Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[C:3]([P:14](=[O:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[I:36]I.Cl>C1COCC1.C1COCC1.CCCCCCC.C(OCC)(=O)C>[I:36][C:4]1[C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=[CH:2][C:3]=1[P:14](=[O:27])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccc2c(c1)oc1ccccc12
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccc2c(oc3ccccc32)c1I
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
9.8 g of (dibenzofuran-3-yl)-diphenyl-phosphine oxide in 100 ml of THF are admixed with 13.3 ml of a 2M solution of lithium diisopropylamide in THF/n-heptane and stirred for a further 10 minutes at -78° C. A solution of 7.9 g of iodine in 30 ml of THF is added at -76° C. Subsequently the mixture is hydrolyzed with 2N HCl, ethyl acetate is added, the solution is washed with sodium thiosulphate solution, water and saturated NaCl solution, dried with MgSO4 and concentrated. 12.7 g (98% of theoretical) of crude product remain.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7].[C:34]([O:38][CH3:39])(=[O:37])[CH:35]=[CH2:36]>>[CH3:39][O:38][C:34](=[O:37])[CH2:35][CH2:36][N:13]1[C:12](=[O:22])[C:11]2([CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]3[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:4]=3)[CH2:24][CH2:23]2)[N:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14]1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: C=CC(=O)OC
Product: COC(=O)CCN1CN(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=558.2 (M+H+), was prepared in accordance with the general method of example 59 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and methyl acrylate.
Reaction SMILES: [Cl:1][C:2](=[C:7]([Cl:12])[C:8]([F:11])([F:10])[F:9])[C:3]([F:6])([F:5])[F:4].II>>[Cl:12][CH:7]([CH2:2][C:3]([F:4])([F:5])[F:6])[C:8]([F:11])([F:10])[F:9].[Cl:12][CH:7]([CH:2]([Cl:1])[C:3]([F:4])([F:5])[F:6])[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(F)C(Cl)=C(Cl)C(F)(F)F
Agent: II
Product: FC(F)(F)C(Cl)C(Cl)C(F)(F)F
Product: FC(F)(F)CC(Cl)C(F)(F)F
Temperature: 260 °C
Reaction time: 6 h

Procedure:
2,3-Dichlorohexafluorobut-2-ene 300 g) and iodine 150 g) were charged into a 1 liter stirred autoclave. The autoclave was sealed, cooled and evacuated. It was then charged with hydrogen to 500 psi at room temperature. The autoclave was heated to 260° C. and the hydrogen pressure was increased to 1500 psi. The temperature was held at 260° C. with periodic additions of hydrogen to maintain a pressure of 1500 psi. After 15 hours no more hydrogen was being consumed by the reaction. The temperature was held for an additional six hours and then the clave was cooled and the gases were vented. The liquid was washed with water, saturated sodium thiosulfate solution, and then analyzed by GC/IR. Analysis showed that it contained 0.5% 1,1,1,4,4,4-hexafluorobutane, 85% 2 chloro-1,1,1,4,4,4-hexafluorobutane, and 13.5% of 2,3-dichloro-1,1,1,4,4,4-hexafluorobutane as two isomers. Distillation on a concentric tube column gave 78 g of 2-chloro-1,1,1,4,4,4-hexafluorobutane, and 25 g of 2,3 -dichloro-1,1,1,4,4,4-hexafluorobutane as two isomers.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:20][O:21][C:22]1[C:23]([CH3:30])=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=[O:26]>C1COCC1>[OH:26][CH:25]([C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[C:23]=1[CH3:30])[CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C:13]1=[O:19]
Reactant: O=C1CCCCC1
