Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:6].Cl.I[CH3:18].[OH-].[Na+]>O.C(O)C>[NH2:1][CH2:2][CH2:3][NH:4][C:5](=[N:7][C:8]1[C:9]([Cl:15])=[CH:10][CH:11]=[CH:12][C:13]=1[Cl:14])[S:6][CH3:18]
Reactant: NCCNC(=S)Nc1c(Cl)cccc1Cl
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSC(=Nc1c(Cl)cccc1Cl)NCCN

Procedure:
A solution of 12.68 g. of 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)thiourea in 80 ml. of ethanol, 4.0 ml. of concentrated hydrochloric acid and 12 ml. of iodomethane was refluxed for 2 hours. On cooling, the mixture was poured onto 200 ml. of water and sufficient 4N sodium hydroxide was added to bring the pH to 11. The aqueous solution was extracted 3×150 ml. of methylene chloride, and the combined organic layers were washed 1×100 ml. of water, dried over potassium carbonate and concentrated. The resulting gum gave a solid on standing, i.e., 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-2-methylthiopseudourea, m.p. 74°-79°, whose spectral data were consistent with the assigned structure. The material was too labile for purification and was acidified with hydrochloric acid and crystallized from ethanol-ether to give 14.10 g. (84%) of 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-2-methylthiopseudourea dihydrochloride, m.p. 179°-184°. Two crystallizations from ethanol-ether gave an analytical sample, m.p. 179°-182°.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=3[CH:18]=[C:19]([CH3:29])[CH:20]=2)=[CH:23][CH:24]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4ccc(F)cc4)c3O2)cc1
Product: CNCC1Cc2cc(C)cc(-c3ccc(F)cc3)c2O1

Procedure:
The title compound was prepared (0.028 g, 25%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(4-fluorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.36 mmol) and methylamine (0.112 g, 3.6 mmol). mp 206-208° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([O:25][CH:26]3[CH2:28][CH2:27]3)[CH:16]=2)=[C:13]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]C(C)(C)C)=[O:37])[CH:31]=2)[C:12]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:11]1[CH:48]=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:23])[F:24])=[C:17]([O:25][CH:26]3[CH2:28][CH2:27]3)[CH:16]=2)=[C:13]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=2)[C:12]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:11]1[CH:48]=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cc2cccc(C(=O)OC(C)(C)C)c2)c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCc2ccccc2)c1C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c(Cc2cccc(C(=O)O)c2)c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCc2ccccc2)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.1 %

Procedure:
To 25 ml of dichloromethane solution containing 1.24 g (1.84 mmol) of ethyl 1-benzyloxymethyl-4-(3-tert-butoxycarbonylbenzyl)-5-(3-cyclopropoxy-4-difluoromethoxyphenyl)-2-formyl-1H-pyrrol-3-carboxylate obtained in Reference example 41-(c) was added 5 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and azeotropic dehydration with toluene was further carried out, and then the residue was dried under reduced pressure to obtain 1.21 g of the title compound as a yellowish oil substantially quantitatively.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1.C([Li])CCC.[CH2:16]([CH:18]([C:21]1[N:26]2[N:27]=[C:28]([CH3:31])[C:29](I)=[C:25]2[N:24]=[C:23]([CH3:32])[CH:22]=1)[CH2:19][CH3:20])[CH3:17]>[Cl-].[Zn+2].[Cl-].C1COCC1>[CH2:16]([CH:18]([C:21]1[N:26]2[N:27]=[C:28]([CH3:31])[C:29]([C:3]3[S:4][C:5]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[C:2]=3[CH3:1])=[C:25]2[N:24]=[C:23]([CH3:32])[CH:22]=1)[CH2:19][CH3:20])[CH3:17]
Reactant: CCC(CC)c1cc(C)nc2c(I)c(C)nn12
Reactant: Cc1csc2cccnc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nc2c(-c3sc4cccnc4c3C)c(C)nn12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 202.3 %

