Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[OH:22])[C:16]([OH:18])=[O:17].[OH-].[Na+].Cl>C(O)C.O>[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:16]([OH:18])=[O:17]
Reactant: CCCCCCCCCCBr
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCOc1ccc(C(=O)O)cc1Cl
Yield: 30.6 %

Procedure:
In 100 ml of ethanol were dissolved 18 g of 1-bromo-n-decane and 9 g of 3-chloro-4-hydroxybenzoic acid, an aqueous solution of 40 g of sodium hydroxide in 100 ml of water was added to the above solution, and the mixture was heated and refluxed for 10 hours. Then the reacted solution was made weakly acidic by an addition of 1N hydrochloric acid and thrown in an enough quantity of water to precipitate the reaction product. The precipitate was recovered by filtration and recrystallized from ethanol to obtain 5 g of 3-chloro-4-decyloxybenzoic acid, then 15 g of thionyl chloride was added to 3 g of 3-chloro-4-decyloxybenzoic acid, and a reaction was carried out under reflux for 3 hours. The unreacted thionyl chloride was removed by distillation under a reduced pressure to obtain 3-chloro-4-decyloxybenzoic acid chloride quantitatively. Then the product was dissolved in a diethyl ether/THF (1/1) mixed solvent, 2.3 g of 4,4'-acetoxybiphenol and 2 g of triethylamine were added to the solution successively, and a reaction was carried out at room temperature with stirring overnight. The reacted solution was washed three times with 1N hydrochloric acid, a 1N aqueous solution of sodium hydrogencarbonate and water, in this order, and the organic phase was dried with anhydrous sodium sulfate. The solvent was evaporated, the reaction product was recovered by the silica gel chromatography, then the reaction product was dissolved in 100 ml of a THF/methanol (9/1) mixed solvent, a 1N aqueous solution of lithium hydroxide was added to the resulting solution which was cooled with ice-cold water, and a reaction was carried out with stirring for 30 minutes. Then the reacted solution was made weakly acidic by addition of 1N hydrochloric acid, extracted with a diethyl ether/benzene (1/1) mixed solvent, and the extract was washed three times with 1N hydrochloric acid, a 1N aqueous solution of sodium hydrogencarbonate and water in this order. The organic phase was recovered and dried with anhydrous magnesium sulfate, and the organic solvent was evaporated to obtain a product. The product was recrystallized from an n-hexane/ethanol mixed solvent. The compound in which Z is fluorine can be similarly obtained by using 3-fluoro-4-hydroxybenzoic acid instead of 3-chloro-4-hydroxybenzoic acid.
Reaction SMILES: [CH2:1]([N:3]([CH3:14])[C:4]1[C:12]([CH3:13])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1)[CH3:2].[CH:15](NC)(C)C>>[CH:1]([N:3]([CH3:14])[C:4]1[C:12]([CH3:13])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1)([CH3:15])[CH3:2]
Reactant: CCN(C)c1ncc(C(=O)O)cc1C
Reactant: CNC(C)C
Product: Cc1cc(C(=O)O)cnc1N(C)C(C)C

Procedure:
The title compound is prepared in analogy to 6-(ethyl-methyl-amino)-5-methyl-nicotinic acid using N-isopropyl-methyl-amine; LC-MS: tR=0.58 min, [M+1]+=209.10; 1H NMR (D6-DMSO): δ 1.23 (d, J=6.5 Hz, 6H), 2.40 (s, 3H), 2.97 (s, 3H), 4.22 (hept, J=6.8 Hz, 1H), 8.07 (s, 1H), 8.43 (d, J=2.0 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:7]=1)=[O:5])C.[ClH:17]>>[ClH:17].[CH2:13]([C:8]1[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:11]=[C:10]([CH3:12])[CH:9]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1cc(C)cc(CC(C)C)n1
Agent: Cl
Product: Cc1cc(CC(C)C)nc(C(=O)O)c1

