Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:25](CC)CC)[CH3:24].ClCC#N>CC(C)=O>[C:17]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:24][C:23]#[N:25])=[O:15])=[N:12][CH:13]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccc(C(c2ccccc2)c2ccccc2)cn1
Reactant: CCN(CC)CC
Agent: N#CCCl
Solvent: CC(C)=O
Product: N#CCOC(=O)c1ccc(C(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Suspend 4.3 g. (0.015 mole) of 5-(diphenylmethyl)-picolinic acid in 100 ml. of acetone with stirring and add 2.3 g. (0.023 mole) of triethylamine. To the resulting solution add dropwise 1.7 g. (0.023 mole) of chloroacetonitrile. Stir the reaction mixture at room temperature (25° C.) for 15 minutes, then reflux for 4 hours. Cool and filter the reaction mixture. Concentrate the filtrate to a residue in vacuo and triturate the residue with hot isopropyl ether to yield the product of this example, yield 3.5 g., m.p. 95°-98° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[CH:4][C:3]=1[OH:16].[CH2:17]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O1CCOCC1.N1C=CC=CC=1>O>[CH2:17]([O:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:1][C:2]2[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[CH:4][C:3]=2[OH:16])=[O:33])=[CH:35][CH:36]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCc1ccc(O)c(N)c1
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCOc1ccc(C(=O)Nc2cc(CCCCCCCC)ccc2O)cc1
Yield: 97.4 %

Procedure:
In a 50 ml-three-necked flask, 0.50 g (2.43 mM) of 2-amino-4-octylphenol, 0.82 g (2.54 mM) of 4-decyloxybenzoyl chloride and 20 ml of dioxane were placed and heated. To the mixture, 0.88 ml of pyridine was gradually added dropwise at around 90° C. under stirring, followed by further stirring for 35 minutes at around 90° C. After the reaction, the reaction mixture was poured into water to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by recrystallization from hydrous acetone to obtain 1.06 g of 2-(4-decyloxybenzoylamino)-4-octylphenol (yield: 90.4%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Cl:22])[N:9]=[C:8]([CH:23]=[N:24][OH:25])[C:7]=1[S:26]([CH3:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[C:1]([O:25][N:24]=[CH:23][C:8]1[C:7]([S:26]([CH3:28])=[O:27])=[C:6]([NH2:5])[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Cl:22])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)ON=Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reaction time: 1 h

Procedure:
Acetyl chloride (0.27 ml) was added to a solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (1.0 g) and triethylamine (0.56 ml) in tetrahydrofuran at 0° C. and the mixture stirred for 1 hour. The solvent was evaporated and the residue chromatographed on silica gel eluting with 3:1 dichloromethane/ethyl acetate to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(acetyl)oxime (0.83 g)as an orange solid m.p.130-134° C. Compound 10.
Reaction SMILES: CS(O[CH:6]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([C:33]#[N:34])[CH:27]=1)[CH2:7][C@@H:8]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=O)=O.[H-].[Na+]>CN(C=O)C>[Si:19]([O:18][C@H:8]1[CH2:9][N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([C:33]#[N:34])[CH:27]=2)[CH2:7]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC[C@@H](CC(OS(C)(=O)=O)c1cc(F)cc(C#N)c1)O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC1c1cc(F)cc(C#N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (3R)-4-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)-1-(3-cyano-5-fluorophenyl)butyl methanesulfonate (I-11) (5.3 g, 10.3 mmol) in DMF (30 mL) at 0° C. was added NaH (0.43 mg of a 60% mineral oil dispersion, 10.8 mmol). The reaction was stirred at room temperature for 12 hours. The reaction was quenched with water and extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield (4R)-tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-(3-cyano-5-fluorophenyl)pyrrolidine-1-carboxylate (I-12). 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1 H), 7.33-7.20 (m, 1 H), 7.20-7.12 (m, 1 H), 4.90 (dd, J=7.6, 56.2 Hz, 1 H), 4.45-4.39 (m, 1 H), 3.78-3.65 (m, 1 H), 3.52 (dd, J=11.2, 36.8 Hz, 1 H), 2.56-2.41 (m, 1 H), 1.89 (t, J=13.2 Hz, 1 H), 1.47 (s, 4 H), 1.23 (s, 5 H), 0.75 (d, J=7.6 Hz, 9 H), 0.03 (s, 3 H), −0.08 (d, J=10.8 Hz, 3 H). MS m/z 443.2 (M+23)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([N+:17]([O-])=O)[C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl.O1CCOCC1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C.ClCCl.O>[NH2:17][C:15]1[CH:16]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]([O:20][CH3:21])=[CH:11][C:12]=1[C:13]#[N:14]
Reactant: COc1cc(C#N)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1cc(C#N)c(N)cc1OCc1ccccc1
Temperature: 20 °C
Yield: 82.5 %

