Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[C:6]1([C@H:16]([N:18]([CH2:26][CH:27]2[CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][NH:29][CH2:28]2)C(=O)OC(C)(C)C)[CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[CH3:38][S:39]([Cl:42])(=[O:41])=[O:40].C(N(CC)CC)C>O>[ClH:42].[CH3:38][S:39]([N:29]1[CH2:30][CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]([CH2:26][NH:18][C@@H:16]([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)[CH3:17])[CH2:28]1)(=[O:41])=[O:40]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H](NCC1CN(S(C)(=O)=O)CC1c1ccccc1)c1cccc2ccccc12
Product: Cl
Temperature: 50 °C

Procedure:
A 10 ml THF solution of 500 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl][(4-phenylpyrrolidin-3-yl)methyl]carbamate was mixed with 0.26 ml of methanesulfonyl chloride and stirred at 50° C. A 0.24 ml portion of triethylamine and 20 ml of water were added thereto, and the solvent was evaporated. This was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate, and the solvent was evaporated. The thus obtained residue was treated with 4 M hydrogen chloride/ethyl acetate solution and recrystallized from ethyl acetate-hexane to obtain 294 mg of (1R)—N-{[(methylsulfonyl)-4-phenylpyrrolidin-3-yl]methyl}-1-(1-naphthyl)ethanamine hydrochloride as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(O)[CH2:41]C[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH:26]2[CH2:39][CH2:38][CH2:37][CH2:41]2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3cc(C)c(NC(=O)OC4CCCC4)cc3C)c2cc1OC
Yield: 69.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cyclopentanol (20 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (47 mg, yield 61%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[Cl-].[Al+3].[Cl-].[Cl-].[Br:15][CH2:16][C:17](Br)=[O:18].O>ClCCl>[Br:15][CH2:16][C:17]([C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[F:1])[NH:8][CH:9]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: Fc1ccnc2[nH]ccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)c1c[nH]c2nccc(F)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-fluoro-1H-pyrrolo[2,3-b]pyridine (2.00 g, 0.0147 mol) (Org. Lett., 2003, 5, 5023-5025) in dichloromethane was added aluminum chloride (3.92 g, 0.0294 mol) in portions, the mixture was stirred at RT for 30 min, then bromoacetyl bromide (4.45 g, 0.022 mol) was added dropwise. The reaction mixture was stirred at 50° C. for 1 h, when TLC indicated no starting material. To the reaction mixture was added 150 mL water, and the resulting suspension was heated at 100° C. for 1 h, then filtered to afford the desired product, 90% pure. H NMR, DMSO-d6: 4.72(s, 2H), 7.12(m, 1H), 8.36(m, 1H), 8.67(s, 1H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][C:8]1[C:12]([CH3:13])=[C:11]([CH:14]=[O:15])[NH:10][C:9]=1[CH2:16][C:17]1[NH:18][C:19]([CH2:26][C:27]2[NH:28][C:29]([CH:40]=[O:41])=[C:30]([CH3:39])[C:31]=2[CH2:32][CH2:33][CH2:34][O:35]C(=O)C)=[C:20]([CH2:24][CH3:25])[C:21]=1[CH2:22][CH3:23])(=O)C.[Li+].[OH-]>CO>[CH:40]([C:29]1[NH:28][C:27]([CH2:26][C:19]2[NH:18][C:17]([CH2:16][C:9]3[NH:10][C:11]([CH:14]=[O:15])=[C:12]([CH3:13])[C:8]=3[CH2:7][CH2:6][CH2:5][OH:4])=[C:21]([CH2:22][CH3:23])[C:20]=2[CH2:24][CH3:25])=[C:31]([CH2:32][CH2:33][CH2:34][OH:35])[C:30]=1[CH3:39])=[O:41]
Reactant: CCc1c(Cc2[nH]c(C=O)c(C)c2CCCOC(C)=O)[nH]c(Cc2[nH]c(C=O)c(C)c2CCCOC(C)=O)c1CC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(Cc2[nH]c(C=O)c(C)c2CCCO)[nH]c(Cc2[nH]c(C=O)c(C)c2CCCO)c1CC
Temperature: 25 °C
