Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][CH2:25][C:24](=O)[C:23]=3[CH:28]=2)[CH:16]=[CH:17][CH:18]=1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=1)[O:33][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].C([BH3-])#N.[Na+]>CO>[F:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][CH2:25][CH:24]([NH:29][C:30]4[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=4)[O:33][CH2:34][C:35]([O:37][CH:38]([CH3:39])[CH3:40])=[O:36])[C:23]=3[CH:28]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)OC(=O)COc1cccc(N)c1
Reactant: O=C1COc2ccc(-c3cccc(F)c3)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)OC(=O)COc1cccc(NC2COc3ccc(-c4cccc(F)c4)cc32)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 5.6 %

Procedure:
Para-toluenesulfonic acid (76 mg, 0.43 mmol) was added to a solution of 5-(3-fluorophenyl)benzofuran-3(2H)-one (212 mg, 0.935 mmol) and isopropyl 2-(3-aminophenoxyl)acetate (202 mg, 0.964 mmol) in methanol (4 mL) at 25° C. The reaction was heated in an 80° C. oil bath and allowed to stir overnight for approximately 16 hours. The reaction was cooled to room temperature and concentrated in vacuo. The mixture was then dissolved in concentrated acetic acid (2 mL) and cooled to 0° C. Sodium cyanoborohydride (386 mg, 6.13 mmol) was added and the solution was stirred for 4 hours at room temperature. The reaction was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (12 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 22 mg (6%) of isopropyl 2-(3-((5-(3-fluorophenyl)-2,3-dihydrobenzofuran-3-yl)amino)phenoxy)acetate.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1.C(OCC)C.Cl>C(=O)=O.CO>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:7]([C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[OH:8])=[CH:14][CH:13]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Agent: O=C=O
Solvent: CCOCC
Solvent: CO
Product: N#Cc1ccc(C(O)c2ccc(Cl)cc2)cc1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a solution of 4-cyanobenzaldehyde (3.93 g) in tetrahydrofaran was added dropwise 1.0M 4-chlorophenylmagnesium bromide-diethylether (30 mL) under nitrogen gas atmosphere and cooling in dry ice/methanol bath and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added 10% HCl solution and the aqueous layer was extracted with ethyl acetate (×2). The organic layer was washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. To the resultant crude product was added diisopropyl ether and the resultant solid materials were collected by filtration to give (4-chlorophenyl)(4-cyanophenyl)methanol (6.98 g, yield: 96%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:12][CH:13]=3)[C:8]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1>>[CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:17][CH2:18][N:19]([C:23]([C:24]5[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=5)=[O:30])[CH2:20][CH2:21]4)=[CH:12][CH:13]=3)[C:8]2=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccnc1
Reactant: O=C1c2cc(N3CCNCC3)ccc2CN1C1CCCCC1
Product: O=C(c1cccnc1)N1CCN(c2ccc3c(c2)C(=O)N(C2CCCCC2)C3)CC1

Procedure:
In the same manner as in Example 35, the title compound was prepared from the compound obtained in step (e) of Example 1 and nicotinic acid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:23][CH2:24][CH3:25])[C:5]1S[C:7]([Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=1)[CH3:2].C([O:28]C(OCC)C1OC=CC=1)C>>[CH2:1]([O:3][CH:4]([O:23][CH2:24][CH3:25])[C:5]1[O:28][C:7]([Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(OCC)c1ccco1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(OCC)OCC)s1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C(OCC)OCC)o1
Yield: 82 %

Procedure:
Following the procedure for preparing 2-(diethoxymethyl)-5-(tributylstannyl)-thiophene as described in step (1) of Example 1, 17 g (10 mmol) of 2-(diethoxymethyl)furan was converted to 32.6 g (82% yield) of 2-(diethoxymethyl)-5-(tributylstannyl) furan (bp 110° C., 1 torr).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)(=O)=O.O.[C-:21]#[N:22].[Na+]>C(O)C>[C:21]([CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)#[N:22]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CC#N)CC1
Reaction time: 24 h
Yield: 58.7 %

