Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH2:33][NH:1][CH2:2][CH2:3][N:4]6[CH2:9][CH2:8][O:7][CH2:6][CH2:5]6)=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: NCCN1CCOCC1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: c1nc(Nc2ccc3[nH]ccc3c2)c2sc(-c3ccc(CNCCN4CCOCC4)cc3)cc2n1

Procedure:
The title compound was prepared from N-(2-aminoethyl)morpholine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 100-111° C.; LC-MS: 485 (MH+); HPLC RT: 4.23 minutes.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O>>[F:10][C:11]([F:22])([F:23])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]#[N:9])=[CH:15][CH:14]=1
Reactant: N#Cc1cccnc1Cl
Reactant: OB(O)c1ccccc1OC(F)(F)F
Product: N#Cc1cccnc1-c1ccc(OC(F)(F)F)cc1
Yield: 71 %

Procedure:
Prepared in 71% yield from 2-chloro-3-cyanopyridine and 2-trifluoromethoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 264.8 (M+H)+; 1H NMR (CDCl3) δ 7.41-7.48 (m, 3H), 7.54-7.60 (m, 2H), 8.09 (dd, J=7.8, 1.7 Hz, 1H), 8.91 (dd, J=5.1, 1.7 Hz, 1H).
Reaction SMILES: [Li]CCCC.[CH:6]([NH:9]C(C)C)(C)[CH3:7].C(#N)C.[Cl:16][C:17]1[CH:26]=[N:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21]C)=O>C1COCC1.CCCCCC>[Cl:16][C:17]1[CH:26]=[N:25][CH:24]=[CH:23][C:18]=1[C:19](=[O:21])[CH2:7][C:6]#[N:9]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)c1ccncc1Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC#N
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccncc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A 2.5 M hexane solution of BuLi (16.79 mL, 42.0 mmol) was added dropwise to a solution of diisopropylamine (6.23 mL, 43.7 mmol) in THF (150 mL) at −78° C. The mixture was stirred at 0° C. for 15 min and cooled to −78° C. Acetonitrile (2.192 mL, 42.0 mmol) was added dropwise. The solution gradually turned to milky white. After 1 h at −78° C., methyl 3-chloroisonicotinate (3.00 g, 17.48 mmol) in THF (10 mL) was added dropwise. The flask was rinsed with THF (2 mL) and added. After 1 h at −78° C., the mixture was quenched with brine (200 mL) and acidified to pH˜1. THF was evaporated in vacuo. The aqueous residue was extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4) and concentrated to give impure 3-(3-chloropyridin-4-yl)-3-oxopropanenitrile as a tan solid (3.12 g, 81% pure, 80% yield). MS (ES+) m/z: 181 (M+H); LC retention time: 1.90 min (analytical HPLC Method A).
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([O:13]C)[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:23]=4)=[C:17]([CH3:34])[N:16]=3)=[CH:9][N:8]=2)[CH2:3]1.Br>CC(O)=O>[F:35][C:2]1([F:1])[CH2:6][CH2:5][N:4]([C:7]2[NH:12][C:11](=[O:13])[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:23]=4)=[C:17]([CH3:34])[N:16]=3)=[CH:9][N:8]=2)[CH2:3]1
Reactant: COc1nc(N2CCC(F)(F)C2)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc(-c2cnc(N3CCC(F)(F)C3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 90 °C
Yield: 54 %

