Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[F:24])(O)[CH3:12])[CH2:10][CH2:9]1.[CH3:25][S:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][CH:34]=[CH:33]2>ClCCl>[CH:8]1([C:11]([C:33]2[C:32]3[C:36](=[C:28]([CH2:27][S:26][CH3:25])[CH:29]=[CH:30][CH:31]=3)[NH:35][CH:34]=2)([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[F:24])[CH3:12])[CH2:10][CH2:9]1
Reactant: CC(O)(c1ccc(C(F)(F)F)cc1F)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(c3ccc(C(F)(F)F)cc3F)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.02 ml (0.24 mmol) of trifluoroacetic acid was added to 50.0 mg (0.20 mmol) of the compound from Example 136A and 35.7 mg (0.20 mmol) of the compound from Example 8A in 4 ml of dichloromethane, and the mixture was stirred at RT overnight. It was concentrated, and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 10.0 mg (12% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:20]1[C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]2[C:29]([O:31][C:32](=O)[C:22]=2[CH:21]=1)=[O:30]>>[C:26]([C:25]1[CH:24]=[C:23]2[C:22](=[CH:21][CH:20]=1)[C:32](=[O:31])[N:1]([C:2]1[CH:3]=[C:4]([C:8]3[O:9][C:10]4[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][C:11]=4[N:12]=3)[CH:5]=[CH:6][CH:7]=1)[C:29]2=[O:30])([OH:28])=[O:27]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: Nc1cccc(-c2nc3ccc(C(=O)O)cc3o2)c1
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cccc(-c3nc4ccc(C(=O)O)cc4o3)c1)C2=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-aminophenyl)benzoxazole-6-carboxylic acid (70 mg, 0.27 mmol) and 1,2,4-benzenetricarboxylic anhydride (53 mg, 0.27 mmol) the title compound was obtained (34 mg, 29%). 1H NMR (DMSO) δ 8.38(m, 1H), 8.31(m, 2H), 8.06(dd, 1H), 7.92(m, 2H), 7.86(s, 1H), 7.78(m, 3H). MS 429 m/z (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[O:12][CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].[S:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:13]([O:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:24]3[CH:25]=[CH:26][S:22][CH:23]=3)[CH:3]=2)[N:8]=[CH:7][N:6]=1)([CH3:15])[CH3:14]
Reactant: CC(C)Oc1ncnc2ccc(Br)cc12
Reactant: OB(O)c1ccsc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)Oc1ncnc2ccc(-c3ccsc3)cc12
Temperature: 50 °C
Yield: 55.2 %

Procedure:
A mixture of 6-bromo-4-isopropoxy-quinazoline (17.9 mg, 0.067 mmol), potassium carbonate (0.13 mmol), tetrakis(triphenylphosphine) palladium (10 mg) and 3-thiophenyl boronic acid (0.08 mmol) in DME (1 ml) and water (0.5 ml) was heated to 50° C. for 30 minutes. The reaction mixture was filtered through a 0.45 micron filter and diluted with ethyl acetate (2 ml). The organic layer was washed with water (1 ml), separated, and concentrated in vacuo. The residue was purified by passage through a pre-packed silica gel column, eluting with ethyl acetate. The solvents were concentrated in vacuo to provide the desired product as a white solid (10 mg, yield: 55%). The resulting compound was characterized as follows: MS (m/z) 271.09 [M+H]+; HPLC Rt=1.83 minutes (Method A).
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]=[O:16])=[CH:10][CH:9]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1.S(=O)(=O)(O)O.[N+:22]([O-])([O-:24])=[O:23].[K+].[OH-].[NH4+]>>[N:1]1([CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]=[O:16])=[C:10]([N+:22]([O-:24])=[O:23])[CH:9]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])[O-]
Reactant: CC(c1ccc(NC=O)cc1)n1ccnc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: CC(c1ccc(NC=O)c([N+](=O)[O-])c1)n1ccnc1
Reaction time: 1.5 h
Yield: 34.6 %

