Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[S:3])=S.[H-].[Na+].[CH2:6]([O:9][C:10]([N:12]1[C@H:16]([CH:17]([OH:26])[C:18]2[N:19]3[CH:25]=[N:24][CH:23]=[C:20]3[S:21][CH:22]=2)[CH2:15][C@@H:14]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:13]1)=[O:11])[CH:7]=[CH2:8].[CH3:35]I>C1COCC1.N1C=CN=C1.O>[CH2:6]([O:9][C:10]([N:12]1[C@@H:16]([CH:17]([C:18]2[N:19]3[CH:25]=[N:24][CH:23]=[C:20]3[S:21][CH:22]=2)[O:26][C:1]([CH3:35])=[S:3])[CH2:15][C@@H:14]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])[CH2:13]1)=[O:11])[CH:7]=[CH2:8]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1csc2cncn12
Reactant: CI
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(OC(C)=S)c1csc2cncn12
Reaction time: 0.33 h

Procedure:
Imidazole (2.7 mg), 0.53 ml of carbon disulfide, and 128 mg of sodium hydride are successively added to a solution of 1.28 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]pyrrolidine (a diastereomer mixture), described in Synthesis Example 7-a), in 20 ml of dry THF under ice cooling, and the mixture is stirred at that temperature for 20 min. Methyl iodide (0.19 ml) is added dropwise to the mixed solution, and the temperature of the mixture is gradually raised and stirred at room temperature overnight. Water is added to the reaction solution, and the mixture is extracted three times with ethyl acetate. The organic layer is washed twice with saturated saline, dried over anhydrous magnesium sulfate, and filtered. The solvent is removed by evaporation under reduced pressure, and the resultant crude product is purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 1.31 g of (3R,5R)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-(imidazo[5,1-b]thiazol-3-yl)-1-(methylthiocarbonyloxy)methyl]pyrrolidine (a diastereomer mixture) as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:12]([Mg]Br)[CH:13]=[CH2:14]>C1COCC1>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:5])[CH2:14][CH:13]=[CH2:12]
Reactant: C=CC[Mg]Br
Reactant: O=C(CCCl)c1ccccc1
Solvent: C1CCOC1
Product: C=CCC(O)(CCCl)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 3-chloro-1-phenylpropan-1-one (170 g, 1.01 mol) in anhydrous THF (1200 mL) was added allylmagnesium bromide (1.2 L, 1 mol/L) at −78° C. under nitrogen. The formed mixture was stirred for 30 min at −78° C. The reaction was quenched with aqueous NaHCO3 solution. The organic phase was separated, dried over Na2SO4 and concentrated to give the crude product, which was purified by column chromatography (petroleum ether/EtOAc=100:1) to afford 1-chloro-3-phenylhex-5-en-3-ol (180 g, 86%). 1H NMR (CDCl3): 2.27 (m, 2H), 2.51 (m, 1H), 2.74 (m, 1H), 3.22 (m, 1H), 3.58 (m, 1H), 5.16 (m, 2H), 5.53 (m, 1H), 7.23 (m, 1H), 7.39 (m, 4H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:7][C:6]=1[CH2:20][N:21](CC1C=CC(OC)=CC=1OC)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])C.CCC([O-])(C)C.[K+].S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[CH2:26]([O:25][C:23]([C:22]1[N:21]=[CH:20][C:6]2[C:5]([C:4]=1[OH:3])=[CH:10][CH:9]=[C:8]([O:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[CH:7]=2)=[O:24])[CH3:27]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1cc(Oc2cc(F)ccc2Cl)ccc1C(=O)OCC
Agent: CCC(C)(C)[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc2cc(Oc3cc(F)ccc3Cl)ccc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
To an ice-water bath cooled solution of 4-(2-chloro-5-fluoro-phenoxy)-2-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-benzoic acid ethyl ester (1.59 g) in THF (20 mL) was added a solution of potassium tert-pentoxide (2.83 mL, 1.7 M in toluene); the mixture was stirred for 2 h at rt after addition; then the mixture was quenched with 2 M HCl, diluted with EtOAc and water, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulphate, filtered off, concentrated to give the desired cyclized intermediate. This intermediate was then dissolved in DCM (20 mL) and treated with thionyl chloride (0.42 mL) overnight. Then concentrated, the residue was dissolved in EtOAc, washed with water, diluted NaCl solution, then dried over sodium sulphate, filtered, concentrated and the residue was column purified to give the desired product (530 mg). LC MS ESI: 362 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C([N:18]([CH2:22][CH3:23])[CH:19]([CH3:21])[CH3:20])(C)C.[OH2:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:23][C:22]([NH:18][C:19]2[CH:20]=[CH:8][CH:3]=[C:4]([CH3:5])[CH:21]=2)=[O:24])[CH2:11][CH2:10]1
Reactant: COc1ccccc1C1CCNCC1
Reactant: O
Reactant: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccccc1C1CCN(CC(=O)Nc2cccc(C)c2)CC1
Yield: 52.3 %

