Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8](O)=O)[CH2:3][C:4](O)=O.[C:11]1([NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17]>C(O)CO.O>[NH:17]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:18]=[C:4]1[CH2:3][N:2]([CH2:7][C:8]1[NH:18][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]=1)[CH3:1]
Reactant: Nc1ccccc1N
Reactant: CN(CC(=O)O)CC(=O)O
Solvent: O
Solvent: OCCO
Product: CN(Cc1nc2ccccc2[nH]1)Cc1nc2ccccc2[nH]1
Temperature: 190 °C
Reaction time: 4 h

Procedure:
A mixture of 4.00 g (27.2 mmol) N-methyliminodiacetic acid and 5.99 g (54.4 mmol) o-phenylene diamine in 30 ml ethylene glycol was stirred at 190° C. for 4 hours. The water produced during was distilled off continuously. At the end of the reaction, the reaction mixture was allowed to cool down to room temperature and then poured in 150 ml water. The obtained slurry was triturated for 30 min, filtered, washed with water (3×30 ml) and dried at 60° C. under reduced pressure for 48 hours. Yield 6.88 g (87.0%). 1H NMR (250 MHz, DMSO-d6), δ 2.25 (s, 3H), 3.90 (s, 4H), 7.15 (m, 4H), 7.47–4.58 (m, 4H), 12.33 (br. s, 2E). Microanalysis, %: Calculated for C17H17N5: C, 70.10; H, 5.84; N, 24.05. Found: C, 70.22; H, 6.05; N, 23.76. +CI MS (m/z): [292]. (+CI-MS is Positive Chemical Ionisation Mass Spectroscopy).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[F-:13].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:13]
Reactant: [F-]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(F)c(Cl)c1
Reaction time: 15 h

Procedure:
A mixture of 3,4,5-trichloronitrobenzene (13.55 g, 59 mmol), potassium fluoride (4.65 g, 80 mmol) and dimethylformamide (DMF; 66 ml) is heated at 140° for 15 hours. An additional 2.5 g of potassium fluoride is added and the mixture is stirred an additional 15 hours at 140°. The reaction mixture is poured into water and extracted with ether. The combined organic layers are washed with water and with brine and filtered, and the solvent is removed to give a dark solid, which is purified by column chromatography to give 3,5-dichloro-4-fluoronitrobenzene, a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]1([CH:30]2[CH:39]3[CH:34]([CH2:35][CH2:36][CH2:37][NH:38]3)[CH2:33][CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:38]2[CH:39]3[CH:34]([CH2:33][CH2:32][CH2:31][CH:30]3[N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:35][CH2:36][CH2:37]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CNC2C(C1)CCCC2N1CCCC1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCCC2CCCC(N3CCCC3)C21
Temperature: 25 °C
Reaction time: 4 h
Yield: 113.6 %

Procedure:
A solution of 873 mg of 3,4-dichlorophenyl-acetic acid and 690 mg of carbonyldiimidazole in tetrahydrofuran was stirred for 1 hour at 20° to 25° C. and then 645 mg of the product of Step C in solution in 3 ml of tetrahydrofuran was added. After stirring for 4 hours at ambient temperature, the tetrahydrofuran was eliminated under reduced pressure at less than 40° C. and the residue was taken up in 20 ml of ether. The solution was washed with a saturated solution of sodium bicarbonate, then with water saturated with sodium chloride and the etheral phase was dried and distilled to dryness under reduced pressure to obtain 1.39 g of the crude product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:12](O)=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].Cl.[CH:26]([S:29]([C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:43])[N:40]([CH3:42])[CH3:41])=[CH:34][C:33]=1[C@H:44]1[CH2:48][CH2:47][CH2:46][NH:45]1)(=[O:31])=[O:30])([CH3:28])[CH3:27]>>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([C@@H:11]([NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:1]([NH2:2])=[O:3])[C:12]([N:45]2[CH2:46][CH2:47][CH2:48][C@@H:44]2[C:33]2[CH:34]=[C:35]([NH:38][C:39]([N:40]([CH3:42])[CH3:41])=[O:43])[CH:36]=[CH:37][C:32]=2[S:29]([CH:26]([CH3:28])[CH3:27])(=[O:31])=[O:30])=[O:13])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)N(C)C)cc1[C@H]1CCCN1
Reactant: COc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1OC
Agent: Cl
Product: COc1ccc([C@@H](Nc2cccc(C(N)=O)c2)C(=O)N2CCC[C@@H]2c2cc(NC(=O)N(C)C)ccc2S(=O)(=O)C(C)C)cc1OC

