Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:6]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:29](=O)[CH2:30][CH:31]([CH3:33])[CH3:32].C(O)(=O)C>ClCCCl>[CH3:32][CH:31]([CH3:33])[CH2:30][CH2:29][NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=2)[N:6]=1
Reactant: N#Cc1ccc(-c2csc(N)n2)cc1
Reactant: CC(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)CCNc1nc(-c2ccc(C#N)cc2)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
Slurry 4-(2-amino-thiazol-4-yl)-benzonitrile (2.0 g, 9.9 mmol), sodium triacetoxyborohydride (6.3 g, 29.7 mmol), isovaleraldehyde (1.7 g, 19.8 mmol) and acetic acid (3.6 mL) in 1,2-dichloroethane (100 mL) at room temperature under a nitrogen atmosphere. Stir the mixture for 16 h at room temperature. Quench the reaction with saturated aqueous NaHCO3 (75 mL, pH to 7.0-7.5). Extract the mixture twice with DCM (100 mL) and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (40 g) eluting with hexane/EtOAc (20:1 to 3:2 gradient) to obtain the desired intermediate (1.8 g, 67%). MS (ES+) m/z: 272 (M−H)+.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33])=[CH:20][CH:19]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O>C(Cl)Cl.Cl>[CH3:2][N:3]([C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:23][CH:22]=1)[OH:4]
Reactant: CNO
Reactant: CCCCCCOc1ccc(CCCCCCCCC(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCCCOc1ccc(CCCCCCCCC(=O)N(C)O)cc1
Yield: 48.5 %

Procedure:
To a cold, stirring suspension of 0.6 gm of N-methyl hydroxylamine hydrochloride and 0.7 gms sodium carbonate in 15 ml CH2Cl2 was added dropwise 2 gms 9(4-hexyloxyphenyl)nonanoyl chloride. The resulting mixture was stirred in the cold for 1/2 hr, then 0.9 ml water was added and the reaction stirred at room temperature for 22 hr. 100 ml CH2Cl2 and 40 ml water was added, and the pH of the aqueous layer was adjusted to 3-4 with a few drops of conc. HCl. The organic layers were separated and the aqueous layer was 3×20 ml CH2Cl2 extracted. The combined organic extracts were washed with water and NaCl solution, and dried over MgSO4. The drying agent was filtered off, the solvent was evaporated in vacuo, and the residue was purified by column chromatography on silica gel in chloroform. The major component had R=0.2. The fractions containing product (as determined by thin layer chromatography) were combined, evaporated in vacuo and the resulting solid recrystallized from hexanes to give 1.0 gm product of m.p. 59°-61°. Elemental analysis calculated C 72.69, H 10.26, N 3.85, O 13.2% found C 72.54, N 10.46, N 3.98%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])=[CH:6][CH:5]=1)(O)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:2][CH2:1][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[CH:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])=[CH:6][CH:5]=1
Reactant: CC(/C=C/c1ccc(C(=O)O)cc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(/C=C/c1ccc(CO)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 1-(4'-carboxyphenyl)-3-phenyl-trans-1-butene (0.35 g, 1.5 mmol) in tetrahydrofuran (25 ml) was added dropwise to a suspension of lithium aluminum hydride (56 mg) in tetrahydrofuran. The reaction was refluxed for 3 hours and cooled to ambient temperature. Excess lithium aluminum hydride was decomposed by the sequential addition of water (0.1 ml), 15% aqueous sodium hydroxide (0.1 ml) and water (0.3 ml). The precipitate was removed by filtration and the filtrate evaporated. The residue was subjected to column chromatography on silica gel (E. Merck No. 7734). Elution with 3:1 hexane-ether afforded pure 1-[4'-(hydroxymethyl)-phenyl]-3-phenyl-trans-1-butene; yield 0.22 g (65%); mass spectrum m/z: 238 (M), 223 (M--CH3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:22][CH:23]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47].C([O-])([O-])=O.[Cs+].[Cs+].[ClH:54]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:30].[ClH:54].[ClH:30].[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:19]=[N:20][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])=[CH:22][CH:23]=2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)CCNc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)CCNc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cn1
Temperature: 80 °C
Yield: 155.2 %

