Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH2:11][C@H:12](O)[CH3:13].CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[C:3]([CH2:11][C@H:12]([S:23]([CH3:22])(=[O:25])=[O:24])[CH3:13])[C:4]=1[F:10]
Reactant: C[C@@H](O)Cc1c(F)c(F)cc(F)c1F
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](Cc1c(F)c(F)cc(F)c1F)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.6 %

Procedure:
A solution of (2R)-1-(2,3,5,6-tetrafluorophenyl)-propan-2-ol (E-1) (1.9 g, 9.13 mmol) and Et3N (0.85 mL, 10.95 mmol) in 40 mL anhydrous DCM was cooled in ice-water bath. Then methylsulfonyl chloride (0.85 mL, 10.95 mmol) was added slowly and the mixture was stirred for 30 min at rt. And then, saturated NaHCO3 solution (10 mL) was added to the solution and extracted with DCM, dried over anhydrous MgSO4 and concentrated, and crystallized with DCM/hexane to give white solid (2.58 g, 99%). MS (ESI) m/z 309.0 [M+Na]+, 1H NMR (CDCl3, 500 MHz) δ 7.02 (m, 1H), 5.04 (m, 1H), 3.14-3.07 (m, 2H), 2.90 (s, 3H), 1.49 (d, =6.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[NH:10][C:9]1=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][O:20][CH3:21]>>[C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[N:10]([CH2:18][CH2:19][O:20][CH3:21])[C:9]1=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N1C(=O)NC2CCCC21
Product: COCCN1C(=O)N(C(=O)OC(C)(C)C)C2CCCC21

Procedure:
The title compound was prepared in accordance with the general method of example 1, step 2 starting from (rac)-(3aSR,6aRS)-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acid tert-butyl ester (Example 1, step 1) and using 1-bromo-2-methoxyethane instead of iodoethane to yield the desired product as a light yellow oil which was directly used in the next step without further characterisation.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:36])[C:18]([OH:35])([C:23]3[CH:24]=[CH:25][C:26]4[O:31][CH2:30][C:29](=[O:32])[N:28]([CH3:33])[C:27]=4[CH:34]=3)[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:37])[CH:12]=2)=[N:6][CH:5]=1.[Li+].[OH-]>>[Cl:37][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[CH:17]([CH3:36])[C:18]([OH:35])([C:23]1[CH:24]=[CH:25][C:26]2[O:31][CH2:30][C:29](=[O:32])[N:28]([CH3:33])[C:27]=2[CH:34]=1)[C:19]([F:20])([F:21])[F:22])[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:38])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)nc1
Agent: [Li+]
Agent: [OH-]
Product: CC(c1ccc(Oc2ccc(C(=O)O)cn2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 228, 6-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-phenoxy}-nicotinic acid methyl ester (Example 229) was hydrolyzed with 1 M aqueous LiOH solution (4 h, r.t.) to give the title compound as a white solid. MS (m/e, ISP neg. ion)=535.1 [M−H+].
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[C:17]1([CH2:16][CH2:15][CH2:14][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: BrCCCc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCCCc2ccccc2)cc1

Procedure:
A mixture of 33 g. of ethyl p-aminobenzoate, 19.9 g. of (3-bromopropyl)benzene and 80 ml. of hexamethylphosphoramide is heated at 110° C. for 20 hours. The mixture is chilled, diluted with 25 ml. of water, chilled, diluted with 50 ml. of ethanol and filtered. The solid is washed with cold ethanol-water (1:1) to give tan crystals, m.p. 80°-83° C. Two recrystallizations from ethanol give tan crystals, m.p. 87°-89° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[CH:14](N(CC)C(C)C)(C)C.CI>CN(C=O)C>[OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([O:11][CH3:14])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(O)COc1ccc(CO)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(CO)cc1
Reaction time: 3 h