Procedure:
A solution of 6-isobutyl-4-methyl-pyridine-2-carboxylic acid ethyl ester (174 mg, 0.78 mmol) in 6 N aq. HCl (20 mL) is stirred at 65° C. for 18 h. The solvent is evaporated and the remaining residue is dried under HV to give give 6-isobutyl-4-methyl-pyridine-2-carboxylic acid hydrochloride as green oil; LC-MS: tR=0.58 min, [M+1]+=194.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:17]([C:18]([O:20]CC[Si](C)(C)C)=[O:19])=[C:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:15]=[C:14]([CH3:33])[CH:13]=2)[N:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.Cl>O1CCCC1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:15]=[C:14]([CH3:33])[CH:13]=2)[N:6]=1
Reactant: COc1cc(OC)nc(Oc2cc(C)nc(-c3ccccc3)c2C(=O)OCC[Si](C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Oc2cc(C)nc(-c3ccccc3)c2C(=O)O)n1
Yield: 61.2 %

Procedure:
2.0 g (0.004 mol) of 2-trimethylsilylethyl 4-(4,6-dimethoxypyrimidin-2-yloxy)-2-phenyl-6-methylnicotinate was dissolved in 30 ml of tetrahydrofuran, and 12 ml of 1 mol aqueous solution of tetrabutylammonium fluoride was added thereto. The resultant mixture was stirred at room temperature for one night. The reaction mixture was then poured into 200 ml of water, and 1.5 ml of concentrated hydrochloric acid was added thereto. The resultant reaction mixture was extracted with ethyl acetate, and was washed with water. The resultant reaction mixture was then dried with magnesium sulfate, and the solvent was distilled off to obtain 0.9 g of the aimed product.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:9][CH:8]=1)=[O:6]>CO.C1COCC1>[C:22]([O:21][C:19]([NH:18][CH2:17][CH2:16][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:15]=2)[CH:11]=[CH:12]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)c1ccc2ccn(CCNC(=O)OC(C)(C)C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCn1ccc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 68 h

Procedure:
Sodium hydroxide (1N, 6.0 mL, 6.00 mmol) was added to a solution of 1-(2-tert-Butoxycarbonylamino-ethyl)-1H-indole-6-carboxylic acid methyl ester (0.501 g, 1.57 mmol) in methanol (12 mL) and THF (4.0 mL). The reaction was stirred at room temperature for 68 hr. The reaction was concentrated in vacuo. The aqueous residue was acidified to pH˜1 with 1N HCl and extracted with ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was carried forward without purification. ESI-MS m/z 327 (M+Na)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[CH2:16][O:15][CH2:14][CH2:13][NH:12]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[CH3:10][C@@H:11]1[N:12]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:13][CH2:14][O:15][CH2:16]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C[C@H]1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H]1COCCN1c1ccc(C#N)cc1
Temperature: 110 °C
Reaction time: 70 h
Yield: 43.4 %

Procedure:
4-Fluorobenzonitrile (359 mg, 2.97 mmol), (S)-3-methylmorpholine (150 mg, 1.48 mmol) and K2CO3 were suspended in DMSO (1.5 ml). The mixture was stirred for 70 hours at 110° C. in a closed high-pressure flask. The reaction was cooled, diluted with water (50 ml) and extracted with EtOAc (3*20 ml). Combined organics were washed with water (20 ml), dried over MgSO4 and evaporated. The product was purified by flash chromatography using pet.ether/EtOAc (3:1) as eluent to give 130 mg (43%) of the title compound as pale solids.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[O:11][C:10](=[O:12])[CH:9]=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([C:27]1[CH:32]=[C:31]([CH2:33][OH:34])[C:30]([CH3:35])=[CH:29][C:28]=1[S:36]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:23]([C:27]1[CH:32]=[C:31]([CH2:33][OH:34])[C:30]([CH3:35])=[CH:29][C:28]=1[S:36][C:9]1[C:10](=[O:12])[O:11][C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)[CH2:7][C:8]=1[OH:13])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C1C=C(O)CC(CCc2cccc(O)c2)(C2CCCC2)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3cccc(O)c3)(C3CCCC3)OC2=O)c(C(C)(C)C)cc1CO
Yield: 81 %

