Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:11]1([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1NC1CCCCC1
Yield: 85.9 %

Procedure:
A mixture of 2-fluoronitrobenzene (5.0 g, 35.4 mmol), cyclohexylamine (4.5 ml, 39.0 mmol) and potassium carbon-ate (17.1 g, 124 mmol) in acetonitrile (100 ml) was heated at reflux for 2 days. The mixture was diluted with EtOAC, washed with water then brine, dried and partially concentrated in vacuo. The solid which precipitated was collected and washed with hexane to yield the title compound (6.7 g, 86%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>N1C=CC=CC=1>[CH3:19][S:20]([O:11][C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH:3]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:2]([CH3:18])([CH3:1])[C:6]=2[CH:7]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)c2cc(O)ccc2OC1N1CCCCC1
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1N1CCCCC1
Temperature: 10 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
To a stirred solution of 2,3-dihydro-3,3-dimethyl-5-hydroxy-2-piperidino-benzofuran (640 parts) in dry pyridine (1000 parts) at 5°-10° C. was added methanesulphonyl chloride (370 parts) over 1 hour. The mixture was stirred for a further 5 hours at about 10° C., then poured into water. The precipitated gum was washed with water (3 × 200 parts) by decantation, then triturated with ethanol (500 parts) when it set to a crystalline moss which was broken up, filtered, and the residue of crude ester was washed with aqueous ethanol (2:1) and sucked dry. Drying at 35° C. in vacuo over phosphoric oxide gave 2,3-dihydro-3,3-dimethyl-2-piperidinobenzofuran-5-yl methanesulphonate (660 parts, 78%) m.p. 97°-8° C.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].Cl[C:26]([O:28][CH3:29])=[O:27]>>[CH3:29][O:28][C:26]([N:11]1[CH2:12][C@H:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])(=[O:17])=[O:16])[CH2:14][C@H:10]1[C:8](=[O:9])[NH:7][C:4]1([C:2]#[N:3])[CH2:6][CH2:5]1)=[O:27]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: COC(=O)Cl
Agent: Cl
Product: COC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was acylated with methyl chloroformate in analogy to experiment L21 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-2-(1-cyano-cyclopropylcarbamoyl)-pyrrolidine-1-carboxylic acid methyl ester as a colorless oil. MS: 412.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([O:11][CH3:12])[CH:3]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:22]([F:30])[CH:23]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Br)cc2[nH]ncc12
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(Br)cc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 65.4 %

Procedure:
To a solution of 6-bromo-4-(methyloxy)-1H-indazole (1.0 g, 4.40 mmol) in dichloromethane (50 mL) was added 4-benzyloxy-3-fluorobenzeneboronic acid (2.16 g, 8.80 mmol), pyridine (0.71 mL, 8.79 mmol), copper acetate (1.2 g, 6.62 mmol) and powdered 4A molecular sieves (2 g). The reaction mixture was stirred at room temperature in the presence of air for 5 days. Celite was added to the mixture and stirred for 10 mins then the mixture was filtered through a pad of celite and then the filtrate was washed with dichloromethane, then washed with water, dried over magnesium sulphate, filtered and concentrated. The product was purified by silica gel chromatography eluting with 5-30% ethyl acetate in hexane to yield the title compound (D9) (1.23 g).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:6]=1[O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:12]=[CH:11]2.ClC(Cl)(Cl)C[O:30][C:31](=O)[NH:32][C:33]1[N:37]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:36]=[C:35]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:34]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[C:45]([C:35]1[CH:34]=[C:33]([NH:32][C:31](=[O:30])[NH:3][CH2:4][C:5]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:6]=2[O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:12]=[CH:11]3)[N:37]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:36]=1)([CH3:48])([CH3:47])[CH3:46]
Reactant: COC(=O)Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cn1ncc2cc(Oc3ccc(F)cc3CNC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)ccc21
Temperature: 80 °C
Yield: 88.6 %

