Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[O:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:25]1[CH2:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1.C(O)(O)=O.COCCOC>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.CCO.O>[O:25]1[CH2:26][CH:27]=[C:28]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[O:17][C:18]5[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=5[N:20]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:29][CH2:30]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Brc1cccnc1Oc1ccc(Nc2nc3ccccc3o2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)O
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: C1=C(c2cccnc2Oc2ccc(Nc3nc4ccccc4o3)cc2)CCOC1
Temperature: 140 °C

Procedure:
A glass microwave reaction vessel was charged with N-(4-(3-bromopyridin-2-yloxy)phenyl)benzo[d]oxazol-2-amine (0.500 g, 1.308 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.414 g, 1.971 mmol), sodium carbonate anhydrous (0.700 g, 6.60 mmol) and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.092 g, 0.131 mmol, Strem). A mixture of 7:3:2 DME:H2O:EtOH (11 mL) was added and the reaction mixture was sealed under argon and heated in a Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 15 min. The reaction mixture was partitioned between EtOAc/water and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco (80 gram)) eluting with EtOAc:hexanes (0:1→1:2) to give a light-orange amorphous solid. MS (ESI, pos. ion) m/z: 386.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:11][C:4]=2[CH:3]=1.C(O)(=O)/C=C\C(O)=O.ClC1[N:36]=[N:35]C2CCNCC=2C=1.ClC1C=C(C=CC=1Cl)C(Cl)=O>CN(C)C=O>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[C:12]([N:10]1[CH2:9][CH2:8][C:5]2[N:6]=[N:7][C:2]([NH:35][NH2:36])=[CH:3][C:4]=2[CH2:11]1)=[O:21]
Reactant: O=C(c1ccc(Cl)c(Cl)c1)N1CCc2nnc(Cl)cc2C1
Reactant: Clc1cc2c(nn1)CCNC2
Agent: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CN(C)C=O
Product: NNc1cc2c(nn1)CCN(C(=O)c1ccc(Cl)c(Cl)c1)C2

Procedure:
The 3-chloro-6-(3,4-dichlorobenzoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8 (g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 3,4-dichlorobenzoyl chloride. M.P. 188°-191° (decomp., from dimethyl formamide).
Reaction SMILES: [ClH:1].O1CCOCC1.[OH:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=1[C:29](=[O:47])[NH:30][C:31]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:32]=1[C:43]([O:45][CH3:46])=[O:44])[O:12][CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1>C(OCC)(=O)C>[ClH:1].[OH:8][C:9]1[CH:10]=[C:11]([O:12][CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[CH:26]=[CH:27][C:28]=1[C:29]([NH:30][C:31]1[CH:36]=[C:35]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=[CH:33][C:32]=1[C:43]([O:45][CH3:46])=[O:44])=[O:47]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC2CCNCC2)cc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl acetate (1 mL) and a 4 mol/L hydrogen chloride-dioxane solution (0.50 mL) were added to the obtained tert-butyl 4-(3-hydroxy-4-(2-(methoxycarbonyl)-5-phenylphenylcarbamoyl)phenoxy)piperidine-1-carboxylate (0.025 g), followed by stirring at room temperature for 3 hours. The solid substance was collected from the reaction mixture by filtration to obtain 0.018 g of methyl 2-(2-hydroxy-4-(piperidin-4-yloxy)benzamido)-4-phenylbenzoate hydrochloride as a white solid.
Reaction SMILES: C(O)C.C([O:6][C:7](=O)/[C:8](=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]2)=[C:26]([O:36][CH3:37])[CH:25]=1)/[CH2:9][CH2:10][CH2:11][NH:12][C@@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@@H:14]1[OH:22])C.[OH-].[Na+].O>C(OCC)(=O)C>[OH:22][C@H:14]1[CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:13]1[N:12]1[CH2:11][CH2:10][CH2:9]/[C:8](=[CH:23]\[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]3)=[C:26]([O:36][CH3:37])[CH:25]=2)/[C:7]1=[O:6]
Reactant: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCN[C@@H]1c2ccccc2C[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1cc(/C=C2\CCCN([C@@H]3c4ccccc4C[C@@H]3O)C2=O)ccc1-n1cnc(C)c1
Yield: 72.8 %

