Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:8]([C:9]([C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH3:19])[CH:18]=2)[C:14]#[N:15])=[O:10])=[C:7]([CH:20]([CH3:22])[CH3:21])[C:6](=[O:23])[NH:5][C:4]1=[O:24])[CH3:2].[H-].[Na+].Br[CH2:28][O:29][C:30](=[O:32])[CH3:31]>CN(C=O)C.O>[C:30]([O:29][CH2:28][N:5]1[C:6](=[O:23])[C:7]([CH:20]([CH3:21])[CH3:22])=[C:8]([C:9](=[O:10])[C:11]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[N:3]([CH2:1][CH3:2])[C:4]1=[O:24])(=[O:32])[CH3:31]
Reactant: CC(=O)OCBr
Reactant: CCn1c(C(=O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(C(=O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)n(COC(C)=O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 3-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile (778 g, 2.39 mol) in anhydrous DMF (5 L) was added 60% NaH (115 g) portion-wise over 30 min at 0° C. The reaction mixture was stirred at room temperature for 3 hours and then the mixture was cooled to −10° C. Acetic acid bromomethyl ester (321 mL) was dropwise added to the reaction mixture for 2 hours at the same temperature and the reaction mixture was stirred at room temperature for 12 hours. The mixture was diluted with water (10 L). The precipitate was collected by filtration, washed with water (5 L) and then dissolved in dichloromethane (10 L). The organic solution was washed with water (4 L), dried with anhydrous magnesium sulfate (1 kg) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate/dichloromethane, 1:20) to give (4-(3-cyano-5-methylbenzoyl)-3-ethyl-5-isopropyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methyl acetate (745 g, 1.87 mol, 79%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(C#N)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C#N)ccc1OC
Temperature: 65 °C
Reaction time: 10 h
Yield: 28 %

Procedure:
A solution of acid methyl 5-cyano-2-hydroxybenzoate (2 g, 11.2 mmol) in dry acetone (50 mL) was cooled to 0° C. and K2CO3 (2.34 g, 16.9 mmol) followed by MeI (1.1 mL, 16.9 mmol) were added dropwise. The reaction mixture was allowed to stir at 65° C. for 10 h and then diluted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield methyl 5-cyano-2-methoxybenzoate (600 mg, crude), which was carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 8.11 (d, J=2.2 Hz, 1H), 7.78-7.74 (dd, J=8.8 Hz, 2.2 Hz, 1H), 7.08-7.05 (d, J=8.8 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H). MS (ESI) m/z: Calculated for C10H9NO3: 191.06. found: 191.8 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)C=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:25]([O:30][CH3:31])([O:28][CH3:29])OC.C(N(CC)CC)C>CO.[Cl-].[Na+].O.C(OCC)(=O)C>[CH3:31][O:30][CH:25]([O:28][CH3:29])[C:6]1[CH:9]=[C:2]([Br:1])[C:3]([O:11][CH3:12])=[CH:4][C:5]=1[F:10]
Reactant: COc1cc(F)c(C=O)cc1Br
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(F)c(C(OC)OC)cc1Br
Yield: 99.2 %

Procedure:
5-Bromo-2-fluoro-4-methoxybenzaldehyde (1 g, 4.3 mmol), p-toluenesulfonic acid monohydrate (163 mg, 0.86 mmol) and trimethyl orthoformate (2.4 mL, 21 mmol) were dissolved in methanol (20 mL) and stirred under heating and reflux for 1 hour. After standing to cool the reaction mixture, triethylamine (2 mL) was added thereto and further stirred for 10 minutes. The mixture was added with saturated brine and ethyl acetate, and the organic layer was separated, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain 5-bromo-2-fluoro-4-methoxybenzaldehyde dimethylacetal (1.19 g, 100%).
