Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[N:22]1([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][CH:31]=[CH:30]3)[CH:26]=[N:25][CH:24]=[N:23]1>>[N:22]1([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[N:32]([C:2]2[N:7]=[CH:6][C:5]([O:8][CH:9]4[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]4)=[CH:4][CH:3]=2)[CH:31]=[CH:30]3)[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: c1ncn(-c2ccc3[nH]ccc3c2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(-n5cncn5)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and 5-(1H-1,2,4-triazol-1-yl)-1H-indole (intermediate 58) (0.440 g, 29%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC(OCC(C)C)=O.[NH2:30][C:31]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](O)=[O:34]>C(Cl)Cl.CN1CCOCC1>[O:34]=[C:33]1[C:32]2[CH:36]=[CH:37][CH:38]=[C:39]([C:40]([F:41])([F:42])[F:43])[C:31]=2[N:30]=[C:19]([CH:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:21]1
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(COCc1ccccc1)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Yield: 39.9 %

Procedure:
Using the procedure of Step A of Example 7, a solution of 29.5 g of BOC-O-benzyl L-serine in 200 ml of methylene chloride, 27.5 ml of N-methyl-morpholine, 26.2 g of isobutyl chloroformate in methylene chloride and 20.5 g of 2-amino-3-trifluoromethyl benzoic acid in 200 ml of methylene chloride and 11 ml of N-methyl-morpholine were reacted for 16 hours. The mixture was extracted with methylene chloride and chromatography on silica gel (eluent: methylene chloride) yielded 18.5 g of 1,1-dimethylethyl N-[1-[4-oxo-8-trifluoromethyl-4H-3,1-benzoxazin-2-yl]-2-(phenylmethoxy)-ethyl]-carbamate melting at 98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH:12]([CH2:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[OH:28][N:29]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.NO.CN1CCOCC1>CN(C)C=O>[OH:28][NH:29][C:13](=[O:14])[CH:12]([CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: O=C(O)C(CS(=O)(=O)c1ccc(Cl)cc1)CS(=O)(=O)c1ccc(Cl)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NO)C(CS(=O)(=O)c1ccc(Cl)cc1)CS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 0.33 h

Procedure:
A mixture of 2-(4-chlorobenzenesulfonylmethyl)-3-(4-chlorobenzenesulfonyl)-propionic acid (0.52 g, 1.1 mmol), 1-hydroxybenzotriazole hydrate (0.16 g, 1.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.25 g, 1.3 mmol), and hydroxylamine hydrochloride (0.083 g, 1.2 mmol) is stirred in an ice bath for 20 minutes and 4-methylmorpholine (0.28 mL, 2.5 mmol) in dimethylformamide (10 mL) is added. After stirring overnight at ambient temperature, the mixture is partitioned between ethyl acetate and aqueous 10% hydrochloric acid. The organic phase is further extracted with aqueous acid, aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The concentrate is chromatographed over silica gel (230-400 mesh) with chloroform/acetone/acetic acid (79/20/1) and the eluate concentrated in vacuo, to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][CH2:6][C:5]2[C:8]([CH:13](O)[C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][N:10]=[C:11]([CH3:12])[C:4]=2[O:3]1.N1C=CC=CC=1.S(Cl)([Cl:31])=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:22])[O:7][CH2:6][C:5]2[C:8]([CH:13]([Cl:31])[C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][N:10]=[C:11]([CH3:12])[C:4]=2[O:3]1
Reactant: Cc1ncc(C(O)c2ccc(Cl)cc2)c2c1OC(C)(C)OC2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ncc(C(Cl)c2ccc(Cl)cc2)c2c1OC(C)(C)OC2

Procedure:
88 mg (0.275 mmole) of (+)-2,2,8-trimethyl-5-(4-chloro-α-hydroxybenzyl)-pyrido-[4,3-e]-1,3-dioxane are poured into a 5 ml flask, dissolved in 1 ml of methylene chloride and the flask is sealed under an atmosphere of nitrogen. 22 μl (0.27 mmole) of anhydrous pyridine are injected via a glass syringe. 36 μl (0.54 mmole) of thionyl chloride are then added dropwise. At disappearance (2 hours later) of the starting material (checked by TLC), the solvent is evaporated off under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:31][N:21]([C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[O:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: Cc1ccc(NS(=O)(=O)c2ccccc2)c(OCCCCNC(=O)OC(C)(C)C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)S(=O)(=O)c2ccccc2)c(OCCCCNC(=O)OC(C)(C)C)c1
Reaction time: 18 h
Yield: 99.1 %

