Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=1[NH2:6].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:1][C:7]1[CH:8]=[C:9]([F:11])[CH:10]=[C:4]([F:3])[C:5]=1[NH2:6]
Reactant: BrBr
Reactant: Nc1ccc(F)cc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(F)cc(F)cc1Br

Procedure:
A solution of bromine (16.0 g; 0.10 mol) in glacial acetic acid (25 ml) is added dropwise to a solution of 2,4-difluoroaniline (12.9 g; 0.10 mol) in glacial acetic acid (75 ml) while maintaining the temperature of the reaction mixture below 25° C. The reaction mixture is stirred an additional 0.5 hour during which time a solution of sodium acetate (5.48 g; 0.137 mol) in water (100 ml) is added. The reaction mixture is then diluted with water (300 ml), the precipitated purple solid is filtered, washed with water (100 ml) and dried under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[F:28][C:29]([F:37])([F:36])[CH2:30][NH:31][C:32](=[O:35])[NH:33][NH2:34].O.CC(OC)(C)C>C(O)C.C(O)(=O)C>[F:28][C:29]([F:37])([F:36])[CH2:30][NH:31][C:32](=[O:35])[NH:33][N:34]=[CH:18][C:17]1[CH:20]=[CH:21][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:23]([F:26])([F:24])[F:25])[O:13][N:12]=2)=[CH:15][C:16]=1[CH3:22]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Reactant: NNC(=O)NCC(F)(F)F
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCO
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=NNC(=O)NCC(F)(F)F
Temperature: 70 °C
Yield: 86.3 %

Procedure:
A mixture of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde (72.5 g, 0.18 mol) and 4-trifluoroethyl semicarbazide hydrochloride (39.92 g, 0.21 mol) in ethanol (50 mL) and glacial acetic acid (40 mL) was heated at 70° C. over night. After this, water was added until the clear solution became turbid, then MTBE (10 mL) was added and the mixture was allowed to cool to ambient temperature. The resulting precipitate was filtered and washed with water to obtain the title compound (84.10 g, 86%).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24]3)=[CH:18][CH:17]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]3)=[CH:20][CH:21]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](Nc2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1nnc(Cc2ccccc2)s1)c1ccc(N[C@H]2CC[C@H](C(=O)O)CC2)cc1
Reaction time: 18 h

Procedure:
50 mg of ethyl trans-4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenylamino]cyclohexanecarboxylate (0.11 mmol, 1 eq.) are placed in 1 mL of tetrahydrofuran. 9 mg of lithium hydroxide monohydrate (0.22 mmol, 2 eq.) dissolved in 1 mL are added and stirring is continued for 18 hours. The reaction medium is diluted with water, washed with ethyl acetate and acidified with aqueous 6% sulfur dioxide solution. The solid obtained is filtered off by suction, and washed successively with water, ethanol and diethyl ether. 13 mg of trans-4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenylamino]cyclohexanecarboxylic acid are obtained.
Reaction SMILES: [CH3:1][C@@H:2]([C@H:5]([OH:9])[CH2:6][CH2:7][CH3:8])[CH2:3][OH:4].CO[C:12](OC)([CH3:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+].P([O-])([O-])([O-])=O>C1COCC1>[CH3:13][C:12]1([CH3:14])[O:9][C@H:5]([CH2:6][CH2:7][CH3:8])[C@H:2]([CH3:1])[CH2:3][O:4]1
Reactant: CCC[C@@H](O)[C@H](C)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CCC[C@H]1OC(C)(C)OC[C@H]1C
Reaction time: 67 h
Yield: 82.5 %

