Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:14][CH2:13][C@@H:12]([OH:15])[CH2:11][N:10]([CH3:16])[C:9]1=[O:17])([CH3:4])([CH3:3])[CH3:2].[N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]OS(C(F)(F)F)(=O)=O)=[N+:20]=[N-:21].C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:14][CH2:13][C@@H:12]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:19]=[N+:20]=[N-:21])[CH2:11][N:10]([CH3:16])[C:9]1=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1C[C@H](O)CC[C@H](NC(=O)OC(C)(C)C)C1=O
Reactant: [N-]=[N+]=NCCCCCCOS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C[C@H](OCCCCCCN=[N+]=[N-])CC[C@H](NC(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
To a stirred solution of ((3S,6R)-6-hydroxy-1-methyl-2-oxo-azepan-3-yl)-carbamic acid tert-butyl ester (0.70 g, 2.6 mmol) in THF (5 mL) cooled to −78° C. is added NaN(Si(CH3)3)2 (2.8 mL 1M THF, 2.8 mmol). After 10 min trifluoro-methanesulfonic acid 6-azido-hexyl ester (0.76 g, 3.1 mmol) is added neat and stirred for 10 min at −78° C. then warmed and stirred at room temperature for 1 h. NaHCO3 (5 mL 1M H2O) is added and the solution is partitioned with H2O/EtOAc, the EtOAc extract is dried with Na2SO4 and evaporated to an oil. The oil is adsorbed on silica and chromatographed (20% EtOAc/CH2Cl2) to give 0.32 g (32%) of [(3S,6R)-6-(6-azido-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester as an oil. 1H NMR (CDCl3) δ 1.34 (s, 9H), 1.24-2.1 (m, 12H), 2.95 (s, 3H), 3.1-3.35 (m, 6H), 3.44 (m, 1H), 3.55 (d, 1H), 4.2 (m, 1H).
Reaction SMILES: C1(S([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([N:19](CC3C=C(Br)C=CC=3OCC(C)=C)[CH2:20][CH3:21])=[N:17]C=2)=[O:12])(=O)=O)C=CC=CC=1.C([NH2:37])C>CO>[CH2:20]([NH:19][C:16]1[N:17]=[N:37][C:13]([C:11]([NH2:10])=[O:12])=[CH:14][CH:15]=1)[CH3:21]
Reactant: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)NS(=O)(=O)c2ccccc2)cn1
Reactant: CCN
Solvent: CO
Product: CCNc1ccc(C(N)=O)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 6-chloropyridazine-3-carboxamide (reference example 13, paragraphs 1 to 3) (28.5 g, 0.18 mol) in methanol (200 ml) was treated with aqueous ethylamine (70% solution, 77 ml). The reaction was heated at reflux for 31/2 hours. The reaction was allowed to cool to ambient temperature and stand overnight. The precipitate was filtered and washed with a small volume of water and dried to give 6-(ethylamino)pyridazine-3-carboxamide as pink solid (8.9 g). [The filtrates were evaporated to a small volume diluted with cold water (100 ml) and more of the desired solid was filtered-off, washed with water and dried (12.8 g). Total yield (21.7 g, 72%)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.Cl.CC[OH:35]>[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([CH3:31])([CH3:30])[C:28]([NH2:29])=[O:35])=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Cn1c(-c2ccccc2)nc(-c2ccc(C(C)(C)C#N)cc2)c1Sc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(-c2ccccc2)nc(-c2ccc(C(C)(C)C(N)=O)cc2)c1Sc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A suspension of 2-(4-{5-[(4-chlorophenyl)thio]-1-methyl-2-phenyl-1H-imidazol-4-yl}phenyl)-2-methylpropanenitrile (Example 76, 120 mg, 0.270 mmol) in 3 mL of EtOH and 2 mL of 2 N NaOH was stirred at 90° C. over two days. The mixture was neutralized with 2 N HCl (pH=ca 5) and the product was extracted with EtOAc. The extracts were concentrated to dryness, and the residue was purified by reverse phase HPLC to afford the title compound. 1H NMR (500 MHz, (CD3OD): 7.88 (d, 2H), 7.74 (m, 2H), 7.58 (m, 3H), 7.44 (d, 2H), 7.26 (d, 2H), 7.31 (d, 2H), 3.64 (s, 3H), 1.58 (s, 6H). LCMS: m/z 462 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.[ClH:36]>O1CCCC1.ClCCl>[ClH:36].[OH:1][C@H:2]([CH2:3][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@H]2CO2)c1
Reactant: C1CCNC1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@H](O)CN2CCCC2)c1
Temperature: 45 °C
Yield: 83.1 %