Procedure:
4-(2-Methoxyphenyl)piperidine (200 mg, 1 mmol), the product from Example 1A (228 mg, 1 mmol) and N,N-diisopropylethylamine (0.185 mL, 1.1 mmol) in toluene (8 mL) were stirred at 60° C. for 18 hours. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (2×30 mL), dried over MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution with dichloromethane:methanol, 9.5:0.5) to provide the title compound 177 mg (52.3%). 1H NMR (300 MHz, DMSO-d6) δ 1.71 (m, 4H), 2.28 (m, 5H), 2.89 (m, 1H), 2.96 (m, 2H), 3.13 (s, 2H), 3.78 (s, 3H), 6.91 (m, 3H), 7.20 (m, 3H), 7.45 (m, 2H), 8.69 (s, 1H); MS (DCI/NH3) m/e 339 (M+H)+. Anal. calcd for C21H26N2O2: C, 74.52; H, 7.74; N, 8.28. Found: C, 74.23, H, 7.71, N, 8.26.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:15]3[C:10]([CH2:11]C[CH2:13][CH2:14]3)=[C:9]([C:16]([O:18][CH3:19])=[O:17])[CH:8]=2)[CH:2]=1.[Cl:20]N1C(=O)CCC1=O.Cl[CH2:29][Cl:30].C(OCC)(=O)C>>[Cl:20][C:8]1[C:9]([C:16]([O:18][CH3:19])=[O:17])=[C:10]2[N:15]([C:7]=1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:14][CH2:13][C:29]([Cl:30])=[CH:11]2
Reactant: COC(=O)c1cc(-c2cccnc2)n2c1CCCC2
Reactant: ClCCl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Cl)c(-c2cccnc2)n2c1C=C(Cl)CC2

Procedure:
Methyl 2,7-dichloro-3-(3-pyridyl)-5,6-dihydroindolizinecarboxylate is prepared as in Example 39, from 1 g of methyl 3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate and 1.56 g of N-chlorosuccinimide. 0.7 g of methyl 2,7-dichloro-3-(3-pyridyl)-5,6-dihydroindolizine-1-carboxylate are thus obtained in the form of an orange oil (Rf=0.33; thin layer chromatography on silica gel; eluent: 8/2 dichloromethane/ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18]O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.FC1C=CC(C[C@H]2CC[C@H](N3CCC[C@H]3CO)CC2)=CC=1.N1C=CC=CC=1.C1(C)C=CC(S([Cl:58])(=O)=O)=CC=1>C(Cl)Cl.C(OCC)(=O)C>[Cl:58][CH2:18][C@@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C@H:10]1[CH2:11][CH2:12][C@@H:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:8][CH2:9]1
Reactant: OC[C@@H]1CCCN1[C@H]1CC[C@@H](Cc2ccc(F)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OC[C@@H]1CCCN1[C@H]1CC[C@H](Cc2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Fc1ccc(C[C@H]2CC[C@@H](N3CCC[C@H]3CCl)CC2)cc1
Reaction time: 16 h

Procedure:
To a stirring solution of {(2S)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methanol and {(2S)-1-[trans-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methanol (390 mg, 1.34 mmol) in 5 ml of methylene chloride at 25° C. under N2 was added pyridine (0.22 ml, 2.75 mmol, EM Science) followed by p-toluenesulfonyl chloride (288 mg, 1.51 mmol, Aldrich). Worked up after 16 hours by adding ethyl acetate then rinsing 3 times with sat'd sodium bicarbonate followed by 1 time time with brine. The organic was dried over magnesium sulfate, and concentrated in vacuo to obtain an oil which was purified over silica gel in 100% ethyl acetate to yield 87 mg of product. MS (ESI) detects 310 (M+H). The other isomer was isolated and used for example 16.
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24].[CH3:28][N:29]([CH3:33])[CH2:30][C:31]#[CH:32]>O1CCOCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:28][N:29]([CH3:33])[CH2:30][C:31]#[C:32][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: CCC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 36.4 %

