Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:29])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:45]1([CH2:51][C:52]([N:54]=[C:55]=[S:56])=[O:53])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(OCC)C>C(O)C.C1(C)C=CC=CC=1.CCCCCC>[F:29][C:4]1[CH:3]=[C:2]([NH:1][C:55]([NH:54][C:52](=[O:53])[CH2:51][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[S:56])[CH:28]=[CH:27][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][N:23]3[CH2:24][CH2:25][CH2:26]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCC4)CC3)c2)c(F)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCC4)CC3)c2)c(F)c1
Reaction time: 0.08 h
Yield: 56.8 %

Procedure:
4-(Azetidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (127 mg) was dissolved in ethanol (3 ml) under a nitrogen atmosphere, and then (S)-(+)-10-camphorsulfonic acid (148 mg) was added thereto, followed by stirring for 5 min. A 0.25 M solution of phenylacetyl isothiocyanate in toluene (1.91 ml) was added thereto, followed by stirring for 12 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:8, ethyl acetate, then ethyl acetate:ethanol=95:5). Fractions containing the target compound were concentrated under reduced pressure to give a residue, to which diethyl ether (3 ml) and hexane (3 ml) were then added to suspend. The solid was filtered off, and dried under aeration to provide the titled compound (104.1 mg, 56.8%) as white powder.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[O:20]1[CH2:24][CH2:23][N:22]=[C:21]1[C:25]([NH2:28])([CH3:27])[CH3:26]>>[O:20]1[CH2:24][CH2:23][N:22]=[C:21]1[C:25]([NH:28][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:27])[CH3:26]
Reactant: O=C(O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Reactant: CC(C)(N)C1=NCCO1
Product: CC(C)(NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1)C1=NCCO1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (Example 14 a) and 1-(4,5-dihydro-oxazol-2-yl)-1-methyl-ethylamine as starting materials, MS (EI): m/e=373.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH:5]=O)([CH3:4])[CH3:3].C(O)(=O)C.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[NH:12][NH2:13]>CO>[C:16]([O:15][C:11]([NH:12][N:13]=[CH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)C=O
Reactant: CC(C)(C)OC(=O)NN
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)C=NNC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 100 %

Procedure:
Pivaldehyde (52.1 g, 454 mmoles, ca. 75% solution in t-butanol) was dissolved in 120 mL methanol in a 1 L, 3-necked round bottom flask with reflux condenser, thermometer, and addition funnel. Glacial acetic acid (1 mL) was added followed by controlled addition of t-butyl carbazate (50 g, 378 mmoles), without removal of heat of the reaction. The mixture was stirred for 4 hours, while monitoring by TLC. Upon completion of the reaction, the solvent was removed in vacuo, the residue was taken up in pentane, and the pentane was evaporated. The resultant oil crystallized upon standing to provide N′-(2,2-dimethyl-propylidene)-hydrazinecarboxylic acid tert-butyl ester (75.7 g, 93%). Rf=0.42 (2:1 hexanes:ethyl acetate, 1% acetic acid); 1H NMR (400 MHz, CDCl3) δ 7.6 (br s, 1H), 7.1 (s, 1H), 1.5 (s, 9H), 1.1 (s, 9H) ppm.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1](=[O:10])[CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCc2ccccc21
Product: O=C1CC(Cc2ccccc2)c2ccccc21

Procedure:
This compound was prepared according to the method described by B. M. Trost and L. H. Latimer in J. Org. Chem. 42 (1977) 3212. The starting compounds were 1-indanone and benzyl bromide.
Reaction SMILES: BrC1C=NC=CC=1CSCCN.C([NH:21][C:22]([NH:35][CH2:36][CH2:37][S:38][CH2:39][C:40]1[C:45]([Br:46])=[CH:44][CH:43]=[CH:42][N:41]=1)=[N:23][CH2:24][CH2:25][S:26][CH2:27][C:28]1[C:33]([Br:34])=[CH:32][CH:31]=[CH:30][N:29]=1)(=O)C1C=CC=CC=1>N1C=CC=CC=1>[Br:46][C:45]1[C:40]([CH2:39][S:38][CH2:37][CH2:36][NH:35][C:22]([NH:23][CH2:24][CH2:25][S:26][CH2:27][C:28]2[C:33]([Br:34])=[CH:32][CH:31]=[CH:30][N:29]=2)=[NH:21])=[N:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(NC(=NCCSCc1ncccc1Br)NCCSCc1ncccc1Br)c1ccccc1
Agent: NCCSCc1ccncc1Br
Solvent: c1ccncc1
Product: N=C(NCCSCc1ncccc1Br)NCCSCc1ncccc1Br

