Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C([N:14]=C=NCCCN(C)C)C.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cccc(C(=O)O)c1N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C(N)=O)c1N
Reaction time: 60 h
Yield: 86.6 %

Procedure:
To 2-amino-3-methylbenzoic acid (1.5 g, 10 mmol) in DMF (5 mL) at rt were added hydroxybenzatriazole (2.0 g, 13 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.3 g, 12 mmol), ammonium chloride (2.3 g, 42 mmol), and diisopropylethylamine (7.5 ml, 42 mmol). The mixture was purged with N2 and stirred for 60 h. The mixture was poured into water and extracte with EtOAc (50 mL×3), and the combined extracts were washed with brine (20 mL×2), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM and purified by silica gel chromatography eluting with 1:1 EtOAc/hexanes to afford 2-amino-3-methyl-benzamide as a white solid (1.3 g, 87%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:7]=[CH:6][C:5]=2[N:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3[CH:22]=[N:23][C:24](F)=[CH:25][C:26]=3[CH3:27])=[O:20])[CH2:15][CH2:14]2)[CH2:3][CH2:2]1.[O:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34]>>[CH:1]1([C:4]2[CH:9]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:7]=[CH:6][C:5]=2[N:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([N:31]4[CH2:32][CH2:33][O:29][C:30]4=[O:34])=[N:23][CH:22]=3)=[O:20])[CH2:15][CH2:14]2)[CH2:3][CH2:2]1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Reactant: O=C1NCCO1
Product: Cc1cc(N2CCOC2=O)ncc1C(=O)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Yield: 32.3 %

Procedure:
By reaction and treatment in the same manner as in Example 240 and using [4-(2,4-dicyclopropylphenyl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (500 mg) described in Preparation Example 142 and oxazolidin-2-one (459 mg), the title compound (190 mg) was obtained.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:19]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]4[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=4[N:20]=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[CH3:36][O:37][C:38]1[C:43]([O:44][CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])=[CH:42][C:41]([CH2:53][OH:54])=[C:40]([Sn](C)(C)C)[CH:39]=1>O1CCOCC1.CCOC(C)=O>[CH3:36][O:37][C:38]1[C:43]([O:44][CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])=[CH:42][C:41]([CH2:53][OH:54])=[C:40]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([C:19]4[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:22]5[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=5[N:20]=4)=[N:7][N:8]3[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=2)[CH:39]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c2ccc(I)cc21
Reactant: COc1cc([Sn](C)(C)C)c(CO)cc1OCOCC[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(-c2ccc3c(-c4nc5ccccc5n4COCC[Si](C)(C)C)nn(COCC[Si](C)(C)C)c3c2)c(CO)cc1OCOCC[Si](C)(C)C
Yield: 60 %

Procedure:
6-Iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazol-2-yl}-1H-indazole [Example 24(a), step (v)] (300 mg, 0.48 mmol) and [4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-phenyl]-methanol (282 mg, 0.63 mmol) were stirred in dioxane (8 mL) under argon at 98° C. for 16 h. The reaction was allowed to cool and was diluted with EtOAc. Organics were washed with sat NaHCO3 and brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (20% EtOAc/hexanes) gave 224 mg (60%) of 6-[5-methoxy-2-hydroxymethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazol as a faint yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.70 (d, 1H, J=8.4 Hz), 7.89–7.92 (m, 1H), 7.63–7.66 (m, 2H), 7.34–7.41 (m, 4H), 6.91 (s, 1H), 6.29 (s, 2H), 5.83 (s, 2H), 5.36 (s, 2H), 4.55 (s, 2H), 3.78–3.92 (m, 5H), 3.59–3.70 (m, 4H), 0.83–1.04 (m, 6H), 0.03 (s, 9H), −0.04 (s, 9H), −0.13 (s, 9 Hz).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)[OH:23]>O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([NH2:15])=[O:23])=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1cn(-c2ccccn2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: O=S(=O)(O)O
Solvent: O
Product: NC(=O)c1cn(-c2ccccn2)nc1-c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Yield: 97 %

