Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:6][C@@H:5]([NH:7][C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10](S(C)(=O)=O)[N:9]=2)[C:4]1([CH3:21])[CH3:20].OC[C@H]1C[C@@H](NC2C(C#N)=CN=C(S(C)=O)N=2)C1(C)C.Cl.[F:43][C:44]([F:54])([F:53])[C:45]1[CH:50]=[CH:49][N:48]=[CH:47][C:46]=1[CH2:51][NH2:52].CCN(C(C)C)C(C)C>C(O)C>[OH:1][CH2:2][C@H:3]1[CH2:6][C@@H:5]([NH:7][C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10]([NH:52][CH2:51][C:46]3[CH:47]=[N:48][CH:49]=[CH:50][C:45]=3[C:44]([F:54])([F:43])[F:53])[N:9]=2)[C:4]1([CH3:21])[CH3:20]
Reactant: NCc1cnccc1C(F)(F)F
Reactant: CC1(C)[C@@H](CO)C[C@H]1Nc1nc(S(C)(=O)=O)ncc1C#N
Agent: CS(=O)c1ncc(C#N)c(N[C@@H]2C[C@H](CO)C2(C)C)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC1(C)[C@@H](CO)C[C@H]1Nc1nc(NCc2cnccc2C(F)(F)F)ncc1C#N
Temperature: 80 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A mixture of 4-(((1R,3S)-3-(hydroxymethyl)-2,2-dimethylcyclobutyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile and 4-(((1R,3S)-3-(hydroxymethyl)-2,2-dimethylcyclobutyl)amino)-2-(methylsulfinyl)pyrimidine-5-carbonitrile (1.0 equiv.), (4-(trifluoromethyl)pyridin-3-yl)methanamine hydrochloride (1.0 equiv.) and DIEA (3.0 equiv.) was combined in ethanol (0.1 M) and heated to 80° C. After 2 h, the reaction mixed was worked up using standard methods to afford the title compound (45% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.71 (d, J=5.08 Hz, 1H), 8.57-8.65 (m, 1H), 8.15-8.25 (m, 2H), 7.65-7.75 (m, 1H), 7.19-7.32 (m, 1H), 4.70 (d, J=5.08 Hz, 2H), 4.23 (t, J=4.88 Hz, 1H), 3.96 (q, J=8.33 Hz, 1H), 3.20-3.29 (m, 1H), 1.73-1.96 (m, 2H), 1.53-1.68 (m, 1H), 1.20 (s, 1H), 0.86 (s, 1H), 0.62-0.77 (m, 6H): MS(ESI) m/z 407.3[M+1]+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[CH:6]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[N:5]=1)[CH3:3].[H-].[Na+].[CH3:29][CH:30]([CH3:33])[CH2:31]I>CN(C)C=O>[CH3:29][CH:30]([CH3:33])[CH2:31][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:4]([CH:2]([CH3:1])[CH3:3])=[N:5][CH:6]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:7]1=[O:15]
Reactant: CC(C)C1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2ccccc21
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A solution of 1,3-dihydro-5-(2-propyl)-3(R,S)-[(benzyloxycarbonyl)-amino]-2H-1,4-benzodiazepin-2-one (500 mg, 1.42 mmol) in dimethylformamide (10 ml) under an atmosphere of nitrogen, was treated with sodium hydride (57 mg of a 57% dispersion in mineral oil, 1.42 mmol) in one portion at 0° C. After 1 h, 2-methylpropyl iodide (0.17 ml, 1.50 mmol) was added and the resulting mixture was stirred at room temperature for 16 h. The solvent was then evaporated and the crude residue partitioned between water (15 ml) and dichloromethane (2×20 ml). The combined organic phase was washed with brine (20 ml), dried (MgSO4) and evaporated. The residue was chromatographed on silica using 1:3 ethyl acetate:petrol as eluent, to afford 1,3-dihydro-1-(2-methylpropyl)-5-(2-propyl) -3(R,S)-[(benzyloxycarbonyl)-amino]-2H-1,4-benzodiazepin-2-one (530 mg, 92%) as a colourless solid. 1H NMR (250 MHz, CDCl3) δ 0.72 (3H, d, J=8 Hz), 0.80 (3H, d, J =8 Hz), 1.02 (3H, d, J=7 Hz), 1.30 (3H, d, J=7 Hz), 1.64 (1H, m), 3.10 (1H, m), 3.42 (1H, dd, J=15 Hz, 5 Hz), 4.30 (1H, dd, J=12.5 Hz, J=7.5 Hz), 5.12 (3H, m), 6.55 (1H, d, J=10 Hz), 7.10-7.70 (9H, m).
Reaction SMILES: CN(C=O)C.P(Cl)(Cl)Cl.[ClH:10].Cl[C:12]([C:22]#[N:23])([CH2:18][CH2:19][CH:20]=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1>[Cl:10][C:22]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=[CH:20][N:23]=1
Reactant: Cl
Reactant: CCOC(=O)C(Cl)(C#N)CCC=O
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccnc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of DMF (5.12 g, 70 mmol) in 80 mL of toluene were added 6.85 g of PCl3 (50 mmol). Anhydrous HCl was introduced for 5 min., keeping the temperature around 60° C. Ethyl 2-chloro-2-cyano-5-oxopentanoate (10.42 g, 50 mmol) in 20 mL of toluene was added in 30 minutes. The resulting mixture was stirred for 1 h at 80° C., cooled to room temperature, quenched with water, extracted with toluene, dried over MgSO4, and concentrated and distilled to give 5.5 g of the title compound (59%).
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[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26](=[O:37])[NH:27][CH2:28][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>C(Cl)Cl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:27][CH2:28][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:37])=[CH:21][CH:20]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CC(=O)NCC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Cc1ccc(C2CCNCC2OCc2ccc3ccccc3c2)cc1)NCC(=O)c1ccccc1

