Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][OH:22].N1C=CN=C1.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl>[C:29]([Si:32]([CH3:34])([CH3:33])[O:22][CH2:21][CH2:20][CH2:19][C:3]1[C:2]([NH2:1])=[C:7]([NH2:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:16])([F:17])[F:18])[CH:4]=1)([CH3:31])([CH3:30])[CH3:28]
Reactant: Nc1cc(-c2ccccc2C(F)(F)F)cc(CCCO)c1N
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCc1cc(-c2ccccc2C(F)(F)F)cc(N)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
3-(4,5-Diamino-2′-trifluoromethyl-biphenyl-3-yl)-propan-1-ol (101 mg, 0.324 mmol, as prepared in the previous step) was placed in an 8 mL vial equipped with a magnetic stir bar, and DCM (2 mL) was added via pipette. Imidazole (1.1 eq., 24.5 mg, 0.356 mmol) and TBSCl (1.1 eq., 53.7 mg, 0.356 mmol) were added sequentially as solids, and the reaction was stirred at RT for 2 h. The reaction was filtered, the precipitate was washed once with DCM (5 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on a 24-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 1:1, v/v over 30 min, yielding 93.2 mg (68%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 7.69 (d, J=7.8 Hz, 1H), 7.49 (t, J=7.5 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 6.61 (s, 1H), 6.59 (s, 1H), 3.66 (t, J=5.9 Hz, 2H), 3.52 (br. s., 4H), 2.65 (t, J=7.3 Hz, 2H), 1.75-1.87 (m, 2H), 0.91 (s, 9H), 0.07 (s, 6H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[S:11][C:12]4[C:18]([N+:19]([O-])=O)=[C:17]([O:22][CH3:23])[CH:16]=[CH:15][C:13]=4[N:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H]>CO.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[S:11][C:12]4[C:18]([NH2:19])=[C:17]([O:22][CH3:23])[CH:16]=[CH:15][C:13]=4[N:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc2nc(-c3ccc4c(c3)OCO4)sc2c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2nc(-c3ccc4c(c3)OCO4)sc2c1N
Yield: 51.7 %

Procedure:
0.96 g (2.9 mmol) of 2-(1,3-benzodioxol-5-yl)-6-methoxy-7-nitro-1,3-benzothiazole is suspended in 100 ml of methanol. 96 mg (10%) of palladium on carbon is added to the reaction mixture which is maintained under stirring under 2.5 bars of hydrogen for 18 hours. The catalyst is filtered out, then the solvents are evaporated off under reduced pressure. 0.45 g (yield=52%) of 2-(1,3-benzodioxol-5-yl)-6-methoxy-1,3-benzothiazol-7-amine is obtained and used in the following stage without other purification.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18](Cl)[C:9]=2[C:8]1=[O:22].[CH3:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1OB(O)O>>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH3:32])[C:9]=2[C:8]1=[O:22]
Reactant: CSc1nc(Cl)c2c(n1)NCCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Reactant: Cc1ccccc1OB(O)O
Product: CSc1nc2c(c(-c3ccccc3C)n1)C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 99.9 %

