Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2([CH:10]3[CH2:12][CH2:11]3)[CH2:8][CH:7](O)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.CS([Cl:17])(=O)=O.[I-].[Na+].[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>CC(C)=O.C(N(CC)CC)C>[ClH:17].[C:20]([NH:24][CH:7]1[CH2:8][C:4]([CH:10]2[CH2:12][CH2:11]2)([CH:1]2[CH2:3][CH2:2]2)[CH:5]=[CH:6]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CS(=O)(=O)Cl
Reactant: OC1C=CC(C2CC2)(C2CC2)C1
Reactant: CC(C)(C)N
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)NC1C=CC(C2CC2)(C2CC2)C1
Product: Cl
Reaction time: 0.17 h

Procedure:
To a solution of 4,4-dicyclopropyl-2-cyclopenten-1-ol (0.52 g) in acetone (5 ml) were added methanesulfonyl chloride (0.27 ml) and triethylamine (0.49 ml) with ice bath cooling. After being stirred for 10 minutes, sodium iodide (0.52 g) was added thereto, and the mixture was stirred for 10 minutes. To the mixture was added t-butylamine (6.4 ml), and the mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, and then cold water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was dissolved in ethyl acetate, and hydrogen chloride in ethanol (8.9N, 0.5 ml) was added thereto, and evaporated in vacuo. The residue was crystallized from diethyl ether to give N-t-butyl-4,4-dicyclopropyl-2-cyclopentenylamine hydrochloride (0.51 g). These crystals were recrystallized from a mixture of isopropyl alcohol and ethyl acetate to give pure one (0.41 g).
Reaction SMILES: CN(C(ON1N=N[C:11]2C=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.NC1(C#N)CCN(C)CC1.CN1CC[O:49]CC1.[C:52]([O:55]CC)(=[O:54])C>CN(C=O)C>[N:15]1([C:52]([OH:55])=[O:54])[CH2:10][CH2:11][O:49][CH2:13][CH2:14]1
Reactant: CN1CCOCC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(C)=O
Agent: CN1CCC(N)(C#N)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: O=C(O)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (R)-3-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-2-[(1-morpholin-4-ylmethanoyl)amino]propionic acid (200 mg, 0.473 mmol), provided as in Reference 1, in CH2Cl2 (3 mL) was combined with HATU (270 mg, 0.71 mmol), HOAt (64.3 mg, 0.473 mmol), 4-amino-1-methyl-piperidine-4-carbonitrile (98 mg, 0.71 mmol), N-methylmorpholine (0.156 mL, 1.42 mmol) and them DMF (3 mL) to obtain a homogenous solution. The mixture was stirred at room temperature for 16 hours, diluted with ethyl acetate (150 mL), washed with saturated aqueous NaHCO3 and then brine, dried (MgSO4) and concentrated. The product was purified from the residue by flash chromatography to provide morpholine-4-carboxylic acid {(R)-1-(4-cyano-1-methyl-piperidin4-ylcarbamoyl)-2-[2-(1,1-difluoro-methoxy-phenylmethanesulfonyl]-ethyl}-amide. 1H NMR: (DMSO) 8.62 (s, 1H), 7.51-7.23 (m, 4H), 7.13 (t, JH,F=74 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 4.70 (m, 1H), 4.57 (s, 2H), 3.57-3.25 (m, 10 H), 2.62-1.82 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[C:5](=[O:16])O[C:3]=1[C:17]([OH:19])=[O:18].[CH2:20]([NH2:23])[CH2:21][CH3:22].Cl>CCO.O.S(=O)(=O)(O)O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[C:5](=[O:16])[N:23]([CH2:20][CH2:21][CH3:22])[C:3]=1[C:17]([OH:19])=[O:18]
Reactant: Cc1c(C(=O)O)oc(=O)c2cc(C(F)(F)F)ccc12
Reactant: CCCN
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCCn1c(C(=O)O)c(C)c2ccc(C(F)(F)F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
A solution of 350 mg (1.3 mmol) 4-methyl-1-oxo-7-(trifluoromethyl)-1H-isochromene-3-carboxylic acid in EtOH (15 ml) was cooled to 0° C. and treated dropwise with a solution of 1.1 ml (12.9 mmol) n-propylamine in EtOH (2 ml) at this temperature. The RS was then stirred at RT for 2 h followed by concentration in vacuo. The residue obtained was diluted with water and acidified with 2M hydrochloric acid to pH˜2 while cooling (ice-water-bath). Afterwards the RS was extracted with a MeOH/EtOAc mixture (1:9 v/v, 100 ml). The organic layer was washed with water (30 ml) and brine (20 ml), dried over Na2SO4 and concentrated in vacuo. This residue obtained was diluted with EtOH (15 ml) and 1 ml conc. sulfuric acid was added slowly at 0° C. The RS was the heated at 80° C. for 2 h. After cooling to RT, the RS was concentrated in vacuo. The residue obtained was diluted with water and extracted with a MeOH/EtOAc mixture (1:9 v/v, 100 ml). The organic layer was washed with water (30 ml) and brine (20 ml), dried over Na2SO4 and concentrated in vacuo to give 360 mg (1.1 mmo, 89%) 4-methyl-1-oxo-2-propyl-7-(trifluoromethyl)-1,2-dihydroisoquinoline-3-carboxylic acid, which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:25][O:26][CH3:27])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1>>[CH:1]1([CH:7]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=2)[C:9]2[C:10]([CH2:25][O:26][CH3:27])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: COCc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 36.6 %

