Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]2[CH:8]=[C:9]3[N:18]([CH3:19])[CH:17]=[CH:16][C:10]3=[N:11][C:12]=2[C@@H:13]([NH2:15])[CH3:14])[CH2:4]1.[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23](Cl)[N:22]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23]([NH:15][C@H:13]([C:12]2[N:11]=[C:10]3[CH:16]=[CH:17][N:18]([CH3:19])[C:9]3=[CH:8][C:7]=2[N:5]2[CH2:6][CH:3]([O:2][CH3:1])[CH2:4]2)[CH3:14])[N:22]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: COC1CN(c2cc3c(ccn3C)nc2[C@H](C)N)C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC1CN(c2cc3c(ccn3C)nc2[C@H](C)Nc2nc(N)nc(N)c2C#N)C1
Temperature: 120 °C
Yield: 15 %

Procedure:
(S)-1-(6-(3-Methoxyazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (469 mg, 1.80 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (367 mg, 2.16 mmol), and N-ethyl-N-isopropylpropan-2-amine (628 μl, 3.60 mmol) were combined in acetonitrile (1.8 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours. Additional 2,4-diamino-6-chloropyrimidine-5-carbonitrile (367 mg, 2.16 mmol) and N-ethyl-N-isopropylpropan-2-amine (628 μL, 3.60 mmol) were added. The reaction mixture was heated in a microwave reactor at 120° C. for 1 hour and then concentrated in vacuo. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 25-50% ACN in water. The fractions containing the desired compound were combined and concentrated in vacuo. The residue was added to a silica gel column and was eluted with EtOAc. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound as an off-white solid (106 mg, 15%). 1H NMR (500 MHz, CD3OD) δ ppm 1.49 (d, J=6.83 Hz, 3 H), 3.40 (s, 3 H), 3.70-3.74 (m, 1 H), 3.82 (s, 3 H), 3.89 (dd, J=7.32, 4.39 Hz, 1 H), 4.15-4.20 (m, 1 H), 4.32-4.40 (m, 2 H), 5.64 (q, J=6.83 Hz, 1 H), 6.51 (dd, J=3.42, 0.98 Hz, 1 H), 7.20 (s, 1 H), 7.31 (d, J=2.93 Hz, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H23N9O, 394.2; found 394.5.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[CH:17]2[N:12]([S:13](=[O:23])(=[O:22])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16]2)[CH2:11][CH2:10][N:9]1C(OC(C)(C)C)=O>>[CH2:8]1[CH:17]2[N:12]([S:13](=[O:22])(=[O:23])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16]2)[CH2:11][CH2:10][NH:9]1
Reactant: CC(C)(C)OC(=O)N1CCN2C(Cc3ccccc3S2(=O)=O)C1
Solvent: O=C(O)C(F)(F)F
Product: O=S1(=O)c2ccccc2CC2CNCCN21
Reaction time: 1 h

Procedure:
Cold trifluoroacetic acid (2 mL) was added to cold 1,1-dimethylethyl 1,2,3,4,11,11a-hexahydropyrazino[1,2-b][1,2]benzothiazine-2-carboxylate 6,6-dioxide (151 mg, 0.446 mmol). After 1 h, the reaction was concentrated in vacuo. The residue was partitioned between dichloromethane (10 mL) and 0.5 N sodium carbonate (2 mL). The organic layer was dried (sodium sulfate) and concentrated in vacuo. The residue was chromatographed (Diacel Chiracel OJ, 5×50 cm, 35% 1:1 methanol/ethanol:hexanes containing 0.3% triethylamine, 50 mL/min). Fractions containing the more rapidly eluting enantiomer concentrated in vacuo. The residue was taken up in 50% aqueous methanol (1 mL) and was loaded onto a 1-g methanol-activated water-equilibrated SCX-type cation exchange column. The column was washed with water (5 mL) and 25% aqueous methanol (5 mL). The column was eluted with 2 N methanolic ammonia. Concentration of this fraction in vacuo provided (−)1,2,3,4,11,11a-hexahydropyrazino[1,2-b][1,2]benzothiazine 6,6-dioxide: LCMS (pos. ion spectrum) m/z 239.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C@H:17]([C:21]([OH:23])=O)[CH:18]([CH3:20])[CH3:19])(=[O:15])=[O:14])=[CH:9][CH:8]=1)[CH:2]=[C:3]=[CH:4][CH3:5].[OH:24][N:25]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[OH:24][NH:25][C:21](=[O:23])[CH:17]([NH:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:1][CH:2]=[C:3]=[CH:4][CH3:5])=[CH:8][CH:9]=1)(=[O:15])=[O:14])[CH:18]([CH3:20])[CH3:19]
Reactant: On1nnc2ccccc21
Reactant: CC=C=CCOc1ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC=C=CCOc1ccc(S(=O)(=O)NC(C(=O)NO)C(C)C)cc1
Yield: 47.8 %

