Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[N:26](C)C=O.C(Cl)(=O)C(Cl)=O>O1CCCC1>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:26])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(-c2ccc(-c3ccc(C(F)(F)F)cc3)o2)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2ccc(-c3ccc(C(F)(F)F)cc3)o2)cc1
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a solution (20 ml) of 4-[5-(4-trifluoromethylphenyl)-2-furyl]benzoic acid -(0.665 g) and N,N-dimethylformamide (0.1 ml) in tetrahydrofuran was added oxalyl chloride (0.209 ml) at 0° C. This mixture was stirred for 10 min., and concentrated. The residue was dissolved in acetonitrile (30 ml), and this solution was added dropwise to 25% aqueous ammonia (50 ml) at 0° C. The mixture was stirred for 10 min. and poured into water. The crystals were collected by filtration and recrystallized from ethanol to give 4-[5-(4-trifluoromethylphenyl)-2-furyl]benzamide (0.506 g, yield 76%) as a colorless crystalline powder. melting point: 263–264° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7](O)[C:6](=[O:15])[C:5]2=[O:16])[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6](=[O:15])[C:5]2=[O:16])[CH2:3][CH2:2]1
Reactant: O=c1c(=O)n(C2CC2)c2ccccc2n1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2n(C2CC2)c1=O
Temperature: 135 °C
Reaction time: 4 h
Yield: 84.1 %

Procedure:
To a solution of 1-cyclopropyl-4-hydroxy-1,4-dihydro-quinoxaline-2,3-dione (31.0 g, 0.14 mol, 1.0 equiv) in N,N-dimethylformamide (250 mL) was added triphenylphosphine (55.9 g, 0.21 mol, 1.5 equiv; [CAS RN 603-35-0]) and the reaction mixture stirred at 135° C. for 4 hours. The reaction mixture was cooled down to 0° C. and dichloromethane (400 mL) was added. The suspension was stirred for 30 min., filtered and washed with dichloromethane (200 mL) providing 23.8 g (83%) of the title compound as a white solid. MS (ISN): m/z=203.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[C:16](OC=O)(=[O:18])C>CN(C)C=O>[CH:16]([NH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5])=[O:18]
Reactant: Nc1ccccc1C(=O)Nc1nnn[nH]1
Reactant: CC(=O)OC=O
Solvent: CN(C)C=O
Product: O=CNc1ccccc1C(=O)Nc1nnn[nH]1

Procedure:
To a solution of 4.7 g of 2-amino-N-(1H-tetrazol-5-yl)benzamide in 30 ml of dimethylformamide, under nitrogen, was added 4.7 g of freshly prepared formic acetic anhydride. The precipitate which formed within a few minutes was separated by filtration and washed with ether to give 2-(formylamino)-N-(1H-tetrazol-5-yl)benzamide melting at about 247°-248° C. This compound has the following structural formula: ##STR2##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:55]1([NH:58][CH2:59][C@@H:60]2[CH2:65][CH2:64][CH2:63][NH:62][CH2:61]2)[CH2:57][CH2:56]1>CN(C=O)C>[CH:55]1([NH:58][CH2:59][C@@H:60]2[CH2:65][CH2:64][CH2:63][N:62]([C:30]([C:26]3[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]4\[C:17](=[O:22])[NH:18][C:19]5[C:15]\4=[CH:14][C:13]([S:10]([CH2:9][C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=5)[NH:28][C:27]=3[CH3:29])=[O:31])[CH2:61]2)[CH2:57][CH2:56]1
Reactant: C1CNC[C@H](CNC2CC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@@H](CNC2CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (200 mg, 0.4 mmol), HOBt (54 mg, 1 eq.), EDAC (77 mg, 1 eq.), TEA (0.17 mL) and cyclopropyl-(R)-1-piperidin-3-ylmethyl-amine (110 mg, 0.48 mmol) in DMF (3 mL) was stirred at rt for overnight. The reaction was concentrated and purified on a silica gel column to give 45 mg of the titled compound.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[CH3:5][C:6]1[CH:7]=[C:8]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[NH2:9].O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH2:9][C:8]1[CH:10]=[C:11]([CH3:13])[C:12]([S:1][C:2]#[N:3])=[C:6]([CH3:5])[CH:7]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: N#C[S-]
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N)cc(C)c1SC#N
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.3 %

