Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[C:32]([O:36][C:37]([N:39]1[CH:43]=[CH:42][CH:41]=[C:40]1B(O)O)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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.C(OCC)(=O)C>[C:32]([O:36][C:37]([N:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:27]1[CH:28]=[CH:29][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:31])([CH3:7])[CH3:6])=[CH:10][CH:11]=3)[N:19]=2)=[CH:25][CH:26]=1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)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: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccn4C(=O)OC(C)(C)C)cc3)oc2C)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl-propionic acid ethyl ester (907 mmol) (see Ex. 2, part B) and 1-(t-butoxycarbonyl)pyrrole-2-boronic acid (0.998 mmol) in toluene:ethanol (18.2 mL of a 1:1 solution) was treated with Na2CO3 (aq) (0.906 mL of a 2M solution). A nitrogen atmosphere was applied, Pd(PPh3)4 (52.5 mg) was added, and the orange mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (20 mL) and H2O (30 mL). The layers were separated, and the aqueous phase was back-extracted with ethyl acetate (2×10 mL). Combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (20 g SiO2, 3:7 ethyl acetate:hexanes) to yield the product in 92% yield as an oil; Rf=0.50 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ7.92 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 7.34 (t, J=2.4 Hz, 1H), 6.79 (d, J=9.4 Hz, 2H), 6.74 (d, J=9.4 Hz, 2H), 6.21 (d, J=2.4 Hz, 2H), 4.20 (q, J=6.8 Hz, 2H), 4.16 (t, J=6.8 Hz, 2H), 2.93 (d, J=6.8 Hz, 2H), 2.34 (s, 3H), 1.49 (s, 6H), 1.33 (s, 9H), MS (EI) 598.2 (M+Na)+, 575.2 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][N:4]=[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[C:6]([O:8][CH3:9])=[O:7].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[F:1][CH:2]([F:17])[O:3][N:4]=[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][Br:36])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(=NOC(F)F)c1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=NOC(F)F)c1ccccc1CBr
Temperature: 20 °C

Procedure:
A solution of 5.1 g of o-tolylglyoxalic acid methyl ester O-difluoromethyl oxime, 0.16 g of dibenzoyl peroxide and 40 ml of carbon tetrachloride is heated to reflux. With radiation from a lamp, 3.55 g of N-bromosuccinimide are added thereto in several small portions, the mixture is left to react under reflux for 30 minutes and is then cooled to 20° C. and the succinimide which precipitates is removed by filtration. The filtrate is concentrated by evaporation; after chromatography on silica gel with hexane/ethyl acetate (6:1) pure 2-(bromomethyl)-phenylglyoxalic acid methyl ester O-difluoromethyl oxime is obtained in the form of a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12](O)([CH3:15])([CH3:14])[CH3:13].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: Cc1ccc(CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
450 g (3 mol) of 4-methylphenylacetic acid, 1.13 l (12 mol) of tert-butanol and 90 g (0.74 mol) of dimethylaminopyridine are dissolved in 2 l of dichloromethane. After addition of 680 g (3.3 mol) of dicyclohexylcarbodiimide, dissolved in 400 ml of dichloromethane, the mixture is stirred at 25° C. for 20 h, the precipitated urea is filtered off with suction and washed with 200 ml of dichloromethane, and the organic phase is washed twice each with 500 ml of 2N hydrochloric acid and water. The organic phase is concentrated and distilled. Yield: 408 g (66% of theory) Boiling point: 73°-78° C./0.2 mm
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.Cl.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[CH:29]([NH2:31])[CH3:30])=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C=O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[CH:29]([NH:31][C:11]([CH:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[O:13])[CH3:30])=[CH:24][CH:23]=1