Procedure:
The procedure of Example 13 was followed using the product from Example 18 (230 mg, 0.67 mmol), 1-hydroxybenzotriazol (80 mg, 0.59 mmol), 1-[3-(dimethylamino)-propyl]-3-ethylcarbodimide hydrochloride (132 mg, 0.69 mmol), N-methylmorpholine (0.81 mmol, 0.74 mmol), and hydroxylamine (0.150 ml, 2.45 mmol) in dimethylformamide (5 ml) to give 100 mg (42%) of the product.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)[C:9]([O-:11])=[O:10].[Na+].N(OCCC(C)C)=O.Cl>C(O)C.OS(O)(=O)=O.O.[Cu]>[Br:19][C:16]1[CH:15]=[CH:14][C:13]2[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:3]3[C:4]([C:18]=2[CH:17]=1)=[CH:5][CH:6]=[CH:7][CH:2]=3
Reactant: Nc1ccccc1C(=Cc1ccc(Br)cc1)C(=O)[O-]
Agent: [Cu]
Agent: CC(C)CCON=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2ccc(Br)cc2c2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
A suspension of the amino-carboxylate 2 (13.3 g, 39.1 mmol) in 155 ml of ethanol was cooled to 0° C. and isoamyl nitrite (18.0 ml, 134 mmol) was added followed by dropwise addition of 15% ethanolic HCl (125 ml) during 1 hour. The resulting brown slurry was stirred at 0° C. for 2 hours more, and was then added gradually to a vigorously stirred suspension of copper powder (1.8 g) in a solution of NaH2PO2.H2O (41.4 g, 391 mmol) and conc. H2SO4 (3 drops) in 63 ml of water which was maintained at 40° C. After the addition was complete, the mixture was stirred at 40° C. for 1 hour and was then cooled to 0° C. and the solid was isolated by filtration, washing with water. Drying in vacuo gave 9.9 g of a brown solid which was taken-up in CH2Cl2 --THF, filtered to remove some inorganic material, and evaporated to yield 7.28 g (62%) of the title compound as a tan solid. This compound was used in the next reaction without purification.
Reaction SMILES: Br[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:26]B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Br
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C

