Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[NH:4][N:3]=1.[CH2:11](I)[CH3:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH2:11][CH3:12])[N:3]=1
Reactant: CCI
Reactant: Brc1n[nH]c2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(Br)c2ncccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 3-bromo-1H-pyrazolo[4,3-b]pyridine (2.22 g), EtI (1.08 mL), and K2CO3 (2.32 g) in DMF (15 mL) was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue purified by basic silica gel column chromatography (hexane/AcOEt) and crystallized from hexane/AcOEt to give the title compound (1.90 g).
Reaction SMILES: [NH2:1][CH2:2][C@@:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[O:27]1[C:35]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]1[N:36]=[C:37](SC)SC>CN(C=O)C>[O:27]1[C:35]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]1[NH:36][C:37]1[O:11][C@:3]2([CH2:2][N:1]=1)[CH:8]1[CH2:7][CH2:6][N:5]([CH2:10][CH2:9]1)[CH2:4]2
Reactant: CSC(=Nc1nc2ncccc2o1)SC
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A 10 ml vial was charged with (S)-3-(aminomethyl)quinuclidin-3-ol.2HCl salt (8.53 mg, 0.044 mmol), DMF (2 ml), DIEA (7.74 μL, 0.04 mmol) and Cs2CO3 (28.9 mg, 0.089 mmol) at room temperature, followed by dimethyl oxazolo[4,5-b]pyridin-2-ylcarbonimidodithioate (10.6 mg, 0.044 mmol). The resulting suspension was stirred at room temperature for 1 hr. LC/MS indicated complete consumption of starting material. The reaction mixture was diluted with MeOH and purified via preparative HPLC to afford the expected product, (R)—N-(oxazolo[4,5-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (13 mg, 0.038 mmol, 86% yield), as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 1.54-1.60 (m, 1H) 1.71-1.77 (m, 2H) 2.16-2.24 (m, 1H) 2.77-2.82 (m, 2H) 2.89 (t, J=7.91 Hz, 4H) 3.13-3.25 (m, 2H) 3.90 (d, J=10.29 Hz, 1H) 4.22 (d, J=10.29 Hz, 1H) 7.13 (dd, J=8.03, 5.02 Hz, 1H) 7.70 (dd, J=7.91, 1.13 Hz, 1H) 8.27 (dd, J=5.14, 1.13 Hz, 1H) 9.11 (br. s., 1H). MS (LC/MS) R.T.=0.443; [M+H]+=300.16.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Brc1cccnc1
Reactant: Cc1cc(NC(=O)c2nc(C)ccc2N)ccn1
Agent: [Pd]
Product: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccnc2)ccn1

Procedure:
The title compound was prepared from 3-tert-Butoxy-carbonylamino-6-methyl-pyridine-2-carboxylic acid methyl ester in accordance with the general method of example 4; step 2 using 2-methyl-4-aminopyridine (CAS: [18437-58-6]) instead of 2-chloro-4-aminopyridine to yield [2-(2-Methyl-pyridin-4-ylcarbamoyl)-6-methyl-pyridin-3-yl]-carbamic acid tert-butyl ester, MS (ISP): m/e=343.1 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide, MS (ISP): m/e=243.4 (M+H+). Palladium catalysed arylation with 3-Bromopyridine as described in example 4 step 4 yielded the final product as a light yellow solid, MS (ISP): m/e=320.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[N:33]1([C:39](=[S:41])[NH2:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.O>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:41][C:39]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:40][C:9]=2[C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1F
Reactant: NC(=S)N1CCOCC1
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=CCOC(=O)Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (20 g, 57 mmol) (Intermediate 20) in DMA (300 mL), NBS (10.2 g, 57 mmol) was added. The reaction mixture was stirred at rt for 1 h. Then morpholine-4-carbothioamide (9.2 g, 63 mmol) was added at 0° C. The mixture was stirred at rt for 2 h. The mixture was poured into water and extracted with EtOAc (1 L×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the title compound (20 g, 83.5% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.20-8.27 (m, 1H), 8.19 (d, J=5.5 Hz, 1H), 7.20-7.26 (m, 1H), 7.08-7.12 (m, 1H), 6.92-6.98 (br, 1H), 6.62 (d, J=5.5 Hz, 1H), 5.90-6.03 (m, 1H), 5.25-5.41 (m, 2H), 5.65-5.70 (m, 2H), 3.57-3.63 (m, 4H), 3.77-3.86 (m, 4H). m/z (ES+): 476 [M+H]+
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4](=[O:6])[CH3:5].[Br:9]Br.C(=O)(O)[O-].[Na+]>CO.C(#N)C.C(#N)C>[Br:9][CH2:5][C:4](=[O:6])[CH:3]([O:7][CH3:8])[O:2][CH3:1]
Reactant: COC(OC)C(C)=O
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COC(OC)C(=O)CBr
Yield: 70.4 %

