Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[OH:6][C:7]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[CH2:10][C:9](=[O:21])[C:8]=1[C:22](=[O:25])[CH2:23][CH3:24]>C(Cl)(Cl)Cl>[OH:6][C:7]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[C:15]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:14]=2)[CH2:10][C:9](=[O:21])[C:8]=1[C:22](=[O:25])[CH2:23][CH3:24]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCC(=O)C1=C(O)CC(c2ccc(SC)c(S(=O)(=O)Cl)c2)CC1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(i) Chlorosulfonic acid (9.5 ml) was added dropwise to a solution of 3-hydroxy-5-[4-(methylthio)-phenyl]-2-propionylcyclohex-2-en-1-one (2.4 g) in chloroform (18 ml) at 0° C. After 15 hr, the solution was warmed to ambient temperature and after a further 3 hr the mixture was poured onto ice. The resulting mixture was extracted with dichloromethane and the organic extract was washed with water. Evaporation of the solvent gave 3-hydroxy-5-[3-chlorosulfonyl-4-(methylthio)phenyl]-2-propionylcyclohex-2-en-1-one (2.42 g). Pmr spectrum (CDCl3 ; δ in ppm): 1.14 (3H, t); 2.61 (3H, t); c.a. 2.6-3.68 (7H, m); 7.39-7.70 (2H, m); 7.94 (1H, s); 18.20 (1H, s).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][CH2:5][CH:6]=[O:7].[O:12]=[C:13](/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(Cl)(Cl)Cl>[CH2:4]([C@@H:5]1[C:6](=[O:7])[O:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][C@@H:20]1[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:2]=1
Reactant: O=CCCc1ccccc1Cl
Reactant: CCOC(=O)C(=O)/C=C/c1ccc(C)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C[C@H](c2ccc(C)cc2)[C@H](Cc2ccccc2)C(=O)O1
Yield: 74 %

Procedure:
Prepared according to the general procedure from 2-chloro-hydrocinnamaldehyde and (E)-ethyl 2-oxo-4-p-tolylbut-3-enoate using 2 mol % 1 as the catalyst in 74% yield as a single diastereomer (colorless oil). [α]D2 (c 1.02, CHCl3)=+310.3; 1H NMR (400 MHz, CDCl3) δ 7.32-7.24 (m, 3H), 7.16-7.07 (m, 4H), 6.93-6.91 (m, 2H), 6.65 (d, 1H, J=6.8 Hz), 4.30 (q, 1H, J=7.1 Hz), 3.58 (t, 1H, J=6.7 Hz), 3.29-3.23 (m, 2H), 2.41 (dd, 1H, J=15.8, 10.9 Hz), 2.35 (s, 3H), 1.33 (t, 3H, J=7.1 Hz); 13C NMR (100 MHz, CDCl3) δ 168.9, 160.7, 142.1, 138.3, 132.8, 130.0, 129.1, 128.8, 128.4, 126.9, 118.9, 62.1, 45.0, 40.3, 32.1, 21.3, 14.3; IR (thin film) ν 3062, 3027, 2982, 2925, 1776, 1732, 1316, 1267, 1106 cm−1; HRMS (ESI) calcd for C22H22O4 [M+Na]+ 373.1410, found 373.1409; 97% ee (4S,5S)-isomer as determined by HPLC (AD-H, 9:1 hexanes/i-PrOH), tr (4S,5S)=21.7 min, tr (4R,5R)=13.4 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>C(O)(=O)C>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:1]2[CH:13]=[CH:17][CH:16]=[CH:15]2)[CH:7]=1
Reactant: CSc1nc(N)cc(Cl)n1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CSc1nc(Cl)cc(-n2cccc2)n1

