Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[C:10]3[N:14]=[CH:13][NH:12][C:11]=3[N:15]=[C:16]([NH2:18])[N:17]=2)=[CH:5][CH:6]=1.[O-]CC.[Na+].[C:23]([O:29][CH2:30]Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>C(O)C>[NH2:18][C:16]1[N:15]=[C:11]2[C:10]([N:14]=[CH:13][N:12]2[CH2:30][O:29][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([O:8][CH2:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[N:17]=1
Reactant: Nc1nc(OCc2ccccc2)c2nc[nH]c2n1
Reactant: CC(C)(C)C(=O)OCCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)C(=O)OCn1cnc2c(OCc3ccccc3)nc(N)nc21
Reaction time: 0.17 h

Procedure:
To 0.24 g (1 mmol) of O6 -benzylguanine under argon was added 1 mL of a 1M solution of sodium ethoxide in ethanol. The homogeneous solution was stirred for 10 minutes. The ethanol was then removed under vacuum. The remaining solid was dissolved in 2 mL of dry DMF. Chloromethyl pivalate (0.145 ml, 1 mmol) was added dropwise to the stirred solution. The mixture was allowed to react for 30 minutes at room temperature. The DMF was removed under vacuum. The residue was triturated with a small volume of 10% ethanol in CHCl3 and the soluble material was loaded on a 2.5×17 cm silica gel column (Davisil grade 633, 200-425 mesh, 60 Å). The product was eluted with 10% ethanol in CHCl3. Yield, 257 mg (72%); mp 161°-162° C.; 1H NMR δ1.09 (s, 9 H, (CH3)3), 5.48 (s, 2 H, CH2N<), 5.96 (s, 2 H, BzlCH2), 6.64 (s, 2 H, NH2), 7.34 (cm, 1 H, p-ArH), 7.39 (cm, 2 H, 2 m-ArH), 7.50 (cm, 2 H, 2 o-ArH), 7.92 (s, 1 H, 8-H); 13C NMR δ26.51 ((CH3)3), 38.20 (C(CH3)3), 65.13 (CH2N), 66.94 (BzlCH2), 113.11 (C-5), 128.05 (p-Ar), 128.38 (2 m-Ar), 128.47 (2 o-Ar), 136.50 (ipso-Ar), 139.96 (C-8), 154.30 (C-4), 160.11 (C-2), 160.18 (C-6), 176.96 (CO2); MS (EI) Calcd. m/z for C18H21N5O3 : 355.1644. Found: 355.1660 (5 ppm error). Anal. Calcd. for C18H21N5O3 : C, 60.83; H, 5.96; N, 19.71. Found: C, 61.11; H, 6.07; N, 19.64.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:10]([C:13]1[CH:14]=[C:15]([C:19](=[S:21])[NH2:20])[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11]>C(O)C>[N+:10]([C:13]1[CH:14]=[C:15]([C:19]2[S:21][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:20]=2)[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: NC(=S)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(-c2cccc([N+](=O)[O-])c2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
A solution of ethyl bromopyruvate (2.14 g) in ethanol (5 ml) was added to a suspension of 3-nitrobenzenecarbothioamide (2.00 g) in ethanol (15 ml) at room temperature. The reaction mixture was stirred at 50° C. for 2 hours and ten minutes. The solvent was removed by evaporation under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate (50 ml) and ethyl acetate (100 ml). The precipitates were collected by filtration and recrystallized from a mixture of chloroform and n-hexane to give ethyl 2-(3-nitrophenyl)-4-thiazolecarboxylate (1.59 g).
Reaction SMILES: NC1C=C(C=C([N+]([O-])=O)C=1C(=O)C1C=CC=CC=1)C(O)=[O:6].N[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([N+:41]([O-:43])=[O:42])[C:31]=1[C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[C:26]([OH:28])=[O:27]>>[OH:6][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([N+:41]([O-:43])=[O:42])[C:31]=1[C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[C:26]([OH:28])=[O:27]
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Reactant: Cc1ccc(C(=O)c2c(N)cc(C(=O)O)cc2[N+](=O)[O-])cc1
Product: Cc1ccc(C(=O)c2c(O)cc(C(=O)O)cc2[N+](=O)[O-])cc1

