Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[C:23]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=4)[CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[Li+].[I-]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[C:23]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=4)[CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1Oc1cccc(C#N)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: N#Cc1cccc(Oc2cc(N3CCN(Cc4ccccc4-c4ccc(Cl)cc4)CC3)ccc2C(=O)O)c1
Temperature: 120 °C

Procedure:
A mixture of EXAMPLE 22A (0.081 g) in pyridine (2 mL) in a 10 mL microwave vial equipped with a magnetic stir bar was treated with LiI (0.402 g), flushed with nitrogen and heated in a CEM microwave reactor at 120° C. for 30 minutes. The mixture was concentrated, acidified with 1N HCl, extracted with ethyl acetate and dried (MgSO4), filtered and concentrated. The concentrate was purified by column chromatography on silica gel, eluting with a gradient of 0-10% methanol in dichloromethane.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].[NH2:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[C:13]=1[C:14]([NH2:16])=[O:15].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(N(C)C)=O.CCOC(C)=O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[NH:16][C:14](=[O:15])[C:13]3[C:12](=[CH:20][C:19]([O:21][CH3:22])=[CH:18][C:17]=3[O:23][CH3:24])[N:11]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C=O)ccc1O
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(O)c(C)c3)nc2c1
Yield: 35.1 %

Procedure:
A mixture of 4-hydroxy-3-methylbenzaldehyde (0.200 g, 1.47 mmol), 2-amino-4,6-dimethoxybenzamide (0.288 g, 1.47 mmol), NaHSO3 (94%, 0.163 g, 1.47 mmol), and p-TsOH.H2O (0.028 g, 0.147 mmol) in DMA (18.4 mL) was heated at reflux for 1 h. The mixture was diluted with EtOAc (300 mL), washed with saturated aqueous NH4Cl (2×150 mL) and brine (75 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was triturated with MeOH and filtered off a yellow solid, which was freeze-dried from MeCN/H2O to provide 2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.161 g, 35%). Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.71 (s, 1H), 10.02 (s, 1H), 7.99 (d, J=1.88 Hz, 1H), 7.89 (dd, J=8.47, 2.29 Hz, 1H), 6.86 (d, J=8.50 Hz, 1H), 6.69 (d, J=2.31 Hz, 1H), 6.48 (d, J=2.31 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.18 (s, 3H); MS (APCI) m/z 313 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C@@H:24]([CH3:28])[C:25]([OH:27])=O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C[N:30](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([O:23][C@@H:24]([CH3:28])[C:25]([NH2:30])=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O[C@@H](C)C(=O)O)cc1OCC2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O[C@@H](C)C(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.3 %

Procedure:
To a solution of (S)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-propionic acid (115 mg, 0.28 mmol) in DMF (3 mL) was added HATU (128 mg, 0.34 mmol), ammonium chloride (23 mg, 0.42 mmol) and triethylamine (67 μL, 0.42 mmol) and the reaction mixture stirred at room temperature (RT) for 5 hours. Further quantities of HATU (106 mg, 0.28 mmol), ammonium chloride (15 mg, 0.28 mmol) and triethylamine (21 μL, 0.28 mmol) were added and the reaction stirred at RT for 16 h. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (10 mL) and the mixture washed with water extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to reverse phase preparative HPLC (C-18 column, 10-90% MeCN in water, 0.1% formic acid, 25 min gradient) to yield 426 as a white solid (68 mg, 58%). LCMS: RT=3.07 min, [M+H]+=384; 1H NMR (400 MHz, d6-DMSO) 9.05 (1H, s), 7.87 (1H, s), 7.86 (1H, s), 7.38 (1H, s), 7.05 (1H, s), 6.41 (1H, s), 5.87 (1H, sept, J=6.6 Hz), 5.17 (1H, q, J=6.9 Hz), 4.59-4.43 (4H, m), 1.47-1.37 (9H, m)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]#[C:12][CH:13]=[O:14].[CH2:15]([Mg]Br)[CH:16]=[CH2:17]>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]#[C:12][CH:13]([OH:14])[CH2:17][CH:16]=[CH2:15]
Reactant: C=CC[Mg]Br
Reactant: O=CC#Cc1ccc2ccccc2c1
Solvent: C1CCOC1
Product: C=CCC(O)C#Cc1ccc2ccccc2c1
Reaction time: 8 h
Yield: 47 %

