Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]O)[CH2:20][CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH2:20][CH3:21]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCCOCCOc1ccccc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCOCCOc1ccccc1COc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 151.5 %

Procedure:
Into a solution of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 2-(2-propoxyethoxy)benzyl alcohol (0.63 g) and triphenylphosphine (782 mg) in THF (10 ml) was added at 0° C. diethyl azodicarboxylate (a 40% solution in toluene, 1.36 ml), and the resulting mixture was stirred at room temperature for 20 hours. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:2) to obtain crude methyl 7-[[2-(2-propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.04 g).
Reaction SMILES: [N:1]1[C:10]2[C:9](=[O:11])[CH:8]=[CH:7][C:6](=[O:12])[C:5]=2[N:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])[CH3:14]>O1CCOCC1>[CH2:13]([O:15][C:16]([N:18]1[CH2:19][CH2:20][N:21]([C:8]2[C:9](=[O:11])[C:10]3[N:1]=[CH:2][CH:3]=[N:4][C:5]=3[C:6](=[O:12])[CH:7]=2)[CH2:22][CH2:23]1)=[O:17])[CH3:14]
Reactant: O=C1C=CC(=O)c2nccnc21
Reactant: CCOC(=O)N1CCNCC1
Solvent: C1COCCO1
Product: CCOC(=O)N1CCN(C2=CC(=O)c3nccnc3C2=O)CC1
Reaction time: 3 h
Yield: 47.5 %

