Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:16])[CH3:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].Cl.[CH3:18][NH:19][CH3:20].C=O.[CH3:23]C(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>C(O)C>[ClH:1].[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:16])[CH2:15][CH2:18][N:19]([CH3:23])[CH3:20])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CNC
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: CC(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Agent: C=O
Agent: Cl
Solvent: CCO
Product: CN(C)CCC(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl

Procedure:
(2,3-Dichloro-4-acetylphenoxy)acetic acid (U.S. Pat. No. 3,453,312) (7.89 g, 0.03 mole), dimethylamine hydrochoride (2.34 g, 0.03 mole), paraformaldehyde (1.05 g, 0.033 mol. equiv.) and glacial acetic (1 ml) were combined and heated on a steam bath for two hours. The reaction mixture was treated with hot ethanol (50 ml) and then cooled. The white solid was separated by filtration, washed with ethanol, dried and recrystallized from a mixture of ethanol and ether to give [2,3-dichloro-4-(3-dimethylaminopropionyl)phenoxy]acetic acid hydrochloride, m.p. 194°-196° C.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].[C:12]([C:20]1[C:21](Cl)=[C:22]2[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:23]2=[N:24][CH:25]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[C:12]([C:20]1[C:21]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])=[C:22]2[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:23]2=[N:24][CH:25]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)=NO
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccccc3)cnc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCn1ncc2c(ON=C(C)C)c(C(=O)c3ccccc3)cnc21
Yield: 72.7 %

Procedure:
In 25 ml of dry tetrahydrofuran (THF hereafter) was dissolved 1.6 g of acetone oxime, followed by 2.46 g of potassium t-butoxide. After stirring 0.5 hour 5.0 g of 5-benzoyl-4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine in 50 ml of THF was added to the solution. After an additional 0.5 hour the reaction was quenched with ammonium chloride solution and the product was extracted with ether. Evaporation of the organic phase and recrystallization of the residue from ethanol gave 4.1 g of product, mp 115°-116° C.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[CH2:15][OH:16].[CH:18](Br)([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>O.CN(C)C=O>[CH:18]([N:1]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:14][CH2:15][OH:16])[CH2:3][CH2:2]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C1CNCCNC1
Reactant: OCCBr
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1CCCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.4 %

Procedure:
To a mixture of homopiperazine (5.0 g), potassium carbonate powder (13.8 g) and N,N-dimethylformamide (80 ml) was added ethylene bromohydrin (6.3 g) and the mixture was stirred at room temperature for 12 hours. Then, benzhydryl bromide (12.4 g) was added and the whole mixture was further stirred at room temperature for 6 hours, diluted with water and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the oily residue was purified by silica gel chromatography [eluent: chloroform-methanol (20:1)] to give 4-benzhydrylhomopiperazine-1-ethanol as an oil (2.7 g, 17.4%). IR(Neat): 3400 cm-1. NMR(CDCl3)δ: 1.6-1.9(2H, m), 2.5-2.9(10H, m), 3.08(1H, s), 3.52(2H, t, J=6), 4.57(1H, s), 7.0-7.5(10H, m).
Reaction SMILES: [S-:1][CH2:2][CH3:3].[Na+].[C:5]([C:9]1[C:14]2[O:15][CH2:16][C:17]([CH3:19])([CH3:18])[C:13]=2[CH:12]=[C:11]([C:20](=[O:23])[CH2:21]Cl)[CH:10]=1)([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([C:9]1[C:14]2[O:15][CH2:16][C:17]([CH3:19])([CH3:18])[C:13]=2[CH:12]=[C:11]([C:20](=[O:23])[CH2:21][S:1][CH2:2][CH3:3])[CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)c1cc(C(=O)CCl)cc2c1OCC2(C)C
Reactant: CC[S-]
Agent: [Na+]
Solvent: CO
Product: CCSCC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reaction time: 2.5 h
Yield: 58.7 %

