Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:20]O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]3[N:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ON=C(Cc1ccc(C(F)(F)F)cn1)c1cccc(Cl)c1
Agent: CS(=O)(=O)Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc2cc(-c3cccc(Cl)c3)nn2c1
Temperature: 35 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a suspension of 1-(3-chlorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (17 g, 54 mmol) in DME (170 ml) at −5° C. was added dropwise methanesulfonyl chloride (4.5 m, 6.0 mmol) and the mixture stirred for 15 mins. Triethylamine (16.5 ml, 120 mmol) in DME (7 ml) was then added dropwise over 15 min. After the addition was complete, the mixture was then warmed to 35° C. for 45 minutes. This was then cooled and filtered, washing with DME (20 ml). To the filtrate was added iron (II) chloride (75 mg) and the mixture heated to 70° C. for 1 hour and then allowed to cool. The reaction was concentrated to half the original volume and water (100 ml) was added. The resulting solid was removed by filtration, washed with water and dried. The solid was dissolved in ethyl acetate and washed with water and brine and then dried over magnesium sulfate. Filtering and evaporation to dryness under vacuum afforded 14.6 g (91%) of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][CH:17]=3)[N:12]=2)=[CH:7][C:6]=1[CH3:26])[CH:2]([CH3:4])[CH3:3].C[O:28][C:29]([CH:31]1[CH2:34][NH:33][CH2:32]1)=[O:30]>[OH-].[Na+].O1CCOCC1>[CH2:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([N:33]4[CH2:34][CH:31]([C:29]([OH:30])=[O:28])[CH2:32]4)=[O:25])=[CH:18][CH:17]=3)[N:12]=2)=[CH:7][C:6]=1[CH3:26])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(-c2nc(-c3ccc(CC(=O)O)cc3)no2)cnc1CC(C)C
Reactant: COC(=O)C1CNC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(-c2nc(-c3ccc(CC(=O)N4CC(C(=O)O)C4)cc3)no2)cnc1CC(C)C

Procedure:
1-(2-{4-[5-(6-Isobutyl-5-methyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-acetyl)-azetidine-3-carboxylic acid is prepared from {4-[5-(6-Isobutyl-5-methyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-acetic acid and azetidine-3-carboxylic acid methyl ester in analogy to Example 55; stirring this material in 3 N aq. NaOH/dioxane at rt for 20 h gives the desired compound; LC-MS: tR=0.60, [M+1]+=434.96.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)[CH2:4][CH2:3]1>[Ni].CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Agent: [Ni]
Solvent: CO
Product: CN1CCN(Cc2cccc(N)c2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 1-methyl-4-(3-nitro-benzyl)-piperazine (6.9 g, 29.14 mmol) and Raney Nickel (2 g) in MeOH (150 mL) is stirred for 5 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford the title compound as a yellow solid: ESI-MS: 206.1 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27]3)=[CH:22][CH:23]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Reactant: c1ccc2[nH]ccc2c1
Product: O=S(=O)(Nc1nccnc1-c1ccc(Cn2ccc3ccccc32)cc1)c1ccccc1Cl
Yield: 71 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide (Intermediate 8), and 1-H-Indole, the title compound was isolated as a yellow solid in 71% yield (98% purity by HPLC).
Reaction SMILES: C(C1C=C2C(C3C=C(C=CC=3)CNC(C3C(=O)N(CC4C=CC(F)=C(F)C=4)C=CC=3)=O)=CNC2=NC=1)#N.[F:38][C:39]1[CH:40]=[C:41]([CH:63]=[CH:64][C:65]=1[F:66])[CH2:42][N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([NH:51][CH2:52][C:53]2[CH:54]=[C:55](B(O)O)[CH:56]=[CH:57][CH:58]=2)=[O:50])[C:44]1=[O:62].[B].[Br:68][C:69]1[CH:70]=[C:71]2[C:77](I)=[CH:76][NH:75][C:72]2=[N:73][CH:74]=1>>[Br:68][C:69]1[CH:70]=[C:71]2[C:77]([C:55]3[CH:54]=[C:53]([CH:58]=[CH:57][CH:56]=3)[CH2:52][NH:51][C:49]([C:45]3[C:44](=[O:62])[N:43]([CH2:42][C:41]4[CH:63]=[CH:64][C:65]([F:66])=[C:39]([F:38])[CH:40]=4)[CH:48]=[CH:47][CH:46]=3)=[O:50])=[CH:76][NH:75][C:72]2=[N:73][CH:74]=1
Reactant: Brc1cnc2[nH]cc(I)c2c1
Reactant: O=C(NCc1cccc(B(O)O)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: [B]
Product: O=C(NCc1cccc(-c2c[nH]c3ncc(Br)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenylboronic acid as activated boron species and 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine as substituted bicyclic heterocycle, to produce the title compound. 1H NMR (400 MHz, DMSO-d6) d ppm 12.169 (s, 1H) 10.093 (t, J=5.8 Hz, 1H) 8.422 (d, J=7.1 Hz, 1H) 8.387 (s, 1H) 8.309 (s, 1H) 8.228 (d, J=6.5, 1H) 7.943 (s, 1H) 7.672 (s, 1H) 7.580 (d, J=7.9 Hz, 1H) 7.469-7.372 (m, 3H) 7.202 (d, J=7.7 Hz, 1H) 7.183-7.130 (m, 1H) 6.602 (t, J=6.9 Hz, 1H) 5.210 (s, 2H), 4.586 (d, J=5.6 Hz, 2H); MS m/z=548.98 M+H.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.O[NH:9][C:10](=[NH:21])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[CH3:6][C:5]1[O:7][N:21]=[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[N:9]=1
Reactant: Cc1ccc(C(=N)NO)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccc(C)c([N+](=O)[O-])c2)no1
Temperature: 25 °C
Yield: 76 %

