Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1C=CC(N[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccc(O)c(Cl)c1
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 3-chloro-4-hydroxybenzoate (available from Aldrich) (5.00 g, 25.0 mmol), N-phenyltriflamide (9.30 g, 26.0 mmol) and TEA (4.2 mL, 30.0 mmol) in DCM (40 mL) with a catalytic amount of DMAP, was stirred at ambient temperature overnight. DCM (150 mL) was added, and the reaction mixture was washed with brine (30×3 mL), dried over MgSO4, and the solvent was removed under reduced pressure. The product B.5 was used in the next step without further purification. MS ESI (pos.) m/e: 335.0 (M+Na)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C@@H:9]2[CH2:13][S:12][C:11]([C:14]3[NH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=4[NH:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:10]2)[CH2:3]1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:42])[CH3:41]>ClCCl>[Cl:23][C:19]1[CH:20]=[C:21]2[C:16](=[C:17]([NH:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:18]=1)[NH:15][C:14]([C:11]1[S:12][CH2:13][C@@H:9]([CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:40](=[O:42])[CH3:41])[CH2:3]3)[N:10]=1)=[CH:22]2
Reactant: CC(=O)Cl
Reactant: N[C@H]1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@H]1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
(2-{(R)-4-[2-((S)-3-amino-pyrrolidin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-chloro-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine (85 mg, 0.19 mmol) prepared in Example 170 was dissolved in dichloromethane (10 mL). Diisopropylethylamine (0.13 mL, 0.75 mmol) and acetylchloride (0.013 mL, 0.19 mmol) were added thereto, and the mixture was stirred for 30 min at room temperature. The reaction was quenched by water, and the reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (39 mg, Yield 42%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([O:15]C(OCC)=O)=O)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(#N)C>[S:3]1[CH:4]=[CH:5][S:1][C:2]1=[C:6]([C:13]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:15])[C:7]([O:9][CH:10]([CH3:11])[CH3:12])=[O:8]
Reactant: C1COCCN1
Reactant: CCOC(=O)OC(=O)C(C(=O)OC(C)C)=C1SC=CS1
Solvent: CC#N
Product: CC(C)OC(=O)C(C(=O)N1CCOCC1)=C1SC=CS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isopropyl 2-(1,3-dithiol-2-ylidene)-2-(ethoxycarbonyloxy-carbonyl]acetate (20 g) and morpholine (6.23 acetonitrile (200 ml). The mixture was stirred at room temperature for 2 hrs. The reaction mixture was evaporated to dryness and the residue was dissolved inmethylene chloride (100 ml). The solution was washed with aqueous sodium hydroxide solution and water. After evaporation the residue was recyrstallized from ethyl acetate and n-hexane to give the titled compound. (15.0 g, 71.1%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32](Cl)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:17]1[CH:16]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=3[Cl:1])[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:14]=[C:13]([F:12])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2cccc(Cl)c2Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 14.1 %

Procedure:
2,3-Dichlorobenzeneboronic acid (49.6 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (9 mg, 14%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Br[C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=1>>[CH3:1][C@@H:2]1[N:7]([C:16]2[CH:21]=[N:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Yield: 49.9 %

Procedure:
Following the procedure of Example 323a, and starting with (3S)-tert-butyl 3-methylpiperazine-1-carboxylate (10.0 g, 50 mmol) and 5-bromo-2-nitropyridine (10.5 g, 50 mmol) afforded 340a as a yellow solid (8.05 g, 50%). MS-ESI: [M+H]+ 323
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:16][C:17]#[N:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[SH2:26]>C(OCC)C>[C:17](=[S:26])([S:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1)[NH2:18]
Reactant: S
Reactant: CC(C)(C)c1cc(SC#N)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)c1cc(SC(N)=S)cc(C(C)(C)C)c1O

