Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:17][CH:18]([C:20]1[CH:21]=[C:22]2[CH:28]=[CH:27][N:26](C(OC(C)(C)C)=O)[C:23]2=[CH:24][N:25]=1)[CH3:19].CCN(C(C)C)C(C)C>CCCCO>[NH:26]1[C:23]2=[CH:24][N:25]=[C:20]([CH:18]([NH:17][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:13]=[C:12]([CH:14]5[CH2:16][CH2:15]5)[NH:11][N:10]=4)[CH:5]=[CH:4][N:3]=3)[CH3:19])[CH:21]=[C:22]2[CH:28]=[CH:27]1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: CC(N)c1cc2ccn(C(=O)OC(C)(C)C)c2cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1nccc(Nc2cc(C3CC3)[nH]n2)n1)c1cc2cc[nH]c2cn1
Temperature: 115 °C

Procedure:
A sealed-cap vial was charged with 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-pyrimidin-4-amine (60 mg, 0.25 mmol), tert-butyl 5-(1-aminoethyl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (93 mg, 0.36 mmol), DIPEA (0.16 mL) and n-BuOH (0.8 mL). The mixture was heated at 115° C. for 72 h. The reaction mixture was concentrated under reduced pressure. The crude mixture was purified by preparative HPLC to afford N2-(1-(1H-pyrrolo[2,3-c]pyridin-5-yl)ethyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine: MS (ESI) m/z: 361.2 [M+1]+.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:10][C:11]1[N:12]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:13]([SH:16])=[N:14][N:15]=1.[I-].[K+]>CN(C=O)C>[NH2:10][C:11]1[N:12]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:13]([S:16][C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:14][N:15]=1
Reactant: Nc1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Reactant: CCOC(=O)C(C)(C)Br
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Sc1nnc(N)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 70 °C
Yield: 27.3 %

Procedure:
Ethyl 2-bromo-2-methylpropanoate (184 μL, 1.239 mmol) was added to a solution of 5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (0.35 g, 1.239 mmol) in DMF (2.5 mL) and heated at 60° C. for 20 hours after which time a few crystals of potassium iodide were added and the mixture heated at 70° C. for a further 24 h. The temperature was then increased to 90° C. and the mixture heated for an additional 6 days. The mixture was allowed to cool to room temperature, concentrated and dissolved in dichloromethane. Triethylamine and water were added and the layers separated. The aqueous layer was extracted with dichloromethane (2×) and the combined organic extracts dried over NaSO4, filtered, concentrated and purified by column chromatography (ethyl acetate) to afford ethyl 2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate as a tan solid (0.134 g, 27%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:23][C:24]4[CH:25]=[C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([OH:38])=O)[CH:31]=5)[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:21][CH:22]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:40]1CCOCC1.ClC(OCC(C)C)=O.N>C1COCC1.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:23][C:24]4[CH:25]=[C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([NH2:40])=[O:38])[CH:31]=5)[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:21][CH:22]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2cccc(CC3CCC=C3c3nc(-c4ccccc4)c(-c4ccccc4)o3)c2)c1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc(-c2cccc(CC3CCC=C3c3nc(-c4ccccc4)c(-c4ccccc4)o3)c2)c1
Reaction time: 0.25 h