Procedure:
As described above, both the dichloro and the difluoro-intermediates provide mixtures of regioisomers when reacted with nucleophiles (cf. 144 in Scheme 19). Although this is useful when both regioisomers are desired, the route shown in Scheme 20 below provides a regioselective synthesis. According to Scheme 20, 4-amino-6-chloro-2-methylthiopyrimidine 151 was reacted with 1 equivalent of 2,5-dimethoxytetrahydrofuran in refluxing acetic acid to provide 6-chloro-2-methylthio-4-(1-pyrrolyl)pyrimidine 152: 1H NMR (CDCl3) δ 2.75 (s,3H), 6.55 (d,2H), 7.05 (s,1H), 7.65 (d,2H). The 6-chloro-2-methylthio-4-(1-pyrrolyl)pyrimidine 152 is either (a) oxidized with 2.2 equivalents of m-chloroperoxybenzoic acid in dichloromethane at 0° C. to provide 6-chloro-2-methylsulfonyl-4-(1-pyrrolyl)pyrimidine 153 or (b) reacted with 1 equivalent of the N-(p-cyanobenzyl)amide of cyclohexylalanine and 1 equivalent of diisopropylethylamine in DMF at 80° C. to provide the 2-methylthiopyrimidine 154. The oxidation and nucleophilic displacement steps are then reversed [i.e. 153 is reacted according to (b) or 154 is reacted according to (a)] to provide the 2-methylsulfonylpyrimidine 155, which is dissolved in n-butanol saturated with ethylamine and heated in a sealed tube to produce 156.
Reaction SMILES: O=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]1[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(OC(OCC)OCC)C>CCO>[O:25]1[CH2:24][CH2:23][CH:22]([N:3]2[CH:2]=[N:10][C:9]3[C:4]2=[N:5][C:6]([C:11]2[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=24)=[N:7][CH:8]=3)[CH2:27][CH2:26]1
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Solvent: CCO
Solvent: CCOC(OCC)OCC
Product: N#Cc1ccn2ncc(-c3ncc4ncn(C5CCOCC5)c4n3)c2c1
Temperature: 123 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a suspension of the compound obtained in example 1 section d (100 mg, 0.30 mmol) in EtOH (1 mL), PTSA monohydrate (5.7 mg, 0.03 mmol) and triethylorthoformate (1 mL) were added. The reaction mixture was heated in a OEM Explorer microwave oven at 123° C. and 270 W for 30 min. Then, it was evaporated to dryness. The crude product thus obtained was chromatographed over silica gel using MeOH/EtOAc mixtures of increasing polarity as eluent, to afford 81 mg of the desired compound (79% yield).
Reaction SMILES: Cl.C(OC([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[CH2:12][CH2:11]1)=O)(C)(C)C>C(O)(C)C>[NH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[CH2:14][CH2:15]1
Reactant: CCCCOC(=O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(C)O
Product: CCCCOC(=O)CN1CCC(N)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 113 %

Procedure:
A solution of hydrogen chloride in isopropanol (6 ml) was added to 1.35 g of n-butyl 4-tert-butoxycarbonylamino-1-piperidineacetate, and the mixture was stirred at room temperature for 15 minutes. The solvent was evaporated, and the residue was added with 5 ml of tetrahydrofuran and 1.3 ml of triethylamine. The precipitated solid was filtered off, and the solvent of the filtrate was evaporated to obtain 1.04 g of colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@@:10]1([CH3:23])[C:15]([O:16][CH3:17])=N[C@H](C(C)C)C(OC)=[N:11]1.O.FC(F)(F)C(O)=[O:28].[Cl-].[NH4+]>C(#N)C>[CH3:17][O:16][C:15](=[O:28])[C@:10]([NH2:11])([CH3:23])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COC1=N[C@@](C)(CCc2ccccc2Cl)C(OC)=N[C@@H]1C(C)C
Reactant: O=C(O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@@](C)(N)CCc1ccccc1Cl
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,5R)-2-[2-(2-chloro-phenyl)-ethyl]-5-isopropyl-3,6-dimethoxy-2-methyl-2,5-dihydro-pyrazine (1.22 g, 3.62 mmol) in acetonitrile (12 ml) were added water (4 ml) and trifluoroacetic acid (2 ml). The mixture was stirred overnight at 40° C. Saturated ammonium chloride solution was added and the mixture was extracted with dichloromethane three times. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, EtOAc/MeOH=95:5 to yield a colorless oil, (0.46 g, 52%); MS (ISP): 242.1; 244.1 ((M+H)+.).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([N:5]1[CH:9]=[C:8]([NH2:10])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1cc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)n1cc(N)cn1
Yield: 91.3 %

