Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](O)=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C(Cl)(=O)C([Cl:24])=O>CN(C=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([Cl:24])=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(Oc2ccc(F)cc2[N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(Oc2ccc(F)cc2[N+](=O)[O-])c1

Procedure:
The product from Example 181b (1.6 g, 5.6 mmol) was treated with oxalyl chloride (0.86 g, 6.7 mmol) and catalytic DMF at room temperature for 6 h. The excess oxalyl chloride was removed under vacuum. The residue was chased with benzene to \give the title compound (1.66 g, 94%).
Reaction SMILES: [CH:1]([NH:4][N:5]=[C:6]([NH2:8])[CH3:7])([CH3:3])[CH3:2].[CH2:9](OC(OCC)OCC)C.C(N(CC)CC)C.O1CCCC1>C(O)C>[CH:1]([N:4]1[CH:9]=[N:8][C:6]([CH3:7])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(N)=NNC(C)C
Reactant: CCOC(OCC)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ncn(C(C)C)n1

Procedure:
N′-isopropylacetohydrazonamide 6 was treated with triethylorthoformate in ethanol, followed by triethylamine and tetrahydrofuran to give 7 (CAS Reg. No. 1401305-30-3).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([O:8][C:9]1[N:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH2:19][CH3:20])[CH:13]=[C:12]2[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:36]=[N:37][N:38]([C:40]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:39]=2)=[CH:25][CH:24]=1)C)=[O:5])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH2:19]([C:14]1[CH:13]=[C:12]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:36]=[N:37][N:38]([C:40]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[N:39]=3)=[CH:27][CH:28]=2)[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:10]=2)[N:15]=1)[CH3:20]
Reactant: CCOC(=O)C(C)Oc1ccc2nc(CC)cc(OCc3ccc(-c4ccccc4-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc3)c2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc2nc(CC)cc(OCc3ccc(-c4ccccc4-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.7 %

Procedure:
A solution of 6-[1-(ethoxycarbonyl)ethoxy]-2-ethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine (1.0 g) in THF (8 ml) was added to a stirred suspension of lithium aluminium hydride (100 mg) in THF (5 ml) at 0° C. The mixture was allowed to warm to ambient temperature and then stirred for 20 hours. Water (0.1 ml), 15% w/v sodium hydroxide solution (0.1 ml) and water (0.3 ml) were added and the mixture was stirred for 30 minutes. The insoluble solid was removed by filtration and the filtrate was concentrated by evaporation. The residue was triturated with ether to give 2-ethyl-6-(1-hydroxy-2-propoxy)-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine (A) (0.89 g), m.p. 146°-150° C.; NMR (d6 -DMSO); 1.25-1.35(m, 6H), 2.8(q, 2H), 3.35-3.45(m, 1H), 3.6(s, 2H), 5.4(s, 2H), 6.8-6.9(m, 6H), 7.05-7.15(m, 3H), 7.2-7.4(m, 10H), 7.45-7.6(m, 5H), 7.8(dd, 1H), 8.1(d, 1H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]>>[CH2:13]([O:12][C:10](=[O:11])[C:9]([C:7]#[N:8])=[CH:1][CH2:2][CH:3]([CH3:5])[CH3:4])[CH3:14]
Reactant: CC(C)CC=O
Reactant: CCOC(=O)CC#N
Product: CCOC(=O)C(C#N)=CCC(C)C

Procedure:
Condensing isovaleraldehyde with ethyl cyanoacetate to form 2-cyano-5-methylhex-2-enoic acid ethyl ester;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C@H:10]([O:35][CH2:36][C@H:37]2[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:45][CH2:46][CH2:47][O:48][CH2:49][C:50]1[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:51]=1[O:57][CH3:58]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:45][CH2:46][CH2:47][O:48][CH2:49][C:50]3[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:51]=3[O:57][CH3:58])=[CH:32][CH:33]=2)[C@H:10]([O:35][CH2:36][C@H:37]2[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3COC(C)(C)O3)[C@@H]2c2ccc(O)cc2)cc2ccccc12
Reactant: COc1ccc(F)cc1COCCCCl
Product: COc1ccc(F)cc1COCCCOc1ccc([C@@H]2[C@@H](OCc3cc(OC)c4ccccc4c3)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@H]2COC(C)(C)O2)cc1