Procedure:
50 mg (0.26 mmol) of copper iodide, 69 mg (0.68 mmol) of triethylamine and 37 mg (0.05 mmol) of dichlorobis(triphenylphosphine)-palladium (11) are added to a suspension of 200 mg (0.52 mmol) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 5 ml of anhydrous dioxan, then this mixture is degassed under argon. After 15 minutes, 65 mg (0.78 mmol) of dimethyl-prop-2-ynyl-amine are added, then the mixture is heated at 100° C. for 6 hours. The raw reaction product is then filtered on celite, the filtrate is evaporated to dryness and the residue is purified by chromatography on silica (ethyl acetate/methanol/ammonia) to give 64 mg (36%) of 8-(3-dimethylamino-prop-1-ynyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [C:1]([N:5]1[CH2:40][CH2:39][CH2:38][CH2:37][C:8]2[C:9]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]#[C:21][CH2:22][C@@H:23]5[CH2:27][O:26]C(C)(C)[O:24]5)[C:16]([O:30][CH3:31])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:41])([CH3:4])([CH3:3])[CH3:2].[OH2:42].N>C(O)(=O)C>[C:1]([N:5]1[CH2:40][CH2:39][CH2:38][CH2:37][C:8]2[C:9]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20](=[O:42])[CH2:21][CH2:22][C@@H:23]([OH:24])[CH2:27][OH:26])[C:16]([O:30][CH3:31])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: O
Reactant: COc1cc2c(cc1C#CC[C@@H]1COC(C)(C)O1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Agent: N
Solvent: CC(=O)O
Product: COc1cc2c(cc1C(=O)CC[C@@H](O)CO)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3

Procedure:
A solution of 40 mg of 28a in 1 mL 80% acetic acid was stirred at room temperature for 16 h. Then water was added and the mixture was made alkaline with ammonia. The mixture was extracted with 2×ethyl acetate. The combined organic phases were dried and concentrated. The crude product was purified by preparative HPLC on a reversed phase C18 column to give 8.8 mg of compound 28b.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1)=[O:4].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C)C=O>[Cl:11][C:10]1[C:5]([C:3](=[O:4])[CH2:2][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])=[N:6][CH:7]=[C:8]([Cl:12])[CH:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CBr)c1ncc(Cl)cc1Cl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 8.6 %

Procedure:
To 3.00 g of the 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone prepared in Step 2 in Synthetic Example 2 in 30 ml of N,N-dimethylformamide, 4.13 g of potassium phthalimide was added, and the mixture was stirred at 80° C. for 3 hours and then at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 150 ml of water and extracted with ethyl acetate (50 ml×2), the resulting organic layers were combined, washed with water (50 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was mixed with 40 ml of a mixture of diisopropyl ether and hexane (1:1), the insolubles were filtered off, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 15:85 to 25:75) as the eluent to obtain 0.32 g of the desired product as a dark brown resinous substance.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([NH2:9])[N:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[CH:1]([C:4]1[CH:8]=[C:7]([NH:9][C:23](=[O:24])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)c1cc(N)n(-c2cccnc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cccnc2)n1
Yield: 75.6 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-amine (179 mg, 0.89 mmol) and potassium carbonate (159 mg, 1.2 mmol) in anhydrous DCM (3 ml) was added dropwise phenyl chloroformate (0.33 ml, 2.6 mmol) as a solution in DCM (0.2 ml). The crude was purified by silica gel chromatography (DCM/MeOH 0-10%) to afford phenyl 3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate (217 mg, 76%). 1H NMR (300 MHz, CDCl3) δ 1.29 (s, 6H), 2.99 (m, 1H), 6.39 (s, 1H), 6.67 (s, 1H), 7.08-7.32 (m, 6H), 7.99 (d, J=7 Hz, 1H), 8.34 (s, 1H), 8.45 (d, J=7 Hz, 1H); LC-MS (ESI) m/z 323 (M+H)+.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[F:31])=[C:15]([F:22])[C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[CH:18]=1)=[O:12]>C(#N)C.C(OCC)(=O)C>[CH3:9][O:10][C:11]([C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[F:31])=[C:15]([F:22])[C:16]2[N:17]([C:19]([I:1])=[CH:20][N:21]=2)[CH:18]=1)=[O:12]
Reactant: COC(=O)c1cn2ccnc2c(F)c1Nc1ccc(C)cc1F
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cn2c(I)cnc2c(F)c1Nc1ccc(C)cc1F
Yield: 100.7 %