Procedure:
To a solution of 176 mg (0.405 mmol) of N- [2- [4-(tert-butoxycarbonylamino)butyloxy]-4-methylphenyl]benzenesulfonamide in 1.5 mL of anhydrous DMF was added 78.4 mg (0.567 mmol) of powdered anhydrous potassium carbonate and 28 mL (0.446 mmol) of iodomethane. After stirring for 18 h, the mixture was partitioned between 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with water (2×15 mL), brine (15 mL), dried (Na2SO4) and concentrated to give 180 mg (99%) of the title compound as a colorless syrup. 1 H-NMR (300 MHz, CDCl3) δ 7.70 (m, 2H), 7.56 (m, 1H), 7.46 (m, 2H), 7.14 (d, 1H, J=2.2 Hz), 7.05 (dd, 1H, J=8.4, 2.2 Hz), 6.68 (d, 1H, J=8.4), 4.53 (br s, 1H), 3.61 (t, 2H, J=6.0 Hz), 3.19 (s, 3H), 3.06 (q, 2H, J=6.3 Hz), 2.28 (s, 3H), 1.46 (s, 9H), 1.30-1.41 (m, 4H). Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. for C23H32 N2O5S: 349.2 (M-BOC+2H). Found: 349.8.
Reaction SMILES: [OH-].[Na+].CC(=NOC[O:15][C:16](=[O:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C1C=CC(Cl)=CC=1.Cl>CO>[C:18]1([CH2:17][C:16]([OH:24])=[O:15])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=NOCOC(=O)Cc1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 193.3 %

Procedure:
1N sodium hydroxide solution (10 ml) was added to a solution of ethyl (E)-α-methoxy-2-((α-methyl-4-chlorobenzylideneaminooxymethyl)phenylacetate (0.70 g, 1.9 mmol) in methanol (10 ml), and the mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH 4 with 1N hydrochloric acid, extracted with methylene chloride and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave the desired compound (E)-α-methoxy-2-α-methyl-4-chlorobenzylideneaminooxymethyl)phenylacetic acid (0.50 g, 77%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]1C(=O)C2=CC=CC=C2C1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN.N.CCOCC>C(Cl)Cl.CO>[C:1]([O:5][C:6]([CH2:8][O:9][NH2:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Agent: N
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CON
Reaction time: 1.5 h