Procedure:
18.2 g of 4-hydroxymethylphenoxyacetic acid are dissolved together with 17.1 ml of N,N-diisopropylethylamine in 50 ml of DMF, and then 6.1 ml of methyl iodide are added to the stirred solution. The mixture warms slightly during this. The reaction is complete after 3 h. The solvent is removed in vacuo. The residue is taken up in ether, and the solution is extracted once with 0.5 N hydrochloric acid. The aqueous phase is then extracted three times with ether, and the combined ether phases are washed with aqueous sodium bicarbonate solution and concentrated. The residue is dissolved in ethyl acetate and filtered through a short silica gel column. The pale yellowish oil which is obtained after concentration crystallizes on being left to stand.
Reaction SMILES: Cl.[NH2:2][OH:3].O=[C:5]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]>CO>[OH:3][N:2]=[C:5]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(=O)c1ccc(C(C)C)cc1
Reactant: NO
Agent: Cl
Solvent: CO
Product: COC(=O)C(=NO)c1ccc(C(C)C)cc1
Reaction time: 8 h

Procedure:
Hydroxylamine hydrochloride (0.87 g) was added to a stirred solution of the previously obtained mixture of methyl 2-oxo-2-(4-isopropyl-phenyl)acetate and methyl 4-isopropylphenyl acetate (1.29 g) in methanol (20 ml). When the solid had dissolved the mixture was left overnight. The solvent was evaporated and the residue partitioned between ethyl acetate and water, the organic phase was washed with water and brine, dried over magnesium sulphate and evaporated. The product (307 mg) was obtained by column chromatography of the residue using gradient elution (Kieselgel 3:1 to 1:1 hexane:ethyl acetate). νmax (CHCl3)/cm-1 3568, 3295 and 1738. δH (250 MHz, CDCl3), 1.28 (6H, d, J 6.87), 2.95 (1H, heptet, J 6.92), 3.88 (3H, s), 7.32 (2H, dd, J 1.81 and 6.47), 7.47 (2H, dd, J 1.83 and 6.65), 9.59 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]3[N:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=O)=[N:20][CH:21]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[NH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]3[N:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[C:24]([NH:27][O:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][O:30]4)=[O:26])=[N:20][CH:21]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cnc(N[C@@H]2CCN(CCc3cccc(F)c3)C2)cn1
Reactant: NOC1CCCCO1
Solvent: ClCCl
Product: O=C(/C=C/c1cnc(N[C@@H]2CCN(CCc3cccc(F)c3)C2)cn1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (2E)-3-[5-({(3R)-1-[2-(3-fluorophenyl)ethyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]acrylic acid (226 mg) and 2-(aminooxy)tetrahydro-2H-pyran and WSCD-HCl was stirred for 24 hours at ambient temperature. CH2Cl2 was added the mixture. The CH2Cl2 layer was washed with water and evaporated in vacuo. The residue was chromatographed on silica gel using a mixture of CHCl3-MeOH (10:1) to give (2E)-3-[5-({(3R)-1-[2-(3-fluorophenyl)ethyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (160 mg) as a solid.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[CH:10][C:11](=O)[NH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:17])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:17][C:11]1[CH:10]=[CH:9][C:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc(Sc2ccccc2)c[nH]1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Clc1ccc(Sc2ccccc2)cn1

Procedure:
A suspension of 5-(phenylthio)-2-pyridone (4.06 g., .02 mole) in 50 ml. of phosphorous oxychloride containing 10 g. of phosphorous pentachloride is heated at reflux for 6 hours. Excess phosphorous oxychloride is removed in vacuo and the residue is poured onto icewater mixture. The mixture is cooled and the pH adjusted to neutral with dilute aqueous sodium hydroxide. The resultant suspension is extracted with methylene chloride. The combined extracts are washed with water, dried and evaporated in vacuo to yield 2-chloro-5-(phenylthio)pyridine.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:35]([NH:37][CH2:38][C:39]([NH:41][C@H:42]([C:52]([NH:54][CH2:55][C:56]([NH:58][C@H:59]([C:70]([N:72]1[CH2:79][CH2:78][CH2:77][C@H:73]1[C:74]([NH2:76])=[O:75])=[O:71])[C@@H:60]([CH3:69])[O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:57])=[O:53])[CH2:43][O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:40])=[O:36])[C@@H:25]([CH3:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:22])[CH2:17][C:18](=[O:20])[NH2:19])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:87]([C:109]([O:111][C:112]([CH3:115])([CH3:114])[CH3:113])=[O:110])[C@H:88]([C:106](O)=[O:107])[CH2:89][CH2:90][CH2:91][NH:92][C:93](=[NH:105])[NH:94][S:95]([C:98]1[CH:104]=[CH:103][C:101]([CH3:102])=[CH:100][CH:99]=1)(=[O:97])=[O:96]>>[NH:87]([C:109]([O:111][C:112]([CH3:114])([CH3:113])[CH3:115])=[O:110])[C@H:88]([C:106]([NH:1][C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:35]([NH:37][CH2:38][C:39]([NH:41][C@H:42]([C:52]([NH:54][CH2:55][C:56]([NH:58][C@H:59]([C:70]([N:72]1[CH2:79][CH2:78][CH2:77][C@H:73]1[C:74]([NH2:76])=[O:75])=[O:71])[C@@H:60]([CH3:69])[O:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:57])=[O:53])[CH2:43][O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:40])=[O:36])[C@@H:25]([CH3:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:22])[CH2:17][C:18](=[O:20])[NH2:19])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:107])[CH2:89][CH2:90][CH2:91][NH:92][C:93](=[NH:105])[NH:94][S:95]([C:98]1[CH:104]=[CH:103][C:101]([CH3:102])=[CH:100][CH:99]=1)(=[O:97])=[O:96]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1)[C@@H](C)OCc1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](COCc2ccccc2)C(=O)NCC(=O)N[C@H](C(=O)N2CCC[C@H]2C(N)=O)[C@@H](C)OCc2ccccc2)[C@@H](C)OCc2ccccc2)[C@@H](C)OCc2ccccc2)cc1
Yield: 72.2 %

