Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[CH2:31]([O:33][C:34]([C@@:36]1([NH2:41])[CH2:38][C@H:37]1[CH:39]=[CH2:40])=[O:35])[CH3:32]>CCOC(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:41][C@:36]1([C:34]([O:33][CH2:31][CH3:32])=[O:35])[CH2:38][C@H:37]1[CH:39]=[CH2:40])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Agent: CC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 22.5 °C
Reaction time: 1.12 h

Procedure:
To a suspension of 138.8 g (600 mmol) of Boc-(2S,4R)-hydroxyproline in 890 mL of EtOAc was added 63.7 g (630 mmol) of NMM at 20-30° C. To this mixture 72.3 g (600 mmol) of pivaloyl chloride was added at 15-22° C. within 10-20 min followed by 50 mL of EtOAc. The mixture was stirred at 20-25° C. for 60-75 min. Then the emulsion of (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester prepared in example 6 was added at a temperature of 20-30° C. within 5-30 min. The dosing funnel was rinsed with 20 mL DMF and 100 mL EtOAc. The reaction mixture was stirred for 4 h at 20-25° C. After complete conversion 450 mL of aqueous HCl (IN) was added. Phases were separated and the aqueous layer was extracted with 600 mL of EtOAc. The organic phase was washed with 200 mL of water, 400 mL of aqueous NaOH (2M) and 200 mL of water. The combined organic phases were concentrated to 400 mL under reduced pressure. To the residue 1500 mL of toluene was added and the mixture was concentrated to 1000 mL under reduced pressure. To the residue 720 mL of toluene was added to yield the (2S,4R)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a 12-13 wt % solution in toluene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][F:21])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1.CO.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][F:21])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: FCCCOc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Reactant: CN
Solvent: CO
Product: CNc1nccc(-c2cc3ccc(OCCCF)cc3s2)n1
Yield: 80.2 %

Procedure:
2-[2-(N-Monomethylamino)pyrimidine-4-yl]-6-(3-fluoropropoxy)benzothiophene (1-38, 56 mg, 81%) was prepared in the same manner as in Example 35 as a yellow solid using 2-(2-chloropyrimidine-4-yl)-6-(3-fluoropropoxy)benzothiophene (105c, 70 mg, 0.22 mmol) obtained in Preparation Example 21 and a 2.0 M methylamine methanol solution (NH2Me in MeOH, 0.17 mL, 0.34 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])=[C:4](F)[C:3]=1[N+:16]([O-:18])=[O:17].[CH3:19][OH:20]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])=[C:4]([O:20][CH3:19])[C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: CCOC(=O)Nc1c(F)cc(Cl)c([N+](=O)[O-])c1F
Reactant: CO
Solvent: C1COCCO1
Product: CCOC(=O)Nc1c(F)cc(Cl)c([N+](=O)[O-])c1OC
Temperature: 65 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 30.6 grams (0.109 mole) of ethyl N-(4-chloro-2,6-difluoro-3-nitrophenyl)carbamate and 18 mL (0.449 mole) of methanol in 175 mL of dioxane was stirred and 218 mL (0.218 mole) of 1M sodium trimethylsilanoate (in tetrahydrofuran) was added dropwise during a 45 minute period. Upon completion of addition, the reaction mixture was heated to 65° C. where it stirred for three hours. At the conclusion of this period, the reaction mixture was allowed to cool to ambient temperature where it stirred for about 18 hours. The reaction mixture was concentrated under reduced pressure to a residue. The residue was taken up in cold 3N hydrochloric acid. The resulting solid was collected by filtration, washed with petroleum ether, and heat dried under vacuum, yielding 21.3 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N1C2=NC=[CH:17][CH:18]=[C:13]2[CH:12]=[CH:11]1>>[CH2:11]([N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:12][CH2:13][CH2:18][CH3:17]
Reactant: c1cnc2[nH]ccc2c1
Reactant: c1cnc2cc[nH]c2c1
Product: CCCCCn1ccc2ncccc21

