Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:27]>>[CH3:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:27])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N
Reactant: Cc1ccccc1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1
Product: Cc1ccccc1COc1cccnc1NC(=N)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of N-[3-(2-methylbenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (0.99 g, 0.0026 mol), yellow mercuric oxide (0.67 g, 0.003 mol) and methanolic ammonia solution (40 ml) was stirred at room temperature for 48 hours. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 0.59 g (62%), m.p. 158°-159 ° C.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH2:13])[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:17]1[C:18]2[N:19]([CH:24]=[CH:25][N:26]=2)[N:20]=[C:21]([Cl:23])[CH:22]=1.[NH4+].[Cl-]>CN(C=O)C>[Cl:23][C:21]1[CH:22]=[C:17]([NH:13][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[N:12]=2)[C:18]2[N:19]([CH:24]=[CH:25][N:26]=2)[N:20]=1
Reactant: Nc1cccc(N2CCCCC2)n1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Clc1cc(Nc2cccc(N3CCCCC3)n2)c2nccn2n1
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of 6-(piperidin-1-yl)pyridin-2-amine (0.725 g, 4.12 mmol) in DMF (8 mL) was added NaH (0.11 g, 60% dispersion in mineral oil, 4.18 mmol) and the mixture stirred for 0.5 h. To this mixture was added 8-bromo-6-chloroimidazo[1,2-b]pyridazine (0.384 g, 1.65 mmol) under N2. The mixture was stirred at room temperature for 16 h. The resulting mixture was treated with a saturated NH4Cl solution (50 mL), extracted with ether (80 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give 6-chloro-N-(6-(piperidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.13 g, 24.1%) as a yellow solid. LC-MS: [M+H]+, 329.0, 331.0, tR=1.912 min
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:6][CH2:5]2.[C:25]1([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:52])[O:33][CH:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][N:42]([CH3:51])[C:43](=[O:50])[CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=O)[CH2:36][CH2:35]1>>[C:25]1([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:52])[O:33][CH:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][N:42]([C:43](=[O:50])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][N:16]([C:17]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:23])[CH3:24])[CH2:6][CH2:5]3)[CH3:51])[CH2:36][CH2:35]1
Reactant: CN(CCCN1CCc2cc(N)ccc2C1=O)C(=O)OC(C)(C)C
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCC=O
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc2c(c1)CCN(CCCN(C)C(=O)OC(C)(C)C)C2=O
Yield: 24.3 %

Procedure:
The compound (149 mg, 0.447 mmol) obtained in Example 61d and the compound (250 mg, 0.536 mmol) obtained in Example 4g were used to give the title compound (85 mg; yield, 24%) as a colorless oily substance according to the method described in Example 45b.
Reaction SMILES: [Na+].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([CH2:11][CH2:12][S:13]S(=O)(=O)[O-])=[CH:3]1.O.P(=O)(O)(O)O.O=O>C(OCC)C>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([CH2:11][CH2:12][SH:13])=[CH:3]1
Reactant: O=S(=O)([O-])SCCc1coc2ccccc12
Agent: O=O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: SCCc1coc2ccccc12

Procedure:
The thiosulfuric acid S-[2-(benzofuran-3-yl)ethyl]ester sodium salt just prepared (3.63 g, contains x mol of water) was suspended in 50 per cent strength phosphoric acid (60 ml) with exclusion of oxygen (argon atmosphere). The reaction mixture obtained was then covered with a layer of diethyl ether (75 ml) and heated under reflux (7 h), with vigorous stirring, until solid was no longer to be observed in the aqueous phase. After cooling, the two phases were separated and the aqueous phase was extracted with diethyl ether (4×15 ml). The combined ethereal phases were washed with water (2×10 ml) and dried over sodium sulfate. The residue (yellowish oil, 1.71 g) obtained after removal of the diethyl ether contained, according to NMR, approx. 80% of the desired thiol Ind-94. Simple purification and dissolving experiments showed that Ind-94 is relatively unstable and by-products already form on standing in an ethereal solution (detection by NMR spectroscopy). The crude product obtained was therefore employed for the thioether synthesis without further working up.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH4+].[Cl-]>CN(C=O)C.CCOCC>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.4 %

