Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[N:14]=[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=3)[NH:12][C:11]=2[C:10](=[O:27])[N:9]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:8]1=[O:36].[NH2:38][NH2:39]>CO.O1CCCC1>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][N:9]1[C:10](=[O:27])[C:11]2[NH:12][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=3)=[N:14][C:15]=2[N:7]([CH2:6][CH2:5][CH2:4][C:3]([NH:38][NH2:39])=[O:2])[C:8]1=[O:36]
Reactant: NN
Reactant: COC(=O)CCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(C)=O)cc3)nc21
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CCCC(=O)NN)cc1

Procedure:
Prepared by the reaction of 4-[8-(4-acetylamino-benzyl)-1-(2-fluorobenzyl)-2,6-dioxo-1,2,6,7-tetrahydro-purin-3-yl]-butyric acid methyl ester with hydrazine (10 equivalents) in methanol/tetrahydrofuran according to the general procedure of Kramer et al. as described in J. Heterocyclic Chem. 1994, 31, 1439. MS, m/z(M+H)=508.2111.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:6][CH2:7]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Oc1cccnc1)N1CCC(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(C(=O)Oc2cccnc2)CC1
Reaction time: 8 h

Procedure:
To a mixture of pyridin-3-yl 4-hydroxypiperidine-1-carboxylate (330 mg), triethylamine (0.25 mL) and DCM (7 mL) was added slowly dropwise methanesulfonic acid chloride (0.13 mL) at room temperature. After stirring overnight, the reaction liquid was purified directly by silica gel column chromatography (hexane/ethyl acetate=50/50 to 0/100) to obtain pyridin-3-yl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (390 mg) as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=1)[CH3:8].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:1]1([C:14]2[CH:15]=[CH:16][C:11]([C:10]([O:9][CH2:7][CH3:8])=[O:18])=[CH:12][CH:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCNCC2)cc1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A suspension of piperazine (129.2 g, 1.5 mol), ethyl-4-fluorobenzoate (84 g, 0.5 mol), and potassium carbonate (103.65 g, 0.75 mol) in DMSO (200 mL) was stirred at 120° C. under N2 for six hours. The reaction mixture was then cooled to room temperature, poured into water (800 mL), and stirred for 30 minutes. The desired product was collected by filtration and carried to the next step without further purification.
Reaction SMILES: [NH:1]([C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[NH2:2].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[C:28]([O:32][C:33]([NH:35][CH2:36][C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29]>ClCCl>[C:28]([O:32][C:33]([NH:35][CH2:36][C:37]([NH:2][NH:1][C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)C(=O)NN
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CCOC(=O)C(=O)NNC(=O)CNC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
To a solution of ethyl 2-hydrazinyl-2-oxoacetate (9-2) (0.516 g, 3.91 mmol) in dichloromethane (14 mL) was added EEDQ (0.78 g, 3.175 mmol) at room temperature and it was stirred for 15 min. Then 2-(tert-butoxycarbonylamino)acetic acid (9-3) (0.55 g, 3.175 mmol) was added. The mixture was stirred at room temperature for overnight. Solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel with gradient eluant (PE/EA=3/1 to 1/1). The product was obtained as a white solid (0.787 g, 85%). 1H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.99 (s, 1H), 5.19 (s, 1H), 4.40 (dd, J=21.7, 7.2 Hz, 2H), 3.93 (d, J=6.1 Hz, 2H), 1.57-1.32 (m, 12H); LRMS (ESI) calculated M+Na for C11H19N3NaO6: 312.2. Found: 312.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([CH2:22][N:23]([CH3:25])[CH3:24])[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:26]#[N:27])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C>[Fe].CO>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([CH2:22][N:23]([CH3:24])[CH3:25])[CH:15]=1)[N:12]=[CH:11][C:10]([C:26]#[N:27])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CN(C)Cc1cc([N+](=O)[O-])cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)Cc1cc(N)cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Yield: 59.8 %