Procedure:
(a-4) To a cooled and stirred solution of 13 parts of N-[4-[1-(1H-imidazol-1-yl)ethyl]phenyl]formamide in 92 parts of concentrated sulfuric acid was added portionwise 6.1 parts of potassium nitrate at a temperature between -5° to -10° C. Upon completion, stirring was continued for 1.50 hour at 0° C. The reaction mixture was poured into crushed ice. The whole was treated with ammonium hydroxide at 0°~-10° C. The product was extracted three times with 195 parts of dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 48 parts of 2-propanol. The product was filtered off and dried, yielding 5.4 parts (34.6%) of N-[4-[1-(1H-imidazol-1-yl)-ethyl]-2-nitrophenyl]formamide; mp. 158° C. (int. 116).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.C([O:40][C@@H:41]([CH3:45])[C:42](Cl)=[O:43])(=O)C>>[CH:33]1([CH2:32][O:31][C:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:36])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:42](=[O:43])[C@@H:41]([OH:40])[CH3:45])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:35]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f33) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:40])[CH2:18][CH:19]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[N:37][O:38]C)[CH2:32][CH2:31]3)[C:20](=O)[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:55][S:56](O)(=[O:58])=[O:57]>>[CH3:55][S:56]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[O:40][C:20]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[C:19]([C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[C:33](=[N:37][OH:38])[CH2:32][CH2:31]4)[CH:18]=2)[CH2:15][CH2:16]1)(=[O:58])=[O:57]
Reactant: CON=C1CCc2cc(C(CC(=O)C3CCN(C(=O)OCc4ccccc4)CC3)C(=O)c3ccncc3)ccc21
Reactant: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CS(=O)(=O)N1CCC(c2cc(-c3ccc4c(c3)CCC4=NO)c(-c3ccncc3)o2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
The product of Example 31, Step 3 (3.0 g, 5.5 mmol) was added to a stirred suspension of phosphorus pentoxide (8 g) in dry methane sulphonic acid (50 ml). After stirring at room temperature for 4 hours the reaction mixture was cautiously poured into a stirred solution of ice cold 50% aqueous sodium hydroxide (final pH 10). The mixture was extracted with chloroform, washed with water and brine, dried and concentrated in vacuo and the residue purified by silica gel chromatography to give the title compound (1.04 g, 50%); MS(ES+) m/e 466 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([Cl:33])(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C(O)(=O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[N:19])=[CH:15][C:16]=2[Cl:33])[CH2:11][CH:10]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=I(=O)Cl
Reactant: N#Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2Cc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CC(=O)O
Product: N#Cc1cc(Cl)c2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a solution of compound 165A (121 mg, 0.3 mmol) in acetic acid (2 mL) at RT was added benzyltrimethylammonium tetrachloroiodate (125.7 mg, 0.3 mmol). The reaction mixture was stirred at RT for 30 min, and then concentrated under reduced pressure. The resultant residue was partitioned between saturated aqueous NaHCO3 solution and CH2Cl2. The separated aqueous layer was extracted with CH2Cl2 (15 mL×2). The combined CH2Cl2 extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified using preparative HPLC (YMC S5 ODS 20×100 mm) eluting with MeOH (50-80%) in H2O for 8 min, and then 80% MeOH in H2O for 7 min to give the title compound (108 mg, 82%) as a white solid. HPLC: 99% at 7.65 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 438 [M+H]+.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[C:10](=[O:11])[N:9]2[CH:12]=[CH:13][C:14]([CH2:16][CH2:17][C:18]3[S:19][CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=3)=[CH:15][C:8]2=[N:7][C:6]=1[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[CH2:32]([Zn]CC)C.CCCCCC.IC.[Cl-].[NH4+]>ClCCl>[OH:1][CH2:2][CH:3]1[CH2:32][CH:4]1[C:5]1[C:10](=[O:11])[N:9]2[CH:12]=[CH:13][C:14]([CH2:16][CH2:17][C:18]3[S:19][CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=3)=[CH:15][C:8]2=[N:7][C:6]=1[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/CO)c(N4CCOCC4)nc3c2)n1
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)c1csc(CCc2ccn3c(=O)c(C4CC4CO)c(N4CCOCC4)nc3c2)n1
Reaction time: 2 h
Yield: 73 %

