Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]([CH2:32][C:33]#[C:34][CH3:35])[C:17](=[O:31])[N:18]3[C:23]2[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH3:30])[CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH2:32]([N:16]1[C:15]2[C:19](=[N:20][CH:21]=[N:22][C:14]=2[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:18]([C:23]2[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH3:30])[CH:24]=2)[C:17]1=[O:31])[C:33]#[C:34][CH3:35]
Reactant: CC#CCn1c(=O)n(-c2ccc(=O)n(C)c2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: O=C(O)C(F)(F)F
Product: CC#CCn1c(=O)n(-c2ccc(=O)n(C)c2)c2ncnc(N3CCNCC3)c21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-[7-(2-Butynyl)-9-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-8-oxo-8,9-dihydro-7H-purin-6-yl]piperazine-1-carboxylic acid t-butyl ester (15 mg) was dissolved in trifluoroacetic acid, and this reaction solution was stirred at room temperature for five minutes and then concentrated. The residue was purified by reverse phase high performance liquid chromatography to give the title compound (10.52 mg).
Reaction SMILES: [CH:1]([N:4]([CH2:8][C:9]1[O:18][C:12]([CH2:13][NH:14][CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].CS[C:21](=[C:24]([C:27]#[N:28])[C:25]#[N:26])[NH:22][CH3:23]>>[CH:1]([N:4]([CH2:8][C:9]1[O:18][C:12]([CH2:13][NH:14][CH2:15][CH2:16][NH:17][C:21](=[C:24]([C:27]#[N:28])[C:25]#[N:26])[NH:22][CH3:23])=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)N(Cc1ccc(CNCCN)o1)C(C)C
Reactant: CNC(SC)=C(C#N)C#N
Product: CNC(NCCNCc1ccc(CN(C(C)C)C(C)C)o1)=C(C#N)C#N

Procedure:
Using Compound g and [(methylthio)(methylamino)methylene]propanedinitrile, the corresponding procedure of Example 1 was followed to give Compound 12 as light yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[C:8]1[S:9][C:10]([C:12](=[O:14])[CH3:13])=[CH:11][C:7]=1[CH2:6][CH2:5]2>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[C:8]1[S:9][C:10]([C:12](=[O:14])[CH3:13])=[CH:11][C:7]=1[CH:6]=[CH:5]2
Reactant: CC(=O)c1cc2c(s1)-c1ccc(Br)cc1CC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2ccc3cc(Br)ccc3c2s1
Temperature: 100 °C
Yield: 85.7 %

Procedure:
1-(7-bromo-4,5-dihydronaphtho[1,2-b]thiophen-2-yl) ethanone (11b) (600 mg, 1.95 mmol) was dissolved in 20 ml toluene and manganese dioxide (943 mg, 9.77 mmol) was added and the mixture was heated at 100° C. for 26 hr. Aliquots were taken in between to check the progress of the reaction by HPLC. Once the reaction was complete, the mixture was filtered over a pad of celite, and the celite pad was washed with ethyl acetate. The ethyl acetate layer was concentrated to obtain the desired compound (11c) (0.51 g, 85%). m/z 304, 306 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([CH2:8][N:9]([CH3:11])[CH3:10])[CH:7]=1>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH2:8][N:9]([CH3:11])[CH3:10])[CH:7]=1)[CH:12]=[O:13]
Reactant: CN(C)Cc1cc(Br)cc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CN(C)Cc1cc(Br)cc(C=O)c1
Temperature: 105 °C
Yield: 80 %

