Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:17][C:18]1[S:26][C:25]2[C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:23][C:22]([Cl:33])=[N:21][C:20]=2[CH:19]=1>O1CCCC1>[Cl:33][C:22]1[N:23]=[C:24]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[C:25]2[S:26][C:18]([CH2:17][N:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[S:10]([CH3:13])(=[O:12])=[O:11])=[CH:19][C:20]=2[N:21]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: CS(=O)(=O)NCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)N(CCN1CCOCC1)Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of N-(2-Morpholin-4-yl-ethyl)-methanesulfonamide in tetrahydrofuran under nitrogen was added sodium hydride, 60% dispersion in mineral (16 mg). The mixture was stirred at room temperature for 40 minutes. A solution of 6-Bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (125 mg) in tetrahydrofuran (5 ml) was added. The reaction mixture was stirred at room temperature for 3.5 hours, then 50° C. for 3.5 hours. The solvents were removed in vacuo to give a crude product which was purified by flash chromatography to yield N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(2-morpholin-4-yl-ethyl)-methanesulfonamide (138 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][CH2:32][NH2:33])[CH3:29].C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([NH:33][CH2:32][CH2:31][N:30]([CH2:34][CH3:35])[CH2:28][CH3:29])[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: CCN(CC)CCN
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCNC(C)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1

Procedure:
N1-(1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethyl)-N2,N2-diethylethane-1,2-diamine was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and N1,N1-diethylethane-1,2-diamine (commercially available) following the procedures described for Example 182. 1H NMR (Acetone-d6) TFA Salt: δ: 8.81 (s, 1H), 8.75 (s, 1H), 8.23 (d, 1H), 7.60 (d, 2H), 7.39 (d, 2H), 7.28 (m, 2H), 4.51 (m, 1H), 3.82 (m, 1H), 3.62 (m, 1H), 3.34 (m, 4H), 3.20 (t, 2H), 2.46 (s, 3H), 2.10 (m, 4H), 1.74 (d, 3H), 1.34 (t, 6H). LRMS [M+H]=456.2
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19]C)=[O:18])=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>O.O1CCCC1>[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([OH:19])=[O:18])=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cccc(C(=O)N2CCN(C(=O)C3CC3)CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(C(=O)N2CCN(C(=O)C3CC3)CC2)c1
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a solution of methyl 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoate (0.95 g, 3 mmol) in water (10 mL) and tetrahydrofuran (10 mL) at 0° C., lithium hydroxide monohydrate (250 mg, 6 mmol) was added. The mixture was stirred at that temperature for 2 h. The resulting mixture was neutralized to pH=5 with hydrochloric acid, and extracted with ethyl acetate (100 mL×4) and concentrated to obtain a white solid of 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoic acid (0.76 g, yield 83%). LC-MS (ESI) m/z: 303 (M+1)+. 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoic acid (610 mg, 2 mmol) was added to thionyl chloride (10 mL), and the mixture was added at room temperature for 48 h. Then the solvent was removed under reduced pressure, dried in vacuum to give 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoyl chloride.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[NH2:45][C:46]1[CH:54]=[CH:53][C:49]([CH2:50][CH2:51][OH:52])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:45][C:46]4[CH:54]=[CH:53][C:49]([CH2:50][CH2:51][OH:52])=[CH:48][CH:47]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccc(CCO)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)Nc5ccc(CCO)cc5)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-aminophenethyl alcohol as the aniline component. (43%, MS=627.3 (M+H))
Reaction SMILES: C(O[C:6](=[O:9])[NH:7][NH2:8])(C)(C)C.[C:10](O)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]C>FC(F)(F)C(O)=O>[C:6]([NH:7][NH2:8])(=[O:9])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCC(=O)NN
Reaction time: 0.25 h
Yield: 76.3 %

