Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=3)[NH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].I.CS[C:24]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)=[NH:25]>C(O)C.[Pd]>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:24]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[NH:25])[CH:16]=3)[NH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CSC(=N)c1cccs1
Reactant: CCN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Agent: I
Solvent: CCO
Product: CCN1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 4 h
Yield: 65.5 %

Procedure:
A solution of 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole (60) (0.1 g, 0.368 mmol) in dry ethanol (5 mL) was treated with 10% Pd—C (0.02 g), purged with hydrogen gas and stirred for 4 h under hydrogen atm. (balloon pressure). The solid was filtered off using celite bed and washed with dry ethanol (2×5 mL). The combined ethanol layer was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.21 g, 0.737 mmol) and stirred for 24 h at room temperature. The solvent was evaporated and product was precipitated with ether (100 mL). The solid was filtered and dissolved into sat. NaHCO3 sol.: CH2Cl2 (50 mL, 1:1). The org. layer was separated and aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (2M NH3 in methanol: CH2Cl2, 5:95) to obtain N-(3-(1-ethylpiperidin-4-yl)-1H-indol-5-yl)thiophene-2-carboximidamide (61) (0.085 g, 66%) as a solid. mp 150-152° C.; 1H NMR (DMSO-d6) δ1.01 (t, 3H, J=6.9 Hz), 1.59-1.75 (m, 2H), 1.90-2.05 (m, 4H), 2.35 (q, 2H), 2.65-2.73 (m, 1H), 2.94-2.97 (m, 2H), 6.23 (brs, 1H), 6.62 (dd, 1H, J=1.2, 8.4 Hz), 6.97 (s, 1H), 7.02 (d, 1H, J=2.1 Hz), 7.09 (t, 1H, J=4.2 Hz), 7.26 (d, 1H, J=8.4 Hz), 7.58 (d, 1H, J=5.4 Hz), 7.70 (d, 1H, J=3.6 Hz), 10.59 (s, 1H); ESI-MS m/z (%): 353 (M+, 100).
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20](Cl)=[O:21])=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([CH:7]2[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][C:8]2=[O:9])=[O:21])=[CH:14][CH:13]=1
Reactant: COc1ccc(CCC(=O)Cl)cc1
Reactant: O=C1CC(=O)NC(=O)N1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(CCC(=O)C2C(=O)NC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
To a suspension of barbituric Acid (6.4 g) in 48 ml of pyridine are added dropwise 11 g of 3-(4-Methoxyphenyl)propionyl chloride and the mixture is stirred at room temperature for 18 hours. The reaction mixture is then poured into ice and acidified to pH=1 by adding 6 N hydrochloric acid. A solid precipitates, which is filtered and resuspended in methanol. The suspension is kept under stirring for 15 minutes, then the solid is recovered by filtration to give 12.2 g of the product m.p. 248-250° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[N:6][CH:7]=1.[BH4-].[Na+].O.[NH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:14])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: N
Reactant: CC(=O)c1cncc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(N)c1cncc(Br)c1
Temperature: 0 °C