Procedure:
By replacing in Example 1, step A, 3-amino-4benzoyl-5-nitrobenzoic acid with 3-amino-4-(4'-methylbenzoyl)-5-nitrobenzoic acid and following the procedure described, 3-hydroxy-4-(4'-methylbenzoyl)-5-nitrobenzoic acid is obtained as a hemihydrate with a melting point of 249.5°-251° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1([C:18]2[O:22][N:21]=[CH:20][C:19]=2[CH2:23][CH2:24][C:25](O)=[O:26])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:26])[CH2:24][CH2:23][C:19]2[CH:20]=[N:21][O:22][C:18]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][CH:10]=1)=[O:7]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC(=O)CCc2cnoc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A mixture of methyl 4-aminobenzoate (0.46 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.60 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.48 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.61 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-methoxycarbonylphenyl)-3-(5-phenyl-4-isoxazolyl)propionamide (0.86 g, yield 89%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 111–112° C.
Reaction SMILES: CO[C:3](=[O:7])[C:4]([CH3:6])=[CH2:5].[NH:8]([CH2:12][CH2:13][OH:14])[CH2:9][CH2:10][OH:11]>C[O-].[Na+].O>[OH:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][OH:14])[C:3](=[O:7])[C:4]([CH3:6])=[CH2:5]
Reactant: C=C(C)C(=O)OC
Reactant: OCCNCCO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: C=C(C)C(=O)N(CCO)CCO

Procedure:
N,N-bis(2-hydroxyethyl)methacrylamide was prepared by the alcoholysis of methylmethacrylate with diethanolamine in the presence of sodium methoxide catalyst, following the general procedure of Gast, Schneider and Cowen (J. Am. Oil Chem. Soc. 43 418 (1966)). The crude product was stripped of volatile materials in vacuo, and then dissolved in water and treated with a strong acid ion-exchange resin, sold under the trade mark Dowex X 50, to remove unchanged diethanolamine and any basic by-products. After removing the water in a rotary vacuum evaporator, a colourless oil was obtained which was shown by NMR analysis to be the desired compound in a satisfactory state of purity.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12]O)[N:9]=1)(=[O:3])[CH3:2].S(Cl)([Cl:16])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][Cl:16])[N:9]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Nc1nc(CCCO)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc(CCCCl)cs1
Temperature: 60 °C

Procedure:
To a suspension of 2-acetylamino-4-(3-hydroxypropyl)thiazole (1.5 g) in chloroform (2 ml) was added thionyl chloride (1.1 ml) and the mixture was warmed at 60° C. After the reaction was finished, the reaction mixture was poured into ice water and neutralized with an aqueous solution of sodium hydrogen carbonate. The mixture was extracted with chloroform and the extract was dried over magnesium sulfate and concentrated to give 2-acetylamino-4-(3-chloropropyl)thiazole (1.50 g).
Reaction SMILES: [C:1](=[O:3])=[O:2].[O-:4][CH2:5][CH3:6].[Mg+2:7].[O-:8][CH2:9][CH3:10]>C(O)C>[C:1](=[O:2])([O-:3])[O:4][CH2:5][CH3:6].[Mg+2:7].[CH2:9]([O:8][C:1](=[O:2])[O-:3])[CH3:10]
Reactant: O=C=O
Reactant: CC[O-]
Agent: [Mg+2]
Solvent: CCO
Product: CCOC(=O)[O-]