Procedure:
Sodium thioethoxide (0.54 g, 6.4 mmol) is added in portions to a solution of 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-2-chloroethan-1-one (1.12 g, 4.0 mmol) in 30 mL of methanol at room temperature. The reaction is stirred for 2.5 h, and concentrated in vacuo. The residue is dissolved in ether, washed with water and with brine, dried over anhydrous magnesium sulfate, and concentrated to give 1.12 g of the crude product. Purification by flash column chromatography on silica gel (5% ethyl acetate-hexane) afforded 0.72 g of the title compound as a light yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]2[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:5]=2[CH:4]=1.[CH3:19][NH:20][CH2:21][CH2:22][CH3:23]>>[ClH:18].[Cl:18][C:17]1[C:5]2[CH:4]=[C:3]([CH2:2][N:20]([CH3:19])[CH2:21][CH2:22][CH3:23])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=[CH:15][CH:16]=1
Reactant: Clc1cccc2c1C=C(CBr)c1ccccc1O2
Reactant: CCCNC
Product: CCCN(C)CC1=Cc2c(Cl)cccc2Oc2ccccc21
Product: Cl
Yield: 25 %

Procedure:
Preparation analogous to Example 2 from 10-bromomethyl-1-chlorodibenz[b,f]oxepine with N-methyl-propylamine; yield: 25%; beige solid; melting point: not determined, (beige foam); 1H-NMR (CDCl3, 200 MHz): 0.88 (t, 3H); 1.55 (m, 2H); 2.28 (s, 3H); 2.43 (t, 2H); 3.55 (s, 2H), 7.08-7.35 (m, 7H); 7.61 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([OH:23])=O)[C:15]=3[N:14]=[C:13]2[C:24](=[O:35])[NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[O:10])=[N:6][CH:7]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[CH:32]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:24]([C:13]2[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[O:23])[C:15]=3[N:14]=2)=[O:35])[CH2:27][CH2:28]1)([CH3:34])[CH3:33]
Reactant: C1COCCN1
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)N4CCOCC4)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(morpholine-4-carbonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 450 mg (0.90 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 87 μl (2.70 mmol) morpholine. The title compound was obtained as its formiate. Subsequent transformation to the corresponding acetate gave a white amorphous solid.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1.[K+].[Br-]>C1COCC1>[CH:1]1([NH:8][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCCC1
Reactant: O=S1(=O)CCCO1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(O)CCCNC1CCCCCC1
Temperature: 25 °C
Yield: 72 %

Procedure:
Cycloheptylamine (3.9 mL, 30 mmol) was added to a solution of 1,3-propane sultone (4.1 g, 33 mmol) in THF (65 mL). The mixture was heated at reflux for 5 hours with a heating mantle. The mixture was cooled to room temperature and the solid was collected by filtration, and then dried in a vacuum oven for 1 hour at 60° C. (6.21 g). The solid material was dissolved in methanol/water (30 mL/3 mL, v/v). The solution was cooled slowly to room temperature, and further cooled with an ice-bath. The solid product was collected by filtration, rinsed with methanol, air-dried for 15 minutes, and further dried in a vacuum oven at 60° C. Compound CK was obtained as small white flakes (5.08 g, 72% yield). m.p. 341-43° C. 1H NMR (500 MHz, D2O) δ 1.21-1.42 (m, 8H), 1.45-1.51 (m, 2H), 1.79-1.89 (m, 4H), 2.76 (7, J=7.3 Hz, 2H), 2.96 (t, J=7.8 Hz, 2H), 3.35 (m, J=4.6 Hz, 1H). 13C NMR (125 MHz, D2O) δ 21.6, 23.3, 27.3, 30.5, 43.6, 48.0, 59.6. FT-IR (KBr) vmax 2924, 1615, 1464, 1243.
Reaction SMILES: C(C1C=[N:6][NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1)(=O)C.C1(C)C=C(C)C=C(C)C=1S(ONC(=O)[O:29][CH2:30][CH:31]=C)(=O)=O.[CH2:35]([NH:37]CC)[CH3:36]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:30]([N:37]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([NH2:6])[CH2:36][CH2:35]1)(=[O:29])[CH3:31]
Reactant: CCNCC
Reactant: CC(=O)C1=Cc2ccccc2NN=C1
Reactant: C=CCOC(=O)NOS(=O)(=O)c1c(C)cc(C)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)N1CCN(N)c2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
4-Acetylbenzodiazepine (28.5 g, 50.15 m) and allyl N-[(mesitylsulfonyl)-oxy]carbamate (53.8 g, 0.18 m) were combined in toluene (270 mL) and heated under reflux for 2.5 h. The reaction was quenched with 0.5 N NaOH. The precipitate that formed was removed by filtration and the aqueous filtrate was extracted with ethyl acetate (3×). The combined organic layers were washed with saturated sodium chloride solution, dried (MgSO4), and evaporated to give a residue which was dissolved in methylene chloride (490 mL) and treated with diethylamine (51 mL, 5 eq.) and tetrakis triphenylphosphinepalladium (115 mg, 0.001 eq). After stirring for 2 h at room temperature, the volatiles were removed under reduced pressure and the residue was purified by chromatography on silica gel eluting with 10-20% methanol in ethyl acetate to give 4-acetyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-1-ylamine (13.5 g, 44%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[F:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=1[F:19]>>[F:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[F:19])[O:20][C:9]1[C:8]([F:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: Oc1ccc(F)c(F)c1
Product: O=Cc1cc(F)c(Oc2ccc(F)c(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3,4-difluorophenol.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]1=2)=[O:5].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C(O)(C)C>[O:25]1[CH2:26][CH2:27][N:22]([CH2:2][CH2:3][C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:9][C:8]3[CH:18]=[CH:19][CH:20]=[CH:21][C:7]2=3)=[O:5])[CH2:23][CH2:24]1
Reactant: O=C1Nc2ccccc2N(C(=O)CCCl)c2ccccc21
Reactant: C1COCCN1
Solvent: CC(C)O
Product: O=C1Nc2ccccc2N(C(=O)CCN2CCOCC2)c2ccccc21

