Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[N:14][C:15]([Cl:19])=[CH:16][CH:17]=2)[CH:12]=[C:11]1[CH:20]=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.CCO>[CH2:3]([N:10]1[C:18]2[C:13](=[N:14][C:15]([Cl:19])=[CH:16][CH:17]=2)[CH:12]=[C:11]1[CH2:20][OH:21])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cc2nc(Cl)ccc2n1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1cc2nc(Cl)ccc2n1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
K2CO3 (0.39 g, 2.8 mmol) and benzyl bromide (0.12 mL, 1.0 mmol) were added to a solution of 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde (0.17 g, 0.94 mmol, from Step 1) in DMF (3.6 mL). After 15 minutes, the reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with two portions of water, one portion of brine, then dried over sodium sulfate, filtered and concentrated to afford 0.26 g of crude 1-benzyl-5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde as a yellow solid. Sodium tetrahydroborate (53 mg, 1.4 mmol) was added to a solution of the crude aldehyde in THF (5.0 mL) and EtOH (5.0 mL). After 15 minutes, the reaction mixture was quenched with saturated NH4Cl, and was extracted with EtOAc. The extracts were washed with water followed by brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-40% EtOAc in hexanes afforded purified product as a white solid (0.21 g, 82%). 1H NMR (300 MHz, CDCl3) δ 7.45 (d, J=8.6 Hz, 1H), 7.33-7.25 (m, 3H), 7.06 (d, J=8.6 Hz, 1H), 7.03-6.88 (m, 2H), 6.66 (s, 1H), 5.47 (s, 2H), 4.78 (s, 2H).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH2:14][C:15](=[O:20])[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])[CH3:2].CO.Cl>O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(=O)CC4
Agent: Cl
Solvent: CO
Solvent: O
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Yield: 66.7 %

Procedure:
Stir 13β-ethyl-17β-hydroxy-gon-5(10)-en-3-one (300 mg.) for 2 hours under nitrogen at room temperature with methanol (10 cc.)-11N hydrochloric acid (0.5 cc.)-water (0.3 cc.). Add sodium bicarbonate (2 g.) and ether (50cc.), filter the mixture, evaporate the ether and recrystallize the residue from ethyl acetate-ether to give 13β-ethyl-17β-hydroxy-gon-4-en-3-one (0.2 g.), m.p. 147°-149°; ultraviolet absorption peak at 242 mμ (ε 17,600); infrared absorption peaks at 2.78, 2.90, 6.02, 6.17.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][O:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[C:1]([O:5][C:6](=[O:14])[CH2:7][CH2:8][N:9]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH2:10][CH2:11][O:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COCCNCCC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: COCCN(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
A solution of 2.23 g (0.011 mole) of 3-(2-methoxy-ethylamino)-propanoic acid tert-butyl ester in 20 mL of water was added dropwise to a solution of 1.94 g (0.01 mole) of 2,4-dichloro-5-nitro-pyrimidine in 20 mL of ethyl ether. At 0 degrees, 2.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-85:15) gave 3.3 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(2-methoxy-ethyl)-amino]-propanoic acid tert-butyl ester (IV-40).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[C:10]([NH:12]C(=O)C(F)(F)F)[CH:9]=[CH:8][C:7]=1[S:19](Cl)(=[O:21])=[O:20])(=[O:4])=[O:3].[NH2:23][C:24]1[CH:25]=[CH:26][C:27]2[CH2:31][O:30][B:29]([OH:32])[C:28]=2[CH:33]=1.N1C=CC=CC=1>C(#N)C>[NH2:12][C:10]1[CH:9]=[CH:8][C:7]([S:19]([NH:23][C:24]2[CH:25]=[CH:26][C:27]3[CH2:31][O:30][B:29]([OH:32])[C:28]=3[CH:33]=2)(=[O:20])=[O:21])=[C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:11]=1
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: CS(=O)(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CS(=O)(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a stirred solution of 2-(methylsulfonylmethyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (680 mg, 1.8 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (400 mg, 2.7 mmol) in 10 mL of ACN was added pyridine (290 uL, 3.6 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours. After the mixture was concentrated, the residue was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. A solution of this crude compound in 7M ammonium in MeOH (10 mL) was stirred in a sealed tube at 50° C. for 4 hours. After concentrated, the crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a white solid (498 mg, yield 70%). MS calcd for (C15H17BN2O6S2): 396.2. MS found (ESI negative): (M−H)−=395.1. 1H NMR (DMSO-d6) δ (ppm): 9.95 (s, 1H), 9.20 (bs, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.72 (s, 1H), 6.47 (d, J=8.8 Hz, 1H), 4.85 (s, 2H), 4.71 (s, 2H), 2.82 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]2[C:8]([O:14]C(=O)C)=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[C:4]=1[C:18](=[O:31])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1>C(#N)C>[N:38]1([CH2:2][C:3]2[O:7][C:6]3[C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=3[C:4]=2[C:18](=[O:31])[C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:42]=[CH:41][N:40]=[CH:39]1
Reactant: c1c[nH]cn1
Reactant: COc1cc(C(=O)c2c(CBr)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(=O)c2c(Cn3ccnc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 8 h
Yield: 19.3 %

