Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11](=[N:25][OH:26])[CH:12]2[CH:17]3[CH:13]2[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16]3)[CH:7]=[CH:8][C:9]=1[Cl:10].[CH2:27](I)[CH3:28]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:11](=[N:25][O:26][CH2:27][CH3:28])[CH:12]2[CH:17]3[CH:13]2[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:16]3)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2C(=NO)c1ccc(Cl)c(Cl)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCON=C(c1ccc(Cl)c(Cl)c1)C1C2CN(C(=O)OC(C)(C)C)CC21
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a suspension of sodium hydride (35 mg, 0.87 mmol, 60% suspension in mineral oil) in dry DMF (3 mL) at 0° C. under nitrogen atmosphere, was added a solution of tert-butyl 6-((3,4-dichlorophenyl)(hydroxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 0.54 mmol), obtained in step-1 of example 1, in DMF (3 mL) The reaction mixture was stirred at the same temperature for 30 min followed by the addition of ethyl iodide (0.09 mL, 1.1 mmol). The reaction mixture was stirred at room temperature overnight. After completion of the reaction as confirmed by TLC, the reaction mixture was quenched by saturated solution of ammonium chloride and the crude compound was extracted with ethyl acetate. The organic layer was washed with water, separated, dried over anhydrous sodium sulphate and concentrated in vacuo to afford tert-butyl 6-((3,4-dichlorophenyl)(ethoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (150 mg, 70%) as a viscous oil which was used without any purification for the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20]N(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:32][C:33]1[CH2:38][CH2:37][CH2:36][C:35](=[O:39])[CH:34]=1>C(O)(=O)C>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][C:34]4[C:35](=[O:39])[CH2:36][CH2:37][CH2:38][C:33]=4[N:32]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NC1=CC(=O)CCC1
Reactant: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Temperature: 100 °C
Yield: 37.1 %

Procedure:
To acetic acid (120 mL) was added molecular sieves (5 Å, 1.50 g), tert-butyl(1-(4-(3-(dimethylamino)-2-phenylacryloyl)phenyl)cyclobutyl)carbamate (8.00 g, 19.0 mmol) and 3-amino-2-cyclohexene-1-one (3.20 g, 28.8 mmol). The reaction mixture was heated to 100° C. under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was partitioned between water (160 mL) and dichloromethane (160 mL) and decanted from the molecular sieves. The layers were separated and the aqueous phase extracted into dichloromethane (2×160 mL). The combined organic phases were washed with saturated NaHCO3 solution (2×160 mL), brine (160 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a yellow/brown solid. This was purified by Biotage chromatography (silica, hexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as a yellow solid (3.30 g, 37% yield). 1H-NMR (500 MHz, CDCl3) δ 8.30 (1H, s), 7.37 (2H, d), 7.30 (2H, d), 7.24-7.27 (3H, m), 7.15-7.20 (2H, m), 5.01 (1H, br s), 3.26 (2H, t), 2.75 (2H, t), 2.42-2.55 (4H, m), 2.26 (2H, p), 2.00-2.10 (1H, m), 1.73-1.85 (1H, m), 1.12-1.44 (9H, br m). LCMS (Method A) RT=7.54 min, M+H+=469.15.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:66][CH3:67])[C:44]([NH:49][C@H:50]2[C@@H:54]([OH:55])[CH2:53][N:52]([C:56]([O:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[O:57])[CH2:51]2)=[N:45][C:46]=1[CH2:47][CH3:48].Br[CH2:69][CH2:70][F:71]>>[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:66][CH3:67])[C:44]([NH:49][C@H:50]2[C@@H:54]([O:55][CH2:69][CH2:70][F:71])[CH2:53][N:52]([C:56]([O:58][CH2:59][C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)=[O:57])[CH2:51]2)=[N:45][C:46]=1[CH2:47][CH3:48]
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Reactant: FCCBr
Agent: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but benzyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylate and 1-bromo-2-fluoro ethane, and making non-critical variations provided the title compound as a oil: 1H NMR (DMSO-d6) δ) 1.07, 1.14, 2.36, 2.65, 3.60, 3.72, 3.79, 3.82, 4.27, 4.42, 4254, 4.62, 5.09, 5.95, 6.98, 7.11, 7.25, 7.38; IR (diffuse reflectance) 2350 (w), 2337 (w), 2058 (w), 1952 (w), 1940 (w), 1710 (s), 1569, 1552, 1483 (s), 1459, 1419 (s), 1397, 1353, 1287, 1228, cm−1 HRMS (FAB) calcd for C29H34ClFN4O4+H 557.2330, found 557.2338.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.C(=O)([O-])O.[Na+].[C:26]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH3:20][C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:5]2[CH:3]1[CH2:2][N:35]([CH2:34][CH2:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:6]2=[O:8]
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc([N+](=O)[O-])c1
Reactant: NCCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(c2cccc([N+](=O)[O-])c2)C2CN(CCCc3ccccc3)C(=O)C21
Temperature: 150 °C