Procedure:
The title compound was prepared as described in General Method 9 using 6-cyclopentyl-4-hydroxy-6-[2-(3-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (0.26 g, 0.9 mmol) from Example AAAAA, toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF; 0.35 g, 1.0 mmol), 0.54 g (3.9 mmol) of K2CO3 in DMF (10 mL). The product was purified by column chromatography on silica gel eluting with EtOAc:hexane:CH2Cl2 (1:1:1) to afford the product in 81% yield as a white solid (m.p. 172-174° C.). 1H-NMR (DMSO-d6) δ 1.47 (s, 9 H), 1.4-1.7 (m, 8 H, 1.9 (s, 3 H), 1.95-2.1 (m, 2 H), 2.35 (t, 1 H), 2.5-2.6 (m, 2 H, partially obscured by DMSO), 2.7 (q, 2 H), 4.35 (s, 2 H), 4.95 (bs, 1 H), 6.55 (t, 3 H), 6.65 (s, 1 H), 7.05 (t, 1 H), 7.25 (s, 1 H), 9.25 (s, 1 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.Br[CH2:12][C:13]1[N:14]([CH3:29])[C:15]2[C:20]([N:21]=1)=[C:19]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[N:18]=[C:17]([Cl:28])[N:16]=2>>[Cl:28][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[C:13]([CH2:12][N:1]3[CH2:6][CH2:5][CH:4]([C:7]([OH:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]3)[N:14]2[CH3:29])=[C:19]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:18]=1
Reactant: Cn1c(CBr)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)(O)C1CCNCC1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Yield: 93.2 %

Procedure:
2-(Piperidin-4-yl)propan-2-ol (0.73 g) was reacted with 4-(8-(bromomethyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (1.6 g) via General Procedure C to yield 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (1.76 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>C(Cl)Cl.CO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)=[CH:36][CH:35]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)cc2)CC1
Yield: 62 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-((2,5-dichloropyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 62% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.53 (d, 1H, J=8.2 Hz), 8.11 (s, 1H), 7.84 (dd, 1H, J=8.2, 1.3 Hz), 7.54 (m, 1H), 7.45 (d, 2H, J=8.2 Hz), 7.22 (m, 3H), 3.47 (s, 2H), 2.72 (s, 6H), 2.48 (bs, 8H), 2.29 (s, 3H); MS (ESI): 516.3 [M+H]+, 258.8 [M+2H]2+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[S:12][C:13]([C:16]3([O:26][CH3:27])[CH2:20][CH2:19][N:18]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:17]3)=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:29][OH:30]>>[OH:30][N:29]=[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[S:12][C:13]([C:16]3([O:26][CH3:27])[CH2:20][CH2:19][N:18]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:17]3)=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: NO
Reactant: COC1(c2ccc(Sc3ccc(C(C)=O)cc3)s2)CCN(CC(F)(F)F)C1
Agent: Cl
Product: COC1(c2ccc(Sc3ccc(C(C)=NO)cc3)s2)CCN(CC(F)(F)F)C1
Yield: 63 %