Procedure:
Charge an oven dried schrenk flask with 3-methylthieno[3,2-b]pyridine (0.213 g, 1.42 mmol) and anhydrous THF (5 mL) and cool to −78° C. under an inert atmosphere. Add n-butyl lithium (2.5 M hexane, 0.72 mL, 1.78 mmol) and stir at reduced temperature for 30 min. Add anhydrous zinc chloride (0.58 g, 4.26 mmol) in one aliquot and stir 15 min at reduced temperature. Allow the reaction to warm to room temperature and stir an additional 30 min. Dilute the reaction with anhydrous THF (5 mL) and add 7-(1-ethyl-propyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (0.406 g, 0.08 mmol). Degas 15 min with positive argon pressure and add dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium (II) dichloromethane (0.093 g, 0.114 mmol). Reflux the reaction overnight in an oil bath (90° C.) under an inert atmosphere. Cool the reaction to room temperature, quench with saturated ammonium chloride, and dilute with ethyl acetate (75 mL). Separate and extract the aqueous portion with ethyl acetate (50 mL). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify using flash chromatography, eluting with 100% hexane/0% (15% ethyl acetate/hexane) to 0% hexane/100% (15% ethyl acetate/hexane) in a step gradient of 10% increments to give a white foam (0.059 g, 14%). ES/MS m/z 365.0 (M+1)+.
Reaction SMILES: [Br-].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:12]=1.[Li]CCCC.[OH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][N:49]1[C:58]2[C:53](=[CH:54][C:55]([CH:59]=[CH:60][CH:61]=O)=[CH:56][CH:57]=2)[CH2:52][CH2:51][CH2:50]1.O>C1(C)C=CC=CC=1>[OH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][N:49]1[C:58]2[C:53](=[CH:54][C:55]([CH:59]=[CH:60][CH:61]=[CH:17][C:14]3[CH:13]=[CH:12][C:11]([C:3]4[O:2][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[N:4]=4)=[CH:16][CH:15]=3)=[CH:56][CH:57]=2)[CH2:52][CH2:51][CH2:50]1
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC=Cc1ccc2c(c1)CCCN2CCCCCCO
Agent: [Br-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: OCCCCCCN1CCCc2cc(C=CC=Cc3ccc(-c4nc5ccccc5o4)cc3)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of 110 g (0.2 mole) of 4-(benzoxazol-2-yl)tolyltriphenylphosphonium bromide in toluene is added dropwise 0.2 mole of n-BuLi at room temperature. After 2 hours a solution of 28.7 g (0.1 mole) of 3-(N-hydroxyhexyl-1,2,3,4-tetrahydroquinolin-6-yl)acrolein in toluene is added dropwise to the mixture, and the reaction is stirred for 18 hours at room temperature. Water is added, and the solids are isolated by vacuum filtration, washed with 60% ethanol/water, and dried under vacuum. The product is purified by recrystallization from benzene.
Reaction SMILES: N[C:2]1[C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:12]=[CH2:13]>[Pd]>[CH2:12]=[CH:13][C:2]1[C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C
Reactant: Nc1ccccc1S(=O)(=O)O
Agent: [Pd]
Product: C=Cc1ccccc1S(=O)(=O)O