Procedure:
1.8 g (4.52 mmol) stearic acid tert-butylcarbazate is dissolved in 3 ml trifluoracetic acid, stirred for 15 min and the solvent is removed under vacuum. The mixture is treated with 30 ml dry ether and the precipitate formed is filtered out and washed twice with 50 ml dry diethyl ether. After drying under high vacuum, 1.03 g stearic acid hydrazide is obtained; Rf=0.66 (ethyl acetate/methanol 1/1)
Reaction SMILES: C[O-].[Na+].[CH2:4]([C:8]([NH2:10])=[O:9])[C:5]([NH2:7])=[O:6].C(O[CH:14]=[CH:15][C:16](=O)[C:17]([F:20])([F:19])[F:18])C.Cl>CO>[O:6]=[C:5]1[C:4]([C:8]([NH2:10])=[O:9])=[CH:14][CH:15]=[C:16]([C:17]([F:20])([F:19])[F:18])[NH:7]1
Reactant: NC(=O)CC(N)=O
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(C(F)(F)F)[nH]c1=O
Temperature: 45 °C
Yield: 82.8 %

Procedure:
Sodium methoxide (74 g, 1.37 mol) was dissolved in methanol (1,000 mL), and malon diamide (100 g, 0.979 mol) was added to this solution at room temperature. To this mixture, 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (191 g, 1.14 mol) was added dropwise at a temperature between 25 and 30° C., and the resultant mixture was refluxed under heating for 2 hours. After cooling to 45° C., concentrated hydrochloric acid was added to the mixed solution to give a pH of 3 to 4, and 500 mL of methanol was distilled off at normal pressure. To the residue, water (500 mL) was added, and the mixture was stirred for a day at room temperature. The resultant product was precipitated while cooling with ice. Thus obtained crystal was collected by filtration, washed with water, and then dried under reduced pressure, to obtain 167 g of a subject compound (yield: 83%).
Reaction SMILES: [CH2:1](C([Sn])=C(CCCC)CCCC)[CH2:2]CC.I[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=1[O:27][CH:28]=[C:29]([C:31]1[CH:40]=[CH:39][C:38]2[C:37]([CH3:42])([CH3:41])[CH2:36][CH2:35][C:34]([CH3:44])([CH3:43])[C:33]=2[CH:32]=1)[CH3:30]>C(#N)C>[CH2:30]([C:29]1([C:31]2[CH:40]=[CH:39][C:38]3[C:37]([CH3:42])([CH3:41])[CH2:36][CH2:35][C:34]([CH3:43])([CH3:44])[C:33]=3[CH:32]=2)[C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=2[O:27][CH2:28]1)[CH:1]=[CH2:2]
Reactant: COC(=O)c1ccc(I)c(OC=C(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Solvent: CC#N
Product: C=CCC1(c2ccc3c(c2)C(C)(C)CCC3(C)C)COc2cc(C(=O)OC)ccc21
Temperature: 80 °C

Procedure:
A mixture of palladium bis(triphenylphosphine)diacetate (0.15 g, 0.2 mmol), tributylvinyltin (0.56 ml, 1.92 mmol) and methyl 4-iodo-3-[2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl]-1-propenyloxy]benzoate (1 g, 1.99 mmol) in acetonitrile (20 ml) is heated at 80° C. for 3 days, adding tributylvinyltin (0.28 ml, 0.96 mmol) every 24 h. The reaction medium is concentrated on a rotary evaporator under vacuum at 40° C. 40 ml of water and 40 ml of ethyl ether are added. After separation of the phases by settling, the organic phase is washed twice with 40 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [CH:1]1[N:6]=[C:5]([Cl:7])[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.P(Cl)(Cl)(Cl)=O.[OH-].[NH4+].[P:27](OC)([O:31]C)([O:29]C)=[O:28]>O>[CH:1]1[N:6]=[C:5]([Cl:7])[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][O:17][P:27]([OH:31])([OH:29])=[O:28])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1
Reactant: COP(=O)(OC)OC
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=P(O)(O)OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
6-Chloropurine riboside (100 mg, 0.35 mmol) was dissolved in 1.75 mL of trimethyl phosphate. Phosphoryl chloride (160 mg, 1.05 mmol) was dissolved in a mixture of 0.17 mL of trimethylphosphate and 6.3 μL of water. Both solutions were cooled to 0° C., mixed and stirred on a magnetic stirrer at 0° C. After 6 hours, ice was added to quench the reaction and the pH was adjusted to 7 by addition of ammonium hydroxide solution. The crude product was then concentrated and purified on a C18 reverse phase column using water as the mobile phase. The fractions containing desired product were combined and lyophilized to dryness to afford 6-chloropurine riboside 5′-phosphate (96 mg, 0.26 mmol, 75%) as a white solid. 1H NMR (D2O, 500 MHz) δ (ppm): 4.20 (m, 2H), 4.42 (m, 1H), 4.55 (t, J=4.6 Hz, 1H), 4.84 (m, 1H), 6.28 (d, J=5.1 Hz, 1H), 8.79 (s, 1H), 8.86 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](O)=O)=[N:4][C:5]([Cl:11])=[C:6]([Cl:10])[C:7]=1[NH:8][NH2:9].ClC1[N:21]=C(C#N)C(Cl)=C(Cl)C=1Cl.NN.Cl>>[Cl:1][C:2]1[C:3]([C:12]#[N:21])=[N:4][C:5]([Cl:11])=[C:6]([Cl:10])[C:7]=1[NH:8][NH2:9]
Reactant: N#Cc1nc(Cl)c(Cl)c(Cl)c1Cl
Reactant: NNc1c(Cl)c(Cl)nc(C(=O)O)c1Cl
Agent: Cl
Agent: NN
Product: N#Cc1nc(Cl)c(Cl)c(NN)c1Cl