Procedure:
A mixture of tert-butyl N-[(1S,2S)-2-{[3-bromo-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]carbamate (1.26 g, 2.96 mmol), methylboronic acid (CAS number 13061-96-6; 0.532 g, 8.88 mmol), tetrakis(triphenylphosphine)palladium (0.342 g, 0.296 mmol) and potassium carbonate (1.303 g, 9.43 mmol) in 1,4-dioxane (10 ml) and water (1.5 ml) was sealed, evacuated and purged with nitrogen and subjected to microwave irradiation at 140° C. for 1 hour. The mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The organics were extracted with ethyl acetate (2×20 ml). The combined organics were washed with brine (20 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-60% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:54][N:55]1[CH2:60][CH2:59][CH:58]([O:61][C:62]2[CH:68]=[CH:67][C:65]([NH2:66])=[CH:64][CH:63]=2)[CH2:57][CH2:56]1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:66][C:65]3[CH:64]=[CH:63][C:62]([O:61][CH:58]4[CH2:59][CH2:60][N:55]([CH3:54])[CH2:56][CH2:57]4)=[CH:68][CH:67]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Reactant: CN1CCC(Oc2ccc(N)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(Oc2ccc(NC(=O)c3cccc(N4CCc5nc(N)ncc5C4)c3)cc2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 69.8 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (41 mg, 0.15 mmol), N,N-diisopropylethylamine (0.105 mL, 0.60 mmol), and HBTU (63 mg, 0.165 mmol) in 1.5 mL DMF was briefly warmed to approx. 50° C. to dissolve solids, then continued stirring at room temperature. After 10 minutes 4-((1-methylpiperidin-4-yl)oxy)aniline (46 mg, 0.225 mmol) was added and the reaction continued at room temperature for 3 hours. The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with EtOAc to give the title compound as an off-white solid (48 mg, 70%). 1H NMR (DMSO-d6) δ: 10.02 (s, 1H), 8.13 (s, 1H), 7.60-7.67 (m, 2H), 7.49 (s, 1H), 7.30-7.40 (m, 2H), 7.20 (dt, J=7.7, 2.0 Hz, 1H), 6.90-6.96 (m, 2H), 6.40 (s, 2H), 4.28 (s, 2H), 4.26-4.35 (m, 1H), 3.64 (t, J=5.9 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H), 2.56-2.66 (m, 2H), 2.17 (s, 3H), 2.10-2.21 (m, 2H), 1.86-1.97 (m, 2H), 1.55-1.69 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:15])=[C:11]([CH3:14])[N+:12]=2[O-])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O.N>C(Cl)(Cl)Cl>[Cl:18][CH2:14][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:9][C:10]=1[CH3:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(-c2ccc(Cl)cc2)[n+]([O-])c1C
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc(Cl)cc2)nc1CCl
Temperature: 0 °C

Procedure:
1.00 g (4.47 mmol) of the compound from example 34A is initially charged in 15 ml of chloroform, and 1.5 ml (16.10 mmol) of phosphoryl chloride are added carefully. With stirring, the reaction mixture is heated at reflux for 30 min. The mixture is then cooled to 0° C. and made weakly basic by addition of aqueous ammonia. The mixture is extracted three times with in each case 20 ml of ethyl acetate. The combined organic phases are washed twice with in each case 5 ml of water and then dried over magnesium sulphate. The solvent is removed on a rotary evaporator. Without further purification, the product obtained in this manner is used for the subsequent reactions.
Reaction SMILES: [CH:1]([NH:5][C:6]([NH2:8])=[O:7])([CH2:3][CH3:4])[CH3:2].Cl[CH:10]([C:16]([C:18]([F:21])([F:20])[F:19])=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH3:2][CH:1]([NH:5][C:6]1[O:7][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:16]([C:18]([F:19])([F:21])[F:20])[N:8]=1)[CH2:3][CH3:4]
Reactant: CCC(C)NC(N)=O
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Product: CCOC(=O)c1oc(NC(C)CC)nc1C(F)(F)F
Yield: 28.5 %

Procedure:
By the procedure of Example 4, 6.96 g (60 mmol) of sec-butyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 3 hours. The product was separated and then Kugelrohr distilled to yield 4.0 g of a colorless oil product (b.p.=100° C. @ 0.25 mm Hg) identified in Table I.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[CH:9]1([C@H:12]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:15]([CH2:24][OH:25])[CH:14]([OH:26])[CH2:13]2)[CH2:11][CH2:10]1>N1C=CC=CC=1.C(Cl)Cl>[Si:5]([O:25][CH2:24][CH:15]1[CH:14]([OH:26])[CH2:13][C@@H:12]([CH:9]2[CH2:10][CH2:11]2)[N:16]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1C(CO)C(O)C[C@H]1C1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C(CO[Si](C)(C)C(C)(C)C)C(O)C[C@H]1C1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
TBSCl (1.35 g, 9.00 mmol) was added to a solution of (5S)-tert-butyl 5-cyclopropyl-3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (32) (1.93 g, 7.50 mmol) in pyridine (15 mL) and the resulting solution was stirred at rt for 18 h. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed with 1 N aq. HCl (10 mL). The organic phase was dried (Na2SO4), filtered and concentrated under vacuum to give (5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-cyclopropyl-3-hydroxypyrrolidine-1-carboxylate (33). Retention time (min)=3.261 method [1], MS (m/z) 394.2 (M+Na)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]([NH:36][C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)=[O:35])[CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[O:27]1[CH2:28][CH2:29][N:30]([CH2:33][C:34]([NH:36][C:37]2[CH:43]=[CH:42][C:40]([NH:41]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:39][CH:38]=2)=[O:35])[CH2:31][CH2:32]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(NC(=O)CN2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CN1CCOCC1)Nc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-morpholinomethylcarbonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([N+:12]2[C:17](Cl)=[CH:16][C:15]([NH2:19])=[CH:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[NH2:21][NH2:22]>O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([N+:12]2[C:17]([NH:21][NH2:22])=[CH:16][C:15]([NH2:19])=[CH:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cn[n+](-c2ccccc2)c(Cl)c1
Reactant: NN
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Product: NNc1cc(N)cn[n+]1-c1ccccc1
Reaction time: 3 h