Procedure:
A solution of N-t-butoxycarbonylmethoxyphthalimide (21g) in methylene chloride (250ml) was treated with 100% hydrazine hydrate (7.6ml) in methanol (15ml), and the mixture was stirred for 1.5 hr. 5N-Ammonia solution was added to dissolve the precipitated solid. The organic layer was separated, and the aqueous layer was further extracted with methylene chloride. The combined extracts were washed with water, dried, and evaporated to give a pale-yellow solid. To this was added ether, the mixture was filtered, and the filtrate evaporated to give t-butoxycarbonylmethoxyamine as a pale yellow liquid, (8.88g, 80%); νmax. (Nujol) includes 3330, 3260 cm.-1 (NH2), 1742 cm.-1 (-COOBut); τ values (DMSO-d6) are 3.75 (-NH2), 5.96 (CH2) 8.55 (But).
Reaction SMILES: O1CCOCC1.Cl.C(Cl)Cl.C(OC([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C@@H:32]3[O:37][C:36]4=[N:38][C:39]([N+:41]([O-:43])=[O:42])=[CH:40][N:35]4[CH2:34][CH2:33]3)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=O)(C)(C)C>C(OCC)(=O)C>[N+:41]([C:39]1[N:38]=[C:36]2[N:35]([CH:40]=1)[CH2:34][CH2:33][C@H:32]([CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]3[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]3)=[CH:25][CH:26]=1)[O:37]2)([O-:43])=[O:42]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCNCC3)cc1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A 4 N hydrochloric acid 1,4-dioxane solution (22 ml) was gradually added to a methylene chloride (22 ml) suspension of 4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (4.51 g), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate and the precipitate was collected by filtration. The solid thus obtained was subjected to triturate with ethanol, collected by filtration and then dried. Hydrochloride of the title product was dissolved in water and neutralized using a 5 N sodium hydroxide aqueous solution under ice cooling, followed by stirring. The precipitate was collected by filtration and dried at 60° C. to afford the title compound as a yellow powder (3.0 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25]([C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]([CH2:45][CH2:46][CH3:47])=[N:5][C:4]=1/[CH:48]=[CH:49]\[C:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52][CH:51]=1>[O-2].[O-2].[Mn+4].C(Cl)Cl>[C:50]1(/[CH:49]=[CH:48]\[C:4]2[N:5]=[C:6]([CH2:45][CH2:46][CH3:47])[N:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:21]4[N:25]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:24]=[N:23][N:22]=4)=[CH:13][CH:14]=3)[C:3]=2[CH:2]=[O:1])[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52][CH:51]=1
Reactant: CCCc1nc(/C=C\c2cccc3ccccc23)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCc1nc(/C=C\c2cccc3ccccc23)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
5-Hydroxymethyl-4-[cis-(naphth-1-yl)ethenyl]-2-n-propyl-1-[(2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl]imidazole (7.86 g, 10.2 mmol, 1 eq), manganese dioxide (4.44 g, 51.1 mmol, 5 eq), and methylene chloride (25 mL) were mixed and refluxed under N2 overnight. The manganese dioxide was filtered through Celite™ and the cake washed with methylene chloride. The filtrate was evaporated, and the residue flash chromatographed in 75:25 pentane/ethyl acetate to 1:1 pentane/ethyl acetate to yield 3.78 g of an orange lass. NMR (CDCl3) δ 9.37 (s, 1H); 8.04 (m, 1H); 7.92 (d, 1H, J=8 Hz); 7.80 (m, 1H); 7.72 (m, 1H); 7.60-7.10 (m, 16H); 7.10-6.70 (m, 10H); 6.53 (d, 2H, J=8 Hz); 5.30 (s, 2H); 2.38 (t, 2H, J=7 Hz); 1.56 (t of q, 2H, J=7,7 Hz); 0.77 (t, 3H, J=7 Hz). Anal. calcd. for C52H42N6O.(H2O)0.7 : C, 80.12; H, 5.61; N, 10.78. Found: C, 80.24; H, 5.91; N, 10.46. ##STR222##
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7](/[CH:10]=[C:11](\[CH2:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)/[C:12](OC)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].C([Al+]CC(C)C)C(C)C.CO.C(O)(=O)C>O1CCCC1.Cl.O>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7](/[CH:10]=[C:11](\[CH2:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)/[CH2:12][OH:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)OC)n1Cc1ccccc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1ncc(/C=C(/CO)Cc2cccs2)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of methyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate, prepared in Example 1, ((2.60 g. 6.06 mmol) in 35 mL of tetrahydrofuran at -78° C. under argon was added a solution of diisobutylaluminum hydride (1.5M, 8.9 mL, 13.3 mmol). After the addition was complete, the reaction mixture was allowed to warm to room temperature, with stirring being continued for one hour. The reaction was worked up by the slow addition of methanol, followed by the addition of glacial acetic acid, then four drops of 10% aqueous hydrochloric acid solution. Water (10 mL) was added and the reaction mixture was stirred at room temperature overnight. The product was extracted with ethyl acetate (3×75 mL) after 40 mL of water had been added to the mixture. The combined extracts were dried with anhydrous magnesium sulfate and the solvents were removed in vacuo. The residue was triturated with diethyl ether. The resulting solid was filtered to give 1.72 g (71%) of product; mp 114°-115° C.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C@@H:10]1[CH3:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:22][C@H:10]1[CH2:11][NH:12][CH2:13][CH2:14][N:9]1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CNCCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(S)-tert-butyl 4-benzoyl-3-methylpiperazine-1-carboxylate (8.16 g, 26.8 mmol) was dissolved in dichloromethane (200 mL). Trifluoroacetic acid (20.7 ml) was added and the reaction was stirred at rt for 1.5 hours. The reaction was quenched into saturated K2CO3 (30 mL) and neutralized by the portion-wise addition of solid NaHCO3. The layers were separated and extracted twice with dichloromethane. The combined organics were dried (MgSO4) and evaporated to give a yellow oil. MS (M+H)+=205.3.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11](=O)[CH2:12][O:13][CH3:14])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O.CCOC(C)=O>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COCC(=O)Nc1ccc(C2CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COCCNc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of this N-(4-cyclopropylphenyl)-2-methoxyacetamide in THF (20 mL) was added LAH (5.0 mL, 2.4 M in THF, 12 mmol) at 0° C. The reaction was stirred at r.t. for 2 h. The solution was diluted with water (0.5 mL) and EtOAc (30 mL), dried (Na2SO4), and concentrated. Purification by silica gel chromatography (0% to 15% MeOH/DCM) gave 912 mg (79%) of the title compound as a yellow oil. [M+H] Calc'd for C12H17NO, 192. Found, 192.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[CH2:14]1C2C(=CC=CC=2)C[CH:15]1C(O)=O.S(=O)(=O)(O)O.C([N-]C1CCCCC1)(C)C.C(Br)C>>[CH2:14]([C:5]1([C:3]([OH:2])=[O:4])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH3:15]
Reactant: COC(=O)C1Cc2ccccc2C1
Reactant: O=C(O)C1Cc2ccccc2C1
Agent: CC(C)[N-]C1CCCCC1
Agent: O=S(=O)(O)O
Solvent: CCBr
Product: CCC1(C(=O)O)Cc2ccccc2C1