Procedure:
To an ethanol (2.0 mL) solution of (E)-5-[(1R,2S)-2-hydroxyindan-1-ylamino]-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valeric acid ethyl ester (120 mg), 2N sodium hydroxide solution (1.0 mL) was added. After carrying out heat-refluxing of the reaction solution for 30 minutes and confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate=1:1->ethyl acetate->ethyl acetate:ethanol=10:1), and 78.9 mg of the title compound was obtained.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C@H:17]3[C@H:15]([O:16]3)[C@H:14]([CH3:18])[C@H:13]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C@@H:12]([CH3:27])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[C:1]1([S:7]([C:10]2[CH2:17][C@H:15]([OH:16])[C@H:14]([CH3:18])[C@H:13]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[C@@H:12]([CH3:27])[CH:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H]1[C@H]2O[C@H]2C(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C=C(S(=O)(=O)c2ccccc2)C[C@@H]1O
Temperature: -78 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
Compound α37 (39 mg, 0.095 mmol) was dissolved in dry toluene (1.0 mL), and the temperature lowered to −78° C. To this cold solution was added THF (10 μL, 0.12 mmol), followed by DIBAL-H solution (0.20 mL of 1.55M in toluene) under nitrogen, and the reaction stirred magnetically at −78° C. for 3 hours. Upon completion, the reaction was quenched by 5% HCl aqueous solution, and extracted with ethyl acetate (3×5 mL). The organic layers were combined and washed with brine, and dried over anhydrous Na2SO4. The crude reaction mixture was purified by flash column chromatography (ethyl acetate/hexanes; 1:3) to afford 34 mg (85%) of a mixture (1,2 vs 1,4-reduction; 4.5:1). 13 mg (35%) of pure 60 was obtained via flash column chromatography eluting with CH2Cl2: CH3CN (25:1). [α]20D=−77.7 (c=0.65, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.87-7.91 (m, 2H), 7.49-7.63 (m, 3H), 7.31 (br d, J=8.4 Hz, 1H), 3.80 (d, J=5.1 Hz, 1H), 3.66 (m, 1H), 3.32 (d, J=9.3 Hz, 1H), 2.94 (m, 2H), 2.57 (dt, J=16.5 Hz, 2.1 Hz, 1H), 1.98 (m, 1H), 1.18 (d, J=7.2 Hz, 3H), 1.13 (d, J=7.2 Hz, 3H), 0.88 (s, 9H), 0.14 (s, 3H), 0.10 (s, 3H); 13C NMR (C6D6, 75 MHz) δ 143.1, 140.4, 138.9, 133.5, 129.1, 128.8, 79.6, 71.0, 39.6, 38.0, 34.4, 25.9, 18.2, 18.0, 15.0, −4.4, −4.8; LRMS (CI): m/z 411 [M+H]+; HRMS (CI) calculated for C21H35O4SSi, 411.2025; found, 411.2025
Reaction SMILES: C[C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.CC([O-])(C)C.[K+].Br[C:17]1[CH:22]=[CH:21]C=C[N:18]=1>C1COCC1.O>[N:18]1[CH:17]=[CH:22][CH:21]=[CH:9][C:2]=1[O:3][CH2:4][CH:5]([OH:6])[CH2:7][OH:8]
Reactant: CC1(C)OCC(CO)O1
Reactant: Brc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: OCC(O)COc1ccccn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 17 %

Procedure:
Following a literature procedure2, a solution of solketal (1.25 mL, 0.01 mol) in THF (20 mL) was stirred and cooled to 0° C. under N2 and KOtBu (1.349 g, 0.012 mol) was added. The mixture was stirred 15 min, 2-bromopyridine (1.1 mL, 0.011 mol) was added, and the mixture was stirred 18 h at room temperature, diluted with H2O, and extracted with CH2Cl2. The combined extracts were dried (Na2SO4), filtered, and evaporated to give the crude title product (288.1 mg, 17%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[CH2:15]([NH2:21])[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20].[OH-:22].[K+]>C(Cl)CCl>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:21][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([O:22][C:2]([F:1])([F:13])[F:14])=[CH:5][CH:6]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: NCCCCCN
Agent: [K+]
Solvent: ClCCCl
Product: O=C(NCCCCCNC(=O)c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1

