Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:27])[C:19]([O:21][CH2:22][CH2:23][CH2:24][S:25][CH3:26])=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:28])[NH:6]2.C1C=C(Cl)C=C(C(OO)=[O:37])C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:27])[C:19]([O:21][CH2:22][CH2:23][CH2:24][S:25]([CH3:26])=[O:37])=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:28])[NH:6]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCCOc1cn2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc2c(F)c(Oc3ncnn4cc(OCCCS(C)=O)c(C)c34)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
To a solution of Example 29 (25 mg, 0.0625 mmol) in dichloromethane at 0° C. was added m-CPBA (77%, 14 mg, 0.0625 mmol). After stirring the mixture at 0° C. for 30 min, triphenylphosphine (5 mg, 0.019 mmol) was added. After stirring at 0° C. for additional 30 min, the reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to afford the title compound (11 mg, 42% yield) as a white solid. MS: (M+H)+=417.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C@@H:15]([CH2:18][CH2:19][C:20]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][C:23]=2[F:34])=[O:21])[C@@H:14]([C:35]([OH:37])=[O:36])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[CH:38](N(CC)C(C)C)(C)C>ClCCl.CO>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C@@H:15]([CH2:18][CH2:19][C:20]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][C:23]=2[F:34])=[O:21])[C@@H:14]([C:35]([O:37][CH3:38])=[O:36])[CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: COc1ccc2ncc(F)c(C(=O)CC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3C(=O)O)c2c1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 1 h

Procedure:
1.58 cm3 of a thionyl chloride solution are added, at a temperature in the region of 20° C., under an argon atmosphere, to 3.33 g (7.23 mmol) of (3R,4R)-1-tertbutyloxycarbonyl-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-oxopropyl]piperidine-3-carboxylic acid in solution in 150 cm3 of dichloromethane. After stirring for 1 hour at a temperature in the region of 20° C., the reaction mixture is poured over a solution of 10.55 cm3 of N,N-diisopropylethylamine in 150 cm3 of methanol. After stirring for 16 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up with 150 cm3 of CH2Cl2, and washed with 3 times 50 cm3 of water and then 50 cm3 of a saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (2.7 kPa) to give 4 g of methyl (3R,4R)-1-tert-butyloxycarbonyl-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-oxopropyl]piperidine-3-carboxylate in the form of an orange oil.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:11]>>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1)=[O:11]
Reactant: CCOC(=O)C(F)F
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Product: O=C(CC(=O)C(F)F)c1ccc(C(F)(F)F)cc1
Yield: 101.4 %

Procedure:
Prepared from commercially available ethyl difluoroacetate (14.49 g, 117 mmol) and commercially available 4-(trifluoromethyl)acetophenone (15.36 g, 80 mmol) as described in example C.1 step 1 to give 4,4-difluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (21.60 g, 101%) as alight brown oil. MS (ISN) 265.0 [(M−H)−].
Reaction SMILES: C1(C#C)C=CC=CC=1.Cl[CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Li]CCCC.BrCCCCl.[I-:31].[Na+]>C1COCC1>[I:31][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCCCC#Cc1ccccc1
Reactant: [I-]
Agent: ClCCCBr
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C#Cc1ccccc1
Product: ICCCC#Cc1ccccc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 80.8 %