Procedure:
Following the procedure as described in PREPARATION 1A, and making non-critical variations using 1H-pyrrolo[3,2-b]pyridine to replace 1H-pyrrolo[2,3-b]pyridine, the title compound was obtained (75%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.39 (d, 1H), 7.56 (d, 1H), 7.25 (d, 1H), 7.05-7.01 (m, 1H), 6.63 (d, 1H), 4.05-3.99 (m, 2H), 1.79-1.72 (m, 2H), 1.31-1.45 (m, 4H), 0.81 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 146.8, 142.9, 131.0, 128.9, 116.5, 116.1, 102.0, 46.6, 30.0, 29.0, 22.2, 14.0; MS (ES+) m/z 189.3 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=O)[CH2:12][NH2:13])=[CH:6][CH:5]=1.[S-:15][C:16]#[N:17].[K+]>C(O)(=O)C.O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[N:17]=[C:16]([SH:15])[NH:13][CH:12]=2)=[CH:6][CH:5]=1
Reactant: N#C[S-]
Reactant: COc1ccc(CC(=O)CN)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Cc2c[nH]c(S)n2)cc1

Procedure:
A solution of 3-(4-methoxyphenyl)-2-oxo-1-aminopropane, hydrochloride (3.0 g, 14 mmole) and potassium thiocyanate (1.36 g, 14 mmole) in acetic acid (60 ml) was heated under reflux for 15 minutes. The reaction was cooled, diluted with water and the product was filtered and recrystallized from ethyl alcohol and dried to give the product was a solid (1.6 g, 52%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[Se:21][C:20]=1[C:28]([NH2:30])=[O:29].CN(C=O)C.[OH-].[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:18][C:19]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:25])[CH3:26])[Se:21][C:20]=1[C:28]([NH2:30])=[O:29]
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: COc1cc2c(Cl)ncnc2c(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3cc(C(C)(C)C)[se]c3C(N)=O)ncnc2c(OC)c1OC

Procedure:
The reaction of 4-chloro-6,7,8-trimethoxyquinazoline with 3-amino-5-tert-butylselenophene-2-carboxamide in presence of DMF/NaOH as described in Example 1 gave the title compound as an off-white color solid, mp 218-220° C. 1H NMR (400 MHz, CDCl3): δ 12.08 (1H, br s, exchangeable with D2O), 8.87 (1H, s), 8.78 (1H, s), 7.20 (1H, s), 5.49 (2H, br s, exchangeable with D2O), 4.15 (3H, s), 4.07 (3H, s), 4.06 (3H, s), 1.47 (9H, s); 13C NMR (100 MHz, CDCl3): δ 169.0, 168.6, 154.7, 153.1, 152.6, 147.9, 147.6, 146.6, 142.0, 121.7, 112.0, 109.4, 95.9, 62.1, 61.3, 56.1, 37.2, 32.6; LC-MS (positive ion mode): m/z 463, 465 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([CH2:27][C:28]3[CH:39]=[CH:38][C:31]([O:32][CH2:33][C:34]([O:36]C)=[O:35])=[CH:30][CH:29]=3)[C:19](=[O:26])[CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:38][CH:39]=3)[C:19](=[O:26])[CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)COCCOC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)C(=O)COCCOC)cc2)cc1

