Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:18]1([P:24](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:18]1([P:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([O:10][C:7]2[CH:8]=[CH:9][C:4]([S:1]([C:11]3[CH:16]=[CH:15][C:14]([O:17][P:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:25])=[CH:13][CH:12]=3)(=[O:3])=[O:2])=[CH:5][CH:6]=2)=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=P(Oc1ccc(S(=O)(=O)c2ccc(OP(=O)(c3ccccc3)c3ccccc3)cc2)cc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 93.6 %

Procedure:
An oven-dried 100 mL 3-necked flask equipped with a magnetic stirring bar, a reflux condenser carrying a CaCl2 -Drierite drying tube, and a heating mantle, was charged with 4,4'-sulfonyldiphenol (3.9 g, 15.6 mmol), 4-dimethylaminopyridine (0.39 g, 3.2 mmol), and anhydrous pyridine (35 mL), and the stirred solution was treated slowly with diphenylphosphinyl chloride (6.5 mL, 34.1 mmol) via syringe. The resulting mixture was heated at reflux for 7 hours, then was allowed to stand at room temperature for 16 hours. The reaction was monitored periodically by HPLC. After completion of the reaction, the mixture was partitioned between water (100 mL) and CH2Cl2 -Et2O (1:3; 400 mL), and the organic phase was washed successively with 50 mL portions of 5 percent NaOH, water, 5 percent HCl, water and brine, then it was dried (MgSO4), filtered and concentrated leaving a white solid residue. Recrystallization from ethyl acetate-THF (9:1) afforded 9.5 g (94 percent yield) of the title compound as a white fluffy solid, m.p. 210-211° C. which had a PDSC (O2) onset/extrap (° C.) of 376/397.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:9]#[N:10])[N:7]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1ccnc(C#N)n1
Temperature: 110 °C
Yield: 56 %

Procedure:
A mixture of 2-chloro-4-methylpyrimidine (725 mg, 5.63 mmol, 1 eq), zinccyanide (396 mg, 3.38 mmol, 0.6 eq) and tetrakis(triphenylphosphine)palladium(0) (716 mg, 0.562, 0.1 eq) in DMF (10 ml) was heated at 110° C. under nitrogen for 1 hr. The mixture was cooled to r.t., diluted with EtOAc and washed twice with 2N ammonium hydroxide (50 ml). The organic layer was washed with brine (20 ml) dried over sodium sulphate and concentrated in vacuum to provide the crude mixture. The crude product was then purified by column chromatography (30% EtOAc in Hexane) to afford 4-methylpyrimidine-2-carbonitrile Yield: 380 mg (56%). 1H NMR (400 MHz, CDCl3): δ2.61 (s, 3H), 7.36 (d, 1H, J=5.2 Hz), 8.66 (d, 1H, J=5.2 Hz),
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([CH2:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=1.CO>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH2:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(CS(=O)(=O)c2cccc3ccccc23)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N)c(CS(=O)(=O)c2cccc3ccccc23)c1
Yield: 64.1 %

Procedure:
A mixture of 3-(naphthalene 1-sulfonylmethyl)-4-nitro-benzoic acid methyl ester (1.5 g, 3.9 mmoles) and 10% Pd/C in THF (10 mL), and methanol (20 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 52 lb/in2 overnight. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum to afford the title compound as an off-white solid (0.9 g, 2.5 mmoles).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([C:21]([OH:23])=[O:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](OC(OCC)N(C)C)[CH3:25]>>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1Cc2ccccc2N(C(=O)OCc2ccccc2)C1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C1Cc2ccccc2N(C(=O)OCc2ccccc2)C1