Procedure:
The reaction of 3-bromo-4-[(2-aminoethyl)thiomethyl]pyridine with N-benzoyl-bis-dimethylthioimidocarbonate in pyridine by the method described in Example 12 yielded N-benzoyl-N',N"-bis-[2-((3-bromo-2-pyridyl)methylthio)ethyl]guanidine which, on acid hydrolysis, yielded the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[CH:36]=[O:37])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:13][O:14][CH:15]([CH:36]([OH:37])[C:35]1[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COCC(=O)OC
Reactant: O=Cc1ccccc1CCCCCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(OC)C(O)c1ccccc1CCCCCCCCc1ccccc1
Reaction time: 0.25 h

Procedure:
To tetrahydrofuran (50 ml), cooled to -78° C. under argon, was added diisopropylamine (5.7 ml, 0.041 mole) followed by n-butyllithium (16 ml, 0.041 mole) slowly. After 15 minutes, methyl methoxyacetate (4.25 g, 0.041 mole) in tetrahydrofuran (10 ml) was added dropwise. The resulting solution was stirred for 30 minutes after which a solution of 2-(8-phenyloctyl)benzaldehyde in tetrahydrofuran (10 ml) was added dropwise. After 2 hours the reaction mixture was quenched with a solution of saturated ammonium chloride and then diluted with ice water. The aqueous layer was extracted with ether. The combined ether extract was washed with 10% sodium hydroxide (ice cold), dried over magnesium sulfate, filtered and evaporated to give the desired product.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:29].[Na+].C(=O)C.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[CH2:28]([N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([I:1])=[CH:11][CH:10]=4)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)[CH3:29]
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CCN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 65.7 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), acetaldehyde (0.15 mL, 2.58 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 33 mg (60%) of the title compound as a yellow solid. MS (ESI) m/z 503.3 (M+H)+1.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH:23]2[CH2:25][CH2:24]2)[C:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[N:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+]>CCO>[CH:23]1([N:7]2[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[N:9]=[C:8]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[CH2:25][CH2:24]1
Reactant: CCOC(=O)c1c(C)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(-c2ccc(OC(F)(F)F)cc2)n(C2CC2)c1C(=O)O
Yield: 61.3 %

Procedure:
To 0.1 g (0.3 mmol) of 3-cyclopropyl-5-methyl-2-(4-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid ethyl ester in 3 ml of EtOH was added 61 microliters of 6 M sodium hydroxide solution (0.4 mmol) and the mixture heated to reflux for 6 h. The solvent was then evaporated, 1M hydrochloric acid solution was added and the resulting precipitate was isolated by filtration, affording 0.06 g (62%) of the title compound as a white solid. MS: 327.1 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]1(=O)[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]1>>[I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=1
Reactant: O=C1CCCC(=O)C1
Reactant: Nc1ccccc1I
Product: O=C1C=C(Nc2ccccc2I)CCC1

Procedure:
A stirred mixture of 2-iodoaniline (22.2 g) and cyclohexane-1,3-dione (11.2 g) was heated under nitrogen at 120° for 1 h, cooled and the resulting solid pulverised under ether (300 ml). The mixture was filtered and the solid (30 g) recrystallised from acetone:hexane (1:1, 400 ml), giving the title compound as prisms m.p. 151°-3° (decomp.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH2:15][CH2:16]2)[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2CCC(=CC#Cc3cccc(C)n3)CC2)cc1
Yield: 64.6 %