Procedure:
To a stirred suspension of 2-bromomethyl-3-(3,4,5-tri-methoxy-benzoyl)-6-methoxy-7-acetoxy-benzo[b]furan (Example 33) (35 mg, 0.071 mmol) and potassium carbonate (20 mg, 0.15 mmol) in dry acetonitrile (1.5 mL) was added imidazole (19 mg, 0.28 mmol) and the reaction mixture was stirred for overnight (tlc). The solvent was distilled under vacuum and the crude was taken in ethyl acetate, filleted and purified over silica gel plate to afford the title compound as a light yellow solid (6 mg, 19%). 1H NMR (300 MHz, CDCl3) δ-7.66 (s, 1H), 7.19 (s, 1H), 7.09 (s, 2H, benzoyl Hs), 7.07 (s, 1H), 6.85 (d, J=8.63 Hz, 1H), 6.74 (d, J=8.63 Hz, 1H), 5.37 (s, 2H), 4.00 (s, 3H, OMe), 3.95 (s, 3H, OMe), 3.79 (s, 6H, 2×OMe).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[NH:7][S:8][C:4]=2[CH:3]=1.[CH2:12]([N:19]=[C:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([N:7]1[C:6](=[O:9])[C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=2[S:8]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1[nH]sc2cc(Cl)ccc12
Reactant: O=C=NCc1ccccc1
Product: O=C(NCc1ccccc1)n1sc2cc(Cl)ccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6z (95% yield) was synthesized from 6-chloro-benzo[d]isothiazol-3-one and benzyl isocyanate as a white solid. IR(CHCl3) 3289, 1713, 1536 cm−1; 1H-NMR (CDCl3) δ4.63 (d, J=5.8 Hz, 2H), 7.22-7.40 (m, 6H), 7.58 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 9.15 (br s, 1H); ESIMS m/e 319 and 321 (M++1, 35Cl and 37Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][CH:31]=O)[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][CH2:31][N:51]4[CH2:52][CH2:53][CH:48]([OH:47])[CH2:49][CH2:50]4)[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=CCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: OC1CCN(CCn2cc3c(-c4ccc(F)cc4)c(-c4ccncc4)c(-c4ccc(F)cc4)nc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.6 %

