Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C1CCCCO1.Cl.O1CCOCC1>C(O)(C)C>[CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Cc1c(O[C@@H]2CCC[C@H](Nc3ccccc3)C2)ccc2c1cnn2C1CCCCO1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Cc1c(O[C@@H]2CCC[C@H](Nc3ccccc3)C2)ccc2[nH]ncc12
Yield: 89.4 %

Procedure:
Under nitrogen, N-[cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylamine (100 mg, 0.247 mmol) was dissolved in isopropyl alcohol (4 ml), followed by adding thereto a 4N-hydrochloric acid/1,4-dioxane solution (4 ml), and the resulting mixture was stirred at room temperature for 20 hours. The solvent was distilled off under reduced pressure and the resulting concentration residue was thoroughly dispersed and suspended in isopropyl alcohol. Thereafter, the solid was collected by filtration, washed with a small volume of isopropyl alcohol and then dried under reduced pressure to obtain N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylamine (71 mg, yield 80.5%) as a whitely yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([NH:14][CH2:15][CH2:16][CH3:17])[CH2:11]2)=[CH:6][CH:5]=1)[CH3:2].[CH3:18][S:19]([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1)(=[O:21])=[O:20].CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([N:14]([CH2:28][CH:25]3[CH2:26][CH2:27][N:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH2:23][CH2:24]3)[CH2:15][CH2:16][CH3:17])[CH2:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCCNC1CCc2ccc(OCC)cc2C1
Reactant: CS(=O)(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc(OCC)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of afford (7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (200 μL of a 0.25M solution in 1,2-dichloroethane, 50 μmole) was added 220 μL of a solution of 1-(methylsulfonyl)-4-piperidinecarboxaldehyde (0.25 M in 1,2-dichloroethane) followed by 30 μL DIEA and 300 μL of a 0.25 M slurry of sodium triacetoxyborohydride in 1,2-dichloroethane. The solution was shaken at 25° C. for 48 h under N2. The reaction was quenched with 1 mL 2% NaOH and the mixture was transferred along with 0.5 mL H2O and EtOAc to workup flasks. The flask was shaken, allowed to settle and the aqueous phase was removed and discarded. The organic phase was washed with water, transferred into a tube and concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford (7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-(1-methanesulfonyl-piperidin-4-ylmethyl)-propyl-amine (8 mg) 104[M+H]+=409.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26](Br)=[N:25][C:24]([Br:28])=[CH:23][N:22]=1)(=[O:19])=[O:18]>>[Br:28][C:24]1[N:25]=[C:26]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:21]([NH:20][S:17]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=2[Cl:9])(=[O:19])=[O:18])=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ncc(Br)nc1Br)c1cccc(Cl)c1Cl
Reactant: OCc1cccnc1
Product: O=S(=O)(Nc1ncc(Br)nc1OCc1cccnc1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using pyridine-3-methanol (0.44 g) and 2,3-dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide (1.0 g). Yield 0.6 g.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.Cl.C[O:16][C:17](=[O:26])[C@@H:18]([NH2:25])[CH2:19][S:20][CH2:21][CH:22]1[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+:31].[K+]>C(O)(C)C>[CH:22]1([CH2:21][S:20][CH2:19][C@H:18](/[N:25]=[C:3](/[C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)\[C:2]([F:13])([F:12])[F:1])[C:17]([O-:26])=[O:16])[CH2:24][CH2:23]1.[K+:31]
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Reactant: COC(=O)[C@@H](N)CSCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C([O-])[C@H](CSCC1CC1)/N=C(/c1ccc(F)cc1)C(F)(F)F
Temperature: 55 °C
Reaction time: 46 h
Yield: 89.8 %

