Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1)[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]2([CH3:18])[CH3:17].[CH2:19](O)[C:20]([CH3:23])([CH3:22])[CH3:21].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:19][C:20]([CH3:23])([CH3:22])[CH2:21][O:13][C:12]([C:10]1[CH:11]=[C:2]([Br:1])[CH:3]=[C:4]2[C:9]=1[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]2([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)CO
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(C(=O)O)c2O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)COC(=O)c1cc(Br)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
A stirred cooled (ice bath) solution of 6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid (Intermediate 41, 0.5 g, 1.6 mmol), neopentylalcohol (0.35 mL, 3.2 mmol) and 4-(dimethylamino)pyridine (0.03 g, 0.24 mmol) in anhydrous dichloromethane (5 mL) was treated with 1,3-dicyclohexylcarbodiimide (0.36 g, 1.76 mmol) and the reaction mixture was allowed to warm to ambient temperature. After 2 h, the reaction mixture was filtered, the filtrate was diluted with ethyl acetate and washed with 2N hydrochloric acid, 2N sodium hydroxide, and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a yellow solid (0.537 g, 88%).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][C:15]1[S:19][C:18]([C:20](O)=[O:21])=[CH:17][CH:16]=1>>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:20]([C:18]2[S:19][C:15]([Cl:14])=[CH:16][CH:17]=2)=[O:21])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: O=C(O)c1ccc(Cl)s1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc(Cl)s2)C1

Procedure:
6.1 Using general procedure D (R)-1-Boc-3-aminopyrrolidine was coupled with 5-chlorothiophene-2-carboxylic acid to give (R)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester. Yellow solid. MS 329.3 ([M−H]−)
Reaction SMILES: [OH:1][CH:2]([CH2:6][OH:7])[CH2:3][C:4]#[N:5].C([Sn](=O)CCCC)CCC.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O>[OH:1][CH:2]([CH2:6][O:7][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])[CH2:3][C:4]#[N:5]
Reactant: N#CCC(O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(O)CC#N)cc1
Reaction time: 2 h

Procedure:
tosylating 3,4-dihydroxybutanenitrile by reacting 3,4-dihydroxybutanenitrile with dibutyltinoxide, p-toluene sulphonyl chloride and a base in the presence of an organic solvent, at a temperature ranging between 25-30° C. under nitrogen atmosphere, for a period of 1-3 hrs., adding water to the above said reaction mixture and separating the organic layer, followed by concentration and purification by known method to obtain the racemic 3-hydroxy-4-tosyloxybutanenitrile, ii) resoluting racemic 3-hydroxy-4-tosyloxybutanenitrile with an acetylating agent in the presence of lipase in an organic solvent, at a temperature of 25-30° C. followed by filtration and washing to obtain (R)-3-hydroxy-4-tosyloxybutanenitrile, iii) converting (R)-3-hydroxy-4-tosyloxybutanenitrile (R)-GABOB and (R)-carnitine by reacting it with a base in an organic solvent under reflux for an overnight period followed by evaporation, adding concentrated HCl to the resultant residue and heating to a temperature in the range of 60-90° C., for a period of about 6 hr followed by evaporation and purification by known method to obtain the desired product.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].[Cl:13][C:14]1[C:15]([F:23])=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C.C1(C)C=CC=CC=1>[Cl:13][C:14]1[C:15]([F:23])=[C:16]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][C:3]=2[OH:12])[CH:17]=[CH:18][CH:19]=1
Reactant: Oc1ccc2ccccc2c1Br
Reactant: OB(O)c1cccc(Cl)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCO
Product: Oc1ccc2ccccc2c1-c1cccc(Cl)c1F

