Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:3]=1[O:4][C@@H:5]([CH3:9])[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.[NH2:23][CH2:24][C@H:25]1[O:29][C@@H:28]([N:30]2[CH:37]=[C:36]([CH2:38][CH3:39])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[C@@H:27]([F:40])[C@@H:26]1[OH:41]>C1(C)C=CC=CC=1.CN(C)C=O.[OH-].[Na+]>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:3]=1[O:4][C@@H:5]([CH3:9])[C:6]([NH:23][CH2:24][C@H:25]1[O:29][C@@H:28]([N:30]2[CH:37]=[C:36]([CH2:38][CH3:39])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[C@@H:27]([F:40])[C@@H:26]1[OH:41])=[O:8]
Reactant: CCc1cn([C@@H]2O[C@H](CN)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Reactant: COc1cc(O[C@@H](C)C(=O)O)c(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1cn([C@@H]2O[C@H](CNC(=O)[C@H](C)Oc3cc(OC)c(Cl)cc3Cl)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Yield: 70.7 %

Procedure:
24.2 g (0.091 mol) of (S)-2-(2,4-dichloro-5-methoxyphenoxy)-propionic acid were suspended in a mixture of 150 ml of toluene and 0.5 ml of dimethylformamide and the suspension was stirred under nitrogen. 15.0 ml (0.17 mol) of oxalyl chloride were added, with vigorous evolution of gas occurring. The mixture was stirred for 1 hour to give a homogeneous solution. The solvents were removed by evaporation, the residue was taken up in 100 ml of diethyl ether and the solution was added to a solution of 24.6 g (0.090 mol) of 1-(5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil in 290 ml of 0.31M sodium hydroxide solution. The heterogeneous mixture was shaken vigorously for 10 minutes to give a white precipitate which was filtered off and washed firstly with water and then with diethyl ether. The crude product was recrystallized from hot methanol to give 33.1 g (69.7%) of 1-[5-[2(S)-(2,4-dichloro-5-methoxyphenoxy)propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil as a white crystalline solid, m.p. 195°-196° C.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OC)=O.CCCCCC.[C:44]([O:47]CC)(=[O:46])[CH3:45]>C(Cl)Cl>[C:44]([OH:47])(=[O:46])/[CH:45]=[CH:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(C)=O
Reactant: CCCCCCCCC/C=C/C=O
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCCCCC/C=C/C=C/C(=O)O
Reaction time: 2 h

