Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[S:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:14]=2[CH3:15])[CH2:17][CH2:18]1)(=[O:23])=[O:24]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3ccccc3Cl)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
To a clear, almost colorless solution of {4-[1-(2-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (108 mg, 0.23 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (106 mg, 4.4 mmol) in water (2.0 mL) The mixture was heated with a heat gun to give a clear solution. The resulting solution was stirred for 15 hours at room temperature. The solvent was removed under vacuum. The residue was diluted with water (˜20 mL) and the mixture was neutralized with 1.0 N HCl. The precipitated white solids were collected by filtration and washed with water and hexanes. After air drying, {4-[1-(2-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (93 mg, 87%) was isolated as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.42 (br. s, 1H), 8.07 (d, J=7.53 Hz, 2H), 783-7.96 (m, 1H), 7.65-7.82 (m, 3H), 7.56-7.64 (m, 1H), 7.28-7.40 (m, 1H), 3.91 (d, J=11.29 Hz, 4H), 3.76 (br. s, 3H), 3.05 (br. s, 2H), 2.36 (s, 3H), 1.68 (d, J=12.3 Hz, 2H). MS cald. for C24H24ClFNO4S [(M+H)+] 476, obsd. 476.1.
Reaction SMILES: Cl.[N+:2]([C:5]1[C:6]([NH:15][C:16](=O)[CH2:17][CH2:18][CH2:19][CH3:20])=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([O-])=O>[Fe].CO>[CH2:17]([C:16]1[NH:15][C:6]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=[CH:14][C:5]=2[N:2]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC(=O)Nc1c(C(=O)OC)cccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: CCCCc1nc2cccc(C(=O)OC)c2[nH]1
Temperature: 25 °C
Yield: 69 %

Procedure:
To a mixture of conc. HCl (5.3 ml) and methanol (35 ml) was added methyl 3-nitro-2-(N-valerylamino)benzoate (2.8 g), to which was added iron powder (1.7 g) in portions while stirring at room temperature. The resultant mixture was heated for 8 hours under reflux. Insoluble material was filtered off, and the filtrate was concentrated. To the concentrate were added water and ethyl acetate. The aqueous layer was made basic with 6N NaOH and was extracted with ethyl acetate. The organic layers were combined, washed with water and dried. The solvent was evaporated, and the residue was purified by column chromatography on silica gel. The crystals thus obtained were recrystallized from isopropyl ether to give colorless needles (1.6 g, 70%), m.p. 97°-98° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:26])=[C:19]([CH:27]([CH3:29])[CH3:28])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:35][O:34][C:32](=[O:33])[CH2:31][O:26][C:20]1[C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:17]([C:9]2[C:10]3[C:14]([CH3:15])=[C:13]([CH3:16])[S:12][C:11]=3[C:2]([Br:1])=[C:3]3[C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]3)=[CH:18][C:19]=1[CH:27]([CH3:29])[CH3:28]
Reactant: COC(=O)CBr
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3cc(C(C)C)c(O)c(C(C)C)c3)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1c(C(C)C)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C(C)C
Yield: 87.5 %

