Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH3:20][O:21][CH2:22][CH2:23][CH2:24][C:25]#[CH:26]>>[OH:19][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:26]#[C:25][CH2:24][CH2:23][CH2:22][O:21][CH3:20])[CH:3]=1)[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: C#CCCCOC
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Br)c1
Product: COCCCC#Cc1cccc(C(O)CCNC(=O)OC(C)(C)C)c1

Procedure:
Sonogashira reaction of 39 with 5-methoxypent-1-yne gave tert-butyl 3-hydroxy-3-(3-(5-methoxypent-1-ynyl)phenyl)propylcarbamate as brown oil. Yield (0.347 g, 66%): 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.27-7.37 (m, 3H), 4.83-4.85 (bs, 1H), 4.69-4.71 (m, 1H), 3.66-3.71 (m, 1H), 3.52 (t, J=6.4 Hz, 2H), 3.48 (m, 1H), 3.36 (s, 3H), 3.29 (bs, 1H), 2.49 (t, J=6.4 Hz, 2H), 1.80-2.02 (m, 4H), 1.45 (s, 9H).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH:18]1([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:24])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COC(=O)c1ccc(OCc2c(C3CCCCC3)noc2C)nc1
Reactant: NC1CCOCC1
Product: Cc1onc(C2CCCCC2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 39 %

Procedure:
As described for example 31e, 6-(3-cyclohexyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (472 mg, 1.0 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (155 mg, 39%) which was obtained as a white solid after purification by chromatography (silica, 0 to 70% ethyl acetate in heptane). MS: m/e=400.3 [M+H]+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:5]=12.C1C(=O)N([Cl:24])C(=O)C1>C1(C)C=CC=CC=1>[Cl:24][C:3]1[N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:5]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCn2ccnc2C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCn2c(Cl)cnc2C1

Procedure:
1,1-Dimethylethyl 5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (I18) (1.563 g, 7 mmol) and NCS (0.935 g, 7.00 mmol) were heated at 80° C. for 2 h in toluene (30 mL). The solvents were removed in vacuo and the residue was purified by flash chromatography (Isolera, 50 g, 0-100% ethyl acetate/iso-hexane) to afford product in 1.55 g.
Reaction SMILES: ClC1C=CC=C(F)C=1C=O.ClC1C=CC=C(F)C=1C=C.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C@H:29]1[CH2:31][C@H:30]1[N:32]=[C:33]=[O:34].[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][N:37]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C@H:29]1[CH2:31][C@H:30]1[NH:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][N:37]=1)=[O:34]
Reactant: O=C=N[C@@H]1C[C@@H]1c1c(F)cccc1Cl
Reactant: N#Cc1ccc(N)nc1
Agent: C=Cc1c(F)cccc1Cl
Agent: O=Cc1c(F)cccc1Cl
Product: N#Cc1ccc(NC(=O)N[C@@H]2C[C@@H]2c2c(F)cccc2Cl)nc1

Procedure:
2-chloro-6-fluorobenzaldehyde (Aldrich), was converted to 2-chloro-6-fluorostyrene according to the method described in Example 377 of WO 93/03022 and then to cis-2-(2-chloro-6-fluorophenyl) cyclopropylisocyanate analogously to the method described in Example 348 of WO 93/03022. This compound was then condensed with 2-amino-5-cyanopyridine of Example 41 in a manner analogous to the method in Example 7 to provide N-(cis-2-(2-chloro-6-fluorophenyl)-cyclopropyl)-N′-(5-cyanopyrid-2-yl)-urea: Mp 189° C. 1H -NMR (250 MHz, DMSO-d6): 1.2 (m, 11H), 1.45-1.55 (m, 1H), 2.2-2.3 (m, 1H), 3.3-3.4 (m, 1H), 7.35-7.6 (m, 41z), 7.9-8.1 (m, 2H), 9.5 (s, 1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([C:9]=1[CH3:10])[CH:7]=[O:8].[CH:13](=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O.O.[Cl-].[Ca+2].[Cl-].CO.[OH-].[K+].Cl>>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([C:9]=1[CH3:10])[CH:7]=[O:8].[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:13]([OH:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:5]([OH:11])=[C:6]([C:9]=1[CH3:10])[CH:7]=[O:8]
Reactant: CCCCCCCCCCCC=O
Agent: Cc1c(Cl)c(O)cc(O)c1C=O
Agent: Cl
Agent: [Ca+2]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCC(O)c1c(O)c(Cl)c(C)c(C=O)c1O
Yield: 20 %