Procedure:
The title compound is prepared analogously to Example 1s) starting from 1.5 g of N-benzyloxycarbonyl-1,2,3,4-tetrahydroquinoline-3(R,S)-carboxylic acid and 3.7 ml of N,N-dimethylformamide diethyl acetal and is purified by means of FC (100 g of silica gel, mobile phases D and B). This gives the title compound: Rf (A)=0.75; MS: (M)+ =339.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([NH2:9])=[O:8])([O-])=O.[H][H]>O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([NH2:9])=[O:8]
Reactant: [H][H]
Reactant: NC(=O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c(S(N)(=O)=O)c1
Solvent: O
Product: NC(=O)c1cc(N)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
To a suspension of 3-nitro-4-phenoxy-5-sulphamyl-benzamide (2.4 g) in water (25 ml) 1N lithium hydroxide (10 ml) was added. The resulting solution was hydrogenated at room temperature and at 1.1 atmospheres hydrogen pressure after addition of Pd-on-carbon catalyst (0.2 g catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the filtrate was then adjusted to pH 7.5 by addition of 4N hydrochloric acid. The precipitated 3-amino-4-phenoxy-5-sulphamyl-benzamide was isolated and dried in vacuo. The compound was obtained with a melting point of 291°-292°C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[C:4]([CH3:15])[CH:3]=1.C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>C(OC(=O)C)C.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.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:23][Si:24]([C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[C:4]([CH3:15])[CH:3]=1)([CH3:26])[CH3:25]
Reactant: Cc1cc(I)ccc1OC1CCCCO1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C#C[Si](C)(C)C)ccc1OC1CCCCO1
Temperature: 58 °C
Yield: 98 %

Procedure:
In a flask equipped with a stirrer and a thermometer, 13.36 g of 1-iodo-4-perhydro-2H-pyrane-2-yloxy-3-methylbenzene prepared in Step 2-1, 0.24 g of dichlorobis(triphenylphosphine)palladium, 0.24 g of triphenylphosphine, 0.12 g of copper iodide (I), and 12.75 g of triethyl amine were suspended in 50 g of ethylacetate under a nitrogen atmosphere, and heated up to 58° C. under stirring. Then a solution of 6.20 g of trimethylsilylacetylene and 6.20 g of ethylacetate was added dropwise at 58 to 64° C. over 2 hours. The resulting mixture was stirred at the same temperature for 3 hours, cooled down to room temperature, and filtered. The residue was washed with ethylacetate, and the resulting filtrate was concentrated at 60° C. under a pressure of 20 Torr. The concentrate was purified through silica gel chromatography using hexane mixed with 0.1 wt % triethyl amine as an eluting solvent, to thereby obtain 11.87 g of 2-(4-(trimethylsilylethynyl)-2-methylphenoxy)perhydro-2H-pyrane at 98% yield.
Reaction SMILES: [F:1][C:2]([F:28])([C:7]1[CH:27]=[CH:26][C:10]([CH2:11][NH:12][C:13](=O)[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4]>C1COCC1>[F:1][C:2]([F:28])([C:7]1[CH:27]=[CH:26][C:10]([CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=2)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: O=C(Cc1cccc(C(F)(F)F)c1)NCc1ccc(C(F)(F)C(F)(F)F)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc(CCNCc2ccc(C(F)(F)C(F)(F)F)cc2)c1
Yield: 83.4 %

Procedure:
Borane-tetrahydrofuran complex solution (1 M in THF, 2.43 mL, 2.43 mmol) was added at 0° C. to a solution of N-(4-pentafluoroethyl-benzyl)-2-(3-trifluoromethyl-phenyl)-acetamide (200 mg, 0.486 mmol) in THF (3.2 mL), and the homogeneous solution was heated at reflux over 90 min. After cooling, excess reagent was destroyed by careful addition of methanol at 0° C. Volatile material was removed by distillation, then the residue was dissolved in 5% ethanolic sulfuric acid solution (2 mL). The solution was refluxed for 2 h, then partitioned between 2 M aq. sodium hydroxide solution and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (161 mg, 83%). Colourless oil, MS (ISP) 398.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH:10]=[CH:14][N:15]([CH3:17])[CH3:16]
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1cc(Cl)ccc1Cl

