Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=O)[CH3:2].[OH:5][N:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][C:7]1([CH3:24])[CH3:23].CO.OO.O>C1CCCCC1>[CH:2]1([O:5][N:6]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([O:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][C:7]2([CH3:24])[CH3:23])[CH2:1][CH2:9][CH2:8][CH2:7][CH2:23]1
Reactant: CC(=O)O
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: OO
Solvent: O
Solvent: C1CCCCC1
Solvent: CO
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCCCC1
Temperature: 55 °C
Yield: 40 %

Procedure:
A solution of 0.101 g (0.37 mmol) of ferric chloride hexahydrate and 0.115 g (1.9 mmol) of glacial acetic acid in 2 ml of water is added to a mixture of 5.00 g (18.1 mmol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, 27 ml of methanol, and 18 ml of cyclohexane. The mixture is heated to reflux, 55° C. A solution of 4.9 g (72 mmol) of 50% aqueous hydrogen peroxide is added dropwise over 2.25 hours to the reaction mixture while the temperature is brought to and maintained at reflux. After the peroxide is added, the reaction mixture tests negative for hydrogen peroxide. The yield of the title compound, after work-up with ethyl acetate and purification by flash chromatography, is 2.63 g (40% yield, GC assay 100%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[Li].[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1C(Cl)=O.Cl>C1COCC1>[O:5]=[C:3]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][N:13]=1)[CH2:2][C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1cnccn1
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cnccn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of diethyl malonate (1.25 ml, 1.32 g) in THF (20 ml) under an atmosphere of nitrogen at −60° C. was added nbutyl lithium (2.5 M, 9 ml) dropwise over 15 min, keeping the temperature constant. The reaction became a cloudy white colour from the formation of the di-lithium salt then became yellowish. After 10 min, the reaction was cooled to −78° C., when a solution of pyrazine-2-carbonyl chloride (0.5 g, dark purple solution in THF (10 ml)) was added dropwise over 15 min. The reaction then warmed to −45° C. and stirred for 1 h. The reaction was then poured into 1 M HCl solution (35 ml) with stirring. This was transferred to a separating funnel, and extracted with CH2Cl2 (2×150 ml). The combined organic layers were then washed with sat. NaCO3 soln (1×30 ml) and then dried over MgSO4, filtered and concentrated in vacuo to give the product as a brown oil. Yield 0.65 g, 45%.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[CH2:6]([OH:10])[CH2:7][CH2:8][CH3:9].CN1C=CN=C1>>[CH3:3][Si:2]([CH3:5])([CH3:4])[O:10][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCO
Reactant: C[Si](C)(C)Cl
Agent: Cn1ccnc1
Product: CCCCO[Si](C)(C)C
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
4.40 g (40.5 mmol) of chlorotrimethylsilane were added dropwise while stirring at 0° C. to a solution of 3.00 g (40.5 mmol) of 1-butanol and 11.1 g (135 mmol) of 1-methylimidazole. The reaction mixture was stirred at from 0 to 5° C. for a further 15 min and at 20° C. for 15 min to form a liquid biphasic mixture. Removal of the upper phase gave 5.30 g (theory: 5.93 g) of 1-trimethylsilyloxybutane as a colorless oil having a purity of 90% (GC).