Procedure:
In an analogous manner to that described in Example 22(l), starting from tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{4-[(2-oxo-2-phenyl-ethylcarbamoyl)-methyl]-phenyl}-piperidine-1-carboxylate by cleavage of the BOC group using trifluoroacetic acid in methylene chloride there was obtained (3RS,4RS)-2-{4-[3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-phenyl}-N-(2-oxo-2-phenyl-ethyl)-acetamide trifluoroacetate as a white powder; MS: 493 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9].[F:24]C1C=CC=CC=1S(Cl)(=O)=O>>[F:24][C:7]1[CH:2]=[C:3]([S:8]([NH:11][C@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H](Cc1ccc(O)cc1)NS(=O)(=O)c1ccccc1F
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: O=C(O)[C@@H](Cc1ccc(O)cc1)NS(=O)(=O)c1cccc(F)c1

Procedure:
Following 17a synthetic method, using 2-fluorobenzenesulfonyl chloride (145.62 μL, 1.1 mmol) instead of 2-fluorobenzenesulfonyl chloride gave the final compound 18a as a colorless oil; (77.34 mg, 45.6%). [α]D25: +21.3 (c=0.25, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 7.95-7.76 (m, 3H), 7.41-7.25 (m, 6H), 5.04-4.97 (m, 1H), 3.45-2.26 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.50, 163.90, 160.62, 139.15, 136.64, 133.50, 129.49, 128.40, 126.89, 124.94, 118.56, 115.15, 109.30, 54.04, 36.79; HRMS (ESI): calcd for: C15H14FNO5S [M+Na]+=362.0469, obsd [M+Na]+=362.0475.
Reaction SMILES: CN(OC)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]=[CH:6][C:5]=1[NH2:15].[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C([Li])CCC.O>O1CCCC1.C(OCC)(=O)C>[NH2:15][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:9][C:4]=1[C:3]([C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:27][NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH:33]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cc(OCC(C)C)ccc1N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(N)c(C(=O)c2cccc(CNC(=O)OC(C)(C)C)c2)c1
Temperature: -78 °C

Procedure:
N-Methyl-N-methyloxy-2-amino-5-isobutyloxybenzamide (0.6 g) and N-tert-butoxycarbonyl 3-bromobenzylamine (0.76 g) were dissolved in tetrahydrofuran (18 ml). The solution was cooled to −78° C., to which was added dropwise, while stirring, 9 ml of a hexanoic solution of n-butyl lithium (1.6 mol./L) over 20 minutes. To the reaction mixture were added water (50 ml) and ethyl acetate (50 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was purified by means of a silica gel column chromatography to give 2-amino-3′-tert-butoxycarbonylaminomethyl-5-isobutyloxy-benzophenone as a yellow oily product (0.38 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[I:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[I-:20].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][N+:11]1[CH:15]=[CH:14][N:13]([CH2:21][CH2:22][CH2:23][CH3:24])[CH:12]=1
Reactant: CCCCI
Reactant: CCCCC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Product: CCCCC(C[n+]1ccn(CCCC)c1)c1ccc(Cl)cc1Cl
Product: [I-]
Yield: 65.6 %