Procedure:
Into a 200 mL three-neck flask were put 5.8 g (26 mmol) of 1-bromo-2-naphthol, 4.5 g (26 mmol) of 3-chloro-2-fluorobenzeneboronic acid, and 0.40 g (1.3 mol) of tri(ortho-tolyl)phosphine, and the air in the flask was replaced with nitrogen. To this mixture were added 150 mL of toluene, 50 mL of ethanol, and 21 mL of an aqueous solution of potassium carbonate (2.0 mol/L). The mixture was degassed by being stirred while the pressure in the flask was reduced, and then the air in the flask was replaced with nitrogen. To this mixture was added 58 mg (0.26 mmol) of palladium(II) acetate, and the resulting mixture was stirred at 90° C. under a nitrogen stream for 7 hours.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]([C:12](=[O:27])[NH:13][C:14]2[S:15][C:16]([CH2:25]O)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[C:42]([N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>ClCCl>[C:45]([O:44][C:42]([N:49]1[CH2:54][CH2:53][N:52]([CH2:25][C:16]2[S:15][C:14]([NH:13][C:12](=[O:27])[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:29][CH:28]=3)([CH3:11])[CH3:10])=[N:18][C:17]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:51][CH2:50]1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccccc2)c(CO)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2sc(NC(=O)C(C)(C)NC(=O)c3ccc(F)cc3)nc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-Fluoro-N-[1-(5-hydroxymethyl-4-phenyl-thiazol-2-ylcarbamoyl)-1-methyl-ethyl]-benzamide (82 mg, 0.20 mmol), MsCl (40 uL) and triethylamine (160 uL) in dichloromethane (3 mL) was stirred at RT for 20 min and concentrated. The residue was taken up in MeCN (5 mL), and N-Boc piperazine (120 mg, 0.644 mmol) and triethylamine (160 uL) were added. The mixture was stirred at RT for 20 min and partitioned between ethyl acetate and aq. K2CO3. The combined organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 582.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([C:15]1[N:19]([CH3:20])[C:18]([C:21]2[CH:26]=[CH:25][C:24](F)=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])=[N:17][N:16]=1)([CH3:14])[CH3:13])[C:5]([NH2:7])=[O:6].[CH3:32][S-:33].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([CH3:14])([C:15]1[N:19]([CH3:20])[C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:33][CH3:32])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])=[N:17][N:16]=1)[CH3:13])[C:5]([NH2:7])=[O:6]
Reactant: Cn1c(-c2ccc(F)cc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(C(N)=O)cc1Br
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(-c2nnc(C(C)(C)Oc3ccc(C(N)=O)cc3Br)n2C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
3-bromo-4-(1-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1-methylethoxy}benzamide (300 mg) was dissolved in DMF (6 ml), and sodium thiomethoxide (210 mg) was added thereto, followed by stirring at room temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid was washed with ethyl acetate to obtain, as a white solid, 3-bromo-4-(1-methyl-1-{4-methyl-5-[4-(methylsulfanyl)-2-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl}ethoxy]benzamide (163 mg).
Reaction SMILES: [CH2:1]([Li])CCC.[F:6][C:7]([F:25])([F:24])[C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:21])=O)[CH:14]=2)[C:11](=[S:22])[N:10]([CH3:23])[N:9]=1.[OH-].[Na+]>CCCCCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[F:6][C:7]([F:25])([F:24])[C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:1])=[CH2:21])[CH:14]=2)[C:11](=[S:22])[N:10]([CH3:23])[N:9]=1
Reactant: CC(=O)c1cccc(-n2c(C(F)(F)F)nn(C)c2=S)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(C)c1cccc(-n2c(C(F)(F)F)nn(C)c2=S)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under a dry nitrogen atmosphere 23.8 ml of a 1.55M solution of n-butyllithium in hexane was added dropwise to a stirred solution of 15.8 g (0.0443 mole) of methyltriphenylphosphonium bromide in 300 ml of dry tetrahydrofuran. This mixture was stirred at room temperature for 2.5 hours, and a solution of 11.1 g of the oil from Step B in 50 ml of tetrahydrofuran was added dropwise. After complete addition, the reaction mixture was heated at reflux for 2.5 hours. The mixture was cooled to room temperature and was poured into 300 ml of an aqueous, 2N sodium hydroxide solution. This mixture was extracted with 300 ml of diethyl ether. The organic extract was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure, leaving a residue. This residue was purified by column chromatography on silica gel eluting with ethyl acetate:n-heptane (25:75) to yield 3.7 g of 3-trifluoromethyl-4,5-dihydro-1-methyl-4-[3-(1-methylethenyl)phenyl]-1,2,4-triazol-5(1 H)-thione as a solid, mp 64°-66° C., Compound 27 of Table 1.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:33])[C:19]([C:28]([O:30]CC)=[O:29])=[CH:20][N:21]3C(C)(C)C)=[CH:16][C:15]=2[F:34])[CH2:10]1)=O)(C)(C)C.[ClH:35].C(OCC)C>C(O)C>[ClH:35].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:33])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][NH:21]3)=[CH:16][C:15]=2[F:34])[CH2:10]1
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: N[C@@H]1CCN(c2nc3[nH]cc(C(=O)O)c(=O)c3cc2F)C1
Temperature: 120 °C

