Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:30]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:35]([C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cccnc3)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cccnc3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step B was prepared from 3-{3-[(4-pyridin-3-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A, and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.05 (d, 1H), 8.80 (m, 2H), 8.60 (d, 1H), 8.06 (m, 1H), 7.91 (m, 1H), 7.44 (m, 4H), 7.21 (d, 2H), 7.15 (m, 1H), 7.06 (d, 1H), 6.92 (d, 1H), 6.87 (s, 1H), 4.41 (s, 2H), 4.38 (s, 2H), 3.65 (s, 3H), 2.82 (t, 2H), 2.51 (t, 2H); MS 502 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:11]2[C:6](=[C:7]([O:18][CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:8]=[C:9]([C:12]#[C:13][Si](C)(C)C)[CH:10]=2)[C:5](=[O:27])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([O:18][CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[CH:8]=1)[C:5](=[O:27])[CH2:4][CH2:3][C:2]2([CH3:28])[CH3:1])#[CH:13]
Reactant: CC1(C)CCC(=O)c2c(OCOCC[Si](C)(C)C)cc(C#C[Si](C)(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(OCOCC[Si](C)(C)C)c2c(c1)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution 4,4-dimethyl-8-(2-trimethylsilanyl-ethoxymethoxy)-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 72, 1.58 g, 3.79 mmol) in methanol (20 mL) was treated with potassium carbonate (0.43 g, 3.11 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (1.28 g, 98%). 1H NMR (300 MHz, CDCl3): δ 7.19 (d, 1H, J=1.2 Hz), 7.15 (d, 1H, J=1.2 Hz), 5.26 (s, 2H), 3.79 (m, 2H), 3.19 (s, 1H), 2.67 (t, 2H, J=6.6 Hz), 1.94 (t, 2H, J=6.6 Hz), 1.33 (s, 6H), 0.95 (m, 2H), −0.016 (s, 9H).
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15]O>C(O)=O>[CH2:1]([S:8]([CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[O:13])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)NCCSCc1ccccc1
Reactant: OO
Solvent: O=CO
Product: NC(=O)NCCS(=O)Cc1ccccc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of 2-benzylthio ethylurea (0.03 mole) in 12 ml of formic acid, there are added 3 ml of H2O2 (110 volumes). The resulting solution is agitated for 2 hours while maintaining the temperature at 30° C. The solution is then concentrated under reduced pressure and the resulting oil residue, taken up in sulfuric ether, solidifies. The product obtained (4.8 g) is crystallized in acetonitrile and has a melting point of 110° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].C(N(CC)CC)C>O1CCCC1.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>[N+:9]([C:5]1[CH:6]=[C:7]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[C:2]([NH2:1])=[N:3][CH:4]=1)([O-:11])=[O:10]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc([N+](=O)[O-])cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc([N+](=O)[O-])cnc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12.0 g 2-Amino-3-bromo-5-nitropyridine, 1.93 g dichlorobis(triphenyl-phosphine)palladium(II) and 0.524 g copper(I) iodide were dispersed under nitrogen in 60 ml dry tetrahydrofuran (THF). 7.03 g trimethylsilylacetylene and 16.71 g triethylamine were added and the mixture was stirred 16 hours (hrs) at room temperature (RT). The mixture was filtered, the filtrate was evaporated and the residue purified by chromatography on silica in ethyl acetate/heptane mixtures.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH2:28][C:27]([F:31])([F:30])[F:26])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(F)(F)F)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a solution of 6-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.28 mmol) and 2,2,2-trifluoroethylamine (38.3 mg, 0.28 mmol) in THF (10 mL) were added at 0° C., 1-hydroxybenzotriazole hydrate (43.3 mg, 0.28 mmol), N-ethyldiisopropylamine (121 μL, 0.69 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (54.2 mg, 0.28 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate:heptane=1:9 to 1:1) to afford the title compound (81 mg, 66%) as a white solid. MS: m/e=440.1 [M−H]−.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[C:22]([OH:24])=[O:23])=[O:15])([CH3:12])([CH3:11])[CH3:10].CI>C1COCC1.CCCCCCC.C1COCC1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1([CH3:2])[C:22]([OH:24])=[O:23])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CI
Product: CC(C)(C)OC(=O)N1CCCCC1(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of LDA (9.6 mL of a 2M solution in THF/Heptane) in THF (15 mL) at 0° C. was added 1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (2 g as a suspension in 4 mL of THF) dropwise via syringe over 10 minutes. The reaction mixture was stirred a further 20 minutes and then MeI (1.238 g) was added in one portion via syringe. The reaction mixture was allowed to warm to RT and stirred for 72 hours. The reaction was quenched with 2N aqueous HCl solution and diluted with EtOAc. The phases were separated and the aqueous phase was extracted with further EtOAc. The combined organics were washed with brine and dried over sodium sulfate. Filtration and evacuation of the volatiles in vacuo afforded a crude residue which was purified by flash column chromatography over silica gel (Heptane/EtOAc) to afford the desired (rac)-2-methyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (810 mg, MS (ES−): 242.4 (M−H), brown crystals).
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([C:13]3[CH:32]=[CH:31][C:16]([CH2:17][CH2:18][N:19](C)[C:20](=O)OCC4C=CC=CC=4)=[CH:15][CH:14]=3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[CH3:20][NH:19][CH2:18][CH2:17][C:16]1[CH:31]=[CH:32][C:13]([C:10]2[O:11][C:12]3[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=[CH:7][C:8]=3[N:9]=2)=[CH:14][CH:15]=1
Reactant: [H][H]
Reactant: CN(CCc1ccc(-c2nc3cccc(C(N)=O)c3o2)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCCc1ccc(-c2nc3cccc(C(N)=O)c3o2)cc1
Yield: 26 %