Procedure:
The 3,5,6-trichloro-4-hydrazinopicolinic acid can be prepared in a variety of ways. In one such method, tetrachloropicolinonitrile is reacted with hydrazine in the presence of a reaction medium and hydrogen chloride acceptor. The 3,5,6-trichloro-4-hydrazinopicolinonitrile product thus formed is reacted with an acid hydrolysis agent to prepare 3,5,6-trichloro-4-hydrazinopicolinic acid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[CH:37](O)[CH3:38]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH:37]([C:31]3[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=3[Cl:29])[CH3:38])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)c1cc(Cl)ccc1Cl
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CC(Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)c1cc(Cl)ccc1Cl

Procedure:
This compound was prepared according to the procedure of example 69, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and 1-(2,5-dichloro-phenyl) ethanol. MS (ESI) m/z 553.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]CC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Br:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Br)cccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1Cc2c(C(=O)O)ncn2-c2cccc(Br)c2C1=O

Procedure:
7.10 g (19 mmol) of ethyl 7-bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3carboxylate in 30 ml of ethanol are heated to boiling for 20 minutes with a solution of 1.13 g (28 mmol) of sodium hydroxide in 15 ml of water. The solution is thereafter neutralized with 7 ml of 4N hydrochloric acid and the ethanol is removed on a rotary evaporator. After cooling the separated solid is filtered off under suction. After drying at 85° in vacuo there is obtained 7-bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylic acid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([S:10][CH3:11])[N:4]=1.S(OCC)(O[CH2:16][CH3:17])(=O)=O>>[CH2:16]([O:9][C:7]1[N:6]=[C:5]([S:10][CH3:11])[N:4]=[C:3]([CH2:2][Cl:1])[CH:8]=1)[CH3:17]
Reactant: CSc1nc(O)cc(CCl)n1
Reactant: CCOS(=O)(=O)OCC
Product: CCOc1cc(CCl)nc(SC)n1

Procedure:
4-Chloromethyl-6-hydroxy-2-methylthio-pyrimidine [known from S. Cohen et al., J.Org. Chem. 27, 3545-3549 (1962)] is treated with diethyl sulphate analogously to the process described in Example 59 in order to produce 6-ethoxy-4-chloromethyl-2-methylthio-pyrimidine which is required as the starting material in Example 19. M.p. (after crystallization from water) 167°-171° C.; 1H-NMR (CDCl3): 1.40 (t, CH3) 2.56 (s, SCH3), 4.45 (q, CH2), 4.47 (s, CH2Cl), 6.55 (s, CH).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=1[C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28].C(Cl)Cl.[CH:33]([NH2:35])=O>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[N:35]=[CH:33][N:1]=[C:2]2[N:6]([C:7]3[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=3[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=12
Reactant: NC=O
Reactant: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)c1ccccc1Cl
Solvent: ClCCl
Product: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c2ncnc(-c3ccccc3Cl)c12
Temperature: 150 °C