Procedure:
In a volumetric flask, 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetaldehyde (0.08 g, 0.2 mmol, obtained in example 94), sodium triacetoxyborohydride (0.08 g, 0.4 mmol), 4-hydroxypiperidine (0.02 g, 0.2 mmol) and 1,2-dichloroethane (3 mL) were introduced under argon atmosphere. The mixture was stirred overnight at room temperature. It was concentrated and a mixture of water and EtOAc were added. The phases were separated. The aqueous phase was extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using increasing polarity mixtures of EtOAc-MeOH as eluent, to afford 19 mg of the title compound (yield: 20%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[N:32]=[CH:33][CH2:34][N:35]([CH3:37])[CH3:36])=[O:26])[CH3:23].C1(N=C=NC2CCCCC2)CCCCC1.ClCCl>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[N:32]([CH2:33][CH2:34][N:35]([CH3:36])[CH3:37])[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C1CCCC1N=CCN(C)C
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1CCCC1N(CCN(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 15.7 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol) and 2-(2-dimethylamino-ethylideneamino)-cyclopentanecarboxylic acid ethyl ester (0.069 g, 0.300 mmol) in N,N-dimethylformamide (1.5 mL) was treated with a 1.0 M solution N,N′-dicyclohexylcarbodiimide in dichloromethane (0.315 mL, 0.315 mmol). The reaction was stirred for 6 h at 25° C., the urea byproduct was filtered off and the crude material was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, 2-{(2-dimethylamino-ethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester (25.4 mg, 0.047 mmol, 15.6%), as a white solid. LC-MS (ESI) calcd for C22H33N5O7S2 543.18, found 544.4 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.[CH:15]1(O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([O:1][C:2]2[CH:14]=[CH:13][C:5]3[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[O:9][C:4]=3[CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC1(C)OC(=O)c2ccc(O)cc2O1
Reactant: OC1CCCCC1
Product: CC1(C)OC(=O)c2ccc(OC3CCCCC3)cc2O1

Procedure:
7-Cyclohexyloxy-2,2-dimethyl-benzo[1,3]dioxin-4-one was prepared from 7-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one and cyclohexanol under conditions analogous to example 51-a. 1H NMR (200 MHz, CDCl3): δ (ppm)=7.82 (d, J=8.8 Hz, 1H), 6.61 (dd, J=8.8, 2.4 Hz, 1H), 6.39 (d, J=2.0 Hz, 1H), 4.30 (m, 1H), 2.02-1.28 (m, 10H), 1.73 (s, 6H).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](#[N:14])/[CH:10]=[CH:11]/[C:12]#[N:13]>>[C:1]1([NH:7][NH:8][CH:11]([CH2:10][C:9]#[N:14])[C:12]#[N:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#C/C=C/C#N
Reactant: NNc1ccccc1
Product: N#CCC(C#N)NNc1ccccc1
Temperature: 77.5 °C
Yield: 44.5 %

Procedure:
A mixture of phenylhydrazine (4.29 g) and fumaronitrile (3.1 g), where the phenylhydrazine served as a solvent, was heated at 75-80° C. for 20 hours. Purification by flash chromatography on silica gel and crystallization from dichloromethane/hexane gave the title compound (3.29 g, 45%), m.p. 97-98° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:20]=[C:21]([F:22])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:22][C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[CH:20]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4cccc(F)c4)cc(F)c3O2)cc1
Product: CNCC1Cc2cc(-c3cccc(F)c3)cc(F)c2O1

Procedure:
The title compound was prepared (0.12 g, 88%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-fluoro-5-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.19 g, 0.45 mmol) and methylamine (0.28 g, 9.1 mmol). mp >250° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][C@@H:15]([OH:25])[C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:27])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:26])[CH2:6][CH2:5]1.[CH:28]([CH:30]=[N+]=[N-])=[CH2:29]>>[CH2:30]([O:25][C@@H:15]1[CH2:14][C@@H:13]2[C@:21]([CH3:23])([CH2:22][C@H:2]([OH:1])[C@H:3]3[C@H:12]2[CH2:11][CH2:10][C:9]2[C@:4]3([CH3:27])[CH2:5][CH2:6][C:7](=[O:26])[CH:8]=2)[C@@:16]1([OH:24])[C:17](=[O:20])[CH2:18][OH:19])[CH:28]=[CH2:29]
Reactant: C=CC=[N+]=[N-]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](O)[C@]2(O)C(=O)CO
Product: C=CCO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO

Procedure:
11β,16α,17,21-Tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added to a solution of vinyl diazomethane in 1:1 methanol-ether at 0°C until nitrogen evolution ceases. The solvent is evaporated to yield the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:19][CH2:18][C:17]2([CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20]2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:19][CH2:18][C:17]4([CH2:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[O:20]4)[CH2:16][CH2:15]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC3)Cc3ccccc3O4)nn2)n1

Procedure:
The object product (200 mg, 87%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (130 mg) obtained in Example 43(2), 3H-spiro[1-benzofuran-2,4′-piperidine] (150 mg) and potassium carbonate (110 mg).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[OH-].[NH4+:11]>>[I:8][C:6]1[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([NH2:11])[CH:7]=1
Reactant: Cc1cnc(F)cc1I
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1cnc(N)cc1I
Temperature: 110 °C

Procedure:
In a 500 mL sealed tube 2-fluoro-4-iodo-5-methylpyridine (4.0 g, 16.81 mmol) in 12N ammonium hydroxide (300 mL) was heated to 110° C. for 72 hours. Upon cooling to room temperature a white solid separated. The solid was collected, washed with water and dried in vacuo to afford 4-iodo-5-methylpyridin-2-amine (I-28A) as an off-white solid which was carried on to the next step without purification. 1H-NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.04 (s, 1H), 4.27 (bs, 2H), 2.24 (s, 3H). MS m/z 235.0 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[O:9]=[CH:10][C:11]1[CH:19]=[CH:18][C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1.Cl[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O>CS(C)=O.O>[CH3:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:17][C:16]1[CH:18]=[CH:19][C:11]([CH:10]=[O:9])=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1cc(C=O)ccc1O
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCOc1ccc(C=O)cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
41.45 g (300 mmol) of potassium carbonate and 27.4 g (165 mmol) of potassium iodide are added to a solution of 22.8 g (150 mmol) of vanillin and 30.7 g (225 mmol) of 6-chlorohexanol in 500 ml of dimethyl sulphoxide (DMSO) and the mixture is stirred overnight at 60° C. under nitiogen. The mixture is then cooled to room temperature, poured into 600 ml of water and extracted three times with 150 ml of ethyl acetate each time. The combined organic phases are washed twice with 200 ml of water each time, dried over magnesium sulphate, filtered and concentrated. Purification of the residue by chromatography on 400 g of silica gel using cyclohexane/ethyl acetate 1:1 yields 29.95 g of 4-(6-hexyloxy)-3-methoxybenzaldehyde.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C@H:5]([O:17][C:18](=[O:21])[CH2:19]Br)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl[Si](C)(C)C>[Zn].CCOCC>[OH:2][C:3]1[CH2:4][C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:17][C:18](=[O:21])[CH:19]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CCOCC
Product: CCCCCCCCCCC[C@@H]1CC(O)=CC(=O)O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22.5 %