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)-cyclopropane carboxylate (Preparation 5, 14.4 g, 48.6 mmol), in N,N-dimethylformamide (120 Ml) was added sodium hydrogen carbonate (12 g, 143 mmol) and 3-phenylpropylamine (38.8 g, 41 ml, 290 mmol). The mixture was heated to 150° C. for 7 h, then cooled to room temperature and poured onto water (1000 ml). The mixture was extracted with diethyl ether (2×500 ml), and the combined extracts were washed with water (2×250 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica (1000 g) column chromatography eluting with dichloromethane then dichloromethane/ethyl acetate 4:1. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (6.2 g, 36%).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[I-].[F:14][C:15]([F:20])([F:19])[CH2:16][CH2:17][Zn+]>CN(C=O)C.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>[CH3:12][C:11]1[C:2]([CH2:17][CH2:16][C:15]([F:20])([F:19])[F:14])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cnc(Cl)c(C)c1
Reactant: FC(F)(F)CC[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(CCC(F)(F)F)c(C)c1
Temperature: 55 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
To a suspension of zinc powder (2.49 g, 38.1 mmol) in THF (15 mL), 1,2-dibromoethane (0.21 g, 1.1 mmol) and trimethylsilyl chloride (0.12 g, 1.1 mmol) are added. After stirring at rt for 20 minutes, 1,1,1-trifluoro-3-iodopropane (6.10 g, 27.2 mmol) is added, and the mixture is stirred at 55° C. for 1 hour to give a solution of (3,3,3-trifluoropropyl)zinc iodide in THF. To a mixture of methyl 6-chloro-5-methylnicotinate (2.02 g, 10.9 mmol, Step-1) and tetrakis(triphenylphosphine)palladium(0) (1.01 g, 0.87 mmol) in DMF (15 mL) is added the zinc reagent, and the mixture is stirred at 55° C. for 12 hours. After cooling to rt, the mixture is poured onto water (100 mL), and the aqueous layer is extracted with EtOAc (30 mL×2). The combined organic layer is dried over sodium sulfate, and after filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (5:1 to EtOAc only) to give 2.32 g (86% yield) of the title compound as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1O>>[Br:11][C:9]1[CH:8]=[C:4]([C:5]2[O:7][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=2)[CH:3]=[C:2]([Br:1])[CH:10]=1
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Reactant: Nc1ccccc1O
Product: Brc1cc(Br)cc(-c2nc3ccccc3o2)c1