Procedure:
A solution of 3-(naphthalen-2-yl)propiolaldehyde (3.97 g, 22.0 mmol) in tetrahydrofuran (250 mL) was added to a solution of allyl magnesium bromide (33.1 mL, 33.0 mmol, 1.5 eq.) at 0° C. over 25 min. Stirring was continued overnight and the reaction was carefully quenched with water (50 mL) at 0° C. tert-butyl methyl ether (100 mL) was added, and the layers were stirred and allowed to separate. The aqueous phase was re-extracted with tert-butyl methyl ether (50 mL) and the combined organic layers were dried over sodium sulphate and filtered. The filtrate was concentrated in vacuo. Purification by silica gel chromatography using 1:6 ethyl acetate/petrol as the eluting solvent to afford the desired compound (2.30 g, 47%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.58-2.65 (2H, m, CH2), 4.71 (1H, t, J=6.3 Hz, CH), 5.24-5.31 (2H, m, CH2), 5.95-6.06 (1H, m, CH), 7.46-7.51 (3H, m, ArH), 7.76-7.83 (3H, m, ArH), 7.96 (1H, s, ArH).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1.[OH-].[Na+]>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:8]1
Reactant: C1CNCCN1
Reactant: Clc1cnccn1
Agent: [Na+]
Agent: [OH-]
Product: c1cnc(N2CCNCC2)cn1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To piperazine (48.0 g) dissolved at 110° C. was added 2-chloropyrazine (5.0 ml) and the mixture was stirred at 150° C. for 2 hr. The reaction mixture was poured into an aqueous sodium hydroxide solution and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (6.4 g) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[CH2:18].O.II.C([O-])([O-])=[O:23].[K+].[K+]>C1COCC1.CCOC(C)=O.[Ag]=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]3([CH2:18][O:23]3)[C:6]3[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([F:13])[C:7]=3[O:14][C:15]2=[CH:16][CH:17]=1
Reactant: C=C1c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Reactant: O=C([O-])[O-]
Agent: O=[Ag]
Agent: II
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Fc1nc(Cl)cc2c1Oc1ccc(Br)cc1C21CO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.1 %

Procedure:
To a solution of 7-bromo-3-chloro-1-fluoro-5-methylene-5H-chromeno[2,3-c]pyridine (33 g, 101 mmol) in THF (450 mL) were added successively water (69.2 mL), iodine (51.3 g, 202 mmol) and silver(II) oxide (46.8 g, 202 mmol) at RT. The reaction mixture was stirred at RT for 10 minutes before adding K2CO3 (41.9 g, 303 mmol). After 30 minutes, the reaction mixture was diluted with EtOAc and filtered through a pad of celite. The filter cake was washed with additional EtOAc. The combined filtrate was concentrated under reduced pressure upon which a white solid precipitated. The solid was filtered off. The filtrate was further concentrated under reduced pressure to obtain a residue which was triturated with ether to afford a white precipitate. The solid was filtered off, combined with the first solid and dried under reduced pressure to afford 7-bromo-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,2′-oxirane] (23.56 g, 68.8 mmol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1.[CH2:12]([N:14]=[C:15]=[S:16])[CH3:13]>>[CH2:12]([NH:14][C:15]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)=[S:16])[CH3:13]
Reactant: CCN=C=S
Reactant: NCCCNc1cnccn1
Product: CCNC(=S)NCCCNc1cnccn1