Yield: 93.6 %

Procedure:
7H, FIG. 7B. 2,5-Bis[(3-acetoxypropyl-5-formyl-4-methylpyrrol-2-yl)methyl]-3,4-diethylpyrrole 7G (5.98 g, 0.011 mol) and LiOH (1.76 g, 0.042 mol) were added to 400 mL of 95% methanol, which had been degassed with nitrogen prior to use, and the mixture heated to reflux under a nitrogen atmosphere. The reaction became homogeneous when heated. After heating for 1.25 hours, the reaction was allowed to cool to room temperature. The product precipitated as a tan color solid as the reaction cooled. The volume of the reaction mixture was reduced to 75 mL on a rotary evaporator and the resulting slurry placed in the freezer for several hours. The product was filtered and then purified by forming a slurry with 400 mL of methanol and 50 mL of water and heating close to boiling. The slurry was first cooled to room temperature, reduced to 1/2 volume under reduced pressure, and placed in the freezer for several hours. The product was collected by filtration and vacuum dried to yield 4.96 g of a tan powder (94%): 1H NMR (CD3OD, 300 MHz): δ 0.96 (6 H, t, CH2CH3), 1.49 (4 H, p, CH2CH2CH2OH), 2.25 (6 H, s, pyrrole-CH3), 2.32-2.43 (8 H, m, CH2CH3 and CH2CH2CH2OH), 3.46 (4 H, t, CH2CH2CH2OH), 3.85 (4 H, s, (pyrrole)2 --CH2),9.34 (2 H, s, CHO); CI MS (M+) 480; HEMS (M)+ 481.2942 (calc for C28H39N3O4, 481.2941).
Reaction SMILES: CC1(C)C2C=C(C#C[C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)C=CC=2C(=O)CC1.[CH:27]1([O:33][CH:34]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([C:44]#[CH:45])[CH:42]=3)[C:37]([CH3:47])([CH3:46])[CH2:36][CH2:35]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([O:33][CH:34]2[CH2:35][CH2:36][C:37]([CH3:47])([CH3:46])[C:38]3[CH:39]=[CH:40][C:41]([C:44]#[C:45][C:14]4[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=4)=[CH:42][C:43]2=3)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C#Cc1ccc2c(c1)C(OC1CCCCC1)CCC2(C)C
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OC2CCCCC2)CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1), 90 mg (0.3 mmol) of 4-cyclohexyloxy-6-ethynyl-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound N) was converted into the title compound using 88 mg (0.32 mmol) of ethyl 4-iodobenzoate, 70 mg (0.1 mmol) of bis(triphenylphosphine)palladium(II) chloride and 19 mg (0.1 mmol) of cuprous iodide.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:37]=2)[C:32]([C:48]2[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=2)=[N:31]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[C:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[CH:34]=[C:33]4[C:38](=[CH:37][CH:36]=3)[N:30]([CH3:29])[N:31]=[C:32]4[C:48]3[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cn1nc(-c2ccncc2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(-c3ccncc3)nn4C)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a vial flushed with argon was added (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (100 mg, 0.207 mmol), 1-methyl-3-(pyridin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (53 mg, 0.16 mmol), Pd(PPh3)4 (18 mg, 16 μmol), and K2CO3 (66 mg, 0.47 mmol). De-gassed dioxane (2 mL) and water (0.5 mL) were then added, and the reaction was heated to 100° C. for 1 h. After cooling to 23° C., the reaction was filtered over a plug of Celite, concentrated, and purified by column chromatography (gradient 0 to 75% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J=5.9 Hz, 2H), 8.64 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.94 (d, J=5.9 Hz, 2H), 7.89 (s, 1H), 7.61-7.39 (m, 5H), 5.21 (s, 1H), 4.18 (s, 3H), 3.75 (s, 3H), 2.60 (s, 3H), 0.99 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:28]=2)=[O:24])[CH:20]=[C:19]([CH3:41])[C:18]=1O.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:18]1[C:19]([CH3:41])=[CH:20][C:21]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:35])[CH3:36])[CH:28]=2)=[O:24])=[CH:22][C:17]=1[Cl:16])(=[O:5])=[O:4]