Procedure:
A suspension of 2,2,2,4′-tetrafluoroacetophenone (48 g; 250 mmol) and (R)-methyl2-amino-3-((cyclopropylmethyl)thio)propanoate hydrochloride (56.4 g; 250 mmol) in isopropanol (IPA; 1100 mL) was added potassium carbonate (69.1 g; 500 mmol; 200 mole %) and the mixture heated at 50-60° C. under a nitrogen atmosphere. After 46 h, the reaction mixture was filtered hot through a pad of celite that was prewashed with hot IPA. The filter was washed with hot IPA (2×) and the combined filtrate and washes were distilled to about 90% of the original volume. Acetonitrile (ACN) was added and the solvent was distilled. This process was repeated two more times with ACN and the product was evaporated to dryness. Potassium (R,Z)-3-((cyclopropylmethyl)thio)-2-((2,2,2-trifluoro-1-(4-fluorophenyl)ethylidene)-amino)propanoate (87 g; 90%) was obtained after drying under high vacuum (1 mm Hg) for 2 hours. This material was used in the next reaction without further purification.
Reaction SMILES: [CH:1](=O)[CH3:2].Cl.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][N:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:23]4[CH2:33][NH:32][CH2:31][CH2:30][CH2:29][C:24]=4[N:25]([CH3:28])[C:26]=3[CH:27]=2)[C:15](=[O:34])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][N:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:23]4[CH2:33][N:32]([CH2:1][CH3:2])[CH2:31][CH2:30][CH2:29][C:24]=4[N:25]([CH3:28])[C:26]=3[CH:27]=2)[C:15](=[O:34])[CH:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCCC2
Reactant: CC=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1CCCc2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc3n2C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
Acetaldehyde (50 μL, 0.88 mmol) and picoline borane complex (47 mg, 0.43 mmol) were added to a suspension of 4-(benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (64 mg, 0.18 mmol) in 10:1 CH2Cl2/AcOH (5.0 mL), and the resulting solution was stirred at ambient temperature for 2 h. Additional acetaldehyde (50 μL, 0.88 mmol) was added to the solution, and the resulting mixture was stirred for 18 h. The mixture was neutralized with saturated NaHCO3 solution and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. Flash chromatography (12 g ISCO CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes to 0:100 over 20 column volumes) provided the title compound (34 mg, 54%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 7.56 (d, J=7.5 Hz, 1H), 7.48-7.41 (m, 5H), 7.39-7.37 (m, 1H), 7.35 (d, J=2.0 Hz, 1H), 6.87 (dd, J=8.5, 2.0 Hz, 1H), 6.07 (dd, J=7.5, 3.0 Hz, 1H), 5.96 (d, J=3.0 Hz, 1H), 5.14 (s, 2H), 3.88 (s, 2H), 3.66 (s, 3H), 3.03-3.01 (m, 2H), 2.94 (t, J=5.5 Hz, 2H), 2.46-2.42 (m, 2H), 1.78-1.76 (m, 2H), 1.01 (t, J=7.0 Hz, 3H); ESI MS m/z 428 [M+H]+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>C1COCC1>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:22]=[C:23]([NH:27][C:28]([N:1]2[C:10]3[C:5](=[CH:6][C:7]([O:11][C:12]4[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:29])[CH:24]=[CH:25][CH:26]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1nccc(Oc2ccc3c(c2)CCCN3)n1
Solvent: C1CCOC1
Product: Nc1nccc(Oc2ccc3c(c2)CCCN3C(=O)Nc2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 242 mg (1 mmol) 4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-pyrimidin-2-ylamine (Step 29.2) in 5 mL of dry THF are added 205 mg (1.1 mmol) of 3-trifluoromethyl-phenylisocyanate at RT. The solution is stirred for 2 h at RT and then the THF is evaporated. The residue is purified by flash-chromatography on silica gel using dichloromethane/methanol 95:5 as eluent. Fractions with pure compound are pooled and evaporated to give the title compound as an amorphous material: MS: [M+1]+=430; HPLC: CtRet=2.14; TLC (dichloromethane/methanol 95:5): Rf=0.45.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[C:20]([CH3:21])=[C:19]2[C:14]([C:15](=[O:30])[C:16]([CH3:29])=[C:17]([C@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[CH2:27][CH3:28])[O:18]2)=[CH:13][CH:12]=1)(=O)C.Cl>CO>[CH2:27]([N:23]1[CH2:24][CH2:25][CH2:26][C@@H:22]1[C:17]1[O:18][C:19]2[C:14]([C:15](=[O:30])[C:16]=1[CH3:29])=[CH:13][CH:12]=[C:11]([OH:10])[C:20]=2[CH3:21])[CH3:28]
Reactant: CCN1CCC[C@@H]1c1oc2c(C)c(OC(C)=O)ccc2c(=O)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCN1CCC[C@@H]1c1oc2c(C)c(O)ccc2c(=O)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
Potassium carbonate (97 mg, 0.70 mmol) was added to a solution of 2-[(2R)-1-ethylpyrrolidin-2-yl]-3,8-dimethyl-4-oxo-4H-chromen-7-yl acetate (58 mg, 0.18 mmol) obtained in Example 3-1 in methanol (4 mL), and then the mixture was stirred at room temperature for 2 hours. A 1 N aqueous hydrochloric acid solution (2 mL) was added dropwise thereto, and then methanol in the reaction solution was distilled off under reduced pressure. Water (2 mL) was added to the residue, and then the pH of the mixture was adjusted to around 8 by the dropwise addition of a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. Ethyl acetate and n-hexane were added to the obtained residue, and the mixture was powdered to obtain 40 mg of the title compound (yield: 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[N+:11]([O-])([OH:13])=[O:12]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:6]#[N:7]
Reactant: COc1cccc(C#N)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C#N)ccc1[N+](=O)[O-]
Yield: 20 %