Procedure:
A solution of 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenol (0.42 g, 0.89 mmol), methyl bromoacetate (0.36 mL, 3.8 mmol), and potassium carbonate (0.42 g, 3.0 mmol) in anhydrous N,N-dimethylformamide (3.5 mL) at room temperature under nitrogen was stirred for 2 days. The reaction mixture was diluted with water and extracted with diethyl ether. Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (95:5) gave the title compound as a white solid (0.42 g, 87%): NMR (DMSO-d6): δ8.20 (d, 1H), 7.66-7.61 (m, 1H), 7.48 (d, 2H), 7.11 (s, 2H), 4.56 (s, 2H), 3.77 (s, 3H), 3.42-3.27 (m, 2H), 2.42 (s, 3H), 1.51 (s, 3H), 1.18 and 1.16 (two doublets, 12H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH2:9][NH:10][C:11](=O)[O:12]CC)=[CH:6][CH:5]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:17]=[C:16]2[C:7]([CH2:8][CH2:9][NH:10][C:11]2=[O:12])=[CH:6][CH:5]=1
Reactant: CCOC(=O)NCCc1ccc(OC(F)(F)F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2ccc(OC(F)(F)F)cc21
Temperature: 110 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
Using an analogous procedure and workup as described for the preparation of intermediate I-1d above, ethyl 4-(trifluoromethoxy)phenethylcarbamate (I-51c: 3.2 g, 11.5523 mmol) in POCl3 (32 mL) was reacted with P2O5 (3.27 g, 23.104 mmol). The resulting mixture was stirred at 110° C. for 1 hour to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in DCM) afforded 110 mg of the product (4.1% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][CH3:10]>C1COCC1>[CH3:8][N:9]([CH3:10])[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccn1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-chloropyrimidine (5g, 43.65mmol) in dry THF (50ml) is saturated with gaseous dimethylamine. The mixture is stirred at ambient temperature for 1 hour followed by evaporation of solvent. The residue is partitioned between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated to leave the product as a brownish oil. Yield 5.07g (94%).
Reaction SMILES: CC([CH:5]([N:25]([C:29]([C:31]1[N:35](COCC[Si](C)(C)C)[CH:34]=[N:33][C:32]=1[Cl:44])=[O:30])C(=O)[O-])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[C:16]([C:22]#[N:23])[CH:15]=2)[C:7]=1[F:24])(C)C.[B-](F)(F)(F)F.[CH3:50]C[O+](CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:44][C:32]1[N:33]([CH3:50])[CH:34]=[N:35][C:31]=1[C:29]([NH:25][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[C:16]([C:22]#[N:23])[CH:15]=2)[C:7]=1[F:24])=[O:30]
Reactant: CC(C)(C)C(c1ccc(Cl)c(Oc2cc(C#N)cc(CO)c2)c1F)N(C(=O)[O-])C(=O)c1c(Cl)ncn1COCC[Si](C)(C)C
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cnc(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(CO)c3)c2F)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
To a solution of 1,1-dimethylethyl[(4-chloro-3-{[3-cyano-5-(hydroxymethyl)phenyl]oxy}-2-fluorophenyl)methyl]{[4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazol-5-yl]carbonyl}carbamate (66 mg, 0.099 mmol) in DCM (5 ml) was added Meerwein's reagent (16.13 mg, 0.109 mmol) and the reaction mixture was stirred for 4 hours at RT. TFA (2.0 ml, 26.0 mmol) was added and the reaction mixture was stirred at RT for another 2 hours. The solvent was removed and the crude material was purified via reverse phase HPLC to give the title compound (34 mg, 76% yield). 1H NMR (DMSO-d6) δ ppm 8.66 (t, 1H) 7.87 (s, 1H) 7.44-7.57 (m, 2H) 7.25-7.39 (m, 2H) 7.19 (s, 1H) 4.51 (s, 2H) 4.45 (d, 2 H) 2.50 (s, 3H). LC-MS (ES+) m/z 449.11 [M+H].
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])/[C:9]1=[O:24])=O)(C)(C)C.[Cl:25][C:26]1[CH:27]=[C:28](/[CH:32]=[N:33]/[CH2:34][Si](C)(C)C)[CH:29]=[CH:30][CH:31]=1.C(O)(=O)C.O>CN(C)P(N(C)C)(N(C)C)=O>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:24])[C:10]3([CH:18]([CH2:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:34][NH:33][CH:32]3[C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=3)[C:11]2=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)C/N=C/c1cccc(Cl)c1
Reactant: CC(C)(C)C/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)CC1CNC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of E/Z-6-chloro-3-(3,3-dimethyl-butylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 4 (2.4 g, 6.9 mmol) in hexamethylphosphoramide (30 mL) was added [1-(3-chloro-phenyl)-meth-(E)-ylidene]-trimethylsilanylmethyl-amine prepared in Example 14 (3 g, 13 mmol), acetic acid (0.6 g, 10 mmol) and H2O (0.2 g, 11 mmol) sequentially. The reaction mixture was stirred at room temperature for 24 h. Water was added. The mixture was extracted with ethyl acetate. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water twice, dried over MgSO4, then concentrated. The residue was dissolved into dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and aqueous saturated NaHCO3 solution. The organic layer was separated, dried over MgSO4, then concentrated. The residue was purified by chromatography (50-75% EtOAc in hexanes) to give rac-(2′R,3′S,4′S)-6-chloro-2′-(3-chloro-phenyl)-4′-(2,2-dimethyl-propyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one as a white solid (Yield, 0.8 g, 29%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:25]([Sn](CCCC)(CCCC)CCCC)=[N+:26]=[N-:27]>C1(C)C=CC=CC=1>[N:25]1[NH:26][N:27]=[N:18][C:17]=1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Solvent: Cc1ccccc1
Product: Nc1cccc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)c1

