Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][N:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH:6]=[C:7]([F:17])[C:8]=1[O:9]CC1C=CC=CC=1)#[N:2]>CO.C1COCC1.[C].[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][N:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH:6]=[C:7]([F:17])[C:8]=1[OH:9])#[N:2]
Reactant: COC(=O)c1ccnc(-c2cc(F)c(OCc3ccccc3)c(C#N)c2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(-c2cc(F)c(O)c(C#N)c2)c1

Procedure:
Methyl 2-(3-cyano-4-benzyloxy-5-fluorophenyl)isonicotinate is stirred at room temperature in methanol-THF (1:1) under a hydrogen atmosphere at normal pressure in the presence of palladium-carbon to obtain methyl 2-(3-cyano-5-fluoro-4-hydroxyphenyl)isonicotinate. FN: 271.
Reaction SMILES: [C:1]1([CH2:11]O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][CH2:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc2c1CCCC2
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: ClCc1cccc2c1CCCC2
Yield: 56 %

Procedure:
61 g (0.376 mol) of (5,6,7,8-tetrahydro-1-naphthyl)methanol with a purity of 78 % are dissolved in 450 ml of chloroform, in the presence of 35 g (0.38 mol) of pyridine. 90 ml of thionyl chloride in solution in 30 ml of chloroform are introduced dropwise and between 30 and 40°C into the solution which is obtained and this is heated under reflux for 6 hours. After partial evaporation of the chloroform and the thionyl chloride excess, washing is carried out with water and with a sodium bicarbonate solution, followed by drying over anhydrous sodium sulphate. Distillation of the oily residue permits the isolation of a liquid of boiling point b.p.0.5 = 81°-83°C, with a purity of 86 % (vapour phase chromatography), and this is taken up in 150 ml of hot hexane. The crystallisation is seeded by scratching with a glass rod. There are isolated 29.5 g of a product melting at 51°-52°C, with a yield of 56 % (theoretical yield = 53 g, depending on the degree of purity of the starting product). Vapour phase chromatography confirms a purity of 100 %.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18]=[O:19])=[CH:16][C:15]2[C:10](=[C:11]([Cl:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][OH:19])=[CH:16][C:15]2[C:10](=[C:11]([Cl:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: O=Cc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl

Procedure:
Prepared according to Procedure B using 2-(2-chlorophenyl)-8-chloroquinoline-3-carbaldehyde (1.18 g, 3.9 mmol), and sodium borohydride (0.222 g, 5.86 mmol, 1.5 eq) in THF (20 mL). (2-(2-chlorophenyl)-8-chloroquinolin-3-yl)methanol was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (1 H, s), 8.10 (1 H, dd, J=8.2, 1.2 Hz), 7.94 (1 H, dd, J=7.6, 1.4 Hz), 7.63 (2 H, t, J=7.8 Hz), 7.44-7.59 (3 H, m), 5.54 (1 H, t, J=5.3 Hz) Mass Spectrum (ESI) m/e=304.0 and 306.1 (M+1)
Reaction SMILES: [O:1]=[C:2]([C:16]1[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[C:17]=1[CH3:23])[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:4]#[N:5].[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C1(C)C(C)=CC=CC=1>[CH3:26][C:25]([CH3:28])([CH3:27])[C:24]([O:1]/[C:2](/[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[C:17]=1[CH3:23])=[C:3](\[C:6]1[CH:7]=[CH:8][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:10][CH:11]=1)/[C:4]#[N:5])=[O:29]
Reactant: Cc1nn(C)c(C(=O)C(C#N)c2ccc(C(C)(C)C)cc2)c1C
Reactant: CC(C)(C)C(=O)Cl
Solvent: Cc1ccccc1C
Product: Cc1nn(C)c(/C(OC(=O)C(C)(C)C)=C(\C#N)c2ccc(C(C)(C)C)cc2)c1C
Temperature: 70 °C
Yield: 95.9 %

Procedure:
In a 10 L-reaction flask, 456 g (1.47 mol) of 3-oxo-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) propionitrile and 2738 g of xylene were added, the temperature was raised to 70° C., and 534 g (4.43 mol) of pivaloyl chloride was added dropwise under reflux over 10 hours while removing hydrogen chloride under a reduced pressure at 68 to 71° C./10 to 13 kPa. After reacting as such for 3 hours, 2181 g of a mixture of pivaloyl chloride and xylene was distilled off at 70° C. under a reduced pressure in order to remove excess pivaloyl chloride. After adding 456 g of warm water of 70° C., 228 g of 2.7% sodium hydrogen carbonate aqueous solution was added dropwise. After separating the resulting aqueous phase, the resulting organic phase was washed with 456 g of warm water of 70° C., the resulting aqueous phase was separated to obtain a xylene solution. A quantitative analysis with liquid chromatography showed that the xylene solution contained 555 g (yield 95.6%) of (2E)-3-(2,2-dimethylpropanoyloxy)-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) acrylonitrile. After distilling off xylene at 90° C., 1141 g of heptane was added, and crystallization was carried out by gradually cooling from 70° C. After aging at 0° C. for 1 hour, the resulting crystal was filtered, and dried to obtain 533 g (yield 91.9%) of (2E)-3-(2,2-dimethylpropanoyloxy)-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) acrylonitrile (melting point: 110° C.).
