Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.CO[C:11]([C:13]1([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:12].Cl>C1COCC1>[C:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][C:13]([C:11](=[O:12])[CH2:2][C:1]#[N:3])([CH3:26])[CH2:18][CH2:17]1)=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: COC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC#N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)CC#N)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
Acetonitrile (3.07 mL, 58.4 mmol) is added to THF (75 mL). At −78° C. 1.6 M BuLi in hexanes is slowly added. After 15 minutes, 4-methylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (6.83 g, 26.5 mmol) dissolved in THF (75 mL) is added dropwise. After 1 hour 2.2 equivalents of 5N HCl is added at −78° C. The reaction is warmed to room temperature and concentrated to about 50 mL volume. EtOAc (50 mL) and saturated aqueous sodium chloride (25 mL) are added to the mixture. The organic layer is separated, dried over Na2SO4, concentrated, and chromatographed on silica gel, eluting with 0-20% EtOAc in dichloromethane, to give the title compound (4.80 g, 68% yield).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[Si]([O:31][CH2:32][C:33]1[C:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:35]([C:38]([O:40][CH3:41])=[O:39])[O:36][CH:37]=1)(C(C)(C)C)(C)C.C(Cl)(Cl)Cl>O>[OH:31][CH2:32][C:33]1[C:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:35]([C:38]([O:40][CH3:41])=[O:39])[O:36][CH:37]=1
Reactant: COC(=O)c1occ(CO[Si](C)(C)C(C)(C)C)c1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1occ(CO)c1-c1ccccc1
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
Tetrabutylammonium fluoride (1 M THF solution: 7.62 ml) was added at 25° C. to a THF (10 ml) solution of methyl 4-(tert-butyldimethylsilyloxymethyl)-3-phenyl-2-furancarboxylate (2.20 g), and stirred for 0.5 hours. Chloroform and water were added to the reaction solution, the organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%→30% ethyl acetate/hexane gradient, thereby giving 1.00 g of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:27]([C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[F:24])[N:9]=[C:4]2[CH:3]=1
Reactant: O=Cc1ccccc1F
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Nc1cc(Br)cc(N)n1
Product: Nc1cc(Br)cc2nc(-c3ccccc3F)nn12

Procedure:
The title compound, MS m/e (%): 290 (M+, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonyl-hydroxylamine, and 2-fluoro-benzaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]([OH:6])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[N:31]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[N:30]=[CH:29][C:28]=1[C:39]([NH:41][CH2:42][C:43]([CH2:49][NH2:50])([OH:48])[C:44]([F:47])([F:46])[F:45])=[O:40]>O1CCCC1.C(N(C(C)C)CC)(C)C>[NH2:26][C:27]1[N:31]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[N:30]=[CH:29][C:28]=1[C:39]([NH:41][CH2:42][C:43]([CH2:49][NH:50][C:4]([C:3]1[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])=[O:6])([OH:48])[C:44]([F:47])([F:46])[F:45])=[O:40]
Reactant: NCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Reactant: O=C(O)c1c(Cl)cccc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1c(C(=O)NCC(O)(CNC(=O)c2c(Cl)cccc2C(F)(F)F)C(F)(F)F)cnn1-c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a solution of 2-chloro-6-(trifluoromethyl)benzoic acid (27 mg) in anhydrous tetrahydrofuran (1 ml) was added anhydrous dimethylformamide (5 μl) followed by a solution of oxalyl chloride in anhydrous tetrahydrofuran (1M, 0.13 ml). The solution effervesced and was stirred under nitrogen for 30 minutes. A solution of 5-amino-N-[2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (36 mg) in anhydrous tetrahydrofuran (1 ml) and diisopropylethylamine (65 μl) was added washed in with further tetrahydrofuran (0.5 ml). It was stirred under nitrogen for 16 hours, blown down, dissolved in dichloromethane (5 ml), washed with 2M hydrochloric acid (2 ml), blown down and purified on a silica SPE cartridge (5 g). Elution with dichloromethane followed by ethyl acetate:cyclohexane (1:5), (1:3), (1:2), (1:1) (4 times). Combination of the appropriate fractions and evaporation gave the title compound (50 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:32]([C:31]3[CH:30]=[CH:29][C:28]([N:25]4[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]4)=[CH:35][CH:34]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: CN1CCN(c2ccc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Br)cnc4[nH]3)cc2)CC1