Procedure:
3,5-Dibromo-benzoic acid and 2-aminophenol were condensed to give 2-(3,5-dibromo-phenyl)-benzoxazole, which was converted to N-[3-benzoxazol-2-yl-5-(1H-indol-4-yl)-phenyl]-acetamide as described in Example 106. 1H NMR (400 MHz, DMSO-d6): δ 11.35 (s, 1H), 10.36 (s, 1H), 8.57 (t, J=1.6 Hz, 1H), 8.13 (d, J=1.6 Hz, 2H), 7.77-7.84 (m, 2H), 7.44-7.48 (m, 2H), 7.39-7.43 (m, 2H), 7.21 (t, J=7.5 Hz, 1H), 7.17 (dd, J=7.2, 1.0 Hz, 1H), 6.64-6.67 (m, 1H), 2.11 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>CN(C=O)C.O>[C:25]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][O:16][C:14]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([F:7])[CH:15]=2)=[CH:27][CH:26]=1
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Reactant: O=Cc1ccc(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1F
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
Potassium tert-butoxide (0.217 g, 1.93 mmol) was added to a solution of 2-fluoro-4-hydroxy-benzaldehyde (0.246 g, 1.76 mmol) in anhydrous DMF (5 mL) at 0° C., and the mixture was stirred for 30 min. 4-(3-Bromo-propoxy)-biphenyl (0.564 g, 1.93 mmol, Example 132, Step D) was added, and the mixture stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with EtOAc (5×15 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 4:1) to give 4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-benzaldehyde as a white solid (540 mg, 88%). 1H NMR (200 MHz, CDCl3): δ 10.19 (s, 1H), 7.80 (t, 1H, J=8.4); 7.55–7.48 (m, 4H); 7.42–7.27 (m, 3H); 6.99–6.93 (m, 2H); 6.78 (dd, 1H, J=8.8, 2.6); 6.64 (dd, 1H, J=12.4, 2.2); 4.27–4.15 (m, 4H); 2.30 (qn, 2H, J=5.9)ppm.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C:11]1([CH2:14][N:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[O:17][C:16]2=[O:31])[CH2:13][O:12]1.C(=O)([O-])O.[Na+].O>C(O)C>[Cl:1][C:2]1[N:3]([CH2:13][C:11]([OH:12])([CH3:10])[CH2:14][N:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=3)[O:17][C:16]2=[O:31])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC1(Cn2nc(-c3ccc(OC(F)(F)F)cc3)oc2=O)CO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)(Cn1cc([N+](=O)[O-])nc1Cl)Cn1nc(-c2ccc(OC(F)(F)F)cc2)oc1=O
Yield: 94.1 %

Procedure:
To a suspension of 2-chloro-4-nitro-1H-imidazole (2.21 g, 14.98 mmol) and 3-(2-methyloxiran-2-ylmethyl)-5-(4-trifluoromethoxyphenyl)-3H-[1,3,4]oxadiazol-2-one (2.37 g, 7.49 mmol) in ethanol (25 ml), sodium hydrogencarbonate (1.32 g, 15.73 mmol) was added followed by stirring under reflux for 8 hours. To the reaction mixture, water was added, and the mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate, and concentrated under reduced pressure to afford 3-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-5-(4-trifluoromethoxyphenyl)-3H-[1,3,4]oxadiazol-2-one (3.27 g, yield 94%) as a light yellow amorphous form.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:4]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29](O)=[O:30])=[CH:23]2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.O1CCCC1>[C:14]([CH2:13][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][C@@H:3]([NH:2][C:29]([C:24]2[NH:25][C:26]3[C:22]([CH:23]=2)=[CH:21][C:20]([Cl:19])=[CH:28][CH:27]=3)=[O:30])[C:4]1=[O:18])([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CN1C(=O)[C@H](N)Cc2ccccc21
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CN1C(=O)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Reaction time: 16 h
Yield: 26.3 %

Procedure:
Alternatively, (R)-3-amino-1-carbomethoxymethyl-3,4-dihydrocarbostyril hydrochloride (19 mg) was added to a mixture of tetrahydrofuran (10 mL), 5-chloroindole-2-carboxylic acid (15 mg), 1-hydroxy-7-azabenzotriazole (12 mg), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (16 mg) at room temperature. Diisopropylethylamine (19 mg) was added, and the resulting yellow suspension was stirred under argon for 16 h, during which a solution formed. The solution was diluted with ethyl acetate (50 mL) and washed sequentially with 1.0 M aqueous hydrochloric acid (25 mL twice), 1.0 M aqueous sodium hydroxide (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate and evaporated under vacuum. One half of the residue was purified by reverse phase preparative HPLC to provide the title compound (7.6 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1)[CH3:2].[CH2:15](C(C)=O)[CH:16](C)C>C(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1)[CH3:2].[CH2:1]([C:3]1[CH:8]=[N:7][C:6]2[C:5]([CH:4]=1)=[CH:12][CH:16]=[CH:15][C:9]=2[OH:11])[CH3:2]
Reactant: CC(=O)CC(C)C
Agent: CCc1cnc(C(=O)O)c(C(=O)O)c1
Solvent: ClCCl
Product: CCc1cnc2c(O)cccc2c1
Temperature: 25 °C