Reactant: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(Cl)c1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(Cl)c1OS(=O)(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
Trifluoromethanesulfonic anhydride (3 mL, 17.7 mmol) was added to a cooled (−78° C.) solution of 2-chloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-phenyl]methyl]amino]carbonyl]-6-methylphenol (6.00 g,14.8 mmol) and triethylamine (8.24 mL, 59.1 mmol) in dichloromethane (60 mL). After stirring for 2 h at −78° C. , the reaction was quenched with solid ammonium chloride (4 g). The mixture was diluted with ethyl acetate (200 mL) and washed with 1N HCl (100 mL), saturated aqueous sodium bicarbonate and brine. The organic layer was dried (MgSO4), filtered, evaporated and chromatographed (20-30% ethyl acetate/hexanes) to give trifluoromethanesulfonic acid, 2-chloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]-6-methylphenyl ester (5.00 g, 63%) as pale orange oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([NH2:7])=[N:4][N:3]=1.[CH:8]1[C:21]2[CH:20]([C:22](Cl)=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>>[CH3:1][C:2]1[O:6][C:5]([NH:7][C:22]([CH:20]2[C:21]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:23])=[N:4][N:3]=1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: Cc1nnc(N)o1
Product: Cc1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)o1

Procedure:
The title compound, white solid, m.p. 261-263° C. and MS: m/e=307.1 (M+) was prepared in accordance with the general method of example 44a from 5-methyl[1,3,4]oxadiazol-2-ylamine and 9-xanthene-carboxylic acid chloride. The 5-methyl[1,3,4]oxadiazol-2-ylamine, white solid, MS: m/e=99 (M+) used in the above reaction was prepared in accordance with the general method of example 48b from acetic acid hydrazide and cyanogen bromide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][C:13]([F:16])([F:15])[CH2:12][N:11]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([O:28]CC)=[O:27])=[C:19]3[CH:18]=2)[CH:6]=[C:7]([F:9])[CH:8]=1)#N.[Li+].[OH-:32].C1COCC1.C[OH:39].O>>[C:1]([C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][C:13]([F:15])([F:16])[CH2:12][N:11]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[C:19]3[CH:18]=2)[CH:6]=[C:7]([F:9])[CH:8]=1)([OH:39])=[O:32]
Reactant: CO
Reactant: CCOC(=O)c1cnn2ccc(N3CC(F)(F)C[C@@H]3c3cc(F)cc(C#N)c3)cc12
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)cc([C@H]2CC(F)(F)CN2c2ccn3ncc(C(=O)O)c3c2)c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of (R)-ethyl 5-(2-(3-cyano-5-fluorophenyl)-4,4-difluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (X-8) (90 mg, 0.22 mmol) in THF:MeOH:H2O 3:2:1 (2.5 mL) was added LiOH (46 mg, 1.1 mmol) and stirred at 50° C. for 12 hours. The reaction was subsequently neutralized and concentrated to dryness. The crude product was purified by column chromatography on silica gel with DCM/MeOH gradient as eluant to yield (R)-5-(2-(3-carboxy-5-fluorophenyl)-4,4-difluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (I-52), which was immediately used in the next reaction. MS m/z 406.1 (M+1)+.
