Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C)cc(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 90 %

Procedure:
A solution of 3,5-dimethyl benzoic acid (25 g, 0.17 mol) in methanol (250 ml) was treated with sulfuric acid (1 ml, cat. amount) and heated to reflux. After 10 hours, the solution was cooled to room temperature, concentrated to approximately 1/2 volume and poured into 200 ml of crushed ice. The mixture was extracted twice with 200 ml portions of diethyl ether. The organic phase was extracted with saturated aqueous sodium carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting solid was recrystallized from hexanes to yield the product (24.5 g, 90% yield) as volatile white plates. mp=32°-35° C. (lit. mp=35°-36° C.)
Reaction SMILES: CS[C:3](=[NH:17])[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[CH3:18][NH:19][CH3:20]>N1C=CC=CC=1>[CH3:18][N:19]([CH3:20])[C:3]([NH2:17])=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CNC
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Solvent: c1ccncc1
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroidide (3.8 g), a 33% ethanolic solution of dimethylamine (5 ml) and pyridine (25 ml) was heated at 80° C. for 6 hours. Pyridine was removed by evaporation under reduced pressure and the residue treated with a mixture of ice and water to give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 142°-144° C.) which was recrystallised from hexane.
Reaction SMILES: N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O:25]1[C:29]2([CH2:34][CH2:33][CH:32](O)[CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1.[I:36]I>C1COCC1>[I:36][CH:32]1[CH2:33][CH2:34][C:29]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:30][CH2:31]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: IC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A mixture of imidazole (111 g, 1.63 mol, 1.2 eq.), PPh3 (428 g, 1.63 mol, 1.2 eq.) and 1,4-dioxaspiro[4.5]decan-8-ol (215 g, 1.36 mol, 1.0 eq.) in THF (1.5 L) was cooled using an ice bath under N2. To this reaction mixture was added slowly a solution of I2 (414 g, 1.63 mol, 1.2 eq.) in THF (1 L) keeping the internal temperature <12° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between H2O (2 L), EtOAc (3 L), and brine (2 L). The aqueous layer was extracted with EtOAc (1 L×2). The combined organic layer was washed with 10% aqueous NaHSO3 (800 mL, organic layer turned light yellow), brine (1 L), dried over Na2SO4, filtered, and evaporated. The crude product was dissolved in diethyl ether (6 L), filtered, and the solid was washed with diethyl ether (300 mL×3). The filtrate was concentrated and purified by column chromatography (100% hexanes to 5% EtOAc in hexanes, Rf=0.3 in 5% EtOAc in hexanes) to give 340 g (93.4% yield) of 8-iodo-1,4-dioxaspiro[4.5]decane. GC-MS: 269 (M+1).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C:7]1[C:8]([CH3:32])=[C:9]2[C:14](=[C:15]([CH3:18])[C:16]=1[CH3:17])[O:13][C:12]([CH3:30])([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)[CH2:11][C:10]2=[O:31])(=[O:5])[CH3:4].CO.Cl>C1C=CC=CC=1>[C:3]([O:6][C:7]1[C:8]([CH3:32])=[C:9]2[C:14](=[C:15]([CH3:18])[C:16]=1[CH3:17])[O:13][C:12]([CH3:30])([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)[CH2:11][CH:10]2[OH:31])(=[O:5])[CH3:4]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(O)CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
160 mg of sodium borohydride were added to a mixture of 1.8 g of 6-acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman-4-one (prepared as described in Preparation 47), 15 ml of methanol and 1 ml of benzene in an ice bath, and the mixture was stirred for 30 minutes. The reaction mixture was then poured into ice-water, neutralized with 10% w/v aqueous hydrochloric acid and extracted with benzene. The benzene extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography eluted with a 9:1 by volume mixture of benzene and ethyl acetate, to give crystals. These crystals were recrystallized from a mixture of benzene and hexane to give the title compound, melting at 139°-141° C.
Reaction SMILES: [C:1]1([C:7]#[C:8]/[CH:9]=[CH:10]/[CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:14][CH2:11]/[CH:10]=[CH:9]/[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC/C=C/C#Cc1ccccc1
Reactant: BrP(Br)Br
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: BrC/C=C/C#Cc1ccccc1
Yield: 65.7 %