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)[CH3:3].C([Li])CCC.CCCCCC.[C:21]1([CH2:27][CH2:28][C:29](Cl)=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:21]1([CH2:27][CH2:28][C:29]([N:5]2[C@H:4]([CH:2]([CH3:3])[CH3:1])[CH2:8][O:7][C:6]2=[O:9])=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(C)C1COC(=O)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)[C@@H]1COC(=O)N1C(=O)CCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
To a stirred solution of 4-(2-propyl)-oxazolidine-2-one in anhydrous tetrahydrofuran (250 ml) under a nitrogen atmosphere at -78° C. were added in a dropwise fashion a solution of n-butyllithium in hexane (50 ml, 77.4 mmol) over 5 to 10 min. After stirring an additional 20 min at -78° C. 3-phenylpropionyl chloride (12.7 ml, 85.2 mmol) was added neat. The reaction was warmed to room temperature and stirred 1 to 2 h. The reaction was quenched by adding 100 ml of saturated aqueous ammonium chloride and the volatiles removed by rotary evaporation. The resulting aqueous residue was extracted three times with ether and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Recrystallization from hexanes/ethyl acetate provided the title compound (16.6 g, 82%); m.p. 86.5° to 87.5° C. Mass spectrum: (M+NH4)+ =279, (M+H)+ =262.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH:7]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C@H:8]([C:13]([NH:15][C@@H:16]([C:31]([NH:33][C@@H:34]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH2:35][CH2:36][CH2:37][CH3:38])=[O:32])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20](C(OC)=O)[CH:19]=1)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]>>[NH:7]([C:49]([O:51][C:52]([CH3:55])([CH3:53])[CH3:54])=[O:50])[C@H:8]([C:13]([NH:15][C@@H:16]([C:31]([NH:33][C@@H:34]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH2:35][CH2:36][CH2:37][CH3:38])=[O:32])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:19]=1)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)Cl
Reactant: CCCC[C@@H](NC(=O)[C@@H](Cc1cn(C(=O)OC)c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Product: CCCC[C@@H](NC(=O)[C@@H](Cc1cn(C(=O)OCC)c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
The title compound was prepared using ethyl chloroformate instead of methyl chloroformate in the same manner described in Example 1-(1) and (2).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19].[NH2:22][CH2:23][CH:24]([NH:51][C:52](=[O:61])[O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:25](=[O:50])[NH:26][CH:27]([C:36](=[O:49])[N:37]([CH2:41][CH:42]([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])[CH:38]([CH3:40])[CH3:39])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1>C(Cl)Cl>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][CH:27]([NH:26][C:25]([CH:24]([NH:51][C:52](=[O:61])[O:53][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:23][NH:22][S:18]([C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[Cl:10])(=[O:20])=[O:19])=[O:50])[C:36](=[O:49])[N:37]([CH2:41][CH:42]([O:43][CH2:44][CH3:45])[O:46][CH2:47][CH3:48])[CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=1
Reactant: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(CN)NC(=O)OCc1ccccc1)C(C)C)OCC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(CNS(=O)(=O)c1ccc(Cl)cc1Cl)NC(=O)OCc1ccccc1)C(C)C)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
1.94 ml (11.09 mmol) of DIEA and 1.5 g (6.1 mmol) of 2,4-dichlorophenylsulfonyl chloride are added to a solution of 3.2 g (5.54 mmol) of benzyl (2-amino-1-{2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate in 75 ml of DCM. The solution is stirred at room temperature overnight. The solution is then concentrated in vacuo, and the residue is purified by column chromatography on 100 g of SiO2 (eluent DCM followed by 20% EtOAc/DCM). 2.78 g of the desired product are obtained as a colorless foam. MW=784.19 (calculated, monoisotopic); measured value (M+Na)+=807.24
Reaction SMILES: [Cl-:1].[Cl:2][CH2:3][C:4]1[NH:9][C:8](=[O:10])[NH:7][C:6](=[O:11])[CH:5]=1>C(O)(=O)C>[Cl:1][C:5]1[C:6](=[O:11])[NH:7][C:8](=[O:10])[NH:9][C:4]=1[CH2:3][Cl:2]
Reactant: [Cl-]
