Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18](=[O:21])[CH2:19][OH:20].[OH-].[K+].C(O)(C)C>O>[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18](=[O:21])[CH2:19][O:20][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1
Reactant: Clc1nc(C(Cl)(Cl)Cl)ns1
Reactant: CC1CCCCN1C(=O)CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC1CCCCN1C(=O)COc1nc(C(Cl)(Cl)Cl)ns1
Temperature: -10 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
17 g (0.07 mol) of 5-chloro-3-trichloromethyl-1,2,4-thiadiazole are added to a stirred mixture which comprises 11 g (0.07 mol) of hydroxyacetic acid 2-methylpiperidide, 4.5 g (0.07 mol) of potassium hydroxide powder and 100 ml of isopropanol and has been cooled to -10° C. The reaction mixture is stirred for 20 hours at -10° C. and then poured into water, and the product is filtered off under suction and washed with water. 18 g (72% of theory) of (3-trichloromethyl-1,2,4-thiadiazol-5-yl)-oxyacetic acid 2-methyl-piperidide are obtained in the form of a white powder of melting point 88° C.
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:13])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)=O.C([O-])=O.[Na+].Cl.[NH2:19]O.C(O)=O>O>[C:1]([C:3]1[C:4]([OH:13])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)#[N:19]
Reactant: O=Cc1cc(C(F)(F)F)cnc1O
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#Cc1cc(C(F)(F)F)cnc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the compound from Step B above (18 g, 95 mmol), sodium formate (7.1 g, 110 mmol), hydroxylamine hydrochloride (7.3 g, 110 mmol), and formic acid (150 mL) was stirred at room temperature for 2 h and then heated to reflux overnight. The reaction mixture was cooled, allowed to stand at room temperature for 7 d, poured into water and extracted with three portions of ethyl acetate. The combined organic layers were washed sequentially with two portions of water, saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated in vacuo to yield the desired product as a brown powder. 1H NMR (400 MHz, CD3OD) δ 8.37 (d, J=2.7 Hz, 1H), 8.19 (q, J=0.7 Hz, 0.3 Hz, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[CH:31][C:32]([C:35]#[N:36])=[N:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[OH:8][CH2:9][C:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[CH:31][C:32]([C:35]#[N:36])=[N:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccc(C#N)nc5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C#N)nc5)cc4)CC3)n2CCS1
Yield: 84.9 %

Procedure:
A solution of the compound (372 mg, 0.70 mmol) obtained in Example 45-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (248 mg, 85%) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17](Br)=[N:18][CH:19]=3)[CH:11]=[N:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH:23]1[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][C:24]=1C.[H-].[Na+].N#N>CN(C=O)C>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:29][C:28]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C:5]4[CH:6]=[CH:21][CH:22]=[C:3]([CH3:1])[CH:4]=4)=[N:18][CH:19]=3)[CH:11]=[N:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccc(Br)nc2)cc1
Reactant: Cc1cccc(O)c1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2ccccc2Oc2ccc(Cn3cncc3Cc3ccc(C#N)cc3)cn2)c1
Temperature: 110 °C

Procedure:
The compound from Example 1 Step 3 (0.11 g 0.20 mmol), m-cresol (0.064 g, 0.59 mmol) and sodium hydride (60% dispersion in oil, 4.0 equiv, 0.032 g) were suspended in DMF (0.5 mL) in an N2 purged sealed tube and heated at 110° C. for 24 hr. The residue was dissolved in methanol and purified on a C18 preperative hplc column. Lyophilized from dioxane/HCl to provide the title compound. FAB-MS: calc: 380.4 found: 381.0. 2 1H-NMR (CD3OD): 2.4 ppm (s, 3H); 4.2 ppm (s, 2H); 5.4 ppm (s, 2H); 6.8-7.6 ppm (11H); 7.9 ppm (s, 1H); 9.1 ppm (s,1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:11]=O)=[CH:7][N:6]=1)=[O:4].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(C=O)cn1
