Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.[NH2:10][C:11]1[N:16]=[CH:15][C:14]2[C:17]([CH3:25])([CH3:24])[C:18](=[O:23])[N:19]([CH:20]3[CH2:22][CH2:21]3)[C:13]=2[CH:12]=1>>[CH:20]1([N:19]2[C:13]3[CH:12]=[C:11]([NH:10][C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][CH:5]=4)=[O:9])[N:16]=[CH:15][C:14]=3[C:17]([CH3:24])([CH3:25])[C:18]2=[O:23])[CH2:22][CH2:21]1
Reactant: Cc1nocc1C(=O)O
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ncc21
Product: Cc1nocc1C(=O)Nc1cc2c(cn1)C(C)(C)C(=O)N2C1CC1

Procedure:
Prepared in analogy to example 26 from 3-methylisoxazole-4-carboxylic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (example 79c). The title compound was obtained as light brown viscous oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH:31]1[C:35]([CH2:36][C:37](O)=[O:38])=[N:34][N:33]=[N:32]1.C(N(CC)CC)C.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>[NH:31]1[C:35]([CH2:36][C:37]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[N:17]=[C:18]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[O:19][C:20]=4[C:21]([F:22])([F:23])[F:24])=[O:15])=[CH:11][CH:12]=3)[CH2:3][CH2:2]2)=[O:38])=[N:34][N:33]=[N:32]1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(O)Cc1nnn[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C2CCN(C(=O)Cc3nnn[nH]3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Yield: 17.2 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (50.7 mg, 0.122 mmol), (1H-tetrazol-5-yl)-acetic acid (15.6 mg, 0.122 mmol), triethylamine (51 uL, 0.366 mmol) and BOP (54 mg, 0.128 mmol) in 1 mL DMF were reacted as above to give a clear oil. The crude product was crystallized from methanol/acetonitrile to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[1-(2-1H-tetrazol-5-yl-acetyl)-piperidin-4-yl]-phenyl}-amide as off-white crystals (11 mg, 17%). ES-MS calcd for C25H22F3N7O3 (m/e) 525.49, obsd 526 (M+H).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.C(N(CC)CC)C.[CH2:17]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2([NH:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[C:29](=[O:46])[CH2:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2([NH:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:35][CH2:36][N:37]([C:3]3[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=3)[CH2:38][CH2:39]2)[C:29](=[O:46])[CH2:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)NC1(CN2CCN(C(=O)OCc3ccccc3)CC2=O)CCNCC1
Reactant: Cc1cc(Cl)ccn1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1(CN2CCN(C(=O)OCc3ccccc3)CC2=O)CCN(c2ccnc(C)c2)CC1
Yield: 53.8 %

