Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:18][C@@H:17]([C:19]2[CH:30]=[CH:29][C:22]3[O:23][C:24]([CH3:28])([CH3:27])[O:25][CH2:26][C:21]=3[CH:20]=2)[O:16][C:15]1=[O:31].P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH3:27][C:24]1([CH3:28])[O:23][C:22]2[CH:29]=[CH:30][C:19]([C@H:17]3[O:16][C:15](=[O:31])[N:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:3][CH2:2][CH2:1][OH:4])[CH2:18]3)=[CH:20][C:21]=2[CH2:26][O:25]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCBr)C(=O)O3)ccc2O1
Reactant: OCCO
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Reaction time: 0.25 h

Procedure:
A solution of ethylene glycol (5.00 ml) in DMF (40 ml) under nitrogen at 0° was treated portionwise with sodium hydride (60% dispersion in mineral oil, 1.292 g) and the mixture was stirred at 0° for 15 min. A solution of (5R)-3-(6-bromohexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (7.40 g) in DMF (10 ml) was added. The mixture was stirred at 0° for 0.5 h then at 20° for 3 h. Phosphate buffer solution (pH 6.5, 40 ml) and water (160 ml) were added and the mixture was extracted with EtOAc (2×100 ml). The combined extracts were washed with water (2×150 ml), brine (50 ml) and were dried (Na2SO4). The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel. Elution with MeOH-EtOAc (1:9) gave the title compound (4.10 g). LCMS RT=2.90 min, ES+ve 394 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(C(OC)=O)[CH2:6][CH2:5]2.[Cl-].[Li+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:6][CH2:5]2
Reactant: COC(=O)C1(c2ccccc2)CCc2cc(F)ccc2C1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccc(F)cc2CCC1c1ccccc1
Temperature: 150 °C
Yield: 87 %

Procedure:
The tetralone from Step B (2.8 g, 9.4 mmole) was dissolved in 45 ml of dimethylformamide. To this solution was added lithium chloride (2.0 g, 47 mmole) and water (0.42 ml, 23 mmole). The reaction mixture was heated to 150° C. for 2.5 hrs and then cooled and partitioned between ether and water. The aqueous phase was separated and extracted three times with ether. The combined organic phases were washed once with water, dried (MgSO4), and concentrated (1.96 g, 87% yield). 1H NMR (CDCl3) δ: 8.13 (1H, dd, J=6,10 Hz), 7.31 (5H, m) 6.99 (2H, m), 3.80 (1H, m), 3.07 (2H, m), 2.43 (2H, m).
Reaction SMILES: C(OC(=O)N[C@H]1CC[C@@H](O)CC1)(C)(C)C.[Cl:16]C1C2C(=C(Cl)C(F)=CC=2)C=CN=1.Cl.Cl.[NH2:31][C@@H:32]1[CH2:37][CH2:36][C@H:35]([O:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][C:48]=2Cl)[C:45]([OH:50])=[N:44][CH:43]=[CH:42]3)[CH2:34][CH2:33]1>>[NH2:31][C@@H:32]1[CH2:37][CH2:36][C@H:35]([O:38][C:39]2[C:40]([Cl:16])=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45](=[O:50])[NH:44][CH:43]=[CH:42]3)[CH2:34][CH2:33]1
Reactant: N[C@H]1CC[C@@H](Oc2cc3ccnc(O)c3cc2Cl)CC1
Reactant: Fc1ccc2c(Cl)nccc2c1Cl
Agent: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Agent: Cl
Product: N[C@H]1CC[C@@H](Oc2ccc3c(=O)[nH]ccc3c2Cl)CC1

Procedure:
Starting from cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester and 1,5-dichloro-6-fluoro-isoquinoline (9), the title compound was prepared as hydrochloride following the route described for 6-(cis-4-amino-cyclohexyloxy)-7-chloro-isoquinolin-1-ol hydrochloride (10). Rt=1.04 min (Method B). Detected mass: 293.1/295.1 (M+H+).
Reaction SMILES: [CH2:1](C(O)(CCCCCCC)CC)C.[CH2:14]([C:16]([OH:28])([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:17][CH3:18])C>>[CH3:14][C:16]([OH:28])([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:17][CH2:18][CH3:1]
Reactant: CCCCCCCCCC(O)(CC)CC
Reactant: CCCCCCCC(O)(CC)CC
Product: CCCCCCCCCC(C)(O)CCC