Procedure:
A mixture of 4-benzyloxy-3-methoxy-6-nitrobenzonitrile (46 g, 162 mmol), sodium bicarbonate (95 g, 1.13 mol), water (750 ml), dichloromethane (550 ml) and tetrabutylammonium chloride (30 g, 108 mmol) was rapidly stirred at 20° C. and treated portionwise with sodium dithionite (66 g, 379 mmol) over 2 hours. The mixture was stirred for a further 1 hour then the phases separated. The aqueous phase was extracted with dichloromethane (2×200 ml) and the combined organic solution washed with water (300 ml) and dried over magnesium sulphate. The solution was concentrated to 250 ml and 4.0 N hydrochloric acid in 1,4-dioxane (150 ml, 0.6 mol) added. The reaction was then diluted with diethyl ether (1000 ml) and cooled on ice. The resulting solid was collected by suction filtration and washed with diethyl ether. The solid was stirred in methanol (1000 ml) and sodium bicarbonate solution (800 ml) added (pH 8) and the mixture stirred for 1 hour. The solid was collected by suction filtration, washed with water, methanol and dried in vacuo to yield 2-amino-4-(benzyloxy)-5-methoxybenzonitrile (34 g, 82% yield) as light brown solid:
Reaction SMILES: C(OC1C2C(=CC(OC)=CC=2)C(C2C=CC=CC=2)=C(C#N)N=1)C=C.Cl[C:26]1[C:35]2[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=2)[C:29]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)=[C:28]([C:45]#[N:46])[N:27]=1.[CH3:47][N:48]1[CH:52]=[C:51]([CH2:53][OH:54])[N:50]=[CH:49]1>>[F:44][C:40]1[CH:39]=[C:38]([C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=3)[C:26]([O:54][CH2:53][C:51]3[N:50]=[CH:49][N:48]([CH3:47])[CH:52]=3)=[N:27][C:28]=2[C:45]#[N:46])[CH:43]=[CH:42][CH:41]=1
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3cccc(F)c3)c2c1
Reactant: Cn1cnc(CO)c1
Agent: C=CCOc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12
Product: COc1ccc2c(OCc3cn(C)cn3)nc(C#N)c(-c3cccc(F)c3)c2c1

Procedure:
Following the procedure for 1-(allyloxy)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using 1-chloro-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile in place of 1-chloro-6-methoxy-4-phenylisoquinoline-3-carbonitrile and (1-methyl-1H-imidazol-4-yl)methanol in place of allyl alcohol, the title compound was synthesized.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[CH:4][C:3]=1[CH2:10][N:11]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[CH2:13][O:12]1.[C:19]1(=O)[O:24][C:22](=[O:23])[CH:21]2[CH2:25][CH2:26][CH:27]=[CH:28][CH:20]12>C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH2:10][N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[CH2:13][O:12]2)=[CH:4][C:5]([N:9]2[C:22](=[O:23])[C:21]3[CH2:25][CH2:26][CH2:27][CH2:28][C:20]=3[C:19]2=[O:24])=[C:6]([F:8])[CH:7]=1
Reactant: CC1(C)CON(Cc2cc(N)c(F)cc2Cl)C1=O
Reactant: O=C1OC(=O)C2CCC=CC12
Solvent: CC(=O)O
Product: CC1(C)CON(Cc2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)C1=O

Procedure:
By the method of Example 2, Step H, 3.0 g (0.011 mole) of 2-[(2-chloro-4-fluoro-5-aminophenyl)methyl-4,4-dimethyl-3-isoxazolidinone and 1.84 g (0.012 mole) of tetrahydrophthalic anhydride were reacted in 10 ml of acetic acid, yielding 3.0 g of N-[4-chloro-2-fluoro-5[(4,4-dimethyl-3-oxoisoxazolidin-2-yl)methyl]phenyl]-3,4,5,6-tetrahydrophthalimide as a yellow solid, m.p. 136°-138° C. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=O)[C:13]([N:15]([CH3:24])[N:16]=[C:17]([CH3:23])[CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])=[O:14])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:14])[N:15]([CH3:24])[N:16]=[C:17]([CH3:23])[C:18]=1[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O

