Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([CH:16]1[CH2:20][CH2:19][N:18](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].C1(O)C=CC=CC=1.[OH-].[Na+].CO>Br.O.CCCCCC.C1(C)C=CC=CC=1>[C:1]([C:3]([CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)N2CCC(C(C#N)(c3ccccc3)c3ccccc3)C2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: Oc1ccccc1
Solvent: CO
Product: N#CC(c1ccccc1)(c1ccccc1)C1CCNC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-(R,S)-(1-cyano-1,1-diphenylmethyl)-1-tosylpyrrolidine (21 g--see Preparation 6(A)) and phenol (21 g) in 48% aqueous hydrobromic acid (240 ml) was heated under reflux for 2 hours. The mixture was cooled to 0° C. in an ice bath and basified (pH 12) by the slow addition of 50% aqueous sodium hydroxide (280 ml). Methanol (10 ml) was added and the mixture was stirred for 15 minutes then diluted with water (300 ml). The mixture was extracted with dichloromethane (3×200 ml), the combined extracts were dried (MgSO4) and concentrated in vacuo to give an oil. The oil was dissolved in 1:1 hexane/toluene (500 ml) and washed with 0.5 M hydrochloric acid (3×500 ml). The aqueous extracts, together with some oil which separated during the extraction, were basified (pit 12) by the addition of aqueous sodium hydroxide (12 g in 20 ml water) and the mixture was extracted with dichloromethane (3×150 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a oil, yield 10 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[SH:13].CS(O[CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[S:13][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=c1[nH]cc(S)c2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(Sc2c[nH]c(=O)c3ccc(Br)cc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
To 6-bromo-4-sulfanylisoquinolin-1(2H)-one (Example 58a, 0.62 g) was added tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (0.676 g) and potassium carbonate (0.769 g). After thoroughly flushing with nitrogen, DMF (6 mL) was added and the reaction stirred at room temperature for 30 min. Further DMF (9 mL) was added, and the reaction stirred at 40° C. for 1 h. Further DMF (10 mL) was added and the reaction stirred at 50° C. for 16 h. The reaction was partitioned between ethyl acetate and water. The aqueous was extracted with further ethyl acetate (3×) and the combined organics were washed with saturated brine (3×100 mL). The organics were dried (MgSO4), filtered and evaporated under reduced pressure. DCM was added, and the resulting suspension was filtered. The filtrate was concentrated under reduced pressure, dissolved in the minimum volume of DCM and purified (SiO2 chromatography, elution with 50%-100% diethyl ether/isohexane followed by ethyl acetate flush) to afford the subtitle compound (0.353 g).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=O)[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:51]1[CH2:56][CH:55]=[C:54]([C:57]2[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=2)[C:60]#[N:61])[CH2:53][CH2:52]1>CN(C)C=O>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([N:51]3[CH2:52][CH:53]=[C:54]([C:57]4[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=4)[C:60]#[N:61])[CH2:55][CH2:56]3)=[O:17])[CH:12]=[N:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Reactant: N#Cc1cccc(C2=CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(C2=CCN(C(=O)c3cncc(C#Cc4ccccc4)c3)CC2)c1
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
A solution of 5-phenylethynyl-pyridine-3-carboxylic acid (0.46 g, 2.1 mmol) in anhydrous dimethylformamide (7 ml) is treated with HATU (0.78 g, 2.1 mmol) and diisopropylethylamine (0.98 ml, 5.6 mmol). The reaction mixture is stirred 15 mins. at ambient temperature before being treated with a solution of 3-(1,2,3,6-tetrahydropyridin-4-yl)-benzonitrile (1.9 mmol) in dimethylformamide (6 ml). The reaction mixture is stirred at ambient temperature 3 hours, concentrated under vacuum and the residue partitioned between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate ((45 ml). The organic layer is dried (magnesium sulfate), concentrated under vacuum and the residue chromatographed on silica gel (dichloromethane/methanol 39:1) to give 3-[1-(5-phenylethynyl-pyridine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-benzonitrile as a yellow oil (0.23 g). This material is dissolved in methanol (15 ml), cooled to 0° C. and saturated with hydrogen chloride gas. The reaction vessel is sealed and allowed to stand at 0° C. for 18 hours. The reaction mixture is concentrated to dryness under vacuum, redissolved in methanol (15 ml) and cooled to 0° C. The solution is saturated with ammonia gas and the vessel sealed before being allowed to stand at 0° C. for 48 hours. The reaction mixture is concentrated to dryness under vacuum and the residue chromatographed on silica gel (dichloromethane/methanol 9:1) to give the title compound as a yellow amorphous solid (0.2 g). 1H NMR (DMSO, 500 MHz) δ8.85 (s, 1H), 8.67 (s, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.80 (m, 1H), 7.75 (m, 1H), 7.60 (m, 3H), 7.48 (m, 3H), 6.38 (m, 1H), 4.38 (br m, 1H), 4.19 (br m, 1H), 3.90 (br m, 1H), 3.60 (br m, 1H), 2.63 (br m, 2H). EI MS M++H: 407.
