Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22](I)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:22]2[N:21]=[CH:20][N:19]([C:11]3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[N:10]=3)[CH:23]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(I)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)c1

Procedure:
N-tert-Butyl-3-{1-[6-(3,4-dichloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(3,4-dichloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.74) (0.485 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.084 g) which was subsequently deprotected.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH2:17]([NH2:22])[CH2:18][CH:19]([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH:22][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccc(Br)cn2)cc1
Reactant: CC(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CCNCc1ccc(Oc2ccc(Br)cn2)cc1

Procedure:
As shown in scheme 7,4-Hydroxybenzaldehyde is treated with potassium carbonate and 2,5-dibromopyridine in DMAC to afford 4-(5-bromo-pyridin-2-yloxy)-benzaldehyde (35). The aldehyde 35 is combined with isoamylamine, sodium triacetoxyborohydride, acectic acid, and dichloromethane to yield the reductive amination product [4-(5-bromo-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-amine (36). The resulting aryl bromide 36 is treated with acetamide, copper iodide, and 1,2 diaminocyclohexane in dioxane to yield the target compound 37.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([CH2:16][CH2:17][C:18]1([OH:29])[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1)=O)C>C(Cl)Cl>[OH:29][C:18]1([CH2:17][CH2:16][CH2:14][OH:13])[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:19]1
Reactant: CCOC(=O)CCC1(O)CN(C(=O)OC(C)(C)C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(O)(CCCO)C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 31.6 %

Procedure:
Diisobutyl aluminium hydride (1.48 mmol, 1.48 ml, 1 M DCM) was added dropwise to a solution of tert-butyl 3-(2-(ethoxycarbonyl)ethyl)-3-hydroxyazetidine-1-carboxylate (0.10 g, 0.37 mmol) in DCM (3 ml) at −78° C. The solution was allowed to warm to 0° C. and stirred for a further 5 hrs. The reaction was quenched with Sat NH4Cl (10 ml) and extracted into ethyl acetate (10 ml), dried (Na2SO4), and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 60% ethylacetate/hexanes to give the title compound as a colorless oil 27 mg, 32%. 1H NMR (CDCl3, 400 MHz) 1.48 (9H, s), 1.69-1.75 (2H, m), 1.93 (2H, t), 3.76 (2H, t), 3.82 (4H, s).
Reaction SMILES: CS[C:3](=[NH:22])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[S:13][C:12]3[N:14]=[CH:15][CH:16]=[N:17][C:11]=3[N:10]([CH2:18][O:19][CH3:20])[C:9]=2[CH:21]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.CO>[C:24]1([NH:23][C:3](=[NH:22])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]3[S:13][C:12]4[N:14]=[CH:15][CH:16]=[N:17][C:11]=4[N:10]([CH2:18][O:19][CH3:20])[C:9]=3[CH:21]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccccc1
Reactant: COCN1c2cc(CC(=N)SC)ccc2Sc2nccnc21
Solvent: CO
Solvent: C1CCOC1
Product: COCN1c2cc(CC(=N)Nc3ccccc3)ccc2Sc2nccnc21

Procedure:
350 mg of methyl(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetothioimidate was dissolved in a solvent mixture of tetrahydrofuran (7 ml) with methanol (15 ml). After adding 0.5 ml of aniline, the resulting mixture was heated under reflux for 5 hours. Then the reaction mixture was brought back to room temperature. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol/aqueous ammonia) to thereby give 250 mg of the title compound as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>O1CCCC1.CO.[C].[Pd]>[NH2:30][C:28]1[CH:27]=[CH:26][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:29]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCC(CN2CCCC2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2cc(NC(=O)N3CCC(CN4CCCC4)CC3)ncn2)c(F)c1
Reaction time: 6 h
Yield: 61.7 %

Procedure:
4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (350 mg) was dissolved in tetrahydrofuran (8 ml) and methanol (8 ml), and then 10% palladium carbon (162 mg) was added, followed by stirring under a hydrogen atmosphere for 6 hrs. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to provide a crude product of 4-(pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (201.4 mg) as pale yellow foam.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[O:5]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:6]1=2>FC(F)(F)C(O)=O>[N+:1]([C:11]1[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:6]2[O:5][CH2:9][CH2:8][C:7]=2[CH:10]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc2c1OCC2
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc([N+](=O)[O-])cc2c1OCC2