Procedure:
EP-A 0 508 264 relates to a process for preparing arylolefins by reaction of aryldiazonium salts with olefins in the presence of a palladium catalyst. Although the use of heterogeneous palladium catalysts is mentioned (cf. EP-A 0 508 264 A1 page 4, lines 2 to 3), it is experimentally verified in only one case, namely the reaction of aniline-2-sulfonic acid with ethylene to give styrene-2-sulfonic acid (Example 6). However, as shown by comparison with Example 4 carried out using Pd(OAc)2, the yield decreases considerably when using a supported palladium catalyst (10% Pd on carbon) (Example 4: 87% yield; Example 7: 74% yield). In both examples the reaction is carried out with the addition of a base which is used in excess based on the aniline-2-sulfonic acid. As the experimental finding proves (see comparative experiment in the experimental section), the method practiced in the examples of EP-A 0 508 264, of preparing the aryldiazonium salts in situ and subsequently processing further, cannot be generally applied to the use of palladium-containing supported catalysts. The comparative experiment verifies that the desired aromatic olefin is not formed even in small amounts.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:22](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[C:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][N:12]([CH3:22])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCNC(c2ccccc2)C1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)OC(C)(C)C)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
To a mixture of tert-butyl 3-phenylpiperazine-1-carboxylate (288 mg, 1.1 mmol), and formaldehyde (185 mg, 6.16 mmol) in methanol (7 mL) was added sodium triacetoxyborohydride (949 mg, 4.48 mmol) at 0° C. After stirring for 3 h at room temperature, the reaction mixture was diluted with 10% sodium bicarbonate solution and ethyl acetate. The aqueous part was extracted with ethyl acetate and the combined organic part was dried over sodium sulfate, filtered, concentrated in vacuo. The residue was purified by flash chromatography (20/1 dichloromethane/methanol) to provide 4-methyl-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester (307 mg, 101%). (M+H)+=277 m/e. To a solution of 4-methyl-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester (307 mg, 1.11 mmol) in THF (3 mL) at 0° C. was added 4M HCl in dioxane (0.9 mL). The reaction mixture was stirred overnight and concentrated in vacuo. The residue was triturated with dichloromethane and filtered to provide 1-methyl-2-phenyl-piperazine dihydrochloride (290 mg), which was used as is for the next step.
Reaction SMILES: C(O)(=O)C(O)=O.C([O:11][C:12](=[O:26])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:15]1=[O:25])(C)(C)C.[CH2:27]([O:34][C:35]([NH:37][C@H:38]([C:50](O)=[O:51])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:41]=1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:27]([O:34][C:35]([NH:37][C@H:38]([C:50]([N:17]1[CH2:18][CH2:19][N:14]([CH2:13][C:12]([OH:11])=[O:26])[C:15](=[O:25])[C@@H:16]1[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:51])[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:45]=1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: ClCCl
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)[C@H](Cc1ccc(C(=O)OC)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
In 7.6 ml of methylene chloride were dissolved 0.76 g of (S)-3-methoxycarbonylmethyl-2-oxopiperazine-1-acetic acid t butyl ester oxalic acid salt and 0.47 g of N-benzyloxycarbonyl-4-methoxycarbonyl-L-phenylalanine. To the solution was added gradually, while cooling with water, 0.44 g of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, over 5 minutes. The mixture was stirred for one hour at room temperature, then methylene chloride was distilled off under reduced pressure. The residue was dissolved in ethyl acetate. The solution was washed with a 5% aqueous solution of potassium hydrogensulfate and a saturated aqueous solution of hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by means of a silica gel chromatography (hexane/ethyl acetate=l/2) to give 0.46 g (51.1%) of the title compound as a colorless oily product.
Reaction SMILES: Br[C:2]1[C:3]([O:37][CH3:38])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1.CC(C)([O-])C.[Na+].C(=[NH:58])(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[F:36][C:32]1[CH:31]=[C:30]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH2:58])[C:3]=3[O:37][CH3:38])[N:7]([C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:6]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COc1c(Br)ccc2c1c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1c(N)ccc2c1c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A total of 810 mg of 5-bromo-3-(3-fluoro-phenyl)-4-methoxy-1-trityl-1H-indazole obtained in Production Example II-18-a was dissolved in 7.2 ml of toluene, 194 mg of sodium t-butoxide, 0.29 ml of benzophenoneimine, 135 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 74.5 mg of tris(dibenzylideneacetone)bispalladium were added, and the mixture was stirred at 80° C. in an atmosphere of nitrogen gas for 8 hours. The reaction mixture was cooled to room temperature, and diethyl ether was added. The mixture was filtrated through Celite, and the filtrate was evaporated. The resulting residue was dissolved in 7.2 ml of tetrahydrofuran and 0.36 ml of 2 N hydrochloric acid was added, followed by stirring at room temperature for 3 hours. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was extracted with diethyl ether. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:3), to give 426 mg of the title compound as reddish brown crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[C:6]2[N:10]=[CH:9][NH:8][C:7]=12.[Br-].[CH2:28]([Zn+])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>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>[CH2:28]([C:2]1[N:3]=[N:4][C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[C:6]2[N:10]=[CH:9][NH:8][C:7]=12)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: FC(F)(F)c1ccc(N2CCN(c3nnc(Cl)c4[nH]cnc34)CC2)nc1
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: FC(F)(F)c1ccc(N2CCN(c3nnc(Cc4ccccc4)c4[nH]cnc34)CC2)nc1
Temperature: 80 °C
Yield: 7.1 %