Procedure:
In a flame-dried flask under N2 a mixture of 659 mg (10.1 mmol) zinc and 755 mg (1.99 mmol)(R)-3-[(bromoacetyl)oxy]tetradecanoic acid methyl ester in 10 mL 20% v:v Et2O:chlorotrimethylsilane was heated at reflux with rapid stirring for 20 min. The mixture was cooled to room temperature and suction filtered through a coarse fritted funnel, using a pad of celite, and washing with 10 mL Et2O. The homogenous filtrate was cooled in an ice/H2O bath and 10 mL tap H2O was added with stirring. After 10 min, the mixture was poured into 100 mL tap H2O and extraction with 3×50 mL Et2O was performed. The combined organic layers were washed with 50 mL brine and dried over MgSO4. The Et2O was removed by rotary evaporation giving 669 mg crude yellow solid. The solid was slurried in 9.0 mL hexanes for 30 min, followed by suction filtration through a medium fritted funnel. The product was dried under 25" vacuum at room temperature for 1.5 h, giving 120 mg (22%) (R)-5,6-dihydro-4-hydroxy-6-undecyl -2H-pyran-2-one as a white powder, mp=86°-7° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[CH2:16][CH2:15]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)c[nH]c12
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To 5-bromo-3-(4-piperidinyl)-1H-indole-7-carboxamide (900 mg, 2.8 mmol) in CH2Cl2 (100 mL) at 0° C., ethanesulfonyl chloride (0.8 mg, 8.4 mmol) and triethylamine (1.6 mL, 11.2 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min., after which time the mixture was partitioned between CH2Cl2 and water. The aqueous phase was extracted with CH2Cl2 (50 mL×2) and the combined organic phase dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by solid phase extraction on a 500 mg aminopropyl column (International Sorbent Technologies) eluting with chloroform (30 mL×2) and ethyl acetate (50 mL) to give 800 mg of the title compound (69%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1>C(#N)C.[Pd](Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[C:5]2[CH:11]=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:20]
Reactant: COC(=O)c1cccc(N)c1C#Cc1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Solvent: CC#N
Product: COC(=O)c1cccc2[nH]c(-c3ccc(Cl)cc3)cc12
Temperature: 75 °C
Reaction time: 17 h

Procedure:
3-amino-2-(4-chloro-phenylethynyl)-benzoic acid methyl ester (0.73 g, 2.54 mmol) and palladium (II) chloride (23 mg, 0.13 mmol) were combined in 10 mL acetonitrile. The yellow solution was stirred under argon at 75° C. for 17 h. The solvent was removed in vacuo leaving an orange solid which was purified by flash chromatography eluting with 50 to 100% CH—Cl3/hecanes. 2-(4-chlorophenyl)-1H-indole-4-carboxylic acid methyl ester; 0.53 g (72%) was isolated as an off-white solid: m.p. 150.0-151.5° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.93 (s, 3H), 7.23 (app t, J=7.8 Hz, 1H), 7.41 (d, J=1.8 Hz, 1H), 7.57 (d, J=8.7 Hz, 2H), 7.68 (d, J=7.8 Hz, 1H), 7.75 (dd, J=7.5, 0.9 Hz, 1H), 7.95 (d, J=8.7 Hz, 2H), 11.99 (br s, 1H). HRMS (MALDI, MH+) Calcd for C16H12ClNO2: 286.0635. Found: 286.0631.
Reaction SMILES: [OH:1][C@@:2]1([CH2:23][CH2:24][CH3:25])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([CH2:12][C:13](=[O:22])[CH2:14][C@@H:15]1[CH3:21])[CH2:10][CH2:9]3.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:26]([O:1][C@@:2]1([CH2:23][CH2:24][CH3:25])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([CH2:12][C:13](=[O:22])[CH2:14][C@@H:15]1[CH3:21])[CH2:10][CH2:9]3)(=[O:28])[CH3:27]
Reactant: CCC[C@]1(O)CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C[C@H](C)[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCC[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C[C@H](C)[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
1.5 g of 17β-hydroxy-1α-methyl-17α-n-propyl-5α-androstan-3-one is allowed to stand at room temperature in 6 ml of pyridine with 3 ml of acetic anhydride for 16 hours, after the addition of 75 mg of 4-dimethylaminopyridine. After the mixture has been precipitated into ice water and recrystallized from hexane, 1.3 g of 17β-acetoxy-1α-methyl-17α-n-propyl-5α-androstan-3-one is obtained, m.p. 128°-129° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:47])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:37]=[C:36]([CH2:38][O:39]C3CCCCO3)[O:35][N:34]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:39][CH2:38][C:36]1[O:35][N:34]=[C:33]([C:29]2[CH:28]=[C:27]([C:26]3[CH2:25][C:24](=[O:47])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:21])([F:22])[F:20])[C:12]([N:14]5[CH2:15][CH2:16][CH2:17][CH2:18]5)=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[CH:37]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cc(CO)on3)c2)=Nc2cc(N3CCCC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-phenyl}-propionylamino)-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M51) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (224 mg).