Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[O:16][CH:17]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[N:19]=3)[CH:6]=[CH:5][C:4]1=2.C([O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)(=O)C.[OH-].[Na+]>CO>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[O:16][CH:17]=[C:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:34][CH2:33][CH2:32][CH2:31][OH:30])[CH2:22][CH2:21]4)[N:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nc(C4CCNCC4)co3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3nc(C4CCN(CCCCO)CC4)co3)ccc21

Procedure:
The preparation was carried out as already described starting from 200 mg (0.32 mmol) of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxazol-4-yl]piperidine hydrochloride and 94 μl (0.64 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 2N NaOH solution in methanol. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([CH2:23][CH2:24][CH2:25][CH:26]([NH:36][C:37](=[O:41])[CH2:38][NH:39][CH3:40])[CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:17]1([CH2:23][CH2:24][CH2:25][CH:26]([NH:36][C:37](=[O:41])[CH2:38][N:39]([C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH3:40])[CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNCC(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.61 g; 2.66 mmol) is dissolved in methylene chloride (20 mL) at ambient temperature. N-methyl-2-aminoacetic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (66) (0.75 g; 2.22 mmol), N,N-diisopropylethylamine (0.63 g; 4.87 mmol) and PyBOP (1.38 g; 2.66 mmol) are added sequentially. The reaction is stirred for 14 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (60%→80% ethyl acetate in hexanes) affording the desired product (67) as a clear oil. CIMS: MH+ 550
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11].[H-].[Na+].[CH2:41]([O:44][P:45]([O:51][CH2:52][C:53]1[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][C:54]=1[C:55](Cl)=[O:56])([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[CH:42]=[CH2:43]>>[CH2:48]([O:47][P:45]([O:51][CH2:52][C:53]1[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][C:54]=1[C:55]([O:38][C@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11])=[O:56])([O:44][CH2:41][CH:42]=[CH2:43])=[O:46])[CH:49]=[CH2:50]
Reactant: C=CCOP(=O)(OCC=C)OCc1ccc(C)cc1C(=O)Cl
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Product: C=CCOP(=O)(OCC=C)OCc1ccc(C)cc1C(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Yield: 43 %

Procedure:
According to a similar procedure to that described in Example 4-(6), 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzoate (690 mg, 1.54 mmol) was treated with trifluoroacetic acid to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzoic acid as a crude product. According to a similar procedure to that described in Example 4-(6), the above product was treated with oxalyl chloride and N,N-dimethylformamide to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzoyl chloride as a crude product. According to a similar procedure to that described in Example 1-(12), 4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (670 mg, 1.23 mmol) described in Reference example 1 was treated with sodium hydride and then reacted with the crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzoyl chloride (the whole amount) obtained above to afford, after purification by column chromatography, the title compound (448 mg, 43% yield) as a pale yellow, candy-like material.
Reaction SMILES: [C@H:1]1([NH:9][C:10]([CH:12]([CH:45]([CH3:47])[CH3:46])[CH2:13][CH:14]([OH:44])[CH:15]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:16][CH:17]([CH2:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[CH:27][N:28]3[CH2:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:24][CH:23]=2)[CH:18]([CH3:20])[CH3:19])=[O:11])[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1.ClS([N:52]=[C:53]=O)(=O)=O.CN(C)C=O>ClCCl>[C:53]([C:26]1[C:25]2[C:29](=[CH:30][C:22]([CH2:21][CH:17]([CH:18]([CH3:19])[CH3:20])[CH2:16][CH:15]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:42])[CH3:41])[CH:14]([OH:44])[CH2:13][CH:12]([C:10](=[O:11])[NH:9][C@H:1]3[C:3]4([CH2:4][CH2:5][O:6][CH2:7][CH2:8]4)[CH2:2]3)[CH:45]([CH3:47])[CH3:46])=[CH:23][CH:24]=2)[N:28]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[CH:27]=1)#[N:52]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COCCCn1ccc2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CC(C(=O)N[C@@H]3CC34CCOCC4)C(C)C)C(C)C)cc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCCn1cc(C#N)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CC(C(=O)N[C@@H]3CC34CCOCC4)C(C)C)C(C)C)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1 mmol of tert-butyl (4-((R)-(6-oxaspiro[2.5]-oct-1-yl)carbamoyl)-2-hydroxy-1-(2-[1-(3-methoxypropyl)-1H-indol-6-ylmethyl]-3-methylbutyl)-5-methylhexyl)carbamate in 15 ml of dichloromethane is mixed with 1.5 mmol of chlorosulphonyl isocyanate and stirred at room temperature for 16 hours. 2 ml of N,N-dimethylformamide are added, and the reaction mixture is again stirred for 2 hours. It is quenched with water, and the suspension is vigorously stirred for 10 minutes. It is poured into 1M sodium bicarbonate solution and extracted with ethyl acetate (3×). The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. The title compound is identified by means of the Rf from the residue by flash chromatography (SiO2 60 F).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:19])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:19]
Reactant: CC=CCC1Cc2ccc(CC)cc2C1=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 0.67 h
Yield: 93 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 40 minutes while stirring through a solution, cooled to -70°, of 7.92 g of (RS)-2-(2-buten-1-yl)-6-ethyl-1-indanone in 150 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 3.36 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 150 ml of dichoromethane and, after the addition of 30 ml of water and 30 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 6.94 g (93%) of (RS)-2-(2-oxoethyl)-6-ethyl-indanone were obtained as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.C([Si]([O:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH:53]2[CH2:55][O:54]2)=[CH:47][CH:46]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:54][C@@H:53]([CH2:55][NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:12][CH2:13][N:14]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)(=[O:19])=[O:18])[CH2:15][CH2:16]2)=[CH:6][CH:5]=1)[CH2:52][O:51][C:48]1[CH:49]=[CH:50][C:45]([OH:44])=[CH:46][CH:47]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Product: Cc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 26.9 %