Procedure:
7-Chloro-4-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-imidazo[4,5-d]pyridazine (149 mg, 0.389 mmol), benzyl zinc bromide (9.34 mL, 0.5M in THF, 4.67 mmol), and tetrakis (triphenylphosphine) palladium0 (23 mg, 0.020). The reaction mixture is heated to 80° C. for 32 h. Add H2O and extract product with EtOAc. Wash combined organics with brine and concentrate in vacuo. The residue is purified by flash chromatography on silica gel (60-100% EtOAc/Heptane flushed with 10% MeOH/EtOAc) to afford the title compound (12.1 mg, 7%).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[OH:13][C:14]([CH2:16][CH2:17][CH2:18][CH2:19][C@H:20]1[C@@H:28]2[C@@H:23]([NH:24][C:25]([NH:27]2)=[O:26])[CH2:22][S:21]1)=O>CC(C)=O>[O:26]=[C:25]1[NH:27][C@@H:28]2[C@H:20]([CH2:19][CH2:18][CH2:17][CH2:16][C:14]([O:12][CH2:11][C@H:9]([C@@H:7]3[C:5]([OH:6])=[C:3]([OH:4])[C:2](=[O:1])[O:8]3)[OH:10])=[O:13])[S:21][CH2:22][C@@H:23]2[NH:24]1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CC(C)=O
Product: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)OC[C@@H](O)[C@H]2OC(=O)C(O)=C2O)N1
Temperature: 40 °C
Reaction time: 32 h

Procedure:
54.1 g of ascorbic acid (306.9 mmol; 5 eq.) and 15 g of biotin (61.4 mmol; 1 eq.) are dissolved in 180 ml of anhydrous acetone under a protective gas, 1 g of lipase (Candida antarctica) is added, and the mixture is shaken at 40° C. for 32 h. The enzyme is filtered off, 50 ml of water are added to the solution, and the product is precipitated by pouring into toluene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:27])[N:13]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=4)(=[O:18])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[C:8]([F:28])[CH:7]=3.C1CCCCC=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:27])[N:13]([S:16]([C:19]4[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=4)(=[O:18])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[C:8]([F:28])[CH:7]=3
Reactant: COc1cccc(S(=O)(=O)N2c3cc(F)ccc3-c3cc(F)ccc3C2C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2ccc(F)cc2-c2ccc(F)cc2N1S(=O)(=O)c1cccc(O)c1

Procedure:
The title compound was prepared from 3,9-difluoro-5-[(3-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (150 mg, 0.37 mmol), cyclohexene (757 μL, 7.5 mmol), and 1.0 M solution of boron tribromide in dichloromethane (2.24 mL) according to the procedure and in the same manner as described in Example 105, step e. The volatile components were removed in vacuo, and the crude residue was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 5%-50% methyl tert-butyl ether in hexane, to afford the product (98 mg, 78%) as a solid, m.p. 167.2-173° C.;
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[F:13])(=O)[CH:2]=[CH2:3].[CH2:14]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH:23]=[CH:24][N:25]2CCCCC2)[CH2:19][CH2:18]1)[CH2:15][CH3:16].Cl.NO.Cl>O.C(O)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]2[CH:2]=[CH:3][C:23]([C@H:20]3[CH2:21][CH2:22][C@H:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19]3)=[CH:24][N:25]=2)=[C:6]([F:13])[CH:7]=1
Reactant: CCC[C@H]1CC[C@H](C=CN2CCCCC2)CC1
Reactant: C=CC(=O)c1ccc(OC)cc1F
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: CCC[C@H]1CC[C@H](c2ccc(-c3ccc(OC)cc3F)nc2)CC1
Reaction time: 2 h