Procedure:
3-[(E)-3-Hydroxy-1-propenyl]-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (81 mg, 0.18 mmol) was added with dichloromethane (3 ml) and a solution of diethyl zinc in hexane (1.02 M, 270 μl, 0.275 mmol) and subsequently added dropwise with iodomethane (30 μl, 0.366 mmol) at room temperature. After the reaction solution was stirred for 2 hours, the reaction was stopped with saturated aqueous ammonium chloride, and the reaction solution was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (chloroform:methanol=15:1) to obtain 61 mg (73%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@H:12]([CH3:13])[O:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])=[N:9]2)=[CH:4][CH:3]=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C(OCC)C.CCCCCC.O.C(O)C>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:10]1[O:11][C@@H:12]([CH3:13])[C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:30][CH:29]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: C[C@@H]1OC(c2c(F)cccc2F)=N[C@@H]1c1ccc(Br)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: C[C@@H]1OC(c2c(F)cccc2F)=N[C@@H]1c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 78 °C
Reaction time: 16 h
Yield: 30.9 %

Procedure:
A 20 mL round bottom flask equipped with a magnetic stirrer, reflux condenser with nitrogen inlet and thermocouple was charged with (4R,5S)-4-(4-bromophenyl)-2-(2,6-difluorophenyl)-5-methyl-4,5-dihydro-1,3-oxazole (100 mg, 0.284 mmol), 4-(trifluoromethoxy)benzeneboronic acid (70 mg, 0.341 mmol), sodium carbonate (60 mg, 0.566 mmol), tetrakis(triphenylphosphine)palladium(O) (20 mg, 0.017 mmol) and ethyl alcohol (4 mL). The reaction mixture was heated to 78° C. for 7 hours and then cooled to 25° C. and stirred for 16 hours. 1N aq HCl (1 mL) and water (10 mL) were added, and the aqueous layer was extracted with diethyl ether (2×20 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (4:1 hexane:diethyl ether) afforded the product (38 mg, 31% yield) as a gummy solid: 1H NMR (CDCl3) δ 7.63-7.54 (m, 4H), 7.48-7.38 (m, 1H), 7.35 (d, 2H, J=8.4 Hz), 7.28 (d, 2H, J=8.4 Hz), 7.01 (t, 2H, J=8.1 Hz), 5.55 (d, 1H, J=9.9 Hz), 5.18 (m, 1H), 1.03 (d, 3H, J=6.6 Hz); EI/MS 433 m/e (M+); Chiracel OJ HPLC column shows 74% ee.
Reaction SMILES: [NH2:1][C:2]1[C:13]([C:14]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[N:23]2[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25][CH2:24]2)=[O:15])=[C:5]2[N:6]=[CH:7][C:8]([CH2:10][C:11]#[N:12])=[CH:9][N:4]2[N:3]=1.NC1C(C(ON2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:13]([C:14]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[N:23]2[CH2:24][CH2:25][CH:26]([NH2:29])[CH2:27][CH2:28]2)=[O:15])=[C:5]2[N:6]=[CH:7][C:8]([CH2:10][C:11]#[N:12])=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccncc2NC(=O)c2c(N)nn3cc(CC#N)cnc23)CC1
Agent: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCc1cnc2c(C(=O)Nc3cnccc3N3CCC(N)CC3)c(N)nn2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31 %