Reaction SMILES: [CH2:1]([C@H:8]([NH:33][C:34](=[O:46])[C@@H:35]([N:39]1[CH2:44][CH2:43][CH2:42][NH:41][C:40]1=[O:45])[CH:36]([CH3:38])[CH3:37])[CH2:9][C@H:10]([OH:32])[C@@H:11]([NH:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:30])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:47]([O:54][P:55]([O:65][CH2:66][C:67]([CH3:73])([CH3:72])[CH2:68][C:69](O)=[O:70])([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:58]([O:57][P:55]([O:65][CH2:66][C:67]([CH3:73])([CH3:72])[CH2:68][C:69]([O:32][C@H:10]([C@@H:11]([NH:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[C:24]([CH3:30])=[CH:25][CH:26]=[CH:27][C:28]=1[CH3:29])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:9][C@@H:8]([NH:33][C:34](=[O:46])[C@@H:35]([N:39]1[CH2:44][CH2:43][CH2:42][NH:41][C:40]1=[O:45])[CH:36]([CH3:38])[CH3:37])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:70])([O:54][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:56])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O
Reactant: CC(C)(COP(=O)(OCc1ccccc1)OCc1ccccc1)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O)OC(=O)CC(C)(C)COP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
To a solution containing the compound of Example 3 (0.075 g, 0.12 mmol), the product from Example 9C (0.056 g), and DMAP (0.017 g) in DMF (1.2 mL) was added EDAC (0.027 g) and the mixture was stirred at room temperature for 16 hours. Additional product from Example 9C (0.056 g) and EDAC (0.027 g) were added and the reaction was stirred at room temperature for 3 hours. The solvent was evaporated and the reaction mixture was partitioned between ethyl acetate and aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with 33% ethyl acetate in chloroform and ending with 5% methanol in chloroform, to give the title compound (0.101 g, 84%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[CH:33]2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH:36]=[CH:35][N:34]=[CH:33]4)[CH:27]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
Prepared from {2′-fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K45) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (176 mg).
Reaction SMILES: C(C1C=C2C(C3C=C(C=CC=3)CNC(C3C(=O)N(CC4C=CC(F)=C(F)C=4)C=CC=3)=O)=CNC2=NC=1)#N.CC1(C)C(C)(C)OB([C:46]2[S:50][C:49]([CH2:51][NH:52][C:53]([C:55]3[C:56](=[O:70])[N:57]([CH2:61][C:62]4[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=4)[CH:58]=[CH:59][CH:60]=3)=[O:54])=[CH:48][CH:47]=2)O1.[B].[NH:73]1[C:77]2=[N:78][CH:79]=[C:80]([CH2:82][OH:83])[CH:81]=[C:76]2[CH:75]=[CH:74]1>>[OH:83][CH2:82][C:80]1[CH:81]=[C:76]2[C:75]([C:46]3[S:50][C:49]([CH2:51][NH:52][C:53]([C:55]4[C:56](=[O:70])[N:57]([CH2:61][C:62]5[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=5)[CH:58]=[CH:59][CH:60]=4)=[O:54])=[CH:48][CH:47]=3)=[CH:74][NH:73][C:77]2=[N:78][CH:79]=1
Reactant: CC1(C)OB(c2ccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)s2)OC1(C)C
Reactant: OCc1cnc2[nH]ccc2c1
Agent: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: [B]
Product: O=C(NCc1ccc(-c2c[nH]c3ncc(CO)cc23)s1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [5-(5-hydroxymethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-ylmethyl]-amide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophen-2-ylmethyl]-amide as activated boron species and (1H-Pyrrolo[2,3-b]pyridin-5-yl)-methanol as substituted bicyclic heterocycle, to yield the title compound. 1H NMR (400 MHz, DMSO-d6) d ppm 11.888 (s, 1H) 10.052 (t, J=6.0 Hz, 1H) 8.401 (dd, J=7.3, 2.1 Hz, 1H) 8.255-8.211 (m, 2H) 8.171 (d, J=1.7 Hz, 1H) 7.782 (d, J=2.5 Hz, 1H) 7.472-7.350 (m, 2H) 7.181 (d, J=3.5 Hz, 1H) 7.192-7.131 (m, 1H) 7.017 (d, J=3.5 Hz, 1H) 6.594 (t, J=6.9 Hz, 1H) 5.193 (s, 2H) 4.672 (d, J=5.8 Hz, 2H) 4.616 (s, 2H); MS m/z=507.33 M+H.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1[C:11]2[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccc(C(=O)O)c2cccnc12
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(=O)O)c2c1NCCC2