Procedure:
0.03 mol of 1-acrylyl-2-fluoro-4-methoxybenzene was mixed at 0° C. with 0.03 mol of 1-[2-(trans-4-propylcyclohexyl)vinyl]piperidine and held at room temperature for 2 hours. The mixture was then treated with 90 ml of ethanol, 10 ml of water, 0.14 mol of hydroxylamine hydrochloride and 1 ml of concentrated hydrochloric acid and heated to reflux for 8 hours. Subsequently, about 2/3 of the solvent were removed by distillation. The concentrated mixture was diluted with 150 ml of water and adjusted to pH 8 with aqueous sodium carbonate solution. The organic layer was extracted with benzene. The extract was washed neutral with water, dried over sodium sulfate, filtered and concentrated. Chromatographic purification of the resulting residue on silica gel with benzene/hexane (vol. 1:1) gave 2-(4-methoxy-2-fluorophenyl)-5-(trans-4-propylcyclohexyl)pyridine in 20% yield; m.p. (C-N) 56.3° C., cl.p. (N-I) 180.6° C.
Reaction SMILES: C([NH:11][C@H:12]([C:14]([N:16]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13])(OCC1C=CC=CC=1)=O>[Pd].C(O)C.O>[NH2:11][C@H:12]([C:14]([N:16]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: C[C@H](N)C(=O)N(CC(=O)O)Cc1ccccc1

Procedure:
A solution of N-carbobenzyloxy-L-alanyl-N-benzyl glycine (6.0 g) and 10% palladium on carbon (2.0 g) in 200 ml ethanol was hydrogenated at 50 psi for 4 hours and filtered. Concentration of the volatiles in vacuo provided a residue which was dissolved in H2O and filtered. The aqueous solution was acidified with 25% aqueous HBr until pH 1 was obtained. The solution was lyophilized. The crystalline product was recrystallized from ether-acetonitrile (m.p. 84°-85° C.).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:32](=O)[CH:33]([CH3:35])[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(CC(C)C)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 18.3 %

Procedure:
To a solution of methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (300 mg; 0.72 mmol) in DCE (15 mL) were added isobutyraldehyde (Aldrich, 0.16 ml, 1.81 mmol) and triacetoxyborohydride (229 mg; 1.08 mmol). The reaction mixture was stirred at 60° C. under N2 atmosphere for 4 hours. The mixture was poured into NaHCO3 (100 mL), then the product was extracted with DCM (2×100 mL), washed with brine (100 mL), dried over magnesium sulfate and filtrated. The solvents were removed under reduced pressure. Purification of this crude by flash chromatography on silicagel (c-Hex/EtOAc, gradient 8:2 to 5:5 to 3:7) then by HPLC preparative with a X-Terra column gave 62 mg (19%) of the title compound as a brown oil. HPLC: 6.19 min (purity=96.4%), LC/MS: M+(ESI): 472.4. 1H NMR (CDCl3) δ: 7.44 (d, J=5.6 Hz, 2H), 7.41 (d, J=5.3 Hz, 2H), 7.25 (m, 1H), 7.14 (t, J=7.5 Hz, 4H), 6.94 (t, J=9.6 Hz, 1H), 6.80 (m, 1H), 4.57 (s, 2H), 3.90 (s, 3H), 3.45 (m, 1H), 3.25 (d, J=7.2 Hz, 2H), 2.61 (t, J=7.7 Hz, 2H), 2.05 (m, 1H), 1.60 (m, 2H), (s, J=7.4 Hz, 2H), 0.95 (m, 9H).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:19])=[C:4]([CH3:18])[C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[CH2:20]([N:27]1[CH2:34][CH:33]2[CH:29]([CH2:30][NH:31][CH2:32]2)[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>C(O)CCCC>[CH2:20]([N:27]1[CH2:34][CH:33]2[CH2:32][N:31]([C:2]3[C:3]([CH3:19])=[C:4]([CH3:18])[C:5]4[N:6]([CH:8]=[C:9]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)[N:10]=4)[N:7]=3)[CH2:30][CH:29]2[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1c(Cl)nn2cc(-c3ccc(F)cc3)nc2c1C
Reactant: c1ccc(CN2CC3CNCC3C2)cc1
Agent: Cl
Solvent: CCCCCO
Product: Cc1c(N2CC3CN(Cc4ccccc4)CC3C2)nn2cc(-c3ccc(F)cc3)nc2c1C
Temperature: 150 °C

Procedure:
A mixture of 3.00 g (10.9 mmol) of 6-chloro-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazine and 6.6 g (33 mmol) of 2-benzyloctahydropyrrolo[3,4-c]pyrrole in 20 mL of pentanol is heated at 150° C. for 2 days in a reactor. The medium is then poured into aqueous 1N hydrochloric acid solution. The aqueous phase is washed with ethyl acetate and then basified with sodium hydroxide.