Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4](/[CH:10]=[CH:11]/[CH2:12][CH:13]([OH:15])[CH3:14])[CH2:3]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:15][CH:13]([CH2:12]/[CH:11]=[CH:10]/[C:4]2[CH2:3][N:2]([CH3:1])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=2)[CH3:14])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC1=CN(C)CC(/C=C/CC(C)O)=C1
Solvent: c1ccncc1
Product: COC1=CN(C)CC(/C=C/CC(C)OS(=O)(=O)c2ccc(C)cc2)=C1

Procedure:
In another embodiment, a compound such as (4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-penten-2-amine can be synthesized by coupling a halo-substituted pyridine, 5-bromo-3-methoxypyridine with an olefin containing a secondary alcohol functionality, 4-penten-2-ol, under Heck reaction conditions; and the resulting pyridinyl alcohol intermediate can be converted to its p-toluenesulfonate ester, followed by treatment with methylamine. Typically, the types of procedures set forth in W. C. Frank et al., J. Org. Chem. 43: 2947 (1978) and N. J. Malek et al., J. Org. Chem. 47: 5395 (1982) involving a palladium-catalyzed coupling of an olefin and an aromatic halide are used. The halo-substituted pyridine, 5-bromo-3-methoxypyridine is synthesized using methodology similar to that described by H. J. den Hertog et al., Rec. Trav. Chim. Pays-Bas 67:377 (1948), namely by heating 3,5-dibromopyridine with 2.5 molar equivalents of sodium methoxide in dry methanol in the presence of copper powder (5%, w/w of the 3,5-dibromopyridine) in a sealed glass tube at 150° C. for 14 hours to produce 5-bromo-3-methoxypyridine. The resulting 5-bromo-3-methoxypyridine, previously described by D. L. Comins, et al., J. Org. Chem. 55: 69 (1990), can be coupled with 4-penten-2-ol in acetonitrile-triethylamine (1:1:1, v/v) using a catalyst consisting of 1 mole % palladium(II) acetate and 4 mole % tri-o-tolylphosphine. The reaction is carried out by heating the components in a sealed glass tube at 140° C. for 14 hours to yield (4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-penten-2-ol. The resulting alcohol is treated with 2 molar equivalents of p-toluenesulfonyl chloride in dry pyridine at 0° C. to produce (4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-penten-2-ol p-toluensulfonate. The tosylate intermediate is treated with 120-molar equivalents of methylamine as a 40% aqueous solution, containing a small amount of ethanol as a co-solvent to produce (4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-penten-2-amine. When 3,5-dibromopyridine is submitted to Heck coupling with N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine, under conditions described above, N-methyl-N-(tert-butoxycarbonyl)-5-(5-bromo-3-pyridinyl)-4-penten-2-amine is produced. This can be coupled in a subsequent Heck reaction with styrene and deprotected (removal of the tert-butoxycarbonyl group), as described previously, to give (4E)-N-methyl-5-[3-(5-trans-beta-styrylpyridin)yl]-4-penten-2-amine. Similar second coupling with ethynylbenzene, and subsequent deprotection, will give (4E)-N-methyl-5-[3-(5-phenylethynylpyridin)yl]-4-penten-2-amine.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][S:38][C:39]1[N:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:42]2[CH:43]=[N:44][C:39]([S:38][CH3:37])=[CH:40][CH:41]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CSc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CSc1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Yield: 87.6 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.5 g, 0.96 mmol), 6-methylsulfanyl-pyridine-3-boronic acid (370 mg, 2.2 mmol) and dichlorobis(triphenylphosphine)palladium (II) (67.4 mg, 0.096 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 0.96 mL, 1.92 mmol). The resulting mixture was subjected to microwave irradiation for 3 h at 100° C. The mixture was diluted with ethyl acetate (80 mL), washed with a saturated aqueous sodium bicarbonate solution (2×20 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methylsulfanyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (400 mg, 88%) as a light yellow solid: LC/MS m/e calcd for C26H25N3O2S2 [M+H]+ 476.64, observed 476.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23](O)=[O:24])=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8].[CH3:35][NH:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23]([N:36]([CH3:35])[CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[O:24])=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8]
Reactant: CNCc1cccnc1
Reactant: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)N(C)Cc3cccnc3)n2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
10-(5-chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step G (0.125 g, 0.262 mmol), 3-(methylaminomethyl)pyridine (0.038 g, 0.314 mmol), 1-hydroxy benzotriazole (0.039 g, 0.288 mmol) and 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.055 g, 0.288 mmol) were combined in amine-free N,N-dimethylformamide (1.1 mL), followed by addition of N,N-diisopropylethyl amine (0.068 mL, 0.393 mmol). The reaction was stirred at room temperature for 16 hours, then diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5% methanol in chloroform, and recrystallized from diethyl ether/pentane to afford 0.140 g of the title compound as a white crystalline solid, m.p. 178-179° C., 98.0% pure by analytical HPLC (Primesphere C-18, 2.0×150 mm, 45% acetonitrile/water, 0.2 mL/min.).