Procedure:
To a solution of tert-butyl N-[1-[3-[[2-amino-6-(cyanomethyl)pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]-4-pyridyl]-4-piperidyl]carbamate prepared according to a method similar to the one described in Example 1 (70 mg, 0.1424 mmol) in DCM (4 mL) was added TFA (1 mL, 12.98 mmol) and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was evaporated to dryness and purified by HPLC: 10-90% ACN in Water (TFA modifier) and the fractions were freeze-dried. The solid residue was dissolved in methanol (1 mL) and loaded onto a pre-wetted (15 mL methanol) 2 g SCX-2 cartridge. The cartridge was washed with methanol (2×15 mL) then the product eluted as a free base using 2M ammonia in methanol solution (3×15 mL). The product-containing fractions were evaporated to dryness, re-dissolved in water/methanol and freeze-dried to afford the desired product as a yellow solid (17 mg, 31%). MS (ES+) 391.1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C@H:13]([OH:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](O)=[O:45]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C@H:13]([O:21][C:44](=[O:45])[CH2:43][N:42]([CH3:47])[CH3:41])[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[O:32][C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CC(=O)O
Reactant: CC(C)(C)c1ccc(CC[C@H](O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: Cl
Product: CN(C)CC(=O)O[C@@H](CCc1ccc(C(C)(C)C)c(NC(=O)CC2c3ccccc3Oc3ccccc32)c1)CC1CCCCC1

Procedure:
Following a procedure similar to that described in Preparation 25, but using (S)-N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 102) and N,N-dimethylglycine hydrochloride as starting materials, in relative proportions similar to those used in that Preparation, the title compound was obtained as a foam-like material.
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][OH:12])[CH2:5][CH2:4]1.[C:13]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[CH3:13][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][OH:12])[CH2:5][CH2:4]1
Reactant: OCCCC1CCNCC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC(CCCO)CC1
Reaction time: 0.33 h
Yield: 81.4 %

Procedure:
Formalin (6.33 g, 211 mmol) is added to a stirred solution of 3-(piperidin-4-yl)-propan-1-ol (3.02 g, 21.1 mmol) in acetonitrile (30 mL) at ambient temperature. The solution is allowed to stir for 20 minutes. Sodium cyanoborohydride (3.31 g, 52.7 mmol) and acetic acid (3 mL) are sequentially added to the reaction mixture and the resultant mixture is stirred for another 2 hours. After concentration, the crude product is dissolved in dichloromethane (150 mL), washed with saturated aqueous NaHCO3 (60 mL×2), dried and concentrated. The crude product is subjected to chromatography on silica gel and eluted with 2 M NH3/CH3OH in dichloromethane 0-15% to give the title compound as an oil (2.70 g).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/C=C\CCCCCCCC.C(O)(=O)CCCCCCC/C=C\C/C=C\CCCCC.C([O:44][C:45](=[O:47])[CH3:46])(=O)C>>[C:45]([OH:44])(=[O:47])[CH2:46][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Product: O=C(O)CCCCCCCCC(=O)O

Procedure:
The prepolymer of sebacic acid (SA) was prepared from the purified diacid monomer by refluxing in excess acetic anhydride for 30 minutes and evaporating the solvent to dryness. The hot clear viscous residue was dissolved in an equal volume of dichloromethane and precipitated in a mixture of ether/petroleum ether (1:1 v/v). The white precipitate was collected by filtration and dried by vacuum at room temperature. Acetyl terminated fatty acid anhydrides were prepared by dissolving the acids in acetic anhydride (120° C., 1:5 w/v) and refluxing for 20 min. Acetate anhydrides of oleic acid, linoleic acid and other cis-double bond containing fatty acid were prepared by refluxing the fatty acid in acetic anhydride for 20 min. and evaporating the solvent to dryness to obtain a liquid. Mixed prepolymers of diacids with the monoacid terminals were prepared similarly.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([NH:8][C:9]([NH:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=NCc1ccccc1
Reactant: Nc1nccs1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: S=C(NCc1ccccc1)Nc1nccs1
Temperature: 100 °C
Yield: 46.1 %

