Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:17]([OH:20])[C:18]#[CH:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.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>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:2]([C:19]#[C:18][CH2:17][OH:20])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)c(NC2CCCCCC2)n1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCC#Cc1cnc(Cl)nc1NC1CCCCCC1
Yield: 56 %

Procedure:
To a yellow solution of 5-bromo-2-chloro-N-cycloheptylpyrimidin-4-amine (18.1 g, 55.5 mmol) in THF (200 mL) were added propargyl alcohol (4.5 mL, 1.4 equiv) and a solution of tetrabutylammonium fluoride in THF (1M, 130 mL, 2.3 equiv) and the resulting brown mixture was treated with a stream of nitrogen for 15 min (bubble in the solution). The mixture was then treated with bis(triphenylphosphine)palladium(II) chloride (2.09 g, 0.054 equiv) and heated to reflux for 5 h. After cooling, the reaction mixture was filtered through a pad of celite (rinsed with EtOAc ˜350 mL). The filtrate was concentrated to remove THF, further diluted with EtOAc (total volume 250 mL), washed with sat. NaHCO3 (2×150 mL) and water (150 mL), dried over Na2SO4, filtered and concentrated. Titration of the residue in acetone and CH2Cl2 provided 3-(2-chloro-4-(cycloheptylamino)pyrimidin-5-yl)prop-2-yn-1-ol (8.65 g) in 56% yield. 1H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 4.45 (s, 2H), 4.19 (septet, J=4.5 Hz, 1H), 1.95 (m, 2H), 1.77-1.52 (m, 10Hz); MS m/z 280.4 (M+H)+
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:36]1[CH:37]=[N:38][C:39]([C:42]([N:44]([CH3:46])[CH3:45])=[O:43])=[N:40][CH:41]=1>>[CH2:28]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:36]2[CH:41]=[N:40][C:39]([C:42]([N:44]([CH3:46])[CH3:45])=[O:43])=[N:38][CH:37]=2)[O:11][CH2:10]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Reactant: CN(C)C(=O)c1ncc(Br)cn1
Product: CN(C)C(=O)c1ncc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)cn1
Yield: 61 %

Procedure:
The title compound was synthesized as described for Intermediate example I-28 in 61% yield starting from (3S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)chroman-3-amine and 5-bromo-N,N-dimethylpyrimidine-2-carboxamide. The reaction mixture was irradiated in a microwave at 140° C. for 20 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.92 (s, 2 H), 7.23-7.34 (m, 8 H), 7.15-7.22 (m, 3 H), 6.84-6.93 (m, 2 H), 4.31-4.39 (m, 1 H), 4.05 (t, 1 H), 3.60-3.76 (m, 4 H), 3.08-3.15 (m, 1 H), 3.06 (s, 3 H), 2.94-3.05 (m, 1 H), 2.88 (s, 3 H), 2.52-2.59 (m, 1 H); MS (ESI) m/z 452[M+H+].
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[NH2:15][CH2:16][CH:17]([OH:25])[CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[OH:25][CH:17]([CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][NH:15][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Reactant: NCC(O)CN1CCCCC1
Product: Cc1[nH]c2c(c1C(=O)NCC(O)CN1CCCCC1)CCCC2=O
Yield: 78 %

Procedure:
Similar procedure as Example 13, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 1-amino-3-(piperidin-1-yl)propan-2-ol 0.34 g (2.1 mmol) was reacted to give 0.26 g (78%) of the titled compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[NH:16]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ncnc2c1
Reactant: Nc1ccccc1
Solvent: CCO
Product: FC(F)(F)c1ccc2c(Nc3ccccc3)ncnc2c1
Yield: 54.7 %