Procedure:
Acetic anhydride (25 mL, 260 mmol) was added to a solution of compound 1a (11.5 g, 58.8 mmol) in a mixture of pyridine (50 mL, 620 mmol) and toluene (200 mL). The reaction mixture was refluxed for 22 h. After cooling to rt, a solution of concentrated HCl (75 mL) in water (200 mL) was added, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, and concentrated in vacuo. The residue was recrystallized from absolute ethanol to afford compound 1b as tan needles (9.8 g, 76%). ESI-MS m/e 220.2 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N+:11]([O-])=O)=[C:8]([OH:10])[CH:9]=1.[H][H]>CCO.O=[Pt]=O>[NH2:11][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][O:2][CH3:1])=[CH:9][C:8]=1[OH:10]
Reactant: [H][H]
Reactant: COCc1ccc([N+](=O)[O-])c(O)c1
Agent: O=[Pt]=O
Solvent: CCO
Product: COCc1ccc(N)c(O)c1

Procedure:
A solution of 2 (20 g, 108 mmol) in EtOH (300 mL) was hydrogenated over PtO2 (300 mg) in Parr pressure apparatus until the theoretical amount of hydrogen was absorbed. The catalyst was removed by filtration through a pad of Celite, and the filtrate was concentrated in vacuo to a solid (21 g, 100%). This solid was combined with material obtained from a smaller run then passed through a pad of silica gel (500 g) eluted with ether. Fractions containing pure product were combined, dried then concentrates, yield 20 g (89%) m.p. 108–108.5° C. (uncorrected).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.Cl[CH:7]([Cl:9])Cl.[F:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16](=[O:22])[CH2:15][CH2:14]2.C([O-])(=O)C.[Na+]>O.CN(C)C=O>[Cl:9][C:7]1[NH:17][C:18]2[C:13]([CH2:14][C:15]=1[CH:16]=[O:22])=[CH:12][C:11]([F:10])=[C:20]([F:21])[CH:19]=2
Reactant: ClC(Cl)Cl
Reactant: O=C1CCc2cc(F)c(F)cc2N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=CC1=C(Cl)Nc2cc(F)c(F)cc2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
76.9 cm3 of phosphoryl chloride are added in the course of 30 minutes, with stirring, at between 10° and 15° C., to a mixture of 800 cm3Of trichloromethane and 74.35 cm3 of dimethylformamide and the mixture is stirred for 1 hour at a temperature close to 20° C. 65.8 g of 6,7-difluoro-3,4-dihydrocarbostyril are added in the course of 10 minutes, at about 20° C., with vigorous stirring, to the solution obtained The solution obtained is heated to a temperature close to 60° C. and kept at this temperature for 2 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. until a pasty mixture is obtained. A mixture of 500 g of ice and 500 cm3 of water is added, with vigorous stirring. The solid obtained is drained at about 5° C. and washed with 3 times 300 cm3 of water at 5° C. The moist product obtained and 60 g of sodium acetate are added simultaneously, in the course of 1 hour, to 1.5 liters of water at 90° C., in such a way as to maintain the pH at about 6. The mixture is stirred for a further 30 minutes at 90° C., the temperature is allowed to fall to about 50° C. and the product is drained at this temperature and washed with 3 times 300 cm3 of water at about 20° C. 70.18 g of 2-chloro-6,7-difluoro-3-formyl-1,4-dihydroquinoline are obtained in the form of a yellow solid melting at 260° C., which is used in this form for the subsequent steps.
