Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][C@@H:24]([C:37]1[N:41]2[C:42]3[S:56][C:55]([CH2:57][CH3:58])=[CH:54][C:43]=3[C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])=[N:45][CH2:46][C:40]2=[N:39][N:38]=1)[CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].[Cl:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[N:66]=[C:67]=[O:68].C(N(CC)CC)C.O>CN(C=O)C>[Cl:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:44]1[C:43]2[CH:54]=[C:55]([CH2:57][CH3:58])[S:56][C:42]=2[N:41]2[C:37]([C@H:24]([NH:23][C:67]([NH:66][C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=3[Cl:59])=[O:68])[CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[N:38][N:39]=[C:40]2[CH2:46][N:45]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: CCc1cc2c(s1)-n1c(nnc1[C@H](N)CCC(=O)OCc1ccccc1)CN=C2c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1cc2c(s1)-n1c(nnc1[C@@H](CCC(=O)OCc1ccccc1)NC(=O)Nc1ccccc1Cl)CN=C2c1ccccc1Cl

Procedure:
Benzyl (R)-4-amino-4-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-yl)butanoate di-p-toluenesulfonate (3.0 g) and 2-chlorophenyl isocyanate (0.46 ml) were dissolved in DMF (30 ml). Triethylamine (1.46 ml) was added and the mixture was stirred and water was added to the reaction mixture. The mixture was washed with an aqueous citric acid solution, saturated brine, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography using ethyl acetate as an eluent to give 2.02 g of benzyl (R)-4-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-yl)-4-(3-(2-chlorophenyl)ureido)butanoate.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([CH2:11][C:12]3[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[O:4]CC1.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1.O>[CH2:21]([N:18]([CH2:19][CH3:20])[C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)=[CH:24][CH:23]=1)[CH3:22]
Reactant: CCN(CC)C(=O)c1ccc(CN2CCC3(CC2)OCCO3)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(CN2CCC(=O)CC2)cc1
Reaction time: 72 h
Yield: 100.5 %

Procedure:
4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-ylmethyl)-N,N-diethylbenzamide (63.9 g, 192 mmol) is dissolved in 193 mL of tetrahydrofuran and treated with a solution of concentrated sulfuric acid (77 mL) in water (309 mL). The solution is allowed to stir for three days and then refluxed for 17 hours. It is neutralized with 2.5N NaOH and extracted with 400 mL, 200 mL and then 100 of methylene chloride. The pooled extracts are dried over Na2SO4 and concentrated in vacuo affording 58.74 g (193 mmol, 100% yield) of product as a yellow oil: IR (thin film) 3500, 2980, 2810, 1720, 1630 cm-1 ; 1H NMR (Me2SO-d6, 400 MHz) δ7.4 (d,J=8.1 Hz, 2H), 7.3 (d,J=8.2 Hz, 2H), 3-3.6 (m, 8H), 2.68 (t,J=6.1 Hz, 2H), 2.34 (t,J= 6.0 Hz, 2H), 1.1 (m, 6H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]2[C:20](=[CH:21][CH:22]=1)[O:19][C:13]1([CH2:18][CH2:17][CH2:16][O:15][CH2:14]1)[CH2:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si]([N:35]=[C:36]=[N:37][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[O:1]([C:8]1[CH:9]=[C:10]2[C:20](=[CH:21][CH:22]=1)[O:19][C:13]1([CH2:18][CH2:17][CH2:16][O:15][CH2:14]1)[CH2:12]/[C:11]/2=[N:37]\[C:36]#[N:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC2(CCCOC2)Oc2ccc(Oc3ccccc3)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#C/N=C1\CC2(CCCOC2)Oc2ccc(Oc3ccccc3)cc21
Temperature: 0 °C
Yield: 25.8 %

Procedure:
To a solution of 6-phenoxy-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (500 mg, 1.27 mmol) and triethylamine (227 mg, 0.73 mmol) in dried CH2Cl2 (10 mL) was added TiCl4 (1 M solution in DCM, 1.47 mmol) dropwise within 15 minutes. The mixture was stirred forl h after addition. To this mixture was added bis-trimethylsilylcarbodiimide (300 mg, 1.16 mmol) dropwise. The resulting mixture was stirred for 18 h after addition. The reaction mixture was poured into ice-water (50 g) and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give (E)-N-(6-phenoxy-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylidene)cyan amide (100 mg, crude), which was used for the next step without further purification.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=1.[Br:30][C:31]1[N:36]=[C:35]([CH:37](O)[CH2:38][CH2:39][O:40][CH3:41])[CH:34]=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:30][C:31]1[N:36]=[C:35]([CH:37]([O:15][C:16]2[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=2)[CH2:38][CH2:39][O:40][CH3:41])[CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Reactant: COCCC(O)c1cccc(Br)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OC(CCOC)c2cccc(Br)n2)cc1C
Temperature: 25 °C
Yield: 57.8 %