Yield: 48.7 %

Procedure:
In a similar fashion to Compound LXXVI, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (40.0 mg, 0.118 mmol) and 4-(4-methyl-piperazin-1-yl)-benzaldehyde (26.6 mg, 0.130 mmol) were reacted to produce 30 mg (49%) of the title compound. mp: 215-218° C., 1H NMR (300 MHz, DMSO-d6): 13.02 (s, 1H), 7.99 (s, 1H), 7.97 (s, 2H), 7.73 (s, 1H), 7.20 (s, 1H), 7.07 (d, J=8 Hz, 2H), 6.99 (d, J=8 Hz, 1H), 6.37 (br s, 2H), 5.27 (t, J=8 Hz, 1H), 3.32 (s, 6H), 2.88 (s, 1H), 2.75 (s, 1H), 2.60 (d, J=7 Hz, 1H), 2.45 (br s, 4H), 2.23 (s, 4H). MS: 522, 524 (M+H), HPLC: 1.86 min (G method).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](=[O:30])[CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OC)=O.O>C1COCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](=[O:30])[CH:21]([CH:2]=[O:4])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C(CCCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Agent: [K+]
Solvent: COC=O
Solvent: O
Solvent: C1CCOC1
Product: O=CC(CCc1ccccc1)C(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
To a solution of potassium t-butoxide (0.673 g) in THF (20 mL) under nitrogen and cooled in an ice bath was added a solution of 1-(1-benzylpiperidin-4-yl)-4-phenylbutan-1-one from Step D (0.71 g) and methyl formate (3.76 mL) in THF (12 mL) over 5 minute. The reaction was stirred for 15 min before being allowed to warm to rt for 2 h. The reaction was poured into water and extracted with ether (4×100 mL), methylene chloride (100 mL), and THF (100 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrate under reduced pressure. The crude product was purified by FC on silica gel eluting with 5 and 20% methanol in ethyl acetate with 4% TEA to afford the title compound (0.8 g). 1H NMR (500 MHz, CDCl3) showed a 3:1 ratio of enol (δ8.54 ppm) and aldehyde (δ9.54 ppm) forms. Other signals from the two forms were only partially resolved. The title compound had a retention time of 9.47 min on a Zorbax SB-C18 column (4.6×75 mm) eluting with 20-100% gradient of acetonitrile in water with 0.1% TFA over 10 min at 1 mL per min.
Reaction SMILES: [C:1](O)(=O)C.CO.[P].C[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1>I>[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:20])[C:17]([O:19][CH3:1])=[O:18])=[CH:12][CH:11]=1
Reactant: COc1ccc(C(C)C(=O)O)cc1
Reactant: CC(=O)O
Agent: I
Agent: [P]
Solvent: CO
Product: COC(=O)C(C)c1ccc(O)cc1

Procedure:
In a mixture of 12ml of hydroiodic acid, 90ml of acetic acid and 1g of phosphorus 10g of 2-(4-methoxyphenyl)propionic acid was refluxed for 3 hours and the reaction mixture was concentrated. 20ml of methanol and 2ml of sulfuric acid were added to the residue and the mixture was refluxed for one hour. After the methanol was concentrated, the water was added to the residue and extracted with ether. The extract was washed over magnesium sulfate and the ether was distilled off. The residue was distilled under reduced pressure to give the object compound having b.p. 150° - 153° C/6mm Hg in a yield of 6.7g (67%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][NH:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=2)[C:14]([CH3:22])=[CH:13]1.C([O-])([O-])=O.[K+].[K+].[CH2:29]([N:33]=[C:34]=[O:35])[CH2:30][CH2:31][CH3:32]>O1CCCC1>[CH2:29]([NH:33][C:34](=[O:35])[O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([NH:11][CH2:10][CH2:9][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1])[CH:13]=[C:14]2[CH3:22])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCN=C=O