Reactant: O=C(O)C1CCc2ccccc2C1
Reactant: CC(N)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)C1CCc2ccccc2C1)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-2-naphthoic acid (Aldrich, 0.50 g, 2.8 mmol) in methylene chloride (10 mL) at 0° C. was added a drop of dimethylformamide and oxalyl chloride (2 M in methylene chloride, 4.3 mL, 8.5 mmol). After stirring at room temperature for 2 h, the reaction mixture was concentrated on a rotary evaporator and dried under vacuum, and the resulting crude acyl chloride (0.55 g) was used without further purification. Thus, the crude acyl chloride (88 mg, 0.45 mmol) was dissolved in 1 mL of methylene chloride and was added 3,4-bis(4-chlorophenyl)-1-methylpropyl-amine hydrochloride salt (Reference Example 1) (Diastereomer α, 0.10 g, 0.30 mmol) and diisopropylethylamine (0.16 mL, 0.91 mmol). After stirring at room temperature for 6 h, the reaction mixture was loaded onto a silica gel column, which was eluted with 10% ethyl acetate to give a faster eluting diastereomer (Diastereomer I) and a slower eluting diastereomer (Diastereomer II) along with some mixed fractions.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[I:13]I.[OH-].[K+].S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C>[I:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: II
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A solution of 5-nitro-1H-indazole (Aldrich, 5.0 g; 30.7 mmol) in DMF (60 ml) was treated with iodine (15.6 g; 61.4 mmol) and potassium hydroxide (6.45 g; 115 mmol) at 65° C. After stirring at 65° C. for 1 hour the mixture was poured into saturated sodium metabisulfate solution (200 ml) and the solid removed by filtration, washed with water and dried to give the title compound as a light brown solid (8.9 g, quant).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([C:13]2[C:14](F)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=2)=[C:6]([N+:21]([O-])=O)[CH:5]=1.NC1C=C(C#N)C=C2C=1C1C=C(C)C=NC=1N2>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15][C:14]=3[NH:10]2)=[C:6]([NH2:21])[CH:5]=1)=[O:24]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(-c2cc(C)cnc2F)c([N+](=O)[O-])c1
Agent: Cc1cnc2[nH]c3cc(C#N)cc(N)c3c2c1
Product: COC(=O)c1cc(N)c2c(c1)[nH]c1ncc(C)cc12
Yield: 88 %

Procedure:
The title compound was prepared in 88% yield from example Compound 128 according to the procedure outlined for the preparation of Compound 124. MS (ES) [m+H] calc'd for C14H13N3O2, 256; found 256.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:19]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[C:4]([O:30][CH3:31])[CH:3]=1.Cl[CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:19]=[C:20]([CH:24]5[CH2:25][CH2:26][N:27]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:28][CH2:29]5)[CH:21]=[CH:22][CH:23]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[C:4]([O:30][CH3:31])[CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1cc(Cl)ccc1-c1cccn2nc(Nc3cccc(C4CCNCC4)c3)nc12
Product: COc1cc(Cl)ccc1-c1cccn2nc(Nc3cccc(C4CCN(CC(=O)N(C)C)CC4)c3)nc12

Procedure:
2-(4-{3-[8-(4-Chloro-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from [8-(4-chloro-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(3-piperidin-4-yl-phenyl)-amine (0.047 g, 0.110 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.017 mL, 0.160 mmol) in a manner analogous to Example 313 to give product (0.012 g, 21%). MP=79-82° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.59 (s, 1H), 8.77 (d, 1H), 7.60 (m, 3H), 7.45 (d, 1H), 7.25 (s, 1H), 7.15 (m, 2H), 7.05 (m, 1H), 6.75 (d, 1H), 3.78 (s, 3H), 3.15 (s, 2H), 3.05 (s, 3H), 2.95 (m, 2H), 2.80 (s, 3H), 2.35 (m, 1H), 2.15 (m, 2H), 1.65 (m, 4H): MS=520 (MH)+.