Procedure:
N-iodosuccinimide (134 mg, 0.60 mmol) was added in a single portion to a solution of 8-fluoro-7-(2-fluoro-4-methyl-phenylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (172 mg, 0.54 mmol) in acetonitrile (10 mL) resulting in a thick precipitate after ten minutes of stirring. The suspension was diluted with ethyl acetate, washed with NaHSO3, saturated NaHCO3, water, brine, and dried over Na2SO4. Concentration provided the desired product as a yellow solid (241 mg, 100%). MS APCI (+) m/z 444 (M+1) detected. 1H NMR (400 MHz, CH3OD) δ 8.78 (s, 1H), 7.62 (s, 1H), 6.95 (m, 3H), 4.00 (s, 3H), 2.33 (s, 3H). 19F NMR (376 MHz, CH3OD) −131.11 (s, 1F), −146.71 (s, 1F).
Reaction SMILES: [C:1](=[O:23])([O:21][CH3:22])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([C:10]#[C:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:5][C:4]=1[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[F:42][C:43]([F:59])([F:58])[O:44][C:45]1[CH:46]=[CH:47][C:48]2[O:53][CH:52]([C:54](O)=[O:55])[CH2:51][NH:50][C:49]=2[CH:57]=1>CC1CCCO1.C(OCC)(=O)C>[C:1](=[O:23])([O:21][CH3:22])[O:2][C:3]1[CH:8]=[C:7]([NH:9][C:54]([CH:52]2[O:53][C:48]3[CH:47]=[CH:46][C:45]([O:44][C:43]([F:59])([F:42])[F:58])=[CH:57][C:49]=3[NH:50][CH2:51]2)=[O:55])[C:6]([C:10]#[C:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:5][C:4]=1[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C(O)C1CNc2cc(OC(F)(F)F)ccc2O1
Reactant: COC(=O)Oc1cc(N)c(C#CCN(C)C)cc1C1CCCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: COC(=O)Oc1cc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(C#CCN(C)C)cc1C1CCCC1

Procedure:
5-Amino-2-cyclopentyl-4-(3-(dimethylamino)prop-1-ynyl)phenyl methyl carbonate (150 mg, 0.47 mmol) was dissolved in 2-methyltetrahydrofuran (3 mL) and T3P (754 mg, 705 μL of 50% w/w, 1.18 mmol). 6-(Trifluoromethoxy)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (125 mg, 0.47 mmol) was added portion-wise over 30 min. After 3 h the reaction was diluted with ethyl acetate, washed with 10% saturated NaHCO3 (2×20 mL) and brine. The solution was dried over Na2SO4, filtered, and dried down to an orange solid. Purification by silica gel chromatography (1% methanol/dichloromethane) provided 2-cyclopentyl-4-(3-(dimethylamino)prop-1-ynyl)-5-(6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)phenyl methyl carbonate as a colorless oil. LC/MS m/z 562.2 [M+H]+. The oil was dissolved in methanol (3 mL) and treated with NaOH (0.5 mL of 5 M, 2.4 mmol) and stirred for 5 min. Water (5 mL) and saturated NaHCO3 (2 mL) were added until a white precipitate formed. The product was extracted into ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide N-(4-cyclopentyl-2-(3-(dimethylamino)prop-1-ynyl)-5-hydroxyphenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide as a off-white solid (90 mg, 34% yield). LC/MS m/z 504.2 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 10.72 (s, 1H), 10.16 (s, 1H), 9.25 (s, 1H), 7.53 (s, 1H), 7.25 (s, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 6.52-6.49 (m, 1H), 4.91 (dd, J=3.0, 6.3 Hz, 1H), 4.32 (t, J=3.8 Hz, 2H), 3.54 (dd, J=3.0, 12.2 Hz, 1H), 3.42 (dd, J=6.3, 12.3 Hz, 1H), 3.14 (quin, J=8.4 Hz, 1H), 2.85 (d, J=4.4 Hz, 6H), 1.91 (m, 2H), 1.72 (m, 2H), 1.63-1.60 (m, 2H), 1.48 (m, 2H).
Reaction SMILES: [NH:1]([C:5]1[C:14]2[C:9](=[C:10]([Cl:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)C(C)=O.[N+:16]([O-])([OH:18])=[O:17].[OH-].[Na+]>CC(O)=O.CCO>[NH2:1][C:5]1[C:14]2[C:9](=[C:10]([Cl:15])[CH:11]=[CH:12][CH:13]=2)[C:8]([N+:16]([O-:18])=[O:17])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cccc2c(Cl)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc([N+](=O)[O-])c2c(Cl)cccc12
Yield: 32 %

