Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=O.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[NH2:51][C@@H:52]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[C:72]([F:75])([F:74])[F:73])[CH2:53][N:54]1[C:62](=[O:63])[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55]1=[O:64]>C(Cl)Cl>[O:63]=[C:62]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55](=[O:64])[N:54]1[CH2:53][C@@H:52]([NH:51][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=[C:2]([F:1])[CH:3]=1)[CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[C:72]([F:74])([F:73])[F:75]
Reactant: Cn1nccc1-c1ccc(C(=O)O)cc1F
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1F
Reaction time: 16 h
Yield: 67.8 %

Procedure:
To a solution of 3-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzoic acid (66 mg, 0.3 mmol), PyBrOP (169 mg, 0.37 mmol) and diisopropylethyl amine (263 μL, 1.5 mmol) in DCM (3 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (105 mg, 0.3 mmol)[prepared according to Preparation 3]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (112 mg, 68%) as a white solid: LC-MS (ES) m/z=551 (M+H)+.
Reaction SMILES: Cl.[C:2]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=2)=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:28])=[CH:10][C:11]=2[Cl:27])[NH:6]1)([OH:4])=[O:3].Cl.[C:30]([C@H]1C[C@H](NC(C2C=CC=C(CN)C=2)=O)C2C(=CC(Cl)=CC=2Cl)N1)(O)=O>>[ClH:27].[CH3:30][O:3][C:2]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=2)=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:28])=[CH:10][C:11]=2[Cl:27])[NH:6]1)=[O:4]
Reactant: NCCc1ccc(C(=O)N[C@H]2C[C@H](C(=O)O)Nc3cc(Cl)cc(Cl)c32)cc1
Reactant: NCc1cccc(C(=O)N[C@H]2C[C@H](C(=O)O)Nc3cc(Cl)cc(Cl)c32)c1
Agent: Cl
Product: COC(=O)[C@H]1C[C@H](NC(=O)c2ccc(CCN)cc2)c2c(Cl)cc(Cl)cc2N1

Procedure:
This compound was prepared by the method given for Example 82 using trans-2-carboxy-5,7-dichloro-4-(4-aminoethylphenyl)carbonylamino-1,2,3,4-tetrahydroquinoline hydrochloride Example 85, in the place of trans-2-carboxy-5,7-dichloro-4(3-aminomethylphenyl)carbonylamino-1,2,3,4-tetrahydroquinoline hydrochloride to give the title compound as a colourless crystalline solid, m.p. 218° C. (dec). δ (DMSO, 360 MHz) 1.78 (1H, ddd, J=13.2, 12.8 and 4.1 Hz, CHACHBHCCHD), 2.25 (1H, dm, J=13.2 Hz, CHACHBHCCHD), 2.92 (2H, t, J=7.0 Hz, CHE2CHF2), 3.04 (2H, t, J=7.0 Hz, CHE2CHF2), 3.71 (3H, s, CH3), 4.06 (1H, dd, J=12.5 and 2.4 Hz, CHACHBHCCHD), 5.26 (1H, m, CHACHBHCCHD), 6.69 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.91 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.94 (1H, s, Ar NHCH), 7.33 (2H, d, J=8.1 Hz, Ar-H), 7.86 (2H, d, J=8.1 Hz, Ar-H), 7.96 (2H, br, s, NH2), 8.70 (1H, d, J=7.1 Hz, NHCO); m/e (CI+, NH3) 422 (M+1); Found C, 48.59; H, 4.55; N, 8.48.C20H21Cl2N3O3.2HCl requires C, 48.51; H, 4.68; N, 8.48%.
Reaction SMILES: [C:1]([O:4][C@@:5]1([C:26]#[CH:27])[C@@H:11]2[CH2:12][C@@H:10]2[C@H:9]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:6]12[CH2:7][CH3:8])[C@@H:21]1[C:16](=[CH:17][C:18](=[O:25])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3)(=[O:3])[CH3:2].[Li]>O1CCCC1>[OH:25][C@H:18]1[CH2:19][CH2:20][C@H:21]2[C:16]([CH2:15][CH2:14][C@@H:13]3[C@@H:22]2[CH2:23][CH2:24][C@@:6]2([CH2:7][CH3:8])[C@H:9]3[C@H:10]3[CH2:12][C@H:11]3[C@@:5]2([O:4][C:1](=[O:3])[CH3:2])[C:26]#[CH:27])=[CH:17]1
Reactant: C#C[C@]1(OC(C)=O)[C@@H]2C[C@@H]2[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Agent: [Li]
Solvent: C1CCOC1
Product: C#C[C@]1(OC(C)=O)[C@@H]2C[C@@H]2[C@H]2[C@@H]3CCC4=C[C@@H](O)CC[C@@H]4[C@H]3CC[C@@]21CC

