Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)([CH3:5])[CH2:3][OH:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[CH3:5][C:2]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)([CH3:1])[CH:3]=[O:4]
Reactant: CC(C)(CO)OC1CCCCO1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)(C=O)OC1CCCCO1
Reaction time: 0.33 h
Yield: 83.2 %

Procedure:
To a suspension of 2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propan-1-ol (1.16 g, 6.68 mmol) in dichloromethane (20 ml) at 0° C. was added portionwise Dess-Martin periodinane (3.26 g, 7.68 mmol), and the reaction mixture was stirred at the same temperature for 20 minutes, followed by addition of saturated aqueous NaHCO3 and Na2S2O3. The resulting mixture was stirred for 3 hours and the reaction mixture was extracted with Et2O. The combined organic phases were dried and concentrated in vacuo to give 2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propanal (958 mg, 5.56 mmol, 83% yield) as a colorless oil which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (s, 3 H) 1.23 (s, 3H) 1.33-1.85 (m, 6 H) 3.32-3.44 (m, 1 H) 3.73-3.89 (m, 1 H) 4.61-4.70 (m, 1 H) 9.44 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][C:4]([CH3:14])([O:6][C:7]1[N:12]=[N:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:5].Br[C:17]1[C:18](=[O:25])[N:19]([CH3:24])[N:20]=[C:21]([Cl:23])[CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[Cl:23][C:21]1[CH:22]=[C:17]([NH:13][C:10]2[N:11]=[N:12][C:7]([O:6][C:4]([CH3:5])([CH3:14])[CH2:3][N:2]([CH3:1])[CH3:15])=[CH:8][CH:9]=2)[C:18](=[O:25])[N:19]([CH3:24])[N:20]=1
Reactant: CN(C)CC(C)(C)Oc1ccc(N)nn1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN(C)CC(C)(C)Oc1ccc(Nc2cc(Cl)nn(C)c2=O)nn1
Temperature: 110 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
In a 15 mL microwave reaction vial was added a solution of 6-(1-(dimethylamino)-2-methylpropan-2-yloxy)pyridazin-3-amine (110 mg, 523 μmol, Eq: 1.00) in dioxane (5 ml) under argon. To the solution was added 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (152 mg, 680 μmol, Eq: 1.3), Cs2CO3 (511 mg, 1.57 mmol, Eq: 3), xantphos (45.4 mg, 78.5 μmol, Eq: 0.15) and bis(dibenzylideneacetone)palladium (22.6 mg, 39.2 μmol, Eq: 0.075). The reaction tube was sealed and heated in oil bath at 110° C. (bath temp) for 7 hrs, then was cooled to room temperature and stirred overnight. The reaction mixture was filtered and the solid was washed with THF (20 mL). The combined filtrate and washes were concentrated in vacuo. The reaction mixture was absorbed on to silica and purified by LC chromatography eluting with 0-5% (MeOH) in 1/1 EtOAc/heptane to afford 130 mg (70%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][CH3:23])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][CH3:21])[CH:14]=2)=[CH:10][CH:11]=1)=[O:4].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:22]([C@@H:2]1[NH:1][C:32](=[O:34])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][CH3:21])[CH:14]=3)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:23]
Reactant: CC[C@H](N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H]1NC(=O)N(c2ccc(Oc3ccc(C)c(OC)c3)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 178.6 %

Procedure:
To a solution of (2S)-2-amino-N-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)butanamide (Intermediate 67, 43 mg) in dry dichloromethane (3 mL), triethylamine (0.095 mL, 0.682 mmol) was added. The reaction mixture was cooled down with an ice bath. A solution of triphosgene (18.21 mg, 0.061 mmol) in dichloromethane (0.750 mL) was then added dropwise and the reaction mixture was stirred during 30 minutes at 0° C. The reaction was quenched with water (10 mL). The organic phase was then separated, dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a column SNAP 10 g and cyclohexane/ethyl acetate from 80/20 40/60 as eluent to afford the title compound as a white solid (37.2 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>C(Cl)Cl.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:9]=[C:6](/[CH:7]=[N:17]/[S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])[C:5]([F:10])=[N:4][CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cc(Br)cnc1F
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.6 %

