Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([NH:21][NH2:22])=[O:20])=[CH:17][CH:16]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:22][NH:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: COc1ccc(C(=O)NN)cc1
Solvent: CC(=O)O
Product: COc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 82 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-methoxybenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave,347 mg of the title compound (82%) as a yellow solid in 99.9% purity by HPLC (Rt: 5.44, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:16]=[CH:17][N:18]=[C:4]2[N:3]=1.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([NH:24][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:5]2[N:16]=[CH:17][N:18]=[C:4]2[N:3]=1
Reactant: Cc1ccc(-c2c(Cl)nc3ncnn3c2Cl)cc1
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(Cl)nc3ncnn3c2NC2CCCC2)cc1
Reaction time: 3 h
Yield: 86.4 %

Procedure:
5,7 Dichloro-6-(4-methylphenyl)-1,2,4-triazolo-[1,5-a]pyrimidine (1.8 g, 6 mmol) was dissolved in tetrahydrofuran. A solution of cyclopentylamine (0.51 g, 6 mmol) and triethylamine (0.61 g, 6 mmol) in tetrahydrofuran (2 ml) was then added with stirring and the stirring continued for a further 3 hours at ambient temperature (20° C.). The reaction mixture was then evaporated in vacuo and the residue extracted with dichloromethane and water (100 ml each). The organic layer was dried over sodium sulphate and the solvent evaporated in vacuo. The residue was crystallized from ethyl acetate to give 1.7 g 5-chloro-6-(4-methylphenyl)-7-cyclopentylamino-1,2,4-triazolo[1,5-a]pyrimidine as yellowish crystals, m.pt. 158° C. Yield: 87% of theoretical 1H-NMR: δ=1.3-1.75 (2 m, 8H); 2.43(s,1H); 3.73 (m,1H); 5.97 (d,1H); 7.25 (m,4H); 8.25(s,1H) ppm
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[F:5][C:6]1[CH:7]=[C:8]([C:12]2([OH:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:21])[CH:9]=[CH:10][CH:11]=1>>[C:1]([CH2:2][CH2:3][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([F:5])[CH:7]=2)([OH:22])[C:13]1=[O:21])#[N:4]
Reactant: C=CC#N
Reactant: O=C1Nc2ccccc2C1(O)c1cccc(F)c1
Product: N#CCCN1C(=O)C(O)(c2cccc(F)c2)c2ccccc21

Procedure:
Reaction of acrylonitrile with 3 -(m-fluorophenyl)- 3-hydroxyindolin-2-one by a procedure analogous to that of Example 1 gives 1-(2-cyanoethyl)- 3-(m-fluorophenyl)- 3-hydroxyindolin-2-one. Hydrogenation of 1-(2-cyanoethyl)- 3-(m-fluorophenyl)-3-hydroxyindolin-2-one by a procedure analogous to that of Example 2 gives 1-(3-aminopropyl)- 3-(m-fluorophenyl)-3-hydroxyindolin-2-one. Cyclodehydration of 1-(3-aminopropyl)-3-(m-fluorophenyl)-3-hydroxyindolin-2-one by a procedure analogous to that of Example 3 gives 10-(m-fluorophenyl)- 2,3,4,10-tetrahydropyrimido[ 1,2-a] indol-10-ol.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17](=[O:19])[CH3:18])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]([CH3:14])[C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH3:1][C:2]1[C:3]([CH:17]([OH:19])[CH3:18])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]([CH3:14])[C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)C(C)CC2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc2c(cc1C(C)O)C(C)(C)CC(C)C2(C)C
Temperature: 25 °C
Yield: 101.1 %