Procedure:
In analogy to the procedure described in example 1 (e) the (3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-4-(4-hydroxy-phenyl)-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was treated with the 2-(3-chloro-propoxymethyl)-4-fluoro-1-methoxy-benzene [example 11 (α)] to yield the (3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as light yellow oil; MS: 790 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][N:13]=1)[C:7](OC)=[O:8])([O-:3])=[O:2].[NH3:14]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][N:13]=1)[C:7]([NH2:14])=[O:8])([O-:3])=[O:2]
Reactant: COC(=O)c1ccnc([N+](=O)[O-])c1
Reactant: N
Product: NC(=O)c1ccnc([N+](=O)[O-])c1

Procedure:
A mixture of 400 mg. of methyl 2-nitroisonicotinate and 2 ml. of 28% aqueous ammonia were stirred at room temperature for 1 hour. The solvent was distilled off, and the residue was recrystallized from ethanol-ether to give 348 mg. of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:19](Cl)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].Cl>CN(C)C=O.O>[C:19]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: Cc1ccc(C(=O)O)cc1N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)Nc1cc(C(=O)O)ccc1C
Yield: 56.5 %

Procedure:
A stirred solution of 3-amino-4-methylbenzoic acid (15.1 g) in dry dimethylformamide (150 ml), containing triethylamine (20.2 g) was treated with n-hexadecanoyl chloride (27.5 g) during 30 minutes. The temperature of the reaction mixture was maintained at 25°-45° C. during the addition by water cooling. The mixture was then stirred for a further hour and was poured into water (1000 ml). The mixture was adjusted to pH 1 by the addition of concentrated hydrochloric acid (strength 0.6% w.v). The solid was collected, was washed with water and was recrystallised from ethanol (1500 ml) to give 3-(n-hexadecanamido)-4-methylbenzoic acid (22.0 g), in the form of a white solid, m.p. 238°-240° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[I:12]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: O=S(=O)(O)O
Product: Cc1c(Br)cc(C(=O)O)cc1I
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-bromo-4-methylbenzoic acid in 96% sulphuric acid (˜0.58 M reaction concentration) was added N-iodosuccinimide (1.1 equiv.) over 1 h maintaining the temperature between 10 and 30° C. The reaction mixture was aged for 10 min then quenched into water. The slurry was filtered and washed with water, sodium bisulfite solution and then finally with water to give the title compound as an off-white solid. 1H NMR (400 MHz, dmso-d6): δ 13.4 (br s, 1 H); 8.30 (s, 1 H); 8.00 (s, 1 H); 2.64 (s, 3 H). HRMS (ES, M−H) Calcd 338.8518. Found 338.8516.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([NH2:15])=O)=[N:11][CH:12]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[N:15])=[N:11][CH:12]=1
Reactant: NC(=O)c1ccc(Br)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(Br)cn1
Temperature: 0 °C
Yield: 82.7 %