Procedure:
A solution of the Compound of Example 3 (60 mg, 0.283 mmol), p-toluenesulfonyl chloride (80.9 mg, 0.425 mmol), TEA (0.425 mmol) in 5 mL of CHCl3 was stirred at r.t. for 1 h. The chloroform solution was washed with NaOH 0.1 N, water, dried over Na2SO4 and evaporated to dryness in vacuo. Purification by flash chromatography (EtOAc—Petroleum Ether 1:1), afforded 67 mg of the title product.
Reaction SMILES: [C:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:18]=2)[C:11]([OH:16])=[C:12]([CH:14]=O)[CH:13]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2].[NH2:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[NH2:37])[C:31]([NH2:33])=[NH:32].C1(=O)C=CC(=O)C=C1>CO>[C:1]([NH:4][S:5]([C:8]1[CH:13]=[C:12]([C:14]2[NH:37][C:36]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[NH:32])=[CH:29][C:28]=3[N:27]=2)[C:11]([OH:16])=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23](=[O:25])(=[O:24])[NH2:26])[CH:18]=2)[CH:9]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)NS(=O)(=O)c1cc(C=O)c(O)c(-c2cccc(S(N)(=O)=O)c2)c1
Reactant: N=C(N)c1ccc(N)c(N)c1
Agent: O=C1C=CC(=O)C=C1
Solvent: CO
Product: CC(=O)NS(=O)(=O)c1cc(-c2cccc(S(N)(=O)=O)c2)c(O)c(-c2nc3cc(C(=N)N)ccc3[nH]2)c1
Temperature: 25 °C
Yield: 14 %

Procedure:
N-acetyl 5-formyl-6-hydroxy-biphenyl-3,3′-disulfonamide (74 mg, 0.19 mmol) was dissolved in methanol (10 mL) and stirred at room temperature. 3,4-Diaminobenzamidine (39 mg, 0.21 mmol) and 1,4-benzoquinone (20 mg, 0.2 mmol) were added to the solution and the mixture was refluxed for 1 hour. The solvent was removed by rotary evaporation under reduced pressure and the residue was dissolved in water and acetonitrile and purified by reverse phase HPLC (0.02N HCl/ACN) to give 2-(5-acetylsulfamoyl-2-hydroxy-3′-sulfamoyl-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine (14.1 mg) as a yellow amorphous powder. MS m/z: 527.4 (M−H+) and 529.3 (M+H+). 1H NMR (400 MHz, DMSO-d6): δ 9.36 (bs, 2H), 8.94 (bs, 2H), 8.08 (d, J=2.2 Hz, 1H), 8.22 (bs, 1H), 8.10 (t, J=1.5 Hz, 1H), 7.96 (d, J=2.2 Hz, 1H) 7.89 (d, J=1.8 Hz, 1H), 7.87-7.85 (m, 2H), 7.76 (dd, J=10, 1.5 Hz, 1H), 7.71 (t, J=7.7 Hz, 1H), 7.46 (s, 2H) and 1.96 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][N:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].[OH-].[Li+].Cl>C1COCC1.O>[C:20]([O:19][C:17]([N:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])[CH2:4][C:3]([OH:24])=[O:2])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)CN(Cc1ccc(F)cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of crude [tert-butoxycarbonyl-(4-fluoro-2-nitro-benzyl)-amino]-acetic acid methyl ester (5.91 g, 17.2 mmol) in THF (50 mL) was added lithium hydroxide (4.35 g, 103.6 mmol,) dissolved in water (17 mL). The reaction was stirred at r.t. overnight. After completion of the reaction, as confirmed by TLC, the reaction mixture was acidified to pH 4 using 10% HCl and crude compound was extracted with MeOH and CHCl3 (1:9, 3×50 mL). The combined organic layers were dried over Na2SO4. The solvents were removed in vacuo to afford 2-(tert-butoxycarbonyl(4-fluoro-2-nitrobenzyl)amino)-acetic acid (5.11 g, 90%) as brown thick gel, which was used as such without any further purification for the next step.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([NH:8][CH2:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]#[N:18])=[O:11])([CH3:7])[CH3:6].[CH:19](OC1C=CC([N+]([O-])=O)=CC=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]([C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C:10](=[O:11])[CH2:9][NH:8][C:5]([CH3:7])([CH3:6])[CH2:4][NH:3][CH:19]=[O:20])#[N:18]
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(CN)NCC(=O)N1CCC[C@H]1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(CNC=O)NCC(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
(S)-1-[(2-Amino-1,1-dimethylethyl)aminoacetyl]-pyrrolidine-2-carbonitrile dihydrochloride (1.48 g) was dissolved in acetonitrile (50 ml), and 4-nitrophenyl formate (1.00 g) and potassium carbonate (1.37 g) were added thereto and stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; dichloromethane:methanol 5:1) to give (S)-N-{2-[2-(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methyl-1-propyl}-formamide (693 mg, Y.:55%).
Reaction SMILES: CC(O)=O.C([N:12]1[CH2:16][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=2)[C@H:14]([NH:28][C:29](=[O:37])[O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:13]1)C1C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CCO.[Pd]>[F:27][C:24]([F:25])([F:26])[O:23][C:19]1[CH:18]=[C:17]([C@@H:15]2[CH2:16][NH:12][CH2:13][C@H:14]2[NH:28][C:29](=[O:37])[O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])[CH:22]=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)CCOC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1c1cccc(OC(F)(F)F)c1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CC(=O)O
Solvent: CCO
Product: C[Si](C)(C)CCOC(=O)N[C@@H]1CNC[C@H]1c1cccc(OC(F)(F)F)c1
Yield: 83.2 %