Procedure:
To a solution of 5-bromo-2-fluoronicotinaldehyde (5 g, 24.51 mmol) and titanium (IV) ethoxide (15.42 ml, 73.5 mmol) in DCM (49.0 mL) was added (R)-2-methylpropane-2-sulfinamide (3.12 g, 25.7 mmol). The reaction mixture was then stirred at rt for 48 h. After 48 h, the reaction mixture was poured into brine at rt while rapidly stirring the mixture. The resulting suspension was filtered through a plug of CELITE®, and the filter cake was washed several times with DCM. The filtrate were separated, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give 7.6 g of crude product which was further purified using silica gel chromatography to yield the desired product (6.97 g, 93%) as an off white solid. MS (ESI) m/z: 330.8 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.C(O)(=O)C.[BH4-].C([Na])#N>CO>[Cl:25][C:22]1[CH:23]=[CH:24][C:2]([NH:1][CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:35][CH:34]=2)=[C:3]([CH:21]=1)[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:6]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Agent: N#C[Na]
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCc2ccc(C(F)(F)F)cc2)c1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 83.6 %

Procedure:
In methanol (20 ml) were dissolved 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.5 g) obtained in Example 1 (2) and 4-trifluoromethylbenzaldehyde (0.28 g). To the solution were added acetic acid (0.1 g) and cyano sodium borohydride (0.17 g). The mixture was stirred for 40 minutes at 60° C. The reaction mixture was concentrated, to which were added ethyl acetate (30 ml) and water (20 ml), followed by extraction. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 5-chloro-2-(4-trifluoromethylbenzylamino)-α-(3-tert-b-utoxycarbonylaminomethylphenyl)benzyl alcohol (0.6 g) as a colorless oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:4][CH:3]=1.[O-:16][C:17]#[N:18].[K+]>Cl.O>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:14][CH:15]=1)[C:17]([NH2:18])=[O:16]
Reactant: Nc1ccc(OCCn2ccnc2)cc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)Nc1ccc(OCCn2ccnc2)cc1
Reaction time: 0.25 h
Yield: 82.5 %

Procedure:
1-[2-(4-Aminophenoxy)ethyl]imidazole (0.6 g) was dissolved in 1N hydrochloric acid (3.0 ml) and a solution of potassium cyanate (0.3 g) in 1 ml of water was added. The mixture was allowed to stand at room temperature for 15 minutes and the resulting solid was filtered off, washed with water and crystallised from water to give 1-[2-(4-ureidophenoxy)ethyl]imidazole (0.6 g), m.p. 199°-201° C. Found: C, 58.20; H, 5.70; N, 23.06. C12H14N4O2 requires: C, 58.52; H, 5.73; N, 22.75%.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:34])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-(3-Chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[N:25]=[C:26]([C:29]([OH:33])([C:31]#[CH:32])[CH3:30])[S:27][CH:28]=1.C(N(CC)CC)C>CS(C)=O.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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:32]#[C:31][C:29]([C:26]4[S:27][CH:28]=[C:24]([CH3:23])[N:25]=4)([OH:33])[CH3:30])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: COCCNc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Reactant: C#CC(C)(O)c1nc(C)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCCNc1nc2ccc(C#CC(C)(O)c3nc(C)cs3)cc2n1-c1ccnc(N)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
A mixture of 1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-1,3-benzodiazol-2-amine (150 mg, 0.37 mmol), 2-(4-methyl-1,3-thiazol-2-yl)but-3-yn-2-ol (137.6 mg, 0.82 mmol), bis(triphenylphosphine)palladium(II) dichloride (150 mg, 0.21 mmol) and triethylamine (0.7 mL) in dimethylsulfoxide (1 mL) under nitrogen in a 10-mL sealed tube was stirred for 1 hr at 70° C. The reaction mixture was cooled to room temperature then purified on a silica gel column (dichloromethane/methanol, 8:1) to give 19.6 mg (11%) of 4-[1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-1,3-benzodiazol-6-yl]-2-(4-methyl-1,3-thiazol-2-yl)but-3-yn-2-ol as yellow oil: 1H NMR (300 MHz, DMSO) delta 8.40 (d, J=5.4 Hz, 2H), 8.22 (t, J=5.0 Hz 1H), 7.49 (s, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.16 (t, J=10.5 Hz, 2H), 6.91 (d, J=5.4 Hz, 1H), 6.89 (s, 1H), 6.86 (s, 1H), 3.62-3.59 (m, 4H), 3.32 (d, J=12.3 Hz, 3H), 2.35 (s, 3H), 1.85 (s, 3H); LC-MS: m/z=+450 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1>C(O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N)cc1
Reaction time: 18 h
Yield: 99 %

