Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:19]N1C(=O)CCC1=O>CN(C=O)C>[Br:19][C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[C:13]([OH:18])[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccccc1NC1CCC2(CC1)OCCO2
Solvent: CN(C)C=O
Product: Oc1cc(Br)ccc1NC1CCC2(CC1)OCCO2
Yield: 32.9 %

Procedure:
A solution of intermediate D19 (1 g, 4.011 mmol) and N-bromosuccinimide (0.785 g, 4.412 mmol) in DMF (15 ml) was stirred at room temperature for 1 h. Subsequently, the reaction mixture was washed with NaHCO3 (aqueous sat. solution). The organic layer was separated, dried (Na2SO4), and the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/EtOAc 8:2 as eluent): The desired fractions were collected and evaporated in vacuo to yield D22 (0.433 g, 32.89%) as a reddish solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[C:16](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)c1ccc(Br)cn1
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
Tert-butyl 5-bromopyridin-2-ylcarbamate (10 g) and cesium carbonate (20 g) were added to 50 mL of DMF. Methyl iodide (4 mL) was subsequently slowly added to the stirring reaction mixture. After 30 minutes tlc indicates that the reaction is complete. The majority of the DMF was removed under hi-vacuum and the reaction mixture was extracted with ethyl acetate and water. The organic layer was dried, filtered and concentrated. The crude product was purified by Isco 0-30% gradient (H/E) over 25 mins. The tubes were pooled and concentrated to get 9.85 g of tert-butyl 5-bromopyridin-2-yl(methyl)carbamate as a clear oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH3:20][O:21]C(Cl)Cl.[Sn](Cl)(Cl)(Cl)Cl.Cl>ClCCl.O>[CH:20]([C:5]1[C:6]([OH:8])=[CH:7][C:2]([OH:1])=[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:21]
Reactant: COC(Cl)Cl
Reactant: COC(=O)Cc1cc(O)cc(O)c1-c1ccccc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1c(C=O)c(O)cc(O)c1-c1ccccc1
Temperature: 4 °C
Reaction time: 0.08 h
Yield: 75.6 %

Procedure:
Compound 1 (0.25 g, 0.97 mmol) obtained in Example 1 was dissolved in dichloromethane (10 mL), and the solution was cooled to 4° C., and then dichloromethyl methyl ether (0.13 mL, 1.4 mmol) and tin(IV) chloride (0.17 g, 1.5 mmol) were added thereto and stirred at 4° C. for 5 minutes. Water (10 mL) and 3 mol/L hydrochloric acid (10 mL) were added to the reaction mixture, and extracted with chloroform (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The residue was purified through preparative thin-layer chromatography (n-hexane/ethyl acetate=1/2) and crystallized (n-hexane/ethyl acetate=1/2) to obtain Compound 55 (0.21 g, 85%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:21][C:22]([C:24]2[N:25]([CH3:48])[C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:33][N:34]2[CH2:39][CH2:38][N:37]([C:40]([CH:42]3[CH2:46][CH2:45][CH2:44][N:43]3[CH3:47])=[O:41])[CH2:36][CH2:35]2)=[O:23])[C:8]([O:19][CH3:20])=[C:9]([NH:11]C(=O)OC(C)(C)C)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:49]>ClCCl.C(O)(C)C>[ClH:49].[ClH:49].[ClH:49].[NH2:11][C:9]1[C:8]([O:19][CH3:20])=[C:7]([NH:21][C:22]([C:24]2[N:25]([CH3:48])[C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:33][N:34]2[CH2:35][CH2:36][N:37]([C:40]([C@@H:42]3[CH2:46][CH2:45][CH2:44][N:43]3[CH3:47])=[O:41])[CH2:38][CH2:39]2)=[O:23])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]=1
Reactant: COc1c(NC(=O)OC(C)(C)C)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)C4CCCN4C)CC3)c2n1C
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1c(N)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)[C@@H]4CCCN4C)CC3)c2n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.59 g tert-butyl [5-tert-butyl-2-methoxy-3-({1-methyl-7-[4-(1-methyl-pyrrolidine-2-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carbonyl}-amino)-phenyl]-carbamate are dissolved in 15 ml dichloromethane, combined with 10 ml of a 5 M solution of hydrogen chloride in isopropanol and stirred for 3 hours at ambient temperature. Then the solvents are eliminated in vacuo. The product thus obtained is further reacted directly.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[C:5](=O)[CH3:6].Cl.[NH2:19]O>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:6])=[N:19][O:16][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)=[O:17]
Reactant: COC(=O)C(C(C)=O)C(=O)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1c(C)noc1-c1ccc(Br)cc1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(4-bromo-benzoyl)-3-oxo-butyric acid methyl ester (11 g, 39 mmol) in acetic acid (50 mL) was added hydroxylamine hydrochloride (2.66 g, 39 mmol) and the reaction was stirred at 115° C. for 1 hour. After cooling, aqueous workup provided the title compound, which was used directly in the hydrolysis step.
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11].[Cl:16][C:17]1[C:22]([NH:23][CH:24]=[O:25])=[C:21](Cl)[N:20]=[C:19]([NH:27][CH:28]=[O:29])[N:18]=1.C(N(C(C)C)CC)(C)C>COCCOCCOC>[Cl:16][C:17]1[C:22]([NH:23][CH:24]=[O:25])=[C:21]([NH:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][P:8]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:15])[N:20]=[C:19]([NH:27][CH:28]=[O:29])[N:18]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: CCOP(=O)(COCCCON)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOCCOC
Product: CCOP(=O)(COCCCONc1nc(NC=O)nc(Cl)c1NC=O)OCC
Temperature: 100 °C
Yield: 63.1 %