Procedure:
To a solution of THF (200 mL) into reaction flask was added (5-chloropent-1-ynyl)benzene Phenylacetylene (10 g, 97.91 mmol). Then the reaction mixture was cooled to −78° C. in a dry ice bath. nBuLi (95.95 mmol, 38.39 mL) was added dropwise and allowed to react for 0.5 h at −78° C. At −78° C., 1-bromo-3-chloropropane was added. Stirred for 5 hours during which the reaction was allowed to warm up to room temperature. Then reaction was refluxed at 90° C. for 3 hours. The solvent was distilled off, then water (150 mL) and ether (150 mL) was added. The crude product was extracted, ether was distilled off and the resulting crude mixture was dissolved in acetone. Sodium iodide (22.92 mmol, 3.44 g) was added into the solution. The reaction mixture, with reflux condenser attached, was heated to 70° C. for two days. Acetone was distilled off using short path distillation apparatus. Ether (150 mL) and water (150 mL) was added and carried out extraction. Ether was then dried over magnesium sulfate and distilled off resulting in 5.00 g of product (yield 98%). No further purification was carried out. 1H NMR (500 MHz, CDCl3) □2.072 (m, 2H, CH2); 2.605 (t, 2H, CH2); 3.697 (m, 2H, CH2); 7.276 (m, 2H, Phenyl); 7.389 (m, 2H, phenyl); 7.484 (m, 1H, phenyl).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:10]=2[CH:11]=1.N1C=CN=C1.[Si:27](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O.C(OCC)(=O)C>[Si:27]([O:1][CH2:2][C:3]1[NH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:10]=2[CH:11]=1)([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(OCc1ccccc1)c1cccc2[nH]c(CO)cc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCc1cc2c(C(=O)OCc3ccccc3)cccc2[nH]1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a solution of benzyl 2-hydroxymethylindole-4-carboxylate (456 mg) and imidazole (364 mg) in N,N-dimethylformamide (10 ml) was added tert-butyldiphenylsilyl chloride (802 mg) and the solution was stirred at ambient temperature for 2 hours. The resulting mixture was diluted with ethyl acetate (30 ml) and washed successively with water and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=1S:1) to give benzyl 2-tert-butyldiphenylsilyloxymethylindole-4-carboxylate (810 mg).
Reaction SMILES: [BrH:1].C(O)(=O)C.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14](=O)[CH2:15][S:16][C:17]#[N:18].O>C(O)(=O)C>[Br:1][C:17]1[S:16][CH:15]=[C:14]([C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[Cl:6])[N:18]=1
Reactant: N#CSCC(=O)c1ccc(Cl)cc1Cl
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(-c2csc(Br)n2)c(Cl)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A 25% hydrogen bromide/acetic acid (60 ml) solution was added to a solution of 2-(2,4-dichlorophenyl)-2-oxoethyl thiocyanate (5.97 g, 24.3 mmol) in acetic acid (60 ml), and the mixture was stirred at 130° C. for 2 hours. Water (120 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 6.89 g (92.0%) of the desired product as a solid.
Reaction SMILES: [OH-].[K+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([OH:12])=[CH:6][C:5]=2[O:4]1.Cl[CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21]>COCCOC>[CH:20]([O:19][CH2:18][CH2:17][C:16]([CH3:23])=[CH:15][CH2:14][O:12][C:7]1[CH:8]=[CH:9][C:10]2[O:11][CH2:3][O:4][C:5]=2[CH:6]=1)([CH3:22])[CH3:21]
Reactant: CC(=CCCl)CCOC(C)C
Reactant: Oc1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(=CCOc1ccc2c(c1)OCO2)CCOC(C)C
Reaction time: 18 h

