Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:17][CH3:18])[C:15]=1[CH3:16])[C:10]([OH:12])=O.[NH2:19][CH2:20][C:21]1[CH:35]=[CH:34][C:24]([CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:23][C:22]=1[N+:36]([O-:38])=[O:37]>CN(C=O)C.C1C=CC=CC=1.ClCCl.C(OCC)(=O)C>[CH3:18][O:17][C:14]1[CH:13]=[C:9]([CH:8]=[C:7]([O:6][CH3:5])[C:15]=1[CH3:16])[C:10]([NH:19][CH2:20][C:21]1[CH:35]=[CH:34][C:24]([CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:23][C:22]=1[N+:36]([O-:38])=[O:37])=[O:12]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)c([N+](=O)[O-])c1
Reactant: COc1cc(C(=O)O)cc(OC)c1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)NCc2ccc(CNC(=O)OC(C)(C)C)cc2[N+](=O)[O-])cc(OC)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
DMF (2 drops) and thionyl chloride (0.080 mL, 1.1 mmol) were sequentially added to a suspension of 3,5-dimethoxy-4-methyl benzoic acid (0.0995 g, 0.507 mmol) in benzene (2 mL). The reaction mixture was heated at reflux for 2 h, and then concentrated. The residue was dissolved in dichloromethane (1 mL) and then added dropwise to a solution of compound 65c (0.144 g, 0.512 mmol) and TEA (0.2 mL, 1.4 mmol) in dichloromethane (1 mL). The reaction mixture was stirred overnight at rt. The mixture was diluted with ethyl acetate and washed with 0.1 N HCl (2×) and saturated sodium bicarbonate solution, dried, and concentrated to give compound 65d (0.233 g, 100%) as a yellow solid ESI-MS m/e 460.4 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:21]2[CH2:22][CH2:23][CH2:24][C:19]([OH:25])([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=3)[CH2:20]2)=[O:6])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)c1cccc(F)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3cccc(F)c3)C2)c1

Procedure:
The compound of Example 2 was prepared according to the general preparation protocol A from 3-fluorobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[C:13]([CH2:25][OH:26])=[N:12][C:11]=2[CH:27]([CH3:29])[CH3:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H][H]>C(OCC)(=O)C.[Pt]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:14]2[C:10]([S:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:11]([CH:27]([CH3:29])[CH3:28])[N:12]=[C:13]2[CH2:25][OH:26])=[CH:17][CH:18]=1
Reactant: CC(C)c1nc(CO)n(Cc2ccc([N+](=O)[O-])cc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)c1nc(CO)n(Cc2ccc(N)cc2)c1Sc1cc(Cl)cc(Cl)c1
Yield: 77.5 %