Procedure:
A mixture of diethyl 3-aminooxypropoxymethylphosphonate (4 g,16.6 mmol), 4,6-dichloro-2,5-diformamidopyrimidine (3.9 g, 16.6 mmol) and diisopropylethylamine (8.67 ml, 49.8 mmol) in diglyme (80 ml) was heated at 100° C. for 2 h. After removal of the solvent under reduced pressure, the residue was chromatographed in chloroform/methanol (100:1, 50:1, 10:1) affording 4-chloro-6-[3-(diethoxyphosphorylmethoxy)propoxyamino]-2,5-diformamidopyrimidine as a yellow oil (4.61 g, 63%); νmax (film) 3200, 2990, 1690, 1590, 1220, 1040 cm-1 ; δH [(CD3)2SO] 1.22(6H, t, J7 Hz, (CH3CH2O)2), 1.85(2H, m, CH2CH2CH2), 3.65(2H, t, J6.3 Hz, CH2OCH2P), 3.40(2H, d, J8.2 Hz, CH2P), 3.92(2H, t, J6 Hz, CH2ON), 4.04(4H, m, (CH3CH2O)2), 8.15(1H, s, CHO), 9.25(1H, br.s, CHO), 9.43(1H, br.s, D2O exchangeable, NH), 10.76(1H, br s, D2O exchangeable, NH), 10.86(1H, br.s,D2O exchangeable, NH); Found: M+ 439.1015; C14H23ClN5O7P requires: M+ 439.1024.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:27]2[CH2:28][CH2:29][CH:24]([C:22](=[O:23])[C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=3)[CH2:25][CH2:26]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Product: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Yield: 98.7 %

Procedure:
Using 4-bromo-2-methylsulfonylbenzoic acid (2.8 g) and (4-chlorophenyl)piperidin-4-ylmethanone (2.6 g) and by the reaction and treatment in the same manner as in Preparation Example 109, the title compound (4.8 g) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Br.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.BrCC1CCCCO1>>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (80%) as a colorless solid: mp 208-209° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ8.58 (d, J=4.8 Hz, 1H), 7.65 (ddd, J=7.7, 7.7, 1.7 Hz, 1H), 7.28-7.15 (m, 4H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.31 (s, 1H), 5.21 (d, J=16.0 Hz, 1H), 4.97 (d, J=16.0 Hz, 1H), 4.96 (d, J=8.7 Hz, 1H), 4.68 (d, J=8.7 Hz, 1H), 4.22-4.17 (m, 2H), 4.15-4.10 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.6, 155.6, 155.3, 149.6, 144.6, 142.2, 138.3, 137.1, 132.2, 128.9, 123.8, 123.5, 122.8, 121.6, 121.1, 111.8, 109.6, 99.4, 80.2, 64.5, 63.9, 58.2, 46.1; MS (ES+) m/z 387.2 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)([CH2:14][NH2:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:1]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][NH:15][S:30]([CH3:29])(=[O:32])=[O:31])([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(C2CCCCC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CNS(C)(=O)=O)(C2CCCCC2)CC1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 92.8 %