Procedure:
To a cooled solution of 3-methoxybenzonitrile (10 g, 75 mmol) in acetic anhydride (150 ml) was added 70% nitric acid (60 mL) at a rate that kept the reaction mixture below 50° C. After 1 h the reaction mixture was poured onto ice (400 cc) and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried (Na2SO4). Concentration under reduced pressure and chromatography with ethyl acetate/hexanes gave 2.69 g (20%) of 3-methoxy-4-nitrobenzonitrile: 1H NMR (DMSO-d6): δ 8.04 (d, 1H), 7.93 (d, 1H), 7.61 (dd, 1H), 3.97 (s, 3H). 3-Methoxy-4-nitrobenzonitrile (2.6 g, 14.6 mmol) was suspended in ethanol(100 mL) and added to a mixture of 5% platinum on carbon (250 mg) in ethanol (150 mL). The reaction mixture was stirred under a hydrogen gas atmosphere. After 24 h the reaction was filtered, concentrated, and chromatographed (ethyl acetate/hexanes, 25/75) to yield 1.3 g (60%) of 4-amino-3-methoxybenzonitrile: 1H NMR (DMSO-d6): δ 7.1 (m, 2H), 6.65 (d, 1H), 5.77 (br s, 2H), 3.79 (s, 3H). 4-Amino-3-methoxybenzonitrile (1.3 g, 8.77 mmol) and 3,4-diethoxy-3-cyclobutene-1,2-dione (1.5 g, 8.82 mmol) in ethanol (50 mL) was heated in an oil bath at 110°-115° C. for 3 days. The reaction mixture was filtered hot, and the filtrate was reduced to half its volume. Filtration gave 0.58 g (24%) of a yellow solid: mp 159°-161° C.; 1H NMR (DMSO-d6): δ 10.42 (br s, 1H), 7.54 (d, 1H), 7.44 (dd, 1H), 7.39 (d, 1H), 4.70 (q, 2H), 3.86 (s, 3H), 1.36 (t, 3H). IR (KBr): 3413, 3026, 2650, 2576, 2439, 1719, 1630, 1548 cm-1 ; MS (m/z) 272 (M+).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C@H:2]2[C@H:7]3[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]3[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:3]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: COC(=O)[C@@H]1[C@@H]2C[C@@H](N)[C@@H](C2)N1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](NS(=O)(=O)c3ccc(C)cc3)C2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of 2-tert-butyl 3-methyl (1R,3S,4R,6R)-6-amino-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 29-3 (321 mg) in pyridine (4 mL), was added p-toluenesulfonyl chloride (249 mg). The mixture was stirred at room temperature for 1 hr. The resulting mixture was evaporated in vacuo, and the residue chromatographed on silica gel eluting with hexane and ethyl acetate (1:1) to give the target compound (440 mg)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:7][C:8]([O:10]C(C)(C)C)=[O:9].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:7][C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1ccc(C=CC(=O)OC(C)(C)C)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C=CC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of t-butyl 3-methoxy-4-methoxycarbonylcinnamate (23.5 g) in anhydrous dichloromethane (100 ml) is added trifluoroacetic acid (50 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure to remove the solvent, and the residue is crystallized from ethanol to give 3-methoxy-4-methoxycarbonylcinnamic acid (8.35 g).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]#[C:15][C:16]2[N:17]=[C:18]([NH2:34])[C:19]3[N:20]=[CH:21][N:22]([C:32]=3[N:33]=2)[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)[CH2:9][CH2:8]1)=[O:6].[OH-].[Na+]>CO.Cl>[Cl:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH2:13][C:14]#[C:15][C:16]2[N:33]=[C:32]3[C:19]([N:20]=[CH:21][NH:22]3)=[C:18]([NH2:34])[N:17]=2)[CH2:11][CH2:12]1)=[O:6]
Reactant: Nc1nc(C#CCC2CCN(C(=O)Oc3ccccc3Cl)CC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(C#CCC2CCN(C(=O)Oc3ccccc3Cl)CC2)nc2[nH]cnc12