Procedure:
200 mg. of natural 17β-acetoxy-18-methyl-17α-ethinyl-15α,16α-methylene-4-estren-3-one is mixed in 20 ml. of absolute tetrahydrofuran with 670 mg. of lithium tri-tert.-butoxyalanate and agitated for 1 hour at room temperature. The mixture is then worked up analogously to Example 17. After chromatography on silica gel, 160 mg. of natural 3β-hydroxy-17β-acetoxy-18-methyl-17α-ethinyl-15α,16α-methylene-4-estrene is obtained.
Reaction SMILES: Cl.C([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:14]C(=O)C)[CH:13]=1)[CH:9]=O)(=O)C.[CH2:18]([SH:21])[CH2:19][SH:20].[OH-].[K+]>CCOCC>[S:20]1[CH2:19][CH2:18][S:21][CH:9]1[C:8]1[CH:7]=[C:6]([OH:5])[CH:13]=[C:12]([CH:11]=1)[OH:14]
Reactant: CC(=O)Oc1cc(C=O)cc(OC(C)=O)c1
Reactant: SCCS
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: Oc1cc(O)cc(C2SCCS2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.8 %

Procedure:
Dry hydrogen chloride was bubbled into a solution of 50.0 g (0.23 mole) of 3,5-diacetoxybenzaldehyde and 21.4 g (0.23 mole) of 1,2-ethanedithiol in 25 ml of ether until the solution became warm. After allowing the solution to stand at ambient temperature for 0.75 hour, the solvent was removed in vacuo and excess methanol was added. A solid of 1,3-diacetoxy-5-(1,3-dithiolan-2-yl)benzene (mp 94°-96° C.) was separated by filtration. It was resuspended in 100 ml of methanol and 21.7 g (0.23 mole) of potassium hydroxide pellets were added. On stirring the mixture at ambient temperature for 0.5 hour, the mixture became homogeneous. The solvent was removed in vacuo and the residue after acidification with 6N hydrochloric acid was extracted with ethyll acetate. The extract was washed with water until neutral, dried and evaporated in vacuo to leave 5-(1,3-dithiolan-2-yl)resorcinol as a gum (41.3 g, 84%) which was used without further purification in the subsequent reaction. The structure was confirmed by the infrared and nuclear magnetic resonance spectra.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18].C(O)(C)C>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:21][CH:20]([O:23][CH2:24][CH3:25])[O:19][CH2:17][CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CBr)OCC
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CCOC(COC1CCN(Cc2ccccc2)CC1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
1-Benzyl-4-hydroxy piperidine (11.5 g.) dissolved in dry dimethylformamide (DMF) (25 ml.) was added dropwise to a stirred suspension of sodium hydride (2.8 g. of 50% dispersion in oil in dry DMF [25 ml.]), under dry nitrogen, and then stirred at room temperature for 3 hours. The suspension was cooled in an ice/water bath while 2-bromoacetaldehyde diethylacetal (13.0 g.) in dry dimethylformamide (25 ml.) was added dropwise, followed by stirring at room temperature for 24 hours. The above process was repeated to add more sodium hydride (2.8 g.) and the acetal (13.0 g.). Iso-propyl alcohol (50 ml.) was added, and the mixture was stirred for 1/2 hour, followed by filtration through "Hyflo" (Trademark). The filtrate was concentrated in vacuo, suspended in water (100 ml.) and basified to pH 11 with 5 N sodium hydroxide. After extraction with chloroform (2×100 ml.) the combined extracts were taken to dryness in vacuo to give an orange oil which was distilled in vacuo to give 1-benzyl-4-(2,2-diethoxyethoxy)-piperidine (14.1 g.), b.p. 152° C.@0.1 mm.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[H-].[Na+].Cl[C:11]1[N:16]=[C:15]([Cl:17])[CH:14]=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:12]=1>O1CCCC1>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][O:3][C:11]1[N:16]=[C:15]([Cl:17])[CH:14]=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:12]=1)[CH3:7]
Reactant: CCOC(=O)CO
Reactant: Clc1ccc(CNc2cc(Cl)nc(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1nc(Cl)cc(NCc2ccc(Cl)cc2)n1

Procedure:
To 4.2 g. of ethyl glycolate in 50 ml. of anhydrous tetrahydrofuran was added 1.7 g. of sodium hydride oil dispersion (57 percent) with stirring. There was added after 20 minutes 11.5 g. of 2,4-dichloro-6-(p-chlorobenzylamino)pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][C:17](F)=[C:16]([Cl:21])[CH:15]=1)(=[O:13])=[O:12]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:17]2[CH:18]=[CH:19][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:15][C:16]=2[Cl:21])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1O
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Product: CS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2N)c(Cl)c1