Procedure:
Second synthetic route disclosed in the same patent is following, as starting material was used 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester, which was prepared by methylation of 2,3-dihydro-1H-indene-2-carboxylic acid in the presence of sulphuric acid. The 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester was reacted with N-isopropylcyclohexylamide and ethylbromide yielding 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid, then thionyl chloride was added and 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride was obtained. In the next step ethoxymagnesiummalonic acid ethyl ester in dry ether was added to 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride and reaction mixture was treated with sulphuric acid, and 1-(2,3-dihydro-2-ethyl-1H-inden-2-yl)ethanone was obtained, then the intermediate was stirred in methylene chloride and bromine was added by giving a new intermediate 2-bromo-1-(2,3-dihydro-2-methyl-1H-inden-2-yl)ethanone, to which was thereafter added formamide and hydrochloric acid yielding crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole. The last step involved hydrogenation of the crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole with 10% palladium on carbon.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:17]([O:20][C:21]1[C:29]([O:30][C:31](=[O:33])[CH3:32])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])(=[O:19])[CH3:18]>ClCCl>[C:17]([O:20][C:21]1[C:29]([O:30][C:31](=[O:33])[CH3:32])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[NH2:9])=[O:24])(=[O:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cccc(C(=O)N(N)C(=O)OC(C)(C)C)c1OC(C)=O
Reaction time: 0.5 h

Procedure:
N-[(t-Butyloxy)carbonyl]hydrazine (12 g) and 10 g of triethylamine were dissolved in 200 ml of dichloromethane and, at 0° C., 24 g of 2,3-bis(acetyloxy)benzoyl chloride in 50 ml of dichloromethane was added dropwise with stirring (30 minutes). After continuous stirring for one hour, the reaction mixture was extracted with 200 ml of ice water, 50 ml of 1% sodium bicarbonate and 100 ml of 5% citric acid. The organic phase was then washed with 100 ml of water, dried over sodium sulfate, and the solvent distilled off. The remaining oil crystallized after stirring with hexane. The result was beige crystals, 26.3 g; melting point 117° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:17]2[N:18]([CH3:22])[CH:19]=[N:20][CH:21]=2)=[N:10][S:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=1[F:23])#[N:2].[CH3:24][Mg+].[Br-]>C1COCC1.CCOCC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:10][S:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[O:12])([C:17]2[N:18]([CH3:22])[CH:19]=[N:20][CH:21]=2)[CH3:24])=[CH:5][C:4]=1[F:23])#[N:2]
Reactant: CC(C)CS(=O)N=C(c1ccc(C#N)c(F)c1)c1cncn1C
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CS(=O)NC(C)(c1ccc(C#N)c(F)c1)c1cncn1C