Procedure:
A 15-mL, round-bottomed flask was purged with nitrogen and then charged with the amine from Step A (0.063 g, 0.213 mmol), 1.7 mL of methylene chloride, and triethylamine (0.045 mL, 0.320 mmol). The reaction mixture was cooled at 0° C. in an ice-water bath and then methanesulfonyl chloride (0.018 mL, 0.23 mmol) was added dropwise via syringe. The resulting mixture was stirred at 0° C. for 50 min, warmed to room temperature, and stirred for 16.5 h. The reaction mixture was then diluted with methylene chloride and washed with two portions of 1N HCl solution, saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (1:1 methylene chloride-acetone) to give the desired product (0.074 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:11]([C:12]([F:15])([F:14])[F:13])[CH2:10][C:9](=[O:16])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[N:26]([CH2:35][CH2:36][OH:37])[CH:27]=[C:28]([CH2:30][C:31]([F:34])([F:33])[F:32])[N:29]=2)[CH2:21][CH2:20]1.CN1CCCC1=O.C(N(C(C)C)CC)(C)C>C(=O)(O)[O-].[Na+]>[OH:37][CH2:36][CH2:35][N:26]1[CH:27]=[C:28]([CH2:30][C:31]([F:32])([F:34])[F:33])[N:29]=[C:25]1[CH:22]1[CH2:21][CH2:20][N:19]([C:2]2[C:3]3[C@H:11]([C:12]([F:15])([F:14])[F:13])[CH2:10][C:9](=[O:16])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:24][CH2:23]1
Reactant: OCCn1cc(CC(F)(F)F)nc1C1CCNCC1
Reactant: O=C1C[C@@H](C(F)(F)F)c2c(Cl)ncnc2N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1C[C@@H](C(F)(F)F)c2c(ncnc2N2CCC(c3nc(CC(F)(F)F)cn3CCO)CC2)N1
Temperature: 150 °C
Yield: 67.9 %

Procedure:
Add (R)-4-chloro-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.70 g, 2.78 mmol), 2-(2-(piperidin-4-yl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-1-yl)ethanol dihydrochloride (1.17 g, 1.2 eq), N-methylpyrrolidinone (10 mL) and diisopropylethylamine (2.20 mL, 5.7 eq) in a microwave tube. Seal with crimp cap. Heat in a microwave reactor at 150° C. for one hour. Dilute the reaction mixture with saturated aqueous sodium bicarbonate and extract with ethyl acetate. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with 5% methanol/dichloromethane to 10% methanol/dichloromethane to 10% 2 M ammonia in methanol/dichloromethane, to give (R)-4-(4-(1-(2-hydroxyethyl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.93 g, 68%). MS (ES) m/z=493 [M]+.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:11]3[CH2:12][C:13]([O:15][C@:10]3([CH3:16])[CH2:9][CH2:8][C@H:7]1[C:6]([CH3:18])([CH3:17])[CH2:5][CH2:4][CH2:3]2)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][OH:28])[CH:20]=1.CC1N(CCCO)C2C=CN=CC=2N=1>>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][O:28][CH:12]2[CH2:13][O:15][C:10]3([CH3:16])[CH2:9][CH2:8][CH:7]4[C:2]([CH3:1])([CH:11]23)[CH2:3][CH2:4][CH2:5][C:6]4([CH3:18])[CH3:17])[CH:20]=1
Reactant: OCCCc1cccnc1
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CC(=O)O[C@]3(C)CC[C@@H]12
Agent: Cc1nc2cnccc2n1CCCO
Product: CC1(C)CCCC2(C)C1CCC1(C)OCC(OCCCc3cccnc3)C12
Yield: 75 %