Reactant: Cc1cn(NCCCc2ccncc2F)c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCNC(=O)Oc1ccc2c(c1)c(C)cn2NCCCc1ccncc1F
Reaction time: 15 h

Procedure:
To a stirred solution consisting of 1-[(3-fluoro-4-pyridinyl)propylamino]-3-methyl-1H-indol-5-ol (2.10 g) and tetrahydrofuran (47 ml) was added milled K2CO3 (1.02 g) followed by dropwise addition of butyl isocyanate (0.87 ml) at room temperature under nitrogen. Stirring was continued for 15 hours, at which time the reaction mixture was filtered through a pad of celite and the solids washed with EtOAc. Concentration afforded the crude product. Purification via flash column chromatography (silica gel, ether) afforded 2.3 g of the desired product as an oil. The product was crystallized from ether/pentane, m.p. 83°-84° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=1[CH3:15])[CH:3]=O.[C:16]([O:23][CH3:24])(=[O:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19].N1C=CC=CC=1>ClC(Cl)(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][CH:2]([CH2:5][CH2:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=1[CH3:15])[CH:3]=[C:17]([C:16]([O:23][CH3:24])=[O:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CC(=O)OC
Reactant: CC1=C(CCC(C)C=O)C(C)(C)CCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=CC(C)CCC1=C(C)CCCC1(C)C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
Under water-free conditions titanium(IV) chloride (91 g, 0.5 mol) in tetrachloromethane (120 ml) are added dropwise within 45 min to tetrahydrofuran at 0° C. The mixture is stirred for another 30 min at this temperature, then 2-Methyl-4-(2,6,6-trimethylcyclohex-1-enyl)butanal 4 (50 g, 0.24 mol) (M. Matsui et al., Agric. Biol. Chem. 50, 1475-1480, 1986) and dimethyl malonate (31.7 g, 0.24 mol) in tetrahydrofuran (50 ml) are added within 15 min at 0° C. followed by dropwise addition of pyridine (76 g) in tetrahydrofuran (240 ml) over 90 min at 0° C. The orange-brown suspension is stirred for 18 h at 25° C., then poured upon ice/water and extracted with tert-butyl methyl ether. The combined organic layers are washed with water and conc. NaCl and dried over MgSO4. After filtration and evaporation of the solvents the crude product (75 g) is short-path-distilled giving 62.5 g (81%) of 3a at 170° C./0.07 mbar. Analytical data: 1H NMR (400 MHz, CDCl3): δ 0.95 (s, 6 H), 1.1 (d, 3 H), 1.4-1.5 (4 H), 1.5-1.6 (2 H), 1.58 (s, 3 H), 1.8-2.0 (2 H), 2.5 (m, 1 H), 3.8 (s, 3 H), 3.85 (s, 3 H), 6.85 (d, 1 H) ppm. 13C-NMR (400 MHz, CDCl3): δ 19.45 (t), 19.55 (q), 19.75 (q), 26.4 (t), 28.5 (q), 32.7 (t), 34.8 (s), 35.7 (d), 36.8 (t), 39.7 (t), 52.1 (q), 52.2 (q), 126.7 (s), 127.1 (s), 136.8 (s), 154.9 (d), 164.4 (s), 166.0 (s). MS (EI): m/z (%) 322 (M+, 10), 307 ([M-15]+, 2), 275 (6), 259 (7), 243 (16), 215 (11), 200 (18), 187 (19), 175 (20), 173 (16), 172 (100), 153 (22), 145 (28), 140 (70), 137 (27), 135 (34), 123 (60), 122 (28), 121 (42), 109 (35), 108 (34), 95 (62), 93 (36), 81 (44), 79 (33), 55 (36), 41 (35). IR (film): 2950 (m), 2926 (m), 2865 (m), 1725 (s), 1642 (w), 1454 (w), 1433 (m), 1363 (w), 1327 (w), 1246 (s), 1221 (s), 1204 (s), 1168 (w), 1104 (w), 1054 (m), 991 (w), 945 (w), 925 (w), 833 (w), 762 (w).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]([F:19])([F:18])[F:17])=[CH:4][C:3]1=[O:20].CCN(CC)CC.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]([F:19])([F:18])[F:17])=[CH:4][C:3]1=[O:20]
Reactant: C1CCNCC1
Reactant: Cn1c(=O)cc(C(F)(F)F)c2cc(S(=O)(=O)Cl)ccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1c(=O)cc(C(F)(F)F)c2cc(S(=O)(=O)N3CCCCC3)ccc21
Reaction time: 8 h
Yield: 53.4 %

Procedure:
A solution of 1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonyl chloride (Preparation 1, 65 mg, 200 μmol) in anhydrous DMF (1.5 mL) was treated with NEt3 (31 μL, 220 μmol) and piperidine (21 μL, 210 μmol), before being stirred overnight under N2. The reaction mixture was diluted with EtOAc (70 mL), before being washed with H2O (30 mL), 1 M HCl (30 mL), H2O (30 mL), saturated aqueous NaHCO3 (30 mL), H2O (30 mL), and brine (30 mL). After drying (MgSO4), the organic phase was filtered and concentrated to give a residue that was recrystallised from EtOAc-PE to furnish the title compound (40 mg, 53%): δH (CDCl3)=1.40–1.50 (m, 2H), 1.60–1.70 (m, 4H), 3.05 (t, 4H), 3.80 (s, 3H), 7.20 (s, 1H), 7.55 (d, 1H), 8.00 (dd, 1H), 8.20 (d, 1H); m/z (ES+)=375.1 [M +H]+.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:3]1.C(O)(=O)C.[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1.[C-:25]#[N:26].[Na+]>O>[C:25]([C:7]1([NH:24][C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[CH2:6][CH2:5][N:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH:2]1[CH3:1])#[N:26]
Reactant: COC(=O)N1CCC(=O)C(C)C1
Reactant: [C-]#N
Reactant: Nc1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)N1CCC(C#N)(Nc2ccc(F)cc2)C(C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 248 parts of methyl 3-methyl-4-oxo-1-piperidinecarboxylate in 660 parts of acetic acid are added 150 parts of 4-fluorobenzenamine and the whole is stirred for 30 minutes. After cooling with ice-water, a solution of 69 parts of sodium cyanide in 195 parts of water is added dropwise at room temperature. Upon completion, stirring at room temperature is continued over week-end. The solid product is filtered off and washed with 2,2'-oxybispropane and petroleumether, yielding 230 parts of methyl 4-cyano-4-[(4-fluorophenyl)amino]-3-methyl-1-piperidinecarboxylate; mp. 90° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17]Cl)([O:15]Cl)=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[CH2:21]([NH:24][CH2:25][CH:26]=[CH2:27])[CH:22]=[CH2:23]>O1CCCC1>[F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17][N:24]([CH2:25][CH:26]=[CH2:27])[CH2:21][CH:22]=[CH2:23])([O:15][N:24]([CH2:25][CH:26]=[CH2:27])[CH2:21][CH:22]=[CH2:23])=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4]
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: C=CCNCC=C
Solvent: C1CCOC1
Product: C=CCN(CC=C)OP(=O)(CN(CC(=O)OCC)C(=O)C(F)(F)F)ON(CC=C)CC=C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (3.3 g, 0.01 mole) in 25 ml of tetrahydrofuran was added diallylamine (4.07 g, 0.042 mole) in 50 ml. of tetrahydrofuran. The mixture was stirred at room temperature overnight and was then filtered and the filtrate concentrated in vacuo. The residue was dissolved in ether, washed with water, 10% HCl, water, dried over MgSO4, and concentrated in vacuo. The residue was extracted with petroleum ether, and by concentrating the petroleum ether soluble material, ethyl N-trifluoroacetyl-N-(bis(diallylamino)phosphonomethyl)glycinate was obtained as a light yellow oil, ND =1.4536.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:4]=1.[CH3:19][NH2:20]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:20][CH3:19])(=[O:11])=[O:10])=[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c(N2CCOCC2)c1
Reactant: CN
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(OC)cc1N1CCOCC1
Reaction time: 15 h

Procedure:
To a stirred solution of 4-methoxy-2-morpholin-4-yl-benzenesulfonyl chloride (37 mg; 0.13 mmol) in dry CH2Cl2 (1 mL) was added methylamine (0.16 mL of 2.0 M solution in tetrahydrofuran; 0.32 mmol) via syringe at room temperature under a nitrogen atmosphere. After stirring for 15 hours, the reaction was diluted with CH2Cl2 (25 mL), washed with water, saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified via HPLC (Biotage with 2:1 hexanes/EtOAc) to provide the sulfonamide as a white solid (12.5 mg; 34%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:11]([O:13][C:14](=[O:25])[CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:12].Br[CH2:27][C:28]1[C:29]([F:40])=[CH:30][N:31]=[C:32]2[C:37]=1[N:36]=[C:35]([O:38][CH3:39])[CH:34]=[CH:33]2.O>C1COCC1.CC(=O)OCC>[CH2:11]([O:13][C:14](=[O:25])[CH:15]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[N:36]=2)[N:31]=[CH:30][C:29]=1[F:40])[CH3:12]
Reactant: COc1ccc2ncc(F)c(CBr)c2n1
Reactant: CCOC(=O)CCNC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CNC(=O)OC(C)(C)C)Cc1c(F)cnc2ccc(OC)nc12