Procedure:
A solution of (±)-1-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-ethanone (10.00 g, 38.7 mmol) in ether (65 ml) was added dropwise during 1 h to a suspension of LiAlH4 (1.48 g, 39.0 mmol) in ether (70 ml) at 0° C. The reaction mixture was left warming up to room temperature and then heated to reflux for 1 day. After cooling to 0° C. more LiAlH4 (0.76 g, 19.5 mmol) was added. After refluxing for another 3 days, the mixture was cooled to 0° C. and water was added dropwise. Extraction of the organic phase with water, drying over Na2SO4 and concentrating gave 10.19 g (99%) of the product.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:34][C:33](=[O:35])[O:32][N:31]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:36][CH2:37][CH3:38])[N:12]3[N:39]=[CH:40][N:41]=[C:11]23)=[CH:6][CH:5]=1)[CH3:3].[BH4-].[Na+]>CO>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:34][C:33](=[O:35])[O:32][N:31]=4)=[CH:22][CH:23]=3)=[C:13]([CH2:36][CH2:37][CH3:38])[N:12]3[N:39]=[CH:40][N:41]=[C:11]23)=[CH:6][CH:5]=1)(=[O:1])[CH3:3]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(C(C)O)cc2)c2ncnn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(C(C)=O)cc2)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a solution (10 mL) of 4-[4-(1-hydroxyethyl)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.05 g) in methanol was added sodium borohydride (0.039 g), and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.036 g, 72%).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[C:10]([O:25][CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:6]2[N:5]=1)=O.[OH-:34].[Na+].O>C(O)(=O)C>[OH:34][C:4]1[N:9]=[CH:8][C:7]2=[C:10]([O:25][CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:6]2[N:5]=1
Reactant: CN(c1ccccc1-c1cc(OCOCC[Si](C)(C)C)c2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN(c1ccccc1-c1cc(OCOCC[Si](C)(C)C)c2cnc(O)nn12)S(C)(=O)=O
Temperature: 120 °C
Yield: 45 %

Procedure:
Into a 8-dram vial, N-{2-[2-Methanesulfinyl-5-(2-trimethylsilanyl-ethoxymethoxy)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methane sulfonamide (480 mg, 0.94 mmol) was added to heated solution of 19.10 M of Sodium hydroxide in Water (5.0 mL, 96 mmol) at 110° C. The reaction mixture was heated at 120° C. for 2 hours. 5 mL of Acetic acid was added to adjust pH to 5. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and NH3 in methanol as eluant (2 to 15% methanol). The collected fractions afforded N-{2-[2-Hydroxy-5-(2-trimethylsilanyl-ethoxymethoxy)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a red solid (195 mg, 45%).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([O:19][CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([C:16]([OH:18])=O)([CH3:15])[CH3:14])[CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][CH2:31][NH2:32].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][CH2:31][NH:32][C:16]([C:13]([CH3:14])([O:12][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([O:19][CH3:20])[C:3]([OH:2])=[O:21])[CH:11]=[CH:10][CH:9]=1)[CH3:15])=[O:18]
Reactant: NCCc1c(Cl)cccc1Cl
Reactant: COC(=O)[C@H](Cc1cccc(OC(C)(C)C(=O)O)c1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1cccc(OC(C)(C)C(=O)NCCc2c(Cl)cccc2Cl)c1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (EXAMPLE 56, step 2) and 2-(2,6-dichloro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H25ClNO5 [M]+: 454, [M+2]+: 456.
Reaction SMILES: [C:1]([C@H:4]1[CH2:13][C@H:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:11]2[C:6](=[CH:7][C:8]([Cl:20])=[CH:9][C:10]=2[Cl:19])[NH:5]1)([OH:3])=[O:2].[CH3:21][C:22](=[CH2:24])[CH3:23].C(=O)([O-])O.[Na+]>ClCCl.S(=O)(=O)(O)O>[CH3:18][O:17][C:15]([CH2:14][C@@H:12]1[C:11]2[C:6](=[CH:7][C:8]([Cl:20])=[CH:9][C:10]=2[Cl:19])[NH:5][C@@H:4]([C:1]([O:3][C:22]([CH3:24])([CH3:23])[CH3:21])=[O:2])[CH2:13]1)=[O:16]
Reactant: COC(=O)C[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C[C@H]1C[C@H](C(=O)OC(C)(C)C)Nc2cc(Cl)cc(Cl)c21