Procedure:
A stirred mixture of 4-[(3-bromophenyl)amino]-8-dimethylaminomethyl-6-nitro-3-quinolinecarbonitrile (5.98 g, 14.1 mmol), iron powder (2.76 g, 49 mg-atoms), acetic acid (5.67 ml, 99 mmol), and 70 ml of methanol was refluxed for 2 h and then evaporated to remove methanol. The residue was stirred with water for 10 m, and the orange solid was filtered off and washed with 2% acetic acid. The total filtrate was basified to pH 10 with 5 N sodium hydroxide. The resulting precipitate was extracted with methylene chloride. The extract was washed with water, dried, and concentrated. The residue was subjected to chromatography on silica gel with ethyl acetate-methanol-triethylamine to give 3.34 g of amber solid; mass spectrum (electrospray, m/e) M+H 396.2, 398.1.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([OH:15])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:22]1([Mg]Cl)C=CC=CC=1.CC1C=CC2C(=O)C3C(C=2C=1)=CC=CC=3>>[CH3:22][C:3]1[C:4]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)([OH:15])[C:5]=2[CH:13]=[CH:14][CH:2]=1
Reactant: Cc1ccc2c(c1)-c1ccccc1C2(O)c1ccccc1
Reactant: Cl[Mg]c1ccccc1
Agent: Cc1ccc2c(c1)-c1ccccc1C2=O
Product: Cc1cccc2c1-c1ccccc1C2(O)c1ccccc1

Procedure:
3-methyl-9-phenyl-9H-fluoren-9-ol: from phenylmagnesium chloride and 3-methyl-9-fluorenone;
Reaction SMILES: [H-].[H-].[H-].[H-].[Al+3].[Li+].[CH3:7][N:8]1[C:12]([NH:13][C:14](=O)[CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:19][CH2:18]2)=[CH:11][C:10]([CH3:32])=[N:9]1>O1CCCC1>[CH3:7][N:8]1[C:12]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:19][CH2:18]2)=[CH:11][C:10]([CH3:32])=[N:9]1
Reactant: COc1ccccc1N1CCN(CCC(=O)Nc2cc(C)nn2C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(CCCNc2cc(C)nn2C)CC1

Procedure:
0.5 g (13 mmol) of lithium aluminum tetrahydride are suspended in 100 ml of tetrahydrofuran and a solution of 3.9 g (11 mmol) of 1,3-dimethyl-5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propionamido}-1H-pyrazole in 50 ml of tetrahydrofuran is added dropwise in the course of 30 minutes. The mixture is kept at ambient temperature during the addition and is then refluxed for 3 hours. The excess lithium aluminum hydride is destroyed, the insoluble inorganic fraction is filtered off, the tetrahydrofuran is removed, the product is dissolved in chloroform, washed with water, dried over anhydrous sodium sulphate and evaporated to dryness and 3 g (81%) of 1,3-dimethyl-5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylamino}-1H-pyrazole are obtained.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C@:3]([OH:8])([CH3:7])[C:4]([OH:6])=[O:5].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2N=N1.[CH2:44](N(CC)CC)C.Cl>O1CCCC1>[F:1][C:2]([F:10])([F:9])[C@@:3]([OH:8])([CH3:7])[C:4]([O:6][CH2:44][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:5]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: C[C@](O)(C(=O)O)C(F)(F)F
Reactant: CCN(CC)CC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: C[C@@](O)(C(=O)OCc1ccccc1)C(F)(F)F
Temperature: 25 °C

Procedure:
(S)-3,3,3-Trifluoro-2-hydroxy-2-methylpropionic acid (1.00 g) was dissolved in tetrahydro-furan (10.0 ml), and thereto were added successively benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (3.64 g) and triethylamine (1.80 ml) under ice-cooling, and the mixture was stirred at room temperature. Ten hours later, to the reaction solution was added a 1N aqueous hydrochloric acid solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=10/1, 5/1) to give the title compound (1.10 g) as a colorless liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:13][N:14]1[CH:19]2[CH2:20][CH2:21][CH:15]1[CH2:16][C:17](=[O:22])[CH2:18]2>>[CH3:13][N:14]1[CH:19]2[CH2:20][CH2:21][CH:15]1[CH2:16][C:17]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:22])[CH2:18]2
Reactant: CN1C2CCC1CC(=O)C2
Reactant: Brc1ccccc1
Agent: [Li]CCCC
Product: CN1C2CCC1CC(O)(c1ccccc1)C2

Procedure:
The title compound was prepared from bromobenzene (42.1 mL, 0.4 mol), n-butyllithium in hexanes (156 mL, 2.5 M, 0.39 mol) and 8-methyl-8-azabicyclo[3.2.1]-octan-3-one (25 g, 0.18 mol). Yield 14 g (36%), m.p. 157-159° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[CH:20][N:21]3S(C3C=CC(C)=CC=3)(=O)=O)=[CH:17][CH:16]=2)[C:11]1=[O:34].CO>C(O)C.C(Cl)(Cl)Cl>[NH:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N:12]3[CH2:13][CH2:14][N:10]([C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:4]=4[CH3:3])[C:11]3=[O:34])[CH:23]=2)[CH:19]=[CH:20]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(N4CCN(c5cnccc5C)C4=O)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccncc1N1CCN(c2ccc3cc[nH]c3c2)C1=O
Temperature: 90 °C
Yield: 47.1 %