Procedure:
4-Chloro-2-methylpyridine hydrochloride (941 mg), triethylamine (1.93 g) and ethanol (50 ml) were added to 4-benzyloxycarbonyl-1-[(4-ethoxycarbonylamino-4-piperidinyl)methyl]-2-piperazinone (2.0 g), and the mixture was reacted at 150° C. for 10 hours in a sealed tube. The reaction mixture was concentrated, a 10% aqueous sodium carbonate solution was added to the residue, and the mixture was extracted with dichloromethane, dried, and concentrated. The resulting residue was purified by column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1) to obtain the colorless amorphous title compound (1.31 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](O)=[O:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:26]([C:22]3[O:21][CH:25]=[CH:24][CH:23]=3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1ccco1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccco1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 2-furancarboxylic acid (CAN 88-14-2) as starting materials; LC-MS (UV peak area/ESI) 98.0%, 397.0566 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:35][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:26][CH2:25][CH2:24][C@@H:23]3[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:7]=2[C:6]=1[CH3:36])=[O:4].[OH-].[Na+].Cl>CO.O>[C:31]([O:30][C:28]([NH:27][C@H:23]1[CH2:24][CH2:25][CH2:26][C@@H:22]1[O:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[NH:13][C:12]1[C:7]2[C:6]([CH3:36])=[C:5]([C:3]([OH:4])=[O:2])[S:35][C:8]=2[N:9]=[CH:10][N:11]=1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCC[C@@H]3NC(=O)OC(C)(C)C)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCC[C@@H]3NC(=O)OC(C)(C)C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.4 g (1S,2S) 4-[2-(2-tert-butoxycarbonylamino-cyclopentyloxy)-4-fluoro-phenylamino]-5-methyl thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and 20 ml 1M sodium hydroxide solution in 50 ml MeOH was stirred at rt overnight. To the reaction mixture was added 20 ml 1M hydrochloric acid until a pH range of 2-3 was reached. The mixture was diluted with water and filtrated. The solid was dried in vacuo at 50° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:5]=[C:4]([Br:14])[C:3]=1[O:15][CH3:16].[N+:17]([O-])([OH:19])=[O:18].C([O-])([O-])=O.[Na+].[Na+]>>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[C:5]([N+:17]([O-:19])=[O:18])=[C:4]([Br:14])[C:3]=1[O:15][CH3:16]
Reactant: O=[N+]([O-])O
Reactant: COc1c(Br)cc(S(F)(F)(F)(F)F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1c(Br)cc(S(F)(F)(F)(F)F)c([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
630 mg of 1,3-dibromo-2-methoxy-5-pentafluorosulfanylbenzene were stirred in 2 ml of a 90% aqueous HNO3 solution at 0° C. for 1 hour. Subsequently, the mixture was stirred at RT for 20 minutes and then poured onto 50 g of ice. An aqueous Na2CO3 solution was used to adjust to pH=6 and extraction was effected three times with 50 ml each of EA. Drying was effected over Na2SO4 and the solvent was removed under reduced pressure. Chromatography on silica gel using 1:3 DIP/HEP afforded 260 mg of a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([CH3:25])=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:31]([O:33]CC)=[CH2:32])CCC>CN(C=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:31]([C:2]1[C:3]([CH3:25])=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[CH:7]=1)(=[O:33])[CH3:32]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(Br)cn2n1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(C(C)=O)cn2n1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
N-[6-Bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (Int. 18, 1.07 g, 2.59 mmol), bis(triphenylphosphine)palladium (II) dichloride (91 mg, 0.13 mmol) and tributyl(1-ethoxyvinyl) tin were suspended in dry DMF (8 mL) and degassed with argon. The reaction mixture was heated at 120° C. for 20 min using microwave irradiation. 1 M HCl (10 mL) was added and the reaction mixture was stirred for 1 hr before being partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with saturated brine, then dried (Na2SO4) and concentrated in vacuo to give a yellow solid. The solid was triturated with EtOAc and the solid collected by filtration, washing with EtOAc, to give the title compound as a cream solid (680 mg).
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:32])(=O)C.[S:33]1(=[O:39])(=[O:38])[CH2:37][CH2:36][CH2:35][NH:34]1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:16]([C:10]3[CH:11]=[CH:12][C:13]([N:34]4[CH2:35][CH2:36][CH2:37][S:33]4(=[O:39])=[O:38])=[CH:14][C:9]=3[N:6]3[CH2:7][CH2:8][NH:4][C:5]3=[O:32])=[O:17])[CH2:23][CH2:22]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: O=S1(=O)CCCN1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCNC3=O)CC2)c(C)c1
Yield: 28.1 %

Procedure:
Using 1-acetyl-3-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (117 mg) described in Preparation Example 234 and isothiazolidine 1,1-dioxide (47 mg) and by the reaction and treatment in the same manner as in Example 649, the title compound (36 mg) was obtained.
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([NH:14][CH2:15][C@H:16]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]([O:19]C)=[O:18])=[O:13])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6]>O1CCCC1>[CH2:3]([O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([NH:14][CH2:15][C@H:16]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[C:17]([OH:19])=[O:18])=[O:13])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCOc1ccc(C(=O)NC[C@@H](C(=O)OC)N2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC#CCOc1ccc(C(=O)NC[C@@H](C(=O)O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.3 %

