Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[C:5]([Cl:13])[CH:4]=1.[NH3:14]>CN(C=O)C>[Cl:13][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[C:9]([F:12])([F:11])[F:10])[CH2:2][NH2:14]
Reactant: FC(F)(F)c1ccc(CBr)cc1Cl
Reactant: N
Solvent: CN(C)C=O
Product: NCc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 4-bromomethyl-2-chloro-1-trifluoromethylbenzene (3.0 g, 11 mmol) in DMF (25 ml) was added dropwise to a mixture of 25% aqueous ammonia (50 ml) and DMF (25 ml). The reaction mixture was stirred at room temperature for 60 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml). The aqueous phase was extracted with ethyl acetate (2×60 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using first ethyl acetate/heptane (1:3) together with 3% triethylamine and subsequently DCM/methanol/25% aqueous ammonia as eluent, to give 250 mg of 3-chloro-4-(trifluoromethyl)benzylamine.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COSC1C=CC=CC=1.C1C=C(SSC2N=CC=CC=2)N=CC=1>C(Cl)Cl>[CH3:19][O:17][C:16](=[O:18])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: COSc1ccccc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C

Procedure:
A mixture of 2.51 g. of N-benzyloxycarbonyl-L-valine, 2.62 g. of triphenyl phosphine, 1.40 g. of benzenesulfenic acid methyl ester, 1.10 g. of 2,2'-dipyridyl disulfide and 50 ml. of methylene chloride is stirred at room temperature for 5 hours. The reaction mixture is treated with the same procedure as in Example 1 (1) to give 2.30 g. of the desired product.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])[CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].Cl.[CH2:25]([CH:32]1[C:37]2[N:38]=[C:39]([C:42]([F:45])([F:44])[F:43])[N:40]=[CH:41][C:36]=2[CH2:35][CH2:34][NH:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)CCl.CN1CCOCC1>C(#N)C>[CH3:23][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])[CH2:9][C:10]([N:33]1[CH2:34][CH2:35][C:36]2[CH:41]=[N:40][C:39]([C:42]([F:45])([F:43])[F:44])=[N:38][C:37]=2[CH:32]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:12])=[O:6])[CH3:3]
Reactant: FC(F)(F)c1ncc2c(n1)C(Cc1ccccc1)NCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2cnc(C(F)(F)F)nc2C1Cc1ccccc1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 115.4 %

Procedure:
A mixture of 133 mg (0.40 mmol) of (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid and 162 mg (0.50 mmol) of 8-benzyl-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, hydrochloride in 1.5 mL of acetonitrile at 0° C. was treated sequentially with 81 mg (0.42 mmol) of EDC and 0.047 mL (0.42 mmol) of N-methyl morpholine. After 10 min, the mixture was warmed to ambient temperature and stirred for 3 h, then partitioned between 10 mL of ethyl acetate and 4 mL of water. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried and concentrated to give 281 mg of the title compound as a mixture of diastereomers. Purification by flash chromatography (silica gel, 10 to 35% ethyl acetate/hexane) followed by HPLC on a Chiralpak AD column (9% ethanol/hexane) gave 51 mg of the faster eluting isomer and 47 mg of the slower eluting isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7](=[CH:22][N:23](C)[CH3:24])[C:8]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O)=[CH:4][CH:3]=1.[O-]CC.[Na+].C(O)C.C(O)(=O)C.C(N)=[NH:40]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8]([C@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])=[N:40][CH:24]=[N:23][CH:22]=2)=[CH:26][CH:27]=1
Reactant: CN(C)C=C(Cc1ccc(Cl)cc1)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: N=CN
Agent: CC[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1ncncc1Cc1ccc(Cl)cc1
Temperature: 90 °C
Yield: 57.1 %

