Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[NH2:35][C@H:36]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:37]([O:39]C(C)(C)C)=[O:38].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:35][C@H:36]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:37]([OH:39])=[O:38])=[O:32])=[CH:33][CH:34]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)N[C@@H](C(=O)O)c1ccccc1
Reaction time: 0.17 h

Procedure:
[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid (0.40 g, 0.827 mmol) was dissolved in CH2Cl2 (40 ml) and tert-butyl (2R)-amino(phenyl)acetate (0.206 g, 0.993 mmol) and N-methylmorpholine (0.251 g, 2.48 mmol) were added. After 10 minutes, TBTU (0.345 g, 1.076 mmol) was added. The reaction was stirred overnight. The resulting tert-butyl ester was concentrated and purified on silica gel (eluted with EtOAc/CH2Cl2 25/75). The pure fractions were collected and concentrated. CH2Cl2 (25 ml) and TFA (3 ml) were added. The mixture was stirred for 5 days and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC using a gradient of 20-70% CH3CN in 0.1M NH4OAc buffer. Freeze-drying of the pure fractions gave the title compound as a colourless solid. M/z: 615.50 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 4.35 (d, 1H), 4.36 (d, 1H), 4.40 (d, 1H), 4.53 (d, 1H), 4.58 (d, 1H), 4.94 (d, 1H), 5.19 (d, 1H), 6.97-7.40 (m, 15H), 8.02-8.06 (m, 2H), 8.26-8.32 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]([CH2:25][CH2:26][OH:27])[N:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=3.I[CH3:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]([CH2:25][CH2:26][O:27][CH3:34])[N:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccnn4CCO)ccc3n(C)c21
Reactant: CI
Product: COCCn1nccc1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C

Procedure:
The process is carried out as in Example 101 above, with compound A, 3-(2,4-dichlorophenyl)-6-[2-(2-hydroxyethyl)-2H-pyrazol-3-yl]-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and iodomethane.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22])[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:30]1[C:31]([CH3:39])=[CH:32][C:33]2[N:34]([N:36]=[CH:37][N:38]=2)[N:35]=1>O1CCCC1>[C:23]1([CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][C:30]3[C:31]([CH3:39])=[CH:32][C:33]4[N:34]([N:36]=[CH:37][N:38]=4)[N:35]=3)[CH2:13][CH2:12]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cc2ncnn2nc1Cl
Reactant: OCCOCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2ncnn2nc1OCCOCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Yield: 64.4 %

Procedure:
190 mg of 60% sodium hydride in oil was suspended in 15 ml of tetrahydrofuran; 1.47 g of 4-(diphenylmethoxy)-1-[2-(2-hydroxyethoxy)ethyl]piperidine was added, followed by heating and refluxing for 1 hour. After cooling, 660 mg of 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine was added, followed by heating and refluxing for 3 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. After the dry product was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (10:1). The desired fraction was collected; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 1.23 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[C:8](Cl)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1)[CH3:2].[NH3:16].C(O)(C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[C:8]([NH2:16])=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)CSc1cnc(Cl)nc1Cl
Reactant: N
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1cnc(Cl)nc1N
Temperature: 25 °C

Procedure:
A solution of ethyl[(2,4-dichloro-5-pyrimidinyl)thio]acetate (2.0 g, 7.49 mmol) in DMF (75 ml) was treated with ammonia in isopropanol (7.49 ml, 14.97 mmol) in a pressure tube. The tube was capped, and the reaction was stirred at ambient temperature. Upon completion, the solution was concentrated under reduced pressure and pumped on to remove any residual DMF. The crude material was chromatographed using a gradient of 0-10% acetone/chloroform. The product contained a small amount of cyclized material (which is the product of the next step). The product was isolated as a light yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>ClCCl.CO>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Solvent: CO
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCOCC1