Reaction SMILES: Cl.[N:2]1([C:7](N)=[NH:8])C=CC=N1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:19]([C:20]3[N:25]=[C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]4)[C:23]([F:33])=[CH:22][N:21]=3)=[CH:18][N:17]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:14]2=[N:15][CH:16]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]2[C:19]([C:20]3[N:25]=[C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][CH2:30][N:29]([C:7](=[NH:2])[NH2:8])[CH2:28]4)[C:23]([F:33])=[CH:22][N:21]=3)=[CH:18][N:17]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:14]2=[N:15][CH:16]=1
Reactant: N=C(N)n1cccn1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(C(=N)N)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of pyrazole-1-carboxamidine hydrochloride (0.12 g, 0.80 mmol) and 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.40 g, 0.80 mmol) in DMF (0.9 mL) was added iPr2NEt (0.14 mL, 0.80 mmol). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted into water, filtered, washed with additional water, then ether. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography using 5-20% MeOH/CH2Cl2 gradient (product elutes with 20% MeOH) to afford 190 mg of the desired product.
Reaction SMILES: O[C:2]1([CH2:11]Cl)[CH2:6][S:5][C:4]([CH2:7][N:8]([CH3:10])[CH3:9])=[N:3]1.C1(C)C=CC=CC=1.[OH-:20].[K+]>O>[CH3:9][N:8]([CH2:7][C:4]1[S:5][CH:6]=[C:2]([CH2:11][OH:20])[N:3]=1)[CH3:10]
Reactant: CN(C)CC1=NC(O)(CCl)CS1
Reactant: [OH-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)Cc1nc(CO)cs1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 100 ml, three-necked, flask equipped with an agitator and condensor were added 3.0 g (0.014 mol) of 4-hydroxy-4-chloromethyl-2-(dimethylaminomethyl)thiazoline (prepared as in Example 1), 47 ml of toluene, 1 ml of water and 0.79 g (0.014 mol) of solid potassium hydroxide. The resulting solution was stirred at room temperature for 45 minutes. A 1 μl sample of the reaction mixture was then removed from the flask and diluted according to the procedure described in Example 4. The HPLC assay set forth in Example 3 indicated that 72.6% of the thiazoline substrate had converted to the desired titled product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[S:9](=[O:28])(=[O:27])[CH2:10][C:11]3[C:15]([C:16]([O:18]CC)=[O:17])=[N:14][N:13]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:12]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[C:8]2[S:9](=[O:28])(=[O:27])[CH2:10][C:11]3[C:15]([C:16]([OH:18])=[O:17])=[N:14][N:13]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:12]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1c(OC)cccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc2c1S(=O)(=O)Cc1c(C(=O)O)nn(-c3ccccc3)c1-2
Reaction time: 4 h
Yield: 94.7 %

Procedure:
To a solution of ethyl 6-methoxy-1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide (0.23 g, 0.57 mmol) in THF (10 mL) is added aq. solution of NaOH (2.8 mL, 1 M, 2.85 mmol, 5 Eq) at 0° C. and the reaction mixture is stirred for 4 h. The solvent is removed under reduced pressure and aq. solution of HCl 1 M is added. The product is extracted with EtOAc (2×). The organic layer is washed with brine, dried over MgSO4 and concentrated under reduced pressure to afford 0.2 g (70%) of the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 13.5 (brs, 1H), 7.61-7.57 (m, 3H), 7.46-7.42 (m, 3H), 7.26 (d, J=8.6 Hz, 1H), 6.35 (d, J=8.0 Hz, 1H), 4.88 (s, 2H), 3.90 (s, 3H). MS (ESI+): 371.0. HPLC (max plot) 98.9%; Rt 3.30 min.