Procedure:
Alcohol 24 (100.0 mg, 0.4057 mmol) was dissolved in 2.0 ml of Et2O and treated with 676 mg of tetrabutylammonium fluoride on silica (1.2 mmol/g, 0.8112 mmol, 2.0 eq) and stirred at 25° C. for 3h at which time alumina (acidic, ca. 1 g) was added. The slurry was filtered through a pad of Celite, concentrated and chromatographed (25 g SiO2, 60% CH2Cl2 /40% EtOac) to yield 27.9 mg of diol 26 (52%) which was protected for characterization. Diol 26 (27.9 mg, 0.211 mmol) was dissolved in 5.0 ml of THF, and treated with 2,2-dimethoxypropane (64 μl, 0.5159 mmol, 2.0 eq) and a crystal of p-toluenesulfonic acid. After 67 h at 25° C., 200 mg of Na2CO3 was added. The mixture was poured onto 7.0 ml of 0.10 M pH 7.0 phosphate buffer, extracted with Et2O (3×10 ml), washed with H2O (1×1 ml), 5% NaHCO3 (2×1 ml), brine (1×1 ml), dried over MgSO4 and concentrated to give 30.0 mg of acetonide 28 as a clear liquid (89%). 1H NMR (CDCl3, 360.134 MHz) δ 4.04 (1H,dd,J=11.56, 2.90 Hz), 3.86 (1H,ddd,J=10.40, 5.29, 2.52 Hz), 3.52 (1H,dd,J=11.44, 0.68 Hz), 1.37 (3H, s), 1.33 (3H, s), 1.45-1.1 (5H,m), 0.99 (3H, d,J=6.92 Hz), and 0.86 (3H,t,J=7.08H). 13C NMR (CDCl3, 90.55 MHz) δ:72.0, 71.2, 67.0, 35.0, 31.7, 29.8, 19.1, 18.5, 14.0, and 10.5. IR (thin film): 2957(m), 2924(s), 2855(m), 1732(br), 1458(m), 1377(w), 1262(m), 1179 9(w), 1074(w), and 800(w) cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:28][CH:27]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:31]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C(O)C(CCc1ccccc1)NS(=O)(=O)c1ccc(Cl)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC(=O)C(CCc2ccccc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 46.5 %

Procedure:
The procedure described in Example 179 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-phenylbutanoic acid (252.0 mg) and ethyl 4-aminophenylacetate hydrochloride (184.3 mg) were condensed in THF (4 ml) in the presence of triethylamine (384.9 μl) and pivaloyl chloride (140.4 μl), and then the resulting crude product was purified by column chromatography (silica gel 50 g, hexane/ethyl acetate=3/1) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-phenylbutanamide (170.5 mg).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:20]([O:22]CC1C=CC=CC=1)=[O:21])[CH2:3][C:4](=[O:19])[NH:5][CH2:6][C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([O:13][CH3:14])=[CH:11][C:8]=1[O:9][CH3:10].O.CN(C=O)C>C(O)(=O)C>[CH3:18][O:17][C:16]1[CH:15]=[C:12]([O:13][CH3:14])[CH:11]=[C:8]([O:9][CH3:10])[C:7]=1[CH2:6][NH:5][C:4](=[O:19])[CH2:3][C@@H:2]([C:20]([OH:22])=[O:21])[NH2:1]
Reactant: COc1cc(OC)c(CNC(=O)C[C@H](NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)c(OC)c1
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(CNC(=O)C[C@H](N)C(=O)O)c(OC)c1
Reaction time: 2 h

