Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[C:4]([CH3:18])[CH:3]=1.[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>ClCCl.C1(C)C=CC=CC=1>[Cl:19][CH2:20][CH2:21][NH:22][C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)=[C:4]([CH3:18])[CH:3]=1)=[O:24]
Reactant: O=C=NCCCl
Reactant: COC(=O)c1ccc(-c2ccc(N)cc2C)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(NC(=O)NCCCl)cc2C)cc1
Yield: 69.6 %

Procedure:
Methyl 4'-amino-2'-methylbiphenyl-4-carboxylate (D2) (1.00 g, 4.1 mmol) and 2-chloroethylisocyanate (0.39 ml, 4.5 mmol) were stirred in dichloromethane (20 ml) for 72 h. The suspension was then diluted with toluene (20 ml), and the solid was filtered off and dried. This gave the title compound (0.99 g, 69%) as a cream solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](=[O:21])[NH:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.N1C=CC=CC=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>ClCCl>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([O:21][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCC[C@@H]3C)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)nc2c1
Temperature: 0 °C

Procedure:
To a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.70 mmol) in dichloromethane (30 mL) was added pyridine (220 mg, 2.78 mmol), and then Tf2O (393 mg, 1.39 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature and then quenched by the addition of ice-water (20 mL), extracted with dichloromethane (2×20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (292 mg, crude).
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[CH:9]([CH3:15])[CH2:10][C:11]#[C:12][CH2:13][CH3:14])(=O)OC.[CH:17]([C@H:19]1[C@H:26]([O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][C@H:24]2[C@@H:20]1[CH2:21][C:22](=[O:36])[O:23]2)=O>>[C:28]([O:27][C@@H:26]1[CH2:25][C@H:24]2[C@H:20]([CH2:21][C:22](=[O:36])[O:23]2)[C@H:19]1/[CH:17]=[CH:7]/[C:8](=[O:16])[CH:9]([CH3:15])[CH2:10][C:11]#[C:12][CH2:13][CH3:14])(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCC#CCC(C)C(=O)CP(=O)(OC)OC
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Product: CCC#CCC(C)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Yield: 90 %

Procedure:
Analogously to Example 1(g), 14.2 g of the title compound was synthesized from 9.85 g of 3-methyl-2-oxooct-5-inylphosphonic acid dimethyl ester and 11 g of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3,3,0]octan-3-one [E. J. Corey et al., J. Amer. Chem. Soc. 91: 5675 (1969)].
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]2[CH2:5][CH2:4][NH:3][CH2:2][CH2:1][C:7]=2[CH:8]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CCNCC2
Product: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reaction time: 0.5 h

Procedure:
2,3,4,5-Tetrahydro-1H-benzo[d]azepine (535 mg/3.63 mmol, neat) was cooled to −10° C. (acetone/ice bath), treated with neat fuming nitric acid (ca. 10 mL, precooled to −10° C.), and allowed to stir for 30 minutes. The yellow solution was then poured onto ice with vigorous stirring. The resulting white solid was collected by filtration and washed with ice cold water and dried in vacuo to afford the nitrate salt of 7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a white solid (650 mg/70%). The filtrate was basified with 1 N sodium hydroxide and extracted with methylene chloride (2×20 mL). The extracts were dried and concentrated to yield an additional 200 mg (25%) of the free base 7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (br s, 2 H), 8.13 (s, 1H), 8.08 (dd, J=8.1 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 3.21 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH:11]1([C:16]([CH3:23])([C:20](Cl)=[O:21])[C:17](Cl)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH:11]1([C:16]2([CH3:23])[C:20](=[O:21])[C:6]3[C:5](=[CH:4][C:3]([O:9][CH3:10])=[C:2]([CH3:1])[C:7]=3[Cl:8])[C:17]2=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(Cl)c1C
Reactant: CC(C(=O)Cl)(C(=O)Cl)C1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(c(Cl)c1C)C(=O)C(C)(C1CCCC1)C2=O