Procedure:
Prepared analogously to Example 1.1.c. from 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and morpholine. Yield: 0.3 g (39.4% of theory); C13H18N2O5 (M=282.29); calc.: molecular ion peak (M+H)+: 283; found: molecular ion peak (M+H)+: 283; Rf value: 0.6 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([OH:13])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(N(CC)CC)C>ClCCl>[Si:16]([O:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:12]=[CH:11]2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc2ccc(C(F)(F)F)nc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C(F)(F)F)nc12
Yield: 101.3 %

Procedure:
A solution of 2-trifluoromethylquinolin-8-ol (11.5 g), tert-butyldimethylsilyl chloride (8.9 g) and triethylamine (6.5 g) in dichloromethane (60 ml) was stirred overnight at room temperature. The reaction mixture was washed with water (2×50 ml), dried over sodium sulfate, filtered and the solvent removed in vacuo to give the product (17.9 g) as a white solid.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:13]2[CH:14]=[C:15]([NH:18][C:19]3[N:24]=[C:23]([NH:25][C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:36])[CH:34]=[CH2:35])[CH:29]=[CH:30][CH:31]=4)[C:22]([F:37])=[CH:21][N:20]=3)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)=O)(C)(C)C.[C:38](OC(=O)C)(=O)C.N1C=CC=CC=1>C(Cl)Cl>[C:6]([N:8]1[C:13]2[CH:14]=[C:15]([NH:18][C:19]3[N:24]=[C:23]([NH:25][C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:36])[CH:34]=[CH2:35])[CH:29]=[CH:30][CH:31]=4)[C:22]([F:37])=[CH:21][N:20]=3)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)(=[O:5])[CH3:38]
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc4c(c3)N(C(=O)OC(C)(C)C)CCO4)ncc2F)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc4c(c3)N(C(C)=O)CCO4)ncc2F)c1

Procedure:
The title compound was prepared by treating the product of Example 85 with acetic anhydride and pyridine in CH2Cl2 at rt for 1 hr, followed by washing with 1N HCl, then with aqueous NaHCO3, drying over Na2SO4 and removal of solvents in vacuo. MS m/z: 449.1 (M+H+).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([N:15]([C:23]3[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=3)[CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[C:32]1([S:38]([NH2:41])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([N:15]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([NH:41][S:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:40])=[O:39])=[O:30])=[CH:27][CH:28]=3)[CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(N(Cc2cccnc2)c2ccc(C(=O)O)cc2)c2cc(C(C)=O)oc12
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N(Cc2cccnc2)c2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2)c2cc(C(C)=O)oc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.7 %