Procedure:
To a solution of 3′-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl}biphenyl-3-carboxylic acid (74 mg) and N-methylmorpholine (0.0197 ml) in THF (4 ml) was added isobutyl chloroformate (0.0232 ml) at 0° C. After stirring for 15 minutes, 28% ammonia solution (0.1 ml) was added thereto. The mixture was stirred at the same temperature for 15 minutes, then stirred at room temperature for 15 minutes. The reaction mixture was diluted with EtOAc, washed with water, 1N HCl, water, and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2-MeOH 25:1) to give 3′-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl}-biphenyl-3-carboxamide (51.8 mg) as a solid.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:34][CH3:35])[CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:21].Cl>>[CH2:34]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7](=[O:15])[C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:30][CH2:29]1)[CH3:35]
Reactant: CCN(CC)CCOCCC1CCNCC1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Agent: Cl
Product: CCN(CC)CCOCCC1CCN(C(=O)N2c3ccccc3NC(=O)c3cccnc32)CC1
Yield: 83 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 4-[2-[2-(diethylamino)ethoxy]ethyl]piperidine in a yield of 83% of theory. The colourless hydrochloride melted at 148°-150° C. (ethyl acetate).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].C(N(C(C)C)CC)(C)C.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:35]=[C:36]([CH2:40][NH2:41])[CH:37]=[CH:38][CH:39]=1>ClCCl>[O:1]=[C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([NH:41][CH2:40][C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:42])[F:43])[CH:35]=1)=[O:21]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCc1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.051 g, 0.173 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.072 g, 0.190 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.045 mL, 0.259 mmol) followed by (3-(trifluoromethyl)phenyl)methanamine (0.030 mL, 0.207 mmol). After stirring overnight, the reaction was loaded onto a silica gel column (SF15-12, Analogix®, Burlington, Wis.), and the title compound was eluted with a gradient of 0.4% to 4.5% methanol/dichloromethane over 20 minutes with a flow rate of 30 mL/minute. 1H NMR (300 MHz, CDCl3) δ ppm 7.50-7.55 (m, 1H), 7.37-7.44 (m, 2H), 7.17-7.34 (m, 11H), 6.30 (t, J=6.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H), 4.07 (s, 2H), 3.50 (t, J=6.5 Hz, 2H), 2.81 (t, J=6.5 Hz, 2H); MS (ESI−) m/z 451 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=O)[N:14]=2)=[CH:5][CH:4]=1.[S:17]1[CH2:23][C:21](=[O:22])[N:20]([CH2:24][C:25]([OH:27])=[O:26])[C:18]1=[S:19].[Cl-].[NH4+].N>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=[C:23]3[S:17][C:18](=[S:19])[N:20]([CH2:24][C:25]([OH:27])=[O:26])[C:21]3=[O:22])[N:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Nc2nc(C=O)cs2)cc1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(Nc2nc(C=C3SC(=S)N(CC(=O)O)C3=O)cs2)cc1

Procedure:
The reaction described in Example 1 was repeated, but using 1 g of 2-(p-anisidino)thiazole-4-carbaldehyde, 0.8 g of rhodanine-3-acetic acid 0.5 g of ammonium chloride, 0.5 ml of 28% v/v aqueous ammonia, and 10 ml of ethanol, giving the title compound as an orange powder.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:3]([CH3:10])[CH:4]=1)=[O:7]
Reactant: Cc1cc(C=O)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1C
Temperature: 40 °C
Yield: 63.6 %

Procedure:
To a solution of 4-hydroxy-3-methyl benzaldehyde (3 g, 22 mmol) and ethyl 2-bromo-2-methylpropionate (6.5 mL, 44 mmol) in DMF (100 mL) was added caesium carbonate (15.8 g, 48 mmol). The resulting mixture was heated at 40° C. for 42 h, then allowed to cool to room temperature. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2×150 mL). The organic solution was dried (MgSO4), filtered and evaporated. Purification by Biotage™ chromatography (Silica, 90 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (3.5 g).
Reaction SMILES: [CH3:1][C:2]1([CH:12]([C:18]#[N:19])C(OCC)=O)[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[Li+].[Cl-].O>CS(C)=O>[C:18]([CH2:12][C:2]1([CH3:1])[CH2:3][C:4]([CH3:11])([CH3:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)#[N:19]
Reactant: CCOC(=O)C(C#N)C1(C)CC(C)(C)CC(C)(C)C1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)CC(C)(C)CC(C)(CC#N)C1
Temperature: 155 °C
Yield: 92.3 %

Procedure:
The mixture of ethyl (1,3,3,5,5-pentamethylcyclohexyl)cyanoacetate (17) (1g, 3,7 mmol), LiCl (0.05 g) and water (0.15 ml) in DMSO (2.5ml) was heated at 150-160° C. for 4 h. Solution was poured into water (70 ml) and extracted with ether (4*20 ml). Ether was washed with saline (2*50 ml), dried over Na2SO4, filtered and evaporated. Crude product was purified on silica gel column, eluting with a petroleum ether-ethyl acetate mixture (20:1) to give 0.66 g (94%) of 18 as an oil.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH2:10][OH:11])[CH:9]=1.[CH3:13]I.[Cl-].[Na+]>C(OCC)C.O1CCCC1>[F:12][C:7]1[CH:6]=[CH:5][C:4]([NH2:3])=[CH:9][C:8]=1[CH2:10][O:11][CH3:13]
Reactant: Nc1ccc(F)c(CO)c1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCc1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a round-bottomed flask, 374 mg of sodium hydride at 60% are introduced into 10 ml of tetrahydrofuran, 1 g of (5-amino-2-fluorophenyl)methanol and 0.441 ml of methyl iodide. After stirring at ambient temperature for one hour, a solution of sodium chloride and diethyl ether are added. The organic phase is extracted and then washed with water until pH=7. It is then dried over magnesium sulphate, filtered, and concentrated under reduced pressure. 900 mg of 4-fluoro-3-(methoxymethyl)aniline are obtained in the form of a black oil, which is used as it is in the next stage.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.Cl>O1CCCC1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:13][CH2:14][NH:15][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: O=C(Cl)C1CCC1
Reactant: COc1ccc(CCN)cc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)C2CCC2)cc1OC
Yield: 104.3 %

