Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:8]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[C:14]([CH3:26])[CH:13]=2)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.O>[C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[S:3][C:4]([S:8]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[C:14]([CH3:26])[CH:13]=3)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=2)=[CH:31][CH:30]=1)#[N:28]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(NS(=O)(=O)c2sc(Br)nc2C)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(NS(=O)(=O)c2sc(-c3ccc(C#N)cc3)nc2C)c1
Temperature: 80 °C
Yield: 33.1 %

Procedure:
A solution of tert-butyl (6-{[(2-bromo-4-methyl-1,3-thiazol-5-yl)sulfonyl]amino}-4-methylpyridin-2-yl)carbamate (0.96 g, 2.08 mmol, 1 equiv), 4-cyanophenylboronic acid (0.336 g, 2.29 mmol, 1.1 equiv), and cesium carbonate (2.03 g, 6.24 mmol, 3 equiv) in 2:1 dimethoxyethane/water (30 mL) was purged with nitrogen for 15 minutes. Dichloro[1,1′-bis(diphenylphosphine)ferrocene] palladium (II) chloride (0.068 g, 0.08 mmol, 0.04 equiv) was then added, and the resulting mixture was purged with nitrogen for another 15 minutes. The reaction was heated to 80° C. for 1 h. After cooling to 24° C., the solution was concentrated in vacuo (˜25 mm Hg). The resulting aqueous mixture was extracted ethyl acetate (60 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by high performance flash chromatography (0→10% ethyl acetate in hexanes) provided the intermediate (0.334 g, 33%). 1H NMR (400 MHz, CDCl3), δ: 7.97 (d, J=8.3 Hz, 2H), 7.73 (d, J=8.3 Hz, 2H), 7.63 (br s, 1H), 7.43 (s, 1H), 6.90 (s, 1H), 2.65 (s, 3H), 2.32 (s, 3H), 1.50 (s, 9H); LRMS (ESI) m/z: 486.1.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2=[CH:9][S:10][CH:11]=[C:4]2[S:3]1(=[O:13])=[O:12].[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[O:26].C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[C:5](=[CH:9][S:10][CH:11]=2)[C:6]=1[C:25](=[O:26])[NH:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[CH3:14]
Reactant: CN1C(=O)Cc2cscc2S1(=O)=O
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)C1=C(O)N(C)S(=O)(=O)c2cscc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature under nitrogen for 3 hours with 0.82 g (4.6 mmol) of 2-methyl-4-nitrophenylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with two 150 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate. The solvent is distilled off, whereby the product crystallizes out. For purification, the product is recrystallized from ca 50 ml of methanol. There is obtained 3-hydroxy-2-methyl-4-(2-methyl-4-nitrophenylcarbamoyl)-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide of melting point 186°-188° C.
Reaction SMILES: C[Si](Cl)(C)C.[C:6]1(=[O:13])[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7]1.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[CH:23]=O)[C:18]#[N:19].[F:25][C:26]([F:38])([F:37])[C:27]1[CH:28]=[C:29]([NH:33][C:34]([NH2:36])=[O:35])[CH:30]=[CH:31][CH:32]=1>CN(C)C=O.C(#N)C>[C:18]([C:17]1[CH:20]=[CH:21][C:22]([CH:23]([C:7]2[C:8](=[O:12])[CH2:9][CH2:10][CH2:11][C:6]=2[OH:13])[NH:36][C:34]([NH:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:37])[F:38])[CH:28]=2)=[O:35])=[C:15]([F:14])[CH:16]=1)#[N:19]
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: O=C1CCCC(=O)C1
Reactant: N#Cc1ccc(C=O)c(F)c1
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CCCC2=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Trimethylsilyl chloride (1 M in dichloromethane, 4.90 mL, 4.90 mmol) is added to a solution of cyclohexane-1,3-dione (0.50 g, 4.46 mmol), 3-fluoro-4-formylbenzonitrile (0.67 g, 4.46 mmol) and 1-(3-(trifluoromethyl)phenyl)urea (0.91 g, 4.46 mmol) in a mixture of N,N-dimethylformamide (2.0 mL) and acetonitrile (2.0 mL). The mixture is stirred at room temperature for 45 min and then poured into ice water. The mixture is stirred over night at room temperature, and the precipitate is filtered and dried. Yield: 1.8 g; ESI mass spectrum [M+H]+=448, Retention time HPLC: 1.02 min (Z018_S04).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:19]1C2C=CC=CC=2N=N1.C(N(CC)CC)C.N>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([NH2:19])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(NC(=O)OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a solution of 2-benzyloxycarbonylamino-2-methyl-propionic acid (1 g) in N,N-dimethylformamide (10 mL) were added 1-hydroxybenzotriazole (0.63 g), 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride (1.21 g), triethylamine (1.76 mL) and 28% aqueous ammonia solution (2 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with 0.5 mol/L hydrochloric acid, water, 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 2-benzyloxycarbonylamino-2-methylpropionamide (0.26 g) This material was dissolved in methanol (5 mL). To the solution was added 10% palladium-carbon powder (30 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.11 g).