Procedure:
A mixture of 31.0 g of 2',5'-dichloroacetophenone and 25 ml of N,N-dimethylformamide dimethyl acetal is heated on a steam bath for 6 hours, then evaporated to dryness in vacuo. The residue is slurried with hexane, and filtered to give 35.3 g of 2',5'-dichloro-3-dimethylaminoacrylophenone as orange crystals, mp 83°-85° C.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:22])(=[O:21])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1.CO>>[CH2:14]([NH:13][S:12]([C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:23])=[O:2])[CH:11]=[CH:10][CH:9]=1)(=[O:22])=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)NCc2ccccc2)c1
Solvent: CO
Product: O=C(O)C=Cc1cccc(S(=O)(=O)NCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a suspension of 3-(3-benzylsulfamoyl-phenyl)-acrylic acid methyl ester (4g) (0.29 g, 0.87 mmol) in methanol (4.5 ml) 1N NaOH solution (2.60 ml, 2.60 mmol) was added and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P2O5 to give the title compound as a white solid (0.22 g, 81%). 1H NMR (DMSO-d6, HMDSO), δ: 4.05 (2H, d, J=6.4 Hz); 6.60 (1H, d, J=16.0 Hz); 7.27 (4H, s), 7.52-8.09 (6H, m); 8.20 (1H, t, J=6.4 Hz); 12.58 (1H, br s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][N:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)O1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)=[CH:3][CH:4]=2)[CH2:9][N:10]([CH3:12])[CH3:11])=[CH:14][CH:15]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CN(C)CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CN(C)CC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
[2,2-Bis-(4-chloro-phenyl)-ethyl]-dimethyl-amine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-B2) Rt 3.07 [M+H]+325.99. 1H NMR (Me-d3-OD) δ 2.5 (OH, s), 2.98 (2H, dd), 4.34 (1H, t), 7.31-7.36 (6H, m), 7.50 (2H, d), 7.92 (2H, s).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][CH3:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=3)[CH2:14][CH2:13]2)[CH3:16])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN[C@H]1CC[C@H](c2ccc(CO)cc2)CC1
Product: CN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CO)cc2)CC1

Procedure:
from trans-4-(4-hydroxymethylphenyl)-N-methylcyclohexylamine and 4-chlorobenzoylchloride. Melting point: 211°-213° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:12][CH2:13][C@H:14]1[O:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:43])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C@H:40]([NH2:42])[CH3:41])=[CH:35][CH:34]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:42][CH:40]([CH3:41])[CH2:39][C:36]1[CH:37]=[CH:38][C:33]([O:32][CH2:31][C:30]([O:29][CH3:28])=[O:43])=[CH:34][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(OC[C@@H]3CO3)cc2OCc2ccccc2)cc1
Reactant: COC(=O)COc1ccc(C[C@@H](C)N)cc1
Product: COC(=O)COc1ccc(CC(C)NCC(O)COc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1

Procedure:
The title compound was prepared from (S)-3-(3,4-dibenzyloxyphenoxy)-1,2-epoxypropane and (R)-4-(2-aminopropyl)phenoxyacetic acid methyl ester according to the method described in Procedure 13.
Reaction SMILES: [Na].[OH:2][C:3]1(C2C=CC=CC=2)[NH:7][C:6](=[S:8])[C:5]([C:9]#[N:10])=[C:4]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:23](Br)([CH3:25])[CH3:24]>C(O)C>[C:23]1([C:4]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:3](=[O:2])[NH:7][C:6]([S:8][CH:11]([CH3:16])[CH3:12])=[C:5]2[C:9]#[N:10])[CH:25]=[CH:5][CH:4]=[CH:3][CH:24]=1
Reactant: N#CC1=C(c2ccccc2)C(O)(c2ccccc2)NC1=S
Reactant: CC(C)Br
Agent: [Na]
Solvent: CCO
Product: CC(C)SC1=C(C#N)C(c2ccccc2)(c2ccccc2)C(=O)N1
Reaction time: 0.33 h