Procedure:
In ethyl acetate was dissolved 800 mg of 5-(3,5-dichlorophenylthio)-2-hydroxymethyl-4-isopropyl-1-(p-nitrobenzyl)-1H-imidazole (103a), and platinum sulfided carbon was added. After replacement with hydrogen atomosphere, the mixture was catalytically hydrogenated under atmospheric pressure at room temperatures After 1 hour, the mixture was filtered through Celite, the filtrate was distilled off under reduced pressure, and to the residue, diethyl ether was added. The precipitated crystals were filtered, and 579 mg of 1-(p-aminobenzyl)-5-(3,5-dichlorophenylthio)-2-hydroxymethyl-4-isopropyl-1H-imidazole (104a)was obtained (yield 78%). mp 130° C. (decomp.)
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[O:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][CH:16]([O:20]C(C)(C)C)[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1.C(N(CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[O:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][CH:16]([OH:20])[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Oc4ccccc43)CCN2C1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: OC1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Oc4ccccc43)CCN2C1
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
8-chloro-11-[(6S)-8-t-butoxy-1,4-diazabicyclo[4.3.0]non-4-yl]-dibenzo[b,f]-1,4-oxazepine (0.211 g, 0.495 mmol), prepared as described above, was dissolved in trifluoroacetic acid (10 mL) and stirred for 15 minutes. The solvent was removed and the resulting residue was redissolved in methylene chloride (20 mL). Triethylamine (0.100 g, 0.991 mmol) was then added via syringe and the resulting solution was stirred for 1 hour. Washing with water (50 mL), drying over MgSO4 and concentrating resulted in a white solid (0.180 g, 99%); mp 94°-96° C.; Rf(35% acetone/hexanes): 0.15; HRMS (FAB) MH+ of C20H20N3O2Cl, calculated 370.1322, found 370.1 318.
Reaction SMILES: Cl[C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][O:11][CH2:12][CH2:13][NH2:14]>O1CCCC1>[CH3:10][O:11][CH2:12][CH2:13][NH:14][C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COCCN
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)NCCOC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.0 g (13.3 mmol) Ethyl 3-chloro-3-oxopropanoate are dissolved in 50 ml tetrahydrofuran and 2.99 g (39.85 mmol) 2-methoxyethylamine are added at 0° C. The reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the product is isolated by column chromatography (silica, eluent dichloromethane/methanol 50:1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:13][C:14]1[C:27]2[CH2:26][CH2:25][C@H:24]3[C@H:19]([CH2:20][CH2:21][CH2:22][NH:23]3)[C:18]=2[CH:17]=[C:16]([F:28])[CH:15]=1>C(Cl)Cl.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:23]3[C@@H:24]4[C@@H:19]([C:18]5[CH:17]=[C:16]([F:28])[CH:15]=[C:14]([F:13])[C:27]=5[CH2:26][CH2:25]4)[CH2:20][CH2:21][CH2:22]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Fc1cc(F)c2c(c1)[C@H]1CCCN[C@H]1CC2
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3cc(F)cc(F)c3CC[C@@H]21
Yield: 72 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-7,9-difluoro-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 72% of theory; TLC: rf=0.37 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=368 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:55][CH2:56][CH2:57][N:58]([CH2:70][CH2:71]Cl)[C:59]1[CH:68]=[CH:67][C:66]2[C:61](=[CH:62][CH:63]=[C:64]([Cl:69])[CH:65]=2)[N:60]=1>ClCCl>[Cl:69][C:64]1[CH:65]=[C:66]2[C:61](=[CH:62][CH:63]=1)[N:60]=[C:59]([N:58]1[CH2:70][CH2:71][N:55]([C:19](=[O:20])[CH2:18][O:17][CH:14]3[CH2:13][CH2:12][CH:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:23])([F:24])[F:25])[CH:6]=4)[CH2:16][CH2:15]3)[CH2:56][CH2:57]1)[CH:68]=[CH:67]2
Reactant: NCCN(CCCl)c1ccc2cc(Cl)ccc2n1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a solution of 2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid (100 mg, 0.28 mmol) in dichloromethane (20 ml) was added EDAC.HCl (79.4 mg, 0.41 mmol, 1.5 eq), HOBt (56 mg, 0.41 mmol, 1.5 eq), triethylamine (111.6 mg, 1.10 mmol, 4 eq), and N-(2-aminoethyl)-6-chloro-N-(2-chloroethyl)quinolin-2-amine (93.8 mg, 0.33 mmol, 1.2 eq). The resulting solution was stirred overnight at room temperature and then quenched by the addition of water (50 ml), extracted with dichloromethane (3×30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The crude material was purified by Pre-TLC using 4% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-[4-(6-chloroquinolin-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (69.8 mg, 42%). (ES, m/z): [M+H]+ 592.35; 1H NMR (300 MHz, CDCl3): δ 8.00 (d, J=9.0 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.61 (s, 2H), 7.52 (s, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.91 (s, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.61-6.65 (m, 1H), 4.45 (d, J=7.5 Hz, 1H), 4.26 (s, 2H), 3.75-3.78 (m, 7H), 3.37-3.50 (m, 2H), 2.14 (d, J=10.5 Hz, 4H), 1.44-1.51 (m, 2H), 1.24-1.35 (m, 2H).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH:29]=[O:30])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH2:29][OH:30])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: COc1ccc(-c2ccc3cc(C=O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3cc(CO)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 89.6 %

