Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH:7]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:8][C:9]([OH:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].O.O1CCCC1>>[CH:12]1([CH:7]([NH:6][C:2]([O:4][CH3:5])=[O:3])[CH2:8][C:9]([OH:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)Cl
Reactant: NC(CC(=O)O)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)NC(CC(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
Methyl chloroformate (54 uL, 0.70 mmol) was added to a mixture of 3-amino-3-cyclohexylpropanoic acid (100.0 mg, 0.5840 mmol) (Key Organics/Bionet, Cat. #7T-0112) and potassium carbonate (160 mg, 1.2 mmol) in water (2.0 mL, 110 mmol) and tetrahydrofuran (2.0 mL, 25 mmol). After stirring at r.t. for 10 min, the mixture was extracted with ether to remove impurity. The aqueous layer was adjusted to pH=2 with HCl, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (130 mg, 97%). Analytic LCMS (M+H)+: m/z=230.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18]1([O:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:25](=[O:26])[O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
A solution of 4-methoxybenzenemethanamine (72.7 g) and triethylamine (83.6 ml) in CH2Cl2 (750 ml) was cooled on an ice-bath. Phenylchloroformate (91.4 g) was added dropwise and the reaction mixture was stirred at RT. The reaction mixture was washed three times with water and the precipitate was filtered off. The organic layer was separated, washed three times with a 5% aqueous NaHCO3 solution, dried (MgSO4), filtered and the solvent was evaporated. The precipitate was stirred in boiling diethyl ether (300 ml), filtered off and dried, yielding 84.4 g (65.5%) of phenyl [(4-methoxyphenyl)methyl]carbamate (interm. 2).
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][S:15][CH3:16])(C1C=CC(C)=CC=1)(=O)=O.[SH:17][CH2:18][CH2:19][CH2:20][OH:21].CC(C)([O-])C.[K+].O>C1COCC1>[CH2:20]([OH:21])[CH2:19][CH2:18][S:17][CH2:12][CH2:13][CH2:14][S:15][CH3:16]
Reactant: OCCCS
Reactant: CSCCCOS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CSCCCSCCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.8 %

Procedure:
To a mixture of 3-methylthio-1-propanol tosylate (14.14 g, 54.3 mmol), and 3-mercapto-1-propanol (5.0 g, 54.3 mmol) in dry THF (300 mL) was added potassium tert-butoxide (8.51 g, 80.0 mmol) in one portion under a blanket of nitrogen, and the resulting mixture was stirred at room temperature for 24 hours. Water (10 mL) was added drop-wise to the reaction mixture to quench excess potassium tert-butoxide, and solvent was evaporated under reduced pressure. The resulting solid was washed with ether (3×100 mL), and filtered. The ether layer was washed with water (3×100 mL) and dried (Na2SO4). Solvent evaporation produced 8.7 g of a light yellow oil. This product was used for acryloylation without further purification.
Reaction SMILES: [OH-].[K+].[CH:3]([O:6][C:7]1[C:8]([CH3:17])=[N:9][CH:10]=[C:11]([CH:16]=1)[C:12]([O:14]C)=[S:13])([CH3:5])[CH3:4]>O.CO>[CH:3]([O:6][C:7]1[C:8]([CH3:17])=[N:9][CH:10]=[C:11]([CH:16]=1)[C:12]([OH:14])=[S:13])([CH3:5])[CH3:4]
Reactant: COC(=S)c1cnc(C)c(OC(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ncc(C(O)=S)cc1OC(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Potassium hydroxide (770 mg) in water (8 mL) is added to a solution of methyl 5-isopropyloxy-6-methylthionicotinoate (1.1 g) in methanol (15 mL) and the mixture stirred at room temperature for 6 hours. After concentrating in vacuo the residue is dissolved in water and acidified to pH 1 with concentrated aqueous hydrochloric acid. The mixture is extracted with ethyl acetate, the extracts washed with water and dried (MgSO4). The solvent is removed in vacuo to give 5-isopropyloxy-6-methylthionicotinic acid as a white solid, m.p. 154-5° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:19]([O:21][C:22](=[O:35])[C:23]([O:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][C:28]=1[CH3:34])([CH3:25])[CH3:24])[CH3:20].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>C1COCC1>[CH2:19]([O:21][C:22](=[O:35])[C:23]([CH3:25])([O:26][C:27]1[CH:32]=[CH:31][C:30]([O:16][CH2:15][C:12]2[N:13]=[N:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[CH:29][C:28]=1[CH3:34])[CH3:24])[CH3:20]
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)nn1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nn2)cc1C

