Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(C2CCNCC2[O:14]CC2C(O)=CC3C(=CC=CC=3)C=2)=CC=1.[BH4-].[Na+].[CH2:29]([N:36]1[CH2:41][CH:40]=[C:39]([C:42]2[CH:47]=[CH:46][C:45]([Br:48])=[CH:44][CH:43]=2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.B(F)(F)F.CCOCC.[OH-].[K+].OO>C(COC)OC.O.C(Cl)Cl>[CH2:29]([N:36]1[CH2:37][CH2:38][CH:39]([C:42]2[CH:43]=[CH:44][C:45]([Br:48])=[CH:46][CH:47]=2)[CH:40]([OH:14])[CH2:41]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Brc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Reactant: Oc1cc2ccccc2cc1COC1CNCCC1c1ccc(F)cc1
Agent: FB(F)F
Agent: OO
Agent: [BH4-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: OC1CN(Cc2ccccc2)CCC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 456 %

Procedure:
1 6.9 g of sodium borohydride were added to a solution of 51.1 g (0.156 mol) of 1-benzyl-4-(4-bromo-phenyl)-1,2,3,6-tetrahydro-pyridine in 350 ml of dimethoxyethane and the reaction mixture was stirred at room temperature for 15 minutes. Thereafter, 95.2 ml of boron trifluoride etherate were added dropwise at 25-30° C. during 30 minutes, the reaction mixture was subsequently stirred at room temperature for 2 hours. Thereafter, firstly a solution of 98.4 g of potassium hydroxide in 530 ml of water was slowly added dropwise and thereafter within 15 minutes 80.7 ml of a 30% hydrogen peroxide solution were added. Subsequently, the mixture was boiled under reflux for 2 hours. For the working-up, the cooled reaction mixture was filtered over Dicalit and this was rinsed with methylene chloride. The solution obtained was treated with 700 ml of methylene chloride, the organic phase was separated and then the aqueous phase was back-extracted with 300 ml of methylene chloride. The combined organic phases were washed twice with 200 ml of water each time, dried over magnesium sulphate and evaporated under reduced pressure. Crystallization of the crude product from acetone yielded 31 g (57% of theory) of (3RS,4RS)-1-benzyl-4-(4-bromo-phenyl)-piperidin-3-ol as colourless crystals; m.p.: 125-129° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([OH:28])=[O:27].C(N(CC)CC)C>O>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](=[CH:14][C:13]1[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=1)[C:26]([OH:28])=[O:27]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: CSc1ccc(C=O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1ccc(C=C(C(=O)O)c2ccccc2Cl)cc1
Temperature: 90 °C

Procedure:
A mixture of acetic anhydride (170 mL), 4-(methylthio)benzaldehyde (20.93 g, 137 mmol), 2-chlorophenylacetic acid (23.43 g, 137 mmol), and triethylamine (14.97 g, 147 mmol) was heated to reflux for 2 hours. The reaction was cooled to 90° C., and water (180 mL) was added through an addition funnel. A yellow solid that separated from the solution was isolated by filtration and air dried to afford the desired acid. The acid was recrystallized from a mixture of ethyl acetate and isooctane to afford 24.62 g (59%): mp 159°-164° C. 1H NMR (CDCl3) 300 MHz 7.97 (s, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.17-7.35 (m, 3H), 7.02 (d, J=8.7 Hz 2H), 6.97 (d, J=8.7 Hz, 2H), 2.43 (s, 3H). High resolution mass spectrum Calc'd. for C16H13ClO2S: 304.0325. Found: 304.0334.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[F:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([C:35]3[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=3)=[CH:31][NH:32]2)=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[F:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([C:35]3[CH2:36][CH2:37][N:38]([CH2:12][CH:13]4[O:18][C:17]5[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:16]=5[O:15][CH2:14]4)[CH2:39][CH:40]=3)=[CH:31][NH:32]2)=[CH:28][CH:27]=1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cccc2c1OC(CN1CC=C(c3c[nH]c4cc(F)ccc34)CC1)CO2