Procedure:
1.2 g. Sodium is dissolved in 150 ml. ethanol, 15.2 g. 5-hydroxy-4,5-diphenyl-2-thioxo-3-pyrroline-3-carbonitrile are added thereto and the reaction mixture is then boiled for 20 minutes. A solution of 7.0 g. isopropyl bromide in 25 ml. absolute ethanol is then added dropwise thereto within the course of 10 minutes and refluxing continued for a further 3 hours. After cooling, the solvent is stripped off on a rotary evaporator and the residue is triturated with 100 ml. water. The precipitate is filtered off with suction and crystallised from ethanol. There are obtained 11.1 g. (64.0% of theory) of the desired product in the form of colourless crystals; m.p. 160° C.
Reaction SMILES: CN.[O:3]=[C:4]1[N:10]2[CH2:11][CH2:12][CH2:13][C@H:9]2[C:8]2=[C:14]([C:17]3[O:21][N:20]=[C:19]([CH2:22][N:23]4C(=O)C5C(=CC=CC=5)C4=O)[N:18]=3)[N:15]=[CH:16][N:7]2[C:6]2[CH:34]=[CH:35][S:36][C:5]1=2>C(O)C>[NH2:23][CH2:22][C:19]1[N:18]=[C:17]([C:14]2[N:15]=[CH:16][N:7]3[C:6]4[CH:34]=[CH:35][S:36][C:5]=4[C:4](=[O:3])[N:10]4[CH2:11][CH2:12][CH2:13][C@H:9]4[C:8]=23)[O:21][N:20]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1noc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2sccc2-3)n1
Agent: CN
Solvent: CCO
Product: NCc1noc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2sccc2-3)n1
Reaction time: 2 h
Yield: 82.7 %

Procedure:
100 ml of methylamine (33% in ethanol) were added dropwise at 70° to a solution of 7.28 g (15.4 mmol) of (S)-2-[5-(8-oxo-10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-1-yl)-1,2,4-oxadiazol-3-yl-methyl]-1,3-dihydro-isoindole-1,3-dione in 100 ml of ethanol and the mixture was stirred at 70° for a further two hours. The reaction mixture was evaporated and the residue was chromatographed (silica gel, methylene chloride/methanol 20:1). There were obtained 4.36 g (83%) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one as colourless crystals of m.p. 156°-158°.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)[C:42]2[C:37](=[CH:38][C:39]([C:52]([OH:54])=O)=[CH:40][CH:41]=2)[N:36]=1.Cl.[CH2:56]1[C:65]2[C:60](=[C:61]([O:66][CH2:67][C:68]3[CH:69]=[C:70]([CH:73]=[CH:74][CH:75]=3)[C:71]#[N:72])[CH:62]=[CH:63][CH:64]=2)[CH2:59][CH2:58][NH:57]1>CN(C)C=O>[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)[C:42]2[C:37](=[CH:38][C:39]([C:52]([N:57]3[CH2:58][CH2:59][C:60]4[C:65](=[CH:64][CH:63]=[CH:62][C:61]=4[O:66][CH2:67][C:68]4[CH:69]=[C:70]([CH:73]=[CH:74][CH:75]=4)[C:71]#[N:72])[CH2:56]3)=[O:54])=[CH:40][CH:41]=2)[N:36]=1
Reactant: N#Cc1cccc(COc2cccc3c2CCNC3)c1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2nc(N)nc3cc(C(=O)N4CCc5c(cccc5OCc5cccc(C#N)c5)C4)ccc23)CC1
Reaction time: 2 h
Yield: 93.7 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (20 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 uL, 0.07 mmol) were added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) and 3-[(1,2,3,4-tetrahydroisoquinolin-5-yloxy)methyl]benzonitrile HCl salt (30 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) at r.t. The reaction was stirred for 2 h. and the product was purified without workup by RP-HPLC (pH=10) to afford the desired compound (0.015 g, 33%) as an amorphous white solid. 1H NMR (500 MHz, DMSO): δ 7.79 (s, 1H), 7.71 (m, 2H.), 7.67 (d, 1H), 7.52 (t, 1H), 7.20 (s, 1), 7.05 (t, 1H), 6.96 (d, 1H), 6.83 (d, 1H), 6.70 (bs, 1H.), 6.02 (s, 2H.), 5.10 (s, 2H), 4.61 (m, 2H), 3.54 (m, 4H), 2.96 (s, 4H), 2.74 (m, 2H.), 2.44 (m, 2H.), 2.18 (s, 3H). (NMR sample heated to 90 c); Analytical LCMS (M+H)+: m/z=534.1.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:13](Cl)(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>O1CCCC1>[C:13]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH2:11][CH3:12])=[O:9])(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)c1ccccc1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)Oc1ccccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a cold (+5° C.) solution of ethyl salicylate (0.136 moles) and stearoyl chloride (0.136 moles) in tetrahydrofuran (200 ml) was added triethylamine (0.136 moles) dropwise over 25 min. After refluxing for 20 hours, the solution was cooled to room temperature. Most of the tetrahydrofuran was removed with a N2 stream during the cooling process. The residue was poured into ice/water (1500 ml), stirred for 1 hour, and a white solid removed by filtration. Washing the solid with water, followed by air drying gave 56 g of the title product, m.p. 50.5°-53.5° C.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[C:7]([C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:32][CH:31]=1>CN1CCCC1=O>[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][N:38]2[CH2:39][CH2:40][N:41]([C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[NH:5][CH:4]=[C:3]4[C:1]#[N:2])=[O:14])[CH2:42][CH2:43]2)=[CH:32][CH:31]=1
Reactant: Fc1ccc(CCN2CCNCC2)cc1
Reactant: N#Cc1c[nH]c2c(C(=O)O)cccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: N#Cc1c[nH]c2c(C(=O)N3CCN(CCc4ccc(F)cc4)CC3)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 g (0.027 mol) of 3-cyanoindole-7-carboxylic acid are dissolved in 40 ml of hot N-methylpyrrolidone, the solution is cooled to 40°, and 7.6 g (0.027 mol) of N,N-carbonyldiimidazole are added. The mixture is stirred at room temperature for a further one hour. A suspension of 1-(2-(4-fluorophenyl)ethyl)piperazine dihydrochloride in 40 ml of N-methylpyrrolidone is subsequently poured in. After 5 minutes, a clear solution is formed and just afterwards white crystals deposit. The mixture is stirred overnight at room temperature. The crystals are filtered off with suction, washed and dried, giving 5 g of 7-{4-[2-(4-fluorophenyl)ethyl]piperazin-1-carbonyl}-1H-indole-3-carbonitrile as the free base having a melting point (m.p.) of 192.0-193.5°.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][CH2:20][C:13]3=[C:12](I)[C:11]=2[CH:10]=1)[CH3:7].[C:22]([O:26][C:27]([N:29]1[C@@H:33]([CH3:34])[CH2:32]OS1(=O)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCC.O1CCCC1>[C:22]([O:26][C:27](=[O:28])[NH:29][CH:33]([CH3:32])[CH2:34][C:12]1[C:11]2[CH:10]=[C:9]([O:8][CH2:6][CH3:7])[CH:17]=[CH:16][C:15]=2[N:14]2[CH2:18][CH2:19][CH2:20][C:13]=12)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOc1ccc2c(c1)c(I)c1n2CCC1
Reactant: C[C@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1)c(CC(C)NC(=O)OC(C)(C)C)c1n2CCC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 61.4 %