Procedure:
To a solution of 5 g (19 mmol) of 5-bromoindol-2-carboxylic acid ethyl ester in 20 mL of anhydrous DMF was added portionwise 1.06 g (24 mmol) of NaH (55% in oil). The mixture was stirred at RT for 45 minutes, treated dropwise with 2.9 mL (24 mmol) of benzyl bromide and stirred for three hours. After addition of a saturated aqueous solution of NH4Cl and Et2O, the phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 6.7g (98%) of crude 5-bromo-1-benzylindole-2-carboxylic acid ethyl ester, orange oil, MS: 358 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CN(C=O)C.[Br:16][CH2:17][C:18](Br)=[O:19]>O1CCOCC1>[Br:16][CH2:17][C:18]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:19]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A solution of 4-aminobenzoic acid (5.0 g, 36 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (7.27 g, 3.16 mL, 36 mmol) was then added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 7.46 g (81%) of the title compound as a white solid, mp 241°-243° C.: 1H NMR (DMSO-d6) δ12.79 (bs, 1H), 10.68 (s, 1H), 7.91 (d, J=9.2, 2H), 7.69 (d, J=9.2, 2H), 4.06 (s, 2H); 13C NMR (DMSO-d6) δ166.79, 165.28, 142.56, 130.47, 125.70, 118.53, 30.29; MS (EI, m/z) 259 (M+).
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[S:14][N:13]=[N:12][C:11]=2[C:15]([NH2:17])=[O:16])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[K+].[Br-]>CN(C=O)C>[CH2:32]([N:9]([C:10]1[S:14][N:13]=[N:12][C:11]=1[C:15]([NH2:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: NC(=O)c1nnsc1Nc1ccccc1
Reactant: CCCCCCCCCCCCCCBr
Agent: [Br-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCN(c1ccccc1)c1snnc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled suspension of NaH (19 mg, 60 wt % in oil, 0.46 mmole) in 3 mL of DMF was added 5-(N-phenylamino)-1,2,3-thiadiazole-4-carboxamide (100 mg, 0.46 mmole). The mixture was stirred at room temperature for 1 h. 1-Bromotetradecane (131 mg, 0.47 mmole) was then added to the reaction mixture which was cooled in ice bath. The reaction was carried out overnight with stirring and then quenched with a mixture of 5 mL of saturated aqueous NH4Cl 5 mL of saturated aqueous NaCl and 10 mL EtOAc. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried with anhydrous Na2SO4, concentrated and then purified by preparative TLC with hexane-EtOAc (1:1) as the eluant. A white powder product was obtained (122 mg, 66%). m.p. 79-81° C. 1H NMR (ppm, CDCl3): 7.60-7.44 (m, 5H), 7.20 (s, br., 1H), 5.63 (s, br., 1H), 2.96 (t, 2H), 1.43-1.00 (m, 24H), 0.88 (t, 3H). FTIR (cm−1, KBr pellet): 3386, 3299, 2918, 2851, 1674, 1657, 1600, 1527, 1503, 1384, 1299, 999, 766, 743, 693.
Reaction SMILES: COC1C=CC(CS[CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])[CH:18]=3)[NH:13][C:12]([CH3:29])([CH3:28])[CH:11]=2)=CC=1.BrCC1[C:43]2[C:38](=[CH:39][CH:40]=[C:41](C3C=CC=CC=3OC)[CH:42]=2)[NH:37]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+]>COC1C=CC(CS)=CC=1>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:29])([CH3:28])[CH:11]=[C:10]2[CH2:9][NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COc1ccc(CSCC2=CC(C)(C)Nc3ccc(-c4ccccc4OC)cc32)cc1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: COc1ccc(CS)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-(4-Methoxybenzylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 100 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 80 mg of potassium carbonate, and 80 μL of 4-methoxy-α-toluenethiol reacted to give 19 mg of the title compound as an oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]([F:18])([F:17])[F:16])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C:11]1([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: OC1(C(F)(F)F)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: OC1(C(F)(F)F)CCNCC1

Procedure:
A suspension of 6.48 g (25.00 mmol) of 1-benzyl-4-trifluoromethylpiperidin-4-ol and 810 mg Pd/C (10%) in 100 mL of MeOH was hydrogenated at RT and 3 bar hydrogen pressure for 17 hours. The catalyst was filtered off and the filtrate evaporated down in vacuo. Yield: 4.22 g (quant. yield); C6H10F3NO (M=169.145); calc.: molpeak (M+H)+: 170; found: molpeak (M+H)+: 17; Rf value: 0.00 (silica gel, cyc/EtOAc 2:1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH2:24][CH:23]([CH2:25][C:26]([OH:28])=O)[O:22][N:21]=3)=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.F[P-](F)(F)(F)(F)F.[N:36]1([O:45][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.NO>CN(C=O)C>[OH:45][NH:36][C:26](=[O:28])[CH2:25][CH:23]1[O:22][N:21]=[C:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:19][CH:18]=2)[CH2:24]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1cc(COc2ccc(C3=NOC(CC(=O)O)C3)cc2)c2ccccc2n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(C3=NOC(CC(=O)NO)C3)cc2)c2ccccc2n1
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
The {3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-acetic acid (0.15 g, 0.4 mmol) was combined with BOP (0.265 g, 0.6 mmol) and diisopropylethylamine (0.5 mL) in DMF (5 mL) under nitrogen atmosphere at room temperature. The reaction was stirred for 15 minutes, and then hydroxylamine hydrochloride (0.042 g, 0.6 mmol) was added. The reaction was stirred overnight, concentrated in vacuo, and triturated with water saturated KH2PO4 solution to give a precipitate. The crude product was purified by HPLC on a C-18 column eluting with an acetonitrile/water/TFA gradient to give the title compound (0.05 g, 25%) as an amorphous solid. MS found: (M+H)+=392.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18].C(=O)([O-])[O-].[Na+:25].[Na+]>O>[Na+:25].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18]
Reactant: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)[O-]
Reaction time: 3 h