Procedure:
A solution of 1,1-bis(methyloxy)-2-propanone (40.1 mL, 339 mmol) in 5% (v/v) methanol/acetonitrile (200 mL) was cooled to <5° C. while stirring. A 1 mL portion of a solution of bromine (17.44 mL, 339 mmol) in acetonitrile (30 mL) was added and the mixture was stirred until the solution was decolorized. The remainder of the bromine solution was added to the reaction mixture over 6-8 hrs while maintaining an internal temperature of <10° C. The mixture was stirred at RT overnight. Sodium bicarbonate (30.2 g, 360 mmol) was added and the mixture was stirred for 1 hr, then filtered. The filtrate was concentrated and t-butyl methyl ether (30 mL) and heptane (15 mL) were added. The mixture was washed with aqueous sodium bicarbonate (6.0 g in 60 mL water) and the organic layer was dried over sodium sulfate. The solvent was evaporated to give the title compound (47.03 g, 70%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 4.64 (s, 1H), 4.13 (s, 2H), 3.35 (s, 6H).
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[CH:15]=[CH:14]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[K+].C(O)CCC.[CH2:35](Br)[CH2:36][CH2:37][CH2:38][CH3:39]>O>[CH2:1]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:22]=1)[CH:15]=[CH:14]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCBr
Reactant: CCCCCCCCCCc1ccc2nc(-c3ccc(O)cc3)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCCCc1ccc2nc(-c3ccc(OCCCCC)cc3)ccc2c1
Yield: 83.8 %

Procedure:
To a solution 0.8 g of 6-decyl-2-(4-hydroxyphenyl)quinoline and 170 mg potassium hydroxide in i2 ml of butanol, 0.5 g of pentyl bromide was added, followed by heat refluxing for 4 hours. After the reaction, the reaction mixture was poured into water and subjected to extraction with toluene. The organic layer was washed with water, dried with anhydrous sodium sulfate and subjected to distilling-off of the solvent, followed by purification by silica gel column chromatography and recrystallization to obtain 0.8 g of 6-decyl-2-(4-pentyloxyphenyl)quinoline. This compound showed the following phase transition series.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:13]([O-])=O)=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]>C1(C)C=CC=CC=1.[Pt]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=1[NH2:13]
Reactant: COC(=O)c1cccc(OC)c1[N+](=O)[O-]
Agent: [Pt]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(OC)c1N

Procedure:
One hundred thirty-three grams (0.63 mol) of methyl 3-methoxy-2-nitro-benzoate are dissolved in 1000 ml of toluene and hydrogenated in an autoclave at ambient temperature and under a hydrogen pressure of 5 bar in the presence of platinum over a period of two hours. The catalyst is removed by filtration, the residue is dried with sodium sulfate, and the toluene is distilled off in vacuo. Oil, RF value: 0.8 [silica gel plate; chloroform/acetone (9:1)],
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:13](=[O:21])[NH:12][C:11]=3[N:10]([CH3:22])[N:9]=2)[CH2:4][CH2:3]1.C=O.[C:25](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH3:25][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:13](=[O:21])[NH:12][C:11]=3[N:10]([CH3:22])[N:9]=2)[CH2:6][CH2:7]1
Reactant: Cn1nc(C2CCNCC2)c2c3ccccc3c(=O)[nH]c21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN1CCC(c2nn(C)c3[nH]c(=O)c4ccccc4c23)CC1
Reaction time: 1 h
Yield: 54.9 %