Procedure:
6.0 gm (0.02 mol) of 5-(3-chloro-propionyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 10 gm (0.11 mol) of morpholine were refluxed in 200 ml of isopropanol for 2 hours. The solvent was distilled off, the residue was dissolved in methylene chloride, and the solution was washed with water. After distilling off the solvent, the residue was recrystallized from isopropanol.
Reaction SMILES: CO[N:3](C)[C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=O.B1(C)O[C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32]C=CC=2)[C@@H]2N1CCC2.[CH3:41][C:42]1[NH:46]N=[N:44][N:43]=1.N1C=NN=N1>>[CH3:41][C:42]1[N:43]=[N:44][N:3]([C@H:4]([C:33]2[CH:28]=[CH:26][C:34]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:32]=2)[C@H:6]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]2)[N:46]=1
Reactant: Cc1nnn[nH]1
Reactant: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Reactant: CON(C)C(=O)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: c1nnn[nH]1
Product: Cc1nnn([C@H](c2ccc3ccccc3c2)[C@H]2CCCNC2)n1

Procedure:
The procedure given in Example 1 was followed using tert-butyl (3S)-3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate was used instead of tert-butyl (3R)-3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate. As a reducing agent, (R)-2-methyl-CBS-oxazaborolidine was used instead of (S)-2-methyl-CBS-oxazaborolidine. And 5-methyl-1H-tetrazole was used as a reactant, instead of 1H-tetrazole, to give (3S)-3-[(S)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine.
Reaction SMILES: [CH:1]1([O:7][CH2:8][C@H:9]2[CH2:14][C@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[NH2:29]O.Cl>CO.O.C(Cl)Cl>[CH:1]1([O:7][CH2:8][C@H:9]2[CH2:14][C@H:13]([C:15]3[O:22][NH:29][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](COC2CCCCC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1COC1CCCCC1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 62.7 %

Procedure:
Trans-methyl 2-(cyclohexyloxymethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (210 mg, 0.57 mmol) (from example 84, step 1) was dissolved in MeOH (3 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (23.87 mg, 0.60 mmol) dissolved in water (0.300 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.037 mL, 0.60 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (2.94 mL, 17.62 mmol) and the mixture was stirred at 80° C. for 20 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(cyclohexyloxymethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (121 mg, 63%) was isolated. MS m/z 339 (M+H)+
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH2:7][C:8]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=1[O:16][CH3:17])=[NH:5])#[N:2].[OH:18][CH2:19][C:20](=O)[CH3:21].Cl>CO.O>[C:13]([OH:14])(=[O:18])[CH3:8].[CH3:17][O:16][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=1[CH2:7][NH:6][C:4]([NH:3][C:1]1[O:18][CH:19]=[C:20]([CH3:21])[N:2]=1)=[NH:5]
Reactant: CC(=O)CO
Reactant: COc1cccc(OC)c1CNC(=N)NC#N
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(=O)O
Product: COc1cccc(OC)c1CNC(=N)Nc1nc(C)co1
Temperature: 40 °C