Procedure:
To (S)-1-(1-(oxiran-2-ylmethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)-pyridin-2(1H)-one (200 mg, 0.48 mmol) in tetrahydrofuran (5 mL) was added LiClO4 (775 mg, 7.28 mmol) followed by pyrrolidine (0.41 mL, 4.9 mmol). The reaction mixture was heated in a 45° C. oil bath for 4.5 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml), washed with water (25 mL) and brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The material was purified by column chromatography (silica gel, 9:1 CH2Cl2/MeOH to 90:9:1 CH2Cl2/MeOH/conc. NH4OH). The dried residue (197 mg, 0.41 mmol) was dissolved in dichloromethane (10 mL) and HCl (1.25 M solution in methanol, 0.36 mL, 0.45 mmol) was added. The mixture was concentrated under reduced pressure and dried to afford the title compound (194 mg, 78%) as a yellow solid: mp 116-119° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.65 (br s, 1H), 8.21 (s, 1H), 8.02-8.00 (m, 2H), 7.89-7.82 (m, 5H), 7.47 (dd, J=9.0, 2.0 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.74 (dd, J=7.0, 2.0 Hz, 1H), 5.75 (br s, 1H), 4.57-4.47 (m, 2H), 4.33 (br s, 1H), 3.56-2.90 (br m, 6H), 1.89 (br s, 4H); ESI MS m/z 483 [M+H]+; HPLC (Method B)>99% (AUC), tR=14.5 min; [α]23D +10.8° (c 0.11, Methanol).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].C(=O)(O)[O-].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>ClCCl>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:10][CH2:11]1)=[O:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(C(=O)C2CCNCC2)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(=O)C2CCN(C(=O)OCc3ccccc3)CC2)c(O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
To a stirred, ice-cooled mixture of 36.1 g of 4-(2-hydroxy-4-methoxybenzoyl)piperidine, 16.3 g of sodium bicarbonate and 350 ml of dichloromethane, was added dropwise 22.9 ml of benzyl chloroformate in dichloromethane. After the addition was complete, the mixture was stirred at ambient temperature for 1.5 hrs, filtered and the filtrate concentrated to an oil. The oil crystallized. The crystals were collected, washed with hexane and dried to yield 42.4 g (76.5%) of product. Recrystallization from isopropanol gave the analytical sample, mp, 89°-91°.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.ClC1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]=[C:26]2[S:35][N:36]=[C:37]([CH3:38])[C:25]=12>CN1CCCC1=O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([N:4]([CH2:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[C:3]2[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]=[C:26]3[S:35][N:36]=[C:37]([CH3:38])[C:25]=23)(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cnc2snc(C)c2c1Cl
Reactant: COc1ccc(S(=O)(=O)N(C)Cc2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cnc2snc(C)c2c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a stirred mixture of 0.366 g (8.4 mmol) of sodium hydride (60% in oil) in 10 ml of dry 1-methyl-2-pyrrolidinone was added (portionwise) 2.34 g (8.4 mmol) of methyl (4-methoxybenzenesulfonyl)pyridin-3-ylmethyl-amine. The mixture was stirred at room temperature until gas evolution ceased and 1.80 g of (7.0 mmol) of ethyl 4-chloro-3-methylisothiazolo[5,4-b]pyridine-5-carboxylate added. The mixture was heated at 80-90° C. for 44 hours, the solvent removed under vacuum and the residue diluted with water. The mixture was extracted with ethyl acetate and the extract washed with 2N citric acid, H2O, 1 N NaHCO3, brine and dried (Na2SO4). The solution was filtered through a thin pad of hydrous magnesium silicate and the pad washed with ethyl acetate. The filtrate was concentrated to dryness to give 2.39 g of ethyl 4-[(4-methoxybenzenesulfonyl)-pyridin-3-ylmethylamino]-3-methylisothiazolo[5,4-b]pyridine-5-carboxylate as a yellow solid, m.p. 142-144° C.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCOCC.[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[O:24])[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)([OH:24])[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1
Reactant: Br[Mg]C1CCCC1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1Nc2cc(Cl)ccc2C1(O)C1CCCC1
Temperature: 25 °C