Procedure:
3-ethyl-3-decanol; 3-ethyl-3-dodecanol;
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([CH:22]([CH3:24])[CH3:23])[C:19]([OH:21])=O)[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(CC(O)=O)N=1)CCCCCCCCC.[CH3:44][O:45][C:46]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[C:49]([O:55][CH3:56])[C:47]=1[NH2:48].C(C1C=CC=C(C(C)C)C=1N)(C)C>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([CH:22]([CH3:24])[CH3:23])[C:19]([NH:48][C:47]2[C:49]([O:55][CH3:56])=[CH:50][C:51]([O:53][CH3:54])=[CH:52][C:46]=2[O:45][CH3:44])=[O:21])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCCCCCCc1nnn(C(C(=O)O)C(C)C)n1
Agent: CC(C)c1cccc(C(C)C)c1N
Agent: CCCCCCCCCCc1nnn(CC(=O)O)n1
Product: CCCCCCCCCCCCc1nnn(C(C(=O)Nc2c(OC)cc(OC)cc2OC)C(C)C)n1

Procedure:
When in the general procedure of Example 88 an appropriate amount of 5-dodecyl-α-(1-methylethyl)-2H-tetrazole-2-acetic acid was substituted for 5-decyl-2H-tetrazole-2-acetic acid and 2,4,6-trimethoxyaniline was substituted for 2,6-diisopropylaniline, the title compound was obtained, mp 135°-137° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]Br>CC(O)=O.O>[Br:12][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:8]
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
The title compound was prepared by dissolving 4-Methyl-2-nitro-phenylamine (20.0 g, 131 mmol) in 200 mL of HOAc. The reaction mixture was then heated to 100° C. until reaction mixture was homogeneous. At this point the reaction mixture was cooled to room temperature and Br2 (25.21 g, 157 mmol) was added drop wise over the course of 10 minutes. An orange solid formed, and upon completion of the addition the reaction mixture was diluted with water and the title compound collected by filtration (29 g, 96%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH2:7][CH2:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1.CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH2:7][CH2:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1)(=[O:27])=[O:26]
Reactant: O=C1CCc2ccc(=O)n3c2N1C[C@H]3CO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CN2C(=O)CCc3ccc(=O)n1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (1S)-1-(hydroxymethyl)-1,2,5,6-tetrahydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (1.909 g, 8.67 mmol) in DCM (100 ml) at 0° C. under argon was treated with Et3N (1.450 ml, 10.40 mmol) and then methanesulfonyl chloride (0.743 ml, 9.54 mmol) and then allowed to warm to rt and stirred at rt for 1 h. The reaction mixture was then treated with saturated aqueous NaHCO3 (100 ml) and the mixture was extracted with DCM (2×100 ml). The combined organic solvents were then dried (MgSO4), filtered, evaporated to give the crude intermediate [(2S)-4,9-dioxo-1,2,8,9-tetrahydro-4H,7H-imidazo[1,2,3-ij]-1,8-naphthyridin-2-yl]methyl methanesulfonate. This was dissolved in dry CH3CN (100 ml) and then treated with pyridine (1.402 ml, 17.34 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (3.47 g, 17.34 mmol) and heated at 70° C. for 20 h. After 20 h more 1,1-dimethylethyl 4-piperidinylcarbamate (3.47 g, 17.34 mmol) and pyridine (1.402 ml, 17.34 mmol) were added and the temperature was increased to reflux (heating block 95° C.) and reaction was stirred at this temperature for a further 4 h. The reaction mixture was then evaporated, treated with saturated aqueous NaHCO3 (200 ml) was then added and the mixture was extracted with DCM (3×200 ml). The combined organic solvents were then dried (MgSO4), filtered, evaporated to give the crude product as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:27]([NH:29][CH2:30][CH2:31][CH3:32])[CH3:28].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:30]([N:29]([CH2:27][CH3:28])[C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH2:31][CH3:32]
Reactant: CCCNCC
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCN(CC)C(=O)Cc1ccc(O)cc1
Temperature: -50 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 4-hydroxyphenyl acetic acid (88.43 g, 653 mmol) in 700 mL tetrahydrofuran at −50° C. was added a solution of 4-methylmorpholine (66.1 g, 653 mmol) in 30 mL tetrahydrofuran. iso-Butylchloroformate (89.3 g, 653 mmol) was added to the mixture and the resulting solution was stirred at −50° C. for 2 hours. A solution of ethylpropylamine (57 g, 654 mmol) in 30 mL of tetrahydrofuran was added over 15 minutes. After 3 hours, the reaction mixture was poured into a 1:1 mixture of ethyl acetate and 1N hydrochloric acid. The ethyl acetate layer was washed with sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated to give a clear colorless oil (135 g). Purification of the technical grade material was accomplished by crystallization from ethyl acetate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)[C:9]([N:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2)C)=O>CO.O>[CH3:9][NH:11][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2
Reactant: CN(C(=O)C(F)(F)F)c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CNc1ccc2[nH]ncc2c1
Yield: 100.2 %

