Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=CC=C[CH:5]=1>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C(Cl)Cl>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH:4]([CH3:9])[CH3:5]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CC(C)C[C@H](N)C(=O)O
Yield: 222.7 %

Procedure:
A solution of compound (16) (211 mg, 0.64 mmol) and CH2Cl2 (20 mL) was purged with argon gas for 10 minutes. Grubbs Catalyst 1 (1.6 mg, 19.2 μmol) was added and the reaction was heated to reflux and monitored by TLC. The reaction was concentrated under reduced pressure and subjected to flash chromatography (2:1 Hexanes/EtOAc) to afford 187 mg (98%) of (17a) as a separable mixture of two diastereomers (17a, and 17a), both as colorless oils.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][CH2:31]Br)[CH:26]=[CH:27][C:28]=1[Cl:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][CH2:31][N:13]2[CH2:14][CH2:15][CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12]2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: Clc1ccc(CCBr)cc1Cl
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NC1CCN(CCc2ccc(Cl)c(Cl)c2)CC1)c1ccccc1
Temperature: 100 °C
Yield: 94.2 %

Procedure:
4-Benzamidopiperidine (204 mg.) and anhydrous potassium carbonate (138 ml.) were intimately ground together and added to 2-(3,4-dichlorophenyl)ethyl bromide (254 mg.). The resulting paste was heated at 100° C. for 2 hours to give a hard solid. This was broken up, washed well with water and ether and dried to give the title compound (355 mg.). Recrystallisation from ethanolic hydrogen chloride and ether gave the hydrochloride (237 mg.), m.p. 286.0° C. (Found: C, 58.2; H, 5.8; N, 6.8. C20H22Cl2N2O.HCl requires C, 58.05; H, 5.6; N, 6.8%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH3:21])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][C:43]([NH2:45])=[O:44])=[CH:38][CH:37]=2)O1.Cl>CN(C)C(=O)C.C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[ClH:1].[CH3:21][N:18]1[C:19]([CH3:20])=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[C:2]([C:36]4[CH:41]=[CH:40][C:39]([CH2:42][C:43]([NH2:45])=[O:44])=[CH:38][CH:37]=4)=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:9][CH2:10]2)[CH:16]=[N:17]1
Reactant: CC1(C)OB(c2ccc(CC(N)=O)cc2)OC1(C)C
Reactant: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(CC(N)=O)cc3)CC2)cnn1C
Temperature: 120 °C
Yield: 37.3 %

Procedure:
Dissolve 3′-chloro-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (307 mg, 1.0 mmol) in N,N-dimethylacetamide (4 mL). Add potassium carbonate (332 mg, 2.4 mmol), 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide (313 mg, 1.2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0050 g, 0.0058 mmol), then water (2 mL) and degas with nitrogen for 5 min. Heat at 120° C. for 20 hr. then purify by SCX-2® chromatography washing with methanol. Elute with 2 M ammonia in methanol and concentrate. Purify using silica gel chromatography (eluting with 5:95 to 20:80 methanol:DCM) to give an oil. Dissolve the free base in acetonitrile and convert to the hydrochloride salt by adding 2 M aq HCl solution. Add water and lyophilize to give the title compound as a light yellow powder (0.165 g, 37%). MS (ES): m/z=406 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH:20]3[CH2:22][CH2:21]3)[N:8]=2)[CH:6]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)O1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:9]([CH:20]3[CH2:22][CH2:21]3)[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][CH:15]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: Clc1ccc(-c2cc(C3CC3)nc(-n3cnc(Br)c3)n2)cc1
Product: Clc1ccc(-c2cc(C3CC3)nc(-n3cnc(-c4cccnc4)c3)n2)cc1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-phenyl)-6-cyclopropyl-pyrimidine (example E.14) (0.15 g, 0.4 mmol) and commercially available 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.08 g, 0.4 mmol) according to the general procedure VI. Obtained as an off-white solid (0.015 g, 10%). MS (ISP) 374.0 [(M+H)+]; mp 180-182° C.
Reaction SMILES: [CH2:1]1COCC1.[CH:6]([C:8]1[CH:9]=[C:10](/[CH:19]=[CH:20]/[C:21]([NH:23][CH:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)=[O:22])[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:7].C[Mg]Br.O.[Cl-].[NH4+]>C(OCC)(=O)C>[OH:7][CH:6]([C:8]1[CH:9]=[C:10](/[CH:19]=[CH:20]/[C:21]([NH:23][CH:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)=[O:22])[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[CH3:1]
Reactant: C1CCOC1
Reactant: O=Cc1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1ccnc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(O)c1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1ccnc1
Reaction time: 1 h