Reactant: C1COCCN1
Product: COC(=O)c1cnc(CN2CCOCC2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 23, Step C, using 5-formyl-pyrazine-2-carboxylic acid methyl ester (0.78 g, 4.7 mmol) and morpholine (0.44 g, 5.2 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=[NH:16].[CH:17]([N:20]=[C:21]=[N:22][CH:23]([CH3:25])[CH3:24])([CH3:19])[CH3:18]>C(O)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=[N:16][C:21]([NH:22][CH:23]([CH3:25])[CH3:24])=[N:20][CH:17]([CH3:19])[CH3:18]
Reactant: N=c1ccccn1CCc1ccccc1Br
Reactant: CC(C)N=C=NC(C)C
Solvent: CC(C)(C)O
Product: CC(C)N=C(N=c1ccccn1CCc1ccccc1Br)NC(C)C
Temperature: 25 °C
Yield: 45.4 %

Procedure:
A solution of 1-[2-(2-bromophenyl)ethyl]-2-iminopyridine (2.77 g, 0.01 mole) and diisopropylcarbodiimide (1.05 g, 0.012 mole) in 30 ml of t-butanol is heated at reflux in a nitrogen atmosphere for 24 hours. The solution is cooled to room temperature and concentrated in vacuo to give a solid. This is recrystallized from 50 ml of hexane to yield a semi-solid, after cooling to -30°C. Recrystallization of this material from 70 ml of hexane yields 1.83 g of the title compound which sinters at 119°C and melts at 125°-128°C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].CC1(C)C(C)(C)OB([C:20]2[O:24][C:23]([Si](C(C)C)(C(C)C)C(C)C)=[N:22][CH:21]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.Cl[Pd]Cl>[F:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[C:20]1[O:24][CH:23]=[N:22][CH:21]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2cnco2)c(F)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-3-fluoro-benzoic acid (1.00 g), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-triisopropylsilanyl-oxazole (1.90 g), PdCl2 [1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (400 mg), and aqueous Na2CO3 solution (2 M; 5.70 mL) in N,N-dimethylformamide (6 mL) is stirred overnight at 80° C. under an argon atmosphere. After cooling to room temperature the reaction mixture is concentrated in vacuo and water is added. The resulting mixture is acidified with hydrochloric acid (4 M; 6 mL) and extracted with ethyl acetate. The combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is triturated with diethyl ether, filtered off and dried to give the title product. LC (method 1): tR=0.87 min; Mass spectrum (ESI+): m/z=208 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:24]3[CH2:27][C@H:26]([CH2:28][O:29]S(C4C=CC(C)=CC=4)(=O)=O)[CH2:25]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[OH-].[K+].O.Cl>O1CCOCC1>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:24]3[CH2:25][C@H:26]([CH2:28][OH:29])[CH2:27]3)=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](c3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)nccn43)C2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nccn2c1c(-c1ccc(Oc3ccccc3)cc1)nc2[C@H]1C[C@H](CO)C1

Procedure:
A solution of trans-toluene-4-sulfonic acid 3-[8-amino-1-(4-phenoxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethyl ester (10.0 mg, 0.0185 mmol), potassium hydroxide (10.4 mg, 0.185 mmol), H2O (1 mL) and 1,4-dioxane (1 mL) was heated to 60° C. overnight. The mixture was titrated to pH 2 with 2M HCl. The dioxane was removed in vacuo. DCM was added to extract the product. The organics were combined, dried (Na2SO4) and removed under reduced pressure to give a residue which was then purified by flash chromatography (5% MeOH in DCM). MS (ES+): m/z 386.94 (100) [MH+]. HPLC: tR=2.23 min (polar—5 min).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][O:28][CH2:29][CH2:30][C:31](O)=[O:32]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][CH2:29][O:28][CH3:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: COCCC(=O)O
