Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][NH:14][C:13]2=[O:20].[H-].[Na+]>CN(C=O)C>[CH2:1]([N:14]1[C:13](=[O:20])[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([Br:9])[CH:11]=2)[N:16]=[CH:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2ccc(Br)cc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)ccc2ncn1Cc1ccccc1
Temperature: 80 °C
Yield: 57.2 %

Procedure:
Benzyl bromide (0.264 mL, 2.22 mmol) was added to a solution of 6-bromoquinazolin-4(3H)-one (0.5 g, 2.22 mmol) and NaH (0.08 g, 3.33 mmol) in DMF (5 mL) at 0° C. The reaction mixture was heated to 80° C. for 4 h. The reaction mixture was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo to afford title compound (0.4 g, 48.1%) as pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.46 (d, J=1.6 Hz, 1H), 8.09 (s, 1H), 7.83 (dd, J1=2.0 Hz, J2=8.8 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.4-7.2 (m, 5H), 5.2 (s, 2H); ESI-MS m/z=315 (M+H)+; LCMS purity: 84.2%
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][NH:10][CH2:9]2)=[CH:6][C:5]([O:18]C)=[C:4]([O:20]C)[CH:3]=1.B(Br)(Br)[Br:23].ClCCl.CO>ClCCl.C(=O)=O.CO>[BrH:23].[F:1][C:2]1[C:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][NH:10][CH2:9]2)=[CH:6][C:5]([OH:18])=[C:4]([OH:20])[CH:3]=1
Reactant: COc1cc(F)c(C2CNCc3ccccc32)cc1OC
Reactant: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CO
Product: Br
Product: Oc1cc(F)c(C2CNCc3ccccc32)cc1O

Procedure:
1.15 g of 4-(6-fluoro-3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline was dissolved in 30 ml of dichloromethane, 26.4 ml of 1M boron tribromide-dichloromethane solution was added to the solution under an argon gas stream under stirring under cooling at the internal temperature of -20° to -30° C. The mixture was stirred for 3 hours at room temperature, and then, 7.0 ml of methanol was added dropwise under cooling in dry ice-methanol bath. The mixture was stirred for 30 minutes at room temperature, the crystals which separated out were collected by filtration, affording 1.0 g of 4-(6-fluoro-3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: [I:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)(=[O:23])=[O:22]>O1CCOCC1>[I:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:30][CH:27]4[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:25][CH2:26]4)[N:12]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)c1nccc(-n2nnc3c(I)cccc32)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC(Nc2nccc(-n3nnc4c(I)cccc43)n2)CC1
Temperature: 110 °C
Yield: 80.6 %

Procedure:
A mixture of 4-iodo-1-(2-methanesulfinyl-pyrimidin-4-yl)-1H-benzotriazole (700 mg) and 1-methanesulfonyl-piperidin-4-ylamine (642 mg) in 1,4-dioxane (20 mL) was stirred under argon, then heated at 110° C. for 4.5 h. The reaction mixture was then cooled, and the solvent removed in vacuo to provide a solid. The solid was chromatographed on silica using 0-100% EtOAc/hexanes to provide [4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-yl]-(1-methanesulfonyl-piperidin-4-yl)-amine (731 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][NH:24][CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1.[I-].[K+].C(N(CC)CC)C>CN(C)C=O>[OH2:5].[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1
Reactant: Fc1ccc(OCCCCl)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC
Product: O
Temperature: 60 °C
Yield: 42.8 %

Procedure:
A mixture of 4.7 parts of 1-(3-chloropropoxy)-4-fluorobenzene, 3.015 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 0.1 parts of potassium iodide, 3 parts of N,N-diethylethanamine and 45 parts of N,N-dimethylformamide was stirred and heated for 18 hours at 60° C. The reaction mixture was poured onto water. The precipitated product was filtered off and dissolved in trichloromethane. The solution was washed with water. The organic phase was separated, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 3.11 parts (42.8%) of cis-4-amino-5-chloro-N-[1-[3-(4-fluoro-phenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate; mp. 109.8° C. (compound 1).
Reaction SMILES: [CH:1]([Mg]Cl)=[CH:2][CH2:3][CH2:4][CH3:5].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[C:29]([F:31])[C:28]([C:32]#[N:33])=[C:27]([F:34])[CH:26]=3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1>C1COCC1>[F:34][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][C@H:18]2[CH2:19][CH2:20][C@H:15]([C@H:12]3[CH2:13][CH2:14][Si@H:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:10][CH2:11]3)[CH2:16][CH2:17]2)[CH:30]=[C:29]([F:31])[C:28]=1[C:32]#[N:33]
Reactant: N#Cc1c(F)cc(CCCC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc1F
Reactant: CCCC=C[Mg]Cl
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCCCc3cc(F)c(C#N)c(F)c3)CC2)CC1