Procedure:
2-(3-(3-Pyridyl)propoxy-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan was prepared by the procedure of Example 2 employing (3aR)-(+)-sclareolide in lieu of undecanoic-gamma-lactone and 3-(3-pyridyl)propanol in lieu of 3-(2-methylimidazo [4,5 -c]pyrid-1-yl)propanol.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:31])[C:26](OCC)=[O:27])=[CH:20][C:19]=1[F:32])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:31])[C:26]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:27])=[CH:20][C:19]=1[F:32])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)C(=O)Nc1ccc(OCc2ccccc2)c(F)c1
Product: O=C(NCCc1ccccc1)C(=O)Nc1ccc(OCc2ccccc2)c(F)c1
Yield: 98 %

Procedure:
Phenethyl-amine (33 mL, 520 mmol) was added to ethyl [(4-benzyloxy-3-fluorophenyl)amino](oxo)acetate (81 g, 260 mmol) and the mixture was sonicated at room temperature for 30 min. The resulting solid was filtered, washed with water and dried to give N-(4-benzyloxy-3-flourophenyl)-N′-(2-phenylethyl)ethanediamide (100 g, 99%). 1H NMR (400 MHz, d6-DMSO): δ 10.72 (br s, 1H), 9.05 (m, 1H), 8.78 (m, 1H), 7.77 (m, 1H), 7.59 (m, 1H), 7.46-7.19 (m, 8H), 5.16 (m, 2H), 3.45 (m, 2H), 2.83 (m, 2H); IR (cm−1): 2980, 2883, 1653, 1522, 1506, 1441, 1385, 1221, 1122, 951, 808, 746, 696, 584; LC/MS (M+H=393).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[CH2:13]([C@@H:15]1[O:17][CH2:16]1)[Cl:14]>CCO.O>[Cl:14][CH2:13][C@H:15]([OH:17])[CH2:16][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Reactant: ClC[C@H]1CO1
Solvent: O
Solvent: CCO
Product: O=C1CSc2ccc(NC[C@@H](O)CCl)cc2N1
Yield: 81 %

Procedure:
A solution of 6-amino-4H-benzo[1,4]thiazin-3-one (18.39 g, 102 mmol; commercial) and (R)-epichlorohydrin (8.0 mL, 1 eq.) in EtOH/H2O (9:1; 450 mL) was heated at 80° C. overnight. The mixture was concentrated under reduced pressure. Residual starting aniline could be removed by addition of Et2O/EA followed by filtration. The filtrate containing the product was concentrated under reduced pressure to afford the title intermediate as a beige solid (22.52 g, 81% yield) which was used as such in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:4]=1[C:5](=[NH:9])OCC.[NH3:15].[ClH:16]>C(O)C.C(OCC)C>[ClH:16].[CH3:1][O:2][C:3]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([NH2:9])=[NH:15]
Reactant: N
Reactant: CCOC(=N)c1cccc(C)c1OC
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: COc1c(C)cccc1C(=N)N
Reaction time: 72 h