Procedure:
A solution of methyl 2-(5-(2-(aminomethyl)-4-fluorophenoxy)-1H-indazol-1-yl)acetate dihydrochloride (17.5 g, 43.51 mmol) in dimethylacetamide (0.5M, 88 mL) was treated with 2,2,2-trichloroethyl-3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (17.96 g, 44.38 mmol), followed by diisopropylethylamine (30.3 mL, 174 mmol) at room temperature. The mixture was heated at 80° C. overnight. The mixture was concentrated in vacuo and the residue distributed between EtOAc and saturated aqueous NH4Cl. The organic layer was separated and washed with brine, filtered through 1PS paper, evaporated in vacuo to a brown foam. The foam was triturated in ether, and the precipitated solids were collected by filtration to provide 22.55 g (89%) of the desired compound. MS (APCI+) m/z 585 (M+1) detected. 1H NMR (400 MHz, DMSO-d6) δ 8.3 (s, 1H), 8.07 (s, 1H), 7.68 (d, 1H, J=8.9 Hz), 6.85-7.37 (m, 8H), 6.24 (s, 1H), 5.4 (s, 2H), 4.28 (d, 2H, J=5.8 Hz), 3.68 (s, 3H), 2.35 (s, 3H), 1.25 (s, 9H).
Reaction SMILES: [CH2:1]([Si:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:2][CH:3]=[CH2:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH2:1]([Si:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC[Si](C(=O)CC(C)C)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CCC[Si](c1ccccc1)(c1ccccc1)C(O)CC(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
To a solution of 33 (3.0 g, 9.3 mmol) in ethyl ether (100 mL) at 0° C. was added lithium aluminum hydride (1.0 M in ethyl ether, 47 mmol). After stirring for 15 min at 0° C. under argon, the reaction mixture was diluted with ethyl ether (300 mL) and quenched with saturated aqueous Na2SO4 until evolution of hydrogen had ceased. The mixture was dried with solid Na2SO4 and filtered, and the residue was extracted with ether (50 mL). The organic extracts were combined and concentrated in vacuo. Flash chromatography over silica gel (1/9 EtOAc:hexane) gave pure 34 as a colorless oil (2.1 g, 69%): Rf=0.60 (1/9 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ 7.57 (m, 4H), 7.37 (m, 6H), 5.87 (m, 1H), 4.97 (dd, J=17.1, 1.7 Hz, 1H), 4.88 (dd, J=10 2, 1.7 Hz, 1H), 4.08 (d, J=12.1 Hz, 1H), 2.12 (m, 2H), 1.85 (m, 1H), 1.58 (m, 1H), 1.26 (m, 4H), 0.88 (d, J=6.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 141.4, 135.7, 133.8, 129.8, 128.2, 113.3, 61.5, 42.4, 27.5, 24.2, 23.7, 20.7, 9.8; IR (neat) 3565 (m), 3452 (m, br), 3069 (m), 3050 (m), 2955 (s), 2910 (s), 2869 (m), 1965 (w), 1894 (w), 1832 (w), 1642 (m), 1469 (m), 1434 (s), 1369 (w), 1116 (s), 1001 m), 916 (m), 743 (s), 705 (s) cm−1; MS (FAB) m/e (rel. intensity) 323 (MH+−2, 5), 269 (21), 238 (11), 198 (57), 183 (100), 181 (10), 177 (23), 161 (14), 159 (56), 123 (15), 99 (12); HRMS (FAB) calcd for C21H27OSi: 323.1831 (MH+−2), found: 323.1824. Anal. Calcd for C21H28SiO: C, 77.72; H, 8.70. Found: C, 77.60; H, 8.67.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)[CH:23]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=Cc1cccc(-c2ccccc2Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1N1CCN(Cc2cccc(-c3ccccc3Cl)c2)CC1