Reaction SMILES: [NH:1]([C:8]([NH:10][C:11]1[CH:39]=[CH:38][C:14]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([CH:25]3[CH2:30][CH2:29][N:28]([C:31](OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[O:24])[CH:17]=2)=[CH:13][C:12]=1[Cl:40])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[OH-].[Na+]>FC(F)(F)C(O)=O>[NH:1]([C:8]([NH:10][C:11]1[CH:39]=[CH:38][C:14]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([CH:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)=[O:24])[CH:17]=2)=[CH:13][C:12]=1[Cl:40])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)Nc4ccccc4)c(Cl)c3)ccn2)CC1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)Nc4ccccc4)c(Cl)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
After dissolving 120 mg of t-butyl 4-{[(4-{4-[(anilinocarbonyl)amino]-3-chlorophenoxy}-2-pyridyl)amino]carbonyl}-1-piperidine carboxylate in 5 ml of trifluoroacetic acid, the solution was stirred at room temperature for 5 minutes. Sodium bicarnobate water and 5N aqueous sodium hydroxide were added and extraction was performed with ethyl acetate. The extract was washed with brine and dried over sodium sulfate. The drying agent was filtered off, and the solvent was distilled off under reduced pressure. After adding 5 ml of tetrahydrofuran, 26 mg of acetic acid, 92 mg of sodium triacetoxyborohydride and 0.5 ml of formaldehyde (37% in water) to the residue, the mixture was stirred at room temperature for 10 minutes. Sodium bicarnobate water and 5N aqueous sodium hydroxide were added to the reaction solution, and extraction was performed with ethyl acetate. The extract was washed with brine and then passed through a glass filter coated with NH type silica gel. The silica gel was washed thoroughly with ethyl acetate, the ethyl acetate layers were combined and subjected to distillation under reduced pressure, and the residue was solidified with ethyl acetate and hexane to obtain 80 mg of a colorless powder.
Reaction SMILES: [Cl:1][O-].[Na+].[CH3:4][N:5]1[C:9]([CH:10]([OH:23])[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([Cl:21])[C:12]=2[Cl:22])=[CH:8][CH:7]=[N:6]1>C(O)(=O)C>[CH3:4][N:5]1[C:9]([C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([Cl:21])[C:12]=2[Cl:22])=[O:23])=[C:8]([Cl:1])[CH:7]=[N:6]1
Reactant: COc1cc(C(O)c2ccnn2C)c(Cl)c(Cl)c1OC
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(C(=O)c2c(Cl)cnn2C)c(Cl)c(Cl)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.3 g of an aqueous 10% sodium hypochlorite solution are added to a solution of 3.9 g of α-(1-methylpyrazol-5-yl)-2,3-dichloro-4,5-dimethoxybenzylalcohol in acetic acid and the mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated to remove acetic acid, and ethyl acetate is added to the residue. The organic layer is separated, washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography to give 2.1 g of (1-methyl-4-chloropyrazol-5-yl)-(2,3-dichloro-4,5-dimethoxyphenyl)-methanone.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[C:6]([CH3:13])=[CH:5][N:4]=1.[SH:14][C:15]1[NH:16][C:17]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=2[N:19]=1>>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][C:18]2[NH:19][C:15]([S:14][CH2:2][C:3]3[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[C:6]([CH3:13])=[CH:5][N:4]=3)=[N:16][C:17]=2[CH:23]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: Cc1cnc(CCl)c(C)c1[N+](=O)[O-]
Product: COc1ccc2[nH]c(SCc3ncc(C)c([N+](=O)[O-])c3C)nc2c1