Procedure:
0.20 g (0.85 mmol) N-cyano-N′-(2,6-dimethoxybenzyl)guanidine were suspended in 20 ml methanol/water (1:1). Subsequently, 63.3 mg (0.85 mmol) hydroxyacetone were added and the mixture was heated to 40° C. The pH-value was adjusted at high temperature with 1 N HCl to 2.5-3 pH. In total, the reaction mixture was heated for 34 hours at 40° C. under constant pH-control until no further educts could be detected by mass spectrometry. The methanol was distilled off under vacuum and a white solid remained which was purified by HPLC (Merck: Chromolith RP-18E, 100-25; eluent water/acetonitrile/0.1 molar acetic acid); 64 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[CH2:16])=[CH:13][CH:12]=1.CC1C=C[C:23]([S:26]C)=CC=1>C1(C)C=CC=CC=1.CCCCCC>[CH3:23][S:26][C:11]1[CH:18]=[CH:17][C:14](/[CH:15]=[CH:16]/[C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CSc1ccc(C)cc1
Reactant: C=Cc1ccc(F)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CSc1ccc(/C=C/c2cc(F)cc(F)c2)cc1

Procedure:
Following the procedure describe in Method 3, but substituting 4-methylthiostyrene (from method 4, step 1) and 1-bromo-3,5-difluorobenzene for 4-fluorostyrene and 4-methylthioanisole, the title product was obtained after flash chromatography (silica gel; toluene/hexane (50:50)) as an orange oil.
Reaction SMILES: [CH2:1]([N:3]1[C:11](Br)=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[N:4]1)[CH3:2].[Li]C(C)(C)C.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>C1COCC1>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][C:19]([OH:18])([C:11]2[N:3]([CH2:1][CH3:2])[N:4]=[C:5]3[C:10]=2[CH:9]=[CH:8][CH:7]=[CH:6]3)[CH2:20][CH2:21]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CCn1nc2ccccc2c1Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCn1nc2ccccc2c1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 22.5 %