Procedure:
Preparation of 5-ethyl-2,3-pyridinedicarboxylic acid ##STR6## The nitrate salt obtained in Example 1 is dispersed in a mixture of 100 mL of methylene chloride and 100 mL of methyl isobutyl ketone, heated at reflux temperature for 1 hour, cooled to room temperature and filtered. The filter cake is washed with a 1:1 mixture of methylene chloride:methyl isobutyl ketone and dried in vacuo to give 5-ethyl-2,3-pyridinedicarboxylic acid, 34.6 g, (89% isolated yield from 3-ethyl-8-hydroxyquinoline), 94.5% pure by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:20]2[C@H:9]3[CH2:10][CH2:11][C@@:12]4([CH2:18][CH3:19])[C@H:16]([C@@H:8]3[CH2:7][CH:6]([CH3:23])[C:5]=2[CH:4]=1)[CH2:15][CH2:14][C@@H:13]4[OH:17].N.[Li].C(O)C>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH:6]([CH3:23])[CH2:7][C@H:8]3[C@H:16]4[C@@:12]([CH2:18][CH3:19])([C@@H:13]([OH:17])[CH2:14][CH2:15]4)[CH2:11][CH2:10][C@@H:9]3[C:20]=2[CH2:21][CH:22]=1
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CC[C@@H]2O
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC[C@]12CC[C@@H]3C4=C(CC(OC)=CC4)C(C)C[C@H]3[C@@H]1CC[C@@H]2O
Yield: 95 %

Procedure:
Add dl-3-methoxy-17β-hydroxy-6-methyl-13-ethylgona-1,3,5(10)-triene (6.80 g) in tetrahydrofuran (200 cc) to liquid ammonia (800 cc) containing tetrahydrofuran (250 cc). Add lithium metal (3.5 g) portionwise and stir the solution for 1.75 hours. Discharge the blue color by dropwise addition of absolute ethanol over 0.25 hours followed by water (2,000 cc). Filter, wash and dry to obtain the dl-3-methoxy-17β-hydroxy-6-methyl-13-ethylgona-2,5(10)-diene (6.5 g), m.p. 176°-182°, λ max. KBr 3.05 μ, 5.90 μ, 6.0 μ, no absorption in the ultraviolet above 220 mμ.
Reaction SMILES: [C:1]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:2][C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:5]([O:7][CH2:8][CH3:9])=[O:6])O.[H][H]>C(O)C>[CH2:2]([C:1]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: [H][H]
Reactant: CCOC(=O)CC(O)(CC(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)CC(CC(=O)OCC)C(=O)OCC
Yield: 54 %

Procedure:
400 ml of triethyl citrate were hydrogenated at 175° C. and 10 bar together with 1100 ml of ethanol and 60 g of catalyst B (4-mm pellets) until the take-up of hydrogen had ceased. The reaction product was freed from ethanol and distilled under reduced pressure, giving 231.8 g (54%) of triethyl 1,2,3-propanetricarboxylate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:16]2[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(OCC)(=O)C.[ClH:30]>C(OCC)(=O)C>[ClH:30].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:16]2[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COCCCc1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCc1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A mixture of tert-butyl 9-(3-methoxypropyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (170 mg, 0.529 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (2 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of isopropyl alcohol and diisopropyl ether to give the desired product (106 mg, 77.9%) as a solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:3]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41].O>C(#N)C>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH:4]2[N:3]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[C:2](=[O:1])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=3)[C:6]3[CH2:18][CH2:19][C:20](=[O:21])[C:5]2=3)=[CH:29][CH:28]=1)#[N:27]
Reactant: COC(=O)CBr
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC#N
Solvent: O
Product: COC(=O)CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 3.00 g, 7.55 mmol) in dry acetonitrile (45 mL) is cooled in an ice bath and treated dropwise with lithium diisopropylamide (2 M in THF, 7.55 mL, 15.1 mmol), while the temperature is kept below 5° C. Methyl 2-bromoacetate (2.31 g, 15.1 mmol) is added and the mixture is stirred for 1.5 h. The mixture is then warmed to room temperature and stirred at room temperature over night. Water (0.5 mL) is added, the mixture is concentrated, and the residue is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 2.64 g; ESI mass spectrum [M+H]+=470; Retention time HPLC: 1.65 min (W018_801).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[C:3]([C:12]([NH:15][C:16]2[NH:20][N:19]=[N:18][N:17]=2)=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1nc2ccccc2nc1Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1nnn[nH]1)c1nc2ccccc2nc1Cl