Procedure:
A solution of (E)-5-phenyl-pent-2-en-4-yn-1-ol (Method 1b) (980 mg, 6.2 mmol) in dry toluene (20 mL) was cooled on ice and phosphorus tribromide (0.59 mL, 6.2 mmol) added slowly. After 16 h at 5° C. the mixture was diluted with ethyl acetate and washed with water (×3). The organic phase was concentrated in vacuo and the residue extracted with heptane (×3). The combined heptane phases were concentrated in vacuo to give 900 mg of crude (E)-(5-bromo-pent-3-en-1-ynyl)-benzene. (According to NMR the product contained ˜5% of the (Z)-isomer).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([N:40]3[CH2:45][CH2:44][CH:43]([C:46]([O:48]CC)=[O:47])[CH2:42][CH2:41]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:51][CH3:52])=[O:5])[CH3:2].[OH-].[K+].Cl>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:27]=3)[C:22]([N:40]3[CH2:41][CH2:42][CH:43]([C:46]([OH:48])=[O:47])[CH2:44][CH2:45]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:51][CH3:52])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2cnc(N[C@H]3C[C@@H](CC)N(C(=O)OCC)c4ccc(OC)nc43)nc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCC(C(=O)O)CC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 50 °C
Yield: 89.1 %

Procedure:
To a solution of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-ethoxycarbonylpiperidin-1-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (245 mg) in ethanol (2 ml) is added aqueous 2N-potassium hydroxide solution (0.332 ml) and the mixture is heated under reflux at 50° C. for 1 hour. The reaction solution is diluted with ethyl acetate and acidified with 1N-hydrochloric acid. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform to chloroform:methanol=90:10) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-carboxypiperidin-1-yl) pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (210 mg). MS (m/z): 711 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)[CH2:21][CH2:20]1.[Li+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][CH2:25][N:22]2[CH2:23][CH2:24][O:19][CH2:20][CH2:21]2)=[CH:29][CH:30]=1)(=[O:35])=[O:36]
Reactant: O=S([O-])c1ccc(CCCN2CCOCC2)cc1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(CCCN4CCOCC4)cc3)c(C)o2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
A mixture of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (2.0 g, 7.55 mmol, 1.00 equiv), lithium 4-(3-morpholinopropyl)benzenesulfinate (4.0 g, 14.55 mmol, 1.93 equiv) and potassium carbonate (1.35 g, 9.78 mmol, 1.30 equiv) in N,N-dimethylformamide (50 mL) was stirred overnight at 70° C. The product was precipitated by the addition of 150 mL ice and water after the reaction was cooled to room temperature. The solid was collected by filtration, washed with 2×15 mL of water and dried in a vacuum oven to give 2.8 g (74%) of methyl 4-(5-methyl-4-((4-(3-morpholinopropyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate as a white solid. LC-MS: (ES, m/z): 499 [M+H]+, 115.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:36])[CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][OH:18])[C@H:9]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH2:8]1.Cl.C([O-])(O)=O.[Na+]>O.C1COCC1>[OH:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14][C@@H:13]([N:10]1[CH2:11][CH2:12][C@@H:7]([CH2:6][C:5]([OH:36])=[O:4])[CH2:8][C@H:9]1[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=1)[CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23]
Reactant: COC(=O)C[C@@H]1CCN([C@H](CCC(C)CO)CCC(F)(F)F)[C@H](c2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)CC[C@H](CCC(F)(F)F)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
A solution of lithium hydroxide (26.2 mg, 1.095 mmol) in water (1.000 ml) was added to a stirred solution of methyl{(2S,4R)-1-[(1R,4R/S)-5-hydroxy-4-methyl-1-(3,3,3-trifluoropropyl)pentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (Example 32, Step 1, 109 mg, 0.219 mmol) in THF (2 ml) at RT. The mixture was stirred at RT o/n. 2N HCl (1 ml) was added The pH of the aqueous layer was adjusted to 7 with NaHCO3 (aq). The aqueous layer was extracted with DCM (×3). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, 2-4-8% MeOH/DCM) to give the title compound (mixture of diastereomers, 46 mg) as a colourless foam. M/Z 484 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH3:14])([CH3:13])[C:5]2=[O:15].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:20]1[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=1)[C:7](=[O:12])[C:6]([CH3:13])([CH3:14])[C:5]2=[O:15]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC1(C)C(=O)Nc2ccc(Br)cc2C1=O
Product: CC1(C)C(=O)c2cc(Br)ccc2N(c2ccc(F)cc2)C1=O
Yield: 75.5 %