Procedure:
[(2R)-8-Methoxy-2,3-dihydro-benzo[1,4]dioxin-2-yl]methyl 4-methylbenzenesulfonate (0.30 g, 0.86 mmole), 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.60 g, 2.7 mmole) and sodium bicarbonate (0.80 g) were added to a mixture of dimethylformamide/tetrahydrofuran (1:1 v/v, 20 mL) and the reaction mixture was refluxed under nitrogen for 18 hours. The solvent was evaporated and the residue partitioned between 400 mL each of water and methylene chloride. The layers were separated and the methylene chloride solution was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous potassium carbonate and filtered. The filtrate was evaporated in vacuum and the residue crystallized from chloroform containing 3% methanol, giving 0.23 g (68%) of the (S)-enantiomer of the title compound as an off-white solid, m.p. 184–185° C.
Reaction SMILES: [CH:1]1C(CCCC(O)=O)=CC=C(N(CCCl)CCCl)C=1.[CH3:20][C:21]([C@H:23]1[CH:27]2[CH:28]3[C@@:41]([CH3:44])([CH2:42][CH2:43][C@@:26]2([C:65]([OH:67])=[O:66])[CH2:25][CH2:24]1)[C@@:40]1([CH3:45])[CH:31]([C@:32]2([CH3:64])[CH:37]([CH2:38][CH2:39]1)[C:36]([CH3:47])([CH3:46])[C@@H:35]([O:48][C:49]([CH2:51][N:52]([O:62][CH3:63])[C@@H:53]1[O:58][CH2:57][C@@H:56]([OH:59])[C@H:55]([OH:60])[C@H:54]1[OH:61])=[O:50])[CH2:34][CH2:33]2)[CH2:30][CH2:29]3)=[CH2:22]>>[CH3:1][C@H:57]1[O:58][CH:53]([N:52]([O:62][CH3:63])[CH2:51][C:49]([O:48][C@@H:35]2[C:36]([CH3:46])([CH3:47])[CH:37]3[C@@:32]([CH3:64])([CH:31]4[C@@:40]([CH3:45])([CH2:39][CH2:38]3)[C@@:41]3([CH3:44])[CH:28]([CH:27]5[C@@:26]([C:65]([OH:67])=[O:66])([CH2:43][CH2:42]3)[CH2:25][CH2:24][C@H:23]5[C:21]([CH3:20])=[CH2:22])[CH2:29][CH2:30]4)[CH2:33][CH2:34]2)=[O:50])[C@H:54]([OH:61])[C@@H:55]([OH:60])[C@H:56]1[OH:59]
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)C(CCC4[C@@]5(C)CC[C@H](OC(=O)CN(OC)[C@@H]6OC[C@@H](O)[C@H](O)[C@H]6O)C(C)(C)C5CC[C@]43C)C12
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)C(CCC4[C@@]5(C)CC[C@H](OC(=O)CN(OC)C6O[C@H](C)[C@H](O)[C@H](O)[C@H]6O)C(C)(C)C5CC[C@]43C)C12

Procedure:
A conformational study of sugar acetylhydrazides by Bendiak indicated that natural hexose and pentose (e.g., D-Glc, D-Gal, D-Xyl, etc.) analogs formed pyranosides, as evidenced by 1H NMR. Similar findings were reported for mono- and oligosaccharide chemoselective ligations with biotinyl, long-chain acyl, peptidyl, and adipyl hydrazides. In contrast, the current chlorambucil study revealed a trend that mirrored that which was observed for the 66-70 subset. Specifically, D-fucoside 72 was formed only as the cyclic compound (67% yield), D-glucuronolactonide 73 and D-xyloside 75 were a mixture of the open and closed conformers (46% and 47%, respectively), and D-threoside 74 adopted the open-chain imine (86%). These results indicate that closure of the glycoside may not only be dependent on the type of sugar but possibly the nature of the aglycon as well. It was also notable that only the β-anomer of the closed-rings was observed while the hydrazyl imines were isolated as mixtures of E- and Z-isomers (FIG. 7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5](I)=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(#N)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)ncc2I)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)ncc2-c2ccccc2)CC1
Yield: 99.5 %