Procedure:
2.5 ml (2.4 mmol) of an aqueous solution of lithium hydroxide having a concentration of 1N are added to a solution of 0.6 g (1.6 mmol) of methyl (S)-3-(4-but-2-ynyloxybenzoylamino)-2-piperidin-1-ylpropanoate in 10 ml of tetrahydrofuran. The reaction medium is then stirred at ambient temperature for 18 h. After evaporating the tetrahydrofuran under vacuum, 2.4 ml of an aqueous solution of hydrochloric acid having a concentration of 1N and water are added then the reaction medium is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography over silica gel eluted with a 90/10 dichloromethane/methanol mixture. 580 mg (100%) of (S)-3-(4-but-2-ynyloxybenzoylamino)-2-piperidin-1-ylpropanoic acid are obtained in the form of a white solid.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[C:21]=1[CH3:22].[NH2:23][C:24]1[C:29]([C:30]#[N:31])=[C:28](Cl)[N:27]=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:23][C:24]1[C:29]([C:30]#[N:31])=[C:28]([NH:14][C@H:12]([C:10]2[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]3[C:21]([CH3:22])=[C:4]([F:3])[CH:5]=[CH:6][C:7]=3[N:11]=2)[CH3:13])[N:27]=[CH:26][N:25]=1
Reactant: Cc1c(F)ccc2nc([C@H](C)N)n(-c3ccccn3)c12
Reactant: N#Cc1c(N)ncnc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c(F)ccc2nc([C@H](C)Nc3ncnc(N)c3C#N)n(-c3ccccn3)c12
Temperature: 90 °C
Yield: 48.5 %

Procedure:
To a solution of (S)-1-(6-fluoro-7-methyl-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (300 mg, 0.87 mmol) in IPA (10 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (135 mg, 0.87 mmol) and DIPEA (448 μL, 2.62 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc). The product was triturated with diethyl ether then subjected to HPLC purification (C18, 10-90% MeCN in H2O, 0.1% formic acid, 20 min gradient) to give 289 as a white solid (164 mg, 48%). 1H NMR 400 MHz 6 (DMSO-d6): 8.55 (1H, br s), 8.00-7.91 (1H, m), 7.81-7.73 (1H, m), 7.70-7.60 (1H, m), 7.53 (1H, dd, J=8.7, 4.6 Hz), 7.55-7.45 (1H, m), 7.21-7.09 (1H, m), 7.06 (1H, dd, J=10.3, 8.7 Hz), 5.65-5.13 (1H, m), 1.63 (3H, s), 1.46 (3H, d, J=6.7 Hz). LCMS (Method K): RT=3.40 min, [M+H]+=389
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][CH2:15][C:16](Cl)=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][CH2:32][C:33]2[CH:34]=[C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([NH:47][CH2:48][CH2:49][N:50]4[CH2:54][CH2:53][CH2:52][CH2:51]4)=[O:46])[CH:40]=3)[CH:36]=[CH:37][CH:38]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>CN(C=O)C.O>[NH2:19][S:20]([C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][N:31]([CH2:32][C:33]2[CH:34]=[C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([NH:47][CH2:48][CH2:49][N:50]4[CH2:54][CH2:53][CH2:52][CH2:51]4)=[O:46])[CH:40]=3)[CH:36]=[CH:37][CH:38]=2)[C:16](=[O:17])[CH2:15][O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:27][CH:28]=1)(=[O:22])=[O:21]
Reactant: NS(=O)(=O)c1ccc(CCNCc2cccc(-c3cccc(C(=O)NCCN4CCCC4)c3)c2)cc1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccc(CCN(Cc2cccc(-c3cccc(C(=O)NCCN4CCCC4)c3)c2)C(=O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Pyridine (0.16 ml) and benzyloxyacetyl chloride (0.16 ml) were added to a solution of 3′-[{2-[4-(aminosulfonyl)phenyl]ethyl}aminomethyl]-N-[2-(1-pyrrolidinyl)ethyl]-[1,1′-biphenyl]-3-carboxamide (506 mg) in DMF (10 ml). The reaction mixture was stirred at room temperature for 16 hours, then diluted with water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residues were purified by silica gel column chromatography (dichloromethane/methanol=98/2), whereby the title compound (257 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([NH2:10])[CH:4]=1.Br[CH:12]([CH2:18]Br)[C:13]([O:15]CC)=[O:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[O:9][CH:12]([C:13]([OH:15])=[O:14])[CH2:18][NH:10][C:5]=2[CH:4]=1
Reactant: CCOC(=O)C(Br)CBr
Reactant: COc1ccc(O)c(N)c1
Product: COc1ccc2c(c1)NCC(C(=O)O)O2

