Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][C@@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=3)=[C:17]([F:28])[CH:16]=2)[CH2:10]1.C(N(CC)CC)C>CN(C=O)C>[F:28][C:17]1[CH:16]=[C:15]([N:11]2[CH2:10][C@H:9]([CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[O:13][C:12]2=[O:14])[CH:20]=[CH:19][C:18]=1[C:21]1[S:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=1
Reactant: NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Reactant: C=C1CC(=O)O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
Diketene (0.0590 ml, 0.648 mmol) is added dropwise to a solution of 2-[4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-4H-[1,3,4]thiadiazin-5-one (0.200 g, 0.617 mmol) and triethylamine (0.0946 ml, 0.679 mmol) in DMF (2 ml) and is stirred overnight at room temperature. The reaction mixture is evaporated to dryness and the residue is purified by PTLC (10% MeOH/DCM) to give a white solid (0.22 g, 89%); 1HNMR (300 MHz, DMSO-d6) δ 2.08 (s, 3H), 3.34 (s, 2H), 3.42-3.54 (m, 2H), 3.59 (s, 2H), 3.78 (dd, J=6.3, 9.1 Hz, 1H), 4.14 (t, J=9.1 Hz, 1H), 4.75-4.83 (m, 1H), 7.37 (dd, J=2.2, 8.5 Hz, 1H), 7.52 (dd, J=2.2, 14 Hz, 1H), 7.69 (t, J=8.8 Hz, 1H), 8.45 (t, J=5.8 Hz, 1H), 11.6 (s, 1H); mp 176-8; MS (m/z): [M+H]+=409.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:8]=[C:7]([Cl:9])[CH:6]=[C:5](OC(F)(F)F)[N:4]=1>C(OC)(C)(C)C>[NH2:1][C:7]1([Cl:9])[CH:6]=[CH:5][N:4]=[C:3]([Cl:2])[NH:8]1
Reactant: FC(F)(F)Oc1cc(Cl)nc(Cl)n1
Reactant: N
Solvent: COC(C)(C)C
Product: NC1(Cl)C=CN=C(Cl)N1
Reaction time: 1 h
Yield: 32.5 %

Procedure:
4.3 g (0.25 mol) of gaseous ammonia were passed into a mixture of 23.3 g (0.1 mol) of 2,4-dichloro-6-trifluoromethoxypyrimidine in 150 ml of methyl tert-butyl ether in the course of 45 minutes while stirring at -50° to -45° C. Stirring was continued for 30 minutes at -50° C., for 1 hour at -30° C. and for 1 hour at 25° C. The precipitate which separated out was filtered off under suction, washed with water and dried, 5.4 g (33.1% of theory) of 4-amino-2,4-dichloropyrimidine of melting point 270°-272° C. being obtained as a byproduct. The filtrate was washed with water, dried, partially evaporated down under reduced pressure and subjected to fractional chromatography using 5:1 petroleum ether/ether, 3 g (12.8% of theory) of starting material being obtained as a colorless oil from the first fractions and 9 g (42% of theory) of the title compound being obtained as colorless crystals of melting point 55°-56° C. from the final fraction. The conversion was 48.3%.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH:14]1[CH2:22][CH:21]2[CH:17]([CH2:18][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]2)[C:16](=[O:30])[CH2:15]1.C(N(CC)CC)C>ClCCl>[C:26]([O:25][C:23]([N:19]1[CH2:18][CH:17]2[CH:21]([CH2:22][CH:14]([CH2:13][O:12][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:15][C:16]2=[O:30])[CH2:20]1)=[O:24])([CH3:27])([CH3:29])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CC(CO)CC(=O)C2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CC(=O)C3CN(C(=O)OC(C)(C)C)CC3C2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.6 %