Procedure:
The titled compound was prepared following the procedure F using methyl [4-({{4-[(4-butylphenyl)ethynyl]benzyl}[(2-methoxyethoxy)acetyl]amino}methyl)phenoxy]acetate and NaOH 1N in the presence of MeOH/THF as a yellow oil (94%). 1H NMR (DMSO-d6, 300 MHz) δ 7.54-7.43 (m, 4H), 7.24 (m, 4H), 7.14 (d, J=8.3 Hz, 2H), 6.86 (m, 2H), 4.62 (s, 2H), 4.41 (m, 4H), 4.28 (s, 1H), 4.20 (s, 1H), 3.59 (m, 2H), 3.42 (m, 2H), 3.21 (s, 1.5H), 3.19 (s, 1.5H), 2.60 (t, J=7.5 Hz, 2H), 1.55 (m, 2H), 1.30 (m, 2H), 0.89 (t, J=7.2 Hz, 3H). M− (ESI): 542.4; M+ (ESI): 544.4. HPLC, Rt: 4.82 min (Purity: 90.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[OH-].[NH4+].[CH3:19]O>>[NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH3:19])=[O:7]
Reactant: CO
Reactant: Nc1ccc(C(=O)O)c(O)c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)c1ccc(N)cc1O
Temperature: 70 °C
Yield: 60 %

Procedure:
To a suspension of 9.18 g (0.06 mole) 4-aminosalicylic acid (7) (Aldrich A7,960-4) in 40 mL of dry methanol was added 8 mL of concentrated sulfuric acid slowly. The mixture was heated under reflux at 70 ° C. for 1.5 hours and then it was cooled in an ice-water bath. Enough concentrated ammonium hydroxide solution was added to adjust the pH to 9 and the precipitate was filtered, rinsed with water and dried to give 6.01 g (60%) of 9 as a solid, mp 118-120° (ref. 120-121°). Infrared (IR) and NMR analysis gave the following results: IR (potassium bromide): 3473 and 3379 (NH2), 1643 (C=O),1284, cm−1. 1H nmr (90 MHz, CDCI3):δ 10.96 (1H, s, OH), 7.6 (1H; d, 3JH5-H6=9 Hz; H-6), 6.20-6.08 (2H, cm, H-3 and H-5), 4.2 (2H; br s; NH2), 3.87 (3H, s, CH3).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]([CH:10]([Cl:12])[F:11])([F:9])[F:8])([F:4])([F:3])[F:2].[Br:13]Br.C(=O)=O>>[C:1]([CH:5]([O:6][C:7]([CH:10]([Cl:12])[F:11])([F:8])[F:9])[Br:13])([F:4])([F:3])[F:2]
Reactant: BrBr
Reactant: FC(Cl)C(F)(F)OCC(F)(F)F
Agent: O=C=O
Product: FC(Cl)C(F)(F)OC(Br)C(F)(F)F

Procedure:
CF3CH2OCF2CHFCl (104 g.) and bromine (85 g.) were vaporized in a stream of nitrogen at 15-20 l/hr. The gaseous mixture was then passed through a 1 × 12 inch glass tube at 475° C. The crude product (137 g.) was condensed in a "Dry Ice" trap and purified by fractional distillation and preparative gas chromatography. The product CF3CHBrOCF2CHFCl had b.p. 109° C., nD20 1.3525 and analyzed as follows:
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:5]=1[C:6]#[N:7])([O-])=O.[CH:15]1([OH:19])[CH2:18][CH2:17][CH2:16]1>>[NH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:19][CH:15]2[CH2:18][CH2:17][CH2:16]2)[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OC1CCC1
Product: N#Cc1c(N)cccc1OC1CCC1
Yield: 34 %

Procedure:
Prepared in a similar manner as example 111c from 2,6 dinitrobenzonitrile and cyclobutanol to provide 2-amino-6-cyclobutoxybenzonitrile (298 mg, 34%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.69 (m, 1H), 1.85 (m, 1H), 2.14 (m, 2H), 2.52 (m, 2H), 4.98 (pent, J=7.3 Hz, 1H), 7.55 (dd, J=8.2, 1.1 Hz, 1H), 7.87 (t, J=8.2 Hz, 1H), 7.92 (dd, J=8.4, 1.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N+:15]([O-])=O)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2.[H][H]>CO.O1CCCC1.[Pd]>[NH2:15][C:5]1[CH:6]=[C:7]2[C:11](=[C:3]([O:2][CH3:1])[CH:4]=1)[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: COc1cc([N+](=O)[O-])cc2cc(C(=O)O)[nH]c12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N)cc2cc(C(=O)O)[nH]c12