Procedure:
The fully protected derivative Z-Asn(Tmob)-OBzl prepared in Step 1 (2.0 g, 3.75 mmol) was dissolved in acetic acid (50 ml), water (14 ml) and DMF (10 ml) by slight warming and vigorous stirring, nitrogen was flushed through the low pressure hydrogenation flask, 5% palladium on carbon catalyst (400 mg) was added, and a gentle stream of hydrogen continuously passed over the vigorously stirred solution for 2 hours. Nitrogen was once more flushed through the system and the catalyst removed by filtration through a doubled fluted Whatman No. 1 filter paper. The filtrate was evaporated, the residue dried in vacuo, and triturated under ethyl acetate to give a white solid. The suspension was cooled overnight to 4 degrees, then filtered and washed with ethyl acetate. Yield after drying 1.16 g (96%), Rf 0.55 single spot n-butanol/acetic acid/water (3:1:1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([O:23][C:24]([N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C@H:27]1[C:32]([O:34][CH3:35])=[O:33])=[O:25])([CH3:22])([CH3:21])[CH3:20].[CH:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1.[Cl-].[NH4+]>[C:19]([O:23][C:24]([N:26]1[C:30](=[O:31])[CH:29]([CH:36]([OH:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:28][C@H:27]1[C:32]([O:34][CH3:35])=[O:33])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)[C@@H]1CC(C(O)c2ccccc2)C(=O)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To 40 ml of tetrahydrofuran were added 1.54 ml (11 m mol) of diisopropylamine and 6.9 ml of 1.6M butyllithium-hexane solution, followed by stirring for 10 minutes under a stream of nitrogen. A solution of 2.43 g of methyl (S)-N-tert-butoxycarbonylpyroglutamate in 15 ml of tetrahydrofuran, was added and stirred for 10 minutes at -78° C. and further for 20 minutes at -40° C. To the reaction mixture which was again cooled to -78° C. was added dropwise a solution of 1.12 ml (11 m mol) of benzaldehyde in 4 ml of tetrahydrofuran. After stirring for 10 minutes, the reaction mixture was diluted with a saturated ammonium chloride solution, stirred until the temperature of the mixture reached room temperature and extracted with ethyl acetate. The combined organic layers were washed with water and then a saturated saline solution, dried over sodium sulfate and distilled to remove the solvent. The residue was subjected to a silica gel column (2.5×40 cm) chromatography (developed by ethyl acetate-hexane=1:3→1:2→1:1) to obtain 2.26 g (65%) of methyl (S)-N-tert-butoxycarbonyl-4-(α-hydroxybenzyl)pyroglutamate as colorless oil.
Reaction SMILES: N1C2C(=CC=CC=2)C=NC=1.[Cl:11][C:12]1[CH:13]=[C:14]([C:16]([F:20])=[CH:17][C:18]=1[Cl:19])[NH2:15].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[C:16]([F:20])=[CH:17][C:18]=1[Cl:19]
Reactant: Nc1cc(Cl)c(Cl)cc1F
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Agent: c1ccc2ncncc2c1
Product: O=[N+]([O-])c1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1

Procedure:
In one particular, which includes a quinazoline that is substituted by one reactive group at position 6 thereof, 3,4-dichloro-6-fluoroaniline is reacted with 4-chloro-6-nitroquinazoline, so as to produce 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-nitroquinazoline, which is reduced, by means of an ethanolic solution of hydrazine hydrate and Raney®Nickel, so as to produce 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-aminoquinazoline. Then, the 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-aminoquinazoline is reacted with a carbon-11 labeled acryloyl chloride so as to produce a carbon-11 labeled N-{4-[(3,4-dichloro-6-fluorophenyl)amino]quinazoline-6-yl}acrylamide (carbon-11 labeled Compound 3).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[C:7]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][C:21](=[O:23])[CH3:22])[C:14]([NH2:16])=[O:15])(=[O:9])[CH3:8]>ClCCCl>[C:7]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][C:21](=[O:23])[CH3:22])[C:14]([N:16]=[C:2]=[O:3])=[O:15])(=[O:9])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1ccc(C(N)=O)cc1OC(C)=O
Solvent: ClCCCl
Product: CC(=O)Oc1ccc(C(=O)N=C=O)cc1OC(C)=O

Procedure:
Oxalyl chloride (10.1 g) was added to a solution of 3,4-diacetoxybenzamide (7.5 g) in 1,2-dichloroethane (80 ml) with stirring under cooling. The mixture was gradually heated to a reflux temperature and allowed to react under reflux for 13 hours. After completion of the reaction, the solvent and excess oxalyl chloride was distilled off under reduced pressure to give 3,4-diacetoxybenzoyl isocyanate which was dissolved in anhydrous dichloromethane (40 ml) for the subsequent reaction.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:12]([O:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:11][C:3]1[CH:4]=[CH:8][CH:9]=[CH:10][CH:2]=1)=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(O)cccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(OCc2ccccc2)cccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 174.7 %

Procedure:
To a solution of 3-hydroxy-2-methylbenzoic acid (1.52 g) in DMF (25 mL) were added benzyl bromide (3.40 g) and potassium carbonate (4.14 g), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration, and dried to give the title compound (2.90 g) as a white solid. This compound was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:17][C:18]1([CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH2:21][O:20][CH2:19]1>>[CH3:27][N:25]([CH3:26])[C:23]([CH2:22][C:18]1([NH:17][C:8]([C:5]2[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])[CH2:19][O:20][CH2:21]1)=[O:24]
Reactant: CN(C)C(=O)CC1(N)COC1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Cl)cn1
Product: CN(C)C(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(Cl)cn2)COC1