Procedure:
61 mg of the target compound (0.16 mmol, 33.7%) was obtained using 1-(2-methoxyphenyl)piperazine (177 mg, 0.92 mmol), 2′-chlorobiphenyl-3-carbaldehyde (100 mg, 0.46 mmol) and NaBH(OAc)3 (297 mg, 1.38 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=O)[NH:14][CH2:15][C@H:16]([OH:24])[CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:5])[CH3:2]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][C@H:16]([OH:24])[CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)NC[C@H](O)CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)c[nH]c1CCNC[C@H](O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
(S)-2-[(2-Hydroxy-3-morpholin-4-yl-propylcarbamoyl)-methyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 1c (16.9 g, 47.9 mmol) was dissolved in 143.6 mL of anhydrous tetrahydrofuran under an argon atmosphere, and borane-tertrahydrofuran complex in tetrahydrofuran (143.6 mL, 1 mol/L, 143.6 mmol) was then added to the solution in an ice-water bath. Upon completion of the addition, the ice-water bath was removed. The reaction system was allowed to warm up to room temperature and refluxed at 95° C. in an oil bath for 1 hour and. The reaction was completed until TLC showed the disappearance of starting materials. The solvent was evaporated under reduced pressure, and 150 mL of hydrochloric acid (2N) was then added to the residue. The mixture was stirred for 0.5 hour, and 50 mL of iced water was then added. The mixture was adjusted to pH about 10 with 10N sodium hydroxide solution and extracted with ethyl acetate (200 mL ×2). The combined organic extracts were washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to give the title compound (S)-2-[2-(2-hydroxy-3-morpholin-4-yl-propylamino)-ethyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 1d (15.6 g, yield 96%) as a brown oil.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.[CH3:12][CH2:13][C:14]([CH2:16][C:17](OC)=[O:18])=O>C(O)(=O)C>[CH2:13]([C:14]1[CH:16]=[C:17]([OH:18])[N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[N:6]=1)[CH3:12]
Reactant: Nc1ncc[nH]1
Reactant: CCC(=O)CC(=O)OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCc1cc(O)n2ccnc2n1
Temperature: 25 °C

Procedure:
20.0 g (151.4 mmol) commercially available (Aldrich) 2-aminoimidazole sulfate and 19.7 g (151.4 mmol) methyl 3-oxo-n-valerate were heated with reflux in 27 ml acetic acid for 7 h. After cooling to room temperature remaining solids were removed by filtration, and the filtrate was diluted with water, neutralized with sodium hydroxide, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, evaporated in vacuo, while the title compound crystallized in colorless crystals, which were filtered with suction, washed with hexane, and dried in vacuo,
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[C:10]([O:14][C:15](=[O:34])[N:16]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][N:27]=1)[CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)([CH3:13])([CH3:12])[CH3:11].[OH-].[K+].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CO>[C:10]([O:14][C:15](=[O:34])[N:16]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]([OH:33])[C:9]2[C:5]3[CH:4]=[N:3][CH:2]=[N:1][C:6]=3[NH:7][CH:8]=2)=[CH:28][N:27]=1)[CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: c1ncc2cc[nH]c2n1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)cn2)cn1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3c[nH]c4ncncc34)cn2)cn1
Temperature: 25 °C
Reaction time: 36 h
Yield: 21.7 %

Procedure:
7H-Pyrrolo[2,3-d]pyrimidine (6, 0.450 g, 3.78 mmol), (5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (71, 1.43 g, 4.16 mmol), potassium hydroxide (0.689 g, 12.3 mmol) and 6.6 mL methanol were combined in a reaction vessel. The reaction mixture was allowed to stir at room temperature for 36 hours, then concentrated under vacuum to provide a thick brown slurry, which was combined with ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer was dried with sodium sulfate, filtered and the filtrate adsorbed onto silica. This was purified by silica gel column chromatography, eluting with a gradient of 1-10% methanol in dichloromethane over 30 minutes. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (72, 380 mg). 1H NMR was consistent with the compound structure.
Reaction SMILES: [CH2:1]([Si:4]([Cl:7])([Cl:6])[Cl:5])[CH:2]=[CH2:3].[Cl-].[Na+].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Cl-].[Al+3].[Cl-].[Cl-]>[CH3:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:2]([CH3:3])[CH2:1][Si:4]([Cl:7])([Cl:6])[Cl:5]
Reactant: Cc1ccccc1
Reactant: C=CC[Si](Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: Cc1ccccc1C(C)C[Si](Cl)(Cl)Cl
Temperature: 50 °C
Yield: 71 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 9.7 g (105 mmol) of toluene and 0.2 g (1.5 mmol) of aluminum chloride were placed. The flask was then immersed in an ice water bath. To the reaction mixture was slowly added dropwise 3.0 g (15 mmol) of allyltrichlorosilane and the solution was stirred for an hour. After confirming that no toluene was left by gas chromatography, 0.48 g (8.0 mmol) of sodium chloride was added to reaction mixture, warmed up to 50° C. and stirred for two hours to deactivate the catalyst. Vacuum distillation of the reaction products gave 16.3 g (bp 74°-76° C./0.6 mmHg) of 3-(methylphenyl)-1,1,1-trichloro-1-silabutane in 71% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17](O)=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.[NH2:26][CH2:27][C@@H:28]([OH:30])[CH3:29]>>[Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([NH:26][CH2:27][C@@H:28]([OH:30])[CH3:29])=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: C[C@H](O)CN
Reactant: O=C(O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: C[C@H](O)CNC(=O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1