Procedure:
Stir 2.3 g of 3-(5-nitro-2-furyl)-1-(2-pyridyl)pyrazole-4-carbonitrile with 4.4 ml of concentrated sulfuric acid for 15 hours at from 35° to 40° C. Pour the resulting solution onto 75 g of ice and water; separate the formed precipitate and wash it with water until it is no longer acid to obtain a 97% yield of 3-(5-nitro-2-furyl)-1-(2-pyridyl)pyrazole-4-carboxamide [m.p. 249.5° to 250.5° C (from dimethylformamide/methanol)].
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[CH2:16]([NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:17]>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:18]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][CH3:17]
Reactant: CCNC1CCCCC1
Reactant: COc1ccc(N)c(CO)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN(Cc1cc(OC)ccc1N)C1CCCCC1

Procedure:
2-Amino-N-cyclohexyl-N-ethyl-5-methoxy-benzylamine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and N-ethyl-cyclohexylamine analogous to Example 1. Proof of structure by IR- and UV-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [CH2:1](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].[I-:20].[Na+]>CC(C)=O>[I:20][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8]
Reactant: [I-]
Reactant: C#CCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCCCCCCI
Yield: 94.2 %

Procedure:
A mixture of 7-octynyl-p-toluenesulfonate (18.3 g, 65.2 mmol), sodium iodide (9.77 g, 65.2 mmol) and acetone (91 ml) was allowed to react for four hours under reflux. After cooling, the precipitates were removed by filtration, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (eluent; hexane) to afford 14.5 g of 8-iodo-1-octyne (yield; 94.2%).
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=1.[OH-].[K+].C(O)C.Cl>O>[CH3:1][CH:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCCCC(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CCCCCCCCCCCCCNc1ccc(C(=O)O)cc1

Procedure:
A 4 g. (10.3 m mole) sample of ethyl 4-(14-methylpentadecyl)aminobenzoate is hydrolyzed with 2.0 g. (3 eq) 85% potassium hydroxide in 60 ml. 95% ethanol by refluxing the solution for 5 hours. The solution is cooled, diluted with 100 ml. water and acidified to pH 4.5 with 37% hydrochloric acid. The precipitate is collected and dried in vacuo to yield the title compound as a white powder.
Reaction SMILES: [CH:1]([NH2:3])=[S:2].[CH2:4]([O:6][C:7](=[O:20])[CH:8](Br)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=O)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[S:2][CH:1]=[N:3][C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=[O:20])[CH3:5]
Reactant: CCOC(=O)C(Br)C(=O)c1ccccc1OC
Reactant: NC=S
Solvent: CCO
Product: CCOC(=O)c1scnc1-c1ccccc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 0° C. solution of thioformamide (prepared according to Eur. J. Med. Chem. 2004, 39, 867-872) (0.70 g, 11.5 mmol) in absolute EtOH (1 ml) was added a solution of 2-bromo-3-(2-methoxyphenyl)-3-oxo-propionic acid ethyl ester (2.4 g, 7.97 mmol) in ethanol abs. (9 ml) in drops. The reaction mixture was stirred at room temperature for 72 hours. After quenching with water and extraction with chloroform, the organics were dried over Na2SO4 and evaporated. Flash chromatography on SiO2 gel (petroleum ether/ethyl acetate, 60/40) gave crude 4-(2-methoxy-phenyl)-thiazole-5-carboxylic acid ethyl ester that was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])C.[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[N:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]3[CH:19]3[CH2:20][CH2:21]3)=[CH:13][C:12]=1[F:17])[CH2:28]2
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: OCc1cccc2c1CNC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cn(C2CC2)c2nc(N3Cc4cccc(CO)c4C3)c(F)cc2c1=O
Yield: 19 %