Procedure:
By using 8.35 g of Boc-Thr(Bzl)-Asn-Thr(Bzl)-Gly-Ser(Bzl)-Gly-Thr(Bzl)-Pro-NH2 and 3.30 g of Boc-Arg(Tos)-OH, and the same procedure as in Reference 15 was repeated to obtain 7.60 g (yield: 70.5%) of the above-mentioned objective product. Melting point: 120°-132° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]([CH3:40])([OH:39])[CH2:22][N:23]1[C:35]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]3N=N[N:38]=[C:27]3[C:26]=2[N:25]=[CH:24]1>ClC1C=CC=CC=1Cl>[NH2:38][C:27]1[C:26]2[N:25]=[CH:24][N:23]([CH2:22][C:21]([CH3:40])([CH3:20])[OH:39])[C:35]=2[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:28]=1
Reactant: CC(C)(O)Cn1cnc2c1c1ccccc1n1nnnc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: CC(C)(O)Cn1cnc2c(N)nc3ccccc3c21
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
Triphenylphosphine (4.5 g, 17.0 mmole) was added to a mixture of α,α-dimethyl-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline-6-ethanol (2.4 g, 8.5 mmole, Example 9) and 1,2-dichlorobenzene. The reaction mixture was heated at reflux for 3 hrs then concentrated under vacuum. The residue was combined with methanol (400 mL) and hydrochloric acid (50 mL of 0.5N) then heated on a steam bath for 2 hours. The resulting precipitate was isolated by filtration then washed with ether. The solid was dissolved in water and the solution was made basic with 10% sodium hydroxide. After stirring for 30 minutes, the reaction mixture was filtered. The collected solid was rinsed with water and ether then recrystallized from N,N-dimethylformamide/ethanol to provide about 1 g of 4-amino-α,α-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol as a solid, m.p, 271-273° C. Analysis: Calculated for C14H16N4O: %C, 65.6; %H, 6.29; %N, 21.86; Found: %C, 65.37; %H, 6.26; %N, 21.61.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]([F:20])([F:19])[C:6]1[CH:18]=[CH:17][C:9]([C:10]([CH:12]2[CH2:14][CH:13]2[C:15]#[N:16])=[O:11])=[CH:8][CH:7]=1>C(OCC)C>[OH:11][C:10]([CH:12]1[CH2:14][CH:13]1[C:15]#[N:16])([C:9]1[CH:17]=[CH:18][C:6]([C:5]([F:19])([F:20])[F:4])=[CH:7][CH:8]=1)[CH3:1]
Reactant: N#CC1CC1C(=O)c1ccc(C(F)(F)F)cc1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(O)(c1ccc(C(F)(F)F)cc1)C1CC1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.0 ml (9.09 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether were added to 1.45 g (6.06 mmol) of the compound from Example 122A in 25 ml of diethyl ether at RT, and the mixture was stirred at RT overnight. The reaction mixture was added to a saturated, ice-cold aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 1.40 g (90% of theory) of a mixture of the diastereomers of the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=2)[NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([NH:9][C:8]1[CH:10]=[CH:11][CH:12]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:7]=1)(=[O:17])[CH3:16]
Reactant: Nc1cccc(-n2ccnc2)c1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1cccc(-n2ccnc2)c1
Temperature: 0 °C
Yield: 85 %

