Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:17]([CH2:18][C:19]([N:23]([CH3:22])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CNc1ccccc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
Under nitrogen atmosphere, oxayl chloride (2.21 g, 0.0174 mole) was added slowly dropwise to a stirred and chilled (~10° C.) suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) in 75 ml of dimethylformamide. After the addition was complete, the reaction was heated at 60° C. for 5 hrs. This acylchloride solution was added dropwise to a stirred and cooled (~10° C.) solution of N-methylaniline (2.02 g, 0.019 mole), triethylamine (1.88 g, 0.019 mole), and 74 ml of dimethylformamide. The reaction was stirred at room temperature overnight. The reaction mixture was poured into 200 ml of water and diluted with water until the cloud point. The mixture was seeded and refrigerated overnight. The solid was collected by filtration and dried under high vacuum. The solid was suspended in dilute, sodium bicarbonate, collected by filtration, washed with water, and dried under high vacuum at 50° C. The solid was recrystallized from isopropyl alcohol-water, collected by filtration, washed with water, and dried under high vacuum first at 56° C., then at 98° C. for 2 days to give 3.0 g (45%) of crystals, mp 170°-171° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C1(C)C=CC=CC=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[N:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[Br:8][C:4]1[N:3]=[C:2]([C:19]2[CH:20]=[N:21][CH:22]=[C:17]([F:16])[CH:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: OB(O)c1cncc(F)c1
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: Cc1ccccc1
Solvent: CCO
Product: Fc1cncc(-c2cccc(Br)n2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Added to a solution of 2.00 g (8.44 mmol) of 2,6-dibromo-pyridine in 80 ml of a 4/1 mixture of toluene and ethanol, are 1.18 g (8.44 mmol) of 5-fluoropyridine-3-boronic acid, 0.48 g (0.42 mmol) of Pd(PPh3)4 and 25 ml of a 1M aqueous solution of sodium carbonate. The mixture is stirred at 90° C. for 2 hours.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:37][CH2:36][C:35]2[NH:34][N:33]=[CH:32][C:31]=2[CH2:30]1.[H-].[Na+].CN(C)C(=O)C.[CH3:46][C:47]1([CH3:50])[CH2:49][O:48]1>O.C(OCC)(=O)C>[OH:48][C:47]([CH3:50])([CH3:49])[CH2:46][N:33]1[CH:32]=[C:31]2[C:35]([CH2:36][CH2:37][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:30]2)=[N:34]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCc3[nH]ncc3C2)c2ncnn12
Reactant: CC1(C)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCc3nn(CC(C)(C)O)cc3C2)c2ncnn12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 11 %

Procedure:
A mixture of 4′-{[5-oxo-7-propyl-4-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.36 g), sodium hydride (0.044 g) and N,N-dimethylacetamide (3 mL) was stirred at 0° C. for 5 min and then at room temperature for 20 min. 2,2-Dimethyloxirane (0.65 mL) was added, and the mixture was stirred at 120° C. for 1.5 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.047 g, 11%).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][CH:17]([CH3:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20].[CH3:24][O:25][CH2:26][C:27]([C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)([CH3:29])[CH3:28]>>[CH3:24][O:25][CH2:26][C:27]([C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:19]([CH2:18][CH:17]([CH3:23])[CH3:16])(=[O:21])=[O:20])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:34][CH:35]=1)([CH3:29])[CH3:28]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: COCC(C)(C)c1ccc(N)cc1
Product: COCC(C)(C)c1ccc(N2CCC3(CCN(S(=O)(=O)CC(C)C)CC3)C2=O)cc1

Procedure:
Light yellow solid. MS (ESI): 437.24 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-methyl-propane-1-sulfonyl chloride, 4-(2-methoxy-1,1-dimethyl-ethyl)-phenylamine (synthesis: Ch. Tegley et al, WO 2005 021532).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCCCCO
Product: OCCCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 24 %

Procedure:
The title compound (24%) was prepared as described in example 41 but using 5-aminopentanol instead of cis-2-buten-1,4-diol in the reaction with trityl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[C:10](C1NC=CN=1)(C1NC=CN=1)=[O:11].C(Cl)(Cl)=O>>[CH3:1][C:2]1[C:3]2[C:4](=[N:8][C:10](=[O:11])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Cc1cccc(N)c1N
Agent: O=C(Cl)Cl
Product: Cc1cccc2c1=NC(=O)N=2