Procedure:
2.5 g of 4-chloro-7-trifluoromethylquinazoline were dissolved in 10 ml of ethanol, and 1.0 g of aniline was added to the solution. Reaction occurred violently and the reaction mixture solidified immediately. After cooling, the solidified product was collected and washed with ethanol. The resulting crystals were pulverized and added to a dilute aqueous solution of sodium hydroxide. Insolubles were filtered off and recrystallized from ethanol to give 1.7 g (yield 60%) of the desired Compound No. 17 in the form of colourless plates melting at 230°-232° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=[C:4]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[NH:26][CH:27]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[N:29]=2)=[CH:20][CH:19]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.CC(O)=O>[Cl:16][C:13]1[S:12][C:11]([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]4[NH:26][CH:27]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[N:29]=4)=[CH:22][CH:23]=3)[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1c[nH]c(Cc2ccc(N)cc2)n1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Cc2nc(C(=O)OC)c[nH]2)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
A 8-mL vial was charged with 4-chloro-2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidine (100 mg, 0.366 mmol, 1.05 eq.), methyl 2-[(4-aminophenyl)methyl]-1H-imidazole-4-carboxylate (81 mg, 0.348 mmol, 1 eq.), AcOH (0.8 ml). To the mixture was added 4N HCl in dioxane (4 drops using 1 ml of a syringe). The resulting mixture was stirred under 110° C. for 2 hrs. After cooling to room temperature, the mixture was added to sodium bicarbonate solution (20 ml). The precipitate was collected by filtration and washed with water then purified by chromatography on silica gel using 1˜1.5% of methanol in dichloromethane as eluent to give the title compound as a foam (79 mg, 48% yield).). MW=467.97. 1H NMR (400 MHz, CDCl3) δ 7.65 (m, 4H), 7.30 (m, 2H), 6.93 (d, J=3.6 Hz, 1H), 6.54 (brs, 1H), 4.18 (s, 2H), 3.90 (s, 3H), 2.64 (q, J=6.8 Hz, 2H), 2.49 (s, 3H), 1.26 (t, J=6.8 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.O[CH2:13][NH:14][C:15](=[O:18])[CH2:16][Cl:17].[Cl-].[Na+]>S(=O)(=O)(O)O>[Cl:17][CH2:16][C:15]([NH:14][CH2:13][C:7]1[CH:6]=[C:5]([C:8](=[O:11])[CH2:9][CH3:10])[CH:4]=[CH:3][C:2]=1[OH:1])=[O:18]
Reactant: O=C(CCl)NCO
Reactant: CCC(=O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: CCC(=O)c1ccc(O)c(CNC(=O)CCl)c1
Yield: 56.4 %

Procedure:
To 40 ml of concentrated sulfuric acid with stirring under ice-cooling is added a mixture of 10 g of 4'-hydroxypropiophenone and 10 g of N-hydroxymethylchloroacetic amide in a small portion. After addition, the reaction mixture is further stirred under ice-cooling for 130 minutes. The resulting mixture is poured into ice-cold water containing sodium chloride and the solution is extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried over sodium sulfate and then filtered. The filtrate is concentrated under reduced pressure and obtained white crystals are recrystallized from a mixture of hexane and ethanol to give 9.6 g of 3'-chloroacetamidomethyl-4'-hydroxypropiophenone as white crystals, melting at 143°-145° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:6]=[CH:5]2.C([Li])(C)(C)C.[C:26]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)(=[O:28])[CH3:27].Cl>O1CCCC1>[OH:35][C:32]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:12]([CH3:13])[CH3:14])[CH:15]([CH3:16])[CH3:17])[CH:6]=[CH:5]3)[CH2:33][CH2:34][N:29]([C:26](=[O:28])[CH3:27])[CH2:30][CH2:31]1
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCC(O)(c2ccc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21 %