Procedure:
α-Linolenic acid serving as a starting material has considerably low water solubility. Therefore, in order to cause α-linolenic acid to function effectively as an enzyme substrate, an α-linolenic acid sodium salt was prepared. Specifically, sodium carbonate (530 mg) was dissolved in purified water (10 mL), and then heated to 55° C. α-Linolenic acid (product of Nacalai Tesque, Inc.) (278 mg) was added dropwise to the resultant solution, and the mixture was stirred for three hours.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]1[CH2:24][CH2:23][C@@H:22](O)[CH2:21]1.C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:22]1[CH2:23][CH2:24][N:20]([CH3:19])[CH2:21]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Reactant: CN1CC[C@@H](O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN1CC[C@@H](OC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)C1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-phenylacetic acid (I3) (400 mg, 1.59 mmol) in THF (20 ml), were added (R)-1-methylpyrrolidin-3-ol (193 mg, 1.91 mmol), N,N′-methanediylidenedicyclohexanamine (394 mg, 1.91 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol (258 mg, 1.91 mmol). The reaction was stirred at RT for 15, hours, and then the solvent was evaporated. The residue was taken up with DCM, the insoluble was filtered off, and the clear solution was washed twice with aq. Na2CO3 and brine, dried over Na2SO4 and evaporated to obtain (R)-1-methylpyrrolidin-3-yl 2-(tert-butoxycarbonylamino)-2-phenylacetate (340 mg; 64% yield).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[NH2:15][C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1>>[N+:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:15][C@H:16]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17]1)[CH:11]=[CH:10]2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: N[C@@H]1CCc2ccccc21
Product: O=[N+]([O-])c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 125 °C
Yield: 44.7 %

Procedure:
A stirred mixture of 2-chloro-6-nitro-quinoline (2.2 g, 11 mmol) and (R)-1-aminoindane (2.8 g, 21 mmol) was heated in a sealed tube for 20 h at 125° C. Purification by flash chromatography on silica gel (ethyl acetate/heptane 0:1=>3:7) yielded (6-nitro-quinolin-2-yl)-(R)-indan-1-yl-amine as a brownish solid (1.5 g, 47%), MS 306.5 [(M+H)+].
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:21])[C@H:10]([NH:13]C(=O)OC(C)(C)C)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:23]Cl.[OH-].[Na+].S(OC)(OC)(=O)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[NH2:13][C@H:10]([CH2:11][O:12][CH3:23])[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC[C@@H](N)C(=O)NCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 90.71 %