Procedure:
m.p. 154°-155° C., 13.8 g., was prepared as in Example 1 using 24.6 g. of 4-trifluoromethoxybenzoyl chloride in 200 ml. of ethylene dichloride, 5.1 g. of 1,5-pentanediamine, 60 ml. of 10% aqueous potassium hydroxide solution, 300 ml. ethylene dichloride and recrystallization from acetonitrile using decolorizing charcoal.
Reaction SMILES: N1C=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC([N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]3[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=3[C:18]=2[NH2:22])[CH2:13]1)=O)C.S(OC)(OC)(=O)=O>O>[N:22]1([C:18]2[C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=3[CH:15]=[C:14]3[C:19]=2[CH2:20][CH2:21][NH:12][CH2:13]3)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: CCOC(=O)N1CCc2c(cc3ccccc3c2N)C1
Reactant: c1ccncc1
Solvent: O
Solvent: COS(=O)(=O)OC
Product: c1ccc2c(-n3cccc3)c3c(cc2c1)CNCC3
Reaction time: 8 h

Procedure:
3 ml of pyridine are added to a mixture of 27.0 g of 5-amino-1,2,3,4-tetrahydrobenzo[g]isoquinolin-2-ylcarboxylic acid ethyl ester in 50 ml of water. 50.4 g of dimethyl sulphate are added dropwise to this mixture within 10 minutes and the mixture is stirred for 8 hours at 55° - 60°. The resulting clear solution is diluted with 100 ml of water, and is extracted several times with chloroform. The extracts are washed neutral with water, are dried over sodium sulphate and concentrated by evaporation. The oily residue is taken up in ether, is made acid with ethereal hydrochloric acid solution and the precipitated product is filtered off and recrystallized from ethanol/ether. M.Pt. of 5-methylamino-1,2,3,4-tetrahydrobenzo[g]isoquinolin-2-ylcarboxylic acid ethyl ester hydrochloride 214° - 215°.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34]=O)=[CH:4][N:3]=1.[CH3:36][NH:37][NH2:38]>O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH:32]2[N:37]([CH3:36])[N:38]=[CH:34][CH2:33]2)=[CH:4][N:3]=1
Reactant: CNN
Reactant: COc1cc(-c2csc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Solvent: O
Product: COc1cc(-c2csc3c(C4CC=NN4C)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
N-(4-{4-amino-7-[(1E)-3-oxoprop-1-enyl]thieno [3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.I0 g, 0.207 mmol) was stirred with methyl hydrazine (0.5 mL) at ambient temperature for 3 hours then water (8 mL) was added and the white precipitate was collected by filtration and dried to give the title compound. Rt=3.62 min (Conditions a) MS m/e: 511 (M+H)30, 509 (M−H)31 .
Reaction SMILES: N1C(C(Cl)=O)=CC=CC=1C(Cl)=O.NC[C:15]1[C:16]2[C:21]([C:22](CN)=[C:23]3[C:28]=1[CH:27]=[CH:26][CH:25]=[CH:24]3)=[CH:20][CH:19]=[CH:18][CH:17]=2.C(N(CC)CC)C.CO>C(Cl)(Cl)Cl>[CH:17]1[C:16]2[C:21](=[CH:22][C:23]3[C:28]([CH:15]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=[CH:19][CH:18]=1
Reactant: NCc1c2ccccc2c(CN)c2ccccc12
Agent: O=C(Cl)c1cccc(C(=O)Cl)n1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: c1ccc2cc3ccccc3cc2c1
Reaction time: 8 h

Procedure:
Clear solutions of 2,6-pyridinedicarbonyl dichloride (84 mg, 0.41 mmol) in 15 mL of chloroform and 9,10-bis(aminomethyl)anthracene (97 mg, 0.41 mmol) in 15 mL of chloroform were simultaneously added dropwise over 10 h to a stirred solution of squaraine 13a (32 mg, 0.05 mmol, synthesized according to E. Arunkumar et al. Chem. Eur. J. 2006, 12, 4884-4690) and triethylamine (81 mg, 0.8 mmol) in 30 mL of chloroform. After overnight stirring, the mixture containing rotaxane 13 and polymer co-products was filtered, washed with chloroform (100 mL) to extract rotaxane 13, and the filtrate was concentrated. Purification of the crude material by column chromatography using silica gel (gradient, 0-1% of MeOH in CHCl3) gave the rotaxane 13. λmax (abs): 651 m, λmax (em): 707 nm, 59% (methanol); λmax (abs): 648 nm, λmax (em): 700 nm, Q.Y.: 65% (chloroform).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11][OH:12])=[CH:4][CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[N:11][OH:12])=[CH:6][CH:7]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccccc1C(CC(=NO)c1ccncc1)c1ccc(Br)cc1
Product: Cc1ccccc1C(CC(=NO)c1ccncc1)c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
In analogy to example 22, from 3-(4-bromo-phenyl)-1-pyridin-4-yl-3-o-tolyl-propan-1-one oxime (example 31) and 4-(methylsulfonyl)phenylboronic acid was prepared the title compound as a mixture of E and Z isomers (2:1) as a white solid, MS (ESI+): m/z=471.1 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]([Cl:16])([Cl:15])[CH2:10][O:11][C:12](Cl)=[O:13].[CH3:17][C:18]1[NH:19][C:20](=[O:24])[CH2:21][S:22][CH:23]=1>>[CH3:17][C:18]1[NH:19][C:20](=[O:24])[CH2:21][S:22][C:23]=1[CH:7]1[CH:6]=[CH:5][N:4]([C:12]([O:11][CH2:10][C:9]([Cl:16])([Cl:15])[Cl:8])=[O:13])[CH:3]=[C:2]1[CH3:1]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC1=CSCC(=O)N1
Reactant: Cc1cccnc1
Product: CC1=CN(C(=O)OCC(Cl)(Cl)Cl)C=CC1C1=C(C)NC(=O)CS1
Yield: 31 %

