Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:4]1[N:8]=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[S:6][N:5]=1)[CH3:3].[C-:17]#[N:18].[Na+].[Na+].[I-]>CN(C=O)C>[C:17]([CH:2]([C:4]1[N:8]=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[S:6][N:5]=1)[CH3:3])#[N:18]
Reactant: [C-]#N
Reactant: CC(Br)c1nsc(NC(=O)OC(C)(C)C)n1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)c1nsc(NC(=O)OC(C)(C)C)n1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
DMF was added to tert-butyl [3-(1-bromoethyl)-1,2,4-thiadiazol-5-yl]carbamate (1.9 mmol), NaCN (1.1 eq) and NaI (1 eq). The reaction mixture was stirred for 30 min at 140° C. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Standard work-up and recrystallization from EtOH afforded tert-butyl [3-(1-cyanoethyl)-1,2,4-thiadiazol-5-yl]carbamate.
Reaction SMILES: [CH2:1]([O:3][Si:4](OCC)([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].FC(F)(F)C([O:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])=O>>[F:23][C:20]([F:21])([F:22])[C:19]([O:18][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[O:24]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCO[Si](OCC)(OCC)OCC
Product: CCO[Si](OCC)(OCC)OC(=O)C(F)(F)F
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Tetraethylorthosilicate (TEOS), 104 g, is loaded into a dried 1.3 L stainless steel pressure reaction vessel. A stoichiometric amount of trifluoroacetic anhydride, 105 g, is added. The reactor is sealed and the contents are heated at 80-100° C. for at least 12 hours. Preferably, the reaction is run at 80° C. for 16 hours. After sufficient time is permitted for conversion into the desired product, the reaction mixture is cooled and transferred to a vacuum distillation apparatus.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:4]=1[OH:10].[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1.[OH-].[Na+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[O:10][C:11]([CH3:16])([CH3:12])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cccc(O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1cccc2c1OC(C)(C)O2

Procedure:
3-Methoxycatechol (25 g) was dissolved in benzene, and dimethoxyacetal (35 ml) and a catalytic amount of p-toluenesulfonic acid were added thereto, followed by heating at reflux for 6 hours. After being allowed to stand for cooling, the mixture was adjusted to alkaline with an aqueous solution of sodium hydroxide, followed by extraction with ether. The organic layer was washed with a saturated saline and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=99/1) to give Compound IIbk-a (19.4 g, 60.5%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][NH2:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[Br:15][C:16]1[S:20][C:19]2=[N:21][C:22]([C:24](O)=[O:25])=[CH:23][N:18]2[CH:17]=1>>[Br:15][C:16]1[S:20][C:19]2=[N:21][C:22]([C:24]([NH:14][CH2:13][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[C:2]([Cl:1])[CH:3]=3)=[O:25])=[CH:23][N:18]2[CH:17]=1
Reactant: NCc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Product: O=C(NCc1ccc(OC(F)(F)F)c(Cl)c1)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLVI, using (3-chloro-4-(trifluoromethoxy)phenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl[C:13]1[C:18]([C:19]([O:21][CH:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:24](=[O:25])[O:23]2)=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH:6][C:13]1[C:18]([C:19]([O:21][CH:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:24](=[O:25])[O:23]2)=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C1OC(OC(=O)c2cccnc2Cl)c2ccccc21
Solvent: Cc1ccccc1C
Product: O=C1OC(OC(=O)c2cccnc2Nc2cccc(C(F)(F)F)c2)c2ccccc21
Yield: 82.2 %

Procedure:
To 80 ml of xylene, under reflux, m-trifluoromethylaniline (32.2 g) is added. Then, 29 g of phthalidyl 2-chloro-3-pyridinecarboxylate prepared in accordance with Example 1, Supra (divided in two fractions) is poured into the mixture with an interval of 15 minutes between each addition. The reaction mixture so obtained is maintained under reflux for 5 hours, and then cooled by pouring the mixture into an ice/water bath. To allow the complete crystallization of the desired product, the poured reaction mixture is maintained for 2 hours at a temperature of 0°-5° C. The precipitate is collected by filtration and dried under vacuum, at a temperature of 40° C. A yield of 34.1 g (82.3% of theory) of phthalidyl 2-(3-trifluoromethylanilino)-3-pyridinecarboxylate is obtained (m.p. 159°-162° C.). Recrystallizing the compound with 6 volumes of ethyl acetate, 28.4 g (68.5% yield) is obtained (m.p. 164°-5° C.).
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>>[Cl:29][C:19]1[C:20]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:30][C:31]1[CH:32]=[C:33]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:12]1[CH2:11][CH2:10][CH:9]([N:8]([CH3:42])[C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:5])[CH3:7])[CH2:14][CH2:13]1)=[O:17]
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Brc1ccccn1
Product: COc1ccc(-c2ccccn2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (500 mg, 0.80 mmol) is coupled to 2-bromopyridine (77 μL, 0.80 mmol) using Method B to give the title compound.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:18]=[C:17](Cl)[N:16]=[C:15]([NH2:20])[N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:21]1[C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24][C@@H:23]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:22]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37].C([O-])(O)=O.[Na+]>O1CCOCC1>[C:1]12([CH2:11][O:12][C:13]3[N:14]=[C:15]([NH2:20])[N:16]=[C:17]([N:28]4[CH2:27][CH2:26][C:25]5([CH2:21][N:22]([C:36]([O:38][CH2:39][C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)=[O:37])[C@H:23]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:24]5)[CH2:30][CH2:29]4)[CH:18]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Nc1nc(Cl)cc(OCC23CC4CC(CC(C4)C2)C3)n1
Reactant: CCOC(=O)[C@@H]1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OCC45CC6CC(CC(C6)C4)C5)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 95 °C