Procedure:
To trans-2-dodecenal (4.5 g) dissolved in methylene chloride (80 ml) was added (carbomethoxymethylene)triphenylphosphorane (8.3 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-tetradecadienoic acid (5.4 g). Potassium hydroxide (6.5 g) was dissolved in a mixed solvent of ethanol-water (1:1) (100 ml). The methyl ester of trans,trans-2,4-tetradecadienoic acid (5.4 g) was added to the mixture, and the resulting mixture was stirred at 60° C. for 40 minutes. After the reaction mixture was cooled, it was adjusted to the weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans,trans-2,4-tetradecadienoic acid (4.4 g). Hereafter, the title compound can be synthesized by the two methods described below.
Reaction SMILES: Br[C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:34][O:35][C:36](=[O:48])[C@H:37]([CH2:46]I)[NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(N(C)C)=O>[CH3:34][O:35][C:36](=[O:48])[C@@H:37]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:46][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C#N)cc(C)c1Br
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H](Cc1c(C)cc(C#N)cc1C)NC(=O)OC(C)(C)C
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A 5 L three-necked round-bottomed flask equipped with a nitrogen inlet, a mechanical stirred, an addition funnel and a thermocouple was charged with 4-bromo-3,5-dimethyl-benzonitrile (210 g, 1.0 mol) and DMAc (750 ml). The resulting suspension was stirred and heated to 35° C. to dissolve the solids. To the resulting mixture was then added P(o-tol)3 (6.0 g, 0.02 mol), Pd2(dba)3 (9.2 g, 0.01 mol) and the resulting mixture heated to about 75-80° C. The cooled mixture prepared in STEP A above was added by cannula to the reaction mixture at a rate which maintained the temperature at about 75-80° C. (about 2 hours). The resulting suspension was cooled to ambient temperature, then aged overnight with moderate agitation. The resulting suspension was then heated to about 35-40° C., filtered with silica (540 g). The silica bed was washed with DMAc (400 mL×2), the combined DMAc solutions cooled to about 0-5° C. and then added slowly to a mixture of ice and deionized water. The resulting mixture was maintained cold for 2 hours, over which time a white solid was observed to precipitate. The resulting mixture was then warmed to ambient temperature and aged overnight. The solid precipitate was cooled by vacuum filtration using a Buchner funnel. The filter cake was rinsed with deionized water (1 L×3), air dried overnight, then dried in a vacuum oven overnight. MeOH (1 L) was added to the solid and the resulting slurry was cooled to about 0-5° C., then aged at this temperature for 1 hour, with stirring. The solid was collected by filtration, washed with cold methanol (400 mL) and dried in a vacuum oven at 45° C. to yield the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:6]([OH:8])[CH:7]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1>CCO>[Cl:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:9][N:10]4[CH2:14][CH2:13][CH2:12][CH2:11]4)=[C:6]([OH:8])[CH:7]=3)=[CH:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(CN2CCCC2)c(O)c1
Solvent: CCO
Product: Oc1cc(Nc2ccnc3cc(Cl)ccc23)ccc1CN1CCCC1
Yield: 42.6 %

Procedure:
5-amino-2-(pyrrolidin-1-ylmethyl)phenol (117 mg, 0.61 mmol) and 4,7-dichloroquinoline (143 mg, 1 eq) were refluxed overnight in 1 mL of EtOH. The reaction mixture was then evaporated and purified by flash chromatography (DCM/MeOH/NH4OH 9:1:0.1) to yield expected compound as a yellow solid (92 mg, 29% yield). LC-MS: m/z (ESI) 354.1-356.1 [M+H]+
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH3:17][O:18][C:19]1[CH:30]=[CH:29][C:22]([C:23](N(OC)C)=[O:24])=[CH:21][CH:20]=1>>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([C:23](=[O:24])[C:22]2[CH:29]=[CH:30][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(C(=O)N(C)OC)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Br
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccc(Cl)cc2C(=O)O)cc1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-chlorobenzoic acid pretreated with n-butyllithium with 4-methoxy-N-methoxy-N-methyl-benzamide. It is used in crude form in the following reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[C:21]([O:20][CH3:19])[CH:22]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc(OC)c3)CC2)ccc1Cl
Yield: 65 %