Procedure:
In a similar manner to Reference Example 10, 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 7; 485 mg) was reacted with 2-methylphenylboric acid (163 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (540 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:18](=[O:19])[C:17]3[CH:21]=[C:22]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:23]=[CH:24][C:16]=3[O:15][CH:12]([CH3:13])[CH3:14])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1NCc2ccc(Cl)cc21
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
0.4 mmol 6-chloro-1-isoindolinone (CAS: 58083-59-3) was dissolved in 3 nml of pyridine. 0.05 mmol of 4-dimethylaminopyridine was added, followed by slow addition of a solution of 0.5 mmol 2-isopropoxy-5-methanesulfonyl-benzoyl chloride (prepared from example B1 and oxalyl chloride in dichloromethane) in 2 ml dichloromethane at room temperature. The reaction mixture is stirred for 10 minutes at room temperature, then the dichloromethane is stripped off in the rotatory evaporator. The remaining solution was then refluxed for 3 hours. The dark red solution was quenched with water, acidified by addition of diluted hydrochloric acid and extracted 3 times with ethyl acetate. The organic phase is dried and concentrated. Chromatography (silica gel; ethyl acetate/heptane) gave the title compound as a slightly yellowish solid. Yield=55%. MS (m/e): 408.2 [M+H]+, 100%).
Reaction SMILES: [ClH:1].[CH:2]1([O:7][C:8]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:18]([OH:20])[CH3:19]>>[ClH:1].[CH:2]1([O:7][C:8]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=2[C:10](=[NH:11])[O:20][CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCO
Reactant: COc1ccc(C#N)c(OC2CCCC2)c1
Agent: Cl
Product: CCOC(=N)c1ccc(OC)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Hydrogen chloride gas was passed through a solution of 2-cyclopentyloxy-4-methoxy-benzonitrile (120 mg, 0.552 mmol) in anhydrous ethanol (15 mL) at 0° C. After 45 min, hydrogen chloride gas was stopped and the reaction vessel was sealed with a septum. After stirring at room temperature for 3 d, the reaction vessel was cooled to 0° C. and the septum was removed. The solvent was removed in vacuo to afford ethyl 2-cyclopentyloxy-4-methoxy-benzimidate hydrochloride as a yellow oil (169 mg). It was dissolved methanol (2 mL) and meso-1,2-bis-(4-chloro-phenyl)-ethane-1,2-diamine (160 mg, 0.569 mmol) was added. The solution was heated at 85° C. for 2 h. The solvent was removed and the residue was taken into diethyl ether. It was washed with sodium bicarbonate solution, water and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 0-25% diethyl ether in methylene chloride to afford 4,5-bis-(4-chloro-phenyl)-2-(2-cyclopentyloxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole as a white foam (102 mg, 37%). HR-MS (ES, m/z) calculated for C27H27N2O2Cl2 [(M+H)+] 481.1448, observed 481.1444.
Reaction SMILES: [CH2:1]([C:5](O)([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[Br-].[Br:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([C:5]([Br:19])([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Br[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC(O)(CCCC)c1ccc(F)cc1
Agent: O=S([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC(Br)(CCCC)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 126.1 %

Procedure:
To a solution of 8.1 g (25 mmol) of benzyl alcohol obtained from Step 2 in 100 mL of DMF at −40 C. was added 47 g (50 mmol) of bromotriphenyphosphonium bromide (Aldrich). The resulting solution was stirred cold for 30 min, then was allowed to warm to 0 C. To the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was washed a few times with water, dried (MgSO4), and concentrated in vacuo. The mixture was stirred in small amount of ethyl acetate/hexane mixture (1:4 ratio) and filtered through a pad of silica gel, eluting with same solvent mixture. The combined filtrate was concentrated in vacuo to give 9.5 g (98%) of the desired product as a colorless oil: 1H NMR (CDCl3) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.55-1.78 (m, 4H), 3.11 (s, 2H), 4.67 (s, 2H), 7.02 (dt, J=8.46, 3.02 Hz, 1H), 7.15 (dd, J=9.47, 2.82 Hz, 1H), 7.46 (dd, J=8.67, 5.64, 1H), 9.45 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:18]1([C:17]2[CH:20]=[CH:21][C:14]([OH:13])=[CH:15][CH:16]=2)[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH2:2][NH:1]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccc(O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Reaction time: 12 h
Yield: 93.9 %

Procedure:
To a stirred solution of tryptamine (5.0 g, 31.2 mmole) in dry CH2Cl2 (100 mL) at RT was added 4-hydroxybenzaldehyde (3.81 g, 31.2 mmole) followed by dropwise addition of trifluoroacetic acid (7.11 g, 62.4 mmole). After 12 hr, the reaction solution was washed with 10% aqueous NaHCO3 (100 mL), H2O (100 mL) and brine. The organic solution was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil. The yellow residue was washed with hexanes and dried under high vacuum to afford the title compound (7.74 g, 94%) as a light yellow solid: MS (ES) m/e 265 (M+H)+.
Reaction SMILES: [OH:1][C:2]1C=CC(C=O)=C(OC)C=1.C([C:14]1[CH:15]=[C:16]([CH:21]=[C:22](C)[C:23]=1[OH:24])[C:17]([NH:19][OH:20])=[NH:18])C>>[OH:24][C:23]1[CH:22]=[CH:21][C:16]([C:17]([NH:19][OH:20])=[NH:18])=[C:15]([O:1][CH3:2])[CH:14]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Product: COc1cc(O)ccc1C(=N)NO