Procedure:
A solution of 2-(3,3-difluoropyrrolidin-1-yl)-4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidine (0.080 g, 0.167 mmol) in AcOH (3 mL) was treated with 48% hydrobromic acid (0.1 mL). The mixture was heated at 90° C. for 3 hours. The mixture was concentrated and the residue was treated with NaHCO3 and EtOAc. The mixture was stirred at RT. The solid was filtered and washed with water, EtOAc, and dried under vacuum to obtain 2-(3,3-difluoropyrrolidin-1-yl)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (42 mg, 52.3% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.76 (br s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.28 (br s, 1H), 8.27 (s, 1H), 7.97 (s, 1H), 7.58 (br s, 1H), 7.24 (d, J=2.4 Hz, 1H), 6.64 (s, 1H), 3.96 (m, 2H), 3.85 (s, 3H), 3.76 (m, 2H), 2.54 (m, 2H), 2.37 (s, 3H), one proton is missing; MS (ESI) m/z: 466.2 (M+H+).
Reaction SMILES: N([O-])=O.[Na+].[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C@H:20]3[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:21]3)=[CH:16][C:15]=2N)=[CH:10][CH:9]=1)(=[O:7])[CH3:6].[Na+].[Cl-:33].[O-]S([O-])=O.[Na+].[Na+]>O.Cl>[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C@H:20]3[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[Cl:33])=[CH:10][CH:9]=1)(=[O:7])[CH3:6]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(C)=O)cc3)c(N)c2)CC1
Reactant: [Cl-]
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])[O-]
Solvent: O
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(C)=O)cc3)c(Cl)c2)CC1

Procedure:
A solution of 7.2 g of NaNO2 in 25 ml of water is added to a suspension of 36.7 g of 4'-acetyl-2-amino-4-(trans-4-pentylcyclohexyl)-biphenyl in 150 ml of 15% aqueous hydrochloric acid at -5° in the course of 0.5 hours. The solution thus obtained is added dropwise, at 0°-5° in the course of 1 hour, to a Cu(I) salt solution which has been prepared from 25 g of CuSO4.5H2O, 8.8 g of NaCl, 6.3 g of Na2SO3, 100 ml of water and 40 ml of 32% hydrochloric acid. After the mixture has been heated to 40° for half an hour, it is cooled and extracted with CH2Cl2 and the product is worked up in the customary manner. 4'-Acetyl-2-chloro-4-(trans-4-pentylcyclohexyl)-biphenyl is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:27]([CH:24]4[CH2:26][CH2:25]4)(=[O:29])=[O:28])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C1CC1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine following General Procedure B-3 (500 mg), cyclopropanesulfonyl chloride (0.24 mL) and triethylamine (0.57 mL) in dichloromethane (5 mL) was stirred at room temperature. After stirring for 24 hours, standard work-up yielded 2-chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH:9]1(O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: OC1CCCCC1
Solvent: O
Product: Cc1ccc(O)c(C2CCCCC2)c1

Procedure:
To carry out the process, a mixture of zeolite and p-cresol is for example heated to the desired reaction temperature with stirring. Cyclohexanol is then added in accordance with the amount of evolved water. In the case of a reaction batch of 2-4 moles of p-cresol, this generally requires a period of 3-6 hours. After all the cyclohexanol has been added, the reaction mixture is stirred at the reaction temperature for a further 2-4 hours. The 4-methyl-2-cyclohexylphenol can then be isolated from the reaction mixture by separating methods known to the person skilled in the art. For instance, it is possible first to remove the zeolite by filtration or centrifuging. However, it is also possible to leave the zeolite at elevated temperature after the reaction has ended and to decant or siphon off the reaction mixture. Such a procedure leaves the repeatedly reusable catalyst in the reaction vessel, in which, after renewed addition of p-cresol and subsequent addition of cyclohexanol, further reaction products can be obtained. The reaction mixture from which the zeolite has been removed can advantageously be worked up further by distillation. The resulting excess p-cresol is recycled.
Reaction SMILES: C(O[C:4](=[O:18])[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[C:6](=[O:8])[CH3:7])C.[NH2:19][C:20]1[CH:21]=[C:22]([OH:27])[CH:23]=[CH:24][C:25]=1[F:26]>>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[CH2:9][CH:5]([C:6](=[O:8])[CH3:7])[C:4]([NH:19][C:20]1[CH:21]=[C:22]([OH:27])[CH:23]=[CH:24][C:25]=1[F:26])=[O:18]
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1Cl)C(C)=O
Reactant: Nc1cc(O)ccc1F
Product: CC(=O)C(Cc1ccc(Cl)cc1Cl)C(=O)Nc1cc(O)ccc1F
Temperature: 120 °C