Procedure:
251.2 g (3.30 mol) of ammonium thiocyanate are rapidly added to a solution, maintained under a nitrogen atmosphere, of 121.2 g (1 mol) of 3,5-dimethylaniline in 1.75 l of anhydrous N,N-dimethylformamide. The temperature rises from 18 to 35° C. One and a half hours later, the temperature of the solution having returned to room temperature, 263.3 g (1.65 mol) of anhydrous cupric sulphate are added rapidly. The reaction medium is left stirring at room temperature for 3 days and is then poured into 8 l of water. The pH is brought to 7.5 by addition of 550 g (6.55 mol) of sodium bicarbonate. The medium is then filtered, the solid part being washed with ethyl acetate and the liquid part being extracted with ethyl acetate. The combined organic liquid phases are washed with 500 ml of water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The pasty residue obtained is crystallized from 500 ml of hexane to give 128.8 g (72%) of 4-amino-2,6-dimethylphenyl thiocyanate which is used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:39][C@H:40]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:41][CH2:42][OH:43]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:39][C@H:40]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:41][CH2:42][OH:43])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: N[C@@H](CCO)c1ccccc1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](CCO)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 81 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (S)-3-amino-3-phenylpropan-1-ol: yield 81%.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18](O)=[O:19])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:1]1([CH2:6][C@H:7]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18](=[O:19])[N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:14][N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc1
Reactant: C1CCNCC1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SCC(=O)N3CCCCC3)s2)cc1

Procedure:
The title compound was prepared from (R)-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic acid and piperidine as described in Example 12. 1H-NMR (CD3OD): δ 7.92 (d, 2H), 7.66 (d, 2H), 7.46 (s, 1H), 3.96 (t, 1H), 3.63 (s, 2H), 3.48 (broad t, 2H), 3.43 (broad t, 2H), 3.09 (s, 3H), 2.25-2.18 (m, 1H), 1.88-1.48 (m, 14H), 1.17 (m, 2H); HPLC-MS: m/z: 536 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCNC3)n2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCN(S(C)(=O)=O)C3)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.5 %

