Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC=CC=1.[C:7]1([S:13]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[CH2:21][CH2:20][CH2:19]3)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH:28](C)[C:29]([O:31][CH2:32]C)=[O:30]>O.[Zn]>[CH3:32][O:31][C:29](=[O:30])[CH2:28][C:22]1([OH:26])[C:23]2[C:18](=[CH:17][C:16]([S:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)(=[O:15])=[O:14])=[CH:25][CH:24]=2)[CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)C(C)Br
Reactant: O=C1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: [Zn]
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)CC1(O)CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution/suspension of anhydrous benzene (25 mL), powdered Zinc metal (0.505 g, 7.72 mmol), 12 (0.01 g) and 6-benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one was stirred for 10 minutes at room temperature. Ethyl bromopropionate (0.784 mL, 1.18 g, 7.07 mmol) was added and the reaction mixture was heated to reflux for 2.5 hours. The reaction mixture was allowed to cool, diluted with 300 mL of water and extracted twice with 250 mL of EtOAc. The combined organic layers were washed with water and saturated brine, dried (MgSO4) and evaporated under reduced pressure to yield (6-benzenesulfonyl-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid methyl ester. MS: 375 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([CH:22]=[C:23]2[S:27][C:26](=[S:28])[NH:25][C:24]2=[O:29])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[C:14]([F:17])([F:16])[F:15].[CH3:30]I.[Al]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([CH:22]=[C:23]2[S:27][C:26]([S:28][CH3:30])=[N:25][C:24]2=[O:29])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[C:14]([F:17])([F:16])[F:15]
Reactant: COc1cc(C=C2SC(=S)NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Reactant: CI
Agent: [Al]
Solvent: CN(C)C=O
Product: COc1cc(C=C2SC(SC)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F

Procedure:
To a solution of 4-[2-Methoxy-4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile (500 mg, 1.15 mmol) in DMF (5 mL) was added CH3I (15 mL) and the solution was heated to 40° C. in an aluminum heating block for 8 h. The solvent was concentrated in vacuo to afford the product. 1H NMR (400 Hz, CDCl3) δ 7.97 (bs, 1H), 7.68 (dd, 1H), 7.63 (s, 1H), 7.17 (m, 3H), 6.77 (d, 1H), 3.08 (s, 3H), 2.95 (s, 3H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11](O)=O)=[CH:4][C:3]=2[O:2]1.C1C[O:17]CC1>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([OH:17])[CH3:11])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: C1CCOC1
Product: CC(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 2-(3,4-methylenedioxy)phenylacetic acid (5 g, 25.75 mmol) in anhydrous THF (20 ml) at 0° C. was added BH3 THF (40 ml, 1.0 M in THF). The mixture was stirred at room temperature for 1 h. To work up, THF was evaporated on a rotavap. The residue was treated with water (100 ml) Acidified and extracted with ether (2×100 ml). Removal of the solvent under reduced pressure gave 2-(3,4-methylenedioxy)phenyl-1-ethanol as an oil (4.7 g, 98% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12]Br)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>CC(O)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:12][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)Nc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(=O)Nc1ccc(CCN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Yield: 48.4 %