Procedure:
1-(Piperidin-4-yl)-3-methyl-pyrazolo[3,4-c]isoquinolin-5(4H)-one hydrochloride (1.0 g) obtained in Example 227 and 35% aqueous formalin solution (0.53 g) were suspended in water (20 mL), and sodium triacetoxyborohydride (1.3 g) was added at room temperature, and the mixture was stirred for 1 hr. After the completion of the reaction, the solvent was evaporated, and aqueous potassium carbonate solution was added to the obtained residue. The mixture was extracted with a mixed solvent (chloroform:methanol=10:1), and the organic layer was dried over magnesium sulfate. The solvent was evaporated, and ethanol was added to the precipitated crystals. The precipitated crystals was collected by filtration and washed with ethyl acetate to give 1-(1-methylpiperidin-4-yl)-3-methyl-pyrazolo[3,4-c]isoquinolin-5(4H)-one (0.51 g) as pale-brown crystals.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:33]2[CH2:34][CH2:35][N:30]([C:24]3[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=3[CH3:22])[CH2:31][CH2:32]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(C)cc4C)CC3)nn2C(C)(C)C)cc1

Procedure:
109 mg (74%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(2,4-dimethylphenyl)piperazine (57 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:7](=[O:10])([O-])[O-:8].[K+].[K+].[Br-].[K+]>CC(C)=O>[OH:8][C@@:7]1([O:10][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:5][CH:4]=[C:3]2[C:3]([CH:4]=[CH:5][CH:6]=[CH:2]2)=[C:2]1[C:4]1[C:5]2[C:3](=[CH:4][CH:5]=[CH:6][CH:6]=2)[CH:2]=[CH:2][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCCCCI
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCO[C@]1(O)CC=c2ccccc2=C1c1cccc2ccccc12
Temperature: 45 °C

Procedure:
The compounds (R)-(+)-2-hydroxy-2-pentoxy-1,1'-binaphthalene and (R)-(+)-2,2'-dipentoxy-1,1'-binaphthalene were prepared as follows. 1 g (3.49 mmol) (R)-(+)-2,2'-dihydroxy-1,1'-binaphthalene and 0.99 g (5 mmol) iodopentane were dissolved in 40 ml acetone while stirring. 6.99 g of potassium carbonate and 7.99 g (57.9 mmol) potassium bromide was added in one portion. After 24 hours stirring at room temperature, 1 g potassium carbonate was added. The reaction mixture was heated to 45° C. for 30 minutes. The excess potassium carbonate and potassium bromide were filtered and the solvent of the filtrate was removed with a rotavap. The crude product was purified by flash column with silica gel and dichloromethane as the eluent to obtain 370 mg of product consisting of 25% of the monosubstituted product and 56% of the disubstituted product.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([NH:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:19])=[O:18])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[S:3].Cl[CH:35](OC(Cl)CCl)[CH2:36]Cl.C(O)(C)C>O>[C:28]1([CH:21]([NH:20][S:17]([C:13]2[CH:12]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][C:2]4[S:3][CH:35]=[CH:36][N:1]=4)[CH:6]=3)[CH:16]=[CH:15][CH:14]=2)(=[O:18])=[O:19])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(NC(N)=S)c2)c1)c1ccccc1
Reactant: ClCC(Cl)OC(Cl)CCl
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(Nc3nccs3)c2)c1)c1ccccc1
Reaction time: 1 h
Yield: 60.9 %