Procedure:
A mixture of 160 mg of 5,8-quinoxalinedione and 316 mg of 1-piperazinecarboxylic acid ethyl ester in 10 ml of dioxane was stirred for 3 hours. The resulting solid was collected, washed with ether and dried, giving 150 mg of the desired product as a red solid, mp 180°-195° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=2[CH2:21][C:22]#[N:23])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+].C(Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl.CN(C)C=O>[C:3]1([CH2:1][O:2][C:3]2[CH:4]=[C:5]([CH2:9][CH2:10][C:11]3[C:16]([O:17][CH2:18][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:15]([O:19][CH2:20][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:14]=[CH:13][C:12]=3[CH2:21][C:22]#[N:23])[CH:6]=[CH:7][CH:8]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCc2c(CC#N)ccc(OC)c2OC)c1
Reactant: BrCc1ccccc1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1CCc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To the 2-[2-[(3-methoxyphenyl)ethyl]-3,4-dimethoxybenzeneacetonitrile (5 g) in dichloromethane (100 ml) at -78°, under nitrogen was added 1M boron tribromide (80 ml) in dichloromethane. The reaction was then stirred at room temperature for 4 hours. Ice/water (50 ml) was added and the aqueous extracted with ether. The ethereal layer was dried (MgSO4) and concentrated to give a purple oil. This oil was dissolved in dry dimethylformamide (100 ml) and then potassium carbonate (22.18 g) followed by benzyl bromide (16.5 g) were added. The reaction was stoppered and stirred at room temperature for 14 hours. Ice/water was added, the aqueous layer extracted with ether, the ethereal layer washed with brine, dried (MgSO4) and concentrated to give a yellow oil. This was purified by flash column chromatography on silica gel using ether:petroleum ether 40°-60°; 1:2; v/v to give 2.6 g of the sub-title compound as a white solid, mp 90° (softens) -95° -97° melts.
Reaction SMILES: C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[C:38]([OH:48])(=[O:47])[C@@H:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[OH:40].[Cl:49][C:50]1[CH:55]=[CH:54][C:53]([N:56]=[C:57]=[O:58])=[CH:52][CH:51]=1.O>ClCCl>[Cl:49][C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:57]([O:40][C@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([OH:48])=[O:47])=[O:58])=[CH:52][CH:51]=1
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)O[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.1 400 mg (0.63 mmol) of dibutyltin dilaurate are added to a solution of 10.0 g (65.7 mmol) of (R)-mandelic acid and 10.0 g (65.1 mmol) of 4-chlorophenyl isocyanate in 100 ml of dichloromethane, and the mixture is stirred at room temperature for 24 hours. The reaction mixture is introduced into water and extracted with ethyl acetate. The organic phase is evaporated, giving (R)-(4-chlorophenylcarbamoyloxy)phenylacetic acid as a colourless solid; ESI 306.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[OH:20][CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][NH:23][CH3:24]>>[OH:20][CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][N:23]([CH3:24])[S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: CNCC(O)c1ccccc1
Product: CCc1cc(-c2ccc(S(=O)(=O)N(C)CC(O)c3ccccc3)s2)c(C)[nH]c1=O
Yield: 58 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (2-hydroxy-2-phenylethyl)methylamine as described in Step 5, Example 24 to give the title compound as a solid (58% yield). LC/MS: RT 2.93 min; m/e 433 (M+H); 1H NMR (δ, ppm): 11.81 (1H, s), 7.59 (1H, d), 7.34 (6H, m); 7.19 (1H, d), 5.61 (1H, d), 4.78 (1H, q), 3.12 (2H), 2.78 (3H, s), 2.38 (2H), 2.31 (3H, s), 1.09 (3H, t).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=O)=[O:4].C(N(CC)CC)C.ClC(OCC)=O.[NH2:30][C@H:31]([C:39]([NH:41][C@H:42]([C:47]([O:49][CH3:50])=[O:48])[CH2:43][CH2:44][S:45][CH3:46])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:30][C@H:31]([C:39]([NH:41][C@H:42]([C:47]([O:49][CH3:50])=[O:48])[CH2:43][CH2:44][S:45][CH3:46])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:9])=[O:4]
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4.43 g of Boc-Gly-Gly-OH, A (2) is dissolved in 30 ml DMF and cooled to 0° C., after which 1 equivalent TEA (triethylamine) is added. The mixture is cooled further to about -10° C., after which 1 equivalent (eq) ethyl chloroformate is added and the whole is stirred for about 10 minutes. 6.6 g H-Phe-Met-OMe.HCl (A.1) in 30 ml DMF and 1.1 eq TEA is then added to the mixture, which is stirred for about 30 minutes at about -10° C. and for a further 20 hours at room temperature. After cooling to about -10° C., TEA.HCl is separated by filtration and the filtrate is evaporated to dryness. The residue is dissolved in 235 ml EtOAc and 55 ml water and is subsequently washed with 30% NaCl solution, 0.1 N HCl, 30% NaCl solution, 5% NaHCO3 solution and 30% NaCl solution. The solution is then dried over Na2SO4 filtered and evaporated to dryness. Melting point 100°-101° C.; Rf in CHCl3 :CH3OH:Wa (70:30:5)=0.94 on SiO2.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13]Cl)[S:10][CH:9]=1)=[O:7]>CN(C=O)C.[Na+].[Cl-]>[CH3:4][O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][C:1]#[N:2])[S:10][CH:9]=1)=[O:7]
Reactant: [C-]#N
Reactant: COC(=O)c1csc(CCl)c1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1csc(CC#N)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 105.1 %