Procedure:
Nitric acid (9 ml) was added to a cooled (ice bath) solution of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (5.1 g, 31 mmol) in trifluoroacetic acid (45 ml). After 4 hours the mixture was quenched into ice-water (150 ml) and the mixture filtered to give 5-nitro-2,3-dihydrobenzo[b]furan-7-carboxylic acid, which was washed with water and used crude (wet) in the next stage.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]([CH3:33])[CH3:32])[C:27]([CH3:35])([CH3:34])[CH2:26]2)=[CH:21][C:20]=1[O:36][CH3:37]>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([N:31]([CH3:32])[CH3:33])[C:27]([CH3:34])([CH3:35])[CH2:26]3)=[CH:21][C:20]=2[O:36][CH3:37])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: COc1cc(N2CCC(N(C)C)C(C)(C)C2)ccc1N
Product: COc1cc(N2CCC(N(C)C)C(C)(C)C2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and 1-(4-amino-3-methoxyphenyl)-N,N,3,3-tetramethylpiperidin-4-amine (INTERMEDIATE 45).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:19](=[O:29])[C:18]3[C:13](=[C:14]([O:30][CH3:31])[CH:15]=[CH:16][CH:17]=3)[NH:12]2)=[CH:7][CH:6]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:19](=[O:29])[C:18]3[C:13](=[C:14]([O:30][CH3:31])[CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(N2C(=O)c3cccc(OC)c3NC2c2ccc(OCCCl)cc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COc1ccc(-n2c(-c3ccc(OCCCl)cc3)nc3c(OC)cccc3c2=O)cc1
Temperature: 25 °C

Procedure:
To a solution of 18.0 g (0.0410 mol) of 2-[4-(2-chloro-ethoxy)-phenyl]-8-methoxy-3-(4-methoxy-phenyl)-2,3-dihydro-1H-quinazolin-4-one in 500 mL of toluene was added 9.31 g (0.0410 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The reaction mixture was stirred and heated under reflux for 3 hours. After cooling to room temperature, the solvent was removed in a rotary evaporator. Ethanol (300 mL) was added to the crude product and stirred at room temperature overnight. The precipitate was collected by vacuum filtration. An analytical sample (mp 151-152° C.) was obtained by recrystallization from ethanol.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:15][CH2:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH2:4]1.C(O[C:20](=[O:22])[CH3:21])(=O)C>>[CH2:4]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH2:14][CH2:15][CH:3]1[N:2]([CH3:1])[C:20](=[O:22])[CH3:21]
Reactant: CNC1CCc2c([nH]c3ccccc23)C1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(C)C1CCc2c([nH]c3ccccc23)C1
Reaction time: 8 h

Procedure:
A mixture of 10.0 g (0.05 mol) of 2,3,4,9-tetrahydro-N-methyl-1H-carbazol-2-amine and 70 ml of acetic anhydride was heated at reflux until complete solution occurred (2-3 min). After standing overnight at room temperature and further cooling at 0°, the precipitated solid was filtered, washed first with small portions of cold acetic anhydride and then thoroughly with anhydrous ether. The crude product was recrystallized from ethanol to give the title compound, mp 215°-216°.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([C:24](=[S:26])[NH2:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH2:27](OC(OCC)CBr)[CH3:28]>>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([C:24]5[S:26][CH:27]=[CH:28][N:25]=5)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(CBr)OCC
Reactant: NC(=S)C1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Product: c1csc(C2(c3ccc(OC4CCN(C5CCC5)CC4)cc3)CCOCC2)n1
Yield: 39 %

Procedure:
The title compound (92 mg, 39%) was prepared from 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carbothioamide and bromoacetaldehyde diethylacetal similarly to the procedure used for example 137. 1H NMR (400 MHz, CDCl3) δ 1.66-1.72 (m, 2H), 1.77-1.89 (m, 5H), 1.95-2.04 (m, 4H), 2.11 (m, 1H), 2.36-2.43 (m, 2H), 2.58-2.72 (m, 5H), 3.71 (t, 2H), 3.84-3.88 (m, 2H), 4.27 (m, 1H), 6.84 (d, 2H), 7.23-7.26 (m, 3H), 7.70 (s, 1H). LRMS APCI+ m/z 399 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15](CCCNC(=O)OC(C)(C)C)[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl>C(O)C>[CH:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10]1[N:14]3[CH2:15][CH2:16][O:17][CH2:18][C:13]3=[N:12][C:11]=1[C:2]([NH2:1])=[N:3]2
Reactant: CC(C)(C)OC(=O)NCCC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Agent: Cl
Solvent: CCO
Product: Nc1nc2ccccc2c2c1nc1n2CCOC1
Temperature: 75 °C
Reaction time: 1 h
Yield: 112.2 %