Procedure:
To a solution of (R)-tert-butyl 2-(2-(4-chlorobenzyl)-3-(dimethylamino)acryloyl)pyrrolidine-1-carboxylate (1.5 mmol) in n-butanol (10 mL) was added sodium ethoxide in ethanol (5.6 mL, 21 wt. %, 15 mmol) and formamidine acetate (1.56 g, 15 mmol). The reaction mixture was heated at 90° C. for 12 h. After removal of the solvents in vacuo, the residue was dissolved in ethyl acetate. The organic layer was washed with brine three times, dried over sodium sulfate and the solvent was removed in vacuo. Purification by silica gel column chromatography (ethyl acetate/hexane gradient, 10-100% EtOAc) afforded the desired product (320 mg, combined yield for step B and step C was 57%). MS: calculated: 373.16 found (MH+): 374.4.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:17])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)S[CH2:9][CH2:8][CH:7]2[CH2:15][CH3:16])(=[O:3])[CH3:2].OO.[S:20]([O-:23])(O)=[O:21].[Na+]>C(O)(=O)C>[C:1]([C:4]1[C:5]([CH3:17])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[S:20](=[O:23])(=[O:21])[CH2:9][CH2:8][CH:7]2[CH2:15][CH3:16])(=[O:3])[CH3:2]
Reactant: O=S([O-])O
Reactant: CCC1CCSc2c(C)cc(C(C)=O)c(C)c21
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC1CCS(=O)(=O)c2c(C)cc(C(C)=O)c(C)c21
Temperature: 25 °C
Yield: 55 %

Procedure:
A mixed solution containing 1.66 g (6.68 mmol) of the 6-acetyl-4-ethyl-5,8-dimethylthiochroman, 2.28 g (20.1 mmol) of a 30% hydrogen peroxide aqueous solution and 2.0 ml of acetic acid was allowed to react at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, a 2% sodium hydrogensulfite aqueous solution was added, and the mixture was extracted with ethyl acetate and washed with a saturated sodium hydrogencarbonate and then with a saturated sodium chloride aqueous solution. An organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel; hexane/ethyl acetate=2:1) to give 1.03 g (yield 55%) of 6-acetyl-4-ethyl-5,8-dimethylthiochroman-1,1-dioxide.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[F:9][C:10]([F:24])([F:23])[CH2:11][NH:12][C:13]([C:15]1[S:16][C:17]([CH:21]=O)=[CH:18][C:19]=1[CH3:20])=[O:14]>C1COCC1.O.CS(C)=O>[F:9][C:10]([F:24])([F:23])[CH2:11][NH:12][C:13]([C:15]1[S:16][C:17]([CH:21]=[N:7][OH:8])=[CH:18][C:19]=1[CH3:20])=[O:14]
Reactant: NO
Reactant: Cc1cc(C=O)sc1C(=O)NCC(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1cc(C=NO)sc1C(=O)NCC(F)(F)F
Reaction time: 3 h

Procedure:
Sodium acetate (90 mg) is added to a solution of hydroxylamine hydrochloride (60 mg) and 5-formyl-3-methyl-thiophene-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (190 mg) in THF (5 ml), water (1 ml) and DMSO (1 ml). After 3 hours at room temperature, the reaction is quenched with water. The reaction mixture is extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and concentrated in vacuo to yield 5-(hydroxyimino-methyl)-3-methyl-thiophene-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide. The crude product obtained (206 mg, yellowish oil) is used without further purification. MS (HPLC/MS): 267 (MH+). Retention time: 2.56 min and 2.64 min (two diastereoisomers).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:30][CH2:29][C:23]5([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[C:16]([CH3:31])=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[C:60](O)(=[O:62])[CH3:61]>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:30][CH2:29][C:23]5([CH2:28][CH2:27][N:26]([C:60](=[O:62])[CH3:61])[CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[C:16]([CH3:31])=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: CC(=O)O
Reactant: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CCC2(CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(CCC(Nc3nc(Nc4ccc5c(C)n(C)nc5c4)ncc3C)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.7 %