Procedure:
17.5 g of p-toluenesulphonyl chloride are added to a solution of 12.4 g of (3aRS,6SR,7aSR)-6-hydroxymethyl-2-tert-butyloxycarbonylperhydroisoindol-4-one and 12.9 cm3 of triethylamine in 250 cm3 of dichloromethane. The mixture is stirred at room temperature for 20 hours, washed with 200 cm3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (diameter 7 cm, particle size 0.06-0.20 mm, height 70 cm), eluting under a pressure of 0.7 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60:40 by volume) and collecting fractions of 250 cm3. Evaporation to dryness of fractions 16 to 24 under reduced pressure (2.7 kPa) gives 12.6 g of (3aRS,6SR, 7aSR)-2- tert-butyloxycarbonyl-6-tosyloxymethylperhydroisoindol-4-one in the form of an oil.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([CH3:19])[C:9]=1[C:10]([NH2:12])=[O:11].[CH3:20][N:21]([CH3:35])[CH2:22][CH2:23][O:24][C:25]1[C:32]([CH3:33])=[CH:31][C:28]([C:29]#N)=[CH:27][C:26]=1[CH3:34]>C1COCC1>[CH3:20][N:21]([CH3:35])[CH2:22][CH2:23][O:24][C:25]1[C:32]([CH3:33])=[CH:31][C:28]([C:29]2[NH:12][C:10](=[O:11])[C:9]3[C:13]([CH:19]=2)=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=3[O:7][CH3:6])=[CH:27][C:26]=1[CH3:34]
Reactant: Cc1cc(C#N)cc(C)c1OCCN(C)C
Reactant: COc1cc(C)c(C(N)=O)c(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN(C)C)c(C)c3)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 8.9 %

Procedure:
n-Butyl lithium (4.2 mL, 10.54 mmol, 2.5 M solution in hexane) was added slowly to a solution of 2,4-dimethoxy-6-methyl benzamide (958 mg, 4.58 mmol) in THF (30 mL) under nitrogen with cooling (ice-salt bath), maintaining the temperature below 20° C. After completion of the addition, the mixture was stirred for 1 h at 0° C., then cooled to −50° C. and a solution of 4-(2-dimethylaminoethoxy)-3,5-dimethyl benzonitrile (1.1 g, 5.04 mmol) (the B-ring building block) in THF (10 mL) was added quickly. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 16 h at room temperature. A saturated NH4Cl solution was added with cooling and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give crude product. The crude product was purified by chromatography to give 3-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (162 mg, 8%) as a hydrochloride. Selected data: MS (ES) m/z: 397.06; MP 261-263° C. at decomposition (HCl).
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c1

Procedure:
Following general procedure A, starting from 2-[4-(1,1-Difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:34])=[C:5]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[C:6]=1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8]>CCO.CCCCCC>[CH3:1][C:2]1[S:3][C:4]([CH3:34])=[C:5]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=2)[C:6]=1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3c(C)sc(C)c3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Solvent: CCCCCC
Solvent: CCO
Product: Cc1sc(C)c(C(=O)NC2(c3ccc(C(=O)O)cc3)CC2)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
Methyl 4-{1-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]cyclopropyl}benzoate from Example 16, Step 3 (172 mg, 0.353 mmol) was reacted under conditions similar to Example 1, Step 11. The crude solid was swished in 10:90 EtOH/hexane and the suspension was filtered. The resulting solid was rinsed with 10:90 EtOH/hexane, then hexane and dried to afford the desired product as a white solid. MS (−ESI): m/z 472 (M−1)−.
Reaction SMILES: [NH2:1][C:2](=O)[CH:3]([NH:13][C:14](=O)[CH2:15][C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH3:12].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1.N1C=CC=CC=1>C(Cl)Cl>[Si:20]([O:19][C:16]([CH3:18])([CH3:17])[CH2:15][C:14]1[S:38][C:2]([NH2:1])=[C:3]([C:4]2[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=2[O:11][CH3:12])[N:13]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(Cl)cc1C(NC(=O)CC(C)(C)O[Si](C)(C)C(C)(C)C)C(N)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1-c1nc(CC(C)(C)O[Si](C)(C)C(C)(C)C)sc1N
Temperature: 95 °C
Yield: 33 %

