Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH:25]1([CH2:24][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([C:10]([F:21])([F:22])[F:9])=[CH:16][CH:15]=2)[C:18]([OH:20])=[O:19])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: ICC1CCCC1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (4-trifluoromethyl-phenyl)-acetic acid (693 mg, 3.4 mmol) in tetrahydrofuran/hexamethylphosphoramide (8.5 mL, 3:1). The resulting solution was stirred at −78° C. for 30 min. Iodomethylcyclopentane (784 mg, 3.7 mmol) was then added in hexamethylphosphoramide (1 mL). The mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). The excess solvent was removed in vacuo. The residue was acidified to pH=1 with a 1N aqueous hydrochloric acid solution. The mixture was then poured into water (150 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acid (634.9 mg, 65%) as a white solid: mp 94–95° C.; EI-HRMS m/e calcd for C15H17F3O2 (M+) 309.1079, found 309.1072.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([CH:27]2[CH2:29][CH2:28]2)[CH:3]=1.[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20]([N:30]5[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]5)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([CH:27]2[CH2:28][CH2:29]2)[CH:3]=1
Reactant: O=C(O)C1CNC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C3CC3)c2)S1
Product: O=C1NC(N2CC(C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C2CC2)c1

Procedure:
1-(5-[1-(4-Chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-dihydro-thiazol-2-yl]-azetidine-3-carboxylic acid was prepared from 5-[1-(4-chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and azetidine-3-carboxylic acid following General Procedure C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:22]1[CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:20][CH2:19][CH2:18][O:17][C:15]2[CH:14]=[CH:13][C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)=[N:9][S:10][C:11]=3[CH:16]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C1CNC1
Product: Brc1ccc(-c2nsc3cc(OCCCN4CCC4)ccc23)cc1

Procedure:
According to the method in example 4, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and azetidine were converted to yield 6-(3-Azetidin-1-yl-propoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole, MS: 404 (MH+, 1Br).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[O:10][N:9]=1.C(C1[O:20][CH2:19]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:1]1[C:7]2[C:2]1=[C:3]([C:8]1[C:12]3[S:13][CH:14]=[CH:15][C:11]=3[O:10][N:9]=1)[CH:4]=[CH:5][C:6]=2[O:20][CH3:19]
Reactant: BrCC1CO1
Reactant: Oc1ccccc1-c1noc2ccsc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2noc3ccsc23)c2c1O2
Temperature: 25 °C
Reaction time: 28 h
Yield: 73.4 %

