Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:37]([O:39][CH2:40][CH3:41])=[O:38])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][C@H:16]([N:18]([CH2:27][C@@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[OH:29])[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:5])[CH3:2].CC1C=CC=C(C)N=1.[Si:50](OS(C(F)(F)F)(=O)=O)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51]>C(Cl)Cl>[CH2:40]([O:39][C:37]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][C@H:16]([N:18]([CH2:27][C@H:28]([O:29][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[C:19]([O:21][CH2:22][C:23]([Cl:25])([Cl:24])[Cl:26])=[O:20])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:38])[CH3:41]
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N(C[C@H](O)c3cccc(Cl)c3)C(=O)OCC(Cl)(Cl)Cl)cc2O1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)C(=O)OCC(Cl)(Cl)Cl)cc2O1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To a -78° C. solution of 3.75 g (5.47 mmol) (R,R)-5-{2-[[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester and 60 mL of CH2Cl2 was added 1.27 mL (1.17 g, 10.94 mmol) of 2,6-lutidene followed by 1.38 mL (1.59 g, 6.03 mmol) of TBSOTf. After stirring at -78° C. for 1.5 h, the reaction mixture was quenched with 50 mL sat. aq. NaHCO3 and warmed to room temperature. After extraction with 3×150 mL Et2O, the combined organics were washed with 1×200 mL sat. CuSO4, 1×200 mL brine, dried over MgSO4, filtered and evaporated to a cloudy white oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (8/1 to 4/1) gave 3.42 g (4.46 mmol, an 82% yield) of the title compound (Rf =0.31; 4/1 hexanes/EtOAc) as a gummy colorless solid; 1H NMR (300 MHz, CDCl3): δ-0.13-(-0.08) (m, 3H), 0.00-0.06 (m, 3H), 0.85-0.91 (m, 9H), 1.05 (d, J=6.7 Hz, 3H), 1.33 (t, J=7.1 Hz, 6H), 2.60-2.75 (m, 1H), 2.77-2.96 (m, 1H), 3.00-3.31 (m, 2H), 3.77-4.00 (m, 1H), 4.35 (q, J=7.1 Hz, 4H), 4.65-4.88 (m, 2H), 5.02-5.20 (m, 1H), 6.60-6.85 (m, 4H), 7.15-7.37 (m, 3H); MS (ES) m/z (relative intensity): 790 (M+ +Na, 100), 768 (M+ +H, 20).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)([OH:13])[CH2:9]1)[C:2]1C=CC=CC=1.N1CCOCC1>CN(C)C=O>[Cl:21][C:16]1[CH:15]=[C:14]([C:10]2([OH:13])[CH2:11][CH2:12][N:8]([CH2:1][CH3:2])[CH2:9]2)[CH:19]=[C:18]([F:20])[CH:17]=1
Reactant: OC1(c2cc(F)cc(Cl)c2)CCN(Cc2ccccc2)C1
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CCN1CCC(O)(c2cc(F)cc(Cl)c2)C1

Procedure:
Preparation according to Example 34: (+)-1-benzyl-3-(3-chloro-5-fluorophenyl)-pyrrolidin-3-ol (0.1 g, 0.33 mmol) iodoethane (1 mL, 12.37 mmol), dimethyl formamid (2 mL), morpholine (2 mL). Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1). Yield: 0.05 g. [α]D=+16.7° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diisopropyl ether: M.p. 113-114° C.; MS m/z (relative intensity, 70 eV) 243 (M+, 6), 157 (7), 129 (11), 72 (33), 71 (bp).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.Cl.[C:22](=N)(OCC)[CH3:23].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:22]([CH3:23])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CCOC(C)=N
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 8 h

Procedure:
To a solution of 2.84 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 60 parts by volume of chloroform is added 2.46 parts of ethyl acetoimidate hydrochloride. The mixture is stirred for 8 hours, and then aqueous sodium bicarbonate is added so as to neutralize the mixture. The chloroform layer is separated, washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue is recrystallized from ethyl acetate to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine as colorless needles. Melting point: 225° C to 226° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[C:16](=[O:31])[C:17]4[CH:22]=[N:21][N:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]#[N:27])[C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N-:39]=[N+:40]=[N-:41].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]([C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=4)[C:16](=[O:31])[C:17]4[CH:22]=[N:21][N:20]([C:23]5[CH:30]=[CH:29][CH:28]=[C:25]([C:26]6[NH:41][N:40]=[N:39][N:27]=6)[CH:24]=5)[C:18]=4[N:19]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)nc5)cc4)nc32)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccc(-c3nc4c(cnn4-c4cccc(-c5nnn[nH]5)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)cn1
Temperature: 90 °C

Procedure:
To a solution of 3-[6-[4-(5-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzonitrile (prepared as described in example 28, 0.375 g, 0.726 mmol) in N,N-dimethylformamide (7 mL), sodium azide (0.236 g, 3.63 mmol), ammonium chloride (0.19 g, 3.63 mmol) are added. The reaction mixture is then heated at 90° C. for 14 h. The reaction mixture is concentrated to a dry residue. It is purified by column chromatography to afford 6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-1-[3-(1H-tetrazol-5-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one. 1H NMR (DMSO-d6, 400 MHz) δ 8.81 (s, 1H), 8.57 (s, 1H), 8.50 (br, 1H), 8.38 (m, 1H), 8.27 (m, 1H), 8.07 (d, 1H), 7.79 (m, 2H), 7.55 (m, 2H), 7.39-7.46 (m, 5H), 6.59 (d, 1H), 6.54 (br, 1H); LC-MS calculated for C29H19ClN10O (M+H+) 559.1, found 559.1.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].[Br:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[C:10]([CH2:18][S:19][CH3:20])[CH:9]=1.[H-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](=[O:13])[CH2:1][C:2]([CH:4]2[CH2:6][CH2:5]2)=[O:3])=[C:10]([CH2:18][S:19][CH3:20])[CH:9]=1
Reactant: CC(=O)C1CC1
Reactant: COC(=O)c1ccc(Br)cc1CSC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCc1cc(Br)ccc1C(=O)CC(=O)C1CC1
Temperature: 0 °C
Yield: 52.1 %

Procedure:
A solution of cyclopropyl methyl ketone (1.1 g) and methyl 4-bromo-2-(methylsulphenylmethyl)benzoate (3.6 g) in tetrahydrofuran was added to a refluxing suspension of sodium hydride (80%, 0.9 g) in tetrahydrofuran. After the addition was complete, the mixture was maintained at reflux temperature for 30 minutes. It was then cooled and poured onto 100 g of ice and 50 ml of saturated aqueous sodium bicarbonate. The mixture was extracted with hexane, the organic solution dried (anhydrous sodium sulphate) and the solvent evaporated to give 1-[4-bromo-2-(methylsulphenylmethyl)phenyl]-3-cyclopropylpropan-1,3-dione as an orange oil (2.23 g), NMR (CDCl3): 1.00 (2H,m), 1.20 (2H,m), 1.75 (1H,m), 2.03 (3H,s), 3.92 (2H,s), 6.00 (1H,s), 7.35 (1H,m), 7.45 (1H,m), 7.58 (1H,m) 14.74 (1H,s).