Procedure:
Trans-2-carboxy-4-methoxycarbonylmethyl-5,7-dichloro-1,2,3,4-tetrahydroquinoline (Example 156) (4 g) was suspended in dichloromethane (50 ml) and isobutylene (50 ml) was condensed at 0° C. Concentrated sulphuric acid (10 drops) was added and the reaction mixture was shaken for 3 days under a nitrogen atmosphere of 30 p.s.i. The solution was poured into saturated sodium hydrogen carbonate solution and diluted with a further amount of dichloromethane (100 ml). The organic layer was separated and the aqueous solution was washed with diethyl ether (100 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The residue obtained was purified by chromatography on silica gel with 20% hexane in dichloromethane as eluent to give the title compound as a colourless oil (4.07 g); δ (250 MHz, DMSO) 1.45 (9H, s, (CH3)3C), 1.64 (1H, ddd, J=13.0, 12.4 and 4.0 Hz, CHACHBHCCHD), 2.10 (1H, dm, J=13.0 Hz, CHACHBHCCHD), 2.49 (2H, m, CHECHFCO2CH3), 3.44 (1H, m, CHACHBHCCHDCHEHFCO2CH3), 3.65 (3H, s, CO2CH3), 3.97 (1H, dd, J=12.4 and 3.4 Hz, CHACHBHCCHD), 6.63 (2H, m, 6-H or 8-H and NH), 6.79 (1H, d, J=2.0 Hz, 6-H or 8-H); m/e (FAB) 374 (M+1); Found C, 54.93; H, 5.67; N, 3.69. C17H21Cl2NO4 requires C, 54.56; H, 5.66; N, 3.74%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:11]1[N:16]=[C:15]2[O:17][C:18]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:19]([C:20]([NH:22][CH3:23])=[O:21])[C:14]2=[CH:13][C:12]=1[CH:31]1[CH2:33][CH2:32]1)[S:7]([CH3:10])(=[O:9])=[O:8].[CH3:34][S:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])(=[O:37])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:31]1([C:12]2[CH:13]=[C:14]3[C:19]([C:20](=[O:21])[NH:22][CH3:23])=[C:18]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)[O:17][C:15]3=[N:16][C:11]=2[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][CH:38]([S:35]([CH3:34])(=[O:37])=[O:36])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[S:7]([CH3:10])(=[O:9])=[O:8])[CH2:33][CH2:32]1
Reactant: CCOC(=O)CS(C)(=O)=O
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCBr)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCCN(c1nc2oc(-c3ccc(C)cc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O)S(C)(=O)=O
Temperature: 120 °C

Procedure:
To 6-(N-(4-bromobutyl)methylsulfonamido)-5-cyclopropyl-N-methyl-2-(p-tolyl)furo[2,3-b]pyridine-3-carboxamide (4.5 mg, 8.42 μmol) was added ethyl 2-(methylsulfonyl)acetate (1.399 mg, 8.42 μmol) and CESIUM CARBONATE (5.49 mg, 0.017 mmol) and KI (1.398 mg, 8.42 μmol) and DMF Heated at 120° C. 20 min. Added water and extracted with EtOAc. Conc. on vac to oil. Added 3 mL ACN and 1 mL water. Filtered with 0.45μ filter Purified via HPLC C18 40-100% ACN/H2O (0.1% NH4OH) 40 mL/min over 10 min. to give ethyl 6-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(p-tolyl)furo[2,3-b]pyridin-6-yl)methylsulfonamido)-2-(methylsulfonyl)hexanoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][C:13]([O:34]C)=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[OH:34][C:13]1[CH:12]=[C:11]2[C:16]([C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)=[CH:20][CH:19]=3)[C@H:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][O:10]2)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccc(F)cc1)[C@H]2c1ccc(OCCCN2CCCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)OC[C@@H](c1ccc(F)cc1)[C@H]2c1ccc(OCCCN2CCCCC2)cc1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-3-(4-fluorophenyl)-7-methoxy-4-(4-(3-piperidinopropoxy)phenyl)chromane (0.476 g, 1.0 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as an off-white foam.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:19]=[CH:18][C:17]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[CH:16][CH:15]=1)[CH:9]=[CH:8]2)(=[O:4])=[O:3].C([N:36](CC)CC)C.N#CBr>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:19]=[CH:18][C:17]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]#[N:36])[CH2:23][CH2:22]3)=[CH:16][CH:15]=1)[CH:9]=[CH:8]2)(=[O:3])=[O:4]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(S(C)(=O)=O)ccc43)nc2)CC1
Agent: N#CBr
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C#N)CC3)cn2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.1 %