Procedure:
2-Cyclopentyl-2,5-dimethyl-4-chloro-6-methoxy-indan-1,3-dione is prepared following substantially the same procedure described in Example 1, Step A using the following substances:2-Methyl-3-chloroanisole 7 g. (0.045 mole)2-Cyclopentyl-2-methylmalonyl chloride 11.2 g. (0.05 mole)Methylene chloride 400 ml.Aluminum chloride 13.5 g. (0.10 mole)
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=2[CH3:17])=[C:5]([CH3:18])[O:4][N:3]=1.[OH-].[Na+]>CCO.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[CH3:17])=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2c(C)noc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1-c1c(C)noc1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Methyl 4-bromo-3-methylbenzoate (Intermediate 17, step 1) (4 g; 17.46 mmol; 1 eq.), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)isoxazole (4.28 g; 19.21 mmol; 1.10 eq.), potassium carbonate (12.07 g; 87.31 mmol; 5 eq.), tetrakis(triphenylphosphine)palladium(0) (2.02 g; 1.75 mmol; 0.10 eq.) were taken in Toluene (20 mL) and water (20 mL) under N2 atmosphere. The reaction mixture was degassed with N2 and then refluxed for 4 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene (200 mL). The filtrate was concentrated to afford a brown oil which was taken up in EtOAc (250 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 solution (100 mL), water (100 mL) and brine (100 mL), dried over MgSO4 and concentrated affording methyl 4-(3,5-dimethylisoxazol-4-yl)-3-methylbenzoate (4.2 g, 99%, HPLC (Method A) Rt 3.93 min) as an orange solid, which was used without further purification. A solution of methyl 4-(3,5-dimethylisoxazol-4-yl)-3-methylbenzoate (3 g; 12.23 mmol; 1 eq.) in EtOH (90 mL) at RT was treated with sodium hydroxide (7.34 mL; 5 M; 36.69 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was concentrated to give a brown solid which was taken up in water (100 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with HCl cc to pH 2. Then it was concentrated until precipitation (volume divided by 2). The suspension was filtered affording the title compound as a brown solid. It was washed with diethyl ether affording the title compound as a beige solid. 1H NMR (DMSO-d6, 300 MHz) δ 13.03 (br s, 1H), 7.95 (s, 1H), 7.86-7.84 (dd, J=7.88, 1.31 Hz, 1H), 7.34-7.32 (d, J=7.88 Hz, 1H), 2.26 (s, 3H), 2.19 (s, 3H), 2.07 (s, 3H). HPLC (Method A) Rt 3.13 min (Purity: 97.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1.[S:35]1[CH:39]=[CH:38][N:37]=[C:36]1[NH2:40].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:40][C:36]4[S:35][CH:39]=[CH:38][N:37]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1nccs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A vial was charged with perfluorophenyl 1-(4-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE NNN) (82.4 mg, 0.160 mmol), thiazol-2-amine (17.60 mg, 0.176 mmol), and THF (799 μl) to give a clear, colorless solution. The vial was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (335 μl, 0.335 mmol) was added drop wise. After 30 min, the mixture was warmed to room temperature and loaded onto a 5-g silica gel loading column with the aid of DCM. The column was dried under vacuum for 5 min then eluted onto a pre-equilibrated 12-g column with 0 to 10% MeOH/DCM to give 1-(4-chloro-2-methoxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (54 mg, 0.125 mmol, 78% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=13.21-11.96 (m, 1H), 8.73-8.62 (m, 1H), 8.52 (d, J=1.8 Hz, 1H), 8.17-8.02 (m, 1H), 7.85 (dd, J=1.9, 8.9 Hz, 1H), 7.75-7.66 (m, 1H), 7.36-7.25 (m, 3H), 7.18 (dd, J=2.0, 8.0 Hz, 1H), 6.85 (d, J=4.6 Hz, 1H), 3.67 (s, 3H); m/z (ESI) 432.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.[CH3:16][N:17]=[C:18]=[O:19]>>[CH3:16][NH:17][C:18]([N:10]1[CH2:9][CH:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:13][CH:12]=2)[CH2:11]1)=[O:19]
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Reactant: CN=C=O
Product: CNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1