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([O:12][CH2:13][C:14]1[CH2:15][S:16][C@@H:17]2[C@H:37]([NH:38][C:39](=[O:49])[C:40]([C:44]3[O:45][CH:46]=[CH:47][CH:48]=3)=[N:41][O:42][CH3:43])[C:36](=[O:50])[N:18]2[C:19]=1[C:20]([O:22]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21])(=[O:11])[NH2:10]>FC(F)(F)C(O)=O>[C:9]([O:12][CH2:13][C:14]1[CH2:15][S:16][C@@H:17]2[C@H:37]([NH:38][C:39](=[O:49])[C:40]([C:44]3[O:45][CH:46]=[CH:47][CH:48]=3)=[N:41][O:42][CH3:43])[C:36](=[O:50])[N:18]2[C:19]=1[C:20]([OH:22])=[O:21])(=[O:11])[NH2:10]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(N)=O)CS[C@H]12)c1ccco1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
Trifluoroacetic acid (20 ml) was added slowly to a mixture of anisole (5 ml) and diphenylmethyl (6R,7R)-3-carbamoyloxymethyl-7-[2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate (syn isomer) (4.7 g, 8 mmole) which had been cooled in an ice-bath. The flask was shaken occasionally during the next 10 minutes to ensure complete solution of the solid. It was then removed from the icebath and excess trifluoroacetic acid was removed on a rotary evaporator. Trituration of the residue with ethyl acetate (5 ml) gave (6R,7R)-3-carbamoyloxymethyl-7-[2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (syn isomer) (3.3 g, 94%) as a solid which was filtered off and washed with diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:5]2[C:6]([OH:10])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O.ClCCl>[Cl:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][O:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH2:1])[N:11]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Clc1cccc(CBr)c1
Reactant: Nc1nc2c(O)cccn2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: Nc1nc2c(OCc3cccc(Cl)c3)cccn2n1
Temperature: 80 °C

Procedure:
260 a)N-(3-Hydroxy-2-pyridinyl)-N′-carboethoxy-thiourea was prepared from 2-amino-pyridin-3-ol (4.00 g, 0.0363 mol) in a manner analogous to Example 2a. The product of the reaction was isolated as a yellow solid. 260 b) 2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-ol was prepared from N-(3-hydroxy-2-pyridinyl)-N′-carboethoxy-thiourea (1.8 g, 5.9 mmol) in a manner analogous to Example 2b. Product was isolated as a beige solid (3.17 g, 58%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.18 (bs, 1H), 8.02 (dd, J=6.41 Hz, 1.2 Hz, 1H), 6.71-6.64 (m, 2H), 5.79 (bs, 2H). MS=151.0 (MH)+. 260 c) 2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-ol (0.200 g, 1.33 mmol) was suspended in acetone (1.9 mL). 1-(bromomethyl)-3-chloro-benzene (0.184 mL, 1.40 mmol) and potassium carbonate (193 mg, 1.40 mmol) were added and the reaction mixture was heated to 80° C. for 1 hour. Reaction mixture was cooled to room temperature, diluted with water, extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated. Resulting oil was taken up in dichloromethane and purified via chromatography (silica gel 0-100% ethyl acetate in hexanes). 8-(3-Chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was isolated as an oil which solidified on standing. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.17 (d, J=6.6 Hz, 1H), 7.56 (s, 1H), 7.44-7.42 (m, 3H), 6.99 (d, J=7.9 Hz, 1H), 6.79-6.75 (m, 1H), 5.94 (bs, 2H), 5.30 (s, 2H). MS=275 (MH)+. 260 d) [8-(3-Chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(3-chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (95.0 mg, 0.346 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (102 mg, 0.399 mmol in a manner analogous to Example 2d. Product was isolated as a pale orange solid (0.073 g, 47%). MP=135-138° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.33 (s, 1H), 8.37 (d, J=6.7 Hz, 1H), 7.58 (s, 1H), 7.51-7.44 (m, 5H), 7.09 (d, J=7.9 Hz, 1H), 6.91-6.86 (m, 3H), 5.35 (s, 2H), 3.04-3.01 (m, 4H), 2.46-2.44 (m, 4H), 2.22 (s, 3H). MS=449 (MH)+.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([CH:7]([CH3:9])[CH3:8])[N:6]=1.B(F)(F)F.CCOCC.N(OC(C)(C)C)=O.[Na].[OH-].[Na+]>C1COCC1.O>[CH3:9][CH:7]([C:5]1[N:6]=[CH:2][S:3][C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:8]