Procedure:
A mixture of 472 mg 7-methoxy-5-nitro-1H-indole-2-carboxylic acid and 0.1 g Pd/C 10% in 10 ml methanol and 20 ml tetrahydrofuran was stirred for 2 h at ambient temperature under a pressure of 3 bar of hydrogen. The catalyst was filtered and the filtrate was evaporated to obtain brown solid.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[C:13]([CH3:20])[C:12]=2[CH3:21])=[CH:7][CH:6]=1>C(O)(=O)C>[Br:1][C:6]1[CH:7]=[C:8]([C:11]2[S:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[C:13]([CH3:20])[C:12]=2[CH3:21])[CH:9]=[CH:10][C:5]=1[O:4][CH3:3]
Reactant: BrBr
Reactant: COC(=O)c1sc(-c2ccc(OC)cc2)c(C)c1C
Solvent: CC(=O)O
Product: COC(=O)c1sc(-c2ccc(OC)c(Br)c2)c(C)c1C
Temperature: 25 °C
Yield: 85.4 %

Procedure:
Liquid bromine (0.58 g, 0.19 ml, 3.60 mmol) was added to a solution of methyl 5-(4-methoxyphenyl)-3,4-dimethylthiophene-2-carboxylate (step-3, 0.83 g, 3.00 mmol) in acetic acid (20 ml) under stirring at 25° C. The reaction mixture was then stirred at 25° C. for 3 hrs. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml). The resulting mixture was washed with saturated sodium bicarbonate solution (30 ml). The separated organic layer was concentrated under reduced pressure to obtain a crude product. The crude product obtained was purified by flash column chromatography using 5% ethyl acetate in hexanes as an eluent to obtain the title compound 9d (0.91 g, 83.0%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:16]([NH:18][C:19](=[O:36])[C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[C:23]([CH3:35])=[CH:22][CH:21]=1)[CH3:17].C(=O)([O-])O.[Na+]>C(O)(C)C.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>[CH2:16]([NH:18][C:19](=[O:36])[C:20]1[CH:25]=[CH:24][C:23]([CH3:35])=[C:22]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH:11]4[CH2:15][CH2:14][O:13][CH2:12]4)=[N:7][NH:8]3)=[CH:4][CH:3]=2)[CH:21]=1)[CH3:17]
Reactant: CCNC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Brc1ccc2c(C3CCOC3)n[nH]c2c1
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: CC(C)O
Product: CCNC(=O)c1ccc(C)c(-c2ccc3c(C4CCOC4)n[nH]c3c2)c1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 32.8 %

Procedure:
A mixture of 6-bromo-3-(tetrahydro-3-furanyl)-1H-indazole (Intermediate 9, 84 mg) N-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate, 10, 91 mg) aqueous sodium hydrogen carbonate (1M, 630 μL) and tetrakis(triphenylphosphine)palladium(0) (7 mg) in isopropanol (4 ml) in a sealed vial was stirred at 150° C. for 15 min in a microwave oven. The solvent was removed under vacuum and the residue was purified by chromatography on a silica column, eluting with a cyclohexane:ethyl acetate gradient, to give the title compound as a white solid (36 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:14]1[C:23](=[O:24])[C:22]2[NH:21][C:20]([C:25]3[N:29]([CH3:30])[N:28]=[C:27]([O:31][CH2:32][C:33](O)=[O:34])[CH:26]=3)=[N:19][C:18]=2[N:17]([CH2:36][CH2:37][CH3:38])[C:15]1=[O:16])[CH2:12][CH3:13]>>[CH3:38][CH2:37][CH2:36][N:17]1[C:15](=[O:16])[N:14]([CH2:11][CH2:12][CH3:13])[C:23](=[O:24])[C:22]2[C:18]1=[N:19]/[C:20](/[N:21]=2)=[C:25]1/[CH:26]=[C:27]([O:31][CH2:32][C:33]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:34])[NH:28][N:29]/1[CH3:30]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=N/C(=C1/C=C(OCC(=O)Nc3ccc(C(=O)O)cc3)NN1C)N=2