Procedure:
To a test tube (outside diameter: 21 mm φ×overall length: 160 mm), 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34-(1)-39) (201.0 mg), potassium carbonate (115.1 mg), and methanol (757 μl) were added under ice-cooling.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[Cl:17])[C:30](=[O:31])[CH2:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Clc1cc(Br)ccc1CNCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1cccs1)N(Cc1ccccc1)Cc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
580 mg of benzyl-(4-bromo-2-chlorobenzyl)amine are dissolved in 10 ml of CH2Cl2 (anhydrous) and treated first with 300 μl of pyridine, then with 330 mg of 2-thiophen-2-ylacetyl chloride. The mixture is stirred at RT for 4 h, then diluted with 100 ml of CH2Cl2 and washed with 50 ml of a saturated aqueous Na2CO3 solution. It is dried over MgSO4 and the solvent is removed in vacuo. It is chromatographed on silica gel using DIP and 490 mg of a colorless oil are obtained.
Reaction SMILES: [NH3:1].[CH:2]1([C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=O)=[CH:16][CH:15]=3)[CH:10]=[C:9]([CH2:25][CH3:26])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1>>[CH:2]1([C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([NH2:1])=[O:23])=[CH:18][CH:19]=3)[CH:10]=[C:9]([CH2:25][CH3:26])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N
Reactant: CCc1cc(Cc2ccc(CC(=O)OC)cc2)nc(C2CCCC2)n1
Product: CCc1cc(Cc2ccc(CC(N)=O)cc2)nc(C2CCCC2)n1
Temperature: 100 °C
Yield: 59 %

Procedure:
A mixture of ammonia (7.0 N in methanol, 4 mL) and methyl 2-(4-((2-cyclopentyl-6-ethylpyrimidin-4-yl)methyl)phenyl)acetate (0.067 g, 0.20 mmol) and heated at 100° C. for 48 h. After this time, the mixture was cooled and filtered through celite with ethyl acetate washings. The filtrate was washed with brine (3×15 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.039 g, 59%) as a white solid. MW=323.43. 1H NMR (DMSO-d6, 500 MHz) δ 7.44 (s, 1H), 7.27-7.11 (m, 4H), 7.01 (s, 1H), 6.86 (s, 1H), 3.95 (s, 2H) 3.31 (s, 2H), 3.29-3.14 (m, 1H), 2.62 (q, J=7.6 Hz, 2H), 2.06-1.91 (m, 2H), 1.90-1.67 (m, 4H), 1.66-1.53 (m, 2H), 1.16 (t, J=7.6 Hz, 3H); APCI MS m/z 324 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:63][N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:24]([N:67]5[CH2:68][CH2:69][N:64]([CH3:63])[CH2:65][CH2:66]5)=[O:26])=[CH:27][CH:28]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(Nc2nccc(-c3c[nH]nc3-c3ccc(Cl)cc3)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Reaction time: 2 h

Procedure:
To the suspension of 600 mg (1.53 mMol; 1 Eq.) of 4-{4-[3-(4-chloro-phenyl)1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzoic acid (Example 30) in 5 mL of DMF at rt is added 186 mg (202 μL; 1.83 mMol; 1.2 Eq.) of N-methylmorpholine ( Fluka 67869); 677 mg (1.53 mMol; 1 Eq.) of BOP (Fluka 12802) and 153 mg (170 μL; 1.53 mMol; I Eq.) of N-methylpiperazine (Fluka 68810). After 2 h at rt, the yellow solution is treated with 50 mL of NaHCO3 satd. solution and extracted with ethyl acetate. The combined organic layers are washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure to approx. 10 mL. The precipitated crystals are collected, washed with a little ethyl acetate and dried at 60° C. under vacuum to obtain (4-{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-phenyl)-(4methyl-piperazin-1-yl)-methanone.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([OH:23])[CH2:22][CH2:21][CH2:20]4)[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:23][C:19]1([C:15]2[N:14]=[C:13]([CH2:12][N:9]3[C:4]4[N:5]=[C:6]([NH2:8])[N:7]=[C:2]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:3]=4[N:11]=[N:10]3)[CH:18]=[CH:17][CH:16]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: OB(O)c1ccccc1
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc(C4(O)CCC4)n3)c2n1
Product: Nc1nc(-c2ccccc2)c2nnn(Cc3cccc(C4(O)CCC4)n3)c2n1

Procedure:
Prepared from 7-chloro-3-{6-[1-hydroxy-1-cyclobutyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and phenylboronic acid by the method described in Example 7 to give the title compound (0.03 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6](=[O:12])[NH:5][C:4](=[O:13])[C:3]=1[N:14]=O.OS([O-])(=O)=O.[Na+]>O>[NH2:14][C:3]1[C:4](=[O:13])[NH:5][C:6](=[O:12])[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:2]=1[NH2:1]
Reactant: CCCCn1c(N)c(N=O)c(=O)[nH]c1=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCn1c(N)c(N)c(=O)[nH]c1=O
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
A suspension of 6-amino-1-butyl-5-nitroso-1H-pyrimidine-2,4-dione (500 mg, 2.36 mmol) in water (8.3 mL) at 85° C. was treated with sodium hydrosulfate (1.23 g, 7.08 mmol). The reaction was stirred at 85° C. for 20 min. At this time, the reaction was cooled to 0° C. The resulting green solid was collected by filtration, washed with water, and air dried for 30 min to afford 5,6-diamino-1-butyl-1H-pyrimidine-2,4-dione (304 mg, 65%) as a pale green solid: LR-MS for C8H14N4O2 (M+H)+ at m/z=199.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(O)(=O)C.[O-:26][C:27]#[N:28].[Na+]>O>[NH2:14][C:11]1[N:10]=[C:9]([NH2:15])[C:8]([O:7][C:6]2[C:5]([CH:17]([CH3:19])[CH3:18])=[CH:4][C:3]([O:20][CH3:21])=[C:2]([NH:1][C:27]([NH2:28])=[O:26])[CH:16]=2)=[CH:13][N:12]=1
Reactant: N#C[O-]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1NC(N)=O
Reaction time: 0.5 h