Procedure:
A solution of benzyl isothiocyanate (1.5 g, 10 mmol) and 2-aminothiazole (1.0 g, 10 mmol) in N,N-dimethylformamide. (25 mL) was heated at 100° C. for 12 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 1.15 g (46%) of the title product:
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8](=[O:9])[CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:6](=[O:17])[N:5]1[CH3:18]>C(Cl)(Cl)Cl>[Br:1][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:8](=[O:9])[N:4]([CH3:3])[N:5]([CH3:18])[C:6]1=[O:17]
Reactant: BrBr
Reactant: CN1C(=O)C(c2ccccc2Cl)C(=O)N1C
Solvent: ClC(Cl)Cl
Product: CN1C(=O)C(Br)(c2ccccc2Cl)C(=O)N1C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A chloroform solution (5 ml) of 0.33 g (2.1 mmols) of bromine was added dropwise to a solution of 0.50 g (2.1 mmols) of 1,2-dimethyl-4-(2-chlorophenyl)pyrazolidine-3,5-dione in 10 ml of chloroform with ice cooling. The obtained mixture was stirred with ice cooling for 30 minutes. The reaction mixture was washed successively with water, an aqueous solution of saturated sodium hydrogencarbonate and a saturated solution of sodium chloride and was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then the residue was washed with hexane, thereby obtaining 0.50 g (yield 75%) of 4-bromo-4-(2-chlorophenyl)-1,2-dimethylpyrazoline-3,5-dione in the form of yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:19][CH2:18][N:17]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:16][CH2:15][N:14]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][CH2:18][N:17]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[CH2:16][CH2:15][N:14]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN1CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CN1CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
34 g (51.4 mmol) of 1,4,7-tris-(benzyloxycarbonyl)-10-(ethoxycarbonylmethyl)-1,4,7,10-tetrazacyclododecane is dissolved in 300 ml of dioxane and mixed with 144 ml of 5% aqueous NaOH solution and stirred for 24 hours at room temperature. After neutralization with concentrated HCl, it is evaporated to the dry state. The residue is taken up in 250 ml of ethyl acetate and extracted twice with 250 ml each of 1N HCl solution. The organic phase is dried on sodium sulfate, and the solvent is evaporated to the dry state.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([CH3:18])=[C:12]([CH3:17])[CH:13]=2)[N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)[CH:7]=1)=[O:5].[CH2:28]1[O:37][C:36]2[C:31](=[CH:32][C-:33]=[CH:34][CH:35]=2)[O:30][CH2:29]1.[Mg+2].[Br-]>C1COCC1>[O:30]1[C:31]2[CH:32]=[CH:33][C:34]([C:4]([C:6]3[C:15](=[O:16])[C:14]4[C:9](=[N:10][C:11]([CH3:18])=[C:12]([CH3:17])[CH:13]=4)[N:8]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)[CH:7]=3)=[O:5])=[CH:35][C:36]=2[O:37][CH2:28][CH2:29]1
Reactant: [c-]1ccc2c(c1)OCCO2
Reactant: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2nc(C)c(C)cc2c1=O
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: Cc1cccc(Cn2cc(C(=O)c3ccc4c(c3)OCCO4)c(=O)c3cc(C)c(C)nc32)n1
Yield: 35.4 %

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 were used with 100 mg (0.273 mmol) of 6,7-Dimethyl-1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl amide, 1.2 mL (0.60 mmol, 0.5M solution in tetrahydrofuran) of 3,4-(ethylenedioxy)phenylmagnesium bromide, and 1 mL of THF. The crude product was purified by flash column chromatography using 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to afford 42.7 mg of 3-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-6,7-dimethyl-1-(6-methyl-pyridin-2-ylmethyl)-1H-[1,8]naphthyridin-4-one. LC-MSD, m/z for C26H23N3O4 [M+H]: 442.17 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 1.9 min.