Procedure:
10% NaOH solution (10 mL) was added to a solution of 1-(4-methyl-pyridin-3-yl)-3-[1-(toluene-4-sulfonyl)-1H-indol-6-yl]-imidazolidin-2-one (I-144a: 94 mg) in ethanol (10 mL). The resulting mixture was heated to reflux at 90° C. for 1 hour. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was concentrated and partitioned between ethylacetate and water. The organic layer was washed with water, brine solution, dried and concentrated. Purification by column chromatography on silica gel (2% MeOH in DCM) afforded 29 mg of the product (47.54% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C1C2C(=CC=CC=2)C=CC=1S(O)(=O)=O>C(O)C.C(O)(C)C>[N:8]1([C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: Clc1ncccn1
Reactant: C1CNCCN1
Agent: O=S(=O)(O)c1ccc2ccccc2c1
Solvent: CCO
Solvent: CC(C)O
Product: c1cnc(N2CCNCC2)nc1

Procedure:
A mixture of 3.2 g of 2-chloropyrimidine and 12.1 g of anhydrous piperazine in 100 ml of absolute ethanol is heated at reflux for 18 hours, then it is thoroughly evaporated under reduced pressure and in the warm. The residue is taken up with 400 ml of diethyl ether, the solution thus obtained is washed with 10 ml of an aqueous solution of sodium hydroxide 1:1, then with 20 ml of water. The organic solution is dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The oil thus obtained is dissolved in 30 ml of isopropanol and 4.38 g of 2-naphtalenesulfonic acid dissolved in 30 ml of isopropanol are added to the solution at about 60° C. From the solution thus obtained a product crystallizes which is filtered and dried to give 2-(1-piperazinyl)pyrimidine napsilate identical to the product of Example 1.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:14][S:13][CH:12](OCC)[S:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:18]([O:20][P:21]([O:25]CC)[O:22][CH2:23][CH3:24])[CH3:19].P(Cl)(Cl)Cl>ClCCl.[Cl-].[Zn+2].[Cl-]>[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][S:13][C@@H:12]([P:21]([O:22][CH2:23][CH3:24])([O:20][CH2:18][CH3:19])=[O:25])[S:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCOP(OCC)OCC
Reactant: CCOC1SCC(CO[Si](C)(C)C(C)(C)C)S1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: CCOP(=O)(OCC)[C@@H]1SC[C@@H](CO[Si](C)(C)C(C)(C)C)S1
Temperature: 0 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
To a solution of 4-(t-butyldimethylsilyloxymethyl)-2-ethoxy-1,3-dithiolane (example 48) (37.1 g, 126 mmol) and triethylphosphite (14.3 mL, 83.0 mmol, 0.66 eq) in dichloromethane (100 mL) were added phosphorus trichloride (3.6 mL, 42.0 mmol, 0.33 eq) and zinc chloride (catalytic) at 0° C. The solution was stirred at 0° C. for 2 hr and at room temperature for 18 hr. The solvent was evaporated and the crude material was purified by flash chromatography with a mixture of hexane and ethyl acetate (80:20 to 60:40) to give 3.64 g of the cis isomer, 8.62 g of the trans isomer and 9.95 g of the mixture (2:1 trans:cis) for a total yield of 46%.
Reaction SMILES: [CH3:1][CH:2]([CH3:35])[C@H:3]([NH:6][C:7]1[CH:12]=[CH:11][N:10]2[N:13]=[CH:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:24]=[CH:25][N:26]=4)=[CH:18][CH:17]=3)=[C:9]2[N:8]=1)[CH:4]=O.[Si:36]([O:43][CH2:44][CH2:45][NH2:46])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C1COCC1>[Si:36]([O:43][CH2:44][CH2:45][NH:46][CH2:4][C@@H:3]([NH:6][C:7]1[CH:12]=[CH:11][N:10]2[N:13]=[CH:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[CH:24]=[CH:25][N:26]=4)=[CH:18][CH:17]=3)=[C:9]2[N:8]=1)[CH:2]([CH3:35])[CH3:1])([C:39]([CH3:41])([CH3:42])[CH3:40])([CH3:38])[CH3:37]
Reactant: CC(C)[C@@H](C=O)Nc1ccn2ncc(-c3ccc(-c4nccn4COCC[Si](C)(C)C)cc3)c2n1
Reactant: CC(C)(C)[Si](C)(C)OCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)[C@@H](CNCCO[Si](C)(C)C(C)(C)C)Nc1ccn2ncc(-c3ccc(-c4nccn4COCC[Si](C)(C)C)cc3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-3-methyl-2-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-ylamino)butanal (27 mg, 0.055 mmol) in DCE (1 mL) was added a solution of 2-(tert-butyldimethylsilyloxy)ethanamine (29 mg, 0.17 mmol) in THF (0.2 mL). The reaction was allowed to stir at ambient temperature for 15 minutes, at which point Na(OAc)3BH was added and the reaction allowed to stir at ambient temperature for 2 hours. The reaction mixture was partitioned between saturated aqueous NaHCO3 and dichloromethane. The aqueous layer was extracted with dichloromethane. The combined extracts were washed with brine, dried and concentrated to give (S)—N1-(2-(tert-butyldimethylsilyloxy)ethyl)-3-methyl-N2-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)butane-1,2-diamine. The crude was used in the next step without further purification. LCMS (APCI+) m/z 650.9 [M+H]+.
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:28])=O>>[CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([Cl:28])=[O:22])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCc1cnc(-c2ccc(C(=O)Cl)cc2)nc1