Procedure:
Phosphorus oxychloride (111 g, 0.720 mol) was added to a mixture of 5-bromopicolinamide (D8) (58 g, 0.288 mol) in dry toluene (300 ml) The mixture was heated to reflux for 2 hours. The mixture was poured into ice/water, and basified to pH=12 with 2N NaOH. The resulting mixture was extracted with ethyl acetate and the organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate 10:1. Collected fractions, after solvent evaporation afforded the title compound (D9) (43.6 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[CH:21]=O)[CH:16]=2)[N:11](COCC[Si](C)(C)C)[N:10]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.Cl([O-])(=O)(=O)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:25]=[CH:24][CH:23]=[C:20]([CH2:21][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:19]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C=O)c3)cc12
Reactant: C1CCNC1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(CN4CCCC4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a solution of 3-[3-(2-Methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzaldehyde (23 mg, 0.050 mmol) and Pyrrolidine (5 ul, 0.082 mmol) in 1.5 ml dichloethane was added 3 ul of AcOH. The mixture was stirred at room temperature for 30 mins, and then to the mixture was added sodium trioxyacetylborohydride (22 mg, 0.10 mmol) in one portion. The reaction was continued at room temperature for another 2 hrs the mixture was then concentrated to yield the SEM product which was treated with a solution of 5% perchlorate in acetic acid (2 mL) at room temperature for 1 hr. Solvents were evaporated, the residue was neutralized with sodium bicarbonate powder and then purified by flash silica gel chromatography using ethyl acetate then a mixture of EtOAc/DCM/MeOH/NH4OH (4/4/1/0.05) to afford 3-(2-Methoxy-phenyl)-5-(3-pyrrolidin-1-ylmethyl-phenyl)-1H-pyrazolo[3,4-b]pyridine (8.50 mg, 44% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ 1.89 (d, J=3 Hz, 4H), 2.76 (d, J=1.5 Hz, 4H), 3.89 (s, 2H), 3.9 (s, 2H), 7.11 (t, J=1 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 7.42 (t, J=7 Hz, 1H), 7.47 (d, J=1.5 Hz, 1H), 7.48 (d, J=2 Hz, 1H), 7.51 (d, J=2.5 Hz, 1H), 7.65 (t, J=6.75 Hz, 1H), 7.72 (s, 1H), 8.39 (d, J=2.5 Hz, 1H), 8.83 (d, J=2 Hz, 1H). MS: m/z 385 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[Cl:14])[CH:10]=[N:11]O)=[CH:5][CH:4]=1>CC(OC(C)=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[Cl:14])[C:10]#[N:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(Cl)=C(C=NO)c2ccc(OC)cc2)cc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C(Cl)=C(C#N)c2ccc(OC)cc2)cc1

Procedure:
1.0 g of 2,3-Bis(4-methoxyphenyl)-3-chloro-acrylaldoxime (3.14 m moles) was refluxed for 2 hours in 25 ml of acetanhydride. After cooling, the mixture was poured onto water. The crystalline solid substance which had precipitated was suction-filtered and recrystallized from methanol. Melting point: 140° to 142° C.
Reaction SMILES: C1([Mg]Br)C=CC=CC=1.[Mg].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][CH2:21][C:22]2=O.Cl>C1COCC1.O.CCOCC>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:12]=1[CH2:22][CH:21]=[C:20]2[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:18]=1
Reactant: O=C1CCc2c(Br)cccc21
Reactant: Brc1ccccc1
Agent: Br[Mg]c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Brc1cccc2c1CC=C2c1ccccc1
Temperature: -10 °C

Procedure:
Under an argon atmosphere, to a solution of PhMgBr in THF [obtained from 7.60 g (0.312 mol) of magnesium turnings, 50.0 g (0.318 mmol) of bromobenzene, and 200 ml of THF], a solution of 43.9 g (0.208 mol) of 4-bromoindan-1-one in 400 ml of THF was added dropwise with vigorous stirring at −10° C. This mixture was stirred overnight at room temperature; and, then, 300 ml of ether was added. The resulting mixture was cooled to 0° C., and 200 ml of cold water and then 200 ml of 12 M HCl were added. The organic layer was separated; and the aqueous layer was extracted with 2×200 ml of dichloromethane. The combined extract was dried over K2CO3 and then evaporated to dryness. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 65 mm, 400 mm, eluant:hexanes) and then recrystallized from hexanes. Yield, 48.4 g (86%) of a white crystalline solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([NH:20][CH3:21])=[O:19])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[Zn][CH2:24][CH:25]([CH3:27])[CH3:26].O.C(OCC)(=O)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][CH:25]([CH3:27])[CH2:26][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([NH:20][CH3:21])=[O:19])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)C[Zn]Br
Reactant: CNC(=O)COC(=O)N1CCN(c2ccc(Br)nc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)N1CCN(c2ccc(CC(C)C)nc2)CC1
Reaction time: 19 h