Procedure:
To a solution of 1-(5-bromo-pyridin-3-yl)-ethanone (400 mg, 2 mmol) in methanolic ammonia (10 mL) was added Ti(O-iPr)4 (1.14 g, 4 mmol). The resulting reaction mixture was heated to reflux and stirred over night. After cooling at 0° C., NaBH4 was added into the mixture and it was allowed to warm up to room temperature and stirred for 3 hours. Water was added and the reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. It was directly used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH:18]([CH3:20])[CH3:19])[NH:5][C:6]([O:8]C1C=CC([N+]([O-])=O)=CC=1)=O.[CH:22]([C:25]1[O:26][CH:27]=[C:28]([CH2:30][NH:31][CH3:32])[N:29]=1)([CH3:24])[CH3:23]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH:18]([CH3:19])[CH3:20])[NH:5][C:6]([N:31]([CH3:32])[CH2:30][C:28]1[N:29]=[C:25]([CH:22]([CH3:23])[CH3:24])[O:26][CH:27]=1)=[O:8]
Reactant: COC(=O)[C@@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)C
Reactant: CNCc1coc(C(C)C)n1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)N(C)Cc1coc(C(C)C)n1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
A solution of N-(((4-nitrophenyl)oxy)carbonyl)-L-valine methyl ester (0.903 g, 0.00305 mol) in anhydrous DMF (6 mL) was added to a solution of 2-isopropyl-4-(((N-methyl)amino)methyl)oxazole (9, 0.470 g, 0.00305 mol) in anhydrous DMF (6 mL) under argon, and the yellow solution was stirred at room temperature for 30 min. Solvent was removed by rotary evaporation in vacuo and the resulting oil dried on high vacuum for 1 hr. The residue was applied to a 150 g SiO2 flash column and eluted with 20% EtOAc/CH2Cl2 and 3% MeOH/CH2Cl2. The material obtained after concentration of the product fractions was repurified on a 100 g SiO2 flash column with a gradient of MeOH/CH2Cl2 (1%, 2%, 3%) to obtain the desired compound as an oil (0.515 g, 0.00165 mol, 54 %): 1H NMR (CDCl3) δ 0.97 (dd, J1 =9 Hz, J2 =6.9 Hz, 6H), 1.33 (d, J=6.9 Hz, 6H), 2.11-2.23 (m, 1H), 2.98 (s, 3H), 3.00-3.13 (m, 1H), 3.77 (s, 3H), 4.23-4.36 (m, 2H), 4.36-4.42 (m, 1H), 5.79-5.86 (br d, 1H), 7.46 (s, 1H). Mass spectrum: (M+H)+ =312.
Reaction SMILES: [CH2:1]([C:8]1([C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[O:15][CH2:16][CH2:17][NH:18][S:19]([C:22]2[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=2)(=[O:21])=[O:20])[CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[F:38][CH2:39][C:40](Cl)=[O:41]>ClCCl>[CH2:1]([C:8]1([C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[O:15][CH2:16][CH2:17][NH:18][S:19]([C:22]2[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=2)(=[O:21])=[O:20])[CH2:11][N:10]([C:40](=[O:41])[CH2:39][F:38])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cnc(S(=O)(=O)NCCOc2cccc(C3(Cc4ccccc4)CNC3)c2)c1
Reactant: O=C(Cl)CF
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: Cn1cnc(S(=O)(=O)NCCOc2cccc(C3(Cc4ccccc4)CN(C(=O)CF)C3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(2-(3-(3-benzylazetidin-3-yl)phenoxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (81 mg, 0.190 mmol) in dry dichloromethane (1.5 ml) containing diisopropylamine (0,066 ml, 0,380 mmol) under argon was added fluoroacetyl chloride (0.022 ml, 0.285 mmol) and stirred at room temperature for 1 h. Washed with 1N HCl, sodium bicarbonate and brine, dried over MgSO4, filtered, evaporated and the crude material was purified by flash silica gel chromatography on 4 g SiO2-cartridge using 5% MeOH in dichloromethane affording 68.7 mg of a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=1>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:20]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: ClCc1cc(-c2ccccc2)no1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cc(-c2ccccc2)no1

Procedure:
Synthesized in a manner similar to Example 23 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-(chloromethyl)-3-phenylisoxazole: 1H NMR (400 MHz, acetone-d6) δ 8.06 (d, J=8.6 Hz, 1H), 7.84-7.80 (m, 2H), 7.69 (d, J=8.4 Hz, 1H), 7.48-7.44 (m, 3H), 6.88 (s, 1H), 6.69 (s, 1H), 5.86 (s, 2H), 2.69 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27][CH2:26]2>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:23]([F:22])[CH:24]=4)[CH2:29]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Reactant: Fc1ccc2c(c1)CCNC2
Agent: Cl
Product: O=C(c1nc(-c2ccc(F)cc2)nc2ccccc12)N1CCc2cc(F)ccc2C1
Yield: 24 %