Procedure:
The 2-chloromethyl-3,5-dimethyl-4-nitropyridine of formula-III is dissolved in a protic solvent and reacted with 2-mercapto-5-methoxy benzimidazole of the formula-VII with a base to get 5-methoxy-2-(((3,5-dimethyl-4-nitro-2-pyridinyl)methyl)thio)-1H-benzimidazole of formula-VIII. After recrystallization from suitable solvents, pure compound-VIII is obtained with an impurity, 5-methoxy-2-(((3,5-dimethyl-4-chloro-2-pyridinyl)methyl)thio-1H-benzimidazole, of formula-XV less than 0.1%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C([Sn](CCCC)(CCCC)[C:33]1[CH2:34][CH2:35][O:36][CH2:37][CH:38]=1)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:36]1[CH2:35][CH:34]=[C:33]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([CH:17]4[CH2:22][O:21][CH2:20][CH2:19][O:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:38][CH2:37]1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(C4=CCOCC4)c3)nc12
Temperature: 100 °C
Yield: 77.2 %

Procedure:
To a stirred solution of 180 mg (0.40 mmol) (±)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide in 10 ml DMF were added 298 mg (0.80 mmol) tributyl-(3,6-dihydro-2H-pyran-4-yl)-stannane, 34 mg (0.05 mmol) bis(triphenylphosphine)palladium(II) chloride, 63 mg (0.24 mmol) triphenylphosphine, 136 mg (3.20 mmol) lithium chloride and a small spatula-end of 2,6-di-tert-butyl-4-methylphenol. The mixture was heated at 100° C. for 24 h and then concentrated in vacuo. Flash chromatography (ethyl acetate) afforded 140 mg (77%) (±)-2-(3,6-dihydro-2H-pyran-4-yl)-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide as an off-white solid. ES-MS m/e (%): 454 (M+H+, 100).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]=[C:16]([C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[CH:8]=1)C.C(O)C.O>[OH-].[Na+]>[Br:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)=[CH:15][CH2:14][O:13][C:9]2[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:31])=[O:3])[CH:12]=[CH:11][CH:10]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)CCc1cccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCc1cccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)c1
Yield: 59.5 %

Procedure:
3-{3-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-propionic acid ethyl ester (example 1) (755 mg, 1.4 mmol) was hydrolysed in 1N NaOH (5.6 ml) and ethanol (15 ml) for 16 h at room temperature. Water (5 ml) was added and ethanol removed by concentration in vacuo. The mixture was neutralised with 6N HCl. The crude product was extracted with ethyl acetate (×3). The organic layers were combined, dried (MgSO4) and evaporated. The residue was dissolved in toluene and the title compound precipitated with petroleum ether, to give 430 mg of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:28])[N:12]([CH2:14][CH2:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[O:20][CH2:21][C:22]([OH:24])=[O:23])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.CCOC(C)=O>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:28])[N:12]([CH2:14][CH2:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[O:20][CH2:21][C:22]([O:24][CH3:35])=[O:23])[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)COc1cccc(CCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)COc1cccc(CCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Reaction time: 5 h