Procedure:
To a solution of N2-(2,3-dimethyl-2H-indazol-6-yl)-5-methyl-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (201.5 mg, 0.4802 mmol), HOAT (106.4 mg, 0.7817 mmol) and EDCI (145.7 mg, 0.7600 mmol) in DCM/DMF (4 mL/1 mL) were added N,N-diethylethanamine (207.6 mg, 2.052 mmol) and acetic acid (36.7 mg, 0.611 mmol). The reaction was stirred at rt for 2 h. The reaction solution was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to give the crude product as a light yellow solid (92 mg). The crude product was recrystallized from acetone/MeOH (6 mL/0.5 mL) to give the title compound as a white solid (50.4 mg, 21.6%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.CS(O)(=O)=O.C(N(CC)CC)C.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.Cl.[NH2:40][CH2:41][C:42]1[C:47]([CH2:48][CH3:49])=[N:46][C:45]2[N:50]([CH2:53][CH3:54])[N:51]=[CH:52][C:44]=2[C:43]=1[NH:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([NH:11][C:27]([NH:40][CH2:41][C:42]2[C:43]([NH:55][CH:56]3[CH2:57][CH2:58][O:59][CH2:60][CH2:61]3)=[C:44]3[CH:52]=[N:51][N:50]([CH2:53][CH3:54])[C:45]3=[N:46][C:47]=2[CH2:48][CH3:49])=[O:29])=[CH:12][CH:13]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: Nc1ccc(C#CCCCBr)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)Nc1ccc(C#CCCCBr)cc1

Procedure:
A suspension of Intermediate 24 methanesulfonic acid salt (1.4 g, 4.2 mmol) in dichloromethane (50 mL) was treated with triethylamine (8.8 mL, 63 mmol) and then the mixture was cooled in an ice-water bath and treated with triphosgene (0.93 g, 3.2 mmol), followed by 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine dihydrochloride (1.3 g, 3.4 mmol). The mixture was quenched by the addition of methanol and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organics were washed with a 5% aqueous potassium hydrogen sulfate solution and saturated aqueous sodium chloride solution and then concentrated under reduced pressure. The crude residue was purified via automated flash silica gel chromatography, using a SiliSep flash column (dichloromethane/methanol/ammonium hydroxide). Concentration of the desired fractions under reduced pressure provided the title compound as a pale tan foam. ES/MS calcd. for C28H36BrN6O2+ 567.2. found m/z=567.2 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[N:3]([C@@H:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][C@H:7]1[O:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])=[N+]=[N-].[N:33]([C@H:36]1[C@H:41]([O:42][S:43]([C:46]2[CH:52]=[CH:51][C:49]([CH3:50])=[CH:48][CH:47]=2)(=[O:45])=[O:44])[CH2:40][CH2:39][N:38]([C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[O:54])[CH2:37]1)=[N+]=[N-]>CO>[NH2:3][C@@H:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:8][C@H:7]1[O:22][S:23]([C:26]1[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=1)(=[O:25])=[O:24].[NH2:33][C@H:36]1[C@H:41]([O:42][S:43]([C:46]2[CH:47]=[CH:48][C:49]([CH3:50])=[CH:51][CH:52]=2)(=[O:44])=[O:45])[CH2:40][CH2:39][N:38]([C:53]([O:55][CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)=[O:54])[CH2:37]1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2N=[N+]=[N-])cc1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@H]2N=[N+]=[N-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2N)cc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@H]2N)cc1
Yield: 64 %

Procedure:
To a 0° C. solution of CuSO4.5H2O (642 mg, 0.5 equiv) in methanol (30 mL), NaBH4 (200 mg, 1.05 equiv) was added. To the stirred black suspension was added a solution of trans-benzyl 4-azido-3-(tosyloxy)piperidine-1-carboxylate and trans-benzyl 3-azido-4-(tosyloxy)piperidine-1-carboxylate (2.21 g, 5.14 mmol) in methanol (20 mL). Additional NaBH4 (578 mg, 3 equiv) was added in four portions over the course of 1 h. The reaction mixture was filtered through a pad of Celite and concentrated. The residue was diluted with CH2Cl2 (70 mL), washed with water (15 mL), satd aq NH4Cl solution (2×10 mL), brine (15 mL), and dried over Na2SO4. Concentration afforded trans-benzyl 4-amino-3-(tosyloxy)piperidine-1-carboxylate and trans-benzyl 3-amino-4-(tosyloxy)piperidine-1-carboxylate (1.34 g, 64%). The product was used for the next step without further purification. MS ESI +ve m/z 405 (M+1).
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)C(=O)O1>O(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[F:21][C:18]([F:19])([F:20])[O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:5][C:6]2=[O:8]
Reactant: CC1(C)OC(=O)C(=CNc2ccc(OC(F)(F)F)cc2)C(=O)O1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1cc[nH]c2ccc(OC(F)(F)F)cc12
Temperature: 250 °C
Reaction time: 0.08 h

