Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH:5]1[NH:14][C:15]([C:17]1[C:18](Cl)=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:16])[CH2:11]2>CC(N(C)C)=O.CCOC(C)=O>[CH:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH:5]1[NH:14][C:15]([C:17]1[C:18]([S:2][CH3:1])=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:16])[CH2:11]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(Cl)nc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CSc1nc(Cl)ccc1C(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 60 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
Sodium thiomethoxide (0.409 g, 5.84 mmol) was added to N-(2-adamantyl)-2,6-dichloro-pyridine-3-carboxamide (2 g, 6.15 mmol) in DMA (10 mL) at 20° C. under nitrogen. The resulting suspension was stirred at 60° C. for 3 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (3×20 mL), and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product which was purified by crystallisation from EtOAc/isohexane to afford N-(2-adamantyl)-6-chloro-2-methylsulfanyl-pyridine-3-carboxamide (1.150 g, 55.5%) as a white solid
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1)[CH3:2].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>>[BrH:10].[BrH:10].[CH2:11]([N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]1=[NH:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]1=[NH:9]
Reactant: CCc1ccnc(N)c1
Reactant: BrCCCCCCCCCCCCCCCCBr
Product: Br
Product: CCc1ccn(CCCCCCCCCCCCCCCCn2ccc(CC)cc2=N)c(=N)c1

Procedure:
Starting from 4-ethyl-2-aminopyridine described by Hansch and 1,16-dibromohexadecane, the derivative of the title, m.p. 105°/110° C., is obtained.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH:20]([CH3:22])[CH3:21])(O)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].Cl.[H][H]>[Pd].CO>[C:1]([N:6]1[CH2:7][CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH:20]([CH3:21])[CH3:22])[CH2:10][CH2:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)N1CCC(O)(c2ccccc2OC(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)N1CCC(c2ccccc2OC(C)C)CC1
Yield: 86 %

Procedure:
A crude solution of XV (36 g), 10% palladium on carbon (1.80 g), 5 mL of concentrated HCl and 125 mL of MeOH was shaken on a Parr apparatus under 55.5 psig of hydrogen at 22° C. for 3 d. The reaction was filtered over Celite, and concentrated to a residue. This material was partitioned between ether and water. The organic solution was dried (MgSO4), filtered, and concentrated to yield 29.34 g of XVI as a light yellow oil which was carried forward without further purification. The structure was supported by MS and 1H NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([CH:20]=O)=[CH:16][CH:17]=[CH:18][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Fc1ccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)cc1

Procedure:
96 mg of the target compound (0.28 mmol, 34.0%) was obtained using 1-(4-fluorophenyl)piperazine (296 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:40]1(B(O)O)[CH2:42][CH2:41]1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([CH:40]3[CH2:42][CH2:41]3)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(C3CC3)nc(-c3ccccc3)n2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 86, step 86.1, 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester replacing 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester and cyclopropylboronic acid replacing phenylboronic acid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[OH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:18]2[CH2:19][CH2:20][CH:15]([OH:14])[CH2:16][CH2:17]2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: OC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(C(F)(F)F)cc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
4-(Trifluoromethyl)benzoyl chloride (1.5 ml, 9.89 mmol) was added to a solution of 4-hydroxypiperidine (1 g, 9.89 mmol) and triethylamine (1.7 ml, 11.9 mmol) in methylene chloride (20 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water, saturated sodium bicarbonate aqueous solution and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/acetone=2/1) to afford 1-(4-trifluoromethylbenzoyl)-4-hydroxypiperidine (2.07 g, yield 77%) as a colorless crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([O:13]C)=[O:12])[CH:6]=1)=[O:4].CN(C)N.Cl>O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[C:11]([OH:13])=[O:12])=[O:4]
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Agent: CN(C)N
Agent: Cl
Solvent: O
Product: COC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 24.4 %