Procedure:
A suspension of 669 mg (1.39 mmol) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2-chlorobenzoyl)-3-methylthiopyrazole in 5 mL of formamide was heated at 150° C. overnight. A pale yellow solid precipitated upon cooling of the reaction mixture. A total of 50 mL of water was added to the stirred suspension to complete the precipitation of the product which was filtered off and washed with water. An inseparable trace of starting material was observed in the product by thin layer chromatography (TLC) and so the above procedure was repeated on the mixture giving a brown solid containing no trace of starting material. Trituration of this solid with methylene chloride gave a pale yellow solution which was concentrated to give the desired product as a white crystalline solid, m.p. 156-158° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>C1COCC1.O>[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:22]2[N:21]=[N:20][C:19]([Cl:18])=[CH:24][CH:23]=2)=[CH:12][CH:11]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(Cl)nn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
Potassium tert-butoxide (0.87 g, 7.75 mmol) was added in portions to a solution of 4-hydroxybenzoic acid methyl ester 1 (1.15 g, 7.56 mmol) in anhydrous THF (25 ml). The mixture was stirred at room temperature for 30 minutes, then 3,6-dichloro-pyridazine (1.12 g, 7.56 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and heated at reflux for 14 h. The mixture was cooled to room temperature and diluted with water (100 ml). The formed precipitate was collected by filtration, washed with water and dried to obtain 1.315 g (66%) of 4-(6-chloro-pyridazin-3-yloxy)-benzoic acid methyl ester which was used for the next step without further purification.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[C:14]([CH2:15][O:16][C:17]3[C:22]([CH:23]=[O:24])=[CH:21][C:20]([O:25]C)=[N:19][CH:18]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.[OH-].[Na+]>O>[O:25]=[C:20]1[CH:21]=[C:22]([CH:23]=[O:24])[C:17]([O:16][CH2:15][C:14]2[C:9]([C:8]3[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][CH:7]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:18][NH:19]1
Reactant: COc1cc(C=O)c(OCc2cccnc2-c2ccnn2C(C)C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)n1nccc1-c1ncccc1COc1c[nH]c(=O)cc1C=O
Reaction time: 20 h

Procedure:
To 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (590 mg) suspended in water (5.0 mL) was added HCl (6 N, 4 mL). Once the mixture turned into a homogeneous solution, it was freeze at −78° C. to an solid and pump under high vacuum O/N. The yellow solid was continued to pump at 45° C. for 20 h, dissolved in water (2.0 mL), and basified to pH 11 with NaOH (2 N). The aqueous layer was washed with DCM three times and the pH of the mixture was adjusted to pH 6-7. The solid was collected and dried to give 2-oxo-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]-1H-pyridine-4-carbaldehyde as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.3 (s, 1H), 8.8 (dd, J=4.7, 1.6 Hz, 1H), 8.1 (dd, J=7.9, 1.5 Hz, 1H), 7.6 (s, 1H), 7.5 (d, J=1.8 Hz, 1H), 7.1 (s, 1H), 7.0 (s, 1H), 6.6 (d, J=1.8 Hz, 1H), 4.9 (s, 2H), 4.7 (sep, J=6.6 Hz, 1H), 1.5 (d, J=6.6 Hz, 6H); MS (ESI) m/z 339.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C(=O)([O-])[O-].[K+].[K+].[Si:16]([O:23][CH2:24][CH2:25]Br)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C)C=O>[Si:16]([O:23][CH2:24][CH2:25][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: OCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccccc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-hydroxybenzyl alcohol (0.4 g) and potassium carbonate (0.67 g) in N,N-dimethylformamide (6 mL) was added 2-(tert-butyldimethylsilyloxy)ethyl bromide (1.05 mL), and the mixture was stirred at room temperature overnight.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][OH:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:25]=[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])[C:19]([C:20]([NH:22][NH2:23])=[O:21])=[CH:18][N:17]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:15][C:16]1[CH:25]=[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])[C:19]([C:20]([NH:22][NH:23][C:10](=[O:12])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][OH:14])=[O:21])=[CH:18][N:17]=1
Reactant: CC(C)(C)OC(=O)NC(CO)C(=O)O
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Nc1cc(Cl)ncc1C(=O)NNC(=O)C(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (500 mg, 2.4 mmol) and 6-chloro-4-(isopropylamino)nicotinohydrazide (10) (2.6 mmol, 1.1 equiv.) in DMF (10 mL), DIPEA (12 mmol, 5 equiv.) and HATU (2.6 mmol, 1.1 equiv.) were added and stirred overnight at room temperature. The reaction mass was concentrated under reduced pressure to remove excess of solvent present. Diluted the residue with EtOAc and washed water followed by brine solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated to get tert-butyl (1-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-3-hydroxy-1-oxopropan-2-yl)carbamate (53).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]=[C:5]1[CH2:8][O:7][CH2:6]1.[NH3:10]>CCO>[CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]1([NH2:10])[CH2:8][O:7][CH2:6]1
Reactant: N
Reactant: COC(=O)C=C1COC1
Solvent: CCO
Product: COC(=O)CC1(N)COC1