Procedure:
50 ml (0.13 mols) of a THF solution of 2.5M of pentenylmagnesium chloride was dropped in a mixed solution of 41.0 g (0.1 mol) of 1-chloro-4-(trans-4-(4-(3,5-difluoro-4-cyanophenyl)butyl)cyclohexyl)-1-silacyclohexane and 300 ml of THF. The resultant product was found to be a mixture of trans and cis isomers with respect to the silacyclohexane ring. The product was subjected to ordinary aftertreatments such as removal of solvent and salts, followed by isolation through chromatography to obtain 40.1 g (yield: 90%) of the intended trans isomer product.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:12]3[CH2:20][NH:19][CH2:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25](F)=[C:26]([CH:29]=1)[C:27]#[N:28].C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CCOC(C)=O.C(#N)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:19]2[CH2:18][CH2:17][C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[C:12]=3[CH2:20]2)=[C:26]([CH:29]=1)[C:27]#[N:28]
Reactant: COc1ccc(CNc2ncnc3c2CNCC3)cn1
Reactant: N#Cc1cc(Cl)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(CNc2ncnc3c2CN(c2ccc(Cl)cc2C#N)CC3)cn1
Yield: 44.5 %

Procedure:
A mixture of N-((6-methoxypyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (440 mg, 1.6 mmol), 5-chloro-2-fluorobenzonitrile (630 mg, 4.0 mmol), N,N-diisopropylethylamine (560 uL, 3.2 mmol), and acetonitrile (4.0 mL) was subjected to microwave irradiation at 180° C. for 4 h. After that an additional 5-chloro-2-fluorobenzonitrile (400 mg) was added and the mixture was subjected to microwave irradiation at 180° C. for another 2 h. After cooling, the mixture was treated with aq. NaHCO3 and EtOAc (100 mL). The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column (EtOAc: 100%) and the obtained solid was washed with ether to yield an off-white solid (290 mg, 44%).
Reaction SMILES: [CH2:1]([O:5][C:6]([O:8][CH:9]([CH3:19])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:22]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42]Cl)=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1.CN(C)C=O.O>[CH2:22]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][O:18][C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH:9]([O:8][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH3:19])=[CH:17][CH:16]=3)=[CH:38][CH:37]=2)=[CH:34][CH:35]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCc1ccc(-c2ccc(CCl)cc2)cc1
Reactant: CCCCOC(=O)OC(C)COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(-c2ccc(COc3ccc(OCC(C)OC(=O)OCCCC)cc3)cc2)cc1
Yield: 24.5 %

Procedure:
A solution of p-(2-(butoxycarbonyloxy)-propoxy)-phenol (1 g) prepared in Example 4 in tetrahydrofuran (20 ml) was dropwise added to a suspension of sodium hydride (0.2 g) in tetrahydrofuran, followed by dropwise adding to the mixture, a solution of 4'-octyl-4-chloromethylbiphenyl (1.2 g) in dimethylformamide (50 ml), agitating the mixture at 60° C. for 10 hours, pouring the reaction solution in water, extracting the resulting material with toluene (300 ml), washing the extract with an acid, then with an alkali and further with water, purifying it according to column chromatography using a column having activated alumina filled therein and recrystallizing from a mixed solvent of ethyl acetate with ethanol to obtain the objective 4'-octyl-4-(4-(2-(butoxycarbonyloxy)-propoxy)-phenoxymethyl)-biphenyl (0.5 g) having a m.p. of 94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C(N([CH2:38][CH3:39])CC)C.ClCC(OC(=O)CCl)=[O:43].[H-].[Na+]>CC(N(C)C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][N:29]4[CH2:39][CH2:38][O:32][CH2:31][C:30]4=[O:43])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CCN(CC)CC
Reactant: O=C(CCl)OC(=O)CCl
Reactant: OCCNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C1COCCN1CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
2-({2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl}amino)ethanol (prepared as described in Example 36/30 mg, 0.07 mmol) and triethylamine (10 μl) were dissolved in DMA (0.7 ml) and chloroacetic anhydride (12 mg, 0.07 mmol) was added at −15° C. The temperature was slowly raised to room temperature and the reaction mixture was stirred for 1 hour. Sodium hydride (60%, 16 mg) was then added and the reaction mixture was stirred for 1 hour. Water was then added and the mixture evaporated and purified by preparative HPLC (column beta-basic, Hypercil 5 □m, 21×100 mm) eluting with a mixture of water and acetonitrile containing 2g/l of ammonium carbonate (gradient) to give the title compound (8 mg, 24%); NMR Spectrum: 3.49 (t, 2H), 3.80-3.84 (m, 4H), 4.04 (s, 2H), 4.46 (t, 2H), 5.28 (s, 2H), 7.24 (d, 1H), 7.36 (t, 1H), 7.58 (d, 1H), 7.76 (dd, 1H), 7.88 (t, 2H), 8.12 (d, 1H), 8.19 (s, 1H), 8.32 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 496 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([SH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[Cl:26])[CH:22]=[N:21][CH:20]=[CH:19]2.C1CCN2C(=NCCC2)CC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][C:25]=2[Cl:26])[CH:22]=[N:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cc2cnccc2cc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(Sc2cc3ccncc3cc2Cl)CC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 73.6 %