Procedure:
1-[β-(2,4-dichlorophenyl)hexyl]imidazole 5.0 g (0.0168 moles) is heated for two hours on a steambath with 3.1g (0.0168 moles) of 1-iodobutane. The reaction is cooled and triturated three times with 50 ml of ether. The oil residue is stripped to dryness to give 5.3g (66%) of the oil product.
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13](=[O:16])([O-])[O-].[Na+].[Na+].[OH2:19]>>[C:13]1(=[O:16])[N:1]([CH:2]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([OH:12])=[O:11])[C:3](=[O:19])[C:4]2=[CH:9][CH:8]=[CH:7][CH:6]=[C:5]12
Reactant: NC(Cc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Reactant: O
Agent: [Na+]
Product: O=C(O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 1.5 h
Yield: 74 %

Procedure:
To a stirred solution of d,1-phenylalanine (4.17 g, 25.0 mmol) and sodium carbonate (2.78 g, 26.25 mmol) in 50 mL of water is added N-carboethoxyphthallmde (5.65 g, 25.0 mmol). The resulting slurry is stirred for 1.5 hour and filtered. The pH of the filtrate is adjusted to 1-2 with 4N hydrochloric acid with stirring. After 20 minutes, the slurry is refiltered and the solid washed with water. The solid is dried in vacuo (60° C., <1 mm) to afford 5.44 g (74%) of 2-phthalimido-3-phenylpropionic acid as a white powder: mp 165°-169° C.; 1H NMR (DMSO-d6, 250 M Hz) δ 12.5(br s, 1H), 7.84(s, 4H), 7.23-7.06 (m, 5H), 5.13 (dd, 1H, J=5.0), 3.26-3.05 (m, 2H); 13C NMR (250 MHz, DMSO-d6) δ 170.0, 167.0, 137.2, 134.8, 130.6, 128.6, 128.2, 126.5, 123.3, 52.8, 33.8. Anal. Calculated for C17H13NO4. Theoretical: C, 69.15; H, 4.44; N, 4.74. Found: C, 69.07; H, 4.34; N, 4.78.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][CH:11]=[C:6]2[C:5]([N:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C:21]2=[O:33])=[CH:4]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl.CO>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][CH:11]=[C:6]2[C:5]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][C:21]2=[O:33])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(N2CCN(C(=O)OC(C)(C)C)CC2=O)c2ccc(OCc3ccccn3)nc21
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(N2CCNCC2=O)c2ccc(OCc3ccccn3)nc21
Reaction time: 1.5 h
Yield: 77.6 %

Procedure:
To a stirred solution of tert-butyl 4-[1-ethyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-oxopiperazine-1-carboxylate (4.952 g, 10.97 mmol) in DCM (20 mL) is added trifluoroacetic acid (4.15 mL, 54.84 mmol) over 2 minutes and the reaction stirred for 90 minutes. The reaction is diluted with MeOH and poured on to a SCX2 ion-exchange column. This is flushed with one column volume of MeOH, and then the product collected in the subsequent one column volume flush of 7 M methanolic ammonia. This solution is then concentrated in vacuo to give a brown oil. This is purified by column chromatography on silica, eluting with 0 to 40% MeOH in EtOAc, to give the title compound as an orange oil (2.989 g, 8.51 mmol). MS (m/z): 352 (M+1).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:16])([F:15])[CH:9]([F:14])[C:10]([F:13])([F:12])[F:11])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:25](#[N:29])[CH2:26][C:27]#[N:28].O>CS(C)=O>[F:15][C:8]([F:16])([CH:9]([F:14])[C:10]([F:13])([F:12])[F:11])[CH2:7][CH:26]([C:25]#[N:29])[C:27]#[N:28]
Reactant: O=S(=O)(OCC(F)(F)C(F)C(F)(F)F)C(F)(F)F
Reactant: N#CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC(C#N)CC(F)(F)C(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.1 %