Procedure:
Using 4-(amino)benzoic acid and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid (Example 36), according to the method described in Example 36.
Reaction SMILES: [C:1]([NH:11][CH:12]([CH2:16][O:17][CH3:18])[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([NH:41][C:13](=[O:15])[CH:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:16][O:17][CH3:18])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COCC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Product: COCC(NC(=O)OCc1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 11 (0.52 g, 2.04 mmol) in dry tetrahdrofuran (10 mL) was cooled to -78° C. in a dry ice-acetone bath under a N2 atmosphere. To this was added via a dry syringe 4-methylmorpholine (0.34 mL, 3.06 mmol). After stirring for 5 minutes, isobutyl chloroformate (0.4 mL, 3.06 mmol) was added via dry syringe and then the mixture stirred for 5 minutes. This was followed by the addition of benzylamine (0.32 mL, 3.06 mmol). After stirring at -78° C. for 5 minutes, the reaction was allowed to warm to room temperature, and stirring was continued at room temperature (30 min). The hydrochloride salt of 4-methyl morpholine was removed from the reaction by filtration. The clear filtrate was evaporated in vacuo and the residue was triturated with ethyl ether (5.0 mL). The white crystalline product obtained was isolated by filtration after washing with small amounts of ether and air-dried (0.55 g, 78%): mp 112°-114° C., Rf 0.6 (10% MeOH/CHCl3)
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH2:5]([O:12][C:13](=[O:21])[N:14]([CH2:18][C:19]#[CH:20])[CH2:15][C:16]#[CH:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(Cl)Cl>C1(C)C=CC=CC=1>[CH2:5]([O:12][C:13]([N:14]1[CH2:18][C:19]2[C:16](=[CH:17][CH:3]=[C:2]([CH2:1][OH:4])[CH:20]=2)[CH2:15]1)=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCO
Reactant: C#CCN(CC#C)C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1Cc2ccc(CO)cc2C1
Temperature: 55 °C
Reaction time: 1 h
Yield: 113 %

Procedure:
A solution of propargyl alcohol (2.11 Kg, 37.7 mol) in toluene (32.48 L) was degassed and heated to 55° C. The solution of di-prop-2-ynyl-carbamic acid benzyl ester (4.06 Kg, 17.86 mol, step 6) in toluene and Wilkinsons catalyst (0.162 Kg) were added in 10 equal portions such that temperature <65° C. (the exotherm was allowed to subside before the next addition was made). The solution was then stirred at 55° C. for 1 h and then cooled to 20° C. DCM (8.12 L) was added and the mixture was concentrated to a small volume. Toluene (8 L) was added and the solution evaporated to constant weight giving the title compound 5.72 Kg (113%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([CH3:15])[CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([CH2:38][C:39]([O:41][CH3:42])=[O:40])=C(C(C3N=CC4CCCCC=4C=3)=O)[NH:23]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([CH2:38][C:39]([O:41][CH3:42])=[O:40])=[C:2]([C:3]([C:5]3[CH:14]=[C:13]4[C:8]([CH2:9][CH2:10][N:11]([CH3:15])[CH2:12]4)=[CH:7][CH:6]=3)=[O:4])[NH:23]2)=[CH:19][CH:18]=1
Reactant: COC(=O)Cc1c(C(=O)c2cc3c(cn2)CCCC3)[nH]c2cc(Cl)ccc12
Reactant: CN1CCc2ccc(C(=O)CBr)cc2C1
Product: COC(=O)Cc1c(C(=O)c2ccc3c(c2)CN(C)CC3)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 7-bromoacetyl-2-methyl-1,2,3,4-tetrahydroisoquinoline* and methyl trans-4-chloro-2-[(phenylsulfonyl)amino]cinnamate (Example 1, step 1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([I:19])[CH:8]=[C:9]([CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:20](OCC)=[O:21].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:20]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:8][C:7]=3[I:19])=[O:21])=[CH:28][CH:27]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(I)cc(CC3CCOCC3)cc2c1O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CC3CCOCC3)cc2c1O
Temperature: 180 °C
Yield: 75 %