Procedure:
Oxetan-3-ylidene-acetic acid methyl ester (Angewandte Chemie, International Edition (2006), 45(46), 7736-7739) ester (1.5 g; 11.72 mmol) in EtOH (20 ml) and liquid NH3 (11 g) are heated in a steel cylinder at 800 C for 5 hours. Evaporation of the solvent delivers the title compound as yellow resin. 1H-NMR (400 MHz; DMSO-d6): 4.42 (d, 2H); 4.34 (d, 2H); 3.61 (s, 3H); 2.77 (s, 2H); 2.33 (bs, 2H). MS (m/z) ES+: 145 (MH+; 15); 96 (100).
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:18])[CH:5]1[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6]1.O>CC(O)C.[C].[Pd]>[ClH:1].[ClH:1].[CH3:3][N:4]([CH3:18])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: CN(C)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CN(C)C1CCNCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 158.3 %

Procedure:
After adding 10% palladium-carbon (2.0 g) to a solution of the crude 4-dimethylamino-1-benzylpiperidine dihydrochloride (30.0 g) in 2-propanol (300 ml)-water (300 ml), the mixture was stirred for 22 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered and washed with 2-propanol. The filtrate was then concentrated. The obtained crystals were suspended in ethanol (50 ml). They were then diluted with diethyl ether (50 ml). The crystals were subsequently filtered and washed with methanol (10 ml). They were then subjected to aeration drying to provide the title compound (16.4 g) as colorless crystals.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].Cl>O1CCCC1>[Br:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]([OH:9])[CH2:1][CH3:2]
Reactant: O=Cc1ccccc1Br
Reactant: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCC(O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution (1 mol/L, 60 mL) of ethylmagnesium bromide in tetrahydrofuran was added to a solution (200 mL) of 2-bromobenzaldehyde (5.55 g, 3.0 mmol) in tetrahydrofuran under ice-cooling, followed by stirring for 1 hour while gradually heating the mixture to room temperature. Next, the reaction solution was poured into ice water, and this mixture was neutralized with hydrochloric acid (1 mol/L) and then extracted with ethyl acetate. After the extract was washed with a saturated brine and then dried over sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developed with ethyl acetate/hexane=1/4) to give 1-(2-bromophenyl)-1-propanol (4.5 g, yield 70%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]([N+:14]([O-])=O)=[C:11]([CH:13]=2)[NH2:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:14])=[C:11]([NH2:12])[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCCCC2)cc1N
Yield: 94.9 %

Procedure:
The nitroaniline derivative (17.0 g, 0.076 mol) (obtained in step 1 above) was hydrogenated using 10% Pd-C (4.0 g) in ethanol (75 mL) by an analogous procedure to that described in preparation 1 (step 4) to yield 4-(piperidin-1-yl)-1, 2-phenylenediamine (13.8 g, 97%) as a viscous oil. IR (Neat) 3390, 1252 cm-1 ; 1H NMR (CDCl3) 6d 1.52 (m, 2H, CH2), 1.70 (t, J=4.7 Hz, 4H, (CH2)2), 2.90 (t, J=5.0 Hz, 4H, N(CH2)2), 3.00 (brs, 4H, 2×NH2), 6.32 (d, J=8.3 Hz, 1H), 6.38 (s, 1H), 6.62 (d, J=8.1 Hz, 1H); Mass (m/z) 191 (M+.).