Procedure:
1-Acetamino-5-chloronaphthalene (150 mg, 0.68 mmol, prepared as described in Example 213A) was dissolved in 1 mL AcOH and treated with 82 μL of red fuming HNO3 and subsequently deacylated with 1 mL 40% aqueous NaOH solution in 3 mL EtOH according to the procedure described in Example 209A to yield 49 mg (32%) of compound 214A as a yellow solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:19][C:18]2[C@H:13]([CH2:14][CH2:15][C:16](=[O:20])[CH:17]=2)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][C:11]2=[O:21])([CH3:9])[C:7](=[O:22])[CH2:6][CH2:5]1.C(Cl)Cl.C(OC(OCC)OCC)C.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)CO>[CH3:1][C@@H:2]1[CH:19]=[C:18]2[C@H:13]([CH2:14][CH2:15][C:16](=[O:20])[CH2:17]2)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][C:11]2=[O:21])([CH3:9])[C:7](=[O:22])[CH2:6][CH2:5]1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2C(=O)C[C@]3(C)C(=O)CC[C@H]3[C@@H]21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: ClCCl
Solvent: OCCO
Product: C[C@@H]1C=C2CC(=O)CC[C@@H]2[C@H]2C(=O)C[C@]3(C)C(=O)CC[C@H]3[C@@H]21

Procedure:
A mixture of 7α-methylestr-4-ene-3,11,17-trione (B, Example 23, 4.1 g), methylene chloride (50 ml), ethylene glycol (31 ml), triethylorthoformate (14 ml) and p-TSA (41 mg) are refluxed for 3 hours. The mixture is then cooled and washed with bicarbonate and water, then dried to a solid. NMR shows a mixture of Δ5 (10) and Δ5 isomers. The product is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[CH3:27][N:28]([CH3:30])[NH2:29]>CO.O1CCCC1.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:26])/[C:4](=[N:29]/[N:28]([CH3:30])[CH3:27])/[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Reactant: CN(C)N
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)/C(=N/N(C)C)c1ccc(OCCOc2ccc3ccccc3c2)cc1

Procedure:
A mixture of 4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (3.5 g), 1,1-dimethylhydrazine (2.28 mL) in methanol (40 mL), tetrahydrofuran (20 mL) and one drop of glacial acetic acid was refluxed for 48 hours and evaporated to dryness. The crude mixture was separated by HPLC (dichloromethane-ether, 49:1) and the more polar component was crystallized from dichloromethane-methanol to provide 0.9 g of (E)-alpha-(dimethylhydrazono)-4-[2-(2-naphthalenyloxy)ethoxy]benzeneacetic acid methyl ester as a colorless solid, mp 137°-138° C.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH:13]=O)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[OH-:16].[Na+].Cl.[NH2:19]O>C(O)C.O>[CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH:13]=[N:19][OH:16])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1cc2c([C@@H]3C[C@H]3C=O)cccn2n1
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc2c([C@@H]3C[C@H]3C=NO)cccn2n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
Trans-2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropanecarbaldehyde (1.62 g, 8.08 mmol), 8 M aqueous sodium hydroxide solution (4.04 mL, 32.3 mmol) and hydroxylamine hydrochloride (1.85 g, 26.7 mmol) was dissolved in ethanol/water (65 mL/13 mL), and the mixture was stirred at 60° C. for 3 hr. The reaction solution was concentrated, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.67 g, yield 96%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O.[NH2:15][NH2:16]>C(O)C>[C:3]([NH:15][NH2:16])(=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NN
Reactant: CCCCCCCCCC(=O)OC
Solvent: CCO
Solvent: O
Product: CCCCCCCCCC(=O)NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
17.5 g of decanoic acid methyl ester is dissolved in 1 l of absolute ethanol and mixed with 350 ml of hydrazine hydrate. It is refluxed for 3 hours and then stirred overnight at room temperature. The solution is concentrated by evaporation to about 300 ml and allowed to stand until the product is crystallized out. After it is filtered off and dried, 16.6 g (=94% of theory) of decanoic acid hydrazide is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12](OCC)=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reactant: C1CCNC1
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)N2CCCC2)C1
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate (100 mg) and pyrrolidine (1 ml) was heated at 120° C. for 15 h to obtain 59 mg of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(pyrrolidin-1-yl)ethanone after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.