Procedure:
AcOH (2 mL) was added to a solution of 2-(trimethylsilyl)ethyl [trans-benzyl-4-(3-trifluoromethoxyphenyl)pyrrolidin-3-yl]carbamate (2.50 g; 6.03 mmol) in EtOH (150 ml). Pd/C (1.25 g, wet, 10% Pd) was then added, and the reaction mixture was put on a par shaker (60 Psi), and reacted for 2 h. The reaction mixture was filtered, and the filtrate was concentrated to provide the title compound (1.96 g, quantitative yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([I:17])=[CH:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(O)C>O>[I:17][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:7][C:2]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:3][CH:4]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2I)cn1
Reactant: C1COCCN1
Solvent: CCO
Solvent: O
Product: COc1ccc(Nc2nc(N3CCOCC3)ncc2I)cn1
Temperature: 140 °C
Yield: 88.9 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-5-iodo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (160 mg, 0.441 mmol), morpholine (0.077 mL, 0.883 mmol) and ethanol (3 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 20 min. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an off-white solid. The crude product was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give 5-iodo-N-(6-methoxypyridin-3-yl)-2-morpholinopyrimidin-4-amine (162 mg, 0.392 mmol, 89% yield). 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J=1.90 Hz, 1H); 8.20 (s, 1H); 7.72 (dd, J=8.77, 2.34 Hz, 1H); 6.75 (d, J=8.92 Hz, 1H); 6.67 (s, 1H); 3.95 (s, 3H); 3.68 (d, J=5.26 Hz, 8H). m/z (ESI, +ve ion) 414.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.O[Li].O.Cl>C1COCC1.O>[OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:21][CH:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1ccc(C#Cc2cccc(O)c2)cc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(C#Cc2cccc(O)c2)cc1