Procedure:
In a 50 mL round bottom flask with a reflux condenser attached was dissolved 2,2-dimethyl-5-((4-(trifluoromethoxy)phenylamino)methylene)-1,3-dioxane-4,6-dione (1.00 g, 3.02 mmol) in Ph2O (8.63 mL, 0.35 M). The mixture was heated to 250° C. in a heating mantle. At about 180° C., the reaction turned from a light yellow and homogeneous to an orange, then to a dark brown color and began to bubble, slowly at first and then more violently. Internal temperature of reaction went up to 230° C., although heating ceased at 180° C. Heating at 250° C. while stirring was continued for five minutes, and the reaction was cooled to RT, diluted with hexane, and the precipitate was filtered to yield 6-(trifluoromethoxy)quinolin-4(1H)-one as a crude brown solid. MS [M+H]=230.1; Calc'd 229.2 for C10H6F3NO2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([CH3:13])=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=[O:12].[BH4-].[Na+].Cl>C(O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([CH3:13])=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][CH:7]2[OH:12]
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(=O)CCS2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(Cl)c2c(c1C)C(O)CCS2
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
88.4 g (311 mmol) of the 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-one obtained in the above step (5) was dissolved in 200 ml of ethanol, and further dissolved in 200 ml of dichloromethane. This solution was cooled to 5˜10° C., and 5.9 g (155 mmol) of sodium borohydride was added. The reaction mixture was stirred at the above temperature for 30 minutes, and further stirred at room temperature for 3 hours. Then, the reaction mixture was poured into 400 ml of a 5% hydrochloric acid aqueous solution and extracted with 900 ml of dichloromethane, and then the resultant organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off to give 86.8 g (yield 97%) of 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-ol.
Reaction SMILES: O.[NH2:2][C:3]1[S:7][N:6]=[C:5]([C:8](=[N:12][O:13][CH2:14][F:15])[C:9](O)=[O:10])[N:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:17].C(OC(C)C)(C)C>C(Cl)Cl>[ClH:17].[NH2:2][C:3]1[S:7][N:6]=[C:5]([C:8](=[N:12][O:13][CH2:14][F:15])[C:9]([Cl:17])=[O:10])[N:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Nc1nc(C(=NOCF)C(=O)O)ns1
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: ClCCl
Product: Cl
Product: Nc1nc(C(=NOCF)C(=O)Cl)ns1
Reaction time: 0.5 h
Yield: 106 %