Procedure:
A solution of diisopropylazodicarboxylate (1.44 mL, 7.31 mmol) in dry THF (50 mL) was added drop-wise, under nitrogen, over 1.5 h (using a syringe pump) to a solution ethyl (4-hydroxy-2-methylphenoxy)acetate (1.10 g, 5.21 mmol), 1-(6-bromo-2-pyridinyl)-3-(methyloxy)-1-propanol (1.29 g, 5.24 mmol) and triphenylphosphine (1.92 g, 7.32 mmol) in dry THF (50 mL) at 0° C. The resulting mixture was stirred under nitrogen and gradually allowed to warm to room temperature over 19 h. The solvent was then removed in vacuo and the residue purified by Biotage (silica, 90 g cartridge), eluting with cyclohexane:EtOAc 85:15 to afford the title compound as a pale yellow oil (1.32 g).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C[Al](C)C.[CH2:9]([N:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][C:14](OC)=[O:15])[CH:10]=[CH2:11]>C1(C)C=CC=CC=1.C1COCC1>[CH2:9]([N:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][C:14]([N:3]([CH3:4])[CH3:2])=[O:15])[CH:10]=[CH2:11]
Reactant: CNC
Reactant: C=CCN(CC(=O)OC)Cc1ccccc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCN(CC(=O)N(C)C)Cc1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of dimethylamine hydrochloride (2.08 g, 25.5 mmol, 8.0 eq) in anhydrous toluene (10 mL) at 5° C. under N2 was added trimethyl aluminum (1.0M in toluene, 25.5 mL, 25.5 mmol, 8.0 eq) dropwise over 1 h. The reaction mixture was heated to 20° C. and stirred for another 2 h. To a mixture of methyl 2-(allyl(benzyl)amino)acetate (0.70 g, 3.19 mmol, 1.0 eq) in anhydrous toluene (50 mL) and THF (15 mL) at 5° C. was added the above reaction mixture and the reaction mixture was heated at 70° C. for 48 h. Then the mixture was cooled to 0° C. and quenched with a small amount of water. The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and filtrated. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (50:1 (v/v) CH2Cl2/CH3OH) to afford the title compound as colorless oil (0.62 g, 77%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 233.3 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.86 (3H, s), 2.94 (3H, s), 3.16 (2H, d, J=6.8 Hz), 3.24 (2H, s), 5.16 (2H, m), 5.86 (1H, m), 7.18-7.27 (5H, m) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([CH3:18])[CH:12]=3)[CH:7]=1.[CH:22]1([C:25](=[O:32])[CH:26]=[C:27](SC)[S:28][CH3:29])[CH2:24][CH2:23]1>O1CCOCC1>[CH:22]1([C:25](=[O:32])/[CH:26]=[C:27](/[NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]3[C:9](=[O:20])[N:10]([CH3:19])[C:11]4[C:16]([CH:17]=3)=[CH:15][N:14]=[C:13]([CH3:18])[CH:12]=4)[CH:7]=2)\[S:28][CH3:29])[CH2:24][CH2:23]1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N)ccc1C)c(=O)n2C
Reactant: CSC(=CC(=O)C1CC1)SC
Solvent: C1COCCO1
Product: CS/C(=C\C(=O)C1CC1)Nc1ccc(C)c(-c2cc3cnc(C)cc3n(C)c2=O)c1
Temperature: 150 °C

Procedure:
The mixture of 3-(5-amino-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 15 (165 mg, 0.589 mmol) and 1-cyclopropyl-3,3-bis(methylthio)prop-2-en-1-one 30 (111 mg, 0.589 mmol) in 1,4-dioxane (2 mL) was heated in a sealed vial at 150° C. overnight. The solvent was removed to yield crude (Z)-3-(5-(3-cyclopropyl-1-(methylthio)-3-oxoprop-1-enylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 31 which was used without further purification. MS m/z 420.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][OH:21])=[CH:16][C:15]=3[CH3:24])=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:4]=2[N:3]=1.BrCCO[CH2:34][CH2:35][CH2:36][P:37](=[O:44])([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][O:21][CH2:34][CH2:35][CH2:36][P:37](=[O:44])([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40])=[CH:16][C:15]=3[CH3:24])=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:4]=2[N:3]=1
Reactant: CCOP(=O)(CCCOCCBr)OCC
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCO)cc3C)cc12
Product: CCOP(=O)(CCCOCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1)OCC