Procedure:
A solution of tert-butyl 4-((2-chloro-5-iodopyridin-4-ylamino)methyl)piperidine-1-carboxylate (0.100 g, 0.22 mmol), sodium carbonate (0.5 M, 0.66 mL), phenyl boronic acid (0.027 g, 0.221 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.011 g, 0.01 mmol) in acetonitrile (2 mL) was heated at 100° C. for 20 min under microwave irradiation. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on a short silica column, eluting with ethyl acetate/petroleum ether (3/7), to give the title compound as a colourless oil (0.088 g, 98%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([CH:9]2[C:22]3[C:21](=[O:23])[CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:15]3[CH2:14][CH2:13][CH2:12][C:11](=O)[C:10]2=3)[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+]>C(O)C>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([CH:9]2[C:22]3[C:21](=[O:23])[CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=3)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCCC2=C1C(c1cccc(C(F)(F)F)c1)C1=C(CCCC1=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CCCC2=C1C(c1cccc(C(F)(F)F)c1)C1=C(CCCC1)N2
Temperature: 70 °C
Yield: 52 %

Procedure:
A mixture of 9-(3-trifluoromethylphenyl)-3,4,6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (2.0 g), sodium borohydride (2.1 g) and ethanol (50 mL) was heated at 70° C. overnight and cooled to room temperature. The mixture was partitioned between water and ethyl acetate; the organic layer dried, filtered and concentrated. Chromatography (eluant: methylene chloride/methanol; 98/2) and recrystallization from ethanol/hexane provided the title compound (1.0 g) as a yellow solid, m.p. 250°-251° C.; NMR: 1.47-1.52 (m,3, CH2), 1.66-1.90 (m,5, CH2), 2.10-2.15 (m,4, CH2), 2.40-2.45 (m,2, CH2), 4.28 (s,1, CH), 7.45 (s,4, Ar), 8.44 (s,1, NH); (CI, CH4) MS: m/z=348(M+1). Analysis for C20H20F3NO: Calculated: C, 69.15; H, 5.80; N, 4.03; Found: C, 69.01; H, 5.83; N, 3.98.
Reaction SMILES: C[N:2]1CCOCC1.[C:8]1([C:14]2[NH:18][N:17]=[C:16]([C:19]([NH:21][CH2:22][C:23]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=4[C:34]([OH:36])=O)[CH2:27][CH2:26]3)=[O:24])=[O:20])[CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ClC(OCC(C)C)=O>C1COCC1>[C:34]([C:33]1[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=1[O:31][CH:28]1[CH2:27][CH2:26][N:25]([C:23](=[O:24])[CH2:22][NH:21][C:19]([C:16]2[CH:15]=[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:18][N:17]=2)=[O:20])[CH2:30][CH2:29]1)(=[O:36])[NH2:2]
Reactant: CN1CCOCC1
Reactant: O=C(NCC(=O)N1CCC(Oc2ccccc2C(=O)O)CC1)c1cc(-c2ccccc2)[nH]n1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Yield: 60.3 %