Procedure:
6-bromo-3,3-dimethylquinolin-2,4-(1H,3H)-dione (1.0 g) and 4-fluorophenyl-boronic acid (1.04 g) were treated in the same manner as described in Reference Example 1(2) to obtain 6-bromo-1-(4-fluorophenyl)-3,3-dimethylquinolin-2,4-(1H,3H)-dione (1.02 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17]>>[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(N)cc1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccc(NS(=O)(=O)c2ccccc2C)cc1

Procedure:
prepared by reaction of p-toluidine with 2-methyl-benzenesulfonyl chloride
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3(O)[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.BrC1C=CC(C#CC2C=CC(OC)=CC=2)=CC=1.C(C1CCC(=O)CC1)CCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH:18]=3)=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: CCCCCC1CCC(O)(c2ccc(C#Cc3ccc(OC)cc3)cc2)CC1
Agent: CCCCCC1CCC(=O)CC1
Agent: COc1ccc(C#Cc2ccc(Br)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CC=C(c2ccc(C#Cc3ccc(OC)cc3)cc2)CC1

Procedure:
0.2 mol of 4-methoxy-4'-(1-hydroxy-4-pentylcyclohexyl)-tolan (prepared by reaction of a Grignard compound of 4-bromo-4'-methoxytolan with 4-pentylcyclohexanone) is heated in 400 ml of toluene and with 1 g of p-toluenesulfonic acid for 1 hour using a water separator. The reaction mixture is washed, dried and evaporated. Customary working up gives 1-(4-methoxyphenyl)-2-[4-(4-pentylcyclohexen-1-yl)-phenyl]-acetylene.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH:3]([OH:6])[C:4]#[CH:5].[CH2:9]([C:11]([C:22]1[CH:27]=[CH:26][C:25](O)=[C:24]([CH3:29])[CH:23]=1)([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:12][CH3:13])[CH3:10]>>[CH2:9]([C:11]([C:22]1[CH:27]=[CH:26][C:25]([C:5]#[C:4][CH:3]([OH:6])[C:2]([CH3:8])([CH3:7])[CH3:1])=[C:24]([CH3:29])[CH:23]=1)([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:12][CH3:13])[CH3:10]
Reactant: CCC(CC)(c1ccc(OC)cc1)c1ccc(O)c(C)c1
Reactant: C#CC(O)C(C)(C)C
Product: CCC(CC)(c1ccc(OC)cc1)c1ccc(C#CC(O)C(C)(C)C)c(C)c1