Procedure:
4-(Adamantan-1-ylmethoxy)-6-chloro-pyrimidin-2-ylamine (89 mg, 0.30 mmol), (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (157 mg, 0.45 mmol) and NaHCO3 (76 mg, 0.9 mmol) were dissolved in dioxane (1.5 mL) and heated to 95° C. for 64 h. Then the reaction was cooled to RT, quenched with water, and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provides (S)-2-benzyl 3-ethyl 8-(6-(adamantan-1-ylmethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[CH2:3]2.[H][H]>CO.[Pt]=O>[ClH:1].[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([NH:10][CH:4]2[CH:5]3[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]3)[CH2:3]2)=[O:21])=[CH:17][CH:16]=1
Reactant: O=C(NC1CN2CCC1CC2)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: Nc1ccc(C(=O)NC2CN3CCC2CC3)cc1

Procedure:
A solution of N-(1-azabicyclo[2.2.2]oct-3-yl)-4-nitrobenzamide hydrochloride (11.55 g, 0.037 mole) in 170 ml of 80% aqueous methanol was shaken in a hydrogen atmosphere with a platinum oxide catalyst on the Parr hydrogenator. The calculated volume of hydrogen was taken up in one hour. The catalyst was filtered off through Celite and the filtrate taken to dryness via rotary evaporator. Several recrystallizations of the colorless crystalline residue from 70% aqueous ethanol produced a solid melting above 310° C. NMR, MS, and IR supported the proposed structure. Yield of title compound was 8.43 g (81.2%).
Reaction SMILES: [Si](OCC1ON=C([C@@H]2CCCN2C(=O)C(F)(F)C2(O)CC(C)(C)CC(C)(C)C2)C=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[Si]([O:63][CH2:64][C:65]1[O:69][C:68]([C@@H:70]2[CH2:74][CH2:73][CH2:72][N:71]2[C:75](=[O:90])[C:76]([F:89])([F:88])[C:77]2([OH:87])[CH2:82][C:81]([CH3:84])([CH3:83])[CH2:80][C:79]([CH3:86])([CH3:85])[CH2:78]2)=[N:67][N:66]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[F:89][C:76]([F:88])([C:77]1([OH:87])[CH2:78][C:79]([CH3:86])([CH3:85])[CH2:80][C:81]([CH3:84])([CH3:83])[CH2:82]1)[C:75]([N:71]1[CH2:72][CH2:73][CH2:74][C@H:70]1[C:68]1[O:69][C:65]([CH2:64][OH:63])=[N:66][N:67]=1)=[O:90]
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2nnc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)o2)C1
Agent: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)on2)C1
Product: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2nnc(CO)o2)C1
Yield: 86.7 %

Procedure:
The procedure of Example 3-(4) was repeated, except that the compound obtained in Example 3-(3) was replaced by the compound (1.378 g) obtained in Example 9-(4); this gave the titled compound (750 mg, colorless solid.)
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N+]([O-])=O)=[CH:15][C:14]=3[N+:22]([O-:24])=[O:23])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O>>[N:1]1([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:26]4[O:25][CH:29]=[CH:28][CH:27]=4)=[CH:15][C:14]=3[N+:22]([O-:24])=[O:23])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccc(Nc2cccc(-n3cccc3)c2)c([N+](=O)[O-])c1
Reactant: OB(O)c1ccco1
Product: O=[N+]([O-])c1cc(-c2ccco2)ccc1Nc1cccc(-n2cccc2)c1
Yield: 83 %