Procedure:
To a solution of 2-acetyl-7-methoxy-N-(4-carboxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzofuran (416 mg, 1.0 mmol), benzenesulfonamide (200 mg, 1.2 mmol), and DMAP (150 mg, 1.2 mmol) in dichloromethane (5 mL) at room temperature was added EDCI (230 mg, 1.2 mmol) in one portion and the mixture was stirred at room temperature for 16 h. The mixture was partitioned between water (25 mL) and EtOAc (25 mL) and the pH was adjusted to 5–6 with 1.0N HCl. The EtOAc was separated, washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography eluting with a linear gradient from 5% to 10% MeOH in EtOAc to give 2-Acetyl-7-methoxy-N-(4-phenylsulfonylaminocarbonylphenyl)-N-(3-pyridylmethyl)-4-aminobenzofuran (415 mg). 1H NMR (300 MHz) δ 8.53 (br,1H), 8.46 (br,1H), 8.06 (d,J=7.3 Hz,2H), 7.8–7.3 (m,6H), 7.21 (m,1H), 7.1–7.0 (m,2H), 6.91 (d,J=8.5 Hz,1H), 6.56 (d,J=7.3 Hz,2H), 4.99 (s,2H), 4.02 (s,3H), 2.54 (s,3H).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15]>O1CCCC1>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:17]2[N:19]=[C:20]([Cl:21])[N:13]=[C:14]([Cl:15])[N:16]=2)=[CH:6][CH:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(Cl)nc(Cl)n2)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
Grignard reaction: In a 500 ml sulfonating flask having a stirrer, dropping funnel, condenser and internal thermometer, 7.3 g (0.3 mol) of magnesium turnings and a few grains of iodine are initially introduced into 60 ml of dry tetrahydrofuran (THF). Under dry protective gas (nitrogen), 56.1 g (0.3 mol) of 4-bromoanisole, dissolved in 100 ml of THF, are slowly added dropwise at 60° C. After the complete dissolution of the Mg turnings, the mixture is stirred at 60° C. for 90 minutes. The Grignard solution is then added dropwise at 5° C. under nitrogen in the course of 60 minutes to a solution of 55.3 g (0.3 mol) of cyanuric chloride in 150 ml of THF. The mixture is evaporated to dryness at room temperature, 500 ml of dil. hydrochloric acid are allowed to run in and the mixture is extracted with 300 ml of methylene chloride. For working-up, the solvent is removed in vacuo, and the semisolid residue is tritrated with a little isopropanol and filtered off with suction. Purification is carried out by recrystallization from toluene/hexane (1:1). 62.8 g (82% of theory) of 6-(4-methoxyphenyl)-2,4-dichloro-1,3,5-triazine are obtained (m.p.: 131-134° C.).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:14]#[N:15])[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC#N.[OH2:19]>CCOC(C)=O>[C:1]([O:5][C:6]([C:8]1([C:14]#[N:15])[CH2:13][CH2:12][S:11](=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(C#N)CCSCC1
Reactant: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1(C#N)CCS(=O)CC1
Reaction time: 8 h

Procedure:
A mixture of 4-cyano-tetrahydro-thiopyran-4-carboxylic acid tert-butyl ester (206 mg) and NaIO4 (217 mg) in MeCN/water (3 mL/3 mL) was stirred between 0° C. and rt overnight; then the reaction was diluted with EtOAc, washed with dil. Na2SO3 solution, water and dil. NaCl solution respectively; EtOAc phase was dried over anhydrous sodium sulphate, filtered, concentrated and column-purified to give the desired product (193 mg). 1H NMR in CDCl3, δ in ppm: 3.2-2.6 (m, 6H), 2.4-2.1 (m, 2H), and 1.52 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([NH2:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2].Cl/[CH:22]=[CH:23]\[CH2:24][CH2:25]Cl.C(N(C(C)C)C(C)C)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([N:20]1[CH:25]=[CH:24][CH:23]=[CH:22]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: Cl/C=C\CCCl
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(N)cc3c2c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3ccc(-n4cccc4)cc3c2c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.25 g of 6-amino-4-methyl-beta-carboline-3-carboxylic-acid-ethylester in 70 ml of ethanol, together with 1.7 ml of 1,4-dichloro-2-cis-butene and 4.5 g of ethyldiisopropylamine is heated for 10 h at 50° C. After stirring in 250 ml of ice water, the precipitate is filtered, washed and dried in vacuum. The raw product (3.4 g of a mixture of dihydropyrrole derivative and pyrrole derivative) is dissolved in 600 ml of methylene chloride and, after addition of 17 g of pyrolusite, is stirred for 2 h at room temperature. After filtering, and distilling off the solvent, 2.75 g of raw product is obtained crystallizing out of acetone. In this manner, 2.13 g of 4-methyl-6-(1-pyrrolyl)-beta-carboline-3-carboxylic-acid-ethylester with a m.p. of 214°-217° C. is obtained.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[F:28])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO>[F:28][C:19]1[CH:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[CH:22]=[CH:23][C:18]=1[C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:32][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)cc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)cc1F
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 99.5 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (430 mg, 1.03 mmol) (from example 73, step 1) was dissolved in MeOH (3 mL) and cooled to −45° C. under nitrogen. Sodium hydroxide (0.302 mL, 1.03 mmol) was added during 10 min and the yellow solution continued to stir at −45° C. for 20 min. Hydroxylamine (50% by weight in water, 0.063 mL, 1.03 mmol) was added during 8 min. The resulting solution was stirred at −45° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (5.28 mL, 31.68 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a slightly yellow oil. Crude trans-methyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (398 mg, quant.) was isolated. MS m/z 387 (M−H)−
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[S:5][C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23].C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O1CCCC1>[CH3:13][O:12][N:9]1[CH2:10][CH2:11][C:6]2([S:5][C:4](=[O:14])[C:3]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])=[C:2]2[O:1][C:32](=[O:33])[O:34][CH2:35][CH3:36])[CH2:7][CH2:8]1
Reactant: CCOC(=O)Cl
Reactant: CON1CCC2(CC1)SC(=O)C(c1c(C)cc(C)cc1C)=C2O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)SC12CCN(OC)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.7 %