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (46 mg, 59%), MS (ISP) m/z=415.4 [(M+H)+], mp 182° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (75 mg, 0.19 mmol) and 3-methoxypropionic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17]COC(=O)C(C)(C)C)=[O:16])=[C:13]([CH3:26])[N:12]([CH2:27][O:28][CH3:29])[C:11]([CH3:30])=[C:10]1[C:31]([O:33][CH2:34][O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:32]>C(OC(C)C)(C)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:31]([O:33][CH2:34][O:35][C:36](=[O:41])[C:37]([CH3:38])([CH3:39])[CH3:40])=[O:32])=[C:11]([CH3:30])[N:12]([CH2:27][O:28][CH3:29])[C:13]([CH3:26])=[C:14]1[C:15]([OH:17])=[O:16]
Reactant: COCN1C(C)=C(C(=O)OCOC(=O)C(C)(C)C)C(c2cccc(Cl)c2Cl)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Solvent: CC(C)OC(C)C
Solvent: O
Product: COCN1C(C)=C(C(=O)O)C(c2cccc(Cl)c2Cl)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
In 15 ml of isopropyl ether saturated with water was dissolved 614 mg of bis(pivaloyloxymethyl) 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-1-methoxymethyl-3,5-pyridinedicarboxylate obtained in Example 6, and 100 mg of Lipase B was added thereto, followed by stirring at 25° C. for 4 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to obtain 405 mg (yield: 81%) of (+)-4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-1-methoxymethyl-5-pivaloyloxymethoxycarbonyl-3-pyridinecarboxylic acid as a colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:10][OH:11])=[O:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]([C@H:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([C:52](=[O:60])[C:53]3[CH:58]=[CH:57][C:56](O)=[CH:55][CH:54]=3)[C@@H:44]([CH3:61])[CH2:43]2)[C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[C:39]([N:38]([C:35]1[CH:34]=[CH:33][C:32]([Cl:31])=[CH:37][CH:36]=1)[C@H:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[N:45]([C:52]([C:53]2[CH:58]=[CH:57][C:56]([O:11][CH2:10][CH:6]3[CH2:7][CH2:8][CH2:9][CH:5]3[C:3]([O:2][CH3:1])=[O:4])=[CH:55][CH:54]=2)=[O:60])[C@@H:44]([CH3:61])[CH2:43]1)(=[O:41])[CH3:40]
Reactant: COC(=O)[C@@H]1CCC[C@H]1CO
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C1CCCC1COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
Trans-2-Hydroxymethyl-cyclopentanecarboxylic acid methyl ester (0.127 g, 0.81 mmol) was dissolved in 10 ml toluene at room temperature with PPh3 (0.211 g, 0.81 mmol), then added N-(4-chlorophenyl)-N-[(2S,4R)-1-(4-hydroxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]acetamide (0.1 g, 0.23 mmol) and stirred for 5 min. DEAD (0.141 g, 0.81 mmol) was added and the reaction was stirred for 18 h at room temperature. The reaction was concentrated and purified by silica gel chromatography (45% dichloromethane/55% ethyl acetate) to afford methyl 2-[(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)methyl]cyclopentanecarboxylate (0.12 g, 90%).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:51])[C@H:9]([CH2:47][CH:48]([CH3:50])[CH3:49])[N:10]([CH2:22][P@:23]([O:45]C)([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:44])[C@@H:31]2[CH2:35][CH2:34][CH2:33][N:32]2[C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:24])[C:11](=[O:21])[CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([NH:7][C:8](=[O:51])[C@H:9]([CH2:47][CH:48]([CH3:49])[CH3:50])[N:10]([CH2:22][P:23]([OH:45])([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:44])[C@@H:31]2[CH2:35][CH2:34][CH2:33][N:32]2[C:36](=[O:43])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:24])[C:11](=[O:21])[CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO[P@](=O)(CCCCNC(=O)[C@@H]1CCCN1C(=O)c1ccccc1)CN(C(=O)CCCc1ccccc1)[C@@H](CC(C)C)C(=O)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)Nc1ccccc1)N(CP(=O)(O)CCCCNC(=O)[C@@H]1CCCN1C(=O)c1ccccc1)C(=O)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of [[(R,S)-methoxy-[N-(N-(benzoyl)-L-prolyl)aminobutyl]phosphinyl]methyl]-4-phenylbutanoyl-L-leucine N-phenylamide (101 mg, 0.14 mmol) in methanol (1 mL) was treated with 2N aqueous sodium hydroxide (0.5 mL) for 3 hours at room temperature. Additional 2N aqueous sodium hydroxide (0.5 mL) was then added, and the mixture was stirred overnight at room temperature. The solvent was removed by evaporation, and the residue was dissolved in water (25 mL). The aqueous solution was extracted with diethyl ether, acidified to ~pH 1 with 6N hydrochloric acid, and extracted with ethyl acetate (3×). The combined organic layers were washed With saturated brine solution, dried (magnesium sulfate), and evaporated. Purification was effected by reverse phase-high performance liquid chromatography using a Waters Prep Nova-Pak HR C18 6 mm column (19×300 mm) (detection at 220 nm; mobile phase: 57% acetonitrile containing 0.1% trifluoroacetic acid-43% water containing 0.1% trifluoroacetic acid; flow rate: 20 mL/min). Evaporation of appropriate fractions gave desired product as an amorphous solid; yield 47 mg; FAB-MS: m/z 703 (M+1),725 (M+Na), 741 (M+K). The 200 MHz NMR spectrum in methanol-d4 was in accord with the desired structure.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][CH2:11][O:12][C:13]([CH2:15][SH:16])=[O:14].CCN(CC)CC>CS(C)=O>[NH2:5][C:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[S:16][C:15]=1[C:13]([O:12][CH2:11][CH3:10])=[O:14]
Reactant: N#Cc1ccccc1F
Reactant: CCOC(=O)CS
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc2ccccc2c1N
Yield: 70.5 %

Procedure:
2-Fluorobenzonitrile (0.61 g, 5 mmol), ethyl thioglycollate (0.60 g, 5 mmol) and NEt3 (1.52 g, 15 mmol) are stirred in DMSO (5 mL) at 100° C. under N2 for 3 h. The reaction mixture is poured onto ice-water (50 mL), and the solid is collected by suction filtration, rinsed with water, and air dried to give ethyl 3-aminobenzothiophene-2-carboxylate (0.78 g, 70%) as a grey-brown solid. 1H NMR (DMSO) δ8.14 (1H, d, J=7.7 Hz), 7.88 (1H, d, J=8.1 Hz), 7.50 (1H, dt, Jd=1.2 Hz, Jt=7.5 Hz), 7.39 (1H, dt, Jd=1.2 Hz, Jt=7.6 Hz), 7.17 (2H, brs), 4.26 (2H, q, J=7.1 Hz), 1.29 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:5]([N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH:8]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][C:28](=[C:31]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[CH2:35][CH2:34][N:33]3[CH:42]=[CH:43][N:44]=[C:32]23)[CH2:27][CH2:26]1.S1C=CC=C1>CO.[Pd]>[N:44]1[CH:43]=[CH:42][N:33]2[CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:31](=[C:28]3[CH2:27][CH2:26][N:25]([C@H:10]4[CH2:11][CH2:12][N:7]([C:5](=[O:6])[C:4]5[CH:3]=[C:2]([CH3:1])[CH:23]=[C:22]([CH3:24])[CH:21]=5)[C@@H:8]([CH2:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH2:9]4)[CH2:30][CH2:29]3)[C:32]=12
Reactant: c1ccc2c(c1)CCn1ccnc1C2=C1CCNCC1
Reactant: Cc1cc(C)cc(C(=O)N2CCC(=O)CC2Cc2ccccc2)c1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: Cc1cc(C)cc(C(=O)N2CC[C@H](N3CCC(=C4c5ccccc5CCn5ccnc54)CC3)C[C@@H]2Cc2ccccc2)c1
Yield: 12.2 %

Procedure:
A mixture of (±)-1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)-4-piperidinone (2.5 g) and 6,11-dihydro-11-(4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine (2.1 g) in methanol (150 ml) and a solution of thiophene (4%; 1 ml) was hydrogenated at 50° C. overnight with palladium on activated carbon (10%; 2 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/ (CH3OH/ NH3) 98/2 to 95/5). The desired fraction was collected, the solvent evaporated, yielding 0.54 g (12.3%) of (±)-cis-4-[4-(5,6-dihydro-11H-imidazo [2,1-b][3]benzazepin-11-ylidene)-1-piperidinyl]-1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)piperidine (comp. 1; mp. 138.7° C.).