Procedure:
0.170 g (0.669 mmol) of the above prepared [6-(4-trifluoromethyl-phenyl)-pyridazin-3-yl]-methanol and 0.163 g (0.684 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) were dissolved in 8 ml of abs. THF and treated successively at 0° C. with 0.162 g (0.800 mmol) of tributylphosphine and 0.139 g (0.804 mmol) of N,N,N′,N′-tetramethylazodicarboxamide. The cooling bath was then removed and stirring continued for one night. The reaction mixture was then poured onto crashed ice, extracted twice with AcOEt, washed with water, and dried over sodium sulfate. Evaporation of the solvents i. V., followed by flash chromatography (SiO2, hexane/AcOEt=7/3) yielded, after recrystallisation from hexane/AcOEt, 0.208 g of a colorless solid.
Reaction SMILES: C1(N[C:8](=[O:16])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[Br:15])C=CC=CC=1.[ClH:17].C(OCC)(=[O:20])C>>[ClH:17].[Br:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:8]([OH:16])=[O:20]
Reactant: CCOC(C)=O
Reactant: O=C(Nc1ccccc1)c1ccncc1Br
Agent: Cl
Product: O=C(O)c1ccncc1Br
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To an RBF equipped with a condenser and outfitted with a heating mantle was placed the N-phenyl-3-bromo-isonicotinamide (34 g, 0.123 mol) and 200 ml of 25% HCl. The reaction was left to stir for 3 days. The mixture was cooled to room temperature, and diluted with ethyl acetate. The aqueous layer was extracted and the two layers separated. To the aqueous layer, solid Na2CO3 was added until the pH˜4-5 and a dark oil layer appeared. This was then diluted and extracted with ethyl acetate. The two layers were separated and the aqueous layer was concentrated under reduced pressure to give an off-white solid. To this 100 ml of 2M HCl was added and the solids collected. The off-white solids were placed in a vacuum oven at 60° C. overnight. Yield: 22.4 g (76% th).
Reaction SMILES: [Cl-].C([C:5]1([CH2:20][CH2:21][CH2:22][C:23]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=2)([CH:26]([CH3:28])[CH3:27])[C:24]#[N:25])[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:15][CH3:16])[CH:12]=2)[CH2:7][NH+:6]1[CH3:19])(O)=O.O=P(Cl)(Cl)[Cl:41]>>[Cl-:41].[CH3:38][O:37][C:31]1[CH:30]=[C:29]([C:23]([CH:26]([CH3:28])[CH3:27])([C:24]#[N:25])[CH2:22][CH2:21][CH2:20][C:5]2[CH2:14][C:13]3[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:15][CH3:16])[CH:12]=3)[CH2:7][N+:6]=2[CH3:19])[CH:34]=[CH:33][C:32]=1[O:35][CH3:36]
Reactant: COc1ccc(C(C#N)(CCCC2(C(=O)O)Cc3cc(OC)c(OC)cc3C[NH+]2C)C(C)C)cc1OC
Reactant: O=P(Cl)(Cl)Cl
Agent: [Cl-]
Product: COc1ccc(C(C#N)(CCCC2=[N+](C)Cc3cc(OC)c(OC)cc3C2)C(C)C)cc1OC

Procedure:
The resulting salt of formula 33 is then decarboxylated to produce a dihydroisoquinolinium salt of formula 34 (step 5). For example, 3-carboxy-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinolinium chloride (33) is treated with Et2N, followed by POCl3, to produce 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,4-dihydroisoquinolinium chloride (34).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][N:6]=1>CN1C(=O)CCC1>[CH3:1][S:2][C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][N:6]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CSc1cc(N)ccn1
Temperature: 200 °C
Yield: 265.2 %

Procedure:
Sodium thiomethoxide (140 mg, 1.98 mmol) was added to a solution of 2-chloropyridin-4-amine (150 mg, 1.17 mmol) in NMP (0.65 mL) in a pressure vessel. The vessel was sealed and heated in a microwave to 200° C. for 800 sec. Purification by silica flash chromatography eluting with 8% MeOH/DCM afforded 2-(methylthio)pyridin-4-amine (435 mg, 50% yield). LC/MS (m/z): 140.9 (MH+), Rt 0.59 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2O[C:12](=O)[C:11]([C:15]#[N:16])=[C:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25]1[CH2:29]O[CH2:27][CH2:26]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:4]3[C:3]4[C:26](=[CH:25][CH:29]=[CH:7][CH:2]=4)[CH2:27][C:12]=3[C:11]([C:15]#[N:16])=[C:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc(Br)cc2)oc1=O
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc(Br)cc2)c2c1Cc1ccccc1-2