Procedure:
To a mixture of 2-(3-acetamidophenylamino)-4-(piperidin-3-ylmethylamino)pyrimidine-5-carboxamide (40 mg, 0.104 mmol) and DIEA (0.100 mL, 0.575 mmol) in CH2Cl2 (2 mL), methanesulfonyl chloride (0.032 mL, 0.413 mmol) was added. The mixture was stirred at room temperature for 18 h. It was then purified by HPLC to give the titled compound (6 mg). MS 462.4 (M+H); UV 204.7, 248.6 nm.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[Cl:22])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Cl:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[CH:5]1[N:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2cccnc2)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2cccnc2)=NC1c1ccc(F)cc1Cl
Yield: 35.2 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(pyridin-3-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2.2 mmol) was reacted with morpholine-3-carboxylic acid (0.29 g, 2.2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.39 g, 35%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]1([C:31]2[C:39]3[C:38]([N:40]4[CH2:45][CH2:44][CH2:43][CH:42]([C:46]([OH:48])=O)[CH2:41]4)=[N:37][CH:36]=[N:35][C:34]=3[S:33][CH:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.[O:56]1[CH2:61][CH2:60][N:59]([CH2:62][CH2:63][NH2:64])[CH2:58][CH2:57]1>C(#N)C>[O:56]1[CH2:61][CH2:60][N:59]([CH2:62][CH2:63][NH:64][C:46]([CH:42]2[CH2:43][CH2:44][CH2:45][N:40]([C:38]3[C:39]4[C:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:32][S:33][C:34]=4[N:35]=[CH:36][N:37]=3)[CH2:41]2)=[O:48])[CH2:58][CH2:57]1
Reactant: O=C(O)C1CCCN(c2ncnc3scc(-c4ccccc4)c23)C1
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCN1CCOCC1)C1CCCN(c2ncnc3scc(-c4ccccc4)c23)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.23099 g, 0.58928 mmol) was added to a suspension of 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidine-3-carboxylic acid (0.1 g, 0.29464 mmol) in acetonitrile (2 mL). Triethylamine (0.123 mL, 0.089443 g, 0.88391 mmol) and 2-morpholinoethanamine (0.0773 mL, 0.076718 g, 0.58928 mmol) were added and the mixture was stirred for 4 hr at room temperature. The solvent was evaporated and the residue was diluted with ethyl acetate (2 mL) and water (2 mL). The layers were separated and the aqueous was extracted with ethyl acetate (2×2 mL). The combined organic layers were washed with saturated aqueous sodium hydrogencarbonate (1×10 mL), dried (magnesium sulfate), filtered and evaporated to give a brown oil. Mass: 0.275 g. This was purified by prep HPLC (basic method 1). Fractions corresponding to the main peak were combined and evaporated to give a yellow oil. Yield=92 mg. LCMS [M+H]+=452; RT=2.89 min Other compounds prepared by Method K using the appropriate starting materials are listed in TABLE 1.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([Cl:13])=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#N)[CH:7]=1.CC(C[AlH]CC(C)C)C.Cl.C1C[O:29]CC1>>[Br:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([Cl:13])=[C:6]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:29])[CH:7]=1
Reactant: COc1cc(Cl)c(C(C)(C)C#N)cc1Br
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Product: COc1cc(Cl)c(C(C)(C)C=O)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(5-bromo-2-chloro-4-methoxy-phenyl)-2-methyl-propionitrile (13 g, 0.045 mol) in dry THF (80 mL) was cooled to −10° C. under argon. DIBALH (1M in THF, 100 mL, 0.10 mol) was added keeping the temperature below 0° C. The mixture was stirred for 30 min/0° C. and then 2 h/25° C. The clear solution was carefully poured into icecold hydrochloric acid (2M, 100 mL). The THF was removed under reduced pressure. The aqueous phase was cooled and the crude product was filtered off and recrystallized from boiling MeOH. Yield: 7.8 g (59%). GCMS: >99%
Reaction SMILES: [Br-].[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH3+:14])[CH2:10][CH2:9]1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl.OS([O-])(=O)=O.[K+].CC(OC)(C)C>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([NH:14][S:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:27])[F:28])=[CH:22][CH:21]=2)(=[O:25])=[O:24])[CH2:12][CH2:13]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: [NH3+][C@H]1CC[C@H](CCCCCBr)CC1
Agent: O=S(=O)([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: O=S(=O)(N[C@H]1CC[C@H](CCCCCBr)CC1)c1ccc(C(F)(F)F)cc1
Reaction time: 1.5 h

Procedure:
A solution of 1.0 g (3.04 mmol) of trans-4-(5-Bromo-pentyl)-cyclohexylammonium bromide in 12 ml CH2Cl2 was first cooled at 0° C., treated with 0.8 g (3.27 mmol) 4-(trifluoromethyl)benzenesulfonylchloride and then with 1.2 ml (7.01 mmol; 2.3 equivalents) of Hünigsbase (during 30 min). After total 1.5 h at 0° C., the mixture was dissolved in aqueous 10% KHSO4/TBME (3×). The organic phases were washed with aqueous saturated NaHCO3 and aqueous 10% NaCl, dried over Na2SO4 and evaporated to give 1.38 g crude product which was crystallized (CH2Cl2/hexane) to give 1.26 g (91%) of pure trans-N-[4-(5-Bromo-pentyl)-cyclohexyl]-4-trifluoromethyl-benzenesulfonamide, MS: 454 (M−H−, 1Br).
Reaction SMILES: [NH:1]=[C:2]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=1)/[CH:3]=[C:4](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH3:15])\[NH2:5].N[C:27](N)=[O:28].Cl>C(O)C.O1CCOCC1>[CH3:25][C:18]1[CH:17]=[C:16]([C:2]2[CH:3]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][CH2:13][CH2:14][CH3:15])[NH:5][C:27](=[O:28])[N:1]=2)[CH:21]=[CH:20][C:19]=1[N+:22]([O-:24])=[O:23]
Reactant: CCCOc1ccccc1/C(N)=C/C(=N)c1ccc([N+](=O)[O-])c(C)c1
Reactant: NC(N)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCCOc1ccccc1-c1cc(-c2ccc([N+](=O)[O-])c(C)c2)nc(=O)[nH]1
Temperature: 75 °C
Yield: 76.4 %