Procedure:
0.97 g of Ethyl 3-[({3′-[(aminocarbothioyl)amino][1,1′-biphenyl]-3-yl}sulfonyl)-amino]-3-phenyl-propanoate 14.1.1 and 0.48 g of 1,2-dichloroethylether were heated in water and i-propanol was added such that a clear solution resulted. After 1 h an additional 100 mg of 1,2 dichloroethylether were added and reflux was continued for 1 h. After aqueous work-up and flash chromatography, 0.62 g of the title compound resulted.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][C:24]([CH3:31])=[C:25]([CH2:27][CH2:28][CH2:29][OH:30])[N:26]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].C(N(CC)CC)C>ClCCl>[CH3:6][S:7]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][C:24]([CH3:31])=[C:25]([CH2:27][CH2:28][CH2:29][O:30][S:2]([CH3:1])(=[O:4])=[O:3])[N:26]=3)=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)(=[O:8])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
Add methanesulfonyl chloride (0.086 g, 0.60 mmol) to a cool (0° C.) solution of 3-[2-(4′-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-propan-1-ol (0.170 g, 0.458 mmol) and triethylamine (0.070 g, 0.69 mmol) in dichloromethane (3 mL). Warm the reaction mixture to room temperature and stir for 1 hour. Add dichloromethane and wash the crude organic material with saturated sodium chloride solution. Dry the organic extracts over Na2SO4, filter, and concentrate to give crude methanesulfonic acid 3-[2-(4′-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-propyl ester (0.206 g, 100%): MS (m/e): 450(M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:18])[N:3]=1.O.[NH2:20][NH2:21]>O1CCCC1>[Cl:18][C:4]1[CH:5]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:7]=[C:2]([NH:20][NH2:21])[N:3]=1
Reactant: COc1ccc(CNc2cc(Cl)nc(Cl)n2)cc1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNc2cc(Cl)nc(NN)n2)cc1

Procedure:
A 5.57 g portion of 2,6-dichloro-4-(4-methoxybenzyl)aminopyrimidine was suspended in 20 ml of tetrahydrofuran, mixed with 3.0 ml of hydrazine monohydrate and heated under reflux for 24 hours. After evaporation of the solvent under a reduced pressure, water was added to the residue and the resulting precipitate was collected by filtration to obtain 5.06 g of 4-chloro-2-hydrazino-6-(4-methoxybenzyl)aminopyrimidine as a white solid. This was suspended in 150 ml of ethanol and mixed with 3.37 g of ethoxymethyleneacetoacetic acid ethyl ester at room temperature, and the mixture was stirred for 1 hour and then heated under reflux for 15 hours. By concentrating the reaction solution to dryness under a reduced pressure, 7.22 g of the title compound was obtained as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CCN(CC)CC.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]1([S:22]([NH:5][C:4]2[CH:3]=[C:2]([I:1])[CH:8]=[CH:7][CH:6]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccc(I)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(I)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of 3-iodoaniline (5 g, 22.8 mmol), in CH2Cl2 (100 mL), were added at room temperature Et3N (6.97 mL) followed by benzenesulfonyl chloride (5.84 mL). The mixture was stirred 4 h then a white precipitate was formed. A saturated aqueous solution of NaHCO3 was added and the phases were separated. The aqueous layer was extracted several times with CH2Cl2 and the combined extracts were dried over (MgSO4) then evaporated. The crude mixture was dissolved in MeOH (100 mL) and NaOMe (6 g), was added and the mixture was heated 1 h at 60° C. The solution became clear with time and HCl (1N) was added. The solvent was evaporated under reduced pressure then the aqueous phase was extracted several times with CH2Cl2. The combined organic extracts were dried over (MgSO4) and evaporated. The crude material was purified by flash chromatography using (100% CH2Cl2) as solvent yielding the title compound 21 (7.68 g, 94%) as yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ncccc1Br
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ncccc1Br
Temperature: 80 °C