Procedure:
2-[4-(Acetylamino)phenyl]ethyl bromide (2.6 g, 10.7 mmol) was added to a mixture of N-tert-butyloxycarbonyl piperazine (2.0 g, 10.7 mmol) and K2CO3 (3.0 g, 21.7 mmol), in IPA (100 ml), and heated at 100° C. for 16 h. The mixture was filtered and the filtrate evaporated under vacuum. The residue was taken up into ethyl acetate and washed with H2O . The aqueous phase was extracted with EtOAc and the combined extracts dried (Na2SO4 /MgSO4) and evaporated. The crude product was chromatographed on silica gel eluting with ethyl acetate to give 1-tert-butyloxycarbonyl-4-[2-(4-(acetylamino)phenyl)ethyl]piperazine (1.8 g, 49%) which was shown to be pure by 1H NMR. A solution of the preceding N-Boc piperazine (1.8 g, 5.19 mmol) in 99% formic acid (30 ml) was stirred at room temperature for 16 h. The solvent was removed under vacuum and the product chromatographed on silica gel eluting with CH2Cl2 / MeOH/NH3 (50:8:1) to give the title-piperazine (1.3 g, 100%) δ(250 MHz, D6 -DMSO) 2.01 (3H, s, Me), 2.26-2.72 (12H, m, 6 of CH2), 7.12 (2H, d, J=8.5 Hz, Ar-H), 7.46 (2H, d, J=8.5 Hz, Ar-H), 9.85 (1H, s, NH).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:20])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[CH3:21][C:22]1[CH:35]=[CH:34][C:25]([CH2:26][C:27]2([OH:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:20])[CH2:2][N:30]2[CH2:31][CH2:32][C:27]([CH2:26][C:25]3[CH:24]=[CH:23][C:22]([CH3:21])=[CH:35][CH:34]=3)([OH:33])[CH2:28][CH2:29]2)=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC(CCl)COc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1ccc(CC2(O)CCN(CC(O)COc3ccc(OCc4ccccc4)cc3)CC2)cc1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
A mixture of (RS)-1-chloro-3-[4-(benzyloxy)phenoxy]-2-propanol (1.0 g, 3.4 mmol), 4-(4-methyl-benzyl)-piperidin-4-ol (0.70 g, 3.4 mmol) and potassium carbonate (0.50 g, 3.6 mmol) in 2-butanone was refluxed for 2 days. It was cooled to room temperature, 50 ml of H2O were added and the organic phase was separated. The water phase was extracted two times with ethyl acetate. The organic phases were then pooled, dried with Na2SO4 and the solvent evaporated. The residue was chromatographed over silica gel (CH2Cl2 --MeOH, 98:2) to give (RS)-1-[3-(4-benzyloxy-phenoxy)-2-hydroxy-propyl]-4-(4-methyl-benzyl)-piperidin-4-ol as a colorless solid (0.75 g, 48%). MS: m/e=462.5 (M+H+)
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]2[C:10]([N:11]([CH3:26])[C:12](=[O:25])[N:13]([CH3:24])[C:14]2=[O:23])=[CH:9]1)C.O.[OH-].[Li+]>C1COCC1>[CH3:26][N:11]1[C:10]2=[CH:9][N:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:27])=[O:3])[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]2[C:14](=[O:23])[N:13]([CH3:24])[C:12]1=[O:25]
Reactant: CCOC(=O)CCCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCCC(=O)O)cc2n(C)c1=O
Temperature: 60 °C
Reaction time: 5 h