Procedure:
Reacting 2-(3-aminopropylamino)pyrazine with ethyl isothiocyanate by the procedure of Example 53 gives N-ethyl-N'-[3-(2-pyrazinylamino)propyl]thiourea.
Reaction SMILES: [CH3:1][CH:2]([C:19]([OH:21])=[O:20])[C:3]1[CH:4]=[CH:5][C:6]2[S:18][C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:10](=[O:11])[CH2:9][C:7]=2[CH:8]=1.NC1C=CC(C(C)C(O)=[O:31])=CC=1CC(O)=O.C1(S)C=CC=CC=1>>[C:10]([CH2:9][C:7]1[CH:8]=[C:3]([CH:2]([CH3:1])[C:19]([OH:21])=[O:20])[CH:4]=[CH:5][C:6]=1[S:18][C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:11])=[O:31]
Reactant: CC(C(=O)O)c1ccc(N)c(CC(=O)O)c1
Reactant: CC(C(=O)O)c1ccc2c(c1)CC(=O)c1ccccc1S2
Agent: Sc1ccccc1
Product: CC(C(=O)O)c1ccc(Sc2ccccc2)c(CC(=O)O)c1

Procedure:
Preparation-I of the invention for preparing Zaltoprofen is characterized in that 2-(4-amino-3-carboxymethylphenyl)propionic acid or its salt is diazotized and then reacted with thiophenol to give 2-(3-carboxymethyl-4-phenylthiophenyl)propionic acid or its salt, and the resulting product is then subjected to cyclization reaction. Preparation-I is illustrated in the following reaction scheme I: ##STR7## 1) Preparation of 2-(3-carboxymethyl-4-phenylthiophenyl)propionic acid or its salt
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:23]([CH:28]=O)=[CH:24][CH:25]=[CH:26][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1
Reactant: Cc1ccccc1-c1ccccc1C=O
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2C)CC1

Procedure:
186 mg of the target compound (0.50 mmol, 97.9%) was obtained using 1-(2-methoxyphenyl)piperazine (196 mg, 1.02 mmol), 2′-methylbiphenyl-2-carbaldehyde (100 mg, 0.51 mmol) and NaBH(OAc)3 (329 mg, 1.53 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:16][C:17]1[NH:18][C:19]2[C:24]([C:25]=1[CH:26]=O)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17]=1[CH3:16])(=[O:5])=[O:4]
Reactant: Cc1[nH]c2ccccc2c1C=O
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1c(C)[nH]c3ccccc13)C(=O)N2

Procedure:
5-Methylaminosulfonyl-2-oxindole was condensed with 2-methylindole-3-carboxaldehyde to give the title compound.
Reaction SMILES: C1(C(C2C=CC=CC=2)([C@@H]2CCCN2)O)C=CC=CC=1.B(OC)(OC)OC.B.C(N(CC)C1C=CC=CC=1)C.[N+:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:62])[CH2:49][CH2:50][C:51]([C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:52])=[CH:44][CH:43]=1)([O-:41])=[O:40].B.CO.Cl>C(OCC)(=O)C.C1COCC1>[N+:39]([C:42]1[CH:47]=[CH:46][C:45]([C@H:48]([OH:62])[CH2:49][CH2:50][C@H:51]([C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)[OH:52])=[CH:44][CH:43]=1)([O-:41])=[O:40]
Reactant: O=C(CCC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: B
Agent: COB(OC)OC
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc([C@H](O)CC[C@@H](O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 17.5 °C
Reaction time: 0.25 h
Yield: 72.4 %