Procedure:
A mixture of N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)-3-(tert-butyldimethylsilyloxy)-3-methylbutanamide (327 mg, 0.76 mmol), Lawesson's reagent (308 mg, 0.76 mmol) and pyridine (2.5 mL) was heated to 95° C. for 18 hours. DCM was added, the organics washed with sodium hydrogen carbonate (sat. aq.) and brine, then evaporated to dryness. The residues were purified by flash chromatography on silica gel (DCM) to afford 107 mg (33%) of 2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methoxyphenyl)thiazol-5-amine LCMS (ESI) m+H=427.3.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13]CC3C=CC=CC=3)[CH:8]=2)=[C:4]([F:23])[CH:3]=1.[H][H]>C(O)=O.CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=2)=[C:4]([F:23])[CH:3]=1
Reactant: [H][H]
Reactant: Nc1ccc(Oc2ccnc(NCc3ccccc3)c2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 26 %

Procedure:
Palladium hydroxide on carbon (10%, 0.050 g) was added to a solution of 4-(4-amino-2-fluorophenoxy)-N-benzylpyridin-2-amine (0.245 g, 0.790 mmol, 1.0 eq) in 5% HCO2H-MeOH (10 mL) under a blanket of hydrogen (from a balloon) at room temperature. The reaction mixture was stirred at room temperature for 12 h, filtered through Celite® and the filtrate concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (YMC ODS-A S10 30×500 mm., 10-90% aqueous MeOH with 0.1% TFA, 30 minute gradient) and the appropriate fractions were concentrated in vacuo. The concentrate was neutralized with saturated aqueous NaHCO3 solution and the mixture was extracted with CHCl3 (3×35 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (0.045 g, 26%) as a solid. 1H NMR (CD3OD) δ 7.62-7.63 (m, 1H), 6.77-6.82 (m, 1H), 6.38-6.47 (m, 2H), 6.09-6.11 (m, 1H), 5.83-5.84 (m, 1H); MS(ESI+) m/z 220 (M+H)+; HRMS(ESI+) calcd.: 220.0886, found: 220.0877.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7](O)[CH:8]([NH:22]C(OCC1C=CC=CC=1)=O)[CH2:9][CH2:10][O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])([CH3:4])([CH3:3])[CH3:2].C[OH:36]>>[C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([NH2:22])[CH:9]([OH:36])[CH2:10][O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(O)C(CCOc1c(F)c(F)cc(F)c1F)NC(=O)OCc1ccccc1
Reactant: CO
Product: CC(C)(C)OC(=O)CC(N)C(O)COc1c(F)c(F)cc(F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
Composition 13 (163 mg, 0.33 mmol) and MeOH (˜15 mL) was added to a dry round bottom flask equipped with a magnetic stir bar. The flask was purged several times with N2 and a catalytic amount of 10% Pd on C was carefully added to the reaction flask. The resulting black heterogeneous mixture was evacuated under vacuum and charged twice with H2 via a rubber balloon with constant stirring. The reaction was stirred at room temperature for 1.5 h and upon completion was filtered thru a pad of Celite, concentrated in vacuo to give 14 (115 mg, 0.32 mmol, 99% yield) as a sticky off-white solid. ESMS: 354.8 (M+H), 376.2 (M+Na+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[C:27]1([C:33]2([OH:41])[CH2:39][CH:38]3[NH:40][CH:35]([CH2:36][CH2:37]3)[CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O.C(OCC)(=O)C>[CH3:24][C:21]1[O:22][C:23]2[C:15]3[O:14][CH:13]([CH2:12][N:40]4[CH:38]5[CH2:37][CH2:36][CH:35]4[CH2:34][C:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([OH:41])[CH2:39]5)[CH2:26][O:25][C:16]=3[CH:17]=[CH:18][C:19]=2[N:20]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Reactant: OC1(c2ccccc2)CC2CCC(C1)N2
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1C2CCC1CC(O)(c1ccccc1)C2)CO3
Temperature: 77.5 °C