Procedure:
The compound was prepared from 3-[4-(trifluoromethyl)phenoxy]azetidine and methylisocyanate as described in Example 3 of U.S. Pat. No. 4,226,861, m.p. 154°-157° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:13]([CH3:14])[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH:13]([CH3:14])[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(Cc2ccccc2)CC1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC1CNCC1NC(=O)OC(C)(C)C

Procedure:
To 3-(t-butoxycarbonylamino)-1-benzyl-4-methylpyrrolidine (3.9 g) are added ethanol (50 ml) and 10% Pd-C (780 mg), and the mixture is subjected to catalytic reduction at 60° C. under atmospheric pressure. After the catalytic reduction, the catalyst is removed off by filtration, and the filtrate is concentrated. The resulting residue is recrystallized from ethyl acetate-petroleum ether to give 3-(t-butoxycarbonylamino)-4-methylpyrrolidine (isomer A) (2.01 g), as colorless prisms, m.p. 86.8°-87° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([N:29]=[CH:30][C:31]=4[C:32](O)=[O:33])[C:20]=3[NH:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37]>>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([N:29]=[CH:30][C:31]=4[C:32]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:33])[C:20]=3[NH:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:14])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cnn2c(NCc3cccnc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3cccnc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12

Procedure:
In the same manner as in Example 1, step 6 and using 6-(4-phenylpiperidine-1-carbonyl)-7-(pyridin-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.11 mmol) obtained in step 2 and methanesulfonamide (0.052 g, 0.550 mmol), compound a-9 (0.03 g, 58%) was obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[N:8]=1)[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[N:23]#[C:24]Br.O>C1COCC1.C(OCC)(=O)C>[F:15][C:13]([F:16])([F:14])[C:9]1[N:8]=[C:7]([CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:24]([NH2:23])=[N:1]2)[CH:12]=[CH:11][CH:10]=1
Reactant: N#CBr
Reactant: N[C@H](CO)CCc1cccc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC1=N[C@@H](CCc2cccc(C(F)(F)F)n2)CO1
Reaction time: 18 h
Yield: 38.6 %

Procedure:
To a stirred mixture of (S)-2-amino-4-(6-trifluoromethyl-pyridin-2-yl)-butan-1-ol (0.224 g, 0.96 mmol) and K2CO3 (0.198 g, 1.43 mmol) in THF (7 ml) under an argon atmosphere was added a solution of cyanogen bromide (0.152 g, 1.05 mmol) in THF (1 ml). The mixture was stirred for 18 hours, then water and ethyl acetate were added. The organic layer was washed with water, dried over MgSO4 and evaporated over Isolute® Flash-NH2 silicagel. Chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/MeOH=90:10) yielded the title compound as off-white solid, (0.096 g, 39%); MS (ISP): 260.0 ((M+H)+.).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH2:24]([N:26](C(C)C)C(C)C)C>ClCCl.O1CCCC1>[C:24]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:19][CH2:20]1)#[N:26]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Temperature: 25 °C

Procedure:
Bromonitirile (1.96 g) is added to a solution of N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide (3.50 g) and ethyldiisopropylamine (9.60 mL) in dichloromethane (125 mL) and tetrahydrofuran (125 mL) and the reaction mixture is stirred over night at room temperature. The reaction mixture is washed with water and the organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is triturated with diethyl ether to afford the title compound. LC (method 3): tR=1.55 min; Mass spectrum (ESI+): m/z=337 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([NH2:15])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]#[N:15])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=O)CCCc1ccc([N+](=O)[O-])cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: N#CCCCc1ccc([N+](=O)[O-])cc1
Yield: 63.4 %