Procedure:
The title compound was synthesized in analogy to Example 23b, using 5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 24c) and 2-(3-Amino-oxetan-3-yl)-N,N-dimethyl-acetamide as starting materials and isolated (4 mg, 5%) as colorless oil; MS (ESI, m/z): 396.4 (M+H+).
Reaction SMILES: [CH2:1]([CH:3]1[C:7]2=[N:8][C:9]3[C:10]([F:17])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]([OH:16])=[C:6]2[C:5](=[N:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[O:4]1)C.Cl.[OH2:25]>>[F:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[C:7]([CH:3]([OH:25])[CH3:1])[C:6]([C:5]([NH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1)=[O:4])=[C:15]2[OH:16]
Reactant: CCC1OC(=Nc2nccs2)c2c1nc1c(F)cccc1c2O
Reactant: O
Agent: Cl
Product: CC(O)c1nc2c(F)cccc2c(O)c1C(=O)Nc1nccs1
Temperature: 50 °C

Procedure:
A mixture of 5 g of the product of Step F and 50 ml of 6N hydrochloric acid was heated at 50° C. for 5 hours and after addition of 50 ml of water, the mixture was cooled to 0° to 5° C. for 30 minutes and was vacuum filtered. The product was washed with water and dried under reduced pressure at 80° C. The product was successively chromatographed over silica gel twice and eluted with a 9-1 chloroform-methanol mixture to obtain 1.15 g of 8-fluoro-4-hydroxy-2-(1-hydroxyethyl)-N-(2-thiazolyl)-3-quinoline-carboxamide.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:11](=[O:13])[CH2:10][NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1)c1ccccc1
Reaction time: 12 h

Procedure:
To a solution of N-benzoyl glycine (1.2 equiv.), 4-chlorophenyl piperazine (1 equiv), HOBt (1.2 equiv) and EDC (1.2 equiv) in DMF was added DIPEA (1.2 equiv). Upon completion of addition the resulting mixture was stirred for 12 h. After this time, the mixture was purified directly via preparative HPLC to provide Example 31. MS found 358.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:26][CH2:27][CH3:28])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:16]=2)=[N:7]1)[CH3:2].Br[C:30]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=1[CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:27]([O:26][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:10]([NH:11][C:30]2[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=2[CH3:39])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH:16]=2)=[N:7]1)[CH3:28]
Reactant: CCOC(Cn1nc(-c2cnn(Cc3ccc(OC)cc3)c2)cc1N)OCC
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCOC(Cn1nc(-c2cnn(Cc3ccc(OC)cc3)c2)cc1Nc1cc([N+](=O)[O-])ccc1C)OCC
Temperature: 150 °C

Procedure:
Under argon, a mixture of the compound from Example 2A (2.9 g, 7.5 mmol), 2-bromo-4-nitrotoluene (2.11 g, 9.78 mmol), palladium(II) acetate (0.17 g, 0.75 mmol), caesium carbonate (4.90 g, 15.1 mmol) and xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; 0.44 g, 0.75 mmol) in 37 ml of 1,4-dioxane was divided into several 20 ml-microwave reactor vessels. Each batch was heated in a single-mode microwave reactor (Biotage Emrys Optimizer) at 150° C. for 30 min. The batches were subsequently combined and filtered through kieselguhr, and the filtrate was concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and washed with semiconcentrated sodium bicarbonate solution and then with concentrated sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated. The crude product was purified chromatographically (Method 26). This gave 2.74 g (70% of theory) of the title compound.
Reaction SMILES: [CH:1]1([SH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[SH:7].Cl[CH:10]([CH3:14])[C:11](=O)[CH3:12]>>[CH3:14][C:10]1[S:8][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[S:7][C:11]=1[CH3:12]
Reactant: SC1CCCCC1S
Reactant: CC(=O)C(C)Cl
Product: CC1=C(C)SC2CCCCC2S1
Yield: 78 %