Procedure:
Potassium carbonate (8.64 g, 62.5 mmol) was added to a solution of 2,2,2-trifluoro-N-(1H-indazol-5-yl)-N-methylacetamide (3.80 g, 15.6 mmol) in a mixture of methanol (95 ml) and water (16 ml) at room temperature, and the resulting mixture was refluxed for 1.5 hours. Then, the reaction solution was concentrated and the resulting residue was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-methyl-1H-indazol-5-amine (2.30 g, 100%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Clc1nc(NCc2ccc(Cl)c(Cl)c2)c2c3c(sc2n1)CCCC3
Product: Clc1ccc(CNc2nc(-n3cccn3)nc3sc4c(c23)CCCC4)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-dichlorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-dichlorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[C:10]([CH2:21][NH:22][CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:26])[CH3:25]>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:26][CH2:24][CH3:25])[CH2:16][CH2:15]2)=[C:10]([CH2:21][NH:22][CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1C1CCC(=O)CC1
Product: CCN[C@H]1CC[C@H](c2ccc(C(=O)OC(C)(C)C)cc2CNC)CC1

Procedure:
from 4-(4-tert.butoxycarbonyl-methylaminomethyl-phenyl)cyclohexanone and ethylamine. Colourless oil. Rf value: 0.45 (alumina, petroleum ether/ethyl acetate=1:1, v:v).
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:14]([C:15]2[NH:16][CH:17]=[C:18]([C:20]#[C:21][C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([C:32]3[N:33]=[C:34]([C@@H:37]5[CH2:42][C@@H:41]6[C@@H:39]([CH2:40]6)[N:38]5C(OC(C)(C)C)=O)[NH:35][CH:36]=3)[CH:26]=[CH:25]4)[N:19]=2)[CH2:13][C@@H:12]2[C@H:10]1[CH2:11]2)=O)(C)(C)C>O1CCOCC1>[ClH:1].[C@@H:10]12[CH2:11][C@@H:12]1[CH2:13][C@@H:14]([C:15]1[NH:16][CH:17]=[C:18]([C:20]#[C:21][C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([C:32]3[NH:33][C:34]([C@@H:37]5[CH2:42][C@@H:41]6[C@@H:39]([CH2:40]6)[NH:38]5)=[N:35][CH:36]=3)[CH:26]=[CH:25]4)[N:19]=1)[NH:9]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc(C#Cc2ccc3cc(-c4c[nH]c([C@@H]5C[C@H]6C[C@H]6N5C(=O)OC(C)(C)C)n4)ccc3c2)c[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: C(#Cc1c[nH]c([C@@H]2C[C@H]3C[C@H]3N2)n1)c1ccc2cc(-c3cnc([C@@H]4C[C@H]5C[C@H]5N4)[nH]3)ccc2c1
Reaction time: 4 h
Yield: 128.3 %