Procedure:
A mixture of dimethyl m-phthalate (40.0 g, 0.206 mol) and 1,1-dimethylhydrazine (78.3 mL, 1.03 mol) was stirred at room temperature for 17 h and refluxed under heating for 21 h. The reaction mixture was concentrated, and the residue was washed with dichloromethane to give a powder, to which were added water (300 mL) and 1N hydrochloric acid (300 mL). The precipitated solids were collected by filtration, dried under reduced pressure, and recrystallized from chloroformmethanol (9:1) to give 9.05 g (24%) of 3-methoxycarbonylbenzoic acid as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C@H:5]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7].[ClH:24]>O1CCOCC1.CO.O=[Pt]=O>[ClH:24].[CH3:1][O:2][C:3](=[O:23])[CH2:4][C@H:5]([NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7]
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccnc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CCCNC1
Reaction time: 2 h

Procedure:
A mixture of N-(3-pyridyl)-3(S)-(tert-butoxycarbonylamino)succinamic acid methyl ester (3.91 g) and 4N HCl in dioxane (3.36 ml) and PtO2 (0.39 g) in methanol (40 ml) was hydrogenated at atmospheric pressure for 2 hours. After the catalyst was removed by filtration, the filtrate was concentrated in vacuo. The residue was recrystallized from diethyl ether to give N-(3-piperidyl)-3(S)-(tert-butoxycarbonylamino)succinamic acid methyl ester hydrochloride (3.67 g).
Reaction SMILES: [C:1]([CH:4]([CH2:14][CH2:15][CH2:16][CH:17]([OH:27])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>CCOCC>[C:1]([CH:4]([CH2:14][CH2:15][CH2:16][CH:17]([O:27][C:28](=[O:30])[CH3:29])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Solvent: CCOCC
Product: CC(=O)OC(CCCC(CCCCCCC(=O)O)C(C)=O)COc1ccc(F)cc1

Procedure:
A mixture of 8-acetyl-12-hydroxy-13-(4-fluorophenoxy)tridecanoic acid (9.5 g., 0.025 mole) and acetic anhydride (6.1 g., 0.06 mole) is heated at 60° for 18 hours. The mixture is then cooled and dissolved in 80 ml. of ether. The solution is extracted with an ice-cold solution of 8 g. of sodium hydroxide in 150 ml. of water. The basic solution is separated and acidified with concentrated hydrochloric acid. The oily acid that separates is taken up in ether, washed with water and dried over sodium sulfate. The ether is evaporated to leave the crude product as a viscous yellow oil.
Reaction SMILES: C[C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[N:7]([C:15]3[CH:20]=[N:19][C:18]([NH:21][C:22](=[O:31])[C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=4[F:30])=[CH:17][N:16]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:32](O)=[O:33].C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[CH2:48]([O:50][CH:51]([O:54][CH2:55][CH3:56])[CH2:52][NH2:53])[CH3:49]>C(Cl)Cl.CN(C=O)C>[CH2:48]([O:50][CH:51]([O:54][CH2:55][CH3:56])[CH2:52][NH:53][C:32]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:15]3[CH:20]=[N:19][C:18]([NH:21][C:22](=[O:31])[C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=4[F:30])=[CH:17][N:16]=3)[C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][C:10]=2[CH:2]=1)=[O:33])[CH3:49]
Reactant: CCOC(CN)OCC
Reactant: Cc1c(C(=O)O)ccc2c1nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(CNC(=O)c1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1)OCC
Temperature: 0 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
Into a 50 mL roundbottom flask, was placed a solution of 1-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylic acid (xiii) (50 mg, 0.11 mmol, 1.00 equiv) in DCM (15 ml) and DMF (1 drop). To the above stirred solution was added oxalyl dichloride (70 mg, 0.55 mmol, 5.00 equiv) dropwise at 0° C. The resulting solution was allowed to stir at 0° C. for 4 hours then was concentrated by evaporation under vacuum using a rotary evaporator. The residue was then taken up by DCM (10 ml) and then add dropwise to a stirred solution of Et3N (40 mg, 3.00 equiv) and 2,2-diethoxyethanamine (15 mg, 0.11 mmol, 1.00 equiv) in DCM (10 mL) at 0° C. The resulting solution was allowed to stir overnight at room temperature, then washed with H2O (2×100 mL) and dried over Na2SO4. Removal of the solvent and volatile components afforded the crude product 1-[5-(2,6-difluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid (2,2-diethoxy-ethyl)-amide (xiv) (50 mg, 64% yield) as a yellow solid that was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[C:4]([Br:9])[C:5]([F:8])=[CH:6][CH:7]=1.C([O:13][CH:14]=[C:15]([C:21](OCC)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.C1(OC2C=CC=CC=2)C=CC=CC=1.C1C2C3C=CC=CC=3OC=2C=CC=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:9][C:4]1[C:3]([F:10])=[C:2]2[C:7]([C:14]([OH:13])=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:21]=[N:1]2)=[CH:6][C:5]=1[F:8]
Reactant: Nc1ccc(F)c(Br)c1F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc2c(c1)oc1ccccc12
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(F)c(Br)c(F)cc2c1O
Temperature: 150 °C
Yield: 78 %