Procedure:
A mixture of ethyl 3-(4-aminophenyl)acrylate (1.5 g) and 10% Pd on activated carbon (0.3 g) in ethanol (20 ml) was hydrogenated at 30 psi for 18 h and filtered over Celite. Removal of the volatiles in vacuo provided ethyl 3-(4-aminophenyl)propionate (1.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.N[C:13](N)=[O:14].C.Cl>[OH-].[Na+]>[O:14]=[C:13]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[S:8](=[O:10])(=[O:9])[NH:11]1
Reactant: Nc1cccnc1S(N)(=O)=O
Reactant: NC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1Nc2cccnc2S(=O)(=O)N1
Temperature: 25 °C

Procedure:
An intimate mixture of 5 g of 3-aminopyridine-2- sulfonamide (Preparation 1) and 1.91 g of urea is progressively brought to a temperature of 200° C. (melting). After gas has ceased to be given off and the mass has solidified, the reaction mixture is cooled to ambient temperature. The solid mass is redissolved in 1N NaOH and the solution obtained, optionally decolored with absorbing charcoal, is then adjusted to a pH of 2 using 1N HCl. The white precipitate corresponding to the title compound is collected on a filter, washed with water and dried.
Reaction SMILES: S(Cl)(Cl)=O.BrCC1C=CC(C(O)=O)=CC=1.BrCC1C=CC(C(Cl)=O)=CC=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.[Br:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([CH2:57][C:58]([N:60]=[C:61]=[S:62])=[O:59])=[CH:53][CH:52]=1>C1(C)C=CC=CC=1.C(O)C>[Br:49][CH2:50][C:51]1[CH:52]=[CH:53][C:54]([CH2:57][C:58]([NH:60][C:61]([NH:46][C:45]2[CH:47]=[CH:48][C:42]([O:41][C:32]3[C:31]4[C:36](=[CH:37][C:38]([O:39][CH3:40])=[C:29]([O:28][CH3:27])[CH:30]=4)[N:35]=[CH:34][CH:33]=3)=[CH:43][CH:44]=2)=[S:62])=[O:59])=[CH:55][CH:56]=1
Reactant: O=C(Cc1ccc(CBr)cc1)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc(CBr)cc1
Agent: O=C(O)c1ccc(CBr)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(CBr)cc4)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 4-(bromomethyl)benzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-[4-(bromomethyl)phenyl]ethanoyl isothiocyanate was prepared using the resultant 4-(bromomethyl)-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-[4-(bromomethyl)phenyl]ethanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (50 mg, yield 52%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:24]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)CCc1cc(O)ccc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)ccc1OCC
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.44 g), ethyl 3-(2-ethoxy-5-hydroxyphenyl)propionate (1.0 g), anhydrous potassium carbonate (0.58 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 3-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4oxazolyl)methoxy]benzyloxy]phenyl]propionate as an oil (1.57 g, 72%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[OH:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[OH:18][C:19]1[CH:24]=[C:23]([C:2]2[C:11]3[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: N#Cc1cnc2c(C(F)(F)F)cccc2c1Cl
Product: N#Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1

Procedure:
The title compound was prepared from 4-chloro-8-(trifluoromethyl)quinoline-3-carbonitrile and 3-hydroxyphenylboronic acid according to the procedure of Example 1. HRMS: calcd for C17H9F3N2O+H+, 315.07397; found (ESI, [M+H]+), 315.0752.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][CH3:14].C1(C2C=CC=CC=2)C=CC=CC=1CN.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:7]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:1]=1
Reactant: CCc1cccn1Cc1ccccc1-c1ccccc1
Agent: NCc1ccccc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCc1cccn1Cc1ccccc1
Reaction time: 18 h