Procedure:
In a manner similar to that described for Examples 1C-D, but replacing 2-methyl-3-butyn-2-ol with 4,4-dimethylpent-1-yn-3-ol, the title compound was prepared from 4-[1-ethyl-1-(4-methoxyphenyl)-propyl]-2-methylphenol: 1H-NMR (CDCl3) δ 7.29 (1H, d, J=8.1), 7.05 (2H, d, J=8.8), 7.00 (1H, d, J=2.3), 6.94 (1H, dd, J=2.3, 8.1), 6.78 (2H, d, J=8.8), 4.26 (1H, s), 3.78 (3H, s), 2.38 (3H, s), 2.05(4H, q, J=7.3), 1.06 (9H, s), 0.60 (6H, t, J=7.3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41].C(OCC)C>CN(C)C=O.C1CCCCC1>[C:1]([O:5][C:6](=[O:15])[CH:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCCCCCBr
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(CCCCCCCCCCCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
29.3 mmol (6.56 mL) of malonic acid di-tert-butyl ester and 29.3 mmol (1.28 g) of sodium hydride in mineral oil (55% (w/w)) were reacted in 120 mL of anhydrous dimethylformamide for 50 min at room temperature according to general procedure B2. 45.4 mmol (23.0 g) of 4′ were added to the mixture and the reaction mixture was stirred for 1 h at 75° C. bath temperature and at room temperature o/n. Additional 16.2 mmol (708 mg) of sodium hydride in mineral oil (55% (w/w)) were added and the reaction mixture was further stirred at room temperature for 7 h. The work-up was performed as described (general procedure B) with diethyl ether. Column chromatography (cyclohexane→cyclohexane/acetone 9:1) gave 5c′ with 67% yield.
Reaction SMILES: [CH:1]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]([NH2:22])=[O:21].S(=O)(=O)(O)O.C(OO)(C)(C)C>>[C:2]1([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH2:22])=[O:21])[CH:15]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC=O
Reactant: c1ccc(C(c2ccccc2)c2ccncc2)cc1
Agent: CC(C)(C)OO
Agent: O=S(=O)(O)O
Product: NC(=O)c1cc(C(c2ccccc2)c2ccccc2)ccn1

Procedure:
Dissolve 20 g. (0.082 mole) of 4-benzhydrylpyridine in 200 ml. of formamide and, with external cooling, add 4.35 ml. (0.082 mole) of sulfuric acid. Adjust the reaction temperature to 5°-10° C. while adding 21.6 g. (0.24 mole) of t-butyl hydroperoxide and 67 g. (0.24 mole) of ferrous sulfate over a 30 minute interval. Remove the iron salts by filtration. Wash the precipitate with chloroform and water and separate the two liquid phases. Extract the aqueous phase with chloroform, wash the combined chloroform phases with water and dry. Concentrate the extract to a residue, dissolve the residue in ether, filter and obtain the product of this step from the ether solution, yield 3.5 g., m.p. 165°-170° C. Additional product may be obtained by extracting the iron salts with refluxing chloroform.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:27])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[C:21]([CH3:23])[C:20]4[C:15](=[CH:16][C:17]([O:24]C)=[CH:18][CH:19]=4)[C:14]3=[O:26])[CH:7]=2)[CH2:3][CH2:2]1.[I-].[Li+].Cl>N1C(C)=CC(C)=CC=1C.[OH-].[Na+]>[CH:1]1([NH:4][C:5](=[O:27])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[C:21]([CH3:23])[C:20]4[C:15](=[CH:16][C:17]([OH:24])=[CH:18][CH:19]=4)[C:14]3=[O:26])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc2c(C)cn(-c3cc(C(=O)NC4CC4)ccc3C)c(=O)c2c1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(C)c2ccc(O)cc2c1=O
Temperature: 200 °C