Procedure:
4-(1,3-Dimethyl-2,4-dioxo-5-phenyl-1,2,3,4-tetrahydro-pyrrolo[3,4-d]pyrimidin-6-yl)-butyric acid ethyl ester (step 1)(1.01 g, 2.73 mmol) was dissolved in THF (10 ml) and water (10 ml) and lithium hydroxide (0.655 g, 27.3 mmol) were added. The mixture was stirred at 60° C. for 5 hours. Further lithium hydroxide (0.655 g, 27.3 mmol) was added and the mixture stirred at 60° C. for a further 24 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was acidified using 1M HCl(aq) and extracted with chloroform (5×). The combined organic phases were passed through a hydrophobic frit and evaporated under reduced pressure. The title product was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH:24]=[N:23][C:22]([NH2:25])=[N:21]2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH:24]=[N:23][C:22]([NH:25][CH:10]3[CH2:11][CH2:12][N:7]([C:5]4[S:4][N:3]=[C:2]([CH3:1])[N:6]=4)[CH2:8][CH2:9]3)=[N:21]2)=[CH:17][CH:16]=1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1ncn(Cc2ccc(F)cc2)n1
Product: Cc1nsc(N2CCC(Nc3ncn(Cc4ccc(F)cc4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(4-fluoro-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[S:10][CH:11]=[C:12]([C:14]#[N:15])[N:13]=2)[CH2:3]1.CN(C=O)C.[Br:21]N1C(=O)CCC1=O.[OH-].[Na+]>O>[Br:21][C:11]1[S:10][C:9]([N:4]2[CH2:3][C@H:2]([CH3:1])[O:7][C@H:6]([CH3:8])[CH2:5]2)=[N:13][C:12]=1[C:14]#[N:15]
Reactant: C[C@@H]1CN(c2nc(C#N)cs2)C[C@H](C)O1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(c2nc(C#N)c(Br)s2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
A flask charged with Intermediate 2 (25.61 g, 114.69 mmol) and DMF (250 mL) was cooled in an ice/water bath. N-bromosuccinimide (24.49 g, 137.63 mmol) was added portionwise (slightly exothermic reaction). The reaction mixture was stirred at room temperature for 10 min. Water (400 mL) was then added dropwise leading to a yellow precipitate, followed by sodium hydroxide 1 M (115 mL). The precipitate was filtered, washed with water (50 mL) and DIPE (10 mL). This solid was recrystallised from acetonitrile. Filtration and overnight drying in a vacuum oven at 50° C. yielded 25.5 g (73%) of Intermediate 3 as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1.O>CN(C=O)C>[Si:17]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1CCOc2cc(O)ccc21
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc2c(c1)OCCC2=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Hydroxy-2,3-dihydro-4H-chromen-4-one (900 mg) was dissolved in DMF (10 mL), and tert-butyl(chloro)diphenylsilane (1.711 mL) and 1H-imidazole (448 mg) were added thereto, followed by stirring at room temperature overnight. To the reaction liquid was added water, followed by extraction with EtOAc three times. The organic layer was combined, washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=90:10 to 80:20) to obtain 7-{[tert-butyl(diphenyl)silyl]oxy}-2,3-dihydro-4H-chromen-4-one (2.08 g) as a colorless transparent syrup.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([CH:16]=1)[C:13]([NH2:15])=[O:14])=[O:7].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].CS(C)=O>O>[C:25]1([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]3[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[C:12]([CH:16]=3)[C:13]([NH2:15])=[O:14])=[O:7])[CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: NC(=O)c1cc(C(=O)CCCCCl)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(C(=O)CCCCN2CCN(c3ccccc3)CC2)ccc1OCc1ccccc1
Temperature: 90 °C
Yield: 84.3 %

Procedure:
A mixture of 2 g of 5-(5-chlorovaleryl)-2-benzyloxy-benzamide, 1 g of 1-phenylpiperazine, 0.6 g of sodium carbonate and 10 ml of dimethyl sulfoxide was heated at 90° C. for 6 hours while stirring. After the reaction was finished, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and concentrated. The thus produced residue was dissolved in acetone and concentrated hydrochloric acid in an amount of 2 equivalents was added thereto to produce crystals. The crystals were filtered off to obtain 2.3 g of 5-[5-(4-phenyl-1-piperazinyl)valeryl]-2-benzyloxy-benzamide (yield: 73%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:26])[O:5][CH2:6][CH:7]([NH:18]C(OC(C)(C)C)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])[CH3:2].[ClH:27]>O1CCOCC1>[ClH:27].[CH2:1]([NH:3][C:4](=[O:26])[O:5][CH2:6][CH:7]([NH2:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:15])([F:16])[F:17])[CH3:2]
Reactant: CCNC(=O)OCC(NC(=O)OC(C)(C)C)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: CCNC(=O)OCC(N)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Of the compound from Example 186A, 345 mg (0.92 mmol) were admixed with 10 ml of a 4N solution of hydrogen chloride in dioxane, and the mixture was stirred at RT for 30 min. All volatile constituents were then removed on a rotary evaporator. The residue (311 mg, 100% of theory) was the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:12]=2)[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:9][CH:10]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:12]=3)[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)Cc1csc(N2CC[C@H](N)[C@H](OC)C2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)Cc1csc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)n1
Yield: 36 %