Procedure:
The title compound (26 mg, 65%) was prepared analogously to example 7 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 3-methoxybenzoyl chloride. MS: 403.4 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][NH2:30])[CH2:24][CH2:23]1.[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:30][CH2:29][CH2:28][CH:25]2[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: CC1CCC(CCN)CC1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC2CCC(C)CC2)ccc1Oc1ccc(C(N)=O)cn1
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.100 g, 0.367 mmol), 2-(4-methylcyclohexyl)ethylamine (0.0571 g, 0.404 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH4 (ca. 3-5 eq in two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give 6-(2-methoxy-4-{[2-(4-methylcyclohexyl)ethylamino]methyl}phenoxy)nicotinamide (0.0958 g, 65.6%). Dissolve the compound in dichloromethane (2.5 mL) and add 1 equivalent of 0.50 M methanesulfonic acid in dichloromethane. Stir the solution for a short time before concentrating to afford the title compound: TOF MS ES+ 398.2 (M+H)+, HRMS calcd for C23H32N3O3 398.2444 (M+H)+, found 398.2440, time 0.52 min; Anal. Calcd for C23H31N3O3.0.5H2O: C, 57.35; H, 7.22; N, 8.36. Found: C, 57.33; H, 6.94; N, 8.34.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[NH:7][CH:8]=[CH:9][N:10]=1)[CH3:3].C(N(CC)CC)C.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:18]([N:7]1[CH:8]=[CH:9][N:10]=[C:6]1[N:5]=[CH:4][N:2]([CH3:3])[CH3:1])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(C)C=Nc1ncc[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C=Nc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the crude 2-[dimethylamino)methylene]aminoimidazole (2) was added methylene chloride (750 mL), triethylamine (98 mL, 700 mmol) and trityl chloride (62.98 g, 226 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 3 hrs. Solvent was removed in vacuo and the crude 3 was crystallized from methanol.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:40][CH2:41][CH2:42][C@@H:43]([C:45]1[N:50]=[C:49]2[N:51]([CH3:60])[C:52](=[O:59])[N:53]([CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:48]2=[CH:47][CH:46]=1)[CH3:44]>ClCCl>[CH3:57][C:55]([CH3:56])([CH3:58])[CH2:54][N:53]1[C:48]2[C:49](=[N:50][C:45]([C@H:43]([CH3:44])[CH2:42][CH2:41][NH:40][C:6]([C:3]3[CH:4]=[CH:5][O:1][N:2]=3)=[O:8])=[CH:46][CH:47]=2)[N:51]([CH3:60])[C:52]1=[O:59]
Reactant: O=C(O)c1ccon1
Reactant: C[C@@H](CCN)c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](CCNC(=O)c1ccon1)c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-Isoxazolecarboxylic acid (0.015 g, 0.13 mmol), and triethylamine (0.1 mL, 0.72 mmol) in dichloromethane (2 mL) was added HATU (0.05 g, 0.13 mmol). The resulting mixture was stirred 20 minutes. To this mixture was added 36-4 (0.03 g, 0.10 mmol) and the resulting mixture was stirred room temperature overnight. The mixture was washed with water and concentrated. Flash column separation using a 0-60% ethyl acetate/hexane gradient, followed by 10-90% reverse phase gradient gave 36-5. (0.017 g, 43%). HRMS (M+H)+: observed=386.2189, calculated=386.2187
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH2:11])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][C:20](=[O:21])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:9][CH2:10]2)=[N:6][CH:7]=1
Reactant: NC1(c2ccc(Br)cn2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1(c2ccc(Br)cn2)CC1)OCc1ccccc1
Reaction time: 1 h

Procedure:
At 0° C., to the mixture of 1-(5-bromopyridin-2-yl)cyclopropanamine (1.07 g, 5.0 mmol), triethylamine (766 ul, 5.5 mmol) was added benzyl chloroformate (785 ul, 5.5 mmol). The resulting mixture was allowed to stir at it for 1 h. After work up, the crude product was purified by column chromatography on SiO2.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([C:14]([OH:21])([CH2:19][CH3:20])[C:15]#[C:16][CH2:17][OH:18])[CH3:13].[OH-].[K+].O>CCOCC>[CH2:12]([C:14]([OH:21])([C:15]#[C:16][CH2:17][O:18][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:19][CH3:20])[CH3:13]
Reactant: CCC(O)(C#CCO)CC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCC(O)(C#CCOS(=O)(=O)c1ccc(C)cc1)CC
Temperature: 0 °C
Yield: 78 %