Reaction SMILES: [CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[CH2:29][CH2:28][C:12]3([C:17]4=[CH:18][CH:19]=[CH:20][N:16]4[C:15]4[CH:21]=[CH:22][C:23]([C:25](O)=[O:26])=[CH:24][C:14]=4[O:13]3)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:32][CH3:33])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+]>O1CCCC1.O>[CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[CH2:10][CH2:11][C:12]3([O:13][C:14]4[CH:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][C:15]=4[N:16]4[CH:20]=[CH:19][CH:18]=[C:17]34)[CH2:28][CH2:29]2)=[O:8])=[CH:5][C:4]=1[O:32][CH3:33])[CH3:2]
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)O)ccc2-n2cccc23)cc1OC
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(CO)ccc2-n2cccc23)cc1OC
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To 1-(4-ethyl-3-methoxy-benzoyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-7′-carboxylic acid (550 mg, 1.2 mmol) in tetrahydrofuran (2.2 mL) at 0° C. was added triethylamine (200 μL, 1.4 mmol) then isobutyl chloroformate (180 μL, 1.4 mmol). The mixture was stirred for 30 min then filtered. The filtrate was added dropwise to a solution of sodium borohydride (70 mg, 1.8 mmol) in water (770 μL) at 0° C. The mixture was allowed to slowly reach room temperature before it was concentrated to ⅓ volume, diluted with ethyl acetate and washed with 1M HCl. The organics were dried over sodium sulfate, filtered and evaporated to yield (4-ethyl-3-methoxyphenyl)(7-(hydroxymethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (330 mg, 62%). ESI-MS m/z calc. 432.5. found 433.5 (M+1)+; Retention time: 1.78 minutes (3 min run).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:3]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36].[Br:37][C:38]1[CH:47]=[CH:46][C:41]([O:42][CH2:43][CH2:44][OH:45])=[CH:40][CH:39]=1>>[Br:37][C:38]1[CH:47]=[CH:46][C:41]([O:42][CH2:43][CH2:44][O:45][C:2]2[N:7]=[C:6]([C:8]3[N:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[N:5]=[C:4]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:3]=2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])=[CH:40][CH:39]=1
Reactant: OCCOc1ccc(Br)cc1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCOc1ccc(Br)cc1

Procedure:
N-{6-Chloro-2-(2-pyrimidyl)-5-(2-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide and 2-(4-bromophenoxy)ethanol are treated in the same manner as in Example 192-(1) to give N-{6-{2-(4-bromophenoxy)ethoxy}-2-(2-pyrimidyl)-5-(2-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide.