Procedure:
N-cyclopropyl-3-(7-methoxy-4-methyl-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide (262 mg, 0.72 mmol) and lithium iodide (174 mg) were stirred in 2,4,6-collidine (3 ml) and heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 200° C. for 1.5 hour and then allowed to cool. The reaction mixture was dissolved in 2N NaOH and then re-acidified with 2N HCl solution. The aqueous phase was extracted with ethyl acetate (×4) and the combined organic layers were concentrated. The residue was triturated with 1N HCl, the solid was collected by filtration, washed with water, diethyl ether, and air dried to give N-cyclopropyl-3-(7-hydroxy-4-methyl-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide as an off white solid (207 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.09 (s, 3H), 2.24 (s, 3H), 2.86 (m, 1H), 7.00 (s, 1H), 7.31 (d, 1H), 7.48 (d, 1H), 7.62-7.65 (m, 2H), 7.74 (s, 1H), 7.85 (d, 1H), 8.45 (d, 1H), 10.04 (s, 1H); Mass Spectrum: M+H+ 349.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([C:25](=[O:27])[NH2:26])[CH2:20][CH2:21][CH2:22][C:23]=3[CH:24]=2)[CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:24]=[C:23]3[C:18](=[N:17][CH:16]=2)[N:19]([C:25]([NH2:26])=[O:27])[CH2:20][CH2:21][CH2:22]3)[CH:12]=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Reaction time: 1 h
Yield: 101.8 %

Procedure:
[5-(8-Carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-ylmethyl]-carbamic acid tert-butyl ester (100 mg, 0.26 mmol) is dissolved in 5.0 mL of DCM and trifluoroacetic acid (0.5 mL) is added. The mixture is stirred for 1 hr and the solvent is removed in vacuo. The residue is dissolved in MeOH and filtered through a StratoSpheres SPE cartridge (PL-HCO3 MP SPE) to remove the acid. The filtrate is then concentrated to give 75 mg of 6-(5-aminomethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide which is used in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:10]=1)=[N:7][S:8][N:9]=2.[C:11]([Cu])#[N:12]>CN(C=O)C.Cl.O>[C:11]([C:2]1[CH:3]=[CH:4][C:5]2=[N:9][S:8][N:7]=[C:6]2[CH:10]=1)#[N:12]
Reactant: N#C[Cu]
Reactant: Brc1ccc2nsnc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2nsnc2c1
Temperature: 150 °C
Yield: 65 %

Procedure:
5-Bromobenzo[1,2,5]thiadiazole from Step 1 was dissolved in anhydrous DMF (160 mL) under nitrogen. Then, CuCN (7.27 g, 81 mmol) was added and the mixture was heated to 150° C. overnight. After cooling down, a solution of FeCl3 (19.7 g) in concentrated HCl (7 mL) and water (40 mL) was added dropwise and the mixture was stirred at 70° C. for minutes. After extraction with DCM (200 ml×2), the combined organic phases were extracted with HCl (6M, 100 mL×3), water (100 mL), and brine (100 mL), and dried over MgSO4. Concentration gave a brown solid which was purified by column chromatography with DCM as the eluent. Finally, a white solid was obtained (2.95 g, 65% yield for two steps). 1H NMR (CDCl3 500 MHz): δ: 8.48 (d, 1H, J=1.5 Hz), 8.16 (d, 1H, J=9.0 Hz), 7.75 (dd, 1H, J=9.0, 1.5 Hz).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28](/[CH:35]=[CH:36]/[CH3:37])[CH2:29][C:30]([O:32]CC)=[O:31])=[C:24]([CH3:38])[CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28](/[CH:35]=[CH:36]/[CH3:37])[CH2:29][C:30]([OH:32])=[O:31])=[C:24]([CH3:38])[CH:23]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: C/C=C/[C@H](CC(=O)OCC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: C/C=C/[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a stirred solution of 28.8 (0.070 g, 0.13 mmol) in THF (2 mL, 0.2 mmol) and EtOH (2 mL, 0.2 mmol) at 23° C. was added a solution of 1 M sodium hydroxide (1.00 mL, 1.0 mmol). The resulting mixture was stirred for 18 hours. The reaction was then concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The resulting product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 28 (44 mg, 67% yield) as a colorless oil. MS ESI (neg.) m/e: 979.5 (2M−H)+, 489.2 (M−H)+.