Procedure:
4-(5-n-Decylpyrimidine-2-yl)benzoic acid (1.80 g) was heated together with excess thionyl chloride for 8 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 4-(5-n-decylpyrimidine-2-yl)benzoic acid chloride.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[I:16])([OH:8])[C:4]([F:7])([F:6])[F:5].[CH3:19][O:20][CH2:21]Cl>C(N(CC)C(C)C)(C)C>[F:18][C:2]([F:1])([F:17])[C:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[I:16])([O:8][CH2:19][O:20][CH3:21])[C:4]([F:7])([F:6])[F:5]
Reactant: COCCl
Reactant: Cc1ccc(I)c(C(O)(C(F)(F)F)C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Product: COCOC(c1cc(C)ccc1I)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Compound 2 (4 g, 10.42 mmol) was dissolved in N,N-diisopropylethylamine (DIPEA, 20 mL) freshly distilled over calcium hydride. The solution was cooled in an ice-bath and the chloromethyl methyl ether (4.75 mL, 62.5 mmol) was added. A white precipitate appeared instantaneously. The reaction mixture was stirred overnight at room temperature. After removal of DIPEA under vacuum, the residue was chromatographied over silica gel using heptane/acetone (97/3) to give 4.23 g (9.89 mmol, 95% yield) of a slightly yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10](=[O:14])[CH2:11][CH2:12][CH3:13])[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH:19]C(=O)C.O.OS(O)(=O)=O>CO.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10](=[O:14])[CH2:11][CH2:12][CH3:13])[C:7]([C:15]([F:17])([F:18])[F:16])=[CH:6][C:5]=1[NH2:19]
Reactant: CCCC(=O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC(=O)c1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 60 °C
Yield: 82.3 %

Procedure:
2-Acetylamino-5-butyryl-4-trifluoromethyl-benzoic acid methyl ester (234 mg, 0.706 mmol) was dissolved in MeOH (2.4 mL). Water (500 uL) was added, followed by dropwise addition of concd H2SO4 (254 uL). The reaction mixture was heated to 60° C. for 1 h to give a light yellow suspension. The reaction mixture was diluted with EtOAc, poured onto water/EtOAc and the pH was adjusted to 8 with sat. aq KHCO3. The organic phase was washed with brine, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo. The obtained residue was purified by flash column chromatography (10 g silica gel, hexanes/EtOAc (1:0→7:3)) to afford the title compound (168 mg, 82%) as a colorless foam. ESI-MS: m/z 290 [M+H]+, m/z 288 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[CH3:19][C:20](OC(C)=O)=[O:21].CCN(CC)CC.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1)(=[O:21])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1cc(-c2ccc(O)cc2)sc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Oc1ccc(-c2cc(=O)c3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.6 %