Procedure:
N-(3-(1-Pyrrolyl)phenyl)-4-(2-furanyl)-2-nitroaniline (7n) was prepared analogously from 6k (Example 9) and 2-furanylboronic acid. Yield: 83%. Isolated as a brownish-red oil.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH2:10]([C:12]1[CH:31]=[CH:30][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)=[CH:14][CH:13]=1)[CH3:11]>C1COCC1>[CH2:10]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]4=[N:29][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]4[CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)=[CH:30][CH:31]=1)[CH3:11]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCc1ccc(Oc2ccc(-c3cccnc3N)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 81 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.085 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(4-ethylphenoxy)phenyl)pyridin-2-amine (117 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 4 hr. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the mixture was extracted. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo to give 9-[4-(4-ethylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide as a white solid. Platinum(IV) oxide (20 mg) was added to a solution of 9-[4-(4-ethylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (153 mg) in THF (dry) (20 mL) and MeOH (20 mL). The mixture was stirred at room temperature under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc). Platinum(IV) oxide (20 mg) was added and the mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (46.7 mg) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Br[CH:13](C([O-])=O)[C:14]([O:16]CC)=[O:15].C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].Cl>CO.CC(CC)=O>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:13]([C:14]([OH:16])=[O:15])[O:1][C:2]=2[CH:9]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CCOC(=O)C(Br)C(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCC(C)=O
Product: COc1ccc2cc(C(=O)O)oc2c1
Reaction time: 6 h

Procedure:
11 g of 2-hydroxy-4-methoxybenzaldehyde, 20.3 g of ethyl bromomalonate, 12.3 g of potassium carbonate, and 51 ml of methyl-ethyl ketone were put into a three-necked flask, and refluxed to hold the reaction thereof for 6 hours. After that to this was added a methanol solution of potassium hydroxide, and at a point of time of completion of the hydrolysis reaction, the hydrolyzed product was put into an aqueous hydro chloric acid solution, and then filtered, whereby a 6-methoxy-benzofuran-2-carboxylic acid having a melting point between 208° C. and 211° C. was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].C([O:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])C>C(O)C>[F:12][C:11]([F:14])([F:13])[C:10]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[O:9]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCCCO
Solvent: CCO
Product: O=C(NCCCCO)C(F)(F)F
Yield: 104.8 %

Procedure:
A solution (100 ml) of 4-aminobutanol (2.50 g, 28.05 mmol) and trifluoroacetic acid ethyl ester (19.92 g, 140.26 mmol) in ethanol was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 4-trifluoroacetamidobutanol (11) (5.44 g, q.) as a colorless syrup.
Reaction SMILES: [CH3:1][O:2][N:3]([C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:4]1[NH:5][C:6](=[O:24])[C:7]2[N:8]=[CH:9][N:10]([C@@H:13]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@@:14]3([C:22]#[CH:23])[F:21])[C:11]=2[N:12]=1.[Si:44](Cl)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][N:3]([C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:4]1[NH:5][C:6](=[O:24])[C:7]2[N:8]=[CH:9][N:10]([C@@H:13]3[O:18][C@H:17]([CH2:19][O:20][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[C@@H:15]([OH:16])[C@@:14]3([C:22]#[CH:23])[F:21])[C:11]=2[N:12]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N(OC)C(c3ccccc3)(c3ccccc3)c3ccccc3)nc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#C[C@@]1(F)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]1n1cnc2c(=O)[nH]c(N(OC)C(c3ccccc3)(c3ccccc3)c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 12 (2.29 mmol) in pyridine (5 ml) at 0° C., was added tert-butyldimethylsilyl chloride (2.75 mmol). The reaction mixture was stirred at room temperature for 24 hours. It was then diluted in DCM and washed twice with H2O. The organic phase was extracted, dried over Na2SO4, filtered and evaporated. The crude material was purified by silica gel chromatography (DCM/MeOH) to yield the title compound. Yellowish oil. Molecular Formula C38H44 FN5O5Si. Scan ES+ 696 (M+H)+, λmax 260 nm. Scan ES− 694 (M+H)−, UV λmax 260 nm
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH:9]1[C:17]2[CH:16]=[C:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:14]=[CH:13][C:12]=2[CH:11]=[CH:10]1>ClCCl>[Cl:1][C:11]1[C:12]2[CH:13]=[N:14][C:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][C:17]=2[NH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1cc2[nH]ccc2cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc2[nH]cc(Cl)c2cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 114.4 %