Procedure:
1.7 g (0.03 mol) of pulverised potassium hydroxide are added to a solution of 4.1 g (0.03 mol) of 3,4-methylendioxy-phenol and 6.2 g (0.035 mol) of 1-chloro-5-isopropoxy-3-methyl-2-pentene in 100 cc of 1,2-dimethoxyethane. The mixture is stirred at 60° for a period of 18 hours, is subsequently filtered and evaporated at reduced pressure. The residue is dissolved in ether, washed with 5% solution of sodium hydroxide and subsequently with saturated salt solution, dried with sodium sulphate and evaporated.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](CN4CCOCC4)=[CH:20][CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1C(N)=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.[N:62]1(C2C=CC(C=O)=CC=2)[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1>>[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([N:62]4[CH2:67][CH2:66][O:65][CH2:64][CH2:63]4)=[CH:20][CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(N5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 20 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-morpholin-4-yl-benzaldehyde were reacted to produce the title compound (20%). 1H NMR (d-chloroform): 15.43 (br s, 1H), 8.06 (d, J=9 Hz, 1H), 8.00 (d, J=9 Hz, 2H), 7.77 (s, 1H), 7.02 (d, J=9 Hz, 2H), 6.50 (m, 1H), 6.42 (m, 1H), 5.91 (br s, 1H), 5.53 (br s, 1H), 5.40 (t, J=8 Hz, 1H), 3.90 (t, J=5 Hz, 4H), 3.30 (t, J=5 Hz, 4H), 3.17 (s, 1H), 3.04 (s, 1H), 2.68 (d, J=8 Hz, 1H), 2.38 (d, J=9 Hz, 1H), 1.67 (d, J=9 Hz, 1H). MS: 466.07 (M+H). HPLC retention time: 2.42 minutes (G Method).
Reaction SMILES: C([O:5][C:6](=[O:55])[C:7]([C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[C:23]3[CH2:24][CH2:25][CH2:26][CH2:27][C:22]=3[S:21][C:20]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:52]=[CH:53][CH:54]=2)[CH2:34][N:35]([CH:47]([CH2:50][CH3:51])[CH2:48][CH3:49])[C:36](=[O:46])[CH2:37][CH2:38][C:39]([CH3:45])([CH3:44])[C:40]([O:42][CH3:43])=[O:41])=[O:30])=[O:18])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:43][O:42][C:40](=[O:41])[C:39]([CH3:44])([CH3:45])[CH2:38][CH2:37][C:36]([N:35]([CH2:34][C:33]1[CH:32]=[C:31]([CH:54]=[CH:53][CH:52]=1)[C:29]([NH:28][C:20]1[S:21][C:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[C:19]=1[C:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]([CH3:9])([CH3:8])[C:6]([OH:55])=[O:5])=[N:15][CH:14]=1)=[O:18])=[O:30])[CH:47]([CH2:48][CH3:49])[CH2:50][CH3:51])=[O:46]
Reactant: CCC(CC)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(C(C)(C)C(=O)OC(C)(C)C)nc2)CCCC3)c1)C(=O)CCC(C)(C)C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(C(C)(C)C(=O)O)nc2)CCCC3)c1)C(=O)CCC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.8 %

Procedure:
A mixture of 675 mg of methyl 5-[{3-[(3-{[6-(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)pyridin-3-yl]carbamoyl}-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)carbamoyl]benzyl}(pentan-3-yl)amino]-2,2-dimethyl-5-oxopentanoate, 10 mL of methylene chloride, and 1.3 mL of TFA was stirred 15 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction by using ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (10% methanol/chloroform), thereby obtaining 550 mg of 2-{5-[({2-[(3-{[(5-methoxy-4,4-dimethyl-5-oxopentanoyl)(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]pyridin-2-yl}-2-methylpropanoic acid.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]([C:11]([CH3:14])=[CH:12][CH:13]=1)[C:9]#[N:10].O.[BrH:16]>S(=O)(=O)(O)O.C(O)(=O)C.[Cu]Br>[Br:16][C:6]1[CH:7]=[C:8]([C:11]([CH3:14])=[CH:12][CH:13]=1)[C:9]#[N:10]
Reactant: Br
Reactant: Cc1ccc(N)cc1C#N
Agent: [Cu]Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(Br)cc1C#N
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
15.2 g (0.22 mol) of sodium nitrite are heated to 70° C. in 160 ml of concentrated sulphuric acid and the solution formed is added dropwise to a solution of 26.4 g (0.2 mol) of the compound from Example XV in 400 ml of glacial acetic acid at 20° C. to 40° C. A solution of 63.1 g (0.44 mol) of copper(I) bromide in 400 ml of concentrated hydrobromic acid is added dropwise to this solution at 10° C. to 20° C. and the mixture is stirred for 0.5 hour. The reaction mixture is introduced into 1 l of water, the precipitate which has separated out is filtered off with suction, washed with water and suspended in methylene chloride and the insoluble material is filtered off with suction. The filtrate is washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to give 19.2 g of the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[CH2:12]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([CH3:26])=[CH:21][CH:22]=2)[CH:17]1[CH2:27][C:28](OCC)=[O:29])[CH:13]([CH3:15])[CH3:14]>O>[CH2:12]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([CH3:26])=[CH:21][CH:22]=2)[CH:17]1[CH2:27][C:28]([NH:10][C:9]([NH2:11])=[NH:8])=[O:29])[CH:13]([CH3:15])[CH3:14]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2cc(C)ccc2C(=O)N1CC(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: Cc1ccc2c(c1)C(CC(=O)NC(=N)N)N(CC(C)C)C2=O
Temperature: 20 °C
Reaction time: 40 h
Yield: 59.6 %