Procedure:
8.0 g of 2,2,3,4,4,4-hexafluorobutyl trifluoromethanesulfonate was dissolved in 15 ml of dimethyl sulfoxide, and 6.9 g of potassium carbonate was added. 5.0 g of malononitrile dissolved in 15 ml of dimethyl sulfoxide was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured to water and then extracted with diethyl ether. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.0 g of 2-(2,2,3,4,4,4-hexafluorobutyl)malononitrile.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C(O)C.O.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>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8](=[O:10])[CH3:9])=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(=O)c1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccccc1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of 1-(2-bromophenyl)ethanone (3.1 g, 15.57 mmol)-4-chlorophenylboronic acid (2.92 g), (Ph3P)2PdCl2 (bis(triphenylphosphine)palladium(II) dichloride) (1.202 g) and Na2CO3 (3.30 g) in dimethoxyethane-ethanol-water (7:2:3, 50 mL) was heated at 100° C. for 3 hours and concentrated. The concentrate was suspended in dichloromethane (30 mL) and the insoluble material was removed by filtration. The filtrate was loaded onto a silica gel column, eluted with 0%-50% dichloromethane in hexane to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=2)=[CH:4][C:3]=1[O:17][CH3:18].[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:17][CH3:18])[CH:4]=1)[C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1)=[O:23]
Reactant: COc1cc(Nc2nc(C(=O)O)cs2)ccc1Cl
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc(C(=O)O)cs2)ccc1Cl
Temperature: 50 °C
Reaction time: 18 h
Yield: 74.5 %

Procedure:
A mixture of 5.0 g (17 mmol) 2-(4-chloro-3-methoxy-phenylamino)-thiazole-4-carboxylic acid, 9.2 g (44 mmol) 2,4-dichloro-benzoyl chloride and 2.45 g (17.7 mmol) potassium carbonate in 250 mL THF was stirred at 50° C. for 18 h. After evaporation of the volatiles the residue was partitioned between water and ethyl acetate. Organic phases were pooled, dried with MgSO4 and the solvent was removed in vacuo. Crystallisation from n-heptane/ethyl acetate yielded 5.8 g (72%) of the title compound.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+]>S(=O)(=O)(O)O>[N+:14]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])=[CH:3][CH:4]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: CN1CCCC1Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCCC1Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
Dissolve 27.9 g of 2-benzyl-1-methylpyrrolidine in 130 ml of conc. sulfuric acid, and add 100 ml of conc. nitric acid dropwise at 0°, with stirring, to the resulting solution. Continue stirring for a further 30 minutes at room temperature. Pour the mixture into 1 liter of ice water and alkalize with sodium hydroxide solution, with cooling. Extract the thus-produced preparation 4 times with, in each case, 150 ml of diethyl ether. Dry the ether phase over sodium sulfate and concentrate it to a red oil to obtain the title compound at a yield of 33.8 g (96% of theory). The hydrogen fumarate (from isopropanol) melts at 145° to 146°.
Reaction SMILES: CC1C=CC([C@@H](N[C:11]([C@H:13]2[CH2:15][C@@H:14]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])C)=NC=1.Cl.[CH2:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C@@H:32]([NH2:34])[CH3:33])=[CH:28][CH:27]=1)[CH3:24]>>[CH2:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C@@H:32]([NH:34][C:11]([C@H:13]2[CH2:15][C@@H:14]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])[CH3:33])=[CH:28][CH:27]=1)[CH3:24]
Reactant: Cc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)nc1
Reactant: CCOc1ccc([C@H](C)N)cn1
Agent: Cl
Product: CCOc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1

Procedure:
Prepared analogously to Compound 2 using IM46 and commercially available (S)-1-(6-ethoxy-pyridin-3-yl)-ethylamine hydrochloride (Supplier Sial Gmbh, Catalog No 528261-HCl, Lot no LNA098). Yield=0.30 g (39%). 1H NMR (500 MHz, DMSO) δ 8.54 (d, 1H), 8.08 (s, 1H), 7.62 (d, 1H), 7.27 (m, 2H), 7.16 (m, 1H), 7.12 (d, 2H), 6.73 (d, 1H), 4.92 (m, 1H), 4.25 (q, 2H), 2.20 (m, 1H), 1.91 (m, 1H), 1.35 (m, 4H), 1.30 (t, 3H), 1.19 (m, 1H). LC-MS (m/z) 311.4 (MH+), tR=1.45 min (method A).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:26][C:27]1[CH:28]=[C:29]([NH:33][NH2:34])[CH:30]=[CH:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:34]2)[CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc(Cl)c1
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 3-chloro-phenylhydrazine according to the method described for example 91. MS: M=433.3 (M+H)+
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CO>[Cl:8][C:7]1[C:2]([O:13][CH2:12][C:11]([O:15][CH3:16])=[O:14])=[N:3][C:4]([Cl:10])=[C:5]([Cl:9])[CH:6]=1
Reactant: COC(=O)CO
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1nc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 75 %