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[C:11]([CH3:12])=[C:10]([NH2:13])[C:9]([O:14][CH3:15])=[CH:8][N:7]=1>O.C(O)(=O)C>[Cl:5][C:6]1[C:11]2[CH:12]=[N:1][NH:13][C:10]=2[C:9]([O:14][CH3:15])=[CH:8][N:7]=1
Reactant: COc1cnc(Cl)c(C)c1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cnc(Cl)c2cn[nH]c12
Temperature: 75 °C

Procedure:
A solution of sodium nitrite (98%, 326 mg, 4.63 mmol) in water (0.6 mL) was added to a solution of C4 (200 mg, 1.16 mmol) in acetic acid (8 mL), and the reaction mixture was heated at 75° C. for 1 hour. After the reaction mixture had cooled to room temperature, it was concentrated in vacuo, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 25% to 50% ethyl acetate in heptane) provided the product as a yellow solid. Yield: 140 mg, 0.763 mmol, 66%. LCMS m/z 184.0 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.74 (s, 1H), 4.06 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH2:13].[CH:14](N1C2C=CC=CC=2N=N1)=[O:15]>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][CH:14]=[O:15]
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Reactant: O=Cn1nnc2ccccc21
Solvent: C1CCOC1
Product: O=CNCc1cccc(C(F)(F)F)c1Cl
Temperature: 22 °C
Reaction time: 18 h

Procedure:
A solution of {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (1.05 g, 5 mmol) in anhydrous tetrahydrofuran (10 ml) was added dropwise to a solution of N-formyl benzotriazole (0.772 g, 5.25 mmol) in anhydrous tetrahydrofuran (10 ml). The reaction was stirred at 22° C. for 18 hrs then reduced in vacuo and the residue partitioned between dichloromethane (75 ml) and 2N aqueous sodium hydroxide (40 ml). The organic layer was separated and extracted with 2N aqueous sodium hydroxide (40 ml). The organic layer was passed through a hydrophobic frit and reduced in vacuo to give a white solid. The crude product was purified by automated flash silica column chromatography (Biotage SP4), eluting with a solvent gradient of 0-10% ethyl acetate in dichloromethane, to give {[2-chloro-3-(trifluoromethyl)phenyl]methyl}formamide as a white solid.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[N+:10]([O-:13])(O)=[O:11].[Br:14][C:15]1[C:16]([F:26])=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([Cl:25])[CH:21]=[CH:20]2.[N+]([O-])(O)=O>>[Br:14][C:15]1[C:16]([F:26])=[CH:17][C:18]([N+:10]([O-:13])=[O:11])=[C:19]2[C:24]=1[N:23]=[C:22]([Cl:25])[CH:21]=[CH:20]2
Reactant: Fc1ccc2ccc(Cl)nc2c1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=[N+]([O-])c1cc(F)c(Br)c2nc(Cl)ccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a solution of 2-bromo-3-fluoroaniline (6.5 g, 34.17 mmol) and pyridine (2.7 g, 34.17 mmol) in 20 ml of CH2Cl2, cinnamoyl chloride (5.95 g, 35.88 mol) in 10 ml CH2Cl2 are added dropwise and mixture was refluxed for 30 min. The reaction mixture is diluted with CH2Cl2, the organic layer washed with diluted HCl, saturated Na2CO3 solution, water, and dried (Na2SO4). The solvent is removed in vacuo to give 10.5 g of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide. To a solution of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide (10.5 g, 32.8 mmol) in 70 ml of chlor-benzene at 130° C. AlCl3 (21.9 g, 0.164 mol) is added portionwise, the mixture is stirred at this temperature 2 h and poured in ice-water. The precipitate is filtered off and dried. Yield 6.05 g (76%). 6 g (24.8 mmol) of 8-bromo-7-fluoro-1H-quinolin-2-one are refluxed in 30 mL of POCl3 during 2 h, then poured on ice, extracted with benzene. the benzene extract dried (Na2SO4) to yield 6.1 g 8-bromo-2-chloro-7-fluoroquinoline after solvent removal. To a mixture of 10 ml 10%-oleum and 1.4 g (22.2 mmol) of fuming HNO3 8-bromo-2-chloro-7-fluoroquinoline (4.8 g 18.5 mmol) is added portionwise. The mixture is heated at 100° C. for 2 h. Additional HNO3 (0.17 g) is added and stirred for additional 1 h. The reaction mixture is poured in ice-water, extracted with EtOAc, filtered through silica gel, and crystallized from heptane-toluene to yield 2.3 g (50%) 8-bromo-2-chloro-7-fluoro-5-nitroquinoline. 2.3 g (7.54 mmol) of 8-bromo-2-chloro-7-fluoro-5-nitroquinoline are heated at 100° C. for 5 h in a solution containing 16 ml of CH3COOH, 3.2 ml of H2O and 5 ml of conc. HCl. The mixture is poured in water, the formed precipitate is filtered off, stirred in EtOAc and filtered to yield 1.71 g. 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one. To a suspension 1.7 g (5.92 mmol) of 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one and 2.3 g (35.5 mmol) of HCOONH4 in 10 ml of ethanol 0.1 g 10% Pd—C are added, and stirred for 2 h at 60° C. A solid disappeared and then formed again. The precipitate is filtered off, dissolved in 3 ml of DMSO and filtered through silica gel. 15 ml of water are added to the eluate, the precipitate is filtered off and dried to yield 0.5 g (47%) 5-Amino-7-fluoro-1H-quinolin-2-one. 1H-NMR (DMSO-d6); δ=6.14 (dd, 1H), 6.20 (dd, 1H), 6.23 (d, 1H), 6.27 (br, 2H), 8.06 (d, 1H), 11.50 (br., 1H).