Procedure:
A mixture of 6.3 g of 3-(2-hydroxyphenyl)thieno[2,3-d]isoxazole, 5 g of epibromohydrin and 2.6 g of potassium carbonate in 37 ml of acetonitrile was stirred under nitrogen at 70°-80° C. until completion of the reaction. The reaction was complete fter 28 hours and the mixture was left to cool to room temperature. Quenching with water, extraction with ether/ethyl acetate (1:1), washing and drying (over anhydrous magnesium sulfate) gave 6.34 g of a crude oil. The epoxide was separated by high performance liquid chromatography (HPLC hereafter) using ethyl acetate/hexane (2:1) as an eluent, yielding 5.22 g of crystal This was recrystallized from ether/hexane, m.p. 65°-67° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=[C:10]([C:21]([NH:35][C@@H:33]([C:30]3[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=3)[CH3:34])=[O:23])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(Oc3ncccn3)cc(C(=O)O)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(Oc3ncccn3)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(pyrimidin-2-yloxy)biphenyl-3-carboxylic acid (20 mg, 0.065 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (30 mg, 0.143 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (60 mg, 0.16 mmol), and N,N-diisopropylethylamine (200 μL, 1.15 mmol). The reaction mixture was stirred at room temperature for 16 hours. LC-MS indicated the reaction was complete. The reaction mixture was purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford a light color solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:16]=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH:16]=[N:15]2)[N:3]=1
Reactant: C#CCCn1cc(-c2ccccc2C)cn1
Reactant: FCc1cccc(Br)n1
Product: Cc1ccccc1-c1cnn(CCC#Cc2cccc(CF)n2)c1
Yield: 30000 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.26 mmol) and 1-but-3-ynyl-4-o-tolyl-1H-pyrazole (50 mg, 0.24 mmol, Example 142(A)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 23 mg (72 mmol, 30%) of 2-(fluoromethyl)-6-(4-(4-o-tolyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a yellow solid with a purity of 81%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:22]([CH3:23])[C:21]([CH3:24])=[N:20][CH:19]=1>CN(C=O)C>[CH3:23][N:22]1[C:18]([CH2:17][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)=[CH:19][N:20]=[C:21]1[CH3:24]
Reactant: Cc1ncc(CBr)n1C
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cnc(C)n2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (764 mg, 5.4 mmol) was dissolved in anhydrous DMF (30 mL), then potassium carbonate (2.23 g, 16.1 mmol) and 5-(bromomethyl)-1,2-dimethyl-1H-imidazole (1.52 g, 8.1 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 20% DCM in MeOH to afford 2-{[(1,2-dimethyl-1H-imidazol-5-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (279 mg, 21% yield for 3 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 2.24 (s, 3H), 3.46 (s, 3H), 4.40 (s, 2H), 5.99 (s, 1H), 6.72 (s, 1H); LRMS (ES+) m/z 251 (50%, M+1).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:7]([SiH:10]([Cl:12])[Cl:11])[CH:8]=[CH2:9]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:11][Si:10]([Cl:12])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:7][CH:8]=[CH2:9]
Reactant: C=CCCCC
Reactant: C=CC[SiH](Cl)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: C=CC[Si](Cl)(Cl)CCCCCC
Yield: 79283.8 %

Procedure:
Using the same apparatus and procedure described in EXAMPLE 1, 59.7 g (0.71 mol) of 1-hexene and 80 μl of 1% chloroplatinic acid in isopropanol were added to the flask. Through the dropping funnel was added dropwise 10 g (0.07 mmol) of allyldichlorosilane for 30 rain while refluxing. After confirming by gas chromatography to complete the reaction, vacuum distillation (48°-50° C./0.5 torr) gave 12.5 g (79.3%) of 4,4-dichloro-4-sila-1 -decene.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH:27]1([N:30]([CH3:37])[C@@H:31]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]2)[CH2:29][CH2:28]1>>[CH:27]1([N:30]([CH3:37])[C@@H:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([N:12]4[C:13]([OH:14])=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=5[CH3:24])[CH:10]=[N:11]4)=[N:16][CH:17]=3)=[O:21])[CH2:32]2)[CH2:29][CH2:28]1
Reactant: CN(C1CC1)[C@@H]1CCCNC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCC[C@@H](N(C)C4CC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)—N-cyclopropyl-N-methylpiperidin-3-amine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.13-0.61 (m, 4H) 1.38-1.64 (m, 2H) 1.64-2.09 (m, 3H) 2.15-2.41 (m, 3H) 2.43 (s, 3H) 2.55-2.86 (m, 2H) 3.04 (br. s., 1H) 3.49-3.87 (m, 1H) 4.33-4.77 (m, 1H) 7.65 (dd, J=8.08, 1.52 Hz, 1H) 7.72 (s, 1H) 7.81 (d, J=8.08 Hz, 1H) 8.05 (dd, J=8.59, 2.02 Hz, 1H) 8.13 (s, 1H) 8.40 (d, J=7.33 Hz, 1H) 8.53 (d, J=1.77 Hz, 1H); ESI-MS m/z [M+H]+ 457.3.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:4]2=[C:3]([C:10]2[N:15]=[C:14](O)[CH:13]=[CH:12][N:11]=2)[CH:2]=1.P(Cl)(Cl)([Cl:19])=O.[OH-].[Na+]>C(OCC)(=O)C>[Cl:19][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([C:3]2[CH:2]=[N:1][N:5]3[CH:6]=[CH:7][N:8]=[CH:9][C:4]=23)[N:15]=1
Reactant: Oc1ccnc(-c2cnn3ccncc23)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Clc1ccnc(-c2cnn3ccncc23)n1
Temperature: 25 °C
Yield: 104.8 %