Procedure:
In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 2-(4-hydroxy-phenyl)-thiochromen-4-one (1.298 g, 5.1 mmol), Ac2O (625 mg, 6.12 mmol), Et3N (619 mg, 6.12 mmol) and catalytic amount of DMAP in DCM (10 mL) and the reaction mixture was stirred for 24 h at rt. The reaction mixture was poured into water and extracted with EtOAc. The organic layer washed with water, dried and concentrated to afford the 2-(4-acetoxy-phenyl)-thiochromen-4-one (1.4 g, 96%).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1.[F:22][C:23]([F:42])([F:41])[O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][C:34]3[O:38][N:37]=[C:36]([OH:39])[C:35]=3[CH:40]=2)=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:62][N:63]1[CH:67]=[C:66]([CH2:68]O)[N:65]=[CH:64]1>C1COCC1>[CH3:62][N:63]1[CH:67]=[C:66]([CH2:68][O:39][C:36]2[C:35]3[CH:40]=[C:31]([C:28]4[CH:29]=[CH:30][C:25]([O:24][C:23]([F:22])([F:41])[F:42])=[CH:26][CH:27]=4)[CH:32]=[CH:33][C:34]=3[O:38][N:37]=2)[N:65]=[CH:64]1
Reactant: Oc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Reactant: Cn1cnc(CO)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cn1cnc(COc2noc3ccc(-c4ccc(OC(F)(F)F)cc4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
Diisopropylazodicarboxylate 40% solution in toluene (0.27 mL, 0.51 mmol) was added under stirring to a solution of 5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-ol (100 mg, 0.34 mmol), triphenylphosphine on resin (3 mmol/g) (330 mg, 1 mmol), and 1-methylimidazol-4-yl methanol (60 mg, 0.51 mmol) in THF. The reaction mixture was stirred at ambient temperature overnight. Volatiles were evaporated under vacuum and the residue was purified on 12 g silica gel with 0-20% methanol in dichloromethane and gave the title compound (40 mg, 0.103 mmol) as yellowish oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([O:6][C:7](=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[N+:17]([O-])=O)[CH3:5].[H][H]>[Pd].CO>[CH3:1][O:2][CH2:3][CH:4]([O:6][C:7](=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[NH2:17])[CH3:5]
Reactant: [H][H]
Reactant: COCC(C)OC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COCC(C)OC(=O)c1ccc(N)cc1N
Yield: 93.9 %

Procedure:
A 500 ml Parr Shaker was charged with 75.6 g of (1-methoxy-2-propyl)-2,4-dinitrobenzoate, 200 ml methanol, and 1.5 g of a 5% palladium on carbon/50% water catalyst. The mixture was hydrogenated at 50 psi hydrogen pressure while maintaining the temperature below 50° C. Hydrogen uptake ceased after 4 hrs. The mixture was cooled, filtered, and the methanol removed under reduced pressure to give 56 g of (1-methoxy-2-propyl)-2,4-diaminobenzoate, a brown viscous liquid.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.CCN(CC)CC.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1.O>CN(C=O)C>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([N:3]2[CH2:8][CH2:7][CH:6]([NH:9][C:10]3[N:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=3)[CH2:5][CH2:4]2)=[O:39])=[CH:33][CH:32]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)/C=C/c1ccc(NC2CCNCC2)nc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(NC2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)nc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To an ice-cooled solution of ethyl (2E)-3-[6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride (309 mg) and Et3N (0.448 ml) In DMF (3 ml) was added 1-chloro-4-isocyanatobenzene (136 mg), the mixture was stirred at 23° C. for 1 hour. The mixed solution was poured into water (20 ml). The precipitate was collected, washed with hexane and water, dried under reduced pressure to give ethyl (2E)-3-{6-[(1-{[(4-chlorophenyl)amino]carbonyl}-4-piperidyl)amino]-3-pyridyl}acrylate (341 mg).
Reaction SMILES: CC([N:5]([CH2:9][C@@H:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[N:28][CH:27]=2)[CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C.C1C(=O)N([Cl:39])C(=O)C1>>[NH2:5][CH2:9][C@@H:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[N:28][C:27]=2[Cl:39])[CH:25]=1)=[O:20])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cn1nncc1-c1csc(C(=O)N[C@@H](Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Cl
Product: Cn1nnc(Cl)c1-c1csc(C(=O)N[C@H](CN)CC2CCCCC2)c1

Procedure:
The title compound was prepared as an off white solid according to the procedure of 261, except substituting 1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-cyclohexylpropyl]carbamate (100 mg, 0.22 mmol) for 1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate, and the amount of NCS was reduced to leg. LCMS (ES) m/z 382.2 (M+H)+, 1H NMR (400 MHz, METHANOL-d4) δppm 8.15 (d, J=1 Hz, 1H), 8.08 (d, J=1 Hz, 1H), 4.45 (m, 1H), 4.16 (s, 3H), 3.14 (m 1H), 3.05 (m, 1H), 2.00-0.90 (m, 13H).