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]c(CCl)c(Cl)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Sulfulyl chloride (120 ml) was added dropwise to a suspension of 163 g of 6-chloromethyluracil in 500 ml of acetic acid at room temperature for 20 minutes and stirred at the same temperature for 3 hours. The reaction mixture was poured into ice water (500 ml) and the resulting crystals were collected by filtration to give 182.3 g of 5-chloro-6-chloromethyluracil (yield 92%). The physical properties of this compound are as follows:
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[N:13]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:15]=2)[C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[N:10]=1)C1C=CC=CC=1.C(O)(=O)C>[Pd].C(O)C>[CH3:23][N:20]1[C:19]([CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]2)=[N:18][C:17]2[C:21]1=[N:22][C:14]([N:13]1[C:12]3[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=3[N:10]=[C:9]1[NH:8][CH3:1])=[N:15][C:16]=2[N:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: CN(Cc1ccccc1)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Reaction time: 18 h
Yield: 16.6 %

Procedure:
A mixture of 2-(1-((2-(2-(benzyl(methyl)amino)-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol 205 (0.2 g, 0.33 mmol) and palladium on carbon (10 wt %, 0.1 g) and acetic acid (0.1 mL) in ethanol (10 mL) was stirred under a hydrogen atmosphere at 60 degrees for 18 hours. The reaction mixture was then filtered though celite and concentrated. The crude product was purified by RP-HPLC to give 206 (28.5 mg, 17%). LCMS m/z: 520.3 (MH+)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:12]F.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(O)(=O)C>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][C:5]([F:12])=[CH:6][N:7]=1
Reactant: FF
Reactant: COC(=O)c1nccnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1nc(F)cnc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 10 mL of acetic acid was dissolved 0.5 g of methyl 3-amino-2-pyrazinecarboxylate. At room temperature, 10% fluorine gas (a fluorine gas diluted with nitrogen gas) was introduced into the solution at a rate of 23 mL per minute for a period of 32 minutes. After stirring the solution for 30 minutes at room temperature, the reaction mixture was added to a mixture of 50 mL of saturated aqueous solution of sodium hydrogen carbonate and 50 mL of ethyl acetate, and the organic layer was separated. The organic layer thus obtained was washed successively with 10 mL of water and 10 mL of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=3:1] to obtain 0.01 g of methyl 3-amino-6-fluoro-2-pyrazinecarboxylate as a light yellow-colored solid product.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:11][O:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2ocnc12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc2ocnc12
Yield: 90.6 %

Procedure:
To a suspension of 4-hydroxybenzoxazole (2.00 g, 14.8 mmol) (Musser et al., J. Med. Chem., 30, pp. 62-67 (1987)) in acetone (80.0 ml) was added dried K2CO3 (2.25 g, 16.3 mmol) followed by iodomethane (1.38 ml, 22.2 mmol). The reaction was heated under reflux under N2 for 4.5 h, then filtered and reduced in vacuo to afford the crude product. The resulting residue was purified by flash chromatography (25:75 ethyl acetate/hexane) to give 2.0 g (91%) of the title compound as a white crystalline solid: m.p. 72-74° C.; IR (KBr) 3089, 1619, 1610, 1503, 1496, 1322, 1275, 1090, 1071, 780, 741; 1H NMR (CDCl3) δ 8.02 (1H, s), 7.32 (1H, t, J=8.0), 7.18 (1H, d, J=8.0), 6.81 (1H, d, J=8.0), 4.04 (3H, s). Anal. Calcd. for C8H7NO2: C, 64.42; H, 4.73; N, 9.39. Found: C, 64.40; H, 4.84; N, 9.31; m/z (EI) 149 (M++1, 100%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.NN.Cl.O>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:11][CH2:12]2)=[CH:27][CH:28]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCC(Oc2ccc(F)cc2)CC1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCN1CCC(Oc2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