Reactant: COc1cccc(C=O)c1C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cccc(C(O)C2CCCCC2=O)c1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To a solution of diisopropylamine (1.44 ml) in THF (8 ml) was added n-BuLi (1.56M solution in hexane, 70 ml) at −60° C. The mixture was warmed to 0° C., stirred for 10 minutes, and recooled to −60° C. To the mixture was added cyclohexanone (0.98 g) in THF (5 ml). After stirring for 1 hour, 3-methoxy-2-methylbenzaldehyde (1.5 g) was added and the mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was quenched with saturated NH4Cl solution, warmed to room temperature, extracted with EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 4:1 to 2:1) to give 2-[hydroxy-(3-methoxy-2-methylphenyl)methyl]cyclohexanone (1.86 g) as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[C:8](=O)[CH2:9][S:10][C:11]1[NH:12][N:13]=[CH:14][C:15](=[O:17])[N:16]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:8]2[N:12]3[N:13]=[CH:14][C:15](=[O:17])[N:16]=[C:11]3[S:10][CH:9]=2)[CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)CSc2nc(=O)cn[nH]2)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(-c2csc3nc(=O)cnn23)cc(C(C)(C)C)c1O

Procedure:
3.7 g (0.01 mol) of 3-[(3,5-di-tert.butyl-4-hydroxyphenacyl)-thio]-2H-1,2,4-triazin-5-one from step (b1) were stirred for 36 hours at room temperature in a mixture of 60 ml of tetrahydrofuran and 50 ml of 2N hydrochloric acid. The cyclocondensation product which slowly precipitated out was filtered off and recrystallized once to three times from tetrachydrofuran/ethanol (3:2).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1.Br[C:34]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:35]=1[CH2:36][CH2:37][N:38]([S:44]([NH:47][C:48]1[S:49][C:50]([F:53])=[CH:51][N:52]=1)(=[O:46])=[O:45])[CH2:39]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[F:53][C:50]1[S:49][C:48]([NH:47][S:44]([N:38]2[CH2:37][CH2:36][C:35]3[C:40](=[CH:41][CH:42]=[CH:43][C:34]=3[C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][C:10]=3[C:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:21][CH:20]=3)[CH2:39]2)(=[O:46])=[O:45])=[N:52][CH:51]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(Nc1ncc(F)s1)N1CCc2c(Br)cccc2C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3c2CCN(S(=O)(=O)Nc2ncc(F)s2)C3)CC1
Yield: 25.9 %

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.027 g, 0.038 mmol), tert-butyl 4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate K, 0.260 g, 0.574 mmol), 5-bromo-N-(5-fluorothiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (Intermediate I, 0.150 g, 0.382 mmol), and potassium phosphate (0.325 g, 1.530 mmol) in 2.5 mL dioxane, 1 mL water was heated to 100° C. 2 hours. The reaction mixture was diluted with EtOAc and washed with 1 N citric acid solution. The organics were dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave tert-butyl 4-(2-(2-(N-(5-fluorothiazol-2-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.063 g, 0.099 mmol). This material was taken up in 1 mL THF, was treated with HCl 4N in dioxane (1.912 ml, 7.65 mmol) and was allowed to stir at room temperature overnight. The reaction mixture was concentrated yielding N-(5-fluorothiazol-2-yl)-5-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride (0.063 g, 0.117 mmol). [M+H]+=538.8 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.82 (br. s., 2H), 7.73 (d, J=7.9 Hz, 1H), 7.60 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.30 (s, 1H), 7.25 (d, J=4.7 Hz, 2H), 7.02 (t, J=4.5 Hz, 1H), 5.71 (br. s., 1H), 4.29 (s, 2H), 3.62-3.68 (m, 1H), 3.53-3.59 (m, 2H), 3.37-3.44 (m, 1H), 3.18-3.28 (m, 2H), 2.85-3.07 (m, 2H), 2.06-2.20 (m, 1H), 1.92-2.02 (m, 1H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=1.[Br:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[Br:20][C:21]1[CH:26]=[C:25]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=3)[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1F
Reactant: OB(O)c1cccc(Br)c1
Product: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1F

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidine (example A.46) (1.50 g, 5.1 mmol) and commercially available 3-bromo-benzene-boronic acid (1.23 g, 6.12 mmol) according to the general procedure IVb. Obtained as a white solid (1.23 g, 58%). MS (EI) 416.0 [(M)+]; mp 103° C.