Procedure:
3,5-Di-tert-butyl-4-hydroxyphenyl thiocyanate (8.7 g) and 0.3 g of triethylamine were dissolved in 80 ml of diethyl ether, and hydrogen sulfide was blown into the solution at room temperature over 4.5 hours. The reaction mixture was concentrated, and the crude product thus obtained was washed with diethyl ether to give 7.5 g of the desired compound as a colorless solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][C:32]#[N:33])[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][C:32]#[N:33])[CH2:26][CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCCN1CCC(N)CC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCCN1CCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 80 °C
Yield: 93.3 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (15.35 g, 45.5 mmol), 3-(4-amino-piperidin-1-yl)-propionitrile (hydrochloride salt) (9.48 g, 50.0 mmol), diisopropylethylamine (24.5 ml, 141 mmol) in propan-2-ol (200 ml) was heated at 80° C. for 18 h. The mixture was cooled to 25° C. and was concentrated to approximately 40 ml volume. This material was partitioned between water (2000 ml) and CH2Cl2 (3×2000 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 6% CH3OH in CH2Cl2) afforded 3-[4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile (19.3 g, 93% over 3 steps) as a yellow-orange foam. LCMS (Method G, ESI): RT=0.69 min, m+H=455.3. This material was used in the next step below without additional characterization.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][N:17]1[C:18](=[O:27])[C:19]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]2[C:21]1=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(NCCCO)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCCON1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a solution of 3-(benzyloxycarbonylamino)-1-propanol (4.0 g, 19 mmol), as prepared in the preceding step, N-hydroxyphthalimide (3.26 g, 20 mmol) and triphenylphosphine (5.25 g, 20 mmol) in tetrahydrofuran (80 mL) was added diethyl azodicaroxylate (3.5 g, 20 mmol). The reaction mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added, the solution washed with saturated NaHCO3 (2×100 mL) and brine (100 mL), and dried over Na2SO4. After evaporating the solvent, the residue was purified by flash column chromatography (methylene chloride to 4% ethyl acetate in methylene chloride) to give the title compound as a white solid (6.85 g, 100%). 1H-NMR (300 MHz, CDCl3) δ 7.83 (m, 2H), 7.77 (m, 2H), 7.36 (m, 5H), 5.67 (br s, 1H), 5.12 (s, 2H), 4.28 (t, J=5.8 Hz, 2H), 3.51 (q, J=6.1 Hz, 2H), 1.99 (pentet, J=6.0 Hz, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=1>>[Cl:16][C:17]1[N:18]=[CH:19][C:20]([N:5]2[CH2:6][CH2:7][C@H:2]([CH3:1])[C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]2)=[CH:21][CH:22]=1
Reactant: Clc1ccc(I)cn1
Reactant: C[C@H]1CCNC[C@H]1NC(=O)OC(C)(C)C
Product: C[C@H]1CCN(c2ccc(Cl)nc2)C[C@H]1NC(=O)OC(C)(C)C
Yield: 19.9 %

Procedure:
The cis product from Example 39C (0.428 g, 2.00 mmol) and 2-chloro-5-iodopyridine (0.523 g, 2.19 mmol; Aldrich) were processed according to the procedure in Example 1A to provide the title compound (0.13 g, 20%). MS (CI/NH3) m/z 326/328 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[C:20]2[C@@H:21]3[C@H:26]([CH2:27][CH2:28][C:19]=2[CH:18]=[CH:17][CH:16]=1)[NH:25][CH2:24][CH2:23][CH2:22]3>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:25]3[C@@H:26]4[C@@H:21]([C:20]5[C:15]([O:14][CH3:13])=[CH:16][CH:17]=[CH:18][C:19]=5[CH2:28][CH2:27]4)[CH2:22][CH2:23][CH2:24]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1cccc2c1[C@H]1CCCN[C@H]1CC2
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: COc1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 55 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-10-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 55% of theory; LC (method 1): tR=2.67 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CO[CH:10]=[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13].CC(N(C)C)=O.Cl>C(OCC)C>[C:21]1([C:11]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:13])=[O:14])=[CH:10][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC=C(c1ccccc1)S(=O)(=O)c1ccccc1
Reactant: Nc1ccccn1
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: O=S(=O)(C(=CNc1ccccn1)c1ccccc1)c1ccccc1
Yield: 12.2 %