Procedure:
A solution of 2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol (Preparation 10b, 150 mg, 0.7 mmol) in phosphorous oxychloride (1.42 mL, 15.51 mmol) was heated overnight at 110° C. After cooling to ambient temperature, the reaction mixture was poured with caution onto water and basified by addition of a 2N aqueous sodium hydroxide solution. Ethyl acetate was then added and the organic phase was separated, washed with water and brine, dried (MgSO4), filtered and evaporated under reduced pressure to yield the title compound (170 mg, 87%) as a solid which was used in the next synthetic step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[N:6]1[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:33][CH3:34].[CH3:36][O:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:1][O:2][C:3](=[O:35])[CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:42]3[CH:41]=[CH:40][CH:39]=[C:38]([O:37][CH3:36])[CH:43]=3)=[CH:18][CH:17]=2)[N:6]1[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:33][CH3:34]
Reactant: COC(=O)CC1c2cccc(F)c2N=C(c2ccc(Br)cc2)N1c1cc(C(F)(F)F)ccc1OC
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)CC1c2cccc(F)c2N=C(c2ccc(-c3cccc(OC)c3)cc2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
Starting from 1.00 g (1.81 mmol) of the bromide from Example 11A, reaction by general method [D] with 0.33 g (2.18 mmol) of 3-methoxyphenylboronic acid, 0.06 g (0.09 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.23 g (2.18 mmol) of sodium carbonate in 20 ml of 1,2-dimethoxyethane and 1 ml of water results in 466 mg (44% of theory) of the target compound.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:7]=1[C:17]#[N:18])C.S(=O)(=O)(O)[OH:21]>>[NH2:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:7]=1[C:17]([NH2:18])=[O:21]
Reactant: O=S(=O)(O)O
Reactant: CCCCCSc1nsc(NC(=O)OCC)c1C#N
Product: CCCCCSc1nsc(N)c1C(N)=O
Temperature: 10 °C
Yield: 100 %

Procedure:
A mixture of (4-Cyano-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acid ethyl ester (2.7 g, 9.0 mmol) and concentrated sulfuric acid (5 mL) was heated to 10° C. for 6 hours. After cooling to ambient temperature, the mixture was diluted with ice water, extracted three times with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, affording 2.2 g (100%) of 5-amino-3-pentylsulfanyl-isothiazole-4-carboxylic acid amide as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.26 (t, 2H, J=7.2 Hz), 1.71 (m, 2H), 1.43-1.19 (m, 4H), 0.86 (1, 3H, J=6.8 Hz) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1I.[C:23]([C:25]1[CH:26]=[C:27]([NH:31][C:32]([C:34]2[O:35][CH:36]=[CH:37][C:38]=2[CH3:39])=[O:33])[CH:28]=[CH:29][CH:30]=1)#[CH:24].C(N(CC)CC)C>CN(C=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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:24]#[C:23][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([C:34]2[O:35][CH:36]=[CH:37][C:38]=2[CH3:39])=[O:33])[CH:26]=1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(I)c1
Reactant: C#Cc1cccc(NC(=O)c2occc2C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3occc3C)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.9 %