Procedure:
Diethyl 3-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)propylphosphonate was prepared following the procedure described for Example 139, but using 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 156) and diethyl 3-(2-bromoethoxy)propylphosphonate. LRMS [M+H]=566.3.
Reaction SMILES: [CH2:1]([S:3]([NH2:6])(=[O:5])=[O:4])[CH3:2].Cl[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([NH:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CCS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCS(=O)(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 130 °C
Yield: 72 %

Procedure:
20.3 g of ethanesulfonamide and 26.0 g of 2-chloro-5-trifluoromethylpyridine were dissolved in 220 ml of dimethylsulfoxide, and 47.4 g of anhydrous potassium carbonate was further added thereto. This solution mixture was heated to 130° C. and reacted for 5 hours. After completion of the reaction, the reaction product was poured into 1 l of water. Undissolved materials in water were extracted with ethyl ether and removed. Then, the aqueous layer was adjusted to pH4 with concentrated hydrochloric acid, and precipitated crystals were collected by filtration and dried to obtain 26.2 g of N-(5-trifluoromethyl-2-pyridyl)ethanesulfonamide having a melting point of from 164° to 165° C.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([N:9]1[CH2:12][CH:11]([CH2:13][NH2:14])[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].CCN(CC)CC.[Cl:22][C:23]1[N:28]=[C:27](Cl)[N:26]=[C:25]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:24]=1>C1COCC1>[C:2]([O:6][C:7]([N:9]1[CH2:12][CH:11]([CH2:13][NH:14][C:27]2[N:28]=[C:23]([Cl:22])[N:24]=[C:25]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:26]=2)[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(CNc2nc(Cl)nc(N3CCOCC3)n2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of the 3-aminomethyl-azetidine-1-carboxylic acid tert-butyl ester HCl salt (945 mg, 4.24 mmol) and NEt3 (856 mg, 8.48 mmol) in THF (10 mL) at 0° C. was added a suspension of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (996 mg, 4.24 mmol) at 0° C. The reaction mixture was stirred for another 1 hr at 0° C. and allowed to warm to 20° C. and stirred for 1-4 hrs to drive the reaction to completion. Silica gel (20 g) was added to the reaction mixture and the solvent was removed so that product was adsorbed on the silica gel. The silica gel plug was placed on top of a column to purify by flash chromatography using CH2Cl2/MeOH/NH3 (20:1:01) eluent. After unifying the product fraction, and evaporation of solvent, (750 mg, 46% yield) product was obtained as yellow solid; MS (ESI) m/z 385
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([OH:33])[CH:31]=2)[CH:26]=[N:25]1.O>CN(C)C=O>[O:33]([C:30]1[CH:31]=[C:32]2[C:27]([CH:26]=[N:25][NH:24]2)=[CH:28][CH:29]=1)[Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc2cn[nH]c2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](Oc1ccc2cn[nH]c2c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
Imidazole (3.0 g, manufactured by Kanto Chemical Co., Inc.) and t-butylchlorodiphenylsilane (12.1 g, manufactured by Tokyo Chemical Industry Co., Ltd.) were added to a solution of 1H-indazol-6-ol (3.0 g) synthesized according to the literature (L. F. Fieser, J. Am. Chem. Soc., 1926, 48, 1097-1107) in N,N-dimethylformamide (100 mL, manufactured by Kanto Chemical Co., Inc.), and the mixture was stirred for 3 hours at room temperature. Water (200 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether (3×200 mL), washed with brine (400 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), to give 7.3 g of the title compound. LC-MS: HPLC retention time 2.05 minutes, m/z 373 (M+H), condition C-1.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:25]([NH:24][CH2:22][CH3:23])=[O:26])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)aniline 1 (102 mg, 0.35 mmol) in 1 mL of dry CH2Cl2 was added ethyl isocyanate (95%, 35 μL, 1.2 eq.) at room temperature. After being shaken at room temperature for overnight, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of the CH2Cl2 afforded N-(1-Boc-piperidin-3-yl-methyl)-N-phenyl-N′-ethylurea (2) (120 mg, 95%). LRMS 285 (M−100)+ 261.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH2:6]O.[CH:12]#[N:13]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][C:12]#[N:13])[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: COc1cc(CO)ccc1O
Reactant: C#N
Solvent: CS(C)=O
Product: COc1cc(CC#N)ccc1O
Reaction time: 2 h

