Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[NH:5][C:4]=1[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=O.C1(P(=[CH:37][C:38]([O:40][CH3:41])=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:38]([CH:37]=[CH:1][C:3]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[NH:5][C:4]=1[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)([O:40][CH3:41])=[O:39]
Reactant: O=Cc1cc(-c2cccs2)[nH]c1-c1cccs1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1cc(-c2cccs2)[nH]c1-c1cccs1
Temperature: 60 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
To a solution of 100 mg (0.386 mmole) of 3-formyl-2,5-dithienylpyrrole in toluene (3 mL) was added methyl (triphenylphosphoranylidene)acetate (129 mg, 0.386 mmol) at room temperature. The reaction mixture was then stirred at 60° C. for 16 hours. The reaction solvent was evaporated under reduced pressure, and the crude product then purified on 50 g of silica gel. Elution with hexane-ethyl acetate, 5:1, gave the title compound (97 mg) in 58% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:30][C:31](=[O:46])[CH2:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:37]=2)=[O:34])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:20][N:19]=3)[S:17][C:10]=12.[C:47](OC(=O)C)(=[O:49])[CH3:48]>>[F:1][C:2]1[CH:3]=[C:4]([NH:30][C:31](=[O:46])[CH2:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([S:42]([CH3:45])(=[O:43])=[O:44])[CH:37]=2)=[O:34])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:26][CH2:27][O:28][CH3:29])[C:47](=[O:49])[CH3:48])=[CH:20][N:19]=3)[S:17][C:10]=12
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5cccc(S(C)(=O)=O)c5)cc4F)c3s2)nc1
Reactant: CC(=O)OC(C)=O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5cccc(S(C)(=O)=O)c5)cc4F)c3s2)nc1)C(C)=O
Yield: 32.4 %

Procedure:
A solution of compound 345 (18.5 mg, 0.028 mmol) in acetic anhydride (1.31 ml, 13.9 mmol) was stirred at room temperature for 60 h. The solvent was removed under reduced pressure and the residue was triturated with water for 3 h. The solid suspension was filtered, the precipitate was rinsed with water and dried under high vacuum to afford compound 346 (6.4 mg, 9.07 μmol, 32.5%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): mixture of rotamers, 10.64 (s, 1H), 10.60 (s, 1H), 8.55-8.49 (m, 2H), 8.38-8.21 (m, 3H), 7.91-7.86 (m, 2H), 7.78 (td, J=8.8, 2.0 Hz, 1H), 7.66-7.60 (m, 2H), 7.51 (t, J=8.8 Hz, 1H), 7.44 (dd, J=9.2, 1.6 Hz, 1H), 6.71-6.67 (m, 1H), 4.71 and 4.59 (2s, 2H), 3.58-3.23 (m, 14H), 3.21 (s, 3H), 2.13 and 2.05 (2s, 3H). MS (m/z): 706.5 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[S:19]1[C:23]([S:24](Cl)(=[O:26])=[O:25])=[CH:22][C:21]2[CH:28]=[CH:29][CH:30]=[CH:31][C:20]1=2>C(Cl)Cl.N1C=CC=CC=1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([S:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][S:24]([C:23]2[S:19][C:20]3[CH:31]=[CH:30][CH:29]=[CH:28][C:21]=3[CH:22]=2)(=[O:25])=[O:26])(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: Nc1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a solution of N-(2-aminophenyl)-4-chlorobenzenesulfonamide (0.5 mmol, prepared as in Example 11) in DCM (1 mL) and pyridine (1 mL), benzo[b]thiophene-2-sulfonyl chloride (0.55 mmol), prepared as above, was added at RT and the reaction mixture was then allowed to stir at RT overnight or until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to afford 180 mg of benzo[b]thiophene-2-sulfonic acid [2-(4-chlorobenzenesulfonylamino)phenyl]-amide. LC: Tr 1.23 min, MS: 479.8 (M+1)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[Cl:7][C:8]1[N:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]([NH2:16])[CH:9]=1.O>CC(O)=O>[Cl:7][C:8]1[N:13]=[C:12]([S:14][CH3:15])[N:11]2[CH:5]=[C:3]([CH2:2][Cl:1])[N:16]=[C:10]2[CH:9]=1
Reactant: CSc1nc(N)cc(Cl)n1
Reactant: O=C(CCl)CCl
Solvent: CC(=O)O
Solvent: O
Product: CSc1nc(Cl)cc2nc(CCl)cn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
1,3-Dichloroacetone (2.89 g, 22.77 mmol) was added to a solution 6-chloro-2-methylsulfanyl-pyrimidin-4-ylamine (4 g, 22.77 mmol) in AcOH (15 mL) and the mixture was stirred at 110° C. for 16 hours. Then H2O was added and the solid formed was filtered off and dried in vacuo to yield 7-chloro-2-chloromethyl-5-methylsulfanyl-imidazo[1,2-c]pyrimidine (2.5 g, 44% yield) as a pale brown solid that was used in the next step without further purification.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(N)CCCC1>C(O)(=O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:2][CH2:3][CH2:5][CH2:6]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Agent: NC1CCCC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1C1CCCC1
Yield: 85 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), cyclopentylamine (0.080 ml, 0.81 mmol), and acetic acid (0.1 ml) were used to give 108.3 mg (0.37 mmol, 85% yield) of the title compound.
Reaction SMILES: [N:1]1([C:8]2[C:17]3[C:12](=[CH:13][C:14](I)=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:19])[CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[N:1]1([C:8]2[C:17]3[C:12](=[CH:13][C:14]([NH:27][CH2:26][C:25]4[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=4)=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:19])[CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(N2CCCCCC2)c2ccc(I)cc2n1
Product: Cc1cc(N2CCCCCC2)c2ccc(NCc3ccc(C(F)(F)F)cc3)cc2n1