Procedure:
N-[(2-Isobutyl-6-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 1, starting with 2.52 g of potassium tert-butoxide, 2.58 g of guanidinium chloride and 1.3 g of ethyl (2-isobutyl-6-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 40 hours and is then poured into 150 cm3 of water and extracted with 3 times 150 cm3 of ethyl acetate. The organic extracts are combined, washed with twice 50 cm3 of water, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. The residue is taken up in diethyl ether and then filtered, giving 0.81 g of N-[(2-isobutyl-6-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine in the form of a white solid melting above 260° C. (Rf=0.28, thin layer chromatography on silica gel, eluent: dichloromethane/methanol (90/10 by volume)). (Analysis C16H22N4O2% calculated C, 63.56; H, 7.33; N, 18.53; O, 10.58%. found C, 63.40; H, 7.33; N, 18.37).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1[C:42]2[C:33](=[CH:34][C:35]3[C:40]([C:41]=2[CH:43]=O)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:32]=[CH:31][CH:30]=1>>[CH:39]1[C:40]2[C:35](=[CH:34][C:33]3[C:42]([C:41]=2[CH2:43][NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]4[C:16]5[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=5)[N:10]=[CH:9][C:8]=4[CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:19]=2)=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:36]=[CH:37][CH:38]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1c2ccccc2cc2ccccc12
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4c5ccccc5cc5ccccc45)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and anthracene-9-carbaldehyde. MS (ESI) m/z 569.
Reaction SMILES: C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][CH2:24][C:25]2(O)[CH2:30][CH2:29][C:28]([N:36]([CH3:38])[CH3:37])([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[CH2:27][CH2:26]2)=[CH:14]1>ClCCCl>[CH3:37][N:36]([CH3:38])[C:28]1([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[CH2:29][CH2:30][C:25]2([C:14]3[NH:13][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[CH2:22][CH2:23][CH2:24]2)[CH2:26][CH2:27]1
Reactant: CN(C)C1(c2cccs2)CCC(O)(CCCc2c[nH]c3ccccc23)CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Product: CN(C)C1(c2cccs2)CCC2(CCCc3c2[nH]c2ccccc32)CC1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Trifluoromethane sulphonic acid trimethylsilyl ester (1.95 g, 159 mL, 8.8 mmol) in absolute 1,2 dichloroethane (100 mL) was added to a suspension of 1-(3-(1H-indol-3-yl)propyl)-4-(dimethylamino)-4-(thiophen-2-yl)cyclohexanol (800 mg, 2.1 mmol), and a clear solution formed. The solution was stirred for 6 h at 50° C. and then overnight at room temperature. The reaction solution was washed with 1 N sodium carbonate solution (2×30 mL), water and saturated sodium chloride solution (30 mL each) one after the other, dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (720 mg) was mixed with methanol (100 mL) and stirred overnight at room temperature, during which a light-coloured solid was formed. This was filtered off, washed with methanol (10 mL) and dried in a vacuum, as a result of which a diastereomer mixture in a ratio of 5:1 was obtained (290 mg, (38%)). This was separated by preparative HPLC.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([N:17]1[C:23]2[N:24]=[CH:25][C:26]([CH2:28][CH2:29][OH:30])=[CH:27][C:22]=2[C:21](=[O:31])[N:20]([CH3:32])[C:19]2[CH:33]=[CH:34][CH:35]=[N:36][C:18]1=2)[CH3:16].O[C:38]1[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][C:39]=1[CH3:48].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:15]([N:17]1[C:23]2[N:24]=[CH:25][C:26]([CH2:28][CH2:29][O:30][C:38]3[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][C:39]=3[CH3:48])=[CH:27][C:22]=2[C:21](=[O:31])[N:20]([CH3:32])[C:19]2[CH:33]=[CH:34][CH:35]=[N:36][C:18]1=2)[CH3:16]
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2cccnc21
Reactant: COC(=O)c1ccc(O)c(C)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3ccc(C(=O)OC)cc3C)cc2C(=O)N(C)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A solution of DIAD (250 μL, 1.27 mmol) in THF (1 mL) was added dropwise to a solution of 11-ethyl-5,11-dihydro-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (346 mg, 1.16 mmol), methyl 4-hydroxy-3-methylbenzoate (212 mg, 1.27 mmol) and PPh3 (333 mg, 1.27 mmol) in THF (5 mL) at 25° C. The reaction mixture was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (Hexane:EtOAc, 1:1) to give the title compound (471 mg, 91% yield) as white solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][CH2:25][OH:26]>C(N(CC)CC)C>[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][CH2:25][O:26][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: OCCc1cccs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
4-toluenesulfonyl chloride (162 g), toluene (363.3 g) and 2-(2-Thienyl)ethanol (104 g) are combined. Triethylamine (93 g) is added maintaining the temperature lower than 45° C. After 4 hrs, the mixture is washed with aqueous phosphoric acid, aqueous sodium hydroxide and then water. The organic phase is distilled off under vacuum. Isopropanol (314 g) and heptanes (365.9 g) are added. The batch is crystallized by cooling and isolated at −15° C. The crystals are filtered and washed with heptanes (175 mL). The crystals are then dried under vacuum at room temperature until a melting point of 30° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([F:12])[C:3]=1F.[N:14]1([CH2:20][CH2:21][OH:22])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]([N:17]2[CH2:18][CH2:19][N:14]([CH2:20][CH2:21][OH:22])[CH2:15][CH2:16]2)=[C:4]([F:12])[C:5]([NH2:6])=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1
Reactant: Nc1c([N+](=O)[O-])cc(Cl)c(F)c1F
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1c([N+](=O)[O-])cc(Cl)c(N2CCN(CCO)CC2)c1F
Temperature: 50 °C
Yield: 67.3 %