Procedure:
75 mL of a pre-cooled (−78° C.) 1.6M solution of n-butyllithium in n-hexane at −78° C. was added over 30 min to a suspension of 32.72 g (0.100 mol) 6-ethoxy-8-iodo-2,3-dihydro-1H-3a-aza-cyclopenta[a]indene in 330 mL dry tetrahydrofuran. The mixture was stirred 5 min at −78° C. and 30.85 g (S)-4-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester was added in one portion. The mixture was stirred 20 min at −78° C. The reaction mixture was allowed to warm to −30° C. over 50 min. To the resulting slightly turbid mixture was added 300 mL of 10% citric acid. The phases were separated and the aqueous phase was extracted with 200 mL hexane. The combined organic phases were washed with 200 mL brine, dried over magnesium sulfate and evaporated. The residue was taken up in 200 mL dichloromethane and purified by chromatography on 1500 g silica gel (43-60 mesh) with dichloromethane (4000 mL) and 19:1 dichloromethane/ethyl acetate (6000 mL). The product fractions were evaporated and the residue was dissolved in 200 mL dichloromethane. The solution was diluted with 1000 mL hexane and the mixture was concentrated to a volume of 800 mL. The resulting suspension was stirred 18 h at room temperature. The mixture was cooled to 0° C. and stirred 30 min. The product was collected by filtration to yield 22.00 g of the title compound. The mother liquor was purified by chromatography, resulting in a further 4.71 g of the title compound. Total yield: 26.71 g (74.5%). m.p.: 89-90° C.