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[CH3:20][C:21]1[N:22]=[CH:23][NH:24][C:25]=1[CH2:26][S:27][CH2:28][CH2:29][NH2:30].C(N(CC)CC)C>C(O)C>[CH3:20][C:21]1[N:22]=[CH:23][NH:24][C:25]=1[CH2:26][S:27][CH2:28][CH2:29][NH:30][C:5]1[C:4]2[N:8]=[CH:9][N:10]([C:3]=2[N:2]=[CH:1][N:6]=1)[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]1[OH:19]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc[nH]c1CSCCNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
5.0 g of 6-chloropurine riboside (0.0179 moles) 4.6 g of 4-methyl-5-[(2 aminoethyl)-thiomethyl]-imidazole (0.019 moles), and 8.78 ml of triethylamine (0.063 moles) are refluxed overnight in 100 ml of ethanol. 15 ml of solvent are then removed with nitrogen gas. The crystals formed therefrom are filtered and washed with ethanol. The crystals are then recrystallized from ethanol and washed with diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:18]=2[N:17]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:14])[CH2:13][CH2:12][N:11]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:18]=4[N:17]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Reactant: OC1(c2cccc(Cl)c2)CCNCC1
Product: OC1(c2cccc(Cl)c2)CCN(c2nc3ccc(C(F)(F)F)cc3[nH]2)CC1

Procedure:
4-(3-Chloro-phenyl)-piperidin-4-ol (0.25 g, 1.18 mmol, Aldrich) reacted with 2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.26 g, 1.18 mmol, Example 1c) under the conditions of Example 94d to give the title compound as a white solid. M.p. 246.7-247.4° C. MS (ESI, pos. ion) m/z: 424 (M+1).
Reaction SMILES: CC(C)CC([O-])=O.[C:8](N1C(C2C=CC=CC=2B(O)O)=NN=N1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[O:42][C:43](=[O:92])[C@@H:44]([N:48]([C:86](=[O:91])[CH2:87][CH2:88][CH2:89][CH3:90])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[C:62]2[N:66](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:65]=[N:64][N:63]=2)=[CH:52][CH:51]=1)[CH:45]([CH3:47])[CH3:46]>>[CH3:90][CH2:89][CH2:88][CH2:87][C:86]([N:48]([C@H:44]([C:43]([OH:42])=[O:92])[CH:45]([CH2:46][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:47])[CH2:49][C:50]1[CH:51]=[CH:52][C:53]([C:56]2[C:57]([C:62]3[N:66]=[N:65][NH:64][N:63]=3)=[CH:58][CH:59]=[CH:60][CH:61]=2)=[CH:54][CH:55]=1)=[O:91]
Reactant: OB(O)c1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@H](C(=O)OC)C(C)C
Agent: CC(C)CC(=O)[O-]
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1)[C@H](C(=O)O)C(C)CC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
WO 2007/005967 discloses the condensation of p-Bromobenzylbromide with valine methyl ester to give (S)-methyl-2-(4-bromobenzylamino)-3-methyl butanoate which on reaction with valeryl chloride to give (S)-methyl-2-(4-bromobenzyl)pentanamido)-3-methylbutanoate. (S)-methyl-2-(4-bromobenzyl)pentanamido)-3-methylbutanoate is treated with 2-(1-trityl-1H-tetrazol-5-yl)phenylboronic acid to give (S)-3-methyl-2-{pentanoyl-[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amino}butyric acid methyl ester and base hydrolysis to give trityl valsartan. Triltyl valsartan is treated with an acid to give valsartan.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19]Br)=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:44]([NH2:48])[CH2:45][CH:46]=[CH2:47].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19][NH:48][CH2:44][CH2:45][CH:46]=[CH2:47])=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCN
Reactant: C=CCOc1ccc(C(CC(=O)N=C(Cc2cc(Cl)c(NC(=O)CBr)c(Cl)c2)NC(=O)OC(C)(C)C)=NOCC)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCNCC(=O)Nc1c(Cl)cc(CC(=NC(=O)CC(=NOCC)c2ccc(OCC=C)cc2)NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl-1-(3-(4-(allyloxy)phenyl)-3-(ethoxyimino)-propanoylimino)-2-(4-(2-bromoacetamido)-3,5-dichlorophenyl)ethylcarbamate (100 mg) in dichloromethane (0.30 mL) at room temperature was added but-3-en-1-amine hydrochloride (45 mg) and diisopropylethylamine (97 μL), and the resulting solution was stirred at room temperature for 2 h. The solvents were removed in vacuo to give the title compound as a white solid, which was used for Step B without purification. retention time: 2.11 min (method A). MS (ESI) (M+H)+ 689.20.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:18]1[C:19]([O:35][CH3:36])=[C:20]([C:31]([O:33][CH3:34])=[O:32])[S:21][C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[C:19]([O:35][CH3:36])=[C:20]([C:31]([O:33][CH3:34])=[O:32])[S:21][C:22]=2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[CH:4][CH:3]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2Cl)c(Br)c1OC
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1OC
Reaction time: 18 h
Yield: 75.6 %

Procedure:
7.75 g of (4-chlorophenyl)boronic acid and then, dropwise, 40.93 ml of a 2M solution of Na2CO3 are added to a solution of 16.21 g of the compound of step B) in 110 ml of toluene. Argon is sparged into the reaction mixture for 30 minutes, then 2.36 g of Tetrakis are added and heating is carried out at 110° C. for 18 hours. After cooling to AT, the reaction mixture is rinsed with 80 ml of distilled water, then extraction is carried out with 80 ml of EtOAc, drying is carried out over Na2SO4, and the solvent is evaporated off under vacuum. The reaction crude is purified by silica gel chromatography, elution being carried out with heptane and then with a heptane/EtOAc mixture (85/15; v/v). 13.23 g of the expected compound are obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[CH2:6]([N:8]1[C:12]2[N:13]=[CH:14][C:15]([C:24]3[O:28][N:27]=[C:26]([CH2:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[N:25]=3)=[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:11]=2[CH:10]=[N:9]1)[CH3:7].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[C:1]([N:33]1[CH2:34][CH2:35][CH:30]([CH2:29][C:26]2[N:25]=[C:24]([C:15]3[CH:14]=[N:13][C:12]4[N:8]([CH2:6][CH3:7])[N:9]=[CH:10][C:11]=4[C:16]=3[NH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[O:28][N:27]=2)[CH2:31][CH2:32]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCNCC4)no3)cnc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCN(C(C)=O)CC4)no3)cnc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Acetyl chloride (0.04 mmol) was added to a stirred solution of Intermediate 125 (0.033 mmol) and diisopropylethylamine (0.1 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 1.5 h, a further quantity of acetyl chloride (0.04 mmol) and diisopropylethylamine (0.1 mmol) were added to the reaction mixture. After 3.5 h the reaction mixture was applied to a SPE cartridge (aminopropyl, 1 g) and the cartridge was eluted sequentially with chlororm, ethyl acetate and methanol. Fractions containing the desired product were combined and blown down under nitrogen. The resulting residue was further purified on a SPE cartridge (silica, 1 g) eluting with a gradient of 30-100% ethyl acetate in petroleum ether to afford Example 175 LCMS showed MH+=454, TRET=2.79 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[CH:7][C:6]=1[CH3:17])=O.[NH2:18][C:19]([NH2:21])=[S:20]>CCO>[CH:14]1([CH2:13][O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:18]=[C:19]([NH2:21])[S:20][CH:2]=3)=[C:6]([CH3:17])[CH:7]=2)[CH2:16][CH2:15]1