Procedure:
A solution of 2-{3-[1-((2-chloro)phenoxycarbanoyl)piperidin-4-yl]propyn-1-yl}adenosine (0.720 g, 1.326 mmol) in methanol (25 mL) and 1.0 M HCl (2.50 mL) was stirred at 90° C. in a pressure apparatus for 22 h. The pH was adjusted to 5 with 1.0 M NaOH and the methanol removed under reduced pressure. After cooling the resulting precipitate was filtered and washed with water to afford the pure product as a white solid: yield 1.481 g, 88%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12](=[S:15])[NH:13][N:14]=1.Br.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>CCO.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:14][N:13]=[C:12]([S:15][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:11]=1
Reactant: COc1cc(C)ccc1-c1n[nH]c(=S)[nH]1
Reactant: BrCc1ccccn1
Agent: Br
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(C)ccc1-c1nc(SCc2ccccn2)n[nH]1
Temperature: 60 °C
Yield: 72 %

Procedure:
To a solution of 5-(2-methoxy-4-methylphenyl)-2H-1,2,4-triazole-3(4H)-thione (Example 1a) (110 mg, 0.5 mmol) in 2 ml of EtOH was added 2-(bromomethyl)pyridine hydrobromide (152 mg, 0.6 mmol). The suspension was heated at 60° C. for 22 h. The reaction was diluted with EtOAc and washed with water, brine, dried over MgSO4 filtered and evaporated to produce an oil. The oil was purified on a preparative TLC plate to produce the desired product (72%). 1H NMR (500 MHz, CDCl3): δ 2.40 (s, 3H), 3.99 (s, 3H), 4.55 (s, 2H), 6.84 (s, 1H), 6.92-6.93 (d, 1H), 7.16-7.19 (dd, 1H), 7.53-7.55 (d, 1H), 7.62-7.65 (m, 1H), 8.15-8.17 (d, 1H), 8.56-8.57 (d, 1H). MS (M+H, 313).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 84.5 %

Procedure:
In a 250-ml, three-necked, round-bottom flask equipped with a magnetic stirrer, heating mantle, thermometer, and condenser were placed 1.76 g. (9.0 mmol) 4-hydroxy-4'-biphenylcarbonitrile, 3.94 g (28.5 mmol) powdered anhydrous potassium carbonate, 1.18 ml (9.92 mmol) α-bromotoluene, and 150 ml acetonitrile. After stirring the mixture under reflux for two hours, TLC analysis showed that none of the phenolic starting material remained. Two-thirds of the acetonitrile was then distilled off, and 200 ml dichloromethane was added. The mixture was filtered through Celite and the solids were washed thoroughly with dichloromethane. Evaporation of the filtrate yielded white crystals which were purified by recrystallization from methanol. 2.17 g (84.4%) of product was obtained; mp 150°-151.5° C. The following structure was confirmed by infrared, nuclear magnetic resonance, and mass spectral analyses. ##STR34##
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]=[C:9]([C:18]#[N:19])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH:15]=3)[N:10]=[C:9]([C:18]#[N:19])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#Cc1nc(NC2CCCC2)c2cc(O)ccc2n1
Reactant: CN1CCN(CCCl)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1CCN(CCOc2ccc3nc(C#N)nc(NC4CCCC4)c3c2)CC1