Procedure:
To a suspension of (6-bromo-4-((6-((2-(dimethylamino)ethyl)amino)pyridin-3-yl)amino)quinolin-3-yl)(cyclopropyl)methanone (91 mg, 0.20 mmol), 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (82 mg, 0.30 mmol) and Pd(dppf)Cl2 (14.6 mg, 0.02 mmol) in dioxane (6 mL) was added Cs2CO3 (1.0 M in H2O, 0.6 mL, 0.6 mmol). The reaction mixture was degassed with nitrogen and heated at 80° C. for 2 h. The solution was cooled to room temperature, diluted with a satd. aq. NaHCO3 solution and extracted with CHCl3/isopropanol (3:1). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA). The desired fractions were combined and concentrated. The residue was dissolved in methanol (4 mL) and HCl (1.25 M in methanol, 1.5 mL, 1.9 mmol) and the mixture was concentrated to give the desired product (97.7 mg, 78%) as an off-white solid. 1H NMR (500 MHz, MeOD) δ 9.38 (s, 1H), 8.32-8.17 (m, 3H), 8.04 (d, J=8.8 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.31-7.23 (m, 2H), 7.01 (d, J=9.2 Hz, 1H), 3.87 (t, J=6.1 Hz, 2H), 3.44 (t, J=6.1 Hz, 2H), 2.98 (s, 6H), 2.89-2.80 (m, 1H), 1.24-1.18 (m, 4H). ESI MS m/z 520 [C28H27ClFN5O2+H]+; HPLC 97.9% (AUC), tR=9.99 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11]>>[CH3:13][Si:12]([C:10]#[C:11][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:15])[CH3:14]
Reactant: O=Cc1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1cccc(C=O)c1

Procedure:
Compound VI was synthesized by the organopalladiumcatalyzed ethynylation of meta-bromobenzaldehyde with ethynyltrimethylsilane as follows: ##STR4##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2>C1C2C(=CC=CC=2)C=CC=1O.C(Cl)(Cl)(Cl)Cl>[CH:2]1[CH:3]=[C:4]2[CH:5]=[CH:6][C:7]([OH:12])=[C:8]([C:8]3[C:9]4[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=4)[CH:5]=[CH:6][C:7]=3[OH:12])[C:9]2=[CH:10][CH:11]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: Oc1ccc2ccccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A reaction flask described in example 9 was charged with a solution of catalyst 1c (12.2 mg, 0.02 mmol) in anhydrous CCl4 (1 mL). The solution was stirred for 10 min under an oxygen atmosphere and then treated with a solution of 6-bromo-2-naphthol (44 mg, 0.2 mmol) in anhydrous CCl4 (1 mL) under 0° C. The reaction mixture was stirred at 0° C. until the reaction was complete (monitored by TLC). The crude mixture was concentrated under reduced pressure, and purified by column chromatography (Ethyl acetate/Petroleum ether-⅓) to give (R)-BINOL 3c, Yield 99%. [α]D25=−33.7 (c=0.4 in EtOAc), 1H NMR (300 MHz, CDCl3) δ (ppm) 8.06 (d, J=1.8 Hz, 2H, 2×HC (4)), 7.89 (d, J=9.0 Hz, 2H, 2×HC (5)), 7.37 (d, J=6.9 Hz, 2H, 2×HC (8)), 7.36 (dd, J=9.0 Hz, 1.8 Hz, 2H, 2×HC (7)), 6.96 (d, J=9.0 Hz, 2H, 2×HC (3)), 5.08 (s, 2H, 2×OH). e.e. 90%, and the configuration was R (Kromasil CHI-TBB column, Hexane/propan-2-ol=80: 20; flow rate 1 mL/min; S-isomer, tR 6.68 min and R-isomer, tR 7.51 min).
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([C:36]3[NH:37][CH:38]=[CH:39][N:40]=3)[CH2:22][C:23]3[CH:31]=[C:30]([CH3:32])[C:29]4[C:25](=[CH:26][N:27]([CH2:33][O:34][CH3:35])[N:28]=4)[CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[C:48]([F:50])[CH:49]=1)[CH2:45]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C@@H:21]([C:36]3[N:37]([CH2:45][C:44]4[CH:43]=[C:42]([F:41])[CH:49]=[C:48]([F:50])[CH:47]=4)[CH:38]=[CH:39][N:40]=3)[CH2:22][C:23]3[CH:31]=[C:30]([CH3:32])[C:29]4[C:25](=[CH:26][N:27]([CH2:33][O:34][CH3:35])[N:28]=4)[CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: COCn1cc2cc(CC(OC(=O)N3CCC(c4cc5ccccc5[nH]c4=O)CC3)c3ncc[nH]3)cc(C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCn1cc2cc(C[C@@H](OC(=O)N3CCC(c4cc5ccccc5[nH]c4=O)CC3)c3nccn3Cc3cc(F)cc(F)c3)cc(C)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(1H-Imidazol-2-yl)-2-(2-(methoxymethyl)-7-methyl-2H-indazol-5-yl)ethyl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (102 mg, 0.19 mmol), 3,5-difluorobenzyl bromide (27.0 μL, 0.21 mmol, 1.1 equiv), and potassium carbonate (54 mg, 3.0 equiv) were combined in dimethylformamide (2.0 mL). After stirring at room temperature for 16 h, the reaction mixture was removed in vacuo and the residue purified by column chromatography to afford 72.0 mg (57%). Mass spec.: 667.4 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[C:4](=[O:15])[CH:3]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)[C:4](=[O:15])[CH:3]=1
Reactant: O=C1CCC(n2ccc(O)cc2=O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3ccc(O)cc3=O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-hydroxy-1-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: C([O:3][C:4](=[O:34])[C@@H:5]([O:31][CH2:32][CH3:33])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)C.[OH-].[Li+].Cl.C(#N)C>C1COCC1.O>[CH2:32]([O:31][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:23])=[O:24])=[CH:18][CH:17]=2)=[CH:11][CH:12]=1)[C:4]([OH:34])=[O:3])[CH3:33]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(S(=O)(=O)c3ccccc3)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(S(=O)(=O)c3ccccc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Yield: 56.6 %