Procedure:
A mixture of benzyl 4-(7-carbamoylbenzo[d]oxazol-2-yl)phenethyl(methyl)carbamate (110 mg, 0.26 mmol), 10% Pd/C (20 mg) in methanol (20 ml) was stirred at room temperature over 1 atm hydrogen for 3 h. Then the mixture solution was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by prep-HPLC to give 2-(4-(2-(methylamino)ethyl)phenyl)benzo[d]oxazole-7-carboxamide (20 mg, yield 26%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.45 (s, 3H), 2.91-2.94 (m, 4H), 7.47-7.52 (m, 3 H), 7.88-7.92 (t, J=7.2 Hz, 2H), 8.26-8.28 (d, J=8.4 Hz, 2H). LC-MS (ESI) m/z: 296 (M+1)+.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH:17]([C:25]2[CH:36]=[CH:35][C:28]([CH:29]=[C:30]([CH3:34])[C:31]([OH:33])=[O:32])=[CH:27][CH:26]=2)[CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[CH2:37](O)[CH3:38].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH:17]([C:25]2[CH:26]=[CH:27][C:28]([CH:29]=[C:30]([CH3:34])[C:31]([O:33][CH2:37][CH3:38])=[O:32])=[CH:35][CH:36]=2)[CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CCO
Reactant: CC(=Cc1ccc(C(CNS(=O)(=O)c2ccc(Cl)cc2)Cc2cccnc2)cc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)=Cc1ccc(C(CNS(=O)(=O)c2ccc(Cl)cc2)Cc2cccnc2)cc1
Reaction time: 3 h