Procedure:
To a solution of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthaldehyde (0.500 g, 1.26 mmol, see Example 9) in 15 mL toluene at −78° C. under an atmosphere of argon was added DIBAL (2.5 mL, 1.0 M in toluene, 3.79 mmol) via needle dropwise. After 1 hour the reaction mixture was quenched with ethyl acetate and the resulting mixture was allowed to warm to RT. The mixture was diluted with ethyl acetate and washed with 1.0 N HCl, water and brine. The organics were dried with magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: CH2Cl2) to give 0.450 g of 6-[3-(1-adamantyl)-4-methoxyphenyl]-naphthalen-2-yl-methylalcohol (90%), mp 169–171° C. 1HNMR (300 MHz; CDCl3): δ 1.80 (s, 6H), 2.10–2.18 (m, 9H), 3.90 (s, 3H), 4.86 (s, 2H), 6.98 (d, J=8.4 Hz, 1H), 7.24–7.25 (m, 1H), 7.46–7.59 (m, 3H), 7.71–7.74 (m, 1H), 7.80–7.89 (m, 3H), 7.97 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)\[CH3:7])[CH3:2].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)\[CH2:7][Br:16])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1ccccc1
Yield: 74.5 %

Procedure:
To a stirred mixture of (E)-3-phenoxy-but-2-enoic acid ethyl ester (5.00 g, 0.024 mol) in carbon tetrachloride (20 mL) under a nitrogen atmosphere was added N-bromosuccinimide (6.50 g, 0.037 mol) and benzoyl peroxide (580 mg, 0.002 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-phenoxy-but-2-enoic acid ethyl ester (5.10 g, 74%) as a yellow oil.
Reaction SMILES: [N:1]1([C@@H:5]([CH3:8])[CH2:6][OH:7])[CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])[CH3:11]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Si:13]([O:7][CH2:6][C@@H:5]([N:1]1[CH2:4][CH2:3][CH2:2]1)[CH3:8])([C:10]([CH3:12])([CH3:11])[CH3:9])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](CO)N1CCC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)N1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
A mixture of (S)-2-(azetidin-1-yl)propan-1-ol (99.7 mmol), TBSCl (15.8 g, 105 mmol), DMAP (1.22 g, 10 mmol), and TEA (30.3 g, 0.30 mol) in toluene (150 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified on a silica gel column eluted with a 1:5 ethyl acetate/petroleum ether then a 1:10 MeOH/DCM, to afford the title compound (2.92 g). 1H NMR (CDCl3): δ 3.54-3.49 (m, 1H), 3.29-3.16 (m, 5H), 2.33-2.27 (m, 1H), 2.07-1.98 (m, 2H), 0.88 (s, 9H), 0.87 (d, 3H), 0.03 (s, 6H); LCMS: 230 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])=[C:3]([C:17](=[O:25])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2cccc(C)c2)c(N)c2ccc(Cl)cc21
Product: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2NS(C)(=O)=O)c1

Procedure:
The title compound was prepared according to the procedure described in Example 33 from ethyl 3-amino-6-chloro-2-(3-methylbenzoyl)-1H-indole-1-carboxylate (step 1 of Example 3) and methanesulfonyl chloride.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:11][CH2:12][CH2:13][CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>CCO>[Br:11][CH2:12][CH2:13][CH2:14][O:10][C:8]1[CH:7]=[CH:6][C:5]2[S:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: Oc1ccc2scnc2c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: BrCCCOc1ccc2scnc2c1
Reaction time: 8 h
Yield: 30.2 %

Procedure:
A mixture of intermediate 25 (1 g, 6.6 mmol), 1,3-dibromopropane (1.83 mL, 18 mmol), anhydrous K2CO3 (828 mg, 6.0 mmol) and EtOH (20 mL) was heated to reflux and stirred overnight. The yellow solid was filtered and purified by column chromatography (elution with PE/EtOAc=3:1) to afford 5-(3-bromopropoxy)benzo[d]thiazole (intermediate 27) (543 mg, 33%) as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[C:26]([O-:29])(=[O:28])[CH3:27].[K+]>CC(C)=O.C(OCC)(=O)C>[C:26]([O:29][CH2:2][C:3](=[O:25])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)(=[O:28])[CH3:27]
Reactant: CC(=O)[O-]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CBr
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 0 °C
Yield: 91.3 %