Procedure:
3-Chloro-2-quinoxalinecarboxylic acid (1.5 g) and N,N'-carbonyldiimidazole (1.2 g) in tetrahydrofuran (50 ml) were heated under reflux for 15 minutes. 5-Amino-1H-tetrazole (0.7 g) in dimethylformamide (5 ml) was added and the solution heated under reflux for 1 hour. The solvent was distilled off and the residue was triturated with dilute hydrochloric acid (25 ml., 2N). The solid was collected and crystallised from aqueous dimethylformamide. It had m.p. 257°-260° (d) (38%).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=2)[CH:5]=1.O.O.[OH-].[Li+].Cl>CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][O:12][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[O:10][CH3:11])[C:3]([OH:22])=[O:2])=[N:16][CH:17]=1
Reactant: COC(=O)c1ccc(OC)c(OCCc2ccc(Cl)cn2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
85 mg 3-[2-(5-Chloro-pyridin-2-yl)-ethoxy]-4-methoxy-benzoic acid methyl ester was dissolved in 1.2 ml of MeOH:water/3:1. 30 mg of lithium hydroxide monohydrate were added to the added to the solution, and the reaction was stirred at RT for 16 h. The reaction mixture was acidified with half-concentrated hydrochloric acid. The suspension was concentrated under reduced pressure, coevaporated twice with toluene (2×10 ml) and then directly subjected to the subsequent amide coupling.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[C:14]([O:22][CH3:23])[CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9].C(O)(=O)C.N(OC(C)(C)C)=O>>[CH3:23][O:22][C:14]1[CH:15]=[C:16]2[C:21]([N:20]=[CH:19][CH:18]=[CH:17]2)=[C:12]2[C:13]=1[C:4]1[C:3]([S:8](=[O:10])(=[O:9])[NH:11]2)=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc(NS(=O)(=O)c2ccccc2N)c2ncccc2c1
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Product: COc1cc2cccnc2c2c1-c1ccccc1S(=O)(=O)N2
Yield: 20.3 %

Procedure:
In a similar fashion using route 16 general procedure 31, 2-amino-N-(6-methoxyquinolin-8-yl)-benzenesulfonamide (Intermediate 169) (100 mg, 0.30 mmol), acetic acid (0.02 ml, 0.32 mmol) and tert-butyl nitrite (60 mg, 0.61 mmol) gave the title compound (19 mg, 36%) after purification by column chromatography with DCM/n-hexane (9:1-1:0) followed by DCM/MeOH (199:1) gradient elution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@:11]3([CH2:16][C@@H:15]([C:17](O)=[O:18])[N:14]([C:20](=[O:35])[C@@H:21]([NH:26][C:27]([O:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:28])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13]3)[O:10][C:9]2=[O:36])[CH:5]=[CH:6][CH:7]=1.[NH2:37][C@@H:38]([CH2:47][CH2:48][CH3:49])[CH:39]([OH:46])[C:40]([NH:42][CH:43]1[CH2:45][CH2:44]1)=[O:41]>>[CH:30]1([O:29][C:27](=[O:28])[NH:26][C@@H:21]([C:22]([CH3:25])([CH3:23])[CH3:24])[C:20]([N:14]2[C@H:15]([C:17](=[O:18])[NH:37][C@@H:38]([CH2:47][CH2:48][CH3:49])[CH:39]([OH:46])[C:40]([NH:42][CH:43]3[CH2:44][CH2:45]3)=[O:41])[CH2:16][C@:11]3([O:10][C:9](=[O:36])[N:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:12]3)[CH2:13]2)=[O:35])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Reactant: CC(C)(C)[C@H](NC(=O)OC1CCCC1)C(=O)N1C[C@@]2(C[C@H]1C(=O)O)CN(c1cccc(Cl)c1)C(=O)O2
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)OC1CCCC1)C(C)(C)C)C(O)C(=O)NC1CC1
Yield: 36 %

Procedure:
Following the same procedure as Example 1 step 1 using (5S,8S)-3-(3-chlorophenyl)-7-((S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylic acid (D3) (10 mg, 20 μmol) and (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (7 mg, 28 μmol) gave 5 mg (7.2 μmol) of Cyclopentyl-(2S)-1-((5S,8S)-3-(3-chlorophenyl)-8-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonan-7-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (E3). LC MS+: 690.38 at 3.31 min (10-90%, 3-5 min, Formic Acid).