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
To a solution of LiHMDS (1M, 17 mL, 2.2 eq.), cooled to −78° C., was added dropwise a solution of 3-tert-butoxycarbonylamino-propionic acid ethyl ester (1.70 g, 7.82 mmol, prepared according to Tetrahedron Lett. (2003), 44, 2807-2811) in THF (20 mL). The solution was stirred at the same temperature for 90 min. A solution of 8-bromomethyl-7-fluoro-2-methoxy-[1,5]naphthyridine (2.12 g, 1 eq., prepared according to WO 2008/078305) in THF (10 mL) was quickly added and the reaction proceeded 2 h, keeping the internal temperature below −50° C. Water (100 mL) and EA (200 mL) were added. The two layers were decanted and the aq. layer was extracted with EA. The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed (Hept-EA 2-1) to afford the title intermediate as a yellow oil (2.38 g, 75% yield).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].C#C.[CH3:7][C@:8]12[CH2:24][CH2:23][C@H:22]3[C@@H:13]([CH2:14][CH2:15][C@@H:16]4[C@@H:21]3[CH2:20][CH:19]=[CH:18][CH2:17]4)[C@@H:12]1[CH2:11][CH2:10][C:9]2=[O:25].[Cl-].[NH4+]>O1CCCC1.CCOCC.O>[OH:25][C@@:9]1([C:1]#[CH:2])[CH2:10][CH2:11][C@H:12]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:7])[C@@H:21]1[C@H:16]([CH2:17][CH:18]=[CH:19][CH2:20]1)[CH2:15][CH2:14]3
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC=CC[C@@H]43)[C@@H]1CCC2=O
Reactant: CC[Mg]Br
Agent: C#C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@@H]4[C@H]3CC[C@@]21C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 20 ml of dry tetrahydrofuran at 0° C. is added 0.75 ml of ethylmagnesium bromide (3 molar in ethyl ether) and through this solution is passed a stream of acetylene gas. After 30 min, 0.50 of ethylmagnesium bromide was added, followed after 30 min by another 0.50 ml of ethylmagnesium bromide. Acetylene gas is passed through the mixture all the time, and is continued for another 2 hr after the last addition. To the Grignard reagent is added dropwise 0.160 g of 5α-estr-2-en-17-one, Compound 6, dissolved in 5 ml of dry tetrahydrofuran. The combined reaction mixture is stirred at 0° C. for 2 hr, and then at room temperature for 16 hr. To the reaction mixture is added dropwise saturated ammonium chloride solution, water (30 ml) and ether (30 ml). The organic phase is separated, and the water phase is extracted once more with 12 ml of ether. The combined organic phase is washed twice with sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent gave a brownish oil, which was purified on a silica gel column to give 0.087 g of Compound Ia, mp 107.5°-109° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:12])=O)=[CH:5][CH:4]=1.COC(OC)[N:16]([CH3:18])C.O.[NH2:22]N.[OH-].[Na+]>CC(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[N:12]=[CH:18][NH:16][N:22]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(N)=O)cc1
Reactant: NN
Reactant: COC(OC)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Cc2nc[nH]n2)cc1
Temperature: 90 °C

Procedure:
A mixture of 2-(4-methoxyphenyl)acetamide (1.51 g, 9.14 mmol) and N,N-dimethylformamide dimethyl acetal (6 ml, 45.0 mmol) in a r.b.f, equipped with a Dean-Stark trap was placed in a 120° C. bath (turned to solution once heated) for 1.5 hours. The reaction was cooled and concentrated, then, added AcOH (18 ml), hydrazine hydrate (0.611 ml, 10.06 mmol), and heated at 90° C. for 1.5 hours. After cooling to RT, added 2M aqueous sodium hydroxide and extracted 3 times with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with MeOH in DCM to afford the title compound. Mass spectrum (ESI) 190.3 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:10]N.C1COCC1.O1CCOCC1>ClCCl>[NH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: NN
Reactant: c1ccc2[nH]ncc2c1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Nc1n[nH]c2ccccc12

Procedure:
Indazole (XV) is treated with hydrazine in an organic solvent such as THF, dioxane or dichloromethane, at a temperature in the range of about 0° C. to about 25° C., to yield the corresponding indazole (IV).