Procedure:
Cyclobutanecarbonyl chloride (19 g) was added dropwise at ambient temperature to a stirred solution of 3,4-dimethoxyphenethylamine (30.5 g) and triethylamine (23.5 ml) in tetrahydrofuran (11). After 1.5 hours the mixture was poured onto dilute hydrochloric acid (1 l) and the product was extracted into ethyl acetate. The extracts yielded N-[2-(3,4-dimethoxyphenyl)ethyl]cyclobutanecarboxamide (44 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]4[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:23]([C:21]2[CH:20]=[CH:19][C:13]3[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:22]=2)=[O:24])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Yield: 61.2 %

Procedure:
4-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (160 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid (180 mg), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (150 mg), HBTU (200 mg), and DIEA (1.2 mL) in DMF (2 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]1
Reactant: Cc1ccnc2c1C(=O)CC(c1sc(Cl)cc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1sc(Cl)cc1Cl)C2
Yield: 123.4 %

Procedure:
A mixture of 7-(3,5-dichlorothiophen-2-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.5 g), aminoguanidine hydrochloride (0.21 g), concentrated hydrochloric acid (0.4 ml), water (0.4 ml) and ethanol (15 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from water. The resulting crystals were washed with ethanol to give 7-(3,5-dichlorothiophen-2-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 121) (0.40 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[C:28]1([CH3:37])[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH2:36])=[CH:30][CH:29]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][NH:36][CH2:35][CH2:34][C:31]3[CH:32]=[CH:33][C:28]([CH3:37])=[CH:29][CH:30]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: Cc1ccc(CCN)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(CCNCC2CCN(C(=O)c3cc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Reaction time: 14 h

Procedure:
1-(1-(4-fluorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carbaldehyde (46 mg, 0.126 mmol) was dissolved in THF (2 mL) and 2-(p-tolyl)ethanamine (0.030 mL, 0.189 mmol) was added. The solution was stirred at rt for 10 h, at which time the THF was removed in vacuo and the residue dissolved in EtOH (5 mL), and sodium cyanoborohydride (24 mg, 0.349 mmol) and a catalytic drop of glacial acetic acid were added. Stirring was permitted for 14 h, at which time the solvent was removed in vacuo, the residue was taken up in EtOAc. The organic phase was washed with 10% aq. sodium carbonate, dried over magnesium sulfate, and concentrated. Purification was accomplished via silica gel flash chromatography (30 g silica gel, 5:95 7M methanolic ammonia:ethyl acetate.) The title compound was obtained as a yellow oil. (Yield: 26 mg, 0.054 mmol, 43%) 1H NMR (400 MHz, CDCl3) 7.62, 7.36, 7.29-7.20, 7.17-7.07, 6.90, 6.58, 5.46, 4.62, 4.08, 2.89-2.65, 2.42, 2.31, 1.60, 1.01, 0.64
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH:35]=O)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38].[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:25])([F:24])[F:26])(=[O:12])=[O:13])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH2:35][N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38]
Reactant: C1COCCN1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCN4CCOCC4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
With 500 mg of the compound obtained in Example 219 and morpholine (0.13 ml) as starting material, 300 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 220.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[CH:2]1.Br[CH2:28]CCC1C2C(=CC=CC=2)CC=1>>[CH2:28]1[C:8]2[C:9](=[CH:1][CH:2]=[CH:6][CH:7]=2)[C:4]([CH2:3][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:17]2)=[CH:5]1
Reactant: O=C(NC1CCN(CCC2=CCc3ccccc32)CC1)c1ccccc1
Reactant: BrCCCC1=CCc2ccccc21
Product: O=C(NC1CCN(CCCC2=CCc3ccccc32)CC1)c1ccccc1

Procedure:
Prepared in a similar manner to the compound of Example 14 but using 3-(3-bromopropyl)indene in place of 3-(2-bromoethyl)indene. The title compound crystallised from isopropanol, m.p. 157°-9° C. (Found: C, 79.8; H, 8.1. N, 7.7. C24H28N2O requires C, 80.0; H, 7.8; N, 7.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[C@H:29]1([CH2:37]O)[CH2:34][CH2:33][C@H:32]([CH2:35][OH:36])[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:37][CH:29]3[CH2:34][CH2:33][CH:32]([CH2:35][OH:36])[CH2:31][CH2:30]3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: OC[C@H]1CC[C@H](CO)CC1
Product: O=C1c2ccccc2C(OCC2CCC(CO)CC2)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 71.1 %