Procedure:
To (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol (2.71 g, 10.70 mmol) was added THF (80 mL) at 23° C. The very thin suspension was treated with trimethyl borate (1.44 g, 13.86 mmol) over 30 seconds, and the resulting solution was mixed at 23° C. for 1 h. The solution was cooled to 16-19° C., and N,N-diethylaniline borane (21.45 g, 132 mmol) was added dropwise via syringe over 3-5 min (caution: vigorous H2 evolution), while the internal temperature was maintained at 16-19° C. After 15 min, the H2 evolution had ceased. To a separate vessel was added the product from Example 1A (22.04 g, 95 wt %, 63.8 mmol), followed by THF (80 mL), to form an orange slurry. After cooling the slurry to 11° C., the borane solution was transferred via cannula into the dione slurry over 3-5 min. During this period, the internal temperature of the slurry rose to 16° C. After the addition was complete, the reaction was maintained at 20-27° C. for an additional 2.5 h. After reaction completion, the mixture was cooled to 5° C. and methanol (16.7 g, 521 mmol) was added dropwise over 5-10 min, maintaining an internal temperature <20° C. (note: vigorous H2 evolution). After the exotherm had ceased (ca. 10 min), the temperature was adjusted to 23° C., and the reaction was mixed until complete dissolution of the solids had occurred. Ethyl acetate (300 mL) and 1 M HCl (120 mL) were added, and the phases were partitioned. The organic phase was then washed successively with 1 M HCl (2×120 mL), H2O (65 mL), and 10% aq. NaCl (65 mL). The organics were dried over MgSO4, filtered, and concentrated in vacuo. Crystallization of the product occurred during the concentration. The slurry was warmed to 50° C., and heptane (250 mL) was added over 15 min. The slurry was then allowed to mix at 23° C. for 30 min and filtered. The wet cake was washed with 3:1 heptane:ethyl acetate (75 mL), and the orange, crystalline solids were dried at 45° C. for 24 h to provide the title compound (15.35 g, 99.3% ee, 61% yield), which was contaminated with 11% of the meso isomer (vs. dl isomer).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:27])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]=[O:24])=[C:17]([CH3:25])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:26]=1.[CH:28]([Mg]Br)=[CH2:29]>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:11]([CH3:27])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]([OH:24])[CH:28]=[CH2:29])=[C:17]([CH3:25])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:26]=1
Reactant: Cc1c(C=O)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Temperature: -78 °C

Procedure:
A suspension of 2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1-H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (2) (100 mg, 0.25 mmol) in THF (3ml) was cooled to −78° C. Vinylmagnesium bromide (1M in THF, 2.0 mmol) was added dropwise, and the brown suspension was warmed gradually to −10° C. over 2 h. The solution was quenched with saturated ammonium chloride and extracted with ethyl acetate, and concentrated in vacuo to provide the title compound, which was used in the next step without purification, mp 235-236° C., MS (ES) 429 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.O.[OH-].[K+]>C1CCCCC1.C(N)(=O)C1C=CC=CC=1>[Cl:9][CH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1cccnc1C
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: NC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCCCC1
Product: Cc1cccnc1CCl
Reaction time: 7 h
Yield: 107.2 %

Procedure:
A mixture of 107.16 g (1 mole) of 2,3-dimethyl-pyridine and 5 g of benzamide in 400 ml of cyclohexane was heated to reflux while adding over 4 hours 130 g (0.56 mole) of trichloroisocyanuric acid (min. 90% available chlorine) in portions and the mixture was stirred for another 7 hours at reflux and then cooled. Under agitation mix with 500 ml of water and 150 ml of 50% potassium hydroxide were added with stirring to obtain a solution. The decanted organic phases were dried over MgSO4 and evaporated to dryness under reduced pressure to obtain 85 g (60%) of 2-chloromethyl-3-methyl pyridine which slowly colored red with a boiling point of 53° to 57° C. at 3 mm H
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]1[C:22]([C:23]#[N:24])=[CH:21][NH:20][N:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]#[N:24])=[C:18]3[N:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(F)c1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(F)c3)nc12
Yield: 46 %

Procedure:
Reaction of 1-(3-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (234 mg, 1.0 mmol), prepared from commercially available 3-fluoro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (141 mg, 46%). MS (ISP) 306.9 [(M+H)+]; mp 199° C.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]([O:20][C:21]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:22]=1[C:23](O)=[O:24])([CH3:19])[CH3:18]>>[CH:17]([O:20][C:21]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:22]=1[C:23]([N:9]1[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:24])([CH3:19])[CH3:18]
Reactant: c1ccc(C2CNCc3ccccc32)cc1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccccc2C(c2ccccc2)C1