Procedure:
Using cyclohexyl{3-(methoxymethyl)-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}methanol (0.75 g) synthesized in Example 33(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.59 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.42 g, 39%) was obtained as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][O:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[Br:14][C:15]1[N:19]2[N:20]=[C:21](Cl)[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1.[F-].[K+]>CS(C)=O>[Br:14][C:15]1[N:19]2[N:20]=[C:21]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH:8]3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1
Reactant: Fc1cccc(C2COCCN2)c1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1cccc(C2COCCN2c2ccc3ncc(Br)n3n2)c1
Temperature: 180 °C

Procedure:
In step 2-5, a suspension of 3-(3-fluorophenyl)morpholine (1.59 g, 6.9 mmol), 3-bromo-6-chloroimidazo[1,2-b]pyridazine (12-1) (1.5 g, 8.29 mmol) and potassium fluoride (1.6 g, 27.6 mmol) in DMSO (6 mL) was heated at 180° C. for 18 hours while stirring. The resulting solution was cooled to room temperature and purified with HPLC to yield 4-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-3-(3-fluorophenyl)morpholine (2-5) as a yellow foam.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[CH:5][CH:4]=[C:3]([OH:15])[CH:2]=1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>>[OH:15][C:3]1[CH:2]=[CH:1][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:18](=[O:19])[N:17]([CH3:16])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Product: CN(C(=O)Oc1ccc(Cc2ccc(O)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4,4′-dihydroxydiphenylmethane and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (21%, white crystals which turn red after standing). HPLC-MS: m/z=324.2 (M+1); Rt: 4.21 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-:9].[Na+].[CH:11](Cl)(Cl)Cl.S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[OH:8])[CH:11]=[O:9]
Reactant: ClC(Cl)Cl
Reactant: Oc1ccccc1F
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=Cc1ccc(O)c(F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 5.6 %