Procedure:
A mixture of 1-tert-butyl-4-nitro-1H-pyrazole (20 g, 118 mmol) and Pd/C (10%, 2 g, 1.9 mmol) in MeOH (100 mL) was hydrogenated under 1 atmosphere of hydrogen at RT for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 1-tert-butyl-1H-pyrazol-4-ylamine (15 g, 93%). 1H NMR (400 MHz, DMSO-d6): δ 7.08 (s, 1 H), 6.90 (s, 1H), 3.70 (s, 2 H), 1.41 (s, 9 H); MS (ESI) m/z: 140.1 [M+H]+.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32]Cl)[CH3:28].C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1)[CH3:28]
Reactant: CCN(CC)CCCCl
Reactant: O=S(=O)(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccccc12
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2c(-c3ccccc3)oc3ccccc23)cc1

Procedure:
A solution of 0.14 g. (0.006 g.-atom) of sodium in 20 ml. of methanol was added to a solution of 1.1 g. (0.003 mol.) of 3-(4-hydroxyphenylsulfonyl)-2-phenylbenzofuran in 25 ml. of dry methanol and the mixture was refluxed for 0.5 hour. The solvent was evaporated and 25 ml. of toluene and 3 ml. of dimethylformamide were added to the residue. A solution of 0.86 g. (0.006 mol.) of 3-diethylaminopropyl chloride in 10 ml. of toluene was added dropwise and the mixture was refluxed for 2.5 hours. An additional 0.162 g. (0.003 mol.) of sodium methoxide and 0.43 g. (0.003 mol.) of 3-diethylaminopropyl chloride were added and the mixture was refluxed for ca. 16 hours. The mixture was filtered, water and methylene chloride were added and the layers were separated. The aqueous phase was extracted with methylene chloride and the organic phase was extracted with water and saturated sodium chloride solution. The organic layers were combined, dried (MgSO4) and evaporated to dryness to give the title compound.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]([CH3:9])([CH2:7][CH3:8])[C:5]#[N:6]>CCCCCCCCCCCCCCCC[N+](C)(C)C.[Cl-]>[N:3]([C:4]([CH3:9])([CH2:7][CH3:8])[C:5]#[N:6])=[N:3][C:4]([CH3:9])([CH2:7][CH3:8])[C:5]#[N:6]
Reactant: CCC(C)(N)C#N
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Product: CCC(C)(C#N)N=NC(C)(C#N)CC
Temperature: 20 °C
Yield: 173.8 %

Procedure:
The resulting aqueous dispersion of N,N-dichloro-2-amino-2-methylbutanenitrile was adjusted to pH7 by the addition of caustic soda and 3 ml of "Arquad 16-29%" surfactant added. After addition of a further 2.2 equivalents of caustic soda, 16.8 gm of 2-amino-2-methylbutanenitrile were added slowly over 60 minutes whilst maintaining the temperature at 20° C. The resulting suspension was filtered, washed and dried to yield 28.6 gm of the title compound (yield 84.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].[ClH:14].[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C@@H:17]([NH:23][C:24]([C:26]1[O:27][C:28]3[CH:34]=[CH:33][C:32](Br)=[CH:31][C:29]=3[CH:30]=1)=[O:25])[CH2:16]2>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:14].[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C@@H:17]([NH:23][C:24]([C:26]1[O:27][C:28]3[CH:34]=[CH:33][C:32]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=4)=[CH:31][C:29]=3[CH:30]=1)=[O:25])[CH2:16]2
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(Br)ccc2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cccc(-c2ccc3oc(C(=O)N[C@H]4CN5CCC4CC5)cc3c2)c1
Temperature: 90 °C