Procedure:
3.0 g of 21-bromo-17-hydroxy-1,4-pregnadiene-3,20-dione is stirred in 60 ml of acetone with 3.0 g of potassium acetate at 50° C. The reaction mixture is introduced into ice water after 2 hours, the thus-precipitated product is suctioned off, dissolved in ethyl acetate, washed with water, and dried over sodium sulfate, thus producing 2.6 g of 21-acetoxy-17-hydroxy-1,4-pregnadiene-3,20-dione, mp 214° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH2:10])[N:3]=1.[CH3:17][C:18]1C=C(COC)N=C(N(C2C=CC=CC=2)N)N=1>>[CH3:8][C:6]1[CH:7]=[C:2]([CH:1]2[CH2:18][CH2:17]2)[N:3]=[C:4]([N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH2:10])[N:5]=1
Reactant: Cc1cc(C)nc(N(N)c2ccccc2)n1
Reactant: COCc1cc(C)nc(N(N)c2ccccc2)n1
Product: Cc1cc(C2CC2)nc(N(N)c2ccccc2)n1

Procedure:
N-(4,6-dimethylpyrimid-2-yl)-N-phenylhydrazine; N-(4-methyl-6-methoxymethylpyrimid-2-yl)-N-phenylhydrazine.
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[N+:26]([O-])=O)[CH:13]=[CH:12]2)([CH3:4])([CH3:3])[CH3:2].NN>C(O)C.C1COCC1.[Pd]>[C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([NH:17][C:18]1[C:19]([NH2:26])=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH:13]=[CH:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Nc2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(Nc2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
([8-(tert-Butyl-dimethyl-silanyloxy)-quinolin-2-yl]-(4-methoxy-2-nitro-phenyl)-amine 1B (21.9 g, 51.3 mMol) was dissolved in a solution of 200 mL ethanol (EtOH) and 70 mL of THF under an atmosphere of dry N2. To this solution was added 10% palladium on carbon (2.18 g) followed by the dropwise addition of 10 mL of anhydrous hydrazine. The reaction mixture was stirred at ambient temperature for 2 hours after which time it was filtered through Celite™ and the Celite™ was washed with DCM. The combined filtrates were concentrated under vacuum and the resulting residue was partitioned between DCM and aqueous saturated NaHCO3. The DCM layer was then washed again with saturated NaHCO3 and then brine, dried over Na2SO4, filtered and concentrated under vacuum to give 18.3 g of a tan solid as the title compound 1C.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([OH:20])=[O:19])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+:23]>CO>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O-:20])=[O:19])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:6]=1.[Na+:23]
Reactant: Cc1ccc(C(=O)c2ccc3n2CCCC3C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C(=O)c2ccc3n2CCCC3C(=O)[O-])cc1

Procedure:
To a solution of 283 mg. of 3-p-toluoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylic acid in 10 ml. of methanol is added 1 molar equivalent of sodium hydroxide, in the form of a 0.1 N solution. The solvent is then evaporated under reduced pressure and the residue taken up in 2 ml. of methanol, followed by precipitation with ether, to yield crude sodium 3-p-toluoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[N:14]=[CH:13][C:12]([NH2:15])=[C:11]([I:16])[CH:10]=1.Br[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[OH-].[K+].[F-].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[F:8][C:9]1[N:14]=[CH:13][C:12]([NH:15][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[C:11]([I:16])[CH:10]=1
Reactant: BrCCOC1CCCCO1
Reactant: Nc1cnc(F)cc1I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [I-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(I)c(NCCOC2CCCCO2)cn1
Temperature: 100 °C
Yield: 65.5 %