Procedure:
0.1 mol of 8-methylquinoline-5-carboxylic acid was suspended in 1.5 1 of ethanol and admixed with 10.0 g of palladium on activated carbon (5%). In an autoclave, the mixture was reduced at 50° C. with hydrogen (1 bar) over a period of 48 hours (HPLC monitoring). The reaction mixture was subsequently filtered, the filter cake was washed with ethanol and the combined organic filtrates were concentrated.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:14]([OH:16])=O)=[N:11][NH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1([C:23]2[C:24]([CH3:31])=[C:25]([NH2:30])[C:26]([NH2:29])=[CH:27][CH:28]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[C:10]([C:14](=[O:16])[NH:30][C:25]2[CH:24]=[CH:31][C:28]([CH2:23][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:27][C:26]=2[NH2:29])=[N:11][NH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)O
Reactant: Cc1c(N2CCOCC2)ccc(N)c1N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)Nc1ccc(CN2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.8 %

Procedure:
A mixture of 4-tert-butoxycarbonylamino-1H-pyrazole-3-carboxylic acid (10.0 g, 44.1 mmol), 4-morpholin-4-yl methyl-benzene-1,2-diamine (10.0 g, 48.5 mmol), EDC (10.14 g, 52.9 mmol) and HOBt (7.15 g, 52.9 mmol) in DMF (150 mL) was stirred at ambient temperature for 20 h and then the majority of the solvent removed in vacuo. The residue was partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 (150 mL), the layers separated and the organic portion washed with brine, dried over MgSO4 and reduced in vacuo to give [3-(2-amino-4-morpholin-4-ylmethyl-phenylcarbamoyl)-1H-pyrazol-4-yl]-carbamic acid tert-butyl ester (17.6 g, 96%) as a brown solid. LC/MS analysis indicates product contains ˜15% of the di-amide. This shows at approx. 5% level in 1H NMR. Di-amide is cleaved in subsequent step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C[Al](C)C.CCCCCCC.C([O:22][C:23]([C:25]1[N:26]=[C:27]([CH3:37])[S:28][C:29]=1[NH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=O)C>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:23]([C:25]2[N:26]=[C:27]([CH3:37])[S:28][C:29]=2[NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:22])[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1nc(C)sc1Nc1cccnc1
Reactant: Cc1cc(N)ccn1
Agent: C[Al](C)C
Solvent: CCCCCCC
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)c2nc(C)sc2Nc2cccnc2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A solution of 2-methyl-pyridin-4-ylamine (0.10 g, 0.91 mmol) in dry dioxane (2.00 ml) was added to a 2N solution of trimethylaluminium in heptane (0.46 ml, 0.91 mmol). The mixture was stirred at room temperature for 1 h, then 2-methyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (0.08 g, 0.30 mmol) was added and the reaction mixture was irradiated in a microwave oven at 150° C. for 15 min. The mixture was quenched with water (1.00 ml) and diluted with dichloromethane. After drying with sodium sulphate, the solvent was evaporated. The residue was purified by flash chromatography (dichloromethane/methanol) yielding the title compound (0.04 g, 41%) as a yellow solid, MS (ISP): m/e=326.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13](OC)[C@:12]1([CH3:30])[OH:29].Br.[Na].[Cl:33][C:34]1[N:39]=[CH:38][NH:37][C:36]2=[N:40][CH:41]=[CH:42][C:35]=12.C(#N)C>ClCCl>[Cl:33][C:34]1[C:35]2[CH:42]=[CH:41][N:40]([C@@H:13]3[O:16][C@H:17]([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@H:11]([O:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C@@:12]3([CH3:30])[OH:29])[C:36]=2[N:37]=[CH:38][N:39]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Agent: Br
Agent: [Na]
Solvent: CC#N
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the compound from Step C (9.42 g, 19 mmol) in anhydrous dichloromethane (285 mL) at 0° C. was added HBr (5.7 M in acetic acid, 20 mL, 114 mmol) dropwise. The resulting solution was stirred at 0° C. for 1 h and then at rt for 3 h, evaporated in vacuo and co-evaporated with anhydrous toluene (3×40 mL). The oily residue was dissolved in anhydrous acetonitrile (50 mL) and added to a solution of sodium salt of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine [for preparation, see J. Chem. Soc., 131 (1960)] in acetonitrile [generated in situ from 4-chloro-1H-pyrrolo [2,3-d]pyrimidine (8.76 g, 57 mmol) in anhydrous acetonitrile (1000 mL), and NaH (60% in mineral oil, 2.28 g, 57 mmol), after 4 h of vigorous stirring at room temperature]. The combined mixture was stirred at room temperature for 24 h, and then evaporated to dryness. The residue was suspended in water (250 mL) and extracted with EtOAc (2×500 mL). The combined extracts were washed with brine (300 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified on a silica gel column (10 cm×10 cm) using ethyl acetate/hexane (1:3 and 1:2) as the eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (5.05 g) as a colorless foam.
Reaction SMILES: CO[C:3]1[C:15]([CH2:16][C@H:17]([NH:31][C:32]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[CH2:39][N:38]([CH2:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)[CH2:37]3)=[O:33])[B:18]2[O:26]C3C(C)(C4CC(C3)C4(C)C)[O:19]2)=[CH:14][CH:13]=[CH:12][C:4]=1[C:5]([O:7]C(C)(C)C)=[O:6].B(Cl)(Cl)Cl>>[OH:26][B:18]1[C@@H:17]([NH:31][C:32]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[CH2:39][N:38]([CH2:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)[CH2:37]3)=[O:33])[CH2:16][C:15]2[CH:14]=[CH:13][CH:12]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=2[O:19]1
Reactant: COc1c(C[C@H](NC(=O)c2ccc3c(c2)CN(Cc2cccnc2)C3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: O=C(N[C@H]1Cc2cccc(C(=O)O)c2OB1O)c1ccc2c(c1)CN(Cc1cccnc1)C2