Procedure:
To 1.78 g of crude 4-Mercapto-piperidine-1-carboxylic acid tert-butyl ester (273) were dissolved in 20 ml degassed DMF was added 1.3 g (7.1 mmol) 6-Fluoro-7-chloroisoquinoline (263) and 1.23 ml (8.2 mmol) DBU. After stirring for 90 min at 80° C. the solvent was evaporated. The residue was taken up in ethyl acetate and washed with brine. The organic phases were dried over Sodium sulfate and evaporated. Purification over silica gel (40% to 60% ethyl acetate in heptane) gave 1.98 g of the expected compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](=[O:14])[C:11]([CH2:21][C:22](O)=[O:23])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]=2[CH:25]=1>C1C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](=[O:14])[C:11]([CH2:21][C:22]([Cl:3])=[O:23])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]=2[CH:25]=1
Reactant: O=C(O)CC1(c2ccccc2)C(=O)Oc2ccc(Cl)cc21
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)CC1(c2ccccc2)C(=O)Oc2ccc(Cl)cc21
Yield: 96.8 %

Procedure:
23.7 g of double-distilled thionyl chloride are added dropwise to a solution, stirred and heated to 70° C., of 30.2 g of 2-(5-chloro-2,3-dihydro-2-oxo-3-phenyl-3-benzofuranyl)acetic acid in 250 ml of anhydrous benzene. When the addition is complete, the mixture is heated to reflux until the evolution of gas has completely ceased. The medium is concentrated under vacuum, the residue washed with 200 ml of anhydrous benzene and the solvent evaporated off. This operation is repeated twice and the product is left to crystallize at room temperature. The crystals are washed with petroleum ether and filtered off, and 31 g of pure product are obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][N:16]2[CH:24]=1.[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:30][C:21]([C:19]2[CH:18]=[CH:17][N:16]3[CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[C:15]3[CH:20]=2)=[O:23])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NC3CCCC3)cc2n1
Yield: 73 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (96 mg, 0.3 mmol) was converted, using cyclopentylamine instead of aminomethylcyclopropane, to the title compound (84 mg, 73%) which was obtained as a light yellow foam. MS: m/e=387.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][CH:7]=1.[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[CH2:23].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C>[N:27]1[CH:28]=[CH:29][C:24]([CH:22]=[CH:23][C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][CH:7]=2)=[CH:25][CH:26]=1
Reactant: C=Cc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Br)c1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(C=Cc2ccncc2)c1
Yield: 79 %

Procedure:
A mixture of 5-bromo-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine (440 mg, 1.25 mmol), 4-vinylpyridine (0.267 mL), Pd(OAc)4 (30 mg), tris(o-tolyl)phosphine (160 mg), and triethylamine (3.5 mL) in acetonitrile (4 mL) was heated at reflux for 16 hours. The solution was then concentrated, and the residue was washed with water and aqueous NaHCO3 solution. The organic layer was dried and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:ethyl acetate 1:3 to afford the title compound (440 mg, 79% yield). MS (DCI/NH3) m/z 382 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 1.49 (s, 3H), 1.85-2.12 (m, 4H), 3/26-3.55 (m, 2H), 3.86-4.08 (m, 1H), 4.08-4.34 (m, 1H), 7.20-7.30 (m, 2H), 7.36-7.42 (m, 2H), 7.71 (br s, 0.5H), 8.22-8.42 (m, 1.5H), 8.58-8.69 (m, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:7]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][S:2]([N:6]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:7]1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3]
Reactant: CCOC(=O)C1CCCCN1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Methanesulfonyl chloride (4.0 g, 35 mmol) was slowly added to a stirring solution of ethyl pipecolinate, (5.5 g, 35 mmol) and triethylamine (4.9 mL, 35 mmol) in anhydrous methylene chloride (88 mL). The reaction was stirred overnight at ambient temperature and then diluted with ethyl acetate. The organic layer was successively washed with water, twice with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride solutions, dried (anhydrous sodium sulfate), and filtered. The solution was concentrated under reduced pressure to give the desired product as a tan liquid (6.9 g, 84%). 1H NMR (CDCl3, 300 MHz) δ 4.72-4.71 (br d, 1H, J=3.6 Hz), 4.24-4.16 (qd, 2H, J=6.9, 2.6 Hz), 3.74-3.68 (m, 1H), 3.22-3.13 (td, 1H, J=12.3, 3.0 Hz), 2.93 (s, 3H), 2.31-2.25 (m, 1H), 1.83-1.51 (m, 5H), 1.32-1.27 (td, 3H, J=7.0, 0.6 Hz), 3.52-3.42 (m, 1H), 3.01 (s, 3H), 2.32-2.22 (m, 1H), 2.11-1.98 (m, 3H). ESI (m/z): 235.9 (M+H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([NH:16][C:17]1[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][N:18]=1)(=[O:15])[CH3:14].O>O1CCCC1>[C:13]([NH:16][C:17]1[CH:22]=[C:21]([CH2:23][O:24][S:9]([CH3:8])(=[O:11])=[O:10])[CH:20]=[CH:19][N:18]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1cc(CO)ccn1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(COS(C)(=O)=O)ccn1
Reaction time: 0.33 h
Yield: 87 %