Reaction SMILES: [CH2:1]1[CH2:11][CH2:10]N2C(=NCCC2)[CH2:3][CH2:2]1.BrCCCCCBr.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[C:28]3[C:37]4[C:32](=[CH:33][C:34]([O:40][CH3:41])=[C:35]([O:38][CH3:39])[CH:36]=4)[CH2:31][CH2:30][N:29]3[C:42]=2[CH3:43])[CH:23]=[CH:24][CH:25]=1>CN(C=O)C>[CH3:41][O:40][C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][C:35]=1[O:38][CH3:39])[C:28]1=[C:27]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([N:19]4[CH2:10][CH2:11][CH2:1][CH2:2][CH2:3]4)[CH:21]=3)=[C:42]([CH3:43])[N:29]1[CH2:30][CH2:31]2
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(=O)c1c(-c2cccc(N)c2)c(C)n2c1-c1cc(OC)c(OC)cc1CC2
Agent: BrCCCCCBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2cccc(N3CCCCC3)c2)c(C)n2c1-c1cc(OC)c(OC)cc1CC2
Temperature: 120 °C
Reaction time: 20 h

Procedure:
168.5 mg (1.11 mmol) of DBU and 84.9 mg (0.37 mmol) of 1,5-dibromopentane were added to a solution of 150 mg (0.37 mmol) of ethyl 2-(3-aminophenyl)-8,9-dimethoxy-3-methyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate (Example 28) in 3 mL of DMF. The mixture was stirred at 120° C. for 20 hours, then evaporated under reduced pressure, and the residue was taken up in an ethyl acetate/water mixture. The layers were separated, the aqueous layer was extracted with ethyl acetate, and the combined organic phases were washed with water, dried over Na2SO4, and the solvent was evaporated under reduced pressure. Chromatography on a short silica gel column using a dichloromethane/ethyl acetate 10:1 mixture as eluant, followed by crystallization from diethyl ether gave the title compound.
Reaction SMILES: [C:1]([C:6]1(CC)[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])([O:3][CH2:4][CH3:5])=[O:2].[O-][CH2:15][CH3:16].[Na+]>>[CH2:15]([CH:8]1[CH2:9][CH2:10][CH:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[C:7]1=[O:11])[CH3:16]
Reactant: CCOC(=O)C1(CC)CCCC1=O
Reactant: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C1CCC(CC)C1=O

Procedure:
2-Carboethoxy-2-ethyl-cyclopentanone is reacted with sodium ethoxide to produce 2-ethyl-5-carboethoxycyclopentanone. (J. Org. Chem. 29, 2782 (1964))
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl.CCN(CC)CC>CCOC(C)=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([O:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[N:6][CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cncc(O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.31 g (2 mmol) of 5-hydroxy-nicotinic acid methyl ester, 0.73 g (4 mmol) of copper acetate, ˜1 g of 4 Å molecular sieves and 0.85 g (7 mmol) of phenylboronic acid were combined in a flask charged with 20 mL of DCM and 2.0 mL (14 mmol) of Et3N. This reaction slurry was stirred overnight at r.t. The reaction mixture was then diluted with 200 mL of EtOAc and washed 3 times with 10% K2CO3. The organic layer was then dried with Na2SO4, evaporated and purified by flash column chromatography (EtOAc/hexanes=1:2) to give 5-phenoxy-nicotinic acid methyl ester, which was subsequently hydrolyzed according to general procedure B to give 5-phenoxy-nicotinic acid and used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]([O:28][C:29]([N:31]([CH3:40])[C@@H:32]([C@@H:36]([CH3:39])[CH2:37][CH3:38])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:33](=[O:34])[C@@H:32]([N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:30])[CH3:40])[C@@H:36]([CH3:39])[CH2:37][CH3:38])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC[C@H](C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CC[C@H](C)[C@@H](C(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC)N(C)C(=O)OC(C)(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (2S,3S)-2-(tert-butoxycarbonyl-methyl-amino)-3-methyl-pentanoic acid to yield (3aR,4S,7aR)-4-[(2S,3S)-2-(tert-butoxycarbonyl-methyl-amino)-3-methyl-pentanoyloxy]-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. This NBoc-protected product was then stirred in hydrochloric acid dioxane solution (4M, 10 equiv.) at room temperature for 6 hrs. Subsequently the solvent was removed the residue dissolved in dichloromethane and washed with saturated sodium hydrogencarbonate solution. The organic layer was tried with sodium sulfate, filtrated and evaporated. The crude product was subjected to silica gel flash chromatography (ISCO CombiFlash; dichloromethane/methanol; 100/0 to 95/5) to yield (3aR,4S,7aR)-4-((2S,3S)-3-methyl-2-methylamino-pentanoyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=5.213 min; HPLC Method I