13.8 g (0.04 mol) of 2-{3-[4-(4-fluorophenoxy)-1-piperidyl]propyl}-1H-isoindole-1,3(2H)-dione and 3.9 ml (0.08 mol) of hydrazine in 280 ml of EtOH are reacted for 3 h at the refluxing temperature, and the mixture is then left overnight. 15 ml of concentrated HCl and 20 ml of H2O are then introduced. The mixture is left for 3 hours at the refluxing temperature, then filtered and concentrated. The residue is taken up with water, filtered and rinsed with water. The filtrate is washed twice with ether, then alkalinised with NaOH and extracted 3 times with CH2Cl2. The solution is dried over Na2SO4, filtered and concentrated.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6][CH:5]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[B-](F)(F)(F)[F:24].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C1COCC1.CN(C=O)C>[F:24][C:5]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:4](=[O:3])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
NaH (2.66 g, 105 mmol) was suspended in THF (300 mL) and cooled to 0° C., and 1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (30 g, 105 mmol) was added as THF solution (550 mL) using an addition funnel over 30 minutes. The mixture was stirred for 30 minutes and then diluted with DMF (200 mL). Selectfluor (41.0 g, 116 mmol) was added as a DMF solution (200 mL). The mixture was warmed to ambient temperature and stirred for 2 hours. The mixture was then concentrated to remove THF and diluted with 1N KHSO4 (300 mL), water (300 mL) and EtOAc (750 mL). The organic layer was washed with brine (2×250 mL). The combined aqueous layers were washed with EtOAc (200 mL) and this organic layer was washed with brine (200 mL). The combined organic layers were then dried over Na2SO4, filtered and concentrated. The crude product was passed through a silica gel plug (1 kg, 20 to 40% EtOAc/hexanes) to provide 23.6 g (74%) of the product as a colorless oil.
Reaction SMILES: [Si:1]([O:18][C@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:22]([NH2:29])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:39]([C:41]1[CH:42]=[CH:43][C:44]2[N:48]=[CH:47][N:46]([C:49]3[N:54]=[C:53](SC#N)[C:52]([N+:58]([O-:60])=[O:59])=[CH:51][N:50]=3)[C:45]=2[CH:61]=1)#[N:40]>C1COCC1>[Si:1]([O:18][C@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:22]([NH:29][C:51]2[C:52]([N+:58]([O-:60])=[O:59])=[CH:53][N:54]=[C:49]([N:46]3[C:45]4[CH:61]=[C:41]([C:39]#[N:40])[CH:42]=[CH:43][C:44]=4[N:48]=[CH:47]3)[N:50]=2)[CH2:21][CH2:20]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CSc1nc(-n2cnc3ccc(C#N)cc32)ncc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@H](N)c2ccccc21)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@H](Nc2nc(-n3cnc4ccc(C#N)cc43)ncc2[N+](=O)[O-])c2ccccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A solution of (1R,4R)-4-(tert-butyldiphenylsilyloxy)-1,2,3,4-tetrahydronaphthalen-1-amine (4.0 g) and DIEA (5.3 mL) in anhydrous THF (20 mL) were added via syringe over 1 min to 6-cyano-1-(5-nitro-4-thiocyanatopyrimidin-2-yl)-1H-benzo[d]imidazole (3.43 g, 10.601 mM) in THF at 0° C. The resulting solution was allowed to warm slowly to RT overnight, then partitioned between water and DCM. Column purification (1% MeOH/DCM) gave the titled product (5.21 g), MH+=666.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=2)=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]
Reactant: N#Cc1cc(Cl)ccn1
Reactant: CNc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1ccc(Oc2ccnc(C#N)c2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 11.5 h
Yield: 76.4 %

Procedure:
A mixture of 4-chloro-2-cyano-pyridine (6.9 g, 0.05 moles), 4-methylamino-3-nitrophenol (8.4 g, 0.05 moles), and K2CO3 (10.4 g, 0.075 moles) in DMSO (80 mL) was heated to 60° C. After 11.5 h, HPLC analysis indicated complete conversion of both starting materials. After cooling to 20° C., water (240 mL) was added to the reaction mixture. The temperature rose to 40° C. before decreasing to ambient temperature. The solid was collected by filtration and washed with water (2×40 mL). The solid was then slurried in heptane (40 mL). The solid was collected and washed with heptane (40 mL). The crude product was dried in a vacuum oven at 50° C. for 16 h to afford 10.33 g (76%) of the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.5 (m, 1H), 8.2 (m, 1H), 7.9 (m, 1H), 7.7 (m, 1H), 7.5 (m, 1H), 7.2 (m, 1H), 7.1 (m, 1H), 3.0 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 165.1, 152.9, 144.4, 140.6, 134.1, 130.4, 130.1, 117.9, 117.1, 117.0, 116.5, 114.9, 29.8; APCI MS [M+H]+=271; HPLC>99% (LCAP).