Procedure:
To a solution of (1Z)-3-imino-3-(3-methyl-4-nitrophenyl)-1-[2-(propyloxy)phenyl]prop-1-en-1-amine (2.20 g, 6.45 mmol) in ethanol (100 mL) was added urea (6.0 g, 100 mmol) and hydrochloric acid in dioxane 4.0 N (25 mL) at room temperature. The reaction mixture was heated to 75° C. for 16 h, at which time it was concentrated in vacuo, diluted with water (200 mL) and adjusted to pH 10 with sodium hydroxide 2.0 N. The product was extracted with chloroform (200 mL) then diluted with hexanes (50 mL) to precipitate the product. The solid was filtered and washed with chloroform/hexanes (1:4) to give 4-(3-methyl-4-nitrophenyl)-6-[2-(propyloxy)phenyl]pyrimidin-2(1H)-one (1.80 g, 81%). MS (EI) for C20H19N4O3: 363 (MH+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[C:22](Cl)[N:21]=2)[CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16].[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[O:33]([C:22]1[N:21]=[C:20]([NH:19][C:11]2[CH:10]=[C:9]([O:8][CH3:7])[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=2)[CH:25]=[N:24][CH:23]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Oc1ccccc1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Nc2cncc(Oc3ccccc3)n2)cc(OC)c1OC
Yield: 71 %

Procedure:
Using Method X (but with no addition of K2CO3) with 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine (150 mg) and phenol, the title compound was obtained (127 mg). Yield: 71%. 1H NMR (250 MHz, DMSO-d6) δ 3.31 (s, 9H), 3.54 (s, 3H), 6.77 (s, 2H), 7.16-7.23 (m, 3H), 7.41 (t, 2H, J=7.9 Hz), 7.75 (s, 1H), 7.95 (s, 1H), 9.53 (s, 1H). 13C NMR (62.9 MHz, DMSO-d6) δ 55.33, 60.03, 95.77, 120.55, 121.17, 124.47, 128.42, 129.74, 132.15, 136.29, 150.52, 152.69, 153.86, 153.86, 157.23. m/z 354.1 [(M+H)+ calcd for C19H19N3O4 353.1].
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[NH:21][C:20]5[CH:22]=[CH:23][C:24]([C:26]([OH:28])=O)=[CH:25][C:19]=5[N:18]=4)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:31]([NH2:37])[C:32]1[O:36][CH:35]=[CH:34][CH:33]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[O:36]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:31][NH:37][C:26]([C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:17]([CH2:16][O:15][C:14]3[CH:29]=[CH:30][C:11]([C:1]45[CH2:10][CH:5]6[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]6)[CH2:2]4)[CH2:8]5)=[CH:12][CH:13]=3)=[N:18][C:19]=2[CH:25]=1)=[O:28]
Reactant: O=C(O)c1ccc2[nH]c(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Reactant: NCc1ccco1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccco1)c1ccc2[nH]c(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
To a solution of 2-(4-adamantan-1-yl-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid (50 mg, 0.124 mmol), furfuryl amine (18 mg, 0.186 mmol) and DMAP (22.78 mg, 0.186 mmol) in DMF (1 mL) was added PyBOP (97 mg, 0.186 mmol) at room temperature. The mixture was stirred for 16 h at room temperature and then poured into water (150 mL). The resulting solid was extracted with a mixture of methanol:MC (10%), washed with brine, aqueous sodium bicarbonate and water, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulted crude product was purified by PLC (methanol: MC=0.5:9.5) to afford 2-(4-adamantan-1-yl-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid (furan-2-ylmethyl)-amide as a colorless solid (43.2 mg, 72% yield).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([N:16]1[C:22](=[O:23])[CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[C@H:18]([CH3:32])[CH2:17]1)[CH2:5][CH2:6][N:7]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[C@H:9]([OH:15])[CH2:8]1.[Li+].[BH4-]>>[Cl:31][C:26]1[CH:25]=[C:24]([N:19]2[CH2:20][CH2:21][C:22](=[O:23])[N:16]([C@H:4]([CH2:3][OH:2])[CH2:5][CH2:6][N:7]3[CH2:14][CH2:13][C:10]4([CH2:12][CH2:11]4)[C@H:9]([OH:15])[CH2:8]3)[CH2:17][C@H:18]2[CH3:32])[CH:29]=[CH:28][C:27]=1[Cl:30]
Reactant: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)N(c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: [BH4-]
Agent: [Li+]
Product: C[C@@H]1CN([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1c1ccc(Cl)c(Cl)c1
Yield: 61 %