Procedure:
(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl 4-methylbenzenesulfonate (0.375 g, 1.00 mmole) and 3-phenyl-8-aza-bicyclo[3.2.1]-octan-3-ol (0.25 g, 1.2 mmole) were combined in 8 mL of DMSO. This solution was heated to 75-80° C. under nitrogen for 8 hours. After completion, the reaction was cooled to room temperature and diluted to 500 mL with ethyl acetate. The mixture was washed twice with 400 mL portions of saturated aqueous sodium bicarbonate, with 300 mL of water and twice with 400 mL of saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The crude oil was column chromatographed on silica gel using first methylene chloride to remove impurities and then 0.5% methanol/methylene chloride to give, after concentration of the product fractions in vacuum, 0.12 g of the (S)-enantiomer of the title compound as an off-white solid, m.p. 203-205° C.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:17]([NH:19][C:20]1([C:30]#[N:31])[CH2:24][CH2:23][N:22]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:21]1)=[O:18]>>[C:30]([C:20]1([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:24][CH2:23][N:22]([CH:25]([CH2:26][CH3:27])[CH2:28][CH3:29])[CH2:21]1)#[N:31]
Reactant: CCC(CC)N1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)C1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Agent: Cl
Product: CCC(CC)N1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC2=NS(=O)(=O)c3ccccc32)C1

Procedure:
The title compound was prepared starting from 3-chloro benzo[d]isothiazole 1,1-dioxide and 2-amino-N-[3-cyano-1-(1-ethyl-propyl)pyrrolidin-3-yl]-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 10, except that the compound was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 40% acetonitrile in water to acetonitrile. MS, m/z 500=M+1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH2:6]O.[ClH:12].C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH2:6][Cl:12]
Reactant: COc1cc(CO)ccc1C
Reactant: Cl
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCl)ccc1C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 3-methoxy-4-methylbenzylalcohol (41.61 g), conc. hydrochloric acid (125 ml) and toluene (83 ml) was stirred at 90° C. for 1 hour. After cooling, ice-water (125 ml) and diisopropyl ether (80 ml) were added to the mixture, and the organic layer was separated, and the aqueous layer was extracted with diisopropyl ether (160 ml). The combined organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over sodium sulfate, and evaporated in vacuo to give 3-methoxy-4-methylbenzyl chloride (46.35 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.O=S(Cl)[Cl:25]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][Cl:25])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of ethyl 6-[(tert-butoxycarbonyl)amino]pyridine-2-carboxylate (456 mg, 1.71 mmol) in anhydrous ethanol (20 ml) was added pulverized CaCl2 (395 mg, 3.42 mmol). The suspension was stirred and cooled to 0° C. and NaBH4 (325 mg, 8.55 mmol) was added slowly. The reaction was stirred at 0° C. for 2 h, quenched with water, and extracted with CHCl3 (×3). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (30→50% ethyl acetate in hexane) to yield a colorless syrup (308 mg) as a mixture containing tert-butyl[6-(hydroxymethyl)pyridin-2-yl]carbamate as the major component (˜4:1 ratio). To a solution of the above mixture in CH2Cl2 (10 ml) was added pyridine (144 μl, 1.79 mmol) and SOCl2 (120 μl, 1.65 mmol). The reaction was stirred at room temperature for 4 h, quenched with water and saturated Na2CO3, and extracted with CHCl3. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (10% ethyl acetate in hexane) to yield the title compound as a colorless syrup (208 mg, 50% over 2 steps).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH2:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH:19][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COCCOCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCCOCCNc1ccc([N+](=O)[O-])c(N)c1
Temperature: 120 °C
Reaction time: 72 h

