Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11](Cl)=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9].[CH3:37][NH2:38].CO>C(O)C>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11]([NH:38][CH3:37])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(Cl)nc2ccccc2c1-c1ccccc1
Reactant: CN
Solvent: CCO
Solvent: CO
Product: CNc1nc2ccccc2c(-c2ccccc2)c1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
To a solution of the compound obtained in Example 269 (100 mg) in ethanol (4 ml) was added 40% MeNH2 -methanol (12 ml), and the mixture was stirred for 4 hours with heating under reflux. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water, dried and evaporated to yield the title compound as colorless crystals (65 mg).
Reaction SMILES: C([O:4][C@H:5]([CH3:22])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]=O)=[C:13]([NH2:19])[N:12]([CH3:20])[C:11]1=[O:21])(=O)C.[SH-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:31]([O:38][CH2:39][C:40](Cl)=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>O.[OH-].[Na+].C(Cl)(Cl)Cl>[CH2:31]([O:38][CH2:39][C:40]1[NH:17][C:14]2[C:15](=[O:16])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:22])[C:11](=[O:21])[N:12]([CH3:20])[C:13]=2[N:19]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c(N=O)c(N)n(C)c1=O
Reactant: O=C(Cl)COCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@@H](O)CCCCn1c(=O)c2[nH]c(COCc3ccccc3)nc2n(C)c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a stirred suspension of (R)-3-(5-acetoxyhexyl)-6-amino-1-methyl-5-nitroso-uracil (prepared as described for CT12452) (23.35 g, 74.8 mmol) in water (230 ml) at 60° C. was added sodium hydrosulfide (61.7 g) in portions. After heating at 60° C. for additional 1 hour, the reaction mixture was cooled to 0-5° C. Chloroform (240 ml) was added followed by potassium carbonate (51.8 g), 37.5 mmol) in portions. The reaction mixture was stirred at 0-5° C. for additional 0.5 hour whereupon benzyloxyacetyl chloride (20.7 g, 112 mmol) was added dropwise. After stirring at 0-5° C. for an additional 1 hour, the mixture was extracted with 10% methanol-chloroform solution (1100 ml). The aqueous phase was further extracted with 10% methanol-chloroform solution (3×250 ml). The combined organic extracts were evaporated under reduced pressure to provide a beige solid which was dissolved in 10% aqueous sodium hydroxide solution (500 ml) and heated at reflux for 0.5 hour. After cooling to 0-5° C., the pH was adjusted to 2-3 by addition of concentrated hydrochloric acid and the mixture was extracted with ethyl acetate (5×250 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (100 ml), dried over magnesium sulfate, and concentrated under reduced pressure to provide a crude product. Recrystallization (ethyl acetate-hexane) provided (R)-8-benzyloxymethyl-1-(5-hydroxyhexyl)-3-methylxanthine (22.0 g, 77% yield) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:40]=[CH:39][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]4[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=4)[CH2:23][CH2:22]3)=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.[OH-].[Li+].C(O)(C(F)(F)F)=O>C1COCC1.CO.O>[Cl:8][C:9]1[CH:40]=[CH:39][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]4[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][CH:38]=4)[CH2:23][CH2:22]3)=[CH:18][CH:19]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(CCN2CCC(Nc3ccc(Oc4ccc(Cl)cc4)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)c1ccc(CCN2CCC(Nc3ccc(Oc4ccc(Cl)cc4)cc3)CC2)cc1
Reaction time: 17 h
Yield: 81.3 %