Procedure:
1.25 g (3.50 mmol) of 2-(methylamino)-2-oxoethyl 4-(6-bromo-3-pyridyl)-1-piperazinecarboxylate, prepared in step 9.1, and 0.12 g (0.17 mmol) of dichlorobis(triphenylphosphine)palladium (Pd(PPh3)2Cl2) suspended in 7 ml of tetrahydrofuran are introduced under an inert atmosphere. 17.50 ml (8.74 mmol) of a solution of bromoisobutylzinc (0.5M) in tetrahydrofuran are then added. Stirring is continued at room temperature for 19 hours. The reaction mixture is poured into 25 ml of water and 25 ml of ethyl acetate. The insoluble material is filtered off through glass fiber. The phases are separated by settling, the aqueous phase is extracted twice with ethyl acetate, the combined organic phases are dried over sodium sulfate and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol, followed by crystallization from diisopropyl ether. 0.36 g of product is obtained in the form of a brown solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH2:8][C@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:4][C:5]([OH:7])=[O:6].[CH3:13]C#N>>[NH2:1][CH2:2][C@@H:3]([CH2:8][C@@H:9]([CH3:12])[CH2:10][CH2:11][CH3:13])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: CC[C@@H](C)C[C@H](CN)CC(=O)O
Reactant: CC#N
Product: CCC[C@H](C)C[C@H](CN)CC(=O)O

Procedure:
A procedure similar to the preparation of example 18 (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid was followed giving example 19. 380 mg; 29.0%. 1H NMR (CD3OD) δ 2.90 (dd, J=3.9, 8.8 Hz, 1H), 2.80 (dd, J=7.6, 5.1 Hz, 1H), 2.40 (dd, J=3.2, 12.51 Hz, 1H), 2.20 (dd, J=8.8, 6.8 Hz, 1H), 2.05 (m, 1H), 1.55 (m, 1H), 1.30 (m, 3H), 1.10 (m, 2H), 0.85 (m, 6H); MS, m/z (relative intensity): 187 [M+1H, 100%], 211 [M+1H+CH3CN, 30%].
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][C@H:10]2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)=O)=[CH:4][CH:3]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[F:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]2[C:21]3[CH:20]=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[CH:17][C:16]=3[C@H:10]3[C@H:9]([CH2:14][CH2:13][N:12]([CH3:15])[CH2:11]3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc([C@@H]2CN(C)CC[C@@H]2NC(=O)c2ccc(F)cc2)cc1OC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(F)cc1

Procedure:
cis-4-(4-Fluorobenzoylamino)-3-(3,4-dimethoxyphenyl)-1-methylpiperidine is cyclized in analogy to the process described in Example 8. The dihydrochloride of the title compound has a M.P. of 250°-255° (from ethanol).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:27]=[CH:26][O:25][CH:24]=1)C1C=CC=CC=1.C(N1CCN(CC2C=CC=CC=2)C[C@@H]1CC)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl.CO>[O:25]1[CH:26]=[CH:27][C:23]([CH2:22][CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)=[CH:24]1
Reactant: c1ccc(CN2CCN(Cc3ccccc3)[C@@H](CCc3ccoc3)C2)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: CO
Solvent: ClCCCl
Product: c1cc(CC[C@H]2CNCCN2)co1
Temperature: 83 °C
Reaction time: 18 h
Yield: 29 %