Procedure:
The title compound is prepared from commercially available 4-hydroxy-2-methoxybenzaldehyde in analogy to literature procedures (see 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine); LC-MS: tR=0.41 min; [M+1]+=183.06; 1H NMR (D6-DMSO): δ3.74 (s, 3H), 5.47 (s, 2H), 6.35 (dd, J=8.3, 1.5 Hz, 1H), 6.45 (s, 1H), 7.21 (d, J=8.5 Hz, 1H), 9.42 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Br[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12].C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: N#Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1nccn1-c1cccc(C#N)c1
Yield: 23.5 %

Procedure:
To a stirred solution of 2-methylimidazole (25 g, 0.3 mol) and 3-bromobenzo-nitrile (55 g, 0.3 mol) in pyridine (60 mL) was added K2CO3 (42 g), CuO (1.5 g), Cu powder (1.5 g) and CuBr (1.5 g) under a nitrogen atmosphere. The resulting mixture was heated at reflux temperature for 64 hr. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane-methanol (10:1) to afford 12.9 g (23%) of 3-(2-methylimidazol-1-yl)benzonitrile as white solids.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Fc1ccccc1
Solvent: Clc1ccccc1Cl
Product: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -12 °C
Yield: 64 %

Procedure:
0.113 mole) in orthodichlorobenzene at -14° C. was slowly added over 5 minutes a mixture of 4-fluorobenzoyl chloride (4.0 g., 0.025 mole) and fluorobenzene (2.4 g., 0.025 mole). The mixture was then maintained at -12° C. for one hour and then allowed to warm up to room temperature overnight then worked up as described in example 1. The crude 4,4'-difluorobenzophenone obtained (3.5 g., 64% yield) had a 90% purity with 0.5% ortho impurities and 5 other small impurity peaks by 19F NMR. 1 HNMR indicated 95% purity with 5% unreacted acid chloride.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[N:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][O:68][C:69]1[CH:74]=[CH:73][C:72]([CH:75]=O)=[CH:71][CH:70]=1>C(O)C.CN(C=O)C>[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[N:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:75]([C:72]3[CH:73]=[CH:74][C:69]([O:68][CH3:67])=[CH:70][CH:71]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3cncnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cncnc5)CC4)c(Cl)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 38.2 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-chloro-3-nitro-4-(4-(pyrimidin-5-ylmethyl)piperazin-1-yl)pyridin-2-amine (19 mg, 0.054 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.16 mmol, 0.16 mL) and 4-methoxybenzene carboxaldehyde (1.1 eq, 0.060 mmol, 8 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (9 mg, 38%) as a pale yellow solid; δH (500 MHz, DMSO-d6) 2.63 (s, br, 4H, piperazine N(CH2)2), 3.64 (s, 2H, CH2), 3.70 (s, br, 4H, piperazine N(CH2)2), 3.84 (s, 3H, CH3), 7.09 (d, J=8.8 Hz, 2H, methoxyphenyl H-2 & H-6), 8.08 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.12 (d, J=8.8 Hz, 2H, methoxyphenyl H-3 & H-5), 8.80 (s, 2H, pyrimidine H-4 & H-6), 9.12 (s, 1H, pyrimidine H-2), 13.32 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][C:13]([F:16])([F:15])[F:14].[Cl:17]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>C(Cl)(Cl)Cl.CO>[Cl:17][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:12][C:13]([F:14])([F:15])[F:16])[C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(O)c(OC(F)(F)F)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Cl)c(O)c(OC(F)(F)F)c1
Temperature: 50 °C
Reaction time: 19 h
Yield: 112.4 %

Procedure:
Methyl 4-hydroxy-3-trifluoromethoxybenzoate (2.05 g) was dissolved in chloroform (20 mL) and methanol (3 mL), and N-chlorosuccinimide (1.39 g) and trifluoromethanesulfonic acid (0.05 mL) were added to the solution, and then the mixture was stirred at 50° C. for 19 hours. The solvent was distilled off under reduced pressure and 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.64 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([N:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH3:14])[N:8]=[C:9]2O)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=2)[CH:6]=[C:7]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH3:14])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(F)cc2c(O)n1
Product: CN(c1ccc(O)cc1)c1cc2ccc(F)cc2c(Cl)n1
Temperature: 0 °C