Reactant: CCOC(=O)c1sc(N)nc1C(C)C
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1scnc1C(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
To a 0° C. solution of ethyl 2-amino-4-(propan-2-yl)-1,3-thiazole-5-carboxylate (3.6 g, 16.7 mmol) in anhydrous THF (60 mL) was added boron trifluoride diethyl etherate (3.0 mL, 23.9 mmol). After 15 minutes of stirring at 0° C., tert-butyl nitrite (10 mL, 84 mmol) was added. The mixture was stirred at 0° C. for 4 hours before more tert-butyl nitrite (10 mL, 84 mmol) was added. The mixture was stirred at 0° C. for 1 hour before a solution of sodium hypophosphonate (6.2 g, 70.1 mmol) in water (20 mL) was added. The mixture was stirred at 0° C. for 2 hours and at room temperature overnight. The solution was basified to pH 9-10 with 5N NaOH and was extracted with EtOAc (3×60 mL). The organic extracts were combined, extracted with brine (1×100 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo, affording ethyl 4-(propan-2-yl)-1,3-thiazole-5-carboxylate (2.1 g, 63% yield). The product was used without further purification.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH2:6][CH:7]1[CH:12]([OH:13])[CH2:11][CH2:10][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8]1)C.[OH-].[Na+]>CO>[OH:13][CH:12]1[CH2:11][CH2:10][CH:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:8][CH:7]1[CH2:6][CH2:5][C:4]([OH:20])=[O:3]
Reactant: CCOC(=O)CCC1CC(c2ccccc2)CCC1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC1CC(c2ccccc2)CCC1O
Yield: 71 %

Procedure:
A solution of 0.68 g. (0.0025 M) of ethyl-4-hydroxy-1-phencyclohexane-3-propionate(g) (obtained in Example 4A) and 1 ml. of 50% sodium hydroxide in 10 ml. of methanol is heated at reflux for about 20 hours. Most of the solvent is removed under vacuum and the residue dissolved in water. The aqueous solution is washed with ether and made acidic with concentrated hydrochloric acid. A solid precipitate is collected on a filter and recrystallized from benzene to give 0.44 g. (71% yield) of 4-hydroxy-1-phenylcyclohexane-3-propionic acid (h) having a melting point of 153.5° to 155° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[CH3:31][C:32]1([CH3:43])[O:36][CH2:35][CH:34]([CH2:37][NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[O:33]1>C(O)C>[CH3:31][C:32]1([CH3:43])[O:36][CH2:35][CH:34]([CH2:37][N:38]([S:39]([CH3:42])(=[O:40])=[O:41])[CH2:31][CH:32]([OH:33])[CH2:43][N:16]2[CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:18][CH2:17]2)[O:33]1
Reactant: CCOC(=O)CN1CCNCCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1
Reactant: CC1(C)OCC(CNS(C)(=O)=O)O1
Solvent: CCO
Product: CCOC(=O)CN1CCN(CC(=O)OCC)CCN(CC(O)CN(CC2COC(C)(C)O2)S(C)(=O)=O)CCN(CC(=O)OCC)CC1

Procedure:
200 ml of absolute ethanol is poured over 8.61 g (20 mmol) of N,N',N"-tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced according to DE 36 25 417 A1) in a bomb tube. After 5.31 g (20 mmol) of N-[(3,3-dimethyl-2,4-dioxa-cyclopentyl)-methyl]-methanesulfonic acid amide is added (Example 21), the bomb tube is closed, flushed with nitrogen, and the resulting reaction mixture is heated for 16 hours to 90° C. After the reaction (TLC control) is completed, the solvent is evaporated in a vacuum and the yellowish, oily residue is chromatographed on silica gel (eluent: chloroform/methanol; methanol: 0-80%).