Procedure:
A solution of methyl 4-[2-[4-[[4-(4-chlorophenoxy)phenyl]amino]-1-piperidinyl]ethyl]benzoate trifluoroacetic acid salt (0.13 g, 0.18 mmol) in THF (4 mL) and methanol was stirred as an aqueous solution of lithium hydroxide (84 mg, 2 mmol) in 4 mL of water was added. The reaction was stirred for 17 hours and acidified with TFA. Purification by reverse phase preparative HPLC using a gradient of acetonitrile in water (plus 0.1% TFA) gave 66 mg of 4-[2-[4-[[4-(4-chlorophenoxy)phenyl]amino]-1-piperidinyl]ethyl]benzoic acid; 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, 2H), 7.44 (d, 2H), 7.35 (d, 2H), 6.86 (d, 4H), 6.64 (d, 2H), 3.62 (dbr, 2H), 3.37 (m, 3H), 3.08 (m, 4H), 2.14 (dbr, 2H), 1.56 (qbr, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([CH:8]2[CH2:15][C:11]3[S:12][CH:13]=[CH:14][C:10]=3[C:9]2=O)=O)=[CH:4][CH:3]=1.O.[NH2:20][NH2:21].C(O)(=O)C>C(O)C>[Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[C:8]3[CH2:15][C:11]4[S:12][CH:13]=[CH:14][C:10]=4[C:9]=3[NH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccc(Br)cc1)C1Cc2sccc2C1=O
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
5-(4-Bromo-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (8.0 g, 25 mmol), hydrazine monohydrate (4.8 mL, 150 mmol), glacial acetic acid (1.8 mL) and ethanol (45 mL) was heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(4-Bromo-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (7.6 g, 24.2 mmol) as white solid in 97% yield.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:19]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[C:20]4[C:21]([N:48]=3)=[N:22][C:23]([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[C:34][CH:35]5[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]5)=[CH:29][CH:28]=3)=[C:24]([Cl:26])[CH:25]=4)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:19]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:54])([CH3:55])[CH3:56])[C:20]4[C:21]([N:48]=3)=[N:22][C:23]([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[C:34][CH:35]5[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]5)=[CH:29][CH:28]=3)=[C:24]([Cl:26])[CH:25]=4)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2ccc(-c3nc4nc(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O[Si](C)(C)C(C)(C)C)n(COCC[Si](C)(C)C)c4cc3Cl)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(C#CC4CCNCC4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 4-((4-(2-(((3R,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)phenyl)ethynyl)piperidine-1-carboxylate (147 mg, 0.178 mmol) in anhydrous DCM (2.0 mL) at room temperature was added trifluoroacetic acid (0.2 mL). The reaction was stirred for 2 h at room temperature, and then poured into saturated aqueous sodium bicarbonate (40 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate, and then concentrated under reduced pressure to afford the title compound as a colorless oil. LC-MS: calculated for C37H53ClN4O5Si2 724.32 observed m/e: 725.32 (M+H)+ (Rt 2.56/4 min).
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH2:7][C:8]1[N:9]=[CH:10][NH:11][C:12]=1[CH3:13])=[NH:5])#[N:2].[ClH:14].C([OH:18])(C)C>>[ClH:14].[ClH:14].[CH3:13][C:12]1[NH:11][CH:10]=[N:9][C:8]=1[CH2:7][NH:6][C:4]([NH:3][C:1]([NH2:2])=[O:18])=[NH:5]
Reactant: CC(C)O
Reactant: Cc1[nH]cnc1CNC(=N)NC#N
Agent: Cl
Product: Cc1[nH]cnc1CNC(=N)NC(N)=O

Procedure:
1.80 g. (0.0101 mole) N-cyano-N'-[(5-methyl-4-imidazolyl) methyl] guanidine is taken up in 100 ml. isopropanol. 2.5 ml. conc. HCl is added. The reaction mixture is then heated for 20 minutes to reflux and refluxed for 65 minutes to obtain complete hydrolysis. The mixture is then cooled and filtered. The material is then recrystallized from MeOH/CH3CN to obtain 1-[(5-methyl-4-imidazolyl)methylamidino]urea dihydrochloride with a m.p. of 214°-214.5° C.
Reaction SMILES: O1[C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([NH2:10])[C:4]=2[CH:3]=[CH:2]1.C(C1C(=O)C2[CH:18]=[CH:19][S:20]C=2CC1)C>>[CH2:3]([CH:4]1[CH:9]([NH2:10])[C:8]2[CH:18]=[CH:19][S:20][C:7]=2[CH2:6][CH2:5]1)[CH3:2]
Reactant: NC1CCCc2occc21
Reactant: CCC1CCc2sccc2C1=O
Product: CCC1CCc2sccc2C1N