Reaction SMILES: [CH:1]1([P:7]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)([C@@H:9]2[CH2:13][NH:12][C@H:11]([CH2:14][P:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=O)[CH2:10]2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[SiH](Cl)Cl>C(#N)C>[CH:29]1([P:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C@@H:9]2[CH2:13][NH:12][C@H:11]([CH2:14][P:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:10]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=P(C[C@@H]1C[C@H](P(=O)(C2CCCCC2)C2CCCCC2)CN1)(c1ccccc1)c1ccccc1
Agent: Cl[SiH](Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: c1ccc(P(C[C@@H]2C[C@H](P(C3CCCCC3)C3CCCCC3)CN2)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
In 4 ml of acetonitrile were dissolved 50 mg (0.1 m-mol) of (2S,4S)-4-dicyclohexylphosphinyl-2-diphenylphosphinylmethylpyrrolidine [X] and 42 mg (0.42 m-mol) of triethylamine, and the air in the reaction vessel was satisfactorily replaced with nitrogen. A solution of 54 mg (0.4 m-mol) of trichlorosilane in 1 ml of acetonitrile was added dropwise to the above solution under ice-cooling. After refluxing the mixture for 3 hours, the mixture was concentrated under reduced pressure at a low temperature. The residual product was dissolved in 15 ml of benzene, and 10 ml of a 30% aqueous solution of caustic soda was added to the benzene solution under ice-cooling. The mixture was stirred in nitrogen atmosphere for 30 minutes at 50°60° C. The benzene phase was separated and the aqueous phase was extracted with 10 ml of benzene. The benzene phases are combined, washed with 10 ml of water, dried over magnesium sulfate and concentrated under reduced pressure whereby 44 mg (yield: 95%) of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9](=[N:12][N+:13]([O-:15])=[O:14])[S:10][CH3:11])=[CH:5][N:6]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].Cl>N1C=CC=CC=1>[C:16]([N:8]([CH2:7][C:4]1[S:3][C:2]([Cl:1])=[N:6][CH:5]=1)[C:9](=[N:12][N+:13]([O-:15])=[O:14])[S:10][CH3:11])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CSC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Agent: Cl
Solvent: c1ccncc1
Product: CSC(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A mixture consisting of 1 g N-(2-chloro-5-thiazolylmethyl)-S-methyl-N'-nitroisothiourea, 1.15 g acetic anhydride and 25 ml pyridine was stirred at room temperature for 3 hours. The reaction mixture was added into an aqueous hydrochloric acid solution (concentrated hydrochloric acid 20 ml, water 50 ml, ice 10 g) for separation into layers. The resultant aqueous layer was extracted with 120 ml of chloroform, while the resultant organic layers were combined together, dried over magnesium sulfate and concentrated to afford 1.15 g of N-acetyl-N-(2-chloro-5-thiazolylmethyl)-S-methyl-N'-nitroisothiourea as a brown crystal, mp 77°-78° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@@H:9]1[C:21](=[O:35])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])=[CH:25][C:24]=1[F:34])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:31][N:30]([CH3:32])[C:29]([C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:21]([C@H:9]2[CH2:10][C@@H:11]([OH:13])[CH2:12][NH:8]2)=[O:35])=[C:24]([F:34])[CH:25]=1)=[O:33]
Reactant: CN(C)C(=O)c1ccc(NC(=O)[C@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1ccc(NC(=O)[C@H]2C[C@@H](O)CN2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
Into a solution of 6 (0.33 g, 0.647 mmol) in anhydrous CH2Cl2 (10 mL) was added TFA (2 mL). The solution was stirred at RT for 4 h before concentrating under reduced pressure to give 7 (0.19 g, 100%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].C(O)=[O:11].O>>[Br:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=CO
Reactant: Cc1ccnc(Cl)c1Br
Solvent: O
Product: Cc1cc[nH]c(=O)c1Br
Temperature: 120 °C
Reaction time: 72 h

Procedure:
To a resealable pressure vessel charged with 3-bromo-2-chloro-4-picoline (1.200 g, 5.81 mmol) was added formic acid (13.1 ml, 348 mmol) and water (4.00 ml, 222 mmol). The tube was sealed and the solution heated to 120° C. After 72 hrs, the solution was cooled to RT and concentrated in vacuo. The residue was purified by reverse phase chromatography (neutral) to afford 3-bromo-4-methylpyridin-2(1H)-one as a white solid. M+H+=188.0.
