Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][C@@H:2]1[CH2:15][NH:16][CH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=2)[NH:22][CH:21]=1)[N:11]=[CH:10][CH:9]=[CH:8]3.C=O.[C:32]([BH3-])#N.[Na+].C(O)(=O)C>CO>[O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][CH:2]1[CH2:15][N:16]([CH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=2)[NH:22][CH:21]=1)[CH3:32])[N:11]=[CH:10][CH:9]=[CH:8]3
Reactant: Fc1ccc2[nH]cc(CCCNC[C@H]3COc4ccc5ncccc5c4O3)c2c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CCCc1c[nH]c2ccc(F)cc12)CC1COc2ccc3ncccc3c2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S)-(2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-[3-(5-fluoro-1H-indol-3-yl)-propyl]-amine (0.13 g, 0.33 mmol) and formaldehyde (37 wt. % in water, 0.26 g, 3.3 mmol) in methanol (20 mL) was added sodium cyanoborohydride (0.038 g, 0.59 mmol) and acetic acid (0.03 g, 0.5 mmol) at room temperature. The mixture was stirred at room temperature under nitrogen overnight, then quenched with 1N NaOH (5 mL). The mixture was extracted with methylene chloride (3×50 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. The crude oil was column chromatographed on silica gel (5% methanol-methylene chloride). The product-containing fractions were concentrated in vacuum to give 0.1 g of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate as a yellow solid (decomposed at 78° C.).
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26]>[Pd]>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]4)[CH2:3]2)[CH2:9]3)=[CH:22][C:21]=1[CH3:26]
Reactant: BrC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccccc1C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1C
Temperature: 150 °C
Reaction time: 24 h
Yield: 82.3 %

Procedure:
To a solution of 1-bromoadamantane (3.25 g, 15.25 mmol) and potassium carbonate (1.05 g, 7.62 mmol) in 1-methoxy-2-methylbenzene (10 mL) was added 10 wt. % Pd/C (2.22 g) and stirred at 150° C. under nitrogen for 24 hours. The reaction mixture was cooled to room temperature and filtered. Solvent was evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give 1-(4-methoxy-3-methylphenyl)adamantane as a white solid (4.9 g, 82.3% yield).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCl)cc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CNc2ccc(C#N)cc2)cc1
Yield: 25.2 %

Procedure:
The procedure of Preparation Example 7 was repeated, except that 2.058 g of 4-(tert-butyldimethylsilyloxy)benzyl chloride was used in place of 4-benzyloxybenzyl chloride, and 0.946 g of 4-aminobenzonitrile was used in place of 4-aminophenol. The resulting crude product was purified by silica gel column chromatography (using a 3:1 mixture of hexane and ethyl acetate as the eluent) to obtain 0.682 g of 4-[N-(4-tert-butyldimethylsilyloxybenzyl)amino]benzonitrile.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][C:7]=1[O:23][CH3:24]>C(O)(=O)C.C(OCC)(=O)C>[OH:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:8][C:7]=1[O:23][CH3:24]
Reactant: COc1cc(C(=O)CCCc2ccccc2)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(C(=O)CCCc2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.79 ml of 65 percent nitric acid in 25 ml of glacial acetic acid is added dropwise to a solution of 2.2 g of 4'-hydroxy-3'-methoxy-4- phenylbutyrophenone in 25 ml of glacial acetic acid and the mixture is stirred at room temperature for an additional 2 hours. The mixture is poured into 150 ml of ice-water and, after treatment with 20 ml of 3N hydrochloric acid, extracted three times with 75 ml of ethyl acetate each time. The organic phase is washed with water, dried over sodium sulfate and evaporated. The crude product obtained is taken up in ethyl acetate and filtered over 75 g of silica gel. After recrystallization from acetonitrile, there is obtained 4'-hydroxy-3'-methoxy-5'-nitro-4-phenylbutyrophenone in the form of yellow crystals of m.p. 120°-121°.
Reaction SMILES: [OH-].[Na+].C(OC([N:10]([C:30]1[C:35]([O:36][CH3:37])=[N:34][C:33]([CH3:38])=[CH:32][N:31]=1)[S:11]([C:14]1[C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=2)=[N:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])=O)C(C)C.O.Cl>CO>[CH2:26]([C:23]1[CH:22]=[CH:21][C:20]([C:15]2[C:14]([S:11]([NH:10][C:30]3[C:35]([O:36][CH3:37])=[N:34][C:33]([CH3:38])=[CH:32][N:31]=3)(=[O:13])=[O:12])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:25][CH:24]=1)[CH:27]([CH3:29])[CH3:28]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CC(C)C)cc1
Yield: 34.4 %