Procedure:
N-Chlorosuccinimide (514 mg) was added to a solution of tert-butyl 1H-pyrrolo[3,2-c]pyridin-6-carboxylate (800 mg) in dichloromethane (16 ml) at room temperature and the mixture was stirred at the room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the resulted residue was dissolved in tetrahydrofuran. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo to give a crude product of tert-butyl 3-chloro-1H-pyrrolo[3,2-c]pyridin-6-carboxylate (1.06 g) as an orange powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH:15][S:16]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22])(=[O:18])=[O:17])=[O:4].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[CH3:58][O:59][CH2:60][CH2:61][CH2:62][NH2:63]>ClCCl.CN(C)C1C=CN=CC=1.O>[CH3:58][O:59][CH2:60][CH2:61][CH2:62][NH:63][C:21]([C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[S:16]([NH:15][C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4])(=[O:17])=[O:18])=[O:22]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2C(=O)O)ccc2ccccc12
Reactant: COCCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: COCCCNC(=O)c1ccccc1S(=O)(=O)Nc1ccc2ccccc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of Example 149B (93.0 mg, 0.241 mmol) in dichloromethane (3.0 mL) was treated with 1-hydroxybenzotriazole hydrate (34 mg, 0.253 mmol) and 4-methylmorpholine (32 μL, 0.297 mmol), stirred at room temperature for 10 minutes, treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (51 mg, 0.266 mmol), 4-dimethylaminopyridine (3 mg, 0.025 mmol), and 1-methoxy-3-aminopropane (37 μL, 0.363 mmol), stirred for 1 hour, heated to 40° C., stirred overnight, treated with 4-dimethylaminopyridine (3 mg, 0.025 mmol) and 4-methylmorpholine (53 μL, 0.482 mmol), heated to 40° C. for 3 days, cooled to room temperature, and treated with distilled water. The aqueous layer was extracted with dichloromethane (2×) and the combined organic phases were washed with brine, dried (MgSO4), filtered, and concentrated. The resulting residue was purified by preparative HPLC to provide the desired product. MS (ESI(+)) m/e 457 (M+H)+, 479, (M+Na)+; (ESI(−)) m/e 455 (M−H)−.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:4][CH2:3]1.Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:4][CH2:3][C@H:2]([O:1][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:7][CH2:6]3)[C:9]3[N:10]([N:33]=[CH:34][CH:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OC(C)(C)C)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (21.1 g) and tetrabutylammonium hydrogen sulfate (1.5 g) in toluene (160 mL)-50% sodium hydroxide (160 mL) was added dropwise tert-butyl bromoacetate (20 mL) at 50° C., and the mixture was stirred at 50° C. for 1.5 hr. The mixture was allowed to cool to room temperature, diluted with ethyl acetate and then neutralized with 6M hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as an amorphous pale-yellow solid (24.4 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1.N[C:17](N)=[O:18]>CC1C=CC(C)=C(C)C=1C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:17](=[O:18])[N:9]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:4]=2[CH:3]=1
Reactant: Nc1ccc(Cl)cc1NC1CCCCC1
Reactant: NC(N)=O
Solvent: Cc1ccc(C)c(C)c1C
Product: O=c1[nH]c2ccc(Cl)cc2n1C1CCCCC1

Procedure:
A mixture of 4.5 g of the compound obtained in Step B), 2.5 g of urea and 10 ml of 1,2,3,4-tetramethylbenzene is heated to 170°-180° C. for 90 minutes.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[C:7](I)=[CH:8][C:9]([O:17][CH2:18][CH3:19])=[C:10]([CH:16]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:5])=[O:4].[CH3:22][N:23](C)C=O>[C-]#N.[Zn+2].[C-]#N.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.O>[C:22]([C:7]1[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:21])[CH3:1])=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([O:17][CH2:18][CH3:19])[CH:8]=1)#[N:23]
Reactant: CCOC(=O)c1cc(S(=O)(=O)N(C)C)c(I)cc1OCC
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCOC(=O)c1cc(S(=O)(=O)N(C)C)c(C#N)cc1OCC
Temperature: 80 °C
Yield: 92 %

Procedure:
Ethyl 5-dimethylsulfamoyl-2-ethoxy-4-iodobenzoate (1.01 g, 2.36 mmol), zinc cyanide (0.167 g, 1.42 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.191 g, 0.165 mmol) were combined under nitrogen in a flame-dried Schlenk tube. Dimethylformamide (9 mL) was added and the reaction mixture was put through three freeze-pump-thaw cycles and then put under a nitrogen atmosphere and heated at 80° C. for 16 h. After cooling to room temperature, water (50 mL) was added and the resulting mixture was extracted with diethyl ether (100 mL, 2×50 mL). The combined organic phases were washed with brine (3×50 mL) and then dried over magnesium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 33% ethyl acetate in hexanes) gave ethyl 4-cyano-5-dimethylsulfamoyl-2-ethoxybenzoate as an off-white solid (0.708 g, 92%). LC-MS: 327.1 [(M+H)+].