Procedure:
The title compound was prepared from 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.273 g, 0.86 mmol), azidotributyl tin (0.314 g, 0.260 mL, 0.95 mmol) in toluene (10 mL). The reaction mixture was heated to reflux temperature for 12 hours resulting in partial conversion to the desired product along with partially and fully deprotected final products. An additional amount of azidotributyl tin was added (0.260 mL) and the reaction was heated to reflux temperature for 18 hours. Toluene was removed under reduced pressure and the crude was dissolved in 5 mL of 1,4-dioxane, 5 mL of 6.0 N aqueous hydrogen chloride, and 2 mL of methanol. The reaction was then heated to 60° C. for 2 days. The reaction was concentrated under reduced pressure and the pH was made basic by adding 2.0 N aqueous NaOH. The aqueous phase was washed with ethyl acetate (3×10 mL). The aqueous phase was then acidified using 6.0 N aqueous hydrogen chloride. The compound was filtered and purified by preparative HPLC (10–100% acetonitrile in H2O, 20 min) (0.050 g, 0.18 mmol, 21% yield over 2 steps): 1H NMR (DMSO-d6) δ 13.8 (br s, 1H), 8.9 (s, 1H), 8.1 (d, 1H), 8.0 (d, 2H), 7.8 (d, 1H), 7.6 (t, 1H), 7.3 (d, 1H); ES-MS (m/z) 278 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)=[N:7][C:6]=2[CH:15]=1.C(N(CC)CC)C.[C:23](Cl)(Cl)=[S:24]>O1CCCC1>[N:1]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)=[N:7][C:6]=2[CH:15]=1)=[C:23]=[S:24]
Reactant: Nc1ccc2sc(-c3cccs3)nc2c1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: S=C=Nc1ccc2sc(-c3cccs3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-2-(2-thienyl)benzothiazole 7.0 g, 0.03 M is dissolved in 400 cc of tetrahydrofuran and 8.4 cc, 0.06 M, of triethylamine. Thiophosgene 2.3 cc, 0.03 M, is added, and the resulting mixture stirred at ambient temperature overnight. The solids which form are filtered, and washed with tetrahydrofuran. The filtrate is concentrated to dryness, and chromatographed on Alumina IV. The product is recrystallized from acetonitrile to yield 5.7 g of colorless needles, 70% of theory, m.p. 147°-149°.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.CC(C)([O-])C.[K+].Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[S:22][CH:23]=1>O1CCCC1>[F:33][C:30]([F:31])([F:32])[C:26]1[CH:25]=[C:24]([C:21]2[S:22][CH:23]=[C:19]([CH2:18][N:1]3[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]3)[N:20]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)cs2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2csc(-c3cccc(C(F)(F)F)c3)n2)c1
Reaction time: 0.33 h
Yield: 71.6 %

Procedure:
To a solution of ethyl 1H-pyrazole-4-carboxylate (140 mg, 1.0 mmol) in tetrahydrofuran (4 mL) was added potassium tert-butoxide (146 mg, 1.30 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 20 min. The compound (278 mg, 1.00 mmol) obtained in Example 21a was added to the reaction mixture, an ice bath was removed and the mixture was stirred for 13 hr. The reaction mixture was further heated under reflux for 1 hr, N,N-dimethylformamide (1 mL) was added and the mixture was stirred at 75° C. for 1.5 hr. The reaction mixture was diluted with water, extracted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (273 mg, 71%) as colorless crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:19]([C:20]3[N:21]=[C:22]([NH:26]C(=O)OC(C)(C)C)[S:23][C:24]=3[CH3:25])=[C:18]3[C:13]([N:14]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:15](=[O:36])[N:16]([CH3:35])[C:17]3=[O:34])=[N:12]2)=[CH:2]1.Cl>O1CCOCC1>[NH2:26][C:22]1[S:23][C:24]([CH3:25])=[C:20]([C:19]2[N:11]([CH2:10][C:3]3[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[S:1][CH:2]=3)[N:12]=[C:13]3[C:18]=2[C:17](=[O:34])[N:16]([CH3:35])[C:15](=[O:36])[N:14]3[CH2:37][CH:38]([CH3:40])[CH3:39])[N:21]=1
Reactant: Cc1sc(NC(=O)OC(C)(C)C)nc1-c1c2c(=O)n(C)c(=O)n(CC(C)C)c2nn1Cc1csc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1sc(N)nc1-c1c2c(=O)n(C)c(=O)n(CC(C)C)c2nn1Cc1csc2ccccc12