Procedure:
5-Bromo-1-triisopropylsilyl-1H-indole (13.7 g, 38.9 mmol) in tetrahydrofuran (250 ml) at -78° C. was treated with t-butyllithium (45.8 ml, 77.8 mmol, 1.7M solution in pentanes) and stirred at this temperature for 15 minutes. The yellow solution formed was added to 1-acetyl-4-piperidone (5.49 g, 38.9 mmol) in tetrahydrofuran (250 ml) at -78° C., and the mixture allowed to warm to room temperature. Hydrochloric acid (40 ml, 1M) was added and the mixture extracted with ethyl acetate (2×500 ml). The extracts were combined, dried (MgSO4) and concentrated. The crude product was purified by flash chromatography using ethyl acetate as eluant, to give 1-[4-hydroxy-4-(1-triisopropylsilyl-1H-indol-5-yl)piperidin-1-yl]ethanone (3.39 g, 21%) as a white solid; δH (DMSO-d6) 1.10 (18H, d, J 7.9 Hz, 6×CH3), 1.70 (3H, m, 3×CH), 2.00 (2H, m, piperidinyl H), 2.05 (3H, s, COCH3), 2.45 (1H, m, piperidinyl H), 3.00 (1H, m, piperidinyl H), 3.30 (1H, m, piperidinyl H), 3.50 (1H, m, piperidinyl H), 3.70 (1H, m, piperidinyl H), 4.30 (1H, m, piperidinyl H), 5.00 (1H, s, OH), 6.60 (1H, d, J 2.8 Hz, ArH), 7.30 (1H, d, J 7.8 Hz, ArH), 7.35 (1H, d, J 2.2 Hz, ArH), 7.50 (1H, d, J 7.9 Hz, ArH), and 7.70 (1H, s, ArH).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[NH:15][N:14]=[CH:13]3)=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:23](I)[CH2:24][CH2:25][CH3:26].C(OCC)(=O)C>CS(C)=O>[CH2:23]([N:15]1[N:14]=[CH:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10](/[CH:9]=[CH:8]/[C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[CH:11]=2)[C:16]1=[O:20])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCI
Reactant: O=c1[nH]ncc2cc(/C=C/c3ccc(O)cc3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCn1ncc2cc(/C=C/c3ccc(O)cc3)ccc2c1=O
Reaction time: 2 h

Procedure:
A solution of 27.5 gm of trans-6-[2-(4-hydroxyphenyl)ethenyl]-1-(2H)-phthalazinone (as prepared in Example 2) in 1300 ml DMSO was treated with 135 ml 2.5N sodium hydroxide solution, followed by 12.5 ml n-butyl iodide. The reaction mixture was stirred for 21/2 hours, then added to 8000 ml ethyl acetate. After stirring for a few minutes the insoluble material was filtered off and washed with a little ethyl acetate. The ethyl acetate was removed on a rotary evaporator and the residue added to 8000 ml water, stirred for an hour and allowed to settle overnight. The clear supernatant liquid was syphoned off and the residual slurry was filtered and the crude product washed thoroughly with water. After air drying it weighed 24.8 gm. The crude product was recrystallized from 125 ml 2-methoxyethanol, filtered and washed with isopropanol and ether. After drying at 60° for 24 hours, it weighed 17.4 gm and melted at 225°-230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:16])=[C:10]([CH2:14]O)[N:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>>[Cl:19][CH2:14][C:10]1[N:11]([CH3:13])[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[CH3:16]
Reactant: Cc1c(-c2ccc(Cl)cc2)nn(C)c1CO
Reactant: O=S(Cl)Cl
Product: Cc1c(-c2ccc(Cl)cc2)nn(C)c1CCl