Procedure:
5-Chloro-2,4-dihydroxy-6-methylbenzaldehyde (112 mg, 0.60 mmol) described in M. M. Joullie et al., J. Org. Chem., 50, 3997 (1985), dodecanal (133 mg, 0.72 mmol) and calcium chloride dihydrate (58 mg, 0.40 mmol) were stirred in a 0.4 M potassium hydroxide methanol solution (2 ml) at 0° C. for 24 hours. The reaction mixture was made acidic with 1 M hydrochloric acid, extracted with ethyl acetate, and after post-treatment, the crude product was purified by silica gel thin-layer chromatography (chloroform:ethyl acetate=15:1) to obtain 5-chloro-2,4-dihydroxy-6-methylbenzaldehyde (68 mg, recovery 61%) and 5-chloro-2,4-dihydroxy-3-(1-hydroxydodecyl)-6-methylbenzaldehyde (45 mg, yield 20%).
Reaction SMILES: [N:1]1([S:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1C(=O)N([Br:25])C(=O)C1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:25][C:15]1[CH:16]=[C:11]([CH2:10][S:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)(=[O:9])=[O:8])[CH:12]=[CH:13][C:14]=1[NH2:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(CS(=O)(=O)N2CCOCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ccc(CS(=O)(=O)N2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a solution of 4-(morpholine-4-sulfonylmethyl)-phenylamine (437 mg, 1.70 mmol, WO 9720822) in DCM (10 mL) was added NBS (304 mg, 1.70 mmol) at 0° C. The solution was allowed to stir at RT for 15 min. Satd aq NaHCO3 (20 mL) was then added and the organic layer was separated, dried (Na2SO4) and concentrated to afford the title compound (564 mg, 98%). 1H-NMR (CDCl3; 400 MHz): δ 7.47 (d, 1H, J=1.9 Hz), 7.15 (dd, 1H, J=8.2, 1.9 Hz), 6.77 (d, 1H, J=8.2 Hz), 4.23 (br s, 2H), 4.12 (s, 2H), 3.65-3.68 (m, 4H), 3.14-3.17 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:25])([CH3:24])[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:26](N1C=CN=C1)(N1C=CN=C1)=[S:27]>C(Cl)Cl>[CH3:24][C:14]([CH3:25])([CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[NH:1][C:26]1=[S:27])[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNc1c(N)cnc2ccccc12
Solvent: ClCCl
Product: CC(C)(CNC(=O)OC(C)(C)C)Cn1c(=S)[nH]c2cnc3ccccc3c21
Yield: 96.8 %

Procedure:
tert-Butyl 3-[(3-aminoquinolin-4-yl)amino]-2,2-dimethylpropylcarbamate (7.16 g, 20.8 mmol) was suspended in 200 mL of CH2Cl2 and treated with 1,1′-thiocarbonyldiimidazole (4.07 g, 22.9 mmol) under an atmosphere of N2. After about 2 hours a precipitate had formed. It was isolated by filtration and dried under vacuum to afford tert-butyl 2,2-dimethyl-3-(2-thioxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (7.78 g) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12](I)[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].[CH:20]1(B(O)O)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:20]1([C:12]2[S:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:22][CH2:21]1
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1C1CC1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
Into a 50-mL 3-necked round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 3-(4-ethylphenyl)-5-iodo-1,2-thiazole-4-carboxylate (300 mg, 0.77 mmol, 1.00 equiv), cyclopropylboronic acid (100 mg, 1.16 mmol, 1.50 equiv), sodium carbonate (246 mg, 2.32 mmol, 3.00 equiv), Pd(dppf)Cl2 (56.7 mg, 0.08 mmol, 0.10 equiv), ethylene glycol dimethyl ether (6 mL), water (3 mL). The resulting solution was stirred for 16 h at 95° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). The collected fractions were combined and concentrated under vacuum. This resulted in 90 mg (39%) of ethyl 5-cyclopropyl-3-(4-ethylphenyl)-1,2-thiazole-4-carboxylate as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:15]=[C:16]3[C:22]4[CH:23]=[C:24]([C:27](O)=[O:28])[CH:25]=[CH:26][C:21]=4[O:20][CH2:19][CH2:18][N:17]3[CH:30]=2)=[N:12][CH:11]=[N:10]1.[N:31]1([CH2:37][CH2:38][OH:39])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:15]=[C:16]3[C:22]4[CH:23]=[C:24]([C:27]([N:34]5[CH2:35][CH2:36][N:31]([CH2:37][CH2:38][OH:39])[CH2:32][CH2:33]5)=[O:28])[CH:25]=[CH:26][C:21]=4[O:20][CH2:19][CH2:18][N:17]3[CH:30]=2)=[N:12][CH:11]=[N:10]1
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3ncnn3-c3ccc(F)cc3F)cn1CCO2
Reactant: OCCN1CCNCC1
Product: O=C(c1ccc2c(c1)-c1nc(-c3ncnn3-c3ccc(F)cc3F)cn1CCO2)N1CCN(CCO)CC1