Procedure:
In 50 ml of methylene chloride, 10.0 g (0.044 mol) of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-fluoromethoxyiminoacetic acid hydrate were suspended, followed by the addition of 13.3 g (0.064 mol) of phosphorus pentachloride at -20° C. After stirring for 30 minutes, 100 ml of isopropyl ether were added dropwise to the reaction mixture to precipitate crystals. The resulting crystals were collected by filtration, washed with 20 ml of isopropyl ether and then dried, whereby 9.33 g of a title compound were obtained (yield: 77%, purity: 89.7%).
Reaction SMILES: B(F)(F)F.CCOCC.[F:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21](O)([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C@@H:22]([C:26]2[CH:38]=[CH:37][C:29]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:28][CH:27]=2)[CH2:23][CH2:24][CH3:25])=[CH:13][CH:12]=1>C(Cl)Cl.CCOC(C)=O>[F:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[C@@H:22]([C:26]2[CH:38]=[CH:37][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)[CH2:23][CH2:24][CH3:25])=[CH:13][CH:12]=1
Reactant: CCC[C@H](c1ccc(C(=O)OC(C)(C)C)cc1)C(O)(c1ccc(OC)cc1)c1ccc(F)c2ccccc12
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CCC[C@H](c1ccc(C(=O)O)cc1)C(c1ccc(OC)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boron trifluoride diethyl etherate (0.074 mL, 0.583 mmol) was added dropwise to a solution of tert-butyl 4-{(1R)-1-[(4-fluoro-1-naphthyl)(hydroxy)(4-methoxyphenyl)methyl]butyl}benzoate (150 mg, 0.291 mmol) in DCM (2 mL) at 0° C. The solution was allowed to warm to RT and stirred overnight. The solution was diluted with EtOAc (30 mL) then washed with water and brine. The organic layer was dried over MgSO4, filtered, then concentrated to provide the title compound which was used directly in the next step without further purification. LC1 1.20 min. [M+H]+ 442.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:17]1[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=1)[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH:27][C:28]1C(C2C3C(=CC=CC=3)N(CCCCC)C2=O)=CC2OCOC=2C=1>>[OH:26][C:25]1[C:17]([C:4]2([CH2:28][OH:27])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])=[CH:18][C:19]2[O:23][CH2:22][O:21][C:20]=2[CH:24]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Product: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (67%): 1H NMR (300 MHz, CDCl3) δ 10.85-10.63 (br, 1H), 7.48-7.35 (m, 2H), 7.28-7.19 (m, 1H), 6.96 (d, 1H), 6.52 (d, 2H), 5.82 (dd, 2H), 4.63 (d, 1H), 4.11 (d, 1H), 3.70 (d, 2H), 2.04-1.74 (br, 1H), 1.65-162 (m, 2H), 1.31-1.24 (m, 4H), 0.84 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 180.3, 152.6, 148.1, 143.2, 141.3, 129.2, 129.1, 126.2, 123.3, 112.4, 109.6, 108.2, 101.9, 101.3, 64.6, 59.8, 40.6, 28.9, 26.9, 22.2, 13.9; MS (ES+) m/z 370.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]=[CH:22][C:23]([N:25]2[CH:29]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:28][O:27][C:26]2=[O:37])=[O:24])[O:10][C:9]1([CH3:39])[CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[O:42][C:43]([CH:45]=[CH2:46])=[CH2:44].[Cl-].C([Al+]CC)C.C1(C)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH2:44][C:43](=[O:42])[CH2:45][CH2:46][CH:22]2[C:23]([N:25]2[CH:29]([CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:28][O:27][C:26]2=[O:37])=[O:24])[O:10][C:9]1([CH3:39])[CH3:38])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=C)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(Cc2ccccc2)C(CC=CC(=O)N2C(=O)OCC2Cc2ccccc2)OC1(C)C
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(Cc2ccccc2)C(CC2CC(=O)CCC2C(=O)N2C(=O)OCC2Cc2ccccc2)OC1(C)C
Temperature: -78 °C
Reaction time: 48 h

Procedure:
A solution of 4-Benzyl-5-[4-(-4-benzyl-2-oxo-oxazolidin-3-yl)-4-oxo-but-2-enyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (13.35 g, 25 mmol) in dichloromethane (500 ml) was stirred at −78° C. under nitrogen during the addition of 2-trimethylsiloxy-1,3-butadiene (26 ml, 150 mmol) and 1.8 M diethylaluminium chloride solution in toluene (70 ml, 125 mmol). The resulting pale yellow solution was stirred at −78° C. for 48 hours then slowly added to vigorously stirred, ice-cold 1 M hydrogen chloride aqueous solution. After 1 hour the two layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried (anhydrous magnesium sulfate) and concentrated in vacuo to give, after purification by flash chromatography on silica gel (ethyl acetate/hexane 1/9 to 4/6), 4-Benzyl-5-[2-(4-benzyl-2-oxo-oxazolidine-3-carbonyl)-5-oxo-cyclohexylmethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (8.7 g) as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][C:6]=1[O:25]COC)[CH3:2].O1CCCC1.C(O)C.Cl>O>[CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][C:6]=1[OH:25])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3O)c2)cc1OCOC
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3O)c2)cc1O
Temperature: 70 °C
Reaction time: 18 h
Yield: 50.7 %

Procedure:
To a solution of 4-[3-cyano-4-(2-hydroxyphenyl)pyrrole-1-yl]-2-methoxymethoxy benzoic acid ethyl ester (0.12 g) in a mixed solvent of tetrahydrofuran (3 mL) and ethanol (5 mL) was added 2 mol/L hydrochloric acid (2 mL), and this mixture was stirred at 70° C. for 18 hours. To this reaction mixture was added water, the precipitated solid was collected by filtration, and this solid was washed with water, dried under reduced pressure at 50° C. to give the title compound (0.054 g).