Reaction SMILES: [C:1]1([P:7](=[O:10])([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2:21]>O>[C:1]1([P:7](=[O:8])([O-:10])[O-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cu+2:21]
Reactant: O=P(O)(O)c1ccccc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: O=P([O-])([O-])c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
130 parts of phenylphosphonic acid was dissolved in 1350 parts of water. To the resulting solution was added 103 parts of copper sulfate pentahydrate, and the resulting mixture was stirred for two hours at room temperature. The precipitate was filtered, washed with water, and then dried under reduced pressure at 100° C., yielding 35 parts of copper phenylphosphonate.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[CH2:26][C:27]([OH:29])=[O:28].C(N(CC)CC)C>O>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26](=[CH:14][C:13]1[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=1)[C:27]([OH:29])=[O:28]
Reactant: O=C(O)Cc1ccc(F)cc1F
Reactant: CSc1ccc(C=O)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CSc1ccc(C=C(C(=O)O)c2ccc(F)cc2F)cc1
Temperature: 90 °C
Yield: 42.2 %

Procedure:
A mixture of acetic anhydride (50 mL), 4-(methylthio)benzaldehyde (3.75 g, 24.6 mmol), 2,4-difluorophenylacetic acid (4.41 g, 24.6 mmol), and triethylamine (2.80 g, 27.7 mmol) was heated to reflux for 3.5 hours. The reaction was cooled to 90° C., and water (100 mL) was added through an addition funnel. A yellow oil formed that solidified upon stirring. The solid was collected by filtration, and dissolved in ethyl acetate, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The solid thus obtained was recrystallized from toluene to give the desired acid (3.18 g, 42%): mp 165°-171° C. 1H NMR (acetone-d6) 300 MHz 7.95 (s,1H), 7.08-7.18 (m, 7H), 2.47 and 2.31 (s, 3H); 19F NMR (acetone-d6) -110.81 (m) -111.75 (m). Mass spectrum: M+H=306.
Reaction SMILES: [CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([OH:23])=[O:22])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl.[CH3:25]O>>[CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH3:25])=[O:22])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Reactant: CO
Agent: Cl
Product: CCCCCCCCCCCc1cc2ccc(C(=O)OC)cc2[nH]1

Procedure:
A solution of 2-(n-undecyl)indole-6-carboxylic acid (15.0 g) in methanol (200 ml) containing aqueous hydrochloric acid (10 ml of strength 36.5% w/v) was refluxed for 8 hours. The solution was concentrated in vacuo to about one half of its volume, diluted with diethyl ether (300 ml) and washed with water. The solution was dried over magnesium sulphate, then evaporated in vacuo and the residue was recrystallised from methanol to give methyl 2-(n-undecyl)indole-6-carboxylate (10.5 g), in the form of an off-white powder, m.p. 84°-86° C.
Reaction SMILES: [SH2:1].[S].[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=[CH2:4]>>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:3]([SH:1])[CH3:4]
Reactant: S
Reactant: C=Cc1ccccn1
Agent: [S]
Product: CC(S)c1ccccn1

Procedure:
The reaction using hydrogen sulfide as the sulfur-containing compound is as follows. That is, vinyl pyridine is reacted with hydrogen sulfide to obtain pyridylethanethiol represented by the above general formula (3) as the pyridylethylthio compound.
Reaction SMILES: O(C(C)(C)C)[Na].[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[CH3:8]>C(O)(C)C>[CH3:8][CH:7]([OH:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)c1ccccc1
Agent: CC(C)(C)O[Na]
Solvent: CC(C)O
Product: CC(O)c1ccccc1
Temperature: 30 °C
Reaction time: 16.5 h

Procedure:
Into a 100-mL stainless-steel autoclave was put 24.0 mg (0.03 mmol) of [CuCl((R,R)-SKEWPHOS) (PPh3)]n obtained in Example 27, triphenyl phosphine of the amount shown in Table 6 below, and 28.8 mg (0.30 mmol) of NaO-t-Bu, followed by replacing with nitrogen in the autoclave, and then 2.0 mL of isopropyl alcohol and 1.05 mL (9.0 mmol) of acetophenone were added. The reaction was carried out with stirring under a hydrogen pressure of 5 MPa at 30° C. for 16 to 17 hours to give 1-phenethyl alcohol which is a hydrogenated compound of acetophenone. The reaction mixture was analyzed by using GC. The results are shown in Table 6.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[N:14]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][N:16]=[CH:15]1>C(O)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=1[C:7]([NH:22][CH2:21][CH2:20][CH2:19][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:9]
Reactant: NCCCn1ccnc1
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Solvent: CCO
Product: Nc1ccc(Br)cc1C(=O)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 9.68 g of 5-bromoisatoic anhydride, 5.0 g of 1H-imidazol-1-propanamine and 75 ml of ethanol was stirred at room temperature for 20 hours and concentrated. The residue was washed onto a filter with ethanol and washed with ether for the desired product, mp 154°-156° C.