Procedure:
Following the procedure for 109, 2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid and 2-(piperazin-1-yl)ethanol gave 162. MS: (ESI+)=522.2
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2N)CC1

Procedure:
tert-Butyl 4-{[2-(2-nitrophenyl)ethyl]amino}piperidine-1-carboxylate and 10% palladium on carbon (1.9 g) were stirred in ethanol (250 mL) overnight under one atmosphere hydrogen. Catalyst was filtered from the solution and solvent removed in vacuo to provide the title compound (17.2 g). MS 320 (M+1)
Reaction SMILES: O1CCOCC1.Br[C:8]1[CH:9]=[C:10]([CH3:15])[C:11]([NH2:14])=[N:12][CH:13]=1.[I-:16].[Na+].CC(C)(N)C(C)(C)N>[Cu](I)I.O>[I:16][C:8]1[CH:9]=[C:10]([CH3:15])[C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: [I-]
Agent: I[Cu]I
Agent: CC(C)(N)C(C)(C)N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(I)cnc1N
Temperature: 110 °C
Yield: 92.7 %

Procedure:
To dioxane (10 mL) was added 5-bromo-3-methylpyridin-2-amine (2 g, 10.6 mmol), sodium iodide (3.2 g, 21.4 mmoL), copper iodide (0.190 g, 1.06 mmol) and the solution degassed followed by addition of tetramethylethane-1,2-diamine (0.803 mL, 1.06 mmol) this mixture heated at 110° C. overnight. After cooling water was added and extracted the crude product with ethyl acetate. The residue was purified by column chromatography to give 5-iodo-3-methylpyridin-2-amine as a beige solid (2.3 g, 93%).
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:3]1.Cl[CH2:18][CH2:19][C:20]([C:22]1[C:26]2[NH:27][C:28](=[O:32])[CH2:29][CH2:30][CH2:31][C:25]=2[S:24][C:23]=1[CH3:33])=[O:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1.O>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:12][CH2:13][N:14]([CH2:18][CH2:19][C:20]([C:22]3[C:26]4[NH:27][C:28](=[O:32])[CH2:29][CH2:30][CH2:31][C:25]=4[S:24][C:23]=3[CH3:33])=[O:21])[CH2:15][CH2:16]2)=[N:3]1
Reactant: Cc1sc2c(c1C(=O)CCCl)NC(=O)CCC2
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1sc2c(c1C(=O)CCN1CCN(c3nsc4ccccc34)CC1)NC(=O)CCC2
Temperature: 60 °C
Reaction time: 5 h
Yield: 38.9 %

Procedure:
The mixture of 2.1 g of 4-(1,2-benzisothiazol-3-yl)piperazine hydrochloride, 2.0 g of 3-(3-chloropropionyl)-2-methyl-4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one, 2,2 g of potassium carbonate and 1.2 g of potassium iodide in 15 ml of N,N-dimethylformamide and 15 ml of toluene was stirred at 60° C. for 5 hours. After the mixture was cooled in a water bath, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with saline solution, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel, dissolved in isopropyl alcohol and crystallized from isopropyl alcohol-isopropyl ether. The resulting crystals were recrystallized from ethanol to give 1.30 g of 3-(3-(4-(1,2-benzisothiazol-3-yl)piperazin-1-yl)propionyl)-2-methyl-4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one as white crystals, m.p. 146°-147° C.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:18]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:24]([OH:26])=O)=[O:19].[Cl:36][C:37]1[CH:46]=[CH:45][C:40]([O:41][CH2:42][CH2:43][NH2:44])=[CH:39][CH:38]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:36][C:37]1[CH:46]=[CH:45][C:40]([O:41][CH2:42][CH2:43][NH:44][C:24](=[O:26])[C:23]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:21]([NH:20][C:18](=[O:19])[C:17]3[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:15]([O:14][CH3:13])[CH:16]=3)[CH:22]=2)=[CH:39][CH:38]=1
Reactant: NCCOc1ccc(Cl)cc1
Reactant: COc1ccc(C(=O)Nc2cc(C(=O)O)ccc2C)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(C(=O)NCCOc3ccc(Cl)cc3)ccc2C)cc1OC
Yield: 67.7 %