Procedure:
Prepared in analogy to example 1.1 from 4-phenyl-1,2,3,4-tetrahydro-isoquinoline (CA [42923-77-3]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:27][N:26]([CH2:28][C:29]([OH:31])=[O:30])[C:25](=[O:32])[CH2:24]2)=[CH:19][CH:18]=1.O[N:34]1[C:38](=[O:39])[CH2:37][CH2:36][C:35]1=[O:40]>O1CCOCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[CH2:27][N:26]([CH2:28][C:29]([O:31][N:34]3[C:38](=[O:39])[CH2:37][CH2:36][C:35]3=[O:40])=[O:30])[C:25](=[O:32])[CH2:24]2)=[CH:21][CH:22]=1
Reactant: O=C(O)CN1CC(c2ccc(F)cc2)CC1=O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C(CN1CC(c2ccc(F)cc2)CC1=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A total of 31.5 g (150 mmol) of dicyclohexylcarbodiimide is added in portions to a solution of 35.6 g (150 mmol) of 2-[4-(p-fluorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid and 17.2 g (150 mmol) of N-hydroxysuccinimide in 570 ml of dioxan, during which operation the temperature of the reaction mixture should be maintained below 30° by cooling in an ice bath. When the exothermic reaction has ceased, the reaction mixture is stirred for 16 hours at room temperature, the precipitated dicyclohexylurea is filtered off and the filtrate is concentrated to dryness by evaporation under reduced pressure at 70°. The residue is dissolved in 200 ml of ethyl acetate, and diethyl ether is added until the solution starts to turn cloudy. The crystalline precipitate which forms directly is filtered off with suction, washed with diethyl ether and dried. N-[4-(p-fluorophenyl)-2-oxopyrrolidin-1-ylacetoxy]-succinimide having a melting point of 120°-123° is obtained.
Reaction SMILES: [C:1]([C:3]1[C:4](I)=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]1)#[N:2].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O.COCCOC>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>[C:1]([C:3]1[C:4]([C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][C:27]=2[Cl:29])=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOC(CF)C2)c(C#N)c1I
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1sc(N2CCOC(CF)C2)c(C#N)c1-c1ccc(Cl)cc1Cl
Yield: 99.7 %

Procedure:
A mixture of ethyl 4-cyano-5-(2-(fluoromethyl)morpholino)-3-iodothiophene-2-carboxylate (288 mg, 0.000679 mol), 2,4-dichlorophenylboronic acid (262 mg, 0.00137 mol), tetrakis(triphenylphosphine)palladium(0) (51 mg, 0.000044 mol) and sodium carbonate (220 mg, 0.0021 mol) in water (3 mL, 0.1 mol) and 1,2-dimethoxyethane (10 mL, 0.1 mol) was flushed with argon and then irradiated in microwave at 140° C. for 12 min. The reaction mixture was filtered and concentrated in vacuum to afford ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-(2-(fluoromethyl)morpholino)thiophene-2-carboxylate (300 mg, 99%). LCMS: (FA) ES+ 443.15.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][Cl:13].[C:14]([OH:17])(=[O:16])[CH3:15]>C1COCC1>[C:14]([OH:17])(=[O:16])[CH3:15].[Cl:13][CH2:12][CH2:11][CH2:10][CH2:9][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: ClCCCCn1ccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of NaH (1.11 g; 46.3 mmol) in dry THF, imidazole (3 g; 44.1 mmol) dissolved in 15 ml dry THF is added drop-wise at RT. After completion of the addition the mixture is refluxed for 1 h. After cooling to RT 1-bromo-4-chloro-butane (15.2 ml; 132 mmol) is added and the reaction is stirred for 16 h at RT. The mixture is acidified with acetic acid, filtered and evaporated. The residue is taken-up in hydrochloric acid (10%, 80 ml) and extracted with EtOAc (2×20 ml). The aqueous layer is adjusted to pH 8 with carbonate buffer and the product is extracted with Et2O. After addition of 1 eq AcOH the organic layer is dried over MgSO4 and concentrated in vacuo to give the compound (6.78 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH3:8])[N:6]=1.[C:9]1([CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:16](=[O:17])[CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:6]1)[CH3:8]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCn1nnc(N)n1
Product: CCn1nnc(NC(=O)C(c2ccccc2)c2ccccc2)n1

Procedure:
The title compound, white solid, m.p. 169-170° and MS: (neg. ions): m/e=306.2 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-ethyl-2H-tetrazole and diphenylacetyl chloride.