Procedure:
A suspension of EXAMPLE 15B (260 mg) in ethanol (60 mL) was treated with HCl gas to saturation, heated at 120° C. for 18 hours then cooled, treated with diethyl ether and filtered to provide the desired product. NMR (300 MHz, DMSO-d6) δ 13.32 (d, 1H), 8.42 (d, 1H), 8.36 (br s, 3H), 8.02 (d, 1H), 4.05-3.83 (m, 5H), 2.44-2.25 (m, 1H), 2.20-2.12 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([CH2:14]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36].CO>CN(C)C(=O)C.ClCCl.C(OCC)(=O)C>[Br:36][CH2:14][C@@H:10]1[C@@H:11]([OH:13])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)[C@@H](O)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](CBr)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 67.5 %

Procedure:
(3R,4R)-(1-tert-Butoxycarbonyl-4-hydroxypyrrolidin-3-yl)methanol (3.64 g) and triphenylphosphine (4.41 g) were dissolved in N,N-dimethylacetamide (84 mL). While the solution was chilled in an ice water bath, carbon tetrabromide (5.57 g) in dichloromethane (16 mL) was added dropwise. The mixture was stirred at room temperature for 13 hours, followed by addition of methanol (8 mL) and concentration under reduced pressure. The resulting residue was dissolved in ethyl acetate (300 mL), washed sequentially with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate: hexane=2:1) to give (3S,4R)-3-bromomethyl-1-tert-butoxycarbonyl-4-hydroxypyrrolidine as a milky white syrup (3.17 g).
Reaction SMILES: [CH:1]([NH:3][C:4]1[N:9]=[C:8]([CH2:10][C:11]([O:13]CC)=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2].[OH-].[Na+].O.Cl>C(O)C>[CH:1]([NH:3][C:4]1[N:9]=[C:8]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: CCOC(=O)Cc1cccc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=CNc1cccc(CC(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution of ethyl 2-(6-formamidopyridin-2-yl)acetate (4.4 g.) in ethanol (44 ml.) was added 2 N sodium hydroxide solution [solvent:water (1 part)+ethanol (4 parts] (15.9 ml.) at 18° to 20° C. over 30 minutes, and then the solution was stirred at room temperature for one hour. After 1 N hydrochloric acid (31.7 ml.) was added to the solution, the solution was concentrated under reduced pressure. The residue was extracted with hot ethyl acetate (500 ml.) and the extract was concentrated under reduced pressure. The residue was washed with ethyl acetate to give 2-(6-formamidopyridin-2-yl)acetic acid (2.5 g.), mp 125° to 126° C. (dec.).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=2)[O:5][CH2:4][CH2:3]1.O.NN>C(O)C.[Pd]>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[N:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC1CCOc2cccc(Oc3ccc([N+](=O)[O-])cn3)c21
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC1CCOc2cccc(Oc3ccc(N)cn3)c21
Temperature: 90 °C
Yield: 111.7 %

Procedure:
In a 50 mL round-bottomed flask 2-(4-methylchroman-5-yl)oxy-5-nitro-pyridine (Intermediate 212, 22.9 mg, 0.08 mmol) was dissolved in Ethanol (10 mL) to give a pale yellow solution. Pd/C (17.88 mg, 0.017 mmol) and hydrazine hydrate (0.4 mL, 4.15 mmol) were added. The reaction mixture was stirred at 90° C. The reaction mixture was filtered and evaporated in vacuo to give the title compound (22.9 mg) as a pale yellow oil.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH2:6]([CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][OH:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:6]([CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][O:15][P:1]([Cl:5])([Cl:3])=[O:2])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCCCC(CO)CCCCCCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCC(CCCCCCC)COP(=O)(Cl)Cl
Temperature: -10 °C
Yield: 34.7 %