Procedure:
94 mg 4-Hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1-thia-8-aza-spiro[4.5]dec-3-en-2-one (from Step 7) and 43 mg triethylamine were dissolved in 10 ml tetrahydrofuran, and a solution of 32 mg ethyl chloroformate in 5 ml tetrahydrofuran was added dropwise. The mixture was stirred at ambient temperature for 18 hours, then partitioned between saturated aqueous sodium bicarbonate and t-butylmethyl ether, the organic layer dried over sodium sulfate, and the solvent evaporated. The residue was purified by chromatography on silica gel with ethylacetate/cyclohexane (1:2) as a solvent, to give 34 mg carbonic acid ethyl ester 8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1-thia-8-aza-spiro[4.5]dec-3-en-4-yl ester (title compound P1.7) as a solid, mp 87-89° C.
Reaction SMILES: [OH:1][C:2]1([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37]Cl)=[CH:28][CH:27]=2)[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][O:14][CH3:15])=[CH:9][CH:10]=2)[O:5][CH2:4][CH:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][CH:17]=1.[I-:39].[Na+]>CC(=O)CC.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[I:39][CH2:37][CH2:36][O:35][CH2:34][CH2:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:2]2([OH:1])[C:11]3[C:6](=[CH:7][C:8]([O:12][CH2:13][O:14][CH3:15])=[CH:9][CH:10]=3)[O:5][CH2:4][CH:3]2[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:21]=2)=[CH:31][CH:30]=1
Reactant: [I-]
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCOCCCl)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CCC(C)=O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCOCCI)cc2)cc1
Yield: 92 %

Procedure:
4-Hydroxy-4-{4-[2-(2-chloroethoxy)ethoxy]phenyl}-7-(methoxymethoxy)-3-[4-(methoxymethoxy)phenyl]chroman (490 mg, 0.9 mmol) was dissolved in 2-butanone (30 ml) under argon atmosphere. Then, sodium iodide (1.4 g, 9.3 mmol) and tetrabutylammonium iodide (1.6 g, 4.5 mmol) were added thereto, and the mixture was refluxed for 16 hours. The reaction solution was cooled down to normal temperature, concentrated, and diluted with ethyl acetate. Then, in order to eliminate the resulting NaCl and the excess sodium iodide and tetrabutylammonium iodide, the solution was filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to flash column chromatography (n-hexane:ethyl acetate=4:1→2:1) to give the title compound (527 mg, yield 90%) which is pale yellow and sticky. Mass [M−H2O]+=619 Step 3) Synthesis of 4-hydroxy-4-{4-{2-[2-(4,4,5,5,5-pentafluoropentylthio)ethoxy]ethoxy}phenyl}-7-(methoxymethoxy)-3-[4-(methoxymethoxy)phenyl]chroman
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:16])[NH:8][C@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[NH:11][CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[C:20]([NH2:25])[N:19]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[CH:1]1([O:6][C:7](=[O:16])[NH:8][C@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[N:11]([C:22]3[CH:23]=[C:18]([Cl:17])[N:19]=[C:20]([NH2:25])[N:21]=3)[CH2:10]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C[C@@H]1CC[C@H](NC(=O)OC2CCCC2)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@@H]1CC[C@H](NC(=O)OC2CCCC2)CN1c1cc(Cl)nc(N)n1
Temperature: 100 °C
Yield: 80.7 %