Procedure:
Generally, magnesium hydrocarbyl carbonate is prepared by reacting carbon dioxide with a magnesium alcoholate. For example, magnesium hydrocarbyl carbonate is formed by suspending magnesium ethoxide in ethanol and adding carbon dioxide until the magnesium ethoxide dissolves forming magnesium ethyl carbonate. If, however, the magnesium ethoxide were suspended in 2-ethylhexanol, magnesium 2-ethylhexyl carbonate, magnesium ethyl carbonate and magnesium ethyl/2-ethylhexyl carbonate may be formed. If the magnesium ethoxide is suspended in a liquid hydrocarbon or halohydrocarbon which is free of alcohol, the addition of carbon dioxide results in the breaking apart of the magnesium ethoxide particles and the magnesium hydrocarbyl carbonate reaction product does not dissolve. The reaction of a magnesium alcoholate with carbon dioxide can be represented as:
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[CH3:5][C:2]([NH:1][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])([CH3:6])[CH2:3][OH:4]
Reactant: CC(C)(N)CO
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CC(C)(CO)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of 2-amino-2-methyl-1-propanol (2.0 g, 21.4 mmol) in tetrahydrofuran (15 mL) was added 1,3-propane sultone (2.66 g, 21.4 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The crude product was collected by filtration, washed with acetone (2×25 mL). The solid was suspended in EtOH (50 mL). The suspension was stirred at reflux for 5 minutes. The solid was collected by filtration and dried in a vacuum oven (50° C.), affording compound DH (2.5 g, 58%): 1H NMR (D2O, 500 MHz) δ ppm 3.48 (s, 2H), 3.04 (t, 2H, J=7.8 Hz), 2.90 (t, 2H, J=7.3 Hz), 2.00 (m, 2H), 1.18 (s, 6H). 13C NMR (D2O, 125 MHz) δ ppm 64.88, 60.27, 48.19, 40.10, 21.92, 20.02. ES-MS 210 (M−1).
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:32](=[O:43])[CH:31]2[C:44]1[C:45]([OH:53])=[CH:46][C:47]2[O:51][CH2:50][CH2:49][C:48]=2[CH:52]=1>>[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:32](=[O:43])[C:31]2([C:44]1[C:45]([OH:53])=[CH:46][C:47]2[O:51][CH2:50][CH2:49][C:48]=2[CH:52]=1)[CH2:5][OH:16]
Reactant: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OCC3)c2cc(Cl)ccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OCC3)c2cc(Cl)ccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl [5-chloro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (99%): MS (ES+) m/z 418.7 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:21]([O:28][C:29](=[O:37])[CH2:30][C@@H:31]([NH2:36])[CH2:32][N:33]([CH3:35])[CH3:34])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29](=[O:37])[CH2:30][C@@H:31]([NH:36][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:32][N:33]([CH3:34])[CH3:35])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=C(O)CCCCCCCCCc1ccccc1
Agent: Cl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCCc1ccccc1

Procedure:
The title compound, m/e=377.3 ([M+H]+), was produced in analogy with intermediate 1, steps 3 and 4. Thus, commercially available 10-phenyldecanoic acid was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-(10-phenyl-decanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH2:3]1.C(OCC)C.N.[Li]>C(O)C>[NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH2:9][CH:10]=[CH:11][CH2:12][C:4]=2[CH2:3]1
Reactant: NC1CCCc2ccccc2C1
Agent: N
Agent: [Li]
Solvent: CCO
Solvent: CCOCC
Product: NC1CCCC2=C(CC=CC2)C1
Reaction time: 0.17 h

Procedure:
A solution of 16.1 g. (0.10 mole) of 6-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene in 100 ml. of diethyl ether and 500 ml. of liquid NH3 is treated portionwise with 15 g. of lithium in small pieces. After 10 minutes, the mixture is treated dropwise with absolute ethanol to completely discharge the color. After removal of NH3, the residue is cooled and treated with water. Further extraction with ether and removal of organic solvent leaves crude 6-amino-1,4,6,7,8,9-hexahydro-5H-benzocycloheptene which is converted to its N-benzoyl derivative with benzoyl chloride-pyridine and thence to the tetrol as described previously.
Reaction SMILES: [CH2:1]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[Br:16][C:17]1[CH:24]=[C:21]([CH:22]=O)[C:20]([O:25][CH3:26])=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:24]=1)[CH:22]=[C:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:2][CH2:1][C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: COc1ccc(Br)cc1C=O
Reactant: c1ccc2c(c1)CCc1ccccc1C2
Product: COc1ccc(Br)cc1C=C1c2ccccc2CCc2ccccc21
Yield: 65.5 %