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:9]([O:21][CH3:22])[C:8]([CH3:23])=[C:7]2[C:3]=1[C:4](=[O:24])[O:5][CH2:6]2.C(N(C(C)C)CC)(C)C.[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39]Cl>C(Cl)Cl>[CH3:22][O:21][C:9]1[C:8]([CH3:23])=[C:7]2[C:3]([C:4](=[O:24])[O:5][CH2:6]2)=[C:2]([O:1][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39])[C:10]=1[CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COCCOCCl
Reactant: COC(=O)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOc1c(C/C=C(\C)CCC(=O)OC)c(OC)c(C)c2c1C(=O)OC2

Procedure:
To methyl (E) 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (61.0 g) in methylene chloride (1000 ml) at 0° C. was added diisopropylethylamine (30.4 g) and methoxyethoxymethyl chloride (29.2 g). After 31/2 hours the solution was washed with dilute hydrochloric acid, dried and evaporated to give methyl (E) 6-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate as an oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.C(Cl)[Cl:17].S(Cl)(Cl)=O>CN(C=O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([Cl:17])=[O:10])=[CH:5][CH:4]=1
Reactant: ClCCl
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
To a 500 mL round-bottomed flask was added 4-(trifluoromethyl)cinnamic acid (231 mL, 116 mmol), DCM (7.44 mL, 116 mmol), thionyl chloride (17.7 mL, 243 mmol), and a few drops of DMF. The resulting mixture was stirred at reflux for about 1.5 hours and followed by LCMS (MeOH quench). Once no starting material was present, the solvents were reduced and the oil was used immediately in the next step.
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]2[N:13]=[CH:14][NH:15][C:11]=2[CH:10]=1.[CH3:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.[Si](C#N)(C)(C)C.[N:37]1([C:42](N2C=CN=C2)=[O:43])C=CN=[CH:38]1>>[CH3:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]2[N:8]([C:9]3[CH:17]=[CH:16][C:12]4[NH:13][CH:14]=[N:15][C:11]=4[CH:10]=3)[C:42](=[O:43])[NH:37][CH2:38]2)=[CH:25][CH:24]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: COCCOc1ccc(C=O)cc1
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])C(F)(F)F
Product: COCCOc1ccc(C2CNC(=O)N2c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized as trifluoroacetate salt starting from 5-aminobenzimidazole (1.3 gmg, 9.99 mmol), 4-(2-methoxyethoxy)benzaldehyde (1.5 g, 8.33 mmol), TMSCN (1.64 mL, 16.66 mmol) 10% Pd—C (200 mg), TEA (2.5 mL, 18.40 mmol), di-(imidazol-1-yl)methanone (1.192 g, 7.36 mmol), as described in method 2. The product was purified by means of preparative HPLC.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]1>>[OH:27][CH:24]1[CH2:25][CH2:26][N:22]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:23]1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: OC1CCNC1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N3CCC(O)C3)cc2c1=O
Yield: 58 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with pyrrolidin-3-ol according to the GPA affording 21 mg (58%) of a red powder. Rt=4.22 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=O)[CH3:11].[CH2:23]([O:25][C:26](=[O:35])[C:27](=[NH:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:24]>C(O)C>[CH2:20]([O:19][C:17]([C:15]1[NH:34][C:27]([C:26]([O:25][CH2:23][CH3:24])=[O:35])=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[C:14]=1[C:13]([O:12][CH2:10][CH3:11])=[O:22])=[O:18])[CH3:21]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CCOC(=O)CC(=N)C(=O)OCC
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C1=C(C(=O)OCC)C(c2cccc(Cl)c2)C(C(=O)OCC)=C(C(=O)OCC)N1

Procedure:
14.1 g of 3-chlorobenzaldehyde, 19 g of oxalacetic acid diethyl ester and 18.8 g of iminosuccinic acid diethyl ester in 60 ccs of ethanol are heated to the boil overnight and subsequently evaporated in vacuo. Yellow oil.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])[CH:2]=1.S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)Cl>[Cl:19][C:2]1[C:3]([C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:15]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)c1cccc(C)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)c1cccc(C)c1Cl
Yield: 103.9 %

Procedure:
To a cold (5° C.) mixture of 137.5 g (1.05 mole) of ethyl acetoacetate, 175 ml. of benzene, 325 ml. of water, and 45.8 ml. of 33% sodium hydroxide was added simultaneously 221.05 g (1.430 mole) of m-toluoyl chloride and 190 ml. of 33% sodium hydroxide as described in Example 4. The aqueous solution of sodium salt of ethyl m-toluoylacetoacetate was stirred with 56.3 g of ammonium chloride overnight and worked up as described in Example 4 to give 38.0 g (17%) of crude ethyl m-toluoylacetate after a Kugelrohr distillation (95°-98° C. at 0.05 mm Hg). A mixture of 20.6 g (0.1 mole) of crude ethyl m-toluoylacetate, 13.6 g (0.105 mole) of sulfuryl chloride, and 30 ml. of chloroform was held at reflux for 6 hours and worked up as described in Example 4 to give 25.0 g of ethyl 2-chloro-m-toluoylacetate, which was used directly as described below. A mixture of 22.5 g (0.1 mole) of ethyl 2-chloro-m-toluoylacetate, 7.6 g (0.1 mole) of thiourea and 100 ml. of ethanal was held at reflux for 2 hours and worked up as described in Example 4 to give 23.0 g of solid, which was recrystallized from ethanol to give 11.6 g (44%) of ethyl 2-amino-4-(m-tolyl)-5-thiazolecarboxylate, m.p. 185°-187° C. An additional 4.5 g (17%) of less pure ethyl 2-amino-4-(m-tolyl)-5-thiazolecarboxylate, m.p. 183°-184° C. was obtained by concentration of the mother liquor. To a cold (-5° C.) mixture of 10.5 g (0.04 mole) of ethyl 2-amino-4-(m-tolyl)-5-thiazolecarb and 80 ml. of 85% phosphoric acid was added 40 ml. of 70% nitric acid. To the vigorously stirred above mixture was added 3.0 g (0.0434 mole) of sodium nitrite in 20 minutes. The reaction mixture was stirred for 10 minutes and poured into a mixture of 4.0 g (0.04 mole) of cuprous chloride, 20 ml. of concentrated hydrochloric acid and 20 ml. of water. After the gas evolution had subsided the reaction mixture was extracted with ether, dried (MgSO4) and concentrated under reduced pressure to give 10 g of oil which was Kugelrohr distilled (135°-140° C. at 0.05 mm) to give 6.5 g of oil, which was crystallized from ethanol to give 3.9 g (34%) of the desired product as a white solid, m.p. 41°-42° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14]C)=[O:13])[CH:6]=[C:5]2[N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]2[NH:26][C:27]([CH3:32])=[C:28]([Cl:31])[C:29]=2[Cl:30])=[O:24])[CH2:18][CH2:17]1.[OH-].[Na+].Cl>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[C:5]2[N:16]1[CH2:17][CH2:18][CH:19]([NH:22][C:23]([C:25]2[NH:26][C:27]([CH3:32])=[C:28]([Cl:31])[C:29]=2[Cl:30])=[O:24])[CH2:20][CH2:21]1
Reactant: COC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c2cc(Cl)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc4ccc(Cl)cc34)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.7 %

Procedure:
Methyl 6-chloro-4-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)quinoline-2-carboxylate (Example 134; 20 mg) was dissolved in 6 ml of 2:1 THF/MeOH, 0.20 ml of 1 N NaOH was added and the resulting solution was stirred at ambient temperature for 20 h. Following neutralization with 0.25 ml of 1 N HCl, the reaction was diluted with 5 ml of water and filtered. The solid was washed with water and dried under vacuum, giving 18.4 mg of a light yellow granular solid.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][C:4](=[O:19])[CH2:5][C@@H:6]([CH2:16][CH:17]=[CH2:18])[C:7]([NH:9][CH:10]([CH2:14][OH:15])[C:11]([O-:13])=[O:12])=O.Cl.[CH2:23](N(CC)CC)[CH3:24].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>O1CCCC1>[CH3:21][C:2]([CH3:1])([CH3:20])[CH2:3][C:4](=[O:19])[CH2:5][C@H:6]([C:7]1[O:15][CH2:14][C@@H:10]([C:11]([O:13][CH2:23][CH3:24])=[O:12])[N:9]=1)[CH2:16][CH:17]=[CH2:18]
Reactant: C=CC[C@H](CC(=O)CC(C)(C)C)C(=O)NC(CO)C(=O)[O-]
Reactant: CCN(CC)CC
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC[C@H](CC(=O)CC(C)(C)C)C1=N[C@H](C(=O)OCC)CO1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A solution of ethyl (2S)-2-{[(2R)-2-(4,4-dimethyl-2-oxopentyl)-4-pentenoyl]amino-3-hydroxypropanoate (Preparation 113) (23.8 g, 72.3 mmol) in anhydrous tetrahydrofuran (300 ml), under a nitrogen atmosphere, was treated with (methoxycarbonylsulfamoyl)triethylammonium hydroxide triethylamine hydrochloride salt (43.5 g, 79.4 mmol) and stirred at reflux for 1.5 hours. After allowing to cool to room temperature the mixture was filtered, washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a solvent gradient of 80:20 (hexane:diethylether) gradually changing to 50:50 (hexane:diethylether) to afford the title compound as a colourless oil (11.0 g).