Procedure:
130 mg (0.86 mmol) of 3-(methoxy)phenylboronic acid and 2.15 ml of 1N sodium hydroxide solution are added to a mixture of 250 mg (0.72 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzofuran-2-carboxamide (Example 3A) and 52 mg (0.07 mmol) of PdCl2(dppf) in 3 ml of DMF. The reaction mixture is heated at 90° C. overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered through kieselguhr. Purification takes place by preparative HPLC. The product fractions are mixed with an excess of 1N hydrochloric acid. The solvent is removed under reduced pressure. Drying under high vacuum results in 208 mg (63% of theory) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[CH3:28][C:29]1([CH3:38])[CH2:34][NH:33][C@H:32]([C:35]([OH:37])=[O:36])[CH2:31][O:30]1>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:33]2[CH2:34][C:29]([CH3:28])([CH3:38])[O:30][CH2:31][C@H:32]2[C:35]([OH:37])=[O:36])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CC1(C)CN[C@H](C(=O)O)CO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CC(C)(C)OC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 67.3 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.24 g, 0.51 mmol) was reacted with (S)-6,6-dimethyl morpholine-3-carboxylic acid hydrochloride (0.1 g, 0.51 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.19 g, 68%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.ClCCl.[CH3:10][O:11][C:12](=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].[Cl-].[NH4+]>C(OCC)(=O)C.C(N(CC)CC)C.CS(C)=O>[CH3:10][O:11][C:12](=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH:20]=[O:21])[CH3:1]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)CCCCCCCCO
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCC(C)C=O
Reaction time: 0.25 h

Procedure:
To a mixture of oxalyl dichloride (18.85 ml) and dichloromethane (60 ml), dimethyl sulfoxide (2.99 ml) was added under a nitrogen atmosphere. The mixture was cooled in an ice-water bath and stirred therein for 15 minutes. 9-Hydroxynonanoic acid methyl ester (2.00 g) was added to the mixture. The mixture was stirred for 1 hour and triethylamine (10.8 ml) was added to the reaction mixture. The reaction mixture was stirred for 1 hour at ambient temperature and poured into a mixture of ethyl acetate (EA) and a saturated aqueous solution of ammonium chloride. The separated organic layer was washed with water and dried over magnesium sulfate. After filtration, the filtrate was concentrated in vacuo. The obtained residue was purified by chromatography on silica gel (eluted with 5% EA in n-hexane). The fractions including 8-formylnonanoic acid methyl ester were collected and concentrated in vacuo to give 8-formylnonanoic acid methyl ester (1.69 g) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[C:20]([C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br)#[N:21]>>[C:20]([C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18])#[N:21]
Reactant: N#Cc1ccccc1CBr
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2ccccc2C#N)c(=O)[nH]c1=O
Yield: 53.5 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (201 mg, yield: 53.5%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:14][OH:15])[CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1)[CH3:2].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH2:16]([CH:3]([CH2:1][CH3:2])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH:12]=[O:13])[CH:9]=[C:8]([CH:7]=1)[CH:14]=[O:15])[CH3:17]
Reactant: CCC(CC)COc1cc(CO)cc(CO)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(CC)COc1cc(C=O)cc(C=O)c1
Reaction time: 16 h
Yield: 26.4 %