Procedure:
A mixture of 2-(2,4-dichlorobenzyl)-3-oxobutyric acid ethyl ester (4.6 g) and 3-amino-4-fluorophenol (1.0 g) was heated by microwave irradiation at 120° C. for 20 minutes. The mixture was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (1:19 to 1:1 by volume) to afford title compound, 0.67 g.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9]O.[O-2].[Ca+2]>[O-2].[Fe+2].[O-2].[Ti+4].[O-2].[O-2].[Cr+3].[O-2].[O-2].[Cr+3].O>[C:6]1([OH:7])[C:5]([CH3:9])=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8]
Reactant: CO
Reactant: Cc1ccccc1O
Agent: [Cr+3]
Agent: [Fe+2]
Agent: [Ti+4]
Solvent: O
Product: Cc1cccc(C)c1O

Procedure:
o-cresol, methanol and water in a ratio of 1:2.5:2.5 were reacted in the same way as in Example 1. The catalyst contained iron oxide, titanium oxide, chromium oxide and calcium oxide in a molar ratio of 100:4,5:0,5. After working up, 2,6-xylenol was obtained with a selectivity of 99.1%.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.[CH2:13]([O:15][C:16](=[O:24])[CH2:17][C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1)[CH3:14].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:13]([O:15][C:16](=[O:24])[CH2:17][C:18]1[N:19]=[C:20]([NH:23][C:10](=[O:11])[CH2:9][NH2:8])[S:21][CH:22]=1)[CH3:14]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1csc(NC(=O)CN)n1

Procedure:
A mixture of N-(tert-butoxycarbonyl)glycine (3.1 g), 2-amino-4-thiazoleacetic acid ethyl ester (3 g) and bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (7.54 g) in N,N-dimethylformamide (20 ml) was treated with N,N-diisopropylethylamine (6 ml). After 25 minutes 4-(dimethylamino)pyridine (1.96 g) was added. After 24 hours the mixture was partitioned between ethyl acetate and brine. The organic phase was washed with saturated aqueous sodium bicarbonate, brine, 1N HCl and brine, dried (MgSO4) and evaporated. The residue was purified by chromatography eluting with 50% ethyl acetate in isohexane. The product (0.77 g) was dissolved in dichloromethane (25 ml) and trifluoroacetic acid (10 ml). After 2 hours the mixture was evaporated. The residue was partitioned between ethyl acetate and sodium bicarbonate solution. The aqueous phase was repeatedly extracted with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1.Br[CH2:14][C:15]1[CH:35]=[CH:34][C:18]2/[C:19](=[C:29](/[CH2:32][CH3:33])\[C:30]#[N:31])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:20]2=[C:21]([CH:24]=1)[O:22][CH2:23][C:17]1[CH:16]=[C:15]([CH2:14][N:8]3[C:7]4[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=4[N:5]=[C:4]3[CH2:3][O:2][CH3:1])[CH:35]=[CH:34][C:18]=1/[C:19]/2=[C:29](/[CH2:32][CH3:33])\[C:30]#[N:31]
Reactant: CC/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: COCc1nc2ccccc2[nH]1
Product: CC/C(C#N)=C1/c2ccc(Cn3c(COC)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 100.3 %

Procedure:
Using 2-(methoxymethyl)-1H-benzo[d]imidazole (61 mg, 0.376 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]butanenitrile (140 mg, 0.376 mmol) obtained in Reference Example 8, and in the same manner as in Reference Example 1A, the title compound (171 mg, 100%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)[NH:8][CH2:7][CH2:6]2.[CH3:27][O:28][C:29](=[O:38])[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)Br>>[CH3:27][O:28][C:29](=[O:38])[CH:30]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]1[CH2:15][CH2:16][C:17]1[CH:18]=[N:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: COc1cc2c(cc1OC)C(CCc1ccc(C(F)(F)F)nc1)NCC2
Product: COC(=O)C(c1ccccc1)N1CCc2cc(OC)c(OC)cc2C1CCc1ccc(C(F)(F)F)nc1