Procedure:
2d (5.88 g, 37 mmol) is stirred in acetic anhydride (30 ml) at ambient temperature for 1 hour. The mixture is poured into ice-water and rendered alkaline by addition of aqueous sodium hydroxide (12M). The product is filtered off, washed with water and dried to yield 2e (6.34 g, 85%). Mp 181-183° C.
Reaction SMILES: [CH:1]12[O:6][CH:2]1[CH2:3][CH2:4][CH2:5]2.O.[N-:8]=[N+:9]=[N-:10].[Na+].[Cl-].[NH4+]>C(O)C>[N:8]([C@@H:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[OH:6])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: C1CC2OC2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=N[C@@H]1CCC[C@H]1O
Yield: 47.6 %

Procedure:
Cyclopentene oxide (5 g) was dissolved in ethanol (100 ml) and water (25 ml) and treated with sodium azide (3.9 g) and ammonium chloride (3.2 g) at reflux for 8 h. the mixture was cooled, excess solvent evaporated off at reduced pressure and extracted with ether. The organic solution was washed with water, dried (MgSO4) and evaporated. The residues were taken up in hexane, washed with water to remove any remaining ethanol, dried (MgSO4) and evaporated to give trans-1-azidocyclopentan-2-ol 3.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[F:46][C:47]([F:61])([F:60])[C:48]1[CH:53]=[CH:52][C:51]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[CH:50][CH:49]=1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([N:57]1[CH2:56][CH2:55][N:54]([C:51]2[CH:50]=[CH:49][C:48]([C:47]([F:60])([F:61])[F:46])=[CH:53][CH:52]=2)[CH2:59][CH2:58]1)=[O:6]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of 2-Chloro-5-methanesulfonyl-benzoic acid (102 mg, 0.43 mmol) in dimethylformamide (20 ml) were successively added TBTU (153 mg, 0.48 mmol), N-ethyldiisopropylamine (0.28 ml, 2.17 mmol) and 1-(4-trifluoromethylphenyl)piperazine (ABCR F07741NB, [30459-17-7], 100 mg, 0.43 mmol). The reaction was then stirred at room temperature for two hours, then concentrated in vacuo and purified by column chromatography (SiO2, 50 g, heptane/ethylacetate=0 to 100%), to give the title compound as a colorless gum (170 mg, 0.38 mmol). MS (m/e): 464.3 (M+NH4+, 100%)
Reaction SMILES: B(F)(F)F.CCOCC.[I:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=O)=[CH:13][CH:12]=1.[BH4-].[Na+]>C1COCC1>[I:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[CH:13][CH:12]=1
Reactant: O=C(Cc1ccc(I)cc1)N1CCOCC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Ic1ccc(CCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
BF3.Et2O (6.43 g, 45.3 mmol) was added to a solution of 2-(4-iodo-phenyl)-1-morpholin-4-yl-ethanone (3.0 g, 9.06 mmol) in THF (75 mL) at 0° C., stirred for 30 min, then NaBH4 (1.72 g, 45.3 mmol) was added at 0° C. The reaction mixture was slowly warmed to RT. After 16 h the reaction mixture was cooled to 0° C., quenched with ice-cold water, extracted with EtOAc (2×100 mL). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. The crude compound was purified by column chromatography using 100-200 mesh silica gel, eluted with 20-30% EtOAc in pet-ether to afford 1.56 g (Yield: 54.3%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][C:6]=1[O:17][CH3:18].S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:23])[C:8]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[CH:7][C:6]=1[O:17][CH3:18]
Reactant: COC(=O)Cc1ccc(C2CCCCC2)cc1OC
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Cc1cc(Cl)c(C2CCCCC2)cc1OC
Reaction time: 60 h