Procedure:
15.3 parts of 1-phenyl-4-amino-6-chloropyridazinium perchlorate is dissolved in 200 parts of water at 80° to 90°C; 5 parts of hydrazine hydrate is added and the whole is boiled for 3 hours. The reaction solution is concentrated to about half its volume and cooled. 13 parts (81.3% of theory, as hydrate) of 1-phenyl-4-amino-6-hydrazinopyridazinium perchlorate is obtained; C10H12O4N5Cl.H2O, obtained with 1 mole of water of crystallization when recrystallized from water. Melting point 63° to 65°C.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH2:7][S:8][CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:3].N1C=CC=CC=1.[NH2:27][C:28]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:29]=1[C:30]([NH:32][C:33]1[CH:37]=[CH:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([CH3:45])[CH:39]=2)[N:34]=1)=[O:31]>ClCCl>[Cl:50][C:47]1[CH:48]=[CH:49][C:28]([NH:27][C:2]([C:4]2[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=2)[CH2:7][S:8][CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:3])=[C:29]([C:30](=[O:31])[NH:32][C:33]2[CH:37]=[CH:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([CH3:45])[CH:39]=3)[N:34]=2)[CH:46]=1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Cl)c1
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3N)n2)cc1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)n2)cc1C
Yield: 41.1 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (185 mg, 0.59 mmol, 1.00 equiv) in dichloromethane (10 mL), and pyridine (140 mg, 1.77 mmol, 3.00 equiv). This was followed by dropwise addition of a solution of 2-amino-5-chloro-N-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-yl)benzamide (200 mg, 0.59 mmol, 1.00 equiv) in dichloromethane (2 mL) with stirring. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1) to yield 150 mg (33%) of product as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH3:17])=[O:10])=[CH:4][C:3]=1[N+:18]([O-])=O>C(O)C.[Pd]>[NH2:18][C:3]1[CH:4]=[C:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH3:17])=[O:10])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CN1CCCC[C@@H]1C(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CN1CCCC[C@@H]1C(=O)Nc1ccc(N)c(N)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 91.9 %

