-09328) was added in one portion. The mixture was stirred and heated at 60° for 5 hour before quenching in water (20 ml) and extracting with ethyl acetate. The extract was washed twice with water and once with saturated brine, dried (magnesium sulfate) and evaporated to an orange oil, which was purified by flash chromatography on silica, eluting with 2.5% methanol in dichloromethane to give the title compound (115 mg) as a colourless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C([O:21][C:22]([N:24]1[CH:29]2CC[CH:25]1[CH2:26]C(=O)[CH2:28]2)=O)(C)(C)C.[Br:33][C:34]1[CH:35]=[CH:36][C:37]2[C:38](=[C:48]3[CH2:54][CH:53]4[NH:55][CH:50]([CH2:51][CH2:52]4)[CH2:49]3)[C:39]3[C:44]([O:45][C:46]=2[CH:47]=1)=[CH:43][CH:42]=[CH:41][CH:40]=3>>[CH2:25]([N:24]([CH2:29][CH3:28])[C:22]([C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:21])[CH3:26].[Br:33][C:34]1[CH:35]=[CH:36][C:37]2[C:38](=[C:48]3[CH2:54][CH:53]4[NH:55][CH:50]([CH2:51][CH2:52]4)[CH2:49]3)[C:39]3[C:44]([O:45][C:46]=2[CH:47]=1)=[CH:43][CH:42]=[CH:41][CH:40]=3
Reactant: O=c1c2ccccc2oc2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: Brc1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2
Product: CCN(CC)C(=O)c1ccc2c(=O)c3ccccc3oc2c1

Procedure:
Using an adaptation of the method described in Procedure 7, substituting 3-bromo-xanthen-9-one, 3a, for 9-oxo-9H-xanthene-3-carboxylic acid diethylamide, 6a (13.69, 46 mmol) and 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester for N-carbethoxynortropinone, the title compound 3-(3-bromo-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]octane, 1b was obtained. MS m/z (MH+) 368.0/370.0
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:17])[CH2:13][C:14]([CH3:16])=O)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[NH2:19][C:20]([NH2:22])=[S:21].S(Cl)(Cl)(=O)=O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[C:6]([NH:11][C:12]([C:13]3[S:21][C:20]([NH2:22])=[N:19][C:14]=3[CH3:16])=[O:17])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC(N)=S
Reactant: CC(=O)CC(=O)Nc1cccc2c1CCC2(C)C
Solvent: c1ccccc1
Solvent: O=S(=O)(Cl)Cl
Product: Cc1nc(N)sc1C(=O)Nc1cccc2c1CCC2(C)C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
1.00 g (4.08 mmol) of N-(1,1-dimethyl-4-indanyl)acetoacetamide and 0.62 g (8.16 mmol) of thiourea were dissolved in 10 ml of benzene and to this solution was added dropwise a solution of 0.55 g (4.08 mmol) of sulfuryl chloride in 5 ml of benzene at room temperature. After reacting for 2 hours at this temperature, the reaction mixture was refluxed for 1 hour, and left overnight. Then, the resulting solution was concentrated and dissolved in hot water and thereafter neutralyzed with 28% aqueous ammonia to give a precipitate. This precipitate was filtered, washed with water and dried to obtain 1.00 g of N-(1,1-dimethyl-4-indanyl)-2-amino-4-methylthiazole-5-carboxamide (yield 81%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1>[CH2:19]([C:18]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:9]([OH:10])[C:11]2[C:12]([CH:17]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC#Cc1ccccc1C(=O)Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCc1cc2ccccc2c(O)c1-c1ccc(F)cc1
Yield: 68.5 %

Procedure:
A solution of 2-(4-fluorophenyl)-1-[2-(1-hexyn-1-yl)phenyl]ethanone (165) (0.37 g, 1.24 mmol) in toluene was treated with a KHMDS solution in toluene to give 0.25 g (69%) of the title compound (166) as a yellow solid upon standing. 1H NMR (400 MHz, CDCl3): δ 0.77 (t, J=7.3 Hz, 3H), 1.15-1.30 (m, 2H), 1.35-1.50 (m, 2H), 2.47 (t, J=7.9 Hz, 2H), 5.10 (s, 1H), 7.20-7.28 (m, 2H), 7.30-7.37 (m, 3H), 7.40-7.50 (m, 2H), 7.75 (d, J=8.0 Hz, 1H), 8.17 (d, J=8.4 Hz, 1H). LCMS (APCI): m/z 295 (M+H) t.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:2]=1.[N:20]([CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])=[O:25])=[N+]=[N-].C(Cl)(=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[CH:23][N:20]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: [N-]=[N+]=NCC(=O)c1ccccc1[N+](=O)[O-]
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Product: Cc1ncc(-c2ccccc2[N+](=O)[O-])o1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Triphenylphosphine, polymer bound, (5.3 g, 3 mmol/g, Fluka Chimica, Buchs, Switzerland) was scurried in toluene (75 mL). A solution of 2-azido-2′-nitroacetophenone (2.18 g, 10.6 mmol) and acetyl chloride (0.848 g, 10.8 mmol) in toluene (25 mL) was added at room temperature, under a nitrogen atmosphere. The solution was stirred at room temperature for six hours, then filtered over celite. All volatiles were removed from the filtrate by evaporation under reduced pressure to yield 0.91 g of crude 2-methyl-5-(2-nitrophenyl)oxazole. Crude 2-methyl-5-(2-nitrophenyl)oxazole (0.905 g, 4.44 mmol) was reduced as in Example 64, and the product purified by silica chromatography to give 0.51 g of 5-(2-aminophenyl)-2-methyloxazole.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([C@@H:52]5[CH2:56][CH2:55][CH2:54][N:53]5[CH3:57])=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si](C(C)C)(C(C)C)C(C)C)=[C:12]([Cl:27])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([C@@H:52]5[CH2:56][CH2:55][CH2:54][N:53]5[CH3:57])=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:27])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCN5C)n4c3)c3ccccc32)cc1Cl)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(O)c(Cl)c4)c4ccccc43)cn12
Yield: 68.1 %