Procedure:
In analogy to example 1a), on reaction of 4-azepan-1-yl-7-iodo-2-methyl-quinoline with 4-trifluoromethylbenzylamine there was obtained (4-azepan-1-yl-2-methyl-quinolin-7-yl)-(4-trifluoromethyl-benzyl)-amine a light brown solid. ISP mass spectrum, m/e: 414.3 (M+1 calculated for C24H26F3N3: 414).
Reaction SMILES: CC1C=CN=CC=1C1C=CC=C2C=1C=NN2.I[C:18]1[C:19]([O:24][CH3:25])=[N:20][CH:21]=[N:22][CH:23]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:29]=1B1OC(C)(C)C(C)(C)O1.CC1(C)C(C)(C)OB(C2C=CC([N+]([O-])=O)=CC=2C)O1>CN(C=O)C>[CH3:25][O:24][C:19]1[C:18]([C:29]2[CH:30]=[CH:31][C:32]([N+:34]([O-:36])=[O:35])=[CH:33][C:28]=2[O:27][CH3:26])=[CH:23][N:22]=[CH:21][N:20]=1
Reactant: COc1ncncc1I
Reactant: COc1cc([N+](=O)[O-])ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1cc([N+](=O)[O-])ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccncc1-c1cccc2[nH]ncc12
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1-c1cncnc1OC
Yield: 25 %