Reaction SMILES: N([O-])=O.[Na+].[N+:5]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[C:13]2N)([O-:7])=[O:6].[F:19][P-](F)(F)(F)(F)F.[H+]>O>[F:19][C:13]1[C:14]2[C:9](=[C:8]([N+:5]([O-:7])=[O:6])[CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: F[P-](F)(F)(F)(F)F
Reactant: Nc1cccc2c([N+](=O)[O-])cccc12
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cccc2c(F)cccc12
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
Sodium nitrite (660 mg, 9.57 mmol) was added portionwise to a suspension of 5-nitronaphthalen-1-amine (1.2 g, 6.38 mmol) in a 1:1 mixture of water/concentrated hydrochloric acid (10 mL) at −5° C. The mixture was stirred for 15 min at −5° C. and a 60% w/w hexafluoro phosphoric acid solution (6 mL) was added. The brown precipitate was filtered and washed with cold water and diethyl ether and then allowed to dry in vacuo. The resulting solid was suspended in toluene and heated to 110° C. for 2 h before the mixture was then allowed to cool to ambient temperature and the solvent removed in vacuo to afford the crude product. Purification by column chromatography over silica gel (100-200 mesh) using petroleum ether as eluent afforded 1-fluoro-5-nitro-naphthalene (450 mg, 37%) as a yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:35]=[C:34]([CH2:36][O:37][CH3:38])[CH:33]=[CH:32][C:10]=1[C:11]([NH:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[C:22]([O:24]CC3C=CC=CC=3)[CH:21]=[CH:20][C:18]=2[CH:19]=1)=[O:12].C1(SC)C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[NH2:8][C:9]1[N:35]=[C:34]([CH2:36][O:37][CH3:38])[CH:33]=[CH:32][C:10]=1[C:11]([NH:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:18]=2[CH:19]=1)=[O:12]
Reactant: COCc1ccc(C(=O)NCc2cc3ccc(OCc4ccccc4)cc3o2)c(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COCc1ccc(C(=O)NCc2cc3ccc(O)cc3o2)c(N)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a trifluoroacetic acid (11 mL) solution of 2-amino-N-(6-benzyloxy-benzofuran-2-ylmethyl)-6-methoxymethyl-nicotinamide (557 mg, 1.33 mmol) described in Example 4 was added thioanisole (626 μL, 5.35 mmol) at 0° C., which was stirred at 0° C. for 3 hours. To the reaction solution were added sodium bicarbonate and water at 0° C. followed by extraction with ethyl acetate and tetrahydrofuran. The organic layer was washed with sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (331 mg, 76%) as a white solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:14][C:15](=[O:28])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)[CH:18]=2)=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10].Cl>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:14][C:15](=[O:28])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)[CH:18]=2)=[C:8]([CH:13]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)Cc1cccc(-c2ccoc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Cc1cccc(-c2ccoc2)c1)Nc1ccc(Cl)cc1C(=O)O
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 88 %

Procedure:
3 mL of THF and 1.2 mL of 1N aqueous sodium hydroxide were added to 0.30 g (0.81 mmol) of methyl 5-chloro-2-({[3-(furan-3-yl)phenyl]acetyl}amino)benzoate at room temperature, and the mixture was stirred at 50° C. for 2.5 hours. After cooling, 1N hydrochloric acid was added to acidify the reaction mixture. Thereafter, the solvent was distilled off under reduced pressure, and water was then added to the residue. Solids were collected by filtration, followed by drying, thereby giving 252 mg of the target 5-chloro-2-({[3-(furan-3-yl)phenyl]acetyl}amino)benzoic acid (yield: 88%).
Reaction SMILES: C[NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].NC1C=CC(O)=CC=1.CNC(C1C=C([Cl:37])C=CN=1)=O>>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:3]([NH2:2])=[O:4])[CH:10]=2)=[CH:13][C:14]=1[Cl:37]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: Nc1ccc(O)cc1
Product: NC(=O)c1cc(Oc2ccc(N)c(Cl)c2)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-aminophenoxy)pyridine-2-carboxylic acid methylamide, substituting 4-amino-3-chlorophenol for 4-aminophenol, and substituting 4-chloro-2-pyridinecarboxamide for 4-chloropyridine-2-carboxylic acid methylamide. 1H-NMR (DMSO-d6) δ 8.45 (d, J=5.4 Hz, 1H), 8.08 (s, 1H), 7.67 (s, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.15 (d, J=2.7 Hz, 1H), 7.09 (dd, J=2.7, 5.4 Hz, 1H), 6.93 to 6.84 (m, 2H), 5.44 (s, 2H); MS LC-MS (M+H)+=264.1, RT=2.40 min.