Procedure:
Example 56 was prepared according to the general coupling condition using 1A and 31A. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.17 (d, J=6.60 Hz, 3 H) 1.42 (d, J=7.15 Hz, 3H) 1.73 (dd, J=12.64, 5.50 Hz, 1H) 1.91-2.21 (m, 2H) 2.47 (dd, J=13.19, 7.70 Hz, 1H) 2.97 (s, 6H) 3.61 (s, 3H) 3.63-3.74 (m, 1H) 3.80-3.85 (m, 3H) 3.87-3.99 (m, 1H) 4.03-4.16 (m, 1H) 5.37 (s, 1H) 5.66 (dd, J=8.25, 4.95 Hz, 1H) 6.79 (s, 1H) 6.83-6.96 (m, 3H) 7.02 (d, J=8.25 Hz, 1H) 7.17-7.28 (m, 3H) 7.39 (dd, J=8.79, 2.20 Hz, 1H) 7.72 (d, J=8.79 Hz, 1H), LC-MS 652 (M+H).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH2:34]([CH:36]1[CH2:41][O:40][CH2:39][CH2:38][NH:37]1)[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:34]([CH:36]1[CH2:41][O:40][CH2:39][CH2:38][N:37]1[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]1[C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=1)[CH3:35]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: CCC1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC1COCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 150 °C
Yield: 31.9 %

Procedure:
A sealable vial was charged with ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (100 mg, 0.189 mmol, Intermediate B), 3-ethylmorpholine (43.6 mg, 0.378 mmol, ChemBridge Corporation, San Diego, Calif.), potassium carbonate (52.3 mg, 0.378 mmol), and 4 mL of MeCN. The vial was sealed and heated to 150° C. for 90 min. Afterwards, the reaction mixture was filtered and the filtrate was concentrated. The crude material was purified via preparatory TLC using 5% MeOH in CH2Cl2 eluent to yield 2-(4-((2S)-2-((3-ethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (33 mg) as a mixture of four isomers.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[CH2:8][CH2:7][CH2:6][C:5]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[C:4]=2[N:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:12][C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][C:5]4([CH2:13][CH2:14][CH2:15][CH2:16]4)[C:4]=3[N:3]=[C:2]([NH2:1])[N:11]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(O)c2c(n1)C1(CCCC1)CCC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCC32CCCC2)cc1
Reaction time: 3 h
Yield: 15.1 %

Procedure:
A solution of Example 1C (2.91 g, 13.27 mmol), p-toluenesulfonyl chloride (3.79 g, 19.91 mmol), and DMAP (324 mg, 2.65 mmol) in CH2Cl2 (60 mL) was treated with TEA (3.7 ml, 4.40 mmol) at ambient temperature, and the resulting solution was stirred for 3 hours. It was then diluted with CH2Cl2 (100 mL) and H2O (50 mL), and the layers were separated. The organic layer was dried with MgSO4 and concentrated under reduced pressure, then the residue was chromatographed on silica gel (1:2:2 EtOAc/CH2Cl2/hexane, eluant) to provide the title product (750 mg). 1H NMR (300 MHz, CD3OD) δ 7.95 (d, 2 H), 7.44 (d, 2 H), 2.45-2.47 (m, 3 H), 2.40-2.45 (m, 2 H), 1.99-2.10 (m, 2 H), 1.79-1.90 (m, 2 H), 1.65-1.75 (m, 6 H), 1.52-1.62 (m, 2 H). MS (DCI+) m/z 374 (M+H).
Reaction SMILES: [ClH:1].C([S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH2:8]/[C:7]/1=[CH:25]\[C:26]1[N:30]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[N:29]=[N:28][CH:27]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CO>[ClH:1].[CH:15]1([C:13](=[O:14])[CH:12]([N:9]2[CH2:10][CH2:11][CH:6]([SH:5])/[C:7](=[CH:25]/[C:26]3[N:30]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[N:29]=[N:28][CH:27]=3)/[CH2:8]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:17][CH2:16]1
Reactant: COC(=O)Cn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1SC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)Cn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Yield: 71.8 %