Procedure:
To a solution of 2-ethyl-3-bromoindazole (3.4 g, 15.18 mmol) in THF (30 mL) was added t-BuLi (1.7 M in pentane, 10.72 mL, 18.22 mmol) dropwise at −78° C. After stirring at −78° C. for 20 min., was added tert-butyl 4-oxo-1-piperidinecarboxylate (3.03 g, 15.18 mmol) in THF (10 mL) dropwise at −78° C. The mixture was stirred at −78° C. for 10 min. and at rt for 18 h. After the reaction was quenched with aq. NH4Cl , the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3×). The combined organic phases were washed with brine, and dried over anhydrous magnesium sulfate. Concentration followed by purification by flash chromatography (hexanes ethyl acetate=4:1, then 1:1) to give 1.18 g of the title compound as a foamy solid.
Reaction SMILES: [CH:1]1([CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6])[CH2:3][CH2:2]1.O1CCOCC1.S(=O)(=O)(O)O.[CH3:21][C:22](=[CH2:24])[CH3:23]>O.C(N(CC)CC)C>[C:22]([O:8][C:7](=[O:9])[C@H:5]([CH2:4][CH:1]1[CH2:3][CH2:2]1)[NH2:6])([CH3:24])([CH3:23])[CH3:21]
Reactant: N[C@@H](CC1CC1)C(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)CC1CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.5 g (27.1 mmol) of (S)-β-cyclopropylalanine were added to a mixture of 50 mL of dioxane and 5 ml of concentrated sulfuric acid (prepared by cautious addition of the acid dropwise to dioxane at 5° C.) at room temperature. The solution was transferred into a sealing tube into which 40 ml of isobutylene were condensed at −78° C. The sealed tube was then shaken at room temperature on a shaker for 24 hours. After the sealed tube had been opened (while cooling), the reaction mixture was cautiously introduced into a stirred mixture of 30 mL of triethylamine and 50 mL of water cooled to 0° C. After removal of excess isobutylene, the product was extracted with ether (2×50 mL). Drying of the ether phases over magnesium sulfate, filtration and removal of the solvent in vacuo resulted in the crude product (pale yellow oil), which was employed without further purification in the subsequent reaction. Yield 4.2 g (84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][S:10](Cl)(=[O:12])=[O:11].[Cl-].[CH:15]1([O:21][C:22]([C:24]2[N:25]=[C:26]([CH:29]3[CH2:34][CH2:33][NH2+:32][CH2:31][CH2:30]3)[S:27][CH:28]=2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C.O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][S:10]([N:32]1[CH2:31][CH2:30][CH:29]([C:26]2[S:27][CH:28]=[C:24]([C:22]([O:21][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:23])[N:25]=2)[CH2:34][CH2:33]1)(=[O:12])=[O:11]
Reactant: O=C(OC1CCCCC1)c1csc(C2CC[NH2+]CC2)n1
Reactant: O=S(=O)(Cl)Cc1cc(F)ccc1F
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OC1CCCCC1)c1csc(C2CCN(S(=O)(=O)Cc3cc(F)ccc3F)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, (2,5-difluorophenyl)methanesulphonyl chloride (226 mg) is added to a solution of 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (VII-1, 330 mg) and triethylamine (303 mg) in dichloromethane (5 ml). The mixture is stirred at room temperature overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate, and the combined organic phases are then dried with sodium sulphate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives cyclohexyl 2-{1-[(2,5-difluorobenzyl)sulphonyl]piperidin-4-yl}-1,3-thiazole-4-carboxylate (156 mg, 32%).
Reaction SMILES: P(OCC)(OCC)OCC.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:21](O)[C:22]=2[CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=1>CN(C=O)C.C(OCC)(=O)C>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:19]=[C:20]([C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[NH:21][C:22]=2[CH2:23][CH2:24][CH3:25])=[CH:16][CH:17]=1
Reactant: CCCc1c(-c2ccc(Br)cc2)nc([C@@H]2CCCN2C(=O)OC(C)(C)C)n1O
Agent: CCOP(OCC)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1[nH]c([C@@H]2CCCN2C(=O)OC(C)(C)C)nc1-c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
The triethyl phosphite (0.9 mL, 5.33 mmol) was added to a solution of (S)-tert-butyl 2-(4-(4-bromophenyl)hydroxy-5-propyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (800 mg, 1.776 mmol) in DMF (2 mL) and stirred for 18 hours at 80° C. Add second 0.8 mL and the reaction was continued an additional 8 hours, cooled, and taken up in ethyl acetate (400 mL) and washed with water and brine. Apply in CH2Cl2 to a 25 (M) Biotage silica gel column. Gradient elution, 15-100%, over 750 mL (A=Hexanes; B=ethyl acetate) gave (S)-tert-butyl 2-(4-(4-bromophenyl)-5-propyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate 585 mg (76%). 1H NMR (500 MHz, DMSO-d6) δ 7.55-7.53 (m, 4H), 4.80-4.69 (m, 1H), 3.53-3.51 (m, 1H), 3.38-3.32 (m, 1H), 2.71 (t, J=7.0 Hz, 2H), 2.24-2.11 (m, 1H), 2.0-1.79 (m, 1H), 1.89-1.79 (m, 2H), 1.63-1.59 (m, 2H), 1.41/1.17 (s, 9H). 0.91 (t, J=7.6 Hz, 3H). RT=1.8 min, (Condition 1) LRMS: Anal. Calcd. for C21H28BrN3O2 434.14. found: 434.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4]C.[I:6][CH2:7][CH2:8][OH:9].[C:10](=O)([O-])[O-].[K+].[K+]>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]([O:9][CH2:8][CH2:7][I:6])([CH3:4])[CH3:10]
Reactant: CC=COC
Reactant: OCCI
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(C)(C)OCCI
Reaction time: 1 h

Procedure:
To 6 mls of cold (0° C.) methoxypropene was added 3 mls of 2-iodoethanol and 1 drop of phosphorous oxychloride (POCl3). The reaction was stirred for 1 hour and then solid potassium carbonate was added. After 10 minutes the liquid was decanted and was concentrated to obtain the product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[NH:12][NH:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>ClCCl>[CH2:23]([NH:25][C:26]([N:13]1[CH2:14][CH2:15][N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]2[NH:12]1)=[O:27])[CH3:24]
Reactant: Fc1ccc(-c2nn3c(c2-c2ccncc2)NNCC3)cc1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)N1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A mixture of 7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (118 mg) and ethyl isocyanate (30 mg) in dichloromethane (2 ml) was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo and the residue was crystallized from ethyl acetate to give 2-ethylcarbamoyl-7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (120 mg).