Procedure:
A solution of potassium cyanide (3.2 g, 48.5 mmol) in DMF (25 mL) is treated with 5-chloromethyl-thiophene-3-carboxylic acid methyl ester (4.4 g, 23.1 mmol) in DMF (30 mL). After stirring for 14 h at room temperature the mixture is warmed to 50° C. for 0.5 h. After cooling, the solution is diluted with saturated aq NaCl and extracted with CHCl3 (3×). The combined organic layers are dried over MgSO4, filtered and concentrated in vacuo to give 5-cyanomethyl-thiophene-3-carboxylic acid methyl ester (4.4 g, 100%). 1H NMR (CDCl3, 300 MHz) δ 8.00 (s, 1 H), 7.44 (s, 1 H), 3.90 (s, 2 H), 3.84 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[C@@H:10]([OH:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1.O>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:17]=[CH:18][CH:19]=2)[C@@H:10]([O:26][CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(-c3ccccc3)c2)[C@@H](O)C1
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(-c3ccccc3)c2)[C@@H](OCc2ccc3ccccc3c2)C1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A suspension of the title B compound, (3R*,4R*)-4-biphenyl-3-yl-3-hydroxy-piperidine-1-carboxylic acid t-butyl ester (318 mg, 0.9 mmol) and sodium hydride (60% dispersion in mineral oil, 72 mg, 1.8 mmol) in 8 mL of dry DMA is shaken for 10 min. at 50° C. After cooling to RT, 2-(bromomethyl)naphthalene (298 mg, 1.35 mmol) is added and the mixture shaken for 16 h at 50° C. After addition of H2O, the aqueous layer is extracted twice with ethyl acetate. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. Flash chromatography of the residue (SiO2, hexane/ethyl acetate) affords (3R*,4R*)-4-biphenyl-3-yl-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as a yellowish viscous oil: MS (LC/MS) 494.2 [M+H]+; Rf 0.30 (hexane/ethyl acetate 8:2).
Reaction SMILES: [CH3:1][C:2]([NH:25]C(=O)OC(C)(C)C)([CH3:24])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]([CH3:23])[CH2:16][CH2:17][O:18]3)=[CH:10][CH:11]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[NH2:25][C:2]([CH3:1])([CH3:24])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]([CH3:23])[CH2:16][CH2:17][O:18]3)=[CH:10][CH:11]=1)=[O:4]
Reactant: CC1CCOc2cccc(Oc3ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cn3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCOc2cccc(Oc3ccc(NC(=O)C(C)(C)N)cn3)c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
In a 50 mL round-bottomed flask tert-butyl N-[1,1-dimethyl-2-[[6-(4-methylchroman-5-yl)oxy-3-pyridyl]amino]-2-oxo-ethyl]carbamate (Intermediate 214, 63.3 mg, 0.093 mmol), was dissolved in Dichloromethane (DCM) (3 mL) to give a pale yellow solution. The reaction mixture was cooled at 0° C. and TFA (3 mL, 38.9 mmol) was added. The reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was evaporated in vacuo to give the crude product as a pale yellow oil. The residue was charged on a 2 g SCX cartridge. It was then flushed with 40 mL of MeOH followed by 40 mL of 2M solution of ammonia in MeOH. The Ammonia eluate was evaporated in vacuo to give the title compound (22.9 mg) as a colourless oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([N:18]1[C:26]2[CH2:25][CH2:24][CH2:23][C:22](=[O:27])[C:21]=2[CH:20]=[N:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:28](Cl)(=[O:30])[CH3:29]>O1CCCC1>[C:28]([CH:23]1[CH2:24][CH2:25][C:26]2[N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:19]=[CH:20][C:21]=2[C:22]1=[O:27])(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: O=C1CCCc2c1cnn2Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)C1CCc2c(cnn2Cc2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 321 ml of 1.0 N lithium bis(trimethylsilyl)amide in 350 ml of anhydrous tetrahydrofuran maintained at -78° C, there was added dropwise a solution of 33 g of 1-benzyl-1,5,6,7-tetrahydro-4H-indazol-4-one in 150 ml of anhydrous tetrahydrofuran. The mixture was stirred at -78° C. for 10 minutes and then a solution of 11.4 g of acetyl chloride in 120 ml of anhydrous tetrahydrofuran was added. The reaction mixture was worked up in the same manner as described in the first paragraph of this example to give 5-acetyl-1-benzyl-1,5,6,7-tetrahydro-4H-indazol-4one as a yellow oil which crystallized on standing.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][Cl:30]>O.C(#N)C>[Cl:30][CH2:29][CH2:28][CH2:27][O:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1
Reactant: ClCCCBr
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCCl)ccc21
Temperature: 70 °C
Yield: 90.6 %

Procedure:
1-Ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.85 g, 7.1 mmol) and potassium carbonate (1.2 g, 8.5 mmol) were added to 50% water-containing acetonitrile (40 ml), and dissolved by heating to 70° C. 1-Bromo-3-chloropropane (2.1 ml, 21 mmol) was added thereto, and heating was conducted under reflux for 6 hours. The reaction mixture was cooled to room temperature. Water was added, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 2.18 g (yield: 91%) of 7-(3-chloropropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([C:31]([C:33]4[S:34][CH:35]=[CH:36][N:37]=4)=[O:32])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:38][C@@H:39]1[CH2:43][CH2:42][NH:41][CH2:40]1.Cl>CN(C)C=O>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([C:31]([C:33]5[S:34][CH:35]=[CH:36][N:37]=5)=[O:32])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:41]3[CH2:42][CH2:43][C@@H:39]([F:38])[CH2:40]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: F[C@@H]1CCNC1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CC[C@@H](F)C3)nc1)C2
Reaction time: 2 h