Procedure:
N-Methyl morpholine (28 mg, 0.28 mmol) was added to a cold (−70° C.) solution of 2-(1-{2-[(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperidin-4-yloxy)-benzoic acid (100 mg, 0.2 mmol) in THF (2 mL) followed by isobutyl chloroformate (41 mg, 0.3 mmol) and stirring was continued at the at −70° C. for 1 hr. After complete formation of anhydride, ammonia gas was bubbled through the reaction mixture at −70° C. for 10 minutes. The resulting mixture was then stirred at room temperature for 1 hr. Water (10 mL) was added, the precipitated was filtered and dried to afford 54 mg (60.6% yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-carbamoyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 448.18, 93.4%. 1H NMR (300 MHz, DMSO-d6): δ 7.9 (m, 1H), 7.8 (m, 2H), 7.5 (m, 3H), 7.4 (m, 1H), 7.3 (m, 1H), 7.1 (m, 2H), 4.3 (s, 2H), 4.0 (m, 1H), 3.8 (m, 1H), 3.5 (m, 2H), 2.1 (m, 3H), 1.9 (m, 3H), 1.1 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:5][C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]([O:37][C:38](=[O:43])[CH2:39]C(O)=O)([CH3:36])([CH3:35])[CH3:34].[O-]CC.[Mg+2].[O-]CC>O1CCCC1>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:5][C:6](=[O:8])[CH2:39][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:43]
Reactant: CC(C)(C)OC(=O)CC(=O)O
Reactant: COC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Agent: CC[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(=O)CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.1 %

Procedure:
In a flask under argon was placed (S)-2-benzyloxycarbonylamino-succinic acid 1-methyl ester (3.0 g, 10.67 mmol) and tetrahydrofuran (50 mL). To this mixture was added carbonyldiimidazole (1.90 g, 11.74 mmol) and the resulting mixture was stirred at 25° C. for 6 h. In a separate round bottom flask was placed malonic acid mono t-butyl ester (1.98 g, 11.74 mmol), tetrahydrofuran (30 mL) and magnesium ethoxide (685 mg, 5.87 mmol) and the resulting mixture stirred at 25° C. for 1 h and then concentrated in vacuo. The residue was taken up in tetrahydrofuran (15 mL) and added to the flask containing the succinic acid and carbonyldiimidazole mixture and stirred at 25° C. for 16 h. The mixture was concentrated in vacuo and partitioned between diethyl ether (200 mL) and a 0.5N aqueous hydrochloric acid solution (200 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (150 mL), dried over sodium sulfate and concentrated. Purification by flash column chromatography (silica gel 60, 230-400 mesh; 40% ethyl acetate/hexanes) afforded (S)-2-benzyloxycarbonylamino-4-oxo-hexanedioic acid 6-t-butyl ester 1-methyl ester (3.04 g, 75%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][N:4]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)[CH:7]=2)(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2OC)cc1
Yield: 80.3 %

Procedure:
2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (200 mg, 0.8 mmol) was treated with 4-methoxybenzene-1-sulfonyl chloride (331 mg, 1.6 mmol) according to the method of Preparation 15b to give 270 mg (77% yield) of the title compound as an oil. Purity 96%.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][C:22]1[N:27]=[C:26]([C:28](=[N:34][OH:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:25](F)=[C:24]([Cl:37])[C:23]=1[N:38]1[CH2:43][C@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH4+].[Cl-]>CN(C=O)C>[Si:3]([O:20][CH2:21][C:22]1[N:27]=[C:26]2[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:34][O:35][C:25]2=[C:24]([Cl:37])[C:23]=1[N:38]1[CH2:43][C@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(=NO)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(Cl)c1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Reaction time: 1 h