Procedure:
(S)-2-Ethoxy-3-(4-{2-[4-(phenylsulfonyl)phenyl]ethoxy}phenyl)propanoic acid ethyl ester (described in Example 89) (0.34 g; 0.70 mmole) was dissolved in THF (5 ml) and water (5 ml). Lithium hydroxide was added to the solution (0.022 g; 0.092 mmole) and the solution was stirred over night at room temperature. Aqueous hydrochloric acid was added until pH=3-4. The solvent was evaporated to a small volume. The remaining product was participated between water and diethyl ether. The water layer was once extracted with diethyl ether. The organic phase was dried with sodium sulfate and the solvent evaporated. Chromatography of the crude product, gradient eluation (99:1, 95:5 and 90:10). The product was isolated as a viscous oil. The oil was dissolved in water and acetonitrile and freezed by liquid nitrogen. Freeze-drying for 24 hours gave 0.18 g (yield 56%) of (S)-2-ethoxy-3-(4-{2-[4-(phenylsulfonyl)phenyl]ethoxy}phenyl)propanoic acid.
Reaction SMILES: CS(O[CH2:6][C:7]1[O:8][CH:9]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][CH:22]=2)[C:11](=[O:13])[CH:12]=1)(=O)=O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>ClCCl>[F:34][C:31]([F:32])([F:33])[C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2[O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]1[C:11](=[O:13])[CH:12]=[C:7]([CH2:6][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[O:8][CH:9]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ccnc3c(C(F)(F)F)cccc23)co1
Solvent: ClCCl
Product: O=c1cc(CN2CCOCC2)occ1OCCCCCOc1ccnc2c(C(F)(F)F)cccc12
Temperature: 45 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
Methanesulfonic acid 4-oxo-5-[5-(8-trifluoromethyl-quinolin-4-yloxy)-pentyloxy]-4H-pyran-2-ylmethyl ester 19 (94 mg, 0.187 mmol) was dissolved in dichloromethane (4 mL). Morpholine (41 μL, 0.47 mmol) was added via syringe. The mixture was stirred at 45° C. for 3 h. CH2Cl2 (75 ml) was added and the solution washed with NaHCO3 10% (3×50 mL) and brine (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=95:5. 5-(5-(8-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(morpholinomethyl)-4H-pyran-4-one EHT 4687 was obtained (46 mg, 50% yield) as a white foam.
Reaction SMILES: C1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12]C3C=CC(S(N4CCC(O)CC4)(=O)=O)=CC=3)[N:11]=2)CCC1.CS(CC1C=C(C=CC=1)N)(=O)=O>>[N:9]1[C:8]2[NH:29][CH:30]=[CH:31][C:7]=2[C:6]([NH2:5])=[N:11][C:10]=1[NH2:12]
Reactant: O=S(=O)(c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1)N1CCC(O)CC1
Agent: CS(=O)(=O)Cc1cccc(N)c1
Product: Nc1nc(N)c2cc[nH]c2n1