Procedure:
In analogy to the procedure described for example 1 b], [5-(4-chloro-phenyl)-2,4-dimethyl-2H-pyrazol-3-yl]-methanol was reacted with thionyl chloride for 20 min at 0° C. to give 5-chloromethyl-3-(4-chloro-phenyl)-1,4-dimethyl-1H-pyrazole as yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([C:13]3[N:14]=[C:15]([NH2:18])[S:16][CH:17]=3)=[C:8]([CH3:19])[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH3:19])[C:9]([C:13]3[N:14]=[C:15]([NH:18][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[S:16][CH:17]=3)=[C:10]([CH3:12])[CH:11]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(OCC2CC2)cc(C)c1-c1csc(N)n1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OCC2CC2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of 4-(4-(cyclopropylmethoxy)-2,6-dimethylphenyl)thiazol-2-amine (4-5, 0.410 g, 1.51 mmol) in CH2Cl2 (10 mL) was added triethylamine (1.0 mL, 7.2 mmol) followed by isonicotinoyl chloride hydrochloride (0.470 g, 2.62 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was filtered, and recrystallized in toluene to give N-{4-(4-(cyclopropylmethoxy)-2,6-dimethylphenyl)thiazol-2-yl}isonicotinamide (4, 0.41 g) as light yellow solids in 72% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.0 (s, 1 H), 8.80 (d, J=4.9 Hz, 2 H), 7.99 (d, J=6.0 Hz, 2 H), 7.10 (s, 1 H), 6.68 (s, 2 H), 3.81 (d, J=7.0 Hz, 2 H), 2.06 (s, 6 H), 1.21 (s, 1 H), 0.57 (d, J=6.5 Hz, 2 H), 0.32 (d, J=5.7 Hz, 2 H). ESI-MS: m/z 380.3 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=2[O:7][CH:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]1=[O:21])#[N:2].Cl.N[C:24]1[C:29]([F:30])=[C:28]([F:31])[CH:27]=[C:26]([F:32])[C:25]=1[SH:33]>C(O)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[O:7][CH:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5](=[O:21])[N:4]([CH2:3][C:1]3[S:33][C:25]4[C:26]([F:32])=[CH:27][C:28]([F:31])=[C:29]([F:30])[C:24]=4[N:2]=3)[C:9]=2[CH:10]=1
Reactant: CCOC(=O)CC1Oc2ccc(F)cc2N(CC#N)C1=O
Reactant: Nc1c(F)c(F)cc(F)c1S
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1Oc2ccc(F)cc2N(Cc2nc3c(F)c(F)cc(F)c3s2)C1=O

Procedure:
Ethyl 2-(4-cyanomethyl-6-fluoro-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl]acetate (500 mg) and 2-amino-3,4,6-trifluorothiophenol hydrochloride (388 mg) were added to anhydrous ethanol (5 ml), and the mixture was refluxed under heating under an argon atmosphere. Fifteen hours later, the solvent was distilled away and water was added to the residue, which was followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was. distilled away.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[S:10]1[C:14]2[CH:15]=[C:16]([C:19]3([C:22]4[N:26]5[N:27]=[C:28]([C:31]6[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=6)[CH:29]=[N:30][C:25]5=[N:24][N:23]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1.Cl.[NH2:41][C@@H:42]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[S:10]1[C:14]2[CH:15]=[C:16]([C:19]3([C:22]4[N:26]5[N:27]=[C:28]([C:31]6[CH:39]=[CH:38][C:34]([C:35]([NH:41][C@@H:42]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])=[O:37])=[CH:33][CH:32]=6)[CH:29]=[N:30][C:25]5=[N:24][N:23]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (42 μL, 0.24 mmol) was added to a mixture of 4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoic acid (33 mg, 0.080 mmol), tert-butyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (23 mg, 0.10 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (42 mg, 0.096 mmol) in DMF (1 mL). The mixture was stirred at RT overnight, and quenched with saturated sodium bicarbonate (5 mL). The reaction mixture was extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was flash chromatographed on a silica gel column with ethyl acetate in hexanes (40%) to afford the desired product. Analytical LCMS: (M+H)+=584.2
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](O)=[O:18])=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC)=O.[OH-].[NH4+:29]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH2:29])=[O:18])=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COc1cc(CCC(=O)O)ccc1OCc1ccccc1
Agent: CCOC(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CCC(N)=O)ccc1OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 3-(4-benzyloxy-3-methoxy-phenyl)-propionic acid (8.38 g, 29.30 mmol) in dry THF (110 ml), under nitrogen, was added TEA (4.5 ml, 32.33 mmol), and the resulting mixture was cooled to −10° C. before ethyl chloroformate (3.1 ml, 32.53 mmol) was added dropwise. After stirring at −10° C. (20 min), ammonium hydroxide (25% in water, 65 ml) in THF (65 ml) was added and the mixture was stirred at −15° C. for 30 min and then at RT for 1.5 h. The reaction mixture was concentrated in vacuo, extracted three times with CH2Cl2 and the combined organic extracts were washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous MgSO4, filtered and concentrated to give the title compound (8.40 g, 29.30 mmol, 100%) as a colorless solid. No further purification of the crude amide was necessary.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]1[C:15](=[O:16])[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:8]=[C:7]1[C:17]([OH:19])=O.[CH3:20][N:21]1[C:25]([NH2:26])=[N:24][N:23]=[N:22]1>N1C=CC=CC=1>[CH3:5][N:6]1[C:15](=[O:16])[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:8]=[C:7]1[C:17]([NH:26][C:25]1[N:21]([CH3:20])[N:22]=[N:23][N:24]=1)=[O:19]
Reactant: Cn1nnnc1N
Reactant: Cn1c(C(=O)O)cc2cccnc2c1=O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cn1nnnc1NC(=O)c1cc2cccnc2c(=O)n1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., 114 mg (0.96 mmol) of thionyl chloride are added to 150 mg (0.74 mmol) of 7-methyl-1,7-naphthyridin-8(7H)-one-6-carboxylic acid and 110 mg (1.1 mmol) of 1-methyl-5-aminotetrazole in 3 ml of pyridine. The mixture is stirred at RT for 16 h. The reaction is then quenched with a little water, the pyridine is evaporated and the residue is purified by HPLC. Yield 27 mg (13%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]([CH3:27])=[C:25]([C:28](O)=[O:29])[CH:24]=[N:23]2)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:28]([C:25]2[CH:24]=[N:23][N:22]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=3)[C:26]=2[CH3:27])=[O:29])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Product: Cc1c(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cnn1-c1ccc(F)cc1