Procedure:
With nitrogen substitution, 540 ml of toluene and 138.0 grams (0.9 moles) of phosphorus oxychloride were added and cooled to −10 degrees C. To this mixture, a solution of 243.5 grams (0.9 moles; 1.0 in molar ratio) of 2-heptylundecanol and 91.1 grams (0.9 moles) of triethylamine was dripped, and the mixture was reacted for 12 hours at 0 degrees C. The mixture was then heated to 25 degrees C., and a triethylamine hydrochloride was removed by filtering to obtain 1003.9 grams of a toluene solution of (2-heptylundecyl)dichlorophosphate (34.7% in concentration).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C1([B:15]2[O:23][C:20]([CH3:22])([CH3:21])[C:17]([CH3:19])([CH3:18])[O:16]2)C=CC=CC=1>>[CH3:18][C:17]1([CH3:19])[C:20]([CH3:22])([CH3:21])[O:23][B:15]([C:7]2[CH:2]=[C:3]([OH:8])[CH:4]=[CH:5][CH:6]=2)[O:16]1
Reactant: Oc1ccccc1I
Reactant: CC1(C)OB(c2ccccc2)OC1(C)C
Product: CC1(C)OB(c2cccc(O)c2)OC1(C)C

Procedure:
The above reaction procedure used for 2-iodophenol was followed. The reaction was faster, being complete before the first sample for gc analysis was withdrawn after 1 h 50 min reaction time. The amount of phenylboronic acid pinacol ester was higher than in the 2-iodophenol reaction (around 7%).
Reaction SMILES: [CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].BrCCBr.S([N:46]=[N+:47]=[N-:48])(C1C=CC(C)=CC=1)(=O)=O.O.O.O.O.O.O.O.O.O.O.[O-]P(OP([O-])([O-])=O)(=O)[O-].[Na+].[Na+].[Na+].[Na+].[K+].[Br-]>C1COCC1.C(OCC)C.O>[CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([N:46]=[N+:47]=[N-:48])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: O=P([O-])([O-])OP(=O)([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(N=[N+]=[N-])ccc1OCc1ccccc1)C(C)C
Reaction time: 4 h

Procedure:
To a mixture of (R)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanamine (10.00 g, 20.81 mmol) (prepared as described in WO 94/11337, Example 1) and Mg (1.57 g, 64.52 mmol) in THF (50 mL) was added 1,2-dibromoethane (3.59 mL, 41.63 mmol) and the solution was self-refluxing for a while. The mixture was refluxed for 1 h whereafter the solution was cooled and tosyl azide (4.10 g, 20.81 mmol) in diethyl ether (100 mL) was added with constant stirring while keeping the temperature at 0° C. wherafter the temperature was allowed to rise to room temperature for 4 h. A solution of tetra-sodium pyrophosphate decahydrate (4.46 g, 10.00 mmol) in 50 mL water was added. A precipitate was filtered off and the filtrate was evaporated. The residue was extracted with diethyl ether, the organic phase was dried (MgSO4) and evaporated. The residue was chromatographed on silica (n-hexane-ethanol, 8:2). The product was crystallised from ethanol to give 1.15 g (13%); IR (KBr) 2116 (N3) cm−1; 1H NMR (CDCl3) δ0.92 (d, 12H), 2.10 (m, 2H), 2.33 (m, 2H), 2.95 (m, 2H), 4.40 (t, 1H), 5.00 (s, 2H), 6.81 (d, 2H), 6.97 (s, 1H), 7.10-7.40 (m, 10H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=S)[O:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].Cl.Cl.[NH:18]1[CH2:22][CH2:21][C@@H:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19]1>C1(C)C=CC=CC=1.ClCCl>[CH2:1]([NH:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([N:18]3[CH2:22][CH2:21][C@@H:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[CH2:19]3)[O:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1ccc2[nH]c(=S)oc2c1
Reactant: C1CCN([C@@H]2CCNC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCNC(=O)c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)oc2c1
Temperature: 130 °C