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 5-ethyl-6,7-dihydro-1-benzothiophen-4(5H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.10, 7.05, 6.99, 3.98, 3.65, 2.87-2.73, 2.06-1.90, 1.74-1.19, 1.05-0.97. (MS/CI) calcd for C10H15NS+H 182.3, found 181.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48](=[O:50])[CH3:49])=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][C:43](=[O:44])[C:42]2[CH:46]=[C:38]([CH2:37][C:31]3[C:32](=[O:36])[C:33]([O:34][CH3:35])=[C:28]([O:27][CH3:26])[C:29](=[O:52])[C:30]=3[CH3:51])[CH:39]=[CH:40][C:41]=2[O:47][C:48](=[O:50])[CH3:49])[CH:7]=1
Reactant: COc1cc(N)ncn1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cc(OC)ncn3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 46.5 %

Procedure:
4-Amino-6-methoxypyrimidine (0.134 g, 1.070 mmol), triethylamine (0.141 g, 1.390 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.118 g, 0.695 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.120 g, 0.249 mmol, 47%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1B(O)O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: Cc1cnc(Cl)nc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cnc(-c2cc(F)ccc2F)nc1N
Temperature: 95 °C

Procedure:
Bis(triphenylphosphine)palladium chloride (0.733 g, 1.045 mmol), 2-chloro-5-methylpyrimidin-4-amine (1.5 g, 10.45 mmol), Na2CO3 (5.22 mL, 10.45 mmol) and 2,5-difluorophenylboronic acid (2.145 g, 13.58 mmol) were combined and heated at 95° C. overnight. The reaction was filtered warm through a pad of Celite®, the solids rinsed with dioxane (3×25 mL) and the filtrate was concentrated directly onto a silica chromatography column which was then eluted with EtOAc (0-100%) in hexanes afforded 2-(2,5-difluorophenyl)-5-methylpyrimidin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (d, J=0.76 Hz, 3H) 6.82 (br. s., 2H) 7.26-7.33 (m, 2H) 7.57-7.64 (m, 1H) 8.06 (d, J=0.76 Hz, 1H). MS [M+H] found 222.2.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH:4]([C:6]([OH:8])=[O:7])[CH3:5].[CH:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O>[NH2:3][C:4]([CH3:5])([CH:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CC(N)C(=O)O
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(N)(C(=O)O)C(O)c1ccccc1
Temperature: 5 °C

Procedure:
Sodium hydroxide (6 g, 150 mmoles) and 8.9 g (100 mmoles) of D,L-alanine are dissolved in 25 mL of water and the solution cooled to around 5° C. while stirring under a nitrogen atmosphere. To the solution is added 21.2 g (200 mmoles) benzaldehyde and the mixture stirred at 5° C. for approximately one hour. The mixture is then warmed to room temperature and maintained for approximately 20 hours. Concentrated hydrochloric acid then is added to bring the reaction mixture to pH 2.0. After stirring the acidic solution for two hours, the aqueous phase is separated, extracted with ethyl acetate and evaporated under vacuum. The resulting material is twice extracted with 80 mL hot absolute ethanol, followed by evaporation of the ethanol. The resulting material is again extracted with 40 mL of absolute ethanol, followed by removal of the ethanol. The extract then is dissolved in at least a 1:1 methanol water solution and absorbed on polymethacrylate column. The column then is eluted with the same 1:1 methanol water solution and the 30 mL fractions are combined and evaporated. Purification on the polymethacrylate column then is repeated using 95% ethanol to yield racemic 2-amino-2-methyl-3-hydroxy-3-phenylpropionic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].BrC#[N:35].O>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]3[CH2:21][CH2:22][N:23]([C:26]#[N:35])[CH2:24][CH2:25]3)=[N:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CN1CCN(c2nn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)CC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CN1CCN(c2nn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.9 %