Reaction SMILES: [C:1]1([O:7][P:8]([O:17][C@@H:18]2[C@@H:30]([CH2:31][O:32][C:33]([O:35][C:36]([CH3:42])([CH3:41])[C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34])[O:29][C@@H:21](OCC[Si](C)(C)C)[C@H:20]([NH:43][C:44]([O:46][CH2:47][C:48]([Cl:51])([Cl:50])[Cl:49])=[O:45])[C@H:19]2[O:52][C:53](=[O:83])[CH2:54][C@H:55]([O:67][C:68](=[O:82])[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC(Cl)[Cl:87]>C(Cl)(Cl)Cl.CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[C:1]1([O:7][P:8]([O:17][C@@H:18]2[C@@H:30]([CH2:31][O:32][C:33]([O:35][C:36]([CH3:41])([CH3:42])[C:37]([Cl:38])([Cl:40])[Cl:39])=[O:34])[O:29][C@H:21]([Cl:87])[C@H:20]([NH:43][C:44]([O:46][CH2:47][C:48]([Cl:50])([Cl:49])[Cl:51])=[O:45])[C@H:19]2[O:52][C:53](=[O:83])[CH2:54][C@H:55]([O:67][C:68](=[O:82])[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O[C@@H]1[C@@H](NC(=O)OCC(Cl)(Cl)Cl)[C@H](OCC[Si](C)(C)C)O[C@H](COC(=O)OC(C)(C)C(Cl)(Cl)Cl)[C@H]1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COC(Cl)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O[C@@H]1[C@@H](NC(=O)OCC(Cl)(Cl)Cl)[C@@H](Cl)O[C@H](COC(=O)OC(C)(C)C(Cl)(Cl)Cl)[C@H]1OP(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A solution of the compound 8 (6.5 g, 4.84 mmol) and dichloromethyl methyl ether (2.18 ml, 24.2 mmol) in CHCl3 (60 ml) at 0° C. was treated with ZnCl2 (1.0 M in ether; 2.41 ml, 2.41 mmol) and then allowed to warm slowly and stir at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with saturated aq. NaHCO3, dried (Na2SO4) and then concentrated. The light yellow oil obtained was purified by flash chromatography on silica gel eluting with 10% EtOAc-hexanes to give 5.4 g (88%) of 2-deoxy-4-O-diphenylphosphono-3-O-[(R)-3-tetradecanoyloxytetradecanoyl]-6-O-(2,2,2-trichloro- 1,1 -dimethylethoxycarbonyl)-2-(2,2,2-trichloroethoxycarbonylamino)-α-D-glucopyranosyl chloride (compound 9) as an amorphous solid: 1H NMR (CDCl3) δ0.88 (˜t, 6H), 1.1-1.6 (m, 42H), 1.78 (s, 3H), 1.88 (s, 3H), 2.18 (t, 2H, J=7.6 Hz), 2.34-2.52 (m, 2H), 4.2-4.4 (m, 4H), 4.70 (d, 1H, J=12 Hz), 4.73 (d, 1H, J=12 Hz), 4.83 (˜q, 1H, J=9 Hz), 5.09 (m, 1H), 5.51 (˜t, 1H J=10 Hz), 5.79 (d, 1H, J=8.0 Hz), 6.26 (d, 1H, J=3.6 Hz), 7.1-7.4 (m, 10H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:23][CH2:22][CH2:21][C:16]=3[N:17]=[C:18](Cl)[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]3[S:23][CH2:22][CH2:21][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3c2SCC3)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2SCC3)CC1
Yield: 38.2 %

Procedure:
200 mg 4-(2-Chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester and 200 mg Raney-nickel in 20 mL methanol was stirred at 65° C. for 10 h under 4 bar hydrogen atmosphere. The reaction was filtered and the filtrate was evaporated. The residue was purified by HPLC to give 69 mg of the desired product. (M+H)+: 323/324, Rt: 1.58 min (method AD)