Procedure:
185g of 3-methoxy-4-hydroxybenzyl alcohol are dissolved in 1,250 ml of DMSO and 35g of anhydrous hydrocyanic acid are passed in over the course of 1 hour at 125°C. The mixture is then stirred for a further 2 hours, and worked up as indicated above. The yield was 160.5g (82% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18]O)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.O.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18][Cl:22])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: OCc1cccc2c(-c3ccc(Br)cc3)nccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: ClCc1cccc2c(-c3ccc(Br)cc3)nccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Bromophenyl)-5-hydroxymethylisoquinoline (17 g) was dissolved in 300 ml of tetrahydrofuran, and 15 ml of phosphorus oxychloride was added. The mixture was stirred at room temperature for 1 hour. After the reaction, water was added, and the reaction mixture was neutralized with an aqueous solution of sodium hydroxide. The mixture was extracted with benzene, and dried. The solvent was distilled off. The residue was recrystallized from ether-hexane to afford 13.2 g of 1-(4-bromophenyl)-5-chloromethylisoquinoline as colorless prisms having a melting point of 115.5° to 118.5° C.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[C:22](=[O:23])[C:21]3[C:24]([CH3:33])=[C:25]([O:29][CH:30]([CH3:32])[CH3:31])[CH:26]=[C:27](Br)[C:20]=3[O:19][CH2:18][CH2:17]2)=[C:13]([CH3:34])[CH:12]=[C:11]([CH3:35])[N:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.[CH3:43][N:44](C)C(=O)C>O>[CH3:34][C:13]1[CH:12]=[C:11]([CH3:35])[NH:10][C:9](=[O:8])[C:14]=1[CH2:15][N:16]1[C:22](=[O:23])[C:21]2[C:24]([CH3:33])=[C:25]([O:29][CH:30]([CH3:32])[CH3:31])[CH:26]=[C:27]([C:43]#[N:44])[C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: CC(=O)N(C)C
Reactant: Cc1cc(C)c(CN2CCOc3c(Br)cc(OC(C)C)c(C)c3C2=O)c(OCc2ccccc2)n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CN2CCOc3c(C#N)cc(OC(C)C)c(C)c3C2=O)c(=O)[nH]1
Temperature: 120 °C
Yield: 19 %

Procedure:
To a solution of 4-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-9-bromo-7-isopropoxy-6-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (116 g, 98 mg, 0.18 mmol) in N,N-dimethylacetamide (2 mL) was added cuprous cyanide (50 mg, 0.55 mmol). The reaction mixture was heated at 120° C. in a sealed tube for 20 hours, cooled to room temperature then additional cuprous cyanide (25 mg, 0.26 mmol) was added and the reaction was heated at 150° C. in a sealed tube for 5 hours. The reaction was cooled to room temperature, diluted with water (5 mL) and extracted with methyl tert-butyl ether (2×5 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate and concentrated under vacuum. The crude residue was taken up in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL, 2 mmol) and stirred at room temperature overnight then concentrated under vacuum. The residue was purified by reverse phase HPLC to provide the title compound (Example 116, 13 mg, 19% yield). 1H NMR (700 MHz, DMSO-d6) δ 7.47 (s, 1H), 5.93 (br. s., 1H), 4.58-4.69 (m, 3H), 4.12 (br. s., 2H), 2.19 (d, J=12.91 Hz, 6H), 2.14 (s, 3H), 1.26 (d, J=6.02 Hz, 6H): MS 396 [M+H].
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:38]=[CH:37][C:16]([O:17][CH2:18][C:19]2[O:23][N:22]=[C:21]([C@@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][N:25]3C(OC(C)(C)C)=O)[N:20]=2)=[CH:15][CH:14]=1.[ClH:39]>>[ClH:39].[NH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@H:24]1[C:21]1[N:20]=[C:19]([CH2:18][O:17][C:16]2[CH:37]=[CH:38][C:13]([CH2:12][N:3]3[C:2](=[O:1])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:4]3=[O:11])=[CH:14][CH:15]=2)[O:23][N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1c1noc(COc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)n1
Agent: Cl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2nc([C@@H]3CCCCN3)no2)cc1