Procedure:
To 0.60 g of 4-[1-(4-chlorobenzenesulfonamido)-3-(3-pyridyl)-2-propyl]-α-methylcinnamic acid thionyl chloride and stirred for one hour. To the mixture was added 5 ml of ethanol at 0° C., and stirred for three hours, followed by dropwise addition of saturated aqueous sodium hydrogencarbonate and extraction with ethyl acetate and then further washing in saturated aqueous sodium chloride solution, and dried over magnesium sulfate to distill off the solvent. The residue obtained was subjected to chromatography on a silica gel column, and from a fraction eluted with methanol-methylene chloride (5:95 v/v) was obtained 0.49 g of ethyl 4-[1-(4-chlorobenzenesulfonamido)-3-(3-pyridyl)-2-propyl]-α-methylcinnamate.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:10][CH2:9][N:8]([C:11](=[O:24])[C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[N:19]=3)=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[K+].Cl>CO>[CH3:23][C:20]1[N:19]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:11]([N:8]3[CH2:9][CH2:10][C:5]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]3)=[O:24])=[CH:17][CH:16]=2)[O:22][N:21]=1
Reactant: COC(=O)C1(c2ccccc2)CCN(C(=O)c2ccc(-c3nc(C)no3)cc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1noc(-c2ccc(C(=O)N3CCC(C(=O)O)(c4ccccc4)CC3)cc2)n1
Temperature: 65 °C
Reaction time: 12 h
Yield: 209.7 %

Procedure:
To a solution of 1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoyl]-4-phenyl-piperidine-4-carboxylic acid methyl ester (156 mg, 0.385 mmol) in methanol (2 mL) was added an aqueous solution of KOH (3M, 770 μL, 2.31 mmol) and stirred at 65° C. for 12 h. The mixture was cooled to 0° C. and adjusted to pH=7 with 1N aqueous HCl. The solvent was evaporated under reduced pressure and the residue was co-evaporated with toluene to give 316 mg (purity ˜48%) 1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoyl]-4-phenyl-piperidine-4-carboxylic acid which was used directly for the next step. MS ISP (m/e): 392.2 [(M+H)+].
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=O>>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cccs1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccs4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with thiophene-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(thiophen-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:2]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[N:24]1([C:21]2[CH:22]=[CH:23][C:18]([NH:16][C:14]3[N:15]=[C:8]4[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)=[CH:12][CH:11]=[CH:10][N:9]4[N:13]=3)=[CH:19][CH:20]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: Nc1nc2c(-c3ccncc3)cccn2n1
Reactant: Brc1ccc(N2CCOCC2)cc1
Product: c1cc(-c2ccncc2)c2nc(Nc3ccc(N4CCOCC4)cc3)nn2c1

Procedure:
8-Pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.0 g, 4.7 mmol) and 4-pyridylboronic acid (0.81 g, 6.6 mmol) in a manner analogous to Step 2c. The product of the reaction was isolated as a pale yellow solid (0.54 g, 54%). MP=209-215° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.69 (dd, J=4.8, 1.4 Hz, 2H), 8.65 (dd, J=6.5, 0.8 Hz, 1H), 8.18 (dd, J=4.7, 1.6 Hz, 2H), 7.94 (dd, J=7.5, 0.9 Hz, 1H), 7.03 (t, J=6.8 Hz, 1H), 6.24 (s, 2H). MS=212 (MH)+. 11b) (4-Morpholin-4-yl-phenyl)-(8-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine was prepared from 8-Pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.4734 mmol) and 4-(4-Bromo-phenyl)-morpholine (160.0 mg, 0.6608 mmol) in an anlogous manner to Step 2d. The title compound was isolated as yellow solid (0.035 g, 20%). MP=266-270° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.54 (s, 1H), 8.86 (d, J=6.5 Hz, 1H), 8.75-8.70 (m, 2H), 8.23-8.20 (m, 2H), 8.04 (d, J=7.3 Hz, 1H), 7.62-7.57 (m, 2H), 7.14 (t, J=7.0 Hz, 1H), 6.96-6.90 (m, 2H), 3.76-3.72 (m, 4H), 3.05-3.00 (m, 4H). MS=373 (MH)+.
Reaction SMILES: [ClH:1].[O:2]([C:9]1[CH:24]=[CH:23][C:12]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1(C)C=CC=CC=1>[ClH:1].[O:2]([C:9]1[CH:24]=[CH:23][C:12]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][NH+:18]=2)=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(Oc2ccc(OCCOc3ccccn3)cc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: c1ccc(Oc2ccc(OCCOc3cccc[nH+]3)cc2)cc1