Procedure:
tert-Butyl 3-[(11S)-6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (689 mg, 1.74 mmol) was dissolved in 10 mL of ethanol and 2 mL of a 4.0 M solution of HCl in ethanol was added. The reaction mixture was heated to 75° C. After 1 hour, the reaction mixture was concentrated under reduced pressure. The resulting residue was treated with 25 mL H2O and 20 mL of CHCl3. The layers were separated and the organic portion was discarded. The aqueous layer was then made basic by addition of 5 mL of concentrated NH4OH solution. The aqueous portion was then extracted with CHCl3 (6×10 mL). The combined organic extracts were concentrated under reduced pressure to give (11S)-1143-aminopropyl)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (469 mg) as a white foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:16][CH:17]1[CH2:22][NH:21][CH:20]([CH3:23])[CH2:19][N:18]1[S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:26])=[O:25]>>[CH3:16][CH:17]1[CH2:22][N:21]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH:20]([CH3:23])[CH2:19][N:18]1[S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:26])=[O:25]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: CC1CN(S(=O)(=O)c2ccc3ccccc3c2)C(C)CN1
Product: CC1CN(S(=O)(=O)c2ccc3ccccc3c2)C(C)CN1C(=O)C1CCN(c2ccncc2)CC1
Yield: 13 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with (2RS,5SR)-2,5-dimethyl-1-(2-naphthylsulphonyl)piperazine to give (2RS,5SR)-2,5-dimethyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)-piperidin-4-ylcarbonyl]piperazine in 13% yield;
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:40]([F:43])([F:42])[F:41])[C:12]2[N:13]([N:16]=[C:17]([CH2:19][CH2:20][C:21]3[N:25](CC4C=CC(OC)=CC=4)[N:24]=[C:23]([N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[N:22]=3)[N:18]=2)[C:14]=1[CH3:15]>>[Cl:8][C:9]1[CH:10]=[C:11]([C:40]([F:42])([F:41])[F:43])[C:12]2[N:13]([N:16]=[C:17]([CH2:19][CH2:20][C:21]3[NH:25][N:24]=[C:23]([N:35]4[CH2:36][CH2:37][CH2:38][CH2:39]4)[N:22]=3)[N:18]=2)[C:14]=1[CH3:15]
Reactant: COc1ccc(Cn2nc(N3CCCC3)nc2CCc2nc3c(C(F)(F)F)cc(Cl)c(C)n3n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cl)cc(C(F)(F)F)c2nc(CCc3nc(N4CCCC4)n[nH]3)nn12
Yield: 40.5 %

Procedure:
Trifluoroacetic acid (9.87 g, 6.67 ml, 86.5 mmol, Eq: 100) was added to 6-chloro-2-(2-(1-(4-methoxybenzyl)-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)ethyl)-5-methyl-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (450 mg, 865 μmol, Eq: 1.00). The mixture was heated under reflux for 4 h and then concentrated to an oil. Water (15 ml) was added and the mixture was alkalized by addition of sodium bicarbonate. The mixture was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to an oil. The crude product was purified by chromatography (SiO2, methanol ethyl acetate) to afford the product (140 mg, 40.5%) as an off white solid. MS: m/z=400.2 (M+H+)
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])[CH:11]=[CH:10][C:8]=2[N:9]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])[CH:11]=[CH:10][C:8]=2[N:9]=1)#[N:2]
Reactant: CC(C)Nc1ccc2nc(Cl)sc2c1
Reactant: [C-]#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)Nc1ccc2nc(C#N)sc2c1
Temperature: 120 °C

Procedure:
Potassium cyanide (18 mg) and 2-chloro-6-isopropylaminobenzothiazole (18 mg) were dissolved in 1 ml DMSO and heated to 120° C. for 4 h. After cooling to room temperature, the reaction was poured into 0.2M potassium phosphate, pH 4.5. The aqueous layer was extracted with ethyl acetate three times, washed with water, and dried over sodium sulfate. The solvent was removed by rotary evaporation and the residue purified by silica gel chromatography (20% ethyl acetate in hexanes). 1H-NMR (d6-DMSO): δ 7.83 (d, 1H, J=9.2 Hz), 7.15 (d, 1H, J=2.4 Hz), 6.97 (dd, 1H, J=2.4, 8.8 Hz), 6.52 (bd, 1H, J=7.2 Hz), 3.61 (m, 1H), 1.15 (d, 6H, J=6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=2[OH:19])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:11]2[C:12]([O:19][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[C:13]([F:18])[C:14]([F:17])=[CH:15][CH:16]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(F)c(F)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)Oc1c(C(=O)Cc2ccc(Cl)cc2)ccc(F)c1F
Reaction time: 5 h