Procedure:
The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and trans-cyclohexane-1,4-dimethanol (728 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a yellow solid (374 mg, 71%). 1H NMR (300 MHz, CDCl3): 8.05-7.92 (m, 3H, O2N—C—CH and C(O)═C═CH), 7.56-7.53 (m, 2H, Ar—H), 7.38-7.10 (m, 7H, Ar—H), 4.59 and 4.35 (d: AB, J=15.0 Hz, 2H, N—CH2), 3.44 (d, J=6.3 Hz, 2H, HO—CH2), 2.65-2.53 (m, 2H, OCH2), 1.81-1.74 (m, 3H, OH and CH), 1.44-1.32 (m, 2H), 0.93-0.79 (m, 5H). 13C NMR (75 MHz, CDCl3): 168.26, 145.41, 144.82, 137.42, 134.84, 132.93, 130.01, 128.63, 128.01, 123.80, 123.24, 123.18, 94.67, 68.41, 68.26, 42.41, 40.59, 38.04, 29.68, 29.31, 28.90. m/z (ES): 521 [M+H]+. Anal.: calc. for C29H29ClN2O5+0.2 H2O: C, 66.38; H, 5.66; N, 5.34. Found: C, 66.23; H, 5.79; N, 4.99.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.CCCCCC.[Cl:22][C:23]1[CH:32]=[C:31]([Cl:33])[C:30]2[C:25](=[CH:26][C:27]([Cl:34])=[CH:28][CH:29]=2)[C:24]=1[CH2:35][CH2:36][CH:37]=[O:38]>O1CCCC1>[Cl:22][C:23]1[CH:32]=[C:31]([Cl:33])[C:30]2[C:25](=[CH:26][C:27]([Cl:34])=[CH:28][CH:29]=2)[C:24]=1[CH2:35][CH2:36][CH:37]([OH:38])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: O=CCCc1c(Cl)cc(Cl)c2ccc(Cl)cc12
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CC(=O)CC(O)CCc1c(Cl)cc(Cl)c2ccc(Cl)cc12
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
A solution of methyl acetoacetate (0.088 g, 0.76 mmole) in dry tetrahydrofuran (2 ml) was added dropwise (5 minutes) to a mixture of sodium hydride (0.036 g, 0.75 mmole) in tetrahydrofuran (3 ml) under nitrogen and with cooling (ice bath). After stirring at about 5° C. for 20 minutes, a solution of n-butyl lithium in hexane (0.55 ml, 0.77 mole) was added dropwise (5 minutes) and the mixture stirred at 5° C. for 30 minutes. The ice bath was replaced by a dry ice-acetone bath and a solution of 3-(2,4,7-trichloronaphthalen-1-yl)propanal (0.20 g, 0.7 mmole) in tetrahydrofuran (5 ml) was added (5 minutes). The reaction mixture was stirred at -70° C. for about 10 minutes and at room temperature for 5 hours and then poured into ice water containing 0.5 ml conc. HCl. After extraction with ether, the ether extracts were combined, washed with cold water and brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give 0.25 g of the title compound as a yellow oil.
Reaction SMILES: O=C(C)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.[CH3:19][C:20]([CH3:31])([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](Cl)=[O:22]>C(Cl)Cl>[CH3:19][C:20]([CH3:31])([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](=[O:22])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(Cc1ccccc1)C(=O)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)C(C)(C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
Ethyl 3-oxobutanoate (1.09 g, 8.3 mmol) in methylene chloride (16 mL) was mixed with anhydrous magnesium chloride (158 mg, 1.66 mmol), and the reaction solution was cooled to 0° C., mixed with pyridine (1.34 mL, 16.6 mmol), stirred for 30 minutes, then mixed with 2,2-dimethyl-3-phenylpropanoyl chloride (1.64 g, 8.3 mmol) and stirred for another 30 minutes at the same temperature. The reaction solution was warmed to room temperature and stirred for 20 hours. The methylene chloride was distilled off under reduced pressure, and the residue was with ethanol (2 mL) and at room temperature for 2 days and with toluene (2 mL) at 60° C. for 5 hours. After completion of the reaction, the reaction solution was washed with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (50 mL×2). The solvent was removed from the resulting organic layer under reduced pressure, and the resulting brown oil was purified by intermediate pressure silica gel column chromatography (silica gel12 g, ethyl acetate:hexane=1:19 to 1:9) to give 370 mg of the desired product as a light brown oil.