Reaction SMILES: [C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:20]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]4[CH:33]=[CH:34][C:35]([CH2:37][OH:38])=[CH:36][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.OI1(=O)C2C=CC=CC=2C(=O)O1.C(OCC)(=O)C>CS(C)=O>[C:1]1([CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][N:19]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:20]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:31])[CH3:32])[C:23]4[CH:33]=[CH:34][C:35]([CH:37]=[O:38])=[CH:36][C:22]=4[N:21]=3)[CH2:16][CH2:17]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCN(CC1CCN(Cc2cccc3ccccc23)CC1)c1nc2cc(CO)ccc2n1COCC[Si](C)(C)C
Agent: O=C1OI(=O)(O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCN(CC1CCN(Cc2cccc3ccccc23)CC1)c1nc2cc(C=O)ccc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of [2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-methanol (467 mg, 0.71 mmol) in dimethylsulfoxide (5 ml) was added to a solution of 297 mg of 1-hydroxy-1-oxo-1H-1λ5-benzo[d][1,2]iodoxol-3-one (1.06 mmol) in dimethylsulfoxide (5 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into ice water (200 ml) and stirred at room temperature for 30 minutes, after which ethyl acetate was added and stirring was continued vigorously for 10 minutes for extraction. After washing with saturated aqueous sodium bicarbonate and then with saturated brine, the mixture was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole-5-carboaldehyde.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25]CC)=O)[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Product: CN1CCN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)CC1
Temperature: 60 °C
Yield: 91.5 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (300 mg, 0.76 mmol) in ethanol (4 ml) was treated with 1-methylpiperazine (0.84 ml, 7.60 mmol) and the resulting mixture was heated at 60° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (98:2) gradually changing to dichloromethane:methanol (95:5) to afford the title compound (312 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH3:28])=[C:16]([CH2:19][NH:20][C:21]4([C:24]([OH:26])=[O:25])[CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30](=O)[CH3:31]>>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH3:28])=[C:16]([CH2:19][N:20]([CH2:30][CH3:31])[C:21]4([C:24]([OH:26])=[O:25])[CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CC1
Reactant: CC=O
Product: CCN(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)C1(C(=O)O)CC1

Procedure:
1-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]cyclopropanecarboxylic acid (prepared as described in Example 27) was reacted with acetaldehyde using an analogous method to that described for the equivalent step in Example 24 to give 1-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(ethyl)amino]cyclopropanecarboxylic acid; 1H NMR Spectrum: (DMSO d6) 0.90 (t, 3H); 0.95-1.30 (m, 4H); 2.90 (m, 2H); 3.91 (s, 3H); 4.08 (s, 2H); 7.12 (s, 1H); 7.28 (dd, 1H); 7.40-7.60 (m, 2H); 8.20 (s, 1H); 8.40 (s, 1H); 9.65 (bs, 1H), 12.18 (bs, 1H); Mass Spectrum: (M+H)+ 445.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:5]
Reactant: NC1CCOCC1
Reactant: O=C(Cl)c1ccc(Cl)nc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCOCC1)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
A solution of 2,6-dichloronicotinoyl chloride (4.21 g, 20 mmol) in DCM (20 mL) was added dropwise to a stirred suspension of 4-aminotetrahydropyran (2.03 g, 20 mmol) and N-ethyldiisopropylamine (4.19 mL, 24 mmol) in DCM (20 mL) at 0° C., over a period of 30 minutes under nitrogen. The resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (200 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in DCM. Pure fractions were evaporated to dryness to afford 2,6-dichloro-N-(tetrahydro-2H-pyran-4-yl)nicotinamide (5.03 g, 92%) as a white solid.