Procedure:
N-[(4-cyano-3-fluoro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methylene]-2-methylpropanesulfinamide (as described above in Step B) (1.50 g, 4.51 mmol) was dissolved in anhydrous THF (30 mL) at 0° C. to which a 3.0M solution of MeMgBr (4.50 mL, 13.5 mmol) in Et2O was added. The reaction was quenched with aq. NH4Cl solution, diluted with saturated NaHCO3 solution and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, concentrated, and recrystallized from 95% EtOAc/Hexane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2ncccc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc2c(c1)CCCN2
Yield: 89 %

Procedure:
A mixture of 6-methoxyquinoline (69 μL, 0.5 mmol), ammonium formate (0.32 g, 5.0 mmol), and 10% Pd/C (0.05 g) in anhydrous MeOH (5 mL) was microwaved for 900 s at 100° C. The mixture was filtered and 2M HCl in Et2O (1.5 mL) was added. The product was redissolved in H2O/DCM and the aqueous layer basified with 0.1M aq. NaOH (pH 8). After extracting three times with DCM, the organic layer was concentrated to give the product in 89% yield. The product was used without further purification. LC/MS (10-99%) M/Z: M+1 obs=164.0; tR=0.40 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.CCN(C(C)C)C(C)C.[N:21]([CH:24]([CH3:26])[CH3:25])=[C:22]=[O:23]>C1COCC1>[CH:24]([NH:21][C:22]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2)=[O:23])([CH3:26])[CH3:25]
Reactant: CC(C)N=C=O
Reactant: Nc1cccc2c1NC(=O)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)NC(=O)Nc1cccc2c1NC(=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a suspension of 7-aminoindolin-2-one (60 mg, 0.41 mmol) in THF (3 mL) was added DIPEA (0.28 mL, 1.62 mmol), and 2-isocyanatopropane (0.05 mL, 0.49 mmol). The mixture was stirred at rt overnight then filtered. The filter cake was washed with diethyl ether to give the title compound as a pale solid (57.3 mg, 61%). 1H NMR (400 MHz, CD3OD) δ 7.09-7.04 (m, 2H), 6.99-6.95 (m, 1H), 3.57 (s, 2H), 2.64 (m, 1H), 1.20 (d, 6H, J=6.4 Hz). MS ESI [M+H]+, calcd for [C12H15N3O2+H]+ 234.12; found m/z 234.0.
Reaction SMILES: [ClH:1].O1CCOC[CH2:3]1.[CH3:8][O:9][C:10](=[O:32])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1>>[ClH:1].[NH:22]1[CH2:23][CH2:24][CH:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]([O:9][CH2:8][CH3:3])=[O:32])[CH2:20][CH2:21]1
Reactant: C1COCCO1
Reactant: COC(=O)CCc1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: CCOC(=O)CCc1ccccc1C1CCNCC1
Reaction time: 8 h
Yield: 98 %

Procedure:
4 M HCl/dioxane (2.2 mL, 8.97 mmol) was added to neat tert-butyl 4-(2-(3-methoxy-3-oxopropyl)phenyl)piperidine-1-carboxylate at 23° C. and was stirred overnight. The reaction mixture was concentrated to yield methyl 3-(2-(piperidin-4-yl)phenyl)propanoate hydrochloride (24, 250 mg, 98% yield). LC/MS RT (5 min method)=1.14 min. Mass observed: 248.16 (M+H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][NH:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][N:41]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][NH:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][N:41]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: COc1ccc(NCCN)nc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(NCCNC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)nc1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
4-geranyloxybenzoic acid(1.92 g) was dissolved in chloroform(50 ml) and triethylamine(1.95 ml), and then diphenylphosphinic chloride(1.34 ml) was added thereto while being cooled with ice. After being stirred for 1 hour, the mixture, with 2-(2-aminoethylamino)-5-methoxypyridine(1.17 g) added thereto, was stirred for 8 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 2.22 g of the aimed compound.