Procedure:
The subtitle compound was prepared by the method of example 3 step viii) using 4-chloro-2-hydroxyaniline and the product from example 3 step vii). Yield 3.0 g.
Reaction SMILES: O=C1CCC(=O)N1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:26]([O-:28])=O)=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[CH:15]=2)[N:10]([CH2:29][C:30]([F:33])([CH3:32])[CH3:31])[N:9]=1.[NH2:34][C@H:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40]>ClCCl.C(OCC)(=O)C>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[C:26]([NH:34][C@H:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40])=[O:28])[N:10]([CH2:29][C:30]([F:33])([CH3:32])[CH3:31])[N:9]=[CH:8]2
Reactant: N[C@H]1CCNC1=O
Reactant: CC(C)(F)Cn1nc(N2C(=O)CCC2=O)c2cc(Oc3ccc(F)cc3F)c(C(=O)[O-])cc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(F)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCNC3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 1032.3 %

Procedure:
To a solution of 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6-carboxylate (prepared according to Example 26; 100 mg, 0.217 mmol) in dichloromethane (1 mL) was added (S)-3-aminopyrrolidin-2-one (4a) 521 mg, 4.56 mmol), and the reaction mixture was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on a silica gel column, eluting with 50% acetone/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-N-(2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide (Ik) (1.00 g, 99%). Mass spec: 447 (M+1). 1H NMR (CDCl3) δ 8.42 (s, 1H), 8.21 (br, 1H), 7.15 (m, 1H), 7.03 (s, 1H), 7.01 (m, 1H), 6.91 (m, 1H), 6.59 (br, 1H), 4.58 (m, 1H), 4.55 (d, 2H), 3.43 (m, 2H), 2.84 (m, 1H), 2.06 (m, 1H), 1.40 (d, 3H), 1.39 (d, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:13][C:14](=[O:16])[CH3:15])=[CH:8][C:7]=1[CH:17]([CH3:19])[CH3:18].[CH3:20][O:21][C:22]1[C:29]([CH3:30])=[C:28]([CH3:31])[C:27]([O:32][CH3:33])=[C:26]([CH3:34])[C:23]=1[CH2:24]Cl.C(N(CC)CC)C>CN(C)C=O>[CH3:20][O:21][C:22]1[C:29]([CH3:30])=[C:28]([CH3:31])[C:27]([O:32][CH3:33])=[C:26]([CH3:34])[C:23]=1[CH2:24][N:2]([CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:13][C:14](=[O:16])[CH3:15])=[CH:8][C:7]=1[CH:17]([CH3:19])[CH3:18])[CH3:1]
Reactant: CNCCOc1cc(C)c(NC(C)=O)cc1C(C)C
Reactant: COc1c(C)c(C)c(OC)c(CCl)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(C)c(C)c(OC)c(CN(C)CCOc2cc(C)c(NC(C)=O)cc2C(C)C)c1C
Temperature: 25 °C
Yield: 75 %

Procedure:
N-Methyl-2-(4-acetylamino-2-isopropyl-5-methylphenoxy)ethylamine (4.94 g) and 2,5-dimethoxy-3,4,6-trimethylbenzyl chloride (4.29 g) were dissolved in N,N-dimethylformamide (70 ml), and triethylamine (1.89 g) was added dropwise while stirring the mixture at room temperature. The mixture was stirred at room temperature for 16.5 hours. After the reaction, the solvent was distilled off, and water was added. The mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (eluent; ethyl acetate/benzene=1/1) to give 6.40 g of a pale-yellow solid. A portion (1.0 g) was taken therefrom and recrystallized from diisopropyl ether to give 0.62 g of the title compound (colorless crystals).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:18])[CH2:9][NH:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)Cl>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:18][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)NCC(=O)c1cccc(Cl)c1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc(-c2cccc(Cl)c2)o1
Yield: 51.6 %

Procedure:
A mixture of the product from Step 79b (1.28 g, 4.70 mmol, 1 eq), benzene (8 mL), and POCl3 (2.0 mL, 21 mmol) is heated under reflux for 65 h and cooled. The mixture is then evaporated and extracted between CHCl3 and water. The organic layer is separated, dried over MgSO4, filtered, and evaporated. The residue is crystallized from EtOH to give the title product (0.61 g, 51%). MS (ESI) for C12H10ClNO3 m/z 252 (M+H)+.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([C:13]1[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:20](Cl)(=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.ClCCl>O>[CH2:6]([C:13]1[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[C:17]=1[C:20]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:29])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1cc(Cc2ccccc2)sc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.7 %