Procedure:
Ethyl 2-methoxy-3-methylbenzimidate borofluoride (28 g.) was mixed with a saturated anhydrous solution of ammonia in ethanol (46 ml.), the mixture was kept at room temperature in a stoppered vessel for 3 days and then evaporated to dryness in vacuo. The residue was dissolved in water (25 ml.) and treated with 5N sodium hydroxide solution (50 ml.). The solution was saturated with sodium chloride and extracted with diethyl ether. The extract was dried over potassium hydroxide and evaporated to give crude 2-methoxy-3-methylbenzamidine, m.p. 72°-74° C. This was dissolved in anhydrous ethanol (40 ml.) and the solution treated with a saturated anhydrous solution of hydrogen chloride in diethyl ether (100 ml.), and diluted with anhydrous diethyl ether (100 ml.). The solid which separated was filtered off and washed with anhydrous diethyl ether to give 2-methoxy-3-methylbenzamidine hydrochloride (17.8 g.), m.p. 208°-209° C. (with decomposition).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[N:10]2[CH3:30])=[C:5]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:4]=1)#[N:2].Br[CH2:36][CH2:37][OH:38].C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:36][CH2:37][OH:38])=[O:16])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:11](=[O:29])[N:10]2[CH3:30])=[C:5]([S:31]([CH3:34])(=[O:32])=[O:33])[CH:4]=1)#[N:2]
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C(C(=O)OCCO)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (74 mg, 150 μmol) was initially charged in dry DMF (2 ml), 2-bromoethanol (75 mg, 600 μmol; 4 eq.) and triethylamine (31 mg, 300 μmol; 2 eq.) were added and the mixture was stirred at 70° C. for 8 h. The reaction mixture was then concentrated under reduced pressure, and the residue was taken up in ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate solution (2×20 ml) and saturated sodium chloride solution (20 ml), dried over solid sodium sulfate, filtered and concentrated under reduced pressure. The crude product was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 1:3). The product-containing fractions were combined and concentrated, the residue was taken up in a little acetonitrile, water was added and the mixture was lyophilized. The title compound was obtained as a colorless solid (63 mg, 78% of theory).
Reaction SMILES: [CH3:1][C:2]1(C)CC[C:9]2[C:4](=[CH:5][C:6]([C:12]#[C:13][Si](C)(C)C)=[CH:7][CH:8]=2)[S:3]1.[OH-].[K+].[CH:21](O)([CH3:23])[CH3:22]>>[CH3:22][C:21]1([CH3:23])[C:9]2[C:4](=[CH:5][C:6]([C:12]#[CH:13])=[CH:7][CH:8]=2)[S:3][CH2:2][CH2:1]1
Reactant: CC1(C)CCc2ccc(C#C[Si](C)(C)C)cc2S1
Reactant: CC(C)O
Agent: [K+]
Agent: [OH-]
Product: C#Cc1ccc2c(c1)SCCC2(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1 g (3.6 mmol) of 4,4-dimethyl-7-trimethylsilylethynyl-thio-chroman (Compound 47) in 10 ml of isopropyl alcohol was added 5 ml of 1N KOH solution. The reaction mixture was stirred at room temperature for 18 hours and the isopropanol was then removed under vacuum. The residue was extracted with ether and the ether extracts were combined and washed with dilute HCl solution, water and saturated NaCl solution, and were thereafter dried (MgSO4). The solvent was removed in vacuo to give impure 4,4-dimethyl-7-ethynyl-thiochroman (Compound 48) as a pale yellow oil. This mixture was used in the next step without further purification.
Reaction SMILES: Cl.[NH2:2]O.[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH:13]=O)[CH2:8][CH2:7][CH2:6][CH2:5]1>C(OC(=O)C)(=O)C>[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[C:13]#[N:2])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NO
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C#N)cc1OC1CCCC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
Hydroxylamine hydrochloride (3.82 g) is added to a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (11.0 g) in acetic anhydride (30 mL) and the suspension heated in an oil bath at 100° C. until refluxing starts. The heating is then removed while the exothermic reaction refluxes gently. Heating at 100° C. is then continued for a further 1 hour. The dark solution is concentrated and the crude product dissolved in cyclohexane (200 mL). The solution is washed with 5% sodium bicarbonate solution (2×50 mL), water (2×50 mL) and brine (50 mL), and dried over magnesium sulfate. Upon evaporation, an amber oil (11.8 g) that is purified by flash chromatography (dichloromethane as eluant on silica column) gives 3-cyclopentyloxy-4-methoxybenzonitrile (8.6 g) as a pale yellow oil. [Elemental analysis: C,71.7; H,6.93; N,6.47%; calculated for C13H15NO2 : C,71.87; H,6.96; N,6.45%⟧
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: C1COCCN1
Reactant: O=Cc1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cccc(Cl)c1N1CCOCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 32.8 %

Procedure:
A 100 mL round-bottom flask was charged with 3-chloro-2-fluorobenzaldehyde (3.00 g, 18.9 mmol, 1.00 equiv), morpholine (2.50 g, 28.7 mmol, 1.52 equiv), potassium carbonate (6.50 g, 47.0 mmol, 2.49 equiv), and dimethyl sulfoxide (30 mL). The resulting solution was stirred for 3 hours at 100° C. in an oil bath and diluted with H2O (30 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with H2O (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/20) to provide 1.40 g (33% yield) of 3-chloro-2-(morpholin-4-yl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 226 [M+H]+.