Procedure:
N-[4-(2-Aminoethyl)phenyl]-1-[(4-methylphenyl)sulfonyl]-4-piperidinamine (0.275 g, 0.65 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.251 g, 0.62 mmol) according to Procedure G to give the title compound (0.130 g, 0.167 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:57][N:58]([CH3:76])[C:59]([CH:61]1[CH2:65][CH2:64][N:63]([CH2:66][C:67]2[CH:72]=[CH:71][C:70]([CH2:73][NH:74][CH3:75])=[CH:69][CH:68]=2)[CH2:62]1)=[O:60]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:74]([CH2:73][C:70]3[CH:69]=[CH:68][C:67]([CH2:66][N:63]4[CH2:64][CH2:65][CH:61]([C:59]([N:58]([CH3:57])[CH3:76])=[O:60])[CH2:62]4)=[CH:72][CH:71]=3)[CH3:75])=[O:23])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CNCc1ccc(CN2CCC(C(=O)N(C)C)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(C(=O)N(C)C)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (40 mg, 0.11 mmol), EDCI (29 mg, 0.15 mmol), HOBt (22 mg, 0.16 mmol), DIPEA (0.04 mL, 0.22 mmol), N,N-dimethyl-1-{4-[(methylamino)methyl]benzyl}pyrrolidine-3-carboxamide dihydrochloride (42 mg, 0.13 mmol) and DCM (5 mL).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)[OH:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=1)[O:34][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[OH:27])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Oc1cccc(C(O)CCCCCOCc2ccccc2)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: OC(CCCCCOCc1ccccc1)c1cccc(OCc2ccc3ccccc3n2)c1
Yield: 24.3 %