Procedure:
1M sodium hydroxide solution (11.2 ml) was added to a solution of N-(isobutoxycarbonyl)-2-(4-isobutylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (2.6 g) in methanol (50 ml) and the mixture was stirred and heated under reflux for 30 minutes. Water (100 ml) was added and the mixture was acidified to pH 3 with 2M hydrochloric acid. This mixture was extracted with ethyl acetate (5×30 ml) and the extracts were washed with water (30 ml) and saturated sodium chloride solution and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 0-15% ethyl acetate/hexane through a silica gel Mega Bond Elut column followed by trituration with ether to give 2-(4-isobutylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (720 mg) as a solid, m.p. 128-129° C.; 1H NMR (CDCl3): 0.95 (d, 6H), 1.9 (m, 1H), 2.3 (s, 3H), 2.55 (d, 2H), 3.8 (s, 3H), 6.6 (s, 1H), 7.1-7.3 (m, 4H), 7.35 (s, 1H), 7.5 (dd, 1H), 8.7 (dd, 1H), 8.8 (dd, 1H); mass spectrum (positive electrospray (+ve ESP)): 413 (M+H)+.
Reaction SMILES: [S:1]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[O:11])[NH:4][CH2:3][CH2:2]1.[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([C:9]1[S:8][C:7]2[S:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[C:6]=2[CH:10]=1)=[O:17]
Reactant: O=C(Cl)CCCCl
Reactant: O=C1NCCSc2sccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(CCCCl)c1cc2c(s1)SCCNC2=O
Reaction time: 3 h
Yield: 59 %

Procedure:
To a mixture of 13 g of 2,3-dihydrothieno[3,2-f][1,4]thiazepin-5(4H)-one and 21.5 g of 4-chlorobutyryl chloride in 200 ml of dichloroethane was added 21.5 g of aluminum chloride under cooling and the mixture was stirred for 3 hours. The mixture was poured into ice-cold water and extracted with chloroform. The organic layer was washed with saline solution, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give 12 g of 7-(4-chlorobutyryl)-2,3-dihydrothieno[3,2-f][1,4]thiazepin-5(4H)-one as white crystals, m.p. 124°-125° C.
Reaction SMILES: [N:1]1([C:6]2[NH:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:16][C:17]1[CH:36]=[CH:35][C:20]2/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=3[O:24][CH2:25][C:19]=2[CH:18]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:22]2=[C:23]([CH:26]=1)[O:24][CH2:25][C:19]1[CH:18]=[C:17]([CH2:16][N:10]3[C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[N:7]=[C:6]3[N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:36]=[CH:35][C:20]=1/[C:21]/2=[C:31](/[CH3:34])\[C:32]#[N:33]
Reactant: c1ccc2[nH]c(N3CCCC3)nc2c1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(N4CCCC4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 89.3 %

Procedure:
Using commercially available 2-(pyrrolidin-1-yl)-1H-benzo[d]imidazole (63 mg, 0.34 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.34 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (141 mg, 91%) was obtained.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.BrCC.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)=[O:20])[CH3:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Brc1cccc2nccn12
Solvent: C1CCOC1
Solvent: CCBr
Product: CCOC(=O)C(=O)c1cccc2nccn12
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
Add Mg turnings (0.25 g, 9.95 mmol) to a solution of 5-Bromoimidazo[1,2-a]pyridine (1.5 g, 7.65 mmol) in tetrahydrofuran (20 ml). Heat the reaction to 60° C. and add bromoethane (1.2 ml, 11.1 mmol). Reflux for another 0.5 hours, cool and cannula dropwise into a solution of diethyl oxalate (5 ml) in tetrahydrofuran (5 ml) at −15° C. Stir at −15° C. for 0.5 hours and at room temperature for 0.5 hours. Quench the reaction by adding pH 7 buffer, extract into ethyl acetate, wash with saturated sodium chloride, dry over magnesium sulfate, and concentrate under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate:hexane: methanol gradient gives the title compound as a light brown oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][O:1][S:21]([CH3:20])(=[O:23])=[O:22])[N:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1nc(CO)cs1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc(COS(C)(=O)=O)cs1
Reaction time: 1 h