Procedure:
The solution of methyl 5-{N-[(6-amino-5-iodopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}pentanoate, (565 mg, 1.28 mmol) in anhydrous DMF (7 mL) was degassed with anhydrous nitrogen and then to the solution was added 3-methyl-furan-2-carboxylic acid (3-ethynyl-phenyl)-amide (376.5 mg, 1.3 eq), bis(triphenylphosphine)palladium(II) dichloride (90.3 mg, 0.1 eq), triphenyl phosphine (8.4 mg, 0.025 eq), triethylamine (0.75 mL, 4 eq) and lastly copper(I) iodide (50 mg, 0.2 eq) under anhydrous nitrogen atmosphere. The reaction mixture was stirred at RT for about 15 minutes and then partitioned between saturated aq NaHCO3 and EtOAc. The organic layer was washed one more time with saturated aq NaHCO3, then with aq NH4Cl (1×), brine (1×), and dried with anhydrous Na2SO4 overnight. The upper solution layer was decanted and concentrated. The oily residue was subject to gradient column chromatography. Concentration of the product eluting fractions gave the title compound as white foam (480 mg, 70%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]([NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24](O)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:51][CH2:52][CH2:53][C:54]#[N:55]>C1COCC1>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]([NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24](=[O:25])[NH:55][CH2:54][CH2:53][C:52]#[N:51])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O
Reactant: N#CCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)NCCC#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
Next, to a solution of (R)-4-biphenyl-4-yl-3-(3-carboxy-propionylamino)-butyric acid ethyl ester (200 mg, 0.522 mmol) in THF (10 mL) at room temperature is added EDC HCl (120 mg, 0.626 mmol) and HOBT (96 mg, 0.626 mmol). The reaction is stirred at room temperature for 10 minutes then added 3-aminopropionitrile (0.046 ml, 0.626 mmol) and TEA (0.087 ml, 0.626 mmol). After 1 hour, 0.5 equivalent of EDC HCl, HOBT, and 3-aminopropionitrile are added and stirred for 16 hours. The reaction mixture is quenched by brine and is extracted with ethylacetate. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue is purified by flash chromatography (silica gel, 2% to 5% EtOH/DCM) to give (R)-4-biphenyl-4-yl-3-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-butyric acid ethyl ester (218 mg, 96% yield). HPLC retention time=0.77 minutes (condition E); MS=436 (m+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[N:18]=[C:17]([NH:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:16]2[C:15]([CH3:27])=[N:14][C:13]([NH2:28])=[N:12][C:11]=2[CH2:10]1.[CH3:29][O:30][C:31]1[N:36]=[C:35](B2OCCN(C3C=CC=CC=3)CCO2)[CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C.C(OCC)(=O)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C@@H:9]2[N:18]=[C:17]([NH:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:16]3[C:15]([CH3:27])=[N:14][C:13]([NH2:28])=[N:12][C:11]=3[CH2:10]2)=[C:2]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([O:30][CH3:29])[N:36]=2)[CH:7]=1
Reactant: COc1cccc(B2OCCN(c3ccccc3)CCO2)n1
Reactant: Cc1nc(N)nc2c1C(NOC1CCCCO1)=N[C@@H](c1ccc(F)cc1Br)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3C(NOC3CCCCO3)=N2)n1
Temperature: 85 °C
Yield: 124.7 %

Procedure:
(7R)-7-(2-bromo-4-fluorophenyl)-4-methyl-5-(tetrahydro-2H-pyran-2-yloxyamino)-7,8-dihydropyrido[4,3-d]pyrimidin-2-amine (0.838 g, 1.86 mmol), 2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (1.33 g, 4.47 mmol), sodium carbonate 2M solution (3.72 mL, 7.44 mmol) were combined in N,N-Dimethylacetamide (12 mL) and then the mixture was purged with nitrogen for 5 minutes. 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (0.136 g, 0.186 mmol) was then added and the reaction was heated in 85° C. oil bath overnight. Next day, the reaction was diluted with ethyl acetate 80 mL, washed with brine (80 mL), dried over sodium sulfate, and concentrated to a crude product which was then purified by flash column chromatography, SiO2, gradient 20-100% ethyl acetate/hexane to give a white solid, 1.11 g of product, contaminated with the impurity of mass 182 (byproduct from the boronic ester, compound 6). MS (ES) [M+H] calc'd for C25H27FN6O3, 479. found, 479.4.
Reaction SMILES: COC([O:7][CH3:8])N(C)C.C[C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:11]=1[C:12]#[N:13].P([O-])([O-])([O-])=O>CN(C=O)C.C1COCC1>[CH:8]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:11]=1[C:12]#[N:13])=[O:7]
Reactant: COC(OC)N(C)C
Reactant: Cc1cccc([N+](=O)[O-])c1C#N
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1c(C=O)cccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 3 h
Yield: 18.8 %