Procedure:
To a solution of (3-{3-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]propyl}phenoxy)acetic acid (100 mg) in DMF (2 mL) was added K2CO3 (46 mg) and iodomethane (41 mg) at ambient temperature. The reaction mixture was stirred for 5 hours at the same temperature. The resulting mixture was diluted with EtOAc and washed successively with water and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=80:20-40:60) to give methyl (3-{3-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]propyl}phenoxy)acetate-.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[C:7]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[C:15]([C:21](O)=[O:22])[NH:16]4)=[CH:8][O:9][C:5]=2[CH:4]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][C:30]([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[C@@H:38]([CH3:43])[CH2:37]2)([OH:33])[CH2:29][CH2:28]1>>[OH:33][C:30]1([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[C@@H:38]([CH3:43])[CH2:37]2)[CH2:29][CH2:28][CH:27]([NH:26][C:21]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[C:12]([O:11][CH2:10][C:7]2[C:6]4[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:9][CH:8]=2)[CH:20]=[CH:19][CH:18]=3)=[O:22])[CH2:32][CH2:31]1
Reactant: COc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCC(O)(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (synthesis described in WO2005077932A2, cmpd 120) and amine 14.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C@H:28]1[NH:33][C@@H:32]([CH3:34])[CH2:31][N:30]([C:35]2[N:39]([CH3:40])[C:38]3[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=3[N:36]=2)[CH2:29]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:33]2[C@H:32]([CH3:34])[CH2:31][N:30]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH2:29][C@@H:28]2[CH3:27])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: C[C@@H]1CN(c2nc3ccccc3n2C)C[C@H](C)N1
Product: C[C@@H]1CN(c2nc3ccccc3n2C)C[C@H](C)N1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-1-methyl-1H-benzimidazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])[CH:14]=1)[C:6](N(OC)C)=[O:7].[CH3:21][Mg]Br>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6](=[O:7])[CH3:21])[CH:12]=[C:13]([S:15]([F:17])([F:20])([F:19])([F:16])[F:18])[CH:14]=1
Reactant: C[Mg]Br
Reactant: COc1cc(C(=O)N(C)OC)cc(S(F)(F)(F)(F)F)c1
Solvent: C1CCOC1
Product: COc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1

Procedure:
3,N-Dimethoxy-N-methyl-5-(pentafluorosulfanyl)benzamide (O3.007; 2.0 g) was dissolved in absolute THF (60 ml), and methylmagnesium bromide (5.2 ml, 3 M in diethyl ether) was added dropwise at 0° C. while stirring. After addition, the ice bath was removed and the mixture was stirred at RT for 2 h. 1 N hydrochloric acid was then added dropwise while cooling, followed by water and ethyl acetate. The organic phase was removed and the aqueous phase was extracted twice more with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (met. A). The product-containing fractions were combined, freed of the acetonitrile and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 1.63 g of the desired compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2(O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(O)CCc3ccccc32)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(C2C=Cc3ccccc32)c1
Yield: 80.5 %

Procedure:
To a mixture of 23 g (0.095 mol) of 1-(3-methoxyphenyl)-indan-1-ol and 100 mg of p-toluene sulfonic acid monohydrate was added 1 L of toluene and the solvent was distilled in vacuo (40 mm) until an oil residue was obtained. The oil was chromatographed (silica, 1:1 hexane/methylene chloride) to afford 17.0 g (80.1%) of 1-(3-methoxyphenyl)-indene as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:24][C@:11]2([O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:12]2)[CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:25]1([CH2:31][C:32]([NH:34][C@@H:35]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36](O)=[O:37])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:24][C@:11]2([O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:12]2)[CH2:10][N:9]1[C:36](=[O:37])[C@@H:35]([NH:34][C:32](=[O:33])[CH2:31][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:39]([CH3:41])([CH3:42])[CH3:40])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@]2(CN1)CN(c1cccc(Cl)c1)C(=O)O2
Reactant: CC(C)(C)[C@H](NC(=O)CC1CCCCC1)C(=O)O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)CC1CCCCC1)C(C)(C)C
Yield: 46.2 %

Procedure:
Following the procedure from Example 1 step G using (5S,8S)-tert-butyl-3-(3-chlorophenyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (B5) (32 mg, 91 μmol, 1 eq.) and (5)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoic acid (25 mg, 100 μmol, 1.2 eq.) gave 25 mg (42 μmol) of (5S,8S)-tert-butyl-3-(3-chlorophenyl)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (C5). LC MS+/−: 590.31/589.47 at 3.95 min (10-90%, 3-5 min, Formic Acid).