Procedure:
A mixture of 3-methylpyridine (0.72 g), 2,2,2-trichloroethylchloroformate (1.33 ml) and 5-methyl-2H-1,4-thiazin-3(4H)-one (0.5 g) was treated in the same manner as described in Example 2 (i) to give the titled compound (0.49 g, yield 31%) as milky white crystals. n-Hexane-ethyl acetate (=1:1) was used as a developing eluant.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH3:23]>CCOCC.O>[NH2:1][C:2]1[C:7]([O:8][CH2:21][CH2:22][CH3:23])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCOc1cccnc1N
Temperature: 50 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
A reaction flask was loaded with 2-amino-3-hydroxypyridine (12 g), dimethylformamide (75 ml), and potassium carbonate (18 g), and they were mixed. The temperature was raised to 50° C. To this mixture, 1-bromopropane (16.1 g) was dropwise added in 30 minutes. After stirring at 50° C. overnight, water and ether were added to the mixture, followed by stirring. The organic layer was collected from this, and washed with water, and then condensed to give 2-amino-3-propoxypyridine (4.0 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:6]=1.Cl[C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]2[O:35][C:34](=[O:36])[NH:33][C@@H:32]2[CH3:37])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:33]2[C@H:32]([CH3:37])[C@H:31]([C:28]3[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=3)[O:35][C:34]2=[O:36])[CH:6]=1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccc(Cl)cc1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CBr)c1
Product: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and (4R,5S)-5-(4-chloro-phenyl)-4-methyl-oxazolidin-2-one.
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)=[O:4])[NH2:2].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:25])=[C:20]([C:22](=O)[CH3:23])[CH:21]=1>CO.C(O)(=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:25])=[C:20](/[C:22](=[N:2]/[NH:1][C:3]([C:5]2[CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=2)=[O:4])/[CH3:23])[CH:21]=1
Reactant: NNC(=O)c1cccc(S(N)(=O)=O)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(N)(=O)=O)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 40.5 %

Procedure:
3-(hydrazinecarbonyl)benzenesulfonamide (50 mg, 0.232 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (39.6 mg, 0.232 mmol) was dissolved in methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the product (E)-3-(2-(1-(5-chloro-2-hydroxyphenyl)ethylidene)hydrazinecarbonyl)benzenesulfonamide (36 mg, 0.094 mmol, 40.4% yield) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.34 (s, 1H), 8.15 (d, 1H, J=7.6 Hz), 8.02 (d, 1H, J=7.6 Hz), 7.73 (t, 1H, J=8.0 Hz), 7.64 (m, 1H), 7.51 (bs, 2H), 7.32 (dd, 1H, J=2.4 & 8.4 Hz), 6.92 (d, 1H, J=8.4 Hz), 2.49 (s, 3H). Mass [M+H]+:368.0
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16]1)[CH2:7][CH2:6]2.[CH3:21][O:22]C1C=C2C(C=CN2)=CC=1>>[CH3:21][O:22][C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH2:12][CH2:13][CH2:14][N:15]2[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)CCN2CCCn1cc(N)cn1
Reactant: COc1ccc2cc[nH]c2c1
Product: COc1ccc2c(c1)N(CCCn1cc(N)cn1)CC2