Procedure:
A stirred mixture of 26 g of 3-amino-2,6-difluorobromobenzene and 27 g of diethyl ethoxymethylenemalonate was heated at 150° C. for 1 hour. After cooling, 100 ml of Dowtherm "A" (commercially available high boiling inert solvent mixture of diphenylether and dibenzofuran) was added and the mixture was heated under nitrogen at 260° C. for 1.5 hour. The mixture was cooled to room temperature and 200 ml of hexanes was added. The resulting precipitate was collected by filtration, washed with hexanes and dried to give a cream solid, m.p. 285° C., yield 78% (32.32 g).
Reaction SMILES: [NH2:1][C@H:2]([C@@H:6]([OH:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[C:10]([O-:13])(O)=[O:11].[Na+].[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]C2C(=O)N(C([O-])=O)C=CC=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.C1COCC1>[OH:9][C@@H:6]([CH2:7][CH3:8])[C@@H:2]([NH:1][C:10]([O:13][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[C:3]([OH:5])=[O:4]
Reactant: O=C([O-])n1cccc(CCCCCc2ccccc2)c1=O
Reactant: O=C([O-])O
Reactant: CC[C@H](O)[C@@H](N)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 59.2 %

Procedure:
To a stirred diastereomeric mixture containing (2R*,3R*) and (2R*,3S*)-2-amino-3-hydroxy-pentanoic acid (0.107 g, 0.81 mmol) and NaHCO3 (0.102 g, 1.21 mmol) in H2O (2.0 mL), at rt, the isomeric mixture containing 5-phenyl-pentyl-2-pyridyl-carbonate and 5-phenyl-pentyl-2-oxopyridine-1-carboxylate (0.346 g, 1.21 mmol) [prepared as for example 32, step 1] in THF (2.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×10 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×20 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.155 g, 60% over 2 steps), as a diastereoisomeric mixture (anti:syn=8:2), as an off-white solid, which was used in the next step without further purification. MS (ESI) m/z: 324[M−H]+; (ESI) m/z: 322 [M−H]−. 1H NMR (DMSO-d6) δ 0.86 (t, J=7.41 Hz, 3H), 1.27-1.50 (m, 4H), 1.51-1.67 (m, 4H), 2.57 (t, J=7.69 Hz, 2H), 3.52-3.66 (m, 1H), 3.93 (t, J=6.63 Hz, 3H), 4.83 (s, 1H), 7.10 (d, J=8.73 Hz, 1H), 7.13-7.22 (m, 3H), 7.22-7.30 (m, 2H), 12.35 (s, 1H) (reported data refer to the major anti diastereoisomer).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:11][C:12]([CH:15]=O)([CH3:14])[CH3:13].[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH:15]([NH:7][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[C:12]([CH3:13])([CH3:14])[CH3:11])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: CC(C)(C)C=O
Reactant: NC(=O)c1cccc(Cl)c1
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(NC(=O)c1cccc(Cl)c1)n1nnc2ccccc21