Procedure:
Manganese(IV) oxide (0.71 g, 8.2 mmol) was added to a solution of {3-bromo-5-[(dimethylamino)methyl]phenyl}methanol (0.40 g, 1.6 mmol, from Step B) in toluene (10 mL). The mixture was heated to 105° C. for 2 hours, then was cooled to room temperature and was filtered and concentrated to afford a light yellow oil (0.31 g, 80%). 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 7.90 (dd, J=1.7 Hz, 1H), 7.82-7.69 (m, 2H), 3.46 (s, 2H), 2.25 (s, 6H). LCMS (M+H)+: 241.9, 243.9.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][N:16]=3)=[CH:29][CH:28]=2)[CH:8]=1
Reactant: O=Cc1ccc(-c2cnccn2)cc1
Reactant: COC(=O)CCc1cccc(CN)c1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 4-pyrazin-2-yl-benzaldehyde, of Preparation 27, using the method described in Example 1, Step A except the imine was formed in MeOH at reflux over 2 h. 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 8.62 (dd, 1H), 8.49 (d, 1H), 7.98 (d, 2H), 7.66 (m, 1H), 7.54-7.43 (m, 3H), 7.24 (m, 1H), 7.09 (m, 1H), 3.88 (s, 2H), 3.80 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.63 (t, 2H); MS 362 (M+1).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:39])[NH:37][NH2:38]>O1CCCC1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:38][NH:37][C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 111.4 %

Procedure:
To a solution of the carboxylic acid (6b, 371 mg, 1.34 mmol) of Example 9 or 16 in tetrahydrofuran (7 mL) were added triethylamine (0.227 mL) and isobutyl chloroformate (218 μl) under ice-cooling, followed by stirring at 0° C. for 15 minutes. To the reaction solution was added t-butyl carbazate (245 mg) at 0° C., followed by stirring at room temperature for 1.5 hours, and then concentrating under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1-0/1) to afford 583 mg of the title compound (yield 98%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([C:7]([C:8](=[CH:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([F:15])[CH:17]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Br)s1
Reactant: O=Cc1cccc(F)c1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1cccc(F)c1)C(=O)c1ccc(Br)s1
Yield: 98.1 %

Procedure:
A solution of ethyl 3-(5-bromothiophen-2-yl)-3-oxopropanoate (2.456 g, 8.86 mmol, from Preparation 1, Step 1), 3-fluorobenzaldehyde (1.034 ml, 9.75 mmol), piperidine (0.088 ml, 0.886 mmol) and acetic acid (0.389 ml, 6.8 mmol) in benzene (50 ml) was heated at 85° C. for 6 h using a Dean-Stark trap to remove the formed water. The reaction solution was concentrated. The crude product was dissolved in a small amount of toluene and charged to 80 g silica gel cartridge which was eluted with a 15 min gradient from 0-5% ethyl acetate in hexane to give ethyl 2-(5-bromothiophene-2-carbonyl)-3-(3-fluorophenyl)acrylate as a viscous yellow oil (3.33 g). HPLC: Rt 3.728 min (Method A); LCMS m/z 407.02, 405.02 (M+23)
Reaction SMILES: [CH3:1][N:2]1[C:8]2[C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:16])[N:5]([CH3:17])[CH2:4][CH2:3]1>CO.[Pd]>[NH2:13][C:9]1[C:8]2[N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH3:17])[C:6](=[O:16])[C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CN1CCN(C)c2c(cccc2[N+](=O)[O-])C1=O
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C)c2c(N)cccc2C1=O
Reaction time: 2 h
Yield: 97.1 %