Procedure:
tert-Butyl 4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (15.3 g) was dissolved in ethanol (80 mL), water (20 mL) and sodium cyanide (4.0 g, 80 mmol) were added, and stirring was conducted at 80° C. for 24 hours. Ethanol was distilled off, water and ethyl acetate were added, and then the resultant mixture was subject to Celite filtration, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by using silica gel column chromatography (hexane:ethyl acetate=3:1→2:1) to give tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate (6.87 g, 77%, 3 steps) as a white solid.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[C:20](O)=[O:21])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[C:20](=[O:21])[N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: C1CCNCC1
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)N1CCCCC1)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 66 %

Procedure:
The title compound (37 mg, 66%) was prepared from (S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid and piperidine as in Example 1, Part C. HPLC: RT=11.00 min. MS (ESI−): mass calcd. for C27H24Cl3N5O4S2, 653.00; m/z found, 650/652 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.70 (m, 1H), 8.38 (d, J=7.0, 1H), 8.21 (d, J=8.8, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.69 (d, J=1.9, 1H), 7.35 (d, J=8.2, 1H), 7.28-7.25 (m, 1H), 7.22 (d, J=1.9, 1H), 7.13 (d, J=7.4, 1H), 6.99 (dd, J=8.2, 1.9, 1H), 6.92 (dd, J=8.4, 1.9, 1H), 5.26-5.21 (m, 1H), 3.62-3.49 (m, 2H), 3.43-3.35 (m, 1H), 3.26-3.19 (m, 1H), 3.08-2.95 (m, 2H), 1.70-1.46 (m, 5H), 1.33-1.23 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:25]([C:26]2[NH:27][CH:28]=[C:29]([CH3:31])[N:30]=2)=[CH:24][N:23]=[C:22]([NH:32][CH2:33][CH2:34][NH:35]C2N=CC(C#N)=CC=2)[N:21]=1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:35][CH2:34][CH2:33][NH:32][C:22]2[N:21]=[C:20]([C:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=3[Cl:12])[C:25]([C:26]3[NH:27][CH:28]=[C:29]([CH3:31])[N:30]=3)=[CH:24][N:23]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(Cl)cc2Cl)n1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Product: Cc1c[nH]c(-c2cnc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc2-c2ccc(Cl)cc2Cl)n1

Procedure:
{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amine was prepared from 2-amino-6-chloro-3-nitropyridine using the general method for 6-[(2-{[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=1[N+:19]([O-])=O)#[N:2].[O-]S(S([O-])=O)=O.[Na+].[Na+]>ClCCl>[C:1]([C:3]1[C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=1[NH2:19])#[N:2]
Reactant: COc1cc([N+](=O)[O-])c(C#N)c(OCC(F)(F)F)c1OC
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(N)c(C#N)c(OCC(F)(F)F)c1OC

Procedure:
The subtitle compound was prepared from 2-cyano-4,5-dimethoxy-3-(2,2,2-trifluoroethoxy)nitrobenzene using Na2S2O4 following the procedure described in Example 10(f) (87%). Rf 0.27 (dichloromethane). MS m/z 294 (MNH4)+
Reaction SMILES: [CH:1]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[OH:11])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:14][O:15][CH2:16]Cl.O>CN(C)C=O>[CH:1]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:11][CH2:14][O:15][CH3:16])[CH2:2][CH2:3][CH2:4]1
Reactant: Oc1ccccc1C1CCC1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccccc1C1CCC1
Reaction time: 0.5 h