Procedure:
A mixture of (R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone (92 mg, 0.165 mmol) and (R)-3-fluoropyrrolidine.HCl (41.6 mg, 0.331 mmol) in N,N-dimethylformamide (2 mL) was stirred in a sealed vial at 40° C. for 1 hour, then at 55° C. for a further 2 hours. The cooled reaction mixture was then purified directly by preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 5-95% acetonitrile in water) to afford ((R)-1-(4-fluorophenyl)-6-((6-((R)-3-fluoropyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone as a white solid (17 mg). LCMS (Method F, ES-API): RT 2.39 min, m+H=609.2; 1H NMR (400 MHz, CDCl3): δ 8.46 (1H, d, J=2.6 Hz), 7.95 (1H, d, J=3.1 Hz), 7.64 (1H, dd, J=9.0, 2.4 Hz), 7.61 (1H, d, J=3.1 Hz), 7.45-7.40 (2H, m), 7.28 (1H, s), 7.19-7.13 (2H, m), 6.52 (1H, d, J=2.3 Hz), 6.27 (1H, d, J=9.1 Hz), 5.48-5.35 (2H, m), 4.17 (1H, d, J=16.8 Hz), 3.92-3.59 (6H, m), 2.92-2.82 (2H, m), 2.77 (1H, d, J=12.3 Hz), 2.59-2.42 (3H, m).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH2:2][CH:3]=[CH2:4].[Cl:8][C:9]([Cl:14])(Cl)[C:10](Cl)=[O:11]>COCCOC.CCOCC.[Cu].[Zn]>[Cl:8][C:9]1([Cl:14])[C:10](=[O:11])[CH2:4][CH:3]1[CH2:2][C:1]([O:6][CH3:7])=[O:5]
Reactant: C=CCC(=O)OC
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: COCCOC
Solvent: CCOCC
Product: COC(=O)CC1CC(=O)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 60 h
Yield: 47.4 %

Procedure:
To a reaction mixture of methyl but-3-enoate (1.0 g, 10 mmol) and zinc-copper couple (2.0 g, 15.5 mmol) in DME (5 mL) and ether (30 mL) was added trichloroacetyl chloride (2.98 mL, 26.7 mmol) under N2 at rt. The reaction mixture was stirred at rt for 2.5 days. The reaction mixture was filtrated through diatomaceous earth (Celite®) and washed with DCM. The filtrate was concentrated and purified by 80 g silica gel cartridge which was eluted with a 20 min gradient of 0-60% EtOAc in hexane to yield methyl 2-(2,2-dichloro-3-oxocyclobutyl)acetate (1.0 g). 1H NMR (400 MHz, CDCl3) ppm 3.66-3.70 (3H, m), 3.42-3.55 (1H, m), 3.23-3.39 (1H, m), 3.05 (1H, dd, J=17.82, 8.78 Hz), 2.90 (1H, dd, J=16.94, 6.65 Hz), 2.67 (1H, dd, J=16.94, 8.16 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:24][C:23]([CH3:25])=[C:22]3[C:18]=2[CH2:19][C@H:20]2[C:26]([CH3:28])([CH3:27])[C@H:21]23)=[O:16])=[CH:8][C:7]=1[CH3:29].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:12][C:11]1[CH:10]=[C:9]([CH2:13][CH2:14][C:15](=[O:16])[C:17]2[S:24][C:23]([CH3:25])=[C:22]3[C:18]=2[CH2:19][C@H:20]2[C:26]([CH3:27])([CH3:28])[C@H:21]23)[CH:8]=[C:7]([CH3:29])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][O:1][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 833.4 %