Procedure:
A mixture of 5-chloro-2-nitroaniline (1.6 g, 9.3 mmol), 2-(2-methoxy-ethoxy)-ethylamine (2.0 g, 16.8 mmol) and anhydrous potassium carbonate (1.38 g, 10 mmol) in N,N-dimethylacetamide (3 ml) was stirred at 120° C. under nitrogen for 3 days. Sample NMR analysis showed 80% conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water (30 ml) and extracted with ethyl acetate. The organic extract was washed with brine, dried and evaporated. The resulting orange yellow oil was subjected to a silica gel filtration on a 5 cm×6 cm silica gel plug, eluting first with 50% ethyl acetate/petroleum spirits (40-60° C.), followed by 100% ethyl acetate. Evaporation yielded an orange-red liquid, 1.1 g (45.8% yields).
Reaction SMILES: Cl[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[CH2:5][CH2:4][CH2:3]1.[C-:17]#[N:18].[Na+]>CS(C)=O>[C:17]([CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[CH2:5][CH2:4][CH2:3]1)#[N:18]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cccc2c1CCCC2Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cccc2c1CCCC2C#N
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In 44 ml. of dimethylsulfoxide is dissolved 4.4 g. of ethyl 1-chloro-1,2,3,4-tetrahydro-5-naphthoate, followed by the addition of 2 g. of sodium cyanide. The mixture is stirred at 50° C for 3 hours and following the addition of 450 ml. of 0.2N hydrochloric acid, the mixture is extracted with ethyl ether. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resultant oily residue is purified by column chromatography on silica gel (100 g. silica gel; eluted with benzene). The procedure gives ethyl 1-cyano-1,2,3,4-tetrahydro-5-naphthoate as an oily product. Infrared absorption spectrum (neat)
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=2[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]3[NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[C:27]=2[F:34])[CH2:8]1)=[O:6].[CH3:35][NH:36][CH3:37].C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:33][C:28]1[C:27]([F:34])=[C:26]([NH:25][C:16]2[C:15]3[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][C@H:9]4[CH2:10][CH2:11][N:7]([C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:36]([CH3:37])[CH3:35])[CH2:8]4)[CH:14]=3)[N:19]=[CH:18][N:17]=2)[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: CNC
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)/C=C/CBr)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)/C=C/CN(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
580 mg of the compound obtained in step 1) was dissolved in 10 ml of tetrahydrofuran at 0° C., and 5 ml of a 1.0 M dimethylamine-containing tetrahydrofuran solution was added thereto. The resulting mixture was stirred at room temperature for one hour, a saturated sodium bicarbonate was added thereto, and the resulting solution was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was purified by column chromatography (chloroform:methanol=30:1) to obtain the title compound (175 mg, 32%).
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)(=[O:3])[NH2:2].[NH2:20][C@@H:21]([CH3:38])[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]2[CH:35]=[C:34]([F:36])[C:31]([C:32]#[N:33])=[C:30]([Cl:37])[CH:29]=2)=[N:24]1>>[Cl:37][C:30]1[CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][N:23]([CH2:22][C@@H:21]([NH:20][C:9]([C:7]3[N:8]=[C:4]([C:1]([NH2:2])=[O:3])[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=3)=[O:11])[CH3:38])[N:24]=2)[CH:35]=[C:34]([F:36])[C:31]=1[C:32]#[N:33]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)nc1C(N)=O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(C(N)=O)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-carbamoyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (500 mg, 1.7 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (472 mg, 1.7 mmol). The product was purified with flash-chromatography. Yield 420 mg. LC-MS: [M+1]=546.19.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([O:19][C:20]1[CH:21]=[C:22]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([O:36][CH3:37])[CH:30]=1)[CH2:16][CH2:17][CH3:18]>C(C(C)=O)C.C(OCC)(=O)C>[CH2:7]([O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][CH2:27][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:21][C:20]=2[O:19][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:30][C:31]=1[O:36][CH3:37])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCOc1cc(CCC(=O)OC)ccc1CCCc1ccc(O)c(OC)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCCCOc1cc(CCC(=O)OC)ccc1CCCc1ccc(OCc2ccccc2)c(OC)c1
Temperature: 70 °C
Yield: 90.7 %

Procedure:
0.2 g (0.75 mmol) of potassium carbonate and then 0.2 ml (0.75 mmol) of benzyl bromide are added to a solution of 0.25 g (0.62 mmol) of methyl 3-{3-butoxy-4-[3-(4-hydroxy-3-methoxyphenyl)propyl]phenyl}propanoate in 25 ml of methyl ethyl ketone. The reaction mixture is heated at 70° C. for 24 hours and then cooled, diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 276 mg (93%) of methyl 3-{4-[3-(4-benzyloxy-3-methoxyphenyl)propyl]-3-butoxyphenyl}propanoate are obtained in the form of a colorless oil.