Procedure:
Reaction of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 11 (24.0% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.90 and 3.13 (2t, 2H), 3.59 and 4.20 (2t, 2H), 4.51 and 5.10 (2s, 2H), 6.79-7.27 (m, 5H), 7.59-7.66 (m, 1H), 7.95-8.05 (m, 2H), 8.16-8.18 (m, 1H), 8.63-8.69 (m, 2H); 19F (282 MHz, DMSO-d6) δ −109.7, −115.1, −115.6; MS (ESI) m/z 402 ([M+H]+).
Reaction SMILES: N#N.[O:3]=[C:4]([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14](Cl)=[O:15])[N:13]=1.[N-:18]=[N+:19]=[N-:20].[Na+]>CC(C)=O.O>[O:3]=[C:4]([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14]([N:18]=[N+:19]=[N-:20])=[O:15])[N:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)CCCCc1nc(C(=O)Cl)co1
Agent: N#N
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)CCCCc1nc(C(=O)N=[N+]=[N-])co1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of this crude 2-(5-oxo-hexyl)-oxazole-4-carbonyl chloride was dissolved in dry acetone (19.0 mL). The solution was cooled to 0° C. and a solution of sodium azide (315 mg, 4.79 mmol) in H2O (2.2 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 1.5 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in CH2Cl2 and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a brown solid. LC-MS-conditions 02: tR=0.82 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4](Cl)[N:3]=1.[C:10]1([P:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:17]C)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClC1C=CC=CC=1Cl>[C:10]1([P:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:2]2[N:7]=[C:6]([P:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:17])[CH:5]=[C:4]([P:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:17])[N:3]=2)=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COP(c1ccccc1)c1ccccc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: Clc1ccccc1Cl
Product: O=P(c1ccccc1)(c1ccccc1)c1cc(P(=O)(c2ccccc2)c2ccccc2)nc(P(=O)(c2ccccc2)c2ccccc2)n1
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a stirred, refluxing mixture of 5.00 g of 2,4,6-trichloropyrimidine in 100 ml of o-dichlorobenzene under nitrogen was added dropwise 26.00 g of methyl diphenylphosphinite. After the addition was completed, the mixture was refluxed for 6.5 hours and then allowed to stand overnight at room temperature. The next day a small amount of the solvent was removed by boiling, and the solution was allowed to stand again overnight. The next day the resulting solid was separated by filtration, washed twice with benzene and three times with hexane, recrystallized from 650 ml of toluene, and dried at 100° C./0.1 mm (13 Pa) to give 11.35 g of 2,4,6-tris(diphenylphosphinyl)pyrimidine (shown by formula in Claim 10) as a white solid, mp 235°-236° C. Anal. Calcd for C40H31N2O3P3 : C, 70.59; H, 4.59; N, 4.12; P, 13.65. Found: C, 70.72; H, 4.90; N, 3.92; P, 13.61.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[Cl:8][CH2:9][C:10](Cl)=[O:11]>>[Cl:8][CH2:9][C:10]([NH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1)=[O:11]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(N)no1
Product: Cc1cc(NC(=O)CCl)no1

Procedure:
A process according to claim 1 wherein, in Step a, 3-amino-5-methylisoxazole is reacted with chloroacetylchloride to form 3-(chloroacetamido)-5-methylisoxazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]#[N:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:20][C:21]([CH2:23]Cl)=[CH2:22].[NH4+]=[S:26]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:23][C:21]([Cl:20])=[CH2:22])[C:10]([NH2:11])=[S:26])=[CH:5][CH:4]=1
Reactant: C=C(Cl)CCl
Reactant: COc1ccc(NC#N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(Cl)CN(C(N)=S)c1ccc(OC)cc1
Temperature: 50 °C
Yield: 94 %

Procedure:
N-(4-methoxyphenyl)cyanamide (2.22 g) was dissolved in DMF (11.10 g), to which powdered potassium carbonate (3.11 g) and potassium iodide (0.26 g) were added at room temperature with stirring. Further, 2,3-dichloro-1-propene (2.00 g) was added dropwise at room temperature with stirring. The mixture was heated to 50° C. and stirred at the same temperature for 1.5 hours. After cooling to room temperature, ammonium sulfide solution, yellow (8.00 g) having an S content of 6% were added dropwise to the reaction mixture at room temperature with stirring. The mixture was heated to 50° C. and stirred at the same temperature for 3 hour. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water. The solvent was removed by distillation under reduced pressure, which afforded 3.63 g of N-(4-methoxyphenyl)-N-(2-chloro-2-propenyl)thiourea as a dark red solid (94% yield in appearance). The percentage area of liquid chromatography was 94%.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([Br:27])[CH:33]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(O)cc2)cccc1[N+](=O)[O-]
Reactant: OB(O)c1cccc(Br)c1
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(Br)c3)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 65B and 3-bromophenylboronic acid were processed as described in Example 48A to provide the title compound. MS (ESI+) m/z 504 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[N:11]1([CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:17][CH:16]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCCN2CCCC2)cc1