Procedure:
To a solution of compound 81 (3.2 g, 22.4 mmol) in DCM (60 mL) was added TEA (10 mL, 77 mmol) at room temperature with stirring. Then to the mixture was added dropwise TFAA (4 mL, 30.8 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 h. Then the mixture was diluted with DCM, washed by water and brine, dried over Na2SO4 and concentrated to dryness to give compound 82 (2.7 g, 93%) as a yellow oil. 1H NMR (400 MHz, CDCl3) 8.12 (d, 2H, J=8.1 Hz), 7.30 (d, 2H, J=8.1 Hz), 2.85 (t, 2H, J=7.5 Hz), 2.31 (t, 2H, J=7.3 Hz), 1.92-2.05 (m, 2H).
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([O:30]C)=[O:29])=[CH:18][CH:17]=2)[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1>C(O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:14]2[C:8]3=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]3[N:6]=[C:5]2[CH2:4][OH:3])=[CH:21][CH:20]=1)([OH:30])=[O:29]
Reactant: COC(=O)c1ccccc1-c1ccc(Cn2c(CO)nc3c(C)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccnc2c1nc(CO)n2Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 82.4 %

Procedure:
A mixture of 8 ml of an aqueous 10% sodium hydroxide solution of 500 mg (1.3 mmol) of 2-hydroxymethyl-3-[(2'-methoxycarbonyl-biphenyl-4-yl)methyl]-7-methyl- 3H-imidazo[4.5-b]pyridine and 20 ml of ethanol was heated for reflux for 2 hours. The insoluble was removed out and the filtrate was concentrated. The residue was mixed with water and washed with ethyl acetate. The aqueous phase was weakly acidified with 2N hydrochloric acid and acetic acid. The precipitates of crystals was taken out and washed with water, dried, to obtain 400 mg of the intended compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:7]=[N:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.O>CS(C)=O>[C:1]([CH2:5][C:6]1[CH:7]=[N:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)#[N:2]
Reactant: ClCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Under nitrogen atmosphere, sodium cyanide (540 mg) was added to a solution of 4-chloromethyl-1-tritylpyrazole (3.58 g) in dimethylsulfoxide (30 ml) at 50° C. After stirring for 1 hour, the mixture was poured into water. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, to afford 4-cyanomethyl-1-tritylpyrazole (3.41 g).
Reaction SMILES: [CH2:1]([O:6]N=O)[CH2:2]C(C)C.N[C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3.O.C(=O)(O)[O-].[Na+]>C(O)C.S(=O)(=O)(O)O>[CH2:1]([O:6][C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:2]
Reactant: CC(C)CCON=O
Reactant: Nc1cc2c(cn1)[nH]c1ccccc12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cc2c(cn1)[nH]c1ccccc12
Temperature: 25 °C