Procedure:
2-cyclobutylphenol (871 mg) was dissolved in N,N-dimethylformamide (5 mL), and 60% sodium hydride (1.30 g) was added to the solution at 0° C. After stirring the mixture for 30 minutes, chloromethyl methyl ether (2.1 mL) was added and the mixture was stirred for 14 hours. Water was added to the reaction solution, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1) to obtain the title compound (1.13 g) as a colorless oily substance.
Reaction SMILES: C(O)=[O:2].[CH:4](=[N:11][N:12]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:30][CH:29]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:18][CH:17]=1)=[O:14])C1C=CC=CC=1>O1CCCC1.C(O)C.[OH-].[Pd+2].[OH-]>[CH:4]([NH:11][N:12]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:30][CH:29]=1)[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=1)=[O:14])=[O:2]
Reactant: O=CO
Reactant: CN(C)CCOc1ccc(NC(=O)N(N=Cc2ccccc2)c2ccc(Oc3ccccc3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)CCOc1ccc(NC(=O)N(NC=O)c2ccc(Oc3ccccc3)cc2)cc1

Procedure:
Palladium(II) hydroxide (60 mg) and formic acid (4.6 g) were added to a solution of 1-benzylidene-2-(4-phenoxyphenyl)-4-[4-(2-dimethylamino-ethoxy)phenyl]semicarbazide (600 mg) in tetrahydrofuran/ethanol (1:1, 30 mL). The mixture was heated under reflux for five hours and then filtered. The filtrate was concentrated and the residue was purified by HPLC. The product with the molecular weight of 434.50 (C24H26N4O4); MS (ESI): 435 ([M+H]+), was obtained in this way.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:36])[S:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[S:18][C:17]([NH:19][C:20]([N:22]([CH:29]3[CH2:34][CH2:33][CH:32]([CH3:35])[CH2:31][CH2:30]3)[CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:21])=[N:16][CH:15]=2)[CH2:9][CH2:8]1)(=[O:6])=[O:5].[CH:37]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH3:2][N:3]([CH3:36])[S:4]([N:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[S:18][C:17]([NH:19][C:20]([N:22]([CH:23]3[CH2:28][CH2:27][N:26]([C:42]([CH:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[O:43])[CH2:25][CH2:24]3)[CH:29]3[CH2:30][CH2:31][CH:32]([CH3:35])[CH2:33][CH2:34]3)=[O:21])=[N:16][CH:15]=2)[CH2:11][CH2:12]1)(=[O:5])=[O:6]
Reactant: O=C(Cl)C1CCCC1
Reactant: CC1CCC(N(C(=O)Nc2ncc(CN3CCN(S(=O)(=O)N(C)C)CC3)s2)C2CCNCC2)CC1
Agent: Cl
Product: CC1CCC(N(C(=O)Nc2ncc(CN3CCN(S(=O)(=O)N(C)C)CC3)s2)C2CCN(C(=O)C3CCCC3)CC2)CC1
Yield: 49.2 %

Procedure:
Prepared as described in general procedure (N) using 4-{2-[3-(4-methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylmethyl}-piperazine-1-sulfonic acid dimethylamide hydrochloride (50 mg, 0.088 mmol), TEA (31 μL, 0.22 mmol) and cyclopentane carbonyl chloride (13 μL, 0.11 mmol) to afford 27 mg (49%) of the desired product after purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][NH2:6].[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][NH:6][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C1CCCC1
Reactant: COC(=O)C(C)(C)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(C)(C)CNC1CCCC1
Reaction time: 22 h
Yield: 95.5 %

Procedure:
To a solution of 21.98 g (0.167 mole) of 3-amino-2,2-dimethyl-propanoic acid methyl ester (from method 6) in 500 mL of dichloromethane cooled to 0 degrees, was added 14.1 g (0.167 mole) of cyclopentanone, 16.0 g (0.181 mole) of sodium acetate and 52.0 g (0.025 mole) of sodium triacetoxyborohydride. The mixture stirred at room temp. for 22 hours, and then quenched by the addition of 500 mL of saturated sodium bicarbonate solution. The mixture was stirred for 1 hour and then extracted twice 400 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 31.8 g of 3-cyclopentylamino-2,2-dimethyl-propanoic acid methyl ester which was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH2:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1)=[O:2].[OH-].[Na+]>CO>[CH:1]([C:3]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH2:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)=[O:2]
Reactant: CCOC(=O)c1ccc(COc2cccc(O)c2C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=Cc1c(O)cccc1OCc1ccc(C(=O)O)cc1