Procedure:
A solution of 2-aminopyridine (1.05 g) and 2-methoxy-1-phenyl-1-phenylsulphonylethene (2.0 g) in a mixture of anhydrous dimethylacetamide (50 ml) and a solution of hydrogen chloride in diethyl ether (6N; 0.5 ml) was heated at reflux for 25 hours, and then it was cooled and poured onto ice (150 g). The yellow precipitate was filtered off, subjected twice to medium pressure chromatography on silica gel, eluting with chloroform, triturated with light petroleum ether (b.p. 60°-80° C.) and recrystallised from a mixture of diethyl ether and light petroleum ether (b.p. 60°-80° C.), to give 1-phenyl-1-phenylsulphonyl-2-(pyrid-2-ylamino)ethene (0.3 g), m.p. 159°-160° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)([O-:3])=[O:2].[Cl:15]N1C(=O)CCC1=O.C(OCC)(=O)C>C(#N)C>[Cl:15][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([C:11]([F:12])([F:13])[F:14])[C:7]=1[NH2:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1c(Cl)cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 150 °C
Yield: 75 %

Procedure:
4-Nitro-2-trifluoromethyl-phenylamine (5.6 g) and N-chlorosuccinimide (4.0 g) were suspended in acetonitrile (15 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. Ethyl acetate (80 mL) was added and the organic phase was washed with 5% aqueous NaOH (2×50 mL), water (2×50 mL) and brine (2×50 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 4.9 g (75% yield) of the title compound as a yellow solid. 1H NMR (500 MHz, CDCl3): 5.35 (b, 2H), 8.35 (b, 1H), 8.37 (b, 1H).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:4]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:26]#[N:27].[N:28]1([CH2:34][CH2:35][O:36][CH2:37][CH2:38][OH:39])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:4]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:26]#[N:27]
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reactant: OCCOCCN1CCNCC1
Agent: [Na]
Product: COc1cc(Nc2c(C#N)cnc3cc(OCCOCCN4CCNCC4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 120 °C

Procedure:
A mixture of sodium (50 mg, 2.2 mmol) in 1 mL of 2-[2-(1-piperazinyl)ethoxy]ethanol is heated at 120° C. for 2 hours. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (150 mg, 0.38 mmol) is added and the reaction mixture is heated at 140-145° C. for 2 hours, then cooled to room temperature. The reaction mixture is partitioned between saturated sodium bicarbonate and ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 3% methanol in dichloromethane to 1% ammonium hydroxide and 30% methanol in dichloromethane followed by recrystallization from acetone and hexane to provide 124 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{2-[2-(1-piperazinyl)-ethoxy]ethoxy)-3-quinolinecarbonitrile, mp 88-90° C.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:13].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:16][CH2:2][CH2:3][N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:13]
Reactant: O=C1c2ccccc2CN1CCO
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2CN1CCCl
Temperature: 20 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
To a solution of 2-(2-hydroxyethyl)isoindolinone (1.0 g, 5.64 mmol) in toluene (3.5 mL) was added thionyl chloride (1.34 g, 11.3 mmol). The reaction mixture was stirred at 20° C. for 3 h then 4 h at 60° C. The reaction mixture was concentrated in vacuo to remove excess thionyl chloride and toluene. 2-(2-Chloroethyl)isoindolinone (1.01 g, 92%) was obtained by flash chromatography on a silica gel column by elution with EtOAc/Hexanes a white solid. 1H NMR (CDCl3, 300 MHz) δ3.81 (t, 2H, J=5.5 Hz), 3.97 (t, 2H, J=5.9 Hz), 4.59 (s, 2H), 7.44-7.58 (m, 3H), 7.86 (d, 1H, J=6.9 Hz) ppm.
Reaction SMILES: [CH3:1]N(C=O)C.[H-].[Na+].[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][N:22]2[CH3:27])=[O:18])=[CH:9]1.CI>C1COCC1>[CH3:1][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][N:22]2[CH3:27])=[O:18])=[CH:9]1
Reactant: CN(C)C=O
Reactant: CN1CCCCC1COC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1CCCCC1COC(=O)c1cn(C)c2ccccc12
Reaction time: 0.25 h

Procedure:
To a DMF (10 ml) suspension of 60% sodium hydride (0.09 g, 2.3 mmol) was dropwise added a DMF (5 ml) solution of (1-methyl-2-piperidyl)methyl 1H-indole-3-carboxylate (0.50 g, 1.8 mmol) at room temperature over a period of 5 min. Onto the reaction mixture stirred for 15 min. was poured a THF (5 ml) solution of methyl iodide (0.29 g, 2.0 mmol). After stirring overnight, a reaction solution was poured onto water followed by extraction with EtOAc. The organic layer was washed successively with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product thus produced was purified by column chromatography on silica gel (20 g, CHCl3) to give 0.43 g of the title compound as a colorless oil.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH:10]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][O:8][CH2:7]1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+].O>CN(C)C=O>[N:20]([CH:6]1[CH2:7][O:8][CH2:9][CH:10]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11]1)=[N+:21]=[N-:22]
Reactant: CC(C)(C)OC(=O)NC1COCC(OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1COCC(N=[N+]=[N-])C1
Temperature: 25 °C
Yield: 137.6 %