Procedure:
To a stirred solution of tert-butyl 4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)oxy)-piperidine-1-carboxylate (0.3 g, 0.63 mmol) in dichloromethane (5 mL) trifluoroacetic acid (2.0 mL) was added at 0° C. and stirred at room temperature for 2-3 h. The solvent was removed in vacuo and the resulting residue was dissolved in dichloromethane (5 mL), triethylamine (0.193 g, 1.91 mmol) and the cyanogen bromide (0.101 g, 0.95 mmol) were added at 0° C. and stirred at room temperature for 2-3 h. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue was purified by flash column chromatography to give 4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)oxy)piperidine-1-carbonitrile (0.160 g, 63%); MS: 397 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:8]=2)[NH:3]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH:11]=[C:10]3[C:12]([F:15])([F:14])[F:13])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: O=c1cc(C(F)(F)F)c2cc(Cc3ccc(S(=O)(=O)Cl)cc3)ccc2[nH]1
Product: O=c1cc(C(F)(F)F)c2cc(Cc3ccc(S(=O)(=O)NCc4ccccc4)cc3)ccc2[nH]1
Yield: 61.9 %

Procedure:
Reaction of 4-(2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-6-ylmethyl)benzene-sulfonyl chloride (Preparation 1, 26 mg, 65 μmol) with an excess of BnNH2 (280 mg, 2600 μmol), by the method described for Example 1, generated the title compound (19 mg, 61%): δH ((CD3)2SO)=3.95 (d, 2H), 4.15 (s, 2H), 7.00 (s, 1H), 7.15–7.25 (m, 5H), 7.35–7.45 (m, 3H), 7.50 (d, 1H), 7.55 (s, 1H), 7.70 (d, 2H), 8.05 (t, 1H); m/z (ES+)=514.2 [M+H +MeCN]+.
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.Br[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>C(O)C>[C:19]1(=[O:28])[N:18]([CH2:17][CH2:16][S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Sc1ccccn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCSc1ccccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.9 %

Procedure:
Triethylamine [12.54 ml (90 mmol)] was added to a suspension of 6.67 g (60 mmol) of 2-mercaptopyridine and 15.24 g (60 mmol) of N-(2-bromoethyl)phthalimide in 200 ml of ethanol and stirred at room temperature for 24 hours. The mixture was heated under reflux for 2 hours. The solvent was distilled off, chloroform was added to the residue, and the mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate/n-hexane=1:2) to obtain 8.00 g of the desired compound (46.9%, colorless crystals).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[F:10][CH:11]1[CH2:14][NH:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:13]2[CH2:14][CH:11]([F:10])[CH2:12]2)=[N:6][CH:7]=1
Reactant: FC1CNC1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Product: FC1CN(c2ncc(Br)cn2)C1

Procedure:
The title compound was prepared following a procedure analogous to that described for Intermediate 27 using 5-bromo-2-chloropyrimidine and 3-fluoroazetidine hydrogen chloride salt. LC (method 5): tR=1.33 min; Mass spectrum (ESI+): m/z=232/234 (Br) [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH2:9][CH2:10][CH3:11].[H-].[Na+].[C:14]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br)([O:16][CH3:17])=[O:15].CCCCCC.C(OCC)(=O)C>CN(C)C=O.C(OCC)(=O)C>[CH3:17][O:16][C:14](=[O:15])[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH2:9][CH2:10][CH3:11]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCCc1c(O)cccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCc1c(O)cccc1OCc1ccccc1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 21 %