Procedure:
The product from step (B) (7.9 g) was suspended in methanol (90 ml) and stirred with 1 N sodium hydroxide solution (90 ml) for 2.5 hours. The resulting dark solution was evaporated to half volume and then diluted with water (160 ml) and acidified with concentrated hydrochloric acid, with cooling in an ice bath. The precipitated product was collected by filtration, washed with water (200 ml), sucked dry and recrystallised from aqueous dimethylformamide. The title compound was isolated as yellow crystals after drying in vacuo at 60° C. m.p. 240°-242° C. (sinters at ~225° C.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:20]=2[CH3:21])=[O:15])[CH2:9][C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:32])=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:20]=2[CH3:21])=[O:15])[CH2:9][C:10]([Cl:32])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)NC(CC(=O)O)c2cccc(Br)c2)cnn1-c1ccc(Cl)c(Cl)c1
Product: Cc1c(C(=O)NC(CC(=O)Cl)c2cccc(Br)c2)cnn1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 3-(3-bromo-phenyl)-3-{[1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-amino}-propionic acid (870 mg, 1.8 mmol) in thionyl chloride (40 mL) is heated at reflux for 1 hour. After cooling to room temperature, the reaction mixture is concentrated in vacuo to afford 3-(3-bromo-phenyl)-3-{[1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-amino}-propionyl chloride as an off-white solid (880 mg, 98%) which is used without further purification.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:4].I[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C1COCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:4][C@@H:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH2:2][CH2:1][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1
Reactant: Nc1ccc(I)cc1
Reactant: CC(C)=CCCC(C)CC[Mg]Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: CC(C)=CCC[C@H](C)CCc1ccc(N)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 905.5 %

Procedure:
Citronellylmagnesium bromide [from S-citronellylbromide (14.46 g, 66 mmol) and magnesium (3.20 g, 132 mmol)] in THF (80 mL) was added to a suspension of 4-iodoaniline (4.38 g, 20 mmol) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (PdCl2(dppf), 0.150 g, 0.2 mmol) in THF (25 mL) maintained at −78° C. under a nitrogen atmosphere. After stirring for 10 minutes at −78° C., the reaction mixture was heated under reflux for 16 hours and then quenched with 5% hydrochloric acid (HCl). The aqueous solution was then extracted with ether (3×30 mL) and the combined fractions were washed with water, dried over magnesium sulfate (MgSO4), and the solvent was evaporated to give 4-[(3S)-3,7-dimethyl-6-octenyl]aniline as a dark oil (41.9 g) which was used in the next step without additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][N:5]2[C:9]([CH:10]=1)=[C:8]([C:11]([OH:13])=O)[C:7]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[CH3:22])=[C:6]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([C:11]([C:8]2[C:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=3[CH3:22])=[C:6]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:5]3[C:9]=2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4]3)=[O:13])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1c(F)cccc1Cc1c(C(=O)O)c2cc(Br)ccn2c1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1c(F)cccc1Cc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2cc(Br)ccn2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of the crude compound obtained in step 2 (219 mg, 0.50 mmol), 1-tert-butoxycarbonyl-piperazine (98 mg, 0.55 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (105 mg, 0.55 mmol) and 1-hydroxybenzotriazole (88 mg, 0.58 mmol) in DMF (5 ml) was added N-methyl-morpholine (330 μl, 3.00 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (HEP/EA). 300 mg of the title compound were obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:12]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C1CCCCCN1
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCCCN1CCCCCC1=O
Yield: 85.4 %