Procedure:
A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.095 g) in methylene chloride (5 ml) was added to a stirred mixture of 3-(3,4-dimethoxybenzamido)-4-methylbenzoic acid (0.157 g), 2-(4-chlorophenoxy)ethylamine (C. Chim. Ther., 1973, 8, 259; 0.086 g), 4-dimethylaminopyridine (0.007 g), 1-hydroxybenzotriazole (0.074 g) and methylene chloride (5 ml). The resultant mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was washed with an aqueous citric acid solution, dried over magnesium sulphate and evaporated. There was thus obtained the title compound as a solid (0.158 g); Mass Spectrum: M+H+ 469.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[C:13](=[O:15])[CH3:14].[Br:17]C1(Br)C(=O)NC(=O)NC1=O.CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[C:13](=[O:15])[CH2:14][Br:17]
Reactant: O=C1NC(=O)C(Br)(Br)C(=O)N1
Reactant: COC(=O)c1c(C(C)=O)cccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C(=O)CBr)cccc1[N+](=O)[O-]

Procedure:
The mixture of 2-acetyl-6-nitro-benzoic acid methyl ester (8.20 g, 36.7 mmol, Step C) and 5,5-dibromobarbituric acid (7.35 g, 25.7 mmol) in 200 mL of THF was heated to reflux under N2 for 64 h. The solvents were removed, and the residue was partitioned between EtOAc and Na2CO3(aq). The organic portion was dried over MgSO4, filtered, condensed, and the titled compound was obtained as a white solid after flash column chromatography (5 to 20% of EtOAc in hexanes).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=O)C.[BrH:19]>O>[BrH:19].[BrH:19].[NH:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13]2[N:14]=[CH:15][CH:16]=[CH:17][N:18]=2)[CH2:10][CH2:11]1
Reactant: CCOC(=O)N1CCC(Nc2ncccn2)CC1
Agent: Br
Solvent: O
Product: c1cnc(NC2CCNCC2)nc1

Procedure:
A solution of 4-(pyrimidin-2-ylamino)-piperidine-1-carboxylic acid ethyl ester (1.07 g, 4.28 mmol) in 48% HBr in water (60 mL) was heated to reflux for 18 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrobromide salt. MS (ISP): 179.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:13][C:3]1[C:2]([CH:14]=[CH2:15])=[C:11]([F:12])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: Fc1cc2ncccc2c(F)c1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1c(F)cc2ncccc2c1F
Temperature: 150 °C
Reaction time: 0.42 h

Procedure:
6-Bromo-5,7-difluoro-quinoline ((viii), 1 g, 4.10 mmol), tetrakis(triphenylphosphine)palladium (0) (47 mg, 0.041 mmol) and tributyl(vinyl)tin (1.34 g, 4.10 mmol) were put together with dioxane (3.7 mL) in a microwave reactor and stirred for 25 min at 150° C. under microwave irradiations. The solvent was removed and the residue was purified by MPLC with hexane and EtOAc. The title compound was obtained as a colorless oil (tR 1.1 min (conditions 4), MH+=192).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][CH:23]([NH2:28])[C:24]([F:27])([F:26])[F:25].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:28][C@@H:23]([CH3:22])[C:24]([F:27])([F:26])[F:25])=[O:18])=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Reactant: CC(N)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1noc(C)c1COc1ccc(C(=O)N[C@@H](C)C(F)(F)F)cn1
Yield: 67.9 %

Procedure:
To a stirred solution of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) in DMF (2 mL) at room temperature under argon was added L-2,2,2-trifluoro-1-(methyl)ethylamine (ABCR F07820EFA, 42.9 mg, 0.38 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (121.7 mg, 0.38 mmol) and N,N-diisopropylethylamine (222.6 mg, 1.72 mmol). After 2.5 h the reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetate=1:0 to 2:1) afforded the title compound (89 mg, 67%) as a light yellow oil. MS: m/e=384.3 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH2:11]2)=[C:6]([F:21])[C:5]=1[F:22])[CH3:2].C([OH:25])C.[OH-].[Na+].OO>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([OH:25])[CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][CH2:11]2)=[C:6]([F:21])[C:5]=1[F:22])[CH3:2]
Reactant: CCO
Reactant: CCCCCC1=CCC(c2ccc(OCC)c(F)c2F)CC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCC1CCC(c2ccc(OCC)c(F)c2F)CC1O
Temperature: 2 °C