Procedure:
Using an analogous procedure to that described in Example 27, 3-[2-(4-acetylphenylthio)thien-5-yl]-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine was reacted with hydroxylamine hydrochloride to give 3-{2-[4-(1-hydroxyiminoethyl)phenylthio]thien-5-yl}-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine as a gum in 63% yield.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])[C:18]3[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.[IH:33]>C(OCC)C>[IH:33].[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[N:16]=[C:15]1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1)#[N:25]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCCCC#N)CC1
Agent: I
Solvent: CCOCC
Solvent: ClCCl
Product: N#CCCCCn1c(N2CCCNCC2)nc2ccccc21
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(4-cyanobutyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.3 mmol) and dichloromethane (5 mL). Add aqueous 48% hydriodic acid solution (0.6 mmol). Heat to 40° C. After 6 hours, cool to ambient temperature dilute with diethyl ether (20 mL), and collect the solid to give the title compound.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10]([OH:12])=[O:11].[CH3:17][S:18]SC>O1CCCC1.CCOCC>[F:6][C:7]1[C:8]([S:18][CH3:17])=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1c(C(=O)O)ccc(F)c1F
Temperature: -70 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
n-Butyllithium (2.5 m in hexane, 35 ml) was added with cooling to a solution of 3,4-difluorobenzoic acid (5.5 g) in dry tetrahydrofuran while maintaining the temperature below -70° C. The mixture was stirred for 2 hours at -70° C. A solution of dimethyl disulphide (19.8 g) in tetrahydrofuran was added and the mixture was stirred at -70° C. for 1.5 hours. It was allowed to warm to room temperature, diluted with ether and washed with water. The aqueous layer was acidified to pH 1 and extracted with ether, washed with water, dried (anhydrous MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was recrystallised from a mixture of cyclohexane and ether to give 3,4-difluoro-2-(methylsulphenyl)benzoic acid (5.9 g) as a white solid, m.p. 149.2°-149.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:18][O:19][C:20]3[C:27]([CH3:28])=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[CH3:29])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:18][O:19][C:20]3[C:27]([CH3:28])=[CH:26][C:23]([C:24]4[N:36]=[N:37][NH:38][N:25]=4)=[CH:22][C:21]=3[CH3:29])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C#N)cc(C)c1OCC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2nn[nH]n2)cc(C)c1OCC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 31, [rac]-4-{2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-3,5-dimethyl-benzonitrile (example 51) was reacted with sodium azide in the presence of triethylamine hydrochloride in DMF to obtain the title compound as brown solid. MS: m/e=527.4 [M+H+].
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[S:3])[NH2:2].[Br:16][C:17]1[CH:26]=[CH:25][C:20]([C:21](=O)[CH2:22]Br)=[CH:19][CH:18]=1>C(O)C>[Br:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]2[N:2]=[C:1]([C@@H:4]3[CH2:8][CH2:7][CH2:6][N:5]3[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[S:3][CH:22]=2)=[CH:19][CH:18]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(N)=S
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(Br)cc2)cs1
Yield: 84 %

Procedure:
A solution of (S)-tert-butyl 2-carbamothioylpyrrolidine-1-carboxylate (compound 11a, 2.2 g, 9.6 mmol) and 4-bromophenacyl bromide (2.9 g, 10.5 mmol) in ethanol (50 ml) was stirred at room temperature for 3 hours. The resulting mixture was extracted with ethyl acetate and the organic layer was dried over MgSO4, filtered and concentrated to give crude product. The crude product was purified with column chromatography (ethyl acetate:n-hexane=1:3) to yield pure product 12a (3.3 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][OH:50])=[CH:45][CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][OH:50])=[CH:45][CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(CO)cc2)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CO)cc4)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of Intermediate 5c (109 mg, 0.300 mmol) and Intermediate 33a (126 mg, 0.300 mmol) in 1,4-dioxane (3 mL) and DIPEA (78 μL, 0.45 mmol) was stirred at 80° C. for 3 h, and then at 95° C. for 2 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-14% MeOH in DCM, to give the title compound as an off-white powder after freeze-drying (95 mg, 50%). LCMS (Method 5): Rt 3.26 min, m/z 635.3 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.81-2.26 (11H, m), 2.31-2.40 (1H, m) 3.10-3.17 (1H, m), 3.99 (1H, br t, J 8.1), 4.56 (2H, d, J 5.6), 4.78-4.87 (1H, m), 5.29 (1H, t, J 5.7), 5.37-5.42 (1H, m), 6.33 (1H, s), 7.11 (1H, d, J 8.7), 7.24-7.47 (9H, m), 7.75 (1H, d, J 9.7), 8.07 (1H, s), 8.24 (1H, br d).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[O:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1>C1COCC1>[CH3:2][O:3][CH:4]=[C:32]1[CH2:33][CH2:34][O:29][CH2:30][CH2:31]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=C1CCOCC1
Temperature: 25 °C
Yield: 35.2 %