Procedure:
Excess of gaseous hydrogen chloride was gradually introduced into a solution of 2-[2-(4-phenoxyphenoxy)ethoxy]pyridine (1.54 mg, 5.0 mmol) in toluene (50 ml) with stirring. The produced white precipitate was collected by filtration, washed with toluene several times and dried to give 2-[2-(4-phenoxyphenoxy)ethoxy]pyridinium hydrochloride (1.65 g) as white crystals. M.P., 138.1° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]([C:15]#[N:16])=[C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]([C:15]#[N:16])=[C:8]([CH:10]([OH:14])[CH:11]([CH3:12])[CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(=O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CCCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 83.8 %

Procedure:
Following a procedure similar to that described in Example 74(b), but using 2.00 g of 2-butyl-4-isobutyryl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (a) above] and 0.22 g of sodium borohydride, 1.68 g of the title compound was obtained as crystals, melting at 127°-128° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:16][CH2:17][C:18]#[N:19]>Cl.O1CCOCC1>[Cl:16][CH2:17][C:18]1[NH:19][C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[N:1]=1
Reactant: N#CCCl
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(=O)[nH]c(CCl)nc2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of dimethyl 2-aminoterephthalate (1.70 g, 8.1 mmol) in 4.0 M hydrochloric acid in 1,4-dioxane (20 mL) was added chloroacetonitrile (0.88 mL, 14 mmol). The reaction mixture was heated to 50° C. and stirred for 3 h. The mixture was then cooled to rt, concentrated and the residue was twice co-evaporated with toluene. Water was added and the solid was filtered to afford methyl 2-(chloromethyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate (1.8 g, 88%). LC-MS: (FA) ES+ 253; 1H NMR (400 MHz, DMSO) δ 12.81 (s, 1H), 8.23 (d, J=8.2 Hz, 1H), 8.14 (d, J=1.1 Hz, 1H), 8.02 (dd, J=8.2, 1.6 Hz, 1H), 4.57 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: CN(C=O)C.Cl[C:7]1[C:8]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:9]=2[N:10]([CH3:15])[C:11](=[O:14])[CH2:12][N:13]=1.[CH:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][N:10]1[C:9]2[CH:16]=[CH:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:19][C:8]=2[C:7]([C:32]2[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=2)[CH:26]=[O:27])=[N:13][CH2:12][C:11]1=[O:14]
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CN=C(c2cccc(C=O)c2)c2cc(-c3ccccc3)ccc21
Temperature: 120 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To 5 mL of degazed DMF were added 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (200 mg, 0.52 mmol), 3-formylbenzene boronic acid (160 mg, 1.32 mmoles), tripotassium phosphate (300 mg, 1.42 mmol), Pd(PPh3)4 (30 mg, 0.03 mmoles). The mixture was stirred for 16 hours at 120° C. under nitrogen atmosphere. The working solution was diluted ten times with water and extracted three times with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated until dryness. The residue was chromatographied: eluant: CH2Cl2/Et2O: 1/1. The title compound was crystallised from ether/pentane to afford the title compound (118 mg): white solid, (yield=25%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].I[CH2:10][CH3:11].[C:12]12([C:22](O)=[O:23])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2>>[CH2:10]([N:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5]/[C:4]/1=[N:8]\[C:22]([C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:23])[CH3:11]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: CCI
Reactant: Cc1nc(N)sc1C
Product: CCn1c(C)c(C)s/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2