Procedure:
310 mg of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4- oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 298 mg of 4-hydroxymethylisoindoline, 0.42 ml of triethylamine, and 5 ml of anhydrous chloroform were processed in a similar manner as in Example 107 to produce 75 mg of 7-(4- hydroxymethyl-2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[CH3:9][C:10]1([CH3:16])[CH2:12][CH:11]1[C:13]([NH2:15])=[O:14].O.N#N>C1(C)C=CC=CC=1>[CH3:9][C:10]1([CH3:16])[CH2:12][CH:11]1[C:13]([NH:15]/[C:2](=[CH:6]\[CH2:7][CH3:8])/[C:3]([OH:5])=[O:4])=[O:14]
Reactant: CCCC(=O)C(=O)O
Reactant: CC1(C)CC1C(N)=O
Agent: N#N
Solvent: Cc1ccccc1
Solvent: O
Product: CC/C=C(\NC(=O)C1CC1(C)C)C(=O)O
Reaction time: 20 h

Procedure:
A solution of 1.74 g (15 mmole) of 2-ketovaleric acid and 1.13 g (10 mmole) of 2,2-dimethylcyclopropanecarboxamide in 20 ml of toluene was refluxed with stirring with collection of H2O in a small Dean-Stark trap. After 20 hrs. the solution was cooled and treated with a gentle stream of N2. Before much of the solvent had evaporated, crystallization was induced by scratching. After standing, the solid was collected on a filter and washed with toluene and some Et2O. Yield of white crystals=0.63 g (30%), mp 154.5°-155.5° (slight prelim. softening). Tlc (4:1 toluene-AcOH) showed only an extremely faint trace of the other isomer. NMR was consistent with the Z-configuration.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[S:9][C:8]([O:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:15][CH:16]=2)=[N:7][CH:6]=1)[NH2:4].[C:21]([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(N=C=NCCCN(C)C)C>ClCCl>[NH2:4]/[C:3](=[N:2]\[O:1][C:31](=[O:32])[CH:29]([NH:28][C:21](=[O:22])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH3:30])/[C:5]1[S:9][C:8]([O:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:15][CH:16]=2)=[N:7][CH:6]=1
Reactant: CC(C)Oc1ccc(Oc2ncc(C(N)=NO)s2)cn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)Oc1ccc(Oc2ncc(/C(N)=N/OC(=O)C(C)NC(=O)OC(C)(C)C)s2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0 %

Procedure:
A solution of Example 81B (370 mg, 1.25 mmol) and N-Boc-alanine (286 mg, 1.51 mmol) in dichloromethane (10 mL) was treated with 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide (361 mg, 1.88 mmol). The reaction was stirred for 15 minutes at 25° C. Dichloromethane (50 mL) was added and the resulting mixture was washed with saturated sodium carbonate (50 mL) and brine (50 mL). The organic layers were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel eluting with a solvent gradient from 10% to 30% ethyl acetate in hexanes to provide 482 ng of the title compound (83%) as white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.26-1.35 (m, J=5.70, 5.70 Hz, 9H) 1.39 (s, 9H) 4.12-426 (m, 1H) 5.14-5.31 (m, 1 H) 6.86 (d, J=8.82 Hz, 1H) 7.05 (s, 2H) 7.37 (d, J=7.72 Hz, 1H) 7.83 (dd, J=9.19, 2.94 Hz, 1H) 7.87 (s, 1H) 8.26 (d, J=2.94 Hz, 1H); MS (ESI) m/z 466.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22].C1C(=O)N([Br:30])C(=O)C1>C(Cl)Cl>[Br:30][C:5]1[S:4][C:3]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:2]([Cl:1])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)c1cc(C)nn2c(-c3sccc3Cl)c(C)nc12
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3Cl)c(C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 3-(3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine. (1.15 g, 3.44 mmol) and CH2Cl2 (12 mL) is added NBS (0.64 g, 3.62 mmol). The solution is stirred at ambient temperature overnight, washed with water (2×75 mL), brine (75 mL), dried over Na2SO4, filtered and concentrated to furnish the title compound (1.36 g, 3.29 mmol, 96%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.49 (s, 3H), 2.53 (s, 3H), 3.26-3.36 (m, 1H), 6.70 (s, 1H), 7.07 (s, 1H). LC/MS (m/z): calcd. for C17H19BrClN3S (M+H)+: 412.1; found: 412.0.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([NH:14][S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[S:12][CH:13]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(Cl)cc3)cs2)cc1