Procedure:
To a stirred mixture, under N2 of 6-fluoro-1-phenylsulfonyl-3-(4-methyl-1-piperazinyl)-1H-indazole (30.0 g, 0.86 mol) of Example 31c, K2CO3 (4.7 g, 0.086 mol) and dimethyl sulfoxide (DMSO) [250 ml] was added, dropwise, BrCN (9.1 g, 0.086 mol) dissolved in DMSO (50 ml). The reaction was stirred at ambient temperature for 2 hours and water was added. The resultant solid was collected and taken up in CH2Cl2, and after washing the organic layer with H2O, drying (K2CO3) and concentrating there remained 25.3 g of the target compound. A sample (5.0 g) was removed and recrystallized from ethyl acetate (twice) to afford 2.3 g (35%) of 4-(6-fluoro-1-phenylsulfonyl-1H-indazol-3-yl)-1-piperazine carbonitrile m.p. 178°-180° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[F:21][C:22]1[CH:23]=[C:24]([NH2:28])[CH:25]=[CH:26][CH:27]=1>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Reactant: Nc1cccc(F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc(Nc2nc(Cl)nc3c2SCC3)c1
Temperature: 120 °C

Procedure:
4 g (II) are placed in 15 ml dimethylformamide, then 4.5 ml diisopropylethylamine and then 2.5 ml 3-fluorophenylamine are added. The reaction mixture is heated to 120° C., until there is no further reaction, and cooled, then evaporated down. The residue is mixed with water. The product is extracted with dichloromethane and purified by chromatography (silica gel, petroleum ether/ethyl acetate 80/20 to 60/40). 2.6 g (III-7) are obtained as a solid.
Reaction SMILES: BrCCCCCC1[O:11]N=C(C)C=1.[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[O:21]CCN=2)[CH:17]=[C:16]([N+:25]([O-:27])=[O:26])[C:15]=1[OH:28].BrC1C=C(C=C([N+]([O-])=O)C=1O)C(NCCO)=O.CO.[C:48]([O:51][CH:52]([CH3:54])[CH3:53])(=[O:50])[CH3:49].OC1C=CC(C(O)=O)=CC=1[N+]([O-])=O>>[Br:13][C:14]1[C:15]([OH:28])=[C:16]([N+:25]([O-:27])=[O:26])[CH:17]=[C:18]([CH:19]=1)[C:20]([OH:21])=[O:11].[C:48]([O:51][CH:52]([CH3:54])[CH3:53])(=[O:50])[CH3:49]
Reactant: Cc1cc(CCCCCBr)on1
Reactant: O=[N+]([O-])c1cc(C2=NCCO2)cc(Br)c1O
Agent: O=C(NCCO)c1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Solvent: CO
Solvent: CC(=O)OC(C)C
Product: O=C(O)c1cc(Br)c(O)c([N+](=O)[O-])c1

Procedure:
Intermediates: 5-(5-bromopentyl)-3-methylisoxazole and 2-bromo-4-(4,5-dihydro-2-oxazolyl)-6-nitrophenol. The latter, a bright yellow solid, was prepared by cyclization of 3-bromo-4-hydroxy-N-(2-hydroxyethyl)-5-nitrobenzamide, yellow solid, m.p. 163°-164° C. (from methanol-isopropyl acetate). The latter was in turn prepared by bromination of 4-hydroxy-3-nitrobenzoic acid to form 5-bromo-4-hydroxy-3-nitrobenzoic acid, m.p. 233°-234° C. (yellow solid from isopropyl acetate), esterification to the corresponding methyl ester, m.p. 128°-130° C. (yellow solid from carbon tetrachloride) and reaction of the latter with 2-hydroxyethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([NH:27][C:28]2[N:37]=[CH:36][C:35]3[N:34]([CH3:38])[C:33](=[O:39])[CH2:32][N:31]([CH:40]([CH3:42])[CH3:41])[C:30]=3[N:29]=2)[CH:20]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:22]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13](=[O:15])[NH:16][C:17]2[CH:22]=[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:20]=[C:19]([NH:27][C:28]3[N:37]=[CH:36][C:35]4[N:34]([CH3:38])[C:33](=[O:39])[CH2:32][N:31]([CH:40]([CH3:42])[CH3:41])[C:30]=4[N:29]=3)[CH:18]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)[C@@H]4CCN(C(=O)OC(C)(C)C)C4)cc(S(C)(=O)=O)c3)nc21
Yield: 12 %