Procedure:
Intermediate 30B was prepared by the procedure described for the preparation of Intermediate 1C using Intermediate 30A and 2-(2-methoxy-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (prepared by the procedure described for the preparation of Intermediate 26A), and was obtained as a gummy yellow solid. The solid was dissolved in DMF and purified by reverse phase preparative HPLC (PHENOMENEX® Luna 30×100 mm column with a linear gradient of Solvent A (10% methanol/90% water with 0.1% TFA) and Solvent B (90% methanol/10% water with 0.1% TFA) over 12 min; monitored at 254 nM). The collected fractions were then applied to a 1 g Waters OASIS® MCX cation exchange cartridge, which was washed with methanol, and the product was then eluted off with 15 mL of 2 M ammonia in methanol. Evaporation of the collected eluent provided Intermediate 30B (46 mg, 25% yield) as a solid. HPLC Ret timed: 1.34 min. MS: m/z=262 [M+H]+; 1H NMR (500 MHz, CD3OD) δ ppm 8.48 (s, 1 H), 8.05 (s, 1 H), 7.94-7.90 (m, 2 H), 7.57 (d, 1 H), 3.93 (s, 3 H), 3.61 (s, 3 H).
Reaction SMILES: [O:1]([NH2:3])[CH3:2].[C:4]1([CH3:14])[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1.O>N1C=CC=CC=1>[CH3:2][O:1][NH:3][S:10]([C:7]1[CH:8]=[CH:9][C:4]([CH3:14])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CON
Solvent: c1ccncc1
Solvent: O
Product: CONS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
Methoxylamine (9.00 g (108 mmol) was suspended in pyridine (30.0 ml). To this, under cooling with ice and with stirring, p-toluenesulfonyl chloride (19.07 g (100 mmol)) was added and the mixture was stirred under cooling with ice for 30 minutes and at room temperature for 2 hours. Water (200.0 ml) was added to the reaction mixture to bring about separation of crystals. After 30 minutes' stirring, the crystals were filtered and washed to give 20.26 g (99%) of N-methoxy-p-toluenesulfonamide as white crystals.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][N:15]([C:17](=[O:26])[C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=3)[CH2:14][CH2:13][N:12]2[C:27](=[O:36])[CH2:28][NH:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:7]=[CH:8][C:9]=1[Cl:10].CCN(C(C)C)C(C)C.[CH:46](=O)[CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.[BH3-]C#N.[Na+]>C(CO)(F)(F)F>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][N:15]([C:17](=[O:26])[C:18]3[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=3)[CH2:14][CH2:13][N:12]2[C:27](=[O:36])[CH2:28][NH:29][CH:30]2[CH2:31][CH2:32][N:33]([CH2:46][CH2:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:34][CH2:35]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=CCCc1ccccc1
Reactant: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CNC3CCNCC3)C(c3ccc(Cl)c(Cl)c3)C2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: OCC(F)(F)F
Product: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CNC3CCN(CCCc4ccccc4)CC3)C(c3ccc(Cl)c(Cl)c3)C2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of compound 1 obtained from Example 9 (0.4 g, 0.7 mmol) in CF3CH2OH (5 mL) was added Hunig's base (0.21 g, 1.6 mmol) at 0° C. After stirring at 0° C. for 10 min, hydrocinnamaldehyde (94 mg, 0.7 mmol) was added. The reaction was stirred at 0° C. for additional 2.5 h, and NaBH3CN (100 mg, 1.6 mmol) was added. The mixture was stirred at 0° C. and gradually warmed to RT overnight. After reaction was complete, it was worked up and purified as described in Example 7 to give the title compound as a white solid, m.p. 52°-54° C.; FAB MS [M+1]+ 35 Cl 621.3.
Reaction SMILES: I[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)#[CH:23]>>[O:11]=[C:9]1[CH2:8][C:7]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])=[N:6][C:5]2[CH:20]=[CH:21][C:2]([C:23]#[C:22][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[CH:3][C:4]=2[NH:10]1
Reactant: C#Cc1cccs1
Reactant: N#Cc1cccc(C2=Nc3ccc(I)cc3NC(=O)C2)c1
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4cccs4)cc3NC(=O)C2)c1
Yield: 82.8 %

Procedure:
Prepared from 3-(7-iodo-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile (Example 50) (185 mg, 0.48 mmol) and 2-ethynylthiophene (78 mg, 0.72 mmol) [prepared from 2-thiophenecarboxaldehyde according to J. Org. Chem. 1982, 47, 2201–2204] according to the general procedure F. Obtained as a light yellow solid (146 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.Cl.[CH3:44][NH:45][O:46][CH3:47]>C(Cl)Cl>[CH3:44][N:45]([O:46][CH3:47])[C:12](=[O:14])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CNOC
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)N(C)OC)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.1 %

Procedure:
(3,4-Dimethoxyphenyl)acetic acid (13.0 g, 66.4 mmol) was suspended in anhydrous CH2Cl2 followed by addition of EDCI (15.3 g, 79.7 mmol), HOBt (20.6 g, 152 mmol), triethylamine (8.06 g, 79.7 mmol), and N,O-dimethylhydroxylamine hydrochloride (6.48 g, 66.4 mmol). The reaction was stirred 3 days at ambient temperature after which the solvent was evaporated at reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with aq. HCl, sat NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo to give 10.5 g (66%) of N-methyl-N-methoxy-(3,4-dimethoxyphenyl)acetamide as a pale brown oil.
Reaction SMILES: [C:1](=[C:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)=O.C[Mg]I.[OH2:18]>C1COCC1.C(OCC)C>[OH:18][C:3]1([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCC(=C=O)C1
Agent: C[Mg]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 3 h