Procedure:
To a solution of 6.79 g of 4-chloro-2,3-difluoro-6-nitroaniline (which was synthesized following WO9856761 or WO9835977) and 4.70 g of 1-piperazine ethanol in 30 ml of dimethylsulfoxide, 9.23 g of potassium carbonate was added, followed by an hour's stirring at 50° C. After cooling the reaction liquid to room temperature, water was added thereto, followed by extraction with chloroform. The chloroform layer was dried on anhydrous magnesium sulfate, the solvent was distilled off and 6.98 g of the title compound in crude form was obtained as a yellow oily substance.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].C([O:20][C:21]([CH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH:30]=[C:31](F)[F:32])[CH2:25][CH2:24]1)=O)C1C=CC=CC=1.OS(O)(=O)=O>C1(C)C=CC=CC=1>[F:32]/[CH:31]=[CH:30]/[CH2:29][CH:26]1[CH2:27][CH2:28][CH:23]([CH2:21][OH:20])[CH2:24][CH2:25]1
Reactant: O=C(OCc1ccccc1)C1CCC(CC=C(F)F)CC1
Agent: COCCO[AlH2-]OCCOC
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCC1CCC(C/C=C/F)CC1
Temperature: 85 °C
Reaction time: 17 h
Yield: 100.1 %

Procedure:
A 3.3 M Red-Al solution in toluene (0.25 ml, 0.82 mmol) was added to a solution of 4-(3,3-difluoro-allyl)-cyclohexanecarboxylic acid benzyl ester (cis:trans=5.4:1) (42.8 mg, 0.145 mmol) in toluene (0.12 mL), and the mixture was stirred at 85° C. for 17 hours. The reaction mixture was poured into ice water, adjusted to pH 3 with a 4 N aqueous H2SO4 solution and extracted with ether. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give [4-((E)-3-fluoro-allyl)-cyclohexyl]-methanol (25.0 mg, 100%).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.CO.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[O:14]1[CH2:19][CH2:18][CH:17]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH2:16][CH2:15]1
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2CCOCC2)CC1

Procedure:
To a solution of tert-butyl piperazine-1-carboxylate (5.15 g) and dihydro-2H-pyran-4(3H)-one (3.05 g) stirred for 24 hours at room temperature in titanium (IV) isopropoxide (16.20 mL), methanol (5 mL) was added followed by careful addition of sodium borohydride (2.092 g). The reaction mixture was quenched with water/NaOH solution, extracted with ether, dried over magnesium sulfate, filtered, and concentrated to yield the product. The crude product was used in next step.