Procedure:
This compound was synthesized by treating tert-butyl 4-[2-(1-benzothien-3-ylmethyl)-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-methyl-1,3-thiazol-2-ylcarbamate with 4M HCl in dioxane at room temperature for 2.5 hours. Mass: 481.15 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4](CC2C=CC(C#N)=CC=2)[CH2:3][CH2:2]1.[CH2:16]([O:18]CC)[CH3:17].Cl.[C:22]1([CH3:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C[Mg]Br>[O:1]1[CH2:2][CH2:3][N:4]([CH2:28][C:22]2[CH:27]=[CH:26][C:25]([C:16](=[O:18])[CH3:17])=[CH:24][CH:23]=2)[CH2:5][CH2:6]1
Reactant: Cc1ccccc1
Reactant: N#Cc1ccc(CN2CCOCC2)cc1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: Cl
Product: CC(=O)c1ccc(CN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 0.2 h
Yield: 70 %

Procedure:
To a stirred suspension of 4-(morpholinomethyl)benzonitrile (preparation 5) (1.00 g, 5 mmol) in toluene (19 ml), 3M methyl magnesium bromide in ethyl ether (5 ml, 15 mmol) was added at room temperature under argon. The resulting suspension was refluxed for 4 h, allowed to reach room temperature and then cooled down to 0° C., acidified with 10% HCl and then heated to reflux for 1 h. The two phases were separated and the aqueous phase rinsed with ethyl acetate, then brought to pH 10 with NH4OH and extracted with DCM. The phases were separated and the organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 1 min hold 100% A followed by a 12 min ramp to 2.5% B and then 5 min hold at 2.5% B. The desired fractions were concentrated to dryness under vacuum to obtain the desired compound as a white solid (0.79 g, 3.6 mmol, Yield: 70%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[ClH:30].O1CCOCC1>ClCCl>[ClH:30].[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(NC(=O)c3ccco3)c2)COC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(c2cccc(NC(=O)c3ccco3)c2)COCC(N)=N1
Temperature: 40 °C

Procedure:
A solution of (5-{3-[(furan-2-carbonyl)-amino]-phenyl}-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (39.9 mg, 0.1 mmol) in dichloromethane was treated with 4M HCl in dioxane (40 eq). The mixture was warmed to 40° C. for 10 h and then evaporated under reduced pressure to yield the title compound (hydrochloride salt) in the form of a colourless solid. 1H-NMR (500 MHz, DMSO-d6): 10.65 (1H, NH+), 10.31 (s, 1H), 9.14 (br, 1H), 8.52 (br, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 7.77 (d, 1H), 7.40 (m, 2H), 7.18 (d, 1H), 6.72 (m, 1H), 4.59 (s, 2H), 3.87 (dd, 2H), 1.64 (s, 3H); MS: 300 [(M+H)+].
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=1[C:11]#[N:12].[OH-:20].[Na+].C1(C)C(C)=CC=CC=1>C(O)(=O)C.S(=O)(=O)(O)O.O>[N+:17]([C:14]1[CH:15]=[CH:16][C:9]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:12][C:11](=[O:20])[C:10]=2[CH:13]=1)([O-:19])=[O:18]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2Sc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
2-(2-Aminophenylthio)-5-nitrobenzonitrile (8.5 g, 25 mmol) was dissolved in a mixture of glacial acetic acid (80 ml), concentrated sulphuric acid (100 ml) and water (80 ml) and then heated under reflux for 6 hours. The cooled mixture was added to ice water (500 ml) and brought to pH 4 by addition of 10N aqueous sodium hydroxide. Extraction with dichloromethane followed by filtration, drying (sodium sulphate), and evaporation of the organic layer afforded a residue which was put into xylene (500 ml) and refluxed for 15 hours with azeotropic removal of water. On cooling a brown powder deposited which was filtered off and purified by chromatography on silica gel eluting with 1:1 v/v ethyl acetate-hexane. Recrystallisation from ethanol gave the product as a greyish powder (2.80 g, m/s M- =272).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH2:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].CO[C:27]1[C:32]2[N:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[N:35]=[CH:36][C:31]=2[CH2:30][CH2:29][N:28]=1.CO>C(OCC)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10](=[O:11])[NH:12][NH:13][C:27]1[C:32]2[N:33]=[C:34]([C:37]([F:39])([F:40])[F:38])[N:35]=[CH:36][C:31]=2[CH2:30][CH2:29][N:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)c(F)cc1F
Reactant: COC1=NCCc2cnc(C(F)(F)F)nc21
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NNC1=NCCc2cnc(C(F)(F)F)nc21)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A mixture of 150 mg (0.433 mmol) of tert-butyl[(1R)-3-hydrazino-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (Intermediate 4), 100 mg (0.433 mmol) of 8-methoxy-2-(trifluoromethyl)-5,6-dihydropyrido[3,4-d]pyrimidine (Intermediate 5) and 4 mL of anhydrous methanol was stirred at room temperature for 5.5 h and then diluted with diethyl ether. The solid was collected on a filter and dried to give the title compound. LC-MS 547 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([F:16])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:27]1[C:32]2=[N:33][CH:34]=[CH:35][N:36]=[C:31]2[CH:30]=[C:29]([Cl:37])[N:28]=1>C1COCC1>[Cl:37][C:29]1[N:28]=[C:27]([NH:1][CH2:2][C:3]2([F:16])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:4]2)[C:32]2=[N:33][CH:34]=[CH:35][N:36]=[C:31]2[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(F)(CN)C1
Reactant: Clc1cc2nccnc2c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(F)(CNc2nc(Cl)cc3nccnc23)C1
Yield: 26.8 %