Procedure:
(5-(2-Ethylbutoxy)-1,3-phenylene)dimethanol (0.50 g, 2.10 mmol) and CH2Cl2 (10 mL) were added to a round-bottom flask. To this solution was added PCC (1.35 g, 6.30 mmol), and the reaction was stirred for 16 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (90% hexanes/EtOAc) afforded the desired product (0.13 g, 25%, 3 steps) as a white semi-solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.01 (s, 2H), 7.90 (s, 1H), 7.62 (s, 2H), 3.94 (d, J=5.5 Hz, 2H), 1.68 (hept, J=6.5 Hz, 1H), 1.46 (dec, J=6.5 Hz, 4H), 0.91 (t, J=7.5 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ ppm 191.1, 160.7, 138.5, 124.1, 120.0, 71.1, 40.9, 23.5, 11.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:17])[NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:5]2[CH2:18][C:19]([O:21]C)=[O:20].[Li+].[OH-].CCOC(C)=O>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:17])[NH:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[C:5]2[CH2:18][C:19]([OH:21])=[O:20]
Reactant: COC(=O)Cc1c(C(=O)NC(C)(C)C)[nH]c2ccc(Br)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1[nH]c2ccc(Br)cc2c1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Step I (2): To a solution of methyl 2-(5-bromo-2-(tert-butylcarbamoyl)-1H-indol-3-yl)acetate (80 mg, 0.22 mmol) in THF (2.0 mL) was added a solution of LiOH (16 mg, 0.66 mmol) in water (0.5 mL). The mixture was stirred at rt for 3 h. 100 mL of EtOAc was added, and the resulting solution was washed with 0.1 N HCl and water. The organic layer was dried over Na2SO4, and the solvents was removed to give the title compound 2-(5-bromo-2-(tert-butylcarbamoyl)-1H-indol-3-yl)acetic acid which was used without further purification. MS (ESI) (M+H)+=355.03.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([F:4])[CH3:3]>C1COCC1.CO.[Pt](=O)=O>[F:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(F)(F)c1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
Platinum(IV) oxide (45 mg) was added to a mixture of 9-(4-(1,1-difluoroethyl)phenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (207 mg) in THF (dry) (120 mL) and MeOH (120 mL). The mixture was stirred at room temperature under hydrogen overnight. Activated carbon powder was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (80.4 mg) as colorless crystals.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]([C:10]1[S:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:9])[C:4]([O:6][CH3:7])=[O:5].[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Cl:15][C:12]1[S:11][C:10]([C:8](=[O:9])[CH:3]([NH:2][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([F:16])=[CH:18][CH:19]=2)[C:4]([O:6][CH3:7])=[O:5])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=O)C(N)C(=O)c1ccc(Cl)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(NC(=O)c1ccc(F)cc1)C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A mixture of methyl 2-amino-3-(5-chlorothiophen-2-yl)-3-oxopropionate hydrochloride (6.0 g), 4-fluorobenzoyl chloride (4.23 g) and sodium hydrogen carbonate (11.2 g) in ethyl acetate (100 ml) and water (10 ml) was stirred at room temperature for 2 hours. The organic layer was collected, washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with diethyl ether to obtain methyl 3-(5-chlorothiophen-2-yl)-2-(4-fluorobenzoylamino)-3-oxopropionate (7.3 g) as colorless powder.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]([NH:23][CH:24]1[C:32]2[C:27](=[C:28]([O:33][CH3:34])[CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)[C:6]1[O:7][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.O=S(Cl)Cl>C(Cl)Cl>[C:11]1([C:9]2[N:10]=[C:6]([CH:5]3[CH2:4][CH2:3][CH2:2][N:23]3[CH:24]3[C:32]4[C:27](=[C:28]([O:33][CH3:34])[CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[O:7][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc2c1CCC2NC(CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1cccc2c1CCC2N1CCCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.8 %

Procedure:
To a solution of 1-[[4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.27 g) in CH2Cl2 (5 ml) was added SOCl2 (1 ml) at 0° C. After being stirred for 17 hours at room temperature, the solvent was evaporated in vacuo and the residue was dissolved in DMF (5 ml). To the mixture was added K2CO3 (2.07 g). After being stirred for 1 day at room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-2,3-dihydro-4-methoxy-1H-indene (0.15 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.[C:19]([S:23]([N:25]=[CH:26][CH2:27][CH:28]([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:24])([CH3:22])([CH3:21])[CH3:20].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:26]([NH:25][S:23]([C:19]([CH3:21])([CH3:20])[CH3:22])=[O:24])[CH2:27][CH:28]([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: Ic1ccccc1-c1ccccc1
Reactant: CCOC(=O)C(C)CC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1ccccc1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of commercially available 2-iodo-1,1′-biphenyl (680 mg; 2.43 mmol) in anh. THF (20 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (1.52 ml; 2.43 mmol). The resulting solution was further stirred at −78° C. for 10 min. A solution of ethyl 4-((tert-butylsulfinyl)imino)-2-methylbutanoate (600 mg; 2.43 mmol) in anh. THF (5 ml) was added to the cooled reaction mixture, and stirring was continued from −78° C. to 0° C. over 1 h. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (80 ml), Et2O (250 ml) and water (75 ml). The separated organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded ethyl 4-([1,1′-biphenyl]-2-yl)-4-(1,1-dimethylethylsulfinamido)-2-methylbutanoate as a mixture of stereoisomers. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 401.79 g/mol and tR=0.94 min.; [M+H]+: 401.80 g/mol.