Procedure:
Starting from (R)-Pyrrolidine-1,3-dicarboxylic acid tert butyl ester (165 mg; 0.768 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (150 mg; 0.384 mmol), 27 mg (0.046 mmol; 12% yield) of the desired compound were obtained.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH:34]([CH3:36])[CH3:35]>CN(C)C=O>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH:34]([CH3:36])[CH3:35])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3C(C)C)CC1
Yield: 54 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a colorless oil (54%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([NH2:20])=[O:19].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][C:32](OC)=O)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].CC(C)([O-])C.[K+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:31][C:32]1[NH:20][C:18](=[O:19])[C:3]2[C:4]([CH3:17])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=2[N:1]=1
Reactant: CCCCCCC(CCC)n1nc(C)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(C)c2c(=O)[nH]c(Cc3ccc(OC)c(OC)c3)nc21
Yield: 25.9 %

Procedure:
6 mg (0.021 mmol) of 5-amino-3-methyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.095 mmol) of methyl 3,4-dimethoxyphenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic potassium tert-butoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 2.4 mg (26%) of a solid, Rf=0.66 (dichloromethane/methanol=15:1).
Reaction SMILES: C([C:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:36])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[CH:14][CH:15]=2)[NH:10][N:9]=1)(OC(C)(C)C)=O.C(Cl)(=O)C1C=CC(OC)=CC=1.NC1C=CC=CC=1C(NC1C=C2C(C=NN2[C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])=CC=1)=O>>[C:63]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:36])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH:12]=2)[CH:8]=[N:9]1)([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64]
Reactant: COc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc3c(C(=O)OC(C)(C)C)n[nH]c3c2)cc1
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(NC(=O)c3ccccc3N)cc21
Agent: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc3cnn(C(=O)OC(C)(C)C)c3c2)cc1

Procedure:
By methods substantially equivalent to those described in Example 1-C, N-(-Boc-6-indazolyl)-2-[(4-methoxybenzoyl)amino]benzamide (280 mg, 39%) was prepared from p-anisoyl chloride and 2-amino-N-(1-Boc-6-indazolyl)benzamide.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([C:23]([O:25][CH3:26])=[O:24])=[C:14]([CH3:22])[C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[N:16][CH:17]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([C:23]([O:25][CH3:26])=[O:24])=[C:14]([CH3:22])[C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[N:16][CH:17]=1
Reactant: COC(=O)c1c(OCCNC(=O)OC(C)(C)C)cnc(OC(C)C)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(OCCN)cnc(OC(C)C)c1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 260.9 %

Procedure:
To a solution of methyl 5-{2-[(tert-butoxycarbonyl)amino]ethoxy}-3-methyl-2-(propan-2-yloxy)pyridine-4-carboxylate (131d, 0.74 g, 2.0 mmol) in dry CH2Cl2 (20 mL) was added TFA (5 mL) at 5° C. The mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under vacuum to give methyl 5-(2-aminoethoxy)-3-methyl-2-(propan-2-yloxy)pyridine-4-carboxylate (131e, 1.4 g) as brown oil.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[NH2:12][C:13]1[N:17]([C:18]2[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=2)[N:16]=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:14]=1.N1C=CN=C1>CN(C=O)C>[C:25]([C:15]1[CH:14]=[C:13]([NH2:12])[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[CH:19]=2)[N:16]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(O)c2)n1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 99.7 %

Procedure:
Triisopropylsilylchloride (1.02 mL, 3.96 mmol) was added to a solution of 3-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenol (915 mg, 3.96 mmol) and imidazole (646 mg, 9.50 mmol) in DMF (15 mL) at 0° C. The reaction was stirred at RT over the weekend then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-40% EtOAc in cyclohexane, to give the title compound (1.53 g, 99%). LCMS (Method 4): Rt 4.78 min, m/z 388 [MH+].