Procedure:
In analogy to the procedure described in example 2, (S)-2-[(R)-4-(3,4-dichloro-phenyl)-3-methyl-7-oxo-[1,4]diazepan-1-yl]-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyric acid methyl ester (example 65) and LiBH4 gave the title compound in 61% yield as white solid. MS: 470.2 (MH+, 2Cl).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:4]1=N)[CH3:2].C(OC(=O)C)(=[O:33])C.Cl>O>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:4]1=[O:33])[CH3:2]
Reactant: CCn1c(=N)c(-c2ccc3ccccc3c2)cc2cnc(Nc3ccccc3)nc21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Product: CCn1c(=O)c(-c2ccc3ccccc3c2)cc2cnc(Nc3ccccc3)nc21

Procedure:
(8-Ethyl-7-imino-6-naphthalen-2-yl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-phenylamine (150 mg) was added to 1 mL of acetic anhydride and heated at reflux for 2 minutes. The reaction was cooled and concentrated, resulting in an oil which was heated at reflux with 10 mL of 6N HCl for 10 minutes. The reaction was cooled, and 40 mL of water was added causing precipitation. The precipitate was removed by filtration and washed with water. The resulting solid was dried in a vacuum oven to provide 8-ethyl-6-naphthalen-2-yl-2-phenylamino-8H-pyrido[2,3-d]-pyrimidin-7-one; mp 254°-256° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:12]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:9]=[N:10][C:11]=3[CH3:24])=[N:16][CH:17]=2)[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Product: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 83 %

Procedure:
As described for example 67, 6-((1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (78 mg, 0.24 mmol), was converted, using cyclopropylamine instead of isopropylamine, to the title compound (72 mg, 83%) which was obtained as a white foam. MS: m/e=368.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[C:2]#[CH:3].Br[C:16]1[C:17]([NH:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:22]([C:19]1[N:20]=[CH:21][C:16]2[CH:3]=[C:2]([CH2:1][C:4]3[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:12])=[O:13])=[CH:6][CH:5]=3)[N:24]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:17]=2[N:18]=1)#[N:23]
Reactant: C#CCc1ccc(CS(N)(=O)=O)cc1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(Cc2ccc(CS(N)(=O)=O)cc2)cc2cnc(C#N)nc21
Temperature: 70 °C
Yield: 60.7 %

Procedure:
To a solution of N.-(4-prop-2-ynyl-phenyl)-methanesulfonamide (1.0 mmol) and 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (0.5 mmol) in DMF (5 ml), triethylamine (1.5 mmol), dichlorobis-dichlorobis(triphenylphosphine)palladium (II) (0.05 mmol) and copper (I) iodide (0.1 mmol) is added. The reaction mixture is heated at 70° C. ca. for 2.5 h. The mixture is quenched with saturated ammonium chloride and extracted with two 50 ml portions of AcOEt. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum to give crude product, which is purified by silica gel column chromatography. Yield: 60.7%. Rf=0.55 (n-hexane:AcOEt=1:1)