Procedure:
50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxamide. MS (Q1) 407.0 (M)+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([F:14])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1cccc(F)c1
Product: Nc1cc2ncnc(Nc3cccc(F)c3)c2cn1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (215 mg, 1.12 mmol) and 3-fluoroaniline (1.16 g, 10.4 mmol) is stirred at 160° C. for 30 min. The resulting product is chromatographed over silica gel (6-7% MeOH/CH2Cl2) to give 7-amino-4-(3-fluoroanilino)pyrido[4,3-d]pyrimidine (185 mg, 65%) as a white solid. 1H NMR (DMSO) δ 9.94 (1H, brs), 9.36 (1H, s), 8.46 (1H, s), 7.91 (1H, brd, J=11.9 Hz), 7.63 (1H, brd, J=8.1 Hz), 7.41 (1H, dd, J=15.7, 7.7 Hz), 6.93 (1H, dt, Jt =8.5 Hz, Jd =2.4 Hz), 6.68 (2H, brs), 6.38 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH3:32])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:31]([O:30][CH2:29][CH2:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1)[CH3:32]
Reactant: CCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
A mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (20 g), 4-(2-ethoxyethoxy)phenyl borate (14.9 g), 1M potassium carbonate solution (130 ml), ethanol (130 ml) and toluene (1000 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (3 g), and the mixture was refluxed under argon atmosphere for 15 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (25.2 g) as colorless crystals.
Reaction SMILES: C[O:2][C:3]1[CH:26]=[CH:25][C:6]2[CH:7]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1>ClCCl>[OH:2][C:3]1[CH:26]=[CH:25][C:6]2[CH:7]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Solvent: ClCCl
Product: Cc1ccc2c(c1)C=Cc1cc(O)ccc1C2c1c[nH]c(=O)[nH]c1=O
Reaction time: 2 h

Procedure:
A solution of borontribromide (1.0M in dichloromethane) (10 ml) was added to a mixture of the product from example 23 step (iv) (1.4 g) in dichloromethane (20 ml). After stirring for 2 hours, the reaction mixture was partitioned between 2M hydrochloric acid and ethyl acetate. The organic layer was washed with water, dried (MgSO4) and evaporated under reduced pressure. Used directly in the next step.