Procedure:
A solution of tert-butyl 3-carbonylpyrrolidine-1-carboxylate (11.17 g, 0.06 mol) in THF (45 mL) was slowly added to a solution of MeMgI (21.41 g, 0.129 mol) in diethyl ether. The reaction was conducted at −20° C. under stirring for 3 hours. A small amount of water was added to the reaction solution. The resulting reaction solution was filtered by suction. The filtrate was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to produce a crude product of tert-butyl 3-hydroxy-3-methyl-pyrrolidine-1-carboxylate. The above crude product was dissolved in 20 mL 1,4-dioxane. To the resulting solution was introduced an HCl gas. The resulting mixute was stirred overnight and filtered by suction to produce the title product as a red solid (1.67 g) in a yield of 20% (two steps).
Reaction SMILES: C1([C@H](N)C)C=CC=CC=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH:21]([CH3:23])[CH3:22])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.Cl>C(#N)C.CCOCC>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C@@H:17]([CH:21]([CH3:23])[CH3:22])[C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1
Reactant: CC(C)C(C(=O)O)c1ccc(F)cc1
Agent: C[C@@H](N)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)[C@@H](C(=O)O)c1ccc(F)cc1

Procedure:
A solution of 63.0 g (0.52 mol) of [R]-(+)-1-phenylethylamine in 800 ml of acetonitrile was added with stirring to a solution of 204.1 g (1.04 mol) of rac. 2-(p-fluorophenyl)-3-methylbutyric acid in 1200 ml of acetonitrile. After 1 hour the crystalline precipitate was filtered off, washed with 300 ml of acetonitrile and dried overnight under reduced pressure at 50°. After repeated recrystallization from ethanol, the corresponding salt was obtained as colorless crystals, m.p. 209°-210°. The salt was suspended in ether and treated with 3N hydrochloric acid to pH 1. The ethereal solution was washed with water, dried and evaporated under reduced pressure, yielding [R]-(-)-2-(p-fluorophenyl)-3-methylbutyric acid, m.p. 56°-57°; [α]D20 =-48.4° (c=1, methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:22])[CH2:18][CH:17]1[C:19](Cl)=[O:20]>O1CCCC1>[CH3:15][C:16]1([CH3:22])[CH2:18][CH:17]1[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: CC1(C)CC1C(=O)Cl
Solvent: C1CCOC1
Product: CC1(C)CC1C(=O)Nc1ccc(C2=NNC(=O)CC2)cc1
Yield: 69 %

Procedure:
5.0 g (26.4 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone, 4.2 g (31.7 millimoles) of 2,2-dimethylcyclopropanecarboxylic acid chloride in 100 ml of absolute tetrahydrofuran are refluxed for 7 hours. The mixture is concentrated to about 50 ml and the product is filtered off at 10° C., washed with water and recrystallized from dimethylformamide/water. 5.2 g (68% of theory) of 4,5-dihydro-6-[p-(2,2-dimethylcyclopropylcarbonylamino)-phenyl]-3(2H)-pyridazinone quarter-hydrate are obtained as almost colorless crystals, of melting point 213°-214° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1(O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:2].C(N(S(F)(F)[F:27])CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1([F:27])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC1(F)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-hydroxypiperidine-1-carboxylate (12 g) in DCM (60 ml) at −78° C. under nitrogen was added by syringe diethylaminosulfur trifluoride (DAST) (8.3 ml). The mixture was stirred at −78° C. for 3 hours, then slowly warming up to rt, the mixture was then poured to aqueous sodium bicarbonate (200 ml), extracted with ethyl acetate (200 ml+100 ml), organic layer dried over sodium sulphate, solvent removed under vacuum. The oily residue was taken into ethanol (150 ml) and water (150 ml). Magnesium sulphate (5.4 g) was then added, followed by potassium permanganate (7.2 g). The mixture was stirred at rt for 1 hour, then extracted with ethyl acetate (600 ml). Organic layer was washed with brine (150 ml), dried over sodium sulphate, solvent removed under vacuum, residue was columned on silica gel using heptane:EtOAc (7:1) as eluant to give tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-fluoropiperidine-1-carboxylate (3.8 g) as a colourless oil. 1H NMR (CDCl3) δ: 4.16 (q, 2H), 3.95 (br, 2H), 3.10 (t, br, 2H), 2.64 (d, 2H), 1.93 (t, br, 2H), 1.6-1.85 (m, 2H), 1.46 (s, 9H), 1.27 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH:25]=[O:26])[S:23][CH:24]=1)=[CH:16][CH:15]=3.[CH3:32][Mg]Br>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH:25]([OH:26])[CH3:32])[S:23][CH:24]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(C=O)n4)ccc3n(C)c21
Reactant: C[Mg]Br
Product: CC(O)c1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cs1