Procedure:
According to the general procedure for synthesis of 1-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenylsulfonyl)piperidin-4-ol, 3-(methylsulfonylmethyl)aniline and 2-Chloro-N-cylclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine gave N4-cyclobutyl-N2-(3-methylsulfonylmethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2,4-diamine (MS calcd for C18H21N5O2S 371.5, found [MH] 372.1; UV 214.5, 267.6, 304.5 nm).
Reaction SMILES: FC(F)(F)CC(=O)[S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:19])[CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:8][CH:7]=1.CCO.Cl>O>[F:18][C:15]([F:16])([F:17])[CH2:14][C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([SH:5])=[CH:7][CH:8]=1)=[O:19]
Reactant: O=C(CC(F)(F)F)Nc1ccc(SC(=O)CC(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(CC(F)(F)F)Nc1ccc(S)cc1
Temperature: 50 °C
Yield: 44.8 %

Procedure:
S-4-(3,3,3-trifluoropropanamido)phenyl 3,3,3-trifluoropropanethioate (44.8 g, 189 mmol) and EtOH (70 mL) are charged to a flask. Concentrated HCl (22.5 mL) is slowly added to keep the temp below 30° C. The reaction is then heated to 50° C. for 17.5 h. The reaction mixture is reduced to 41 mL by vacuum distillation at 50° C. Cool the reaction to room temperature and H2O (51 mL) is added. The slurry is filtered and the filter cake is washed with H2O (3×35 mL). The solid is dried under vacuum to produce the desired compound (19.9 g, 58%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.BrBr.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])O.[Na+]>O.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccn1
Reactant: CC(=O)c1cccc(Br)c1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cccc(-c2cn3ccccc3n2)c1
Yield: 25.6 %

Procedure:
Dissolving 10 g (50 mmol) of 3′-bromoacetophenone into 20 milliliter of acetic acid and adding 7.0 g (44 mmol) of bromine at the temperature of about 5 to 10° C., stirred at the temperature of about 5 to 10° C. for 4 hours until the color of bromine disappeared. After completion of the reaction, adding water and an extraction was carried out using dichloro-methane. Further, washing with water, dried with the use of sodium sulfate. The solvent was removed by distillation and the resultant crude 2,3′-dibromo acetophenone was dissolved into 30 milliliter of ethanol, adding 5.0 g (53 mmol) of 2-aminopyridine and 7.0 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 8 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and methanol, thereby obtaining 3.5 g of 2-(3-bromo-phenyl)-imidazo [1,2-a] pyridine (yield: 26%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25](N)=[O:26])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Br:14])[N:7]=1.[OH-:28].[Na+]>CCO>[NH2:1][C:2]1[C:3]([C:25]([OH:28])=[O:26])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Br:14])[N:7]=1
Reactant: CC(C)n1nc(-c2nc(C(N)=O)c(N)nc2-c2ccccc2Br)ccc1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)n1nc(-c2nc(C(=O)O)c(N)nc2-c2ccccc2Br)ccc1=O

Procedure:
A solution of 3-amino-5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarboxamide (695 mg) in a mixture of 5N aq. NaOH (4 ml) and EtOH (4 ml) was refluxed for 4 hours. After removal of EtOH by evaporation, the mixture was adjusted to pH 4 with 1N HCl to give a precipitate. The precipitate was collected by filtration and dried under reduced pressure to give 3-amino-5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarboxylic acid (664 mg).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[Cl:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[N:15]=[C:16]=[S:17])[NH:8][CH:7]=1>C(Cl)Cl>[NH2:3][CH2:2][CH2:1][NH:4][C:16](=[S:17])[NH:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:6]([Cl:5])=[CH:7][NH:8]2
Reactant: NCCN
Reactant: S=C=Nc1cccc2[nH]cc(Cl)c12
Solvent: ClCCl
Product: NCCNC(=S)Nc1cccc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
Ethylenediamine (0.711 mL, 10.6 mmol) is added to a solution of 3-chloro-4-isothiocyanatoindole (0.370 g, 1.77 mmol) in methylene chloride (15 mL). The resulting solution is stirred at room temperature for 1 hour. The reaction mixture is concentrated by rotary evaporation and the crude material purified via silica gel column chromatography using 7% methanol (ammonium hydroxide treated)/methylene chloride as the eluent. The appropriate fractions are combined and the solvents removed by rotary evaporation to yield 0.484 g of 4-[N'-(2-aminoethyl)thioureido]-3-chloroindole as a white solid (90% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[F:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[CH:6]=[CH:5]2
Reactant: Fc1cc2[nH]ccc2cc1Br
Reactant: Fc1ccc(I)cc1
Product: Fc1ccc(-n2ccc3cc(Br)c(F)cc32)cc1