Procedure:
A mixture of 0.3 g of 4-(4-chlorophenyl)-thiazol-2-ylamine hydrobromide with 0.22 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a hot mixture of 20 ml of ethanol and 30 ml of water. 0.05 g of N-[4-(4-chlorophenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide separated as colorless crystals upon cooling.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[O:12][CH2:13][CH:14]([OH:17])[CH2:15][CH3:16])([CH3:4])([CH3:3])[CH3:2].C(C1C=CC=CC=1OCC(O)CC)(C)(C)C>[Pd]>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH3:11])[CH2:7][CH:6]1[O:12][CH2:13][CH:14]([OH:17])[CH2:15][CH3:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(O)COc1cc(C)ccc1C(C)(C)C
Agent: [Pd]
Agent: CCC(O)COc1ccccc1C(C)(C)C
Product: CCC(O)COC1CC(C)CCC1C(C)(C)C
Yield: 62.9 %

Procedure:
The synthesis was carried out in the same manner as described in Example 3b, except that 50 g (0.21 mol) of 1-(2-tert-butyl-5-methylphenyloxy)-2-butanol were used instead of 50 g (0.23 mol) of 1-(2-tert-butylphenyloxy)-2-butanol and the amount of the same palladium catalyst was increased to 2.5 g to effect the reaction for 4 hours, to obtain 32 g of 1-(2-tert-butyl-5-methylcyclohexyloxy)-2-butanol (bp. 139° to 140° C./3.5 mm Hg) in a 63% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([NH2:12])[CH2:9][CH2:10][NH2:11]>C1(C)C=CC=CC=1>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[NH:11][CH2:10][CH2:9][CH2:8][NH2:12]
Reactant: NCCCN
Reactant: Clc1ncccn1
Solvent: Cc1ccccc1
Product: NCCCNc1ncccn1
Yield: 164.1 %

Procedure:
2-chloro-pyrimidine (24.3 g) was added portionwise to a mixture of 1,3-propanediamine (85 g) in toluene (240 mL) while stirring at reflux temperature. The reaction mixture was stirred and refluxed for 3 hours. The reaction mixture was cooled, the precipitate was filtered off and the filtrate was evaporated. The residue was distilled in vacuo, yielding 53 g (65.7%) of N-2-pyrimidinyl-1,3-propanediamine (intermediate 1).
Reaction SMILES: [CH3:1][C@H:2]1[C@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][NH:3]1.[CH3:17][N:18]=[C:19]=[O:20].O>O1CCCC1>[CH3:17][NH:18][C:19]([N:3]1[CH2:4][C@@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[C@@H:2]1[CH3:1])=[O:20]
Reactant: C[C@@H]1NC[C@H]1Oc1cccc(C(F)(F)F)c1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1C[C@@H](Oc2cccc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 16 h
Yield: 91.4 %

Procedure:
A stirred solution of 6 g (0.015 mole) of crude trans-2-methyl-3-[3-(trifluoromethyl)phenoxy]azetidine in 50 ml of tetrahydrofuran was treated with 0.94 g (0.0165 mole of methyl isocyanate added dropwise and stirred for 16 hr under a blanket of nitrogen. Dilution of the reaction mixture with water produced an oil which solidified. After decanting the aqueous tetrahydrofuran phase, the solid residue was recrystallized from ethanol-water to yield 3.95 g (91.4%) of fine white crystals, m.p. 104.5°-106° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]([F:51])[F:50])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:52][O:53][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]([F:50])[F:51])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:52][OH:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CC(=O)Cl
Solvent: CO
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 34.5 %

Procedure:
[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-silane 12g (4.10 g, 4.78 mmol) was dissolved in 30 mL methanol, followed by addition of acetyl chloride (51 μL, 0.72 mmol). The reaction mixture was stirred for 1 hour. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography to obtain the title compound [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoro-ethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 12h (1.23 g, white grease), yield: 34.6%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.Br[CH2:10][CH2:11]Cl.[H-].[Na+].Cl>CS(C)=O.O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2([C:7]#[N:8])[CH2:11][CH2:10]2)=[CH:2]1
Reactant: ClCCBr
Reactant: N#CCc1ccsc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccsc2)CC1