Procedure:
A mixture of 1-[2-(4-nitrophenoxy)ethyl]pyrrolidine (from Combi-Blocks, LLC, 5.00 g, 0.0212 mol) in 100 mL of MeOH was hydrogenated in the presence of 0.5 g 10% Pd/C, under balloon pressure of hydrogen, overnight. After filtering off the catalyst, the filtrate was evaporated to dryness and used directly in next step (4.36 g, 99.88%). LCMS (M+H) 207.4.
Reaction SMILES: Cl[C:2]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][C:5]([C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:44]([O:47][CH3:48])[C:45]#[CH:46].C(NCC)C>CN(C=O)C.[Cu](I)I>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[C:2]([C:46]#[C:45][CH2:44][O:47][CH3:48])=[N:3][CH:4]=[C:5]([CH:16]=2)[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:19][CH:20]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: C#CCOC
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COCC#Cc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
To a mixture of 6-chloro-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide (450 mg), 52 mg bistriphenylphosphinpalladium dichloride, 14 mg copperiodide, 146 mg triphenylphosphine and methyl propargyl ether (0.12 mL) in 10 mL DMF is added diethylamine (1.9 L). The mixture is heated in the microwave oven for 40 min at 120° C. The reaction mixture was cooled to room temperature and partitioned between 1 N hydrochloric acid and ethyl acetate. The organic phase was purified by gradient chromatography on silica gel with heptane:ethyl acetate to yield 0.13 g of the title compound as a light yellow solid, MS (ISP) 399.1 (M+H)−.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.O=S(Cl)Cl.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCOCC1
Reactant: OCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C1CCOCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A mixture of tetrahydropyran-4-yl-carboxylic acid (910 mg, 6.99 mmol) and SOCl2 (5.0 mL) was stirred for 1 h at 60° C. and concentrated in vacuo. To the residue were added benzyl alcohol (1.52 g, 14.1 mmol) and tetrahydrofuran (5.0 mL) at ambient temperature. The resulting mixture was stirred for 13 h at ambient temperature and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (silica gel, eluting with hexane/ethyl acetate (2:1)) to give 1.08 g (70%) of the title compound as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[C:17]2[C:16](=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:15][C:14]([CH:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>CCOC(C)=O>[CH3:26][CH:25]([O:27][C:28](=[O:30])[CH3:29])[C:14](=[N:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:7])[C:17]=1[C:16](=[O:15])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CC(=O)OC(C)c1nc2cccc(C)c2c(=Nc2ccccc2)o1
Solvent: CCOC(C)=O
Product: CC(=O)OC(C)C(=Nc1cccc(C)c1C(=O)Nc1ccccc1)N1CCCCC1
Reaction time: 19.5 h