Procedure:
A suspension of 3-chlorobenzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1C to provide the title compound.
Reaction SMILES: BrBr.[CH2:3]([O:5][C:6]([CH:8]1[CH2:19][N:18]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:11]2[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=2[C:9]1=[O:26])=[O:7])[CH3:4].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:3]([O:5][C:6]([C:8]1[C:9](=[O:26])[C:10]2[CH:15]=[N:14][C:13]([S:16][CH3:17])=[N:12][C:11]=2[N:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH:19]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C1CN(C2CCCCC2)c2nc(SC)ncc2C1=O
Agent: BrBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(SC)ncc2c1=O
Reaction time: 0.08 h
Yield: 102 %

Procedure:
Bromine (0.15 g, 0.94 mmol) was added to a solution of 8-cyclohexyl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.28 g, 0.79 mmol) in DCM (10 mL). After 5 min, the solution was concentrated and the crude residue was redissolved in DCM (10 mL) and diisopropylethylamine (0.42 mL, 2.4 mmol) was added. After 15 h, the reaction mixture was partitioned between water and DCM, the organic layer was separated, dried (MgSO4) and concentrated to provide 0.28 g (87%) of the title compound.). Mass Spectrum (LCMS, ESI pos.) Calcd. For C17H21N3O3S: 347.13, found: (M+H) 348.3.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23]S(C)(=O)=O)[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].[I-:28].[Na+]>C(C(C)=O)C>[C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][I:28])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1O[C@H](CS(C)(=O)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(=O)O[C@@H]1O[C@H](CI)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 104.3 %

Procedure:
A 1 L round bottom flask containing 500 mL of methyl ethyl ketone was charged with 1,2,3,4-tetra-O-acetyl-6-deoxy-6-methanesulfonyl-β-D-glucopyranose (4.45 g, 10.44 mmol) and sodium iodide (15.73 g, 104.9 mmol). The reaction was heated at reflux for 24 hours. The solvent was removed in vacuo and the resulting residue was taken up in 250 mL dichloromethane. The organic layer was washed with sodium thiosulfate (2×100 mL), water (2×100 mL) and once with 100 mL of brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo to yield crude 1,2,3,4-tetra-O-acetyl-6-deoxy-6-iodo-β-D-glucopyranose as a white solid (4.99 g) which was used directly in Preparation 4.
Reaction SMILES: C1C=CN=CC=1.[FH:7].[CH3:8][O:9][C:10]1[C:11]([N+:18]([O-:20])=[O:19])=[CH:12][C:13]([CH3:17])=[C:14](N)[CH:15]=1.N([O-])=O.[Na+]>N1C=CC=CC=1>[F:7][C:14]1[CH:15]=[C:10]([O:9][CH3:8])[C:11]([N+:18]([O-:20])=[O:19])=[CH:12][C:13]=1[CH3:17]
Reactant: COc1cc(N)c(C)cc1[N+](=O)[O-]
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cc(F)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 76 %