Procedure:
A solution of cyclopentyl magnesium bromide in ether (2.0 M, 12.5 mL, 25 mmol) (Aldrich) was added dropwise to a suspension of 6-chloroisatin (1.82 g, 10 mmol) (prepared according to the procedure of Kraynack, E. A. et al., supra) in tetrahydrofuran (40 mL) under argon with cooling in a −25° C. bath and magnetic stirring at such a rate that reaction temperature was kept below −10° C. (approximately 30 minutes). Cooling bath was then removed and mixture allowed to warm to room temperature. After stirring for an additional 1 hour, 15% aqueous ammonium chloride solution (50 mL) was added and mixture extracted with ethyl acetate (2×75 mL). Ethyl acetate layers were then washed with water (75 mL), brine (75 mL), combined, dried (MgSO4), filtered and concentrated. Residue was stirred in dichloromethane (100 mL) at room temperature for 30 minutes and filtered to give crude rac-6-chloro-3-cyclopentyl-3-hydroxy-1,3-dihydro-indol-2-one as a white powder. (Yield 0.62 g, 24.6%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[NH:16][N:15]=[CH:14][C:12]=2[N:13]=1.IC>O1CCCC1>[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[N:16]([CH3:1])[N:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CC(C)(C)[O-]
Reactant: Clc1ncc2[nH]ncc2n1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1ncc2nc(Cl)ncc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.8 %

Procedure:
Potassium t-butoxide (1.68 g, 14.67 mmol, 1.14 equiv) was added to a solution of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine (2.1 g, 12.91 mmol, 1.00 equiv, 95%) in tetrahydrofuran (50 mL) at 0° C. After the reaction mixture was stirred at 0° C. for 30 min, iodomethane (3 g, 20.71 mmol, 1.60 equiv, 98%) was added dropwise at 0° C. The resulting solution was stirred for 4.5 h at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/ethyl acetate (10/1) to give 300 mg (14%) of 5-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine as a white solid.
Reaction SMILES: [BH4-].[Na+].O.[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([F:38])[C:25]([F:26])=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH:36]=[O:37])=[CH:29][CH:28]=3)[CH:23]=[CH:22][CH2:21]2)=[CH:16][CH:15]=1)(=[O:7])[CH:5]=[CH2:6]>O1CCOCC1>[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([F:38])[C:25]([F:26])=[C:24]([C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][OH:37])=[CH:31][CH:32]=3)[CH:23]=[CH:22][CH2:21]2)=[CH:16][CH:15]=1)(=[O:7])[CH:5]=[CH2:6]
Reactant: C=CC(=O)OCCCCOc1ccc(C2(F)CC=CC(c3ccc(CCCC=O)cc3)=C2F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=CC(=O)OCCCCOc1ccc(C2(F)CC=CC(c3ccc(CCCCO)cc3)=C2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A mixture of 0.119 g of sodium borohydride and 10 ml of water was treated dropwise at 0° C. with a solution of 5.00 g of 4-[2',3'-difluoro-4"-(4-oxo-butyl)-1,2':4',1"-terphenyl-4-yloxy]-butyl acrylate in 50 ml of dioxan. The mixture was subsequently stirred at room temperature for 1 hour. The reaction mixture was poured into 50 ml of water, the phases were separated and the aqueous phase was extracted twice with 25 ml of ethyl acetate each time. The combined organic phases were washed twice with 50 ml of water each time, dried over magnesium sulphate, filtered and concentrated. Chromatographic purification of the residue on silica gel with cyclohexane/ethyl acetate (vol. 8:2) gave 4.49 g of 4-[2',3'-difluoro-4"-(4-hydroxy-butyl)-1,2':4',1"-terphenyl -4-yloxy]-butyl acrylate.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13](Br)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:16])[CH:22]=3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCCCc1cc(Br)c2ncccc2c1
Product: CCCCc1cc(-c2cccc(Cl)c2)c2ncccc2c1

Procedure:
6-(n-butyl)-8-bromoquinoline and 3-chlorobenzene boronic acid can be combined to form 6-(n-butyl)-8-(3-chlorophenyl)quinoline,
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:21])=[C:16]([F:20])[C:17]=3[Cl:19])[C:12](=[O:22])[C:11]([C:23]([O:25]CC)=[O:24])=[CH:10]2)[CH:5]=[N:6][C:7]=1[Cl:8].Cl>>[NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:21])=[C:16]([F:20])[C:17]=3[Cl:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1cn(-c2cnc(Cl)c(N)c2)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)cnc1Cl
Yield: 92.2 %