Reaction SMILES: C([N:8]1[CH2:29][CH2:28][CH2:27][C:10]2([CH2:15][N:14]([C:16]3[CH:21]=[C:20]([N+:22]([O-])=O)[C:19]([NH2:25])=[C:18]([CH3:26])[CH:17]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.[Cl:34][C:35]1[C:40]([CH:41]=O)=[C:39]([I:43])[CH:38]=[CH:37][N:36]=1>CO.[Pd]>[Cl:34][C:35]1[C:40]([C:41]2[NH:22][C:20]3[CH:21]=[C:16]([N:14]4[CH2:13][CH2:12][CH2:11][C:10]5([CH2:27][CH2:28][CH2:29][NH:8][CH2:9]5)[CH2:15]4)[CH:17]=[C:18]([CH3:26])[C:19]=3[N:25]=2)=[C:39]([I:43])[CH:38]=[CH:37][N:36]=1
Reactant: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc([N+](=O)[O-])c1N
Reactant: O=Cc1c(I)ccnc1Cl
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(N2CCCC3(CCCNC3)C2)cc2[nH]c(-c3c(I)ccnc3Cl)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
To a solution of 4-(8-benzyl-2,8-diaza-spiro[5.5]undec-2-yl)-2-methyl-6-nitro-phenylamine (394 mg, 1.0 mmol) in MeOH (47.5 mL) were added Pd/C (10%, 40 mg) and acetic acid (2.5 mL). The mixture was stirred under atmospheric hydrogen (balloon) at the room temperature for 3 h and filter over Celite. The filtrate was mixed with 2-chloro-3-formyl-4-iodopyridine (267.5 mg, 1.0 mmol), stirred at the room temperature for 18 h, and evaporated to dryness under reduced pressure. The residue was dissolved in MeOH (10 mL) and 28% aqueous NH4OH solution (0.5 mL) was added. After it was stirred for 5 min, the mixture was concentrated and chromatographed (100:9:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (288 mg, 55%). 1H NMR (CDCl3) δ 1.28-1.72 (8H), 2.57 (s, 3H), 2.57-3.12 (8H), 6.82 (s, 1H), 6.92 (s, 1H), 6.73 (d, J=6 Hz, 1H), 7.98 (d, J=6 Hz, 1H). ESI-MS m/z 522 (MH+).
Reaction SMILES: [OH-:1].[K+].[CH3:3][C:4]1[N:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:20]=[C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:22]=[C:23]([C:24]#[N:25])[C:6]=2[N:5]=1.OO>O.C1COCC1>[CH3:3][C:4]1[N:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:20]=[C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:22]=[C:23]([C:24]([NH2:25])=[O:1])[C:6]=2[N:5]=1
Reactant: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(C(N)=O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 35 °C
Yield: 72 %

Procedure:
A solution of KOH (45 mg, 0.8 mmol) in water (10 mL) was added dropwise to solution of 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carbonitrile (prepared using the same procedure as Example 24, 150 mg, 0.4 mmol) and 30% H2O2 (3 ml) in THF (15 mL) at rt. The mixture was heated to 35° C. for 1 h. When TLC showed no starting material remaining, water (50 mL) was added, then it was filtered. The filter cake was purified by silica gel chromatography eluted with petroleum ether:EtOAc=1:2 to give the product (115 mg, 72%), as a white solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.47 (s, 3H), 3.05 (t, 4H, J=4.8 Hz), 3.69 (t, 4H, J=4.8 Hz), 6.05 (s, 2H), 6.34 (d, 1H, J=7.2 Hz), 7.25 (d, 1H, J=2.4 Hz), 7.34 (t, 1H, J=7.8 Hz), 7.53 (d, 1H, J=2.4 Hz), 7.63-7.70 (m, 2H,), 7.77 (d, 1H, J=3.0 Hz), 7.86 (d, 1H, J=8.1 Hz), 8.01 (d, 1H, J=7.2 Hz), 8.24 (d, 1H, J=8.1 Hz), 9.24 (d, 1H, J=3.0 Hz); LC-MS: m/e=401 [M+1]+
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][N:20]([CH3:28])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[N:22]=2)=[CH:17][CH:16]=1.[B:31](OC(C)C)([O:36]C(C)C)[O:32]C(C)C.[Cl-].[NH4+]>C1COCC1>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]([CH3:28])[C:21]2[N:22]=[C:23]([F:27])[C:24]([B:31]([OH:36])[OH:32])=[CH:25][CH:26]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(CN(C)c2cccc(F)n2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(CN(C)c2ccc(B(O)O)c(F)n2)cc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