Procedure:
To 5-(5-amino-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (314 mg, 1.09 mmol) suspended in water (3 mL) was added acetic acid (0.25 mL, 4.34 mmol). Once all solids had dissolved, sodium cyanate (71 mg, 1.09 mmol, dissolved in 1.5 mL water) was added dropwise. After 30 minutes, the reaction was concentrated and purified with silica gel column chromatography eluting with 92/8/0.1 dichloromethane/methanol/ammonium hydroxide to yield [5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-urea as an off-white solid (244 mg, 68%, M+H)+=333), which was converted to a hydrochloride salt:
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[NH:23]([C:30]1[CH:31]=[C:32]2[C:37](=[O:38])[NH:36][C:34](=O)[C:33]2=[CH:39][C:40]=1[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[NH:23]([C:30]1[CH:31]=[C:32]2[C:37](=[O:38])[NH:36][C:34](=[S:10])[C:33]2=[CH:39][C:40]=1[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1NC(=O)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCl
Product: O=C1NC(=S)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc21

Procedure:
138 mg (0.36 mmol) of Lawesson reagent [=2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiaphosphetane] are added to a solution of 100 mg (0.3 mmol) of 4,5-bis-(anilino)phthalimide (Example 1) in 15 ml of dichloromethane and the mixture is boiled under reflux for 4 hours. The reaction mixture is concentrated by evaporation and chromatographed directly on silica gel with hexane/ethyl acetate 2:1. The product fractions are concentrated by evaporation, yielding the title compound in the form of yellow crystals, FAB-MS: 346 [M+ +H].
Reaction SMILES: Cl[CH:2]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[N:4]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+].[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C(=O)C>[CH:13]1([CH:2]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH3:12])[N:4]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cn1nc(C(Cl)C2CCCCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2nn(C)c3ccccc23)C2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
To a mixture of 3-[chloro(cyclohexyl)methyl]-1-methyl-1H-indazole (465 mg) synthesized above, ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (531 mg) synthesized in Example 2(2), sodium iodide (531 mg) and N,N-dimethylacetamide (10 mL) was added sodium carbonate (375 mg), and the mixture was stirred under argon atmosphere at 100° C. overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:2, volume ratio) to give a white solid. To a mixture of the obtained solid, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (356 mg, 45%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:35]>>[CH2:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Cl:35])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCc1ccc(CO)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCOCc1ccc(CCl)cc1
Temperature: 25 °C
Yield: 86 %

Procedure:
A mixture of (4-butoxymethyl-phenyl)-methanol (190 mg, 0.98 mmol) described in Manufacturing Example 33-1-3, triphenylphosphine (310 mg, 1.2 mmol) and carbon tetrachloride (3 mL) was stirred under reflux for 7 hours. The reaction mixture was cooled to room temperature, and concentrated under a reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate:heptane=1:15) to obtain the title compound (180 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.Br[CH2:38][CH2:39][OH:40]>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][N:26]([CH2:38][CH2:39][OH:40])[CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F
Reactant: OCCBr
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCN(CCO)C[C@H]1F

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-3-fluoro-1-(2-hydroxyethyl)piperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 273) and 2-bromoethanol following General Procedure S.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]([CH3:17])[C:14]([NH2:16])=[O:15])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br.O>CC(C)=O>[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]([CH3:17])[C:14]([NH2:16])=[O:15])[CH2:6][CH2:5]2
Reactant: Fc1ccccc1CBr
Reactant: CC(C(N)=O)N1CCc2cc(O)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C(N)=O)N1CCc2cc(OCc3ccccc3F)ccc2C1=O
Reaction time: 8 h

Procedure:
2-(6-Hydroxy-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-propionamide (50 mg, 0.213 mmol), was solved in dry acetone (1 mL) and potassium carbonate (38.3 mg, 0.276 mmol) was added followed by 2-fluorobenzyl bromide (42.36 mg, 0.224 mmol). The mixture was stirred overnight. Water was added and a precipitate appeared. The precipitated was filtrated and the title compound was obtained as a white solid (58 mg, 79%). MS: m/e=343.2 (M+H+).