Procedure:
A solution of triethylamine (1.7 mL, 12 mmol) and methanesulfonyl chloride (0.70 mL, 9.0 mmol) in anhydrous tetrahydrofuran (3.0 mL) was added to a solution of (2-acetylaminopyridin-4-yl)methanol (Reference compound No. 12-1, 1.0 g, 6.0 mmol) in anhydrous tetrahydrofuran (9.0 mL) under ice-cooling, and the mixture was stirred for 20 minutes. Water (30 mL) was added to the reaction mixture, the whole was extracted with ethyl acetate (40 mL) three times, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was filtered off with hexane. The solid was dried under reduced pressure at 40° C. to give 1.3 g of the title reference compound as a pale yellow solid. (Yield 87%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH2:33][C:34]([C:37]([O:39]C)=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH2:33][C:34]([C:37]([OH:39])=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: COC(=O)C(C)(C)COc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(COc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 60 °C
Yield: 69.2 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (106 mg, 0.16 mmol) in methanol (6 mL) was added a solution of NaOH (30 mg, 0.75 mmol) in water (3 mL). The mixture was heated at 60° C. for 5 h, evaporated to remove most of methanol, cooled to room temperature, and acidified to “pH” 2 with aqueous HCl solution. The precipitate was collected and dried to give title product as a white solid (70 mg). m/z (M+H)+: 631
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][CH:3]1[NH:22]C(=O)OCC1C=CC=CC=1.I[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>>[NH2:22][C@@H:3]1[C:2](=[O:1])[N:8]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4]1
Reactant: O=C(NC1N=C(c2ccccc2)c2cc3c(cc2NC1=O)OCO3)OCc1ccccc1
Reactant: Ic1ccccn1
Product: N[C@H]1N=C(c2ccccc2)c2cc3c(cc2N(c2ccccn2)C1=O)OCO3

Procedure:
Intermediate 3E was prepared from Intermediate 3D and 2-iodopyridine according to the procedure described for Example 1. The racemate was purified by preparative SFC chromatography (Berger SFC MGII, OD-H 250×30 mm ID, 5 μm, 73/17 CO2/MeOH, 85 mL/min) to give Intermediate 4E. RT=1.668 min (H2O/CH3OH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=3 min, wavelength=220 and 254 nm); MS(ES):m/z=373.2 [M+H+].
Reaction SMILES: Br[CH:2]([CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2>>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:26][N:35]2[CH2:34][CH2:33][C:32]3[C:37](=[CH:38][C:39]([O:40][CH3:41])=[C:30]([O:29][CH3:28])[CH:31]=3)[CH2:36]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(C(CCCCC(C)Br)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Product: COc1ccc(C(CCCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 38 %

Procedure:
The procedure of Example 49 is repeated using 5.22 g of 4-[6-bromo-1-[(4-methylphenyl)thio]heptyl]-1,2-dimethoxybenzene, 3.29 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This affords 2.49 g of the desired product as a yellow gum. MS(HI res): m/z Calcd for C33H43NO4S 549.29126 Found 549.291 Calcd for C33H43NO4S H2O C=69.81, H=7.99, N=2.47, S=5.64 Found C=70.19, H=7.83, N=2.41, S=5.70
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[C:25]([F:26])=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=1/[CH:31]=[CH:32]/[C:33](O)=[O:34]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33](=[O:34])/[CH:32]=[CH:31]/[C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[C:25]([F:26])[C:20]=3[F:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)c(F)c1F
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(C(F)(F)F)c(F)c3F)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2,3-difluoro-4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 01b: tR=0.97 min; [M+H]+=440.1.