Procedure:
Ethyl 2-(4-((3-hydroxyphenyl)ethynyl)phenoxy)acetate (48.0 mg, 0.162 mmol) was dissolved in THF (1 mL), and LiOH.H2O (20.4 mg, 0.486 mmol) in water (1 mL) was added. The mixture was stirred over night. and 14% HCl (0.2 mL) was added until pH<1. Water (10 mL) was added, and the mixture was extracted with EtOAc (3×10 mL). The combined EtOAc phases was washed with brine (10 mL), dried over MgSO4, and concentrated under reduced pressure. The product was white/yellow and solid (39.5 mg, 92%). Rf=0.02 (EtOAc:hexanes 1:1 v/v). 1H-NMR (DMSO-d6): □ 4.52 (s, 2H, CH2OH); 7.1 (m, 8H, Ph); 9.71 (s, 1H, OH); 12.94 (s, 1H, COOH). 13C-NMR (DMSO-d6): □ 64.5 (OCH2); 88.2 (CC); 88.7 (CC); 114.7, 114.9, 116.0, 117.6, 122.0, 123.5, 129.8, 132.9, 157.3, 158.0 (Ph); 169.9 (COO). EI-MS: m/z calculated for C16H12O4 [M]+268; [C14H9O2]+209; [C8H8O3]+ 152. found 268, 207, 152.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C([BH3-])#N.[Na+].[O:21]1CCC[CH2:22]1>ICI.C[Li]>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][CH2:22][OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1Oc1ccccc1
Reactant: C1CCOC1
Agent: [BH3-]C#N
Agent: [Li]C
Agent: [Na+]
Solvent: ICI
Solvent: O
Product: OCCc1ccccc1Oc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 2-phenoxybenzaldehyde (535 mg) in tetrahydrofuran (5 ml), 0.326 ml of diiodomethane and 5.4 ml of methyllithium (1.0M diethyl ether solution) were added under ice-cooling, and the reaction solution was stirred at the same temperature for 30 minutes and then at room temperature for 1 hour. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford a crude product as a yellow oil. To a solution of the crude product in tetrahydrofuran (5 ml), 284 mg of sodium cyanoborohydride and 0.569 ml of trifluoroborane-diethyl ether complex were added under ice-cooling, and the reaction solution was stirred at the same temperature for 50 minutes. To the reaction solution was added a saturated saline solution, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (95:5-50/50)) to afford the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18](I)[C:9]=2[C:8]1=[O:20].[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18]([C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)[C:9]=2[C:8]1=[O:20]
Reactant: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OB(O)c1ccc(F)cc1
Product: O=C1c2c(-c3ccc(F)cc3)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 100.7 %

Procedure:
In a similar manner to Reference Example 4, 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (300 mg) was reacted with 4-fluorophenylboronic acid (143 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (284 mg, 100%).
Reaction SMILES: [H-].[K+].[Br:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH2:11][CH:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH:20]([CH2:25][CH2:26][CH3:27])[CH2:21][O:22]3)=[CH:17][C:16]=2[F:28])[CH2:13][OH:14])=[C:6](F)[CH:5]=1.C(O)C>C1COCC1.CCOCC>[Br:3][C:4]1[CH:5]=[C:6]2[C:7]([CH2:11][CH:12]([C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH:20]([CH2:25][CH2:26][CH3:27])[CH2:21][O:22]4)=[CH:17][C:16]=3[F:28])[CH2:13][O:14]2)=[CH:8][C:9]=1[F:10]
Reactant: CCCC1COc2cc(C(CO)Cc3cc(F)c(Br)cc3F)c(F)cc2C1
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC1COc2cc(C3COc4cc(Br)c(F)cc4C3)c(F)cc2C1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
1.2 g (10.5 mmol) of potassium hydride (35 percent in paraffin oil) are initially introduced in 40 ml of THF, and a solution of 4.50 g (8.12 mmol) of 3-(4-bromo-2,5-difluorophenyl)-2-(6-fluoro-3-propylchroman-7-yl)propan-1-ol in 20 ml of THF is added dropwise at 30° C. The batch is subsequently stirred at 60° C. for 4 h, a little ethanol is added, and the batch is diluted with MTB ether and washed with sat. sodium chloride soln. The org. phase is dried over sodium sulfate, the solvent is removed in vacuo, and the crude product is filtered through silica gel with toluene and recrystallised from heptane/ethyl acetate, giving 7-bromo-6,6′-difluoro-3′-propyl-3,4,3′,4′-tetrahydro-2H,2′H-[3,7′]-bichromenyl as colourless crystals.