Procedure:
Tin tetrachloride (4.6 mL, 71.76 mmol) was added dropwise over a 10 minute period to a stirred, −78° C. solution of 2-benzyl-4,5-dimethylthiophene (6.6 g, 32.62 mmol), anisoyl chloride (5.90 g, 34.6 mmol) and dichloromethane (120 mL) under a dry nitrogen atmosphere. After 5 hours at −78° C., the reaction mixture was slowly warmed to room temperature over a 2 h period. The reaction mixture was added to water and extracted with ether. The ether extract was washed with sat. aq. sodium bicarbonate and brine. The solvent was removed and the resultant solid was triturated with ether to give the title compound as a off-white solid (9.62 g, 88%): mp 85-86° C.: NMR (CDCl3); δ7.80 (ddd, J=8, 8, 1 Hz, 2H), 7.24-7.10 (m, 5H), 7.92 (ddd, J=8, 8, 1 Hz, 2H), 3.93 (s, 2H), 3.88 (s, 3H), 2.28 (s, 3H), 1.90 (s, 3H); MS (EI): 336 (100%, MI); Anal. Calc. for C21H20O2S: C, 74.97; H, 5.99; N, 0.00. Found: C, 75.11; H, 6.02; N, 0.05.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]=[C:14]([CH3:26])[CH2:15][P:16]([O:22][CH:23]([CH3:25])[CH3:24])([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=[CH:29][CH:28]=1>ClCCl.C(O)C>[CH2:28]([O:11][C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:13]=[C:14]([CH3:26])[CH2:15][P:16]([O:22][CH:23]([CH3:25])[CH3:24])([O:18][CH:19]([CH3:20])[CH3:21])=[O:17])[CH3:29]
Reactant: CC(=C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)CP(=O)(OC(C)C)OC(C)C
Reactant: c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)[C@@H](C=C(C)CP(=O)(OC(C)C)OC(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
0.09 g of 1-amino-1-chloro-N,N,2-trimethylpropene is added at 0°-5° to a solution of 0.2 g of acid 3 according to c) in 15 ml of dry dichloromethane. After stirring for 30 minutes at 0°, 0.4 g of pyridine in 5 ml of ethanol is added. The mixture is stirred further at 0° for 90 minutes and at room temperature for 15 hours, and is then diluted with 20 ml of dichloromethane and washed twice with 20 ml of water each time. The organic phase is dried using sodium sulphate, concentrated by evaporation and chromatographed on 25 g of silica gel. Elution with ethyl acetate/ methanol 10:1 yields 0.12 g of 4. 1H-NMR (300 MHz, CDCl3): 1.2-1.4 (m, 2(CH3)2CHO, CH3CH2O); 1.45 (s, (CH3)3CO); 1.98 (d, J=3, CH3 -C(4)); 2.55 (d, J=23, 2H-C(5)); 4.2 (m, CH3CH2O); 4.69 (m, 2 (CH3)2CHO); 5.0 (m, H-C(2)); 5.16 (m, H-C(3), NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][C:12]([CH3:14])=O)[C:7]=2[CH:15]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([CH:12]([CH3:14])[CH2:11][C:8]4[C:7]5[CH:15]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[O:10][CH:9]=4)[CH2:29][CH2:28]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: Clc1cc(N2CCNCC2)c2ncccc2c1
Reactant: COc1ccc2occ(CC(C)=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc2occ(CC(C)N3CCN(c4cc(Cl)cc5cccnc45)CC3)c2c1

Procedure:
6-chloro-8-{4-[2-(5-methoxy-1-benzofuran-3-yl)-1-methylethyl)piperazin-1-yl]quinoline was prepared by generally following the procedure outlined in example 38, step 2, starting from the 1-(5-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1. mmol) and 6-chloro-8-piperazino quinoline (247.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a yellow oil.Yield: 54 mg (12%); (M+H): 436; 1HNMR (400 MHz, CDCl3): δε8.82˜8.81 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.02˜8.00 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.99˜6.58 (m, 7H); 3.87 (s, 3H); 3.46˜2.62 (m, 11H); 1.15˜1.13 (d, J=6.0 Hz, 3H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=3)[CH:12]=[C:11]([CH2:25][OH:26])[N:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[C:32]([C:34]1[S:35][CH:36]=[CH:37][C:38]=1[C:39](O)=[O:40])=O>>[OH:26][CH2:25][C:11]1[N:10]=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([N:1]3[C:39](=[O:40])[C:38]4[CH:37]=[CH:36][S:35][C:34]=4[C:32]([C:31]4[CH:42]=[C:43]([O:47][CH3:48])[C:44]([O:45][CH3:46])=[C:29]([O:28][CH3:27])[CH:30]=4)=[N:2]3)[CH:8]=2)[C:18]2[C:13]([CH:12]=1)=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=2
Reactant: CCOc1cc2cc(CO)nc(-c3ccnc(NN)c3)c2cc1OCC
Reactant: COc1cc(C(=O)c2sccc2C(=O)O)cc(OC)c1OC
Product: CCOc1cc2cc(CO)nc(-c3ccnc(-n4nc(-c5cc(OC)c(OC)c(OC)c5)c5sccc5c4=O)c3)c2cc1OCC