Procedure:
Following a procedure similar to that described in Example 151, (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-5-yl]methylidene}piperidine hydrochloride (560 mg) was treated with potassium carbonate in methanol and the concentrated extract was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 30/70, v/v) to afford the title compound (370 mg, yield: 72%) as a yellow amorphous solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[Cl:8][C:7]1[C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Clc1cccnc1Cl
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: COCCOC
Solvent: O
Product: O=Cc1ccc(-c2ncccc2Cl)cc1
Yield: 81 %

Procedure:
{circle around (1)} 100 g (0.676 mol) of 2,3-dichloropyridine, 101.4 g (0.676 mol) of (4-formylphenyl)boronic acid and 86 g (0.811 mol) of sodium carbonate were dissolved in 500 mL of 1,2-dimethoxyethane and 500 mL of distilled water, and 78 g (0.0676 mol) of Pd(PPh3)4 was added. The mixture was heated to reflux for 18 hours so that it was allowed to react. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove 1,2-dimethoxyethane, and then extracted with ethyl acetate. The extract was treated with magnesium sulfate, filtered and concentrated under reduced pressure, yielding 4-(3-chloropyridin-2-yl)benzaldehyde as represented below in a 81% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]#[N:7].[N+:19]([O-])([OH:21])=[O:20].[K]>C(O)(=O)C>[N+:19]([C:8]1[CH:9]=[C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]#[N:7])([O-:21])=[O:20]
Reactant: COc1cc(C#N)ccc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Agent: [K]
Solvent: CC(=O)O
Product: COc1cc(C#N)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
3-methoxy-4-benzyloxybenzonitrile (4.78 g, 20 mmol) in acetic acid (10 ml) was slowly added to nitric acid (d=1.42, 25 ml) at 20-30° with cooling in an ice bath. The mixture was then stirred at room temperature for 6 hours. The reaction mixture was treated with potassium hydroxyde (10N) at 0° C. The basic mixture (pH 10) was extracted with CH2Cl2, the organic phase was dried over MgSO4, concentrated to give title compound (3.62 g, 64%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][C:6](=[O:12])[C:5]2=O.Cl.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][N:24]=[C:5]2[C:4]3[C:8](=[CH:9][C:10]([CH3:11])=[C:2]([OH:1])[C:3]=3[CH3:14])[NH:7][C:6]2=[O:12])=[CH:19][CH:18]=1
Reactant: Cc1cc2c(c(C)c1O)C(=O)C(=O)N2
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc(NN=C2C(=O)Nc3cc(C)c(O)c(C)c32)cc1
Yield: 41 %

Procedure:
1H NMR (DMSO-d6): δ 2.17 (s, 3H), 2.30 (s, 3H), 6.45 (s, 1H), 8.29 (s, 1H), 10.65 (s, 1H); ESI-MS m/z 190 (M−H)−. The isatin was combined with 4-methylphenylhydrazine hydrochloride according to Procedure H to provide the title compound in 41% yield.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CN(C)C=O>[CH2:17]([N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCN1c2ccccc2Sc2ccccc21
Yield: 81 %

Procedure:
Adding phenothiazine (5 g, 25 mmol), sodium hydride (1.8 g) into the N,N-dimethyl formamide (30 mL), stirring, and then dropping n-octyl bromide (5.4 g, 28 mmol) into the mixture. Cease reaction after 2 hours, putting the mixture into 300 mL distilled water for, extracting by n-hexane, rotary evaporation of the solvent, using n-hexane as eluent to elutriate the crude product, then separating by silica gel column chromatography to obtain a yellow sticky product, the yield was 81%.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1.S(Cl)([Cl:21])(=O)=O>CN(C)C=O>[Cl:21][C:15]1[CH:16]=[N:17][C:7]2[O:6][CH:5]([CH2:4][CH2:3][Cl:2])[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]=2[CH:14]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Agent: Cl
Solvent: CN(C)C=O
Product: CN1CC(CCCl)Oc2ncc(Cl)cc2C1=O
Yield: 6.4 %