Procedure:
An ice-cold solution of 4-toluenesulfonyl chloride (6.4 g) and 4-ethylhex-2-yn-1,4-diol (McLamore, W. M. et al., J. Org. Chem., 19, 570-574 (1954) and Gouge, M., Ann. Chim., 6, 648-702 (1951)) (4.0 g) in ether (40 ml) was stirred with powdered potassium hydroxide (15 g) for 2 h. Water was added and the mixture was extracted with ether (2×250 ml). Work-up with chromatography using ether/pentane 1:1 (v/v) gave the title compound (6.5 g). 1H NMR: 0.91 (t, 6H), 1.55 (q, 4H), 1.83 (s, 1H), 2.45 (s, 2H), 4.76 (s, 2H), 7.36 (d, 2H), 7.82 (d, 2H).
Reaction SMILES: [C:1]1([P:7](Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([OH:17])[CH3:16].N1C=CC=CC=1>CCOCC>[C:1]1([P:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:17][CH2:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: ClP(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOP(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of diphenylphosphinous chloride (135 mmol) in dry ether (120 mL) was treated dropwise at 5° C. with a solution of ethanol (200 mmol) and pyridine (134 mmol) in ether (120 mL). After addition was complete, the mixture was warmed to room temperature, filtered under argon, and the solid hydrochloride washed with ether. Evaporation of the solvent gave an oil which was purified by Kugelrohr distillation at 95° C. (0.1 mmHg). Yield: 119 mmol (88%); 1H NMR (CDCl3) δ 7.6-7.2 (m, 10 H), 3.95 (doublet of quartets, JH-H =7 Hz, JP-H =10 Hz, 2 H), 1.30 (t, J=7 Hz, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[N:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:25][C:26]([N:28]=[C:29]=[S:30])=[O:27])[CH3:24].O>CS(C)=O>[CH2:23]([O:25][C:26](=[O:27])[NH:28][C:29]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])[CH:9]=2)=[CH:16][N:17]=1)=[S:30])[CH3:24]
Reactant: CCOC(=O)N=C=S
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc(N)nc2)c1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)OC(C)(C)C)c2)cn1
Temperature: 25 °C
Reaction time: 120 h
Yield: 69.4 %

Procedure:
To a solution of tert-butyl{3-[(6-aminopyridin-3-yl)oxy]phenyl}carbamate (4.60 g, 15.2 mmol) in dimethyl sulfoxide (90 mL) was added ethoxycarbonyl isothiocyanate (2.00 mL, 16.7 mmol), and the mixture was stirred at room temperature for 5 days. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (400 mL). The organic layer was washed with 5% aqueous ammonium chloride solution (200 mL), 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→50/50), and fractions containing the object product was concentrated under reduced pressure to give the title compound (4.56 g, 69%) as a colorless solid.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1)[CH2:2][CH2:3][CH3:4].[Br:12]C1CC(C(C)C)CCC1=O>>[Br:12][CH:8]1[CH2:9][CH2:10][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][C:7]1=[O:11]
Reactant: CCCCC1CCCC(=O)C1
Reactant: CC(C)C1CCC(=O)C(Br)C1
Product: CCCCC1CCC(Br)C(=O)C1