Procedure:
The procedure of Example 1(a) was followed using 1,2-cyclohexanedithiol and 3-chloro-2-butanone to give 4a,5,6,7,8,8a-hexahydro-2,3-dimethyl-1,4-benzodithiin as a colorless oil, bp 100°-102°/0.2 mm. Yield 78%. NMR 1.07-2.2 (8m), 1.85 (6s), 2.9-3.2 (2m). IR 2924, 2850, 1615, 1440, 1335, 1275, 1180, 985.
Reaction SMILES: [CH:1]1([N:4]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:5]2[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[C:31]([Cl:60])=[C:32]([N:38]2[CH2:43][CH2:42][C@@H:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C@H:40]([O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])[CH2:39]2)[CH:33]=[C:34]([C:36]#[N:37])[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Si:53]([O:52][C@H:40]1[C@H:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:42][CH2:43][N:38]([C:32]2[CH:33]=[C:34]([C:36]#[N:37])[CH:35]=[C:30]([NH:29][C:7]3[N:6]=[C:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[C:10]4=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]4[N:8]=3)[C:31]=2[Cl:60])[CH2:39]1)([C:56]([CH3:57])([CH3:58])[CH3:59])([CH3:55])[CH3:54]
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 50 °C
Yield: 72.8 %

Procedure:
A mixture of 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl) imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 2, 185 mg, 0.464 mmol), (+/−)-tert-butyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethyl silyl)oxy)piperidin-4-yl)carbamate (223 mg, 0.464 mmol) and cesium carbonate (302 mg, 0.927 mmol) in DMF (5 mL) was heated at 50° C. for 4 h. LCMS showed completion of reaction. The reaction mixture was diluted with ethyl acetate and the solid was filtered off. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 10-35% ethyl acetate/hexanes). (+/−)-tert-butyl ((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (270 mg) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[CH3:34])=[CH:17]/[C:18]2[N:19]=[C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:21](S(=O)(=O)N(C)C)[CH:22]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C([O-])(O)=O.[Na+]>Cl.CC(C)=O>[CH3:1][C:2]1[C:3](/[C:16](/[CH3:34])=[CH:17]/[C:18]2[N:19]=[C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[NH:21][CH:22]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1nc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cn1S(=O)(=O)N(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1nc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)c[nH]1
Reaction time: 0.5 h
Yield: 186.8 %

Procedure:
Ethyl (E)-4-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-1-N, N-dimethylsulfamoyl-2-imidazolecarboxylate (Compound 4, 0.295 g, 0.605 mmol) was dissolved in a solution of 3M HCl (2.5 mL) and acetone (20 mL) at room temperature and the solution stirred for 30 min. The solution was neutralized with 5% aqueous NaHCO3 and the organic material was extracted with dichloromethane, washed with brine, dried (K2CO3) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes/ethyl acetate=3:2) to give the title compound as a light yellow solid (430 mg, 70%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[N:29]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:28](=[O:38])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:39])[CH:26]=3)[N:21]=2)[CH:19]=1)=[O:14])[CH3:11]>C(Cl)Cl>[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[N:29]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:28](=[O:38])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:39][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:26]=3)[N:21]=2)[CH:19]=1)=[O:14])[CH3:11]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N)cc3c(=O)n2COCC[Si](C)(C)C)c1
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2nc3ccc(NC(=O)c4ccccc4)cc3c(=O)n2COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.5 %

Procedure:
Benzoyl chloride (81.1 μL, 0.698 mmol) was added dropwise to a solution of 1-[6-amino-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.200 g, 0.466 mmol), TEA (0.162 mL, 1.16 mmol), and DCM (2.3 mL). The reaction mixture was stirred at room temperature for 1.5 h and was then diluted with DCM (25 mL) and quenched with water (15 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried (MgSO4), and concentrated. The residue was purified by FCC (10-70% EtOAc/hexanes) to yield the titled compound (0.240 g, 97% yield). MS (ESI/Cl): mass calcd. for C27H31N5O5Si, 533.2; m/z found, 476.2 [M+H−58]+.