Procedure:
The 5-amino-5,6-dihydro-4H-imidazo(4,5,1-ij)quinolin-2-ones of the invention may also be prepared by the route shown in Scheme 6. 3-Methyl-1,2-benzenediamine is reacted with carbonyl diimidazole or phosgene to give 4-methylbenzimidazolone (XXXVI). This is refluxed with phosphorus oxychloride to give XXXVII which is protected and reacted with N-bromo-succinimine to give compound XXXIX. This is coupled with VIIb and the resulting adduct LX is hydrolyzed to LI. Reduction with lithium aluminum hydride alcohol LXlI which was treated with carbon tetrabromide/triphenylphosphine to give compound 51. Compound 51 was refluxed in acetic acid to effect conversion to compound 6.
Reaction SMILES: CC([O-])(C)C.[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][C:29]=1[Cl:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO>C1COCC1.O>[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][C:17]#[N:18])=[CH:30][C:29]=1[Cl:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: N#CCc1ccc(OCc2ccccc2)c(Cl)c1
Reaction time: 0.25 h
Yield: 34.9 %

Procedure:
To a suspension of t-BuOK (11.7 g, 96 mmol) in THF (200 mL) was added a solution of TosMIC (9.4 g, 48 mmol) in THF (100 mL) at −78° C. The mixture was stirred for 15 minutes, treated with a solution of 4-benzyloxy-3-chloro-benzaldehyde (7.5 g, 30 mmol) in THF (50 mL) dropwise, and continued to stir for 1.5 hours at −78° C. To the cooled reaction mixture was added methanol (30 mL). The mixture was heated at reflux for 30 minutes. Solvent of the reaction mixture was removed to give a crude product, which was dissolved in water (300 mL). The aqueous phase was extracted with EtOAc (3×100 mL). The combined organic layers were dried and evaporated under reduced pressure to give crude product, which was purified by column chromatography (petroleum ether/EtOAc 10:1) to afford 2-(4-(benzyloxy)-3-chlorophenyl)acetonitrile (2.7 g, 34%). 1H NMR (400 MHz, CDCl3) δ 7.52-7.32 (m, 6H), 7.15 (dd, J=2.4, 8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 5.26 (s, 2H), 3.73 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 154.0, 136.1, 129.9, 128.7, 128.7, 128.1, 127.2, 127.1, 127.1, 124.0, 123.0, 117.5, 114.4, 70.9, 22.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.[C:24]([NH:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:31]3[CH:32]=[CH:33][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[CH:29][CH:30]=3)=[CH:17][C:9]1=2
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Product: CC(=O)Nc1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Yield: 42 %

Procedure:
1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (90 mg) was reacted with 4-acetamidophenylboronic acid as in General Procedure 4B to give the title compound as a light gray solid (42% yield). m.p.=244° C., LCMS: m/z=461.24 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.13 (3H, s), 3.49 (2H, m), 3.65 (2H, m), 3.82 (2H, s), 4.61 (2H, s), 6.58 (1H, s), 7.28 (2H, d, J=8.1 Hz), 7.36 (1H, d, J=7.3 Hz), 7.51 (3H, m), 7.60 (1H, s), 7.65 (1H, d, J=8.6 Hz).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[Cl:12][S:13](O)(=[O:15])=[O:14].C(Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl.CCCCCC>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: O=S(=O)(O)Cl
Reactant: CC#CCOc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
To a solution of 0.146 g (1.0 mmol) of the but-2-ynyloxy-benzene in 0.3 mL of dichloromethane in an acetone/ice bath under N2 was dropwise added a solution of 0.073 mL (1.1 mmol) of chlorosulfonic acid in 0.3 mL of dichloromethane. After the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 2 h. To the reaction was then dropwise added 0.113 mL (1.3 mmol) of oxalyl chloride, followed by 0.015 mL DMF. The reaction was heated to reflux for 2 h and then diluted with hexane and poured into ice water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 0.130 g (53%) of the desired product as a light brown solid.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[I:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18].[CH3:24][Si:25]([CH3:37])([CH3:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Si](C)(C)C>C(Cl)Cl>[O-:19][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:18])=[O:16].[C:10]1([I+:9][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[Si:25]([CH3:37])([CH3:36])[CH3:24])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: Ic1ccccc1
Reactant: C[Si](C)(C)c1ccccc1[Si](C)(C)C
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[Si](C)(C)c1ccccc1[I+]c1ccccc1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Yield: 65.2 %