Procedure:
Under nitrogen in a nalgene bottle, a stirring solution of pyridine (17.1 mL, 3.2 M, −70° C.) was treated dropwise with HF-pyridine (51.91 mL). Next, 5-methoxy-2-methyl-4-nitro-phenylamine (10.0 g, 54.9 mmol) was added followed by sodium nitrite (6.4 g, 92.76 mmol). The dry ice/acetone bath was removed and the reaction was allowed to warm to room temperature. The solution was then heated at 60° C. for 2 h (or until nitrogen evolution stops.) After cooling to room temperature, the nalgene bottle was placed in an ice bath and 375 mL of water was slowly added to the solution. The resulting orange precipitate was collected by suction filtration and washed with 250 mL of water. Purification of the solid via silica gel flash chromatography (30% ethyl acetate in heptane) provided 1-fluoro-5-methoxy-2-methyl-4-nitro-benzene (7.69 g, 76%) as a light orange solid: mp 71–74° C.; Rf 0.56 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 7.82 (d, J=7.5 Hz, 1 H), 6.75 (d, J=10.5 Hz, 1 H), 3.93 (s, 3 H), 2.25 (d, J=2.1 Hz, 3 H); ESI-LC/MS m/z calcd for C8H8FNO3: 185.1; Found 186.0 (M+1)+. Anal. calcd for C8H8FNO3: C, 51.90; H, 4.36. Found C, 52.11; H, 4.47.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[N:10]=[N:11][N:12]([CH3:14])[N:13]=2)=[CH:4][C:3]=1[CH3:15].[F:16][C:17]1[CH:18]=[CH:19][C:20](B2OC(C)(C)C(C)(C)O2)=[C:21]2[C:25]=1[C@H:24]([O:26][C:27]1[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=1)[CH2:23][CH2:22]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:15][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[N:11][N:12]([CH3:14])[N:13]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:20]1[CH:19]=[CH:18][C:17]([F:16])=[C:25]2[C:21]=1[CH2:22][CH2:23][C@H:24]2[O:26][C:27]1[CH:40]=[CH:39][C:30]2[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=2[CH:28]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6nnn(C)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 5-(4-bromo-3,5-dimethylphenyl)-2-methyl-2H-tetrazole and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.26 min; Mass spectrum (ESI+): m/z=529 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11](S(C1C=CC(C)=CC=1)(=O)=O)[C:10]1[C:9](=[O:26])[CH2:8][CH2:7][CH2:6][C:5]2=1.[OH-].[K+].[C:29]1([CH:35]=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO>[CH:35](=[C:8]1[CH2:7][CH2:6][C:5]2[C:4]3[C:12](=[CH:13][C:14]([Cl:15])=[C:2]([Cl:1])[CH:3]=3)[NH:11][C:10]=2[C:9]1=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCCC3=O)cc1
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2ccccc2)CCc2c1[nH]c1cc(Cl)c(Cl)cc21
Temperature: 75 °C
Yield: 69.4 %

Procedure:
To a solution of 6,7-dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (intermediate 1c) (0.8 g, 3.16 mmol) in MeOH (15 mL), KOH (53 mg, 0.94 mmol) followed by PhCHO (2.6 g, 24.5 mmol) were added. The reaction mixture was heated to 70-80° C. for 12 h. The solids were filtered and dried in vacuo to afford the title compound as a light yellow solid (0.75 g, 70%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 12.07 (s, 1H), 8.05 (s, 1H), 7.64 (d, J=13.0 Hz, 2H), 7.54 (d, J=7.0 Hz, 2H), 7.49-7.46 (m, 2H), 7.41 (d, J=7.5 Hz, 1H), 3.21-3.18 (m, 2H), 3.05-3.02 (m, 2H).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]1([CH3:19])[CH2:16][CH2:15][CH2:14][C:13]([CH3:18])([CH3:17])[NH:12]1>O>[Cl:3][C:2]1[N:1]=[C:8]([N:12]2[C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][CH2:16][C:11]2([CH3:19])[CH3:10])[N:7]=[C:5]([N:12]2[C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][CH2:16][C:11]2([CH3:19])[CH3:10])[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC1(C)CCCC(C)(C)N1
Solvent: O
Product: CC1(C)CCCC(C)(C)N1c1nc(Cl)nc(N2C(C)(C)CCCC2(C)C)n1
Reaction time: 10 h

Procedure:
18.4 g of cyanuric chloride and 113 g of 2,2,6,6-tetramethylpiperidine are heated for 10 hours at 180° and then for 10 hours at 210° in a 300 ml autoclave. The contents of the autoclave are then taken up in 500 ml of water, and the insoluble residue is filtered off by suction, washed with water and dried. The brownish residue is crystallized from ligroin. 2-Chloro-4,6-bis-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine is obtained as colorless crystals having a melting point of 188°.