Procedure:
A reaction vessel was charged with 43.4 g (0.2 mole) of 2,3,5,6-tetrachloropyridine, 108 g (1.2 mole) of methyl glycolate, and 26.6 g (0.25 mole) of anhydrous sodium carbonate. The resulting mixture was stirred and heated to 110° C. at atmospheric pressure with methanol distillate being removed, as it formed, through a distillation head. After 3.5 hours, 6.5 g of methanol distillate was collected. This distillate, along with 64.0 g of additional methanol was added to the reaction mixture and reflux was continued for 1 hour. The solution was cooled to room temperature and anhydrous hydrogen chloride was sparged in slowly, until the solution was acidic to thereby minimize hydrolysis. The solution was refluxed at 70° C. for two more hours, and volatiles were removed in a vacuum. One hundred and eighteen grams of methanol and methyl glycolate were recovered. Perchloroethylene (150 g) was used to extract the ester. After washing the resulting perchloroethylene solution with water and cooling to 20° C., crystals of the product precipitated. These crystals were filtered and dried to give 41.2 g (0.15 mole) of methyl 3,5,6-trichloro-2-pyridinyloxyacetate, m.p. 99°-103° C. The ester product was analyzed by gas-liquid chromatography and was shown to be about 98% pure. Further recrystallization from methanol gave the pure ester, m.p. 104.5°-106° C. In the filtrate from the original crystallization there was another 8.2 g (0.03 mole) of product, and therefore, the total amount of product was 49.4 g (0.18 mole), which represented a 90% yield based on the tetrachloropyridine.
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].Cl[CH2:22][C:23]#[N:24]>C(#N)C>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:22][C:23]#[N:24])[CH2:3][CH2:2]2)=[N:8]1
Reactant: N#CCCl
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#CCN1CCN(c2n[nH]c3ccccc23)CC1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
To a stirred suspension of 3-piperazin-1-yl-1H-indazole (6.0 g, 29.7 mmol) and NaHCO3 (2.7 g, 32.7 mmol) in dry acetonitrile (125 ml) was added chloroacetonitrile (2.1 ml, 31.2 mmol) at room temperature, under nitrogen. The suspension was warmed to reflux for 17.5 hours, cooled to room temperature, and subsequently filtered. The remaining solids were washed with dichloromethane and the combined filtrates were concentrated. The resulting brown oil was purified via flash column chromatography (silica gel, 0°-50% EtOAc/DCM) to give 4.0 g of product as an off-white solid, m.p. 121°-123° C.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[CH:13][C:12]([C:25]([O:27]CC)=[O:26])=[N:11]2)[CH:7]=[CH:8][CH:9]=1.Cl>CO.O>[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[CH:13][C:12]([C:25]([OH:27])=[O:26])=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
8.5 g (152 mmol) of potassium hydroxide are added to a solution of 6 g (15.2 mmol) of ethyl 1-(3-chlorophenyl)-5-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylate from example 4A in 80 ml of methanol and the mixture is stirred for 30 minutes under reflux. The reaction mixture is diluted with water and rendered acidic using 1 molar hydrochloric acid. The mixture is extracted with ethyl acetate. The organic phase is washed with a sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue obtained is crystallized from diethyl ether/pentane. The crystals are collected by suction filtration, washed with a little pentane and dried. 5.2 g (14.2 mmol, 93% yield of theory) of product are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:12]=O)[S:10][CH:11]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9](/[CH:12]=[CH:22]/[CH:23]=[O:24])[S:10][CH:11]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1cc(-c2ccccn2)cs1
Product: O=C/C=C/c1cc(-c2ccccn2)cs1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 4-(2-pyridinyl)-2-thiophenecarboxaldehyde (prepared as described in Reference Example 91) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 216 (M+H)+.