Reactant: NC(N)=S
Reactant: Cc1cc(OCC2CC2)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(OCC2CC2)cc(C)c1-c1csc(N)n1
Yield: 61.4 %

Procedure:
A mixture of 2-bromo-1-(4-(cyclopropylmethoxy)-2,6-dimethylphenyl)ethanone (4-4, 2.06 g, 7.0 mmol) and thiourea (0.61 g, 8.0 mmol) in 95% EtOH (30.0 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50.0 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and washed with hot water. The solids were filtered and dried under vacuum to give 4-(4-(cyclopropylmethoxy)-2,6-dimethylphenyl)thiazol-2-amine (4-5, 1.18 g) as yellow solids in 61% yield: 1H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 2 H), 6.73 (s, 2 H), 3.81 (d, J=7.0 Hz, 1 H), 2.10 (s, 6 H), 1.19 (s, 1 H), 0.55 (m, 2 H), 0.30 (m, 2 H).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[CH2:21]([O:23][CH2:24][CH:25]=[O:26])[CH3:22]>C1COCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[CH:25]([OH:26])[CH2:24][O:23][CH2:21][CH3:22]
Reactant: CCOCC=O
Reactant: Fc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOCC(O)c1c(F)cncc1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-BuLi (2.66 mL, 4.26 mmol) was added to a solution of diisopropylamine (0.607 mL, 4.26 mmol) in THF (10 mL) at −78° C. After 30 min, 3-bromo-5-fluoropyridine (0.500 g, 2.84 mmol) in THF (10 mL) is added dropwise. The mixture was stirred at −78° C. for 1 hr, and 2-ethoxyacetaldehyde (0.464 g, 4.26 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 2 hrs. The reaction is quenched with a saturated aqueous NaHCO3 solution and the cooling bath was removed. The mixture was shaken with ethyl acetate and the organic phase is washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography employing heptane-ethyl acetate (4:1) to give 1-(3-bromo-5-fluoro-pyridin-4-yl)-2-ethoxy-ethanol. MS (ESI) m/z 266.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].O.[NH:14]1[CH2:17][CH2:16][CH:15]1C(O)=O>C1(C)C=CC=CC=1>[N:14]12[CH2:17][CH2:16][CH:15]1[CH2:3][CH:2]1[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]1
Reactant: C=CCN(CC=O)C(=O)OCC
Reactant: O=C(O)C1CCN1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC3CCN3C2C1

Procedure:
17.1 g (0.1 mol) of ethyl N-allyl-N-(2-oxoethyl)-carbamate are heated under reflux overnight in a water separator with 10 g (0.1 mol) of azetidine-2-carboxylic acid in 200 ml of toluene. Unreacted amino acid is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]([N:17]3[CH:21]=[CH:20][C:19]([CH3:22])=[N:18]3)=[C:12]([C:14]([OH:16])=O)[CH:13]=2)[CH:5]=[N:6][CH:7]=1.[CH3:23][N:24]1[C:33]2[C:28](=[CH:29][C:30]([CH2:34][NH2:35])=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1.CCCP(O)(O)=O.CCN(C(C)C)C(C)C>C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]([N:17]3[CH:21]=[CH:20][C:19]([CH3:22])=[N:18]3)=[C:12]([C:14]([NH:35][CH2:34][C:30]3[CH:29]=[C:28]4[C:33](=[CH:32][CH:31]=3)[N:24]([CH3:23])[CH2:25][CH2:26][CH2:27]4)=[O:16])[CH:13]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1cncc(-c2cnc(-n3ccc(C)n3)c(C(=O)O)c2)c1
Reactant: CN1CCCc2cc(CN)ccc21