Procedure:
A sample of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5-(4H)-one hydrochloride (10 g, 136 mole) was dissolved in dimethylformamide (150 ml) and heated to reflux. Sulfuryl chloride (20 g, 0.148 mole) was then added dropwise over a period of 40-50 minutes. The reaction was allowed to stir at reflux for 30 minutes following the addition of SO2Cl2. After cooling, the contents of the flask were partitioned between water (150 ml) and benzene (150 ml). The benzene layer was saved and the water layer extracted with an additional amount of benzene (2×50 ml). The benzene extracts were combined and washed with dilute aqueous potassium hydroxide (2×50 ml) followed by dilute aqueous hydrochloric acid (2×50 ml). The benzene layer was dried over sodium sulfate and concentrated by rotary evaporation (~70° C., water aspirator) yielding 2.61 g of crude material. The crude material was recrystallized from isopropyl ether giving 1.25 g (12.6%) of off-white crystals, m.p. 78°-79° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:3]=1.[NH2:23][NH2:24]>>[NH:23]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:3]=1)[NH2:24]
Reactant: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1Cl
Reactant: NN
Product: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1NN
Yield: 60 %

Procedure:
The title compound was prepared by (a) of diethyl ethoxymethylenemalonate (6.3 g, 29 mmol) with 4-trifluoromethylphenylbenzamidine (5.5 g, 29 mmol) to afford 50% of ethyl 4-hydroxy-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 4-hydroxy-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate (3 g, 9.6 mmol) with POCl3 (49 g, 322 mmol) to afford 97% of ethyl 4-chloro-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of ethyl 4-chloro-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate (2 g, 6 mmol) with hydrazine (0.6 g, 18 mmol) to afford 60% of ethyl 4-hydrazino-2-(4'trifluoromethylphenyl)pyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate (1 g, 3 mmol) with citraconic anhydride (1 g, 9 mmol) to afford 40% (0.5 g) of the title compound (m.p. 148-150° C.) in analogy to Example 21.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:6][CH2:5]1.[NH:27]1[CH2:33][CH2:32][CH2:31][CH:30]([OH:34])[CH2:29][CH2:28]1>>[OH:34][CH:30]1[CH2:31][CH2:32][CH2:33][N:27]([CH2:2][CH2:3][N:4]2[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[C:19]([O:22][CH2:23][CH:24]([CH3:25])[CH3:26])[CH:18]=[CH:17][CH:16]=4)=[O:12])[CH2:8][CH2:9]2)[CH2:28][CH2:29]1
Reactant: OC1CCCNCC1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCO)CC3)cc12
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCC(O)CC4)CC3)cc12

Procedure:
This compound is synthesized analogously to example 150 from 4-isobutoxy-1H-indole-2-carboxylic acid [1-(2-hydroxy-ethyl)-piperidin-4-yl]-amide, 190 and azepan-4-ol.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-phenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 69% overall yield. FDMS m/e=366 (M+ of free base). α[D]589 =-10.45 (c=0.61, methanol).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[C:32]([CH3:43])[CH:31]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=3)[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2]>[Pd].CO>[C:1]([C:4]1[CH:5]=[C:6]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)=[C:32]([CH3:43])[CH:31]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2]
Reactant: Cc1cc(-c2cc(C(N)=O)c3[nH]c4cc(C5=CCN(C(=O)OC(C)(C)C)CC5)ccc4c3c2)ccc1CN1CCOCC1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(-c2cc(C(N)=O)c3[nH]c4cc(C5CCN(C(=O)OC(C)(C)C)CC5)ccc4c3c2)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-(8-carbamoyl-6-(3-methyl-4-(morpholinomethyl)phenyl)-9H-carbazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate 484 (12 mg, 0.021 mmol) and palladium on carbon (20 mg, 0.019 mmol) were mixed with MeOH (10 ml) in a sealed microwave tube. The mixture was stirred at r.t. with H2 in a balloon overnight. The mixture was filtered and then purified using preparative HPLC (MeOH/H2O/TFA) to give titled product. MS (ESI) m/z 583.19 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)=[CH:4][C:3]=1[CH3:20].CO.[H][H]>[Pd].C(O)(=O)C>[NH2:8][C:7]1[CH:6]=[C:5]([N:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16]2)[CH:4]=[C:3]([CH3:20])[C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: CC(=O)N1CCN(c2cc(C)c(N)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)N1CCN(c2cc(C)c(N)c(N)c2)CC1
Yield: 99.4 %