Procedure:
A solution of 1.2 mmol of 4-(hydroxymethyl)-2-isopropylthiazole and 1.3 mmol of diisopropylethylamine in 20 ml of dichloromethane was cooled to -20° C. and treated dropwise with 1.3 mmol of methanesulfonyl chloride. The resulting mixture was stirred for 1 h, quenched with aqueous citric acid, separated, dried over Na2SO4, and concentrated in vacuo to provide the desired compound.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:27])C=1.O>ClCCl>[N:1]1([C:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[O:8])[CH2:2][CH2:3][S:4](=[O:27])[CH2:5][CH2:6]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCSCC1
Solvent: ClCCl
Solvent: O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCS(=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
13.1 g (49.0 mmol) of 4-nitrophenyl thiomorpholine-4-carboxylate were initially charged in 135 ml of dichloromethane and admixed at 0° C. with 7.6 g (44.1 mmol) of m-chloroperbenzoic acid in portions. The mixture was stirred at RT for two hours, water was added and the organic phase was removed. The organic phase was washed rapidly with saturated aqueous sodium hydrogencarbonate solution, filtered and concentrated under reduced pressure. The crude product was purified by means of preparative HPLC. Yield: 7.8 g (56% of theory)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2=[C:8]([CH3:14])[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1.[ClH:26]>C(O)C>[ClH:26].[NH2:1][C:2]1[NH:7][CH:6]([CH2:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:25])[C:5]2=[C:8]([CH3:14])[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1
Reactant: CCCc1nc(C)c2cnc(N)nn12
Reactant: COc1ccc(C(C)=O)cc1
Agent: Cl
Solvent: CCO
Product: CCCc1nc(C)c2n1N=C(N)NC2CC(=O)c1ccc(OC)cc1

Procedure:
2-Amino-5-methyl-7-propylimidazo[5,1-f]-as-triazine (Example 4) (1.9 g.), p-methoxyacetophenone (1.65 g.) and concentrated hydrochloric acid (2 ml.) in ethanol (50 ml.) were heated under reflux for 1.5 hours. The solvent was distilled off and the residue was treated with 2N sodium carbonate. The mixture was extracted with ethyl acetate and the extract was dried over magnesium sulphate, filtered and evaporated. The residue was crystallised from a mixture of ethyl acetate and light petroleum and had m.p. 193°-195°. The solid in ethanol (20 ml.) was treated with hydrogen chloride in ether. The mixture was further diluted with ether and the solid that crystallised from a mixture of isopropanol and ether and had m.p. 122°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([Cl:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:21][CH2:22][CH2:23][CH2:24]I>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([Cl:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:24][CH2:23][CH2:22][Cl:21])[C:6]=2[CH:12]=1
Reactant: Cc1c(Cl)cc2c(c1Cl)OCC(=O)N2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1c(Cl)cc2c(c1Cl)OCC(=O)N2CCCCl
Yield: 79.1 %

Procedure:
6,8-Dichloro-7-methyl-4H-benzo[1,4]oxazin-3-one (81MF2225a) (2.33 g, 10.0 mmol), Cs2CO3 (4.88 g, 15.0 mmol) and 3-chloro-1-iodopropane (2.25 g, 11.0 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF2225b) (2.44 g, 79%). 1H NMR (CDCl3) δ 7.02 (s, 1H), 4.67 (s, 2H), 4.06 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.2, 2H), 2.43 (s, 3H), 2.18-2.10 (m, 2H); 13C NMR (CDCl3) δ 163.7, 140.5, 130.3, 128.3, 127.6, 124.1, 113.5, 67.9, 42.2, 39.3, 30.0, 17.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH2:31][C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=1[CH2:31][C:17]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:19]2[N:24]([C:16]=1[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15])[CH:23]=[CH:22][CH:21]=[CH:20]2
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cc3c(F)cccc3Cl)c(-c3ccccc3)c3ccccn23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(c1c(Cc2c(F)cccc2Cl)c(-c2ccccc2)c2ccccn12)N1CCNCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
The compound of step 3 (0.886 g, 1.62 mmol) was dissolved in DCM (6.5 ml). The solution was cooled at 0° C. and a 4 N solution of hydrogen chloride in dioxane (2.02 ml, 8.08 mmol) was added. After stirring overnight at room temperature, the mixture was concentrated to dryness. The residue was triturated several times with diethyl ether, filtered, rinsed with diethyl ether and dried in a vacuo at 65° C. to give 0.70 g of the title compound in the form of [2-(2-chloro-6-fluoro-benzyl)-1-phenyl-indolizin-3-yl]-piperazin-1-yl-methanone hydrochloride as an off-white powder with the following characteristics:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15](=O)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1(Br)C[CH2:19]1.O[Li].O>C(O)(C)C.O>[CH:16]1([CH2:15][S:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH2:19][CH2:18]1
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrC1CC1
Agent: [Li]O
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(SCC2CC2)CC1
Temperature: 25 °C