Procedure:
1,1-Dimethoxy-N,N-dimethylmethanamine (13.56 mL, 102 mmol) was added to a solution of 2-methyl-6-nitrobenzonitrile (15.0 g, 92.5 mmol) in anhydrous DMF (60 mL) under nitrogen and was heated at 130° C. for 15 h. Ice water (300 mL) was added, and the resultant dark precipitate was collected by filtration and dried under vacuum. Phosphate buffer (pH 7, 350 mL) and then NaIO4 (40 g, 187 mmol) were added to a solution of the dark precipitate in THF (350 mL) and stirred at rt for 3 h. The mixture was extracted with EtOAc, the combined extract was washed with brine and dried with MgSO4. The filtrate was concentrated and the residue was purified by chromatography on silica using the solvent gradient hexanes→EtOAc, to give 3.07 g (19%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (t, J=8.4 Hz, 1H), 8.41 (dd, J=1.2, 7.6 Hz, 1H), 8.62 (dd, J=1.2, 8.4 Hz, 1H), 10.25 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:32])[CH2:8][CH2:9][CH2:10][C:11]([CH3:31])(O)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH3:29])(O)[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:3].CCCCCCC>[Pd].C(O)(=O)C>[CH3:26][CH:24]([CH2:23][CH2:22][CH2:21][CH:20]([CH2:19][CH2:18][CH2:17][CH:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][CH2:8][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:32])[CH3:31])[CH3:29])[CH3:27])[CH3:25]
Reactant: CC(C)CCCC(C)CCCC(C)(O)CCCCC(C)(O)CCCC(C)CCCC(C)C
Agent: [Pd]
Solvent: CCCCCCC
Solvent: CC(=O)O
Product: CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C

Procedure:
In a 300 ml autoclave were placed 20 g of 2,6,10,15,19,23-hexamethyltetracosane-10,15-diol, 40 ml of n-heptane, 0.4 ml of acetic acid and 0.4 g of 5 % palladium on active carbon and the mixture was hydrogenated at 200° C under a hydrogen pressure of 100 kg/cm2 for 15 hours to give squalane quantitatively.
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][CH2:9][CH2:10][Cl:11])=[O:7])[CH:2]([CH3:4])[CH3:3].C(O)C.[N:15]([O-])=[O:16].[Na+]>Cl.O>[CH2:1]([NH:5][C:6]([N:8]([CH2:9][CH2:10][Cl:11])[N:15]=[O:16])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: O=N[O-]
Reactant: CC(C)CNC(=O)NCCCl
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)CNC(=O)N(CCCl)N=O
Reaction time: 2 h
Yield: 70 %

Procedure:
A 2 g (11.2 mmol) quantity of 1-isobutyl-3-(2-chloroethyl) urea was dissolved in 25 ml of concentrated HCl:ethanol, 2:1, and cooled to 5° C. A solution of 773 mg (11.2 mmol) of sodium nitrite in 5 ml of water was added in portions and the mixture was stirred at this temperature for 2 hrs. The crystalline yellow solid was filtered and dried in vacuo overnight giving 1.6 g (70%) of the product, MP 51° C. (decomposes). IR analysis showed peaks at 1705/cm (C=O) and 1525/cm (C--N=O). NMR: Doublet (6H, J=6.8 Hz) at 0.9 ppm, multiplet (1H) at 2.0 ppm, multiplet (6H) at 3.7 ppm.