Reaction SMILES: [H-].[Na+].[C:3](=[N:6][OH:7])([NH2:5])[CH3:4].[C:8]1([C:14]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:15]2[CH2:20][CH:19]([C:21](OC)=O)[CH2:18][N:17]=[CH:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[C:31]1([C:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:15]2[CH2:20][CH:19]([C:21]3[O:7][N:6]=[C:3]([CH3:4])[N:5]=3)[CH2:18][N:17]=[CH:16]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(N)=NO
Reactant: COC(=O)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(C2CN=CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Sodium hydride (60% dispersion in mineral oil 26 mg, 0.65 mmol) and acetamidoxime (48 mg, 0.65 mmol) were suspended in dry THF (4 ml) in an oven dried round bottom flask with stirring under nitrogen at 0° C. After 15 minutes stirring the ice bath was removed and the grey suspension refluxed 45 minutes to give a white suspension. 1-Triphenylmethyl-1,4,5,6-tetrahydro-5-methoxycarbonylpyrimidine (250 mg, 0.65 mmol) was added dissolved in dry THF (3 ml) and reflux continued 18 hours. The solvents were evaporated in vacuo and the residue taken up in water (10 ml). The aqueous suspension was extracted exhaustively with chloroform and the organics dried over MgSO4. After evaporation the organic residue was chromatographed (silica, chloroform/methanol, 9:1) to yield 93 mg (rf=0.26, 35%) white crystals, mp 72°-74° C. identified by 300 MHz nmr and ms m/z=408. Calculated: C 76.44, H 5.9, N 13.7; found: C 76.27, H 6.06, N 13.59.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8](=[O:85])([O:17][C@H:18]1[C@:22]([F:24])([CH3:23])[C@H:21]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][C:28]([NH:36]C(C2C=CC(OC)=CC=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=[N:29][C:30]=3[O:34][CH3:35])[O:20][C@@H:19]1[CH2:60][O:61]C(C1C=CC(OC)=CC=1)(C1C=CC(OC)=CC=1)C1C=CC=CC=1)[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:8](=[O:85])([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[O:17][C@H:18]1[C@:22]([F:24])([CH3:23])[C@H:21]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][C:28]([NH2:36])=[N:29][C:30]=3[O:34][CH3:35])[O:20][C@@H:19]1[CH2:60][OH:61]
Reactant: COc1ccc(C(Nc2nc(OC)c3ncn([C@@H]4O[C@H](COC(c5ccccc5)(c5ccc(OC)cc5)c5ccc(OC)cc5)[C@@H](OC(=O)OCc5ccccc5)[C@@]4(C)F)c3n2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](OC(=O)OCc2ccccc2)[C@@]1(C)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A 1 vol % of TFA solution in DCM (50 mL) was added to a flask loaded with 4 (2.69 g, 2.56 mmol). The mixture was stirred at room temperature for 2 h and it was complete. Sat. NaHCO3 (20 mL) was added and the mixture was partitioned in water and DCM. The organic layer was concentrated and solid residue was purified by column chromatography (silica gel, 0˜5% 2-PrOH in DCM) to afford 1.01 g of product, 5, as a white foam solid (yield 88%). 1H-NMR (CDCl3): δ 7.82 (s, 1H), 7.39-7.33 (m, 5H), 6.02 (d, 1H, J=19.2 Hz), 5.77 (dd, 1H, J=20.8, 8.8 Hz), 5.32-5.30 (m, 1H), 5.20 (s, 2H), 5.04 (s, 2H), 4.34 (d, 1H, J=8.8 Hz), 4.15 (m, 1H), 4.04 (s, 3H), 3.85-3.79 (m, 1H), 1.21 (d, 3H, J=22.8 Hz).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](B(O)O)[CH:23]=2)[CH:18]=[CH:17]1>>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:2]3[N:6]([CH3:7])[CH:5]=[N:4][C:3]=3[C:8]3[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=3)[CH:23]=2)[CH:18]=[CH:17]1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc2cc[nH]c2c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 6-indolylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H13N5, 300. Found, 300.