Procedure:
7B was treated with ethyl 2,3-dibromopropionate to form the ethyl ester of 6-methoxy-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid, and this was converted to 7, mp: 83°-85° C., by the procedures described in the other examples.
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(C(C)C)CC)(C)C.[Si:19]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][CH:43]([CH3:45])[CH3:44])([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[Si:19]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:42]([CH:43]([CH3:45])[CH3:44])[C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])([C:32]([CH3:34])([CH3:35])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCCCCC(=O)O
Reactant: CC(C)NCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCC(=O)N(CCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.6 %

Procedure:
Heptanoic acid (2.06 g, 15.86 mmol), and diisopropylethylamine (2.72 mL, 21.14 mmol; DIPEA) were added to a stirring solution of the amine 4 (4.00 g, 10.57 mmol) in anhydrous DMF (20 mL) under an argon atmosphere. After 5 min, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (3.04 g, 15.86 mmol; EDCI) was added as a solid. After stirring for 12 h at room temperature, the reaction mixture was diluted with EtOAc (100 mL), washed with water (2×30 mL), and brine (20 mL). The combined aqueous layers were back-extracted with EtOAc (3×30 mL). The combined organic extracts were dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by SiO2 column chromatography using 30% EtOAc/hexanes as eluent to give amide 5 (4.75 g, 91%) as a viscous oil. TLC: EtOAc/hexanes (3:7), Rf˜0.60; 1H NMR (400 MHz, 1:1 mixture of rotamers) δ 7.65-7.67 (m, 4H), 7.30-7.40 (m, 6H), 4.62-4.72 and 3.96-4.80 (m, 1H, rotamers), 3.62 and 3.68 (t, J=4.8 Hz, 2H, rotamers), 3.02 and 3.16 (t, J=5.2 Hz, 2H, rotamers), 2.38 and 2.24 (t, J=5.3 Hz, 2H, rotamers), 1.50-1.68 (m, 6H), 1.26-1.44 (m, 8H), 1.18 and 1,12, (d, J=7.3 Hz, 6H, rotamers), 1.03 and 1.04 (s, 9H, rotamers), 0.88 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, 1:1 mixture of rotamers) δ 173.38, 172.76, 135.80, 135.78, 134.36, 134.12, 129.85, 129.73, 127.88, 127.82, 64.22, 63.68, 48.43, 45.62, 43.64, 41.27, 34.13, 34.05, 32.61, 32.36, 31.96, 31.93, 31.51, 29.63, 29.47, 27.10, 27.03, 25.94, 25.78, 24.03, 23.77, 22.81, 21.63, 20.78, 19.47, 14.33, 14.28.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10](Br)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#[CH:18].C(N(CC)CC)C>C(#N)C.C1COCC1.[Cu]I.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:18]#[C:17][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(Br)n1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(N)c(C#Cc2ccccc2)n1
Temperature: 45 °C
Reaction time: 70 h