In a microwave tube was placed 2,6-difluoropyridine (0.183 mL, 2.00 mmol) and (4-methoxyphenyl)-N-methylmethanamine (0.604 g, 4.00 mmol) in 2 mL of water. The mixture was heated at 150° C. for 20 min. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layer were dried over anhydrous sodium sulfate, filtered and concentrated to give 470 mg of a crude yellow oil, which was purified by column chromatography (3/1 hexanes/ethyl acetate) to give 400 mg of N-(4-methoxybenzyl)-6-fluoro-N-methylpyridin-2-amine as a clear, colorless oil. To a solution of diisopropylamine (1.92 mL, 13.6 mmol) in 25 mL of THF at 0° C. was added butyllithium (1.6 M in hexanes, 8.93 mL, 14.3 mmol). The mixture stirred for 30 minutes and was then cooled to −60° C. and N-(4-methoxybenzyl)-6-fluoro-N-methylpyridin-2-amine (1.760 g, 7.15 mmol) was added dropwise in 10 mL of THF. The reaction stirred for 1 h at −60° C. and then triisopropyl borate (2.88 mL, 12.5 mmol) was added and the reaction allowed to warm up to RT and stirred for 1 h. Ammonium chloride (sat.) was added and the reaction was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 2.13 g of a crude yellow foam, which was purified by column chromatography (3/1 hexanes/ethyl acetate to 1/1 ethyl acetate/hexanes) to give 750 mg of a off-white solid. ES+=291.2 (M+H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=O)[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.C(OC([N:33]1[CH2:37][CH2:36][CH:35]([CH2:38][NH2:39])[CH2:34]1)=O)(C)(C)C.C(Cl)CCl>CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH:39][CH2:38][CH:35]3[CH2:36][CH2:37][NH:33][CH2:34]3)=[O:22])[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCC1CCNC1)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 9 (2.2 mmol) was coupled with 3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5 mmol) using EDC (3 mmol) in DMF (20 mL). The DMF was removed by rotary evaporation and the residue purified by flash chromatography on silica gel (ethyl acetate as eluent.) The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 418. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.9 (s, 1H) 8.5-8.75 (m, 2H) 8.3 (m, 1H) 8.0 (d, 1H) 7.65 (m, 1H) 7.3 (m, 1H) 7.05 (m, 2H) 6.68 (d, 2H) 3.6 (m, 2H) 3.4 (m, 2H) 3.2-3.4 (m, 2H) 2.48 (m, 3H) 2.0 (m, 2H) 1.7 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[C@H:18]([CH2:19][CH2:20][C:21](=[O:25])[CH:22]=2)[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].O>N1C=CC=CC=1.C(OCC)C>[C:27]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[C@H:18]([CH2:19][CH2:20][C:21](=[O:25])[CH:22]=2)[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 94 g of crude 7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione in 620 ml of pyridine is slowly mixed with 310 ml of acetic anhydride and stirred for 2 hours at 25° C. Then, it is slowly mixed with 116 ml of water while being cooled with ice, diluted with 3 l of diethyl ether, and, after washing with sodium bicarbonate solution, the organic phase is dried and concentrated by evaporation. The residue is chromatographed on silica gel, and 84.4 g of 7α-(5-acetoxypentyl)-estr-4-ene-3,17-dione is obtained as an oil.