Reaction SMILES: C([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:7]=2[CH2:6][CH2:5]1)(=O)C.[ClH:21]>>[ClH:21].[CH3:20][O:19][C:13]1[CH:12]=[CH:11][C:8]2[CH2:9][CH2:10][NH:4][CH2:5][CH2:6][C:7]=2[C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: COc1ccc2c(c1S(C)(=O)=O)CCN(C(C)=O)CC2
Agent: Cl
Product: COc1ccc2c(c1S(C)(=O)=O)CCNCC2

Procedure:
Following the procedure of Example 4, 3-acetyl-7-methoxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3benzazepine is treated with hydrochloric acid to give 7-methoxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3benzazepine hydrochloride which is treated with 48% hydrobromic acid to give 7-hydroxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:6][CH2:5]2.CCCCCC.C([Li])CCC.CN(C)[CH:31]=[O:32].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH:31]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:6][CH2:5]2)=[O:32]
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)CCC2OC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1ccc2c(c1)CCC2OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8.1 g of 5-bromo-1-(tetrahydropyran-2-yloxy)indane was dissolved in 100 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere. To the solution was dropwise added 20 ml of a 1.5N n-butyllithiumhexane solution at -65° C. in 10 minutes. The resulting mixture was stirred at the same temperature for 5 minutes. Thereto was added 2.3 ml of anhydrous N,N-dimethylformamide. The reaction mixture was heated to room temperature and added to a mixture of 100 ml of ice water, 100 ml of diethyl ether and 2 g of ammonium chloride. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant:toluene/ethyl acetate=15/1) to obtain 6.5 g of 5-formyl-1-(tetrahydropyran-2-yloxy)indane.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=[C:6]2[CH:5]=[C:4]([CH3:16])[N:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=[C:6]2[CH:5]=[C:4]([CH3:16])[N:3]=1
Reactant: CCOC(=O)c1cn2c(C)nc(C)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2nc(C(=O)O)cn2c(C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 120.4 %

Procedure:
Ethyl 5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxylate (1.268 mmol, 0.278 g) was dissolved in ethanol (10 ml) and cooled to 0° C. 2 M NaOH solution was added to the reaction mixture. The resulting mixture was stirred at 0° C. for 30 min and for an hour at RT. The solvent was evaporated and water added to the residue. The water phase was made acidic with 1 M HCl and extracted three times with EtOAc. The combined organics were dried, filtered and evaporated. 0.292 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 2.46 (s, 3H), 2.83 (s, 3H), 7.39 (s, 1H), 8.57 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][N:14]1[C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:12][C@H:13]1[CH2:18][N:17]([C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:16][CH2:15][N:14]1[C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:22])[F:23]
Reactant: C[C@H]1CNCCN1C(=O)[C@@](C)(O)C(F)(F)F
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(C(=O)c2ccc(C#N)cc2)CCN1C(=O)[C@@](C)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
4-Cyanobenzoyl chloride (0.30 g) was added to a stirred solution of the (R)-[2-(S)-methyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (Example 27; 0.40 g) and triethylamine (0.30 ml) in DCM (10 ml). The reaction mixture was allowed to stir at room temperature for 17 hours (overnight), and then partitioned between DCM (20 ml) and 2 M HCl (20 ml). The organic phase was separated, dried and concentrated to give a gum. The residue was purified by chromatography on an 8 g silica Biotage cartridge eluting 1:1 EtOAc/isohexane to give the title compound (0.445 g) as a white solid. NMR (DMSO-d6, 100° C.): 1.17 (d, 3H), 1.58 (s, 3H), 3.05-3.14 (m, 1H), 3.23-3.29 (m, 2H); 3.73 (brs, 1H), 3.88 (brs, 1H), 4.47 (d, 1H), 4.79 (brs, 1H), 6.79 (s, 1H), 7.58 (d, 2H), 7.88 (d, 2H); m/z 368.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[F:29][C:30]1([F:44])[O:34][C:33]2[CH:35]=[CH:36][C:37](/[CH:39]=[CH:40]/[C:41](O)=[O:42])=[CH:38][C:32]=2[O:31]1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:41](=[O:42])/[CH:40]=[CH:39]/[C:37]4[CH:36]=[CH:35][C:33]5[O:34][C:30]([F:44])([F:29])[O:31][C:32]=5[CH:38]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Reactant: O=C(O)/C=C/c1ccc2c(c1)OC(F)(F)O2