Procedure:
2-Chloromethyl quinoline (3.6 g) was refluxed with 3-(6-benzyloxy-1-hydroxyhexyl)phenol (4.2 g), powdered potassium carbonate (8 g) and potassium iodide (0.2 g) in dry acetone (150 ml) overnight (16 hrs.). The suspension was filtered, the filtrate was concentrated in vacuo and then taken up in ethyl acetate. This solution was washed with 5% NaOH solution, water and brine and then dried. All solvent was removed to obtain the crude product which was purified by chromatography (silica gel; 30% ethyl acetate in hexanes). The pure compound was dissolved in ether, and was precipitated as the hydrochloride salt with a dry ethereal solution of HCl. The pure salt was filtered, washed with cold water, and dried in vacuo to yield a tan powder (1.5 g), mp 86°-89° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[O:5][CH2:4][C@@H:3]1[NH:10][C:11](=[O:19])[O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>ClCCl>[CH3:30][S:27]([O:1][C@@H:2]1[C@@H:3]([NH:10][C:11]([O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])=[O:19])[CH2:4][O:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)(=[O:29])=[O:28]
Reactant: CC1(C)C[C@H](O)[C@@H](NC(=O)OCC[Si](C)(C)C)CO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C[C@H](OS(C)(=O)=O)[C@@H](NC(=O)OCC[Si](C)(C)C)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 124.4 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl (3S,4S)-4-hydroxy-6,6-dimethyl-tetrahydro-2H-pyran-3-ylcarbamate (1.0 g, 3.5 mmol) and triethylamine (1.4 mL, 10 mmol) in dichloromethane (10 mL) at 0° C. was dropwise added mesyl chloride (600 mg, 5.20 mmol). The reaction mixture was stirred at room temperature for 4 hours and then diluted with dichloromethane (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (1.6 g, crude) as a yellow oil which was directly used in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]3=[O:22])=[CH:12][CH:11]=2)[CH2:5]1.C(N(CC)CC)C.[Cl:30][C:31]1[S:35][C:34]([C:36](Cl)=[O:37])=[CH:33][CH:32]=1>C(#N)C>[Cl:30][C:31]1[S:35][C:34]([C:36]([NH:2][CH2:3][C@@H:4]2[O:8][C:7](=[O:9])[N:6]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C:17]4=[O:22])=[CH:12][CH:11]=3)[CH2:5]2)=[O:37])=[CH:33][CH:32]=1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Reactant: O=C(Cl)c1ccc(Cl)s1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
Under an atmosphere of nitrogen to a suspension of 0.164 g of 4-((S)-5-aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl-morpholin-3-one hydrochloride (MW=327.77; 1 eq.) in 7 mL of acetonitrile were added 0.101 g of triethylamine (MW=101.12; 2.0 eq.). After stirring for 10 min at room temperature, the suspension was cooled to 0° C. and then 0.091 g of 5-chloro-thiophene-2-carbonyl chloride (MW=181.04; 1.0 eq.) were added. After stirring for 80 min at 0° C., the resulting slurry was filtered and the cake washed with 5 mL of acetonitrile and 5 mL of water. After drying in vacuo at 30° C., 0.180 g of the title compound in the form of a white crystalline powder was isolated. Yield=82.7%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.Cl.[C:12](=N)(OCC)[CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:13]([C:12]1[NH:10][C:4]2[CH:3]=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=2[N:9]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(=N)OCC
Reactant: Cc1cc(N)c(N)cc1C
Agent: Cl
Product: CCCCc1nc2cc(C)c(C)cc2[nH]1
Yield: 74.9 %

Procedure:
Using the procedure of Step A of Example 1, 2.04 g of 4,5-dimethyl-1,2-phenylene diamine and 3.73 g of ethyl pentanimidoate hydrochloride [J.A.C.S., Vol. 64, p. 1827 (1942)] were reacted to obtain 3.48 g of crude product which was chromatographed on silica (eluant: methylene chloride-methanol (9-1)) to obtain 2.27 g of the expected compound melting at 110° C. An analytical sample was prepared by crystallization of 120 mg of the product from isopropyl ether to obtain 88 mg of product melting at 110° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:10]=[C:9]2[CH3:19])=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[Cl-].[CH:26]1([Zn+])[CH2:28][CH2:27]1>C1COCC1>[CH:26]1([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([C:13]#[C:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:10]=[C:9]3[CH3:19])=[CH:4][N:3]=2)[CH2:28][CH2:27]1
Reactant: [Zn+]C1CC1
Reactant: Cc1nc(C#C[Si](C)(C)C)cn1-c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(C#C[Si](C)(C)C)cn1-c1ccc(C2CC2)nc1

Procedure:
2-Chloro-5-(2-methyl-4-trimethylsilanylethynyl-imidazol-1-yl)-pyridine (425 mg, 1.47 mmol) were dissolved in 0.4M cyclopropylzinc chloride in THF (7.33 mL, 0.4M in THF) and tetrakis(triphenylphosphin)palladium (34 mg, 0.03 mmol) were added. The reaction mixture was refluxed for 16 hrs and poured into 50 mL sat. sodium bicarbonate solution. The mixture and extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->1:1 gradient) and the desired product was obtained as a light yellow solid (395 mg, 91%), MS: m/e=296.2 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([O:30][CH3:31])[C:23]=4[CH:22]=3)=[CH:19][N:20]=2)[N:17]=1>C1COCC1>[CH3:31][O:30][C:24]1[C:23]2[CH:22]=[C:21]([C:18]3[N:16]4[N:17]=[C:12]([O:8][CH2:7][C@@H:2]5[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]5)[CH:13]=[CH:14][C:15]4=[N:20][CH:19]=3)[O:29][C:28]=2[CH:27]=[CH:26][N:25]=1
Reactant: OC[C@@H]1CCCCN1
Reactant: COc1nccc2oc(-c3cnc4ccc(Cl)nn34)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nccc2oc(-c3cnc4ccc(OC[C@@H]5CCCCN5)nn34)cc12
Temperature: 40 °C
Reaction time: 72 h