Procedure:
Sodium hydride, 60% dispersion in mineral oil (0.063 g, 1.56 mmol) was added to a flask and DMF, 5 ml, was added to give a white slurry. The mixture was cooled in an ice bath. Ethyl 2-(6-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-((2R,6S)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)-2-(hydroxyimino)acetate (Intermediate 197, 0.786 g, 1.25 mmol) in 5 ml DMF was added to the sodium hydride suspension. There was some gas evolution, and the mixture became an orange solution. The reaction was worked up after 1 hour. Then saturated NH4Cl solution was added; the mixture was extracted with EtOAc, and washed with water (3×). The combined organic phase was dried over MgSO4 and concentrated. The residue was purified by chromatography on SiO2 using 0-40% EtOAc/hexanes to recover 544 mg (71%) of the title compound as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:6][C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9].BrC(Cl)(Cl)C(Cl)(Cl)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.ClCCl>[Cl:1][C:2]1[C:7]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]2[N:4]([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[N:13][N:12]=2)[N:3]=1
Reactant: C[Si](C)(C)c1cc(NNC(=O)c2ccccc2F)nnc1Cl
Agent: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)c1cc2nnc(-c3ccccc3F)n2nc1Cl
Temperature: 1 °C
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
To a stirred suspension of 3-chloro-6-[2-(2-fluorobenzoyl)hydrazino]-4-(trimethylsilyl)pyridazine (9.72 g, 28.7 mmol) and 1,2-dibromotetrachloroethane (18.68 g, 57.4 mmol) in anhydrous acetonitrile (170 ml), cooled under nitrogen to 1° C., was added portionwise, over 21 min, solid triphenylphosphine (30.10 g, 115 mmol), keeping the temperature below 5° C. The mixture was stirred at 2° C. for 10 min, then anhydrous triethylamine (32.0 ml, 230 mmol) was added dropwise over 18 min, keeping the temperature below 6° C. The mixture was then stirred at 0-3° C. under nitrogen for 85 min. The mixture was then diluted with dichloromethane (150 ml) and washed with water (200 ml). The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 20-40% EtOAc/hexane) to afford 7.67 g (83%) of the title compound as a white solid; 1H NMR (360 MHz, CDCl3) δ0.48 (9H, s), 7.30 (1H. dd, Jd=10.1 and 8.8 Hz), 7.36 (1H. td, J=7.6 and 1.1 Hz), 7.58 (1H, m). 7.90 (1H, td. J=7.3 and 1.8 Hz), 8.30 (1H, s); MS (ES+) m/e 321/323 [MH]+.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[N+:5]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)([O-:7])=[O:6].[OH-].[Na+]>C(O)C>[CH3:3]/[C:2](=[CH:12]\[C:11]1[CH:14]=[CH:15][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=1)/[CH:1]=[O:4]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C/C(C=O)=C\c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
Propionaldehyde (14.3 ml, 11.5 g, 0.20 mol) was added to a solution of 4-nitro benzaldehyde (20.0 g, 0.13 mol) in 50% aqueous ethanol (300 ml). An aqueous solution of 1M sodium hydroxide (36 ml, 0.04 mol) was then added dropwise, with stirring, at room temperature. After stirring for 1.5 h the precipitated solid was collected by filtration and recrystallised from aqueous ethanol to give 19.4 g (77%) of the product as a yellow solid, mp 112-114° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]=2[S:9][C:10]=1[NH2:11])=[O:5])C.[C:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18].Cl>O1CCOCC1>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C:17]1[N:18]=[C:4]([OH:5])[C:6]2[C:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]=3[S:9][C:10]=2[N:11]=1)[CH3:24]
Reactant: CCOC(=O)c1c(N)sc2c1CCCCC2
Reactant: CCOC(=O)CC#N
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Cc1nc(O)c2c3c(sc2n1)CCCCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.3 %

Procedure:
A mixture of 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid ethyl ester (7 g, 0.02928 mol) and ethyl cyanoacetate (6.5 g, 0.05857 mol) in 72 ml of 1,4-dioxane was saturated with HCl gas while cooling the mixture. The mixture was stirred for 18 h at ambient temperature, then quenched with solid NaHCO3, diluted with 100 ml water and extracted with ethyl acetate (100 ml×3). The organic layer was separated, dried over Na2SO4 and concentrated under vacuum. The crude solid was triturated with diethyl ether (100 ml) to give (4-hydroxy-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benz[a]azulen-2-yl)-acetic acid ethyl ester (5.5 g, 62%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 11.84 (brs, 1H), 4.18-4.28 (m, 2H), 3.78 (s, 2H), 3.22-3.32 (m, 2H), 2.80-2.90 (m, 2H), 1.83-1.93 (m, 2H), 1.58-1.75 (m, 5H), 1.26 (t, 3H); LC-MS: [M+H]=307.1 m/z.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[OH:15])[CH:5]=[C:4]([Cl:16])[N:3]=1.Br[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:16][C:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: BrCC1CCCCC1
Reactant: Nc1nc(Cl)cc(-c2cc(Cl)ccc2O)n1
Product: Nc1nc(Cl)cc(-c2cc(Cl)ccc2OCC2CCCCC2)n1
Yield: 20 %