Procedure:
To a THF (0.5 mL) solution of (E)-3-(3-formyl-4-(1H-imidazol-1-yl)phenyl)-N-indan-1-ylacrylamide (23 mg) obtained in Example 437, methyl magnesium bromide (3M ether solution, 0.04 mL) was added under nitrogen atmosphere under ice-cooling and the reaction mixture was agitated for 1 hour. A saturated ammonium chloride water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: methanol-ethyl acetate system), and 10 mg of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:24]1[CH:29]=[C:28]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:22])[CH:16]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2cccc(Cl)c2)c1
Yield: 66.6 %

Procedure:
3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 3-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.048 g (66%) of 3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH2:15][CH2:14]1)=[O:12].C(N(CC)C(C)C)(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:15][CH2:14]1)=[O:12]
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCN(C(=O)c2cnccc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Yield: 25.9 %

Procedure:
To a solution of 0.10 g (0.25 mmol) [4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (Example 3) in 2 mL dichloromethane were added 0.08 mL (0.50 mmol) N,N-diisopropylethylamine followed by dropwise addition of 0.02 mL (0.27 mmol) methanesulfonylchloride. After 16 hours another 0.08 mL (0.50 mmol) N,N-diisopropylethylamine and 0.02 mL (0.27 mmol) methanesulfonylchloride were added. The reaction mixture was poured on water and was extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silical gel column, CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50) followed by a second chromatography on a 10 g silica gel column using a gradient from n-heptane:tert-butyl methyl ether (100:0 to 25:75) to give 31 mg (26%) of the desired compound as a light brown foam. MS (ESI): m/z=478.039 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH2:20]1[N:29]2[C@H:23]([CH2:24][O:25][CH2:26][C:27]3[CH:33]=[C:32]([NH2:34])[CH:31]=[CH:30][C:28]=32)[CH2:22][CH2:21]1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:34][C:32]2[CH:31]=[CH:30][C:28]3[N:29]4[C@H:23]([CH2:24][O:25][CH2:26][C:27]=3[CH:33]=2)[CH2:22][CH2:21][CH2:20]4)=[N:3][CH:4]=1
Reactant: Nc1ccc2c(c1)COC[C@@H]1CCCN21
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)COC[C@@H]2CCCN32)ncc1Cl

Procedure:
As per the procedure described in Example 1, the reaction of 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and (S)-(2,3,3a,4-Tetrahydro-1H,6H-5-oxa-10b-aza-benzo[e]azulen-8-yl)amine gave 2-{5-Chloro-2-[(S)-(2,3,3a,4-tetrahydro-1H,6H-5-oxa-10b-aza-benzo[e]azulen-8-yl)amino]-pyrimidin-4-ylamino}-N-methyl-benzamide, upon purification by flash chromatography (Dichloromethane:MeOH 98:2) followed by trituration with Et2O:MeOH (9:1), as solid (21%); 1H NMR (400 MHz, DMSO-d6) δ11.59 (s, 1H), 9.24 (s, 1H), 8.74 (br s, 1H), 8.17 (s, 1H), 7.74 d, J=7.87 Hz, 1H), 7.48 (m, 2H), 7.36 (d, J=8.40 Hz, 1H0, 7.12 (m, 1H0, 6.83 (d, J=8.40 Hz, 1H0, 7.12 (m, 1H), 6.83 (d, J=8.71 Hz, 1H), 4.56 (d, J=13.03 Hz, 1H0, 4.30 (d, J=13.02 Hz, 1H), 3.89 (d, J=11.55 Hz, 1H), 3.31-3.2 (m, 4H), 2.90 (m, 1H), 2.81 (s, 3H), 2.12-1.45 (3m, 4H); MS (m/e) 465, 466 (M+H); mp 216-218° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH:21]2[CH2:26][CH2:25][CH:24]([O:27][C:28](=[O:30])[CH3:29])[CH2:23][CH:22]2[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)=O)=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.O>ClCCl>[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=3)[CH:22]3[CH:21]([CH2:26][CH2:25][CH:24]([O:27][C:28](=[O:30])[CH3:29])[CH2:23]3)[N:20]=2)=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOc1ccc(C(=O)NC2CCC(OC(C)=O)CC2c2ccc(OC)c(OC)c2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCOc1ccc(C2=NC3CCC(OC(C)=O)CC3c3cc(OC)c(OC)cc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 87.4 %