Procedure:
To a solution of 3-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (2.00 g, 4.85 mmol) in DCM (60 mL) and DIPEA (1.33 mL, 7.76 mmol) is added methane sulfonylchloride (0.452 mL, 582 μmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. Another portion of methane sulfonylchloride (0.452 mL, 5.82 mmol) is added and stirring is continued for 30 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 3-{2,6-dimethyl-4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenoxy}-propyl ester (2.38 g) as a brown oil; LC-MS: tR=1.15 min, [M+1]+=491.34.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])#[N:2].[OH-:15].[Na+].Cl>CS(C)=O.O>[CH3:14][O:13][C:6]1[C:7]([C:8]([OH:10])=[O:9])=[CH:12][C:3]([C:1]([NH2:2])=[O:15])=[CH:4][CH:5]=1
Reactant: COC(=O)c1cc(C#N)ccc1OC
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C(N)=O)cc1C(=O)O
Temperature: 80 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
Methyl 5-cyano-2-methoxybenzoate (2 g) prepared in step A was dissolved in 24 mL of dimethyl sulfoxide, and 12 mL of a 1 M aqueous solution of sodium hydroxide was added. After stirring for 4 hours and a half at 80° C., the mixture was cooled in an ice bath, and adjusted to pH of about 4 with the use of 10 mL of 1 M hydrochloric acid. The resulting solution was diluted with 200 mL of water, and cooled for several hours in a refrigerator. The precipitate formed was separated by filtration, washed with cold water, and then dried over diphosphorus pentoxide under reduced pressure to obtain 1.3 g (63%) of 6-methoxyisophthalamic acid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](/[CH:10]=[C:11](/[C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:31])\[CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]>CO.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][CH:11]([C:16]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=3)=[N:18][C:17]=2[CH3:31])[CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCCC/C(=C\c1ccc(C#N)c(F)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCC(Cc1ccc(C#N)c(F)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 25 °C
Yield: 74.7 %

Procedure:
1.6 g 2-Fluoro-4-{(E)-2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-hex-1-enyl}-benzonitrile were dissolved in a mixture of 10 ml methanol and 10 ml ethyl acetate. 300 mg palladium (5% on charcoal) were added and the mixture stirred at room temperature under a hydrogen atmosphere. After three hours the catalyst was filtered off through a pad of celite and the filtrate evaporated in vacuo. The residue was purified by reversed phase HPLC to obtain 1.2 g 2-Fluoro-4-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-hexyl}-benzonitrile as a lyophilisate. C24H22F4N2S (446.51), MS (ESI): 447.2 (M+H+).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[CH2:28][CH2:27][CH2:26]2.Br[CH2:35][C:36]([O:38][CH3:39])=[O:37]>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[CH:28]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:27][CH2:26]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: COC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)CC1CCc2cc(OC)ccc2C1=O
Temperature: 25 °C

Procedure:
To a solution of LDA, prepared from diisopropylamine (0.84 ml) and n-butyl lithium (3.44 ml, 1.6M in hexane) in 10 ml of THF at -78° was added dropwise a solution of 6-methoxy-1-tetralone (0.88 g, 5.0 mmol) in 5 ml of THF in an atmosphere of nitrogen. To the stirred solution at -78° was then added methyl bromoacetate (0.5 ml, 6.0 mmole) and the mixture was allowed to warm to room temperature. Aqueous work-up and extraction with ether gave, after chromatography on silica gel, the title compound, m.p. 110`-112°.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=[O:7].[CH2:20](O)[CH3:21]>>[Cl:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:19])([CH3:18])[C:15]([O:17][CH2:20][CH3:21])=[O:16])=[CH:10][CH:9]=1)=[O:7]
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Yield: 97 %

Procedure:
Add anhydrous hydrogen chloride gas (18.0 g) to anhydrous ethanol DB (210 g) by purging the solution. Add this hot solution (60° C.) to a solution of 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid (31 g, 115.6 mmol) and reflux under a nitrogen atmosphere for 2.5 hours. Evaporate the solvent in vacuo, dissolve the residue in methylene chloride (150 mL) and wash with water (2×100 mL). Dry (MgSO4), filter through silica gel, washing the gel with methylene chloride (250 mL). Combine the organic washings and evaporate the solvent in vacuo to give the title compound as a colorless oil (33.3 g, 97%).