Procedure:
The title compound was synthesized according to above mentioned procedure for 1-[3-(5-methoxy-2,3-dihydro-indol-1-yl)-propyl]-1H-pyrazol-4-ylamine, starting form 6-methoxyindole. LC-MS conditions B: tR=0.46 min, [M+H]+=273.23.
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]#[N:22]>C1(C)C=CC=CC=1>[ClH:7].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([NH2:1])=[NH:22]
Reactant: [NH4+]
Reactant: N#CCc1ccccc1-c1ccccc1Cl
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cl
Product: N=C(N)Cc1ccccc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of NH4Cl (1.4 g, 26.43 mmol) in dry toluene (40 mL) was added tri-methyl aluminium (2M in toluene, 13.2 mL, 26.43 mmol) at 5° C. The reaction mixture was then warmed to room temperature and stirred for 2 h. A solution of (2′-chloro-biphenyl-2-yl)-acetonitrile (15) (2 g, 8.8 mmol) in toluene (10 mL) was added to the reaction mixture, which was then stirred for 14 h at 80° C. After completion of the reaction, it was quenched with a suspension of silica gel in chloroform and the reaction mixture was stirred for half an hour at room temperature and then filtered through a sintered funnel. The silica gel was washed with methanol and the combined filtrates were concentrated under reduced pressure to get 2-(2′-chloro-biphenyl-2-yl)-acetamidine hydrochloride salt as a crude product (5-02) (2 g, 80.97%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[F:54][C:55]([F:73])([F:72])[C:56]1[CH:57]=[C:58]([NH:62]C2C=CC=CC=2C(O)=O)[CH:59]=[CH:60][CH:61]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[F:54][C:55]([F:72])([F:73])[C:56]1[CH:57]=[C:58]([NH:62][C:29]2[CH:30]=[CH:31][CH:2]=[CH:3][C:4]=2[C:5]([NH:7][CH:8]([C:10]2[N:15]=[N:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[N:12][CH:11]=2)[CH3:9])=[O:6])[CH:59]=[CH:60][CH:61]=1
Reactant: O=C(O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3Nc3cccc(C(F)(F)F)c3)nn2)cc(OC)c1OC
Yield: 80 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid (240 mg, 0.85 mmol), diisopropylethylamine (0.34 mL, 1.95 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (350 mg, 0.92 mmol) in dimethylformamide (5 mL) gave 2-{[3-(trifluoromethyl)phenyl]amino}-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (297 mg, 80%) as a yellow solid. MS m/z 568 (M+1).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:20][C:21]1[CH:26]=[C:25](Cl)[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][C:22]=1[OH:31].[OH-].[K+]>CN(C)C(=O)C>[CH2:19]([O:31][C:22]1[CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[C:25]([O:12][C:9]2[CH:8]=[CH:7][C:6]([C:1]([CH2:4][CH3:5])([CH3:2])[CH3:3])=[CH:11][CH:10]=2)=[CH:26][C:21]=1[NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(C)(C)c1ccc(O)cc1
Reactant: Cc1ccccc1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CCC(C)(C)c1ccc(Oc2cc(N)c(OCc3ccccc3)cc2[N+](=O)[O-])cc1
Temperature: 90 °C
Yield: 91 %

Procedure:
In a 500-ml flask, place 32.0 g (0.15 m×1.3) of 4-t-pentylphenol, 250 ml of toluene, 15 ml of N,N-dimethylacetamide, and 1 1.22 g (0.15 m×1.2@90%) of KOH flakes. Heat the mixture under reflux with Dean-Stark trap to collect approximately 5 ml of water and 20 ml of toluene over 1 hr. Cool white slurry mixture to 90° C., and add 41.8 g (0.15 m) of 2-benzyloxy-5-chloro-4-nitroaniline (2) and 1 g of tetrabutylammonium bromide. Heat under reflux for 1 hr. Addition of 1 g of phase transfer agent, tetrabutylammonium bromide, and heat under reflux for 1 hr period is repeated 3 more times. At the end of the 4 hrs reflux period, cool the reaction mixture to 90° C., add 100 ml of hot water and stir for a few min. Separate toluene solution, wash with 100 ml of hot water, concentrate the reaction mixture by distilling off toluene under a reduced pressure at a pot temperature of 60° C. Add 200 ml of heptane slowly at 60° C., cool to room temperature, and let it stand over night. Collect solid, wash with 10% toluene in heptane, dry in air to give 55.5 g (91%) of 2-benzyloxy-5-(4-t-pentylphenoxy)-4-nitro-aniline (3b; Y=4-t-pentylphenoxy).