Procedure:
To 100 mg of ethyl 1-(5-amino-6-chloropyridine-3-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate was added 3 ml of concentrated hydrochloric acid, and the mixture was heated under reflux for 2 hours. The reaction solution was allowed to cool, and the solid precipitated was collected by filtration. The solid was washed with ethanol to obtain 86 mg of the title compound as a pale yellow powder.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6][NH:5]1.Cl[CH2:21][CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:25]=1[F:34].O>CN(C=O)C>[F:34][C:25]1[C:26]([C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=[CH:29][C:24]=1/[CH:23]=[CH:22]/[CH2:21][N:5]1[C:4](=[O:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6]1
Reactant: Fc1c(C=CCCl)cccc1C(F)(F)F
Reactant: CCOC(=O)Cc1n[nH]c(=O)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nn(C/C=C/c2cccc(C(F)(F)F)c2F)c(=O)c2ccccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
64.8 g (1.62 mol) of a 60% suspension of sodium hydride in oil are added portionwise under a nitrogen atmosphere to a solution of 341.9 g (1.472 mol) of ethyl 3,4-dihydro-4-oxo-1-phthalazineacetate (prepared according to the process described in Patent EP 2895) in 5 l of anhydrous DMF, the temperature being maintained between 25° and 30° C. The addition lasts approximately one hour. The mixture is then heated for 30 minutes at 60° C. The mixture is cooled to room temperature and a mixture of 421.6 g (1.76 mol) of 1-(3-chloro-1-propenyl) -2-fluoro-3-(trifluoromethyl) benzene (prepared according to Example D1) and 98 ml of anhydrous DMF is added over 30 min. The temperature rises to 38° to 40° C. The mixture is then heated for 3 hours at 60° C. and is then allowed to return to room temperature overnight. The mixture is poured into 7 l of water and extracted with 2 times 4 l of ethyl acetate. Washing is carried out with water, the organic phase is dried over Na2SO4, filtered and evaporated under vacuum and the solid obtained is recrystallized from a hexane/ethyl acetate (4/1 ) mixture. Weight obtained: 474.7 g (Yd.=74%) M.p.=104°-106° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:42])=[C:5]([C:26]([O:28][CH2:29][CH2:30][N:31]2C(=O)C3=CC=CC=C3C2=O)=[O:27])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][C:18](=O)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]=1[N+:8]([O-:10])=[O:9].O.NN.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:42])=[C:5]([C:26]([O:28][CH2:29][CH2:30][NH2:31])=[O:27])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC1=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C(c2ccccc2OC(=O)c2ccccc2)C([N+](=O)[O-])=C(C)N1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1=C(C(=O)OCCN)C(c2ccccc2OCc2ccccc2)C([N+](=O)[O-])=C(C)N1
Reaction time: 2 h

Procedure:
14.5 g (26.22 mmol) of β-phthalimido-ethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-benzoyloxyphenyl)-pyridine-5-carboxylate are suspended in 260 ml of ethanol, and 7 ml (140 mmol) of hydrazine hydrate in 20 ml of ethanol are added dropwise, while boiling. The mixture is boiled for 2 hours, cooled and filtered with suction. The resulting solid product is stirred with 200 mmol of 0.5 N sodium hydroxide solution for 30 minutes, filtered off with suction, washed with water and ethanol and dried. 9.5 g of crystals which are red-orange in color and have a melting point of 216° C. are obtained.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[S:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cu][C:17]#[N:18].N>CN1CCCC1>[N:1]1([CH:6]([C:10]2[S:11][CH:12]=[C:13]([C:17]#[N:18])[CH:14]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCC(c1cc(Br)cs1)n1ccnc1
Reactant: N#C[Cu]
Agent: CN1CCCC1
Agent: N
Product: CCCC(c1cc(C#N)cs1)n1ccnc1
Temperature: 180 °C
Reaction time: 5 h
Yield: 78.1 %