Reaction SMILES: C[C:2]1([CH3:9])[CH:7](O)[C:5](=[O:6])[O:4]C1.[CH3:10][O:11][C:12]1[CH:22]=[CH:21]C(C=CC(Cl)=O)=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:22]=[CH:21][C:9]([CH:2]=[CH:7][C:5]([OH:4])=[O:6])=[CH:14][CH:13]=1
Reactant: CC1(C)COC(=O)C1O
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)cc1
Yield: 92.6 %

Procedure:
16.3 g of <R>-pantolactone (0.125 mol) and 28 g of 4-methoxycinnamic acid chloride (about 0.14 mol) are placed in 170 ml of CH2Cl2 while gassing with argon in a 350 ml 4-necked sulphonation flask provided with a thermometer, a reflux condenser, a magnetic stirrer as well as a 20 ml dropping funnel. A solution of 11 g (0.139 mol) of pyridine in 30 ml of CH2Cl2 is now added dropwise within 30 minutes, whereby the temperature rises slowly. The reaction mixture is finally heated to reflux temperature for 3 hours. The reaction mixture is washed with 150 ml of water, 2× with 40 ml of 5% HCl, 2× with 40 ml of 5% NaHCO3 and 1× with 100 ml of water. The organic phase is separated and dried over Na2SO4. The solvent is removed on a rotary evaporator. The thus-obtained crude product is recrystallized from 100 ml of ethyl acetate/hexane (60:100). There are obtained 33.6 g of white crystals of the <R>-pantolactone ester of p-methoxycinnamic acid (yield 92.6%).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH2:18]([Mg]Br)[CH3:19]>O1CCCC1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]([OH:17])[CH2:18][CH3:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CC[Mg]Br
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(O)CC)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
To a solution of 0.25 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 10 ml of dry tetrahydrofuran, cooled to 0° C., is added 1.63 ml of 2.0M ethyl magnesium bromide in tetrahydrofuran. The reaction mixture is stirred for 30 minutes at 0° and quenched with 20 ml of saturated ammonium chloride solution and 20 ml of water. The reaction mixture is extracted with 9:1 chloroform-methanol, dried over magnesium sulfate, filtered and evaporated in vacuo to give 0.26 g of the desired product.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[N:13]=[C:12]2I)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[CH2:25]([Sn:29]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:31][CH2:32][CH2:33][CH3:34])Cl)[CH2:26][CH2:27][CH3:28]>C1COCC1>[Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[N:13]=[C:12]2[Sn:29]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:25][CH2:26][CH2:27][CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(O[Si](C)(C)C(C)(C)C)cc12
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
The solution of 5-(tert-butyldimethylsilyloxy)-3-iodo-1-methyl-1H-indazole (3.8 g, 10 mmol) in 30 mL of dry THF was cooled to −20° C. under nitrogen, isopropylmagnesium chloride (6 mL, 12 mmol, 2M in THF) was added and stirred for 15 min at −20° C. Tributylchlorostannane (12 mL, 14 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was quenched with saturated solution of ammonium chloride, extracted with ethyl acetate (3×50 mL), dried over sodium sulfate and concentrated to give 5-(tert-butyldimethylsilyloxy)-1-methyl-3-(tributylstannyl)-1H-indazole (5.2 g, crude) as a colourless oil, which was used directly in the next step without further purification.