Procedure:
4M HCl (1.546 mL, 6.18 mmol) in dioxane was added to a solution of tert-butyl (1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (200 mg, 0.309 mmol) in dioxane (3 mL) and the reaction was vigorously stirred for 4 h. The reaction slurry was concentrated to yield an HCl salt of (1R,3S,5R)-3-(5-(6-((2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)ethynyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (177 mg) as a yellow solid. LC-MS retention time 3.403 min; m/z 893.29 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) d ppm 8.42 (s, 1 H), 8.16 (s, 2 H), 8.05 (d, J=8.8 Hz, 1 H), 8.03 (d, J=8.8 Hz, 1 H), 7.97 (dd, J=8.8, 1.8 Hz, 1 H), 7.74 (s, 1 H), 7.66 (dd, J=8.5, 1.5 Hz, 1 H), 5.01 (dd, J=10.8, 7.8 Hz, 1 H), 4.78 (dd, J=10.8, 8.3 Hz, 1 H), 3.57-3.77 (m, 2 H), 3.50-3.56 (m, 1 H), 2.61-2.92 (m, 4 H), 2.13-2.21 (m, 1 H), 2.06-2.13 (m, 1 H), 1.25 (ddd, J=7.8, 5.0, 2.5 Hz, 1 H), 0.99-1.14 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][N:16]=1.S(Cl)([Cl:25])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:25][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a mixture of 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine-5-methanol (12.2 g)land toluene (200 ml) was added thionyl chloride (5.39 g) and the mixture was stirred at room temperature for 1 hr. Ice water was added to the reaction mixture and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (11.7 g, yield 90%) was obtained as a colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point: 86–87° C.
Reaction SMILES: Cl[CH:2]([Cl:4])[CH3:3].[C:5]1([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7]C=1.[CH2:19]([Li])CCC.CCCCCC>O.C(OCC)C>[Cl:4][C:2]1([CH3:19])[CH2:3][C:12]1([C:11]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:5]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [Li]CCCC
Reactant: C(=Cc1ccccc1)c1ccccc1
Reactant: CC(Cl)Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CC1(Cl)CC1(c1ccccc1)c1ccccc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Under a nitrogen atmosphere, 1,1-dichloroethane (30.0 g, 303 mmol), diphenylethylene (5.59 g, 31.0 mmol) and diethyl ether (62 ml) were placed in a reaction flask and cooled to −40° C. To the mixture, n-butyllithium in hexane (45 ml, 1.56M, 70.2 mmol) was added gradually and the mixture was stirred at the same temperature for one hour, followed by warming to room temperature. Then, water was added to the reaction mixture and the organic layer was extracted with toluene. The toluene extract was dried over anhydrous magnesium sulfate and then the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol to give the title compound (5.91 g, 78%) as white crystal.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:6][N:7]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:20](=[O:21])[O:22][CH2:23][CH3:24])[CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:15]([NH:17][CH3:18])=[O:16]
Reactant: CCOC(=O)Cl
Reactant: CNC(=O)c1nc(-c2cccc(N)c2)cnc1N
Product: CCOC(=O)Nc1cccc(-c2cnc(N)c(C(=O)NC)n2)c1
Yield: 55 %

Procedure:
Ethyl (3-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}phenyl)carbamate was synthesized according to the procedure described in above from 3-amino-6-(3-aminophenyl)-N-methylpyrazine-2-carboxamide and ethyl chloroformate. Yield 55%: 1H NMR (400 MHz, d6-DMSO): 9.60 (br s, 1H), 8.68 (br s, 2H), 8.12 (br s, 1H), 7.80 (d, 1H), 7.52 (d, 1H), 7.39 (t, 1H), 4.06 (q, 2H), 2.85 (br s, 3H), 1.24 (t, 3H); MS (EI) for C15H17N5O3: 316 (MH+)
Reaction SMILES: ClC(Cl)(Cl)C(N)=O.[C:8](N)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(=O)[NH:21][C:20](=O)[C:19]2=CC=CC=[C:18]12>>[OH:15][CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:20]([NH2:21])[CH2:19][CH2:18]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: NC(=O)c1ccccc1
Agent: NC(=O)C(Cl)(Cl)Cl
Product: NC1CCC(O)c2ccccc21