Procedure:
The (4-cyclohexyl-2-methyoxyphenyl)-acetic acid methylester obtained as above is dissolved in 500 ml of methylene chloride, and 5.5 ml of sulphuryl chloride and 200 mg of silica gel are added. After stirring at 22° for 60 hours, there is substantial evaporation, and the residue is chromatographed on 300 g of silica gel. A homogeneous product is extracted with methylene chloride.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3I)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C-:22]#[N:23].O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([C:22]#[N:23])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: Ic1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Temperature: 160 °C
Yield: 78.9 %

Procedure:
A mixture of (R)-indan-1-yl-(5-iodo-quinolin-2-yl)-amine (example 6, step A) (1.44 g, 3.73 mmol), zink cyanide (482 mg, 4.1 mmol) and tetrakis-(triphenylphosphine)-palladium (431 mg, 0.37 mmol) in DMF (20 ml) was heated at 160° C. for 15 min in a microwave reactor. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (diethyl ether/hexane) to yield 2-((R)-indan-1-ylamino)-quinoline-5-carbonitrile as light yellow solid (840 mg, 79%). M.p. 150° C.; MS: m/e=286.2 (M+H+).
Reaction SMILES: [ClH:1].[CH:2]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:27][CH2:26][C:14]3([N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][CH2:16][CH:15]3[OH:25])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[H-].[Na+].[CH3:30]OS(OC)(=O)=O>CN(C)C=O>[ClH:1].[CH:2]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:12][CH2:13][C:14]3([N:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:17][CH2:16][CH:15]3[O:25][CH3:30])[CH2:26][CH2:27]2)[CH2:7][CH2:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)[C@H]1CC[C@@H](N2CCC3(CC2)C(O)CCN3c2ccccc2)CC1
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCN(c2ccccc2)C12CCN([C@H]1CC[C@@H](C(C)C)CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
RS)-8-(cis-4-Isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol hydrochloride (0.3 mmol) was dissolved in dimethylformamide (15 ml), sodium hydride (1.2 mmol) was added and the mixture stirred for 1 h at room temperature. Dimethylsulfate (0.9 mmol) was added and stirring continued for 5 h. The mixture was quenched with ice-water (10 ml) and saturated sodiumbicarbonate solution (10 ml) and extracted three times with dichloromethane. The organic phases were pooled, dried with Na2SO4 and concentrated. Chromatography on silica gel (ethyl acetate) yielded the desired product which was crystallized as its HCl-salt from ethanol. 55 mg (44%) (RS)-8-(cis-4-isopropyl-cyclohexyl)-4-methoxy-1-phenyl-1,8-diaza-spiro[4.5]decane hydrochloride (1:1) as a colorless solid, m.p. 214-215° C. and MS: m/e=371.4 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([O:19][C:20](C)(C)C)=[O:18])[N:12]1[C:24](=[O:29])[CH:25]([Br:28])[CH2:26][Br:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([O:19][CH3:20])=[O:18])[N:12]1[C:24](=[O:29])[CH:25]([Br:28])[CH2:26][Br:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1CCCN(C(=O)OCc2ccccc2)N1C(=O)C(Br)CBr
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CCCN(C(=O)OCc2ccccc2)N1C(=O)C(Br)CBr
Yield: 96.6 %

Procedure:
1.0 g of tert.butyl 1-benzyloxycarbonyl-2-(2,3-dibromopropionyl)-hexahydro-3-pyridazinecarboxylate (2 racemates) was stirred for 1 hour at room temperature with 15 ml of trifluoroacetic acid and the mixture was then evaporated. The resulting oil was dissolved in 10 ml of ethanol and esterified using a solution of diazomethane in diethyl ether to give 0.89 g (95%) of methyl 1-benzyloxycarbonyl-2-(2,3-dibromopropionyl)-hexahydro-3-pyridazinecarboxylate (2 racemates) in the form of a white solid of melting point 132°-134° C. (from ethanol/diethyl ether).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([NH2:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1>[CH2:8]([NH:24][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCCCCCCCCCN
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNC(=O)/C=C\C(=O)O
Yield: 65.7 %

Procedure:
19.6 g of maleic acid anhydride are dissolved in 500 ml of toluene at 90° C. The temperature is maintained at 90° C. while 48.2 g of hexadecylamine, dissolved in 200 ml of toluene are added dropwise within 45 minutes. After one more hour at 90° C. followed by cooling, the resulting precipitate is suction filtered and washed with methanol. 44.5 g of N-hexadecylmaleic amide melting at 101° to 102.5° C. are obtained.