Procedure:
The process is carried out as indicated in Example 139 above, with compound A, 4-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-thiazole-2-carbaldehyde, and methylmagnesium bromide.
Reaction SMILES: Br[CH:2]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:11][C:12]([NH2:14])=[S:13]>CCO>[NH2:14][C:12]1[S:13][C:2]2[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[N:11]=1
Reactant: NC(N)=S
Reactant: O=C1CCCCC(=O)C1Br
Solvent: CCO
Product: Nc1nc2c(s1)C(=O)CCCC2

Procedure:
To a solution of 2-bromocycloheptane-1,3-dione (45.17 mmol) in abs. EtOH (100 mL) was added thiourea (3.61 g, 47.43 mmol). The reaction mixture was stirred at room temperature overnight at which point the EtOH was removed under reduced pressure and the resulting dark orange residue was triturated with DCM. The residue was recrystallized from EtOH to afford 26z as an off white solid (6 g, 50% overall crude yield from cycloheptane-1,3-dione). 1H NMR (300 MHz, DMSO-d6): δ 8.87 (br s, 2H), 2.87 (t, J=6 Hz, 2H), 2.64 (t, J=6 Hz, 2H), 1.89-1.85 (m, 2H), 1.81-1.77 (m, 2H);
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[CH2:15]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][C:17]#[CH:18]>>[N:19]1([CH2:15][CH2:16][C:17]#[C:18][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[N:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Brc1cccc(CN2CCCCC2)n1
Reactant: C#CCCN1CCCCC1
Product: C(#Cc1cccc(CN2CCCCC2)n1)CCN1CCCCC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 18, Step D, using 2-bromo-6-piperidin-1-ylmethyl-pyridine and 1-but-3-ynyl-piperidine (56%). MS (ESI): exact mass calcd. for C20H29N3, 311.46; m/z found, 312.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.54 (t, J=7.7, 1H), 7.38 (d, J=7.7, 1H), 7.20 (d, J=7.4, 1H), 3.58 (s, 2H), 2.67-2.57 (m, 4H), 2.46-2.34 (m, 8H), 1.60-1.50 (m, 8H), 1.44-1.36 (m, 4H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=2[O:2]1.Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]([CH3:32])=[C:23]([CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[N:24]=2)=[CH:16][CH:15]=1>>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:21][C:22]([CH3:32])=[C:23]([CH2:25][CH2:26][N:27]5[CH2:28][CH2:29][CH2:30][CH2:31]5)[N:24]=4)=[CH:16][CH:15]=3)=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Product: Cc1oc(-c2ccc(-c3ccc4c(c3)OCO4)cc2)nc1CCN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 35 starting from 3,4-Methylenedioxybenzene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 377.1 (M+1)
Reaction SMILES: [CH2:1]([NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:18]([NH:21][S:22](Cl)(=[O:24])=[O:23])[CH2:19][CH3:20]>>[CH2:1]([NH:17][S:22]([NH:21][CH2:18][CH2:19][CH3:20])(=[O:24])=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCNS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCN
Product: CCCCCCCCCCCCCCCCNS(=O)(=O)NCCC
Yield: 70 %

Procedure:
The title compound was prepared following the method described in Example 6. The starting reactants are 0.15 g (0.6 mmol) of N-hexadecylamine and 0.10 g (0.6 mmol) of N-propylsulfamoyl chloride. 0.15 g of a white solid were obtained. Yield 70%; m.p. 108-110° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.CC(C)([O-])C.[K+].Cl[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.O>CN(C)C=O>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH:5]=1
Reactant: Clc1cnccn1
Reactant: COC(OC)c1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1cccc(Oc2cnccn2)c1
Temperature: 60 °C

Procedure:
A solution of 168 mg of 3-hydroxybenzaldehyde dimethyl acetal in 10 ml of anyhydrous dimethylformamide was stirred under nitrogen and 220 mg of potassium tert-butoxide were added. The mixture was heated at 60° C. for 1 hour, then cooled to room temperature and 115 mg of 2-chloropyrazine were added in portions. The mixture was then heated at 160° C. for 18 hours. After cooling 15 ml of water were added and the product was extracted with 50 ml of ethyl acetate. The extract was washed with 25 ml of 1M sodium hydroxide solution and 25 ml of brine and then dried over anhydrous magnesium sulphate. After filtration and evaporation of the filtrate the residual yellow oil was purified by column chromatography on silica gel using ethyl acetate/hexane (1:1) for the elution to give 3-(2-pyrazinyloxy)-benzaldehyde dimethyl acetal as a yellow oil.