Procedure:
0.3 g of 2-[1-(1-imidazolyl)-butyl]-4-bromothiophene is dissolved in 5 ml of N-methylpyrrolidine and mixed with 0.3 g of copper(I) cyanide and stirred for 5 hours at 180° C. Then the reaction mixture is poured into 100 ml of dilute ammonia solution and extracted with ethyl acetate. The ethyl acetate phase is concentrated by evaporation in a vacuum and distilled on a bulb tube, boiling point 180° C./0.03 mbar. 0.190 g of 2-[1-(1-imidazolyl)-butyl]-thiophene-4-carbonitrile is obtained.
Reaction SMILES: [Cl-].[CH3:2][Ga+:3][CH3:4].[CH3:5][N:6]([CH2:8][CH2:9][CH2:10][Li])[CH3:7]>CCCCC>[CH3:5][N:6]([CH2:8][CH2:9][CH2:10][Ga:3]([CH3:4])[CH3:2])[CH3:7]
Reactant: C[Ga+]C
Reactant: [Li]CCCN(C)C
Agent: [Cl-]
Solvent: CCCCC
Product: CN(C)CCC[Ga](C)C
Reaction time: 24 h

Procedure:
12 g (89 mmol) of dimethylgallium chloride are made ready for use in 300 ml of pentane and cooled to -78°. 8.3 g (89 mmol) of dimethylaminopropyllithium are added thereto as a solid. The solution is allowed to come to room temperature and is stirred for a further 24 hours. The lithium chloride precipitated is separated off, the solvent is removed and the residue is distilled in vacuo. Dimethylaminopropyl(dimethyl)gallium is obtained as a white solid with a B.p. of 65°/10 mbar.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1>>[C:9]1([C:3]2[N:4]=[C:5]([NH2:8])[N:6]=[N:7][C:2]=2[O:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][C:16]([F:15])([F:25])[F:26])[CH:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: Oc1cccc(OC(F)(F)F)c1
Product: Nc1nnc(Oc2cccc(OC(F)(F)F)c2)c(-c2ccccc2)n1
Yield: 3.2 %

Procedure:
5-Phenyl-6-[3-(trifluoromethoxy)phenoxy]-1,2,4-triazin-3-amine (22 mg, 3%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3-(trifluoromethoxy)phenol (0.42 g, 2.39 mmol) according to the general procedure of Example 3.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH2:5][N:6]1[C:11](=[O:12])[C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:9]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:8]=[C:7]1SC.[C:30]1([CH2:36][CH2:37][CH2:38][NH2:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[C:11](=[O:12])[N:6]3[CH:5]=[C:4]([CH3:3])[N:39]([CH2:38][CH2:37][CH2:36][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:7]3=[N:8][C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)n1CC#C[Si](C)(C)C
Reactant: NCCCc1ccccc1
Product: Cc1cn2c(=O)c(-c3ccc(F)cc3)c(-c3ccncc3)nc2n1CCCc1ccccc1
Temperature: 190 °C

Procedure:
A neat mixture of 3-(3-trimethylsilyl-2-propynyl)-5-(4-fluorophenyl)-2-methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone (50 mg, 0.12 mmol) and 3-phenyl-1-propylamine (67 mg, 0.47 mmol) was warmed to 190° C. for 17 h. After cooling to 23° C., the reaction mixture was applied directly to purification via flash chromatography (step gradient 1%MeOH:CHCl3 then 2%, then 3%;) to afford the desired product: MS (m/z) 439 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[CH2:40][C:41]1[C:42]([C:49]2[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:56])=[N:43][O:44][C:45]=1[CH:46]1[CH2:48][CH2:47]1>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:40][C:41]2[C:42]([C:49]3[C:50]([Cl:56])=[CH:51][CH:52]=[CH:53][C:54]=3[Cl:55])=[N:43][O:44][C:45]=2[CH:46]2[CH2:48][CH2:47]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.2 %

Procedure:
To a solution of 13.05 g (64.83 mmol) of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester in THF (120 mL) is added at 0° C. (ice bath) 18-crown-6 (19.6 g, 73.48 mmol) and potassium tertiary butoxide (8.68 g, 73.48 mmol). The resulting mixture is stirred for 20 min at room temperature, and added dropwise to a solution of 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (15 g, 43.22 mmol) in 75 mL of THF. The resulting mixture was stirred at room temperature for 14 h. To the reaction mixture is added water (500 mL), and it is extracted with EtOAc (3×200 mL). The organics are washed with brine (2×250 mL), dried (Na2SO4), filtered and concentrated to afford a crude which is purified by flash chromatography eluting with Hexanes/EtOAc 8:2, to obtain the title compound as a pale yellow oil (16 g (79%)). MS (m/e): 467 (M+1)