Procedure:
A mixture of 6-(4-bromophenyl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (358 mg), indanone-2 (132 mg) and NaH (31 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 212-212° C.; ESIMS 430 (M++2); IR (KBr) 2211 cm−1 (CN).
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:14]=[O:15])C1C=CC=CC=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:25]=1[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:31]([O:30][C:26]1[C:25]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:29]=[CH:28][C:27]=1[CH:14]=[O:15])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CN(C=O)c1ccccc1
Reactant: c1ccc(COc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
Kolonits, P. et al., Acta Chim. Hung. 113:367 (1983). POCl3 (155 mL, 1.66 mol) was slowly added to N-methylformanilide (175 mL, 1.4 mol) at room temperature under Ar which resulted in formation of a yellow solid. After 2 h, the solid was treated with a solution of 1,2,3-tribenzyloxybenzene 8 (20 g, 51 mmol) in anhydrous DMF (40 mL) and heated to 60° C. After 3 h, the resulting crimson solution was cooled to room temperature and then poured into ice water (3 L) with vigorous stirring for 12 h. The resulting brown precipitate was filtered, washed with hexanes (3×100 mL) and finally recrystallized from MeOH to afford 10 (19.8 g, 93%) as a white powder. mp 73-74° C. 1H NMR (CDCl3): δ10.11 (s, 1 H), 7.57 (d, J=9 Hz, 1 H), 7.44-7.28 (m, 15 H), 6.83 (d, J=9 Hz, 1 H), 5.21(s, 2 H), 5.16 (s, 2 H), 5.08 (s, 2 H); 13C NMR (CDCl3): δ188.8, 158.5, 155.9, 141.1, 136.9, 136.2, 135.8, 128.6, 128.5 (2), 128.3 (2) 128.2, 127.5, 124.0, 109.1, 76.8, 75.5, 70.9. Anal. Calcd for C28H24O4: C, 79.22; H, 5.70. Found: C, 79.17; H, 5.80. HRMS (FAB) calcd for C28H24O4 (M+H+): 424.1675. Found: 424.1669.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:18]4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C@H:27]3[CH2:30][C@H:29]([CH2:31]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:43]1[CH2:46][CH2:45][CH2:44]1>C1COCC1>[N:43]1([CH2:31][C@H:29]2[CH2:30][C@H:27]([N:8]3[C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[C:10]([C:11]4[CH:20]=[C:19]5[C:14]([CH:15]=[CH:16][C:17]([C:21]6[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=6)=[N:18]5)=[CH:13][CH:12]=4)=[CH:9]3)[CH2:28]2)[CH2:46][CH2:45][CH2:44]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](n3cc(-c4ccc5ccc(-c6ccccc6)nc5c4)c4c(N)ncnc43)C2)cc1
Reactant: C1CNC1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@H](CN2CCC2)C1
Reaction time: 8 h

Procedure:
A solution of toluene-4-sulfonic acid trans-3-[4-amino-5-(2-phenylquinolin-7-yl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl ester and azetidine (0.30 mL, 254 mg, 4.5 mmol) in THF (4 mL) was heated in a sealed tube to 50° C. overnight. More azetidine (0.30 mL, 254 mg, 4.5 mmol) was added, and heating was continued overnight. THF was evaporated, water and saturated NaHCO3 solution were added, the mixture was extracted with CH2Cl2 (5×20 mL), and the combined CH2Cl2 extracts were washed with water and brine and dried over MgSO4. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-9)→5% MeOH in CH2Cl2 (10-31)→6.6% MeOH in CH2Cl2 (32-55)→6.6% MeOH in CH2Cl2+NH3 (0.05 M) (56-86)], yielding the title compound as a highly viscous yellow oil. This oil was dissolved in CDCl3 (0.7 mL), tBuOMe was added, and the off-white precipitate was filtered off and dried in vacuo yielding the desired product. 1H NMR (CDCl3, 400 MHz) δ 2.15 (quint, J=7.2 Hz, 2H), 2.33-2.54 (m, 4H), 2.57-2.70 (m, 3H), 2.73 (d, J=7.4 Hz, 2H), 3.33 (t, J=7.2 Hz, 4H), 5.26 (brs, 2H), 5.44 (quint, J=8.1 Hz, 1H), 7.37 (s, 1H), 7.46-7.52 (m, 1H), 7.52-7.58 (m, 2H), 7.70 (dd, J=1.7, 8.3 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.93 (d, J=7.2 Hz, 1H), 8.17-8.22 (m, 2H), 8.26 (d, J=8.6 Hz, 1H), 8.28-8.31 (m, 1H), 8.35 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135) δ 17.73 (−), 27.06 (+), 33.60 (2C, −), 46.72 (+), 55.51 (2C, −), 63.99 (−), 101.05 (Cquart), 116.12 (Cquart), 118.85 (+), 120.57 (+), 125.86 (Cquart), 127.29 (+), 127.45 (2C, +), 128.18 (+), 128.34 (+), 128.76 (2C, +), 129.41 (+), 136.31 (Cquart), 136.46 (+), 139.30 (Cquart), 148.38 (Cquart), 150.73 (Cquart), 151.83 (+), 157.07 (Cquart), 157.95 (Cquart). MS (ES+): m/z 461.2 (11) [MH+], 338.2 (14) [MH+−C4H5CH2azetidine]. HPLC: tR=2.0 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH:1]1([N:4]2[CH:9]3[CH2:10][CH2:11][CH2:12][CH:5]2[CH2:6][C:7](=O)[CH2:8]3)[CH2:3][CH2:2]1.Cl.[NH2:15][OH:16]>C(O)C>[CH:1]1([N:4]2[CH:9]3[CH2:10][CH2:11][CH2:12][CH:5]2[CH2:6][C:7](=[N:15][OH:16])[CH2:8]3)[CH2:3][CH2:2]1
Reactant: O=C1CC2CCCC(C1)N2C1CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: ON=C1CC2CCCC(C1)N2C1CC1