Agent: CCCP(=O)(O)O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cncc(-c2cnc(-n3ccc(C)n3)c(C(=O)NCc3ccc4c(c3)CCCN4C)c2)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of 5′-methyl-6-(3-methyl-1H-pyrazol-1-yl)-3,3′-bipyridine-5-carboxylic acid (5-2, 0.025 g, 0.085 mmol) and 1-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)methanamine (0.015 g, 0.085 mmol) in ACN (0.85 mL) was added 1-propylphosphonic acid cyclic anhydride (T3P, 0.15 mL, 0.255 mmol) followed by Hunig's base (0.089 mL, 0.51 mmol) and the system was stirred at 40° C. for 1 h in an oil bath. The reaction mixture was cooled and partitioned between EtOAc and water, washed with saturated sodium bicarbonate and dried over magnesium sulfate. The reaction mixture was filtered, concentrated and purified via normal phase chromatography (0→10% MeOH in EtOAc) to afford the title compound (5-3) as a bone powder. 1H NMR (500 MHz, CDCl3) δ 8.68 (m, 1H), 8.51 (m, 1H), 8.29 (m, 1H), 8.22 (m, 1H), 7.72 (m, 1H), 7.12 (m, 1H), 7.0 (m, 1H), 6.90 (m, 1H), 6.54 (m, 1H), 6.27 (m, 1H), 4.46 (m, 2H), 3.22(m, 2H), 2.88 (s, 3H), 2.74 (m, 2H), 2.44 (s, 3H), 2.28 (s, 3H), 1.97 (m, 2H). HRMS [M+H] C27H28N6O calc'd 453.2391, found 453.2397.
Reaction SMILES: [C:1]([Si:3]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])[CH:4]([CH3:6])[CH3:5])#[CH:2].[Li]CCCC.[CH3:18][N:19]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20]1>O1CCCC1.CCOC(C)=O>[CH3:18][N:19]1[CH2:23][CH2:22][C:21]([C:2]#[C:1][Si:3]([CH:7]([CH3:9])[CH3:8])([CH:4]([CH3:6])[CH3:5])[CH:10]([CH3:12])[CH3:11])([OH:24])[CH2:20]1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: CN1CCC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[Si](C#CC1(O)CCN(C)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure B. Into a solution of Ethynyl-triisopropyl-silane (1.1 g, 6 mmol) in tetrahydrofuran (10 mL) was dropped in n-BuLi (2.4 mL, 6 mmol) at −78° C. The solution was stirred for 0.5 h. Then 1-Methyl-pyrrolidin-3-one (0.5 g, 5 mmol) was added. The solution was allowed to warm up to room temperature and stirred for 3 h. Then the reaction mixture was added in 50 mL EtOAc and washed with water three times. The solvent was removed under vacuum to afford 1-Methyl-3-[(triisopropylsilanyl)-ethynyl]-pyrrolidin-3-ol (0.55 g, 39%). 1H NMR (DMSO-d6, 400 MHz): δ 5.53 (s, 1H), 2.74-2.63 (m, 2H), 2.46-2.44 (m, 1H), 2.23 (s, 3H), 2.13-1.96 (m, 2H), 1.07-0.97 (m, 21H). A solution of 1-Methyl-3-[(triisopropylsilanyl)-ethynyl]-pyrrolidin-3-ol (1.0 g, 3.6 mmol) in tetrahydrofuran (10 mL) was treated with Tetrabutyl-ammonium fluoride (0.94 g, 3.6 mmol). The solution was stirred overnight at room temperature. Then the reaction mixture was purified by column (eluent: CH2Cl2: MeOH=10:1) to afford 3-Ethynyl-1-methyl-pyrrolidin-3-ol (0.26 g, 58%). 1H NMR (DMSO-d6, 400 MHz): δ 5.55 (s, 1H), 3.31 (s, 1H), 2.74-2.56 (m, 3H), 2.49-2.46 (m, 1H), 2.22 (s, 3H), 2.11-1.91 (m, 2H).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:20]1(B(O)O)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[CH:20]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2CC2)C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 39.7 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.609 mmol), cyclopropylboronic acid (78.5 mg, 0.914 mmol), saturated aqueous sodium carbonate solution (3 ml), and tetrakis(triphenylphosphine)palladium(0) (19.0 mg, 0.0172 mmol) in dimethoxyethane (5 ml) was stirred at 90° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (70.0 mg, 39.8%) as an oil.