Procedure:
On the other hand, o-fluorophenol (500 g, 4.46 mols) was added to a solution of NaOH (1,250 g, 31.26 mols) dissolved in water (2 l), followed by dropwise adding chloroform (1,230 g), agitating the mixture at about 60° C. for 2 hours, acidifying it with sulfuric acid, filtering off the residue on heating, and recrystallizing the deposited crystals from a mixed solvent of water-methanol to obtain 3-fluoro-4-hydroxybenzaldehyde (35.3 g) having a m.p. of 119.5°~123.5° C. This product (30 g, 0.21 mol) was dissolved in methanol (300 ml), followed by adding and dissolving KOH (12 g, 0.21 mol), dropwise adding optically active p-toluenesulfonic acid 1-methyl-heptyl ester (65 g, 0.23 mol) prepared above, keeping the mixture under reflux for 4 hours, cooling, adding toluene (200 ml) and 6N-HCl (100 ml), washing the resulting toluene layer with 2N-NaOH aqueous solution, further washing with water till the washing layer became neutral, and distilling off toluene to obtain as residue, optically active 3-fluoro-4-(1-methyl-heptyloxy)-benzaldehyde (14.7 g). This product (10 g, 0.04 mol) was dissolved in acetic acid (200 ml), followed by dropwise adding a solution of chromic anhydride (4 g, 0.04 mol) dissolved in acetic acid (50 ml) and water (40 ml), agitating the mixture at 40°~50° C. for about 6 hours, pouring the resulting reaction material in ice water and filtering off the deposited crystals to obtain optically active 3-fluoro-4-(1-methyl-heptyloxy-benzoic acid (6.1 g) having a m.p. of 57.2°~59.2° C., adding thionyl chloride (4.2 g, 0.035 mol) to the above product (6 g, 0.022 mol), heating the mixture under reflux with stirring for one hour, and distilling off excess thionyl chloride to obtain optically active 3-fluoro-4-(1-methyl-heptyloxy)benzoic acid chloride (6.1 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:29])([CH3:28])[CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)=[CH:6][CH:5]=1)[CH3:2].ClC1C=C(C(C)(C)COCC2C=CC(F)=C(OC3C=CC=CC=3)C=2)C=CC=1OCC>C1C=CC=CC=1>[O:21]([C:16]1[CH:15]=[C:14]([CH3:13])[CH:19]=[CH:18][C:17]=1[F:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:28])([CH3:29])[CH2:11][OH:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(C)(C)COCc2ccc(F)c(Oc3ccccc3)c2)cc1
Agent: CCOc1ccc(C(C)(C)COCc2ccc(F)c(Oc3ccccc3)c2)cc1Cl
Solvent: c1ccccc1
Product: CCOc1ccc(C(C)(C)CO)cc1
Product: Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C

Procedure:
The reaction mixture was cooled to room temperature and the residual pressure was released, and 100 ml of benzene was added into the autoclave to dissolve the oily portion. Then, the catalyst was removed by filtration, and the filtrate was sufficiently shaken and allowed to stand still to cause phase separation. Then, the obtained benzene layer was washed with 100 ml of water three times and benzene was removed by distillation under reduced pressure to give an oily product. From the results of the analysis of the oily product by gas chromatography according to the internal standard method, it was found that the oily product comprised 98.2% of 3-phenoxy-4-fluorobenzyl 2-(4-ethoxyphenyl)-2-methylpropyl ether and 0.7% of starting 3-phenoxy-4-fluorobenzyl 2-(3-chloro-4-ethoxyphenyl)-2-methylpropyl ether, and that the content of each of 3-phenoxy-4-fluorotoluene and 4-ethoxyneophyl alcohol formed by cleaving of the ether linkage was lower than 0.2%. Moreover, 0.8% of 3-phenoxybenzyl 2-(4-ethoxyphenyl)-2-methylpropyl ether presumed to have been formed by reduction of the fluorine atom was contained.
Reaction SMILES: [CH3:1][N:2]([C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:3].C1C=CC(P2([Se]P(C3C=CC=CC=3)(=[Se])[Se]2)=[Se:19])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:4](=[Se:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:3]
Reactant: CN(N)C(=O)c1ccccc1
Reactant: [Se]=P1(c2ccccc2)[Se]P(=[Se])(c2ccccc2)[Se]1
Solvent: Cc1ccccc1
Product: CN(N)C(=[Se])c1ccccc1
Temperature: 25 °C
Yield: 194.7 %