Reaction SMILES: [C:1](Cl)(=[O:7])[O:2][CH2:3][CH2:4][CH2:5][Cl:6].O.Cl.Cl.[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[NH:21][C:22]1[N:23]=[CH:24][C:25]2[CH2:30][NH:29][CH2:28][C:26]=2[N:27]=1.C(N(CC)CC)C>O1CCCC1.ClCCl>[CH2:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH:13]1[NH:21][C:22]1[N:23]=[CH:24][C:25]2[CH2:30][N:29]([C:1]([O:2][CH2:3][CH2:4][CH2:5][Cl:6])=[O:7])[CH2:28][C:26]=2[N:27]=1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CNC3)C2
Reactant: O=C(Cl)OCCCCl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCCCl)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Reaction time: 18 h
Yield: 100.5 %

Procedure:
Add a solution of 3-chloropropyl carbonochloridate (0.55 mL; 1.48 equiv; 4.54 mmoles) in tetrahydrofuran (21 mL) dropwise over 1 hour to a mixture of N-(2,3-dihydro-1H-inden-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride hydrate (1.0 g; 1.0 equiv; 3.07 mmoles) and triethylamine (2.2 mL; 5.1 equiv; 15.78 mmoles) in tetrahydrofuran (21 mL). Stir the solution for 18 hours, then dilute with dichloromethane and wash with sodium bicarbonate solution. Further extract the aqueous layer with dichloromethane (2×). Dry the combined organic extracts over sodium sulfate, filter, and concentrate to afford 3-chloropropyl 2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (1.15 g; 100%) as a brown solid: MS (m/z): 373(M+1).
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([CH:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[CH:33][CH:34]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Reactant: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(NCc5ccccc5N(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-[2-({2-[4-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-phenyl]-methanesulfonamide was prepared from N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 4-(1-methyl-piperidin-4-yl)-phenylamine (44.0 mg, 0.231 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.019 g, 18%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.81 (d, J=6.6 Hz, 1H), 7.55-7.47 (m, 3H), 7.38-7.28 (m, 3H), 7.20 (d, J=8.4 Hz, 2H), 6.69-6.64 (m, 2H), 6.37 (d, J=7.7 Hz, 1H), 5.23 (t, J=5.9 Hz, 1H), 4.72 d, J=6.1 Hz, 2H), 3.31 (s, 3H), 3.02-2.95 (m, 5H), 2.50-2.40 (m, 1H), 2.33 (s, 3H), 2.10-2.00 (m, 2H), 1.88-1.74 (m, 4H). MS=520 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]=[O:13])[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[Mg]Br.OS(O)(=O)=O>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]([OH:13])[C:24]1[S:23][CH:27]=[CH:26][CH:25]=1)[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(C=O)cc2OC1C(F)(F)F
Reactant: Br[Mg]c1cccs1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCOC(=O)C1=Cc2cc(Cl)c(C(O)c3cccs3)cc2OC1C(F)(F)F
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
The title product from Example 170 Step 1 (100 mg, 0.31 mmol) was dissolved in 1.0 mL of Et2O and cooled to −30° C. To this solution was added 0.31 mL thiophene-2-yl magnesium bromide solution (1.0 M in THF). After 10 minutes, the reaction mixture was pipetted over ice and diluted with ether and a dilute solution of H2SO4. The organic extracts were washed with a saturated solution of NaHCO3, dried over MgSO4, filtered, and evaporated under reduced pressure to dryness to provide 112 mg of a yellow oil. This oil was used as is without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=[O:17])[CH:5]=[C:6]2[C:11]=1[O:10][C:9](C)(C)[CH2:8][C:7]2([CH3:15])[CH3:14].CC1(C)C2C(=CC=CC=2)OC(C(O)=O)C1>>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=[O:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C:7]2([CH3:14])[CH3:15]
Reactant: CC1(C)CC(C)(C)c2cc(C(=O)O)cc(Br)c2O1
Agent: CC1(C)CC(C(=O)O)Oc2ccccc21
Product: CC1(C)CCOc2c(Br)cc(C(=O)O)cc21

Procedure:
Using the same procedure as for the synthesis of 8-bromo-2,2,4,4-tetramethylchromanoic acid (Compound P) but using 4,4-dimethylchromanoic acid (100 mg, 0.49 mmol), the title compound was obtained as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]1[CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:6]2[CH2:5][C@@H:4]([CH3:8])[NH:3][C@@H:2]([CH3:1])[CH2:7]2)=[CH:12][C:11]=1[CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]1[CH3:25]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: C[C@H]1COCCN1Cc1cc(C=O)ccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(Br)c(CN3CCOC[C@@H]3C)c2)C[C@H](C)N1