Procedure:
Similarly, the corresponding trichloroacetamide, benzamide and phthalimide are hydrolyzed to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[SH:11][CH2:12][C:13]([OH:15])=O.N1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[NH:8]1[C:4]2[CH:3]=[C:2]([N:1]3[C:13](=[O:15])[CH2:12][S:11][CH:17]3[C:18]3[C:10]4[C:2](=[CH:3][CH:4]=[CH:5][CH:9]=4)[CH:21]=[CH:20][CH:19]=3)[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: O=C(O)CS
Reactant: C1CCNCC1
Reactant: Nc1ccc2nc[nH]c2c1
Product: O=C1CSC(c2cccc3ccccc23)N1c1ccc2nc[nH]c2c1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.133 g, 1.0 mmol), 4-naphthalen-1-yl carbaldehyde (0.157 mL, 1.0 mmol), mercapto acetic acid (0.157 g, 1.5 mmol), piperidine, according to method 9 step A yield: 54 mg (15.6%), MS m/z: 346.3 (M+H)+, HPLC [A]): rt 6.86 min (95%)
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1.CN(C)C=O>O>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][S:26][C:23]2[CH:24]=[CH:25][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Reactant: CC(C)(C)c1ccc(S)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(SOC(=O)CCC2CCN(C(=N)N)CC2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 45.2 %

Procedure:
A mixture of 3 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 2.2 g of p-t-butyl thiophenol, 2.6 g of dicyclohexylcarbodiimide and 18 ml of dry dimethylformamide was stirred at room temperature for 10 hours. After removal of any insoluble materials, the solvent was removed under reduced pressure. The residue was washed with ether and dissolved in t-butanol. Ether was added to the solution to give an oily substance. Water was added to the oily substance, and the mixture was allowed to stand overnight in cold conditions to give crystals. The crystals were washed with ethyl acetate and then with ether and air-dried to obtain 2.3 g (yield: 46.9%) of p-t-butylphenylthio 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 86° to 88° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:28]=[CH:27][C:26]=1B(O)O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:26]4[CH:27]=[CH:28][C:29]([CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][C:25]=4[F:24])[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cc1ccc(B(O)O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(CS(C)(=O)=O)cc4F)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2-fluoro-4-(methanesulfonylmethyl)-phenylboronic acid acid following a procedure analogous to that described in Example 28. LC (method 7): tR=1.18 min; Mass spectrum (ESI+): m/z=491 [M+H]+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:10][CH2:9][C:8]([F:12])([F:11])[S:7]1(=[O:14])=[O:13].FC(F)(F)C(O)=O>C(Cl)Cl>[F:11][C:8]1([F:12])[S:7](=[O:14])(=[O:13])[NH:6][CH2:10][CH2:9]1
Reactant: COc1ccc(CN2CCC(F)(F)S2(=O)=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S1(=O)NCCC1(F)F
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 76.4 %

Procedure:
To a 0° C. solution of 2-(2,4-dimethoxybenzyl)-5,5-difluoroisothiazolidine-1,1-dioxide (0.100 g, 0.3 mmol) in methylene chloride (6 mL) was added trifluoroacetic acid (2.182 mL, 29.4 mmol). The resulting red/purple solution was stirred at 0° C. for 3.5 hrs and concentrated in vacuo. The crude material was purified by silica gel chromatography (30-75% ethyl acetate/hexanes) to give a tan oil (0.036 g). 1H NMR (CDCl3, 300 MHz) δ 4.78 (br s, 1H), 3.46-3.40 (q, 2H, J=6.6 Hz), 2.79-2.65 (m, 2H). 19F NMR (CDCl3, 282 MHz)-105.96-106.07 (t, J=15.4 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[NH:19][C:18](=[O:32])[N:17]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:41](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[N:19]([CH3:41])[C:18](=[O:32])[N:17]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2CC(=O)OCC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(C)c(=O)n2CC(=O)OCC
Temperature: 25 °C
Reaction time: 13 h
Yield: 77.9 %

Procedure:
4-[3-Ethoxycarbonylmethyl-2,6-dioxo-7-(2-vinylphenyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (60 mg) was dissolved in N,N-dimethylformamide (2 ml), methyl iodide (17 μl) and potassium carbonate (17 mg) were added to the solution, and the mixture was stirred at room temperature for 13 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 48 mg of the title compound.