Procedure:
Following example 10, from 10.2 g of 50% sodium hydride-mineral oil dispersion (5.1 g NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-one and 33 g (0.2 M) of 1-bromohexane on 19 hr. reflux was obtained 29.8 g (85.3%) of colorless product; b.p. 122°-128°/0.4 mm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CS(O[CH2:27][CH2:28][C@H:29]([F:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=O)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:27][CH2:28][C@H:29]([F:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:19][CH:20]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC[C@@H](F)CCOS(C)(=O)=O
Reactant: CCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCCCOc1cnc(-c2ccc(OCC[C@H](F)CCCCC)cc2)nc1
Yield: 57 %

Procedure:
The titled compound was synthesized from 5-heptyloxy-2-(4-hydroxyphenyl)pyrimidine and (R)-3-fluorooctyl methanesulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][Si:32]([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:34])[CH3:33])[CH2:6][CH2:5]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCc2cc(Br)ccc21
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1CCc2cc(Br)ccc21
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2,3-dihydro-1H-inden-1-ol (1 g, 4.69 mmol), triethylamine (1.44 mL, 10.3 mmol) and dimethylaminopyridine (0.12 g, 0.94 mmol) in DCM (20 mL) at 0° C. was added TBSCl (1.56 g, 5.16 mmol). The reaction mixture was allowed to reach room temperature overnight, and then was quenched with a saturated solution of sodium bicarbonate (20 mL). The phases were separated and the aqueous layer was extracted twice with DCM (2×20 mL). The organics layers were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified on silica eluting with Et2O and pentane to afford the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[N+:31]([O-])=O)=[CH:21][CH:20]=3)=[C:7]3[N:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[C:11]([CH3:12])[N:6]3[N:5]=2)[CH2:3][CH2:2]1.[H][H]>[Ni].CO.C1COCC1>[CH:1]1([C:4]2[C:17]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[NH2:31])=[CH:23][CH:24]=3)=[C:7]3[N:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[C:11]([CH3:12])[N:6]3[N:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(C)n2nc(C3CC3)c(Cc3ccc(-c4ccccc4[N+](=O)[O-])cc3)c2n1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)n2nc(C3CC3)c(Cc3ccc(-c4ccccc4N)cc3)c2n1
Yield: 168.7 %

Procedure:
A solution/suspension of 1.59 g methyl 2-cyclopropyl-7-methyl-3-[(2'-nitrobiphen-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxylate and/0.5 g Raney Nickel in 30 mL methanol and 150 mL THF was stirred under 1 atm hydrogen for 2.5 hours. The mixture was filtered through Celite, stripped of solvent in vacuo, then was chromatographed on silica gel under medium pressure using 10% ethyl acetate in hexanes to give 2.50 g (17% yield) of the title compound as a light yellow crystalline solid. Rf 0.24 in 20% EtOAc/hexanes, visualized by UV, iodine, and ammonium molybdate/ceric sulfate stain.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([CH3:11])[C:3]=1[N+:12]([O-])=O.[H][H]>CO.[Pd]>[NH2:12][C:3]1[C:4]([CH3:11])=[CH:5][C:6]2[N:7]=[CH:8][NH:9][C:10]=2[C:2]=1[CH3:1]
Reactant: Cc1cc2nc[nH]c2c(C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc2nc[nH]c2c(C)c1N

Procedure:
A heterogeneous mixture of 4,6-dimethyl-5-nitrobenzimidazole (410 mg, 2.14 mmol) and 10% palladium-on-carbon (50 mg) in methanol (25 mL) is treated with an atmosphere of hydrogen (1 atm, balloon) for 16 hours. The resulting mixture is filtered through Celite and rotary evaporated. The residue is purified by chromatography on silica gel (95:5 methylene chloride:methanol) to afford 5-amino-4,6-dimethylbenzimidazole as a white solid.