Procedure:
Iodobenzene diacetate (9.66 g, 30 mmol) was dissolved in CH2Cl2 (60 mL) with stirring and the solution chilled to 0° C. Triflic acid (5.1 mL, 58 mmol) was added dropwise to the solution and the reaction mixture was stirred for 2 h. A solution of 1,2-bis(trimethylsilyl)benzene (6.67 g, 30 mmol) in CH2Cl2 (10 mL) was added at 0° C. and the reaction was allowed to stir at room temperature for 2 h. Concentration of the reaction mixture gave crystals which were triturated in ether and collected by filtration to yield white crystals (9.82 g, 65.14%). 1H NMR (400 MHz, CDCl3) δ 8.11-7.47 (m, 9H, ArH), 0.42 (s, 9H, CH3); 13C NMR (400 MHz, CDCl3): δ 139.0, 138.4, 133.3, 133.2, 132.4, 132.3, 132.1, 109.6, 0.1.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:32]C)=[C:7]([C:9]2[N:18]=[C:17]([NH:19][C@H:20]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:8]=1)=O.[NH2:34][NH:35][C:36]([NH2:38])=[S:37]>C(O)C>[NH2:38][C:36]1[S:37][C:1]([C:3]2[CH:4]=[CH:5][C:6]([OH:32])=[C:7]([C:9]3[N:18]=[C:17]([NH:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH:8]=2)=[N:34][N:35]=1
Reactant: COc1ccc(C=O)cc1-c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccccc2n1
Reactant: NNC(N)=S
Solvent: CCO
Product: Nc1nnc(-c2ccc(O)c(-c3nc(N[C@H]4CCNC4)c4ccccc4n3)c2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-tert-Butyl 3-(2-(5-formyl-2-methoxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate (0.160 g, 0.357 mmol) was dissolved in ethanol (2 mL) and thiosemicarbazide (0.033 g, 0.362 mmol) was added and the solution was stirred at room temperature for 16 h. The solid was filtered off and washed with ethanol (2×1 mL). The solid was suspended in water (16 mL) and ferric chloride (0.267 g, 1.00 mmol) was added and the solution was heated at 60° C. for 16 h. A further portion of ferric chloride (0.267 g, 1.00 mmol) was added and the solution heated at 90° C. for 2.5 h. The reaction mixture was partitioned between water (20 mL) and dichloromethane (20 mL), but the bright yellow product was visibly in the aqueous phase so the aqueous phase was concentrated in vacuo and the residue was purified by ion exchange chromatography on SCX-2 (solute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. The basic fractions were combined and purified by HPLC. Semi-prep HPLC was performed on an Agilent 1200 series with a Phenomex Gemini 250 mm×10 mm i.d. column at a temperature of 20 C and a flow rate of 5 mL/min using a gradient of 10%-100% acetonitrile in water over 30 mins.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=O)[CH2:6][CH:5]1[CH3:15])(=[O:3])[CH3:2].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[N:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[F:16])[CH2:6][CH:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2C(=O)CC1C
Reactant: Nc1ccccc1F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccccc2C(=Nc2ccccc2F)CC1C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
[Step 1] 50 mg of 1-acetyl-4-oxo-2-methyl-1,2,3,4-tetrahydroquinoline and 83 mg of 2-fluoroaniline were dissolved in 2 mL of toluene, and 125 μL of titanium tetrachloride (1.0 M dichloromethane solution) was added to the solution under ice cooling. The resulting mixture was stirred for one hour under ice cooling, and then was stirred for 3 hours at 80° C. After completion of the reaction, the reaction liquid was filtered through Celite and was concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (diethyl ether:hexane=2:1), and thus 60 mg (81%) of 1-acetyl-2-methyl-4-[(2-fluorophenyl)imino]-1,2,3,4-tetrahy droquinoline was obtained as a yellow oily substance.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.[CH3:28][O:29][CH2:30][CH2:31][C:32](O)=[O:33]>>[CH3:28][O:29][CH2:30][CH2:31][C:32]([NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:8]3[C:7]4[CH:6]=[CH:5][S:4][C:12]=4[CH:11]=[CH:10][N:9]=3)[CH2:14][CH2:15]2)[CH2:22][CH2:23]1)=[O:33]
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Reactant: COCCC(=O)O
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1

Procedure:
The title compound was prepared in analogy to example 4 starting from trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate B) (100 mg, 0.22 mmol) and 3-methoxypropionic acid (24 mg, 0.23 mmol). Purification by flash chromatography on silica gel (CH2Cl2/MeOH 95:5). White crystals (61 mg, 64%), MS (ISP) m/z=431.3 [(M+H)+].
Reaction SMILES: C(#N)C.Br.[CH2:5]([O:7][C:8]([CH:10]1[CH2:19][CH2:18][C:13]2[N:14]=[C:15]([NH2:17])[S:16][C:12]=2[CH2:11]1)=[O:9])[CH3:6].[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(N(CC)CC)C>[CH2:5]([O:7][C:8]([CH:10]1[CH2:19][CH2:18][C:13]2[N:14]=[C:15]([NH:17][C:20](=[O:22])[CH3:21])[S:16][C:12]=2[CH2:11]1)=[O:9])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1CCc2nc(N)sc2C1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C1CCc2nc(NC(C)=O)sc2C1
Yield: 120.1 %