Procedure:
Following the method described in Example 72, 2-(2-amino-6-chloro-pyrimidin-4-yl)-4-chloro-phenol and bromomethyl-cyclohexane provided 4-chloro-6-(5-chloro-2-cyclohexylmethoxy-phenyl)-pyrimidin-2-ylamine (20% yield).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[N:14][C:13]=2[C:19]([O:21]CC)=O)[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[NH3:26]>>[C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[N:14][C:13]=2[C:19]([NH2:26])=[O:21])[CH:8]=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)(C)C)n1
Reactant: N
Solvent: CO
Product: CC(C)(C)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
In a 100 mL round bottom flask, ethyl 4-(6-tert-butylpyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (539 mg, 1.61 mmol) was suspended in ammonia 7M in methanol (7.87 g, 10.0 mL, 70.0 mmol). Sealed and stirred at room temperature for 18 h. The solvents were evaporated and the residue dried in high vacuum to give clean 4-(6-tert-butylpyridin-2-ylamino)-6-chloropyridazine-3-carboxamide (492 mg, 99.9% yield) as an off-white solid. 1H NMR (DMSO-d6) δ: 11.94 (s, 1H), 9.23 (s, 1H), 8.84 (s, 1H), 8.19 (s, 1H), 7.74 (t, J=7.9 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.92 (d, J=7.9 Hz, 1H), 1.34 (s, 9H); LC-MS 306.1, 308.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH2:5]1[O:15][C:8]2([CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[O:7][CH2:6]1.[C:16]([OH:21])(=[O:20])[C:17]([OH:19])=[O:18]>C(O)C.C(O)(C)C.CO.[Pd]>[C:16]([OH:21])(=[O:20])[C:17]([OH:19])=[O:18].[CH2:5]1[O:15][C:8]2([CH2:13][CH2:12][CH:11]([NH:4][CH2:1][CH2:2][CH3:3])[CH2:10][CH2:9]2)[O:7][CH2:6]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCCN
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: CCO
Solvent: CO
Product: CCCNC1CCC2(CC1)OCCO2
Reaction time: 0.5 h

Procedure:
N-propylamine (88.5g, 123 mL, 1.5 mol) is added to a solution of 1,4-cyclohexanedione monoethylene ketal (156 g, 1 mol) in ethanol (780 mL). 5% Pd/C (50% water) is added to the mixture. The mixture is hydrogenated at 3 bar for several hours. Once the reaction has ended, the solvent is eliminated and the residue is dissolved in isopropanol (1.560 mL). A solution of oxalic acid (132 g, 1.5 mol) in MeOH (200 mL) is added dropwise to this solution. The suspension is stirred for 30 minutes and filtered on a plate, obtaining 274 g (95%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][CH:23]=[N:24]4)=[C:19](Cl)[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][CH:23]=[N:24]4)=[C:19]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Clc1nc(-c2cccc3c2ccn3Cc2ccccc2)cc2ncccc12
Product: c1ccc(Cn2ccc3c(-c4cc5ncccc5c(N5CCOCC5)n4)cccc32)cc1
Yield: 91 %

Procedure:
A flask charged with 7-(1-benzyl-1H-indol-4-yl)-5-chloro-1,6-naphthyridine, 3 (94 mg, 0.25 mmol, 1 eq) and morpholine (1.6 mL, 18 mmol, 70 eq) was heated at 100° C. overnight under Ar(g). Once cooled down, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography with hexane/EtOAc (3:2-0:1) to yield the product as pale yellow solid (96 mg, 91%).