Procedure:
A mixture of N-methylbenzohydrazide (450 mg, 3.0 mmol) and the Woollins' Reagent (540 mg, 1 mmol) in anhydrous toluene (10 ml), was heated at 120° C. for 1 h. The resulting orange solution was cooled to room temperature, the solvent was removed in vacuo and the selenoamide purified by column chromatography on silica gel (3:1 Hexane:EtOAc) and to give N-methylbenzoselenohydrazide (415 mg) in 65% yield.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4].[CH3:12][O:13][C:14]1[N:19]=[CH:18][C:17]([CH:20]([NH:32][C:33]2[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=2)[C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:21](=[O:31])[O:22][C@@H:23]2[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[CH:16][CH:15]=1>CCOC(C)=O>[Br-:1].[CH2:39]([O:38][C:36]([C:35]1[CH:34]=[C:33]([NH:32][CH:20]([C:17]2[CH:18]=[N:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[C:21]([O:22][C@@H:23]2[CH:28]3[CH2:29][CH2:30][N+:25]([CH2:2][C:3]([C:5]4[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=4)=[O:4])([CH2:26][CH2:27]3)[CH2:24]2)=[O:31])[CH:43]=[CH:42][CH:41]=1)=[O:37])[CH3:40]
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccc(OC)nc2)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2C[N+]3(CC(=O)c4ccc(O)cc4)CCC2CC3)c2ccc(OC)nc2)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
2-Bromo-1-(4-hydroxyphenyl)ethanone (24.5 mg, 0.11 mmol) was added to a solution of ethyl 3-(1-(6-methoxypyridin-3-yl)-2-oxo-2-((R)-quinuclidin-3-yloxy)ethylamino)benzoate (C65) (50 mg, 0.11 mmol) in EtOAc (2 ml). The reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was triturated with Et2O, filtered and dried. The product was purified by flash-chromatography (DCM/MeOH=97/3 to 9/1) to obtain (3R)-3-(2-(3-(ethoxycarbonyl)phenylamino)-2-(6-methoxypyridin-3-yl)acetoxy)-1-(2-(4-hydroxyphenyl)-2-oxoethyl)-1-azoniabicyclo[2.2.2]octane bromide (37.3 mg, 50.1% yield).
Reaction SMILES: [Na].[C:2]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:3][C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:5].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].C(O)(=O)C>C(O)C>[CH3:17][N:18]([CH:20]=[C:3]([C:4](=[O:5])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:2]([O:12][CH2:13][CH3:14])=[O:11])[CH3:19]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)C(=CN(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To a solution of diethyl oxalacetate sodium salt (100 g, 476 mmol) in ethanol (250.00 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (113 g, 952 mmol) and the reaction was stirred at room temperature for 30 min. Acetic acid (54.5 mL, 952 mmol) was added slowly over a period of 3 h and stirred at room temperature for 24 h. The volatile components were evaporated under reduced pressure and the oily residue was purified by silica gel chromatography (750 g REDISEP® column, eluting with 30% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 104A (43 g, 30.8%). MS(ES): m/z=244 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 7.84 (s, 1H), 4.31 (q, J=7.2 Hz, 2H), 4.18 (q, J=5.4 Hz, 2H), 3.35 (s, 3H), 3.04 (s, 3H), 1.36 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:40])[CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]#[C:23][CH3:24])[C:16]([N:25]3[CH2:30][CH2:29][CH2:28][CH:27]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26]3)=[N:15][C:14]=2[N:13]([CH3:39])[C:11]1=[O:12].[C:41](=[O:44])([O-])[O-:42].[K+].[K+].O>CN(C)C=O>[C:35]([O:42][C:41]([NH:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:40])[CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]#[C:23][CH3:24])[C:16]([N:25]3[CH2:30][CH2:29][CH2:28][CH:27]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:26]3)=[N:15][C:14]=2[N:13]([CH3:39])[C:11]1=[O:12])=[O:44])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1O)c(=O)n2C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1OCCNC(=O)OC(C)(C)C)c(=O)n2C
Temperature: 55 °C
Reaction time: 8 h

Procedure:
187 mg of tert.-butyl 2-bromo-ethyl-carbaminate are added to 400 mg of 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine and 150 mg of potassium carbonate in 6 ml N,N-dimethylformamide and the reaction mixture is stirred overnight at 55° C. Then a further 90 mg of tert.-butyl 2-bromo-ethyl-carbaminate are added. After another eight hours at 55° C. the reaction is complete. The cooled reaction mixture is combined with water, the precipitate formed is suction filtered, washed with water and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)=[O:6].Br[CH:28]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:36][CH:35]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(OCC)(=O)C.O>ClCCl>[CH2:40]([C:37]1[CH:36]=[CH:35][C:34]([CH:28]([NH:1][C:2]2[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=2)[C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=2)=[O:6])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:39][CH:38]=1)[CH:41]([CH3:43])[CH3:42]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cccc(N)c2)c2ccccc21
Reactant: CCCCCC(Br)c1ccc(CC(C)C)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCC(Nc1cccc(C(=O)c2cn(CCCC(=O)OCC)c3ccccc23)c1)c1ccc(CC(C)C)cc1
Yield: 54.4 %