Procedure:
A mixture of the above described 9-cyclopropyl-9-aza-bicyclo[3.3.1]nonan-3-one (890 mg, 5.0 mmol) in ethanol (20 mL) and hydroxylamine hydrochloride (366 mg, 5.3 mmol) was refluxed for 6 h. The reaction mixture was evaporated totally, the residue extracted with ethyl acetate and sodium bicarbonate solution, the organic layers dried over Na2SO4, filtered and the solvents evaporated to give the title compound as a white solid. (890 mg, 100%); MS: m/e=195.2 (M+H+).
Reaction SMILES: N.[Na].[C:3](#[N:5])[CH3:4].[Cl:6][C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]>O1CCCC1.C(OCC)C>[NH2:10][C:9]([C:8]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:7]=1[Cl:6])=[CH:4][C:3]#[N:5]
Reactant: N#Cc1ccc(Cl)cc1Cl
Reactant: CC#N
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CC=C(N)c1ccc(Cl)cc1Cl

Procedure:
A 150 ml. portion of ammonia is condensed in a reaction flask and a small piece of sodium is added. The blue color is discharged by the addition of ferric chloride and 3.22 g. of sodium are added. After the color is discharged, 5.75 ml. of acetonitrile in 10 ml. of diethyl ether are added. The reaction is cooled in a dry ice-acetone bath and 16.6 g. of 2,4-dichlorobenzonitrile in 25 ml. of tetrahydrofuran are added dropwise. The ammonia is allowed to evaporate, the solvent is blown off with nitrogen and water is added. The mixture is extracted with methylene chloride. The organic extracts are dried over sodium sulfate and filtered through Magnesol®. The filtrate is evaporated with the addition of hexanes giving β-amino-2,4-dichlorocinnamonitrile as a white crystalline solid.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([F:26])[C:19]([CH3:25])=[C:20](B(O)O)[CH:21]=1)=[O:15])[CH3:12].C(=O)([O-])O.[Na+].O>C(O)(C)C.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>[CH2:11]([NH:13][C:14](=[O:15])[C:16]1[CH:21]=[C:20]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[CH:4][CH:3]=2)[C:19]([CH3:25])=[C:18]([F:26])[CH:17]=1)[CH3:12]
Reactant: Ic1ccc2cn[nH]c2c1
Reactant: CCNC(=O)c1cc(F)c(C)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCNC(=O)c1cc(F)c(C)c(-c2ccc3cn[nH]c3c2)c1
Temperature: 150 °C

Procedure:
A stirred mixture of 6-iodo-1H-indazole (0.5 g, {5-[(ethylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (Intermediate 17, 0.56 g), tetrakis(triphenylphosphine)palladium(0) (0.05 g) and aqueous sodium hydrogen carbonate (1M, 1 ml) in isopropanol (10 ml) was heated at 150° C. for 30 min in a microwave oven. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (3×20 ml). The extracts were dried (Na2SO4) and concentrated under vacuum. The residual oil was purified by column chromatography on silica (50 g) eluting with ether/ethyl acetate (4:1). The resultant product was triturated with a small quantity of dichloromethane to give the title compound as a pale yellow solid (0.15 g).
Reaction SMILES: [O:1]=[C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][C:9]([C:15]#[N:16])=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[OH-].[K+].[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>C1COCC1.O>[O:1]=[C:2]1[C:14]2[N:13]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:12]3[C:7](=[CH:8][C:9]([C:15]#[N:16])=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CCCC3=O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c3c(c4cc(C#N)ccc42)CCCC3=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.4 %