Procedure:
A solution of (R)—N-(4-amino-3-nitrophenyl)-1-methylpiperidine-2-carboxamide (2.17 g, 7.8 mmol) in ethanol (75 mL) was degassed under vacuum and then backfilled with argon. 10% Palladium on carbon (0.44 g) was added and the mixture again degassed under vacuum. Hydrogen was introduced by a balloon and the reaction stirred at room temperature for 23 hr. The mixture was degassed by bubbling argon through it, and was then filtered through a pad of diatomaceous earth. The filtrate was concentrated to give (R)—N-(3,4-diaminophenyl)-1-methylpiperidine-2-carboxamide as a purple solid (1.78 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([NH:9][C:10]1[NH:14][N:13]=[N:12][N:11]=1)=[O:8])([O-])=O.Cl>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([NH:9][C:10]1[NH:14][N:13]=[N:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1nnn[nH]1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1cccc(C(=O)Nc2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-(3-nitrobenzoylamino)tetrazole (4.0 g), l0 palladium on carbon (1.0 g) in ethanol (200 ml) was stirred at room temperature in H2 gas at 3 atm. for 4 hours. The reaction mixture was poured into 1N HCl and filtered. 1N sodium hydroxide was added to the filtrate and the pH was adjusted to 5-6 to afford the white powder. 5-(3-Aminobenzoylamino)tetrazole was obtained by filtration, washed with water, and vacuumed to dryness.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH3:19])[CH:15]=2)[CH:10]=[C:9]1[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:18]([O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[C:9]([C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)[NH:8]2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCOc1ccc2cc(-c3ccc([N+](=O)[O-])cc3)n(C(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc2cc(-c3ccc([N+](=O)[O-])cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a solution of 6-ethoxy-2-(4-nitro-phenyl)-indole-1-carboxylic acid tert-butyl ester (8.1 g, 21.2 mmol) in CH2Cl2 (8 mL) was added TFA (8 mL). This mixture was stirred at room temperature for 2 h and concentrated. The residue was diluted in EtOAc and washed with sat.aq. NaHCO3. The organic layer was concentrated and purified by silica gel chromatography (7:3 CH2Cl2/hexane, followed by 100% CH2Cl2) to provide 6-ethoxy-2-(4-nitro-phenyl)-1H-indole (4.5 g, 68%) as an orange-red solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=1>>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:22])[C:13]1[CH:18]=[C:17]([N+:1]([O-:4])=[O:2])[C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)c2ccccc2F)ccc1O
Product: COc1cc(C(=O)c2ccccc2F)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
7.8 ml of 65 percent nitric acid are added dropwise at 20° within 20 minutes to 29.4 g of 2'-fluoro-4-hydroxy-3-methoxybenzophenone (dissolved in 450 ml of acetic acid). After stirring for 1.5 hours, the reaction mixture is poured into 2 1 of ice-water and the precipitate formed is filtered off, washed with water and dissolved in methylene chloride. The methylene chloride solution is washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from methanol. There is obtained 2'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone of m.p. 127°-129°.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]3[C:22]([N:23]=[C:24]4[CH2:30][CH2:29]CC[CH2:26][C:25]=24)=[CH:21][CH:20]=[N:19]3)=[CH:13][CH:12]=1.ClCCCOC1C=CC(C2N3C(=CC=N3)N=C3C=2CCC3)=CC=1.CC1CCCN1>>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]3[C:22](=[CH:21][CH:20]=[N:19]3)[N:23]=[C:24]3[C:25]=2[CH2:26][CH2:29][CH2:30]3)=[CH:13][CH:12]=1
Reactant: CC1CCCN1CCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Agent: CC1CCCN1
Agent: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1
Product: CC1CCCN1CCCOc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1

Procedure:
Using the method described for the preparation of 10-{4-[3-(2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 8-[4-(3-chloro-propoxy)-phenyl]-6,7-dihydro-5H-1,4,8a-triaza-s-indacene and 2-methyl-pyrrolidine provided the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>ClCCl>[C:17]([O:10][C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])(=[O:19])[CH3:18]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C)cc(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
In dichloromethane (150 mL) was dissolved 15.09 g (0.1108 mol) of 2,3,5-trimethylphenol, and 17.82 mL (0.2204 mol) of pyridine, then 20.78 mL (0.2202 mol) of acetic anhydride were added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with dichloromethane. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane:ethyl acetate, gradient) to obtain 20.08 g (0.1127 mol, Yield: quantitative) of 2,3,5-trimethylphenyl acetate.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][NH2:10]>C1COCC1>[Cl:8][C:7]1[C:2]([NH:10][CH3:9])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nccnc1Cl
Yield: 43.4 %

Procedure:
2,3-dichloropyrazine (15 g, 101 mmol), methanamine (9.48 g, 101 mmol), and 100 mL of THF were stirred at room temperature for 24 h. The solvent was evaporated. The residue was dissolved in dichloromethane and washed with NaOH solution. The organic layer was separated and dried over MgSO4. After evaporating solvent, the residue was purified by column using dichloromethane as solvent to give 3-chloro-N-methylpyrazin-2-amine (6.3 g, 43.6% yield).