Procedure:
1 ml of isoamylnitrite is added to a suspension of 1 g of 3-amino-β-carboline in 100 ml of ethanol and 2 ml of concentrated sulfuric acid. The mixture is stirred at room temperature for an hour and then refluxed for an hour. As a result, a clear solution is obtained. After cooling, it is poured into a mixture of 100 ml of water and 100 ml of saturated sodium bicarbonate solution. It is extracted three times with 100 ml of ether each time and the evaporation residue of the combined ether extracts is chromatographed (silica gel, methanol/chloroform=95:5) and recrystallized from hexane. Yield: 0.3 g of 3-ethoxy-β-carboline with a melting point of 130°-133° C.
Reaction SMILES: [C:1]([C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]>CCO.[Ni]>[NH2:2][CH2:1][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)(C)C#N
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C(C)(C)CN
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a slurry of Raney-Ni (1.6 g, 50% in H2O, rinsed 3 times with EtOH before use) in EtOH (78 mL) was added ethyl 2-cyano-2-methylpropanoate (5 g, 35 mmol). The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 20 hours. The liquid was then carefully decanted into another flask and the metal was washed twice with EtOH. The combined EtOH solution was concentrated in vacuo to give the title compound in 4.5 g, which was used in the subsequent step without further purification. 1H NMR (CDCl3, 200 MHz): δ=4.13 (q, 2H, J=7.0 Hz), 2.74 (s, 2H), 1.26 (t, 3H, J=7.0 Hz), 1.17 (s, 6H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][N:12]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([C:20](OC)=[O:21])=[N:13]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C1COCC1>[CH3:11][N:12]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([CH2:20][OH:21])=[N:13]1
Reactant: COC(=O)c1nn(C)cc1[N+](=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cn1cc([N+](=O)[O-])c(CO)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisobutyl aluminum hydride (34.2 ml of a 1 M solution in toluene) was added to a solution of methyl 1-methyl-4-nitro-pyrazole-3-carboxylate (2.92 g) in anhydrous THF (100 ml) at −20° C. over a period of 5 minutes. The reaction was stirred at room temperature overnight and then poured into sat. citric acid (100 ml). The organic phase was separated and the aqueous washed with EtOAc (4×100 ml). The combined organic phases were washed with brine (100 ml), dried, filtered and concentrated in vacuo. The crude material was columned on silica (50 g), eluting with EtOAc. The product fractions were combined and washed with sat. aq. potassium sodium L-tartrate solution (3×100 ml) and brine (100 ml). The solvent was removed in vacuo to yield (1-methyl-4-nitropyrazol-3-yl)methanol as a pale yellow solid, 2.0 g, 74%.
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10]([CH3:13])(C)[C:9]2[C:8](=[O:14])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3Br)[CH2:5][C:4]=2[N:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.NC1N=C(C)C2C(=O)CC(C3C=CC=CC=3C3C=CC=CC=3)CC=2N=1>>[NH2:1][C:2]1[N:11]=[C:10]([CH3:13])[C:9]2[C:8](=[O:14])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: OB(O)c1ccccn1
Reactant: CC1(C)NC(N)=NC2=C1C(=O)CC(c1ccccc1Br)C2
Agent: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1ccccc1)C2
Product: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1ccccn1)C2

Procedure:
The title compound was prepared from 2-amino-4-methyl-7-(2-bromo-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/i stage 2/3) and pyridin-2-ylboronic acid, following the procedure describing the synthesis of 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 5/a stage 1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[C@@H:10]([NH2:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:22][S:24]([CH3:23])(=[O:26])=[O:25])[C@@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)c2ccc(Cl)s2)[C@@H](N)C1
Reactant: CS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)N1CC(NS(C)(=O)=O)[C@@H](NC(=O)c2ccc(Cl)s2)C1

Procedure:
35.3 In analogy to example 20.2 (S)-3-amino-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester was reacted with methane sulfonylchloride to give (S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methanesulfonylamino-pyrrolidine-1-carboxylic acid tert-butyl ester. White solid. MS 424.0 ([M+H]+)
Reaction SMILES: [CH3:1][CH:2]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH2:3][CH2:4]OC1C=CC=CC=1.[BrH:17]>C(Cl)(Cl)Cl>[BrH:17].[CH3:1][CH:2]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH2:3][CH2:4][Br:17]
Reactant: CCN(CC)C(C)CCOc1ccccc1
Agent: Br
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(C)CCBr
Yield: 78 %

Procedure:
5 g of the 1-methyl-3-phenoxypropyldiethylamine was reacted with 30 ml of 40% hydrobromic acid at 150° C. for 7 hours with stirring. The reaction solution was cooled, 20 ml of chloroform and was added and then the solution was separated into two phases, which phases were then separated from each other. The hydrobromic acid was removed under reduced pressure and the residue was recrystallized from 5 ml of ethyl alcohol to give 4.88 g of 1-methyl-3-bromopropyldiethylamine hydrobromide in a yield of 78%.