Procedure:
A solution of 5-(tert-butoxycarbonylamino)-tetrahydro-2H-pyran-3-yl methanesulfonate (90 mg, 0.3 mmol) and sodium azide (30 mg, 0.5 mmol) in 10 mL of dry N,N-dimethylformamide was heated to 100° C. for 3 h. The reaction mixture was cooled to room temperature, 40 mL of water were added, product extracted with ethyl acetate (2×50 mL), organics combined dried with sodium sulfate, filtered and concentrated to give tert-butyl 5-azido-tetrahydro-2H-pyran-3-ylcarbamate (100 mg, crude) which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[O:23]([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:37]([NH:36][C:33]2[CH:34]=[CH:35][C:30]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:31][CH:32]=2)=[O:38])=[CH:20][CH:21]=1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Oc5ccccc5)cc4)cc3)c2cc1OC
Yield: 60 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (53 mg) was dissolved in toluene (3 ml) with heat, 4-phenoxyphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 30 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 55 mg of the title compound (yield: 60%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:4][N:5]([C:7]2[N:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9]([O:11]CC)=[O:10])[CH:6]=1.[OH-].[Na+]>CO>[F:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:4][N:5]([C:7]2[N:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9]([OH:11])=[O:10])[CH:6]=1
Reactant: CCOC(=O)c1cccnc1-n1cc(F)c(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccnc1-n1cc(F)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To ethyl 2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinate (1.49 g, 4.79 mmol) in methanol (40 ml) 8.5 ml of an aqueous 2 m NaOH-solution (17 mmol) was added dropwise at 10° C., and the mixture stirred for 2 h at room temperature and then for 3 h at 65° C. After completion of the reaction the mixture was concentrated under reduced pressure, dissolved in water and acidified using 2 n HCl. The precipitate formed was filtered off, washed with water and dried to give 1.23 g of a white amorphous solid. ESI-MS [M+H]+: 284.1
Reaction SMILES: [Na].C[O-].[Na+].[CH:5](OCC)=[O:6].[S:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13](=[O:20])[CH2:12][CH2:11]1>C1C=CC=CC=1.CO>[OH:6][CH:5]=[C:12]1[C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:10][CH2:11]1
Reactant: O=C1CCSc2ccccc21
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: c1ccccc1
Product: O=C1C(=CO)CSc2ccccc21
Reaction time: 8 h

Procedure:
From 9.2 g of sodium (0.4 mol) and 160 ml of absolute methanol there is prepared sodium methanolate. Then the surplus of methanol is evaporated in vacuo and 200 ml of dry benzene and 32.6 g of ethyl formate (0.44 mol) are added to the dry residue. While stirring and passing nitrogen through the mixture, there are added 32.8 g of 2,3-dihydro-4H-1-benzothiopyran-4-one, dissolved in 160 ml of dry benzene dropwise to it to keep the reaction temperature in the range from 0° to 50° C. All components become dissolved and after that, the sodium salt of the 2,3-dihydro-3-(hydroxymethylene)-4H-1-benzothiopyran-4-one precipitates. After allowing the reaction mixture to stand overnight at room temperature, 400 ml of water are added for dissolving the sodium salt. The aqueous layer is separated from the organic solvent and, after agitating twice with ether and treatment with charcoal, it is acidified with half-concentrated aqueous hydrochloric acid. The oily title compound is extracted with chloroform, dried with sodium sulphate and after evaporation of the solvent, distilled in vacuo. b.p. 0.3 mm, 134°-138°; yield: 32.9 g (85.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: COC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 76.6 %

Procedure:
Using general procedure A, methyl 4-aminobenzoate (380 mg, 2.51 mmol) and 1-Boc-4-piperidone (500 g, 2.51 mmol) afforded 4-(4-methoxycarbonyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (643 mg, 77%).