Procedure:
At 0° C. 86 mg (0.44 mmol) (2S)-piperidin-2-ylmethanol were added to 132 mg (3.3 mmol) sodium hydride (60% in mineral oil) in 4 mL anhydrous THF. After 15 min of stirring on the ice bath, 141 mg (0.33 mmol) of 6-chloro-3-(4-methoxyfuro[3,2-c]-pyridin-2-yl)imidazo[1,2-b]pyridazine were added. The ice bath was removed and the mixture was stirred for 72 h at 40° C.
Reaction SMILES: [OH:1]S(O)(=O)=O.CC1(C)C[O:10][C:9]([C:12]2[C:20]([CH2:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=N1>O1CCOCC1>[CH2:21]([C:20]1[CH:19]=[C:18]([O:23][CH3:24])[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]=1[C:9]([OH:10])=[O:1])[CH3:22]
Reactant: O=S(=O)(O)O
Reactant: CCc1cc(OC)cc(C(=O)O)c1C1=NC(C)(C)CO1
Solvent: C1COCCO1
Product: CCc1cc(OC)cc(C(=O)O)c1C(=O)O
Temperature: 130 °C

Procedure:
A solution of 6.00 mol/L H2SO4 (aq.) (700 mL) was added to a solution of compound G (65.7 g, 237 mmol) in 1,4-dioxane (700 mL) at room temperature. The mixture was heated at 130° C. (oil bath temperature) and stirred. After 64 h the mixture was concentrated in vacuo, and cooled to 0° C. The precipitate was filtered and rinsed with a small amount of water to give the desired compound H (23.8 g, 106 mmol) as an off-white solid. The filtrate was extracted twice with ethyl acetate and the combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo to give the desired compound H (10.8 g, 48.2 mmol) as an off-white solid. The aqueous phase (after salting with NaCl) was extracted with CHCl3/MeOH (4/1), and the combined organic phases were dried over Na2SO4 and concentrated in vacuo to recover the starting material G (26%). 1H NMR (DMSO-d6 400 MHz): δ 1.14 (3H, t, J=7.6 Hz), 2.60 (2H, q, J=7.6 Hz), 3.80 (3H, s), 7.04 (1H, d, J=2.4 Hz), 7.16 (1H, d, J=2.4 Hz). EIMS (+): 224 [M]+
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]#[C:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)=[CH:25][C:24]=3[O:42][CH3:43])[N:13]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2]>[Pd].CN(C=O)C>[CH3:43][O:42][C:24]1[CH:25]=[C:26]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:27]=[CH:28][C:23]=1[NH:22][C:14]1[N:13]=[C:12]([CH2:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:1]([NH2:2])=[O:3])[C:17]([C:18]([F:19])([F:20])[F:21])=[CH:16][N:15]=1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(C#Cc2cccc(C(N)=O)c2)n1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2cccc(C(N)=O)c2)n1
Reaction time: 20 h

Procedure:
A mixture of tert-butyl 4-(4-((4-((3-carbamoylphenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I35) (0.073 g, 0.12 mmol) and 10% palladium on activated carbon (0.042 g) in DMF (3 mL) was stirred under a hydrogen atmosphere for 20 hours. The resulting mixture was filtered and filtrate evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (20-100% acetone/petroleum benzine 40-60° C.) to give the title compound (I36) (0.070 g, 95%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CC(O)C>[CH:18]([NH:17][C:15]([C@H:12]1[CH2:13][CH2:14][C@@H:9]([NH:8][C:6]2[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=[C:2]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:7]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:20])[CH3:19]
Reactant: C1COCCN1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Solvent: CC(C)O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(N3CCOCC3)ncc2[N+](=O)[O-])CC1

Procedure:
A suspension of cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (100 mg, 0.293 mmol) and morpholine (0.256 mL, 2.93 mmol) in 2-propanol (1 mL) was irradiated in the microwave for 1 hour at 150° C. The reaction mixture was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide cis-N-isopropyl-4-(2-morpholino-5-nitropyridin-4-ylamino)cyclohexanecarboxamide as a yellow powder (121 mg, quantitative yield). MS, m/z (C19H29N5O4): Calcd, 508.3. found, 509.1 [M+H].