Procedure:
A mixture of 1,3-dihydroxy-2-propylbenzene (5.00 g, 33.3 mmol) in dimethylformamide (10 mL) was treated with 97% sodium hydride (880 mg, 36.6 mmol ) as room temperature for 20 minutes. 2-(Carbomethoxy)benzyl bromide (7.62 g, 33.3 mmol) was added in one portion and the resulting mixture stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate and washed once with brine. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo to provide a brown oil. Silica gel chromatography (hexane/ethyl acetate) provided 2.10 g (21%) of the title intermediate as a colorless oil: 1H--NMR (CDCl3), 8.08 (d, J=8 Hz, 1H), 7.84 (d, J=8 Hz, 1H), 7.61 (t, J=8 Hz, 1H), 7.41 (t, J=8 Hz, 1H), 7.02 (t, J=8 Hz, 1H), 6.58 (d, J=8 Hz, 1H), 6.50 (d, J=8 Hz, 1H), 5.52 (s, 2H), 5.16 (s, 1H, --OH), 3.94 (s, 3H), 2.78 (t, J=7 Hz, 2H), 1.67 (hextet, J=8 Hz, 2H), 1.03 (t, J=8 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OC(C)(C)C)=O.CC#N.O>C(Cl)Cl.O.CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=[O:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)(C)OC=O
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC

Procedure:
The title compound is prepared in a similar manner as described for Example 9/reaction step I, from (3S*,4R*)-3-hydroxymethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (4.9 g, 9.95 mmol) and Dess-Martin periodinane (4.22 g, 9.95 mmol) in CH2Cl2 (30 mL), slowly wet CH2Cl2 (0.20 mL of water in 30 mL of CH2Cl2) as colorless oil. MS: 437.2 [M+H-BOC]+. tR (HPLC, Nucleosil C18 column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/1.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 4.99 min.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)O)=[CH:5][CH:4]=1>C(O)(=O)C.C(Br)(=O)C>[Br:1][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=1)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: OC(c1ccc(Cl)cc1)c1cccnc1
Reactant: Br
Agent: CC(=O)Br
Solvent: CC(=O)O
Product: Clc1ccc(C(Br)c2cccnc2)cc1
Temperature: 20 °C

Procedure:
3-[Bromo(4-chlorophenyl)methyl]pyridine is obtained in the following manner: 3.5 cm3 of a 48% solution of hydrobromic acid in acetic acid and 1 cm3 of acetyl bromide are added to 1.5 g of (4-chlorophenyl)pyridin-3-ylmethanol. The amber-colored mixture thus obtained is heated under reflux for 4 hours and then cooled to 20° C., concentrated to dryness at 40° C. under 2.7 kPa, giving 1.53 g of 3-[bromo(4-chlorophenyl)methyl]pyridine (Rf=75/90, 254 nm, Silica Plates, reference 1.05719, Merck KGaA, 64271 Darmstatd, Germany).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:20][CH2:21]OC)[CH2:11][CH2:10][N:9]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[F:28][C:29]([F:39])([F:38])[O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>CCCCCCC>[CH3:18][C:15]([CH3:16])([CH3:17])[CH2:14][CH2:13][C:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:35]([C:34]3[CH:36]=[CH:37][C:31]([O:30][C:29]([F:28])([F:38])[F:39])=[CH:32][CH:33]=3)[CH2:21][CH2:20]2)[CH2:11][CH2:10]1)=[O:19]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)CCC(C)(C)C)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: CC(C)(C)CCC(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Yield: 40.1 %

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(4,4-dimethyl-pentanoyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.115 g), dimethylaluminium chloride in heptane (0.9 molar, 0.78 ml) and 4-trifluoromethoxyanilin (0.068 g) to give the desired 8-(4,4-dimethyl-pentanoyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (0.06 g) as an off-white solid. MS (ESI): 427.2 (MH+).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[I:12]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+].[Ag+]>[I:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][C:2](=[O:11])[CH2:3][CH2:4]2
Reactant: II
Reactant: O=C1CCc2ccccc2N1
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: O=C1CCc2cc(I)ccc2N1
Reaction time: 6 h

Procedure:
3,4-Dihydroquinolin-2(1H)-one (7.5 g; 51 mmol) and silver (I) sulfate (17.5 g; 56.1 mmol) were suspended in ethanol (250 mL). A solution of iodine in ethanol (250 mL) was added slowly to the reaction over 1 hour. After 6 hours, the reaction was filtered through CELITE diatomaceous earth and washed copiously with methanol. The volatiles were removed under vacuum and the crude residue was triturated with ether. The solids were collected on a fritted funnel and dried under vacuum. This provided the title compound.