Procedure:
A suspension of ethyl 4-hydroxy-8-iodo-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxylate (0.8 g) and 4-chlorobenzylamine (1.54 mL) is heated to 180° C. for 1 h. The reaction is cooled to room temperature. The resulting solid is collected and washed with Et2O. The crude solid is adsorbed onto silica and chromatographed (Biotage flash 40S, eluant 1% MeOH/CH2Cl2 then 2% MeOH/CH2Cl2). Fractions homogeneous by TLC are combined and concentrated. The resulting solid is triturated with EtOAc/hexanes to yield 0.73 g (75%) of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxamide as a white solid, m.p. 257-259° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[CH:6][CH:7]=1.[OH-].[NH4+].[H][H]>C(O)C.[Pd]>[CH3:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][C:5]1[N:4]=[N:3][CH:2]=[CH:7][CH:6]=1
Reactant: Cc1ccccc1Cc1ccc(Cl)nn1
Reactant: [H][H]
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1Cc1cccnn1
Reaction time: 1.5 h
Yield: 90.8 %

Procedure:
A solution of 3-chloro-6-(2-methylbenzyl)pyridazine (34 g.) in ethanol (370 ml.) containing aqueous ammonium hydroxide solution (s.g. 0.880; 38 ml.) was treated with hydrogen in the presence of palladium on charcoal (5% Pd) at ambient temperature and normal atmospheric pressure for 1.5 hours. After filtration, the filtrate was evaporated to dryness and the residue extracted with chloroform (3 × 100 ml.). The chloroform solution was washed with water, dried over magnesium sulphate and evaporated to dryness. The light brown solid thus obtained was triturated with n-hexane to give 3-(2-methylbenzyl)pyridazine (26 g.), m.p. 88°-89° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Br:15][C:16]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:17]=1[CH:18]=[CH:19][C:20](O)=O>>[Br:15][C:16]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: O=C(O)C=Cc1cc2c(cc1Br)OCO2
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc4c(cc3Br)OCO4)nc2n(CC)c1=O
Yield: 36.8 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.77 g (13.9 mmol) of 2-bromo-4,5-methylenedioxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylsulfoxide/water to give 2.01 g (yield 38%) of Compound 158 as a yellow powder.
Reaction SMILES: [CH3:1][C@H:2]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:17][S:18](O)(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[F:15][C:12]([F:13])([F:14])[C:11]([NH:10][C@@H:2]([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:18]([Cl:17])(=[O:20])=[O:19])=[CH:6][CH:5]=1)=[O:16]
Reactant: O=S(=O)(O)Cl
Reactant: C[C@@H](Cc1ccccc1)NC(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C[C@@H](Cc1ccc(S(=O)(=O)Cl)cc1)NC(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a solution of 2.0 g (8.64 mmol) of (S)-N-(1-methyl-2-phenylethyl)trifluoroacetamide (15) in 200 mL of chloroform was added 24 mL of chlorosulfonic acid dropwise at 0° C. The mixture was stirred at 0° C. for 4 hours. The reaction mixture was poured into 100 mL of ice water and extracted with 3×200 mL of chloroform. The organic layers were combined, dried over anhydrous sodium sulphate and evaporated to yield 2.58 g (7.82 mmol, 90%) of (S)-4-[2-[(trifluoroacetyl) amino]propyl]-benzenesulfonyl chloride (16) as a white solid. NMR, IR and MS data confirmed compound identity.