Procedure:
Following the procedures essentially as described for Preparation 5 and Example 28 above, using dibenzosuberane (15.0 g, 77.2 mmol) and 5-bromo-o-anisaldehyde (16.6 g, 77.2 mmol), recrystallization from boiling toluene/hexanes affords 19.78 g (65%) of the title compound as a tan solid. 1H-NMR (CDCl3) δ 2.76-3.70 (br m, 4H), 3.81 (s, 3H), 6.69 (d, 1H), 6.76 (d, 1H), 6.88-7.29 (m, 9H), 7.53 (m, 1H); HPLC shows 100% purity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[NH:10][C:11](N)=[S:12].C[Si](OP(=O)=O)(C)C.C(=O)(O)[O-].[Na+].[F:27][C:28]([F:33])([F:32])C(O)=O>>[F:1][C:2]1[C:3]2[N:10]=[C:11]([C:28]([F:33])([F:32])[F:27])[S:12][C:4]=2[C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: COc1ccc(F)c(NC(N)=S)c1
Reactant: O=C(O)C(F)(F)F
Agent: C[Si](C)(C)OP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1ccc(F)c2nc(C(F)(F)F)sc12
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A mixture containing crude 3-amino-4-fluoro-2-sulfanylphenol (C15) (Step 1) and polyphosphoric acid trimethylsilyl ester (10 mL) in trifluoroacetic acid (20 mL) was stirred at 95° C. for 18 hours. After cooling to room temperature the reaction was treated with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 30% tert-butyl methyl ether in heptanes) afforded the title compound as a solid. Yield: 1.66 g, 7.0 mmol, 59%. GCMS m/z 237 (M+). 1H NMR (400 MHz, CD3OD) δ 6.90 (dd, J=8.7, 3.3 Hz, 1H), 7.21 (dd, J=10.2, 8.7 Hz, 1H).
Reaction SMILES: F.N1C=CC=CC=1.[Si]([O:15][CH:16]([C:18]1[CH:19]=[C:20]2[C:25](=[N:26][C:27]=1[CH:28]([O:31][CH3:32])[O:29][CH3:30])[N:24]([C:33]([NH:35][C:36]1[CH:41]=[C:40]([NH:42][CH2:43][CH2:44][O:45][CH3:46])[C:39]([C:47]#[N:48])=[CH:38][N:37]=1)=[O:34])[CH2:23][CH2:22][CH2:21]2)[CH3:17])(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C1COCC1>[C:47]([C:39]1[C:40]([NH:42][CH2:43][CH2:44][O:45][CH3:46])=[CH:41][C:36]([NH:35][C:33]([N:24]2[C:25]3[C:20](=[CH:19][C:18]([CH:16]([OH:15])[CH3:17])=[C:27]([CH:28]([O:31][CH3:32])[O:29][CH3:30])[N:26]=3)[CH2:21][CH2:22][CH2:23]2)=[O:34])=[N:37][CH:38]=1)#[N:48]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(C(C)O[Si](C)(C)C(C)(C)C)c(C(OC)OC)nc32)ncc1C#N
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCCNc1cc(NC(=O)N2CCCc3cc(C(C)O)c(C(OC)OC)nc32)ncc1C#N
Reaction time: 18 h

Procedure:
Pyridine hydrofluoride (0.130 ml, 1.012 mmol) was added to a suspension of (racemic) 6-(1-((tert-butyldimethylsilyl)oxy)ethyl)-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 184, 296 mg, 0.506 mmol) in THF (2.5 ml) and stirred for 18 h. The reaction mixture was poured into saturated aqueous NaHCO3 and DCM was added. Phases were separated and the water phase was back extracted with DCM (3×). Organic phases were combined, dried using Na2SO4, filtered and concentrated. The crude product was purified using silica gel column chromatography eluting with MeOH (0-4%) in DCM to yield the title compound as a colorless solid. (UPLC-MS 3) tR 0.90 min, ESI-MS 471.2 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 13.62 (s, 1H), 8.27 (s, 1H), 7.84 (s, 1H), 7.53 (s, 1H), 6.92 (t, 1H), 5.45 (s, 1H), 5.23-5.16 (m, 2H), 3.98-3.88 (m, 2H), 3.53 (t, 2H), 3.41-3.31 (m, 8H), 3.30 (s, 3H), 2.89-2.83 (m, 2H), 1.95-1.86 (m, 2H), 1.30 (d, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[C:12]([C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=1)(=[O:14])[CH3:13]>ClCCl>[C:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:1]([O-:4])=[O:2])=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:16]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1cccc(C(C)=O)c1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C(C)=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.5 %