Reaction SMILES: [F:1][S:2]([C:5]([C:8]([O:11][C:12]([C:15]([O:18][C:19]([C:21]([O:27][C:28]([C:31]([C:34]([F:37])([F:36])[F:35])([F:33])[F:32])([F:30])[F:29])([C:23]([F:26])([F:25])[F:24])[F:22])=[O:20])(F)[F:16])([F:14])[F:13])([F:10])[F:9])([F:7])[F:6])(=[O:4])=[O:3].[F-:38].[Na+]>>[C:23]([C:21]([C:19]([F:38])=[O:20])([O:27][C:28]([C:31]([C:34]([F:36])([F:37])[F:35])([F:32])[F:33])([F:30])[F:29])[F:22])([F:25])([F:26])[F:24].[F:1][S:2]([C:5]([C:8]([O:11][C:12]([C:15]([F:16])=[O:18])([F:13])[F:14])([F:9])[F:10])([F:7])[F:6])(=[O:4])=[O:3]
Reactant: O=C(OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)S(=O)(=O)F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: [F-]
Agent: [Na+]
Product: O=C(F)C(F)(F)OC(F)(F)C(F)(F)S(=O)(=O)F
Product: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 140 °C

Procedure:
FSO2CF2CF2OCF2CF2OCOCF(CF3)OCF2CF2CF3(3.1 g) obtained in Example 3 was charged into a flask together with NaF powder (0.02 g) and heated at 140° C. for 10 hours in an oil bath with vigorous stirring. At the upper portion of the flask, a reflux condenser having the temperature adjusted at 20° C., was installed. After cooling, the liquid sample (3.0 g) was recovered. As a result of the analysis by GC-MS, CF3CF(OCF2CF2CF3)COF and FSO2CF2CF2OCF2COF were confirmed to be the main products, and the NMR yield was 71.2%. Further, FCOCF(CF3)OCF2CF2CF3 was obtained in a yield of 74.0%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([Cl:20])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:15]1[C:14]2[CH:13]=[C:12]([Cl:20])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: CCOC(=O)c1cc(Cl)sc1N
Reactant: N#Cc1ccccn1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc2c(Cl)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 2-cyanopyridine and 2-amino-5-chloro-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([CH3:15])=[C:13]([C:16]#[N:17])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>CO.[Pd]>[NH2:17][CH2:16][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:14]=1[CH3:15]
Reactant: Cc1c(C#N)ccnc1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(CN)ccnc1NC(=O)OC(C)(C)C
Yield: 84.3 %

Procedure:
A solution of 175 mg (0.75 mmol) of 2-t-butyloxycarbonylamino-4-cyano-3-methylpyridine and 88 μL (1.5 mmol) of acetic acid in 10 mL of MeOH was hydrogenated over 75 mg of 10% Pd-C at 55 psi overnight on a Parr apparatus. The catalyst was removed by filtration, concentrated at reduced pressure, and the residue partitioned between CHCl3 and 10% Na2CO3. The aqueous layer was extracted with CHCl3 and the combined organic layers were dried over Na2SO4 and concentrated to give 150 mg of the title compound as a colorless oil:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[N:45]=[C:44]([O:52][C@@H:53]2[CH2:57][C@@H:56]([C:58]([O:60][CH3:61])=[O:59])[NH:55][CH2:54]2)[C:43]=1[C:62]#[C:63][CH2:64][CH2:65][CH2:66][C@@H:67]1[CH2:69][C@H:68]1[O:70][C:71]([NH:73][C@@H:74]([C:78]1([CH3:84])[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]1)[C:75](O)=[O:76])=[O:72])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[CH2:34]([O:41][C:42]1[C:51]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[N:45]=[C:44]2[O:52][C@H:53]3[CH2:54][N:55]([C:75](=[O:76])[C@H:74]([C:78]4([CH3:84])[CH2:79][CH2:80][CH2:81][CH2:82][CH2:83]4)[NH:73][C:71](=[O:72])[O:70][C@@H:68]4[CH2:69][C@H:67]4[CH2:66][CH2:65][CH2:64][C:63]#[C:62][C:43]=12)[C@H:56]([C:58]([O:60][CH3:61])=[O:59])[CH2:57]3)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2nc3ccccc3c(OCc3ccccc3)c2C#CCCC[C@@H]2C[C@H]2OC(=O)N[C@H](C(=O)O)C2(C)CCCCC2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1(C)CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCC#Cc1c(nc3ccccc3c1OCc1ccccc1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
A round-bottom flask was charged with HATU (1711 mg, 4.50 mmol) and dry DMF (2.25E+04 μl) at 0° C. N,N-diisopropylethylamine (1531 μl, 9.00 mmol) was added followed by addition of a solution of the product of step 3 (1827 mg, 2.25 mmol) in dry DMF (2.25E+04 μl) via syringe pump over 1 hour. After addition was complete the reaction was stirred at room temperature for 2 hours. LCMS and MS analyses showed a complete reaction. The reaction mixture was concentrated to almost dryness in rotavap (high vacuum) and the residue was diluted with ethyl acetate (200 mL). The mixture was washed with water (50 mL), aq. 1M HCl (50 mL), half-saturated sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in rotavap. The residue was purified on a Redisep (120 g) silica gel column (gradient: 0 to 40% ethyl acetate in hexanes) to give the title compound (900 mg, 1.324 mmol, 58.8% yield) as a white powder.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.ClCCl>C(O)C.CC(C)=O>[ClH:24].[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:16][CH2:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C(O)[C@@H]1CCCN(CCOCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