Procedure:
The same operation as in Example (1g) was performed using ethyl cis(±)-[2-(4-amino-3-methoxypiperidin-1-yl)-1,3-thiazol-4-yl]acetate obtained in Example (64d) (about 0.29 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (45 mg, 0.26 mmol), WSC hydrochloride (150 mg, 0.78 mmol) and HOBT (35 mg, 0.26 mmol), to obtain 42.6 mg of the title compound (36%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5]C1C=C2C(C=CN2)=CC=1.COC(=O)CO[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30](=[O:32])[NH2:31])[CH:25]=[C:24]2[N:33]=[C:34]=[O:35]>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:29]1[CH:28]=[C:27]2[C:23]([C:24]([N:33]=[C:34]=[O:35])=[CH:25][N:26]2[C:30](=[O:32])[NH2:31])=[CH:22][CH:21]=1
Reactant: COC(=O)COc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Reactant: COC(=O)COc1ccc2cc[nH]c2c1
Product: COC(=O)COc1ccc2c(N=C=O)cn(C(N)=O)c2c1

Procedure:
was prepared from (1H-indol-6-yloxy)-acetic acid methyl ester using the protocol described for the preparation of (1-carbamoyl-3-isocyanato-1H-indol-5-yloxy)-acetic acid methyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([C:29]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=4)[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[O:36]1[C:38]2([CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:37][C:38]5([OH:36])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)=[CH:31][CH:30]=4)[C:21]([C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: C1CC2(CCO1)CO2
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c2ccc(C(F)(F)F)c3-c2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c2ccc(C(F)(F)F)c3-c2ccc(OCC3(O)CCOCC3)cc2)cc1
Temperature: 100 °C

Procedure:
((1S,2S)-2-{4-[(R)-4-(4-Hydroxy-phenyl)-5-trifluoromethyl-indan-1-yloxy]-phenyl}-cyclopro-panecarboxylic acid ethyl ester (crude from step 2), 1,6-dioxa-spiro[2.5]octane (US2012/46304, 44 mg) and cesium carbonate (198 mg) are suspended in dry N,N-dimethylformamide and heated at 100° C. for 3 hours. The mixture is diluted with water, acidified with 0.2 M HCl solution and extracted with ethyl acetate. The combined organic extracts are concentrated under vacuum and the residue purified by flash chromatography (0-30% EtOAc in cyclohexane) ti give the title compound (yield 50 mg).
Reaction SMILES: [CH2:1]([NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[C:16](OCC)(=[O:22])[C:17](OCC)=[O:18].CC(C)([O-])C.[K+].Cl>CN(C=O)C>[CH2:1]([N:5]1[C:17](=[O:18])[C:16]([OH:22])=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:6]1(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCCNS(=O)(=O)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
N-Butyl-1-phenylmethanesulfonamide (2.0 g, 8.80 mmol) was dissolved in dry DMF (13 mL) under an atmosphere of nitrogen. Diethyl oxalate (1.44 g, 9.83 mmol) was added and the reaction mixture was cooled to 0° C. using an ice-bath. Potassium tert-butoxide (1.25 g, 11.14 mmol) was added in one portion and the reaction mixture was stirred for 5 mins at 0° C., followed by 19 h at rt. The mixture was cooled in an ice-bath and HCl (2M) was carefully added to give a pH˜1 of the mixture. Most of the solvents were evaporated and the residue was partitioned between HCl (2M) and EtOAc. The combined organic layers were washed with water several times, dried over MgSO4 and evaporated to dryness. The residue was purified using preparative HPLC (ACE C8, 0.1M NH4OAc/MeCN, gradient) to give the title compound (0.96 g, 39%); 1H NMR (400 MHz, DMSO-d6): δ 7.88-7.83 (m, 2H), 7.22-7.29 (m, 3H), 7.14 (bs, 1H), 6.98-7.15 (m, 2H), 3.48 (t, 2H), 1.59-1.67 (m, 2H), 1.27-1.37 (m, 2H), 0.88 (t, 3H); 13C NMR (100 MHz, DMSO-d6): δ 163.1, 158.4, 132.3, 128.7, 124.2, 123.2, 37.8, 30.9, 20.2, 14.1; Mass Spectrum: M−H+ 280.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]=[C:14]([CH:5]1[CH:6]([C:11]([OH:13])=[O:12])[CH:7]2[CH2:10][C:4]1([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]2)[OH:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: NCc1ccccc1
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NCc1ccccc1