Procedure:
1,4-Dimethyl-9-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (#) (300 mg, 1.27 mmol) was dissolved in MeOH (20 ml) and placed in a Parr bottle. Pd—C (10%, 30 mg) was added, and the resulting mixture was shaken under 20 psi H2 for 2 h. The reaction mixture was filtered through celite, washed with MeOH, and concentrated to afford 9-Amino-1,4-dimethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a light grey solid (253 mg, 99%). mp 165-166° C.; LCMS: m/z=206.29 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.06 (m, 2H), 6.86 (m, 1H), 3.34 (m, 4H), 3.19 (s, 3H), 2.79 (s, 3H).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:21]([CH3:34])=[C:22]([CH3:33])[C:23]4[O:27][C:26]([CH3:29])([CH3:28])[CH:25](O)[C:24]=4[C:31]=3[CH3:32])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH2:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH2:42]([NH:49][CH:25]1[C:24]2[C:31]([CH3:32])=[C:20]([N:17]3[CH2:16][CH2:15][N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=4)[CH2:19][CH2:18]3)[C:21]([CH3:34])=[C:22]([CH3:33])[C:23]=2[O:27][C:26]1([CH3:29])[CH3:28])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Reactant: NCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(NCc3ccccc3)C(C)(C)O4)CC2)cc1
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
Methane sulfonyl chloride (0.12 mL, 1.55 mmol) was added dropwise to a solution of 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol (300 mg, 0.757 mmol) obtained in Reference Example 18 and triethylamine (0.4 mL, 2.87 mmol) in THF (3 ml) under ice cooling. The reaction mixture was stirred for 10 minutes and then benzylamine (0.4 mL, 3.66 mmol) was added. The resulting mixture was stirred under ice cooling for 1 hour. The reaction mixture was poured into 1N aqueous potassium carbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane then hexane/ethyl acetate=5/1) to obtain 280 mg (yield 76%) of the title compound via recrystallization (ethanol). mp. 93–95° C.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:14]([O:19][CH3:20])=[N:15][CH:16]=[N:17][CH:18]=1)=[S:11])(=O)C1C=CC=CC=1.Cl>CC[O-].[Na+]>[CH3:20][O:19][C:14]1[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[CH:18][N:17]=[CH:16][N:15]=1
Reactant: COc1ncncc1NC(=S)NC(=O)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: COc1ncncc1NC(N)=S
Reaction time: 1 h
Yield: 60 %

Procedure:
6.0 g N-benzoyl-N'-(4-methoxy-5-pyrimidyl)-thiourea are dissolved in 120 ml sodium ethylate solution (0.8 g sodium). After 1 hour, the solution is neutralized with diluted hydrochloric acid. The mixture is concentrated and the residue is washed with water and recrystallized from a methanol/water mixture. 2.3 g N-(4-methoxy-5-pyrimidyl)-thiourea having a melting point of 182° to 183° C. (decomp.) are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[O:9]=[C:10]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[S:22][C:23]([C:32]#[N:33])=[C:24](NC3C=CC=CC=3)[C:13]=2[CH:12]=[CH:11]1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]2[C:13]3[CH:12]=[CH:11][C:10](=[O:9])[N:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:14]=3[S:22][C:23]=2[C:32]#[N:33])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: N#Cc1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Product: N#Cc1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1cccc(Br)c1