The ester prepared in Example 35 (0.6 g, 1.3 mmol) was dissolved in ethanol (10 ml) and a 12 N sodium hydroxide solution (0.5 ml) was added. The reaction mixture was stirred at room temperature for 5 h. A concentrated hydrochloric acid solution was added with cooling on an ice-bath until pH 1 and dichloromethane (300 ml) was added. The resulting emulsion was dried over sodium sulphate ant the solvent evaporated in vacuo to give a residue which was agitated with acetone. This afforded 0.3 g (50%) of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].Br[CH2:14][CH2:15][O:16][C:17]1[C:24]([O:25][CH3:26])=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[Cl:27].[CH2:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][NH:29]1.FC(F)(F)C(O)=O>N.CO.ClCCl>[Cl:27][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:25][CH3:26])[C:17]=1[O:16][CH2:15][CH2:14][N:29]1[CH2:30][CH2:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28]1)[CH:21]=[N:8][NH:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([Cl:1])[CH:3]=1
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Reactant: c1ccc2c(c1)CCNC2
Reactant: COc1cc(C=O)cc(Cl)c1OCCBr
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C=NNC(=O)c2ccc(O)c(Cl)c2)cc(Cl)c1OCCN1CCc2ccccc2C1

Procedure:
This compound was prepared analogously to the compound described in the previous example starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin—[building block 1]) (2 g, 2 mmoles), 4-(2-bromoethoxy)-3-chloro-5-methoxybenzaldehyde ([building block 2]) (0.81 g, 1.5 equivs.), and 1,2,3,4-tetrahydroisoquinoline ([building block 3]) (2.5 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1.0 g) was dissolved in 15 ml of a mixture of 25% aq. ammonia, methanol and dichloromethane (1:9:90) and purified by column chromatography on silica gel (25 g) eluting with a mixture of methanol and dichloromethane (1:12). This afforded 0.11 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36](=[O:44])([O:41][CH2:42][CH3:43])[O:37][CH:38]([Cl:40])[CH3:39]>C(#N)C>[Cl-:40].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:35])([C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11])[CH2:29][NH+:30]1[CH2:34][N:33]([CH:38]([O:37][C:36]([O:41][CH2:42][CH3:43])=[O:44])[CH3:39])[CH:32]=[N:31]1
Reactant: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCOC(=O)OC(C)Cl
Solvent: CC#N
Product: CCOC(=O)OC(C)N1C=N[NH+](C[C@](O)(c2ccc(F)cc2F)[C@@H](C)N2CCN(c3ccc(-n4cnnn4)cc3)C2=O)C1
Product: [Cl-]
Temperature: 95 °C
Reaction time: 38 h
Yield: 1 %

Procedure:
To a mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidinone (0.61 g) and 1-chloroethyl ethyl carbonate (3.7 g) was added acetonitrile (1 ml), and the mixture was stirred for 38 hours at 95° C. The reaction mixture was concentrated under reduced pressure. To the residue was added diisopropyl ether (10 ml), and the resulting powder was collected by filtration. The powder was subjected to ODS column chromatography (eluent: methanol/water=3/2). The eluate was concentrated in vacuo. The residue was dissolved in water (10 ml), and lyophilized to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[-1-(ethoxy-carbonyloxy)ethyl]-1H-1,2,4-triazolium chloride (Compound 7,90 mg) as a white powder.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O:29]CC)C>>[CH2:1]([N:8]1[C:9](=[O:29])[S:10][N:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:25]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=NCc1ccccc1
Reactant: O=C=Nc1ccccc1Cc1ccccc1
Reactant: CCOCC
Product: O=c1sn(-c2ccccc2Cc2ccccc2)c(=O)n1Cc1ccccc1

Procedure:
Reagents: Benzylisothiocyanate (6.5 mmol, 0.85 mL), 2-benzylphenyl-isocyanate (6.5 mmol, 0.82 mL) and SO2Cl2 (6.5 mmol, 0.5 mL) in diethyl ether (25 mL). Isolation: filtration of reaction mixture. Purification: recrystallization from EtOH