Procedure:
2-Hydrazino-4-(3-hydroxymethyl-6,7-diethoxyisoquinolin-1-yl)pyridine and 2-(3,4,5-trimethoxybenzoyl)-3-thiophenecarboxylic acid are treated in the same manner as in Example 7-(4) to give 4-(3-hydroxymethyl-6,7-diethoxyisoquinolin-1-yl)-2-[7-(3,4,5-trimethoxyphenyl)thieno[2,3-d]pyridazin-4(5H)-on-5-yl]pyridine.
Reaction SMILES: [ClH:1].[NH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.C(OCC)(=O)C>[ClH:1].[NH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(N)CCc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(N)CCc1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
4-(3-Amino-3-methylbutyl)phenol hydrochloride (1.14 g, 5.3 mmol), 4-fluorobenzonitrile (0.77 g, 6.4 mmol, 1.2 eq.) and potassium carbonate (1.65 g, 11.6 mmol, 2.2 eq.) were suspended in N,N-dimethyl-acetamide (15 ml) and stirred for 16 hours at 110° C. After this time, the darkened mixture was allowed to cool to ambient temperature. The suspension was diluted with ethyl acetate (100 ml) and washed with 1N NaOH (2×100 ml). The organic layer was treated with 5N HCl (100 ml), producing a white precipitate at the biphasic interface. The solid material was filtered and dried, triturated with pentane and dried in vacuo for 14 hours to produce a white solid (1.04 g, 71%). NMR, MS
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[S:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:7][C:6]1[C:2]([O:1][CH3:13])=[C:3]([C:9]([O:11][CH3:12])=[O:10])[S:4][C:5]=1[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1sc(C)c(C)c1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1sc(C)c(C)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-hydroxy-4,5-dimethylthiophene-2-carboxylate (Preparation 1) (29.7 g, 160 mmol) in anhydrous acetone (500 ml) was added anhydrous potassium carbonate (24.5 g, 178 mmol) and the mixture stirred for 1 hour at room temperature. Dimethyl sulphate (22.4 g, 178 mmol) was added and the mixture stirred under reflux for 2.5 hours. The solvent was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was washed with brine, dried with sodium sulphate and evaporated to give crude product which was used in the following preparation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:17][C:18]([C:20]2[S:21][C:22]([Br:26])=[CH:23][C:24]=2[NH2:25])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH2:27](O)C>>[Br:26][C:22]1[S:21][C:20]2[C:18](=[O:19])[N:17]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:27]=[N:25][C:24]=2[CH:23]=1
Reactant: CCO
Reactant: COc1cc(NC(=O)c2sc(Br)cc2N)ccc1OCCN1CCCC1
Product: COc1cc(-n2cnc3cc(Br)sc3c2=O)ccc1OCCN1CCCC1

Procedure:
A solution of 3-amino-5-bromothiophene-2-carboxylic acid [3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]amide (415 mg) was heated in ethyl o-formate (12.4 mL) at 105° C. overnight; the ethanol produced was distilled off. The reaction solution was then mixed with ethyl acetate and water. The aqueous phase was extracted several times with ethyl acetate, and then the combined organic phases were dried over sodium sulfate and concentrated. The product with the molecular weight of 450.36 (C19H20BrN3O3S) was obtained in this way; MS (ESI): 451, 453 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:18][CH2:19][C:20]([F:23])([F:22])[F:21].C1C(=O)N([Br:31])C(=O)C1>C(Cl)(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:4][C:5]([C:8]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[Br:31]
Reactant: CCOC(=O)C1(c2ccc(N)c(OCC(F)(F)F)c2)CCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1(c2cc(Br)c(N)c(OCC(F)(F)F)c2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a stirred solution of ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (1.2 g, 4.0 mmol) in dry CCl4 (60 mL), NBS (0.427 g, 3.2 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to give ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (920 mg) as a yellow solid.