Procedure:
The title compound was prepared from 3-bromoaniline (155 mg, 0.9 mmol) following the method described for the compound of Example 18 to give the product as a pale yellow solid (183 mg). δH (CDCl3) 7.91-7.83 (3H, m), 7.83-7.66 (2H, m), 7.62 (1H, d, J 9.7 Hz), 7.52-7.44 (3H, m), 7.23 (1H, dt, J 7.1, 1.7 Hz), 6.81 (1H, d, J 9.7 Hz), 6.74 (1H, bs). LCMS (ES+) 422 (M+H)+ 79Br, 424 (M+H)+ 81Br.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([F:20])[C@H:17]([OH:21])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C@:24]1([OH:32])[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1)#[CH:23].C(N(CC)CC)C.N>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:23]#[C:22][C@:24]2([OH:32])[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([F:20])[C@H:17]([OH:21])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1F
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O[C@@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@@H]1F
Temperature: 75 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
A mixture of 50 mg of 2-benzyl-6-[(3R,4S)-3-hydroxy-4-fluoropyrrolidine-1-yl]-3-iodopyridine, 21 mg of (3R)-3-ethynyl-3-quinuclidinol, 15 mg of tetrakis(triphenylphosphine)palladium(0), 1 mg of cuprous iodide, 53 μl of triethylamine and 3.0 ml of N,N-dimethylformamide was heated under stirring for 3 hours at 75° C. in a nitrogen atmosphere. The reaction solution was poured into an aqueous dilute ammonia, was then extracted with ethyl acetate. Then, the organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1), to give 37 mg of the target compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C.[NH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28].C(N(CC)CC)C>C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCCN1
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1CCCN1C(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
15.9 g. of p-benzyloxybenzoyl chloride, 500 ml. of absolute diethyl ether and 6.3 ml. of 2-pyrrolidinone are treated with 13.4 ml. of triethylamine at 0° C. to 10° C. while stirring. The mixture is stirred at reflux for 9 hours, then cooled down and treated at 0° C. with cold water and ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated. The residue is triturated with diethyl ether and the insoluble constituents are chromatographed over silica gel (particle size 0.2-0.5 mm). The constituents elutable with methylene chloride are triturated with diethyl ether. The insoluble constituents are filtered off and there is obtained 1-(p-benzyloxybenzoyl)-2-pyrrolidinone, having a melting point of 115°-117° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[CH:5][C:6]2[S:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.II.[C:14]([CH:17]1[CH2:19][CH2:18]1)(=[O:16])[CH3:15]>O1CCCC1.C(#N)C.O>[S:10]1[C:6]2[CH:5]=[CH:4][C:3]([C:14]([CH:17]3[CH2:19][CH2:18]3)([OH:16])[CH3:15])=[CH:11][C:7]=2[CH:8]=[CH:9]1
Reactant: Brc1ccc2sccc2c1
Reactant: CC(=O)C1CC1
Agent: II
Agent: [Mg]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(O)(c1ccc2sccc2c1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.60 g (24.64 mmol) of magnesium turnings were dried by heating under argon and, after cooling to RT, 30 ml of tetrahydrofuran were added. 5.00 g (23.46 mmol) of 5-bromo-1-benzothiophene in 30 ml of tetrahydrofuran, and traces of iodine, were added to the mixture, which was stirred at RT for 30 min. Addition of 2.17 g (25.81 mmol) of acetylcyclopropane in 30 ml of tetrahydrofuran was followed by stirring for 2 h. The reaction solution was mixed with water and acetonitrile, and the mixture was filtered through kieselguhr. The organic solvents were removed in a rotary evaporator, and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). The acetonitrile was removed from the combined product phases in a rotary evaporator, and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were again washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the solvents were removed in vacuo. 2.39 g (46% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=O.S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]([NH2:27])=[O:26])[C:20](=[O:28])[CH2:19]2>CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]([NH2:27])=[O:26])[C:20](=[O:28])[CH:19]2[C:8](=[O:10])[C:4]1[S:5][CH:6]=[CH:7][C:3]=1[O:2][CH3:1]
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: COc1ccsc1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: O=S(Cl)Cl
Product: COc1ccsc1C(=O)C1C(=O)N(C(N)=O)c2ccc(Cl)cc21
Yield: 29 %