Procedure:
tert-butyl 3-(aminomethyl)-3-fluoropiperidine-1-carboxylate (3.86 g, 16.6 mmol) and DIPEA (3.22 g, 24.9 mmol) were added to a solution of 5,7-dichloropyrido[3,4-b]pyrazine (3.32 g, 16.6 mmol) in THF (60 mL) and the mixture was refluxed overnight. The volatile components were evaporated and the residue was extracted with ethyl acetate. Ethyl acetate was washed with brine and dried. The solvent was removed in vacuo The crude residue was purified by silica-gel chromatography eluting with Hexane-50% EtOAc/Hexane (gradient) then C18 column to afford the subtitled compound as pale yellow solid 1.76 g. MS (m/z): 396 (M+H)+
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[N+:20]([O-])=O)[CH:5]=[C:6]1[C:10](=[O:11])[O:9][C:8]([CH3:12])=[N:7]1.C(OC(=O)C)(=O)C.[H][H]>[Pt].C(O)(=O)C>[CH3:19][C:16]1[CH:15]=[C:14]2[C:13]([C:4](/[CH:5]=[C:6]3\[N:7]=[C:8]([CH3:12])[O:9][C:10]\3=[O:11])=[CH:3][NH:20]2)=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: CC1=NC(=CC(=CN(C)C)c2ccc(C)cc2[N+](=O)[O-])C(=O)O1
Agent: [Pt]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC1=N/C(=C\c2c[nH]c3cc(C)ccc23)C(=O)O1
Yield: 35 %

Procedure:
A 500-ml. Parr bottle was charged with 3.17 g. (10 mmol) of 4-[3-dimethylamino-2-(4-methyl-2-nitrophenyl)-2-propen-1-ylidene]-2-methyl-2-oxazolin-5-one, 5 ml. of acetic anhydride, 95 ml. of glacial acetic acid, and 600 mg. of 10% platinum on charcoal, and was shaken under 3 atmospheres of hydrogen for 12 hours. During this time, 34 mmol of hydrogen were absorbed. The reaction was treated as in Example 4. 0.83 g. (35%) of (Z)-4-(6-methylindol-3-ylmethylene)-2-methyl-2-oxazolin-5-one (mp 194°-196° C.) was thereby obtained.
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[CH:15]1([NH:14][CH2:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:17][CH2:16]1
Reactant: [H][H]
Reactant: c1ccc(CN2CCC(CNC3CC3)C2)cc1
Agent: [Pd]
Solvent: CO
Product: C1CC(CNC2CC2)CN1
Yield: 76.1 %

Procedure:
A mixture of 13.6 g (59.0 mmol) of 1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinemethanamine, 0.5 g of 20% palladium on carbon and 140 ml of methanol was shaken in an atmosphere of hydrogen at about 4.5×105Pa and room temperature for 24 hours. The catalyst was removed by filtering through Celite, the filtrate concentrated and distilled in vacuo to give 6.3 g of N-cyclopropyl-3-pyrrolidinemethanamine, bp 88°-90°/13 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13](=[S:21])OC1C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13]([N:35]1[CH2:34][CH2:33][N:32]([C:26]2[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=2)[CH2:37][CH2:36]1)=[S:21]
Reactant: COc1nc2c(cc1NC(=S)Oc1ccccc1)CCC2
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3cc4c(nc3OC)CCC4)CC2)c1
Yield: 55 %

Procedure:
Phenyl N-(2-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)thiocarbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.