Procedure:
1670 mg of phosphorous pentachloride are suspended in 2.5 ml of dichloromethane. 1119 mg of (±)-acetic acid (1RS,3RS,4RS)-4-{[1-(4-butoxy-phenyl)-methanoyl]-amino}-3-(3,4dimethoxy-phenyl)-cyclohexyl ester (compound A7) dissolved in 15 ml of dichloromethane are added and the mixture stirred for 18 h. The mixture is cooled to 0° C. and 10 ml of triethylamine added, then 5 ml of water. After phase separation and removal of solvent the solid residue is purified by flash chromatography [silica, toluene/dioxane=2:1 (containing 0.5% of ammonia)] to give 940 mg of the title compound as a colorless foam (87% of theory).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH:20]([SnH3])=[CH2:21].C(Cl)Cl>C1(C)C=CC=CC=1>[C:14]1([S:11]([N:6]2[C:7]3[C:3](=[C:2]([CH:20]=[CH2:21])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21
Reactant: C=C[SnH3]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 110 °C
Yield: 61.4 %

Procedure:
4-Bromo-1-(phenylsulfonyl)-1H-indole (8.52 g, 25.3 mmol, Intermediate 44) was dissolved in dry toluene (20 mL) under an N2(g) atmosphere before vinylstannane (16.07 g, 50.7 mmol) and bis[triphenylphosphine)palladium(II) acetate (0.95 g, 1.3 mmol) was added. The reaction was heated to 110° C. for 16 h cooled the reaction mixture to RT and filtered the reaction mixture through a celite pad, and evaporated the solvent. Dissolved the obtained oil in acetonitrile and hexanes, separated the phases. Evaporated the acetonitrile phase and purified the obtained crude product by flash chromatography using 30% DCM in hexanes. Isolated 4.4 g of the desired product as a white solid, yield 62%. MS (ESI+) for C16H13NO2S m/z 284 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH3:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:15]([O:18][C:19]1[CH:20]=[C:21]([CH2:28][C:29](Cl)=[O:30])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])(=[O:17])[CH3:16].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl.CCCCC>[C:15]([O:18][C:19]1[CH:20]=[C:21]([CH2:28][C:29]([NH:1][C:2]2[N:7]=[CH:6][C:5]([CH:8]([CH3:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=2)=[O:30])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])(=[O:17])[CH3:16]
Reactant: CC(=O)Oc1cc(CC(=O)Cl)ccc1[N+](=O)[O-]
Reactant: COC(=O)CC(C)c1ccc(N)nc1
Solvent: CCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC(C)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(OC(C)=O)c2)nc1
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 84.7 %