Procedure:
Fuming white nitric acid (3.6 g) was added dropwise to acetic anhydride (12 ml) at 0° C. and stirred for 15 minutes. The N-(3-acetyl-phenyl)-acetamide (2 g; 11.3 mmol) was then added portionwise and the reaction mixture allowed to warm to room temperature. After stirring at room temperature for 15 minutes, the reaction mixture was poured onto ice (200 ml). Dichloromethane (200 ml) was added and the organic layer was separated, dried (magnesium sulphate), filtered and evaporated to give the crude residue. This was purified by column chromatography to give N-(5-acetyl-2-nitro-phenyl)-acetamide (515 mg), which was directly hydrolysed by heating in 6M hydrochloric acid (15 ml) at 80° C. for 2 hours. The cooled reaction mixture was basified using saturated sodium bicarbonate solution and then extracted into ethyl acetate (6×30 ml). The organic layers were dried (magnesium sulphate), filtered and evaporated to give the crude residue. This was purified by column chromatography (50% ethyl acetate in heptane) to give 3-amino-4-nitroacetophenone (226 mg, 11%).
Reaction SMILES: CC(C)([O-])C.[Na+].I[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[C:18]([O:22][C:23](=[O:32])[NH:24][CH2:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:21])([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[C:18]([O:22][C:23](=[O:32])[NH:24][CH2:25][CH:26]1[CH2:27][CH2:28][N:29]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH2:30][CH2:31]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 90 °C
Yield: 81 %

Procedure:
To a mixture of sodium tert-butoxide, 1-iodo-4-(trifluoromethyl)benzene (686 μl) and tert-butyl(piperidin-4-ylmethyl)carbamate (1.00 g) in toluene (10 ml) was added 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (286 mg) and tris-dibenzylideneacetone palladium(0) (211 mg). The mixture was heated to 90° C. for 15 h. The mixture was cooled to room temperature, concentrated in vacuo, and diluted with dichloromethane. This solution was filtered through a short plug of silica gel and concentrated. The residue was purified via flash chromatography on a Biotage Horizon, 40M column, eluting with 10 column volumes of 33% ethyl acetate in hexanes to provide 1.36 g (81%) of the title compound. Mass spectrum (ESI) 303.0 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1Cl
Reactant: c1nc[nH]n1
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(Cl)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,6-dichloro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-chloro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C@H:16](CN)[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H]([NH:57][CH:58]=[O:59])C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1>>[CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C@H:16]([NH:57][CH:58]=[O:59])[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1
Reactant: C[C@]12CCCCC1C[C@@H](CN)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCCCC1[C@@H](NC=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCCCC1C[C@@H](NC=O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Yield: 92 %

Procedure:
17,17-Bis(ethylendioxy)-7α-formamidoandrostane was prepared in 92% yield from 3,3:17,17-bis(ethylendioxy)-7α-aminomethylandrostane by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6α-formamidoandrostane (Prepn. 20). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 8.10 (1H, m), 7.98 (1H, m), 4.05 (1H, m), 3.89-3.20 (8H, m), 1.93-0.50 (20H, m), 0.80 (3H, s), 0.78 (3H, s)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][CH:11]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:10][CH2:9]1
Reactant: O=C1CCC(c2cnccc2O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3cnccc3O)CC2)C1

Procedure:
The title compound was prepared as a white solid from the reductive amination of 4-(4-hydroxy-pyridin-3-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[S:7][C:6]1=[NH:12])[CH2:2][CH2:3][CH3:4].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH:22]=1)[C:19](O)=[O:20].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:1]([N:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[S:7]/[C:6]/1=[N:12]\[C:19](=[O:20])[C:18]1[CH:22]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=1[O:23][CH3:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CC(C)(C)SC1=N
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: CCCCN1CC(C)(C)S/C1=N\C(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
A mixture of the compound from Example 2A (1.2 g, 6.4 mmol), 5-chloro-2-methoxy-benzoic acid (1.4 g, 7.7 mmol), EDCI (2.45 g, 12.8 mmol), HOBt (1.7 g, 12.8 mmol) and DMAP (78 mg, 0.64 mmol) in pyridine (40 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, eluting with ethyl acetate/hexanes 1:3) to provide 919 mg of title compound. MS (APCI) m/z 355 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.4 Hz, 3H) 1.31 (m, 2H) 1.45 (s, 6H) 1.60 (m, 2H) 3.53 (m, 2H) 3.63 (t, J=7.4 Hz, 2H) 3.77 (s, 3H) 7.09 (d, J=8.9 Hz, 1H) 7.45 (dd, J=8.9, 2.8 Hz, 1H) 7.64 (d, J=2.8 Hz, 1H).