Procedure:
4,5-Dimethylthiazol-2-ylamine, iodoethane and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 1.20-1.29 (m, 3H) 1.68 (q, J=11.96 Hz, 6H) 1.84 (d, J=2.50 Hz, 6H) 1.94-2.03 (m, 3H) 2.16 (s, 3H) 2.21 (s, 3H) 4.14 (q, J=7.18 Hz, 2H); MS (ESI) m/z 319 (M+H)+.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:5]=[C:6]([CH:11]([OH:39])[CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31]CC4C=CC=CC=4)=[O:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH:7]=[CH:8][C:9]=1[OH:10])=[O:2]>CN(C)C=O.[C].[Pd]>[CH:1]([NH:3][C:4]1[CH:5]=[C:6]([CH:11]([OH:39])[CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([OH:31])=[O:30])=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH:7]=[CH:8][C:9]=1[OH:10])=[O:2]
Reactant: O=CNc1cc(C(O)CNCCOc2ccc(-c3ccc(C(=O)OCc4ccccc4)cc3)cc2)ccc1O
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=CNc1cc(C(O)CNCCOc2ccc(-c3ccc(C(=O)O)cc3)cc2)ccc1O
Reaction time: 0.67 h
Yield: 26.4 %

Procedure:
A mixture of benzyl 4′-{2-[2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]ethoxy}biphenyl-4-carboxylate (0.016 g) and 10% palladium-carbon (50% wet, 0.01 g) in N,N-dimethylformamide (10 mL) was stirred for 40 minutes under an atmosphere of hydrogen. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by ODS column chromatography (eluent: acetonitrile/water=1/1) to afford the title compound (0.0035 g)
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]=1[CH:14]=[O:15]>CO.C1COCC1>[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]=1[CH2:14][OH:15]
Reactant: O=CC1=C(Cl)c2ccccc2CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCC1=C(Cl)c2ccccc2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
To a mixture of sodium borohydride (2.83 g, 0.075 mol) in methanol (150 mL) at 0° C., was added dropwise a solution of 1-chloro-2-formyl-3,4-dihydronaphthalene (9.59 g, 0.05 mol) in dry THF (150 mL). The reaction was stirred at room temperature for 1 hour, carbon dioxide was cautiously bubbled through the reaction mixture for 15 minutes, and the resulting mixture was concentrated under reduced pressure. The residue was diluted with water (150 mL), extracted with ether (3×150 mL), dried (MgSO4) and concentrated to give 9.95 g (102%) of product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=2[C:16]=1[O:17][CH3:18].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)(=[O:35])=[O:34])[C:23]([Cl:41])=[CH:22][N:21]=1>>[Cl:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)(=[O:35])=[O:34])=[N:25][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=3[C:16]=2[O:17][CH3:18])=[N:21][CH:22]=1
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Reactant: COc1c(N)ccc2c1CCC(NCCO)CC2
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CCCC3)n2)ccc2c1CCC(NCCO)CC2
Yield: 27 %

Procedure:
In an analogous manner to Experimental 691, part c, 2-(2-amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethanol and (2,5-dichloro-pyrimidin-4-yl)-[2-(pyrrolidine-1-sulfonyl)-phenyl]-amine were combined to yield 2-(2-{5-Chloro-4-[2-(pyrrolidine-1-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethanol (105.68 mg, 27% yield) as a brown foam. 1H-NMR (CDCl3) δ 9.75 (2s, 1H), 8.65 (dd, J=8.6 8.2 Hz, 1H), 8.15 (s, 1H), 7.96 (m, 2H), 7.58 (m, 1H), 7.48 (s, 1H), 7.23 (m, 1H), 6.82 (d, J=7.7 Hz, 1H), 5.30 (s, 1H), 3.73 (s, 3H), 3.26 (br s, 5H), 2.83 (m, 3H), 2.70 (m, 3H), 2.70 (m, 1H), 2.48 (m, 1H), 2.22 (m, 7H, 1.31 (m, 2H). LC/MS (ESI+)=587 (M+H).