Procedure:
A solution of (RS) methyl 3-(6-amino-pyrid-3-yl)-butanoate (3.26 g, Reference Example 19) in dichloromethane (20 mL) at 10° C. was treated dropwise with a solution of (3-acetoxy-4-nitrophenyl)-acetyl chloride (4.32 g, Reference Example 17) in dichloromethane (30 mL) over 5 minutes. The mixture was stirred at 10° C. for a further 5 minutes then treated dropwise with triethylamine (2.47 mL) over 5 minutes. The resulting dark solution was stirred at room temperature for 1 hour, then left to stand overnight, then subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (3:2, v/v) to give the title compound (5.9 g) as a viscous gum.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]([NH2:14])([CH3:13])[CH3:12]>>[CH:11]([NH:14][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)N
Product: CC(C)Nc1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 1-fluoro-4-nitrobenzene and isopropylamine
Reaction SMILES: [CH:1]1([C:6]2[C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[N:25]=[C:24]([C:29]([O:31]C)=[O:30])[CH:23]=[CH:22]5)=[CH:15][CH:14]=3)=[C:9]([CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[O:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Na+]>C1COCC1>[CH:1]1([C:6]2[C:10]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[N:25]=[C:24]([C:29]([OH:31])=[O:30])[CH:23]=[CH:22]5)=[CH:17][CH:18]=3)=[C:9]([CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[O:8][N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(C5CCCC5)noc4C4CCCC4)cc3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc(-c3ccc(OCc4c(C5CCCC5)noc4C4CCCC4)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 844.8 %

Procedure:
A solution of methyl 6-(4-{[(3,5-dicyclopentyl-4-isoxazolyl)methyl]oxy}phenyl)-2-quinolinecarboxylate (65 mg, 0.13 mmol) in THF (1.3 mL) was placed in a microwave reaction tube. Methanol (0.7 mL) was added followed by 1.0 N sodium hydroxide (0.2 mL, 0.2 mmol) before the tube was sealed and stirred at room temperature for 30 minutes. The mixture was heated at 100° C. for 10 minutes. The solution was concentrated and the residue was suspended in water before neutralization with 1 N HCl. The resulting mixture was filtered and the sample was dried in a drying oven at 45° C. under reduced pressure with P2O5 to yield 6-(4-{[(3,5-dicyclopentyl-4-isoxazolyl)methyl]oxy}phenyl)-2-quinolinecarboxylic acid (0.53 g, 84%). 1H NMR (400 MHz, DMSO-d6): δ 8.47 (d, J=9 Hz, 1H), 8.27 (s, 1H), 8.18-8.11 (m, 2H), 8.07 (d, J=9 Hz, 1H), 7.82 (d, J=9 Hz, 2H), 7.16 (d, J=9 Hz, 2H), 4.98 (s, 2H), 3.40-3.20 (m, overlapping H2O), 3.16-3.12 (m, 1H), 1.99 (m, 4H), 1.76-1.56 (m, 12H). HRMS C30H30N2O4 m/z 483.2278, (M+H)+Cal; 483.2277 (M+H)+Obs.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CS(C)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:13][N:14]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=3)[CH2:15][CH2:16]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCC3(CCNC3)C2)cc1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCC3(CCN(Cc4ccccc4)C3)C2)nc1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-benzyl-2,7-diazaspiro[4.4]nonane (1.00 g, 4.68 mmol), methyl 6-chloronicotinate (800 mg, 4.68 mmol) and K2CO3 (700 mg, 5.07 momol) in 5 mL of DMSO was stirred under microwave irradiation for 20 min at a temperature of 150° C. The mixture was poured into EtOAc and washed with sat'd NaHCO3, dried (Na2SO4), filtered and concentrated, giving methyl 6-(7-benzyl-2,7-diazaspiro[4.4]non-2-yl)nicotinate. A bottle containing a suspension of the benzyl amine and 20% Pd(OH)2/C (600 mg, 0.857 mmol) in 20 mL of EtOH was evacuated and purged with H2 gas three times. Using a Parr shaker apparatus, the suspension was agitated under 50 psi of H2 for 20 h. The pressure was released and the mixture filtered through a pad of Celite and concentrated, giving methyl 6-(2,7-diazaspiro[4.4]non-2-yl)nicotinate: 1H NMR (600 MHz, DMSO-d6) δ 8.59 (d, J=2.1 Hz, 1H), 7.89 (dd, J=9.1, 2.3 Hz, 1H), 7.27 (d, J=4.4 Hz, 1H), 6.44 (d, J=8.8 Hz, 1H), 3.74 (s, 3H), 3.13 (br s, 4H), 2.89 (t, J=7.3 Hz, 2H), 2.72 (AB, J=7.6 Hz, 2H), 1.92 (br m, 2H), 1.69 (AB, J=7.3 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[CH2:11](Br)/[CH:12]=[C:13](/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])\[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:14][C:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:12][CH2:11][O:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: Oc1ccc2c(c1)OCC2
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)=CCCC(C)=CCOc1ccc2c(c1)OCC2
Reaction time: 70 h