Procedure:
1-(biphenyl-2-ylmethyl)-2-ethyl-1H-pyrrole, 13: To the crude 12 (14 g, 83 mmol) in dry benzene (200 mL) at room temperature is added biphenyl-2-ylmethanamine solution (100 mmol) and triethylamine (110 mmol). The solution is heated to reach 65° C. and stirred for 18 h. The resulted reaction mixture is filtered and concentrated. The crude product was purified by silica gel chromatography to afford 13
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][NH:32][CH2:33][CH3:34]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:32]([CH2:33][CH3:34])[CH3:31])=[O:26])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CCNC
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: CCN(C)C(=O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 153) and 13.9 mg (0.23 mmol) of methylethylamine are reacted together by general method E. 50.1 mg (91.4% of theory) of the title compound are obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[C:23]([CH3:35])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[N:24]=[C:23]([CH3:35])[C:22]([CH2:21][O:19][C:6]3[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]4[CH:18]=[CH:17][N:16]=[N:15]4)=[C:4]([CH3:3])[CH:5]=3)=[CH:27][CH:26]=2)=[CH:29][CH:30]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(-c3ccc(F)cc3)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
36 mg (0.89 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 197 mg (0.85 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 8.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.85 mmol) 3-chloromethyl-6-(4-fluoro-phenyl)-2-methyl-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, and ether. 325 mg (89%) of the title compound were obtained as pale beige powder.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]2[N:17]=[CH:18][CH:19]=[CH:20][C:4]=2[N:3]=1.[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH2:26])[CH3:22]>>[CH2:21]([N:23]([CH2:24][CH2:25][NH:26][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]2[N:17]=[CH:18][CH:19]=[CH:20][C:4]=2[N:3]=1)[CH2:27][CH3:28])[CH3:22]
Reactant: CCN(CC)CCN
Reactant: COc1ccc(-n2c(=O)c(Cl)nc3cccnc32)cc1
Product: CCN(CC)CCNc1nc2cccnc2n(-c2ccc(OC)cc2)c1=O

Procedure:
Preparation as in Example 39 but using 2-chloro-3,4-dihydro-4-(4-methoxyphenyl)-3-oxopyrido[2,3-b]pyrazine and N,N-diethylethylene diamine gave the title compound mp 167°-168° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20](C(N[C@H](C#C)CC(O)=O)=O)[CH2:19]2)=[O:17])[CH2:10][CH2:9]1.Cl.[CH2:35]([OH:37])[CH3:36]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:35]([O:37][C:3](=[O:5])[CH2:2][C@@H:9]([C:10]#[CH:11])[NH:8][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:19]1)[CH3:36]
Reactant: C#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1
Reactant: CCO
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: C#C[C@H](CC(=O)OCC)N[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-[(R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine trifluoroacetate (0.57 g) and 4.9 HCl in ethanol (30 ml) was stirred at ambient temperature for 2 hours, and the mixture was evaporated in vacuo. The residue was purified by HPLc on C18 silica gel eluting with a solution of 18% CH3CN in 0.1% aqueous TFA solution, and the fractions containing object compound were combined and evaporated in vacuo and freeze-dried to give N-[(R)-1-{3-(4-piperidyl)propionyl}-3-piperidyl]-3(S)-ethynyl-β-alanine ethyl ester trifluoro acetate (0.52 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N+:3]=1[O-].[Si]([C:16]#[N:17])(C)(C)C.CN(C)C(Cl)=O.C([O-])(O)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:16]#[N:17])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: C[Si](C)(C)C#N
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: N#Cc1cc([N+](=O)[O-])cc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
2-chloro-4-nitropyridine 1-oxide (1.8 g, 10.31 mmol) was slowly added to a solution of TMS-CN (4.98 ml, 37.1 mmol) in 1,2-dichloroethane (25 ml) at RT under N2 and dimethylcarbamic chloride (3.41 ml, 37.1 mmol) was then slowly added. The mixture was stirred for at RT overnight then heated to 85° C. for 5 days. The reaction was cooled RT and sat. NaHCO3 was added and then extracted with CH2Cl2. The organic was dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with 0-10% EtOAC in hexane to give the product as a white solid (0.79 g, 42%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.63 (1H, d) 7.59 (1H, d).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:12])=[NH:11])=[CH:5][C:4]=1[N+:13]([O-])=O.O1CCCC1>[Pd].CO>[ClH:1].[NH2:13][C:4]1[CH:5]=[C:6]([NH:9][C:10]([NH2:12])=[NH:11])[CH:7]=[CH:8][C:3]=1[NH2:2]
Reactant: N=C(N)Nc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: N=C(N)Nc1ccc(N)c(N)c1
Yield: 98.6 %

Procedure:
A mixture comprising N-(4-amino-3-nitrophenyl)guanidine hydrochloride (12.0 g, 51.8 mmol), 10% palladium on carbon (1.0 g), tetrahydrofuran (100 mL) and methanol (100 mL) was hydrogenated at one atmosphere, filtered and concentration in vacuo to provide N-(3,4-diaminophenyl)guanidine hydrochloride (10.3 g, 98% yield) as a dark solid; 1H-NMR (300 MHz, DMSO-d6): 9.4 (s), 7.2 (s), 6.5 (d), 6.3 (s), 6.2 (d), 4.7 (s).