Procedure:
Mix 6-fluoro-4-iodopyridin-3-amine TFA salt (0.36 g, 1.50 mmol), 2-[(2-bromoethyl)oxy]tetrahydro-2H-pyran (1.38 g, 6.60 mmol), potassium hydroxide (0.19 g, 3.30 mmol), potassium fluoride (0.19 g, 3.30 mmol), and tetrabutylammonium iodide (0.11 g, 0.3 mmol) in 1,4-dioxane (1.5 mL) in a seal reactor. Heat the reaction mixture at 100° C. overnight. Cool the reaction mixture to RT. Quench with water. Extract with ethyl acetate, wash the organic layer with water and saturated aqueous sodium chloride. Dry over MgSO4. After filtration, concentrate and purify by FCC (0.1% to 1% 2 M NH3 methanol solution/CH2Cl2) to give the title compound (0.36 g, 66%) with 100% HPLC purity. MS (ES) m/z 367 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]([CH3:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[S:5](=[O:17])(=[O:16])[NH:4][C:3]=1[C:18](OC)=[O:19].[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[N:8]([CH3:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[S:5](=[O:17])(=[O:16])[NH:4][C:3]=1[C:18]([NH:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[O:19]
Reactant: Nc1nccs1
Reactant: COC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1
Solvent: Cc1ccccc1C
Product: Cn1c2c(c3ccccc31)S(=O)(=O)NC(C(=O)Nc1nccs1)=C2O
Yield: 60.3 %

Procedure:
3.0 gm (9.7 millimols) of methyl 2,5-dihydro-4-hydroxy-5-methyl-1,2-thiazino-[5,6-b]indole-3-carboxylate-1,1-dioxide, 1.0 gm-(10 millimols) of 2-amino-thiazole and 150 ml of xylene were refluxed for 3.5 hours in a Soxhlett-apparatus filled with a 4-A-molecular sieve. The reaction mixture then was filtered and yielded 2.2 gm (63% of theory) of crystalline 2,5-dihydro-4-hydroxy-5-methyl-N-(2-thiazolyl)-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide; M.p.: 260° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[C:19]2\[C:20](=[O:31])[N:21]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH2:22][CH2:23]\2)/[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](=[C:19]2\[C:20](=[O:31])[N:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:22][CH2:23]\2)/[C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN1CC/C(=C(/c2ccc(Cl)cc2)c2ccc(S(C)(=O)=O)cc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(/C(=C2\CCN(CCC(=O)O)C2=O)c2ccc(Cl)cc2)cc1
Temperature: 50 °C
Yield: 81.9 %

Procedure:
1 g (0.0045 mole) of ethyl (Z)-3-[3-[1-(4-chlorophenyl)-1-[4-(methylsulphonyl)phenyl]methylene]-2-oxo-pyrrolidin-1-yl]propanoate are placed in a solution in a mixture of 15 ml of ethanol and 20 ml of water and treated with 0.28 g (1.5 eq.) of sodium hydroxide. The medium is heated at 50° C. for 4 h. The ethanol was evaporated off and the aqueous phase is then extracted with ethyl acetate, acidified with a dilute hydrochloric acid solution, and extracted with dichloromethane. The organic phase is washed with water dried and concentrated. The residue is taken up into t-butyl methyl ether. 1.6 g of (Z)-3-[3-[1-(4-chlorophenyl)-1-[4-(methylsulphonyl)phenyl]methylene]-2-oxo-pyrrolidin-1-yl]propanoic acid are thus obtained as a beige solid of melting point 178-179° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH:10]([C:15](OCC)=[O:16])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH:10]([CH2:15][OH:16])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1CCc2cc(NC(C)=O)ccc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(=O)Nc1ccc2c(c1)CCC(CO)O2
Temperature: 0 °C
Yield: 95.2 %

Procedure:
To a solution of 3.0 grams of ethyl 6-acetamidochromane-2-carboxylate (Example 12) dissolved in 20 mL of dry ether is added dropwise a solution of 1 mL of lithium aluminum hydride (70% in benzene) dissolved in about 2 mL of dry ether, and the solution is refluxed for about 1 h. An additional 1 mL of lithium aluminum hydride is added to the mixture, and the mixture refluxed for an additional 1-2 h. The reaction mixture is cooled to 0° C. and the excess hydride quenched by adding 10-12 mL of 1 N H2SO4, followed by 100 mL of water. The precipitate is filtered and washed well with ether. The aqueous phase is separated, extracted several times with 60-mL aliquots of ether. The combined extracts are washed with water and dried over anhydrous MgSO4. Evaporation to dryness under vacuum affords about 2.4 g of 6-acetamido-2-hydroxymethylchromane (about 90% yield).