Temperature: 25 °C

Procedure:
(2S,6R)-2,6-Dimethylpiperazine (0.304 g, 2.67 mmol) and (S)-4-bromo-3-((3-methylmorpholino)methyl)benzaldehyde (0.530 g, 1.78 mmol) in DCM (10 ml) were stirred at RT under nitrogen for 30 minutes. Sodium triacetoxyborohydride (0.565 g, 2.67 mmol) was then added and the resulting solution was stirred at RT over the weekend. The reaction mixture was quenched with saturated NaHCO3. The reaction mixture was extracted with DCM (×3). The organic layer was dried over MgSO4, filtered and evaporated to afford the sub-title compound as a yellow oil. Yield: 0.620 g
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][NH:24]C(OC(C)(C)C)=O)[CH:16]=2)=[C:7]([NH:32][C:33]([NH:35][C:36]2[C:41]([CH:42]([CH3:44])[CH3:43])=[CH:40][CH:39]=[CH:38][C:37]=2[CH:45]([CH3:47])[CH3:46])=[O:34])[C:6]1=[O:48])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][NH2:24])[CH:16]=2)=[C:7]([NH:32][C:33]([NH:35][C:36]2[C:37]([CH:45]([CH3:46])[CH3:47])=[CH:38][CH:39]=[CH:40][C:41]=2[CH:42]([CH3:44])[CH3:43])=[O:34])[C:6]1=[O:48])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCNC(=O)OC(C)(C)C)c2)c2cccnc21
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCN)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a solution of N-[1-butyl-4-{3-(3-tert-butoxycarbonylamino-1-propynyl)phenyl}-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropyl-phenyl)urea (104 mg, 0.16 mmol) in chloroform (5 ml) was added trifluoroacetic acid (1 ml) at under ice-cooling. The mixture was warmed to room temperature, and then stirred for 1.5 hour. The mixture was concentrated under reduced pressure to remove the solvent, and to the residue was added 5% aqueous sodium chloride solution. The mixture was treated with aqueous ammonia to be converted into a free form, and then extracted with ethyl acetate. The oily layer was washed with 5% aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (4% methanol in chloroform) to give the title compound (64 mg, 0.12 mmol).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([O:23]C)=[O:22])=[CH:12][CH:11]=2)[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH-].[Na+]>CO>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([OH:23])=[O:22])=[CH:12][CH:11]=2)[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccccc2n1Cc1ccc(C2CCCC2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nc2ccccc2n1Cc1ccc(C2CCCC2C(=O)O)cc1
Yield: 62.6 %

Procedure:
A mixture of methyl 2-[4-[(2-propyl-1H-benzimidazol-1yl)methyl]phenyl]cyclopentane-1-carboxylate (530 mg, 1.41 mmol), 1N NaOH (2.8 mL), and MeOH (5.0 mL) was heated under reflux for 6 h. The mixture was concentrated, diluted with water (10 mL), and extracted with ether (discarded). The aqueous phase was neutralized with 1N HCl (2.8 mL) and the white precipitate was collected by filtration. Recrystallization from EtOH gave 320 mg (63%) of product, mp 179°-180° C.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[CH2:5]([C:12]1[C:13]2[CH2:36][NH:35][CH2:34][CH2:33][C:14]=2[N:15]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)[N:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[CH2:5]([C:12]1[C:13]2[CH2:36][N:35]([CH2:2][C:3]#[N:4])[CH2:34][CH2:33][C:14]=2[N:15]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)[N:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CCBr
Reactant: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CNCC3)ccc1-n1cnc(C)c1
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CN(CC#N)CC3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
Bromoacetonitrile (0.031 mL, 0.45 mmol) was added to a solution of 4-benzyl-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (175 mg, 0.41 mmol, Example 106) and TEA (0.063 mL, 0.45 mmol) in THF (3 mL). The solution was stirred at RT for 2 hours. Solvent was evaporated and the crude product was purified on a prepHPLC yielding 2-(4-benzyl-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)acetonitrile (72.0 mg, 37.7%). MS (ES+) m/z 466.3 (M+H)+