Procedure:
Piperidine (1 mL) was added to compound 178 (0.161 g, 0.5 mmol) and the reaction mixture was stirred for 19.5 h. The reaction mixture was then concentrated under reduced pressure to give a yellow gum. Trituration with 1:4 EtOAc:hexanes gave a small amount of compound 179 (0.041 g). Flash chromatography (1:4 EtOAc:hexanes) of the filtrate gave only a partially separable mixture of the expected products, the acetoxyquinazolinone compound 179 and the hydroxyquinazolinone (total mass 0.122 g). ESI-MS m/z=408 (MH+). The reaction described above and compound 179 are shown below.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:11].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:24](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Cl:11][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[C:9]2[C:2]=1[NH:1][N:24]=[CH:10]2
Reactant: CC(C)CCON=O
Reactant: Cc1cc(C#N)cc(Cl)c1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(Cl)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-3-chloro-5-methylbenzonitrile (3.00 g, 18.0 mmol) in CHCl3 (50 mL) was added acetic anhydride (3.9 mL, 41.4 mmol). The mixture was stirred at room temperature overnight and then heated at reflux for 5 hours. The reaction mixture was cooled to room temperature and potassium acetate (530 mg, 5.40 mmol) and isoamyl nitrite (5.28 mL, 39.6 mmol) were added. The mixture was heated at reflux for 3 days. The reaction mixture was washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated. To this was added methanol followed by water (25 mL) and 38% HCl (25 mL). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the pH was adjusted to about 7. The solids were isolated by filtration and then washed with water (2×30 mL) and heptane (2×30 mL). Purify by Biotage chromatography (CH2Cl2-heptane (1:1)/MeOH gradient to afford 7-chloro-1H-indazole-5-carbonitrile was isolated as a white solid (585 mg, 18%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([CH:13]([CH3:15])[CH3:14])[C:11](=[O:16])[O:10][C:9]2=O)=[CH:4][CH:3]=1.[O:18]=[C:19]1[N:23](CO)[C:22](=[O:26])[CH2:21][N:20]1[CH2:27][C:28]#[CH:29]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:12]([CH:13]([CH3:14])[CH3:15])[C:11]([O:10][CH2:9][N:23]2[C:22](=[O:26])[CH2:21][N:20]([CH2:27][C:28]#[CH:29])[C:19]2=[O:18])=[O:16])=[CH:6][CH:7]=1
Reactant: C#CCN1CC(=O)N(CO)C1=O
Reactant: Cc1ccc(N2C(=O)OC(=O)C2C(C)C)cc1
Product: C#CCN1CC(=O)N(COC(=O)C(Nc2ccc(C)cc2)C(C)C)C1=O

Procedure:
Following the above procedure, 3-(4-methylphenyl)-4-isopropyloxazolidine-2,5-dione is reacted with (2,4-dioxo-1-propargyl-3-imidazolidinyl)methanol to give (2,4-dioxo-1-propargyl-3-imidazolidinyl)methyl 2-(4-methylphenylamino)-3-methylbutanoate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1C
Reactant: c1cn[nH]c1
Product: Cc1sc2nc(-n3cccn3)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][O:16][CH:15]([CH2:19][OH:20])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][O:16][CH:15]([CH2:19][O:20][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(COS(C)(=O)=O)C1
Temperature: 0 °C
Yield: 92 %

Procedure:
Methane sulfonyl chloride (71 μl; 0.92 mmol; 1.0 eq.) was added to a solution of 2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (200 mg; 0.92 mmol; 1.0 eq.) and TEA (190 uL; 1.38 mmol; 1.5 eq.) in anhydrous DCM (3 mL) maintained at 0° C. and under nitrogen atmosphere. The reaction mixture was stirred at RT O/N. The reaction mixture was washed with 10% citric acid solution and brine. Organic phase was dried over magnesium sulfate, filtered and concentrated to give the title compound as a brown oil (250 mg, 92%). 1H NMR (300 MHz, DMSO) δ 4.33-4.13 (m, 2H), 3.91-3.78 (m, 2H), 3.75-3.55 (m, 4H), 3.42 (td, J=11.6, 2.8 Hz, 1H), 3.20 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][S:15]SC>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:15][CH3:14])=[CH:4][N:3]=1
Reactant: CSSC
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CSc1ccc(Br)nc1
Temperature: 22 °C
Reaction time: 18 h

Procedure:
A stirring suspension of 2,5-dibromopyridine (10 g, 0.042 mol) in anhydrous diethyl ether (240 mL) was cooled to −78° C. under nitrogen before the dropwise addition of n-butyl lithium (1.6M in hexanes, 0.044 mol, 27.5 mL). The reaction was stirred at −78° C. for 4 hours before the dropwise addition of methyl disulphide (0.044 mol, 3.91 mL). The reaction was allowed to warm to 22° C. and stirred for a further 18 hours. The reaction was quenched with water (100 mL) and the aqueous and organic layers partitioned. The aqueous layer was extracted with diethyl ether (×3). The extracts were combined with the organic layer, washed with brine, dried (MgSO4) and the solvent removed. The crude product was purified by crystallisation from diethyl ether at −20° C. to afford the title compound as a white solid: 1H NMR (CDCl3)-δ 2.50 (s, 3H), 7.38 (dd, 1H), 7.42 (dd, 1H), 8.23 (d, 1H).