Procedure:
The title compound was prepared by the method of Preparation 7 from tert-butyl (2S)-2-[5-(4-[(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)methyl]-phenoxymethyl)-1,2,4-oxadiazol-3-yl]-1-piperidinecarboxylate [see Preparation 14] and hydrogen chloride gas to afford 2-[4-(3-[(2S)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzyl]-1,3-isoindolinedione hydrochloride as a white solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].C([O:6][C:7]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)[N:11]([C:21]2[N:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=2)[N:10]=1)=[O:8])C>CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:11]([C:21]3[N:22]=[N:23][C:24]([O:2][CH3:1])=[CH:25][CH:26]=3)[N:10]=[C:9]([C:7]([OH:6])=[O:8])[CH:13]=2)=[N:15][CH:16]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cn2)n(-c2ccc(Cl)nn2)n1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-n2nc(C(=O)O)cc2-c2ccc(Cl)cn2)nn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Sodium methoxide (150 mg) was added to the above-obtained 1-(6-chloro-3-pyridazinyl)-5-(5-chloro-2-pyridyl)pyrazole-3-carboxylic acid ethyl ester (500 mg) in methanol (10 mL), followed by stirring at room temperature for 15 hours. The reaction mixture was partitioned by use of aqueous 1N hydrochloric acid and chloroform. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give the title compound as an amorphous product (483 mg, >100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9](I)[CH:10]=1)=[O:4].[CH2:19]([C:21]1[NH:22][CH:23]=[CH:24][N:25]=1)[CH3:20].N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([N:22]2[CH:23]=[CH:24][N:25]=[C:21]2[CH2:19][CH3:20])[CH:10]=1)=[O:4]
Reactant: CCc1ncc[nH]1
Reactant: COC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCc1nccn1-c1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Temperature: 100 °C
Yield: 41.1 %

Procedure:
A mixture of 5-iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester (2.0 g, 5.7 mmol), 2-ethyl-imidazole (1.1 g, 11.4 mmol), (L)-proline (0.26 g, 2.28 mmol), CuI (0.22 g, 1.14 mmol) and K2CO3 (1.57 g, 11.4 mmol) in DMSO (30 mL) was flushed with N2, then heated to 100° C. overnight. After cooling to room temperature, the reaction mixture was extracted with EtOAc. The combined organic layers were separated, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to afford 5-(2-ethyl-imidazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester as a white solid (750 mg, 41.1%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH2:8][C@@H:9]([CH3:11])[O:10][C:6]=2[C:5]([NH2:12])=[CH:4][C:3]=1[CH3:13].C[C@H]1CC2C=C(C)C=C(N)C=2O1>>[Br:1][C:2]1[C:7]2[CH2:8][C@H:9]([CH3:11])[O:10][C:6]=2[C:5]([NH2:12])=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(N)c2c(c1Br)C[C@@H](C)O2
Agent: Cc1cc(N)c2c(c1)C[C@H](C)O2
Product: Cc1cc(N)c2c(c1Br)C[C@H](C)O2

Procedure:
The title compound 5f was prepared according to the method for preparation of compound 3g of Example 3 by replacing 3f with 5e. MS-ESI (m/z): 242 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:29]5[C@H:36]([CH3:37])[CH2:35][CH2:34][C:30]=5[N:31]=[CH:32][N:33]=4)[CH2:24][CH2:23]3)=[O:21])[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][CH:3]=1.[ClH:38]>C(Cl)Cl.O1CCOCC1>[ClH:1].[ClH:38].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:20]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[C:29]5[C@H:36]([CH3:37])[CH2:35][CH2:34][C:30]=5[N:31]=[CH:32][N:33]=4)[CH2:26][CH2:27]3)=[O:21])[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1CCc2ncnc(N3CCN(C(=O)C4(c5ccc(Cl)cc5)CCN(C(=O)OC(C)(C)C)C4)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)C4(c5ccc(Cl)cc5)CCNC4)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of tert-butyl 3-(4-chlorophenyl)-3-(1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-4-carbonyl)pyrrolidine-1-carboxylate (25 mg, 0.048 mmol) in DCM (2.5 mL) was added to a 4.0M HCl solution in dioxane (0.8 mL). The mixture was stirred at room temperature overnight. The solvents were removed in vacuo to give (3-(4-chlorophenyl)pyrrolidin-3-yl)(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone dihydrochloride (24 mg, 100%). LCMS (APCI+) [M+H]+ 426.2; Rt: 2.09.