Procedure:
To 1-[4-(4-amino-3-methyl-5-nitro-phenyl)-piperazin-1-yl]-ethanone (4.5 g, 16.2 mmol) and 10% palladium on carbon (400 mg) were added methanol (50 mL) and acetic acid (5 mL) under nitrogen. The reaction mixture was stirred under hydrogen atmosphere (hydrogen balloon) for 14 h. The dark solution was filtered through a pad of celite and the filtercake was washed with methanol. Concentration of the filtrate gave the title compound (4.00 g, 100%) which was used for the next step without purification. LCMS (M+H)+ m/z 207 (t=0.41 min.). Procedure for the Preparation of 5-fluoro-3-methyl-2-nitro-aniline:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][OH:25]>CN(C=O)C.S([O-])([O-])(=O)=O.[Ag+2]>[OH:25][CH2:24][CH2:23][CH2:22][NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C1=C1OCc2ccc(NCCCO)cc21
Temperature: 120 °C
Yield: 9.8 %

Procedure:
A mixture of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (25.0 mg, 0.095 mmol), 3-bromo-1-propanol (85.5 μL, 0.946 mmol), and silver sulfate (59.0 mg, 0.189 mmol) in 0.8 mL DMF was heated at 120° C. for 1.5 h. The mixture was partitioned between EtOAc and H2O and the organic layer separated from the silver salts. The solution was washed with H2O, brine and then dried with Na2SO4. Concentrating the solution in vacuo gave a residue which was purified by chromatography (silica gel, CHCl3/MeOH, 96:4) to give the title compound (3 mg, 10%) as a yellow solid.
Reaction SMILES: O[N:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=2)=[CH:3]1.[H][H]>[Pd].O>[NH2:11][C:7]1[N:6]=[C:5]2[C:4]([CH:12]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]3)=[CH:3][NH:2][C:10]2=[CH:9][CH:8]=1
Reactant: CN1CC=C(c2cn(O)c3ccc(N)nc23)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reaction time: 3 h
Yield: 81.3 %

Procedure:
A suspension of 1 gm (3.15 mMol) 1-hydroxy-5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine (H) dihydrochloride and 0.20 gm 10% palladium on carbon in 10 mL demineralized water was hydrogenated at ambient temperature with an initial hydrogen pressure of 45 p.s.i. After four hours the reaction mixture was filtered and the filtrate treated with 6 mL 2N aqueous sodium hydroxide. After the addition of 0.2 mL tetrahydrofuran the reaction mixture was stirred for 3 hours and the resulting precipitate collected by filtration. The solid was dried under reduced pressure at 50° C. to provide 0.59 gm (94%) of the title compound.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([C:11]3[NH:12][C:13](=O)[C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:4][C:3]=2[O:2]1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][CH2:1][O:2][C:3]=3[CH:4]=2)[N:12]=1
Reactant: O=c1[nH]c(-c2ccc3c(c2)OCCO3)cc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc(-c2ccc3c(c2)OCCO3)cc2ccccc12

Procedure:
The resulting 3-(3,4-ethylenedioxyphenyl)isoquinolin-1-one (1.94 g) was reacted with phosphorus oxychloride (20 ml) according to the method of Example 10-2, to give 1-chloro-3-(3,4-ethylenedioxyphenyl)isoquinoline. The resulting compound was reacted, as it was, with N-ethylpiperazine (6 ml) at 100° C. overnight. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The resulting ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 1.63 g of the free compound of the title compound as a pale yellow oil.