Procedure:
Prepared from tert-butyl 2-methoxy-3-((2R)-2-(2-(pyridin-3-ylmethyl)isoindoline-5-carboxamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)benzoate and BCl3 following the procedure described in Step 2 of Example 3. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 344 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][NH:18][CH2:19][C:20]1[CH:34]=[CH:33][C:23]2[N:24]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[CH:25]=[N:26][C:22]=2[CH:21]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([N:18]([CH3:17])[CH2:19][C:20]4[CH:34]=[CH:33][C:23]5[N:24]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][O:28]6)[CH:25]=[N:26][C:22]=5[CH:21]=4)[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: CNCc1ccc2c(c1)ncn2C1CCCCO1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(Cc1ccc2c(c1)ncn2C1CCCCO1)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 120 °C
Yield: 27.7 %

Procedure:
A tube was charged with 53 (846 mg, 3.6 mmol), 68 (880 mg, 3.6 mmol), DIPEA (5 mL) and IPA (10 mL), degassed, sealed and then heated at 120° C. overnight. The solvent was evaporated in vacuo to afford 444 mg (27%) N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-methyl-N2-((1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)-pyrimidine-2,4-diamine (70) as a yellow solid; MS (ESI) m/z=445.2 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[Se](=O)=[O:14]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[O:14])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)ccc2n1
Reactant: O=[Se]=O
Product: O=Cc1ccc2cc(F)ccc2n1
Yield: 70 %

Procedure:
The title compound was prepared from 6-fluoro-2-methylquinoline (6e) and selenium dioxide using methods as described in the literature for similar compounds (Barbier et al., 2000) in 70% yield.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li].N>C(O)C>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH2:10]1
Reactant: CNCCc1ccccc1
Agent: N
Agent: [Li]
Solvent: CCO
Product: CNCCC1C=CC=CC1

Procedure:
46 g. (0.34 moles) of N-methylphenethylamine are reduced by treatment with 16 g. of lithium (2.3 g. atom) in 1.5 1. of ammonia and 250 ml. ethanol according to the procedure of Example 1(a) to yield crude N-methyldihydrophenethylamine.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O([CH2:15][CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])S(C(F)(F)F)(=O)=O.Cl.[CH3:29][O:30][C:31]([C@H:33]1[CH2:38][CH2:37][C@H:36]([C:39]([O:41][CH3:42])=[O:40])[CH2:35][NH:34]1)=[O:32]>O.C(Cl)Cl>[C:21]1(=[O:22])[N:17]([CH2:16][CH2:15][N:34]2[CH2:35][C@@H:36]([C:39]([O:41][CH3:42])=[O:40])[CH2:37][CH2:38][C@@H:33]2[C:31]([O:30][CH3:29])=[O:32])[C:18](=[O:27])[C:19]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]12
Reactant: O=C1c2ccccc2C(=O)N1CCOS(=O)(=O)C(F)(F)F
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)OC)NC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](C(=O)OC)N(CCN2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
To a well-stirred bi-phasic mixture consisting of sodium carbonate (500 g, 4.72 mol) in water (3 liters) and trans-2,5-piperidine dicarboxylate dimethyl ester hydrochloride (280 g, 1.18 mol in methylene chloride (4.5 liters), a solution of 2-phthalimido-ethyl triflate (417 g, 1.29 mol) in methylene chloride (3 liters) was added in a steady stream over a 3 hour period. The organic layer was separated, and the aqueous layer was extracted with fresh methylene chloride (3 liters). The combined organic extracts were washed with water (3 liters), then with brine (3 liters), dried with anhydrous magnesium sulfate and finally, concentrated in vacuo to a solid. The entire residue was triturated in resulting ether (3 liters), with vigorous stirring, for 15 minutes. After cooling to ambient temperature, the solution was poured into hexanes (3 liters), and the resulting mixture was stirred for 18 hours. The resulting colorless solid was collected by filtration, and the filter cake was washed with hexanes (1 liter). In vacuo drying afforded 437.3 g (99.1% yield) of the title compound as a colorless solid. TLC Rf (ethyl acetate/methylene chloride=1:1 in volume; iodoplatinate spray): 0.5.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Cl:9][C:10]1[C:11]([OH:17])=[CH:12][C:13](=[O:16])[NH:14][CH:15]=1>N1C=CC=CC=1>[Cl:9][C:10]1[C:11]([O:17][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[CH:12][C:13](=[O:16])[NH:14][CH:15]=1
Reactant: O=C(Cl)c1ccco1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Solvent: c1ccncc1
Product: O=C(Oc1cc(=O)[nH]cc1Cl)c1ccco1
Yield: 34 %