Procedure:
A mixture of 4-[N-(7-fluoro-1-hydroxyisoquinolin-3-yl)-N-methylamino]phenol (2.08 g) and phosphorus oxychloride was heated under reflux for approximately 10 minutes at which stage a clear solution had been obtained. The mixture was cooled and poured into ice-water. The precipitated solid was collected and purified by column chromatography over silica gel (eluant dichloromethane/ethyl acetate; 90:10) to give 4-[N-(1-chloro-7-fluoroisoquinolin-3-yl)-N-methylamino]phenol (2.00 g) as a yellow crystalline solid mp 130° C.
Reaction SMILES: C[NH:2][S:3]([CH2:6]Cl)(=[O:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.C(N(CC)CC)C>CCOCC>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:6][S:3](=[O:5])(=[O:4])[NH:2][C:16]2=[O:17])=[CH:11][CH:10]=1
Reactant: CNS(=O)(=O)CCl
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C1NS(=O)(=O)CN1c1ccc(Cl)cc1
Yield: 31.3 %

Procedure:
A 50-ml flask was charged with 5.0 grams (0.035 mol) of N-methyl chloromethane sulfonyl chloride (from Example 1) and 5.3 grams (0.035 mol) of p-chlorophenylisocyanate. Then 3 ml of triethylamine were added. There was an exothermic reaction, and the mixture turned solid. After standing for 3/4 hour at 25° C., ether was added to form a slurry. This slurry was filtered to give a white solid which was reslurried in ether, filtered and dried to give 2.7 grams of 4-p-chlorophenyl-1,2,4-thiadiazolidine-1,1,3-trione having a melting point of 155°-157° C. Analysis for C9H9ClN2O3S: S, 12.3%; Cl, 13.6%. Found, S, 12.4%; Cl, 13.7%. The infrared spectra had strong absorption at 1720, 1485, 1435, 1370, 1340, 1280, 1255, and 1145 cm-1. The NMR spectra in 6D-dimethylsulfoxide had major peaks at 7.7 (4H), 5.6 (2H), and 3.3 (3H) ppm, and minor peaks at 4.0 and 2.8 ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:30])=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:19]([NH:21][CH:22]3[CH2:25][CH2:24][CH2:23]3)=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1.[I-].[K+].[CH3:33][NH:34][CH:35]([CH3:37])[CH3:36]>CC(N(C)C)=O.C(OCC)(=O)C>[CH:22]1([NH:21][C:19](=[O:20])[C:18]2[CH:26]=[CH:27][C:28]([CH3:29])=[C:16]([N:11]3[CH:10]=[C:9]([CH3:30])[C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:34]([CH:35]([CH3:37])[CH3:36])[CH3:33])=[CH:6][CH:7]=4)[C:12]3=[O:15])[CH:17]=2)[CH2:23][CH2:24][CH2:25]1
Reactant: Cc1ccc(C(=O)NC2CCC2)cc1-n1cc(C)c2ccc(OCCCl)cc2c1=O
Reactant: CNC(C)C
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CCC2)cc1-n1cc(C)c2ccc(OCCN(C)C(C)C)cc2c1=O
Temperature: 150 °C

Procedure:
A mixture of 3-[7-(2-chloroethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-N-cyclobutyl-4-methylbenzamide (131 mg), potassium iodide (102 mg), and N-methylisopropylamine (0.19 ml) were stirred in DMA (2 ml) and heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water (×5), brine (×2), dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting using initially 10% methanol/ethyl acetate and then a 99:1 mixture of 10% methanol/ethyl acetate and aqueous ammonia solution gave N-cyclobutyl-3-[7-{2-[isopropyl(methyl)amino]ethoxy}-4-methyl-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzamide (74 mg) as a cream solid; NMR Spectrum: (DMSOd6) 0.98 (d, 6H), 1.68 (m, 2H), 2.06 (m, 2H), 2.11 (s, 3H), 2.21 (m, 2H), 2.25 (s, 3H), 2.28 (s, 3H), 2.77 (t, 2H), 2.84 (m, 1H), 4.15 (m, 2H), 4.43 (m, 1H), 7.09 (s, 1H), 7.45-7.51 (m, 2H), 7.71-7.74 (m, 2H), 7.80 (s, 1H), 7.89 (d, 1H), 8.60 (d, 1H); Mass Spectrum: M+H+ 462.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:33])[NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[CH:30]=[CH:29][C:28](C=O)=[CH:27][CH:26]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:46]([O:51][CH3:52])([O:49][CH3:50])OC>CO>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:33])[NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[CH:26]=[CH:27][C:28]([CH:46]([O:49][CH3:50])[O:51][CH3:52])=[CH:29][CH:30]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(-c2ccccc2CNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(OC)c1ccc(-c2ccccc2CNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Yield: 93.1 %