Reaction SMILES: O.[OH-].[Li+].[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:10][CH2:11][C:12]#[C:13][CH:14]=[CH:15][C:16]#[C:17][Si](C)(C)C.CCCCCC>O1CCCC1.O.CCOCC>[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:10][CH2:11][C:12]#[C:13][CH:14]=[CH:15][C:16]#[CH:17]
Reactant: C[Si](C)(C)C#CC=CC#CCOC1CCCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: C#CC=CC#CCOC1CCCCO1
Yield: 98 %

Procedure:
Lithium hydroxide monohydrate (22.55 g, 0.54 mol) was added in one portion to a solution of 21.62 g (82.38 mmol) silyl diynene (compound N of step (b)) in 240 mL tetrahydrofuran and 40 mL water stirring at 25° C. The reaction was stirred for 1.58h and then diluted with 1:1 ether:hexane and water. The aqueous layer was reextracted with three portions of ether and then the combined organic extracts were dried over anhydrous sodium sulfate. Flash chromatography over silica gel using a gradient of 2.5 to 10% ethyl acetate/hexane as eluent provided 15.69 g (98%) of brown liquid:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:34][N:33]=[C:32]([CH3:35])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[O:34][N:33]=[C:32]([CH3:35])[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(C(F)(F)F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (5-chloro-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M45) (0.20 g, 0.37 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (131 mg, 84%).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16].C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:13]([NH:17][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1)[CH2:14][CH2:15][CH3:16]
Reactant: Clc1nnnn1-c1ccccc1
Reactant: CCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCNc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
5-Chloro-1-phenyl-1H-tetrazole (1.00 g, 5.54 mmol), butylamine (0.547 mL, 5.54 mmol), and diisopropylethylamine (1.48 mL, 8.31 mmol) were dissolved in DMF (5 mL), and stirred overnight at room temperature. Reaction diluted with EtOAc and washed with water and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo. Residue purified by flash chromatography on silica gel eluting with 35% EtOAc/Hexanes to afford the desired product as a white solid (625 mg, 52%). m/e (DCI) 218 (MH+)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1([NH:19]C(=O)OC(C)(C)C)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:19][C:13]1([CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1(CNC(=O)OCc2ccccc2)CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(CNC(=O)OCc2ccccc2)CCOCC1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (4-(((benzyloxycarbonyl)amino)methyl)tetrahydro-2H-pyran-4-yl)carbamate (G16, 141 mg) in methylene chloride (2 mL), trifluoroacetic acid (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The solvent was evaporated under reduced pressure, and then ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the residue. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain benzyl ((4-aminotetrahydro-2H-pyran-4-yl)methyl)carbamate (G17, 106 mg).
Reaction SMILES: C([SiH](CC)CC)C.CC([Si](C)(C)O[C@H]1CC[C@H](C(OCC)=O)CC1)(C)C.[Bi](Br)(Br)Br.C1(C=O)CC1.C([O-])(O)=O.[Na+].[CH:41]1([CH2:44][O:45][C@H:46]2[CH2:51][CH2:50][C@H:49]([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:48][CH2:47]2)[CH2:43][CH2:42]1>C(#N)C>[CH:41]1([CH2:44][O:45][CH:46]2[CH2:51][CH2:50][CH:49]([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:48][CH2:47]2)[CH2:42][CH2:43]1
Reactant: CCOC(=O)[C@H]1CC[C@H](OCC2CC2)CC1
Agent: Br[Bi](Br)Br
Agent: CCOC(=O)[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: CCOC(=O)C1CCC(OCC2CC2)CC1
Reaction time: 1 h

Procedure:
Triethylsilane (10 mL, 63 mmol) was added to a solution of ethyl 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D1, 13.6 g, 47.4 mmol), bismuth tribromide (923 mg, 2.06 mmol) and cyclopropanecarbaldehyde (4.25 mL, 56.8 mmol) in acetonitrile (60 mL) at rt under Ar. A black precipitate and an exotherm occurred on the addition of the triethylsilane. The mixture was stirred for 1 h before being poured on to sat. NaHCO3 (200 mL). The reaction was extracted with EtOAc (2×) and the combined organics were washed (sat. NaCl), dried (Na2SO4) and concentrated by rotary evaporation to give a mixture of cis and trans ethyl 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylate (D42, 20.8 g, 97%, contained silyl residues) as a colourless oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][C:10]([CH2:15][NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])([CH3:14])[C:9]=3[O:22][C:4]=2[CH:3]=1.CC1C=CC2C=CC3C=CC(C)=NC=3C=2N=1.CN(C)C=O.[F:44][C:45]1[CH:46]=[C:47]([SH:51])[CH:48]=[CH:49][CH:50]=1.CC(C)([O-])C.[Na+]>[Cu]I>[F:44][C:45]1[CH:46]=[C:47]([S:51][C:2]2[CH:7]=[CH:6][C:5]3[C:8]4[CH2:13][CH2:12][NH:11][C:10]([CH2:15][NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])([CH3:14])[C:9]=4[O:22][C:4]=3[CH:3]=2)[CH:48]=[CH:49][CH:50]=1
Reactant: Fc1cccc(S)c1
Reactant: CC(C)C(=O)NCC1(C)NCCc2c1oc1cc(I)ccc21
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: Cc1ccc2ccc3ccc(C)nc3c2n1
Solvent: CN(C)C=O
Product: CC(C)C(=O)NCC1(C)NCCc2c1oc1cc(Sc3cccc(F)c3)ccc21
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To N-(7-iodo-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl)-isobutyramide (230 mg, 0.56 mmol), neocuproine (11.6 mg, 0.0558 mmol) and copper (I) iodide (53.1 mg, 0.279 mmol) was added dry N,N-dimethylformamide (4 mL, 50 mmol). 3-Fluorobenzenethiol (104 μL, 1.23 mmol) was added neat followed immediately by the addition of the sodium tert-butoxide (118 mg, 1.23 mmol). The reaction mixture was stirred at 100° C. After 48 h, the reaction mixture was cooled to room temperature and concentrated. The residual solid was partially dissolved into a 5% MeOH in DCE solution and flushed through a plug of Celite. The concentrated filtrate was chromatographed with DCM-MeOH—NH4OH to afford a brownish yellow gum. MS m/z 413 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cncc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
6.74 g (29.3 mmol) of ethyl 5-bromonicotinate, 8.35 g (43.9 mmol) of 4-trifluoromethylphenylboronic acid, 0.17 g (0.15 mmol) of tetrakis(triphenylphosphine)palladium(0) and 6.21 g (58.6 mmol) of sodium carbonate were dissolved in a mixture of 75 ml of 1,2-dimethoxyethane, 15 ml of water and 184 ml of dimethylformamide and stirred at 85° C. for 18 h. For work-up, some of the dimethylformamide was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulphate and the crude product was purified by flash chromatography (dichloromethane/acetonitrile 100:2→100:5). Yield: 6.22 g (72% of theory)
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([CH:7]([CH2:35][CH3:36])[CH:8]1[O:34][CH:9]1[C:10]1[N:14]=[CH:13][N:12](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:11]=1)[CH3:6].[ClH:37]>>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:5]([CH:7]([CH2:35][CH3:36])[CH:8]([OH:34])[CH:9]([Cl:37])[C:10]1[N:14]=[CH:13][NH:12][N:11]=1)[CH3:6]
Reactant: Cl
Reactant: CCC(CC)C1OC1c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=[PH](O)O
Product: CCC(CC)C(O)C(Cl)c1nc[nH]n1

Procedure:
Diethyl (2RS,3RS)-2,3-epoxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.39 g, prepared as described in Example 52) was treated with hydrochloric acid, as described in Example 53 for the (RS,SR) isomer, to give diethyl (2RS, 3RS)-3-chloro-2-hydroxy-3(1,2,4-triazol-3-yl)propane phosphonate (0.21 g) as a colourless oil, probably as its hydrochloride. NMR(D2O): δ 1.15(6H,t), 2.15(2H,m), 4.00(4H,m), 4.45(1H,m), 5.17(1H,d), 8.75(1H,s). (No internal standard, solvent signal at δ 4.67).