Procedure:
A 2.15 g quantity of 2-furoyl chloride was added to a suspension of 2.00 g of 5-chloro-4-hydroxy-2-pyridone in 100 ml of pyridine. The same subsequent procedure as in Example 39 was conducted, thereby producing 1.13 g of the title compound in a yield of 34%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:20][O:21][C:22](=O)[O:23]C.[Cl-].[NH4+]>C1COCC1.C(OC(=O)C)C>[CH3:20][O:21][C:22](=[O:23])[CH2:1][C:2]1[CH:3]=[CH:4][N:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COC(=O)OC
Reactant: Cc1ccncc1C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccncc1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
2.52 g of 4-methyl-nicotinonitrile was dissolved in 15 mL of anhydrous THF and dropwisely added with 45 mL of 1M LHMDS at −78° C. and stirred for about 1 hour. At the temperature the above mixture was dropwisely added with 1.98 mL of dimethylcarbonate, stirred for about 1 hour. The mixture was then heated to 0° C. and stirred further for about 2 hours. The above mixture was added with 5 mL of saturated solution of ammonium chloride, diluted with 300 mL ethylacetate. Then, the organic solvent layer was washed with water, and saturated solution of sodium chloride, dried with anhydrous sodium sulfate and filtered. The filtrate was concentreated under reduced pressure and a silica gel column chromatography was performed on the resulting residue by using a mixed eluant of ethylacetate and hexane, wherein ethylacetate and hexane are mixed in 1:3 volume ratio, and 3.21 g (85%) of (3-cyano-pyridine-4-yl)-acetic acid methyl ester was obtained in colorless oil.
Reaction SMILES: CC(C)([O-])C.[Na+].P.Cl[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(#N)C.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:12]1([CH3:15])[CH:13]=[CH:14][C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:10][CH:11]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(N2CCOCC2)cc1
Temperature: 100 °C
Reaction time: 14 h

Procedure:
In a nitrogen-atmosphere glovebox, a microwave vial equipped with a magnetic stir bar was charged with sodium tert-butoxide (56.9 mg, 0.592 mmol, 1.5 equivalents), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) (3.62 mg, 0.00395 mmol, 0.01 equivalents), phosphine ligand (0.00869 mmol, 0.022 equivalents) and dioxane (0.79 mL). To the slurry was added 4-chlorotoluene (47 μL, 0.395 mmol, 1 equivalents) and morpholine (42 μL, 0.474 mmol, 1.2 equivalents). The vial was sealed with a crimp top and stirred at 100° C. After 14 hours, the vial was removed from the heating block, cooled to room temperature and brought out of the glovebox. To assay the crude reaction, an aliquot (7 μL) was taken and diluted in acetonitrile (1.5 mL), then injected onto an HPLC instrument. For isolation purposes, the reaction solution was worked up by diluting with CH2Cl2 (2 mL) and filtering into a round-bottom flask. The vial was rinsed with CH2Cl2 (5 mL), followed by washing of the filter cake with CH2Cl2 (2 mL). The volatiles were removed on a rotary evaporator and the crude concentrate was purified by silica gel column chromatography (25 g silica gel, 85:15 heptane:ethyl acetate). The purified product was isolated as a beige solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.10 (d, J=8.2 Hz, 1H), 6.88-6.81 (m, 2H), 3.87 (dd, J=5.7, 3.9 Hz, 4H), 3.15-3.09 (m, 4H), 2.29 (s, 3H).