Procedure:
Tert-butyl-N-(5-amino-6-bromopyridin-2-yl)carbamate A5 (617 mg, 1.82 mmol), ethynylbenzene (420 μl, 3.82 mmol), copper(I) iodide (35 mg, 0.18 mmol), 1,1′-Bis-(diphenylphosphino)ferrocene]dichloropalladium(II) (66.4 mg, 0.09 mmol) and triethylamine (631 μl, 4.55 mmol) are stirred under argon atmosphere in a mixture of ACN (10 ml) and THF (5 ml) for 2 h at RT. The mixture is warmed to 45° C. and stirred for 70 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 320 mg (57%). HPLC-MS: M+H=310; tR=2.05 min (*Method—2).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([C:22]3([CH2:25][N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:24][CH2:23]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.Cl.[OH-].[Na+]>C(O)(C)C>[CH3:32][N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:22]2([C:14]3[O:13][N:12]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=4)[C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)[CH2:31][CH2:30]1
Reactant: COCOc1ccc(-c2noc(C3(CN4CCN(C)CC4)CC3)c2-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CN1CCN(CC2(c3onc(-c4ccc(O)cc4)c3-c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture consisting of 1-{1-[3-(4-methoxymethoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropylmethyl}-4-methyl-piperazine (this example, Step B) in isopropanol is added 6 N hydrochloric acid solution. The mixture is stirred at room temperature overnight. The mixture is titrated to pH 8 with an aqueous sodium hydroxide solution and is extracted with ethyl acetate. The organic layer is separated and dried over anhydrous sodium sulfate. The mixture is filtered and the filtrate is concentrated under reduced pressure. The concentrate is purified to afford the title compound 1H NMR (400 MHz, CDCl3) δ 7.40-7.20 (m, 7H), 6.70 (d, 2H), 2.45 (m, 8H), 2.25 (s, 3H), 1.05 (m, 2H), 0.78 (m, 2H); MS (EH+) m/z 390 (MH+.)
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[N:5]=[N:4][N:3]=1.[ClH:15]>CO.[Pd]>[ClH:15].[CH3:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])[N:5]=[N:4][N:3]=1
Reactant: Cc1nnnn1-c1ccccc1C#N
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1nnnn1-c1ccccc1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-(5-methyl-1H-tetrazol-1-yl)benzonitrile (1.0 equiv.) in MeOH (0.4 M) was added palladium on charcoal and concentrated hydrochloric acid (1.0 equiv.). The reaction mixture was stirred at room temperature under hydrogen atmosphere (50 psi) overnight. After reaction completion, the mixture was filtered through celite. The filtrate was concentrated in vacuo to give the crude product (81% yield), which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.85-7.75 (m, 3H), 7.66-7.64 (m, 1H), 3.96 (s, 2H), 2.60 (s, 3H); MS (ESI) m/z 190.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)(Cl)Cl>[CH2:22]([O:21][C:19]([O:12][CH:9]1[CH2:8][CH2:7][C:6]2[N:5]=[CH:4][C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([OH:1])[C:11]=2[CH2:10]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cnc2c(c1O)CC(O)CC2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2c(c1O)CC(OC(=O)OCc1ccccc1)CC2

Procedure:
A well stirred mixture of 5 g of ethyl 4,6-dihydroxy-5,6,7,8-tetrahydroquinoline-3-carboxylate and 3.0 g of KHCO3 in 300 mL of CHCl3 is ice-cooled. To the cooled mixture, benzyl chloroformate (3.6 g) is added over a period of 10 minutes maintaining the reaction temperature below 10°. The reaction mixture is vigorously stirred at room temperature overnight, then filtered. The filtrate is washed with H2O, dried (MgSO4), and evaporated to dryness. The dried residue is purified by flash chromatography on a silica gel column to yield ethyl 6-benzyloxycarbonyloxy-4-hydroxy-5,6,7,8-tetrahydroquinoline-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[CH:24]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: OB(O)c1ccc(F)c(F)c1
Product: CCCNC(=O)c1nnc2c(-c3ccc(F)c(F)c3)cccc2c1N
Yield: 95.6 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 3,4-difluorophenyl boronic acid (202 mg, 1.28 mmol) were reacted to afford the title compound (108 mg, 98.7% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (br, 1H), 7.89 (dd, J=7.9 Hz, J′=1.9 Hz, 1H), 7.68-7.80 (m, 2H), 7.48-7.59 (m, 1H), 7.37-7.45 (m, 1H), 7.23-7.33 (m, overlapped with CHCl3), 3.47 (q, J=6.7 Hz, 2H), 1.68 (m, J=7.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H) MS APCI, m/z=343 (M+H) HPLC 2.01 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8].CO[CH:11](OC)[N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[CH:13]([N:12]([CH:11]=[N:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8])[CH:16]([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: COC(OC)N(C(C)C)C(C)C
Reactant: Nc1ccncc1O
Solvent: Cc1ccccc1
Product: CC(C)N(C=Nc1ccncc1O)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-amino-3-pyridinol (3.0 g), N,N-diisopropylformamide dimethyl acetal (9.54 g) and 15 ml dry toluene was stirred at room temperature for 18 hours and thereafter heated to 60°-70° C. After 90 minutes, the mixture was cooled to room temperature, concentrated in vacuo and chromatographed on silica using 10:90 CH3OH/ethyl acetate as an eluent. The fractions containing the desired product were combined and concentrated to a thick oil, which solidified on refrigeration. This solid (5.3 g) was triturated with hexane three times to provide the product as a white solid, m.p. 77°-79° C.