Procedure:
To a vigorously stirred mixture of methanol (250 mL) containing aldehyde (S29) (17.0 g, 39.3 mmol) and p-toluenesulfonic acid monohydrate (0.75 g, 3.9 mmol) was added trimethyl orthoformate (17 mL, 160 mmol). After 1.5 h of moderate heating (flask equipped with short path to drive reaction forward), the reaction was quenched with a 1:1 mixture of saturated sodium bicarbonate and water (150 mL) and diluted with CH2Cl2 (200 mL). The aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a pale yellow solid (17.5 g, 36.6 mmol, 93%) which was used without further purification. 1H NMR (400 MHz, d6-DMSO): δ 7.88 (d, 2H, J=7.7 Hz), 7.79 (t, 1H, J=5.9 Hz), 7.68 (d, 2H, J=7.3 Hz), 7.43–7.30 (m, 11H), 7.19 (d, 1H, J=7.0 Hz), 5.40 (s, 1H), 4.29 (d, 2H, J=7.0 Hz), 4.20 (t, 1H, J=7.0 Hz), 4.11 (d, 2H, J=5.9 Hz), 3.25 (s, 6H). FAB/MS: 502 (M+Na+).
Reaction SMILES: COC(C1C=C(OC2C=CC(C(N3CCC3)=O)=CC=2)C2CC(C)(C)OC=2C=1)=O.[CH3:29][O:30][C:31]([C:33]1[CH:43]=[C:42]([OH:44])[C:36]2[CH2:37][C:38]([CH3:41])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32].[C:45]([O:49][C:50](=[O:60])[C:51]1[C:56]([F:57])=[CH:55][C:54](Br)=[CH:53][C:52]=1[F:59])([CH3:48])([CH3:47])[CH3:46]>>[CH3:29][O:30][C:31]([C:33]1[CH:43]=[C:42]([O:44][C:54]2[CH:53]=[C:52]([F:59])[C:51]([C:50]([O:49][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:60])=[C:56]([F:57])[CH:55]=2)[C:36]2[CH2:37][C:38]([CH3:41])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)c1c(F)cc(Br)cc1F
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Agent: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2cc(F)c(C(=O)OC(C)(C)C)c(F)c2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 35b, from 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) and 4-bromo-2,6-difluoro-benzoic acid tert-butyl ester. 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1 H) 7.23 (s, 1 H) 6.48 (d, J=8.84 Hz, 2 H) 3.89 (s, 3 H) 2.88 (s, 2 H) 1.59 (s, 9 H) 1.49 (s, 6 H); LCMS for C23H24F2O6 m/z 457.20 (M+Na)+.
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[F:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([NH:24][NH2:25])=[O:23])=[CH:20][CH:19]=1>C(O)C.O.Cl>[F:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([NH:24]/[N:25]=[C:14](/[C:11]2[NH:12][CH:13]=[C:9]([C@@H:2]([OH:1])[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6])[N:10]=2)\[CH3:15])=[O:23])=[CH:20][CH:19]=1
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Reactant: NNC(=O)c1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: C/C(=N\NC(=O)c1ccc(F)cc1)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 55 °C
Reaction time: 48 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (172 mg, 0.74 mmol) was suspended in ethanol (4 ml) and water (1 ml). 4-fluorobenzoic acid hydrazide (131 mg, 0.85 mmol, 1.1 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 55° C. for 48 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The reaction mixture was cooled to room temperature, and partially concentrated in vacuo. The resulting white precipitate was collected and washed with ethanol to yield the product, as one apparent isomer, as a white solid: 97 mg (35%).