Procedure:
To an argon purged solution of tert-butyl-4-(acetylthio)piperidine-1-carboxylate (51, 1.50 g, 5.86 mmol) in a 5:1 mixture of isopropanol-water (55 mL) was added cyclopropyl bromide (1.52 g, 11.72 mmol) followed by solid LiOH.H2O (1.0 g, 68.67 mmol). The mixture stirred at room temperature and stirred for 16 h and was concentrated under reduced pressure. The residue was dissolved in EtOAc (90 mL) and washed with H2O (25 mL), brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 4-(cyclopropylmethylthio)piperidine-1-carboxylate as a colorless syrup (52, 1.1 g, 69%); 1H NMR (300 MHz, CDCl3) δ 2.98-2.75 (m, 3H), 2.61 (m, 1H), 2.48 (d, J=6.9 Hz, 2H), 2.39-2.28 (m, 1H), 1.74-2.01 (m, 2H), 1.43-1.55 (m, 2H), 1.45 (s, 9H), 1.01-0.88 (m, 1H), 0.52-0.59 (m, 2H), 0.15-0.25 (m, 2H);
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:12][CH:11]=[CH2:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1cc(C)cc(C)c1
Yield: 104.6 %

Procedure:
46.73 g (383 mmol) of 3,5-dimethylphenol (Compound No. 1) was dissolved in 100 ml of methyl ethyl ketone. To this solution, 55.6 g (460 mmol) of allyl bromide and 79.3 g (575 mmol) of anhydrous potassium carbonate were added. The thus obtained mixture was refluxed overnight under an argon atmosphere. The reaction mixture was then extracted with hexane. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated, whereby 65.0 g of a crude 3,5-dimethyl-1-(2-propenyloxy)benzene (Compound No. 2) was obtained as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].Cl.[F:31][C:32]1([F:37])[CH2:36][CH2:35][NH:34][CH2:33]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:34]2[CH2:35][CH2:36][C:32]([F:37])([F:31])[CH2:33]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: FC1(F)CCNC1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Agent: Cl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCC(F)(F)C2)c1OCCC(C)c1ccc(F)cc1
Yield: 54 %

Procedure:
Example 8a (83 mg, 0.17 mmol) was reacted with 3,3-difluoropyrrolidine hydrochloride (2.5 eq.) as described under General Procedure K and the crude mixture was purified by flash chromatography (silica gel, hexane/Et2O 70:30) to afford the title compound as a pale yellow oil (47 mg, 54%). 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.03 (t, J=5.6 Hz, 2H), 3.95 (dt, J=2.1, 6.8 Hz, 2H), 3.83 (s, 3H), 2.97 (m, 1H), 2.95 (t, J=13.4 Hz, 2H), 2.79-2.71 (m, 4H), 2.49 (s, 3H), 2.33-2.21 (m, 2H), 2.18 (s, 3H), 2.06-1.98 (m, 2H), 1.30 (d, J=6.9 Hz, 3H). MS (ES+) m/z 514.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]=1[O:16][CH3:17])[C:6](N1C=CN=C1)=[O:7].[C:21](=[N:24][OH:25])([NH2:23])[CH3:22]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]=1[O:16][CH3:17])[C:6]([O:25][N:24]=[C:21]([NH2:23])[CH3:22])=[O:7]
Reactant: COc1cc(C(=O)n2ccnc2)cc([N+](=O)[O-])c1OC
Reactant: CC(N)=NO
Solvent: CN(C)C=O
Product: COc1cc(C(=O)ON=C(C)N)cc([N+](=O)[O-])c1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
10.0 g of 1-(3,4-dimethoxy-5-nitrobenzoyl)imidazole in 50 ml of dimethylformamide are treated with 6.95 g of acetamidoxime, whereupon the mixture is stirred at 70° for 1 hour. After cooling, the mixture is poured into 500 ml of ice-water and stirred for 30 minutes. The separated crystals are filtered under suction and washed with water. After crystallization from ethyl acetate there is obtained N'-[(3,4-dimethoxy-5-nitrobenzoyl)oxy]acetamidine in the form of colorless crystals of m.p. 165°-166°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[N:11]1[N:12]=[CH:13][NH:14][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: c1nnc[nH]1
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1cc(Cl)ccc1-n1cncn1
Temperature: 45 °C