Procedure:
4-Cyclopentylamino-6-hydroxy-quinazoline-2-carbonitrile (0.4 mmol), 1-(2-Chloro-ethyl)-4-methyl-piperazine dihydrochloride (0.55 mmol) and cesium carbonate (4 mmol) are stirred in DMF (5 ml) at RT for 20 hours. The suspension is filtered, washed with little DMF and water is added to the filtrate until the solution gets turbide. The precipitate formed is filtered off, washed with water and dried (vacuum). A powder with mp. 110-112° C., Rf=0.48 (CH2Cl2/MeOH=9:2) is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].O=[CH:30][CH2:31][NH:32]C(=O)OC(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)Cl.Cl.O1CCOCC1.CCOCC>>[NH2:32][CH2:31][CH2:30][N:26]1[CH2:25][CH:24]=[C:23]([C:20]2[C:15]3[CH:16]=[N:17][C:18]([NH2:19])=[C:13]([O:12][C@@H:10]([C:3]4[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[Cl:1])[CH3:11])[C:14]=3[O:22][CH:21]=2)[CH2:28][CH2:27]1
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(CCN)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (35.0 mg, 0.0829 mmol), tert-butyl N-(2-oxoethyl)carbamate (26.4 mg, 0.166 mmol), sodium triacetoxyborohydride (19.3 mg, 0.0912 mmol) and DCM (3 mL, 50 mmol) was stirred at rt for 30 min. The solution was transferred to a separatory funnel and extracted with DCM and sat. NaHCO3. The organic layer was concentrated in vacuo, redissolved in 1,4-dioxane and transferred to a sealed tube. 4 M of HCl in 1,4-Dioxane (0.5 mL, 2 mmol) was added, and the mixture was heated to 50° C. for 2 h. The solution was concentrated in vacuo, redissolved in DCM and transferred to a separatory funnel. The organic layer was washed with sat. NaHCO3, concentrated in vacuo, and loaded onto a prep TLC plate, eluting with 7% (7N NH3 in MeOH)/DCM. The band containing the pure product was filtered off using 1:1 MeOH/DCM. To the filtrate was added 2.0 M of HCl in Et2O (0.207 mL, 0.414 mmol) to form the HCl salt, and the mixture was stirred for 30 min at rt. The material was concentrated in vacuo to afford the title compound as bis-HCl salt. 1H NMR (CD3OD, 400 MHz): δ=1.88 (d, J=6.8 Hz, 3H), 2.56 (d, J=1.5 Hz, 2H), 2.79 (ddd, J=19.3, 5.8, 5.7 Hz, 4H), 3.12 (t, J=5.9 Hz, 2H), 3.28 (d, J=2.5 Hz, 2H), 6.27 (br, s, 1H), 6.50 (q, J=6.8 Hz, 1H), 7.22 (t, J=8.6 Hz, 1H), 7.40 (dd, J=9.0, 4.9 Hz, 1H), 7.63 (s, 1H), 8.17 (s, 1H). MS (ES+): m/z 465.04 [MH+]. HPLC: tR=2.43 min (ZQ3, polar—5 min).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][C:12]([NH:14][CH3:15])=[O:13])[CH:8]=2)[CH:3]=[N:2]1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CC(NC)=O)C=C1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH:8]=2)[CH:3]=[N:2]1
Reactant: CNC(=O)C=C(c1ccccc1)c1ccc2cn[nH]c2c1
Agent: CNC(=O)CC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNC(=O)CC(c1ccccc1)c1ccc2cn[nH]c2c1

Procedure:
3-(1H-Indazol-6-yl)-N-methyl-3-phenyl-propionamide CCXXIX was prepared from 3-(1H-indazol-6-yl)-N-methyl-3-phenyl-acrylamide using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-propionamide XIX (Example 4). A portion of the 3-(1H-Indazol-6-yl)-N-methyl-3-phenyl-propionamide CCXXIX was used without further purification in the next step, while a portion was purified via chiral preparative HPLC. The two enantiomers CCXXIX-A and CCXXIX-B were separated by multiple injections onto 50×500 mm Chiralpak AD preparative column using a mixture of 85/15 hexane/isopropanol at 50 ml/minute.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14]Br)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2
Reactant: C1COCCN1
Reactant: Nc1ncnn2c(CCCBr)cc(Br)c12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1ncnn2c(CCCN3CCOCC3)cc(Br)c12
Yield: 48.3 %

Procedure:
A solution of 5-bromo-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (931 mg, 2.78 mmol), morpholine (1.214 g, 13.94 mmol, 5.0 eq), triethylamine (1.16 ml, 8.36 mmol, 3.0 eq), and sodium iodide (63 mg, 0.42 mmol, 0.15 eq) in anhydrous DMF (20 mL) was stirred at 55° C. for 17 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 followed by saturated brine. It was dried over Na2SO4, filtered, concentrated at reduced pressure to first remove EtOAc followed by some DMF with pumping. The crude was dissolved in THF and then preloaded by evaporation onto about 5 ml silica gel and then chromatographed on 40 g silica gel using a gradient from 0-10% MeOH in CH2Cl2 to provide 457 mg (47.9%) of the desired product as a white solid along with another 435 mg (46%) of mixed fractions contaminated with the dibromide which came from the tribromide contaminant in the starting material as noted above in step 4. 1H-NMR (DMSO-d6) 7.86 (s, 1H), 6.65 (s, 1H), 3.56 (t, 4H, J=4.6), 2.84 (t, 2H), 2.25-2.35 (m, 6H), and 1.80 (pent, 2H, J=7.4); MS LC-MS=340.2/342.2, RT=1.09 min.