Procedure:
The bromination of 3-butylcyclohexanone takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7][CH:6]1[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:4].[Li+].[OH-]>CO.O>[C:17]([O:16][C:14]([NH:13][CH2:12][C:5]1([C:3]([OH:4])=[O:2])[CH2:7][CH:6]1[CH2:8][CH:9]([CH3:10])[CH3:11])=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: COC(=O)C1(CNC(=O)OC(C)(C)C)CC1CC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)CC1CC1(CNC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-2-isobutyl-cyclopropanecarboxylic acid methyl ester (9.1 g, 31.9 mmol) in MeOH (260 mL) was added a solution of LiOH (3.34 g, 79.7 mmol) in water (80 mL). The reaction mixture was heated to reflux for 3 hours and cooled to room temperature. Excess of solvent was removed and the residue was dissolved in water (100 mL). The aqueous solution was washed with ether, acidified to pH=3 with 2N HCl and extracted with EtOAc (2×150 mL). The combined organic phase was washed with brine, dried (Na2SO4) and evaporation of the solvent gave 8.4 g (97%) of 1-(tert-butoxycarbonylamino-methyl)-2-isobutyl-cyclopropanecarboxylic acid as a colorless oil: 1H NMR (300 MHz, CD3OD) δ 0.71 (dd, J=4.0, 6.4 Hz, 1H), 0.95 (t, J=6.4 Hz, 6H), 1.35 (m, 1H), 1.43 (s, 1H), 1.49-1.55 (m, 1H), 1.64-1.69-(m, 2H) 3.23 (d, J=14.2 Hz, 1H), 3.40 (d, J=14.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:35])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][C:27]([C:29]#[C:30][Si](C)(C)C)=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+]>CO.O>[F:36][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:35])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][C:27]([C:29]#[CH:30])=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2cc(C#C[Si](C)(C)C)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccn2c(C(=O)Nc3cc(-c4noc(C5CC(F)(F)C5)n4)ccc3C)cnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-7-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridine-3-carboxamide (52) (50 mg, 0.1 mmol) was dissolved in MeOH (1 mL) and K2CO3(42 mg, 0.3 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL). The resulting precipitate was filtered and dried to give N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-7-ethynylimidazo[1,2-a]pyridine-3-carboxamide (53). MS m/z 434.1 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]=1.N1C=CC=CC=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27].C(=O)([O-])O.[Na+]>ClCCl>[CH2:11]([C:4]1[CH:3]=[C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:24]=[C:23]([O:22][CH3:21])[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=2)[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1)[CH2:12][CH2:13][CH3:14]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CCCCc1cc(N)n2nccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1cc(NC(=O)c2cc(OC)c(OC)c(OC)c2)n2nccc2n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 62.5 %

Procedure:
7-Amino-5-n-butylpyrazolo[1,5-a]pyrimidine (1.90 g) and pyridine (20 ml) were dissolved in 20 ml of dry dichloromethane. A dry dichloromethane solution (10 ml) containing 2.6 g of 3,4,5-trimethoxybenzoyl chloride was slowly added dropwise thereto and stirred at room temperature for 10 hours. After addition of 50 ml of a 10% aqueous sodium hydrogen carbonate solution, the reaction mixture was extracted with chloroform. The organic layer was collected, washed with 10% aqueous hydrochloric acid and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane=1:2) and recrystallized from diethyl ether-n-hexane to provide 2.4 g of the object compound as colorless crystals. Table 1 shows the structure and melting point of the compound obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH:21]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:25]([CH:21]3[CH2:24][CH2:23][CH2:22]3)=[O:26])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(Cl)C1CCC1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)C2CCC2)CC1
Reaction time: 2 h
Yield: 22 %

Procedure:
1-(5-chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.063 g, 0.22 mmol, from Example 47, Step 1) was combined with cyclobutanecarboxylic acid chloride (0.037 mL, 0.32 mmol) and triethylamine (0.090 mL, 0.64 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and then concentrated. The resulted residue was purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (18 mg, 22%). LCMS calculated for C20H23ClN3O2 (M+H)+: m/z=372.1; Found: 372.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:37]Br>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:37][C:36]2[CH:39]=[CH:40][C:41]([Cl:42])=[C:34]([Cl:33])[CH:35]=2)[CH:6]=1
Reactant: COC(=O)Cc1c[nH]c2ncccc12
Reactant: Clc1ccc(CBr)cc1Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(Cc2ccc(Cl)c(Cl)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To an ice cold solution of (1H-pyrrolo[2,3-b]pyridine-3-yl)-acetic acid methyl ester (50 mg, 0.26 mmol) in DMF (1 mL), is added BEMP (0.122 mL, 0.42 mmol). The reaction mixture is stirred at ambient temperature for 40 minutes, then 3,4-dichlorobenzyl bromide (0.101 g, 0.42 mmol) is added and the reaction mixture is stirred for 16 hours at ambient temperature. The reaction mixture is poured into ice cold water (40 mL) and extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude product is purified by column chromatography on silica gel using a pre-packed Isolute™ silica column (2 g) eluting with 1:20 EtOAc/iso-hexane, furnishing [1-(3,4-dichloro-benzyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]-acetic acid methyl ester; MH+=349.