Procedure:
This compound is prepared by reaction of 6,7-dimethoxy-1-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-1,2,3,4-tetrahydroisoquinoline with α-bromo-phenyl-acetic acid methyl ester.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][C:25]1[O:24][CH2:23][CH:22]([N:31]3[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]3)[CH2:21][C:20]2=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][C:25]1[O:24][CH2:23][CH:22]([N:31]3[CH2:32][CH2:33][CH:34]([NH:37][C:12]([C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[CH2:35][CH2:36]3)[CH2:21][C:20]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC(N1CCC(N)CC1)CO3
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2ncc3c(c2c1)CC(N1CCC(NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CO3
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (31 mg, 0.14 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-yl)-piperidin-4-ylamine (50 mg, 0.14 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by 1-hydroxybenzotriazole (21 mg, 0.15 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (31 mg, 0.16 mmol, 1.15 eq) and N,N-diisopropylethylamine (53 μL, 0.31 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-yl)-piperidin-4-yl]-amide as an off-white lyophilizated powder (24 mg, 33% yield).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([N:16]([CH3:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]2=[O:29])=[CH:2]1.[CH2:30](O)[CH2:31]CC>CN(C)C1C=CN=CC=1.CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([N:16]([CH3:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH2:28][CH2:30][CH3:31])=[O:25])[C:12]2=[O:29])=[CH:2]1
Reactant: CCCCO
Reactant: CCOC(=O)C1=C(N(C)Cc2cccs2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: CN(C)c1ccncc1
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: CCCCOC(=O)C1=C(N(C)Cc2cccs2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 8.4 %

Procedure:
A solution of the compound (0.050 g, 0.12 mmol) of Example 108, 1-butanol (0.50 mL, 5.5 mmol), 4-dimethylaminopyridine (0.0030 g, 0.024 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0058 g, 0.0061 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 150° C. for 1.5 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0044 g, y. 6%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].Cl[C:10]1[C:11]2[N:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:12]=2[N:13]=[C:14]([NH:16]C(=O)C)[N:15]=1>C1COCC1>[Cl:24][C:22]1[CH:21]=[CH:20][C:12]2[N:13]=[C:14]([NH2:16])[N:15]=[C:10]([O:1][CH:2]3[CH2:6][CH2:5][O:4][CH2:3]3)[C:11]=2[N:23]=1
Reactant: CC(=O)Nc1nc(Cl)c2nc(Cl)ccc2n1
Reactant: O[C@@H]1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(OC2CCOC2)c2nc(Cl)ccc2n1
Reaction time: 1 h
Yield: 51 %

Procedure:
(R)-(−)-3-hydroxy-tetrahydrofuran (0.62 mL) was added to a suspension of NaH (0.31 g, 7.7 mmol) in THF (15 mL). After stirring for 1 hour, the resulting mixture was added to a suspension of N-(4,6-dichloro-pyrido[3,2-d]pyrimidin-2-yl)-acetamide (0.9 g, 3.5 mmol) in THF (15 mL). The mixture was stirred at room temperature for 20 minutes, then diluted with EtOAC (100 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated to afford 6-chloro-4-(tetrahydro-furan-3-yloxy)-pyrido[3,2-d]pyrimidin-2-ylamine as a yellow solid (0.55 g, yield: 51%) which was characterized by its mass spectrum as follows: MS (m/z) 309.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1
Reactant: NCCO
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NCCO)n2n1)c1cccnc1
Temperature: 120 °C
Yield: 29.3 %

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq) and ethanolamine (44 μL; 0.73 mmol; 5.0 eq), heated at 120° C., to give the title compound as a white solid (15 mg, 28%). HPLC, Rt: 1.91 min. (purity 97.9%). LC/MS, M+(ESI): 366.8, M−(ESI): 364.9.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>>[OH:21][C:18]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=2)[CH2:19][CH2:20][C:15]2([O:11][CH2:12][CH2:13][O:14]2)[CH2:16][CH2:17]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: NC(=O)c1ccc(Br)cc1
Product: NC(=O)c1ccc(C2(O)CCC3(CC2)OCCO3)cc1