Procedure:
N-Ethyl-2-thioxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide (Example 93A, 56 mg, 0.253 mmol) and (R)-1-(pyrrolidin-3-yl)piperidine (Reference Example 5c, 39 mg, 253 mmol) were combined in toluene (1 mL) and heated to 130° C. for one hour. The reaction mixture was diluted with dichloromethane, washed with a 1 N aqueous solution of sodium hydroxide, and the organic layer was absorbed on silica gel. The crude mixture was purified using silica gel chromatography (12 g column) eluting with a gradient of methanol/dichloromethane (1-18%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.26 (t, J=7.34 Hz, 3 H) 1.40-1.53 (m, 2 H) 1.59-1.69 (m, 4 H) 1.89-2.07 (m, 1 H) 2.22-2.35 (m, 1 H) 2.36-2.60 (m, 4 H) 2.89-3.03 (m, 1 H) 3.42-3.58 (m, 3 H) 3.59-3.68 (m, 1 H) 3.82-3.92 (m, 1 H) 3.97 (dd, J=10.11, 7.34 Hz, 1 H) 5.98-6.11 (m, 1 H) 7.31 (d, J=8.33 Hz, 1 H) 7.53 (dd, J=8.33, 1.59 Hz, 1 H) 7.78 (d, J=1.59 Hz, 1 H); MS (ESI+) m/z 343.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][C:4]=1[NH2:12])#[CH:2].S(=O)(=O)(O)[OH:14].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][C:4]=1[N:12]=[O:14])#[CH:2]
Reactant: C#Cc1ccc(C(N)=O)cc1N
Reactant: O=S(=O)(O)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: C#Cc1ccc(C(N)=O)cc1N=O
Reaction time: 0.05 h
Yield: 12 %

Procedure:
0.46 g (2.87 mmol) 4-ethynyl-3-aminobenzamide (Compound XI-1), 10 ml water, were added into a 50 ml single-neck flask, then 1.2 g 58% sulfuric acid was added, and then 0.92 g 18.5% potassium dichromate solution. The mixture was stirred for 3 minutes until completing the reaction, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 0.06 g 4-ethynyl-3-nitrosobenzamide (Compound I-28, yellow-green solid), yield 12%, stored at −20° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[C:30](=[O:41])[N:29]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[CH:28]=1>C1COCC1>[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[C:30](=[O:41])[N:29]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[CH:28]=1
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: COc1ccc(Cn2cc(Cl)c3ccc(S(=O)(=O)Cl)cc3c2=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)cn(Cc4ccc(OC)cc4)c(=O)c3c2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 48.9 %

Procedure:
A round-bottom flask was charged with N-(4-methoxybenzyl)thiazol-2-amine (0.213 g, 0.967 mmol) and THF (4.40 mL), and the vessel was cooled to −78° C. for 15 minutes. LHMDS (1.0 M in THF) (1.055 mL, 1.055 mmol) was then added drop wise over 1 minute. The reaction was stirred for 10 minutes, and then a solution of 4-chloro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-7-sulfonyl chloride (0.350 g, 0.879 mmol) in THF (1.60 mL) was added drop wise. The bath was removed, and the resulting mixture was stirred for 45 minutes, until complete conversion to 4-chloro-N,2-bis(4-methoxybenzyl)-1-oxo-N-(thiazol-2-yl)-1,2-dihydroisoquinoline-7-sulfonamide. The reaction was diluted with saturated ammonium chloride (aq.) solution (30 mL), and was washed with ethyl acetate (20 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting material was purified via silica gel chromatography (ISCO, 40 g), eluting with 0 to 100% ethyl acetate in heptanes to provide 0.250 g of 4-chloro-N,2-bis(4-methoxybenzyl)-1-oxo-N-(thiazol-2-yl)-1,2-dihydroisoquinoline-7-sulfonamide. m/z (ESI) 583.2 (M+H)+.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=1[O:35][CH2:36][C:37]([F:40])([F:39])[F:38]>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:22][CH2:23][N:24]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[CH2:25][CH2:26]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Reactant: Nc1ncnc(Cl)c1OCC(F)(F)F
Product: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4OCC(F)(F)F)CC3)n2)ccn1

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “1” by using 4-[1-(2-azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H -imidazol-4-yl]-2-isopropyl-pyridine and 6-chloro-5-(2,2,2-trifluoro-ethoxy)-pyrimidin-4-ylamine as the starting materials. LC-MS (M+H=545, obsd=545).
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[N:15]=[C:14]([CH3:16])[O:13][N:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@H:22]1[O:24][CH2:23]1)(=O)=O>>[CH2:21]([O:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[N:15]=[C:14]([CH3:16])[O:13][N:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:22]1[O:24][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: Cc1nc(-c2cc3c(O)cccc3o2)no1
Product: Cc1nc(-c2cc3c(OC[C@@H]4CO4)cccc3o2)no1
Yield: 47.6 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 3-(4-hydroxybenzo(b)furan-2-yl)-5-methyl-1,2,4-oxadiazole (0.75 g) and (S)-glycidyl nosylate (0.93 g), the title compound (0.45 g) was obtained as white crystals.