Procedure:
In a reaction flask charged tert-butyl [(1R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxoethyl]carbamate (110.0 gms) and tetrabutylammonium bromide (18.07 gms) in solvent dichloromethane (550 ml), stirred and cooled to −10° C. Charged aqueous solution of sodium hydroxide (75.0 gms in 195 ml of DM water) maintaining temperature at −10° C. to −5° C. Charged slowly within 1 hour, dimethyl sulfate (141.4 gms) maintaining temperature at −10° C. to −5° C. and maintained the reaction mass at −10° C. to −5° C. for 3.5 to 4.5 hrs. After completion of the reaction, charged DM water (550 ml) and stirred for 15 minutes at 25-30° C. Separated the organic layer and charged in the reaction flask. Charged conc. Hydrochloric acid (440 ml) within 15 min and maintained the reaction mixture at 25-30° C. for 1-2 hours. After completion of 2 hours charged DM water (330 ml) and stirred for 20-25 minutes. Separated the organic layer and washed with DM water (330 ml). Combined both aqueous layers and cooled to 15-20° C. to adjust pH of the solution to 13-14 with the help of 50% sodium hydroxide solution. Extracted the aqueous layer with dichloromethane (1×550 ml, 2×330 ml). Combined all dichloromethane layers and washed with DM water and stirred at 25-30° C. for 10-15minutes. Charcoalised dichloromethane layer at 25-30° C. for 30 minutes, filtered and washed the hyflow bed with dichloromethane (2×110 ml). Concentrated the filtrate under reduced pressure below 40° C. and degas under vacuum at 35-40° C. for 3-4hrs to get oily mass of (2R)-2-Amino-N-benzyl-3-methoxypropanamide.
Reaction SMILES: [F:1][C:2]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[C:8]([O:17][C@@H:18]([C@@H:20]2[CH2:24][O:23]C(C)(C)[O:21]2)[CH3:19])[N:7]=1.C(O)(C(F)(F)F)=O>CO>[F:1][C:2]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[C:8]([O:17][C@H:18]([CH3:19])[C@@H:20]([OH:21])[CH2:24][OH:23])[N:7]=1
Reactant: C[C@@H](Oc1cc(NS(C)(=O)=O)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1cc(NS(C)(=O)=O)nc(SCc2cccc(F)c2F)n1)[C@@H](O)CO
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of N-(2-[(2,3-difluorobenzyl)thio]-6-{(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy}pyrimidin-4-yl)methanesulfonamide (0.23 g) in MeOH (2 ml) was added TFA (0.4 ml) and the reaction was stirred at room temperature for 20 h. The mixture was evaporated, suspended in saturated sodium carbonate solution and then re-acidified to pH5 with glacial acetic acid with stirring. The resulting solid was collected, washed with H2O and dried to give the title compound as a cream solid. Yield 0.17 g.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16](COCC[Si](C)(C)C)[CH:17]=3)[N:10]3[CH:26]=[CH:27][N:28]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.C(Cl)[Cl:30].Cl.O1CCOCC1>>[ClH:30].[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:26]=[CH:27][N:28]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1
Reactant: ClCCl
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(COCC[Si](C)(C)C)c3)n2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-(1-Methyl-1H-pyrazol-4-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (75 mg, 0.19 mmol) was dissolved in DCM (950 μL, 0.19 mmol). To this was added 4N HCl in dioxane (950 μL, 0.95 mmol) and stirred at ambient temperature for 1 hour, and the mixture was concentrated down to dryness to provide the title compound. MS (apci) m/z=266.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH2:16][O:17][CH3:18].C([Li])CCC.[CH3:24][S:25]SC.C(OCC)C>C1(C)C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C.CN(C)CCN(C)C>[CH3:14][O:13][C:6]1[CH:5]=[C:4]([O:15][CH2:16][O:17][CH3:18])[C:3]([O:2][CH3:1])=[C:8]([S:25][CH3:24])[C:7]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: COCOc1cc(OC)c(OCOC)cc1OC
Reactant: CSSC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COCOc1cc(OC)c(OCOC)c(SC)c1OC
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
259 Milligrams of 1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene was dissolved in a mixed solvent of 12 ml of toluene with 3 ml of hexamethylphosphoric triamide, and further 0.303 ml of N,N,N',N'-tetramethylethylenediamine was added thereto, and the mixture was cooled to -78° C. on a dry ice-acetone mixture bath. 1.34 Milliliters of n-butyllithium (1.6 M, n-hexane solution) was added dropwise to the reaction mixture and stirred for 20 minutes. Then 0.14 ml of dimethyl disulfide was added dropwise thereto, and reacted for additional 2 hours with stirring. The reaction mixture was warmed until room temperature, then 30 ml of diethyl ether was added thereto, and the organic layer was washed three times with 20 ml of water, then washed three times with 20 ml of a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The diethyl ether extract was concentrated under a reduce pressure, the residue obtained was purified by means of a thin layer chromatography (thickness: 2 mm, adsorbent: silica gel, developing solvent: 40%-ethyl acetate-n-hexane). There was obtained 152 mg of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-3-methylthiobenzene. Colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)=[CH:9][CH:8]=1.C(O)CC.[OH-].[K+].[Br-].[C:28](#[N:31])[CH2:29][CH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[N:15][N:16]([CH2:30][CH2:29][C:28]#[N:31])[N:17]=2)=[CH:11][CH:12]=1
Reactant: CCC#N
Reactant: Clc1cccc(COc2ccc(-c3nnn[nH]3)cc2)c1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Product: N#CCCn1nnc(-c2ccc(OCc3cccc(Cl)c3)cc2)n1

Procedure:
To a solution made tepid of 10-2 mole of 5-[4-(3-chloro benzyloxy) phenyl] tetrazole in 60 ml of n-propanol containing 10-2 mole of KOH, 1.2×10-2 mole of propionitrile bromide (IIa) is added and the reaction mixture is heated to reflux for 25 hours. After concentration by evaporating the solvent, the residue is taken up in ether, the etherated solution is washed twice with 20 ml of 0.5N aqueous NaOH, then with water, dried and concentrated. After recrystallization in methanol, the expected compound is obtained.