Procedure:
The title compound was prepared as a white solid from 4-bromobenzamide (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C:8]([NH:16][CH:17]([CH2:21][C:22]#[CH:23])C(O)=O)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1.O>[C:8]([NH:16][CH:17]([C:5](=[O:7])[CH3:6])[CH2:21][C:22]#[CH:23])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#CCC(NC(=O)c1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: C#CCC(NC(=O)c1ccccc1)C(C)=O
Temperature: 90 °C

Procedure:
Acetic anhydride (150 ml) was added to a solution of 2-benzoylamino-4-pentynoic acid (J. Org. Chem. 1983, 48, 3318) (73 g, 0.34 mol) in pyridine (200 ml) and the solution was heated to 90° C. for 1 hour, then allowed to cool to 60° C. and water (150 ml) was added. The mixture was heated to 85°-90° C. for 20 minutes, then cooled, diluted with water (300 ml) and extracted with chloroform (2×400 ml). The combined extracts were washed with water, 1N hydrochloric acid (3×500 ml), sodium bicarbonate and brine, and dried over magnesium sulfate. The chloroform solution was decolorized with charcoal, filtered and concentrated. The residue was recrystallized from butyl chloride to yield a tan solid (51 g, mp 101°-103° C.).
Reaction SMILES: CC(C)([O-])C.[K+].CO[C:9](=[O:21])[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=O.[CH3:22][N:23]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH2:35][C:36]([NH2:38])=[O:37])=[CH:33][N:34]=2)[CH:31]=1)[CH3:24].[NH4+].[Cl-].C1CCN2C(=NCCC2)CC1>O1CCCC1.CCOC(C)=O.O>[CH3:22][N:23]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([C:35]3[C:36](=[O:37])[NH:38][C:9](=[O:21])[C:10]=3[C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][CH:13]=3)=[CH:33][N:34]=2)[CH:31]=1)[CH3:24]
Reactant: CN(C)Cc1ccc2ncc(CC(N)=O)n2c1
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CN(C)Cc1ccc2ncc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)n2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
Potassium tert-butoxide (1.0 M in THF, 0.55 ml, 0.55 mmol, 2.7 equiv) is added dropwise at room temperature under an atmosphere of argon to a solution of (1H-indol-3-yl)-oxo-acetic acid methyl ester (45 mg, 0.22 mmol, 1.1 equiv) and of 2-(6-dimethylaminomethyl-imidazo[1,2-a]pyridin-3-yl)-acetamide (50 mg, 0.20 mmol) in anhydrous tetrahydrofuran (5.0 ml, dried over molecular sieves). The reaction mixture is stirred for 30 minutes at 0° C. It is then diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. The residue is dissolved in N,N-dimethylformamide (5 ml), treated with DBU (0.27 ml, 1.8 mmol, 8.9 equiv) and heated to 110° C. for 10 minutes. After cooling, the reaction mixture is diluted with water and extracted three times with CH2Cl2. The combined organic layers are ished with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via preparative HPLC affords the title compound (34 mg, 43%) as its trifluoroacetate salt. 1H NMR (400 MHz, d6-DMSO): δ=12.11 (s, 1H), 11.27 (s, 1H), 9.47 (br s, 1H), 8.21 (d, J=2.9 Hz, 1H), 8.05 (s, 1H), 7.78-7.76 (m, 2H), 7.73 (d, J=8.0 Hz, 1H), 7.29 (dd, J=8.0/4.0 Hz, 1H), 6.94 (t, J=8.0 Hz, 1H), 6.49 (t, J=8.0 Hz, 1H), 5.95 (d, J=8.0 Hz, 1H), 3.48-3.40 (m, 2H), 2.16 (s, 6H). MS (ES+): 386 (M+H)+.