Procedure:
A mixture of ethyl 4-[3-(3-aminobenzoyl)indol-1-yl]-butyrate (176 mg), 1-(1-bromohexyl)-4-isobutylbenzene (233 mg) and diisopropytethylamine (194 mg) in dichloromethane (5 ml) was refluxed for 20 hours. The reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was separated and washed-with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel column eluting with a mixture of n-hexane-and ethyl acetate (3:1) to give ethyl 4-[3-[3-[1-(4-isobutylphenyl)hexylamino]benzoyl]-indol-1-yl]butyrate (155 mg) as an oil.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:54]#[N:55])[C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[C:28](=[O:53])[N:29]([C@H:40]4[CH2:45][CH2:44][C@H:43]([O:46][CH:47]([CH3:52])[C:48]([OH:51])([CH3:50])[CH3:49])[CH2:42][CH2:41]4)[C:30]4[N:31]([N:36]=[C:37]([CH3:39])[N:38]=4)[C:32]=3[CH2:33][CH2:34][CH3:35])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1>C(OCC)(=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][C:27]3[C:28](=[O:53])[N:29]([C@H:40]4[CH2:45][CH2:44][C@H:43]([O:46][CH:47]([CH3:52])[C:48]([OH:51])([CH3:49])[CH3:50])[CH2:42][CH2:41]4)[C:30]4[N:31]([N:36]=[C:37]([CH3:39])[N:38]=4)[C:32]=3[CH2:33][CH2:34][CH3:35])=[CH:24][CH:25]=2)=[C:16]([C:54]2[NH:3][C:4](=[O:7])[O:5][N:55]=2)[CH:15]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccc(F)cc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2nc(C)nn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccc(F)cc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.43 g), sodium hydrogen carbonate (0.69 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4-fluoro-4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.24 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.079 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.067 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.15 g, 56%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@:12]2([F:20])[CH3:19])=[C:4]([N:21]2[CH2:24][CH2:23][CH2:22]2)[N:3]=1.N1C=NN=N1.C(#N)C.C(N([CH:40]([O:48][P:49](N)[O-:50])N(C(C)C)C(C)C)C(C)C)(C)C>N1C=CC=CC=1>[P:49]([OH:50])([OH:15])[OH:48].[N:21]1([C:4]2[N:3]=[C:2]([NH2:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[O:15][C@H:14]3[C@@H:13]([O:18][P:49]([O:48][CH3:40])[O:17][CH2:16]3)[C@:12]2([F:20])[CH3:19])[CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)N(C(C)C)C(OP(N)[O-])N(C(C)C)C(C)C
Reactant: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N3CCC3)nc(N)nc21
Agent: c1nnn[nH]1
Solvent: CC#N
Solvent: c1ccncc1
Product: COP1OC[C@H]2O[C@@H](n3cnc4c(N5CCC5)nc(N)nc43)[C@](C)(F)[C@@H]2O1
Product: OP(O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 12 %

Procedure:
(2R,3R,4R,5R)-5-(2-Amino-6-azetidin-1-yl -purin-9-yl)-4-fluoro-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-ol (14, 340 mg, 1.0 mmol) was dissolved in anhydrous pyridine (6 ml) at ambient temperature. A solution of 0.45 M 1H -tetrazole in acetonitrile (5.5 mL, 2.5 mmol) was added followed by bis (N,N-diisopropylamino)methylphosphoramidite (317 μL, 1.1 mmol). The mixture was stirred at ambient temperature for 17 h. The solvent was concentrated under reduced pressure and the residue was triturated with ethyl acetate (20 mL). The resulting precipitant of salts was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of ethyl acetate in hexanes (40-80%). The product containing fractions were combined and concentrated to a white solid, 47 mg (12% yield).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.I(O)(=O)(=O)=[O:15].S(OS([O-])=O)([O-])=O.[Na+].[Na+]>C(#N)C.C(Cl)Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH:1]1([S:4]([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:15])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(SC2CC2)cc1
Reactant: [O-][I+3]([O-])([O-])O
Agent: Cl[Fe](Cl)Cl
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.3 %

Procedure:
350 mg of 1-(cyclopropylsulfanyl)-4-nitrobenzene is dissolved in 5 ml of acetonitrile and mixed with 10 mg of iron(III)-chloride hexahydrate. After 10 minutes of stirring at room temperature, 450 mg of periodic acid is added thereto while being cooled. The mixture is stirred for 30 minutes at room temperature, cooled in an ice bath and mixed drop by drop with semi-saturated sodium disulfite solution. It is diluted with methylene chloride, washed with water, sodium bicarbonate solution and saturated sodium chloride solution, and concentrated by evaporation. After purification by flash chromatography, 270 mg of (RS)-1-(cyclopropylsulfinyl)-4-nitrobenzene is obtained.