Procedure:
To a solution of 1-oxo-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile (intermediate 2a) (0.20 g, 0.95 mmol) in THF (2.0 mL), KOH (0.27 g, 4.8 mmol) in water was added followed by TsCl (0.27 g, 1.4 mmol). The reaction mixture was stirred at room temperature for 12 h and then extracted with EtOAc (3×15 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by column chromatography [EtOAc-hexane (1:4) as eluant] to obtain the title compound as an off-white solid (0.23 g, 65%). 1H NMR (200 MHz, CDCl3, δ in ppm) 8.0 (d, J=8.4 Hz, 2H), 7.82 (d, J=2.0 Hz, 1H), 7.43 (dd, J=12.0, 2.0 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.30 (d, J=12.5 Hz, 1H), 2.95 (t, J=9.0 Hz, 2H), 2.66 (t, J=9.0 Hz, 2H), 2.40 (s, 3H), 2.30 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[CH3:22]>C(OC(=O)C)(=O)C>[CH3:21][C:18]1[CH:19]=[CH:20][N:15]=[C:16](/[CH:22]=[CH:11]/[C:10]2[CH:13]=[CH:14][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)[CH:17]=1
Reactant: Cc1ccnc(C)c1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccnc(/C=C/c2ccc(-c3ccccc3)cc2)c1
Temperature: 150 °C
Yield: 45.3 %

Procedure:
A mixture of 4-phenyl benzaldehyde (6.45 g), 2,4-lutidine (7.59 g) and acetic anhydride (10 ml) was heated at a bath temperature of 150° C. for 12 hr, and refluxed under heating for 12 hr. The reaction mixture was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1-5/1) to give the objective compound (4.35 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(Cl)cc(C(C)Nc2cc(F)ccc2S(C)(=O)=O)c1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(Cl)cc(C(C)Nc2cc(N3CCN(C)CC3)ccc2S(C)(=O)=O)c1OC
Yield: 7.5 %

Procedure:
N-(1-(5-Chloro-2,3-dimethoxyphenyl)ethyl)-5-fluoro-2-(methylsulfonyl)benzenamine (0.50 g, 1.29 mmol), 1-methylpiperazine (0.60 g, 6.40 mmol), N,N-diisopropylethylamine (0.66 g, 5.15 mmol) were stirred at 110° C. in dry acetonitrile (3 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 10% methanol in dichloromethane to afford the title compound (45.1 mg, 7.5% yield). 1H NMR (400 MHz, CDCl3): δ 7.54 (d, 1H), 6.87 (d, 1H), 6.76 (d, 1H), 6.52 (d, 1H), 6.22 (dd, 1H), 5.91 (d, 1H), 4.85 (m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.19 (m, 4H), 3.04 (s, 3H), 2.43 (m, 4H), 1.54 (d, 3H); MS (ESI) m/z: 468.0 (M+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1F)[C:18]#[N:19]>>[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1)[C:18]#[N:19]
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: N#Cc1ccc(F)c(F)c1
Product: N#Cc1ccc(Oc2ccc(C=O)c3ccccc23)c(F)c1

Procedure:
Using the procedure outlined in Preparation 82, 4-hydroxynaphthaldehyde and 3,4-difluorobenzonitrile were converted to the title compound: RT=3.90 min; m/z (ES+)=292.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-:3])=[O:2].[NH2:15][C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1>>[C@H:16]1([NH:15][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[N+:1]([O-:3])=[O:2])[N:9]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: O=[N+]([O-])c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12

Procedure:
5-Nitro-2-chloroquinoline (CAS 13067-94-2, 2.4 g, 11.5 mmol) and (R)-1-aminoindane (3.13 g, 23 mmol) were stirred in a sealed tube at 120° C. overnight. The reaction mixture was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0→50:50 gradient). (R)-Indan-1-yl-(5-nitro-quinolin-2-yl)-amine was obtained as a brown solid (2.67 g, 76%), MS: m/e=306.3 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1>>[N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: N#Cc1ccc(Br)cc1
Reactant: c1cn[nH]c1
Product: N#Cc1ccc(-n2cccn2)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-pyrazole (205 mg, 3.0 mmol) is coupled with 4-bromobenzonitrile (364 mg, 2.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50) to provide 330 mg (98% isolated yield) of the desired product as a white solid.