Procedure:
3-Bromopyridin-2-amine (500 mg, 2.89 mmol) and pivaloyl chloride (420 mg, 3.48 mmol) were added to a 50 mL round-bottomed flask. Pyridine (10 mL) was then added and the mixture stirred and heated at 80° C. for 4 h. The reaction was then cooled to rt and stirred overnight. The reaction mixture was then concentrated to dryness and the resultant residue subjected to FCC to provide the title compound. MS (ESI): mass calcd. for C10H13BrN2O, 256.02; m/z found, 257.1 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:48]1[CH:53]=[CH:52][C:51]([CH:54]([CH3:73])[C:55]([C:61]2[CH:62]=[CH:63][C:64]3[O:69][CH2:68][C:67](=[O:70])[N:66]([CH3:71])[C:65]=3[CH:72]=2)([OH:60])[C:56]([F:59])([F:58])[F:57])=[C:50]([Cl:74])[CH:49]=1.[NH:75]1[CH2:80][CH2:79][CH:78]([C:81]([O:83][CH2:84][CH3:85])=[O:82])[CH2:77][CH2:76]1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:84]([O:83][C:81]([CH:78]1[CH2:79][CH2:80][N:75]([C:48]2[CH:53]=[CH:52][C:51]([CH:54]([CH3:73])[C:55]([OH:60])([C:61]3[CH:62]=[CH:63][C:64]4[O:69][CH2:68][C:67](=[O:70])[N:66]([CH3:71])[C:65]=4[CH:72]=3)[C:56]([F:59])([F:58])[F:57])=[C:50]([Cl:74])[CH:49]=2)[CH2:76][CH2:77]1)=[O:82])[CH3:85]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.2 %

Procedure:
To a suspension of 2,2′-bis(diphenylphosphino)-1,1′binaphthyl (3.1 mg), tris(dibenzylideneacetone)dipalladium (0) (1.5 mg) and sodium-tert.-butylate (19 mg) in toluene (15 ml) were added 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3, 80 mg) and ethyl piperidine-4-carboxylate (29 mg). The mixture was stirred at room temperature overnight. 2,2′-Bis(diphenylphosphino)-1,1′binaphthyl (3.1 mg), ethyl piperidine-4-carboxylate (29 mg) and tris(dibenzylideneacetone)dipalladium (0) (1.5 mg) were added and the mixture was stirred at 80° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc. The organic phase was washed with water, dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>4:1) to give the title compound (3 mg) as light yellow oil. MS (m/e)=555.3 [M+H+].
Reaction SMILES: [CH3:1][CH:2]([CH:5]=[CH2:6])[CH2:3][OH:4].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1>CCOCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][CH:2]([CH2:3][O:4][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)[CH:5]=[CH2:6]
Reactant: C=CC(C)CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: C=CC(C)COC1CCCCO1
Yield: 75.3 %

Procedure:
To a suspension of magnesium turnings (50.4 g, 2.1 m) in ether (1500 ml) under a nitrogen atmosphere is added a solution of crotyl bromide (135.0 g, 1.0 m) in ether (125 ml), at room temperature over a period of four hours. The reaction mixture is then cooled to 0° C. and formaldehyde [formed by pyrolysis of paraformaldehyde (45.0 g, 0.5 ml)] is bubbled through the mixture. The resulting mixture is allowed to come to room temperature and stirred overnight. The reaction mixture is then decanted into a solution of ammonium chloride (212 g, 4.0 m) in ice water (2 l). The mixture is extracted with ether (2×3000 ml) and the combined ether extracts are dried (Na2SO4) and filtered. The solvent is removed in vacuo to give 57.2 g of 2-methyl-3-buten-1-ol (66%); nmr (CDCl3,δ): 0.99 (d, J=7 Hz, 3H, ##STR18## 2.10-2.70 (m, 1H, ##STR19## 3.30-3.60 (bd, J=6 Hz, 2H, ##STR20## 4.83-6.13 (m, 3H, vinyl protons); ir(neat): 3257, 1640 cm-1. (b) A solution of 2-methyl-3-buten-1-ol (54.16 g, 0.63 m), dihydropyran (52.92 g, 0.63 m), and p-toluenesulfonic acid (0.5 g) in ether (800 ml) is stirred at room temperature under a nitrogen atmosphere overnight. The reaction mixture is then diluted with ether (1 l) and washed with 5% sodium bicarbonate solution (1 l). The ether extract is dried (Na2SO4), filtered and solvent removed in vacuo to give 95.8 g of crude product. The crude product is purified by column chromatography on silica gel (500 g, hexane) to give (75%) 3-methyl-4-(tetrahydropyran-2-yloxy)-1-butene (80.62 g). ##STR21##