Procedure:
5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylic acid (40 mg) was reacted with (S)-(+)-1-amino-2-propanol via General Procedure B to yield 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)pyridine-3-carboxamide. Crude 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)pyridine-3-carboxamide (46 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 7.6 mg of 342. MS (Q1) 516.5. (M)+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]=[C:6]2[S:20][CH:19]=[C:18]([CH3:21])[N:7]2[C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:3].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]2[NH:29][CH:30]=[N:31][C:24]=12.C(N(CC)C(C)C)(C)C>C(O)CCC.CO>[F:16][C:12]1[CH:11]=[C:10]([C:9]2[C:8](=[O:17])[N:7]3[C:18]([CH3:21])=[CH:19][S:20][C:6]3=[N:5][C:4]=2[C@@H:2]([NH:1][C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[NH:29][CH:30]=[N:31][C:24]=23)[CH3:3])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1csc2nc([C@H](C)N)c(-c3cccc(F)c3)c(=O)n12
Reactant: Clc1ccnc2[nH]cnc12
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1csc2nc([C@H](C)Nc3ccnc4[nH]cnc34)c(-c3cccc(F)c3)c(=O)n12
Temperature: 140 °C
Yield: 10.4 %

Procedure:
A solution of 7-[(1S)-1-aminoethyl]-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (50 mg, 0.16 mmol), 7-chloro-3H-imidazo[4,5-b]pyridine (51 mg, 0.33 mmol), and N,N-diisopropylethylamine (57 μL, 0.33 mmol) in 1-butanol (0.5 mL) in a sealable vial was degassed with nitrogen, sealed, and heated at 140° C. for 48 hours. The reaction mixture was diluted with methanol and purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (7 mg, 10%) as a white solid. LCMS for C21H18FN6OS (M+H)+: m/z=420.8. 1H NMR (400 MHz, CD3OD): δ 8.04 (s, 1H), 7.83 (d, J=5.9 Hz, 1H), 7.55-7.49 (m, 1H), 7.23-7.12 (m, 3H), 6.86 (d, J=1.2 Hz, 1H), 5.96 (d, J=5.9 Hz, 1H), 4.69-4.67 (m, 1H), 2.75 (s, 3H), 1.57 (d, J=6.4 Hz, 3H).
Reaction SMILES: [ClH:1].Cl.C([N:10]1[CH2:29][CH2:28][C:13]2([C:17](=[O:18])[N:16]([O:19]CC3C=CC=CC=3)[C:15](=[O:27])[CH2:14]2)[CH2:12][CH2:11]1)C1C=CC=CC=1>[Pd].CO>[ClH:1].[OH:19][N:16]1[C:15](=[O:27])[CH2:14][C:13]2([CH2:12][CH2:11][NH:10][CH2:29][CH2:28]2)[C:17]1=[O:18]
Reactant: O=C1CC2(CCN(Cc3ccccc3)CC2)C(=O)N1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C1CC2(CCNCC2)C(=O)N1O
Reaction time: 12 h

Procedure:
In a mixture solvent consisting of methanol (100 ml) and 1N hydrochloric acid (50 ml) was dissolved 8-benzyl-2-benzyloxy-2,8-diazaspiro[4,5]decane-1,3-dione hydrochloride (16.0 g). The solution was subjected to catalytic reduction at 40° C. for 12 hours under atmospheric pressure, using palladium as the catalyst. After the reaction, the catalyst was removed, and the solvent was evaporated off under reduced pressure. The residual solid was recrystallized from ethanol to obtain 8.9 g of a colorless solid, m.p. 250° to 277° C.
Reaction SMILES: CC1(C)CO[CH:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)=[C:20]5[NH:38][C:23](=[C:24]([CH:30]6OCC(C)(C)C[O:31]6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)[O:4]C1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH:5]([C:8]1[C:9]2[NH:13][C:12]([C:14]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[C:15]3[N:45]=[C:18]([C:19]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[C:20]4[NH:38][C:23](=[C:24]([CH:30]=[O:31])[C:25]5[CH:26]=[CH:27][C:28]=1[N:29]=5)[CH:22]=[CH:21]4)[CH:17]=[CH:16]3)=[CH:11][CH:10]=2)=[O:4]
Reactant: CC1(C)COC(c2c3nc(c(C4OCC(C)(C)CO4)c4ccc([nH]4)c(-c4ccccc4)c4nc(c(-c5ccccc5)c5ccc2[nH]5)C=C4)C=C3)OC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=Cc1c2nc(c(C=O)c3ccc([nH]3)c(-c3ccccc3)c3nc(c(-c4ccccc4)c4ccc1[nH]4)C=C3)C=C2
Yield: 86.8 %