Procedure:
A 2.00 g (12.69 mmoles) sample of 3-methoxy-2-thiophenecarboxylic acid (prepared according to Gronowitz, S., Arkiv. for Kemi. 12:239 (1958)) was reacted with 10 ml of thionyl chloride according to Example 32. Evaporation of excess thionyl chloride left 2.17 g of 3-methoxy-2-thiophenecarbonyl chloride as a crystalline solid, m.p. 86°-88° C. The acid chloride was coupled to 2.16 g (10.24 mmoles) of 5-chloro-2-oxindole-1-carboxamide in the presence of 3.30 g (27 mmoles) 4-(N,N-dimethylamino)pyridine according to the procedure in Example 32. Aqueous acid quench followed by filtration gave a yellow solid which was purified by recrystallization to give 1.04 g (2.96 mmoles, 29% yield) of 5-chloro-3-(3-methoxy-2-thenoyl)-2-oxindole-1-carboxamide as a yellow solid, m.p. 272°-274° C. (acetic acid).
Reaction SMILES: [Li+].[OH-].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C@@H:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[CH2:32][CH2:31][CH2:30][NH:29][C:28]=4[N:27]=3)=[CH:19][CH:18]=2)[CH2:10][C:11]([O:13]CC)=[O:12])[CH:4]=1.Cl>C1COCC1.O>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C@@H:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[CH2:32][CH2:31][CH2:30][NH:29][C:28]=4[N:27]=3)=[CH:19][CH:18]=2)[CH2:10][C:11]([OH:13])=[O:12])[CH:4]=1
Reactant: CCOC(=O)C[C@H](Cc1ccc(OCCc2ccc3c(n2)NCCC3)cc1)c1cccnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@H](Cc1ccc(OCCc2ccc3c(n2)NCCC3)cc1)c1cccnc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
1.0 M LiOH (2.6 mL, 2.6 mmole) was added to a solution of ethyl (S)-3-(pyridin-3-yl)-4-[4-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy]phenyl]butanoate (572 mg, 1.28 mmole) in THF/H2O (8 mL), and the mixture was heated at 50° C. After 18 hr, the reaction was cooled to RT and acidified to pH 6.0 with 10% HCl. The precipitated solid was collected by suction filtration, washed with H2O, and dried in vacuo to afford the title compound (414 mg, 77%): 1H NMR (400 MHz, MeOH-d4) δ 8.28 (dd, J=4.9, 1.4 Hz, 1 H), 8.21 (d, J=1.8 Hz, 1 H). 7.68 (d, J=8.0 Hz, 1 H), 7.25-7.27 (m, 2 H), 6.91 (d, I=8.6 Hz, 2 H), 6.71 (d, J=8.6 Hz, 2 H), 6.53 (d, J=7.3 Hz, 1 H), 4.08-4.22 (m, 2 H), 3.30-3.45 (m, 3 H), 2.90-3.05 (m, 3 H), 2.70-2.85 (m, 3 H), 2.68 (dd, J=15.2, 6.7 Hz, 1 H), 2.58 (dd, J=15.2, 8.5 Hz, 1 H), 1.80-1.97 (m, 2 H); MS (ES) m/e 418 (M+H)+. Anal. Calcd for C23H25N3O3.0.25H2O: C, 71.15; H, 6.57; N, 9.96. Found: C, 71.11; H, 6.66; N, 9.82.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)=[O:11])=[CH:3][CH:2]=1.[N:25]1([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][C:15]([N:28]3[CH2:29][CH2:30][N:25]([C:31](=[O:32])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:42])([F:40])[F:41])[CH2:26][CH2:27]3)=[CH:16][CH:17]=2)=[O:11])=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NCCc1ccc(-c2ccccc2)cc1)c1ccc(Cl)nn1
Product: O=C(NCCc1ccc(-c2ccccc2)cc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-biphenyl-4-yl-ethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (63.2% yield). 1H NMR (500 MHz, CDCl3) δ 8.07, 7.98, 7.76, 7.64, 7.60-7.52, 7.44, 7.38-7.30, 7.00, 4.06, 3.88, 3.82-3.68, 3.36, 2.98.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([NH:5][CH:6]1[CH2:10][CH2:9][NH:8][C:7]1=[O:11])=[O:4].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].Cl>O1CCCC1>[CH2:28]([O:27][C:25]([N:8]1[CH2:9][CH2:10][CH:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:12])[F:13])[C:7]1=[O:11])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1NCCC1NC(=O)C(F)(F)F
Reactant: O=C(Cl)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(NC(=O)C(F)(F)F)C1=O
Temperature: 25 °C

Procedure:
To Intermediate 3 (3.5 g) in tetrahydrofuran (100 ml) at −70° C. was added lithium hexamethyldisilazide (20 ml). After ¼ h, benzyl chloroformate (2.8 ml) was added. The mixture was warmed to room temperature for 1 h and 1 M hydrochloric acid (25 ml) added. After extraction with ethyl acetate (3×25 ml), the combined extracts were washed with 2% ammonia solution, 2M hydrochloric acid and brine, then dried (MgSO4). After solvent removal, the white solid was recrystallised from ethyl acetate: hexane 5:1 to give the title compound (4.2 g), T.l.c. silica (18:2 ethyl acetate: methanol) Rf 0.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[OH:32]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:26]3[C:25]([F:24])=[CH:30][CH:29]=[CH:28][C:27]=3[F:31])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: Oc1c(F)cccc1F
Product: COc1ccc(-c2cc(Oc3c(F)cccc3F)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0.613 mmol) and 2,6-difluorophenol were reacted as starting materials at 150° C. for 72 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless crystalline powder (101.0 mg, 39.3%). Melting point: 204.7-206.4° C. (chloroform-hexane).