Procedure:
A solution of Intermediate 50a (280 mg, 0.345 mmol) and TBAF (1M in THF, 0.41 mL, 0.41 mmol) in THF (3 mL) was stirred at RT for 0.5 h. Water was added and the mixture extracted with DCM (3×15 mL). The combined organics were concentrated in vacuo. The residue was purified by FCC, using 0-14% MeOH in DCM, to give the title compound (154 mg, 68%). LCMS (Method 5): Rt 3.52 min, m/z 655.2 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.82-2.26 (11H, m), 2.31-2.39 (1H, m), 3.10-3.16 (1H, m), 3.99 (1H, d, J=8.2 Hz), 4.77-4.85 (1H, m), 5.35-5.42 (1H, m), 6.28 (1H, s), 7.03-7.10 (2H, m), 7.22-7.38 (6H, m), 7.43 (1H, d, J=2.5 Hz), 7.75 (1H, dd, J=9.9 Hz), 7.99 (1H, s), 8.24 (1H, br d), 10.56 (1H, v br).
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[C:5]([F:11])[CH:4]=1.[OH2:13]>CCO.[N+]([O-])([O-])=O.[Ag+]>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[O:13])=[CH:4][C:5]=1[F:11])#[N:10]
Reactant: O
Reactant: N#Cc1ccc(C(Br)Br)cc1F
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: N#Cc1ccc(C=O)cc1F
Reaction time: 18 h

Procedure:
To a solution of α,α-dibromo-4-cyano-3-fluorotoluene, as described above in Step B, (5.60 g, 19.1 mmol) in EtOH (255 mL) and water (45 mL) was added AgNO3. The mixture was heated to reflux for 3 hrs, then stood at ambient temperature for 18 hrs, then the solid was removed by filtration and the filtrate was concentrated under reduced pressure to a volume of approximately 20 mL. Water (30 mL) was added, and the mixture was concentrated to dryness in vacuo. The residue was partitioned between sat. aq. NaHCO3 (20 mL) and CH2Cl2 (50 mL). The aqueous layer was extracted further with CH2Cl2 (2×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dried for several days at ca. 0.5 mm Hg to yield the desired aldehyde as a pale solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]2[NH:11][CH:12]=[C:13]([CH:14]=[O:15])[C:7]=2[CH:6]=1>CO.C1COCC1.O.C(=O)([O-])[O-].[K+].[K+]>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][CH:12]=[C:13]2[CH2:14][OH:15]
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2[nH]cc(CO)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
To a solution of sodium borohydride (2 grams, 0.05 mol) in methanol (15 ml), a solution of 5-methoxy-1H-indol-3-carboxaldehyde 2 (1 gram, 0.006 mol) dissolved in THF (20 ml) and methanol (15 ml) were combined and stirred at ambient temperature for 16 hours. The reaction was diluted with water and potassium carbonate (to saturation) and stirred to quench unreacted sodium borohydride. Diethyl ether was used to extract the product from the quenched solution. Following layers separation, the aqueous layer was further extracted (2×) with diethyl ether. The combined organic pats were dried over sodium sulfate and evaporated to dryness to yield a light colored solid 141 (736 mg, 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:12](=[O:13])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:25][CH2:24]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(F)ccc2[N+](=O)[O-])CC1
Yield: 93 %

Procedure:
Method 1 was followed using 1 eq each of 1,3-difluoro-4-nitrobenzene, 4-(N-Boc-amino) piperidine, and TEA yielding tert-butyl 1-(5-fluoro-2-nitrophenyl)-piperidin-4-ylcarbamate (93%). LCMS (m/z): 340.1 (MH+); LC Rt=3.24 min.