Procedure:
A solution of 2-(4-chlorophenyl)-1-(3,4-difluoro-2-hydroxy-phenyl)-ethanone (4.5 g, 87% pure, 13.85 mmol) and triethylamine (1.7 g, 2.35 ml, 16.8 mmol, 1.2 eq.) in methylene chloride (100 ml) is treated dropwise at ambient temperature with isobutyryl chloride (1.79 g, 1.76 ml, 16.8 mmol, 1.2 eq.). After stirring for 5 h, the solution is washed successively with 2M HCl solution and saturated sodium hydrogen carbonate solution. The organic phase is dried over anhydrous magnesium sulphate, filtered and evaporated to dryness in vacuo to afford a black residue. This is triturated with methanol at room temperature overnight to afford a brown solid, which is filtered and washed with methanol. The solid is purified twice by flash chromatography (ethyl acetate/cyclohexane=1:9) to furnish the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=C(c1cc([N+](=O)[O-])ccc1F)N1CCN(c2ccccc2)CC1
Reactant: C1COCCN1
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccccc2)CC1

Procedure:
The title compound was prepared according to the procedure described for example 1 from (2-Fluoro-5-nitro-phenyl)-(4-phenyl-piperazin-1-yl)-methanone and morpholine (87%, yellow solid, MS (m/e): 397.3 (M+H, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](O)=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:56][C@H:57]1[CH2:62][CH2:61][CH2:60][C@@H:59]([CH3:63])[NH:58]1>CN(C)C=O>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:4]1[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([N:58]3[C@H:59]([CH3:63])[CH2:60][CH2:61][CH2:62][C@@H:57]3[CH3:56])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:26]
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: O=C(Nc1cc(Cl)cnc1N1CCC(C(=O)O)CC1)c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H]1CCC[C@H](C)N1C(=O)C1CCN(c2ncc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.7 %

Procedure:
To a solution of 0.040 g (0.11 mmol) of 5′-chloro-3′-(3-chloro-benzoylamino)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid in N,N-dimethylformamide (2 mL) is added 0.048 g (0.15 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate followed by 0.042 mL (0.304 mmol) of triethylamine. The mixture is stirred at room temperature for 1 h then 0.034 g (0.304 mmol) of cis-2,6-dimethylpiperidine is added and the mixture is stirred at room temperature overnight. The mixture is concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC to provide 0.002 g (4%) of the title compound (273) as a white solid. [M+H]+=489.2.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.C(=O)(O)[O-].[Na+].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH3:2][O:3][C:4](=[O:11])[C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
This ester was added in portions to a stirred mixture of 1500 mL of 1 N aqueous sodium bicarbonate and 500 mL of dichloromethane at 0-5° C., then 80 mL (97 g, 0.69 mol) of benzoyl chloride was added dropwise at 0-5° C., and the mixture was stirred at room temperature overnight. The phases were separated and the aqueous phase was extracted with dichloromethane (twice with 250 mL). The organic phases were combined, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was triturated with toluene to afford 112.98 g (90.7% from cis4-hydroxy-D-proline) of N-benzoyl-cis-4-hydroxy-D-proline methyl ester as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Mg].[CH3:10][C:11](=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:12]>C(OCC)C.[Cu]Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH3:10])[CH3:12])=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Agent: Cl[Cu]
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 1 g (5.23 mmol) of 1-bromo-4-chlorobenzene in 2.5 ml of diethyl ether was added slowly to 254 mg (10.45 mmol) of magnesium turnings in 5 ml of diethyl ether. After the reaction had started, a further 1 g (5.23 mmol) of 1-bromo-4-chlorobenzene in 2.5 ml of diethyl ether was metered into the reaction mixture. The reaction mixture was stirred at room temperature for 30 min, 103 mg (1.05 mmol) of copper(I) chloride were added and the mixture was then cooled to −10° C. 2.09 g (10.45 mmol) of diethyl propan-2-ylidenemalonate were then slowly added dropwise. The reaction mixture was subsequently heated to reflux and stirred at this temperature for 3 h. 20 ml of ice-cold 1 M hydrochloric acid were then added very slowly. After separation of the phases, the aqueous phase was extracted three more times with diethyl ether. The combined organic phases were dried over magnesium sulphate and then concentrated to dryness. The crude product was purified by preparative HPLC (mobile phase methanol/water 70:30). This gave 800 mg of the title compound (25% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:25]=[CH:26][C:27]([C:29]#[N:30])=[CH:28][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:25]=[CH:26][C:27]([C:29](=[N:32][OH:33])[NH2:30])=[CH:28][C:17]=3[N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCC1
Yield: 72 %

Procedure:
2-(4-Benzyloxyphenyl)-5-cyano-1-cyclopentylbenzimidazole (400 mg) obtained in Example 14 was suspended in ethyl alcohol (3 ml) and water (1.5 ml), and hydroxylamine hydrochloride (141 mg) and sodium hydrogencarbonate (170 mg) were added. The mixture was refluxed under heating overnight. The reaction mixtures was allowed to cool and the precipitated crystals were collected by filtration to give the title compound (312 mg, yield 71%).