Procedure:
A 500 ml reactor equipped with mechanical stirrer, thermometer and condenser was loaded with 280 ml of acetonitrile, 71 g of 2-amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester [(III), R1=ethyl] and 38.75 g of acetic anhydride. 38.03 g of triethylamine were dropwise added to the resulting suspension in about 10 minutes. The suspension was refluxed, obtaining complete dissolution at a temperature ranging from 70 to 75° C. After approx. 2 hours 30 minutes the solution was concentrated to dryness, and the residue was crystallized from 450 ml of isopropanol to obtain 74.5 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]\[C:20]2[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O.O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15](/[CH:18]=[CH:19]\[C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:8]3[CH2:9][CH2:10][C:5]4[CH:4]=[CH:3][O:2][C:6]=4[CH2:7]3)=[O:27])=[CH:24][CH:25]=2)=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccc(/C=C\c2ccc(Cl)cc2)cc1
Reactant: c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccc(/C=C\c2ccc(Cl)cc2)cc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.173 g (7.349 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 1.90 g (7.35 mmol) of (Z)-4-chloro-4'-stilbenecarboxylic acid and 4.10 ml (29.4 mmol) of triethylamine in 30 ml of N,N-dimethylformamide, 1.34 ml (8.82 mmol) of diethyl cyanophosphonate was added dropwise, followed by overnight stirring at room temperature. This mixture was poured into water and extracted with diethyl ether 3 times. The combined organic layer was dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to yield the desired product.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[CH3:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=[O:18])[NH:9]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Br:1][CH:2]([CH3:6])[C:3]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:18])[NH:9][CH:8]2[CH3:7])=[O:4]
Reactant: CC(Br)C(=O)Br
Reactant: CC1NC(=O)Nc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Br)C(=O)c1ccc2c(c1)C(C)NC(=O)N2

Procedure:
2-Bromopropionyl bromide (16 g) is added dropwise to a mixture of 3,4-dihydro-4-methyl-2(1H)-quinazolinone (6.1 g) and anhydrous aluminum chloride (12.5 g) in carbon disulfide (110 ml). The reaction mixture is refluxed overnight under nitrogen, the carbon disulfide is decanted and the residue treated with hydrochloric acid (6N). The acidic residue is treated with ethyl acetate and the layers separated. The aqueous layer is extracted with ethyl acetate and the combined organic extracts washed with sat'd. aqueous sodium bicarbonate and water and dried. The organic layer is filtered and the filtrate stripped in vacuo, affording an oil which crystallizes in vacuo, M.P. 153°-156° C.
Reaction SMILES: C(C1C=CC(C2C=CC=CC=2F)=CC=1)#C.[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)#[CH:17].S(=O)(=O)(O)O.[H][H]>>[CH2:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH3:17]
Reactant: C#Cc1ccc(-c2ccc(F)cc2)cc1
Reactant: [H][H]
Agent: C#Cc1ccc(-c2ccccc2F)cc1
Agent: O=S(=O)(O)O
Product: CCc1ccc(-c2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
The procedure of Example 1 was repeated, except that the 1-ethynyl-4-(2-fluorophenyl)benzene was replaced with 1.5 g of 1-ethynyl-4-(4-fluorophenyl)benzene, the amount of catalyst was reduced to 0.5 g, the sulfuric acid was omitted, initial hydrogen pressure was 48 psig, and the reduction was allowed to proceed overnight. Evaporation of the benzene left a solid which was recrystallized from hexane to give 1-ethyl-4-(4-fluorophenyl)benzene, mp 60°-63°. The following elemental analysis was obtained:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]=[C:18]=S)[CH:12]=1.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:30][NH2:31]>C1COCC1.O.C(O)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]3[NH:30][N:31]=[C:18]([NH:17][C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=4)[C:7]=3[CH2:8][C:2]1=2
Reactant: O=C1CCc2sccc21
Reactant: Fc1cccc(N=C=S)c1
Reactant: NN
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Fc1cccc(Nc2n[nH]c3c2Cc2sccc2-3)c1
Reaction time: 8 h
Yield: 33 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Fluoro-3-isothiocyanato-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(3-fluoro-phenyl)-amine as brown solid in 33% yield.