Procedure:
As described for 5, a solution of 17 (30 mg, 44 μmol) in CH2Cl2 (5.0 mL) was treated with TFA/water (2.0 mL, 1:1) at room temperature for 3 days. The standard workup including chromatography (silica, CHCl3/hexanes) afforded a purple solid (19.8 mg, 88%): IR (neat) 1672, 1548, 1166 cm−1; 1H NMR δ−2.19 (s, 2H), 7.76-7.83 (m, 6H), 8.15-8.17 (m, 4H), 8.66 (s, 2H), 8.93 (d, J=4.8 Hz, 2H), 9.79 (s, 2H), 9.89 (s, 2H), 12.28 (s, 2H); 13C NMR δ194.8, 141.0, 134.5, 128.7, 127.2, 109.7, 100.1; LD-MS obsd 519.18; FAB-MS obsd 519.1839, calcd 519.1821 (C34H22N4O2); λabs 440, 535, 607, 655 nm.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH:8]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:28]([CH3:39])[CH:27]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:10]=1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][CH2:7][CH:8]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:28]([CH3:39])[CH:27]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=2)[N:10]=1
Reactant: CCOC(=O)COc1ccc(OC(CO[Si](C)(C)C(C)(C)C)c2cccc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OC(CO)c2cccc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.2 %

Procedure:
To a stirred solution of ethyl ({4-[(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}ethyl)oxy]-2-methylphenyl}oxy)acetate (208 mg, 0.352 mmol) in THF (3.5 mL) was added TBAF (1M in THF, 0.458 mL) dropwise over 1 min. The resulting solution was then stirred at ambient temperature for 18 h. The mixture was then reduced under vacuum and the residue purified by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 15:1 to 2:1) to afford the title compound (89 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]2[NH:29][C:28](=[O:30])[CH:27]([CH3:31])[N:8]2[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[N-:32]=[N+:33]=[N-:34].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:1]([C:5]1[N:6]=[C:7]2[NH:29][C:28](=[O:30])[CH:27]([CH3:31])[N:8]2[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:34][N:33]=[N:32][N:25]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc2n(c(=O)c1Cc1ccc(-c3ccccc3C#N)cc1)C(C)C(=O)N2
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCc1nc2n(c(=O)c1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C)C(=O)N2
Yield: 45 %

Procedure:
A solution of 0.2 g of 7-butyl-6-((2'-cyanobiphenyl-4-yl)methyl]-3-methylimidazo[1,2-a]pyrimidin-2,5-dione in 4 ml of toluene and 1 ml of DMF is added with 38 mg of sodium azide and 0.17 ml of tributylstannyl chloride. After 72 h under reflux, the solvent is evaporated under reduced pressure and the residue is taken up in a NaOH diluted solution and extracted with toluene. The aqueous phase is acidified to pH 5 with AcOH, to separate a white solid which is filtered off and washed first with H2O, and then with a mixture of hexane-toluene to obtain g 0.1 of a white solid, after crystallization (45% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]=[C:7]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21](Cl)[C:16]=2[CH2:15][CH2:14][C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)[CH3:3].C(O)(=O)[C@H]([C@@H](C(O)=O)O)O>C(O)C>[CH3:1][N:2]([CH2:4][CH2:5][CH:6]=[C:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]1=2)[CH3:3]
Reactant: CN(C)CCC=C1c2ccccc2CCc2c(Cl)cccc21
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCO
Product: CN(C)CCC=C1c2ccccc2CCc2ccccc21

Procedure:
1-Chloro-amitriptyline (196 mg) in 3 ml. absolute ethanol was added to an ethanolic solution of 1.1 eq. d-tartaric acid and warmed for 5-10 mins. The title compound was precipitated with ethyl ether as a white powder. After purity and identification checks, the overall yield from amitriptyline base was 32%.