Procedure:
A mixture of 27.7 g. of 6-hydroxy-2,3-dihydrobenzofuran, 52.1 g. of geranyl bromide and 41.4 g. of anhydrous powdered potassium carbonate in 200 ml. of methyl ethyl ketone is heated under reflux with stirring for 70 hours. The cooled reaction mixture is filtered, the residual potassium carbonate washed with acetone and the filtrate evaporated. By chromatography on silica gel with hexane/diethyl ether (4:1 parts by volume) there is obtained pure 6-[(3,7-dimethyl-2,6-octadienyl)-oxy]-2,3-dihydrobenzofuran of boiling poiint 130° C./0.001 mmHg.; nD20 = 1.5414.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[SH:11].Br[CH2:13][CH2:14][C:15]([OH:17])=[O:16]>O>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[S:11][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: Cc1ccc(C)c(S)c1
Reactant: O=C(O)CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C)c(SCCC(=O)O)c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
43.4 g (1.086 mol) of sodium hydroxide was added to 230 mL of water, 75.0 g (0.543 mol) of 2,5-dimethylthiophenol (purchased from Aldrich Chemical Company) was then added and the mixture was cooled to about 10° C. 91.30 g (0.597 mol) of 3-bromopropionic acid (purchased from Aldrich Chemical Company) was added in portions while keeping the temperature below 25° C. The mixture was warmed to room temperature, stirred for 2 h under nitrogen, and was then washed with diethyl ether (3×500 mL). The aqueous layer was acidified with 1N HCl and filtered to yield 112.79 g of the title compound of Step A as a solid melting at 97-98° C. 1H NMR (CDCl3): δ2.3 (s,3H), 2.34 (s,3H), 2.68 (t,2H), 3.1 (t,2H), 6.9 (d,1H), 7.06-7.14 (2H).
Reaction SMILES: N1C=CN=C1.[CH2:6]1[O:8][C@@H:7]1[CH2:9][OH:10].[CH3:11][C:12]([Si:15](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:14])[CH3:13]>CN(C=O)C>[C:12]([Si:15]([O:10][CH2:9][C@@H:7]1[CH2:6][O:8]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:14])([CH3:11])[CH3:13]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC[C@@H]1CO1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@@H]1CO1)(c1ccccc1)c1ccccc1
Yield: 37 %

Procedure:
Imidazole (6.6 g, 97.2 mmol) and DMF (75 ml) were added to (R)-glycidol (2.7 ml, 40.5 mmol) (13a), and the resulting mixture was stirred. Then, TBDPSCl (12.6 ml, 48.6 mmol) was added and reacted at 0° C. overnight. Next day, after disappearance of the spots of the raw material was observed by thin-layer chromatography (TLC) (hereinafter referred to as TLC), the product was extracted with ethyl acetate and distilled water, to recover an organic layer. The organic layer was washed with saturated sodium hydrogen carbonate and a saturated salt solution, and dried with anhydrous sodium sulfate. The solvent was evaporated using a vacuum evaporator, and the residue was isolated and purified by silica gel column chromatography (hexane:ethyl acetate=50:1). Thus, a compound (13b) (S)-tert-butyl(oxiran-2-ylmethoxy)diphenylsilane (4.5664 g, 15 mmol, 37%) was obtained as a colorless and transparent liquid.