Procedure:
A solution of thiophene-3-acetonitrile (30 g) and 1-bromo-2-chloroethane (40.8 ml) in dimethyl sulphoxide (120 ml) was added slowly dropwise to a well stirred suspension of sodium hydride (60% dispersion in mineral oil; 38.8 g) in dimethyl sulphoxide (800 ml) at 30°-35° C. The solution was stirred at ambient temperature for 21 hours then water (100 ml) was carefully added followed by hydrochloric acid (2M; 100 ml). The mixture was extracted with ether (6×80 ml) and the combined extracts washed with water (2×100 ml) then brine and then dried over magnesium sulphate. The solvent was removed in vacuo and the residue washed with petroleum ether (bp 60°-80° C.) before distillation under reduced pressure which gave 1-(3-thienyl)cyclopropanecarbonitrile as an oil (26.3 g), bp 82°-86° C./2 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([CH2:18][CH2:19][C:20]([NH:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[O:21])[CH:15]=[CH:14][C:4]=1[C:5]([CH2:7]P(=O)(OC)OC)=[O:6].[C:32]([OH:36])(=[O:35])[CH:33]=O.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([CH2:18][CH2:19][C:20]([NH:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[O:21])[CH:15]=[CH:14][C:4]=1[C:5](=[O:6])/[CH:7]=[CH:33]/[C:32]([OH:36])=[O:35]
Reactant: O=CC(=O)O
Reactant: COc1cc(CCC(=O)Nc2nc3ccccc3s2)ccc1C(=O)CP(=O)(OC)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CCC(=O)Nc2nc3ccccc3s2)ccc1C(=O)/C=C/C(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl [{2-methoxy-4-[2-(2-benzothiazolylaminocarbonyl)ethyl]benzoyl}methyl]phosphonate (6.4 g) in tetrahydrofuran (100 ml) is added 40% glyoxylic acid (7.7 ml), and further thereto is added dropwise a 5% aqueous sodium hydroxide solution (70 ml) under ice-cooling. The mixture is stirred for 30 minutes, and the mixture is acidified with 5% hydrochloric acid. The precipitated yellow powder is collected by filtration, washed with ethanol, dried, and then recrystallized from dimethylformamide-ethanol to give 2-{2-[3-methoxy-4-(trans-3-carboxyacryloyl)phenyl]ethylcarbonyl amino}benzothiazole (4.0 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O1CCCC1>[CH3:12][O:11][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: COc1ccc(CCl)cc1C#N
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: COc1ccc(CN2CCOCC2)cc1C#N
Yield: 98.9 %

Procedure:
To a solution of 5-chloromethyl-2-methoxy-benzonitrile (246 mg, 1.354 mmol, example 29) in tetrahydrofuran (10 mL) at room temperature was added morpholine (1.193 mL, 13.54 mmol). The reaction mixture was heated at reflux for 4 h. The reaction was concentrated in vacuo (with heating) to remove morpholine and tetrahydrofuran to afford 2-methoxy-5-morpholin-4-ylmethyl-benzonitrile as a yellow oil (311.2 mg, 99%). The crude product was used without further purification.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12](O)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1.C(C1C=CC(N)=CC=1)(C)(C)C>>[F:28][C:27]([F:30])([F:29])[C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][N:22]=4)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=S1(=O)N=C(O)c2ccc(-c3ncccc3Cl)cc21
Agent: CC(C)(C)c1ccc(N)cc1
Product: O=S1(=O)N=C(Nc2ccc(C(F)(F)F)cn2)c2ccc(-c3ncccc3C(F)(F)F)cc21

Procedure:
The title compound was prepared using the procedure as described in Example 1C, substituting the product of Example 7B for the product of Example 1B, and substituting 2-amino-5-trifluoromethylpyridine for 4-tert-butylaniline. 1H NMR (300 MHz, CDCl3) δ 8.92 (d, 1H), 8.72 (d, 1H), 8.67 (s, 1H), 8.45 (brs, 1H), 8.15-8.19 (m, 2H), 8.11 (dd, 1H), 7.95 (d, 1H), 7.89 (d, 1H), 7.57 (dd, 1H). MS (m/z) 473.1.