Procedure:
53 g of 1-ethoxy-2,3-difluoro-4-(4-pentylcyclohex-3-enyl)benzene were dissolved in 500 ml of THF, and the mixture was cooled to 2° C. 195 ml of borane/THF complex were subsequently added dropwise over the course of 30 minutes with stirring. After the mixture had been stirred for a further 2 hours, 48 ml of ethanol were added dropwise to the solution at RT. Subsequently, firstly a solution of 10.6 g of sodium hydroxide and then 63 ml of 30% hydrogen peroxide were added dropwise. The mixture was subsequently refluxed for 2 hours and subjected to conventional work-up, giving 5-(4-ethoxy-2,3-difluorophenyl)-2-pentylcyclohexanol.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])(=[O:8])[O:5]CC)C.[CH3:14][Si:15](I)([CH3:17])[CH3:16]>C(Cl)(Cl)(Cl)Cl>[CH3:14][Si:15]([O:3][P:4]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])(=[O:8])[O:5][Si:15]([CH3:17])([CH3:16])[CH3:14])([CH3:17])[CH3:16]
Reactant: CCOP(=O)(CCCC#N)OCC
Reactant: C[Si](C)(C)I
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)OP(=O)(CCCC#N)O[Si](C)(C)C
Temperature: 0 °C

Procedure:
In an experiment to demonstrate this method, 4.0 g of diethyl-3-cyanopropylphosphonate in 12 ml of carbon tetrachloride, was treated with 5.6 ml of trimethylsilyl iodide. This was cooled to 0° C. and stirred for ten minutes, and allowed to warm to room temperature, forming bis(trimethylsilyl)-3-cyanopropylphosphonate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([I:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[CH:9]=[C:8]([C:13]([O:15]CC)=O)[C:7]2=[O:18].CCCCCC.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:13]([C:8]2[C:7](=[O:18])[C:6]3[C:11](=[C:2]([F:1])[CH:3]=[C:4]([I:19])[CH:5]=3)[N:10]([CH3:12])[CH:9]=2)=[O:15])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cn(C)c2c(F)cc(I)cc2c1=O
Reactant: NCc1ccc(Cl)cc1
Solvent: CCCCCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)cc(F)c21
Temperature: 25 °C

Procedure:
A solution of ethyl 8-fluoro-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate from Preparation No. 13 (15.8 g) in p-chlorobenzylarnine (15.4 mL) is warmed to 190° C. The mixture is then cooled to room temperature, and hexane is added. The resulting precipitate is collected by filtration to give the title compound as a solid. An analytical sample is prepared by recrystallization from EtOH.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[N:18]=[N:17][C:15]2=[O:16])=[CH:10][CH:9]=1.Cl>CC#N>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([N:17]2[C:15](=[O:16])[N:14]([C:11]3[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=3)[C:19](=[O:20])[NH:18]2)=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C1N=NC(=O)N1c1ccccc1
Agent: Cl
Solvent: CC#N
Product: O=c1[nH]n(-c2ccc(O)cc2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.9 %

Procedure:
To a solution of phenol (11.3 mg, 0.120 mmol) in 100 mM pH 7.0 NaH2PO4/Na2HPO4 buffer (3.0 mL)-CH3CN (3.0 mL) was slowly dropped the 0.3 M solution of PTAD 17a (0.442 mL, 0.132 mmol) in CH3CN at room temperature. The resulting solution was stirred at room temperature for 30 minutes. The reaction mixture was acidified with 1M HCl and extracted with ethyl acetate twice. The organic layer was dried over Na2SO4 and concentrated in vacuo. The obtained crude material was purified by flash column chromatography (ethyl acetate) to give para-adduct 27 (4.8 mg, 15%) and para-ortho-di-adduct 27′ (10.1 mg, 19%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 11.35 (br, 1H), 9.60 (s, 1H), 7.53-7.35 (m, 7H), 6.83 (m, 2H), 13C NMR (75 MHz, DMSO-d6): δ 156.11, 152.73, 150.41, 132.22, 129.22, 128.78, 128.66, 127.19, 122.99, 116.22. HRMS: calcd for C14H11N3O3 (MH+) 270.0873. found 270.0873.