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc3c(c2)OC(F)(F)O3)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-3-(2,2-difluoro-1,3-benzodioxol-5-yl)prop-2-enoic acid, by the method of Example 1, step K, giving a solid that was mostly the more polar cyclohexyl diastereomer by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C31H34F2N4O4: 565 (M+H). Found: 565
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][CH2:30][CH2:29]3)=[C:20]([C:38]([F:41])([F:40])[F:39])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:43]>C(O)C>[ClH:43].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30][CH2:29]2)=[C:20]([C:38]([F:39])([F:40])[F:41])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCC3CCCc4ccccc43)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCC2CCCc3ccccc32)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 94-3 (400 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (270 mg) as a white powder.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Na+].Cl[CH2:7][C:8]1[N:9]([CH2:35][CH2:36][CH3:37])[C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:34])(=[O:33])[NH:27][CH2:28][CH2:29][O:30][CH2:31][CH3:32])=[CH:22][CH:21]=3)[N:14]=2)=[CH:11][N:12]=1.O>C(O)(C)C>[CH:2]([O:3][CH2:7][C:8]1[N:9]([CH2:35][CH2:36][CH3:37])[C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([S:26](=[O:34])(=[O:33])[NH:27][CH2:28][CH2:29][O:30][CH2:31][CH3:32])=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][N:12]=1)([CH3:4])[CH3:1]
Reactant: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOCC)cc3)n2)cnc1CCl
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOCC)cc3)n2)cnc1COC(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.1 %

Procedure:
Sodium isopropoxide (87 mg, 1.05 mmol) was added to a stirred suspension of 4-[2-(chloromethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine (Method 116; 100 mg, 0.21 mmol) in isopropanol (20 ml). The reaction was stirred for 48 hours at ambient temperature, and was then poured into water (80 ml) and extracted with EtOAc (3×30 ml). The extracts were combined washed with brine (2×40 ml), dried and the volatiles removed by evaporation. The residue was purified by reverse phase HLPC (C18 column) eluting with aqueous ammonia/water/acetonitrile (5:90:5 decreasing in polarity to (5:0:95) to give the title compound (18 mg, 17%) as a brown gum. M/z 503.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])[C:3]1=[O:25].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>O1CCCC1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])[C:3]2=[O:25])=[O:35])=[CH:29][CH:28]=1
Reactant: CCNC(=O)CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCNC(=O)CN1C(=O)C(NC(=O)Nc2ccc(Cl)cc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-ethylaminocarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 293° C. (d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])/[CH:5]=[CH:6]/[C:7]([OH:9])=O.[CH3:14][C@@H:15]1[CH2:21][NH:20][C:19](=[O:22])[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:6]/[C:7]([N:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][CH2:21][C@H:15]2[CH3:14])=[O:9])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: O=C(O)/C=C/c1ccc(Cl)c(Cl)c1
Reactant: C[C@@H]1CNC(=O)CCN1
Product: C[C@@H]1CNC(=O)CCN1C(=O)/C=C/c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described in intermediate 78C, (E)-3,4-dichlorocinnamic acid and (R)-2-methyl-[1,4]diazepan-5-one gave the title compound as a colorless gum, MS: m/e=327.3 (MH+).