Procedure:
In analogy to example 23.3, 5-Bromo-6-fluoro-1H-indole and 1-fluoro-4-iodobenzene were converted to yield 5-Bromo-1-(4-fluoro-phenyl)-6-fluoro-1H-indole as a light yellow solid, MS: 307 (M, 1Br).
Reaction SMILES: [N:1]([CH2:4][C:5]1[NH:14][C:13](=O)[C:12]2[CH2:11][C:10]([CH3:17])([CH3:16])[CH2:9][CH2:8][C:7]=2[N:6]=1)=[N+:2]=[N-:3].P(Cl)(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[N:1]([CH2:4][C:5]1[N:14]=[C:13]([Cl:20])[C:12]2[CH2:11][C:10]([CH3:17])([CH3:16])[CH2:9][CH2:8][C:7]=2[N:6]=1)=[N+:2]=[N-:3]
Reactant: CC1(C)CCc2nc(CN=[N+]=[N-])[nH]c(=O)c2C1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)CCc2nc(CN=[N+]=[N-])nc(Cl)c2C1
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of 2-(azidomethyl)-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one (151 mg, 0.65 mmol) in chloroform (1.2 mL) was treated with phosphorus oxychloride (600 uL) at 60° C. for 1 h 20 min. After cooling to rt, the volatile materials were removed in vacuo, and the resulting residue was dissolved in ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate, and the aqueous phase was back extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 2-(azidomethyl)-4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazoline (136 mg, 0.54 mmol, 83% yield) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 4.47 (s, 2H), 2.94 (t, 2H), 2.55 (s, 2H), 1.68 (t, 2H), 1.05 (s, 6H); MS (EI) for C11H14ClN5: 252 (MH+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]2[N:10]=[CH:11][N:12]=[CH:13][C:8]=2[C:7](=[O:14])[NH:6][CH:5]=1.CI.[CH3:17]C(=O)OCC>CN(C=O)C>[Br:3][C:4]1[C:9]2[N:10]=[CH:11][N:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:17])[CH:5]=1
Reactant: CCOC(C)=O
Reactant: O=c1[nH]cc(Br)c2ncncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(Br)c2ncncc2c1=O
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
Sodium hydride (21 mg, 0.53 mmol, 60% in mineral oil) was added to the title compound of step 2 (100 mg, 0.44 mmol) in DMF (10 mL) at 0° C. After stirring 0.5 h, MeI (126 mg, 0.88 mmol) was added and stirring continued at 0° C. for 2 h. Following extractive work up with EA, the title compound (80 mg, yield: 75.3%) was obtained as a yellow solid. 1H NMR: (DMSO-d6, 400 MHz) δ: 9.47 (s, 1H), 9.46 (s, 1H), 8.53 (s, 1H), 3.54 (s, 3H). LCMS: 240.0, 242.0 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][C:13]([OH:15])=O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:16](=[O:17])[O:18][C:13](=[O:15])[CH2:12]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: O=C(Cc1ccccc1)N[C@H]1CC(=O)OC1=O
Yield: 96.7 %

Procedure:
After cooling to 0°-5° C. and filtration the reaction mixture was dried to obtain N-phenyl acetylaspartic acid (120 g), 99.77% titer. 78 g of N-phenylacetyl aspartic acid were suspended in 80 ml of acetic anidride. The mixture was heated to 80° for 2 hours. 70 g of N-phenylacetyl aspartic anhydride were obtained after cooling and insolubilization with a solvent. 52 g of N-phenylacetyl aspartic anhydride suspended in 52 ml of glacial acetic acid and 100 ml of dichloroethane cooled to 10° C. were added with 200 ml of dichloroethane containing 40.2 g of phenylalanine methyl ester.