Procedure:
Dissolve a mixture of (S)-1,4-dibenzyl-2-(2-furan-3-yl-ethyl)-piperazine and (S)-1,4-dibenzyl-2-ethyl-piperazine (2.29 g, 6.35 mmol) in 1,2-dichloroethane (10 mL). Cool on an ice bath and add 1-chloroethyl chloroformate (2.06 ml, 19.1 mmol) dropwise. Remove ice bath and heat to 83° C. for 5.5 h. Concentrate the reaction, dissolve the residue in methanol (50 mL) and heat to reflux for 2 h. Cool to ambient temperature and stir 18 h. Filter and concentrate to a solid. Purify by silica gel chromatography using 7N ammonia in methanol-methylene chloride (2.5%–10%) as the eluent to give 330 mg (29%) of the title compound: mp 112–4° C. Mass spectrum (ion spray): m/z=181 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34].[C:36]1([CH3:45])[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>O1CCOCC1>[N+:33]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:27]=1[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[CH3:45])([O-:35])=[O:34]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1ccccc1-c1ccncc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
Triphenylphosphine (2.10 g, 1.89 mmol) and potassium carbonate (7.80 g, 56.7 mmol) were added to a slurry of 4-chloro-3-nitropyridine (3.00 g, 18.9 mmol, CAS RN 13091-23-1) and 2-tolylboronic acid (2.83 g, 20.8 mmol, CAS RN 16419-60-6) in dioxane stirring under an argon atmosphere. The reaction mixture was heated to 120° C. for 16 hours and then cooled to room temperature. The solids were removed by filtration through celite and all volatiles were removed in vacuo resulting in a dark colored heavy oil. The product was isolated as a heavy oil by flash chromatography on silica gel (25-33% EtOAc in n-hexane) (1.75 g, 43%).
Reaction SMILES: ClC1C=CC([C:8]2[S:9][C:10]([C:14]([O:16]CC)=[O:15])=[C:11]([CH3:13])[N:12]=2)=CC=1[N+]([O-])=O>C(NCC)C>[CH3:13][C:11]1[N:12]=[CH:8][S:9][C:10]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)c([N+](=O)[O-])c2)nc1C
Solvent: CCNCC
Product: Cc1ncsc1C(=O)O
Yield: 56 %

Procedure:
Ethyl 2-(4-chloro-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate in diethylamine was heated in the same manner as that of Example 35 and hydrolyzed to give 2-(4-N,N-diethylamino)-3-nitrophenyl)-4-methyl-5-thiazolecarboxylic acid (yield: 56%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cccc(Cl)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (59 mg, 72%), MS (ISP) m/z=329.4 [(M+H)+], mp 182° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 3-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([N:22]3[CH2:27][CH2:26][CH2:25][CH:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:23]3)[CH:3]=2)=[N:13][C:14]=1[O:20][CH3:21]
Reactant: COc1ccc(Nc2cc(Cl)nn3ccnc23)nc1OC
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Product: COc1ccc(Nc2cc(N3CCCC(NC(=O)OC(C)(C)C)C3)nn3ccnc23)nc1OC
Temperature: 160 °C
Yield: 15.1 %

Procedure:
A suspension of 6-chloro-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (1.3 g, 4.24 mmol) and tert-butyl piperidin-3-ylcarbamate (3.4 g, 16.99 mmol) was heated to 160° C. for 2 h. The residue was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH=120:1) to give the tert-butyl 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-ylcarbamate (300 mg, 15%) as brown solid. LC-MS: 470 [M+1]+, tR=1.44 min
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([S:12][CH3:13])[N:6]=1)([CH3:3])[CH3:2].[I:14]Cl>CO>[I:14][C:10]1[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]([S:12][CH3:13])=[N:8][C:9]=1[CH3:11]
Reactant: ClI
Reactant: CSc1nc(C)cc(NC(C)C)n1
Solvent: CO
Product: CSc1nc(C)c(I)c(NC(C)C)n1
Reaction time: 3 h

Procedure:
To a crude solution of N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine (44.6 g, 224 mmol), prepared using analogous procedures as described in Example 1, in 400 mL of methanol was added ICl (40.0 g, 246 mmol) in small portions at room temperature. The reaction mixture was then stirred at for 3 h monitoring by LC/MS. After evaporation of solvent by rotary evaporator, the residue was triturated with acetone to yield 5-iodo-N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine. 1H NMR (400 MHz, CDCl3) δ 6.37 (br m, 1H), 4.47 (m, 1H), 2.78 (s, 3H), 2.67 (s, 3H), 1.41 (d, J=6.4, 6H).