Procedure:
To a solution of cis-cyclopentyl[6-methyl-3-piperidinyl]carbamate (107 mg, 0.473 mmol) in ethanol (3 mL) were added 4,6-dichloro-2-pyrimidinamine (116 mg, 0.709 mmol) and K2CO3 (98 mg, 0.709 mmol) in a 5 mL sealable vial. The solution was capped and heated at 100° C. overnight. The reaction was then check with LCMS and was not complete. Additional 4,6-dichloro-2-pyrimidinamine (30 mg) and K2CO3 (50 mg) were added and the resulting mixture was heated overnight. The reaction was concentrated, then 5 mL of DMF were added. Some solids were not soluble. Water (10 mL) was added, and the resulting mixture was extracted 3× with EtOAc. The organics were combined, washed with brine, dried over MgSO4, filtered and concentrated. The clear oil was then purified on Biotage SNAP 10 g column with gradient of 0 to 50% EtOAc in hexane over 30 minutes to afford the title compound (135 mg) as a clear oil. LC-MS (ES) m/z=354 [M+H]+.
Reaction SMILES: II.[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[Mg].[CH2:13]([N:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[CH2:13]([N:20]1[CH2:24][CH2:23][C:22]([CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[F:3])([OH:25])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Fc1ccccc1CCl
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: OC1(Cc2ccccc2F)CCN(Cc2ccccc2)C1

Procedure:
A crystal of iodine followed by a few mls of a solution of 20.6 g of 2-fluorobenzyl chloride in 100 ml of ether is added to a suspension of 3.4 g of magnesium shavings in 50 ml of ether. Thereafter, the reaction is initiated via a hot air gun before adding dropwise, while maintaining the reaction at reflux, the remaining 2-fluorobenzyl chloride solution. After total addition, the reaction is maintained at reflux with stirring for an additional hour before successively adding 100 ml of ether and adding dropwise, with vigorous stirring, a solution of 25.0 g of N-benzyl-3-pyrrolidinone in 100 ml of ether. After complete addition, the resulting suspension is refluxed for an additional 2 hours, stirred at ambient temperature for 16 more hours, and then filtered. The filter cake is washed well with ether and then hydrolyzed by stirring in an ice-ammonium chloride solution. The aqueous solution is extracted thrice with ether and the combined ether extracts are washed successively with water and a sodium chloride solution and then dried. The solvent is removed and the residue is distilled at 135°-140° C., 0.1 mm pressure, to provide a viscous yellow oil which solidifies upon standing. The solid is recrystallized twice from an ethanol-water mixture to give the product, 1-benzyl-3-(2-fluorobenzyl)-3-pyrrolidinol, mp 75°-77° C.
Reaction SMILES: C(O[CH2:9][CH2:10][C:11]1[N:12]([CH2:28][CH2:29][OH:30])[C:13]([S:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=1)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:37]([O:39][CH2:40][CH3:41])C>O>[CH2:40]([O:39][CH2:37][CH2:9][CH2:10][C:11]1[N:12]([CH2:28][CH2:29][OH:30])[C:13]([S:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=1)[C:41]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)c1nc(CCOCc2ccccc2)n(CCO)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CC(C)c1nc(CCCOCc2ccccc2)n(CCO)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
In 30 ml of dry diethyl ether was dissolved 3.0 g (5.8 mmol) of the ester (130d), to the mixture was added 220 mg (5.8 mmol) of lithium aluminium hydride under ice-cooling. The mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and further recrystallized from n-hexane to provide 2.4 g (yield 87%) of 2-(2-(3-benzyloxypropyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazol-1-yl)-ethanol (136e) as crystals. mp 104-106° C.