Procedure:
102 g of allyl-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid anhydride and 85.6 g of benzylamine are boiled under reflux for 2 hours. Water and excess benzylamine are then distilled off (39 ml at 105° C. under 4,132 Pa).
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=4[F:37])=[C:22]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:23]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=4[F:37])=[C:22]([CH2:24][C:25]([CH3:28])([CH3:26])[CH3:27])[CH:23]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)CC(c1cccc(OCc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ncc(COc3cccc(C(CC(=O)O)C4CC4)c3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-yl)methoxy)phenyl)propanoate (143 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 4 hr. 1N Hydrochloric acid (2.0 mL) was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (129 mg) as a white amorphous solid.
Reaction SMILES: [CH3:1][SiH:2]([CH3:7])[O:3][SiH:4]([CH3:6])[CH3:5].[CH:8]([Si:10]([O:15][CH3:16])([O:13][CH3:14])[O:11][CH3:12])=[CH2:9]>>[CH3:12][O:11][Si:10]([O:15][CH3:16])([O:13][CH3:14])[CH:8]([Si:2]([CH3:7])([CH3:1])[O:3][SiH:4]([CH3:6])[CH3:5])[CH3:9]
Reactant: C[SiH](C)O[SiH](C)C
Reactant: C=C[Si](OC)(OC)OC
Product: CO[Si](OC)(OC)C(C)[Si](C)(C)O[SiH](C)C
Temperature: 65 °C
Yield: 93 %

Procedure:
A four-necked flask equipped with a reflux condenser, stirrer, addition funnel and thermometer was thoroughly purged with nitrogen. In the nitrogen blanket, the flask was charged with 134.3 g (1 mol) of 1,1,3,3-tetramethyldisiloxane and 0.026 g (0.1 mmol) of RhCl3.3H2O to form a mixture. The mixture was heated to 60-70° C. and maintained at the temperature. With stirring, 148.2 g (1 mol, equimolar to 1,1,3,3-tetramethyldisiloxane) of vinyltrimethoxysilane was added dropwise to the mixture from the addition funnel over 6 to 7 hours. After the completion of dropwise addition, the reaction mixture was maintained at 60-70° C. and aged for 1 to 2 hours, driving the reaction to completion. On vacuum distillation, a product having a boiling point of 92-95° C. at 1.3 kPa was collected. The 1-(trimethoxysilyl)ethyl-1,1,3,3-tetramethyldisiloxane product was obtained in a yield of 93%. On gas chromatography analysis, the product was identified to be a mixture of two isomers, alpha-adduct:
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[CH:6][CH:5]=[CH:4][N:3]=1.C[C@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:10]1
Reactant: Clc1cccnc1Cl
Reactant: C[C@H]1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: c1ccc(N2CCNCC2)nc1
Temperature: 25 °C

Procedure:
Dissolve 2,3-dichloropyridine (7.4 g, 0.05 moles) and (S)-(−)-2-methylpiperazine (5.0 g, 0.05 moles) in DMA (125.0 mL) under nitrogen atmosphere. Add anhydrous powdered K2CO3 (20.75 g, 0.15 moles) to this mixture and stir at 135-140° C. for 56 hours. Cool the reaction mixture to room temperature, dilute with water (400 mL), extract with EtOAc (3×200 mL) and wash the combined organic extract with brine (2×150 mL). Dry over MgSO4, and concentrate under vacuum to afford crude product as yellow liquid. Purify by flash column chromatography using CHCl3 to afford pyridylpiperazine derivative as yellow viscous oil.