Procedure:
To a stirred suspension of (methoxymethyl)triphenylphosphonium chloride (24.82 g, 72.41 mmol) in THF (250 mL) cooled in an ice-water bath was added n-BuLi (24.76 mL or 2.42M solution in hexane, 59.93 mmol). The reaction mixture was allowed to warm to room temperature for 1 h and then recooled in an ice-water bath and a solution of tetrahydro-4H-pyran-4-one (5.00 g, 49.94 mmol) in THF (10 mL) added. After 20 min the reaction mixture was concentrated to an oily reside, the residue was triturated with Et2O (150 mL), and the supernatant was decanted. This process was repeated (6×75 mL), and the combined supernatants were concentrated to give crude title compound (7.3 g) as an orange oil. Flash chromatography (10×18 cm) eluting with a gradient (5-10%) of EtOAc/hexane gave the title compound (2.25 g, 35%) as a volatile, colorless oil. TLC: Rf 0.13 (5:95 EtOAc:hexane). 1H NMR: δ 5.85 (s, 1H, vinyl), 3.69-3.61 (m, 4H, CH2OCH2), 3.56 (s, 3H, OCH3), 2.32 and 2.06 (pr t, 4H, 2×CH2).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:11](=O)[CH2:12][CH:13]([CH3:17])[C:14](O)=[O:15])[S:9][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:20][NH2:21]>>[N:1]1([C:6]2[CH:7]=[C:8]([C:11]3[CH2:12][CH:13]([CH3:17])[C:14](=[O:15])[NH:20][N:21]=3)[S:9][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(CC(=O)c1cc(-n2ccnc2)cs1)C(=O)O
Reactant: NN
Solvent: O
Product: CC1CC(c2cc(-n3ccnc3)cs2)=NNC1=O

Procedure:
This product is produced from 4-(imidazol-1-yl)-thiophen-2-aldehyde which is reacted with methacrylo nitrile to yield 4-[4-(imidazol-1-yl)-thien-2-yl]-2-methyl-4-oxo-butyric acid nitrile. This compound is hydrolized to 4-[4-(imidazol-1-yl)-thien-2-yl]-2-methyl-4-oxo-butyric acid and which is subjected to reaction with hydrazine hydrate to yield 4.5-dihydro-6-[4-(imidazol-1-yl)-thien-2-yl]-4-methyl-3(2H)-pyridazinone.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C@H:10]([C:21](O)=[O:22])[CH2:9]1.[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:39]=[CH:40][CH:41]=1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C@H:10]([C:21]([N:45]2[CH2:46][CH2:47][N:42]([C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([C:35]([F:34])([F:48])[F:49])[CH:37]=3)[CH2:43][CH2:44]2)=[O:22])[CH2:9]1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)O)N(Cc2ccc(Cl)cc2)C1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)N(Cc2ccc(Cl)cc2)C1
Yield: 10 %

Procedure:
As described for Example 64e, (2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methyl-amino]-1-(4-chloro-benzyl)-pyrrolidine-2-carboxylic acid (1 mmol) was converted, using 1-(3-trifluoromethyl-phenyl)-piperazine instead of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, to the title compound (70.8 mg) in 10% yield as colorless oil. MS m/e=708.1 [M+H]+.