Procedure:
To a reaction vessel was added 5-chloro-2-fluorobenzaldehyde (1.29 g, 7.89 mmol), 4H-1,2,4-triazole (0.574 g, 7.89 mmol), Cs2CO3 (2.83 g, 8.68 mmol) and DMSO (15.78 ml). The mixture was capped and heated at 45° C. for 4 hrs before cooling down to rt and stirred at rt over weekend. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered, concentrated and purified by flash chromatography to yield 71A as white solid product (674 mg, 41%). 1H NMR (500 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.17 (s, 1H), 8.33 (s, 1H), 7.99-7.91 (m, 2H), 7.84 (d, J=8.5 Hz, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])[C:8]#[N:9].[OH2:18].N>O>[NH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])[C:8]([NH2:9])=[O:18]
Reactant: O
Reactant: N#CC(N)c1ccc(F)cc1F
Agent: N
Agent: O=S(=O)(O)O
Product: NC(=O)C(N)c1ccc(F)cc1F
Reaction time: 3 h
Yield: 61 %

Procedure:
Then, 51 g of concentrated sulfuric acid was added to 2.67 g of water, to which 40 g of 2-amino-2-(2,4-difluorophenyl)acetonitrile was added under ice cooling, and the mixture was heated at 50° to 60° C. under stirring for 3 hours. After completion of the reaction, the reaction mixture was poured into 250 ml of concentrated ammonia water cooled with ice in such a manner that the temperature of the solution became not higher than 20° C. The precipitated crystals were collected by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was combined with the previously collected crystals, followed by recrystallization, which afforded 27.2 g (yield, 61%) of 2-amino-2-(2,4-difluorophenyl)acetamide, m.p. 142.9° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][NH2:17])[CH2:11]2)=[CH:4][CH:3]=1.C1([O:24][C:25](=O)[NH:26][C:27]2[S:28][C:29]([C:33](=[O:35])[CH3:34])=[C:30]([CH3:32])[N:31]=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[C:33]([C:29]1[S:28][C:27]([NH:26][C:25]([NH:17][CH2:16][CH:12]2[CH2:13][CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:11]2)=[O:24])=[N:31][C:30]=1[CH3:32])(=[O:35])[CH3:34]
Reactant: NCC1CCCN(CCc2ccc(F)cc2)C1
Reactant: CC(=O)c1sc(NC(=O)Oc2ccccc2)nc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)c1sc(NC(=O)NCC2CCCN(CCc3ccc(F)cc3)C2)nc1C
Yield: 67.6 %

Procedure:
A solution of C-{1-[2-(4-fluorophenyl)ethyl]-piperidin-3-yl}methylamine (25 mg, 106 μmol), (5-Acetyl-4-methylthiazol-2-yl)-carbamic acid phenyl ester (24 mg, 106 μmol) and triethylamine (29 μL, 210 μmol) in acetonitrile (3 mL) was stirred for 18 hours and concentrated. The residue was purified by flash chromatography, eluting with 5% methanol in dichloromethane, to provide an off-white solid (30 mg, 68%). 1H NMR (300 MHz, CD3OD) δ7.21 (m, 2H), 6.98 (t, J=9 Hz, 2H), 3.16 (m, 2H), 3.02 (m, 2H), 2.82 (m, 2H), 2.61 (m, 2H), 2.56 (s, 3H), 2.47 (s, 3H), 2.09 (m, 1H), 1.85 (m, 4H), 1.65 (m, 1H), 1.05 (m, 1H). Mass spec (ES+) m/z 419.2 (M+H+, 100%).